Improving the Outcomes Of Patients with ANCA Associated ...

Improving the Outcomes

Of Patients with

ANCA Associated Vasculitis

Dr Nina Brown

A thesis submitted to the University of Manchester for the

degree of Doctor of Philosophy (PhD) in the Faculty of Biology,

Medicine and Health

School of Medical Sciences

2016

2

CONTENTS

Abstract .................................................................................................................................... 9

Declaration and Copyright ..................................................................................................... 11

Preface ................................................................................................................................... 12

Definition of my role in this work .......................................................................................... 12

Collaborations and Acknowledgements ................................................................................ 13

Publications and abstracts ..................................................................................................... 15

Abbreviations ......................................................................................................................... 17

Introduction ........................................................................................................................... 21

1.1 Background ...................................................................................................................... 21

1.1.1 What is ANCA Associated Vasculitis? An overview of disease pathogenesis 21

1.1.2 PR3 versus MPO: the role of antigens and antibodies................................... 22

Figure 1. Putative representation of AAV disease pathogenesis343 ............................... 23

1.1.3 Neutrophils and NETs in AAV ......................................................................... 24

1.1.4 The role of B cells, T cells and complement ................................................... 24

1.2 Epidemiology of AAV .............................................................................................. 26

1.2.1 Genetics of AAV ............................................................................................. 26

1.2.2 Environmental exposure and epigenetics ...................................................... 27

1.3 The role of infection in disease pathogenesis ....................................................... 28

1.4 Diagnosis and classification ................................................................................... 30

Table 1. Description of AAV according to ANCA positivity and organ involvement6 ..... 30

Table 2. Chapel Hill Consensus Conference classification of AAV 201263 ...................... 31

1.5 Treatment .............................................................................................................. 32

Table 3. Definition of disease severity according to EULAR72 ........................................ 33

1.6 Prognosis ................................................................................................................ 37

1.6.1 Mortality ........................................................................................................ 37

1.6.2 Relapse ........................................................................................................... 39

1.6.3 Biomarkers to predict disease activity ........................................................... 40

1.7 Treatment and disease associated morbidity ........................................................ 41

1.7.1 Infection as a significant complication of therapy ......................................... 42

Table 4. Summary of infections reported in the 4 combined EUVAS trials90 ................. 43

1.7.2 Cardiovascular disease ................................................................................... 43

1.7.3 Bone Health .................................................................................................... 44

1.7.4 Malignancy ..................................................................................................... 44

1.7.5 Sexual health and fertility .............................................................................. 45

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1.8 Current challenges to care for patients with AAV ................................................. 45

2 The Pathway of the UK Vasculitis Patient- from symptoms to diagnosis and beyond .. 47

2.1 Introduction ........................................................................................................... 47

2.2 Materials and Methods .......................................................................................... 48

2.2.1 Patient questionnaire..................................................................................... 48

2.2.2 Subjects .......................................................................................................... 49

2.2.3 Statistical analysis .......................................................................................... 49

2.3 Results .................................................................................................................... 49

2.3.1 Responder characteristics .............................................................................. 49

Table 1. Presenting symptoms ....................................................................................... 50

2.3.2 Symptoms ...................................................................................................... 50

Table 2. Relationship of patient characteristics to time to diagnosis (** statistically

significant when compared with time to diagnosis for those with skin symptoms) ..... 51

Table 3. Alternative diagnoses received prior to vasculitis ........................................... 52

2.3.3 Utilisation of healthcare ................................................................................. 52

Figure 1. Vasculitis patient health care utilisation ........................................................ 53

2.4 Discussion ............................................................................................................... 53

3 Vasculitis patient awareness of medication side- effects and uptake of preventative/

prophylactic measures: a UK questionnaire study ................................................................ 66

3.1 Background ...................................................................................................................... 66

3.2 Patients and Methods ............................................................................................ 67

3.3 Results .................................................................................................................... 68

3.3.1 Pilot/validity check ......................................................................................... 68

3.3.2 Main study ..................................................................................................... 68

Table 1. Characteristics of the Sample .................................................................... 69

Figure 1: Reported exposure to immunosuppression ................................................... 70

Figure 2. Patient reported awareness of potential medication side effects ................. 71

Figure 3. Patient reported uptake of preventative therapy .......................................... 73

3.4 Discussion ............................................................................................................... 73

4 A Delphi study to Assess Prevention of Treatment and disease related morbidity In

Vasculitis (ADAPTIV): Delphi methodology ............................................................................ 77

4.1 Introduction ........................................................................................................... 77

4.1.1 Objective ........................................................................................................ 78

4.1.2 Target Audience ............................................................................................. 78

4.1.3 Stakeholder groups ........................................................................................ 78

4.1.4 Co-ordination Team ....................................................................................... 78

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4.1.5 Expert panel members (Delphi contributors) ................................................ 79

4.1.6 Other Stakeholder representatives................................................................ 80

4.2 Delphi Study ........................................................................................................... 80

4.3 Results .................................................................................................................... 82

4.4 Discussion ............................................................................................................... 84

4.5 Appendix 1. Round 1 questions ............................................................................. 85

4.6 Appendix 2: Statements generated following Round 1 ......................................... 88

4.7 Appendix 3. Consensus Statements ..................................................................... 102

4.8 Appendix 4. Summary of main consensus statement and levels of consensus ... 112

5 Literature review: methods and results ....................................................................... 118

5.1 Search strategy .................................................................................................... 118

5.2 Results .................................................................................................................. 119

5.2.1 Section 1: Bone health ................................................................................. 119

5.2.2 Section 2: Cardiovascular and thromboembolic risk ................................... 121

5.2.3 Section 3: Cancer Risk .................................................................................. 123

5.2.4 Section 4: Fertility ........................................................................................ 124

5.2.5 Section 5: Vaccination .................................................................................. 125

5.2.6 Section 6: Infection Prophylaxis ................................................................... 127

5.3 Summary .............................................................................................................. 129

5.4 Appendix 1: Search strategies .............................................................................. 130

5.4.1 Bone Health search strategy ........................................................................ 130

5.4.2 Cardiovascular/ thromboembolic risk search strategy ................................ 133

5.4.3 Cancer screening search strategy ................................................................ 138

5.4.4 Fertility preservation search strategy ......................................................... 140

5.4.5 Vaccination search strategy ......................................................................... 142

5.4.6 Pneumocystis search strategy...................................................................... 145

5.4.7 Viral and fungal prophylaxis search strategy ............................................... 150

Appendix: Evidence Tables .................................................................................................. 154

6 A Delphi study to Assess the Prevention of Treatment and disease related morbidity In

Vasculitis (ADAPTIV): recommendations ............................................................................. 229

6.1 Bone Health.......................................................................................................... 230

6.2 Cardiovascular risk modification .......................................................................... 232

6.3 Fertility preservation ............................................................................................ 234

6.4 Cancer recommendations .................................................................................... 236

6.5 Infection prevention ............................................................................................ 239

6.6 Education and monitoring ................................................................................... 243

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6.7 Applicability and utility ........................................................................................ 243

6.7.1 A statement of potential organizational barriers to introduction ............... 243

6.7.2 Potential costs implications for introduction of guideline ........................... 243

6.7.3 Suggested audit measures ........................................................................... 243

7 Development of a Vasculitis Care Optimisation Tool .................................................. 246

7.1 Part A: Concept development and user engagement .......................................... 246

7.1.1 Introduction ................................................................................................. 246

7.1.2 Identification and engagement of stakeholders .......................................... 247

7.1.3 Methods ....................................................................................................... 247

Table 1. Characteristics of patients selected for interview ......................................... 250

1.1.1 Figure 1. VasCOT user map .......................................................................... 252

1.1.2 Figure 2. VasCOT concept ............................................................................ 253

Table 2. Themes from patient interviews .................................................................... 256

Table 3. Clinician “problem” and “wish” list ................................................................ 258

Table 4. Patient “problem” and “wish” list .................................................................. 259

Table 5. Survey responder characteristics ................................................................... 260

7.2 Section B: Design of patient and clinician interfaces ........................................... 261

7.2.1 Patient data capture .................................................................................... 261

7.2.2 Clinical data capture..................................................................................... 261

7.2.3 Frequency and scope of use ........................................................................ 263

7.3 Part C: Development of VasCOT ‘Engine’ (Functional Specification) ................... 264

7.3.1 Platform and Strategy .................................................................................. 264

7.3.2 Audit ............................................................................................................. 264

7.3.3 Security and Authentication ........................................................................ 265

7.3.4 Data Protection ............................................................................................ 265

7.3.5 Feature Access ............................................................................................. 265

7.3.6 Settings ......................................................................................................... 266

7.3.7 Role Editor .................................................................................................... 266

7.3.8 User Editor ................................................................................................... 266

7.3.9 Patient Creation ........................................................................................... 266

7.3.10 User Verification .......................................................................................... 266

7.3.11 Self-Registration ........................................................................................... 267

7.3.12 Patient Queues ............................................................................................. 267

7.3.13 Requesting Patient Access ........................................................................... 267

7.3.14 Accepting / Rejecting Patient Access Requests ........................................... 268

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7.3.15 Access, Data Input and Versioning ............................................................... 268

7.3.16 Patient Editor ............................................................................................... 268

7.4 Discussion ............................................................................................................. 269

Appendix 1. Patient questionnaire and results .................................................................... 272

Appendix 2. Clinical data specifications……………………………………………………………………………275

Appendix 3: Patient view wireframes .................................................................................. 283

Appendix 4. Clinician view wireframes ................................................................................ 289

Appendix 5. Detailed Functional specifications ................................................................... 296

8 Discussion ..................................................................................................................... 315

8.1 Recognition and identification of disease ............................................................ 315

8.2 Initial management .............................................................................................. 317

8.3 Longer term management ................................................................................... 317

8.4 Further work ........................................................................................................ 319

8.5 Future therapies ................................................................................................... 320

8.6 Epigenetics ........................................................................................................... 321

8.7 Summary .............................................................................................................. 321

9 Publications .................................................................................................................. 322

10 Bibliography ................................................................................................................. 328

Word count 82 083

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TABLES AND FIGURES

Chapter 1

Table 1. Description of AAV according to ANCA positivity and organ involvement6 ..... 30

Table 2. Chapel Hill Consensus Conference classification of AAV 201263 ...................... 31

Table 3. Definition of disease severity according to EULAR72 ........................................ 33

Table 4. Summary of infections reported in the 4 combined EUVAS trials90 ................. 43

Chapter 2

Table 1. Presenting symptoms ....................................................................................... 50

Table 2. Relationship of patient characteristics to time to diagnosis) ........................... 51

Table 3. Alternative diagnoses received prior to vasculitis ........................................... 52

Figure 1. Vasculitis patient health care utilisation ........................................................ 53

Chapter 3

Table 1. Characteristics of the Sample .................................................................... 69

Figure 1: Reported exposure to immunosuppression ................................................... 70

Figure 2. Patient reported awareness of potential medication side effects ................. 71

Figure 3. Patient reported uptake of preventative therapy .......................................... 73

Chapter 5

Appendix 1: Search strategies .............................................................................................. 130

Bone Health search strategy ........................................................................................ 130

Cardiovascular/ thromboembolic risk search strategy ................................................ 133

Cancer screening search strategy ................................................................................ 138

Fertility preservation search strategy ......................................................................... 140

Vaccination search strategy ........................................................................................ 142

Pneumocystis search strategy ..................................................................................... 145

Viral and fungal prophylaxis search strategy ............................................................... 150

Appendix: Evidence Tables .................................................................................................. 154

Chapter 7

Table 1. Characteristics of patients selected for interview ......................................... 250

Figure 1. VasCOT user map .......................................................................................... 252

Figure 2. VasCOT concept ............................................................................................ 253

Table 2. Themes from patient interviews .................................................................... 256

Table 3. Clinician “problem” and “wish” list ................................................................ 258

Table 4. Patient “problem” and “wish” list .................................................................. 259

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Table 5. Survey responder characteristics ................................................................... 260

Appendix 1. Patient questionnaire and results .................................................................... 272

Appendix 2. Clinical data specifications……………………………………………………………………………275

Appendix 3: Patient view wireframes .................................................................................. 283

Appendix 4. Clinician view wireframes ................................................................................ 289

Appendix 5. Detailed Functional specifications ................................................................... 296

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ABSTRACT

For submission to the University of Manchester, for the degree of Doctor of

Philosophy (PhD)

Title: Improving Outcomes for Patients with ANCA Associated Vasculitis

Dr Nina Brown, December 2016

Background: ANCA Associated Vasculitis (AAV) is a relatively rare autoimmune

condition with the potential to cause life-threatening organ inflammation and

failure. Due to the relative rarity, and the heterogenous way in which the disease

may present, delay to diagnosis is common. Although initial immunosuppressive

treatment is usually effective at controlling disease, morbidity associated with

treatment is high and disease relapses frequent, necessitating further

immunosuppression exposure.

Aims and Objectives: This body of work therefore seeks to address 2 of the main

challenges faced by the AAV population; 1) identifying factors that may contribute

to a delay to diagnosis and disease recognition 2) reducing morbidity associated

with the disease and the treatment.

Methods: Patient pathways, knowledge and uptake of protective therapy were

explored through a national patient report study. Patient care guidelines to assist

with morbidity prevention were informed through Delphi consensus methodology

and comprehensive literature review. The development of software to support

implementation of a rigorous systematic approach to the assessment of the

vasculitis patients was achieved through collaboration with information technology,

business development and system architecture and design experts.

Results: Patient presentation including symptoms, initial mis-diagnosis and eventual

diagnosis appear to influence time to diagnosis. There is substantial delay from

symptom onset to diagnosis demonstrating the need for increased awareness and

education. Equally patient awareness of treatment related morbidity is low with

variable uptake of protective therapy.

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A Delphi study has produced consensus on which guidelines can be based to

address some of these inadequacies. A software programme: “Vasculitis Care

Optimisation Tool (VasCOT)”, has been designed to support implementation of

these guidelines.

Discussion: The various approaches used in this body of work have so far allowed

evaluation of areas where patient care needs to be improved. This in part will be

addressed through the publication of national vasculitis care guidelines, informed

by this work and the ongoing development of VasCOT.

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DECLARATION AND COPYRIGHT

No portion of the work referred to in the thesis has been submitted in support of an

application for another degree or qualification of this or any other university or other

institute of learning.

i. The author of this thesis (including any appendices and/or schedules to this thesis) owns

certain copyright or related rights in it (the “Copyright”) and s/he has given The University

of Manchester certain rights to use such Copyright, including for administrative purposes.

ii. Copies of this thesis, either in full or in extracts and whether in hard or electronic copy,

may be made only in accordance with the Copyright, Designs and Patents Act 1988 (as

amended) and regulations issued under it or, where appropriate, in accordance with

licensing agreements which the University has from time to time. This page must form part

of any such copies made.

iii. The ownership of certain Copyright, patents, designs, trade marks and other intellectual

property (the “Intellectual Property”) and any reproductions of copyright works in the

thesis, for example graphs and tables (“Reproductions”), which may be described in this

thesis, may not be owned by the author and may be owned by third parties. Such

Intellectual Property and Reproductions cannot and must not be made available for use

without the prior written permission of the owner(s) of the relevant Intellectual Property

and/or Reproductions.

iv. Further information on the conditions under which disclosure, publication and

commercialisation of this thesis, the Copyright and any Intellectual Property University IP

Policy (see http://documents.manchester.ac.uk/display.aspx?DocID=24420), in any

relevant Thesis restriction declarations deposited in the University Library, The University

Library’s regulations (see http://www.library.manchester.ac.uk/about/regulations/) and in

The University’s policy on Presentation of Theses.

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PREFACE

This report will follow the alternative (journal paper) thesis format. This is felt to be

appropriate for this body of work due to the various methodologies used and as

some sections have been published, with others submitted for publication, or

shortly about to be.

DEFINITION OF MY ROLE IN THIS WORK

Chapters 2 and 3: I led on the development of the questionnaire with support from

the steering group outlined below. I wrote the application to the Research and

Ethics committee for approval of the pilot work and carried out this pilot along with

the data collection and analysis from patient health records for validation. With

regards to the full questionnaire study, I performed the majority of data entry and

analysis with assistance from those outlined below. The manuscripts were prepared

by me with acknowledgement of those involved below.

Chapter 4, 5 and 6: The idea for the Delphi study was generated by me. I assisted in

the identification and recruitment of panel members and stakeholders. I created

the original questions for Round 1 of the Delphi. I supported and supervised DT (see

below) in the administration of the rounds 2 and 3 of the Delphi and in

streamlining/ clarifying statements between rounds. I led in the organisation and

chairing of the 2 consensus conferences and was responsible for documenting and

translating the outcomes into written format.

I conducted the literature reviews in chapter 5 with assistance as outlined below.

I was responsible for the creation of the guidelines from the combination of

consensus statements and evidence.

Chapter 7: The idea for VasCOT was generated and developed by me, with support

as outlined below. I worked with information technology, business development

and design experts to translate my vision into something more tangible.

13

I produced the clinical data specifications, with input as listed below. I produced the

content of all the wire frames seen in the Appendix, which were translated into the

patient and clinician views by the design team. I obtained industry support for the

initial development phases through presentation of the concept in various forums. I

directed the IT team to produce the functional specifications, based the anticipated

requirements of the software.

COLLABORATIONS AND ACKNOWLEDGEMENTS

Chapters 2 and 3: The initial questionnaire development was supported by a

steering group consisting of;

• Dr Michael Venning, Renal Unit, Manchester Royal Infirmary

• Professor Ian Bruce, Arthritis Research Epidemiology Unit, University of

Manchester

• Professor Paul Brenchley, Chair of renal immunology, University of

Manchester

• Professor Ann Louise Caress, School of Nursing and Midwifery, University of

Manchester

• Dr Ed O’Riordan, Renal Unit, Salford Royal

• Dr Jon Sussman, Neurology, Salford Royal

• Dr Ajay Dhaygude, Renal Unit, Royal Preston Hospital

• Shelley Harris, Renal Research, Manchester Royal Infirmary

• With input from the patient support group Vasculitis UK.

• Dr Faisal Ali (trainee in dermatology) contributed the questions on skin

monitoring for the questionnaire.

• Dr Zoe Cousland and Dr Heather Arya assisted with data entry.

Chapter 2: Some of the data analysis and figure production in this section was

completed by Dr. Zoe Cousland under my direction. She has also been involved in

the drafting of this article planned for submission shortly.

14

Chapter 3: In addition to those mentioned in the steering group, Dr. Matthew

Helbert was involved in the preparation of this article.

Chapter 4, 5 and 6: The ADAPTIV study was carried out under the auspice of the UK

and Ireland Vasculitis Rare Disease Group, with Professor Mark Little and Professor

Richard Watts as chair. Access to the Delphi 7comms software was enabled though

the creator of this software, Professor Kevin Mackway-Jones. David Tooth, then

medical student, carried out the co-ordination of the Delphi study using the

software under my supervision. Angela Summers provided support in addition,

particularly during my absence for maternity leave. The literature review was

undertaken with assistance from David Tooth, Dimitrios Chanouzas and Patrick

Hamilton. Professor Mark Little and Dr Matthew Morgan provided guidance in the

latter part of the process, particularly the drafting of the guidelines.

Chapter 7: Bruce Magill, previously Northwest ehealth, now SAP, helped with the

development of the design for VasCOT into a product from initial concept. Hitachi

carried out the detailed patient and physician interviews and questionnaire and

analysed the results to produce the “wish-lists”. In addition, the product schema

and wireframes were produced by Hitachi Design Centre Europe under direct

instruction from myself. Central Manchester Foundation Trust IT department, Chris

Anderson (Xibble Ltd) and Chris Lee (OBEC ltd), produced the functional

specification for VasCOT, under my direction. The UK and Ireland Vasculitis RDG

provided clinical expertise to review the content of the clinical dashboards.

Dr Mike Venning, has provided input into all aspects of this work. In particular he

was actively involved with development of the questionnaire, he actively supported

the Delphi process and was involved with the development of the concept and

content of VasCOT.

Professors Paul Brenchley and Ian Bruce have provided guidance and comment on

the entire thesis, with additional independent review from Professor Rick Body.

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PUBLICATIONS AND ABSTRACTS

Medication-related side effects in vasculitis: a patient self-report survey of

awareness and reported uptake of protective therapy. Brown N, Bruce IN,

O'Riordan E, Dhaygude A, Helbert M, Caress AL, Sussman JD, Venning MC.

Rheumatology 2016;55:186-189.

Lack of awareness of skin cancer amongst immunocompromised patients with

ANCA-associated vasculitis: a questionnaire survey. Ali FR*, Brown N*, Lear J,

Helbert M, Bruce I N, Venning M C. British Journal of Dermatology (2014) 171,

pp193-5.(*joint first authorship)

Development of a Vasculitis Care Optimisation Tool (VasCOT), in Collaboration with

Hitachi Europe. Brown N, Magill B, Mills J, Luqmani R, Venning M. Nephron

2015;129(suppl2):47

A Delphi Study for Assessing Prevention of Disease and Treatment Related

Morbidities in ANCA Associated Vasculitis (ADAPTIV). Brown N, Tooth D, Morgan M,

Little M, Venning M. Nephron 2015;129(suppl2):128

Vasculitis care in the UK: How do patients perceive the care provided and what

should the future hold? Arya H, Brown N, Venning M, Bruce I. Annals Rheumatic

Diseases 2014; 71(Suppl 3):627-62

ADAPTIV: A Delphi study to assess morbidity prevention and treatment in vasculitis.

Brown N, Tooth D, Summers A, Venning M. La Presse Médicale 04/2013; 42(4):746-

747.

Prevention of treatment related morbidity in ANCA-associated vasculitis: the

patient’s perspective. Brown N, Bruce IN, Venning MC. EDTA Conference. Paris, May

2012

https://www.researchgate.net/publication/273573180_SAT0458_Vasculitis_care_in_the_UK_How_do_patients_perceive_the_care_provided_and_what_should_the_future_hold?ev=prf_pub

https://www.researchgate.net/publication/273573180_SAT0458_Vasculitis_care_in_the_UK_How_do_patients_perceive_the_care_provided_and_what_should_the_future_hold?ev=prf_pub

https://www.researchgate.net/researcher/2069196299_H_Arya

https://www.researchgate.net/publication/273419233_ADAPTIV_A_Delphi_study_to_assess_morbidity_prevention_and_treatment_in_vasculitis?ev=prf_pub

https://www.researchgate.net/researcher/2036014850_N_Brown

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Skin cancer awareness and surveillance in vasculitis patients: the lost tribe? Ali F,

Brown N, Lear J, Bruce IN, Venning MC. British Association Dermatology.

Birmingham, June 2012.

ANCA-associated vasculitis: the patient’s perspective on the route to diagnosis.

Cousland Z, Brown N, Bruce IN, Venning MC. Renal Association. Gateshead, June

2012

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ABBREVIATIONS

AAV ANCA Associated Vasculitis

ACR American College of Rheumatology

ANCA Anti-neutrophil cytoplasmic antibody

ANOVA Analysis of variance

BCG Bacillus Calmette–Guérin

Blys B lymphocyte stimulator

Bregs regulatory B cells

BMD Bone mineral density

c-ANCA cytoplasmic ANCA

CIN Cervical intra-epithelial neoplasia

CKD Chronic Kidney Disease

CMV Cytomegalovirus

CPG 5’-C-phosphate-G-3’

cPR3 Complementary PR3

CRP C reactive protein

CSS Churg Strauss syndrome

CVD Cardiovascular disease

CYC cyclophosphamide

DEXA Dual-energy X-ray absorptiometry

eGFR Estimated glomerular filtration rate

EGPA Eosinophilic Granulomatosis with Polyangiitis

ELISA enzyme-linked immunosorbent assay

18

EMEA European Medicines Agency

ENT Ear Nose and Throat

ESRD End stage renal disease

EULAR European League against Rheumatism

EUVAS European Vasculitis Study Group

GP General Practice

GPA Granulomatosis with Polyangiitis

GWAS Genome wide association study

HR Hazard Ratio

HSV Herpes simplex virus

HZV Herpes zoster virus

Ig Immunoglobulin

IL interleukin

IQR Interquartile range

I.v. intravenous

LAMP2 Lysosomal-associated membrane protein 2

MMF Mycophenolate mofetil

MPA Microscopic Polyangiitis

MPO myeloperoxidase

MTX methotrexate

NET neutrophil extracellular traps

NMSC Non-melanomatous skin cancer

OR Odds Ratio

p-ANCA peri-nuclear ANCA

19

PBMC Peripheral blood mononuclear cells

PCP Pneumocystis pneumonia

PCT Procalcitonin

PHE Public Health England

PjP Pneumocystis jirovecii pneumonia

PMN Polymorphonuclear leucocyte

PR3 proteinase-3

RCT randomised controlled trial

ROS Reactive oxygen species

RTX rituximab

SNP Single nucleotide polymorphism

SLE Systemic Lupus Erythematosus

TB tuberculosis

Th T helper

Tregs regulatory T cells

TREM Triggering receptor expressed on myeloid cells

UTI Urinary tract infection

VTE venous thromboembolism

WCC white cell count

20

DEDICATION

This thesis is dedicated to my boys, Ewan and Finlay, who were both born during the course

of this PhD. They have been my inspiration and sunshine throughout it all.

Thank you to my incredibly patient husband, Ross, whose support and encouragement

enabled me to keep going.

To my parents who have always been there for me.

Thank you to my supervisors and advisor, Ian, Paul and Mike who provided so much

guidance.

And finally, to the patients who it is a privilege to care for, without whom none of this

would be possible.

21

INTRODUCTION

1.1 BACKGROUND

ANCA (anti-neutrophil cytoplasmic antibody) associated vasculitis (AAV) is an umbrella

term for a group of rare, multi- system autoimmune diseases causing potentially life-

threatening inflammation of small blood vessels. Although it appears that outcomes from

this disease are generally improving, morbidity and mortality is still high. This thesis aims to

identify some of the contributors to this morbidity and to describe possible barriers to

improving outcomes for this population including how these barriers may be overcome.

To better identify the possible contributory factors to this morbidity and mortality, this

introduction will give an overview of the disease, from diagnosis to treatment and longer

term outcomes.

1.1.1 What is ANCA Associated Vasculitis? An overview of disease pathogenesis

AAV is an autoimmune disorder that causes small to medium sized blood vessel

inflammation leading to organ damage and possibly failure. Histologically, vascular damage

and destruction may be visualised but classically the lesions are pauci-immune. However, it

is now firmly established that the pathogenesis of this disease is linked with formation of

antineutrophil cytoplasmic antibodies (ANCA). ANCA was first described in association

with glomerulonephritis in an Australian case series in 19891. These antibodies were

observed in a cohort of patients with what we now recognise to be ANCA Associated

Vasculitis and the aetiology of the antibodies was postulated to be linked with exposure of

the patients to Ross river virus (a group A arbovirus) due to the geographical clustering.

Following this initial discovery their pathogenic potential for causing vascular injury was

first described by Falk et al in 19902. This work originated from the observation that ANCA

were present in the serum of around 80% of patients with pauci-immune systemic

vasculitis or glomerulonephritis. The group went on to demonstrate, in an in vitro setting,

that ANCA could activate neutrophils resulting in release of reactive oxygen species (ROS)

and postulated that this was the mechanism by which tissue damage was effected in AAV.

Since then there has been a growing body of evidence supporting the pathogenic nature of

ANCA including animal models and a case report of trans placental transfer of these

antibodies causing neonatal disease3–5.

22

On immunofluorescence, these antibodies are classified as c-ANCA (cytoplasmic) or p-

ANCA (peri- nuclear) depending on their pattern of staining. Through ELISA we can now test

specifically for ANCA directed against the antigenic components expressed on the

neutrophil membrane, proteinase 3 (PR3) and myeloperoxidase (MPO). These antigen

specific antibodies tend to segregate with clinical phenotype. Granulomatosis with

polyangiitis (GPA) is predominantly linked with c-ANCA antibodies formed against PR3

(70%) and Microscopic Polyangiitis with p-ANCA against MPO (50%)6.

1.1.2 PR3 versus MPO: the role of antigens and antibodies

It has relatively recently been demonstrated that MPO and PR3 associated disease are

genetically different (discussed later)7. This was likely unsurprising to the majority of

clinicians who, for many years, have observed that patients with different antibodies

appear to have different diseases, both phenotypically and prognostically. Both MPO and

PR3 are neutrophil membrane proteins that are expressed predominantly in the earlier

stages of neutrophil development, promyelocyte and myeloblast stages8, in the healthy

population. It has been demonstrated that level of expression of PR3 on neutrophil

membranes appears to be under genetic regulation, and that patients with GPA have a

higher percentage of membrane PR3 expressing neutrophils, compared with healthy

controls9.

Current opinion on the pathogenesis of this disease is that an inflammatory stimulus, such

as infection, primes these neutrophils, leading to membrane expression of MPO or PR310.

IgG ANCA are produced by B cells against these neutrophil membrane antigens, under the

stimulus of inflammatory cytokines and T cell dysregulation. Binding of the antibody to

antigen on the neutrophil surface causes neutrophil activation, in the setting of priming by

certain inflammatory cytokines, which may result in adherence to and migration through

the vessel wall, activation of reactive oxygen species, neutrophil degranulation and enzyme

release. It is through these mechanisms, further perpetuated by complement activation,

that tissue damage occurs11,12(see Figure 1).

The role of MPO in disease development has been the most extensively studied with Xiao’s

successful animal model of MPO associated pauci-immune glomerulonephritis and

pulmonary capilleritis13 contributing significantly to understanding of pathogenesis. Indeed,

it was the MPO murine model that uncovered the role of the alternative complement

23

pathway in induction of disease14, in turn leading to clinical trials of a C5a receptor inhibitor

in ANCA associated glomerulonephritis (discussed below). Essentially, activation of

neutrophils can cause relocation of MPO from azurophilic granules within the neutrophil to

the surface of the cell membrane, whereby anti- MPO antibodies can bind causing

neutrophil degranulation. However, in addition, MPO is released extracellularly within

Neutrophil Extracellular Traps (NETS), the role of which are discussed subsequently.

One of the most recent descriptions of the potential role of MPO in disease development

includes a schema in which not just MPO targeted antibodies are pathogenic but also with

possible roles for MPO reactive T cells and even direct MPO toxicity15. Low level anti- MPO

ANCA has been demonstrated in the healthy population, but further work has elucidated

that this appears to be a different epitope than the one present in active disease16.

PR3 associated disease has proven to be a much more difficult entity to replicate with the

most successful model resulting from creation of a human-mouse chimeric immune system

prior to passive transfer of human IgG from patients with PR3. This produced vasculitic lung

and renal injury in a substantial proportion of the mice adding further weight to the

evidence for the pathogenic nature of ANCA17.

Figure 1. Putative representation

of AAV disease pathogenesis343.

24

1.1.3 Neutrophils and NETs in AAV

Adding to the models for disease development, there has been recent suggestion that

Neutrophil Extracellular Traps (NETs) may have a role to play in pathogenesis. NETs are a

chromatin mesh containing cytoplasmic components including MPO and PR318. There are

two models of NET production. In the first, termed NETosis, NETs are formed through

release of cytoplasmic contents, this being a form of cell death. The second involves DNA

and enzyme extrusion but does not appear to result in cell death19. NETs have been

identified in the kidneys (through analysis of renal biopsy samples) of patients with AAV. In

addition, abnormally shaped NETs can be shown in animal models to induce MPO ANCA

formation and pulmonary capilleritis20.

1.1.4 The role of B cells, T cells and complement

Plasma cells are obviously implicated in the pathogenesis of disease through production of,

predominantly IgG, ANCA. However, the role of B cells in this disease appears to extend

beyond this, supported by the efficacy of the anti CD20 monoclonal antibody Rituximab in

the treatment of AAV. Studies have explored the potential role of B regulatory (Bregs) cells

(which may have a role in T cell regulation) in AAV, finding that regulatory B cells (classed

as IL10+ B cells) were significantly diminished in patients with AAV compared with healthy

controls21. Another group has demonstrated that in active disease Bregs (in this study

identified as CD5+ cells) were lower in those AAV patients with active disease22. However,

subsequent studies have failed to demonstrate the use of CD5+ Bregs as biomarkers for

disease activity with further phenotyping of these cells required23.

B lymphocyte stimulator (Blys), a neutrophil produced B-cell survival signal24 is another area

of research interest, with Belimumab, an anti-Blys monoclonal antibody having been shown

to be effective in the treatment of Systemic Lupus Erythematosus25. It has been

demonstrated that AAV patients with active disease have higher levels of Blys, and that

Blys release from primed neutrophils may be stimulated by the presence of PR3 ANCA24.

The currently underway phase III clinical trial BREVAS (ClinicalTrials.gov Identifier:

NCT01663623) aims to evaluate the efficacy/safety of Belimumab in combination with

azathioprine for maintenance of remission in AAV (versus azathioprine alone).

T cells have been known for some time to play a significant role in the pathogenesis of GPA

with the presence of over-active peripheral T cells, as well as the presence of T cells in

25

granulomatous lesions in GPA being previously reported12. However, the discovery of Th17,

which secretes the pro-inflammatory IL-17 has reawakened interest in this area.

Increased presence of Th-17 cells has been demonstrated in patients with GPA26, with

higher levels of IL-17 present during acute vasculitic episodes27. IL-23 is an upstream

cytokine vital for Th17 lineage induction. In the previous study, IL-23 levels were found to

correspond with disease activity27. It has been shown that infections such as

Staphylococcus aureus may influence development of the Th17 lineage through IL-23

production28.

The production of these Th17 cells may also be dependent on regulatory T cells (Tregs). A

number of groups have demonstrated that Tregs from patients with AAV are unable to

suppress T –cell proliferation12,29. It may be that increased Th17 cell development in part

follows this diminished suppressive action of Tregs or indeed that Th17 cells are possibly

even able to develop directly from Tregs30. AAV is predominantly a disease of the elderly

with the peak age of incidence being 65-74 years31. It is well established that the risk of

autoimmunity increases with age with theories such as involution of the thymus with

compensatory T cell proliferation and changes in T cell apoptosis suggested in explanation

of this phenomenon. However, from cohort studies of those with “limited” GPA it can be

noted that this is a disease in which the age of onset appears to be earlier. Limited GPA has

been found to be associated with a predominantly Th1 helper response and systemic

disease with a Th2 response32. With increasing age, the cytokine response to stimulus shifts

from Th1 to Th2, perhaps explaining why the elderly are more prone to development of

systemic versus local disease.

There has been recent focus on the role of the alternative complement pathway in the

pathogenesis of vasculitis, with data supporting that this occurs through neutrophil

activation generating C5. C5 then appear to not only cause chemotaxis of neutrophils but

also further primes neutrophils 33. Inhibition of C5 using monoclonal antibodies provided a

protective effect against the development of glomerulonephritis in a murine model of MPO

IgG induced glomerulonephritis34. Following this a C5a receptor antagonist has been

developed as a potential therapeutic agent and is undergoing Phase 2 trials with early

results suggesting a potential therapeutic role in ANCA vasculitis glomerular disease35.

26

1.2 EPIDEMIOLOGY OF AAV

ANCA associated vasculitis is a rare disease with a combined incidence of between 13 and

20 per million in Europe36. Of these GPA is the predominant disorder in Northern Europe

with an annual incidence in one study of 11.3/million compared with 5.9/million for MPA37.

This trend is reversed in Southern Europe and Southern Asia with MPA representing the

majority of disease in these areas38. This pattern of distribution supports two theories

concerning the development of AAV. The first, that this is a disease with genetic

contribution to susceptibility and secondly, that environmental factors are likely to play a

role in disease development. Both theories now have substantial evidence in their support.

1.2.1 Genetics of AAV

The first work looking at genetic predisposition to development of AAV was published in

1992 when a highly significant association between HLA DR1 and disease was reported in

those with GPA compared with healthy controls39. Subsequently in 2003, Schreiber et al.

published research revealing that the general population appeared to be divided into 2

subgroups- those with high levels of PR3 expressed on neutrophil membranes and those

with low levels9, and that the level of expression appeared to remain stable over time (12

months). They then investigated a group of patients with GPA and discovered that these

patients had a significantly higher number of neutrophils expressing membrane PR3.

Comparison of PR3 membrane expression in monozygotic twins, compared with dizygotic,

demonstrated significant correlation between expression levels in the monozygotic twins.

This supported the argument that the degree of PR3 expression on neutrophil membranes

appeared to be under genetic control. This link was further strengthened by the

observation that first-degree relatives of those with GPA had a relative risk of developing

the disease of 1.5640.

Following this, increasing availability of gene array testing has allowed identification of

Single Nucleotide Polymorphisms (SNPs) which appear to confer risk to the individual of

developing AAV. There have been two Genome Wide Association Studies (GWAS) in AAV

published in recent years. The first European identified a strong association in a SNP at

HLA- DPB1 with the presence of disease. This study also demonstrated significant

differences at several loci including SERPINA1, MHC and PRTN3, associated with PR3

positive but not MPO positive disease7. The US GWAS41, including only patients with GPA,

27

also identified the same HLA association, but in addition identified a SNP near SEMA6A

associated with the presence of GPA.

1.2.2 Environmental exposure and epigenetics

Genetic predisposition in isolation is obviously insufficient to lead to disease development

as vasculitis is not a “classically” inherited disease, and remains relatively rare. For many

autoimmune diseases, epigenetics (the study of “mechanisms that determine and/or

perpetuate heritable genomic functions without changes in DNA sequence”42) has helped

to explain the “two hit theory” of disease susceptibility and disease development following

environmental exposure. In AAV the environmental exposure that leads to development of

disease is far from certain and is likely to differ according to patient. However, there have

been several well described associations which deserve some focus here.

Exposure to silica has been reported as a trigger for AAV in addition to other autoimmune

and respiratory diseases. A systematic review of the literature examining the possible

association with AAV was published in 201343. This found an association with “ever” having

been exposed to silica and subsequent development of AAV with a summary OR of 2.56.

Hypotheses to explain this association include the causation of neutrophil apoptosis by

silica and trapping of silica in alveoli leading to a systemic inflammatory response through T

cell activation. However, to prove a definite association prospective longitudinal studies are

ideally required which remain unlikely due to the disease rarity.

Other possible occupational exposures associated with AAV development include farming.

A recent German questionnaire study found a strong association between reported regular

farm exposure and development of GPA, with the strongest association for those with

regular exposure to cattle44. Both of these possible environmental risk factors were

detailed in a New Zealand case- control study, with reported associations to disease (GPA)

development including exposure to silica and grain dust, occupation as a farm worker or

having undertaken specific gardening activities45.

28

1.3 THE ROLE OF INFECTION IN DISEASE PATHOGENESIS

Although occupational exposure may well for some be the trigger for disease development,

perhaps the most extensively observed and explored hypothesis is the link between

infection and AAV. Sixty-three percent of patients with GPA, compared with 25% of healthy

controls, have been found to have chronic nasal carriage of Staphylococcus aureus46. The

persistence of nasal carriage of S. aureus has been found to strongly increase the risk of

relapse in this population47. Several mechanisms have been suggested to explain this

including S.aureus super- antigen stimulus of B and T cells, neutrophil priming and

molecular mimicry46. The use of anti-staphylococcal agents including co- trimoxazole has

been shown to support disease control with reduction in the rate of relapses48. The

protective mechanism of this anti-microbial is uncertain but one possibility is that it may be

mediated through an alteration of the balance of nasal flora49. Others had postulated that

perhaps S.aureus proteins and ANCA target epitopes were homologous, with a theory of

molecular mimicry. However, this was found to not be the case.

In 2004, an alternative “theory of autoantigen complementarity” was investigated.

Prendergraft et al. discovered that a proportion of their patients with AAV appeared to

additionally be producing an antibody against an epitope present in the central portion of

the PR3 antigen, an antibody they named “complementary PR3” (cPR3). They

demonstrated that not only did mice injected with the cPR3 antigen produce cPR3

antibodies but they also produced PR3 antibodies50. The discovery that the cPR3 epitope

shared homology with pathogens including Staph.aureus gave rise to the theory that the

formation of cPR3 antibodies may provide the missing link between infection and the

pathogenesis of vasculitis. Subsequently Tadema et al.51 were unable to find any

association between levels of complementary PR3 and disease activity in those with AAV,

and conversely actually found that levels of cPR3 activity appeared to be lower in those

with vasculitis than healthy controls. They were also unable to find any association

between cPR3 levels and exposure to S. aureus (as defined by being a nasal carrier of S.

aureus). However, they did accept that it was possible that the formation of anti- cPR3 and

anti- PR3 complexes may be masking true measurement of cPR3 activity. Adding strength

to these theories is the observation that Staph. aureus has been shown to trigger NET

formation52.

29

Multiple other pathogens have been described in association with ANCA production53. Kain

et al. have focused on a possible mechanism of molecular mimicry between a protein

(FimH) on the fimbriae of gram- negative pathogens and the antibody LAMP-2. They

postulated that other, currently unmeasured antigen targets, aside from MPO and PR3,

may be responsible for inducing ANCA production. They discovered that antibodies to the

heavily glycosylated protein LAMP-2 were detectable by immunofluorescence in 95% of

their AAV population54, but absent in their healthy controls. They went on to demonstrate

the potential pathogenic nature of these antibodies by inducing glomerulonephritis in rats

through injection of LAMP-2 antibodies, and further showed that immunisation of the rats

with FimH protein not only induced LAMP-2 antibody formation but was also capable of

stimulating the development of a clinical picture of glomerulonephritis and pulmonary

haemorrhage compatible with vasculitis. However, work attempting to validate these

findings in other cohorts has yet to be successful. Investigators from Chapel Hill, North

Carolina have attempted to replicate this work in a cohort of 329 patients with AAV

glomerulonephritis, healthy controls and patients with Gram-negative urinary tract

infections (UTIs)55. They found that LAMP-2 antibodies were present in only 21% of their

patients with AAV but also in 16% of patients with UTIs. They were also unable to replicate

induction of glomerulonephritis in the rats through immunisation of the LAMP-2

antibodies.

Two individual groups have demonstrated a less specific link between infection and

vasculitis by stimulating B cells in from patients with AAV in vitro with bacterial DNA56,57.

Both groups demonstrated that ANCA production could be provoked by B cell exposure to

CpG deoxynucluotides (hypomethylated DNA found in bacteria and viruses). In both

studies, however, these responses were more pronounced in those PR3 positive patients

than MPO positive, reinforcing the link between this particular AAV and infection.

Essentially further work is required to try to elucidate this link between exposure to

infectious agents and development of vasculitis.

30

1.4 DIAGNOSIS AND CLASSIFICATION

Once disease has developed in a genetically predisposed individual, the greatest challenge

perhaps for the patient, is receiving timely and accurate diagnosis and classification of their

disorder, allowing for appropriate treatment. It is clinically relevant to ensure the correct

immunological and clinical subtype are identified as this has significant prognostic

implications. AAV may be categorised as Microscopic Polyangiitis (MPA), Granulomatosis

with Polyangiitis (GPA) or Eosinophilic Granulomatosis with Polyangiitis (EGPA). However,

due to increasing evidence that EGPA comprises a uniquely different spectrum of disorders

it is only the two most common of these, MPA and GPA, shall be considered here.

Granulomatosis with Polyangiitis (formally known as Wegener’s Granulomatosis) causes

small vessel inflammation in association with granuloma formation. It is associated with

initial upper airway disease in over 70% of patients and may remain limited to these

organs. However, in the multi- system form it can affect the lungs, causing granulomatous

disease or pulmonary haemorrhage, renal failure or nerve and skin involvement, amongst

other rarer manifestations58.

Vessel

size

Granulomas ANCA positivity Organ

involvement

%renal

involvement

GPA Small Yes 95 %

70% PR3/cANCA

25% MPO/pANCA

ENT

Lungs

Renal

systemic

80

MPA Small No 90%

40% PR3/cANCA

50% MPO/pANCA

Lungs

Renal

systemic

90

Table 1. Description of AAV according to ANCA positivity and organ involvement6

Granulomatosis with Polyangiitis was first described by Klinger in 193159 as a form of

polyarteritis nodosa and then defined as a distinct clinical entity by Wegener in 1936 and

193960. For 80 years, this inflammatory condition, characterised by granulomatous

inflammation with a predilection for the renal and respiratory tract (commonly including

the ear and nose) was known as Wegener’s Granulomatosis. This condition has recently

31

been renamed as Granulomatosis with Polyangiitis (GPA) by the Board of Directors for the

American College of Rheumatology (ACR), the American Society of Nephrology and the

European League against Rheumatism (EULAR) partly in keeping with the movement away

from eponymous syndromes and following concerns regarding potential affiliations Dr.

Wegener may have had with the Nazi Party in the Second World War61.

Microscopic Polyangiitis was first recognised as a condition causing rapidly progressive

glomerulonephritis, in association with systemic illness, chest and abdominal signs. The

glomerulonephritis was identified by the presence of fibrinoid necrosis and crescents in the

kidney at autopsy in a case series published in 194862 and the term “microscopic

periarteritis” was coined. Prior to this there had been debate as to whether patients

suffering from this form of vasculitis actually had periarteritis nodosa (polyarteritis nodosa)

with an “independent” glomerulonephritis. MPA is differentiated from GPA pathologically

by the absence of granulomas and phenotypically by the (usual) absence of upper

respiratory tract involvement. Current disease classification criteria are outlined in Table 2.

ANCA-associated vasculitis (AAV) Necrotizing vasculitis, with few or no immune

deposits, predominantly affecting small vessels (i.e.,

capillaries, venules, arterioles, and small arteries),

associated with myeloperoxidase (MPO) ANCA or

proteinase 3 (PR3) ANCA. Not all patients have ANCA.

Add a prefix indicating ANCA reactivity, e.g., MPO-

ANCA, PR3-ANCA, ANCA-negative.

Microscopic polyangiitis (MPA) Necrotizing vasculitis, with few or no immune

deposits, predominantly affecting small vessels (i.e.,

capillaries, venules, or arterioles). Necrotizing arteritis

involving small and medium arteries may be present.

Necrotizing glomerulonephritis is very common.

Pulmonary capillaritis often occurs. Granulomatous

inflammation is absent.

Granulomatosis with polyangiitis (Wegener's) (GPA) Necrotizing granulomatous inflammation usually

involving the upper and lower respiratory tract, and

necrotizing vasculitis affecting predominantly small to

medium vessels (e.g., capillaries, venules, arterioles,

arteries and veins). Necrotizing glomerulonephritis is

common.

Table 2. Chapel Hill Consensus Conference classification of AAV 201263

32

As a complex and heterogenous group of disorders, with a myriad of presentations,

diagnosis and classification of AAV can be challenging. Although there is suggestion that

time to recognition and diagnosis of these disorders may be improving64 there is still recent

documentation of significant delay to diagnosis65,66. A recent publication of the combined

outcomes of EUVAS clinical trials showed that 34.5% of patients had at least 1 item of

damage at baseline (as measured by the Vasculitis Damage Index), likely reflecting damage

accruing from disease manifestations prior to diagnosis67.

Classification of disease has been historically challenging with the first American College of

Rheumatology classification system omitting MPA68. Due to a need for accurate

classification for inclusion of patients in clinical trials and epidemiological studies, the EMEA

classification algorithm was developed and published in 2007 which was validated to

successfully classify patients into a single category69. Since then disease classification has

moved on, with the publication of the GWAS study and the suggestion of MPO positive and

PR3 positive disease as distinct entities7 and with the publication of the updated 2012

classification criteria63. The ongoing Diagnostic and Classification in Vasculitis (DCVAS)

international study aims to assist in this area by assisting with development and validation

of diagnostic and classification criteria for all, not just small vessel, vasculitis70.

1.5 TREATMENT

Following accurate diagnosis and classification of disease, timely and appropriate

treatment can be delivered. Treatment strategies for AAV can be divided into “induction”

and “maintenance” phases. Induction therapy conventionally involves high dose steroid

therapy e.g. prednisolone at 1mg/kg of body weight and may include one to three initial

intravenous steroid infusions, depending on disease severity (See Table 3). Steroid dose is

then tapered down after the first month, with recommendations that the steroid dose is

not reduced to less than 15mg for the first 3 months then tapered to 10mg or less during

remission57. Remission can be defined as the absence of disease activity attributable to

vasculitis as measured by a standardised, validated scoring system such as the Birmingham

Vasculitis Activity Score (BVAS)71.Disease category

33

Table 3. Definition of disease severity according to EULAR72

Patients with severe organ or life threatening disease may also be treated with plasma

exchange, supported by evidence from the MEPEX trial73 which showed that the use of 7

plasma exchange sessions for patients presenting with AAV and serum creatinine >

500µmol/l had a reduction in risk of 24% of progression to end stage renal failure at 12

months, when compared with those treated with 3 pulses of intravenous

methylprednisolone (1g).

Alongside steroid treatment, patients with organ or life-threatening disease should be

treated with cyclophosphamide which can be administered as daily oral or pulsed

intravenous (i.v.) therapy, until remission is reached (usually at 3 to 6 months). The

publication of initial outcomes from the CYCLOPS clinical trial comparing pulsed

intravenous cyclophosphamide therapy to daily oral, supported pulsed therapy, allowing a

much lower total cyclophosphamide dose to be administered. The CYCLOPS study indicated

that the two regimens were equivalent for time to remission but with fewer leucopenic

episode in the pulsed intravenous group, indicating perhaps a safety advantage74. However,

longer term follow-up data (median follow-up 4.3 years) has suggested that those receiving

a lower cumulative dose of cyclophosphamide are more likely to relapse (20.8% daily oral

Definition

Localised Upper and/or lower respiratory tract disease

without any other systemic involvement or

constitutional symptoms

Early systemic Any, without organ threatening or life-

threatening disease

Generalised Renal or other organ threatening disease, serum

creatinine <500 µmol/ litre (5.6 mg/dl)

Severe Renal or other vital organ failure, serum

creatinine >500 µmol/litre (5.6 mg/dl)

Refractory Progressive disease unresponsive to

glucocorticoids and cyclophosphamide

34

versus 39.5% i.v.) although the increased relapse rate was not associated with an increase

in morbidity or mortality75.

For patients in whom preservation of fertility is desirable, or with significant previous

cyclophosphamide exposure, the other first-line option (in keeping with FDA approval and

NICE guidance) is Rituximab. Rituximab was first developed as an adjunct to chemotherapy

for treatment of B cell lymphomas. In AAV, it has been found that higher numbers of

activated B cells can correlate with disease activity76, therefore logically leading to the

potential use of Rituximab as a therapy for AAV. Initially Rituximab was used in patients

with refractory, relapsing disease77 but the publication of two Randomised Controlled Trials

have demonstrated non- inferiority to cyclophosphamide for induction of disease

remission. The American “RAVE” trial78 compared administration of Rituximab (375mg/m2,

weekly for four weeks) with daily oral cyclophosphamide converted to oral azathioprine at

remission (3- 6 months). The steroid regime was the same in both groups (tapered and

discontinued by 5 months in those remaining without disease flare). 130/ 197 patients

(66%) had renal involvement. 63/99 patients (64%) who had received Rituximab met the

primary end point of no disease activity plus no steroids at 6 months, compared with 52/98

(53%) in the cyclophosphamide group. This allowed the authors to conclude that Rituximab

was non- inferior to cyclophosphamide for induction of remission, including for those

patients with severe disease. In terms of adverse events, leucopenia was more common in

the group treated with cyclophosphamide (10% versus 3%) but infection rates were

identical between the two groups (occurring in 7% of the patients). The European

RITUXIVAS study79 differed in that all the patients included had renal involvement. The

treatment protocols also varied in that this trial used pulsed intravenous cyclophosphamide

for the control arm, and the patients in the Rituximab group also received two doses of

cyclophosphamide (15mg/kg) with the first and third doses of Rituximab. The steroid dose

was tapered but patients remained on 5mg prednisolone/ day from 6 months. This was an

unblinded study and the follow- up period was longer than the RAVE trial at 12 months.

Sustained remission was achieved in 25/33 (76%) of the patients receiving Rituximab and

9/11 (82%) of the control group. 36% of patients receiving Rituximab had at least 1

infectious episode compared with 27% of the cyclophosphamide group. The authors

therefore concluded that in their trial, Rituximab was not superior in inducing remission or

at avoiding treatment related toxicity in this population, compared with cyclophosphamide.

35

This may be explained by the fact that some of the adverse events such as infectious

episodes may be related to the steroid regimes which were identical between intervention

and control arms. Indeed, it can be noted that the RAVE trial, which aimed to have patients

off steroids completely by 6 months, had a much lower reported infection rate than

RITUXIVAS.

It has been suggested that patients treated with Rituximab do not appear to be at

increased risk of serious infection despite their complete B cell depletion due to reasonably

well preserved IgG levels (but a fall in IgM levels)80. However, repeated courses are likely to

affect the ability of the humoral immunity to fight new pathogens. A cohort study of 29

patients with GPA evaluated immunoglobulin levels in patients receiving pre-emptive

“maintenance” Rituximab therapy (1g biannually or 2g annually, median dose 9g

received)81. Of these patients, eight discontinued therapies due to

hypogammaglobulinaemia, defined as total IgG levels < 6g/L. Five of these had severe or

recurrent infections. This paper described risk factors for severe hypogammaglobulinaemia

requiring treatment withdrawal as being male, having renal involvement and receiving the

1g biannual regime. The Cambridge group have subsequently described the use of

replacement intravenous immunoglobulins (IvIg) in patients with recurrent infections and

hypogammaglobulinaemia following Rituximab therapy82. Of these, six continued to receive

Rituximab alongside the IvIg replacement, for disease control.

These issues become more relevant as the evidence gathers to support the use of

Rituximab in maintenance of remission. For patients having received cyclophosphamide,

once remission is achieved the patient can be switched to maintenance

immunosuppression, first-line with azathioprine, or with mycophenolate mofetil,

methotrexate or leflunomide as other possibilities83. However, it is less clear-cut how to

continue or alter treatment for those patients initiated on Rituximab. Equally, for patients

who relapse on maintenance oral therapy, and require Rituximab to induce remission,

there is little evidence to guide whether to continue their oral agent. Recommendations for

the use of Rituximab in AAV, published in 2011, did not issue firm guidance with regards to

this area, stating the available evidence to be that whilst many published series had

continued other agents alongside Rituximab, the RCTs had not84. However, these patients

would require pre-emptive Rituximab to ensure maintenance of remission. Whilst this is

supported by the current NHS England funding policy for relapsing/ refractory patients

36

requiring Rituximab, maintenance therapy with Rituximab is not commissioned for patients

receiving it first-line85.

However, this position may alter in future as evidence builds. The MAINRITSAN study was a

non-blinded randomized controlled trial comparing Rituximab (5 x 500mg doses over 18

months) with azathioprine (2 mg per kilogram per day for 12 months, and then 1.5 mg per

kilogram per day for 6 months and 1 mg per kilogram per day for 4 months), following

achievement of remission with standard cyclophosphamide and steroid therapy. Both arms

received tapering prednisolone doses as part of their maintenance therapy86. This study

reported superiority of Rituximab over azathioprine for prevention of major relapses over

28 months’ follow-up with 29% of patients in the azathioprine group relapsing compared

with 5% in the rituximab group (HR for relapse 6.61). A follow-up study, MAINRITSAN 2

(ClinicalTrials.gov Identifier: NCT01731561) is currently underway aiming to assess whether

Rituximab for maintenance therapy is best administered at regular time points or based

upon returning B cells and ANCA titres. This will further contribute to how this treatment is

best used in control of AAV.

The ongoing UK study RITAZAREM (ClinicalTrials.gov Identifier: NCT01697267) will provide

additional data, comparing 4 monthly 1g Rituximab infusions, over 20 months with

Azathioprine (withdrawn by month 27) following induction of remission with Rituximab for

relapsing disease. The primary outcome is time to relapse with a follow-up period of 4

years.

Other agents have been considered for treatment of AAV. Following on from the success of

B cell depleting therapies for this disease, as mentioned above the BREVAS study

(Clinicaltrials.gov Identifier: NCT01663623) is a phase 3 clinical trial comparing Belimumab,

with placebo, alongside azathioprine for maintenance of remission. Belimumab has

recently received NICE approval for treatment of active lupus with some evidence for

clinical effectiveness from 2 clinical trials87. Abatacept inhibits T cell activation by blocking

engagement of CD-28 with its ligand. Based on this mechanism of action and the known

roles of T cells in GPA, an open label trial of Abatacept was undertaken in 20 patients with

relapsing non-severe GPA88. Patients were continued in addition on their maintenance

immunosuppression agent. Eighty percent of patients achieved remission, with a median

time to remission of 1.9 months. An acceptable adverse event profile in addition suggests

that this may be a drug warranting further investigation for this population.

37

The mainstay of new clinical trials in AAV involves minimization of steroid exposure due to

the significant side effect profile from these agents. However, until new treatments are

available it remains prudent to maintain vigilance for possible complications of

immunosuppression due to the associated possible morbidity and mortality.

1.6 PROGNOSIS

1.6.1 Mortality

The average time to death prior to the development of modern treatment strategies for

patients with AAV was 5 months89, yet with advances in treatment, mortality rates have

significantly improved with recent data for 1 year mortality reported as 11%90.

Historically, reported outcomes for this patient group was largely confined to single-centre

experience. However, in more recent years collaboration between centres on a national

and international level has allowed for wider experience, with larger patient numbers to be

published.

The first of these by the “Pan- Thames” group included patients presenting to 7 London

hospitals with a new diagnosis of renal vasculitis between 1995 and 200091. 313 patients

were included with the majority having a diagnosis of MPA 120 (49%) or GPA 82 (33%).

Survival rates at 1 and 5 years were 84% and 76% respectively. Predictors for mortality

were poorer renal function at presentation (with those presenting with end stage renal

failure having a 5-year survival of 53%, p= 0.01) and age greater than 60 years (p=0.0002).

Infection and leucopenia were the most common adverse events, with treatment induced

leucopenia occurring in 99 (41%) of patients and being strongly associated with sepsis (p<

0.001). Seventy- three episodes of sepsis were reported (although it is not stated in how

many patients they occurred), the presence of which were a predictor of mortality (p=

0.048) with the most common infection being pneumonia at 23 episodes (31.5%), followed

by neutropenic sepsis at 12 episodes (16.4%) then herpes zoster virus at 11 episodes

(15.1%). It should be noted that this study only included patients with renal involvement,

and therefore this is likely to have had an impact upon mortality and possibly adverse

events. There was no mention of adjustment of cyclophosphamide dose for renal function,

but the majority of centres used oral therapy, compared with intravenous (2/7). Similarly,

the French Vasculitis Group retrospectively analysed 595 patients with a diagnosis of MPA,

Eosinophilic Granulomatosis with Polyangiitis or Polyarteritis Nodosa diagnosed and

38

treated between 1953 and 199992. 60 patients (10%) died in the first year following

diagnosis with 33 (55%) of these deaths related to active vasculitis and 27 (45%) to

infection. They also found that older age, renal involvement, and central nervous system

involvement was predictive of mortality. Of note in this study is the extensive time period

from which these patients were recruited, meaning that therapy was variable depending

on the era in which patients were treated. Analysis by time of diagnosis showed that

mortality has improved significantly since 1990, compared with patients presenting prior to

this date (p< 0.01).

In 2007 the European League Against Rheumatism (EULAR) Systemic Vasculitis Task Force

also published a systematic review of outcome data from patients with AAV that included

44 studies. They reported 1-year survival rates of 85-97% in GPA, 82-92% in MPA and 93-

94% in EGPA. Five- year survival rates were only available for patients with GPA and

reported as 75-88%93. Age and renal function were found once again to predict mortality

but also the presence of damage, as measured by the Vasculitis Damage Index (VDI). The

VDI is a validated assessment tool which records damage accrued not only due to vasculitis,

but also due to treatment for the condition94.

In recent years, the European Vasculitis Study Group (EUVAS) have completed a number of

randomised controlled trials in patients with AAV to answer questions with regards to the

efficacy of specific therapeutic options; CYCLOPS74, NORAM95, CYCAZAREM96, MEPEX73 and

IMPROVE97 in addition to the Rituximab study outlined above. A combined review of

outcomes for the first 4 of these studies has provided follow- up data for a median duration

of 5.2 years in 535 patients98. The leading cause of death in the first year was infection at

47.5 % of deaths followed by active vasculitis at 18.6% then cardiovascular disease at

15.3%. After the first year, cardiovascular disease became the commonest cause of death

at 25.7% followed by malignancy at 21.6%, with infection still contributing significantly at

20.3%. Significant predictors of mortality were the presence of both MPO and PR3 ANCA

(dual positivity), age greater than 75 years and estimated glomerular filtration rate (eGFR) <

15mls/min (chronic kidney disease stage 5). There is currently data collection underway for

the 10 year follow- up for this study which will provide more valuable long-term data for

this cohort.

Specific to those patients with renal involvement, the Chapel Hill group has recently

published outcomes for 554 patients with AAV with a median follow- up of 31 months99.

39

This study, encompassing outcomes for patients diagnosed between 1985 and 2009,

reported that renal function at diagnosis has improved over time; patients having a median

eGFR of 11 ml/min/1.73 m2 in the earliest time period and 23 ml/min/1.73 m2 in the latest

period. This would explain the observation that significantly fewer patients developed ESRD

over time. There was no significant difference in the adjusted relapse rate over time with

no factors identified associated with relapse (including ANCA type or duration of

cyclophosphamide therapy). The authors suggested that this may be due to the inclusion of

only those with renal involvement having received cyclophosphamide, therefore excluding

many patients perhaps with airway limited PR3 associated disease. Data from other

sources additionally supports that generally outcomes from AAV are improving with a

decline in Standardised Mortality Ratios from 2.1 to 1.03, in subsequent German vasculitis

cohorts over a 36 years period64. However, it is clear that morbidity from treatment is still

significant and ways of approaching prevention of this shall be addressed in later sections.

1.6.2 Relapse

The risk of disease relapse for patients with AAV appears to be in the order of

50%100,101(with follow- up over 44 months in 2 cohorts). One group’s reports have

suggested that relapse rates may be reducing, with a relapse rate of 35.3% in patients

diagnosed from 1999 to 2002, compared with 51.2% of those diagnosed between 1994 and

199864. As mentioned above, however, the Chapel Hill study did not report an

improvement in relapse rates with their 5-year relapse rate being 35%. Furthermore,

longer term follow-up data from the CYCLOPS trial has shown that those treated with

pulsed i.v. therapy were significantly more likely to have relapsed at follow-up (median

duration 4.3 years) but this was not associated with a difference in mortality or morbidity

between the two arms75. Other studies have shown the pattern of organ involvement to

help predict relapse risk with respiratory involvement, cardiac involvement and lack of

significant renal involvement (creatinine clearance >60ml/min) all being risk factors for

relapse93,101. PR3 positivity has been recurrently demonstrated to be a risk factor for

relapse102, however, the relationship between ANCA titres and relapse is complex and is

discussed in more detail below.

Nasal carriage of Staph.aureus has been shown to be associated with a higher rate of

disease relapse47 with treatment with co-trimoxazole shown to be efficacious in reducing

relapse rates48.

40

The mechanism behind this association is not as yet fully understood with roles for

molecular mimicry, Toll Like receptors and Neutrophil Extracellular Traps all suggested as

potential explanations103.

1.6.3 Biomarkers to predict disease activity

However, although ANCA type has become an important part of disease classification, it is

still an inexact tool to predict disease activity including relapse, in addition not being

helpful for disease monitoring in the 5-10% of GPA/MPA ANCA negative patients6.

In ANCA positive patients, the sensitivity and positive predictive value of ANCA rises in

predicting disease relapses have been reported at anything from 20 to almost 100%104. One

publication evaluated ANCA titres in relapsers and non- relapsers in the NORAM trial using

9 different ELISAs. However, although a PR3 peak could be identified to correspond with

disease activity in all relapsers, the monthly increment in PR3 levels prior to the peak was

the same for relapsers and non- relapsers105.

There does appear to be MPO detectable in healthy populations, however, it is likely that

the type of ANCA antibody i.e. the epitope, determines the pathogenicity. The Chapel Hill

group has published data on varying MPO ANCA epitopes. They were able to identify a

pathogenic MPO ANCA epitope in ANCA negative patients along with demonstration of the

presence of a masking protein present in sera, preventing routine antibody detection16.

In summary, although commercially available ANCA titres may in some cases correlate with

disease activity, they cannot be relied upon to distinguish active disease from other

pathology. At present the management of AAV is challenging with uncertainty as to the

balance between drug-maintained disease control, with drug-related morbidity and

mortality and, on the other hand, the risks of relapse with attendant morbidity and

mortality if drug therapy is reduced or withdrawn. Thus, other biomarkers of active disease

are needed to enable improved long term disease management. In addition, earlier

diagnosis and prompt treatment of AAV is needed to reduce damage accruing early on in

disease.

Due to the similarities of presentation between flares of disease activity and possible

infection (e.g. affecting the renal tract, chest or sinuses) some researchers have focused on

serological markers which potentially could be used to distinguish active vasculitis from

infection.

41

The first of these was procalcitonin (PCT), a peptide precursor of the hormone calcitonin,

the levels of which were compared with other inflammatory markers such as CRP and IL-6

in patients with SLE or AAV106,107. It was found that in the absence of infection the PCT

levels were normal in 95 of 98 samples from patients with AAV. However, in the presence

of infection (16 episodes) PCT became markedly elevated. The authors concluded that PCT

appeared to have a specificity of 84% and sensitivity of 100% for the detection of systemic

infection in patients with autoimmune disease such as AAV. However, subsequent studies

have commented that PCT may be raised in patients with active vasculitis and additionally

may be normal in patients with localised, rather than systemic, infection108.

Other markers which have been evaluated include anti-β-glucan antibody109, with a study

demonstrating, perhaps unsurprisingly, that patients on immunosuppressive treatment for

AAV had lower titres of this antibody, and the mean was further lowered in 3 patients who

developed the infectious complications of Pneumocystis pneumonia (PjP) or aspergillus.

However, it did not appear that level of this antibody could be used as a diagnostic marker

of infection. Another marker which perhaps suggests more promise is the serum level of

soluble triggering receptor expressed on myeloid cells-1 (TREM-1). The presence of this

receptor has been shown to be up regulated in the presence of bacterial and fungal

infection, however investigation of levels in patients with AAV failed to distinguish between

those with inactive vasculitis and infection and those with active vasculitis and no

infection110. However, the ratio of serum TREM-1 to serum creatinine appeared to be

higher in those with infectious complications. Overall, the above studies all conclude that

some of these markers may be useful but ultimately further investigation is required in

these areas.

1.7 TREATMENT AND DISEASE ASSOCIATED MORBIDITY

The majority of patients now survive their initial disease episode. However, this means that

vasculitis has shifted from being an acute life limiting disease to a chronic relapsing

condition. Due to the paucity of prospective data as to which patients are at higher risk

from the initial disease and subsequent relapse, patients are often treated aggressively

with high dose immunosuppression. Equally, there is uncertainty as to how long

maintenance immunosuppression should be continued meaning that patients often

continue for years on treatment. Although there have been risk factors for relapse

42

identified (as previously discussed), it remains a challenge to ascertain the optimal time

and regimen for withdrawal of immunosuppression. Leading from this, morbidity

associated with drug exposure is not uncommon, and in fact now may be linked to the

majority of deaths in this population.

1.7.1 Infection as a significant complication of therapy

The risk of infection in vasculitis is likely predominantly linked with immunosuppression

exposure. However, other possible contributory factors in this population may include

susceptibility to infection due to previous organ damage from vasculitis or even an

aberrant immune response.

Hoffman’s series of 158 patients with GPA reported in 1992 included 140 serious infections

in 73 patients (46%), resulting in a rate of 0.11 infections per patient year. The most

commonly presenting infections were bacterial pneumonias at 57 episodes (39%), followed

by skin infections at 38 episodes (26%)100. A full breakdown of the nature of the infections

reported in the combined EUVAS clinical trials is outlined in Table 490. A further review of

240 consecutive patients with AAV presenting to a Birmingham centre over 10 years

reported 91 deaths, of which 33 (36%) were attributable to infection. Patients attending

this centre were treated with a regime of oral cyclophosphamide 2mg/kg until remission

was achieved, with the dose reduced by 25% if the patient became leucopenic (WCC<4.0

x109L) or if the patient was greater than 65 years old. Those patients presenting with

pulmonary haemorrhage or serum creatinine > 500µmol/L were also treated with pulsed

methylprednisolone plus seven sessions of plasma exchange over 14 days. Maintenance

therapy was with azathioprine 1.5mg/kg plus prednisolone tapered to 7.5 mg and

maintenance therapy was continued for 5 years. This study reported identified risk factors

for infection in this population as older age and leucopenia111 .

43

Infection Number(%) of infections % of total

population

Respiratory:

Lower

Upper

40 (24)

7 (4)

7.6

1.3

Hepatitis B 2 (1) 0.4

Urine 9 (5) 1.7

Miscellaneous 37 (22) 7.1

Unknown 22 (13) 4.2

Opportunistic: 48 (29)

Pneumocystis carinii 5* (3) 0.9

CMV 12 (7) 2.2

Candidiasis 16 (10) 3.1

HSV 7 (4) 1.3

Epstein Barr virus 1 (0.6) 0.2

Clostridium difficile 3 (2) 0.6

Parvovirus 1 (0.6) 0.2

HZV 5 (3) 0.9

Table 4. Summary of infections reported in the 4 combined EUVAS trials90

1.7.2 Cardiovascular disease

It has been known for some time that patients with AAV have an increased risk of

thromboembolic disease, particularly associated with periods of active disease112. This

initially was thought to be due to endothelial changes and hypercoagulability associated

with both the disease and the treatment. However, more recently the presence of anti-

plasminogen antibodies has been demonstrated in patients with AAV. In addition, the

presence of these antibodies has been shown to retard fibrinolysis in vitro113.

44

With regards to cardiovascular disease, matched cohort studies have demonstrated an

increased incidence of events in AAV patients, with an observed to expected ratio of 1.9 in

one study compared with the background population and a hazard ratio of 2.23 compared

with a CKD population114,115. This observation has led to the development of a model for

predicting cardiovascular events in AAV patients with age, diastolic hypertension and

absence of PR3 antibodies being identified as risk factors for cardiovascular events in newly

diagnosed AAV116. However, as yet there is no evidence or consensus as to whether

patients with AAV should be treated any differently from patients with traditional

cardiovascular risk factors.

1.7.3 Bone Health

Due to the ongoing reliance on immunosuppressive regimens with significant corticosteroid

exposure this population is at risk from steroid induced osteoporosis. In addition, there is a

likely contributory effect from cytokines involved in the inflammatory disease117.

The only study into bone density in AAV reported a prevalence of 57% osteopenia and 21%

osteoporosis in 99 patients118. There is no study reporting fracture rates as a complication

of bone disease in this population but due to current lack of steroid- sparing treatment

regimens available for this population, awareness of, and the need for assessment and

modification of this risk, is required.

1.7.4 Malignancy

Early studies in AAV, with a substantially greater cyclophosphamide load for patients

reported a 2.4-fold increase for all malignancies, with higher rates of bladder cancer and

lymphoma100. Since the introduction of a switch from cyclophosphamide to maintenance

therapy at 3 to 6 months and a trend towards pulsed intravenous therapy rather than daily

oral, resulting in a much lower total cyclophosphamide dose, this risk appears to have

diminished somewhat. A recent analysis of the available data suggests a SIR of malignancy

of 1.6-2.0 compared with the general population. The majority of this risk can be attributed

to the increased incidence of skin malignancy in this population. With studies supporting

the preferential use of azathioprine for maintaining remission in AAV, an agent which has

shown to be associated with increased risk of skin cancer119, it is prudent that these

patients receive appropriate education and screening.

45

1.7.5 Sexual health and fertility

Other considerations of possible complications of therapy in these patients include the

effect of treatment on fertility and cervical cytology. In the lupus population, it has been

demonstrated that there appears to be a relationship between intravenous

cyclophosphamide dose and development of cervical intraepithelial neoplasia (CIN). This

appears to reverse following cessation of therapy 120.

Similarly, the majority of data on the effect of cyclophosphamide exposure on fertility is

derived from the lupus population, with a rate of around 30% of cessation of menstruation

following exposure to cyclophosphamide121. However, this risk varies depending on

cumulative cyclophosphamide exposure and age at cyclophosphamide administration.

It is also well established that exposure to cyclophosphamide in men causes significant

sperm abnormalities associated with a reduction in fertility122. Therefore, the possible

ramifications of exposure to cyclophosphamide for those of child-bearing potential should

be considered when choosing the optimal treatment strategy for an individual patient.

1.8 CURRENT CHALLENGES TO CARE FOR PATIENTS WITH AAV

In summary, it can be seen that the major challenges for patients with AAV are; firstly,

receiving a correct and timely diagnosis, with historical difficulty in disease classification.

This may be compounded by a lack of awareness of vasculitis as a potential diagnosis due

to the rarity and heterogeneous presentation of the disease. Secondly, even following

appropriate treatment, the patient remains at significant risk of relapse, with monitoring

often dependent on inexact immunological markers. This is in part due to the lack of

complete understanding of the underlying disease pathogenesis. Delays to both

identification of initial disease and subsequent flares may result in accrual of damage and

may necessitate higher exposure to immunosuppression than would have been necessary

with earlier identification of disease activity. Again, treatment of relapse commensurate

with the severity of disease activity is also important in maintaining the balance between

disease damage and treatment complications. Thirdly, no matter how timely the diagnosis

and appropriate the treatment, as outlined above current immunosuppression regimens

carry with them significant morbidity. Until there are significant changes in

immunosuppression strategy it is essential that there is vigilance regarding side effects of

these agents. There is the need for awareness and for clinicians to work with the patient to

optimise preventative approaches to try to limit disease and treatment related morbidity.

46

Alongside this there is a parallel need to focus on identification of alternative future

therapeutic targets which could have reduced treatment complication profiles. This body of

work will use a variety of approaches to explore potential contributors to these obstacles

faced by patients and to attempt to provide means of addressing some of the challenges

faced.

47

2 THE PATHWAY OF THE UK VASCULITIS PATIENT- FROM

SYMPTOMS TO DIAGNOSIS AND BEYOND

2.1 INTRODUCTION

The ANCA- Associated Vasculitides (AAV) are a heterogeneous group of conditions that may

cause small to medium vessel inflammation in a number of different organ systems. The

three AAV are classified as Granulomatosis with Polyangiitis (GPA, formally known as

Wegener’s Granulomatosis), Microscopic Polyangiitis (MPA) and Eosinophilic

Granulomatosis with Polyangiitis (EGPA, formerly known as Churg- Strauss Syndrome).

Historically, interventions and outcomes for this diverse patient group have often been

studied together, in part due to their rarity. However, data is emerging to support that

these are definite distinct disease entities with different disease courses and outcomes,

including differing underlying genetic predispositions7.These conditions are often treated

with initial aggressive “induction” therapy followed by long-term maintenance

immunosuppression, which has served to improve mortality but carries with it substantial

morbidity itself93.

Depending on the disease type, organ involvement may vary meaning that patients can

present with a wide spectrum of initial symptoms and, therefore, to multiple clinical

disciplines. This can provide significant challenges for the diagnosing clinician, particularly if

the patient presents to a discipline which may not commonly see these conditions.

There have been some reports of time from first symptoms to diagnosis in the

Granulomatosis with Polyangiitis cohort. Holle et al. compared a number of parameters

and outcomes across a single centre cohort, stratified according to date of presentation.

They reported that the median time to diagnosis did appear to be improving over time,

from 8 months for those patients diagnosed between 1966 and 1993, to 5 months between

1994 and 1998, and 4 months from 1999 to 200264. A similar pattern was reported in a

Finnish study of GPA patients with median time from onset to diagnosis improving from 17

months from 1981 to 1985 to 4 months between 1996 to 2000123. A further Scandinavian

study reported characteristics of patients with GPA but also MPA, EGPA and polyarteritis

48

nodosa diagnosed between 1997 and 2006. The median “diagnostic delay” was reported

here as 2 months for those with GPA, 1.5 months for MPA and 2.5 months for those with

EGPA124.

Providing comprehensive ongoing care for this patient group is a further challenge.

Alongside variable initial presentation, these patients have the potential for other organ

manifestations to subsequent evolve in the future. In addition, the burden of

immunosuppressive treatment means that patients may develop local or systemic

complications of therapy, such as bone disease, immune deficiencies or cardiovascular

disease, which requires specialist management and support.

Currently, the majority of care for these patients is provided in secondary and tertiary

centres. Due to evolving care models, with a greater focus on utilisation of primary care

resources, those planning future care for this population may look to see whether aspects

of vasculitis care can be devolved to primary care. Although there are some models in

place, such as shared care monitoring of blood tests for those on immunosuppression, this

is a practice which is not uniformly implemented at present.

We sought to gain an overview of the UK vasculitis patients’ pathway, from presenting

symptoms, through diagnosis and including post diagnosis care.

2.2 MATERIALS AND METHODS

The intention was firstly to establish how and where patients with vasculitis present in the

UK to explore factors influencing time to diagnosis. Secondly, we wished to evaluate where

patient care continues to be provided after a diagnosis has been made, and how patients

view the role of their different care providers, including primary care, in managing their

health and disease.

2.2.1 Patient questionnaire

To achieve this, a multi-disciplinary research group including clinicians with expertise in

vasculitis care, qualitative and nursing researchers and a patient representative was

assembled. This group collaborated to produce a self-report patient questionnaire

49

encompassing areas including: experience surrounding presentation and diagnosis, current

medical care and therapy (full questionnaire available in Appendix 1).

2.2.2 Subjects

This questionnaire was distributed to all 700 members of the UK national patient support

group, Vasculitis UK, using their established mailing list. Ethical approval was not required

(confirmed in writing by Preston REC) as participants were identified by the patient support

group and remained anonymous to the researchers.

2.2.3 Statistical analysis

Simple descriptive statistics were used to analyse the majority of the data. Kruskal- Wallis

analysis or Mann-Whitney testing was used to compare the medians between patient

groups. Thematic analysis was used for the semi- qualitative data describing symptoms. All

statistical analysis was carried out using GraphPad Prism (v.7).

2.3 RESULTS

2.3.1 Responder characteristics

Three hundred and seventy-eight completed questionnaires were returned, giving a

response rate of 54%. Within these, responses were excluded if there was no diagnosis

stated, or any diagnosis other than systemic vasculitis, ANCA-associated vasculitis,

Wegener’s Granulomatosis, Granulomatosis with Polyangiitis, Microscopic Polyangiitis or

Churg-Strauss syndrome (now known as Eosinophilic Granulomatosis with Polyangiitis). In

total, 306 patient questionnaires (81% of those returned) were analysed.

Of the analysed questionnaires, the mean responder age was 61.7 (range 21-87) years.

Responders were predominantly white British (93%) with 62% being female.

50

% patients

GPA(n=24

1)

EGPA(n=

41)

MPA

(n=15)

Other (disease not

specified)(n=9)

Nasal/sinus 34.1 40.3 17.1 6.7 0

Fatigue 26.6 24.8 36.6 33.3 28.6

Musculoskeletal joint

symptoms

25.6 27.7 14.6 14.6 0

Respiratory 24.3 21 48.8 26.7 0

Ear 22.6 27.7 7.3 0 0

Other pain 11.2 9.7 19.5 13.3 14.3

Flu/cold/viral 10.2 10.5 9.8 13.3 0

Skin 9.9 9.2 17.1 6.7 0

Eyes 9.2 10.1 0 20 0

Weight loss 6.9 7.6 7.3 0 0

Headaches 5.6 6.3 4.9 0 0

Peripheral nerve 3.0 2.1 12.2 0 0

Musculoskeletal muscle

symptoms

3.0 2.9 2.4 6.7 0

Haematuria/renal 1.6 2.1 0 0 14.3

Mood/cognitive 1.6 1.7 2.4 0 0

Table 1. Presenting symptoms

2.3.2 Symptoms

The most common initial symptoms for all patients were categorised as nasal/sinus

(34.1%), followed by fatigue (26.6%). When analysed according to eventual diagnoses,

patients with GPA most commonly presented with nasal/sinus symptoms (40.3%), EGPA

with respiratory symptoms (48.8%) and MPA with fatigue (33.3%). Median time to

diagnosis was reported as being 6 months ().

51

Characteristics Median time to diagnosis

(IQR) months

P value

Diagnosis

GPA (n=217) 6 (13.75) 0.0793 (comparing

across all gps)

MPA (n=13) 13.5 (24)

EGPA (n=38) 13.5 (32)

Predominant presenting symptom

Ears/Nasal/sinus (n=155) 6 (17.5)

Fatigue (n=74) 6 (12.25)

Musculoskeletal symptoms (n=80) 6 (20.25)

Respiratory symptoms (n= 66) 10 (17.5) 0.0013**

Skin (n=28) 4 (6.5)

Eye (n=25) 9 (19)

Neurological (n=10) 7 (14)

Discipline seen pre-diagnosis

Rheumatology (n=71) 8.5 (26.5) 0.9699

Nephrology (n=25) 9 (56.5)

ENT (n=117) 10 (22.5)

Chest (n=60) 9 (31)

Table 2. Relationship of patient characteristics to time to diagnosis (** statistically

significant when compared with time to diagnosis for those with skin symptoms)

Time to diagnosis appeared to differ (though not significantly) by eventual diagnosis

received but not by initial clinical discipline consulted. Those patients presenting with skin

manifestations had the shortest reported time to diagnosis (median 4 months), this was

significantly shorted than those who reported the longest time to diagnosis following

presentation with chest symptoms (p=0.0013). The majority, 70.9%, of patients reported

receiving an initial alternative diagnosis before later being given a diagnosis of vasculitis.

Most commonly, this was infection, followed by sinusitis/rhinitis in the GPA population,

52

asthma (which is acknowledged to often precede the onset of EGPA) followed by

psychological disorders in EGPA and viral infection in MPA.

% All

patients

GPA EGPA MPA Other

Sinusitis/rhinitis 11.7 13.7 4.9 6.7 0

Viral infection 10.8 11.2 9.8 13.3 0

Other infection 13.0 15.8 4.9 0 0

Psychological 7.2 6.6 12.2 6.7 0

Asthma 5.2 2.0 26.8 0 0

Malignancy 4.9 6.2 0 0 0

Tuberculosis 4.2 5.0 2.4 0 0

Allergy 2.9 3.7 0 0 0

Polymyalgia rheumatica 2.9 2.9 2.4 6.7 0

Other rheumatological disease (e.g. RA, SLE, connective tissue disorder)

13.7 12.5 9.8 46.7 14.3

Other 21.5 20.3 24.4 26.7 42.9

Table 3. Alternative diagnoses received prior to vasculitis

2.3.3 Utilisation of healthcare

The majority of patients (73.2%) initially consulted their general practitioner (GP), and

81.8% patients reported attending a hospital specialist appointment before their diagnosis

of vasculitis was made. Many patients reported being seen by more than one discipline

with the median number of disciplines consulted prior to receipt of diagnosis being two.

The most common clinics attended prior to diagnosis were ENT (26.2%), in keeping with the

most common presenting symptoms of nasal and sinus disease, followed by rheumatology

(15.8%).

Subjects were asked who they viewed as the main person looking after their vasculitis from

a list of hospital doctor, specialist nurse and GP, with the majority, 259 (84.6%), choosing

hospital doctor. Patients were then asked to report how often they had seen this individual

in the preceding year. 245 patients gave a numerical answer (with the remainder answering

non- specifically e.g. “often” or “a lot”). The median frequency was 3 (IQR 2-5). The specific

53

clinics attended can be seen in Figure 2, and are primarily rheumatology (49.5%) and

nephrology (41%).

Finally, patients were asked to describe how they perceived the role of their GP in the

management of their condition. 51.3% stated they would see their GP as the first point of

contact for any health problem, 64.1% for any health problem not relating to vasculitis,

36.9% for blood tests and 35.6% for blood pressure monitoring. Only 12.1% reported that

they saw their GP as having no role in their disease management. When asked about more

specific medical scenarios, the majority would contact their GP in the first instance for each

of the following; for a chest infection (79.6%), other infection (80.3%), joint problem

(59.9%), eye problem (62.5%), skin problem (75%) or ENT/sinus problem (58.6%).

Figure 1. Vasculitis patient health care utilisation

2.4 DISCUSSION

In this patient reported historical study we novelly explore the alternative diagnoses often

received by vasculitis patients prior to their definitive diagnosis. We report that a majority

of patients initially present to primary care and their symptoms are attributed to more

common disease processes.

Our data is in keeping with previous published time to diagnosis of between 4 and 8

months, depending on era of diagnosis64. However, our study attempts to further evaluate

other factors contributing to length to diagnosis, with this time period appearing to vary

0

50

100

150

Pat

ien

t n

um

ber

s

Clinical discipline

Disciplines accessed pre and post diagnosis

Pre Post

54

according to initial presentation, but not by the discipline patients first present to. Our data

suggests that those patients who present with a visible manifestation of their disease such

as a skin rash are significantly more likely to receive a timely diagnosis than those who

present with respiratory symptoms. This study highlights the need for increased education

and awareness of vasculitis as a possible diagnosis in the broader medical community, in

light of the fact that the majority of patients initially present to primary care. We have also

identified those initial diagnoses that may alert health care providers of the need to

potentially seek an alternative explanation for persistent patient symptoms.

Contrary to the perhaps anticipated opinion that vasculitis patients would wish to

predominantly be managed in secondary care we report that patients appear to have

confidence in their primary care providers and the majority would see their GP as the first

point of contact in any health scenario. However, it is unclear whether the patients

recognised some of the given health scenarios as potentially being linked with their

vasculitic illness, which may highlight the need for better patient education regarding

symptom recognition.

This work has significant implications for the planning of future health care delivery for this

patient population. The British Society of Rheumatology guidelines suggest that patients

with vasculitis be managed within networks of care, involving expert vasculitis centres83. It

may be that future care models would allow patients to have designated parts of their care

carried out in a community setting (e.g. blood monitoring, co-morbidity prevention) under

guidance from expert centres. This may allow remote monitoring to become a possibility

for some patients with stable disease, avoiding unnecessary travel and clinic waiting times

and allowing prioritisation of vasculitis out- patient appointments for those with unstable

or challenging disease.

We acknowledge this study has limitations. Firstly, it was necessary to design a new

questionnaire for our purposes meaning that only limited validation of the questions in this

survey could be undertaken prior to the full study. Although this was a lengthy

questionnaire, pilot testing showed that the questions were predominantly completed in

full.

55

One of the major limits of a historical questionnaire study is that it relies on retrospective

patient report which is not infallible. With regards to time from first symptom as recalled

by the patient to diagnosis, it is unclear and impossible to verify whether this truly was a

manifestation of the vasculitis. This is likely to apply particularly to those patients with

EGPA with a preceding diagnosis of asthma. Equally this study only included members of a

national patient support group and were furthermore self-selected by being responders.

This is likely to have had an impact on the demographic as noted in the gender and

ethnicity of those included. There also was a predominance of GPA in our surveyed

population, meaning that there were insufficient numbers of the other vasculitides

involved from which to draw robust conclusions. However, whilst this will be relevant for

the symptomatology related data, information regarding areas such as utilisation of

healthcare pathways, may be transferrable across other groups. It also may be that

patients had been misclassified, leading to an over reporting of GPA and an under reporting

of MPA. However, patients with GPA are more likely to relapse and are more likely to have

ongoing difficult to control symptoms originating from ENT or respiratory systems, meaning

that this particular disease group may be more likely to be members of a patient support

group. The strengths of this study are the inclusion of a large number of patients with a

rare disease and across a wide geographical area. In addition, this study contributes

previously unreported possible contributory factors to diagnostic delay, including the most

frequent “misdiagnoses” received by this patient group.

We therefore feel that the results are important in highlighting the need for improved

awareness and recognition of vasculitis, identifying ways in which patients may present and

acknowledging that that this may influence time to diagnosis. In addition, defining current

pathways pre-and post diagnosis can help to inform those involved in planning of services

for this diverse and challenging patient population.

56

Appendix 1. Full Questionnaire

From the North- West Vasculitis

Group

In association with

Vasculitis UK

Questionnaire for people living with

vasculitis

To help us improve diagnosis and care provided

66

3 VASCULITIS PATIENT AWARENESS OF MEDICATION SIDE-

EFFECTS AND UPTAKE OF PREVENTATIVE/ PROPHYLACTIC

MEASURES: A UK QUESTIONNAIRE STUDY

3.1 BACKGROUND

ANCA- associated vasculitis (AAV) is a small to medium vessel systemic vasculitis with a

combined annual incidence in the UK of 10- 15 per million31. This umbrella term currently

refers to patients with a diagnosis of Granulomatosis with Polyangiitis (GPA), Microscopic

Polyangiitis (MPA) and Eosinophilic Granulomatosis with Polyangitiis (EGPA, formerly Churg

Strauss Syndrome).

While these are genetically and phenotypically distinct disease entities, when evaluating

non- disease related factors it is still reasonable to group these patients together for study

due to their rarity and exposure to similar therapeutic regimes. Early descriptive data

reports the average survival for GPA following diagnosis as just 5 months89. Since the

introduction of immunosuppressive agents to treat this spectrum of diseases, this has

significantly improved with 5 year survival currently at 75%125. Most patients now survive

their initial vasculitic episode suggesting that AAV now needs to be viewed not only as an

acute life- threatening illness, but increasingly as a chronic relapsing / remitting disease.

Although developments in care have resulted in improved patient survival, there remains

substantial morbidity and mortality associated with the disease and the treatment125. Care

for this complex group of patients may be delivered in a number of care settings including

single specialty Rheumatology, Nephrology, Neurology, Respiratory, and multi-disciplinary

clinics. The physician faces challenges in maintaining awareness of all possible

manifestations of this multi- system disease, as well as awareness of the wide spectrum of

complications of immunosuppressive therapy to which this population is susceptible.

Current evidence-based induction therapy for acute, organ or life- threatening disease

consists of high dose corticosteroids and cyclophosphamide or Rituximab. This is followed

by a period (which may continue for many years) of maintenance therapy, with oral

steroids often continuing alongside other immunosuppressive agents such as azathioprine

67

or mycophenolate. All of these are associated with possible long-term adverse events

including infection, bone disease, increased cardiovascular and malignancy risk. The aims of

the work reported here were to assess patients’ level of knowledge and awareness of

potential side effects of their therapy. Alongside this we evaluated uptake of protective and

prophylactic measures aiming to reduce disease and therapy related complications.

3.2 PATIENTS AND METHODS

A multi-disciplinary expert panel including clinicians with expertise in vasculitis

(nephrology, rheumatology, neurology, ENT and ophthalmology), research methodologists

and patient representatives was assembled. This group developed a self-report patient

questionnaire addressing patients’ experience surrounding presentation and diagnosis,

current medical care and therapy. The topics to be covered in this questionnaire were

identified through clinical experience and published literature and questions were

reviewed and modified by patient representatives prior to distribution. It was necessary to

design a new questionnaire for this study as none existed which addressed the areas of

patient knowledge and reported care we wished to evaluate. This paper focuses on data

relating to vasculitis treatment, patients’ knowledge of side effects and adoption of

measures aimed at reducing disease and treatment-related side effects.

Questionnaire piloting and assessment of validity of self-reports was undertaken with a

local cohort of patients with AAV and Systemic Lupus Erythematosus prior to use. The

main study was a national questionnaire survey using the already established mailing list

from the UK national patient support group, Vasculitis UK. This questionnaire was

distributed to all 700 members across the UK. Ethical approval was not required for the

main study (confirmed in writing by the NRES Committee North West, Preston) as

participants were identified by the patient support group and remained anonymous to the

researchers.

Statistical analysis: Simple descriptive statistics were used to analyse the majority of the

data. Unpaired t- tests were used for comparison of unmatched data sets e.g. the

characteristics of those reporting knowledge of side effects compared with those without.

Fisher’s exact test was used for comparison of proportions of patients within a group

reporting certain behavior. Thematic analysis was used for responses to open-ended

questions (e.g. those describing side-effects).

68

3.3 RESULTS

3.3.1 Pilot/validity check

The questionnaire was piloted with a sample of 30 local patients with AAV or Systemic

Lupus Erythematosus. Patients were asked to complete the questionnaire designed for the

above study and answers were validated by case note review. As these were recruited via

NHS hospitals, ethical approval for this stage of the study was granted by the NRES

committee North West, Preston. Full medical information was available on 73% of patients.

Of these, the diagnosis given by the patient was confirmed using ACR criteria and EMEA

algorithm in 94.4% of cases. Regarding exposure to immunosuppressive medication, there

was agreement between patient reporting and medical notes in 76% of cases. With regards

to receipt of prophylactic/ preventative measures, patient responses could be corroborated

in the medicines history in 78.9% of cases. This level of agreement was considered

acceptable.

3.3.2 Main study

For the main postal survey, a response rate of 54% (378 completed questionnaires) was

achieved. Analysis included only those with a self- reported diagnosis of “Systemic

Vasculitis”, “ANCA Associated Vasculitis”, “Wegener’s Granulomatosis” (now known as

Granulomatosis with Polyangiitis), “Microscopic Polyangiitis” or “Churg Strauss Syndrome”

(306 patients). Of the 306 eligible questionnaires, the majority were completed by women

(62%) with the mean age of the population 61.7 years (range 21 to 87). (See Table 1 for

sample demographics). Given the study methodology we do not have demographic data on

those who did not complete and return the questionnaire. The responding population

differs from the profile typically seen in practice by the female preponderance. Also,

although GPA is accepted to be twice as common as MPA in Northern Europe, 79% of our

questionnaire respondents reported a diagnosis of GPA. However, this study aim was to

assess patient knowledge. Therefore, due to common drug exposure for the differing

disease subtypes, the diagnosis although of interest, is not of particular importance.

69

Demographics Patient numbers (%)

Granulomatosis with Polyangiitis

(previously Wegener’s Granulomatosis)

241 (79%)

Churg Strauss Syndrome 41 (13%)

Microscopic Polyangiitis 15 (5%)

Other "Systemic vasculitis/ANCA

Associated Vasculitis"

Total

9 (3%)

306

Female

Male

Not specified

190 (62%)

112 (37%)

4 (1%)

Age 61.7 years (range 21-87)

White British

White other

Other

Not specified

285 (93%)

5 (2%)

10 (3%)

6 (2%)

Table 1. Characteristics of the Sample

3.3.2.1 Awareness of side effects of therapy

Patients were asked to choose the drugs they had been prescribed to treat their vasculitis

from a list, with room for expansion for those not included. They were then asked to

describe any potential side- effects of therapy of which they were aware. This was done in

a free text format so as not to influence possible answers.

The most frequently reported drug received by 295 (96%) patients at some point in their

disease course was oral steroids. The next most frequent drug to which they had been

exposed was cyclophosphamide at 74.5% (oral and intravenous combined) followed by

azathioprine at 69%. Further information on drug exposure is provided in Figure 1. The

majority of patients (74.8%) reported awareness of at least one potential drug side effect.

However, some patients commented that awareness of these side- effects had only come

70

through experiencing them, rather than being counselled regarding them prior to drug

exposure.

Figure 1: Reported exposure to immunosuppression

The most commonly recognised side effects were those associated with steroid exposure,

with 27% of patients recognising bone thinning/ osteoporosis as a potential steroid related

problem. The next most common group of adverse effects recognised appeared to be those

that the patients would be aware of having experienced, such as weight gain with steroids

and hair loss with cyclophosphamide. The most common themes in the “other” category

were fatigue, headaches, dizziness and cognitive impairment. Only 4% of patients reported

symptoms that were unlikely to be attributed to their medication. There was generally low

awareness of the increased infection risk associated with immunosuppression and

potential increased long- term cancer risk. There was also very little awareness of the

increased cardiovascular disease associated with steroid exposure (Figure 2).

A sensitivity analysis was performed in addition for patients with current exposure to drugs

versus all (current versus previous). This was carried out for patients exposed to

azathioprine and the associated awareness of skin damage (defined by warts, sun damage

or skin cancer) as a potential side effect of the drug.

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Twelve of 98 patients currently taking azathioprine (12.2%) had an awareness of these side

effects, versus 18 of 212 (8.5%) having ever taken it (p=ns).

The most frequent source of drug information reportedly used by patients was their

hospital doctor (56.6%) followed by the drug information leaflets inside the medication box

(52%). Following this, the internet was the third most frequent source of information, with

a trend for those under 60 years old to utilise this resource compared with those over 60,

but this did not reach statistical significance (p=0.06). Further investigation of the

characteristics of the group who reported no awareness of any possible medication side

effect showed a mean age of 76 years (compared with 59 years in the group with

awareness of side effects and a longer time since diagnosis, 5217 days, compared with

4398 days (p=ns)). This may simply reflect that due to the longer time lapse since diagnosis,

information regarding drug side effects may have been forgotten. However, the focus on

patient education has increased over the years making those diagnosed recently perhaps

more likely to be better informed.

Figure 2. Patient reported awareness of potential medication side effects

(GI= gastrointestinal, CVD= cardiovascular disease).

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Men made up 56% of the group with no awareness of side effects, compared with only 31%

of the group reporting awareness. This may highlight men as being a group who potentially

need more dedicated education regarding drug counselling. Of those men who did report

an awareness of side-effects, the majority utilised the secondary care clinician as a source

of information (62.8%) followed by the drug information leaflet accompanying the

medication (51.3%) and the internet (26.9%). Men were least likely to use patient

information leaflets (such as those provided in clinic) as information sources. The women

surveyed in this study were less likely, although not statistically significantly, to report using

a specialist nurse (p= 0.23) but more likely to use a patient information leaflet (p= 0.07) as

an information source, when compared with men. We were unable to perform any analysis

between the level of education/ socioeconomic status and knowledge levels, as the

majority of patients reported their employment status as retired, and did not specify

previous occupation. 123 (40.2%) of patients reported having had to discontinue a therapy

at some point due to side- effects.

3.3.2.2 Reported uptake of prophylaxis/ screening

We explored patient reported practice regarding therapy aiming to reduce the

complications of immunosuppressive therapy using a list of potential prophylaxis or

screening measures which may have been recommended by a health care professional.

Patients were asked to indicate which of these they had received.

73

Figure 3. Patient reported uptake of preventative therapy

Our results showed that, in line with the awareness reported above, uptake of bone

protection was good. Other steroid prophylaxis such as gastro-protection was also

commonly reported.

Current Department of Health recommendations are that those over 65 years or in “at risk”

groups, including those on immunosuppression, should receive influenza and

pneumococcal vaccination85.The majority of patients had received ‘flu vaccine (85%), with

further analysis demonstrating that 50% of these having received the vaccine were less

than 65 years old. This may demonstrate awareness amongst primary care of the need for

‘flu vaccination in the younger immunosuppressed population. However, pneumococcal

vaccine was less frequently delivered at 40.2%. Use of skin protection in the sun was low

(17.6%) considering the high percentage of these patients (69%) that had been exposed to

azathioprine.

3.4 DISCUSSION

Patient outcomes from vasculitis are improving but, particularly until steroid sparing

regimes can be identified, treatment continues to carry high levels of morbidity. Provision

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of care for vasculitis patients is becoming increasingly complex as patients survive longer

with multiple co- morbidities. Although research for this patient group has primarily

focused on improving outcomes from active disease, it is important to also remain aware of

other areas where patient care could potentially be improved.

The strengths of this study include the large number of respondents; particularly for a rare

disease such as vasculitis. Validation of self-report in our local cohort demonstrated

generally good concordance with what is documented in hospital records. However, we

accept the limitations associated with a patient reported questionnaire study. The

responders were mainly female (a characteristic not generally reflected in the disease

population). Also the majority of patients reported their clinical diagnosis as GPA. This may

reflect some misclassification of disease or potentially that patients who may have

“limited” GPA have a better prognosis and therefore were more likely to survive to

participate in this study. The responding group are likely to represent a more motivated

population, potentially being better informed about their disease and treatment. However,

this means that the results from this study probably represent a “best- case scenario”. As

participants were anonymous to the researchers we were not able to identify those a priori

for whom English was not their first language who may have required translated material.

This is likely to mean that non- English speakers were excluded from this study. Some

questionnaires were completed by relatives/ spouses of those who were not able to

complete the questionnaire for other reasons (e.g. visual impairment). However, we

appreciate that the requirement for self- reporting of data in this study have excluded

those who with disability or severe illness.

Our study has highlighted that there are deficiencies in patient knowledge regarding

potential adverse effects associated with vasculitis treatment. This will reflect patient recall

as well as initial imparting of information by health care providers. This is supported by the

sensitivity analysis which showed that more patients currently taking azathioprine were

aware of skin side effects compared with the population who had ever taken azathioprine

(12.2% versus 8.5%), though not significantly so. However, overall, this was still a very ow

level of awareness of a potentially serious but preventable adverse effect.This study also

potentially highlights that men and women may prefer to access information in different

ways and that this may need to be taken into consideration during drug counselling.

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There are relatively few studies evaluating patient knowledge of drug side-effects. Those

that have been carried out in populations with osteoarthritis, inflammatory bowel disease

and lymphoma re-iterate our findings that knowledge of potential drug side- effects is

poor126–128. It is important to bear in mind that valid consent for treatment includes patient

awareness of potential adverse effects. This is particularly important, as studies in other

groups of patients receiving immunosuppressive therapy have found that side-effects can

have a significant impact on patients’ quality of life, the impact of which may be under-

estimated by health professionals129,130. Furthermore, as some patients may largely self-

manage their condition and may have only infrequent contact with specialists, good

awareness of side effects is essential in enabling patients to accurately recognise problems

early and take appropriate action. The data highlight areas where improved patient

information and self-management education may be required.

It is likely that overall cancer risk is reducing in the vasculitis population, due to a trend to

move towards pulsed intravenous cyclophosphamide resulting in a lower total dose.

However, it may be some years before this reduced risk filters through and until current

long- term data is available as to what this absolute risk is, surveillance and awareness of

potential malignancy in this population should be maintained. Of particular concern is the

lack of awareness of skin cancer, which is potentially preventable if appropriate sun

avoidance/ protection strategies are adopted. It has long been common practice for solid

organ transplant clinics to provide annual skin surveillance for their patients on long- term

immunosuppressive agents. As the data starts to suggest that vasculitis patients may need

to remain on their maintenance phase of therapy for longer (with current evidence

favouring azathioprine as the agent of choice for maintenance72), it may be time to ensure

that other patient groups on chronic immunosuppression are afforded the same level of

vigilance.

Infection continues to be a significant problem in this population, with vaccine preventable

organisms such as Pneumococcus a major cause of morbidity and mortality. There have

been some studies in recent years that have sought to evaluate the immune response of

this patient group to influenza vaccination131,132. However, these studies have been small

and primarily have excluded patients on significant immunosuppression- those most at risk

from infection. Further studies evaluating both the efficacy and the clinical effectiveness of

vaccination in this patient population are required. However, until this evidence is available

76

it would seem reasonable to extrapolate from recommended practice for other groups with

immunodeficiencies133.

In summary, our study demonstrates that vasculitis patient awareness of potential adverse

effects of therapy is low. Patient reported practice regarding uptake of measures to reduce

these adverse effects is variable. This may indicate that there is room for improvement in

the care we deliver for patients with vasculitis. Future work should focus on long-term

studies to evaluate on going treatment related morbidity in this population including

identification of risk factors and potential prevention strategies. Alongside this, clinical

services should be developed to include comprehensive and systematic regular assessment

of the vasculitis patient. This would enable identification and monitoring of therapy-related

complications and provide patient information and self-management education. With

these strategies, it would be hoped that the mortality and morbidity of patients diagnosed

with vasculitis can continue to fall.

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4 A DELPHI STUDY TO ASSESS PREVENTION OF TREATMENT

AND DISEASE RELATED MORBIDITY IN VASCULITIS (ADAPTIV):

DELPHI METHODOLOGY

4.1 INTRODUCTION

Primary systemic vasculitis (PSV) is a multi-organ, life-threatening, inflammatory disease

requiring aggressive initial immunosuppressive therapy. Even following treatment of the

presenting episode, due to the risk of relapse (approximately 50% over 5 years)134,135 long-

term immunosuppression is often required. The most common group of PSV seen in the UK

is ANCA Associated Vasculitis (AAV), with a prevalence of around 220/million in 200838.

Whilst mortality from initial disease is improving; only 14% of deaths at 1 year following

diagnosis from active disease90, patients now increasingly survive to experience side effects

of the both the disease and the therapy. Initial life or organ threatening disease is treated

with cyclophosphamide or Rituximab, a B cell depleting agent, and high dose steroids,

whilst once remission has been achieved the patient may require years of therapy with low

dose corticosteroids and a steroid sparing agent such a azathioprine or mycophenolate (see

British Society of Rheumatology publication 2014 for full treatment guidelines)83.

Due to the often intensive immunosuppressive regimen, this population has a high level of

treatment related morbidity and mortality. Infection accounts for 50% of deaths in the first

year following diagnosis of AAV90. Beyond the first year, this risk continues, though at a

lower level (20% of deaths), with the risks of cancer and cardiovascular disease increasing

along with the cumulative immunosuppressive burden98. Other problems frequently faced

by this population include steroid related bone disease and sub-fertility or infertility as a

result of cytotoxic therapy. Due to the relative rarity of these diseases, there is a paucity of

evidence for best practice in the prevention/ reduction of these co-morbidities. Although

some evidence can be extrapolated from other disease groups, it is increasingly apparent

that the risks of co-morbidities relate not only to drug exposure but also to the underlying

disease pathogenesis. Therefore, these guidelines have been produced, using both the

78

available evidence and expert consensus, by the UK and Ireland Rare Disease Group for

Vasculitis to inform clinical care for this population.

4.1.1 Objective

To produce comprehensive, clinically relevant guidelines to inform the screening for and

prevention of co-morbidities of patients with ANCA Associated Vasculitis (AAV). Although

these guidelines do focus particularly on this disease group, they may equally be applicable

to other patients on chronic immunosuppression for whom robust guidelines in this area

are not available.

4.1.2 Target Audience

Any primary care or secondary clinician involved in the care of patients with AAV including

but not limited to; rheumatologists, nephrologists, Ear, Nose and Throat (ENT) specialists,

respiratory physicians, neurologists, and specialty trainees and specialist nurses in these

fields.

4.1.3 Stakeholder groups

The following were identified as key stakeholders to contribute to the guideline

development

• Primary care

• Patients

• Nephrologists

• Rheumatologists

• Immunologists

• Virologists

• Vaccinologists/Public Health England

• Cardiologists

• Endocrinologists

• Oncologists

• Fertility specialists

4.1.4 Co-ordination Team

The below were responsible for the organisation and running of the Delphi process.

79

Dr Nina Brown

Dr David Tooth

Dr Angela Summers

Dr Michael Venning

4.1.5 Expert panel members (Delphi contributors)

Professor Richard Watts, Rheumatologist, Norwich

Professor Mark Little, Nephrologist, Dublin

Professor David Scott, Rheumatologist, Norwich

Dr David Jayne, Nephrologist, Cambridge

Professor Ray Borrow, Vaccinologist, HPA

Dr Ken Mutton, Virologist, HPA

Dr Matt Morgan, Nephrologist, Birmingham

Dr Oliver Flossman, Nephrologist, Reading

Dr Peter Andrews, Nephrologist, St. Helier’s, London

Dr Joanne Ledingham, Rheumatologist, Portsmouth

Professor John Lear, Dermatologist, Manchester

Professor Peter Selby, Endocrinologist, Manchester

Professor Alistair Hutchison, Nephrologist, Manchester

Dr Ajay Dhaygude, Nephrologist, Preston

Dr Jaqueline Andrews, Rheumatologist, Leeds

Dr Sara Mackie, Rheumatologist, Leeds

Dr Yasmin Sajjid, Fertility consultant, Manchester

Dr Cheryl Fitzgerald, Fertility consultant, Manchester

Dr Yousef Karim, Immunologist, Frimley

Dr Louise Mercer, Rheumatologist, Manchester

Professor Alan Salama, Nephrologist, Royal Free, London

Dr Alison Brown, Nephrologist, Newcastle

Dr Chetan Mukhtyar, Rheumatologist, Norwich

Professor Ian Bruce, Rheumatologist, Manchester

Professor David Wheeler, Nephrologist, Royal Free, London

Dr James Galloway, Rheumatologist, King’s London.

Dr Michael Venning, Nephrologist, Manchester

80

4.1.6 Other Stakeholder representatives

Provided feedback regarding applicability/ practicality of study

John Mills, Patient chair of Vasculitis UK

Dr Ivan Bennet, General practitioner and Central Manchester CCG lead

Involved in consensus conferences to provide additional expertise

Dr Alex Richter, Clinical immunologist, Birmingham

Dr Tomaz Garcez, Immunologist, Manchester

Professor Lorraine Harper, Nephrologist, Birmingham

Professor Alistair Hall, Cardiologist, Leeds

Professor Derek Crowther, Oncologist, Manchester

4.2 DELPHI STUDY

The Delphi technique can be described as “a method of combining the judgements of

knowledgeable individuals”136. The process was originally developed by the RAND

corporation (an American not for profit think tank) in the 1940s as a way of more

effectively using group information137. The three key elements that are today understood

to comprise a Delphi study are the same as those described by the RAND corporation in

1969; a) anonymity (between panel members) 2) controlled feedback and 3) a statistical

group response136. Essentially, a Delphi study uses an expert panel to reach consensus on

areas where evidence or consensus are not available. This is usually done through

structured questioning with iterative feedback from the panel members between rounds.

The level of consensus required is set “a priori” and statements are removed from the

process once they achieve this level of consensus. If further consensus is required to be

reached following completion of the rounds, then consensus conferences can be held to

achieve final resolution.

The Delphi technique is often used to create national and international guidelines for

health management138–140. The reason for this is that guidelines are required usually where

the evidence to support clinical practice is limited or unclear. The ideal alternative to a

Delphi would be randomised controlled trials (RCTs) to provide the evidence required to

inform practice. However, the cost of RCTs is substantial and even then may not provide

the answers sought. Particularly in a rare disease such as vasculitis, patient recruitment, as

well as cost, adds an additional obstacle to conducting robust clinical trials. The breadth of

81

clinical areas to be covered by these guidelines is therefore unlikely to be supported by

definitive evidence in the near future. Therefore, an alternative method has to be sought to

produce guidance for the care of this vulnerable population.

We chose to conduct a three round Delphi survey with two further subsequent consensus

conferences held. Experts were identified from the stakeholder groups highlighted above.

Expertise was defined through; clinical expertise, involvement in guideline creation or

involvement in service development on a national level. Initial questions for generating

statements were informed by the literature including existing guidelines for clinical care

(see Appendix 1 for initial questions). Initial questions additionally focussed on the areas of

treatment and monitoring. However, following liaison with the British Society of

Rheumatology who were conducting a parallel Delphi study covering these areas83, these

topics were removed. Twenty- seven experts accepted the invitation to participate in the

study and submitted comments in response to the questions in Round 1. They are listed

above. Of the participants who answered round 1, 20 took part in round 2.

Responses to the initial questions were reviewed by 2 members of the co-ordination team

(NB, DT) and edited into statements to which the panel could express agreement or

disagreement. Following formation of initial questions to guide the clinicians, subsequent

rounds were carried out with the assistance of the Delphi software. This software provided

analysis of responses enabling automatic identification of statements which had reached

consensus and could be removed from the process. This programme also subsequently

generated the following round, with these statements removed.

Two hundred and eighty statements were generated in the first round (see Appendix 2).

The panel were asked to rank statements according to level of agreement using a Likert

scale from 1-7 (1 being “I strongly disagree” and 7 being “I strongly agree”). The panel

members were also given the option of selecting not to answer particular questions due to

insufficient knowledge. The decision was taken to include this response due to the wide

range of specialties covered by this study. For statements to reach consensus a level of

agreement of 80% was required. Statements that reached consensus following round 2

were removed. Remaining statements continued to round 3 where panel members could

view other participants (anonymised) responses from the previous round to aid the

decision making process. Clarification was also offered if feedback had indicated that a

82

decision had not been reached in the previous round due to ambiguity of a statement.

Some statements which were very similar or contained no additional information were

removed between rounds 2 and 3.

Following Round 3, remaining areas of non- consensus were discussed at two subsequent

consensus conferences to which all panel members were invited. Round 4 consisted of two

consensus conferences, the first attended by 14 of the expert panel members, covering the

spectrum of clinical disciplines. During this round, results from the 2 previous rounds were

reviewed along with any outstanding areas of non- consensus according to category. One

further conference was held specific to the area of infection risk/ immune monitoring as

there were ongoing areas of non- consensus. This was attended by nephrologists with a

specialist interest in infection risk (MM, LH, ML), with representatives from Public Heath

England (RB, KM) and immunology (AR). Final consensus statements were then further

circulated for review and confirmation of agreement from the participants. The final

guidelines document will be additionally reviewed by the UK and Ireland Vasculitis Rare

Disease Group members (including patient representatives) for ratification prior to

publication.

4.3 RESULTS

Following Round 2, 69 statements reached consensus and were therefore removed from

the process as having already attained a level of “expert consensus”. A further 24

statements reached consensus in Round 3 (see Appendix 3 for consensus statements).

Some of these statements were combined where similar into single statements to avoid

repetition. Further consensus was reached during the consensus conferences.

As mentioned previously, due to the parallel study conducted by the British Society for

Rheumatology to produce guidelines for management of disease, including therapy and

monitoring, these areas were excluded from the final recommendations. A summary of all

consensus statements can be found in Appendix 3. The resulting recommendations, level of

consensus and supporting evidence can be viewed in the ADAPTIV recommendations

section.

83

Bone health

There was general agreement that steroid exposure should be minimised and that patients

should be formally assessed with regards to risk of glucocorticoids. However, areas that

were more contentious included the use of more novel agents and the surveillance and

treatment of the subset of patients with significant renal disease.

Cardiovascular health

Similarly, the panel were quick to reach agreement with regards to the notion that patients

with vasculitis have an augmented CV and thromboembolic risk and therefore conventional

risk factors should be aggressively modified. Areas where agreement was more difficult to

reach included to what degree patients’ risk was elevated and therefore, whether this

group should be treated any differently to the general population for primary prevention of

CVD.

Similarly, a particularly contentious issue was that of anti-coagulation for patients having

had one episode of VTE. There were those who felt that due to the reported risk in the

literature of VTE in AAV, these patients would warrant life- long anti-coagulation following

a single VTE episode. However, there was also generalised agreement that the major risk

appeared to be associated with episodes of disease activity and therefore this would seem

excessive in times of disease remission.

Cancer

There was uniform consensus that patients were at increased risk of skin cancers and

therefore should be more vigilant with regards to this risk. There was less agreement with

regards to the use of Mesna and bladder cancer but the recommendation for its use still

reached consensus. An area of contention was that of cervical screening frequency,

particularly for patients during the intensive phases of immunosuppression.

Infection

This was one of the most challenging areas to reach consensus, with infection perhaps

posing one of the biggest clinical threats to this population. Once again, the panel were

quick to agree with regards to the increased risk faced by this patient group and the fact

that increased vigilance and surveillance was required. During the initial rounds, no

consensus could be reached on how to identify those at the highest risk for infection and

84

thresholds for commencing protective anti-infective prophylaxis (with the exception of PJP

prophylaxis for those on cyclophosphamide and “high dose” steroids). For this reason, and

due to the lack of supportive evidence in the literature recommendations in this section are

fairly generic with a clear need identified for information to guide practice in this area.

4.4 DISCUSSION

During this study, a Delphi methodology has been successfully used to reach expert

consensus on a national level for holistic management of the vasculitis patient. The

recommendations derived from this process are presented elsewhere (please see Chapter

6). However, for those areas above where consensus could not be reached and evidence is

not available to inform guidance, the default position of the recommendations made are in

line with population guidance (e.g. for primary CV prevention, anti-coagulation following

VTE, population cancer screening). This clearly highlights the need for at minimum, high

quality longitudinal data for this population, in the likely ongoing absence of clinical trials to

address these issues.

We accept that the Delphi methodology is not perfect. It is a time- consuming process,

requiring commitment from a large group of busy experts. In addition, this method has

come under scrutiny in the past with regards to reliability and validity141. We have sought

to address these potential issues through using a large, heterogeneous expert panel,

including the use of consensus conferences to clarify more difficult areas and, in parallel,

conducting a comprehensive literature review to support the consensus reached and

subsequent recommendations made.

One of the advantages of using the Delphi process, particularly when reaching the

consensus conference stage, is that we found it encouraged further collaboration in driving

similar work forward in the vasculitis community. This study has also aided in identification

of the most pressing areas where better evidence is required to improve the safety and

quality of patient care. In summary, the use of a large “classical” Delphi study has enabled

consensus to be reached to provide guidance in some of the grey areas of clinical practice

for this population

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4.5 APPENDIX 1. ROUND 1 QUESTIONS

1) How often should a patient with stable vasculitis be seen for supervision of the

vasculitis in secondary/ tertiary care?

2) Is there a role for primary care in supervision of the vasculitis patient?

3) How frequently should a patient have BVAS assessed?

4) How frequently should a patient have VDI assessed?

5) How frequently should ANCA levels be tested?

6) Do you have anything to add to standard UK guidelines (NICE/BHS/RA) for primary

prevention of cardiovascular disease with regards to lifestyle and blood pressure control in

vasculitic patients?

7) Do you think that standard national guidelines for aspirin/ lipid therapy should be

modified for patients with vasculitis?

8) Do you think that patients with vasculitis should be treated with standard or

augmented thromboembolic risk measures?

9) Do you have any additional comments to add to current guidelines for prevention

of glucocorticoid induced osteoporosis (vitamin d/calcium/bisphosphonate use) (NOS 2002,

NICE guidelines due June 2012)

10) What frequency of routine DEXA scans indicated for patients with vasculitis?

11) What should be the recommendation for vaccination of vasculitis patients in

addition to annual flu vaccine? With particular reference to pneumococcal and Hib

vaccines?

86

12) When and how often should vasculitis patients receive pneumococcal and Hib

vaccines?

13) How should a patient’s response to vaccine be assessed?

14) What are the indications for co-trimoxazole prophylaxis in vasculitis patients?

15) What are the indications for co-trimoxazole use in the treatment of vasculitis?

16) What are the indications for fungal and viral prophylaxis (e.g.aciclovir and

fluconazole use) in vasculitis patients?

17) Would you recommend any additional routine monitoring of patients’ immune

profiles to assess infection risk (e.g. lymphocyte subsets, immunoglobulins)?

18) Would you set thresholds for altering immunotherapy based on the patient’s

immune profile (neutrophil count, lymphocyte count, CD4 count, IgG level etc.)?

19) Should any group of patients with vasculitis be screened at presentation, for

underlying malignancy (e.g. gastroscopy; colonoscopy; CT chest/abdo/pelvis; blood

markers)?

20) Should vasculitis patients under follow- up undergo any additional cancer screening

compared with an age and sex matched population? (including breast, bowel and

prostate)?

21) What is your opinion on cervical cancer screening in vasculitis patients?

22) What should the recommendations be for bladder cancer screening and mesna use

in patients exposed to cyclophosphamide?

23) Do you recommend additional sun protection or regular skin cancer screening for

vasculitis patients?

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24) Should cyclophosphamide use be avoided in any patient group with regards to

preservation of fertility or other factors?

25) What is the maximum dose of cyclophosphamide that can be administered

concerning;

a) the preservation of fertility?

b) malignancy risk?

26) What is the role of sperm banking/ oocyte retrieval in vasculitis patients?

27) What is the role of GnRH antagonists to preserve fertility? What other therapeutic

options would you recommend?

Sources

(1) Vaccinations in the Immunocompromised Person. Guidelines for the Patient taking

Immunosupppressants, Steroids and New Biological Therapies142.

(2) EULAR Recommendations for vaccination in the adult patients with autoimmune

inflammatory rheumatic diseases143.

(3) BSR and BHPR Guidelines for the management of adults with ANCA associated

vasculitis144.

(4) Glucocorticoid-induced osteoporosis. A concise guide to the prevention and

treatment145.

(5) EULAR Recommendations for the management of primary small and medium vessel

vasculitis72.

(6) Immunisation against infectious disease: The Green Book146.

(7) Hypertension in adults; diagnosis and management147.

(8) Chronic Kidney Disease: Early identification and management of chronic kidney disease

in adults in primary and secondary care148.

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4.6 APPENDIX 2: STATEMENTS GENERATED FOLLOWING ROUND 1

Question and Statement

1) Do you have any suggestions for approaches to therapy to add to existing EULAR/BSR guidelines for

vasculitis?

1.1 EULAR and BSR guidelines need to be updated.

1 .2 EULAR and BSR treatment algorithms and protocols need to be devised.

1 .3 Treatment of relapsing disease needs to be updated.

1.4 'Fixed dose' protocol based therapy may result in over immunosuppression of some patients

and under treatment of some patients.

1.5 Rituximab should be used for induction and remission therapy, instead of cyclophosphamide

or methotrexate.

1.6 Rituximab is the first line therapy for patients with relapsing/persistent disease.

1.7 Rituximab shouldn’t be recommended as first line therapy until long term safety data is

available.

1.8 Pulsed cyclophosphamide leads to an increase in relapse rate.

1.9 Dose reduction of cyclophosphamide for the elderly is not needed.

1.10 A high dose of 0.8g/m2 cyclophosphamide given every 3-4 weeks is safe.

1.11 Current guidelines focus on total WBC and neutrophil count, as cyclophosphamide

predominantly affect lymphocyte counts, effect of lymphocyte count should be taken in to

account while prescribing cyclophosphamide dose.

1.12 Before cyclophosphamide therapy, pre-dose lymphocyte count should be maintained above

0.4 x10^9/L; during maintenance therapy lymphocyte count should be maintained above 0.7

x10^9/L.

1.13 The roles of methotrexate, mycophenolate and leflunomide should be included in the

guidelines.

1.14 Methotrexate can be used at a maximum dose of 35mg/week.

1.15 Use of Methotrexate for less severe disease leads to an increased risk of relapse.

1.16 If initial pulsed intravenous steroids are used then oral steroids can be started as low as

0.5mg/Kg.

1.17 There is no evidence to support continuation of high dose oral steroids for 3 months.

1.18 Current recommendations for plasma exchange should be reduced as there is insufficient

evidence to support them.

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1.19 Supervision of treatment should be by expert centres.

1) How often should a patient with stable vasculitis be seen for supervision of the vasculitis in

secondary/ tertiary care?

2.1 No change to BSR 2006 guidelines (Follow-up after 12 months should be as dictated by the

clinical condition of the patient, but should not be less frequent than every 6 months).

2.2 Frequency of follow up depends on risk of relapse, previous immunotherapy and current

immunosuppression.

2.3 Once every 2 weeks while on induction therapy.

2.4 In remission and on maintenance therapy once a month for 3 months then every 3 months for

the first 2 years.

2.5 Every 3 months if still on med-high steroids / MMF.

2.6 After 2 years, every 3-6 months.

2.7 If on small dose steroid without relapse for several years - annually

2.8 If off all immunosuppression and clinically stable for > 12 months, not at all.

2.9 Efforts should be made to engage patient in follow up care. Teaching them how to dipstick

their own urine and appropriate use of self-referral pathways if unwell.

2) Is there a role for primary care in supervision of the vasculitis patient?

3.1 Primary care has no role in the supervision of the vasculitis patient.

3.2 Primary care should be involved, especially with stable patients.

3.3 Primary carers should be aware of the immunosuppressive medications the patient is taking.

3.4 Primary care should be responsible for cardiovascular risk assessment.

3.5 Primary care should be responsible for drug monitoring.

3.6 Primary care should be responsible for urine and blood testing.

3.7 Primary care should be responsible for screening for skin and bladder malignancy.

3.8 Primary care should be responsible for lifestyle (diet, alcohol intake and exercise) advice.

3.9 Primary care physicians are key to advising patients how to avoid intercurrent infection and

picking up infections at an early stage.

3.10 This process should only be used in areas where primary care has the appropriate IT facilities

to view and communicate results with secondary care.

3.11 Solid shared care protocols are needed.

3.12 Unwell vasculitis patients should have a direct route to secondary care.

3) How frequently should a patient have BVAS assessed?

4.1 Informally, the questions can be asked at every visit but a score need not be recorded.

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4.2 Each clinical encounter.

4.3 Current recommendations for initial score, then monthly including at 3 months to confirm

response, then as dictated clinically subsequently.

4.4 If the patient is stable every 3-6 months after induction.

4.5 If the patient is unstable every 1-3 months.

4.6 No role outside research studies, a recording tool rather than an assessment tool. Although it

can be useful as an aide-memoire for less common disease manifestations in inexperienced

clinicians.

4) How frequently should a patient have VDI assessed?

5.1 Informally every visit, the questions may be asked but no need to calculate a score.

5.2 Formally at time points dictated by trials or at induction then at 3 and 6 months.

5.3 Every 3-6months.

5.4 Every 6-12 months.

5.5 Every clinical visit.

5.6 Research tool only. Would be a useful guideline addition to enable comparison between

different units.

5.7 VDI can be carried out by a specialist nurse.

5) How frequently should ANCA levels be tested?

6.1 No more frequently than every 4-6weeks as half-life of IgG is 3 weeks.

6.2 Every 2-3 weeks until remission.

6.3 Every 3 months for the first 2 years then every 4-6 months thereafter.

6.4 Every 3 months for the first 5 years once stable.

6.5 Annually.

6.6 As per clinical symptoms.

6.7 If clinically stable no need to check.

6.8 At each clinical visit if ANCA-positive.

6.9 If ANCA negative, measure if new clinical evidence of Vasculitis develops.

6.10 Should be tested by both ANCA immunofluorescence and MPO/PR3 antigen specific tests.

7)Do you have anything to add to standard UK guidelines (NICE/BHS/RA) for primary prevention of

cardiovascular disease with regards to lifestyle and blood pressure control in vasculitic patients?

7.1 Vasculitis appears to be a risk factor for cardiovascular disease therefore treatment threshold

should be lowered.

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7.2 Steroids/immunosuppression appear to be risk factors for cardiovascular disease therefore

treatment threshold should be lowered.

7.3 Given the increase risk in Vasculitis patients, they should be started on “stage 1” of the

hypertension treatment ladder according to NICE guidelines.

7.4 Lower BP targets, typically below 130/80.

7.5 Treating inflammation is more important than treating cholesterol.

7.6 Stopping smoking is critical.

7.7 PR3 is a possible risk factor for cardiovascular disease.

7.8 There is a new cardiovascular risk calculator for use in AAV which modifies the Framingham

calculator, this needs to be taken into account

7.9 Annual assessment of CVD risk.

7.10 No specific interventions that have been demonstrated to be efficacious in clinical trials.

8)Do you think that standard national guidelines for aspirin/ lipid therapy should be modified for

patients with vasculitis?

8.1 Current guidelines for aspirin/lipid therapy should not be modified for patients with vasculitis

8.2 Further evidence for the need for modification of these guidelines in a large cohort study is

needed.

8.3 Yes with some sort of adjustment made (e.g. as per Rheumatoid Arthritis guidelines

multiplication of risk of CVD by 1.5).

8.4 Overemphasized, focus on BP.

8.5 Consider all Vasculitis patients on steroid therapy for aspirin treatment.

8.6 Caution about statins as the side effects can mimic systemic symptoms (myalgia).

8.7 Treat all patients as being high risk for cardiovascular disease.

9)Do you think that patients with vasculitis should be treated with standard or augmented

thromboembolic risk measures?

9.1 Augmented all the time.

9.2 Augmented if active, normal if stable.

9.3 Augmented if any loss of mobility or history of thromboembolic event.

9.4 Standard measures at presentation only, no measures after.

9.5 Standard due to risk of pulmonary haemorrhage.

9.6 Aspirin only for most patients.

10)Do you have any additional comments to add to current guidelines for prevention of glucocorticoid

induced osteoporosis (vitamin D/calcium/bisphosphonate use) (NOS 2002, NICE guidelines due June

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2012)?

10.1 Follow the RCP guidance- nothing to add to current guidelines.

10.2 Minimise steroid exposure.

10.3 The 2006 BSR guidelines should be used in preference to current NOS guidelines (higher

steroid dose used for vasculitis treatment compared to studies informing NOS guidelines).

10.4 Measuring bone turnover markers at 3-6 months to check compliance with oral

bisphosphonates.

10.5 Add DEXA to guide therapy and therapy withdrawal.

10.6 Monitoring of vitamin D level can be incorporated.

10.7 Stop bisphosphonates in advanced renal disease. Pressing need for evidence based

intervention that is effective for patients with GFR<30.

10.8 Calcichew D3 is an appropriate alternative to bisphosphonates especially in pregnant

Vasculitis patients.

10.9 Denosumab should be considered as an alternative in patients whom bisphosphonates have

been contraindicated.

10.10 Denosumab therapy needs evidence before being used in immunosuppressed patients due to

infection risk.

10.11 Patients should be counselled regarding potential bisphosphonate side effects prior to

commencing therapy (osteonecrosis of the jaw, avascular necrosis of the hip, and "frozen

bone"/sub trochanteric hip fracture).

10.12 Patients should have dentition assessed prior to commencing bisphosphonates.

11)What frequency of routine DEXA scans indicated for patients with vasculitis?

11.1 The following patients should have DEXA scans (applies to the next 8 statements);

All patients should have DEXA scan at baseline.

11.2 Patients on steroids- every 2-3 years

11.3 Patients only on prednisolone greater than 10mg/day- every 2-3 years.

11.4 If on steroids and older than 50 years.

11.5 If greater than 65 years.

11.6 Every 3-5 years dependent on results.

11.7 No more than once every 5 years if already on bisphosphonates and no fracture.

11.8 In young patients who bisphosphonate therapy doesn’t work very well e.g. premenopausal

women.

11.9 Patients should have overall fracture risk assessed rather than just BMD.

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12)What should be the recommendation for vaccination of vasculitis patients in addition to annual flu

vaccine? With particular reference to pneumococcal and Hib vaccines?

12.1 Avoid live vaccines in the severely immunosuppressed.

12.2 Patients should have every vaccine available on the market.

12.3 An individual risk assessment should be undertaken for a number of vaccines which may be

given if low immunosuppression, e.g. MMR and VZV.

12.4 One-off Pneumococcal (unconjugated) prior to start of treatment. If low titres try a booster

with conjugated vaccine.

12.5 VZV prior to treatment.

12.6 BCG should only be given before immunosuppression.

12.7 HPV if at risk and in licensed age range.

12.8 Consider Hep A/Hep B (particularly for any one with renal involvement).

12.9 Use inactivated polio only.

12.10 Dual vaccination may be required if on rituximab.

13)When and how often should vasculitis patients receive pneumococcal and Hib vaccines?

13.1 5 yearly.

13.2 5 yearly is inappropriate. Need for vaccine should be assessed on antibody levels taken every

1-2 years.

13.3 Pneumococcal once, repeat if titres are inadequate.

13.4 Pneumococcal and Hib vaccine as soon as possible at presentation, preferable before

immunotherapy starts.

13.5 If already immunosuppressed then vaccinate after immunosuppressive therapy has finishes

e.g. 6 months after rituximab, shorter for other agents.

14)How should a patients response to vaccine be assessed?

14.1 No point-not cost effective.

14.2 Antibody levels at 4-6 weeks.

14.3 Specific antibody titre testing including type specific antibody.

14.4 Need for vaccine should be assessed on antibody levels taken every 1-2 years.

14.5 If initial vaccine response to pneumococcus is inadequate Prevenar13, a conjugate vaccine

may be considered.

14.6 Annual check of pneumococcal and Hib antibody status if antibody deficient 2 months post

vaccine.

14.7 3-yearly check of pneumococcal and Hib antibody status if antibody status okay 2 months

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post vaccine

15) What are the indications for co-trimoxazole prophylaxis in vasculitis patients?

15.1 Give to everyone.

15.2 Give if starting high dose immunosuppressive especially in GPA.

15.3 Give for 3 months if treatment with induction of cyclophosphamide or MMF therapy.

15.4 Give for the first 6 months especially if on high dose cyclophosphamide or MMF.

15.5 Continue indefinitely in those with sino-nasal granulomatous disease.

15.6 Continue for 6months after cyclophosphamide therapy.

15.7 Give if on Prednisolone 20mg/day for greater than 4 weeks plus additional

immunosuppressant.

15.8 Give if on Prednisolone greater than 40mg/day for greater than 12 weeks.

15.9 During high dose steroid therapy >60mg/day.

15.10 Give during initial therapy and then tailor co-trimoxazole therapy to CD4 counts.

15.11 Patients with previous PJP infection.

15.12 Blanket guidelines are unlikely to work.

15.13 If lymphocyte count <0.6 x10^9/L, or if consistently <0.7 x10^9/L

15.14 If CD4 count <200 x10^6/L.

15.15 If other opportunistic infections (e.g. warts, shingles, thrush, chest infections) and CD4 of

<400x 10^6/L or lymphocytes <1.0 x10^9/L.

15.16 Guidelines are needed for PJP prophylaxis in patients treated with Rituximab which is being

used more frequently.

15.17 Consideration of additional prophylaxis options for Pneumocystis jirovecii e.g. azithromycin,

atovaquone

16) What are the indications for co-trimoxazole treatment in vasculitis patients?

16.1 There are no indications for co-trimoxazole in the treatment of vasculitis.

16.2 Do not use as monotherapy in any circumstances.

16.3 ENT disease in general warrants antibiotic prophylaxis. Could be macrolides or Septrin.

16.4 Can be used alone as “treatment” for limited GPA or with low dose steroids.

16.5 All patients with ENT disease should be treated with Septrin

16.6 All GPA should be treated with Septrin

16.7 Persistent disease should be treated with Septrin

16.8 Remission maintenance in a few if they have local disease and cannot tolerate methotrexate,

leflunomide or azathioprine.

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16.9 The highest dose tolerated should be used (960-1920mg daily).

16.10 Control of respiratory tract infection.

17)What are the indications for fungal and viral prophylaxis (e.g.aciclovir and fluconazole use) in

vasculitis patients?

17.1 Fungal and viral prophylaxis should be initiated before starting high-dose

immunosuppression.

17.2 Fungal and viral prophylaxis should be used in patients receiving cyclophosphamide and high

dose steroids or rituximab or TNFa blockers.

17.3 There are no indications for viral prophylaxis as it is not cost effective.

17.4 Viral prophylaxis if frequent recurrent HSV infections.

17.5 CMV prophylaxis with valganciclovir and VZ prophylaxis after rituximab.

17.6 If previous history of fungal or Zoster infection then consider prophylaxis if intense therapy is

repeated.

17.7 Fungal prophylaxis should be offered to high risk patients (those living in endemic

histoplasmosis areas, or those that go caving in the Cheddar gorge).

17.8 The incidence of invasive fungal disease doesn’t warrant the risk of fluconazole therapy.

17.9 Fluconazole when on high dose steroids.

17.10 No regular prophylaxis outside nystatin use.

17.11 Topical oral anti-fungal (nystatin pastilles) for ten days of first treatment or when pred

>20mg.

17.12 Aciclovir only if symptoms/signs/ past history of recurrent herpes.

17.13 If lymphocyte <0.6 x10^9/L or persistently <0.7 x10^9/L.

17.14 If CD4 count <200 x10^6/L.

17.15 If other opportunistic infections (warts, shingles, thrush, chest infections), and CD4 < 400

x10^6/L or lymphs < 1.0 x10^6/L.

17.16 A role for hepatitis B screening and prophylaxis or monitoring.

18)Would you recommend any additional routine monitoring of patients immune profiles to assess

infection risk (e.g. lymphocyte subsets, immunoglobulins)?

18.1 There is no role for routine monitoring of immune profiles to assess infection risk (e.g.

lymphocyte subsets/ Igs).

18.2 Only if there are infectious complications.

18.3 Immunoglobulin levels should measure yearly.

18.4 Lymphocytes or immunoglobulins should be measured if on cyclophosphamide or rituximab

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therapy.

18.5 CD4 count should be measured if lymph <1.0 x10^6/L

18.6 Measure CD 19 and 20 if rituximab considered.

18.7 Lymph count is useful to detect if abnormalities are drug related or pre existing

18.8 There is no evidence that measuring lymphocyte subsets is any better than peripheral blood

lymphocyte count.

18.9 IgGs at start of treatment and subsequently if recurrent infection.

18.10 Patients that require >1 induction therapies should have additional monitoring.

18.11 Patients on long term maintenance e.g. >2 years should have additional monitoring.

18.12 Immunoglobulin monitoring if repeated rituximab use.

18.13 PJP prophylaxis should not be titrated to CD4 counts.

18.14 More evidence is required re: the use of these to validate.

19)Would you set thresholds for altering immunotherapy based on the patient’s immune profile

(neutrophil count, lymphocyte count, CD4 count, IgG level etc.)?

19.1 The aim should be to use the minimum necessary immunosuppression in an individual patient

according to their clinical history.

19.2 Thresholds should be for individual patients.

19.3 If thresholds can be agreed, prophylaxis regimens and vaccine recommendations should be

adjusted according to CD4.

19.4 Antimicrobial and antifungal prophylaxis should be adjusted with neutrophil count.

19.5 The significance of lymphopenia has not been established.

19.6 Immunosuppression should be based on neutrophil count alone.

19.7 The following should guide alterations to immunotherapy (applies to the next 6 statements);

Total WCC

19.8 Neutrophils.

19.9 IgG levels.

19.10 CD4+.

19.11 CD19.

19.12 Total lymphocyte count.

19.13 Lymphocyte count <0.6 x109/L or consistently <0.7 x10^9/L or CD4 count < 200 x10^6/L or

Other opportunistic infections (warts, shingles, thrush, chest infections), and CD4 < 400

x10^6/L or lymphocytes < 1.0 x10^6 or IgG < 3 g/L.

19.14 The infection history is more important rather than the absolute IgG level.

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19.15 Immunoglobulin monitoring will need to be explored for rituximab in the future if this

becomes the choice for remission maintenance.

20)Should any group of patients with vasculitis be screened at presentation, for underlying

malignancy (e.g. gastroscopy; colonoscopy; CT chest/abdo/pelvis; blood markers)?

20.1 Not unless clinically indicated (e.g. change in bowel habit, or with major weight loss/night

sweats).

20.2 CXR in smokers.

20.3 Yes all (as in Membranous Glomerulonephritis).

20.4 Patients presenting outside the "usual" age groups, with unusual presentations or who have

not responded to treatment as expected.

20.5 Patients should have CXR and abdo USS rather than CT chest/abdo/pelvis (due to high

radiation dose) unless there is a high index of suspicion.

20.6 Iron deficiency/hypercalcaemia might raise the index of suspicion.

20.7 Blood tumour markers are not very helpful, even as a screening tool.

21)Should vasculitis patients under follow- up undergo any additional cancer screening compared

with an age and sex matched population? (including breast, bowel and prostate)?

21.1 Patients with vasculitis shouldn’t have any additional cancer screening but there is a need for

enhanced awareness of malignancy risk during follow-up.

21.2 Due to increased immunosuppression, patients with vasculitis should have additional cancer

screening.

21.3 Such screening is not cost effective (avoid feeding a screening industry dominated by zealots

and big pharma).

21.4 Not routine but lower threshold for further investigations if patients are symptomatic or have

abnormal findings such as worsening anaemia.

21.5 Patients should be encouraged to attend for the routine population screening.

21.6 Due to increased immunosuppression, patients with vasculitis should have additional cancer

screening.

21.7 Vasculitis patients should have periodic urine analysis and cytology if they have received

significant cyclophosphamide load to screen for bladder cancer.

21.8 Skin cancer surveillance.

22)What should the recommendations be for bladder cancer screening and mesna use in patients

exposed to cyclophosphamide?

22.1 Always use mesna during cyclophosphamide therapy.

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22.2 Mesna and screening if received > 10g cyclophosphamide.

22.3 No need for mesna in pulsed cyclophosphamide therapy.

22.4 Any cyclophosphamide patient with persistent micro haematuria needs a cystoscopy and

cytology assessment of urine.

22.5 Check urinalysis for blood at every hospital visit.

22.6 Patients with significant cyclophosphamide exposure in the past should have regular

monitoring of urine with dipsticks (6-12 monthly).

23)What is your opinion on cervical cancer screening in vasculitis patients?

23.1 Cervical cancer screening should be as per the general population.

23.2 At risk women should have a smear annually for the first 3 years after induction therapy.

23.3 Cervical screening should be undertaken dependent on age and degree of

immunosuppression.

23.4 Recommend all female patients should attend for a cervical screening update after 3 months

of treatment when in remission, screening thereafter as per national guidelines.

23.5 HPV vaccination makes the cost effectiveness of screening even less favourable.

24)Do you recommend additional sun protection or regular skin cancer screening for vasculitis

patients?

24.1 All patients on immunosuppression require sun protection and regular screening if on

immunosuppressants.

24.2 Only patients on azathioprine- require sun protection and regular screening.

24.3 Only for patients who require long-term immunosuppression (>5years)-should undergo skin

screening.

24.4 Avoidance of tanning beds is wise.

24.5 Patients should be educated to perform self-checking for skin cancer.

24.6 GPs should perform six-monthly visual check of "moles" / other skin lesions.

24.7 Examination of the skin for suspicious lesions should be part of an annual review.

24.8 Take into account patient’s history including family history and repeated episodes of sun-burn

/ high levels UV exposure earlier in life (e.g. living abroad).

24.9 Research related to non-melanoma skin cancer is flawed.

24.10 Regular screening is unnecessary as data arises from cohorts who were over-

immunosuppressed in an era when sunbathing was the norm.

25)Should cyclophosphamide use be avoided in any patient group with regards to preservation of

fertility or other factors?

99

25.1 Rituximab should be substituted for those who fear risk of infertility e.g. young women and

men unable to undergo sperm banking/retrieval.

25.2 Rituximab may be used in those felt to be at high risk of infectious complications, those with

active infection or those with evidence of marrow fragility.

25.3 After Rituximab exposure, pregnancy should be avoided for a year.

25.4 Advice should be given regarding the severe effect that kidney failure has on fertility and of

the importance of not using a "soft touch" for organ threatening disease.

25.5 Cyclophosphamide should never be avoided in life threatening disease.

25.6 Cyclophosphamide avoidance or minimisation in pre-menopausal females.

25.7 In female patients who are above 35 years of age, do not have organ threatening

involvement, and want children, cyclophosphamide should be avoided.

25.8 Avoid cyclophosphamide (or at least markedly reduce the dose) in those with GFR< 60.

25.9 Large previous cyclophosphamide load is a relative contraindication to further

cyclophosphamide use; e.g. >15g.

26)What is the maximum dose of cyclophosphamide that can be administered concerning;

a) the preservation of fertility?

b) malignancy risk?

26.1

(a)

There is no minimum safe dose that would completely eradicate risk.

26.2

(a)

6g is the minimum modern dose of cyclophosphamide.

26.3

(a)

10g if >25 years.

26.4

(a)

<12g.

26.5

(a)

7-14g depending on age.

26.6

(a)

1.2g per pulse.

26.7

(a)

Depends on sperm and ovarian viability before treatment begins.

26.8

(a)

Depends on body surface area.

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26.9

(a)

Depends on patient age.

26.10

(a)

Evidence here is not robust.

26.11

(a)

The effects of cyclophosphamide on fertility are not related to the strength of dose but to

duration of treatment (small doses over a long period are more damaging to fertility than

several big heavy doses).

26.12

(b)

36g.

26.13

(b)

An increased risk of leukaemia / MDS or bladder cancer is only seen with cumulative dose

>30g.

26.14

(b)

25-35g depending on age.

26.15

(b)

20g-30g for depending on age.

26.16

(b)

20g but needs to be corrected for body surface area.

26.17

(b)

15 g/m2.

26.18

(b)

Up to 10 g

26.19

(b)

Recent EUVAS data suggests no increased risk of cancer with the current low doses of

cyclophosphamide although further follow up will be necessary.

27)What is the role of sperm banking/ oocyte retrieval in vasculitis patients ?

27.1 Men should be offered the chance to store sperm if they wish before starting

cyclophosphamide (as long as it does not interfere with medically urgent therapy).

27.2 Any man under 55 should be actively encouraged to bank even if he feels that he will not

want to use the sperm as his thoughts may change.

27.3 Any women wanting to start a family or <42 years with a partner should be offered the

opportunity to (applies to the next 3 statements):

Store fertilised eggs prior to starting therapy (procedure takes possible three weeks).

27.4 To store vitrilised eggs (better success rates than storing fertilised eggs. Takes about 3

weeks).

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27.5 To freeze a wedge section of the ovary containing the immature eggs and the supporting

cells.

27.6 Should be performed if possible in anyone being treated with cyclophosphamide of

childbearing age.

27.7 Oocyte retrieval in unwell females with active vasculitis is not currently feasible.

27.8 Links with the appropriate local reproductive health departments should be established.

28)What is the role of GnRH antagonists to preserve fertility? What other therapeutic options would

you recommend?

28.1 Should be offered to younger women at risk of ovarian damage from cyclophosphamide.

28.2 There is a role for Goserelin (Gonaderelin analogue) to preserve fertility.

28.3 Anti-mullerian hormone level should be checked prior to commencing treatment (predictor of

ovarian reserve.)

28.4 The oral contraceptive pill or long acting hormone injection can be used instead of GnRH

agonists (less side effects).

28.5 There is insufficient evidence for other options such as the OCP.

28.6 There is no role for the use of GnRH antagonists.

28.7 We would ask national experts e.g. David Jayne

102

4.7 APPENDIX 3. CONSENSUS STATEMENTS

Round 2 consensus statements (agreement unless otherwise stated)

Advice for Current BSR/EULAR Guidelines

• EULAR and BSR guidelines need to be updated.

• Treatment of relapsing disease needs to be updated.

• 'Fixed dose' protocol based therapy may result in over immunosuppression of some

patients and under treatment of some patients.

• The roles of methotrexate, mycophenolate and leflunomide should be included in the

guidelines.

• There is no evidence to support continuation of high dose oral steroids for 3 months.

• Supervision of treatment should be by expert centres.

Monitoring of Disease Activity

• The number of follow ups the patient will require depends on risk of relapse, previous

immunotherapy and immunosuppression.

• Efforts should be made to engage the patient in follow up care. Teaching them how to

dipstick their own urine and appropriate use of self-referral pathways if unwell.

• After two years patients should be seen every 3-6 months

• Primary care has a role in supervision of the vasculitis patient and should especially be

involved with stable patients.

• Primary carers should be aware of the immunosuppressive medication the patient is

taking and be responsible for patient lifestyle (diet, alcohol intake and exercise) advice.

• Unwell vasculitis patients should have a direct route to secondary care.

• Solid share care protocols are needed.

• VDI assessment can be carried out by a specialist nurse.

• ANCA levels should only be tested as per clinical symptoms

• No need to test ANCA levels if the patient is clinically stable. (Disagree)

• If initially negative measure if new clinical evidence of vasculitis develops.

• Patients should be tested by both ANCA immunofluorescence and MPO/PR3 antigen

specific tests.

103

Cardiovascular and Thromboembolic Risk

• Stopping smoking in the vasculitis patient is critical.

• They should have an annual assessment of CVD risk and the new cardiovascular risk

calculator, which modifies the Framingham calculator for use in AAV, needs to be taken

into account.

• The national guidelines for aspirin/lipid should be modified for patients with vasculitis

with some sort of adjustment made (e.g.as per Rheumatoid Arthritis guidelines

multiplication of risk of CVD by 1.5).

• Further evidence for the need for modification of these guidelines in a large cohort study

is needed.

• Patients with vasculitis should be treated with augmented thromboembolic risk measure

if any loss of mobility or history of thromboembolic event.

Bone Health

• Minimise steroid exposure.

• Patients should be counselled regarding potential bisphosphonate side effects prior to

commencing therapy (osteonecrosis of the jaw, avascular necrosis of the hip, and "frozen

bone"/subtrochanteric hip fracture).

• Denosumab should be considered as an alternative in patients whom bisphosphonates

have been contraindicated.

• Patients should have overall fracture risk assessed rather than just BMD.

Infection Risk

• Avoid live vaccines in the severely immunosuppressed.

• Use inactivated polio only.

• Give co-trimoxazole if starting high dose immunosuppressive especially in GPA.

• Give co-trimoxazole to patients with previous PJP infection.

• Guidelines are needed for PJP prophylaxis in patients treated with Rituximab which is

being used more frequently.

• Consideration of additional prophylaxis options for Pneumocystis jirovecii eg

azithromycin, atovaquone.

• There are indications for co-trimoxazole in the treatment of vasculitis.

104

• Viral prophylaxis if frequent recurrent HSV infections.

• If previous history of fungal or Zoster infection then consider prophylaxis if intense

therapy repeated.

• Aciclovir only if symptoms/signs/ past history of recurrent herpes.

• Lymphocytes or immunoglobulins should be measured if on cyclophosphamide or

rituximab therapy.

• Immunoglobulin monitoring if repeated rituximab use.

• The aim should be to use the minimum necessary immunosuppression in an individual

patient according to their clinical history.

• The following should guide alterations to immunotherapy-neutrophils, total lymphocyte

count.

• The infection history is very important rather than the absolute IgG level.

• Immunoglobulin monitoring will need to be explored for rituximab in the future if this

becomes the choice for remission maintenance.

• Thresholds should be for individual patients

• Immunosuppression should not be based on neutrophil count alone.

Cancer Risk

• Vasculitis patients should not be screened for malignancy prior to treatment unless

clinically indicated (e.g. change in bowel habit, or with major weight loss/night sweats).

• CXR in smoker.

• Iron deficiency/hypercalcaemia might raise the index of suspicion.

• Follow-up patients should be encouraged to attend for the routine population screening

• Periodic urine analysis and cytology if significant cyclophosphamide load to screen for

bladder cancer.

• Skin cancer surveillance.

• Any cyclophosphamide patient with persistent micro haematuria needs a cystoscopy and

cytology assessment of urine.

• Check urinalysis for blood at every hospital visit.

• Patients with significant cyclophosphamide exposure in the past should have regular

monitoring of urine with dipsticks (6-12 monthly).

• Avoidance of tanning beds is wise.

• Patients should be educated to perform self checking for skin cancer.

105

• Take into account patient’s history including family history and repeated episodes of sun-

burn / high levels UV exposure earlier in life (eg living abroad)

• Only if on azathioprine- avoid sun exposure, and use sun cream if sun-exposure is

unavoidable. (disagree)

Fertility

• Cyclophosphamide avoidance or minimisation in pre-menopausal females.

• Rituximab may be used in those felt to be at high risk of infectious complications, or those

with active infection, or those with evidence of marrow fragility.

• Advice should be given regarding the severe effect that kidney failure has on fertility and

of the importance of not using a "soft touch" for organ threatening disease.

• There is no minimum safe dose of cyclophosphamide that would completely eradicate risk

of infertility.

• The maximum dose of cyclophosphamide that would preserve fertility depends on patient

age.

• Evidence on maximum dose of cyclophosphamide that would preserve fertility here is not

robust.

• Recent EUVAS data suggests no increased risk of cancer with the current low doses of

cyclophosphamide although further follow up will be necessary.

• Men should be offered the chance to store sperm if they wish before starting

cyclophosphamide (as long as it does not interfere with medically urgent therapy).

• Oocyte retrieval in unwell females with active vasculitis is not currently feasible.

• Links with the appropriate local reproductive health departments should be established.

• There is insufficient evidence for other options such as the OCP.

Round 3 consensus

Disagree

How often should a patient with stable vasculitis be seen for supervision of the vasculitis in

secondary/ tertiary care?

· If off all immunosuppression and clinically stable for > 12 months, not at all.

How frequently should a patient have VDI assessed?

· Every clinical visit.

How frequently should ANCA levels be tested?

106

· Every 2-3 weeks until remission.

· Every 3 months for the first 5 years once stable.

Do you think that standard national guidelines for aspirin/ lipid therapy should be modified for

patients with vasculitis?

· Caution about statins as the side effects can mimic systemic symptoms (myalgia)

Do you think that patients with vasculitis should be treated with standard or augmented

thromboembolic risk measures?

· Standard due to risk of pulmonary haemorrhage.

What should be the recommendation for vaccination of vasculitis patients in addition to annual

flu vaccine? With particular reference to pneumococcal and Hib vaccines?

· Patients should have every vaccine available on the market.

What are the indications for co-trimoxazole prophylaxis in vasculitis patients?

· Give to everyone.

· Continue for 6months after cyclophosphamide therapy

Do you recommend additional sun protection or regular skin cancer screening for vasculitis

patients?

Regular screening is unnecessary as data arises from cohorts who were over-immunosuppressed

in an era when sunbathing was the norm.

What is the maximum dose of cyclophosphamide that can be administered concerning malignancy

risk?

An increased risk of leukaemia / MDS or bladder cancer is only seen with cumulative dose >30g.

25-35g depending on age

Agree

How often should BVAS be assessed?

· Informally, the questions can be asked at every visit but a score need not be recorded.

What should be the recommendation for vaccination of vasculitis patients in addition to annual flu

vaccine? With particular reference to pneumococcal and Hib vaccines?

BCG should only be given before immunosuppression

Consider Hep A/Hep B (particularly for any one with renal involvement).

Would you recommend any additional routine monitoring of patients immune profiles to assess

infection risk (e.g. lymphocyte subsets, immunoglobulins)?

107

· More evidence is required re: the use of these to validate.

Would you set thresholds for altering immunotherapy based on the patients immune profile

(neutrophil count, lymphocyte count, CD4 count, IgG level etc)?

· The following should guide alterations to immunotherapy ;

Total WCC

What is your opinion on cervical cancer screening in vasculitis patients?

· Cervical screening should be undertaken dependent on age and degree of

immunosuppression

Do you recommend additional sun protection or regular skin cancer screening for vasculitis

patients?

· All patients on immunosuppression require sun protection and regular screening if on

immunosuppressants.

· Examination of the skin for suspicious lesions should be part of an annual review.

Should cyclophosphamide use be avoided in any patient group with regards to preservation of

fertility or other factors?

· In female patients who are above 35 years of age, do not have organ threatening

involvement, and want children, cyclophosphamide should be avoided.

· Large previous cyclophosphamide load is a relative contraindication to further

cyclophosphamide use; eg: >15g.

What is the role of sperm banking/ oocyte retrieval in vasculitis patients?

· Any man under 55 should be actively encouraged to bank even if he feels that he will not

want to use the sperm as his thoughts may change.

What is the role of GnRH antagonists to preserve fertility? What other therapeutic options would

you recommend?

· Should be offered to younger women at risk of ovarian damage from cyclophosphamide.

Round 4 Consensus

In the absence of life threatening disease cyclophosphamide should be avoided in women and

men of child-bearing potential.

There is emerging data that pregnancy may be safe in the months following Rituximab exposure

However, until more data is available patients should be counselled to avoid pregnancy post

Rituximab exposure for 12 months.

108

Patients exposed to Rituximab in the preceding 12 months should be referred for discussion in a

specialised joint obstetric/ rheum or renal clinic.

All vasculitis patients of future child- bearing potential should be considered for referral for

sperm banking/ egg retrieval including those treated with Rituximab due to the potential for

future exposure to cyclophosphamide.

Individual cases, such as sperm banking following exposure to 1 or 2 doses of cyclophosphamide

or for patients who are physically incapable of sperm banking should be discussed with the local

reproductive health department

There is insufficient evidence to routinely recommend the use of GnRH agonists/ GnRH

analogues/or OCP to protect fertility. This requires prospective studies

Patients with non- life threatening relapsing disease and previous treatment with

cyclophosphamide should avoid further exposure to cyclophosphamide i.e. consider Rituximab

treatment. This is supported by current funding policies for Rituximab.

Patients exposed to pulsed intravenous cyclophosphamide should receive:

· Mesna

The educated patient and GP may be better placed to perform regular (annual) skin screening

than the clinician in the vasculitis clinic. However, patients with skin lesions require regular

appropriate follow- up (i.e. dermatology).

Cervical screening should be carried out annually for first 3 years then as per population (see

BSR guidelines).

Patients should be warned in advance of cyclophosphamide exposure regarding the potential

increase in CIN changes on cervical screening.

The rheumatoid arthritis model of multiplying traditional CV risk by 1.5 may not be appropriate

for this population. AAV may be more comparable to the lupus population but more data is

required.

Vasculitis and the therapy, particularly steroids appear to be risk factors for cardiovascular

disease. Therefore to manage these risk factors the disease should be appropriately treated and

unnecessary steroid exposure avoided

Early identification of CKD in this group is imperative due to the additional risk of cardiovascular

disease this confers

Awareness of increased CVD risk in Vasculitis should be raised in both primary and secondary

care and to the patient.

109

Vasculitis patients should receive standard therapy after assessment of traditional risk factors

as there is currently no evidence to support escalation of therapy in this population. However,

the awareness of the higher risk status of CVD in these patients means that risk factors should

be rigorously addressed and modified. (exercise/ weight/ BP/ smoking/ cholesterol)

Due to steroid exposure in this population the increased risk of GI blood loss associated with

concurrent aspirin prescription should be borne in mind.

Awareness of the risk of the increased risk of VTEs is important in this population, with standard

VTE prophylaxis being used if there is any loss of mobility.

Vasculitis patients having had more than one VTE should receive life-long anticoagulation.

There is no evidence to support the role of aspirin in VTE prophylaxis

Vitamin D levels should be checked at baseline with replacement and maintenance therapy

prescribed as required. Recheck levels 3-6 months post replacement, thereafter not required.

Awareness is required in interpreting results for the seasonal variation in vitamin D levels.

In pts with advanced renal impairment (CKD 4 and 5) there is limited safety data for

bisphosphonates which should not be routinely used.

Specialist management of their (CKD 4 and 5) bone disease is required.

Other unlicensed treatments for steroid induced osteoporosis may be considered.

Teriperatide may be considered within the remit of the NICE guidelines

Caution should be advised in the prescription of bisphosphonates to women of childbearing

age- it is unusual for premenopausal females to require bisphosphonates.

Ensure adequate calcium and vitamin D nutrition in pregnancy.

Outside of pregnancy (where they are contra-indicated), if bisphosphonates are prescribed

ensure adequate calcium and vitamin D by checking levels and nutritional intake. Dietetic

review may be required to ensure this.

DEXA scanning in CKD 4/5 may not provide valid information

DEXA should be performed:

· If assessing risk with a view to starting bisphosphonate therapy

· If > 50 on steroids/ no fracture

· Repeat 18-36 months following above.* or according to NOGG recommendations 2014

PJP prophylaxis is recommended during induction therapy and with reintroduction of therapy

for relapse

110

Co-trimoxazole should be first line (with discussion of other options if not tolerated/

contraindicated in text)

There are no evidence based biomarkers of risk of PJP in AAV, however, prolonged high dose

steroids should be recognised as a risk factor.

Education of pts with regards to risk of infection and potential symptoms is key in conjunction

with prescription of prophylaxis

PJP prophylaxis should be continued for 6 months post Rituximab.

There is no consensus as to the duration of continuation of prophylaxis post cyclophosphamide

however it would seem reasonable to follow the guidance for Rituximab (i.e. consider

continuing for 6 months post cessation of cyclophosphamide in those felt to be high risk).

Clinicians should be aware of other potential markers of immunosuppressed status, including

the development of opportunistic infections such as warts, thrush and shingles. These patients

may benefit from more detailed profiling of their immune status such as measurement of

lymphocyte subsets.

However, there is no evidence in this population to support a CD4 count below which PJP

prophylaxis is recommended.

Vaccination ('flu, pneumococcal, other as indicated) should be undertaken where possible,

ideally 6 weeks and at least 2 weeks prior to Rituximab

We recommend ‘flu vaccination for all pts- including those undergoing induction therapy with

Rx/cyclophos (where usual ‘flu vaccination season falls during the pts induction regime)

There is good evidence that vaccination does not cause disease relapse

We advise education of patients and primary care to encourage early presentation and

treatment for immunosuppressed pts at risk during flu epidemic with ‘flu like symptoms.

Latent TB- screening and treatment as per BTS guidelines

Monitoring of Ig levels pre/ post induction therapy may be helpful in those pts who develop

infections as a complication of therapy.

Individual investigation of the pt who declares themselves at risk of recurrent infection should

be assessed with regards to immunosuppression and immune status

The evidence in other immunosuppressed pts does not support topical, non- absorbed fungal

prophylaxis, such as topical nystatin and amphotericin.

For pts on induction therapy immunosuppression (or high dose steroids for relapse) or pts with

an episode of candidiasis/previous candidiasis may require prophylaxis with a therapy of

proven efficacy such as fluconazole.

111

Pretesting of varicella zoster immunity should be carried out prior to commencement of

immunotherapy. However, one should be aware that pts immune status may change following

exposure to immunosuppression.

Exposure to varicella in the immunosuppressed pt should necessitate early presentation for

assessment of varicella immune status and need for pre-emptive therapy (VZV Ig hyperimmune

or consideration of antivirals in situations where Ig cannot be used)

Current UK recommendations from the Green Book state Varicella Zoster vaccine is

contraindicated in immunosuppressed patient as a live vaccine, however, there is evidence to

suggest administration may be safe in those on low dose immunosuppression ( e.g. less than

20mg/ day prednisolone)

Measurement of Haemophilus iinfluenzae B immunity (ab) may not be helpful as this is against

non- typable strains. We therefore do not recommend routine ab measurement and

immunisations but there may be benefits for those travelling overseas. The Hib vaccine is

immunogenic and safe.

Serotype-specific Pneumococcal IgG antibody monitoring may be relevant for assessing immune

response to vaccination.

WHO guidelines state that protective antibody levels to pneumococcus are regarded as

antibodies to 2/3 of serotypes ≥ 0.35 µg/mL. However, there is no evidence base or consensus

as to whether this is useful in guiding further immunisation.

112

4.8 APPENDIX 4. SUMMARY OF MAIN CONSENSUS STATEMENT AND LEVELS OF

CONSENSUS

Statement Round reaching consensus

Level of consensus

%

There is no robust evidence that there is a safe dose of cyclophosphamide that would completely eradicate risk of infertility

2 87

In the absence of life threatening disease cyclophosphamide should be avoided in women and men of child-bearing potential.

4

Advice should be given regarding the severe effect that kidney failure has on fertility and of the importance of not using a "soft touch" for organ threatening disease

2 88

There is emerging data that pregnancy may be safe in the months following Rituximab exposure

4

However, until more data is available patients should be counselled to avoid pregnancy post Rituximab exposure for 12 months.

4

Patients exposed to Rituximab in the preceding 12 months should be referred for discussion in a specialised joint obstetric/ rheum or renal clinic.

4

Links with the appropriate local reproductive health departments should be established, including urgent referral pathways should be available, particularly for sperm banking for those patients who present acutely requiring rapid treatment.

2 94

Men should be offered the chance to store sperm if they wish before starting cyclophosphamide (as long as it does not interfere with medically urgent therapy).

2 94

Oocyte retrieval in unwell females with active vasculitis is not currently feasible.

2 92

All vasculitis patients of future child- bearing potential should be considered for referral for sperm banking/ egg retrieval including those treated with Rituximab due to the potential for future exposure to cyclophosphamide.

4

Individual cases, such as sperm banking following exposure to 1 or 2 doses of cyclophosphamide or for patients who are physically incapable of sperm banking should be discussed with the local reproductive health department

4

There is insufficient evidence to routinely recommend the use of GnRH agonists/ GnRH analogues/or OCP to protect fertility. This requires prospective studies

4

113


Level of consensus

A large previous cyclophosphamide load (e.g.>15g) is a relative contraindication to further cyclophosphamide treatment

3 92%

Patients with non- life threatening relapsing disease and previous treatment with cyclophosphamide should avoid further exposure to cyclophosphamide i.e. consider Rituximab treatment. This is supported by current funding policies for Rituximab.

4

Patients exposed to pulsed intravenous cyclophosphamide should receive:

4

· Pre-hydration where possible

· Mesna 4

Recent EUVAS data suggests no significant increase risk of cancer *with the current low doses of cyclophosphamide although further follow up will be necessary. *except non- melanoma skin cancer

2 85

All patients should be encouraged to attend for routine age and gender determined population cancer screening

2 94

All patient on immunosuppression require sun protection and regular (annual) skin screening

3 94

The patient’s history (including family and repeated history of high level of UV exposure early in life e.g. living abroad) should be taken into account regarding skin cancer risk

2 88

The avoidance of tanning beds should be advised. 2 94

Patients should be educated to perform self-checking for skin cancer with knowledge of the appropriate place to present to for further investigation.

2 89

The educated patient and GP may be better placed to perform regular (annual) skin screening than the clinician in the vasculitis clinic. However, patients with skin lesions require regular appropriate follow- up (i.e. dermatology).

4

Urinalysis for blood at every hospital visit (at least 12 monthly) 2 94

with cystoscopy and cytology assessment in any cyclophosphamide patient with persistent haematuria

2 88

Cervical screening should be carried out annually for first 3 years then as per population (see BSR guidelines).

4

Patients should be warned in advance of cyclophosphamide exposure regarding the potential increase in CIN changes on cervical screening.

4

114


Level of consensus

CVD assessment should be carried out annually 2 94

with smoking cessation critical. 2 95

The rheumatoid arthritis model of multiplying traditional CV risk by 1.5 may not be appropriate for this population. AAV may be more comparable to the lupus population but more data is required.

4

Vasculitis and the therapy, particularly steroids appear to be risk factors for cardiovascular disease. Therefore to manage these risk factors the disease should be appropriately treated and unnecessary steroid exposure avoided

4

Early identification of CKD in this group is imperative due to the additional risk of cardiovascular disease this confers

4

Awareness of increased CVD risk in Vasculitis should be raised in both primary and secondary care and to the patient.

4

Vasculitis patients should receive standard therapy after assessment of traditional risk factors as there is currently no evidence to support escalation of therapy in this population. However, the awareness of the higher risk status of CVD in these patients means that risk factors should be rigorously addressed and modified. (exercise/ weight/ BP/ smoking/ cholesterol)

4

Due to steroid exposure in this population the increased risk of GI blood loss associated with concurrent aspirin prescription should be borne in mind.

4

Awareness of the risk of the increased risk of VTEs is important in this population, with standard VTE prophylaxis being used if there is any loss of mobility.

4

There is no evidence to support the role of aspirin in VTE prophylaxis.

4

115


Level of consensus

Steroid exposure should be minimised. 2 94

Vitamin D levels should be checked at baseline with replacement and maintenance therapy prescribed as required. Recheck levels 3-6 months post replacement, thereafter not required.

4

Awareness is required in interpreting results for the seasonal variation in vitamin D levels.

4

Patients should have overall fracture risk assessed rather than just BMD.

2 81

DEXA scanning in CKD 4/5 may not provide valid information 4

DEXA should be performed:

· If assessing risk with a view to starting bisphosphonate therapy:

4

· If > 50 on steroids/ no fracture 4

· Repeat 18-36 months following above.* or according to NOGG recommendations 2014

4

Treatment with Denosumab (not licensed) should be considered for use in patients where bisphosphonates have been contraindicated

2 86

Patients should always be counselled regarding the potential side effect of bisphosphonates (osteonecrosis of the jaw, avascular necrosis of the hip and “frozen bone”/subtrochanteric hip fracture) prior to commencing therapy.

2 94

In pts with advanced renal impairment (CKD 4 and 5) there is limited safety data for bisphosphonates which should not be routinely used.

4

Specialist management of their (CKD 4 and 5) bone disease is required.

4

Other unlicensed treatments for steroid induced osteoporosis may be considered.

4

Teriperatide may be considered within the remit of the NICE guidelines

4

Caution should be advised in the prescription of bisphosphonates to women of childbearing age- it is unusual for premenopausal females to require bisphosphonates.

4

Ensure adequate calcium and vitamin D nutrition in pregnancy. 4

Outside of pregnancy (where they are contra-indicated), if bisphosphonates are prescribed ensure adequate calcium and vitamin D by checking levels and nutritional intake. Dietetic review may be required to ensure this.

4

116


Level of consensus

Rituximab may be used in those felt to be at high risk of infectious complications or those with evidence of marrow fragility.

2 85

PJP prophylaxis is recommended during induction therapy and with reintroduction of therapy for relapse

4

Co-trimoxazole should be first line (with discussion of other options if not tolerated/ contraindicated in text)

4

There are no evidence based biomarkers of risk of PJP in AAV, however, prolonged high dose steroids should be recognised as a risk factor.

4

Education of pts with regards to risk of infection and potential symptoms is key in conjunction with prescription of prophylaxis

4

PJP prophylaxis should be continued for 6 months post Rituximab.

4

There is no consensus as to the duration of continuation of prophylaxis post cyclophosphamide however it would seem reasonable to follow the guidance for Rituximab (i.e. consider continuing for 6 months post cessation of cyclophosphamide in those felt to be high risk).

4

Clinicians should be aware of other potential markers of immunosuppressed status, including the development of opportunistic infections such as warts, thrush and shingles. These patients may benefit from more detailed profiling of their immune status such as measurement of lymphocyte subsets.

4

However, there is no evidence in this population to support a CD4 count below which PJP prophylaxis is recommended.

4

Vaccination ('flu, pneumococcal, other as indicated) should be undertaken where possible, ideally 6 weeks and at least 2 weeks prior to Rituximab

4

BCG vaccine should only be give prior to immunosuppression 3 80

Hepatitis A/B vaccine should be administered for anyone with renal involvement

3 81

We recommend ‘flu vaccination for all pts- including those undergoing induction therapy with Rx/cyclophos (where usual ‘flu vaccination season falls during the pts induction regime)

4

There is good evidence that vaccination does not cause disease relapse

4

We advise education of patients and primary care to encourage early presentation and treatment for immunosuppressed pts at risk during flu epidemic with ‘flu like symptoms.

4

Latent TB- screening and treatment as per BTS guidelines 4

117

Monitoring of Ig levels pre/ post induction therapy may be helpful in those pts who develop infections as a complication of therapy.

4

Individual investigation of the pt who declares themselves at risk of recurrent infection should be assessed with regards to immunosuppression and immune status

4

The evidence in other immunosuppressed pts does not support topical, non- absorbed fungal prophylaxis, such as topical nystatin and amphotericin.

4

For pts on induction therapy immunosuppression (or high dose steroids for relapse) or pts with an episode of candidiasis/previous candidiasis may require prophylaxis with a therapy of proven efficacy such as fluconazole.

4

Pretesting of varicella zoster immunity should be carried out prior to commencement of immunotherapy. However, one should be aware that pts immune status may change following exposure to immunosuppression.

4

Exposure to varicella in the immunosuppressed patient should necessitate early presentation for assessment of varicella immune status and need for pre-emptive therapy (VZV Ig hyperimmune or consideration of antivirals in situations where Ig cannot be used)

4

Current UK recommendations from the Green Book state Varicella Zoster vaccine is contraindicated in immunosuppressed patient as a live vaccine, however, there is evidence to suggest administration may be safe in those on low dose immunosuppression ( e.g. less than 20mg/ day prednisolone)

4

Measurement of Haemophilus influenza B immunity (ab) may not be helpful as this is against non- typeable strains. We therefore do not recommend routine ab measurement and immunisations but there may be benefits for those travelling overseas. The Hib vaccine is immunogenic and safe.

4

Serotype-specific Pneumococcal IgG antibody monitoring may be relevant for assessing immune response to vaccination.

4

WHO guidelines state that protective antibody levels to pneumococcus are regarded as antibodies to 2/3 of serotypes ≥ 0.35 µg/mL. However, there is no evidence base or consensus as to whether this is useful in guiding further immunisation.

4

118

5 LITERATURE REVIEW: METHODS AND RESULTS

5.1 SEARCH STRATEGY

In parallel to the Delphi study, a review of the available literature was undertaken. This

review was undertaken with a formal search strategy as outlined below. Articles were

reviewed in a structured format for methodological and reporting quality as well as

summarising the principle findings. Articles were not graded (e.g. according to STROBE

criteria) due to the volume, breadth and heterogeneity of articles covered by this review.

The search was conducted using Ovid Medline and Embase (1946- 2016) along with a

review of the Cochrane database, National Institute for Health and Care Excellence (NICE),

Royal College of Physicians (RCP), Scottish Intercollegiate Guidelines Network (SIGN), BSR

and EULAR guidelines that may be relevant.

The searches were conducted between May and August 2016. Where searches were

conducted prior to this, they were updated during this window. The search was limited to

English language and human subjects. Single case reports and letters were discarded.

Conference abstracts were discarded if there was insufficient data to include. The full

search strategy and evidence table for each area is included below. Search strategies varied

slightly depending on the volume of literature available within the subject area. Where

data was scarce, the disease categories were widened to include others such as Systemic

Lupus Erythematosus, from which possible analogies may be drawn relevant to the

vasculitis population. Where literature was in abundance, the search terms were narrowed

in specificity to ensure only the most relevant articles were included and that the volume of

literature to be reviewed was manageable.

Literature searches were performed by three of the authors NB, DT and DC. All literature

searches, review of titles and abstracts for suitability for inclusion and extraction of

relevant data from articles will be performed by two independent reviewers prior to

publication (currently underway). Final analysis for data inclusion was performed by NB.

119

5.2 RESULTS

5.2.1 Section 1: Bone health

The questions to be answered by this section were;

1. What is the prevalence of osteoporosis in patients with ANCA Associated

Vasculitis?

2. What screening or prophylactic bone protection strategies should be carried out in

this population?

3. What treatment should patients with AAV and GIOP receive?

It was not possible to undertake a review of all the evidence for prevention and treatment

of Glucocorticoid Induced Osteoporosis (GIOP) as part of this process. Review of available

guidelines identified the following relevant national/ international guidelines.

1) National Osteoporosis Guideline Group: Guideline for the diagnosis and management of

osteoporosis in postmenopausal women and men from the age of 50 years in the UK.

Updated March 2014149.

2) Scottish Intercollegiate Guidelines Network: Management of osteoporosis and the

prevention of fragility fractures A national clinical guideline. Updated March 2015150.

3) EULAR evidence-based recommendations on the management of systemic glucocorticoid

therapy in rheumatic diseases151.

Review of references revealed that the NOGG report contained the most up –to – date

evidence with their systematic review informing the guidelines including articles published

up to and including 2012.

Therefore, the majority of recommendations were taken from this document, with a

further literature review encompassing 2012- 2016 undertaken. The evidence table from

this process is included below.

Results

The prevalence of osteoporosis in the AAV population appears to be in the region of 14-

16%67,152. However, this is likely to be in patients on prophylaxis as at least one of the

studies providing this data included compulsory use of calcium, vitamin D and

bisphosphonate therapy. Earlier data, prior to the routine use of bisphosphonates in the

prevention of GIOP reported higher rates at 21%118, perhaps indicating the possible

effectiveness of these preventative strategies.

120

Current recommendations

Patients should have overall fracture risk assessed rather than just Bone Mineral Density

(BMD) using a validated risk prediction model. The National Osteoporosis Guidelines Group

advise the following adjustments to fracture risk (multiples of FRAX probabilities) based on

UK data;

For postmenopausal women and men aged ≥50 years;

For hip fracture

• adjust by 0.65 for daily doses <2.5 mg/day prednisolone or its equivalent

• adjust by 1.20 for daily doses ≥7.5 mg/day prednisolone or its equivalent

For major osteoporotic fracture

• adjust by 0.8 for daily doses <2.5 mg/day prednisolone or its equivalent

• adjust by 1.15 for daily doses ≥7.5 mg/day prednisolone or its equivalent

Higher doses of steroids (e.g. ≥15mg prednisolone/day) may require further upward

adjustment of fracture probability.

Algorithms for determining whether BMD measurements are required are available from

the NOGG guidelines: Osteoporosis clinical guideline for prevention and treatment.

However, in general the following groups exceed the intervention threshold and should be

considered for bone protective therapy;

• women > 70yrs

• women with previous fragility fracture

• women taking >15mg prednisolone /day.

Therefore, BMD measurement is likely to be indicated prior to treatment for younger

women and men and following the recommended treatment duration (see below) for

those not in a high risk category.

GIOP prevention options include alendronic acid, risedronate or zolendronic acid for which

there is clinical trial evidence for all three150. There is now RCT evidence to support the

safety and tolerability of once yearly zolendronic acid infusion for patients on

glucocorticoids. However, this study was only above to demonstrate a significant difference

when compared with risedronate at preserving or increasing bone mineral density in men

as a subgroup153. Treatment review is recommended after 5 years for alendronate,

risedronate or ibandronate or 3 years for zolendronic acid. However, those who are high

risk should generally continue treatment without the need for review, including; those over

121

age 75 years, those with previous hip/vertebral fracture and those continuing on

prednisolone doses greater than 7.5mg/day.

5.2.2 Section 2: Cardiovascular and thromboembolic risk

The questions to be answered in this section are;

1) What is the incidence of Venous Thromboembolism (VTE) in the AAV population?

2) What is the incidence of Cardiovascular disease (CVD) in the AAV population?

3) What are the risk factors for VTE in the AAV population?

4) What are the risk factors for CVD in the AAV population?

5) Is there any evidence for strategies to reduce this risk specific to this population?

It is well recognised that all of the AAV may present or relapse with cardiac involvement.

This can range from direct inflammation of the coronary arteries to eosinophilic or

granulomatous infiltration of the myocardium in EGPA or GPA. Due to the high rate of

cardiac involvement in EGPA, to include cardiac involvement as part of the primary disease

manifestations is not possible within this review. Therefore, articles were limited for

inclusion in the below narrative synthesis of evidence if cardiovascular disease was

reported as an outcome rather than a disease manifestation.

Thromboembolic Risk

The rate of VTE has been reported variably in the literature with interest in this area having

been primarily provoked by the observation of a high number of VTEs in the WGET clinical

trial154. This study reported 29 of 180 patients (16%) with GPA developing a VTE. Of these,

16 occurred in patients with no history of VTE giving an incidence rate of 7.0 per

100/person years. In addition, this was one of the first studies to report the observation

between VTEs and vasculitis disease activity, with the median time from active disease to

VTE being 2.07 months in this trial. Subsequent reports of VTE rates in this population

range from 1.84/100/person years in all follow up increasing to 7.26/100/person years in

periods of disease activity155, with significant associations to VTE development reported as

older age at time of vasculitis diagnosis, male sex, previous VTE, nephrotic range

proteinuria >3 g/24 h and/or stroke with motor deficit. A further study has reported

122

outcomes corresponding to an incidence rate of 4.3 per 100 person- years during all follow-

up156. However, it must be noted that these studies are retrospective cohort studies.

Some have attempted to draw comparisons of the rate of VTEs with other “at risk”

populations with a systemic lupus VTE incidence rate of 1.0 per 100/person years and those

having had a previous VTE having an incidence rate of recurrent VTE of 7.20 per 100/

person years. However, the definitions and methods of identification of VTEs in these

studies were different making them unsuitable for direct comparison154. One systematic

review has specifically addressed the rate of arterial and venous thromboembolism in EGPA

reporting arterial event rates at between 3.1 and 18.7% and VTEs at 5.8- 30%157.

In summary it is now widely accepted and clearly reported that patient with AAV have a

higher rate of VTE than anticipated and that this risk is highest during periods of disease

activity. Postulated mechanisms to explain this include the contribution of endothelial cell

dysfunction, neutrophil activation (NETosis), and the demonstrated presence of anti-

plasminogen antibodies associated with active disease113,158.

Cardiovascular risk

The first studies to evaluate the relationship between AAV and CVD disease included small

groups of patients, usually with a matched control population, and looked at surrogate

markers for cardiovascular disease such as common carotid intimal medical thickness,

ultrasound vascular plaque detection and Ankle-brachial pressure index (ABPI)159–161. These

all showed that patients with vasculitis had higher rates of atherosclerotic disease, as

detected by these surrogate methods. Some, in addition, were able to demonstrate a

relationship with cumulative relapses and atherosclerotic burden.

Although there was initial data reported at conferences in 2002-3 of an increased incidence

of CVD in vasculitis patients, perhaps the most convincing data was published as recently as

2009. This year saw data from a UK cohort with AAV, matched to CKD controls,

demonstrating a HR for CV events of 2.23. Risk factors for events included a history of CVD,

ever having required dialysis, ever having smoked, male sex, age, and (lower)cholesterol at

presentation115. Alongside this, a large Danish retrospective cohort study reported an

observed to expected event rate of 1.9 for patients with GPA compared with the

background population114.

123

The recent reporting of the EUVAS combined clinical trials contributed further data by

reporting that after the first year (following diagnosis) CVD is primary cause of death at

25.7% in this population98.

Subsequent analysis of the events in these trials has served to produce a model for

predicting CV events in the AAV population from the time of diagnosis. This model

identified independent risk factors as age> 72.4 years, absence of PR3 antibody and

diastolic hypertension >90mmHg116. It should be borne in mind that the reason for data

being available on diastolic as opposed to systolic hypertension is that the presence of

diastolic hypertension is a scoring item on the Birmingham Vasculitis Activity Score.

Therefore, all patients being scored as having diastolic hypertension had this attributed to

active vasculitis. It is possible that there were patients with pre-existing hypertension who

would not have been captured by this categorisation.

For both VTE and CVD events, there is no trial based evidence to support prophylactic

measures over and above current recommendations for the general population.

5.2.3 Section 3: Cancer Risk

1) What is the risk of cancer for patients diagnosed with AAV?

2) Is there a “safe” dose of cyclophosphamide with regards to cancer risk?

3) Do patients with AAV require additional screening for cancer, over and above

population cancer screening?

Historical data regarding the incidence of cancer in AAV stems from Hoffman’s reported

series of outcomes for 158 patients with GPA100. Cumulative cyclophosphamide doses were

high in this series, e.g. 2mg/kg/day oral therapy continued for at least 1 year after achieving

remission; this would equate to around 60g of cyclophosphamide being administered to a

60kg patient over 18 months. This study reported a 2.4-fold increase in all malignancies

(compared with the background population), with a 33-fold increase in bladder cancer and

an 11-fold increase in lymphomas. However, the most recent data from this population

suggests that this risk has significantly diminished with more recent SIRs of 3.6- 7.2

reported for bladder cancer and SIR of only 1.1 for lymphoma162 . There is, in addition, a

significant increase in non- melanomatous skin cancer which the patient should be

124

counselled about with regards to appropriate sun protection and skin monitoring (SIR 2.8-

10.4)162. This apparent reduction in cancer rates would logically follow from the reduction

in cumulative cyclophosphamide exposure over time.

With regards to cyclophosphamide and bladder cancer, it has been reported that each 10g

increment in cyclophosphamide dose is associated with a doubling of the risk of bladder

cancer development, with cumulative doses of greater than 25g being associated with a

5-fold risk163. However, with regards to bladder cancer, the long latency (11-16 years after

first cyclophosphamide exposure164) needs to be borne in mind.

In addition, other populations with immune mediated disease treated with

cyclophosphamide have been reported to have a significantly increased risk of cervical

intra-epithelial neoplasia (CIN). In a study of women with SLE treated with i.v.

cyclophosphamide, the overall 3-year incidence of CIN was 9.8%. A dose relationship was

observed between cumulative cyclophosphamide dose and CIN with each increase of 1g

corresponding to a 13% increased risk of CIN (p=0.04)120. Whether this is predominantly

contributed to by the disease or the drug is not established. There is currently no data on

the rate on CIN in AAV compared with the background population. However, it would seem

prudent to ensure patients are counselled regarding the importance of attending routine

cervical screening.

5.2.4 Section 4: Fertility

1) Is there a “safe” dose of cyclophosphamide with regards to preservation of fertility

for women?

2) Is there evidence to support the recommendation of measures to try to protect

fertility for those receiving cyclophosphamide?

The risk of amenorrhea following cyclophosphamide exposure has been repeatedly

demonstrated to relate to cumulative dose and age at exposure. Ioannidis calculated the

risk of amenorrhoea for a patient receiving 15 g of CYC (5 to 10% for patients <25 years,

30% for patients aged 25 to 31 years and 90% for patients >32 years)165. Boumpas reported

100% of those with a long course of CYC (pulsed every 1-3 months, up to 24 doses) plus >

125

31 years of age developed sustained amenorrhoea versus 0% of those age < 25yrs plus

short course CYC(7 monthly pulses)166.

A comprehensive systematic review of the effectiveness of gonadotropin-releasing

hormone agonist (GnRHa) therapy for women undergoing chemotherapy for breast cancer

or lymphoproliferative disorders or those receiving cyclophosphamide for SLE was

undertaken in 2010. This included a meta-analysis of 19 prospective studies167. Fifteen of

these, including 681 patients, evaluated “fertility preservation” as defined by regular

menses or by FSH levels, following GnRHa. This analysis yielded a significant benefit for

GnRHa in preserving the menstrual cycle (RR 0.26, 95% CI 0.22–0.34). However, the three

RCTs that included pregnancy rates as outcomes failed to show an advantage for the use of

GnRHas. This review acknowledged though that the studies included had many limitations

including lack of stratification by age, different chemotherapy regimens and inaccurate

definitions of preservation of ovarian reserve.

The only data published subsequent to this is a retrospective case study of patients with

SLE, reporting a non- statistically significant increase in preservation of menses following

co-administration of GnRHas with cyclophosphamide121.

In summary, there may be benefits of co-administration of GnRHas with cyclophosphamide

but there is limited data to support this, with further RCTs required.

5.2.5 Section 5: Vaccination

1) Which vaccinations should patients with AAV routinely receive?

2) What is the optimal timing of vaccination for patients undergoing induction

therapy with cyclophosphamide or Rituximab?

Guidance for vaccination is predominantly derived from the Green Book as it is not possible

to identify and review the evidence for recommending population wide vaccination for

those on immunosuppression.

Influenza vaccine is recommended annually, within the ‘flu season. Pneumococcal

vaccination, in the form of Pneumococcal Polysaccharide Vaccine (PPV) is recommended

126

once. However, a booster after 5 years is recommended in those with “chronic renal

disease”168.

With regards to timing of vaccination, the Green Book recommends “individuals due to

commence immunosuppressive treatments, inactivated vaccines should ideally be

administered at least two weeks before commencement. In some cases this will not be

possible and therefore vaccination may be carried out at any time and re-immunisation

considered after treatment is finished and recovery has occurred”133.

Studies in the vasculitis population have evaluated firstly the safety of vaccination in

patients and secondly the response to vaccination. With regards to safety, concerns have

been raised regarding the possibility of triggering disease activity with several case reports

detailing patients who presented for the first time with vasculitis following an

immunisation169.

However, there have been 2 clinical trials (one specifically designed to answer the question

of vaccination safety) that have reported no increase in disease activity in a vasculitis

population with stable disease following vaccination against ‘flu, pneumococcus,

Haemophilus influenza and meningococcal disease170,171.

With regards to effectiveness of vaccination, initial studies evaluated the immune response

(antibody and cell mediated) to influenza vaccination in patients with AAV, finding it to be

comparable to that of a healthy control population131,172.

However, these studies excluded patients on high dose immunosuppression (prednisolone

> 30mg/day or cyclophosphamide). There is no data with regards to the effectiveness of

vaccination following cyclophosphamide in this population. However, there is significant

literature regarding the effect of Rituximab on the response to vaccination, including, at

which point following treatment, vaccination response reconstitutes.

Generally, as expected, most studies report an impaired response to vaccination following

Rtx, however, this was often not statistically significant173. One study reported that at 6 to

10 months following Rituximab patients mounted a moderate IgG response to ‘flu

vaccine174. However, one study specifically compared antibody responses in those patients

127

immunised 6 days pre-Rtx versus those immunised 6 months post-Rtx, finding that those

immunised pre- had a better B cell response to ‘flu vaccine175.

Therefore, despite PHE recommendations to immunise 2 weeks prior to therapy it might be

that vaccines given within a week prior to induction therapy will be more effective than

waiting until after therapy has completed, and in addition may provide some protection for

patients during their most vulnerable period.

5.2.6 Section 6: Infection Prophylaxis

1) Which patients should receive PJP prophylaxis and what should they receive?

2) Do patients require routine fungal or viral prophylaxis?

A recent Cochrane review concluded that PJP prophylaxis is justified for any patient

population with an event rate of greater than 6.2%176. It is difficult to ascertain the true

incidence of PJP in AAV as the more recent studies, with larger patient numbers and better

data quality recommend PJP prophylaxis (although uptake of this is not reported, making

interpretation of the rate of infection during these studies challenging)90.

However, historical data, prior to the routine recommendation of prophylaxis suggests an

incidence of 20%135. Although it could be argued that immunosuppression exposure was

much higher in this era, a more recent single study of rheumatology patients receiving

cyclophosphamide reported an annual incidence rate of 9.5% in those not receiving

prophylaxis versus 5.3% in those who did177. The 2009 EULAR guidelines “encouraged”

prophylaxis against PJP72, with the 2014 BSR guidelines suggesting prophylaxis should be

considered83. However, the more recent Canadian guidelines recommend that “prophylaxis

against pneumocystis jiroveci infection should be given to patients receiving

cyclophosphamide or Rituximab”178. With regards to recommendations for prophylaxis

following Rituximab therapy, there have been multiple case reports of PJP following

Rituximab administration. Indeed, the head to head trials of Rituximab versus

cyclophosphamide showed no significant difference in infection rates between the 2 arms

(although there were no reported cases of PJP in the RITUXVAS trial with detail of infection

not provided in the RAVE trial78,79. However, extrapolating from this, PJP prophylaxis, for at

least 6 months from the date of administration of rituximab would seem reasonable and

128

indeed this is what the FDA advises in the licensing agreement for the use of Rituximab in

AAV179.

Risk factors for the development of PjP have been reported as exposure to “high dose

steroids” (defined in some series as > 15mg day and in some as > 30mg day), low

lymphocytes (mean lymphocyte count 495/mm3 in one series180 in the patient cohort who

developed infection) or low CD4 counts, older age, worse renal function/ dialysis

dependency and lung involvement180–185.

There is the most evidence to support co-trimoxazole as a first-line agent for the prevent of

PjP176. A review of evidence appears to support that there is no significant difference in

outcome between those patients receiving “full dose” (960mg/day) and those on “low

dose” (480mg/day or 960mg alternate days) co-trimoxazole prophylaxis186.

With regards to requirements for additional prophylaxis against fungal or viral infection in

this immunocompromised population there is very little data to guide practice. Coming

back once more to the results from the combined EUVAS clinical trials, details of the

infections experienced by this population demonstrated 10% of infection was attributable

to candidiasis, 7% CMV, 4% HSV and 3% HZV90. In the French series of 113 patients with

GPA, 13 of 53 serious infections were viral (HZV, HSV, CMV) with only one candidiasis187.

With regards to data for efficacy of primary preventative viral or fungal prophylaxis, this

has to be extrapolated from other immunosuppressed populations. A review of the

evidence for prevention of candidiasis in people with immunosuppression following cancer

treatment, found that absorbed (e.g. fluconazole) or partially absorbed antifungal drugs

prevented oropharyngeal candidiasis compared with non-absorbed antifungal drugs

(nystatin or amphotericin B) which may be no more effective than placebo188. There were

insufficient studies in tissue transplant recipients to draw any conclusions. A separate

systematic review of antifungal prophylaxis in solid organ transplant recipients showed no

reduction in mortality but demonstrated a significant reduction in invasive fungal infections

for fluconazole (RR 0.28, 95% CI 0.13 to 0.57) in liver transplant recipients. The overall rate

of proven invasive fungal infections in the control arm (i.e. no prophylaxis) of these four

studies was 13% (range 4 to 23%) therefore perhaps more comparable to the AAV

population than those receiving haemopoetic stem cell transplants(HSCTs) who receive a

higher burden of immunosuppression189. However, the only data for anti-viral prophylaxis

129

arises from the HSCT population, with an RCT of acyclovir versus prophylaxis showing a

highly significant reduction in VZV disease, with no difference in adverse effects between

the 2 groups190.

In summary, the evidence supports the prescription of PjP prophylaxis for patients

receiving high dose immunosuppression, with risk factors for infection appearing to be

steroid dose, older age, worse renal function, low lymphocyte/CD4 counts and lung

involvement. There appears to be a significant burden of fungal and viral infections in this

population in addition. Although there is little evidence to support routine prescription of

prophylaxis, those at risk would likely benefit from an absorbed/ partially absorbed anti-

fungal. Equally, the prescription of acyclovir as an anti-viral appears safe and effective but

data are absent in the AAV or comparable populations.

5.3 SUMMARY

A comprehensive and structured review of the literature has been undertaken in parallel to

the Delphi study. This will allow the recommendations made to be strengthened with the

best available evidence. The guidelines formed from the combination of Delphi and

literature review are outlined in the following section.

130

5.4 APPENDIX 1: SEARCH STRATEGIES

5.4.1 Bone Health search strategy

133

5.4.2 Cardiovascular/ thromboembolic risk search strategy

135

A total of 24 articles were included in the evidence table for review

137

From these a total of 15 articles were found to be relevant for inclusion in the evidence

table below

138

5.4.3 Cancer screening search strategy

140

5.4.4 Fertility preservation search strategy

142

5.4.5 Vaccination search strategy

145

5.4.6 Pneumocystis search strategy

150

5.4.7 Viral and fungal prophylaxis search strategy

153

Search repeated with Embase. No new articles identified. After review, 9 articles were

found to be relevant and are included in the evidence tables

154

APPENDIX: EVIDENCE TABLES

Article Population Study design Comparisons Outcome Comments/quality

Long-term follow-up of a

randomized trial on 118

patients with polyarteritis

nodosa or microscopic

polyangiitis without poor-

prognosis factors. Samson M et

al.

Autoimmunity reviews. 13

(2):197-205, 2014152.

118 pts between

November 1993 and

January

2005, and treated in

France and the UK with

PAN or MPA

Long-term

outcomes

reported from

RCT

Mean ± SD overall follow-up was 98.2 ±

41.9 months. Primary outcomes, relapse,

remission, death. No comparisons between

groups made. Patients received initial

treatment with oral prednisone (1

mg/kg/day for 3 weeks tapered by 5 mg

every 10 days to a dosage of 0.5 mg/kg/day,

then by 2.5 mg every 10 days

until a dosage of 15 mg/day was obtained

and, finally, by 1 mg

every 10 days to the minimal effective dose

or, when possible,

until definitive withdrawal.

Calcium, vitamin D3, and

Bisphosphonates adjuvant treatment was

compulsory.

16% of patients had osteoporosis documented

at follow-up

Population are those with

non- severe disease. Also

57/124 had PAN. Need to

refer to original article for

steroid regime and

prophylaxis. Little discussion

of limitations.

Damage in the ANCA-associated

vasculitides: long-term data

from the European vasculitis

study group (EUVAS)

therapeutic trials.

Robson J et al.

Annals of the Rheumatic

Diseases. 74(1):177-84, 201567 .

GPA /MPA pts

recruited to 4 RCTs

Long-term

follow- up

reporting from

RCTs

Outcomes reported according GPA vs MPA

mean length of glucocorticoid use being

40.4 months

Osteoporosis in 15.6% (MPA) and 14.4% (GPA)

pts at LTFU (mean 87 months). Four hundred

and sixty-seven patients (87.3% of the 535) had

data at LTFU.

Good discussion of study

limitations and

acknowledgement of absent

LTFU data. No data on

steroid doses just duration

or osteoporosis prophylaxis

Bone protection evidence

155

Prevalence of reduced bone

mineral density in patients with

anti-neutrophil cytoplasmic

antibody associated vasculitis

and the role of

immunosuppressive therapy: a

cross-sectional study.

Boomsma M et al. Osteoporosis

International. 13(1):74-82,

2002118.

Ninety-nine

consecutive patients

(48 men, 51 women)

with a mean (SD) age

of 55 (16) years Pts

with MPO or PR3

assoc. vasculitis in

single centre under

follow-up between

January 1998 and

December 1999 During

high-dose CS

treatment, all patients

received calcium

carbonate combined

with alphacalcidol or

dihydrotachysterol

therapy

Cross-sectional

cohort study

Measurement of

BMD of the proximal femur, lumbar spine

and radius were measured by DXA .Sixty-

nine patients were treated with 10.7 g

(median cumulative dose; range 0.4–67.2g)

of CS

Overall, 21 of 99 (21%) patients had BMD values

indicating osteoporosis as defined by the WHO

criteria (BMD T-score: <–2.5 SD) and 56 of 99

(57%) patients had osteopenia (WHO; BMD T-

score: –1 SD to –2.5 SD) at least at one site. In 22

of 99 (22%) patients normal BMD (WHO; BMD T-

score >–1.0 SD) values were measured at all

three sites.

Fracture rate 8%

Control values for

comparison extracted from

the general population

(no study control data)

A meta-analysis of alendronate

for the prevention and

treatment of glucocorticoid-

induced osteoporosis. Yang L,

Tian JH, He ZY, Tang XL, Yang

KH. Chinese Journal of Internal

Medicine. 2013;52(10):838-

843191.

(DARE abstract only as article in

Chinese)

Seven studies with

1111 patients were

included

Meta-analysis

PubMed,

EMBASE,

Cochrane

Library, Web of

Science,

Chinese

BioMedical

Literature

Database (CBM)

and Wanfang

Alendronate vs placebo on the outcomes of

BMD and fracture rate

Compared with placebo, alendronate

significantly increased bone mineral density

(BMD) at the lumbar spine[MD = 3.35, 95%CI

(2.67-4.02), P = 0.000] and the femoral neck[MD

= 1.90, 95%CI (0.89-2.92), P = 0.000] after 12

months of therapy. After 24 months of therapy,

alendronate significantly increased BMD at the

lumbar spine[MD = 3.91, 95%CI (2.37-5.45), P =

0.000], but not at the femoral neck[MD = 1.91,

95%CI (-1.15-5.02), P = 0.22]. Compared with

placebo, no significant reduction was found by

156

Data were

searched for all

randomized

controlled trials

(RCT) of

alendronate vs.

placebo.

the use of alendronate in the incidence of

vertebral fractures [RR = 1.00, 95%CI (0.49-2.07),

P = 0.99] or nonvertebral fractures [RR = 1.02,

95%CI (0.49-2.14), P = 0.95]. No difference was

shown with the adverse event between the two

groups[RR = 0.97, 95%CI (0.90-1.05), P = 0.47].

Effect on bone turnover

markers of once-yearly

intravenous infusion of

zoledronic acid versus daily oral

risedronate in patients treated

with glucocorticoids.

Devogelaer JP, Sambrook P,

Reid DM, Goemaere S, Ish-

Shalom S, Collette J, Su G, Bucci-

Rechtweg C, Papanastasiou P,

Reginster JY

Rheumatology (Oxford,

England). 52(6):1058-69,

2013192.

833 patients (771

completed trial) 18 and

85 years (54 centres/16

countries) being

treated with at least

7.5 mg oral prednisone

daily (or equivalent)

and expected to

continue GCs for at

least another 12

months.

Pts with creat

clearance < 30mls/min

were excluded

Randomised

controlled trial

(double blind-

double dummy)

Non- inferiority study comparing once-

yearly i.v. infusion of ZOL 5mg and daily oral

placebo capsules or daily oral RIS 5mg

capsules and a once-yearly i.v. infusion of

placebo infusion and continuing throughout

the trial. Patients classified according to

duration pre-study GC therapy (prevention

subpopulation <=3 months, treatment

subpopulation >3 months), gender (male

and female) and menopausal status in

females (premenopausal and post-

menopausal).

Outcomes- bone turnover markers 3,6,12

months

Once-yearly i.v. infusion of ZOL 5 mg was well

tolerated in different subgroups of GIO patients.

ZOL was non-inferior to RIS and even superior to

RIS in the response of BTMs in GIO patients.

Post hoc analysis of original

RCT. Randomisation

methods not discussed but

have been in original article.

Limitations: short duration

and not designed to evaluate

bone turnover markers in

primary analysis.

Unlikely to have direct

influence on clinical practice.

Authors comment that bone

turnover markers in these

pts suggested that

underlying inflammatory

condition rather than GCs

causing bone resorption in

this population

Bisphosphonates and

glucocorticoid osteoporosis in

men: results of a randomized

controlled trial comparing

zoledronic acid with

risedronate.

Same study as above-

subgroup analysis of

men (265 pts)

BMD and bone turnover markers- subgroup

analysis of “prevention” and treatment

arms

In the treatment subpopulation, ZOL increased L-

spine (LS) BMD by 4.7% vs. 3.3% for RIS and at

total hip (TH) the percentage changes were 1.8%

vs. 0.2%, respectively. In the prevention

subpopulation, bone loss was prevented by both

treatments. At LS the percentage changes were

“Once-yearly ZOL preserves

or increases BMD within 1

year to a greater extent than

daily RIS in men receiving

glucocorticoid therapy.”

157

Sambrook PN, Roux C,

Devogelaer JP, Saag K, Lau CS,

Reginster JY, Bucci-Rechtweg C,

Su G, Reid DM

Bone. 50(1):289-95, 2012153 .

2.5% vs. -0.2% for ZOL vs. RIS and at TH the

percentage changes were 1.1% vs. -0.4%,

respectively. ZOL significantly increased lumbar

spine BMD more than RIS at Month 12 in both

the prevention population (p=0.0024) and the

treatment subpopulation (p=0.0232) in men

Post hoc analysis of a single IV

infusion of zoledronic acid

versus daily oral risedronate on

lumbar spine bone mineral

density in different subgroups

with glucocorticoid-induced

osteoporosis.

Roux C, Reid DM, Devogelaer JP,

Saag K, Lau CS, Reginster JY,

Papanastasiou P, Bucci-

Rechtweg C, Su G, Sambrook PN

Osteoporosis international :

23(3):1083-90, 2012193

Same study as above

Once-monthly oral ibandronate

provides significant

improvement in bone mineral

density in postmenopausal

women treated with

glucocorticoids for

inflammatory rheumatic

diseases: a 12-month,

randomized, double-blind,

placebo-controlled trial.

Hakala M, Kroger H, Valleala H,

140 post menopausal

women with any

rheumatic disease

receiving 5-15mg/day

pred

Randomized,

double-blind,

placebo-

controlled,

parallel-group

study

Patients were randomized 1:1 to receive

either monthly oral ibandronate 150mg or

placebo for 12months. Primary endpoint

was the relative change in mean LS BMD

from baseline to 12 months.

Significant increases in mean LS BMD of 2.6%

and 3.2% with ibandronate and 0.3% and –0.1%

with placebo from baseline to 6 and 12 months

Reports same adverse events (rx vs placebo),

more SAE in treatment group but no single type

No discussion of those who

did not complete study.

As this was placebo

controlled, those with

severe osteopenia or

osteoporosis were excluded.

No comparison with other

bisphosphonates. Not

powered to evaluate effect

in fracture rate

158

Hienonen-Kempas T, Lehtonen-

Veromaa M, Heikkinen J,

Tuomiranta T, Hannonen P,

Paimela L, ONCE trial group

Scandinavian journal of

rheumatology. 41(4):260-6,

2012194 .

Prevention of glucocorticoid-

induced osteoporosis in

immunobullous diseases with

alendronate: a randomized,

double-blind, placebo-

controlled study.

Tee SI, Yosipovitch G, Chan YC,

Chua SH, Koh ET, Chan YH, Tan

SS, Tsou IY, Tan SH

Archives of dermatology.

148(3):307-14, 2012195 .

Abstract only available

29 pts with

immunobullous disease

(14 vs 15)

RCT- double

blind placebo

controlled

Oral alendronate sodium (10 mg/d) or a

matching placebo for 12 months on BMD at

12/12

Statistically significant increases in BMD at both

the lumbar spine (P = .01) and the femoral neck

(P = .01) with alendronate therapy. Adverse

events minor and no difference between groups

Efficacy of calcitriol in treating

glucocorticoid induced

osteoporosis in patients with

nephrotic syndrome: An open-

label, randomized controlled

study.

Chen Y, Wan J-X, Jiang D-W, Fu

B-B, Cui J, Li G-F, Chen C-M

Clinical nephrology. 84 (5):262-

9, 2015196 .

Abstract only

66 pts with nephrotic

syndrome on GCs

Open label RCT Groups were: calcitriol alone (n = 22),

calcitriol plus calcium carbonate (n = 23), or

calcium carbonate alone (n = 21). Serum

markers of bone metabolism and bone

mineral density (BMD) were tested at 3

different time points: the initiation of GC

treatment (baseline), 12 weeks, and 24

weeks after the initiation of treatment.

Patients who received calcitriol had significantly

higher BMD of the lumbar spine than patients

who received calcium carbonate alone

No data available on renal

function

159

Author, Date and Title. Target Population. Study Design. Comparisons. Outcomes. Comments and quality of evidence

Cardiovascular disease due

to accelerated

atherosclerosis in systemic

vasculitides.

Best Practice & Research

Clinical Rheumatology 27

(2013) 33–44

Terveart197

Systemic vasculitis Review (not

systematic)with

focus on

mechanisms

HDL generally decreased in systemic

vasculitis but quantative measures not

predictive of atherosclerosis in these

conditions

Pro-inflammatory HDL is increased

during prednisolone therapy of >7.5

mg day, all cholesterol (HDL/LDL and

total) increased by steroids

RR of CHD in AAV is 2-4x that of

controls. Odds ratio of CVA 3-4

Impaired endothelial function,

abnormal ABPI and increased arterial

stiffness reported in AAV

Active disease seems to correlate

with increased atherosclerosis with

this returning to normal in disease

control

Recommends most pts with systemic

vasculitis should be treated with

statins. Treatable risk factors for

statin-induced myopathy should be

addressed (e.g., vitamin D deficiency

and hypothyroidism)

“Preventive therapy for accelerated

atherosclerosis in vasculitis includes

aggressive therapy of inflammation

and an aggressive approach against

classic risk factors for cardiovascular

disease such as smoking, lack of

physical activity, obesity and

unhealthy diet”

Accelerated atherosclerosis

in patients with Wegener's

granulomatosis.

K de Leeuw et al.

Ann Rheum Dis

2005;64:753–759159.

Case control study

29 GPA pts- consecutive,

in remission, 26 controls

(age and sex matched)

Common carotid

intimal medial

thickness (IMT)

assessed by USS

Plus sCRP and

traditional CV RF

Increased IMT was a sign of

accelerated development of

atherosclerosis in WG patients,

assessed during inactive disease,

compared with controls, not

accounted for by conventional risk

factors. Interestingly number of

exacerbations of disease negatively

Overall disease burden measured by

“cumulative BVAS” not VDI.

Limited number of patients and

controls meant that multi-variate

analysis could not be undertaken.

The clinical relevance of a raised IMT

was not explored

Cardiovascular risk evidence table

160

assoc with IMT in pt group. No diff in

cumulative pred dose between those

with and without raised IMT.

Increased Incidence of

Cardiovascular Events in

Patients With

Antineutrophil Cytoplasmic

Antibody – Associated

Vasculitides A Matched-Pair

Cohort Study. Morgan et al.

Arthritis and Rheumatism.

Vol. 60, No. 11, November

2009, pp 3493–3500115.

113 AAV pts matched to

CKD patients in single

centre

Retrospective

matched cohort

study

Matched to CKD controls- age at

diagnosis within 5 years, same sex,

smoking status as ever smoked or

never smoked, previous history of a

cardiovascular disease (prior to

diagnosis of CKD or AAV), and same

CKD stage (at time of presentation for

CKD patients and at 1 year for AAV

patients).

23 cardiovascular events in the AAV

group compared with 16 events in the

CKD group. HR 2.23

Preexisting history of cardiovascular

disease ever required dialysis, ever

having smoked, male sex, age, and

(lower)cholesterol at presentation

were significant risk factors for CVD in

AAV

Matching used to address majority

of confounders.

Increased morbidity from

ischemic heart disease in

patients with Wegener's

granulomatosis.

Arthritis and Rheumatism.

M Faurschou et al.Vol. 60,

No. 4, April 2009, pp 1187–

1192114 .

Cohort of 293 Danish

patients diagnosed as

having WG between

1973 and 1999

Retrospective

cohort study

WG patients were found to have a 3.6-

fold increased risk of acute MI

occurring

<5.0 years after the date of the WG

diagnosis

2.2-fold, significantly increased risk of

IHD-associated cardiovascular events

occurring >=10 years after the

diagnosis of WG. Significantly

Acknowledges lack of statistical

power in evaluating risk IHD in

women and the young with WG.

Data not available on cumulative

steroid dose and disease activity.

161

increased risks of IHD and acute MI

were found in elderly WG patients

(defined as patients>=50 years old at

the time of WG diagnosis), in male

patients, and in patients who received

a cumulative dose of>36 gm of CYC.

The risk of IHD from the fifth to the

ninth year of follow-up matched the

risk in the background population

Long-term patient survival

in ANCA-associated

vasculitis. Flossmann et al.

Ann Rheum Dis

2011;70:488–49498.

535 MPA/GPA from 4

EUVAS clinical trials

Retrospective

analysis of

combined RCT

outcomes.

After 1st year CVD primary cause of

death 25.7%

Study quality assessed elsewhere.

A model to predict

cardiovascular events in

patients with newly

diagnosed Wegener's

granulomatosis and

microscopic polyangiitis.

Suppiah et al. Arthritis Care

& Research Vol. 63, No. 4,

April 2011, pp 588–596116.

535 pts from combined


Retrospective

analysis of

combined RCT data

to produce risk

prediction model.

CVD events in first 5 years of f/u

reviewed

Then prognostic tool created and

validated in WGET cohort

(events= non-fatal MI or CVA)

74(13.8%) of 535 patients had at least

1 CV event: 3.7 x higher than the

background population

independent risk factors established=

age> 72.4 years, absence of PR3 (MPO

positive) diastolic HTN >90

Note that diastolic HTN was defined

as being attributed to active

vasculitis (due to BVAS scoring) for

the purpose of the EUVAS studies,

but not for validation cohort.

Data not available to allow inclusion

of cholesterol or CV meds in model.

108 pts could not be included in the

development of the model due to

pre-existing CVD or missing values.

Mortality in Wegener's

granulomatosis: a bimodal

pattern. Luqmani et al.

255 pts from GPRD Retrospective

cohort study

Mortality rate, cause and pattern Identified increased risk of mortality,

highest in first year from diagnosis

then again 10-15 years from diagnosis.

Deaths at > 5 years, numbers too

small to draw any conclusions

162

Rheumatology 2011;50:697-

702198.

Major causes of death > 5years

malignancy, MI, renal and resp failure.

Translational Mini-Review

Series on Immunology of

Vascular Disease:

Accelerated atherosclerosis

in vasculitis. JC Terveart.

Clinical and Experimental

Immunology, 156: 377–385.

2009199.

Review of

association/

pathophysiology of

atherosclerosis in

vasculitis.

Not systematic r/v

no search strategy

Zaenker et al. reported that patients

with Wegener’s granulomatosis had a

higher frequency of cardiovascular

diseases compared with healthy

controls [odds ratio (OR) 6·7}In line

with these findings, patients with

ANCA-associated vasculitis more often

had stroke and/or myocardial

infarction (OR 3–4)

Conflicting reports in IMT studies

and vasodilatation studies reported.

Abnormal ABPI and arterial stiffness

reported- seems to correlate with

periods of active inflammation.

Increase in HTN DM and weight gain

all reported in AAV (likely in assoc

with GC exposure). Other RF;, CKD,

proteinuria and persistently raised

CRP.

Author suggests primary prevention

with aspirin, ACE/RB and statin.

Increased prevalence of

subclinical atherosclerosis in

patients with small-vessel

vasculitis. Chironi et al.

Heart 2007;93:96–99160.

50 consecutive pts with

PSV (mixed disease

group) recruited

between 2002-2005

matched with 2 controls

from database of 1881

pts referred to CV

preventative medicine

centre (age sex, hx of

CVD)

Case control study Pts underwent ultrasonography of

fem, carotid and aorta (abd)

looking for plaque/IMT

Traditional CV RF and inflamm

markers also measured in all pts

Following adjustment for high risk

status, plaques sig. more common in

the pts at aortic and combined 3 vessel

sties. The odds ratio of having three-

vessel plaques was 1.34 (95%

confidence interval (CI) 1.09 to 1.68)

by presence of vasculitis, 1.27 (95% CI

1.02 to 1.60) by presence of high-risk

status and 1.75 (95% CI 1.08 to 3.02)

by each increase of 1SD in CRP level.

No difference between carotid IMT

between cases and controls but diff

technique used in comparison with

other study.

Interestingly no increase in % “high

risk” pts in vasculitis group when

compared with controls suggesting

that mechanism may not be

corticosteroid mediated.

Confounders acknowledged.

However; heterogenous disease gp,

under powered and outcome

dichotomous (plaque or no- plaque)

Clinical outcomes of ANCA-

associated vasculitis in

93 consecutive AAV pts

between1998 and 2012

Retrospective single

centre cohort study.

Those over 65years compared with

those less than 65yrs

Treatment comparable across whole

cohort

Event numbers, particularly in the

younger group were low. Study

163

elderly patients. A Haris et

al.

Int Urol Nephrol (2014)

46:1595–1600200.

primary end points were all cause

mortality, mortality due to

cardiovascular disease, active vasculitis

or infections. HTN and DM more

prevalent in elderly. Main cause of

death in the elderly was CVD- this

likely due to increased prevalence of

CVD at baseline

aimed to report efficacy of a reduced

immunosuppression strategy in the

elderly not CV event rates.

Cardiac involvement in

systemic inflammatory

diseases. DC Knockaert

European Heart Journal

(2007) 28, 1797–1804201.

Systematic review

MEDLINE database

was searched for

the period January

1, 1990 through

September 2005,

using PubMed for

articles containing

‘cardiac’,

‘cardiovascular’,

‘heart disease’, and

the SIDs discussed

in this review

Search terms not fully

comprehensive and no MESH terms

used. Encompassed many SIDs so

only the data for those of interest

examined.

Predominantly reports on cardiac

involvement due to active disease

rather than CVD risk as a composite

outcome, therefore data not

included.

Risks of treatments and

long-term outcomes of

systemic ANCA-associated

vasculitis. O Flossman.

Presse Medicale. 44(6 Pt

2):e251-7, 2015202.

Informal review of

lit (conference

paper)

Studies reported are covered

elsewhere.

Factors associated with

major cardiovascular events

in patients with systemic

Forty-two patients (27

males, age 54 ± 15 yrs)

were included. SNV

Retrospective single

centre cohort

review

To identify factors predictive

of major CV events (MCVE) in

patients with SNV by analysing the

After a mean follow-up of 7.1 ± 2.6

years, 8 patients (19%) with SNV had

MCVE: 4 had myocardial infarction or

“this longitudinal follow-up indicated

that patients with SNV had 2-fold to

3-fold accelerated atherosclerosis”

164

necrotizing vasculitides:

results of a longterm

followup study.

B Terrier et al. Journal of

Rheumatology. 41(4):723-9,

2014203.

diagnoses were GPA in

20 patients, EGPA in 9,

MPA in 8, and PAN in 5.

long-term follow-up for CV risk and

subclinical atherosclerosis.

hospitalization for unstable angina, 2

underwent arterial revascularization, 1

had a stroke, and 1 died of CV causes.

Respective 5-year and 10-year MCVE

rates of 9.5% and 26.8% markedly

exceeded the expected 10-year

Framingham CV risk score (9%). PR3

neg more likely to have CVD but not

stat sig. plaque detection in abdo aorta

and CIMT was assoc with MCVE as was

being “high risk” or BMI >30

Note HTN defined in addition as “use

of antihypertensive drugs”.

Acknowledges heterogeneous group,

small numbers and lack of controls

as limitations (uses Framingham risk

scores for “expected data”)

The interface of

inflammation and

subclinical atherosclerosis in

granulomatosis with

polyangiitis (Wegener's): a

preliminary study. Hajj-Ali,

Rula A. et al. Translational

Research: The Journal Of

Laboratory & Clinical

Medicine.166(4):366-74,

2015204

N=46 GPA pts (38 in

remission, 8 with active

disease)

Case control study

(28 healthy

controls)

Classic atherosclerotic risk factors,

platelet aggregation responses, and

circulating micro- particle (MP)

levels were recorded. All patients

underwent carotid artery intima-

media thickness (IMT)

measurement as outcome for

subclinical atherosclerosis

Number of disease relapses, diastolic

blood pressure, and age at disease

onset independently correlated with

IMT in patients with GPA

Authors comment that the

correlation with disease relapses and

subclinical atherosclerosis could be

because of glucocorticoid use and

not the inflammatory process in

GPA, giving the inherent bias that

exists with the use of glucocorticoid

with each relapse.

Damage in the ANCA-

associated vasculitides:

long-term data from the

European vasculitis study

group (EUVAS) therapeutic

trials. Robson J et al.


Diseases. 74(1):177-84,

735 AAV pts enrolled in


Review of combined

LTFU (up to 7 years)

data from 6

combined EUVAS

RCTs

Comparison of damage at baseline

compared with at f/u

+ 36.7% increase in HTN from baseline.

+ 4.1% in MI, + 7.4% angina/CABG, +

3.7% CVA

165

2015205.

Atherosclerotic factors in

PR3 pulmonary vasculitis.

Zycinska, K et al. Advances

in Experimental Medicine &

Biology. 755:283-6, 2013206.

21 GPA pts Cross-sectional case

control study

Comparison of the prevalence of

traditional CV RFs between pts and

controls

Prevalence of traditional risk factors

differed significantly between the WG

patients and control subject. Patients

had higher blood pressure and body

mass index, and had a family history of

cardiovascular disease. Total

cholesterol, LDL, and TG

concentrations were all higher and

HDL was lower in the WG group

No CV outcome data provided.

Simply cross- sectional.

Risk of subsequent coronary

heart disease in patients

hospitalized for immune-

mediated diseases: a

nationwide follow-up study

from Sweden. Zöller, B et al.

PLoS ONE. 7(3):e33442,

2012207.

333 GPA pts 40 PAN Retrospective

cohort study

CHD All individuals in Sweden

hospitalized with a main diagnosis

of an IMD (n = 336,479) without

previous or coexisting, between

January 1, 1964 and December 31

2008, were followed for first

hospitalization for CHD

SIR CHD in 1st year after hospitalisation

polyarteritis nodosa 3.81 (95% CI 2.72-

5.19), GPA 2.21(1.98-2.46)

Association of cigarette

smoking with organ damage

in primary systemic

vasculitis. Mohammad, A J

Segelmark, M

Scandinavian Journal of


2011208.

86 PSV pts (46 WG, 27

MPA, four CSS, and nine

PAN)- 77 included in

analysis

Retrospective case

control study

median f/u 10

(smoker)/9.5 (non-

smoker) yrs

Comparison of damage accrual as

per VDI in AAV pts who had been

ever vs never smokers

MI- 15% of smokers/ex- smokers 0%

of never smokers

Outcomes reported for whole group

but likely to be different amongst

the disease subgroups.

Patients with Wegener's

granulomatosis: a long-term

follow-up study. De Leeuw,

K. Clinical & Experimental

23 GPA pts Prospective case

control study

Comparison IMT in pts vs controls

at 2 time points

IMT increased at both entry and f/u

but no evidence of accelerated

progression compared with controls.

Equally no evidence of increased rate

Outcomes may be explained by low

disease activity in pt group and good

control of traditional CV risk factors.

No adjustment of confounders such

166

Rheumatology. 28(1 Suppl

57):18-23, 2010209.

of progression in those with relapses

vs none.

as smoking possible due to small

numbers

Ankle-brachial pressure

index: a simple tool for

assessing cardiovascular risk

in patients with systemic

vasculitis.

Sangle, SR et al.

Rheumatology. 47(7):1058-

60, 2008161.

54 consecutive vasculitis

pts

Case control study Measurement of ABPI compared

with healthy controls

Hypertension, family history of CV

events, the elevated BMI (>25) were

significantly more common in

vasculitis patients.

The ABPI was abnormal in 11/54

(20.4%) of the SV patients and 2/49

(4%) of the control group

ABPI has been used in other

populations to predict CV outcomes

Too heterogenous a disease

population to draw any meaningful

conclusions

Atherosclerosis in ANCA-

associated vasculitides.

Pagnoux C et al.

Annals of the New York

Academy of Sciences.

1107:11-21, 2007210.

Review Zaenker and coworkers reported

(compared to healthy

controls/patients with fibromyalgia or

OA), 50 GPA patients had higher

frequency of CVD (coronary artery

disease, stroke, peripheral arterial

occlusive disease), OR 6.7 (95% CI:

1.6–31.8), and wider

ultrasonographically measured intima–

media thicknesses of common carotid

arteries and carotid bulb(previously

proven to be predictive of

cardiovascular events in other

populations).

50 patients with systemic necrotizing

vasculitides, compared to 100 sex- and

age-matched “healthy” controls.

Found no significantly different carotid

intima–media thicknesses for patients

167

and controls (0.60 vs. 0.59mm,

respectively), but patients had a higher

frequency of ultrasonographically

detected plaques in, aorta, and/or

femoral arteries, independently of

other cardiovascular risk factors

Cardiovascular events were also more

frequent, but not always significantly,

2 studies by the group on patients with

AAV reported incidence of coronary

artery disease higher (587/105

patients) in their first study on 265

patients compared to local “healthy”

subjects (133/105 inhabitants), but

was not strikingly different from that

of individuals included in the MONICA

cohort study (554/105 subjects). In

second study on 116 patients, the

odds ratio of MI was 4.0 (95% CI: 0.5–

14), stroke incidence was 414/105 for

the patients versus 130/105 for the

local “healthy” controls. Booth and

colleagues demonstrated aorta and

systemic arteries were significantly

stiffer in patients with active AAV than

controls

Accelerated atherogenesis

in autoimmune rheumatic

diseases. Bacon, Stevens,

Carruthers, Young, & Kitas.

Includes PSV plus RA and

SLE

review Reports endothelial cell dysfunction in

PSV, this has been widely reported in

other populations to be a marker of

CAD

Not systematic so not formally

appraised

168

Autoimmunity Reviews.

1(6):338-47, 2002211

Enhanced endothelium-

dependent microvascular

responses in patients with

Wegener's granulomatosis.

Neinhuis et al.

Journal of Rheumatology.

34(9):1875-81, 2007212.

28 WG patients with

inactive disease and 28

age and sex matched

controls

Case control study IMT measurement WG patients had increased IMT

compared to controls. IMT correlated

positively with age and BMI.


Inflammation and arterial

stiffness in systemic

vasculitis: a model of

vascular inflammation.

Booth AD, Wallace S,

McEniery CM, Yasmin,

Brown J, Jayne DR, et al.

Arthritis and Rheumatism

2004;50:581-8213

Thirty-one patients with

AASV (15 with

active disease) and 32

age-matched controls

Case control study Pulse wave velocity (PWV) and the

augmentation index (AIx)

No sig difference in PWV and AIx

between pts in remission and controls.

AIx was sig different between patients

with active disease and in remission

Authors conclude that arterial

stiffness in AAV may be “modifiable”

as correlates with inflammation as

opposed to disease.

Small numbers, controls matched on

age only but no sig difference across

groups reported.

169

Author, Date and Title. Target Population. Study Design. Comparisons. Outcomes. Comments and quality of evidence

Best Practice & Research

Clinical Rheumatology 27

(2013) 57–67. Thrombosis in

vasculitis, Gaffo214.

AAV pts Review of the

literature. Not

systematic- no

search strategy

detailed. Reviews 4

studies in AAV- see

comments

7 VTEs over 100 pt/yrs in WGET

trial sparked interest- VTEs

usually occurring during

episodes of active disease.

Weidner 2006, 4.3

episodes/100pt yrs. 81% during

active episodes. Stassen-

1.8/100ptyrs increasing to

6.7/100/pt years if only periods

of active disease included.

French study 1.58 increasing to

7.26 for active disease. Risk

factors: older age at diagnosis,

male sex, history of prior VTE

and history of stroke with

motor deficiency

Bham CV events HR 2.23 when

c/ CKD matched controls- CVD

papers reviewed elsewhere

Multiple references obtained .

Not a systematic review so not formally

appraised

Venous thromboembolism

with concurrent pulmonary

haemorrhage in systemic

vasculitis

E de Sousa et al. Nephrol

Dial Transplant (2012) 27:

Retrospective cohort

study. (sequential pts

with PH referred to a

single unit)35 pts with

PH. 7/35 (20%) had VTE.

(AAV in 4/7)

Majority of concurrent PH and

VTEs were in initial

presentations responding to

PLEX. No worsening of PH

occurred in 5/6 with anti-coag

but precipitated PH in the 6th.

Small descriptive study highlighting a clinical

conundrum

Thromboembolic risk evidence table

170

4357–4361215. Anti-plasminogen antibodies

may explain this increased risk.

Conventional

immunomodulation and anti-

coag effective in all but 1

High frequency of venous

thromboembolic events in

Churg-Strauss syndrome,

Wegener's granulomatosis

and microscopic polyangiitis

but not polyarteritis

nodosa: a systematic

retrospective study on 1130

patients. Y Allenbach et al.

Ann Rheum Dis

2009;68:564–567155.

1130 pts EGPA,GPA,PAN

and MPA enrolled in

FVSG between 1989 and

2006

Retrospective

cohort study. VTE

included if in 6/12

prior to or following

diag. Events and

characteristics of

study group clearly

defined.

Characteristics of non VTE gp vs

VTE gp using multi and univariate

analyses.

83 VTEs in 74 pts (6.5% of all

pts).Fifty-seven (68.7%) of the

VTE occurred within 3 months

before the SNV diagnosis or 6

months after (n=42), or a

relapse (n=15). Rate of 7.26 per

100 person-years for AAV

during this period (1.84

throughout all f/up). At first

VTE diagnosis, mean BVAS was

12.6 (10.5) and mean CRP was

67.0 (80.9) mg/l. Older age at

SNV diagnosis (p=0.002), male

sex (p=0.04), previous VTE

(p=0.02), nephrotic range

proteinuria >3 g/24 h (p=0.03)

and/or stroke with motor

deficit (p=0.03) were

significantly associated with

VTE.

Reports increased risk of VTE in AAV, assoc.

with periods of disease activity and risk

factors identified through multi-variate

analysis.

Eosinophilia and

thrombophilia in Churg

Strauss syndrome: a clinical

and pathogenetic overview.

Ames, P. R. J.

Reviewed all literature

1951 to 2010 reported

thrombotic episodes in

EGPA

Systematic review.

Pubmed, Embase

and google search.

Search strategy

clearly defined. Case

18 case series,

24 pt case reports. However,

primary aim of all bar one series

was to report clinical

manifestations of disease therefore

Reported prevalence of 3.1-

30% arterial or venous TE in

EGPA.

Arterial 3.1-18.7, venous 5.8-

30%

Fairly robust review of all VTEs reported in

associated with EGPA. Suggestion that VTEs

may be more prevalent in ANCA negative

disease with tissue infiltration by eosinophils.

Highlight that VTEs likely underreported

171

Margaglione, M.

Mackie, S.

Delgado Alves, J.

Clinical and Applied

Thrombosis/Hemostasis

16(6) 628-636. 2010157

reports and series

reviewed.

likely underestimating prevalence before possible association with AAV became

known

Brief communication: high

incidence of venous

thrombotic events among

patients with Wegener

granulomatosis: the

Wegener’s Clinical

Occurrence of Thrombosis

(WeCLOT) Study. Merkel PA,

Lo GH, Holbrook JT Ann

Intern Med. 2005;142:620–

6154.

180 pts enrolled in the

WGET trial

RCT (subgroup

analysis- cohort

study)

29 of 180 patients (16%) with

WG had had a VTE at some

point. The 16 new VTEs in 167

patients with no history VTE

occurred over 228 person-years

(incidence rate 7.0 per 100

person-years).

Median time fromm active

disease to VTE was 2.07

months.

For 13 of 16 patients (81%) who

had VTEs during WGET, AAV

was active at the time of the

event or within 2 months

before the event.

Otherwise age was only risk

factor for VTE.

Comparison with baseline in

population- healthy same age

Swedes incidence rate of first

VTE of 0.31 per 100 person-

years.

Lupus VTE incidence rate of 1.0

per 100 person-years

However, rate of VTEs in comparison

populations were defined and identified

differently so not truly comparable.

172

Previous VTE: incidence rate of

recurrent VTE of 7.20 per 100

person-years

Thromboembolic events as

a complication of

antineutrophil cytoplasmic

antibody- associated

vasculitis. Weidner S,

Hafezi-Rachti S, Rupprecht

HD. Arthritis Rheum.

2006;55:146–9156.

Review of records of 105

incident pts with SVV in

a single centre 1986-

2001.

All pts had renal

involvement.

Retrospective

cohort review

13 VTEs in 105 pts in active

phase of disease (3 Pes when

pts in remission).

In summary, during

retrospective follow-up of 105

patients, 16 VTEs occurred over

367.5 person-years of

observation, corresponding to

an incidence rate of 4.3 per 100

person- years (95% confidence

interval 1.6–10.2).

Patients observed to be

predominantly PR3 positive

No data available on those pts who did not

develop VTEs making derivation of

associations impossible.

Small numbers and essentially a descriptive

case series

Venous thromboembolism

in ANCA-associated

vasculitis—incidence and

risk factors. Stassen et al.

Rheumatology 2008;47:530–

534112.

198 AAV pts diagnosed

1990-2005

Retrospective

cohort study plus

patient

questionnaire

VTEs counted if 3/12 prior to or

after diagnosis.

52% VTEs occurred in 3/12

prior- 3/12 post diagnosis (total

no VTEs= 23)

The incidence of VTE during

Those with GPA/PR3 were less likely to have

VTEs in this study.

Some acknowledgement of limitations

through retrospective study design and an

attempt to address this through pt

questionnaire though no comment on the

173

active disease was 6.7/100

person-years compared with

1.0/100 person-years inactive.

Overall found an increased

incidence of VTE just prior to

and after the diagnosis of AAV

of 1.8/100 person-years,

compared with 0.3 in a healthy

population of the same age

fallibility of pt recollection.

Consensus task force

recommendations for

evaluation and

management of eosinophilic

granulomatosis with

polyangiitis syndrome.

(Churg-Strauss). Groh et al.

Europ J Int Med. 28 (4) (pp

321-326), 2015216

Venous thromboembolic

events (VTE) and pulmonary

embolism

should be treated according to

general guidelines for the

management

of thromboembolic disease; it

is unknown whether

anticoagulation should be

prolonged in selected patients

with persistent

or recurring disease activity

Do neutrophil extracellular

traps contribute to the

heightened risk of

thrombosis in inflammatory

diseases? Rao et al.

World Journal of Cardiology.

7 (12) (pp 829-842), 2015217

Mechanistic review New ref. NETs may contribute

to thrombosis is AAV and other

diseases

A meta-analysis of the risk

of venous

Meta-analysis up to

June 2014

4 studies of AAV(N =16,295)

resulted in VTE cumulative

No new refs

Search limited to full text English language

174

thromboembolism in


diseases. Lee JJ, Pope

JE.Arthritis Res Ther.

2014;16:435218

MEDLINE,

Embase, PubMed

and the Cochrane

databases

incidence of 7.97% (95% CI:

5.67% to 10.28%). (compared

with 7.29% for SLE)

papers.

Descriptive statistics only on AAV pts- not

included in meta-analysis

Thrombosis in vasculitis:

From pathogenesis to

treatment. Emmi et al.

Thrombosis Journal. 13 (1),

2015. Article Number: 15158

NETs are able to promote

thrombosis by inhibiting the TF

pathway inhibitor and by

recruiting platelets Engelmann

B, Massberg S. Thrombosis as

an intravascular effector of

innate immunity. Nat Rev

Immunol. 2013;13:34–45.

Thrombosis in vasculitic

disorders-clinical

manifestations,

pathogenesis and

management. Katz, Brenner

& Horowitz.

Thrombosis Research.

136(3):504-12, 2015219

1 new ref

High risk of pulmonary

embolism and deep venous

thrombosis but not of

stroke in granulomatosis

with polyangiitis

(Wegener's). Faurschou,

Obel, & Baslund. Arthritis

care & research.

66(12):1910-4, 2014220.

180 prevalent Danish

GPA pts 1993-2011

Case control study Controls 19:1 age and sex matched The occurrence of VTEs was

substantially increased in GPA

patients during first 2 years of

followup, with IRR estimates

for PE and DVT of 25.7 and

20.2, respectively. No increase

in CVA compared with controls

175

Risk of pulmonary embolism

in patients with

autoimmune disorders: a

nationwide follow-up study

from Sweden. Zöller, Li,

Sundquist, & Sundquist.

Lancet. 379(9812):244-9,

2012221.

Pts without VTE at

inception and

autoimmune disease

15085 GPA

Retrospective case

control study

Incidence PE in autoimmune

disorders compared with reference

group (remainder of population)

SIR for hospital admission for

PE in GPA 6.57 in 1st year

Clinical and laboratory

characteristics of 19

patients with Churg-Strauss

syndrome from a single

South Australian centre.

Whyte AF, Smith WB, Sinkar

SN, Kette FE, Hissaria P.

Intern Med J. 2013;43:784–

90222

EGPA case series Single centre case

series

Thrombosis was a feature at

diagnosis in six patients

(31.6%): two patients had PE,

one had

thrombosis of subclavian,

internal jugular and external

jugular veins, one had internal

capsule ischaemic

stroke, one had internal jugular

and lower limb deep vein

thrombosis (DVT) and one had

lower limb DVT only.

Two had recurrence of DVT

with relapse of vasculitis. One

patient had a past history

of DVT.

176

Article Study population Study Design Comparisons Outcomes Comments

Rituximab versus

Azathioprine for

maintenance in ANCA-

associated vasculitis.

Guillevin et al. NEJM

2014;371(19):1771-178086.

115 patients with newly

diagnosed or relapsing AAV in

complete remission after

combined treatment with GC

and pulse CYC

Open label randomized

controlled trial

1:1 randomisation to

maintenance treatment with

Rtx (every 6 months until

month 18) or AZA (daily oral

until month 22). Follow up

until month 28.

2 patients developed a

malignancy in the AZA group

and 1 patient in the Rtx

treated group

Small number of malignancies

and short duration of follow

up preclude adequate

conclusions to be drawn in

terms of risk of malignancy

associated with AZA versus

Rtx in AAV.

Survival of patients with

ANCA-associated vasculitis

on chronic dialysis: data from

the French REIN registry from

2002 to Romeu et al.

2011.QJM 2014;107(7):545-

55223.

425 patients with MPA or

GPA that commenced chronic

dialysis between 2002 and

2011 – single centre.

Prospective observational

data collection

Matched non-AAV dialysis

group of 794 patients

Higher percentage of deaths

from malignancy in control

group compared to AAV

group (15% vs. 4%, p=0.001)

Cancer under-represented in

AAV group potentially due to

short follow up (median 23

months). No information

provided on type / duration

of immunosuppressive

therapy received.

Caveolin-1 single nucleotide

polymorphism in


antibody associated

vasculitis. Chand et al. PLOS

One 2013;8(7):e69022224.

187 patients with AAV from

single centre in the UK

(Birmingham)

Association of a single

nucleotide polymorphism of

caveolin-1 with outcome in

AAV. Retrospective analysis

Validation of results sought

from 589 AAV patients from 2

European cohorts

Presence of a CC genotype is

associated with reduced

incidence of cancer in the

Birmingham cohort (HR 5.55,

p=0.007). This was not

replicated in the validation

cohort.

Over a median follow-up

period of 9.2 years the

incidence of cancer in the

Birmingham cohort was

11.8% and over a median

follow-up period of 7.4 years

2.9% in the European cohort

(NMSC excluded).

Caveolin-1 has been

associated with prognosis in

several cancers. However,

further research is necessary

Cancer evidence table

177

before these results can be of

clinical relevance in AAV.

Paraneoplastic

rheumatologic syndromes.

Azar et al. Curr Opin

Rheumatol 2013;25(1):44-

9225.

Review. Review of rheumatic

syndromes that can be a

paraneoplastic manifestation

of an underlying malignancy.

The association between

cancer and vasculitis is

uncommon and difficult to

establish. Overall,

paraneoplastic vasculitides

are estimated to represent

about 2-5% of all vasculitides.

However, descriptions of AAV

as paraneoplastic

manifestations are even more

exceedingly rare.


and malignancy: current

evidence for cause and

consequence relationships.

Mahr et al. Best Pract Res

Clin Rheumatol

2013;27(1):45-56162.

Review Review of the relationship of

AAV with malignancy

specifically looking at de novo

overall and specific cancer

incidence, role of specific

immunosuppressive agents in

cancer development and

cancer as a trigger or cause of

AAV

Overall cancer incidence

SIR ranges from 1.6 to 3.8.

Cancer SMR estimated at 2.2.

Most data from GPA rather

than MPA. Cancer incidence

may have decreased over

time due to use of CYC

sparing regimes.

Specific cancer-type

incidences

Urinary – long latency (6.9 -

18.5 years) after 1st CYC

exposure. Early studies show

SIR of 31-33 whilst recent

studies show SIR of 3.6 – 7.2

potentially reflecting lower

Recommendations made by

authors: Systematically co-

prescribe mesna and

hyperhydration with IV CYC.

Consider mesna with

prolonged oral CYC (> 4-6

months). Patients exposed to

CYC should have 6-12

monthly urine cytology; non-

glomerular haematuria

should be investigated. CYC

contraindicated in patients

with CYC induced

haemorrhagic cystitis and

those patients should have

routine cystoscopy once or

twice yearly.

178

CYC doses and potentially

also reflecting the use of

mesna.

Leukaemia – dose dependent

complication of CYC.

NMSC – SIR 2.8 – 10.4.

Lymphoma – equivocal

results.

Cancer as trigger of vasculitis

Inadequate evidence to

suggest this – but numbers is

studies very small.

NMSC – avoid sun exposure,

use sun blockers. Annual skin

examination advocated.

Adherence to regular cervical

screening.

Encouragement to quit

smoking.

In GPA with atypical disease

or inadequate response to

therapy, investigations for

cancer should be considered

on a case-to-case basis.

Cancer incidence in

pulmonary vasculitis.

Zycinska et al. Adv Exp Med

Biol 2013;788:349-53226.

[Full text not available

therefore limited

information]

117 patients with biopsy

proven pulmonary vasculitis

treated with CYC between

1990 and 2008 in Warsaw,

Poland.

Observational SIRs were calculated based on

general population incidence

of the cancers examined.

During the observation period

15 cancers occurred. A

significantly increased SIR was

observed for NMSC (SIR 5.2;

CI 2.3- 8.7), AML (SIR 4.3; 2.1

– 11.2) and bladder cancer

(SIR 3.4; 1.6 – 5.2).

Full text not available

therefore limited information

however this study suggests

an increased risk of NMSC,

AML and bladder cancer

following CYC treatment in

patients with pulmonary

vasculitis.

Long-term outcome of


antibody-associated small

vessel vasculitis after renal

transplantation. Marco et al.

Clin Transplant

2013;27(3):338-47227.

51 patients with AAV that

received a kidney transplant

between 1984 and 2007

(pooled data from 6 units in

Barcelona).

Retrospective observational

study.

Matched control group

(kidney transplant recipients),

n=49.

Probability of developing a

malignancy was similar in

both groups (10% in AAV vs.

12.8% in control group at 5-

year follow up; p=0.65)

Data suggests no excess risk

of cancer incidence in AAV

following transplantation

compared to a matched

cohort. However, the

relatively young age of

patients (median 52.9) and

medium duration of follow up

(median 5.2 years) has to be

179

taken into account.

TNF-alpha blocker therapy

and solid malignancy risk in

ANCA associated vasculitis.

Silva F et al. Curr Rheumatol

Rep 2012;14(6):501-508.

Review Review of the risk of solid

malignancies with TNF-alpha

blocker therapies in AAV

The authors discuss the short

and long-term follow up of

the WGET trial.

They suggest that etanercept

should be avoided in patients

with AAV, particularly in cases

with long-standing relapse

history, CYC exposure and

previous history of

malignancy.

Myelodysplasia and

malignancy-associated

vasculitis Agha et al. Curr

Rheumatol Rep

2012;14(6):526-31228.

Review The authors review available

evidence suggesting a link

between malignancy and

vasculitis as a secondary

phenomenon. They suggest

that myelodysplasia is more

commonly associated with

vasculitis than are solid

tumours. However in both

cases the most common

manifestation is

leukocytoclastic vasculitis.

There remains uncertainty

about the nature of the

association between vasculitis

and malignancy.

They suggest that in atypical

cases of AAV that do not

respond to standard

treatment, clinical suspicion

for an underlying malignancy

should be high.

Complications of long-term

therapy for ANCA-associated

systemic vasculitis. Wall &

Harper Nat Rev Nephrol

2012;8(9):523-32229.

Review Cytotoxic therapy increases

malignancy risk by greater

than two-fold compared to

the background incidence.

Increased risk varies

The authors make the

following recommendations:

Routine surveillance for non-

glomerular haematuria

(urinalysis every 3-6 months),

180

according to organ affected:

4.8-33-fold increase in

bladder cancer, 10-fold

increase in NMSC, and 4.2-11-

fold increase in lymphoma.

Additionally there are reports

of a predisposition to

malignancy inherent of AAV

itself although this is

controversial.

Recent publications are

contradictory about the risk

of malignancy using current

CYC regimes: at 5 years follow

up, risk was increased only for

NMSC for patients enrolled in

4 EUVAS trials that employed

lower CYC cumulative doses

than previously; however a

French study suggested still a

5-fold increase in urinary tract

cancer compared to the

background population

although oral administration

and cumulative dose were

important predictors of risk in

that study.

which should be continued

indefinitely in patients that

have ever received CYC.

Urine microscopy, culture and

cytology should be performed

if haematuria is detected and

clinicians should have a low

threshold for urology referral

and cystoscopy.

Mesna and adequate

hydration should employed.

AAV patients should receive

education about increased

NMSC risk, reduce exposure

to UV light and use sunscreen

– low threshold for

dermatology referral for

suspected skin lesions.

Patients should be

encouraged to participate in

age and gender appropriate

national cancer screening

programs as, for example,

cervical neoplasia has been

shown to be increased with

immunosuppression.

Pulse versus daily oral

cyclophosphamide for

induction of remission in

Long-term follow up of the

CYCLOPS study. Median

duration of follow up 4.3

Long-term follow up of

randomized controlled non-

blinded clinical trial

Pulse CYC versus daily CYC

No difference in the incidence

of malignancy between the 2

groups.

Relatively short follow up.

181

ANCA-associated vasculitis:

long-term follow up. Harper

et al. Ann Rheum Dis

2012;71(6):955-6075.

years.

[Identified from the

references from paper 10]

Long-term patient survival in

ANCA-associated vasculitis.

Flossmann et al. Ann Rheum

Dis 2011;70(3):488-9498.

535 patients who had been

recruited at the time of

diagnosis to four randomized

controlled trials between

1995 and 2002.

Prospectively collected

baseline data. Outcome data

were collected via

questionnaires sent to

participating doctors.

After the 1st year of diagnosis,

malignancy was the second

most common cause of death

accounting for 22% of deaths

in this cohort.

Out of 16 malignancies

recorded, 12 were solid organ

cancers and 4 haematological

malignancies.

Unfortunately this study does

not contain detail in relation

to treatment characteristics

or SIRs, which would have

been useful given the

relatively recent nature of the

clinical trials involved.



Improved outcome in 445

patients with Wegener’s

granulomatosis in a German

vasculitis center over four

decades. Holle et al.

Arthritis Rheum

2011;63(1):257-6664.

167 patients diagnosed with

GPA between 1999 and 2002

were compared to 123

patients diagnosed between

1994 and 1998. The two

cohorts were compared to a

historical cohort diagnosed

between 1966 and 1993.

Retrospective analysis. Incidence of malignancies and

mortality related malignancy

was examined and compared

to cancer incidence and

cancer mortality in the

general population.

18 malignancies were

documented in 445 patients

overall. In the 3 cohorts

together, there was neither

an increased SIR nor SMR

compared to the general

population.

Incidence of malignancy in

this study was much lower

than previously reported.

The authors suggest that this

might have been due to

universal administration of

mesna irrespective of route of

CYC administration (i.e. oral

and pulse).

Interestingly there was a

reduction of total CYC dose

moving from the oldest to the

newest cohort (median CYC

dose 67 vs. 36 vs. 24g),

however this was not

associated with any

differences in the incidence of

182

malignancy or CYC induced

cystitis amongst the 3 cohorts

(p=0.233 and 0.228

respectively).

Incidence of malignancy in

patients treated for

antineutrophil cytoplasm

antibody-associated

vasculitis: follow-up data

from European Vasculitis

Study Group clinical trials.

Heijl et al. Ann Rheum Dis

2011; 70(8):1415-21230.

535 with newly diagnosed

AAV from 15 countries

enrolled between 1995 and

2002 in 4 European clinical

trials

Observational prospective

collection of additional data


SIRs for different types of

cancer were calculated.

SIRs (95% CI) were 1.58 (1.17

to 2.08) for cancers at all

sites, 1.30 (0.90 to 1.80) for

cancers at all sites excluding

NMSC, 2.41 (0.66 to 6.17) for

bladder cancer, 3.23 (0.39 to

11.65) for leukaemia, 1.11

(0.03 to 6.19) for lymphoma

and 2.78 (1.56 to 4.59) for

NMSC – importantly, the only

significantly increased SIR was

found to be that for NMSC.

Cancer rates for AAV patients

treated with conventional

immunosuppressive therapy

exceeded those expected for

the general population. This

cancer excess was largely

driven by an increased

incidence of NMSC. The

smaller cancer risk magnitude

in this cohort, compared with

previous studies, might

reflect less extensive use of

CYC in current treatment

protocols.



Incidence and predictors of

urotoxic adverse events in

cyclophosphamide-treated

patients with systemic

necrotizing vasculitides.

Arthritis Rheum Le Guenno

et al. 2011;63(5):1435-45231.

805 CYC treated patients with

GPA, MPA, CSS or PAN with a

mean follow up period of 5.3

years.

Retrospective analysis. The observed incidence of

urinary tract cancer was

compared to the expected

incidence in the general

population by calculating

SIRs.

Amongst 27 patients there

were 22 episodes of

haemorrhagic cystitis and 7

episodes of urinary tract

cancer. The SIR for urinary

tract cancer was 5.00.

Cumulative CYC dose, ever

oral use of CYC as well as GPA

diagnosis were predictors of

haemorrhagic cystitis and / or

urinary tract cancer after

multivariate adjustment.

There was a wide range of

CYC cumulative dose of 0.72 –

463g (mean +/- SD, 25.1 +/-

38g).

183

Having ever smoked also

predicted the above

outcomes on univariate

analysis only.

Life expectancy, standardized

mortality ratios, and causes

of death in six rheumatic

diseases in Hong Kong, China

Mok et al. . Arthritis Rheum

2011;63(5):1182-9232.

Hospital registry analysis

(1999 – 2008) – 1636 patients

with systemic vasculitis

included.

Hospital registry analysis.

SMRs calculated.

SMRs calculated. SMR for systemic vasculitis

was 2.64. Loss of life

expectancy was 19.3 – 28.3

years.

Suggests a high incidence of

malignancy in systemic

vasculitis although this was

not standardized / compared

to the general population.

Mycophenolate mofetil vs

azathioprine for remission

maintenance in


antibody-associated

vasculitis. Hiemstra et al.

JAMA 2010;304(21):2381-897.

156 patients with AAV

assigned to AZA (n=80) or

MMF (n=76) and were

followed up for a median of

39 months.


controlled clinical trial

AZA vs MMF for maintenance

of remission.

No difference between the

incidences of malignancy in

the 2 groups.

Limited by short follow-up

but would suggest no

difference in malignancy rates

when MMF is used in place of

AZA.



EULAR recommendations for

the management of primary

small and medium vessel

vasculitis Mukhtyar et al.

Ann Rheum Dis

2009;68(3):310-1772.

Modified Delphi technique.

Expert panel group comprised

of rheumatologists,

nephrologists, immunologists

and general physicians.

In relation to CYC

administration the authors

suggested that pulse therapy

has been associated with a

higher likelihood of remission

and lower risk of side effects

but with a higher risk of

relapse compared to daily

oral CYC. They recommended

hydration and Mesna for

pulse CYC administration.

A recommendation was made

to investigate persistent

The level of evidence for the

recommendation to

investigate persistent

unexplained haematuria in

patients with prior CYC

exposure was 2B and the

grade of recommendation C.

184

unexplained haematuria in

patients with prior CYC

exposure. Specifically they

suggested periodic urine

analysis for the duration of

follow up and urgent

urological opinion in the

presence of non-glomerular

haematuria.

Cancer preceding Wegener’s

granulomatosis: a case

control study. Faurschou et

al. Rheumatology (Oxford)

2009;48(4):421-4233.

293 patients with GPA. 10

gender and age matched

controls were selected

randomly for each GPA

patient from the Danish

Central Population Registry.

Retrospective case control

study.

Occurrence of malignancies

before GPA diagnosis among

patients and before GPA

diagnosis of their matched

case among controls

(reference date) was

compared by calculation of

prevalence OR.

The OR for a prior cancer at

any site was not significantly

increased. A significantly

increased prevalence was

found for testis cancer on the

basis of 2 GPA patients

(cancer diagnosed 10.8 and

19.6 years prior to GPA

diagnosis). An increased

prevalence was also found for

malignancies listed as kidney

cancers. NMSC prevalence

within 2 years prior to GPA

diagnosis was increased

compared to the reference

group.

The authors conclude that

there is no clear evidence of

an increased prevalence of

preceding cancer in their GPA

cohort, suggesting that

shared risk factors for cancer

and GPA are of minor

importance for the excess of

malignancies that occur in

GPA patients after the

diagnosis of vasculitis.

They postulate that the

increased prevalence of

NMSC within 2 years of

diagnosis may represent a

state of acquired

immunological dysfunction

that predisposes to both

conditions.

Their data does not support

that patients with newly

185

diagnosed GPA should be

examined for the presence of

serious underlying

malignancy.



Malignancies in Wegener’s

granulomatosis: incidence

and relation to

cyclophosphamide therapy in

a cohort of 293 patients.

Faurschou et al. J

Rheumatol 2008;35(1):100-

5234.

293 patients diagnosed with

GPA in a Danish hospital


Retrospective analysis. Cancer incidence in the

cohort was assessed through

2003 by linkage to the Danish

Cancer Registry and

compared to that of the

general population by

calculation of SIR. Analyses

were stratified according to

low (<36g) or high (>36g)

cumulative CYC doses.

SIR of cancer overall was 2.1.

Significantly elevated SIR

were observed for AML (19.6

CI 4.0-57), bladder cancer (3.6

CI 1.2-8.3), and NMSC (4.7 CI

2.8-7.3).

Latency period for bladder

cancer and AML was 6.9 to

18.5 years after first CYC

exposure.

Risk of these malignancies

was not increased in patients

that had never received CYC

or had received < 36g

cumulative dose, with the

exception of NMSC.

In contrast, patients in the

>36g group had very high

rates of both bladder cancer

(SIR 9.5 CI 2.6-24) and AML

(SIR 59 CI 12-172).

Azathioprine or

methotrexate maintenance

for anca-associated

vasculitis. Pagnoux et al. N

Engl J Med

2008;359(26):2790-803235

126 patients with AAV were

assigned on a 1:1 basis to

receive either AZA or MTX for

maintenance of AAV and

were followed up for a mean

period of 29 months.


controlled clinical trial

AZA vs MTX for maintenance

of remission

No difference between the

incidence of malignancy in

the 2 groups

Very low event rate for

malignancy (total of 3) and

short duration of follow up

precludes any firm

conclusions.

Vasculitides associated with

malignancies: analysis of

sixty patients Fain et al.

Arthritis Rheum

2007;57(8):1473-80236.

60 patients with a mean

follow up duration of 45.2

months. Vasculitides were

cutaneous leukocytoclastic

(45%), PAN (36.7%), GPA

(6.7%), MPA (5%) and HSP

(5%).

Retrospective analysis Vasculitides were diagnosed

concurrently with malignancy

in 38% of cases. Independent

of subtype patients with

vasculitides associated with

MDS more frequently, had

renal manifestations (p=0.02),

steroid dependence (p=0.04)

and achieved remission less

Not very helpful for this

process.

186

often (p=0.04) compared with

vasculitides associated with

other malignancies.



Urinary bladder cancer in

Wegener’s granulomatosis;

risk and relation to

cyclophosphamide. Knight et

al. Ann Rheum Dis 2004;

63(10):1307-11163.

1065 patients with GPA were

identified from the

nationwide Swedish Inpatient

Register (1969 – 1995).

Cases of bladder cancer were

identified through linkage

with the Swedish Cancer

Register.

Each bladder cancer case was

then matched with 3 controls

from the same cohort in a

nested matched case control

study.

There were 11 confirmed

incident cases of bladder

cancer with a diagnosis of

GPA – 10 of those had been

treated with CYC.

20 of the 25 controls had

been exposed to CYC.

Median cumulative CYC dose

was 113g in cases as opposed

to 25g amongst controls.

Each 10g increment in CYC

dose was associated with a

doubling of bladder cancer

development. Cumulative

doses > 25g were associated

with a 5-fold risk.

8 of the 1065 patients had

developed bladder cancer

before the GPA diagnosis –

this amounted to a relative

risk of 2.1 (CI 0.6 – 3.6)

compared to the expected

prevalence of bladder cancer

in Sweden, suggesting a risk

factor different than CYC

administration in GPA;

however this association was

not significant.

Haemorrhagic cystitis did not

precede bladder cancer in

these cases – however only 1

of the cases had had a

previous cystoscopy prior to

the cancer diagnosis.

The authors suggest that the

two conditions may not arise

from the same mechanisms.

Particularly, the toxic

metabolite acrolein that

causes haemorrhagic cystitis

can be protected against by

mesna whereas it is possible

that the carcinogenic

187

properties are mediated

through molecular changes

cause by the alkylating

properties of CYC. In that

respect, haemorrhagic cystitis

may not be a good marker of

bladder cancer risk and

mesna may not necessarily be

cancer protective.

Malignancy is increased in

ANCA associated vasculitis.

Pankhurst et al.

Rheumatology (Oxford)

2004;43(12):1532-5237.

200 consecutive patients with

GPA or MPA

Retrospective analysis.

Malignancies preceding or

concurrent with vasculitis (up

to 6 months following

diagnosis of vasculitis) were

recorded

The incidence of malignancy

was compared with those in a

population of 129 patients

with HSP, 333 patients with

SLE and a control population

in the West Midlands, UK.

Patients with AAV had an

increased risk of malignancy

compared with HSP patients

(RR 0.85, CI 0.69-1.05,

p=0.034) and SLE patients (RR

0.31, CI 0.14-0.7, p<0.0001).

The rate of malignancy

compared with an age

matched control group was

increased in AAV (RR 6.02, CI

3.72-9.74). The presence of

ANCA was not predictive of

malignancy.

Authors suggest that

malignancy should be

considered as part of the

differential diagnosis in

patients with ANCA-

associated vasculitis

[Identified from references

from paper 6]

Increased incidence of

cervical intraepithelial

neoplasia in women with

systemic lupus

erythematosus treated with

intravenous

61 women with SLE under

active follow up. Study

excluded women that were

treated with oral

cyclophosphamide, had an

abnormal cervical smear at

screening or had no previous

sexual exposure.

Observational prospective

study. Cervical smears were

obtained at baseline and at 3

and 7 years. Results were

analysed according to

treatment received for SLE.

The overall 3-year incidence

of CIN was 9.8%. A dose

relationship was observed

between cumulative

intravenous CYC exposure

and CIN with each increase of

1g of IV CYC exposure

corresponding to 13%

Suggests a risk of CIN with

CYC exposure.

188

cyclophosphamide

Ognenovski et al. J

Rheumatol 2004;31(9):1763-

7120.

increased risk of CIN (p=0.04).



Cancer incidence in a

population based cohort of


granulomatosis. Knight et al.

Int J Cancer 2002;100(1):82-

5238.

All individuals (n=1176)

discharged with the diagnosis

of GPA within the Swedish

Inpatient Register were

identified.

A total of 1065 patients had

complete data.

The cohort was linked to the

Nationwide registers

including the Swedish Cancer

Register.

SIRs and SMRs were

constructed.

Among 1065 patients, 110

incident cancers were

registered during 5708

person-years of follow up (SIR

2.0 CI 1.7-2.5). SMR due to

cancer (2.2 CI 1.7-2.8).

Bladder cancer SIR 4.80 (CI

2.6-8.1).

Squamous skin cancer SIR 5.7

(CI 2.3-12). Leukaemia SIR 5.7

(CI 2.3-12). Lymphoma SIR 4.2

(1.8 – 8.3). Hepatic cancer SIR

3.8 (CI 1.2-8.8).

Increased risk of cancer noted

overall, particularly for

bladder cancer, NMSC and

lymphoma / leukaemia.

However, this suggests a

lower risk compared to

previous studies.

Unfortunately, this study does

not provide treatment details

such as CYC dose.

Relapse rate, renal survival,

and cancer morbidity in


granulomatosis or

microscopic polyangiitis with

renal involvement Westman

et al. J Am Soc Nephrol

1998;9(5):842-52239.

Consecutive series of 123

patients with GPA (n=56) or

MPA (n=67) with biopsy

proven renal involvement,

followed up for a median of

55 months (range 0.1 – 273.2

months).

Retrospective analysis. Standardised morbidity ratios

were calculated using

expected values from the

health care region.

There was a 10.4 times higher

risk of developing skin cancer.

When calculating

standardized morbidity ratios

for malignancy with a latency

period of greater than 60

months, treatment with CYC

for greater than 12 months

resulted in a standardized

morbidity ratio for overall

cancer of 3.7, 181.3 for vulva

cancer and 20.2 for bladder

cancer.

Standardised morbidity ratios

were constructed on the basis

of only a few cases for each

cancer type.

189

Skin carcinoma had the

strongest relationship with

AZA > 12 months (24.7 times

more likely) and GC > 48

months (20.8 times more

likely).

Side-effects of intravenous

cyclophosphamide pulse

therapy Martin et al. Lupus

1997;6(3):254-7240.

75 patients with a variety of

autoimmune disorders that

received pulse CYC monthly

and were followed up for 26.7

+/- 22.1 months.

Retrospective analysis. Examined rates of adverse

effects during the follow up

period.

Haemorrhagic cystitis was not

observed.

Only 4 patients developed a

neoplastic condition.

Mean cumulative CYC dose

was low at 4.7g. Follow up

was relatively short therefore

it is difficult to draw accurate

conclusion with regards to

malignancy risk that has

previously been shown to

have a potentially long

latency period.

[Identified from references

from paper 6]

Cyclophosphamide induced

cystitis and bladder cancer in


granulomatosis. Talar-

Williams et al. Ann Intern

Med 1996;124(5):477-84241.

145 patients who received

CYC for the treatment of GPA

and were followed up for 0.5

to 27 years

Retrospective observational

analysis

50% of patients developed

non-glomerular haematuria.

Bladder cancer developed in

5% of the cohort representing

a 31-fold increase in

incidence. Estimated

incidence of bladder cancer at

15 years after first exposure

to CYC was 16%. Only

microscopic non-glomerular

haematuria was found to be a

significant risk factor for the

development of bladder

cancer (p=0.02). Smokers

developed non-glomerular

Patients in this cohort

received large doses of CYC

(13.8 % received cumulative

doses > 200g). CYC was

continued a minimum of 12

months in all patients.

Authors recommended

urinalysis every 3-6 months

even after cyclophosphamide

is discontinued. As urine

cytology is useful for

detecting higher grade

bladder cancer they suggest

doing this every 6-12 months.

190

haematuria and / or bladder

cancer with shorter duration

and lower dosage of CYC

exposure.

However, the authors make

the point that urine cytology

is relatively insensitive for

detecting lower grade

malignant lesions and

therefore recommend routine

cystoscopy every 1-2 years for

all patients with CYC induced

haematuria.



Wegener’s granulomatosis –

an analysis of 158 patients.

Hoffman et al. Ann Intern

Med 1992;116(6):488-98100.

158 patients enrolled in the

National Institutes of Health

(NIH) cohort

Retrospective analysis The malignancy rate among

patients with GPA was

compared to the National

Cancer Institute Registry for

the general population

2.4-fold overall increase in

malignancies

33-fold increase in bladder

cancer

11-fold increase in lymphoma

Latency period – 7 months to

12 years

Large doses of

cyclophosphamide –

2mg/kg/day as standard dose

but some patients received 3-

5mg/kg/day



Cyclophosphamide induced

bladder toxicity in Wegener’s

granulomatosis. Stillwell et

al. Arthritis Rheum

1988;31(4):465-70242.

111 patients with GPA and

prior CYC exposure seen at

the Mayo Clinic from 1966 to

1985.

Retrospective analysis 17 patients developed

haemorrhagic cystitis.

Bladder cancer developed in 3

patients with haemorrhagic

cystitis.

Incidence of toxicity was not

correlated to CYC dose.

Incidence of Malignancies in

Patients With Antineutrophil

Cytoplasmic Antibody-

Associated Vasculitis

Diagnosed Between 1991

and 2013. Rahmattulla et al.

138 pts with

histopathologically confirmed

AAV (68% GPA, 32% MPA)

Single centre retrospective

cohort review

Primary malignancies were

identified via the Dutch

National Pathology Database-

compared with expected

number of malignancies

(defined as the person-years

Thirty-six patients developed

malignancies (total of 85

malignancies) during the

followup period (mean 9.7

years) 61 were NMSCs, in 22

patients.

191

Arthritis & Rheumatology.

67(12):3270-8, 2015243.

at risk multiplied by the

national cancer incidence

rate)

Subgroup analysis diagnosed

pre vs post 2003

sex-, age-, and calendar year–

adjusted malignancy risk was

2.21-fold higher than the risk

in the general population

(95% CI 1.64–2.92) Increased

risk was attributable solely to

an increased risk of

developing NMSC SIR 4.23

Risk was sig increased in

those diagnosed pre 2003

(cycazarem) compared with

gen population whereas was

not for those post 2003.

Also duration CYC directly

assoc with ca risk but risk not

increased among patients

who had been exposed to CYC

for <1year.

Incidence of Cancer in ANCA-

Associated Vasculitis: A

Meta-Analysis of

Observational Studies. Shang

W et al.

PLoS ONE 10(5):e0126016,

2015244.

258 cases of cancers

identified in a total cohort of

2,578 individuals

Meta- analysis of 6 studies- all

already identified by search

cohort studies that estimate

the influence of AASV on

cancer risk with odds ratio

(OR), risk ratio (RR), hazard

ratio (HR), or standardized

incidence/mortality

rate(SIR/SMR) (2) defined

AASV as one of the exposure

interests and cancer as one of

the outcome of interests

SIR of cancers within the six

individual study populations

ranged between 0.8 and 2.5,

with an overall meta-

analytical SIR of 1.74 NMSC,

leukaemia and bladder cancer

more frequently observed in

patients with AASV with SIR

of 5.18 ,4.89 and 3.84

respectively

(risk of lymphoma, liver and

lung ca also increased)

Moderate heterogeneity

noted

192

ANCA-associated diseases

and lung carcinomas: a five-

case series. Chemouny et al.

Clinical Nephrology.

81(2):132-7, 2014

Five patients with ANCA-

associated diseases who had

associated lung carcinomas or

were diagnosed within 2

years after vasculitis onset.

Abstract only


associated with renal cell

carcinoma. Tatsis, Reinhold-

Keller, Steindorf, Feller, &

Gross,

Arthritis & Rheumatism.

42(4):751-6, 1999245.

477 patients with biopsy-

proven WG


study

Pts compared with control

group of 479 patients with

(RA) for the frequencies and

types of malignant neoplasms

occurring before or

simultaneously with the

diagnosis of the rheumatic

disorder.

4.8 % pts vs 3.8% controls

developed ca. 7 cases of renal

ca vs 1 control. Simultaneous

occurrence of cancer and WG

was observed in 14 patients

in the WG group compared

with 1 patient in the control

group

Authors suggest a link

between GPA and RCC

Incidence and prevention of

bladder toxicity from

cyclophosphamide in the

treatment of rheumatic

diseases: a data-driven

review. Monach PA, Arnold

LM, Merkel PA (2010)

Arthritis Rheum 62: 9–21164

PubMed search:search terms

[cyclophosphamide AND

(cystitis OR bladder cancer)

AND (vasculitis OR arteritis

OR granulomatosis OR

rheumatoid OR lupus OR

scleroderma OR non-

Hodgkin’s)]

Then

[(cyclophosphamide

ifosfamide) AND cystitis AND

mesna]

Plus references reviewed

Review- see search strategy Conclusions:

1)daily oral

cyclophosphamide is

associated with an increased

risk of haemorrhagic cystitis

and bladder cancer, in a dose-

dependent and/or duration-

dependent manner (mean

cyclophosphamide exposure

of pts with haemorrhagic

cystitis was >100 gm over a

mean of>30 months;

increased risk of bladder

cancer associated with

cyclophosphamide treatment

was observed in all studies

(OR range 3.6–100) 2)

In summary- low dose pulsed

iv CYC is likely to be assoc

with a low risk of cystitis and

bladder ca. there is little

evidence to support the use

of mesna in this setting,

However, as there may be

some benefit and mesna is

well tolerated, expert

consensus is that the use of

mesna may be considered in

this setting

193

haemorrhagic cystitis ( during

cyc treatment) is associated

with an increased risk of

bladder cancer years later

(11-16 yrs); 3)pulsed IV

cyclophosphamide therapy

carries a low risk of cystitis

and probably also of bladder

cancer; 4) evidence for the

effectiveness of mesna in

preventing cystitis is based

largely on its use with

ifosfamide in patients with

cancer and on data from

animal models, both of which

are of uncertain relevance to

the use of cyclophosphamide

in patients with rheumatic

diseases; 5) there is no direct

evidence for the effectiveness

of mesna in preventing

bladder cancer in humans.

High risk of human

papillomavirus type 16

infections and of

development of cervical

squamous intraepithelial

lesions in systemic lupus

erythematosus patients.

Nath R, Mant C, Luxton J,

30 women with SLE, 67 with

abnormal smears from

colposcopy clinics, and 15

community subjects with

normal smears

Prospective case control

study

Polymerase chain reaction

results for viral DNA and HPV-

16 sequencing data were

correlated to cytology and

colposcopic findings

SLE patients were more likely

to be both HPV DNA positive

and HPV-16 DNA positive (i.e.,

have a high viral load:

colposcopy patients were

more likely to be only HPV

DNA positive. (both more

likely to be positive compared

Study notes that although

more HPV 16 in SLE vs

colposcopy group they were

ethnically diff which is

relevant for HPV

epidemiology

“60% of patients with SLE had

a history or

194

Hughes G, Raju KS, Shepherd

P, et al. (2007) Arthritis

Rheum 57: 619–625246.

with controls)

Ten (36%) SLE patients had a

high HPV-16 viral load, 7 of

these patients had current

abnormal histology. No assoc

between HPV status and

current or previous drug

therapy. HCQ appeared to

exert a protective effect-

(?confounding by disease

severity as this is used for

milder disease therefore

cervical disease likely to be

assoc with more aggressive

disease or therapy) when this

was removed from analysis

other immunosupp were

assoc with OR 1.4 on

presence SIL (squamous

intraepithelial lesions). SIL

rate 27%

current evidence of cervical

disease”

Multiple other references

here for lupus and CIN

The below ref selected for

inclusion as most recent and

relevant.


abnormal Pap results in

systemic lupus

erythematosus. Bernatsky S,

Ramsey-Goldman R, Gordon

C, Joseph L, Boivin JF, Rajan

R, et al. Rheumatology

(Oxford) 2004;43:1386–9247.

1015 pts with SLE from 3

centres

Cross-sectional cohort study

(pt self- report survey)

To determine the factors

associated with lifetime

occurrence of an abnormal

Pap test in women with SLE,

and to determine the

influence of immunosup-

pressive exposure on the

odds of abnormal Pap test

results occurring after

13.3% had abn smear, with

half occurring after diag SLE.

mean duration of SLE at the

time of the abnormal test was

12.1 yr

STD and OC assoc with abn

smear

OR for the effect of

immunosuppressive exposure

Limitations of a self- report

survey acknowledged

195

diagnosis of SLE. on abnormal results occurring

after diagnosis of SLE, when

adjusted for smoking,

nulliparity, OC use, STD

history, age, race and centre,

was 1.6.

196

Article Study population Study Design Comparisons Outcomes Comments

Fertility, ovarian failure, and

pregnancy outcome in SLE

patients treated with

intravenous

cyclophosphamide in Saudi

Arabia.

Alarfaj A.S., Khalil N.

Clinical Rheumatology. 33

(12) (pp 1731-1736), 2014248

Saudi Arabian women with SLE

treated with IV CYC (188) vs.

not (347) over 26 year period

Retrospective analysis Rates of amenorrhoea.

Rates of conception, abortion,

foetal loss and pre-term births.

Higher rate of amenorrhoea

in the IV CYC group.

Older age at time of

receiving IV CYC and higher

cumulative dose of IV CYC

were risk factors.

Rates of conception, foetal

loss and live birth similar

between 2 groups but IV CYC

group had more pre-term

births.

Older age at time of CYC

exposure and cumulative

dosage correlated with rates

of amenorrhoea.

Pharmacological

interventions for fertility

preservation during

chemotherapy: A systematic

review and meta-analysis.

Ben-Aharon I., Gafter-Gvili

A., Leibovici L., Stemmer

S.M.

Breast Cancer Research and

Treatment. 122 (3) (pp 803-

811), 2010167.

Cancer and SLE patients

treated with chemotherapy

agents at risk of chemotherapy

induced ovarian failure

Meta-analysis and

systematic review

Randomised controlled and

observational studies that

assessed GnRH analogs

(GnRHa) or the oral

contraceptive pill for fertility

preservation prior to

chemotherapy.

GnRHa effective in reducing

amenorrhoea in all patients.

Pregnancy rate higher in the

GnRHa arm.

However, the advantage of

GnRHa was only shown in

observational studies and

not in clinical trials.

Inconclusive results from

studies evaluating use of oral

contraceptive pill.

Preservation of fertility and

ovarian function and

minimizing gonad toxicity in

young women with systemic

Women of reproductive age

with severe connective tissue

disease

Observational study 8 women that received GhRHa

together with chemotherapy

versus 9 women that did not.

None of the women treated

with GnRHa developed pre-

mature ovarian failure

whereas 5 out of 9 of the

Study was not controlled.

Mean age as well as mean

total dose of

cyclophosphamide was

Fertility preservation evidence table

197

lupus erythematosus

treated by chemotherapy.

Blumenfeld Z., Shapiro D.,

Shteinberg M., Avivi I.,

Nahir M.

Lupus. 9 (6) (pp 401-405),

2000249.

women that did not receive

GnRHa did experience pre-

mature ovarian failure.

higher in the group that did

not receive GnRHa.

Hormonal Strategies for

Fertility Preservation in

Patients Receiving

Cyclophosphamide to Treat

Glomerulonephritis: A

Nonrandomized Trial and

Review of the Literature.

Cigni et al. American

Journal of Kidney Diseases.

52 (5) (pp 887-896), 2008250 .

28 consecutive patients (11

men, 17 women) with various

forms of glomerulonephritis

treated with CYC

Clinical Trial 11 men: all received

testosterone with CYC

17 women: 13 patients

received CYC plus GnRHa and 4

patients received only CYC

All 4 patients in group B of

the female patients (CYC

only) developed sustained

amenorrhoea as opposed to

group A.

Authors suggest a protective

effect of testosterone and

triptorelin against CYC

induced gonadal damage.

Very small numbers in this

study.

The sub-study in men was

not controlled i.e. all men

received testosterone.

The sub-study in women was

not randomized.

Furthermore the group that

did not receive GnRHa was

comprised only of 4 patients.

Therapy Insight: Preserving

fertility in

cyclophosphamide-treated

patients with rheumatic

disease.

Dooley M.A., Nair R.

Nature Clinical Practice

Rheumatology. 4 (5) (pp

250-257), 2008251.

CYC treated patients with

rheumatic disease

Review Patient's age at treatment

and the cumulative dose

received are important risk

factors for CYC-induced

gonadal failure in both males

and females.

Storing male gametes prior

to chemotherapy widely

practiced and technically

successful.

Questionable benefit of oral

contraceptives for females

and testosterone for males.

198

Fertility preservation

treatment for young women

with autoimmune diseases

facing treatment with

gonadotoxic agents.

Elizuret al.


1506-1509), 2008252.

7 patients that required CYC

treatment and underwent

fertility preservation

treatments. One of the

patients had MPA.

Case series. Describes successful fertility

preservation in 7 female

patients prior to

commencing CYC therapy.

Authors suggest that oocyte

or embryo cryopreservation

should be considered for

fertility preservation in

young women with systemic

autoimmune rheumatic

diseases who face imminent

gonadotoxic treatment.

The impact of

cyclophosphamide on

menstruation and

pregnancy in women with

rheumatologic disease.

Harward L.E., Mitchell K.,

Pieper C., Copland S.,

Criscione-Schreiber L.G.,

Clowse M.E.B.

Lupus. 22 (1) (pp 81-86),

2013121.

Women diagnosed with SLE,

scleroderma or vasculitis prior

to the age of 35.

Case series. Comparison of patients with

CYC exposure versus not.

Comparison of patients with

GnRH co-therapy and CYC

versus not.

Amenorrhoea was related to

CYC use, older age at time of

therapy as well as CYC

dosage received.

More women with GnRHa

co-therapy had maintained

menses however this value

did not reach statistical

significance.

Higher conception rates in

women that received

GnRHa.

All pregnancies after CYC

exposure resulted in elective

termination, miscarriage or

pre-term birth.

Does not provide sufficient

evidence to routinely

recommend GnRHa.

Fertility preservation Total of 2836 patients within Retrospective analysis of Most patients opted for a Advocates for GnRHa co-

199

methods in young women

with systemic lupus

erythematosus prior to

cytotoxic therapy:

Experiences from the

FertiProtekt network.

Henes M., Henes J.C.,

Neunhoeffer E., Von Wolff

M., Schmalzing M., Kotter I.,

Lawrenz B.

Lupus. 21 (9) (pp 953-958),

2012253.

the FertiPROTEKT network.

Out of those 68 were

counselled for severe SLE.

prospectively collected data.

Also literature review.

fertility preservation

method. The largest

proportion (91.2%) opted for

GnRHa co-therapy. Ovarian

tissue removal for

cryoconservation (25%) and

stimulation therapy for

cryoconservation of fertilized

egg cells (4.4%) was also

performed.

therapy although does not

provide any data for GnRHa

effectiveness.

Authors suggest

cryoconservation of ovarian

tissue if no active disease.

Causes and management of

infertility in systemic lupus

erythematosus.

Hickman R.A., Gordon C.


1551-1558), 2011254.

Review of causes and

management of infertility in

SLE.

Literature review. Advocates for GnRHa use in

female patients and use of

testosterone in male

patients.

Risk of ovarian failure and

fertility after intravenous

cyclophosphamide. A study

in 84 patients.

Huong D.L.T., Amoura Z.,

Duhaut P., Sbai A.,

Costedoat N., Wechsler B.,

Piette J.-C.

Journal of Rheumatology. 29

(12) (pp 2571-2576), 2002255.

Study of 84 women that

received CYC.

Approximately one third of the

patients had GPA or other

systemic vasculitis.

Retrospective analysis. Confirms that the risk of

ovarian failure depends on

the age of the woman at the

time of CYC therapy.

It is possible to conceive

during CYC therapy;

however, the outcome is

almost always negative

therefore efficient

contraception during CYC

therapy is mandatory.

In this cohort, after iv CYC

200

withdrawal pregnancy was

possible with favourable

outcome in two thirds of

cases.

Ovarian failure in systemic

lupus erythematosus

patients treated with pulsed

intravenous

cyclophosphamide.

Katsifis G.E., Tzioufas A.G.

Lupus. 13 (9) (pp 673-678),

2004256.

Review of ovarian failure in SLE

patients treated with CYC.

Review. Supports the evidence that

premature ovarian failure

after CYC therapy depends

on the age of the patient at

the time of treatment and

the CYC dosage.

Advocates consideration of

ovarian banking prior to CYC

therapy in selected patients.

Prevention of gonadal

toxicity and preservation of

gonadal function and

fertility in young women

with systemic lupus

erythematosus treated by

cyclophosphamide: the

PREGO-Study.

Manger K., Wildt L., Kalden

J.R., Manger B.

Autoimmunity reviews. 5 (4)

(pp 269-272), 2006257.

63 pre-menopausal women

with SLE without ovarian

protection that received CYC.

Prospective study. Tested concentrations of FSH

and LH before and after CYC

treatment.

60% of patients treated with

CYC suffered from pre-

mature ovarian failure.

Again, the age and dosage

were found to be crucial

determinants of pre-mature

ovarian failure.

Absence of conclusive

evidence for the safety and

efficacy of gonadotropin-

releasing hormone analogue

treatment in protecting

against chemotherapy-

Comment on the impact of

gonadotoxic therapy on

women with malignant and

non-malignant diseases.

Review and commentary. Comprehensive review of

literature on the

effectiveness and safety of

GnRHa therapy.

Most studies that show

benefit have used control

201

induced gonadal injury.

Oktay K., Sonmezer M.,

Oktem O., Fox K., Emons G.,

Bang H.

Oncologist. 12 (9) (pp 1055-

1066), 2007258.

groups retrospectively

selected from historical

patients treated with similar

regimens. In some studies,

the mean follow-up was

longer in the control group

and dosage of CYC in the two

groups was not clear.

Concerns exist on the safety

of administering GnRHa

during chemotherapy.

Fertility and pregnancy in

vasculitis.

Pagnoux C., Mahendira D.,

Laskin C.A.

Best Practice and Research:

Clinical Rheumatology. 27

(1) (pp 79-94), 2013259.

Review of fertility and

pregnancy in vasculitis

Review. No systematic so not

formally appraised

Ovarian failure and

strategies for fertility

preservation in patients

with systemic lupus

erythematosus.

Raptopoulou A.,

Sidiropoulos P., Boumpas

D.T.

Embase Lupus. 13 (12) (pp

887-890), 2004260.

Editorial. Comments on current

literature (up to 2004).

Ovarian toxicity an important

consideration for CYC

treatment. Drug toxicity

cumulative and dose

dependent therefore

advocates use of small

effective dose and shortest

duration.

Advocates use of GnRHa.

In terms of male fertility,

202

sperm banking is the only

proven method for male

fertility preservation.

Adverse effects of therapy

for ANCA-associated

vasculitis.

Turnbull J., Harper L.

Embase Best Practice and

Research: Clinical


391-401), 2009261.

Review of adverse effects of

therapy in AAV.

Review. Includes section on fertility

although limited.

No new information with

regards to CYC.

Methotrexate also

associated with infertility

particularly in men.

Recommends informed

discussion before

commencement of therapy.

Suggests that

cryopreservation of sperm is

done when time allows prior

to CYC therapy and possibly

also methotrexate.

Suggests GnRHa may be able

to protect female fertility.

Impact of systemic lupus

erythematosus on ovarian

reserve in premenopausal

women: evaluation by using

anti-Muellerian hormone.

Lawrenz B et al.

Lupus. 20(11):1193-7,

2011262.

33 premenopausal SLE patients

without previous

cyclophosphamide- treatment

compared with 33 age-

matched healthy controls

Not relevant as pts not

exposed to CYC and not

disease group of interest

Cyclophosphamide-induced

gonadal toxicity: a

Review (not systematic) 6 studies reviewed

examining relationship

Most relevant ref

Ioannidis JPA, Katsifis GE,

203

treatment dilemma in

patients with lupus

nephritis? Wetzels et al.

Netherlands Journal of

Medicine. 62(10):347-52,

2004263.

between CYC dose/ age and

amenorrhea.

cumulative dosages CYC of

12 to 25 g. mean age of the

patients was 28 years. Risk of

amenorrhoea ranged from

27 to 60%)sustained in >

80%). Generally developed

average of four months after

starting CYC.

Risk of sustained

amenorrhea dependent on

dose and age.

Ioannidis calculated the risk

of amenorrhoea for 15 g CYC

(5 to 10%

for patients <25 years, 30%

for patients aged 25 to 31

years and 90% for patients

>32 years). V low risk if

<10g/ young.

Male data extrapolated from

pts usually treated pre-

puberty- concludes dose of

12g appears safe for 70kg

adult

Occurred 2-3 months

following exposure and

recovery occurred and 3

years (70% of those <

Tzioufas AG, Moutsopoulos

HM. Predictors of sustained

amenorrhea from pulsed

intravenous

cyclophosphamide in

premenopausal women with

systemic lupus

erythematosus. J Rheumatol

2002;29:2129-35.

10.

204

7.5g/m2)

Mentions lack of evidence

for OCP, possible benefit of

GnRH agonists (but RCTs

needed and may be

associated with disease

flares). Mentioned one study

showing possible benefit of

concurrent testosterone for

preserving fertility in men.

Predictors of sustained

amenorrhea from pulsed

intravenous

cyclophosphamide in

premenopausal women

with systemic lupus

erythematosus. Ioannidis

JPA, Katsifis GE, Tzioufas

AG, Moutsopoulos HM. J

Rheumatol 2002;29:2129-

35165.

67 premenopausal women

with SLE who were treated

with a monthly regimen of IC

pulses for lupus nephritis or

other indications at the

Department of

Pathophysiology, National

University of Athens, between

January 1992 and June 2001

Retrospective cohort study Predictors of CYC induced

sustained amenorrhoea(AM)

including cox Ph models to

predict dose of CYC that would

result in amenorrhoea

Twenty-one women (31%)

developed sustained

amenorrheoa of at least 12

months’ duration during

followup. For those >=32yrs,

90% expected to develop

sustained AM by 12g CYC.

Confirms dose/duration CYC

and age as determinants of

amenorrheoa

Risk for sustained

amenorrhea in patients with

systemic lupus

erythematosus receiving

intermittent pulse

cyclophosphamide therapy.

Boumpas, D T. et al.

Annals of Internal Medicine.

119(5):366-9, 1993166.

Pts with SLE < 40yrs old,

participating in two

prospective therapeutic trials

for lupus nephritis from 1973

to 1990 and in a retrospective

study for neuropsychiatric

lupus.

Retrospective cohort study Risk of sustained amenorrhea

(defined as > 12/12) in those

with short course (7 doses

n=16) vs long course (at least

15 doses, n=23)

100% of those with long

course CYC plus > 31 yrs. age

developed sustained

amenorrhoea vs 0% of those

age < 25yrs plus short course

205

The effect of

cyclophosphamide pulses

on fertility in patients with

lupus nephritis. Langevitz,P

et al.

American Journal of

Reproductive Immunology.

28(3-4):157-8, 1992264.

17 females with LN, mean age

29.4 years. Receiving 2-13

pulses CYC, some requiring

repeat therapy.

Retrospective cohort study Descriptive outcomes Menopause appeared in four

females, three of them

44-45 years old. Early

menopause occurred in one

28-year- old female who

received a total of 11 g of

cyclophosphamide. The

menstrual cycle remained

unchanged in 11 females,

14-33 years old, who

received between 2.4 and 9

g of cyclophosphamide

Authors conclude < 10g

appears safe for those <

40yrs

206

Article Patients Design Comparisons Outcomes Comments/refs

Effect of methotrexate,

anti-tumor necrosis factor

alpha, and rituximab on the

immune response to

influenza and

pneumococcal vaccines in

patients with rheumatoid

arthritis: a systematic

review and meta-analysis.

Hua, Barnetche, Combe, &

Morel.

Arthritis care & research.

66(7):1016-26, 2014173.

Pts with RA Meta-analysis for studies of

human subjects published in

English or French up to

March 2013 in Medline (via

PubMed), EMBase, Cochrane

Library, and databases for

the American College of

Rheumatology (ACR) and

European League Against

Rheumatism (EULAR) annual

meetings. The key- words

were “influenza vaccines,”

“pneumococcal vaccines,”

and “rheumatoid arthritis,”

with no limit on the date of

publication.

12 studies included in meta-

analysis: 6 of influenza vaccine,

5 of pneumococcal vaccine, 1

both

Two studies assessed the

humoral response to

influenza vaccine with

(experimental group) and

without (control group) RTX

treatment. The response

rate was reduced with RTX,

but the pooled OR was not

significant for the H1N1

strain.

For the 2 studies evaluating

the response to

pneumococcal vaccine in

patients receiving RTX,

response rate was reduced

for both serotypes in the

experimental group with RTX

treatment as compared with

the control group, but the

pooled OR did not reach

significance for serotype 23F

Rituximab impairs

immunoglobulin (Ig)M and

IgG (subclass) responses

after influenza vaccination

in rheumatoid arthritis

23 RA patients on RTX

(treatment of 11 patients 4–8

weeks before vaccination and

of 12 patients 6–10 months

before vaccination. Controls on

RCT Ab levels measured before and

28 days following vaccination

Reduced IgG and particularly

IGM response to vaccine in

RTX pts. However, there was

a modest IgG response in

those 6-10 months since RTX

Conclusion regarding BAFF

and T cell response

somewhat confusing

Vaccination evidence table

207

patients.

Westra et al Clinical &

Experimental Immunology.

178(1):40-7, 2014174.

MTX and healthy controls

Efficient boosting of the

antiviral T cell response in B

cell-depleted patients with

autoimmune rheumatic

diseases following influenza

vaccination. Muller RB et al.

Clinical & Experimental


30, 2013265


16 pts having received Rtx

Prospective cohort study Influenza virus-specific

immune responses were

analysed after the first and a

booster vaccination with

PandemrixTM

2/7 with low (<10%) and 4/9

with normal (>10%) B cells

developed significant

antibody responses after first

vaccination. Booster

vaccination led to an

antibody response in one

additional patient. After the

first vaccination, virus-

specific CD4+ and CD8+ T cell

responses were significantly

lower in patients with low B

cells than in those with

normal B cells. Of

importance, the booster

vaccination stimulated the

antiviral T cell response only

in patients with low B cells.

T cell response to vaccine

may help compensate for

those who are B cell deplete

Rituximab-treated patients

have a poor response to

influenza vaccination.

Eisenberg et al.

Journal of Clinical

Immunology. 33(2):388-96,

2013266.

17 pts anticipated to receive

RTX


study

Seroconversion (4 fold increase

in ab titres) following ‘flu

vaccination measured.

Vaccinated at 7-9/12 following

RTX

2/12 vs 10/12 controls had

seroconversion following

vaccination

Patients with B cell counts of

>1 cell/mm3 did have some

response to vaccine (2 fold

rise in titre to one serotype),

while those subjects who

had B cell counts <1

cell/mm3 did not respond

Immunization responses in N= 69 RA pts with MTX plus RCT Ab responses post vaccine Response to tetanus toxoid “to maximize response,

208

rheumatoid arthritis


rituximab: results from a

controlled clinical trial.

Bingham et al.


62(1):64-74, 2010267.

RTX vs MTX alone vaccine same across groups

and no evidence of impaired

DTH response.

Reduced response to

pneumococcal vaccine

(secondary outcome)

polysaccharide and primary

immunizations should be

administered prior to

rituximab infusions”

Vaccination response to

protein and carbohydrate

antigens in patients with

rheumatoid arthritis after

rituximab treatment.

Rehnberg et al.

Arthritis Research &

Therapy. 12(3):R111,

2010175

19 RA pts with RTX

patients were vaccinated 6

months after RTX treatment

(post-RTX group, n = 11), or 6

days before RTX treatment

(pre-RTX group, n = 8). As a

control group, 10 patients

never treated with RTX were

included.


study

Vaccine specific B cells at 0, 6,

21 days

Pts immunised 6 days pre-

RTX had a better response at

21 days than those receiving

RTX 6 months previously.

Formation of influenza-

specific B cells was lower in

post-RTX group at day 6

compared with the pre-RTX

group and controls (P =

0.04). Polysaccharide-specific

B cells were found in 27% to

50%, being equally

distributed between the

groups. On day 21,

impairment of humoral

responses was more

pronounced for influenza

compared with

pneumococcal vaccine

(affecting both IgG and light-

chain production). Total

absence of influenza-specific

IgG production was observed

It is prob better to immunise

6 days before than 6 months

after RTX

209

in 55% of the post-RTX group

The Green Book- chapter

7133

“individuals due to

commence

immunosuppressive

treatments, inactivated

vaccines should ideally be

administered at least two

weeks before

commencement. In some

cases this will not be possible

and therefore

vaccination may be carried

out at any time and re-

immunisation considered

after treatment is finished

and recovery has occurred”

Rituximab and abatacept

but not tocilizumab impair

antibody response to

pneumococcal conjugate

vaccine in patients with

rheumatoid arthritis. Crnkic

Kapetanovic, Saxne,

Jönsson, Truedsson, &

Geborek.


Therapy. 15(5):R171,

2013268

55 RA pts with RTX Prospective case control

study

Ab response 4-6 weeks post

vacc

Pts with RTX had sig

diminished ab response

following pneum vaccine. no

statistically significant

differences in antibody

responses between patients

vaccinated within ≤180 days

compared to those receiving

vaccination >180 days after

the last rituximab treatment

Time from RTX to vaccine

very variable. (Range 0-894

days)

Randomized trial

investigating the safety and

31 GPA/MPA pts in remission

for > 3 /12 (24 vacc, 7 unvacc)

Open prospective

randomised study

Comparing ab response of AAV

vacc vs not vacc and non AAV

>70% AAV vac achieved

seroprotection at 28 days

No significant change in CRP,

disease activity as measured

210

efficacy of influenza

vaccination in patients with


antibody-associated

vasculitis. Jeffs et al.

Nephrology. 20(5):343-51,

2015170

vacc post vac to 2/3 strains by BVAS activity scores or

ANCA titres post- vaccination

Risk factors for severe

bacterial infections in

patients with systemic

autoimmune diseases

receiving rituximab.

Heusele et al. Clinical


805, 2014269.

AI pts having received RTX Retrospective case controls

study

Risk factors for infection History of pneumococcal

vaccination significantly

decreased the risk of Serious

bacterial Infections

(OR=0.11, 95%CI= 0.03–0.41,

p=0.0009)


following influenza

vaccination: causal

association or mere

coincidence? Birck, Kaelsch,

Schnuelle, Flores-Suárez, &

Nowack.

Journal of Clinical


91, 2009169.

Abstract only available 4 cases of new onset or

relapsing antineutrophil

cytoplasmic antibodies

associated vasculitis

occurring in “timely

association” with influenza

vaccination


patients show an adequate

antibody response to

influenza vaccination.

Holvast et al. Annals of the

GPA pts in randomly assigned

to receive influenza

vaccination (n = 49) or to

participate as controls (n = 23)

remission. 47% of vacc not on

RCT Ab response to vaccination at

0,1 and 3-4 months

WG patients achieved high

seroprotection rates to all

three influenza strains,

comparable with healthy

controls

No evidence of an increase

in ANCA or disease activity

following vaccination

Pts excluded if “active

disease” pred>30 mg/od or

211

Rheumatic Diseases.

68(6):873-8, 2009172.

IS cyc.

Cell-mediated immune

responses to influenza

vaccination in Wegener’s

granulomatosis. Holvast et

al.

Ann Rheum Dis

2010;69:924–927131

24 pts with GPA- all in

remission. 45.8% on

immunosuppression


study

Vaccine response at 28 days Found no differences in cell-

mediated immune responses

to subunit influenza

vaccination between

patients with WG and

controls

Responses were, at least

largely, independent of

previous vaccination status

and the use of

immunosuppressive drugs.

Antibody response to

inactivated subunit

influenza vaccine in

patients with Wegener's

Granulomatosis. Zycinska et

al.

Journal of Physiology and

Pharmacology. 2007, 58

suppl 5, p819-828270.

35 GPA pts in remission vacc

compared with 28 pts not vacc

(plus 35 healthy controls)


study

Ab response at 1 month >70% vac pts ab

seroprotection rate to 2/3

strains (compared with >85%

healthy subjects)

EULAR recommendations

for vaccination in adult

patients with autoimmune


diseases. van Assen et al.

414 Ann Rheum Dis

2011;70:414–422143.

Systematic lit review plus

Delphi

The vaccination status

should be assessed in the

initial investigation of

patients with AIIRD

Vaccination in patients with

AIIRD should ideally be

administered during stable

disease

Live attenuated vaccines

should be avoided whenever

possible in

immunosuppressed patients

212

with AIIRD

Vaccination in patients with

AIIRD can be administered

during the use of DMARDs

and TNFα blocking agents,

but should ideally be

administered before starting

B cell- depleting biological

therapy

Influenza vaccination should

be strongly considered for

patients with AIIRD

23-valent polysaccharide

pneumococcal vaccination

should be strongly

considered

for patients with AIIRD

Influenza vaccination does

not result in an increase in

relapses in patients with


Stassen PM, Sanders JS,

Kallenberg CG, Stegeman

CA Nephrol Dial Transplant

2008; 23: 654–658271

All consecutive AAV patients

from one centre who had a

follow-up of at least 1 year


Retrospective nested case

control study

Relapses occurring within 1

year of the vaccination were

attributed to that vaccination

The relapse rate per 100

patients at risk over the

period 1999–2004 was lower

in patients who had been

vaccinated within the

previous year (3.4) than in

patients who had not been

vaccinated against influenza

(6.3).

213

Article Patients Design Comparisons Outcomes Comments/refs

Cochrane review

Prophylaxis for

Pneumocystis pneumonia

(PCP) in non-HIV

immunocompromised

patients. Stern, A

Green, H

Paul, M

Vidal, L

Leibovici, L. 2015176

Cancer patients

(haematological and solid

organ malignancy) • Bone

marrow recipients • Solid

organ transplant patients •

Patients receiving

corticosteroids • Patients

receiving other

immunosuppressive

medications

(for connective tissue disease,

chronic lung disease,

inflammatory bowel disease) •

Severe malnutrition • Primary

immune-deficiency diseases

Electronic searches of the

Cochrane Central Register

of Controlled

Trials(CENTRAL)

(TheCochraneLibrary2014,

Issue 1),MEDLINE and

EMBASE (to March 2014),

LILACS (to March 2014),

relevant conference

proceedings; and

references of identified

trials

Thirteen trials performed

between the years 1974

and 2008 were included,

involving 1412 patients.

Any chemoprophylaxis

administered for the

prevention of Pneu-

mocystis infections versus

placebo, no intervention,

or an antibiotic(s) with no

activity against

Pneumocystis pneumonia.

Trials that compared

different antibiotics for the

prevention of

Pneumocystis infections

also included

Compared to no treatment or

treatment with fluoroquinolones

(inactive against Pneumocystis)

there was an 85% reduction in

the occurrence of PCP in

patients receiving prophylaxis

with

trimethoprim/sulfamethoxazole,

RR of 0.15 (95% CI 0.04 to 0.62;

10 trials, 1000 patients). The

evidence was graded as

moderate due to possible risk of

bias.

No significant differences in

overall adverse events or events

requiring discontinuation were

seen comparing

trimethoprim/sulfamethoxazole

to no treatment or placebo (four

trials, 470 patients, moderate

quality evidence)

Given an event rate of 6.2% in

the control groups of the

included trials, prophylaxis for

PCP using

trimethoprim/sulfamethoxazole

is highly effective among non-

HIV immunocompromised

patients, with a number needed

to treat to prevent PCP of 19

patients (95% CI 17 to 42).

Prophylaxis should be

considered for patients with a

similar baseline risk of PCP.

A Systematic Review of Two

Different Trimethoprim–

Sulfamethoxazole

Regimens Used to Prevent

576 solid organ transplant

recipients

Electronic searches of

MEDLINE, EMBASE and

Cochrane reviews Key

words were prophyl*,

4 studies comparing full-

dose

prophylaxis (160/800 mg/d

every day), low-dose

Incidence of PJP among patients

undergoing full- dose

prophylaxis was 0% (0/181),

1% in those undergoing

There appeared to be no sig

difference in incidence of

infection between those on full

or low dose prophylaxis.

Pneumocystis evidence table

214

Pneumocystis jirovecii and

No Prophylaxis

at All in Transplant

Recipients: Appraising the

Evidence. Di Cocco et al.

Transplantation

Proceedings, 41, 1201–1203

(2009)186

transpl*, trimethophrim,

sulfamethoxazole,

Pneumocystis carinii

and jiroveci, prevent*, and

pneumonia. Quality of

studies assessed using

GRADE system

prophylaxis (80/400 mg/d

every day or 160/800

mg/d every other day) , or

no prophylaxis at all were

analysed

low-dose prophylaxis (1/105;

range, 0%–2%);

and 11%

in those who did not receive

prophylaxis (31/284; range, 4%–

41%).

Pneumocystis jirovecci

pneumonia in connective

tissue diseases: Comparison

with other

immunocompromised

patients. Teichtahl et al.

Seminars in Arthritis &

Rheumatism. 45(1):86-90,

2015183.

90 subjects who fulfilled the

diagnostic criteria of

either a positive P. jirovecii PCR

(64%) or toludine blue O stain

(36%) with a concurrent

respiratory illness were

included in the study. 11 of

these had CTDs


case control study.

(i) to examine the

contribution of CTDs to the

total number of PJP

diagnoses and (ii) to

determine any between

group differences in

subject characteristics and

basic laboratory

parameters between

people with non-CTDs and

CTDs who had been

diagnosed with PJP

Around the time of PJP

diagnosis, people with CTDs

were significantly older, had

greater lymphopaenia and worse

renal function than non-CTD

subjects and were more likely to

have been exposed to

corticosteroids or other

immunosuppression

Small study (i.e. numbers of

CTD patients) but interesting

results.

CTD pts contributed 21.6% of

the PJP cases in this centre

once HIV population had been

excluded. Mortality from PJP

27.3 % vs 2.5% in the non- CTD

population

Pneumocystis jirovecii

pneumonia in patients with

autoimmune disease on

high-dose glucocorticoid.

Chew, Maceda-Galang, Tan,

Chakraborty, & Thumboo.

Journal of Clinical


2015272.

1063 pts hospitalised to

Singapore General Hospital

between January 2003 and

December 2007. Patients with

concomitant diagnosis of

HIV/AIDS were excluded


cohort study

Patient demographics,

mean glucocorticoid dose

(in the last 1 month), and

the outcomes of patients

who developed PCP were

analysed.

4 pts developed PJP, none of

whom had received prophylaxis.

Authors conclude that the RR of

developing PJP on high dose

(>30mg/day) pred vs low dose is

19 as ¾ pts who developed PJP

were on high dose.

Overall incidence of PJP in this

study in AI disease was 0.075%

Small numbers

Predisposing factors, clinical 62 HIV-negative adult patients Single centre retrospective The aim of this study was 50% had haematological

215

characteristics and outcome

of Pneumonocystis jirovecii

pneumonia in HIV-negative

patients. Kofteridis et al.

Journal of Infection &

Chemotherapy. 20(7):412-

6, 2014273.

admitted to

the University Hospital of

Heraklion, Crete, Greece and

diagnosed with PCP from

January 2004 through to May

2013

cohort study to investigate the

predisposing factors,

clinical features and

outcome of Pneumocystis

pneumonia in HIV-

negative patients

malignancies, 26% solid tumour

and 24% chronic inflammatory

disease. 34% of those

developing PCP had received co-

trimoxazole prophylaxis.

Mortality rate 29%.


pneumonia in HIV-negative

patients: a prospective

study with focus on

immunosuppressive drugs

and markers of immune

impairment. Roblot et al.

Scandinavian Journal of

Infectious Diseases.

46(3):210-4, 2014274

Abstract only Low lymph/CD4 and high

corticosteroid exposure seem to

be risk factors for development

of PJP

A dose-escalation regimen

of trimethoprim-

sulfamethoxazole is

tolerable for prophylaxis

against Pneumocystis

jiroveci pneumonia in

rheumatic diseases.

Takenaka, Komiya, Ota,

Yamazaki, & Nagasaka.

Modern Rheumatology.

23(4):752-8, 2013275

41 pts with rheumatic diseases

receiving co-trimoxazole as

prophylaxis due to (1)

treatment with 0.8 mg/kg/day

or more of prednisolone (PSL),

(2) 0.5 mg/kg/day or more of

PSL with immunosuppressive

agents, (3) 0.5 mg/kg/day or

more of PSL in patients with

pulmonary complications, (4)

20 mg/day or more of PSL in

patients over 80 years of age

Retrospective single centre

cohort study

Dose escalation of

TMP/SMX from 10% to

100% over > 3 days vs

starting on full dose

6 month retention rate on

TMP/SMX higher in the

incremental group but not stat

sig. Almost half pts were on

smaller doses than

recommended. 1 case of PJP in

the routine group after cessation

of TMP/SMX

Dose escalation may be helpful

to increase tolerability. Small

doses than recommended of

TMP/SMX may protect against

PJP.

Pneumocystis jirovecii 8 patients with RA who Case series and review R/v- discussed RF for This describes PJP outbreak in

216

pneumonia in rheumatoid

arthritis patients: Risks and

prophylaxis

recommendations.

Mori S., Sugimoto M.

Clinical Medicine Insights:

Circulatory, Respiratory and

Pulmonary Medicine. 9 (pp

29-40), 2015182.

developed PJP in a single

centre between March 2005

and October 2009

development- older, steroids,

higher dose, pre-existing lung

disease lymphopenia, carriage of

PJP.The Japanese Ministry of

Health, Labor and Welfare Study

Group recommended the use of

TMP-SMX or pentamidine as a

prophylactic against PCP for

patients with inflammatory

rheumatic diseases over the age

of 50 receiving steroids

equivalent to 1.2 mg/kg/day of

prednisolone or more, 0.8

mg/kg/day of prednisolone or

more plus immunosuppressives,

or peripheral lymphocyte counts

<500/mL during

immunosuppressive therapy.

pts on methotrexate only.

Suggests short term prophylaxis

for all those on IS if new case

identified in dept (i.e. 5-7 days)

Increasing Pneumocystis

pneumonia, England, UK,

2000-2010. Maini R et al.

Emerging Infectious

Diseases. 19(3):386-92,

2013276.

All patients coded in HES as

having had PJP between 2000

and 2010. 2258 cases identified

Retrospective cohort study Number of cases 2000 till

2010 and proportion of

disease groups

contributing

HIV related PJP reducing but

incidence PJP increasing. Largely

contributed to by haem

malignancy and transplant

patients


pneumonia in two patients

with systemic lupus

erythematosus after

rituximab therapy. Bonilla-

Abadia, F. et al.

2 pts with lupus Case reports 1 pt developed PJP with

refractory lupus requiring 2g RTX

every 9 months over 4 years plus

pred 5 and aza 50mg- survived.

2nd pt developed PJP 6 weeks

after first dose RTX- died

217

Clinical Rheumatology.

33(3):415-8, 2014277.

Should Pneumocystis

jiroveci prophylaxis be

recommended with

Rituximab treatment in

ANCA-associated vasculitis?

Besada & Nossent

Clinical Rheumatology.

32(11):1677-81, 2013181

67 yo male GPA, previous CYC,

MTX relapsed on MMF. Given

RTX and developed PCP 3/12

later

Case study and review Review includes 6 pts with PCP

following RTX with AAV. PJP

reported at developing 2,3

months but also as late as 32

months following last RTX. 50%

on RTX monotherapy

Retrospective study from a

single centre—Mayo Clinic

Rochester between 1998 and

2011—identifies 30 patients that

developed PCP after RTX

treatment: 90 % had

haematological malignancies.

10% on RTX monotherapy.

Patients mostly older males—73

% males with a median age of 70

years—and 27 % have chronic

renal disease. PCP occurred after

a median of four RTX Cycles and

a mean of 77 days after its last

administration. Patients have

low lymphocytes (0.38×109/L),

CD4 (0.025× 109/L) and CD8

(0.077×109/L) counts at PCP

onset with undetectable B cell

counts.

In summary, a thorough

assessment of the patient’s

net state of immunodeficiency

before administering RTX can

help stratify the risk for both

colonisation and PCP

development. Risk factors to be

considered are age, renal or

lung involvement, previous

infections due to T cell-

mediated immunity

dysfunction, blood tests

(lymphocytopenia, low CD4 cell

count and inverted ratio) and

concomitant therapy

Pneumocystis pneumonia in


30 patients who received

rituximab and developed PcP


cohort review

To establish the underlying

conditions, clinical course,

Only 1 pt had GPA, majority had

haem malignancy. The mean

3 patients developing PcP were

on single immunosuppression

218

rituximab. Martin-Garrido,

Carmona, Specks, & Limper.

Chest. 144(1):258-65,

2013278.

at Mayo Clinic Rochester over

the years 1998 to 2011

possible risk factors, and

potential association

between RTX and PcP

number of days from last

administration of rituximab to

development of PcP was 76.8 +/-

21.6 day. Only 1 pt had received

prophylaxis. Mortality was 30%

with RTX

Increased risk of




Jarrousse et al . Clin Exp

Rheumatol. 1993 Nov-

Dec;11(6):615-21180

6 cases of Pneumocystis carinii

pneumonia (PCP) in 23 patients

with biopsy-proven WG and

renal involvement over 10

months (pts were in clinical

trial of either intermittent

high-dose pulse Cy or daily oral

low-dose Cy in combination

with oral prednisone.)

Full text not available-

therefore abstract

reviewed

Mean delay of onset of PCP was

2.5 months after the beginning

of the immunosuppressive

therapy. None of the patients

experienced severe leukopenia

at the time of diagnosis, but the

mean lymphocyte count

decreased to 495/mm3 (range

100 to 830/mm3) and 2 patients

had inverted CD4/CD8 T-cell

ratios. Renal function was

significantly impaired (creatinine

= 493.5 vs 195.4 micromol/l; p =

0.03) in the 6 patients

presenting PCP vs those without.

High-dose co-trimoxazole

therapy was successful in 3

patients, but 3 others who

required mechanical ventilation

died.

26% over 10 months= 31% over

12 months

Fact or fiction: does the

non-HIV/AIDS

immunosuppressed patient

need Pneumocystis jiroveci

pneumonia prophylaxis? An

A review to answer the

questions (1) at what level of

immunosuppression should

one initiate prophylaxis, and

(2) what is the best type of

Search was conducted

with “appropriate MeSH

terms”, using PubMed,

Medline, and The

Cochrane Database. MeSH

Included 7 articles, with

199 patients who

developed PJP (cancer,

transplant, inflammatory

conditions)

25% of patients developed PJP

after 8 wk of therapy with dose

equivalent of 30 mg prednisone.

Median duration of

corticosteroid therapy before

Vague search strategy

219

updated literature

review.Grewal & Brassard.

Journal of Cutaneous

Medicine & Surgery.

13(6):308-12, 2009279.

prophylaxis to use for non- HIV

immunosuppressed pts

terms included PJP, PCP,

prophylaxis, Pneumocystis,

non-HIV, non-AIDS, and

immunosuppression.

the development of PJP was 12

wk

Corticosteroid use, whether it

was stable or being tapered, was

a risk factor in 77% of patients

developing PJP

Audit of pneumocystis

pneumonia in patients seen

by the Christchurch Hospital

rheumatology service over

a 5-year period. Meuli et al.

Internal Medicine Journal.

37(10):687-92, 2007177.

Rheumatology pts having been

prescribed MTX (n=547, 50

randomly selected for more

detailed case review) or

Cyclophos (n=50)


case review

Comparison for the risk of

developing PJP whilst on

CYC vs MTX

4/597 pts develop PJP, 2 on MTX

and 2 on CYC

Only 14 of 47 (29.7%) CYC-

treated patients received PCP

prophylaxis. The annual

incidence of PCP was 0.17%

(95% confidence interval (CI)

0.02–0.63) and 5.33% (95%CI

0.65–19.24) in patients

prescribed MTX and CYC,

respectively. For the 33 patients

receiving CYC without

concomitant PCP prophylaxis the

annual incidence was 9.50%

(95%CI 1.15–34.33).

Infection-related morbidity

and mortality in patients

with connective tissue

diseases: a systematic

review. Falagas, Manta,

Betsi, & Pappas. Clinical


70, 2007280.

CTD patients with infections Systematic review. Search

terms=

“systemic lupus

erythematosus”,

“rheumatoid arthritis”,

”dermatomyositis”,

“polymyositis”,

“Wegener’s

granulomatosis”, “Sjogren

7 articles included with PJP

reported as an outcomes,

of these 64 patients had

GPA

Mortality in this population

reported as between 41 and

61.3%.All pts for whom there

was data for were on high dose

steroid (1mg/kg/day or 60mg)

plus additional IS

220

syndrome”,

“systemic

sclerosis/scleroderma”,

“connective tissue

disease”,

“steroid treatment”,

“methylprednisolone”,

“infection”,

“prophylaxis”,

“Pneumocystis carinii

jiroveci”

Autoimmune inflammatory

disorders, systemic

corticosteroids and

pneumocystis pneumonia: a

strategy for prevention.

Sowden & Carmichael.

BMC Infectious Diseases.

4:42, 2004 Oct 16184.

Pts with AID and PJP General review(not

structured)

Risk factors for PJP in this

population mentioned as

steroids, > 15mg/day steroid,

other immunosuppression, low

lymphs, low CD4, ? presence of

underlying lung disease but

likely presence of steroids plus

inflammation.

They suggest the following

approach to prophylaxis

Given the laboratory costs, we

would argue in favour of

performing CD4+ counts after

one month's

immunosuppression only on

patients who satisfy the

following three screening

criteria:

• Steroid dosage >15 mg

prednisolone or equivalent/day

• >three months corticosteroid

treatment proposed • total

lymphocyte count <600

cells/mm3

A CD4+ count <200 cells/mm3

might then warrant the use of

prophylactic co-trimoxazole, if

221

the annual risk of PCP in these

patients is greater than 9%.

Most cases of PCP in patients

with AID would be captured by

these criteria, according to

published series.

Adverse events and

infectious burden, microbes

and temporal outline from

immunosuppressive

therapy in antineutrophil

cytoplasmic antibody-

associated vasculitis with

native renal function.

McGregor et al. Nephrology

Dialysis Transplantation. 30

Suppl 1:i171-81, 2015281

Biopsy-proven AAV patients

(diagnosed 1/1991–6/ 2011)

followed in an inception

cohort.

374 pts with 2 years f/u

Prospective cohort study Description of infection

rate and type, adverse

events, ESKD, death

Cumulative incidence infection

(any) at 5 years 65% 9severe

infection 26%.

1 PJP 6/52 post induction

therapy. This patient had not

received prophylaxis

Adds little to PJP data but good

for infection overall

Frequency, risk factors and

prophylaxis of infection in


Kronbichler, Jayne, &

Mayer. European Journal of

Clinical Investigation.

45(3):346-68, 2015282.

Includes 17 articles with

opportunistic infection

described as an outcomes

Review Description of infections as

outcome

Number of cases of PJP within

reviewed articles (ND=not

documented)

1. PJP 3/133- Flossman

2. Charlier ND

3. PJP 12/38- Bligny

4. PJP 6 Aasarod

5. PJP 2 Goupil

6. PJP 1 Harper

7. PJP 1.4% Booth

8. Weldanz ND

9. Lionaki ND

10. PJP 1 Charles

Risk factors (for infection)

identified as being: older age,

high creat/dialysis, lung

disease, steroids, leucopenia,

lymphopaenia, neg/falling

ANCA, IS on dialysis,

Total n=47 (plus from Booth n=

? unable to find raw data)

Authors recommend PJP

prophylaxis on CYC, on RTX

until pred < 10mg, or when

222

11. PJP 1 Cartin Ceba

12. Chen ND

13. Itabashi ND (but 4

deaths due to PJP)

14. PJP 8 Palsson

15. PJP 1 Uezono

16. Matsumoto ND

17. PJP 12 Godeau

lymph count <300

Incidence of Pneumocystis

jiroveci pneumonia among

groups at risk in HIV-

negative patients. Fillatre

et al. American Journal of

Medicine.

127(12):1242.e11-7, 2014283

All pts with PJP in 20 yr period,

HIV neg


cohort review

From 1990 to 2010, 293 cases of

PJP documented, of which 154

(52.6%) tested negative for HIV.

The main underlying conditions

were haematological

malignancies (32.5%), solid

tumours (18.2%), inflammatory

diseases (14.9%), solid organ

transplant (12.3%), and vasculitis

(9.7%).

GPA pts ranked as high risk

(incidence rates >45 cases per

100,000 patient- year)

Value of anti-infective

chemoprophylaxis in

primary systemic vasculitis:

what is the evidence?

Moosig, Holle, & Gross.


Therapy. 11(5):253, 2009284

Review Recommends PJP proph as TMX

for all those receiving pred >

15mg/day plus additional IS or

pentamadine for those with

intolerance

Cost-effectiveness of

prophylaxis against

Hypothetical cohort A Markov state-transition

model was developed to

1) no prophylaxis; 2)

trimethoprim/sulfamethox

Prophylaxis using TMP/SMX

alone increased life expectancy

223



Wegner's granulomatosis

undergoing

immunosuppressive

therapy. Chung, Armstrong,

Schwartz, Albert, & Al.


43(8):1841-8, 2000.285.

follow a hypothetical

cohort of WG patients

over their lifetimes

starting from the time of

initial exposure to the

immunosuppressive

therapy

azole (TMP/SMX) 160

mg/800 mg 3 times a

week, which is

discontinued if patients

experience an adverse

drug reaction (ADR); and

3) TMP/SMX 160 mg/800

mg 3 times a week, which

is replaced by monthly

aerosolized pentamidine

(300 mg) if patients

experience an ADR

and reduced cost for patients

with WG receiving


Replacing TMP/SMX with

monthly aerosolized

pentamidine in cases of ADR

further increased life

expectancy, although at an

increased cost.

Pulmonary complications of

combination therapy with

Cyclophosphamide and

prednisone. Sen, Walsh,

Fisher, & Brock. Chest.

99(1):143-6, 1991.286

Case series HIV neg PJP (4 pts) Single centre case series Risk factors identified as;

hypoalbuminemia (serum

albumin level less than 3.0 g/dl)

and daily (pred plus CYC) therapy

were associated with increased

risk for development of PCP (p

less than 0.05). None of the

patients had leukopenia (less

than 3,500/cu mm) or

neutropenia

Note n=4



pneumonia in Wegener's

granulomatosis. Godeau et

al.


Diseases. 54(12):991-4,

1995.185

12 pts with GPA and PJP

compared with 32 pts with

GPA and without PCP (1984-

1992 in 4 centres)


study

Pt characteristics PCP vs

no PCP compared.

Excluded if has received

primary prophylaxis

Mean delay before onset of PCP

was 128 (SD 127) days after the

beginning of immunosuppressive

therapy (median 90 days, range

50-510)

smallest lymphocyte count was

significantly less in the PCP

group (244 (362)/mm3 (range 0-

Threshold of 600 lymphocytes

per mm3 during the first three

months after diagnosis

suggested to define the group

of patients at greater risk of

PCP.

224

1200) v 738

(543)/mm3 (range 60-2400); p =

0001).

Mean cum CYC dose higher in

PJP gp (may represent more

aggressive disease though)


pneumonia: a major

complication of

immunosuppressive

therapy in patients with


Ognibene FP et al. Am J

Respir Crit Care Med 1995,

151:795-799287

Abstract only available.

11 cases of GPA in 180 pts

Retrospective cohort

review

All patients were receiving daily

steroids and a second


Lymphocytopaenia was noted in

all patients, with a mean +/- SEM

total lymphocyte count of 303

+/- 69 cells/microL

A prospective, multicenter,

randomized trial comparing

steroids and pulse

cyclophosphamide versus

steroids and oral

cyclophosphamide in the

treatment of generalized

Wegener’s granulomatosis.

Guillevin L, et al. Arthritis

Rheum 1997, 40:2187-

2198135.

50 pts with GPA Prospective RCT Pulsed iv cyc vs daily oral

cyc, remission at 6 months

and longer follow up

compared

Pneumocystis carinii pneumonia

was higher in oral CYC-treated

patients (30.4%) than in pulse

CYC-treated patients (11.1%).

Total of 10/50 cases 20%

(prophylaxis added after first 12

pts due to high rate PCP)

225

Population Study design Comparisons Outcomes Comments

Mould-active compared with fluconazole

prophylaxis to prevent invasive fungal

diseases in cancer patients receiving

chemotherapy or haematopoietic stem-

cell transplantation: a systematic review

and meta-analysis of randomised

controlled trials. Ethier et al. Br J Cancer.

2012 May 8;106(10):1626-37

288.

Cancer pts receiving

chemotherapy or

haematopoetic SCT

Systematic review and

meta-analysis of RCTs from

984 reviewed articles, 20

were included in this review

Primary outcome

was proven/probable

invasive fungal

infections (IFI)

Mould-active compared with fluconazole

prophylaxis significantly reduced the number

of proven/probable IFI (RR 0.71, 95% CI 0.52 to

0.98; P=0.03). Mould-active prophylaxis also

decreased the risk of invasive aspergillosis (IA;

RR 0.53, 95% confidence interval (CI) 0.37–

0.75; P=0.0004) and IFI-related mortality (RR

0.67, 95% CI 0.47–0.96; P=0.03) but is also

associated with an increased risk of adverse

events (AEs) leading to antifungal

discontinuation (RR 1.95, 95% CI 1.24–3.07;

P=0.004). There was no decrease in overall

mortality (RR 1.0; 95% CI 0.88–1.13; P=0.96).

Baseline incidence IFI on

fluconazole in HSCT seems to be

around 15%, higher that in AAV

as “candidiasis” (not qualified as

invasive or not) in combined

EUVAS only 10%. No aspergillosis

mentioned

Candidiasis (oropharyngeal). C

Pankhurst. British Medical Journal:

Clinical Evidence. 2013 188.

Oropharyngeal candidiasis

affects between 15% and

60% of people with

haematological or

oncological malignancies

during periods of

immunosuppression

What are the effects

of interventions to

prevent and treat

oropharyngeal

candidiasis in adults

undergoing

treatments that

cause

immunosuppression?

In people with immunosuppression following

cancer treatment, absorbed (ketoconazole,

itraconazole, or fluconazole) or partially

absorbed antifungal drugs (miconazole,

clotrimazole) prevent oropharyngeal

candidiasis compared with placebo or non-

absorbed antifungal drugs.

• Non-absorbed antifungal drugs (nystatin or

amphotericin B) may be no more effective

than placebo at preventing candidiasis

Too few studies in those pts

having tissue transplants to draw

conclusions.

Antifungal agents for preventing fungal

infections in solid organ transplant

Fourteen unique trials

with 1497 randomised

Systematic r/v Invasive Fungal

Infections (IFI) rates

Antifungal prophylaxis did not reduce

mortality (RR 0.90, 95% CI 0.57 to 1.44). In

The overall rate of proven

infections (IFI) in the control arm

Viral and fungal prophylaxis evidence table

226

recipients. Playford, Webster, Sorell, &

Craig.

EBM Reviews - Cochrane Database of

Systematic Reviews

Cochrane Database of Systematic

Reviews. 4, 2009189.

participants were

included, SOT

liver tx recipients, a significant reduction in

IFIs was demonstrated for fluconazole (RR

0.28, 95% CI 0.13 to 0.57). Although less data

was available for itraconazole and liposomal

amphotericin B, indirect comparisons and one

direct comparative trial suggested similar

efficacy. Fluconazole prophylaxis did not

significantly increase invasive infections or

colonisation with fluconazole-resistant fungi.

In renal and cardiac transplant recipients,

neither ketoconazole nor clotrimazole

significantly reduced invasive infections.

Overall, strength and precision of comparisons

were limited by paucity of data.

i.e. no prophylaxis, of these four

studies was 13%(range 4 to 23%)-

therefore perhaps a rate more

comparable to the AAV

population rather than HSCT

Asymptomatic cytomegalovirus viremia

is associated with increased risk of

pneumocystis and fungal infections.

Poglajen G.et al.

Journal of Heart and Lung

Transplantation. Conference: 34th

Annual Meeting and Scientific Sessions of

the International Society for Heart and

Lung Transplantation, ISHLT 2014 San

Diego, CA United States.

70 consecutive adult heart

transplant recipients

To investigate the

aetiology and time

course of

opportunistic

infections in pts with

asymptomatic CMV

viraemia

In CMV Group, we found a significantly higher

incidence of PJP (45% vs. 2%, P< 0.001) and

fungal infections (27% vs. 1%; P< 0.001). On

average, PJP infections occurred 4.2+/-3.1

months after CMV viremia, and fungal

infections occurred 1.4+/-0.7 months after

CMV

Mean time from transplantation

to CMV viremia was 10.4+/-1.5

months (PJP, CMV and fungal

prophylaxis continued for 6

months post-transplant)

Duration of prophylaxis against fungal

infection in kidney transplant recipients

Guerra C Formica R Kulkarni S et. al.

Progress in Transplantation, 2015289.

84 KTR recipients Single centre retrospective

case-control study

Compare the efficacy

of two strategies

prophylaxis with

nystatin suspension

(NPx) in kidney

transplant recipients

Primary outcome was the incidence of thrush

and Candida esophagitis within 3 months post-

transplantation

Limiting the administration of NPx to the

duration of admission after tx appears

sufficient for prophylaxis of fungal infections in

227

(KTR). (KTR prior to

the protocol change

received NPx

500,000 units swish

and swallow for 2

month (pre group)

and KTR after the

change received NPx

for the duration of

admission (post

group)

KTR.

Risk factors for invasive fungal disease in

heart transplant recipients.

Rabin A.S., Givertz M.M., Couper G.S.,

Shea M.M., Peixoto D., Yokoe D.S.,

Baden L.R., Marty F.M., Koo S.

Journal of Heart and Lung

Transplantation. 34 (2) (pp 227-232),

2015290.

Not so relevant as risk factors are

drugs not used in vasculitis and

the surgery itself

Efficacy and safety of measles, mumps,

rubella and varicella live viral vaccines in

transplant recipients receiving

immunosuppressive drugs.

Danerseau A, Robinson J. World Journal

of Pediatrics

2008 vol: 4 (4) pp: 254-258291.

Six case series studies

(n=112 children) and 2

case reports (adults)- SOT

Systematic review Post-immunisation titres were in the immune

range in 57% (82/145) of situations where they

were measured (17-100%) following a single

dose of vaccine, in 68% (15/22) of situations

following two doses and in two of two cases

following three doses. Three cases of mild

varicella There was one case of rejection three

weeks post-immunisation of MMR and

measles vaccines

Insufficient published data to

derive evidence-based guidelines

for use of live viral vaccines in

transplant recipients on

immunosuppression. Preliminary

data on efficacy and safety

suggested that the use of these

vaccines in transplant recipients

still on immunosuppression could

be a reasonable strategy.

Long-term acyclovir for prevention of 77 hematopoietic cell Double blind placebo VZV disease at 1 year Highly significant reduction of VZV disease was Authors conclude “acyclovir given

228

varicella zoster virus disease after

allogeneic hematopoietic cell

transplantation--a randomized double-

blind placebo-controlled study.

Boeckh M, Kim HW, Flowers ME, Meyers

JD, Bowden RA

Blood. 107(5):1800-5, 2006190.

transplant recipients at

risk for VZV reactivation

were randomized to

acyclovir 800 mg twice

daily (38) or placebo (39)

given from 1 to 2 months

until 1 year after

transplantation.

controlled RCT was the primary end

point

seen in acyclovir recipients. no sig diff in

adverse effects

at 800 mg twice daily until 1 year

after transplantation is a safe and

highly effective strategy to

prevent clinical VZV infections in

hematopoietic cell transplant

recipient”

B Cell Therapies, Approved and

Emerging: A Review of Infectious Risk

and Prevention During Use. Md Yusof,

Vital, & Buch. Current Rheumatology

Reports. 17(10):65, 2015292.

Non- systematic review Data from RCTs and LTE studies in 3194

patients with RA

reported 108 cases of herpes zoster in 100

patients (including

two cases of ophthalmic herpes zoster and five

SAEs) in the all exposure group compared to

13 cases in the placebo+MTX group, rates of

9/1000 and 11.7/1000 patient-years,

respectively. This is comparable to the rate in

the general RA population, 11.5/1000 patient-

years.

229

6 A DELPHI STUDY TO ASSESS THE PREVENTION OF

TREATMENT AND DISEASE RELATED MORBIDITY IN VASCULITIS

(ADAPTIV): RECOMMENDATIONS Overarching Recommendations

1. Patients should be educated to engage in follow up care. This may include the

appropriate use of self-referral pathways to secondary care when unwell.

2. Primary care should be involved with stable patients, being aware of the

immunosuppressive medication they are taking and be responsible for lifestyle advice.

3. With regards to maintaining bone health, patients should have overall fracture risk

assessed rather than just Bone Mineral Density (BMD). Patients with CKD 4/5 should

have bone disease managed in conjunction with specialist centres (renal/ endocrine).

4. Patients with vasculitis have a higher cardiovascular (CV) risk than the general

population and therefore CV risk assessment should be carried out on an at least annual

basis. Awareness of increased CVD risk in vasculitis should be raised in both primary and

secondary care and to the patient.

5. There is a need for recognition of the increased infection risk of patients with ANCA

associated vasculitis. We recommend vaccination against ‘flu and pneumococcus for this

population and Pneumocystic jiroveci prophylaxis for those on “induction” therapy.

6. There should be awareness of the possible effects of cyclophosphamide therapy on

both female and male fertility. Therefore, in the absence of life/organ threatening

disease alternatives should be considered. Where alternative therapies are not possible,

strong links with the local reproductive health unit should be in place to enable gamete

storage where appropriate.

7. Patients should be counselled and educated with regards to possible increased cancer

risk. These patients should be strongly encouraged to attend routine population cancer

screening and should undergo regular skin surveillance.

230

Level of evidence

Grading of recommendations and evidence levels

Levels of evidence for studies of intervention are defined as follows:

Ia from meta-analysis of randomised controlled trials (RCTs)

Ib from at least one RCT

IIa from at least one well designed controlled study without randomization

IIb from at least one other type of well-designed quasi-experimental study

III from well-designed non-experimental descriptive studies, e.g. comparative studies,

correlation studies, case-control studies

IV from expert committee reports or opinions and/or clinical experience of authorities

The quality of the guideline recommendations is similarly graded to indicate the levels of

evidence on which they are based:

grade A: evidence levels Ia and Ib

grade B: evidence levels IIa, IIb and III

grade C: evidence level IV

6.1 BONE HEALTH

ANCA Associated Vasculitis is predominantly a disease of the older population with peak

age of onset being 65-74 years38. In addition, due to the ongoing reliance on

immunosuppressive regimens with a significant corticosteroid exposure, these patients are

at risk from glucocorticoid-induced osteoporosis (GIOP). The disease process itself likely

contributes further to this risk through effects from cytokines involved in the inflammatory

process 117.

Fracture risk increases early on during glucocorticoid exposure (the first 3 to 6 months) and

reduces again following steroid withdrawal. The risk increases to be most significant for

those taking a dose of greater than or equal to 7.5 mg/day prednisolone and it is the risk of

vertebral fractures that increases most293. The following recommendations are therefore

made for preservation of bone health in patients with AAV. The recommendations here

231

mirror the currently available national/ international guidelines for prevention and

treatment of GIOP, which will require updating on a regular basis.

1) Patients should have overall fracture risk assessed rather than just Bone Mineral

Density (BMD) using a validated risk prediction model (Evidence A, 1a) (expert consensus

level 81%)

Currently validated assessment tools include FRAX and QFracture 2012. However, FRAX has

limitations in that it assumes an average dose of prednisolone of between 2.5 and 7.5mg

per day149. Adjustments are recommended for those taking prednisolone doses outside this

range (see NOGG for details). Algorithms for determining whether BMD measurements are

required are available from the NOGG. However, in general women over 70 years, or with

previous fragility fracture or taking > 15mg prednisolone/day should be considered for

bone protective therapy. Preventative therapy options for GIOP includes; alendronic acid,

risedronate or zolendronic acid for those patients who are intolerant of oral

bisphosphonates and in whom adherence to oral therapy may be difficult150. Treatment

review is recommended after 5 years (alendronate, risedronate or ibandronate) or 3 years

(zolendronic acid) but those who are high risk should generally continue treatment (over

age 75 years, those with previous hip/vertebral fracture and those continuing on

prednisolone doses greater than 7.5mg/day).149

2) Specialist management of bone disease in patients with stage Chronic Kidney Disease

(CKD) Stages 4 and 5 is required (Evidence IV).

In patients with advanced renal impairment (CKD 4 and 5) there is limited safety data for

bisphosphonates. Alendronate is not recommended in patients with a creatinine clearance

of <35mls/min and risendronate is contraindicated with a creatinine clearance <30mls/min.

The use of ibandronate is recommended with caution at creatinine clearance <30mls/min

and zolendronate at <35mls/min. In addition, it should be borne in mind that DEXA

scanning in patient with CKD stage 3 to 5 may not provide valid information in the presence

of metabolic bone disease294.

3) All patients should be counselled regarding risks prior to bisphosphonate therapy

including osteonecrosis of the jaw, avascular necrosis of the hip and “frozen

bone”/subtrochanteric hip fracture (Grade C, Evidence IV) (expert consensus level

94%)

232

Dental assessment and pre-emptive treatment is recommended prior to commencement

with bisphosphonates due to the risks of non-healing following extraction if on therapy.

However, dental treatment on bisphosphonate therapy is not contra-indicated if it is

required149.

4) Vitamin D levels should be checked at baseline with replacement and maintenance

therapy prescribed as required (Grade A, Evidence 1b).

More frequent lower dose vitamin D should be considered as annual high dose vitamin D

has shown an increase in falls and fractures. There should be awareness of seasonal

variation in vitamin D levels. Increased dietary calcium may be preferable to calcium

supplementation due to concerns regarding increased cardiovascular event rates in a study

of calcium supplementation, although the majority of studies have reported calcium as

having a neutral or beneficial effect on CV event rates295.

5) Treatment with Denosumab should be considered for use in patients where

bisphosphonates have been contraindicated (Grade A, Evidence 1a) (expert consensus

86%).

Denosumab is NICE approved in this scenario for the primary prevention and treatment of

osteoporosis in post-menopausal women296. Denosumab should never be administered in

the presence of hypocalcaemia. Patients with eGFR less than 30ml/min are at higher risk of

hypocalcaemia and therefore should have regular calcium monitoring whilst on

Denosumab297.

6.2 CARDIOVASCULAR RISK MODIFICATION

It is acknowledged that patients with AAV have an increased risk of thromboembolic

disease, particularly associated with periods of active disease112. In more recent years

epidemiological cohort studies and analysis of the EUVAS clinical trial follow- up data has

supported that this patient population has a higher rate of CVD in addition, with this

contributing to later death in the bimodal pattern of mortality seen in this population198.

233

1) Patients with vasculitis have a higher cardiovascular risk than the general

population and therefore cardiovascular (CV) risk assessment should be carried out on an

at least annual basis (Grade B, Evidence III)(expert consensus level 94%)

Matched cohort studies have demonstrated an increased incidence of CV events in AAV

patients, with an observed to expected ratio of 1.9 in one study compared with the

background population 114 and a hazard ratio of 2.23 compared with a CKD population 115.

This observation has led to the development of a model for predicting cardiovascular

events in AAV patients with age, diastolic hypertension and absence of PR3 antibodies

being identified as risk factors for cardiovascular events in newly diagnosed AAV 116. A

smaller French study has recently suggested that the risk of cardiovascular events in this

population may be 2- 3 times that which may be anticipated through conventional risk

factor stratification203. However, as yet there is insufficient evidence to support that

patients with AAV should be treated differently to other patient groups with regards to

primary prevention of CVD.

There are multiple smaller studies in addition, reporting abnormal surrogate markers for CV

outcomes such as intimal medial thickness (IMT) on USS or Ankle-brachial Pressure Index

(ABPI) in patients with vasculitis 159–161. It should also be noted that patients with AAV may

have cardiac involvement as a manifestation of their disease that may be asymptomatic

and not detectable using conventional cardiac imaging such as echocardiography298,299.

2) Awareness of increased CVD risk in vasculitis should be raised in both primary

and secondary care and to the patient (Grade C, Evidence IV).

Although there is currently no evidence for augmented primary prevention in this

population, the awareness of the higher risk status of CVD means that known risk factors

should be rigorously addressed and modified, including attention to exercise, BMI, blood

pressure control, and lipid monitoring with smoking cessation critical (expert consensus

level 95%) BMI has been shown to predict major cardiovascular events in this population

203, with smoking status associated with MI and progression to ESRD in patients with

vasculitis208.

In addition, early identification of Chronic Kidney Disease (CKD)/ proteinuria in this group is

imperative due to the additional significant risk of cardiovascular disease this confers300.

234

3) Awareness of the increased risk of Venous Thromboembolism (VTEs) is important

in this population, with standard VTE prophylaxis being used if there is any loss of

mobility (Grade B, Evidence III).

VTEs are much more frequent in AAV than the background population. The rate varies from

1.58 episodes/ 100 patient years increasing to 7.26/ 100 patient years during active disease

in one study155. Other risk factors aside from periods of disease activity for the

development of VTEs include, older age, male, previous VTE, CVA with motor deficit and

nephrotic range proteinuria 214.

Vasculitis patients having had more than one VTE should receive long-term anticoagulation,

as per other populations301. There is a clear need for further research to determine the

relationship between VTE risk, disease activity and autoantibodies (including non-ANCA

autoantibodies). There is no evidence to support the role of aspirin in primary or secondary

VTE prophylaxis.

6.3 FERTILITY PRESERVATION

1) In the absence of life or severe organ threatening disease, the routine use of

cyclophosphamide should be avoided in women of child-bearing potential (Grade A,

Evidence level 1b- i.e. Rituximab versus cyclophosphamide).

The majority of data on the effect of cyclophosphamide exposure on fertility is derived

from the lupus population, with a rate of around 30% of cessation of menstruation

following exposure to cyclophosphamide121. However, this risk varies depending on

cumulative cyclophosphamide exposure and age at cyclophosphamide administration. It

has been reported that premature ovarian failure can be induced with a dose of 20.4g for

women 20-30 years old or 5.2g for women >40259. However, there is no robust evidence

that there is a safe dose of cyclophosphamide that would completely eradicate the risk of

infertility (expert consensus level 87%).

It is also well established that exposure to cyclophosphamide in men causes significant

sperm abnormalities associated with a reduction in fertility 122. Therefore, careful

consideration should be given to the use in men (with non- life or severe organ threatening

disease) who have not completed their family. However, it should equally be noted that

kidney failure due to inadequately treated disease would have a significant effect on

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fertility, and therefore it is prudent to ensure organ threatening disease is treated

appropriately (expert consensus level 88%).

Links with the appropriate local reproductive health departments should be established,

including urgent referral pathways should be available, particularly for sperm banking for

those patients who present acutely requiring rapid treatment (expert consensus level 94%).

Men should be offered the chance to store sperm before starting cyclophosphamide (if it

does not interfere with medically urgent therapy) (expert consensus level 94%). Individual

cases, such as sperm banking following exposure to 1 or 2 doses of cyclophosphamide or

for patients who are physically incapable of sperm banking should be discussed with the

local reproductive health department. Oocyte retrieval in unwell females with active

vasculitis is not currently feasible (expert consensus level 92%).

It should be borne in mind that all vasculitis patients may have the potential for future

cyclophosphamide exposure (in severe relapse) and therefore may wish to explore the

option of gamete storage (sperm banking or oocyte retrieval) prospectively.

2) Current recommendations are that patients should be counselled to avoid

pregnancy for 12 months following Rituximab exposure179(Grade C, Evidence IV)

However, there is emerging data that patients can have successful pregnancy outcomes in

the months following Rituximab exposure. A reported series of 8 pregnancies in 6 such

vasculitis patients with Rituximab exposure between 1 week and 16.5 months prior to

conception demonstrated successful outcomes in 7 of the 8 pregnancies. In addition, of

interest, foetal CD20+ B lymphocytes measured in cord blood at time of delivery did not

appear to be affected 302. Therefore, the patient who becomes pregnant following

Rituximab exposure should be referred for counselling /management in a specialist joint

vasculitis- obstetric clinic. Ideally, all patients with vasculitis who are pregnant or

considering pregnancy should be referred to a specialist joint clinical service.

3) There may be some benefit in preservation of fertility from GnRH agonists/ GnRH

analogues to protect fertility. However, there is insufficient current evidence to

recommend routine use with this requiring prospective studies.(Grade B, evidence level

III)

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There are multiple examples in the literature of GnRH analogues used to help maintain

fertility and aid pregnancy after cyclophosphamide therapy121,253,303 but these are typically

small, retrospective studies. Literature reviews generally support the use of GnRH

analogues but meta-analyses are conflicted254,260,304,167. The most recent of these does

conclude that GnRHas appear effective in reducing amenorrhoea in all patients, with

pregnancy rates higher in the GnRHa arm. However, these were observational studies with

clinical trial evidence not available167.

6.4 CANCER RECOMMENDATIONS

1. Patients with non- life threatening relapsing disease and previous treatment with

cyclophosphamide should avoid further exposure to cyclophosphamide i.e. consider

Rituximab treatment. This is supported by current funding policies for Rituximab. (Grade

B, Evidence level III)(expert consensus level 92%)

Early studies, with a substantially greater cyclophosphamide load for patients reported a

2.4 fold increase for all malignancies, with this increase predominantly being accounted for

by bladder cancer and lymphoma134. Since the introduction of a switch from

cyclophosphamide to maintenance therapy at 3 to 6 months and a trend towards pulsed

intravenous therapy rather than daily oral, resulting in a much lower total

cyclophosphamide dose, it is hoped that this risk has diminished somewhat. However, data

from the long-term follow-up (median 4.3 years) of the CYCLOPS trial (comparing daily oral

to pulsed intravenous cyclophosphamide) showed no difference in malignancy rates75. This

suggests that it may be many more years before this change in practice translates to an

actual reduction in malignancy rates.

With regards to cumulative cyclophosphamide dose, one series of 293 GPA patients

reported no increased in cancer risk (with the exception of Non Melanomatous Skin

Cancers NMSC) for those patients receiving less than 36g in total305. However, with regards

to bladder cancer, a series of 1065 GPA patients reported that cumulative

cyclophosphamide doses of greater than 25g were associated with a 5-fold risk of bladder

cancer, with each 10g increment associated with a doubling of cancer risk163.

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A recent meta-analysis of the risk of cancer in AAV included 6 observational studies. This

study reported that NMSC, leukemia and bladder cancer were more frequently observed in

patients with AASV with SIRs of 5.18 ,4.89 and 3.84 respectively and with rates of

lymphoma, liver and lung also increased. However, evidence is accumulating for the

reported increased incidence of cancer in AAV to be predominantly attributable to the

increased risk of NMSC230,243.

In summary, patients with previous significant cyclophosphamide exposure are likely to

have increased ongoing cancer risk that requires continued vigilance. In particular, patients

should receive education and advice with regards to prevention and screening for skin

cancer (see below).

2. Patients should be encouraged to attend for age and gender appropriate routine

population cancer screening (Grade B, Evidence level III/IV) (expert consensus level 94%)

3. CXRs should be carried out in smokers but no other routine cancer, aside from

population screening should be carried out unless otherwise clinically indicated (e.g.

change in bowel habit, major weight change or night sweats). (Grade B, Evidence level

III).

Clinicians should have a high degree of suspicion for investigating for possible malignancy

in atypical cases of AAV not responding to treatment. However, there is no clear evidence

that cancer predisposes to develop of AAV233.

4. Cervical screening should be carried out as per the population screening

There is currently insufficient evidence to support annual cervical screening of this

population. However, in other populations with autoimmune disease an increased

incidence of CIN has been described120,246. It is unclear whether this risk relates to an

association with more aggressive disease or more aggressive therapy. Therefore, patients

should be counselled in advance of immunosuppression exposure regarding the potential

increase in CIN changes on cervical screening and the need to attend routine population

screening re-enforced.

Clinicians should be aware of patient’s HPV status/ immunisation status, with HPV positivity

being well established as a risk factor for CIN and cervical cancer.

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5. All patients on immunosuppression require counselling regarding the need for sun

protection and regular (annual) skin screening (Grade C, Evidence level IV)(expert

consensus level 94%)

The recent data for malignancy in AAV suggests that the only truly significant increase in

cancer risk in this population may be in non-melanomatous skin cancer230. Both

azathioprine and cyclophosphamide are likely to be significant in terms of risk for

NMSC306,307. The patient’s history (including family and repeated history of high level of UV

exposure early in life e.g. living abroad) should be taken into account regarding skin cancer

risk (expert consensus level 88%). The avoidance of tanning beds should be advised (expert

consensus level 94%). Patients should be educated to perform self-checking for skin cancer

with knowledge of the appropriate place to present to for further investigation (expert

consensus level 89%). Skin protection and vigilance should be led through education of the

patient, with support from primary care and appropriate links to secondary care when

required.

6. Patients exposed to cyclophosphamide should be considered for: (Grade C, Evidence

level IV)

· Pre-hydration where possible (prior to pulsed intravenous cyclophosphamide)

· Mesna

It has been well reported that very high doses of cyclophosphamide leads to a significant

increase in the risk of bladder cancer163, with one series reporting a substantial increase in

the rate of bladder cancer in those receiving more than 36g cyclophosphamide

cumulatively (SIR 9.5)234. However, a more recent review of the data available for the use of

cyclophosphamide to treat rheumatic disease concluded that low dose pulsed intravenous

cyclophosphamide is likely to be associated with a low risk of cystitis and bladder cancer164.

In this setting, there is little evidence to support the use of mesna. However, as there may

be some benefit and mesna is well tolerated, expert consensus is that the use of mesna

may be considered. Patients with a previous history of cyclophosphamide exposure should

in addition have urinalysis for blood at every relevant hospital visit (at least 12 monthly)

(expert consensus 94%) with cystoscopy and cytology assessment in any cyclophosphamide

patient with persistent non- glomerular haematuria (expert consensus level 88%).

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6.5 INFECTION PREVENTION

Nearly half of all deaths accounting for the 11%, 1 year mortality for patients with AAV are

now attributable to infection, with the majority of these being lower respiratory tract

infections 90. A recent review of infections within this population reports between 20 and

60% of patients with AAV experiencing significant infections, depending on the cohort,

immunosuppression exposure and prophylaxis282. Again, the majority of articles reviewed

report LRTI as the most frequent but opportunistic infections are not insignificant with

Cytomegalovirus, Pneumocystis jirovecii, Candidiasis and herpes/varicella zoster all being

reported.

1) There is a need for recognition of the increased infection risk of patients with

ANCA associated vasculitis (Grade C, Evidence IV).

The risk of infection within this population is likely to arise from both the

immunosuppression and the underlying disease pathology itself.

We advise education of patients and primary care with regards to this increased infection

risk to encourage early presentation and treatment for immunosuppressed patients with

infective symptoms.

2) PJP prophylaxis is recommended during induction therapy and with

reintroduction of therapy for major relapse. (i.e. during treatment with high dose

steroids/Rituximab/cyclophosphamide) (Grade A, evidence level 1a)

A meta- analysis of evidence for PJP prophylaxis in immunocompromised patients

concluded that the rate of PJP infection within a population needs to be around 6.2% for

prophylaxis to be effective308. There are few large studies on the rate of infection in the

AAV population without prophylaxis. In recent years, the protocols for EUVAS trials have

included suggested PJP prophylaxis but data is not available as to how many received this,

and the effect on infection rates. However, earlier trial data suggests an incidence of PJP in

this population during induction therapy of around 20%309.

Known risk factors for PJP development in this population include; lymphopenia, low CD4

count, steroid use, higher dose steroid use, and cytotoxic therapy272,279,177,185,183. In addition,

a substantial number of cases of PJP have been reported following treatment with

rituximab, as early as days to weeks following exposure and up to 32 months from last

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administration310,181,277. In acknowledgement of this risk, the FDA licensing for the use of

Rituximab in the US for GPA and MPA includes advisement of concurrent PJP prophylaxis

prescribing for at least 6 months following the last Rituximab infusion179.

Co-trimoxazole should be first line prophylaxis as there is the most data to support safety

and efficacy308 (Evidence 1b). If the patient is unable to take co-trimoxazole, sulfonamide or

trimethoprim then other options include dapsone, atovaquone and nebulised

pentamadine. If using dapsone there should be awareness of the possible side- effect of

methaemogloginaemia 311, and this should be screened for if there is any clinical suspicion

(symptoms or an unexplained drop in haemoglobin). There is very little data directly

comparing the effectiveness of these alternative prophylactic agents, with no evidence in

favour of a particular agent in the small number of comparisons that have been made308.

Awareness should be maintained of the potential serious interaction between

methotrexate and co-trimoxazole, with fatalities due to cytopaenias reported312.

There is no evidence on which to base a recommendation for continuation of prophylaxis

for any given time period post cyclophosphamide treatment. PJP risk may continue post

cessation of cyclophosphamide with cases being reported up to 24 months in a patient

treated with rituximab and cyclophosphamide as part of chemotherapy regimen for

haematological malignancy313, although this patient had received an investigational drug

shortly prior to development of PJP.

Education of patients and primary care with regards to the risk of PJP infection and

potential symptoms is key in conjunction with prescription of prophylaxis.

3) Clinicians should be aware of markers of potential over- immunosuppression in

patients.(Grade C, evidence level IV)

Clinical markers such as the development of previous opportunistic infections may be

helpful in the identification of potentially over immunosuppression, and as a predictor for

future infection. Frequency of infection has been shown to be associated with an increased

risk of future severe infection, and in turn, all-cause mortality281. Other risk factors for

infection in this population include; leucopenia, lymphopenia, older age, female gender,

higher steroid exposure and dialysis dependency111,187,281,314. These patients may benefit

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from more detailed profiling of their immune status such as measurement of lymphocyte

subsets and immunoglobulin levels, and consideration of reduction in immunosuppression.

Low CD4 count, B cells and IgG levels have been demonstrated to correlate with infection

rate in this population171.

4) We recommend ‘flu and pneumococcal vaccination for immunosuppressed

patients with vasculitis.

In patients who have not yet commenced immunosuppression, inactive vaccinations should

ideally be administered at least 2 weeks prior to initiation of therapy133.

For patients having received Rituximab, there is some evidence that there may be an

antibody response to vaccination >6 months following administration for those in whom B

cell reconstitution has begun to occur174,266. However, patients should be counselled that

vaccine response is still likely to be suboptimal.

For those where usual ‘flu vaccination season falls during the patient’s induction regime

(i.e. within the first 6 months following initiation of rituximab or cyclophosphamide)

individual risk- benefit analysis should be undertaken as to whether to administer ‘flu

vaccine during this time period. There is no evidence that vaccination will trigger disease

relapse in patients with stable disease171,172,271.

Pneumococcal vaccination should be with Pneumococcal Polysaccharide Vaccine (PPV 23)

as per the Green Book. Where possible PPV should be given 4-6 weeks prior to initiation of

immunosuppression but where not possible, at least 2 weeks before or delay until 3

months following cessation of “induction therapy”. Patients with chronic renal disease

should be re-immunised every 5 years with PPV 23.168. Serotype-specific Pneumococcal IgG

antibody monitoring may be relevant for assessing immune response to vaccination.

5) Prior to commencement of immunosuppressive therapy patients should be screened/

treated for latent TB as per British Thoracic Society guidelines315

Current BTS guidelines recommend: “In adults who are anticipated to be or are currently

immunocompromised, a risk assessment is undertaken to establish whether testing should

be offered, taking into account:

1)risk of progression to active TB based on how severely they are immunocompromised

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and for how long they have been immunocompromised

2)risk factors for TB infection, such as country of birth or recent contact with an index

case with suspected infectious or confirmed pulmonary or laryngeal TB.

For adults who are immunocompromised, consider an interferon-gamma release assay

alone or an interferon-gamma release assay with a concurrent Mantoux test. If either test

is positive (for Mantoux, this is an induration of 5 mm or larger, regardless of BCG history),

assess for active TB.

If this assessment is negative then patients should be offered treatment for latent TB

infection.”

6) Patients on induction therapy immunosuppression (or high dose steroids for relapse)

or patients with an episode of candidiasis/previous candidiasis may require fungal

prophylaxis (Grade B, evidence level III).

This should be with a therapy of proven efficacy such as fluconazole as the evidence in

other immunosuppressed patients does not support non- absorbed fungal prophylaxis,

such as topical nystatin and amphotericin 188.

Equally, anti-viral prophylaxis (acyclovir) should be considered for prophylaxis against

herpes simplex/zoster if there is evidence of previous infection or if the patient is thought

to be at high risk of opportunistic infection (Grade C, evidence level IV).

7) Ideally, routine pretesting of varicella zoster immunity should be carried out prior to

commencement of immunotherapy. (Grade C. Level IV))

However, clinicians should be aware that patients’ immune status may change following

exposure to immunosuppression. Exposure to varicella in the immunosuppressed patient

should necessitate early presentation for re-assessment of varicella immune status and

need for pre-emptive therapy. Varicella Zoster Immunoglobulin G (VZIG) prophylaxis is

recommended for individuals who fulfil all of the following three criteria:316

1) significant exposure to chickenpox or herpes zoster

2) a clinical condition that increases the risk of severe varicella (includes

immunosuppressed patients)

3) no antibodies to VZ virus (VZIG administration should not be

delayed past seven days after initial contact while an antibody test is done.

Under these circumstances, VZIG should be given on the basis of a negative

history of chickenpox).

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Current UK recommendations from the Green Book state Varicella Zoster vaccine is

contraindicated in the immunosuppressed patient as a live vaccine316.

6.6 EDUCATION AND MONITORING

1) All vasculitis patients, including those off immunosuppression and clinically stable for

more than 12 months, should continue to receive secondary care follow- up (Grade C,

Level IV)

The frequency of secondary/ tertiary care review for a patient with stable vasculitis

depends upon risk of relapse, previous immunotherapy, and current degree of

immunosuppression. However, after 2 years, every 3-6 months may be reasonable (if

clinically stable).

2) Patients should be educated to engage in follow up care. This may include the

appropriate use of self-referral pathways to secondary care when unwell (Grade C, Level

IV).

3) Primary care should be involved with stable patients, being aware of the

immunosuppressive medication they are taking and be responsible for lifestyle advice

(Grade C, Level IV).

6.7 APPLICABILITY AND UTILITY

6.7.1 A statement of potential organizational barriers to introduction

Vasculitis patients are complex often requiring input from multiple, cross-specialty care

providers. The development of cohesive networks of care, involving all relevant stake-

holders, on a regional and national level will support optimal delivery of care for this

population. This is in line with current recommendations for this population83.

6.7.2 Potential costs implications for introduction of guideline

There should be no major cost implications for the introduction of these guidelines as the

majority of the recommendations reflect best clinical practice.

6.7.3 Suggested audit measures

Cumulative dose cyclophosphamide

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Indications for use of Rituximab

Compliance with NOGG for GIOP prevention and management

Compliance with Green Book recommendations for vaccinations

Compliance with BTS guidelines for pre- treatment TB screening

Documentation of patient drug education prior to initiation of therapy

245

Following on from the process to define standards of care for this population, the next

logical step was to consider how these standards could be best applied.

This initially took the form of a checklist, covering the areas outlined in the Delphi and

subsequent recommendations.

However, following extensive discussions with those involved in electronic healthcare this

“checklist” soon evolved into the concept of software which would allow efficient use of all

currently available relevant healthcare data, in addition to aiding with the systematic

review of the required areas. This concept was named the “Vasculitis Care Optimisation

Tool” or VasCOT.

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7 DEVELOPMENT OF A VASCULITIS CARE OPTIMISATION TOOL

7.1 PART A: CONCEPT DEVELOPMENT AND USER ENGAGEMENT

7.1.1 Introduction

Vasculitis is a rare autoimmune inflammatory condition that may affect multiple organ

systems. The severity of the disease can vary greatly from patient to patient, as can

treatment and assessment within the NHS. Untreated, life- expectancy averages 5 months89

but advances in immunosuppressive therapy has resulted in a 75% survival at 5 years98.

However, beyond initial aggressive treatment, long- term therapy to control the disease is

often required.

Evidence has shown that some of the most significant ongoing problems for this population

are infections, cardiovascular disease and cancer, with these accounting for the majority of

deaths 90,98. Despite this, systematic assessment of these risks and application of

preventative measures are not widely implemented and patients remain relatively unaware

of these risks 317,318. Variable awareness is made worse by the fragmented nature of the

information systems used in the NHS.

Clinics for patients with vasculitis may have no access to advanced information on patient

health and as a consequence clinics are not running at maximum efficiency. To address

these problems we have designed the Vasculitis Care Optimisation Tool (VasCOT). VasCOT

is a web- based package designed to improve the comprehensive nature of patient care

and to be applicable and usable at every Vasculitis centre in the UK. It provides a method of

structured assessment with co-ordination of available electronic patient data (primary/

secondary care and patient entered). This is initially intended to facilitate identification of

patients at risk of developing disease and treatment related co-morbidities. However, once

established, it could also assist with patient self-reporting of disease status, enabling better

prioritisation of patient appointments. This tool may be used across the spectrum of

vasculitis care providers, to facilitate seamless care and efficient communication to all,

including the patient themselves. Indeed, the patient will be able to input and edit

information including reporting of health events and quality of life measures.

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In other complex chronic disease groups, a structured approach using an electronic health

record has shown improved clinical outcomes, in addition to high levels of patient and

clinician satisfaction319–9. It is anticipated that the benefits of this system will include

improving patient safety and involvement in their care, and improving the efficiency of care

delivered.

7.1.2 Identification and engagement of stakeholders

The first stage within this process was to identify all key parties for involvement in both

initial development and building of the prototype but also those who may be involved in

future use and dissemination of the product.

The following were consulted and contributed to this development process:

• Primary care: Dr Ivan Bennet: Chair Central Manchester CCG

• Secondary care clinicians: Rheumatology and nephrology

• UK and Ireland Vasculitis Rare Disease Group

• Patients: Vasculitis UK and individual patients locally (see patient interviews)

• Specialised Service Commissioning (SSC)

• NorthWest EHealth: business analysis: requirements elicitation, wire framing and

solution feasibility and commercialisation consultancy

• Hitachi Design Centre Europe: user experience design, commercialisation

• Trusttech: commercialisation

• Central Manchester Foundation Trust Information Technology, Chris Anderson

(Xibble Ltd) and Chris Lee (OBEC ltd): functional specification.

7.1.3 Methods

Concept (the concept was developed by Dr Brown, with support from Dr Venning. All

development leading from the concept was supervised and guided by input from Dr Brown)

The idea for VasCOT initially developed from the observation that due to the number and

complexity of areas for review in a clinical encounter it would be helpful to have a

structured method of assessment (e.g. a checklist). This was noted alongside the use of an

established model of “annual review” in the local renal transplant population323. Following

initial exploratory discussions with local clinicians and patients, alongside a dialogue in the

wider vasculitis community through the UK and Ireland Rare Disease Group network, the

concept of VasCOT was developed and the user map outlined (represented in Figure 1. and

2.)

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In summary:

1. The patient, attending a secondary care clinic for their vasculitis management is

invited to participate in VasCOT and their account is created and linked to a primary and

secondary care provider, and a named vasculitis clinician.

2. An automated data feed from primary to secondary care is then established with

events and data required predefined using primary care (READ/SNOMED) codes (following

consent from patient and primary care). This data is limited to relevant items including

prescriptions, vaccinations, cancer screening attendance/ results and events such as

infections.

3. This data prepopulates some of the fields in the “health review” pages.

4. Prior to clinic review the patient is invited to log-in and to verify demographic data,

medication, lifestyle and family history and to complete a quality of life assessment (EQ-

5D). This further populates some of the data fields. The patient also has the opportunity to

highlight any particular issues that they would like addressing within the upcoming clinical

encounter.

5. On attending the clinic, the clinician logs in to the system with the patient present.

The clinician can then validate events entered by the patient or primary care. The clinician

can then perform a detailed “health review” for the patient covering the areas of

cardiovascular risk, infection prevention, bone health, fertility and cancer screening and

steroid “other”. Each area has its own screen with the existing information from primary

care and the patient available to view. Fields containing missing data or values outside pre-

set limits will be flagged. Disease assessment scoring is not included in VasCOT but it is

envisaged that this will be provided through a link to the validated Birmingham Vasculitis

Activity Score324 which is currently being updated.

6. Following review, a summary is generated which will form part of the patient’s

hospital record (Electronic Patient Record or paper). In addition; the patient, primary care

and other nominated care providers will receive a copy.

7.1.3.1 Identification of existing products and intellectual property

Vasculitis patients are predominantly cared for by nephrologists and rheumatologists.

Therefore, a search of existing health informatics systems used by these two departments

within the NHS in the UK was undertaken. Two products of interest were identified and are

reviewed below.

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1. 4S-DAWN

4S-DAWN is a clinical software company that produces software designed for the

monitoring of rheumatology patients (as well as other disease groups). The primary

function of this software appears to be monitoring of disease activity of common

rheumatic diseases (e.g. Rheumatoid Arthritis) as well as facilitating monitoring of required

blood tests for patients on immunosuppression. It does provide a configurable option to

add relevant screening test for your population such as DEXA or TB screening. However, the

main focus is to support safety of drug monitoring and it does not have longer-term

sequelae of immunosuppression grouped into systematic review. In addition, it is only a

secondary care clinician portal, with no patient or primary care access.

2. (Renal) Patient View (RPV)

RPV was established in 2004 to provide patients with renal disease access to their health

information. It has since undergone rebranding as “generic” PatientView with a plan to

make it accessible to patients with other diagnoses, starting with Inflammatory Bowel

Disease and Diabetes in 2014. RPV is well established and accepted by the majority of renal

units in the UK with over 11 000 renal patients having been reported as registered by

2009325. It enables patients to view blood results, clinic letters and to enter symptoms and

parameters such as blood pressure readings. In summary, PatientView fulfils the criteria for

the patient section of VasCOT. However, PV does not offer the functionality for clinicians to

review data and does not organise and present data in the format envisaged will be

provided by VasCOT.

In summary, although there are systems in existence that provide some of the functionality

required for VasCOT, there is no identified system that appears to provide both clinician

and patient access to primary, secondary care and patient entered data, amalgamated and

presented to facilitate review of risk factors for patients on long-term immunosuppression.

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Patient id Gender Age Diagnosis Duration

Disease

Disease

manifestations

1

2

3

4

5

6

7

8

Male

Male

Male

Female

Male

Female

Male

Female

54

64

60

76

78

41

56

73

MPA

MPA

GPA

GPA

MPA

GPA

GPA

MPA

1 year

4.5 years

14 years

9 years

4 years

13 years

24 years

7 years

Renal

Renal

Renal, nerve, ENT

Renal, lung

Renal, lung

ENT

Eye, renal, ENT

Renal, lung

Table 1. Characteristics of patients selected for interview

7.1.3.2 User engagement

Following identification of the need for this product a user-centred iterative design

approach was taken in collaboration with Hitachi Design Centre Europe to develop the

patient and clinician user interfaces. In order to ascertain whether the proposed solution

was applicable and relevant to the user groups, initial detailed interviews were conducted.

Patients (n=8) were selected by the project lead (Dr Brown) to represent a broad age and

socioeconomic spread. In addition, patients were selected with a wide variety of disease

manifestations and duration (see Table 1 for patient characteristics). A team of two people

conducted the interviews; a member of the Hitachi Design Centre Europe and an external

ethnographic researcher. The purpose of the investigation was to understand patients’

experiences, feelings and needs of their everyday life with vasculitis. In order to understand

the role of the supportive network and their perspectives, partners or family members of

the vasculitis patients were invited to join. The individual interviews were approximately

one hour, audio-recorded and were semi-structured with open-ended questions. All

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information was treated as strictly confidential and anonymised prior to presentation or

publication. Interviews covered the following areas

• General health history

• Vasculitis diagnosis, treatment and maintenance

• Everyday life

• Mental states, motivation and influences

• Tools and Information.

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1.1.1 Figure 1. VasCOT user map

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1.1.2 Figure 2. VasCOT concept

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Thematic analysis informed by grounded theory and phenomenological approaches was

used to identify recurring and significant areas of concern to the patient326,327. These are

detailed in Table 2.

Areas

Overarching themes

Individual vasculitis

Vasculitis type and severity varies significantly among patients. Patients experience individual treatment journeys and care. Rare disease: Lack of knowledge from healthcare professionals. Some patients feel alone: ‘guest in a ward’ Some patients feel ‘special’. “There is no solution” - patients are aware of trial and error approach.

Accepting vasculitis

Most patients experience frustration towards different care providers before the diagnosis. Accepting the disease is a process and takes time. With increasing years, patients seem to be more okay with it. Patients show different approaches for accepting it: religion, engagement, education, pragmatism.

Learning a new lifestyle

Patients have to learn a new language, medication, symptoms and body systems. With changing medication patients continue to adapt. Over time they become their own expert. Medication becomes part of their life - and with it the risk for side effects. Patients develop their own routines and organisation systems. Some patients face temporary diets; some struggle with weight gain. Patients face limitations in activities, energy, holiday planning. “You have to learn to pace yourself”. Some patients struggle with depression and disconnection.

Not taking over life

All patients emphasise that they don’t want vasculitis to take over their life. Many patients have no need to talk about the disease with friends or peers. With growing experience some patients get bored of it. They don’t want reminders.

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Unpredictable life

Patients experience good phases and relapses of different severities. Unpredictability and uncertainty is one of the biggest challenges. Fatigue/exhaustion is a key symptom. Patients have good days and bad days.

Looking forward

Future thoughts include fear, restrictions and uncertainty. Patients look forward to get off certain medication (steroids) and/or overcoming symptoms/relapses. Patients often focus on the ‘now’; “grateful for every day I get”.

Partner In some cases, the partner becomes the main supporter; emotionally and practically. There can be a high emotional impact on the partner due to the unpredictability and limitations. The role of the partner seems to depend on the individual case.

Having a champion Patients have the desire to have a lead clinician = a ‘champion’. They want someone they can trust in regards to treatment and medication, coordination, managing fears, motivation, advice. Patients who have a champion seem to worry less and be more satisfied with their care.

Feeling lucky All patients describe themselves as ‘lucky’. They know they could be ‘worse off’. All patients show a positive life attitude. Their vasculitis journey gives them a sense of strength, uniqueness and achievement. They are grateful for the treatment they received, and for kind people they met.

Being in control Patients want to be in control in regard to living with the disease and treatment decisions. Education and experience influence this striving for control. Patients want to be involved in decisions. The individuality and lack of general knowledge strengthen the need for control. The management of the disease is a ‘balancing act’ of:

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- emotions - medication - symptoms - life. They don’t want to give up routines when being an in-patient. All patients emphasise to ‘self-medicate’

Care co-ordination

The coordination of different care providers and medication is a big challenge. Processes are slow, not supportive and increase complications. There is too little exchange of the GP, different clinics, consultants and hospitals.

Reassurance touch points Several patients take regular measurements on their own (blood pressure, blood tests, morning routine) for self-monitoring. Phone numbers of their clinicians give them a sense of security. Although they never/rarely use it. The regular check-ups give patients reassurance. Some (who are in control) feel it is “a bit of waste of time”. Some patients have access their blood results to keep track.

Emotional bonding with medication Patients feel grateful for medication, despite the physical and emotional impact of steroid or chemotherapy treatment. Changing medication after several years makes patients feel vulnerable. Medication becomes part of their life and life test.

Table 2. Themes from patient interviews

7.1.3.3 Clinician interviews

Following this, six clinicians were interviewed. All were chosen by the project team as

having involvement in the care of patients with vasculitis and were as follows; consultant

nephrologist tertiary centre n=3, consultant rheumatologist tertiary centre n=3. Interview

questions involved exploration of current clinical and information systems in use and the

challenges involved in the care of the vasculitis patient. In addition, draft wireframes of

some of the proposed clinician view pages were presented for review.

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The results from both the patient and clinician interviews were analysed to produce a

patient and clinician “problem list” and “wish list” (See Tables 3 and 4).

7.1.3.4 Patient questionnaire

Once it had been identified that the proposed solution appeared to align with the needs of

patients and clinicians, further information was sought with regards to the proposed

method of patients entering and accessing information and to the level of clinical

information accessible to patients. This was undertaken through a larger national patient

questionnaire. All patients attending a national vasculitis patient conference were invited

to participate. N= 66 responses were analysed with responder characteristics outlined in

Table 5. The questionnaire and results can be viewed in Appendix 1. In summary, the

results from this supported that the majority of patients completing this questionnaire

currently used the internet to access health information with a substantial majority

wanting complete access to their own health data. This is in keeping with studies

supporting the patient perceived benefits of an “open notes” or “shared record”

system328,329,330.

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Clinician “problem list” Central Care (CC) expertise- Local care delivery, missing links Letter system: filtered (incomplete) information data access only if in CC (need for) common way of information capture and exchange Incomplete information: difficult to get external information and results currently: chasing information; different systems no official way to get results from GP tertiary referrals often incomplete Disempowered patients: different specialists create lack of holistic care educated patients better to manage Leader and supporter: (need for) coordination between vasculitis lead and supporters (need for) clear distinction of roles Information collection: patient medication intake might differ from prescription medication therapy = key data cause for co-morbidities need for original documents/results; vasculitis interpretation different specific tools measure specific aspects at specific places trends are important (renal, inflammation) blood test results (not available until) 1 day after check-up need for better data overview/collection (raw data, specific links, verification, decision reasoning) Standardising Vasculitis Care: scores needed to justify actions (currently) no triggers/reminders for long-term risk assessments

Clinician “wish list”

Key data overview pulling together all data streams (specialists, GP, patient) objective raw data (diagnosis, medication, results) key data only; incl. relevant trends/changes GP data (events, medication) validated by patient Complementing care no conflict with established systems/routines (letters) no double work/administrative effort aligning care activities data transparency Long-term risk control reminder/trigger for actions (scans, reviews, results) links to proven (specific) tools scores/standardisation to justify actions providing context for risk assessment VasCOT elements diagnosis medication (current, immunosuppression, history) patient report (symptoms, medication, lifestyle) long-term risk dimensions (infection, malignancy, medication, cardiovascular, bone health, woman’s health) Patient role empowering patients preparing for check-up confirming GP data reminding and reporting symptoms and incidents well-being (lifestyle and mental health) education: what to look for, how to take care

Table 3. Clinician “problem” and “wish” list

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Patient “problem list” Unpredictable life risk for relapses risk for side effects fatigue “it never stops” Care coordination frustration due to little data exchange/patient knowledge slow processes, waiting for letters care not aligned, different medication advice no vasculitis lead; feeling alone many appointments at different places Medication Patients bond with long-term medication and feel vulnerable when it changes Patients self-medicate (no data capture of actual in-take) Patients lose control over their medication as in-patients Individuality ‘trial and error’ approach rare disease: feeling alone versus feeling special Learning and accepting “you have to learn to pace yourself” accepting process takes time impact on work and private life Patient “wish list” Trust in care clear vasculitis leader - ‘champion’ information and education better coordination between different specialist fields and GP reassurance through touchpoints (results, check-ups, contacts) Being in control being involved in decisions, team effort respect for their own methods and routines access and understanding of key data (blood results) reading signs, knowing what to do balancing act: emotions, medication, symptoms, life Data availability access to vasculitis data for other clinicians/health care providers key information at hand (medication, diagnosis) better vasculitis knowledge of healthcare providers Taking worries accepting living with vasculitis learning a new lifestyle Not taking over life living a ‘normal’ life not constantly thinking/talking of vasculitis looking forward (holidays, family, hobbies) Individuality receiving personalised care GP privileges

Table 4. Patient “problem” and “wish” list

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Table 5. Survey responder characteristics

Patient characteristics N=66

Number responders

Age in years

< 30 5

31-40 1

41-50 6

51-60 19

62-70 25

>70 10

Gender

Female 38

Male 22

Not specified 6

Diagnosis

GPA 31

MPA 6

EGPA 11

HSP 2

GCA 6

AAV not specified 1

Other 9

Year of diagnosis

Before 2000 6

2000-2005 10

2006-2010 15

2011 onwards 30

Not yet 2

Country of diagnosis

England 16

Scotland 1

Wales 1

UK not specified 46

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7.2 SECTION B: DESIGN OF PATIENT AND CLINICIAN INTERFACES

7.2.1 Patient data capture

Following patient consultation, the initial drafts of the patient view pages were produced.

The wireframes of this interface can be viewed in Appendix 3.

The following areas will be included

Demographics: Patients will be asked to update demographics if they change

Relevant family history: in order to facilitate accurate calculation of fracture and CV risk

scores relevant family history will be requested

Lifestyle: Including smoking status, alcohol intake and weight.

Medication: The record will be pre-populated with the patient’s most recent primary care

prescription. Patients will be required to corroborate/ amend this as appropriate as it is

widely accepted that medication adherence may be poor in those with chronic

conditions331.

EQ-5D: This quality of life measure has been chosen for several reasons. Firstly, it is short

and therefore not too onerous for the patient to complete, Secondly, it has been shown to

have some relationship with improvement following treatment in a sub-group of

vasculitis332. In addition, data from the EQ-5D can be used in health economic

calculations333, which will be essential to support wider diffusion of the use of VasCOT.

“Significant events”: Patients will be asked to select health events that have occurred since

previous review from a drop down list. The comprehensive list is included in Appendix 2

but will include items such as infection, cardiovascular events, fracture and other steroid

related events.

Topics for review: Patients will be able to highlight areas of particular concern that they

would like to focus on in their upcoming clinic encounter.

Education: Patients will be able to request links to disease, lifestyle and health topics that

can then be added by their clinician.

7.2.2 Clinical data capture

The clinical data screens are split into relevant systems for review. The topics included

were informed by systematic literature review and a Delphi study performed with UK

expert members to inform “standards of care” for this population (full methodology and

results reported elsewhere). The five health review areas are defined as; Bone health,

cardiovascular risk, infection risk, cancer screening/fertility and steroid “other”.

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The specifics of which data to include and the data sources (e.g. primary, secondary care or

patient entered) were determined by Dr Brown with input from Dr Venning, with advise on

availability and access to data from North-west Ehealth. Following this, the list of data

items was circulated to the UK and Ireland Vasculitis RDG for review and feedback

incorporated. A full list of data specifications including data source can be viewed in

Appendix 2. but the main areas for review covered by each page are outlined below.

Wireframes for these pages can be viewed in Appendix 4.

Bone Health: Patients will input some of the data required to inform fracture risk

assessment (to be undertaken using FRAX calculator334). Other data, such as DEXA reports

may have to be manually entered, unless present in the primary care record.

Infection risk: Data from primary care will include vaccination types and dates and

infection events. The page will include triggers for secondary care to consider prophylaxis

for PJP, fungal, viral infections where relevant.

Cardiovascular risk: This section will include data from primary care including blood

pressure readings cholesterol, and patient entered risk factors such as smoking status and

family history. This will enable a validated risk score such as the Qrisk score335 to be

undertaken but with information regarding the likely increased risk of CVD in the vasculitis

population highlighted.

Cancer risk: This section will include information on cumulative cyclophosphamide dose to

allow an awareness of previous exposure when continuing vigilance with regards to cancer

screening. Urinalysis in addition to population cancer screening data (breast, cervical,

bowel) from primary care will be displayed here.

Steroid other: This section will allow screening for and to prompt an awareness of steroid

related side effects including easy bruising, thin skin, raised blood glucose and glaucoma or

cataracts.

Following completion of the health review a summary can be produced which can be

communicated electronically to the patient and all relevant health care providers with any

pertinent recommendations highlighted. It is intended that there will in addition be an

education section with links to topics either suggested by the clinician or requested by the

patient.

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7.2.3 Frequency and scope of use

Initial consultations with both patients and clinicians (including interview feedback) suggest

that this tool will be of most value in the chronic phase of disease management i.e. 6

months plus from presentation. It is therefore intended that the pilot of this will only

include prevalent vasculitis patients and that the use of the tool initially be piloted for 6

monthly use with a view for it to be used at 6 to 12 monthly intervals. Patients will be

invited to contribute data in the 2 weeks leading up to their clinical review but will be able

to enter data as they feel relevant at any time point. Equally, other clinicians and primary

care (once registered as linked with a patients account) will be able to view the records

whenever required but there will be no mandatory manual data entry from any sources

apart from the patient and lead vasculitis clinician. This is to encourage engagement with

the tool, particularly by the already overburdened primary care providers.

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7.3 PART C: DEVELOPMENT OF VASCOT ‘ENGINE’ (FUNCTIONAL SPECIFICATION)

Following identification and specification of the content of both the clinical and patient

view pages the next stage was to consider the functional specification for the software.

This stage was undertaken by Chris Anderson (Xibble Ltd) and Chris Lee (OBEC ltd) on

behalf of Central Manchester Foundation Trust Information Technology product

development department. Consultation regarding the functionality of the product was

provided throughout by Dr Brown.

The below solutions to the following areas are proposed. The full requirements for each

area can be viewed in Appendix 5.

7.3.1 Platform and Strategy

The VasCOT solution will be an independent application existing within its own framework

and platform, although it will have the ability to consume data from other sources. With

this in mind, the solution will be capable of defining and maintaining its own security –

including access, users and roles, any required system metadata and implementation

methodology.

Uptake of the VasCOT solution by Providers and Patients will be gradual and the solution

will support this phased approach to achieving a National Diffusion. System Administrators

will be granted the ability to create these entities dynamically, supported by any Standard

Operating Procedures (SOP’s) used to validate the creation.

7.3.2 Audit

All CRUD (Create, Review, Update and Delete) actions will be audited and stored by VasCOT

in such a way as to be readable by a System Administrator. All audit entries will be date /

time stamped and if applicable, include: a username, action performed, value change from

/ to and the patient ID. A front end user interface will be provided to interrogate the audit

data.

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Consideration should be given to the storage of audit log data due to sheer volume. It may

be necessary to archive sections of logs after defined amounts of time, to ensure the logs

do not grow to a size which may impact core operations.

7.3.3 Security and Authentication

User authentication and access to patient information will be a key concern of the VasCOT

solution. Enough flexibility will exist for the system to be usable, whilst ensuring the

security of confidential information.

7.3.4 Data Protection

As the VasCOT solution will be accessible via the internet, the necessary technical design

must seek to reduce vulnerabilities and inhibit attacks designed to access or steal patient

information, including but not limited to: Cross Site Scripting (XSS) attacks, SQL injections,

unauthorised redirects and man-in-the-middle attacks. In addition, guidelines published by

the HSCIC dictate that all transfers of patient data must be encrypted and preferably to

AES256 (Advanced Encryption Standard).

7.3.5 Feature Access

The solution itself will offer Role Based Access Control (RBAC) as a way of managing and

maintaining user access to the features and data. Although a role editor will be required to

define privileges at a granular level, there will be certain ‘Roles’ which will be integral to the

way in which the system works. First of all, there will be the ability to create overarching

System Administrators. These users will have the ability to create other System

Administrators and access all system functionality – most important of which will be the

ability to create Providers and Super Users. ‘Providers’ is the term used to describe a

healthcare facility (a Trust, GP Practice, etc). Users will belong to a Provider and nominated

users within a Provider will be identified as Super Users. These Super Users will be the local

administrators for that Provider, devolving system maintenance to a local level and

removing the responsibility from the System Administrators.

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7.3.6 Settings

The Settings Menu will be restricted to System Administrators and Super Users. It is a

dedicated sub-menu into the various Editors required to setup and maintain the system.

Although Super Users will have access to this screen, they will be further restricted to only

the functions which are applicable to their Role and again, restricted to Settings for their

own Provider.

7.3.7 Role Editor

The introduction of a Role Editor will future proof the system for further scope and roll out,

past the pilot phase. The editor will offer the ability to define new roles, as well as making

all system features available to be assigned to a Role, thus providing complete flexibility

whilst maintaining governed access and control.

7.3.8 User Editor

The User Editor will be available to System Administrators and Super Users (as defined by

role). The difference being that System Administrators will be able to view and maintain a

Global list of Users, whereas Super Users will be restricted to a list of Users local to their

own Provider. In addition, although Patients could also technically exist in VasCOT as Users,

they will not be created and maintained here. Instead, they will be created by the Lead

Clinician and maintained via their Patient Record, to which they will also have access to for

self-maintenance. Therefore, the User Editor is used only for creation and maintenance of

Administrative and Clinical users.

7.3.9 Patient Creation

Patients will be created by the Lead Provider (as defined by Role) as there will not (initially)

be an integrated demographic service. The patient demographic details will be entered, as

will the association to any Providers available in the system.

7.3.10 User Verification

Whenever a new user is setup and enabled - regardless of whether they are a Patient or a

Clinician – a verification email will be sent to the registered email address of that User. The

email will contain a secure link, valid for a predetermined amount of time, which the user

267

will need to click. Following the link will allow the user create a password for their account

and complete the User Creation process. The purpose of this is ensure that the user has

access to the email address they have registered and so that they are forced to create a

personalised password before accessing VasCOT.

7.3.11 Self-Registration

The Registration form offers a self-service approach to sign up for clinical users; whether

the potential user belongs to a ‘known Provider’ or not. The behaviour of the Registration

screen will change depending on the information entered. If the domain of the email

address entered is recognised as a ‘known Provider’, then the Provider information on the

right hand side of the screen will remain hidden and upon submission, the access request

will be sent to the Super User of that Provider – as they are more likely to be able to

validate the access the request. If the domain is unrecognised, the new user will be

required to complete all of the Provider information too. This request will be sent to the

System Administrator, as the new Provider will need to be validated and created.

Patients will be registered by their Lead Provider during consultation once as identified as

being a suitable candidate and as a way of authenticating the patient-user

7.3.12 Patient Queues

Patient Queues will become the default Home Screen for clinical users (as defined by role).

The queue will be split into tabs – “My” and “Our” Patient. The “Our” tab will present all

patients to which the Provider (not the individual) is associated. The “My” tab will be a

further refined list of the “Our” patients, filtered to only show patients where the logged in

user is also the Named Clinician on the Provider tab of the Patient Editor. This ensures that

we provide a user specific list of patients for convenience but also provides a full provider

specific list of patients, in order to mitigate any bottlenecks caused by only associating a

patient to an individual clinician. In addition, we will also highlight patient specific

notifications within the Patient Queues to identify the number of notifications awaiting

acknowledgment by the Provider.

7.3.13 Requesting Patient Access

Until a Provider is associated to a Patient, then the Patient will not appear in the Patient

Queues and the Provider will not have access to Clinical information. Therefore, the system

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needs to provide a mechanism to request patient access, as well as the ability to approve

or reject this request.

In addition, a Provider may want to change their association to a patient – such as a

Satellite Clinic taking over as the Lead Provider. In both of these scenarios, a “Handshake”

process will need to exist to facilitate the handover of patient access.

7.3.14 Accepting / Rejecting Patient Access Requests

Access to patient data will trigger a notification to be routed to the Lead Provider. A user

within this Provider has the ability to review these requests and decide whether to accept

or reject the request. Depending on the request and the action taken, the user may or may

not grant access to the patient information – in the same way clinicians today approve

patient data requests manually via phone, fax or email.

7.3.15 Access, Data Input and Versioning

Access to the Patient Record will be defined through an association to a Provider. Users

within that Provider will have access and the ability to the Patient Record as a result –

unless explicitly defined through Roles. However, if a Provider hands over responsibility to

another E.g. A GP Practice change or a switch in Lead Provider, the original Provider will still

require access to the information they contributed to the Record, even though they may no

longer be able to contribute or view information captured since their handover.

The system will need to maintain versions of the Patient Record and attribute those

versions to the appropriate Provider, as and when the Record is modified. This will ensure

that Providers can always access information they are (or have been) responsible for.

7.3.16 Patient Editor

The Patient Editor will be available to all users with patient access, including the Patients

themselves. It is the same screen as used during the Patient Creation process but provides

access to update patient information as well as Provider Association. Roles will determine

exactly which fields can be updated.

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7.4 DISCUSSION

Here it has been outlined how the idea of a “checklist” approach to co-morbidity

prevention for patients has undergone extensive development, with input from many areas

of expertise to become a fully specified and designed concept.

During this process, involvement has been sought from those with the technical and design

knowledge to guide and inform this process. In addition, the content and format has been

driven in the majority by the target audience, patients and clinicians. We have worked

extensively with individual patients locally, alongside seeking feedback from larger national

patient groups to ensure the resulting product will meet the needs of this population. It is

hoped that VasCOT will facilitate patients in chronic disease self- management and

promoting their health as well as providing an educational resource.

Alongside this, it is paramount to ensure that within the constraints of a busy NHS clinic,

this tool will add value for the clinician, by aiding in a more efficient and comprehensive

assessment of the patient, and not just providing more boxes to be ticked. Through the

planned use of existing, mainly primary care, data, organised and displayed in a relevant

and systematic fashion it is hoped that VasCOT will facilitate holistic care in a user- friendly

way. In addition, VasCOT will aid in communication between the often many clinical

disciplines that may be involved in a single patient’s care.

It is highly likely that further adjustments will be required to both the content/ design and

functional specification. However, this next stage will be informed through pilot testing of

the product with small numbers of patients and clinicians. Funding is required for the initial

product development, with several avenues currently being explored.

Once we have a successful first version of this product the next stage will involve ensuring

that clinical and patient outcomes can be captured to start to support a health economic

model for wider scale use. It will be difficult, initially, to demonstrate a significant

difference in hard end-points and it is likely that surrogate parameters such as patient

satisfaction, quality of life and care quality indicators will be useful in this stage. It is

possible, however, that an impact on the more frequent complications such as infection or

even hospital admissions may be able to be demonstrated.

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It has taken a significant amount of work to develop the concept and design of this

innovation to the point where it can now undergo product development for field testing.

Alongside this process this tool has garnered substantial support from clinicians,

commissioners, patients and industry which will hopefully translate to success in the

clinical testing phase.

VasCOT has been supported by the UK and Ireland Vasculitis Rare Disease Group which will

aid in increasing awareness on a national level of this project, and eventually will support

national diffusion.

As this product is essentially a long-term immunosuppression management tool (as

opposed to being disease specific) VasCOT can readily be adapted for use in other disease

groups. It is therefore intended that alongside the initial clinical pilot, the software will

undergo slight adaption for use in patients with Systemic Lupus Erythematosus (another

multi-system autoimmune disease requiring long-term immunosuppression). It is

anticipated that future work will include further adaption for use in other renal and

rheumatology autoimmune disease groups, Inflammatory Bowel Disease (IBD) and the solid

organ transplantation population.

Although outcomes from vasculitis are improving, data over recent years has supported

that we need to move from viewing vasculitis as an acute life- limiting illness to a chronic

disease. Alongside this shift in perception, a change in how care is delivered to this

population is required. It is clear that areas such as cardiovascular disease, cancer and

infection could be better addressed and that the key to achieving this is to define and

consistently apply standards of care to this population. In an already stretched system

caring for a complex heterogeneous patient group, the use of a web-based platform to

support holistic care could provide the ideal solution.

The 5-year forward view for the NHS focuses on giving patients greater autonomy over

their healthcare, breaking down the barriers between primary and secondary care and

supporting innovation to develop new models of care336. In this changing landscape of

healthcare provision, an innovation such as VasCOT fulfils all of these requirements, in

addition to providing the basis for standardising care in this, and other complex,

populations.

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Here I have outlined results from initial scoping work involving key stakeholders (patients

and clinicians) which support the design of our solution. I have also detailed work that has

been carried out to define the clinical content, initial user interfaces of both the clinician

and patient view and the functional specification. Subsequent stages of development and

testing will allow further improvements to these initial designs following user testing.

Future work will include collection of clinical outcome and health economic data to support

the business model for wide spread adoption within the NHS to enable improvement of

outcomes for this challenging population.

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APPENDIX 1. PATIENT QUESTIONNAIRE AND RESULTS

5%21%

74%

1) Do you use the internet to access information about

your health?

a) never

b) rarely

c) often

54

13

37

18

37

21

2) Which websites do you use for information about your health?

31 34 37

16

3) What devices do you use for accessing health information online?

14%

86%

4) Do you use renal patient view?

Yes

No 67%

33%

5) If so, how often?

a) onlyimmediatelyfollowingclinicsappointments

b) regularly toupdate myinformation 89%

11%

6) If not, would you like the option of being able to see your

blood tests online?

Yes

No

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69%

25%

6%

7) Do you receive copies of hospital correspondence following your

visit to the vasculitis clinic?

Yes

No

sometimes

100%

0%

8) If not, would you like to?

Yes

No

1%25%

74%

9) How much information do you like to receive about your health?

a) on a need to knowbasis only

b) enough so Iunderstand what is goingon but not every detail

c) as much as possible

82%

15%3%

10) If you could log into your hospital records would you like to

be able to view;

a) everything (thesame informationyour doctor sees)

b) a summary ofyour health andcurrent issues

c) I would not liketo access mymedical records

54%

5%

41%

11) Do you think that more information about your health

would make you;

a) less worriedabout your health

b) More worriedabout your health

c) Have no effect

19%

51%

22%

8%

12) How do you currently organise and manage your

health information?

a) Diary

b) Folder

c) Computer

d) I don't collecthealth information

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APPENDIX 2: CLINICAL DATA SPECIFICATIONS

Data type

Input source

Automated or manual

Notes

PAGE 1

Patient name Auto populated by login GP Records or Hospital Records A

Patient postcode Patient M

Patient DOB Patient M

Ethnicity Patient M

Date of registration Auto populated by system System A

GP name/code Auto populated by GP system or

select from list

GP

GP practice name/code GP record A

Hospital Name

Hospital clinician name Auto populated from login Hospital A

Diagnosis - Manual from hospital

records/UKIVAS

Hospital/GP A/M

Year of diagnosis per

diagnosis

Manual from hospital

records/UKIVAS

Hospital/GP A/M

Induction regime Manual from hospital

records/UKIVAS

Hospital A/M

Previous maintenance

exposure

Manual from hospital

records/UKIVAS

A/M

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Current

immunosuppression

Drop down list Pt/hospital M

Steroids Y/N Pt/hospital M

dose

Immunosuppression

monitoring frequency =

Number picker, frequency picker-

day/week/month/year

Pt/hosp M

PAGE 2- CVD RISK

BP target <140/90 2y care entered M

or <130/80 if proteinuria

BP actual Double free numeric fields GP Records A

Cholesterol total Free numeric field GP Records A

Cholesterol HDL Free numeric field GP Records A

Cholesterol LDL Free numeric field GP Records A

Cholesterol HDL/LDL ratio Free numeric field Calculated from above A

Smoker current: light < 10/day patient

moderate 10-19/day

heavy > 20 /day

previous

never

Pack years? Free text GP Records

CV/thromboembolic

history

Drop down:

MI

GP records A Code in GP records needs to be

translated to one of dropdown

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IHD

DVT

PE

CVA

TIA

AF

options

1 degree Family CV

history<60 yrs

Drop down:

Heart Attack

Angina

None

Patient entered

CKD (if CKD 3/ above) 2y care entered Associated further information

available (e.g., have 'I' button

which displays info when click

on it)

Urine PCR/ACR Numeric value GP or 2y care entered M If PCR>30 or ACR>50 then BP

target should become <130/80

CV meds Anti-platelets GP extracted/ patient entered M/A Code in GP records/text from

patient needs to be translated

to one of options

Ace/ARB

Statin

Other anti-hypertensive

Other lipid lowering drugs

Link to Qrisk calculator GP/2y care A

277

(http://www.qrisk.org/)

PAGE 3- BONE HEALTH

DEXA result T score GP or 2y care entered M

L spine

Fem neck

forearm

Vit D level Free numeric field GP/2y care M

Vit D status adequate/inadequate/borderline 2y care M Red if 'Inadequate'

Bisphosphonate Date commenced GP A At 3 or 5 years from 'Date', need

to flag that 'biphosphonate

holiday' should be considered.

The time period is dependent on

'Other medication'.

Fracture history Read/medcode GP A Translate from codes

Steroid exposure (graphed

over time)

Monthly dose (mean) Patient entered M

Post-menopausal Y/N Patient entered/2y care entered M

Alcohol intake units/week Patient entered M Flag if >14 for female, >21 for

male

Parent hip fracture Y/N Patient entered M

Link to FRAX

calculator(http://www.she

f.ac.uk/FRAX/tool.jsp)

278

PAGE 4 CANCER

SCREENING/FERTILITY

Cyclophosphamide

exposure

y/n 2y care entered Flag if Dose (cumulative) >15g

dates UKIVAS

cumulative dose

Urine RBC (graphed over

time)

0-3+ 2y care M

cystoscopy Date GP A

Action required:

No action required

Repeat

Treatment

2y care M If Action = Repeat then need to

enter a date

USS KUB Date 2y care M

Action required:

No action required

Repeat

Treatment

2y care If Action = Repeat then need to

enter a date

Skin check Y/N GP Records/hospital/ patient M

Date Date is autopopulated with date

entered Y but allow clinician to

change it. Flag if over a year

since last check

279

skin awareness education Y/N GP Records/hospital/ patient M Link to the relevant site should

appear in this table and also in

Patient's Education tab.

Date Date is autopopulated with date

clicked the link on Eduation tab

but allow clinician to change it.

Flag if 'Y' over a year since last

had it.

Cancer screening for Attended: Y/N GP records A Translation to

bowel/breast/cervical cancer

bowel, breast, cervical Result A This is not needed

Action required:

No action required

Repeat

Treatment

2y care If no action required then

generate next screening date.

Next due A

PAGE 5 STEROID OTHER

BMI Graphical over time vs target BMI Calculated Generate flag

if sig change

occurs

between visits

Flag if move from one band to

another and put links to diet and

lifestyle on Education Topics

page in patient application

Target BMI Range

Last recorded weight Patient entered/2y care M

280

Height Patient entered M

Blood glucose Numeric value (random or fasting) GP or Hospital records A

Status: Set status and action according

to rules on Diabetes and IGR

Action required:

No action required

Repeat

Treatment

HbA1c (graph over time) Numeric value GP or hospital records A

Bruising Y/N Patient M

Site of bruising Drop down selector or body map Patient

Other steroid side effects Drop down: M

Cataracts

Glaucoma

Skin tears

Mood change

PAGE 6 INFECTION RISK

Episode infection Read code/medcode Patient entered A/M

GP Display READ code as well as

term translated to

Action required Antimicrobial translation required as patient

entered

Hospital admission

281

nil

PJP prophylaxis Co-trimoxazole 2y care M

Dapsone

Atovaquone

pentamidine

Indication Induction 2ycare M

Previous infection

Other

Anti-viral prophylaxis Acyclovir 2y care M

other

indication As above

Anti-fungal prophylaxis Fluconazole

other 2ycare M

Indication As above

Flu vaccination date GP A

Date Repeat Required 365 days

Pneumococcal vaccine Date GP A

Date Repeat Required If CKD = Y then need booster in 5

years

Episode leucopenia last

12 months

Lymph Gp/2y care M

Neut

both

282

Action required Nil 2y care/patient M

Meds withheld

Dose reduced

Meds changed

Immunoglobulins IgA 2y care M

IgM

IgG If <6 flag

Date picker

Varicella ab status Positive 2y care M

Negative

date

HPV immunisation Y/N GP A

283

APPENDIX 3: PATIENT VIEW WIREFRAMES

289

APPENDIX 4. CLINICIAN VIEW WIREFRAMES

296

ID Requirement Comments

1. VasCOT landing page will provide functionality to navigate through different sections of the website.

It is envisaged that users can visit the ‘VasCOT’ website for information / guidance / updates before choosing the Log In or Register

2. Website content design and content will be defined by Hitachi

3. From the landing page, the user will have the option to:

• Login – routed to “Login” page

• Register – routed to “Registration” page.

4. Clicking “Register” will route the user to the Registration Page See Self-Registration

5. Clicking “Login” will route to a dedicated Login Page. Here the user will have 3 options:

• Register

• Login

• Forgotten Password

6. Clicking “Register” will route the user to the Registration Page See Self-Registration

7. “Forgotten Password” – Clicking this link button will guide the user to a dedicated screen. No wireframes available.

7.1. “Cancel” - User will be routed back to the System Login page.

7.2. On this screen the user will be prompted to enter the email address they use to access VasCOT

7.3. Once an email address has been entered the user will be able to click a “Submit” button

7.4. Validation will check that the email is recognised. If not, the user will be presented with an on-screen message.

7.5. If the email address is recognised, the submit button will trigger an on-screen message to the user to notify the user that a “Reset password” email has been sent to their email address and will be valid for 48 hours.

7.6. An email with a secure URL, valid for 48 hours will be generated and emailed for the user See User Verification

7.7. The URL will take the user to a dedicated password reset screen which will prompt the user to enter a new password and confirm that password. The user will submit this information.

7.7.1. .......................................................................................................................................................... The system will need to check that the passwords entered match, if they do not, an on-screen message will be displayed.

7.8. After submission, if the passwords match, the user will be presented with a “Log In” button which will route them back to the Log In screen

7.9. If the 48 hour expiry on the URL has passed, the system will prompt the user to acknowledge this and be routed back to the Forgotten Password screen to initiate the process again.

APPENDIX 5. DETAILED FUNCTIONAL SPECIFICATIONS

297

8. Log In - If a user enters a username and password, they will have the ability to click the “Log In” button

8.1. If incorrect, an on-screen notification will be displayed informing the user of the number of attempts left.

8.1.1. .......................................................................................................................................................... This defined number of attempts should be defined as a variable within the system to allow for easy configuration

8.1.2. .......................................................................................................................................................... If an incorrect username and password combination is entered x times (defined above), the account will become locked and a notification will be sent to the Provider’s Super User (if the username is identified correctly)

See Notifications

8.2. If correct, the system will direct the user to appropriate Home Page defined by Role:

8.2.1. .......................................................................................................................................................... • Clinical User – Patient Queues

• System Administrator - Dashboard

• Super User – Provider Specific Dashboard

• Patient – Patient Summary

See Dashboards, See Patient Queues and Patient Summary as defined by Hitachi


9. The system will offer a “Settings” menu located on the Dashboard Toolbar. The “Settings Screen” will provide access to administrative type functions, including:

• A User editor

• A Role editor

• A Provider editor

• Notification Settings

10. There will be the ability to restrict the “Settings” menu to specific roles

10.1. System Administrators and Super Users will have access to the Settings Menu. However, Super Users will only have access to the “User Editor”.

11. Breadcrumbs will detail the user navigation to the Settings screen from the Home Page, providing a way back.

298


12. The system will offer a Role Editor in order to attribute system wide and screen specific CRUD Features to Roles. These Roles will then be attributed to users.

CRUD = Create, Review, Update and Delete

13. There will be some system defined / default Roles available within the system.

• Clinical User

• System Administrator

• Patient

• Super User

• Read Only

13.1. System Administrator – Has complete CRUD access to all users and providers within the VasCOT community but cannot view Patient Data. A System Administrator can create another System Administrator and has full access to the Settings menu

13.2. Super User – Is restricted to a single Provider but has complete CRUD access to all users within that Provider. Can create other Super Users but cannot create System Administrators or Providers. Limited access to the Settings menu.

13.3. Patient – Has no access to anything other than their own data.

13.4. Read Only – Will have access to the screens as defined by roles but will supersede the ability to Create, Update or Delete

13.5. Clinical User – Has access to view and add information to patient records associated to their Provider.

14. Features will include but will not be limited to: as follows

299


15. Clicking into the Provider Editor from the “Settings” screen will allow the System Administrator to search for an existing Provider or create a new Provider.

16. Breadcrumbs will display the path taken to reach this screen as well as provide navigation functionality to return to previous screens.

17. Search – The system will perform a text match search based on the entered string compared with all existing Provider names.

17.1. There will be validation to ensure a minimum of 3 characters are entered prior before a search can begin

17.2. The user will be required to click / touch the search button to initiate the search

17.3. This will be a Global search across all Providers

18. Search results will appear in the table below, detailing:

• Provider name

• Domain

• Type

• Address

• Telephone number

18.1. Pagination controls will be presented at the bottom of the screen to limit the number of results per ‘page’

Guidance required on the number of results to be display on each page.

19. The user will be able to click / touch a search result to navigate through to the details of that particular Provider, providing options to Edit, Delete or Cancel.

UI guidance required by Hitachi – Will use a link, a row select, a dedicated button, etc

19.1. When viewing an individual Provider, it will be initially displayed in read only mode. The available action buttons on this screen will include:

19.2. “Cancel” button – return to Provider Search screen without saving

19.3. “Edit” button – Makes fields editable and presents “Save” and “Cancel” buttons

19.4. “Delete” button – Deletes the provider from visible view (deactivates) but not from the database for reporting purposes

19.4.1. ........................................................................................................................................................ It will not be possible to delete a Provider if there are associated Users (including patients)

19.4.2. ........................................................................................................................................................ “Delete” – Modal window for user to confirm if they wish to delete record. “Yes” – Record deleted and will no longer be available. “No” – Return to provider overview page.

19.4.3. ........................................................................................................................................................ The system will not allow the Provider to be deleted if there are patients associated to it

19.5. “Edit” – Selecting edit will enable changes to be made to the below fields:

300

• Provider name

• Type

• Address

• Telephone number

19.5.1. ........................................................................................................................................................ Domain field will not be editable.

19.5.2. ........................................................................................................................................................ When ”Edit” is selected the below button options will become available: “Save” – All changes made to record will be saved, overwriting original information. “Cancel”- Return user to “Provider Overview” page


20. To create a new Provider the User will select the “New” button on the Search screen. Selecting “New” will route the User to “Provider Editor” screen.

21. To create a new Provider the User will be required to populate the following fields:

21.1. Provider Enabled – A non-mandatory Boolean value which dictates whether the Provider is active or not

21.1.1. ........................................................................................................................................................ If disabled, it will not be possible to create Users under this Provider or associate Patients to it

21.1.2. ........................................................................................................................................................ It will not be possible to disable the Provider if there are Users (patients or clinical users) associated with it.

21.1.3. ........................................................................................................................................................ This field is of particular use when a user attempts self-registration and their Provider is unknown by VasCOT. The system will populate the Provider information but will not enable it, so that the System Admin can review and enable once verified as a true Provider

See Self-Registration

21.2. Type – Mandatory combo box selection containing: o Hospital o GP Practice o Satellite Clinic

21.3. Code – All providers will have a unique national code available to them. Free text. Mandatory.

21.4. Name – Free text field. Mandatory

21.5. Domain – The email domain associated to that Provider and the same domain users at that Provider will use when they sign up using their email address. Mandatory.

21.6. Telephone Number – Number field

21.7. 1st line of address – free text. No lookup

21.8. 2nd line of address – free text. No lookup

21.9. 3rd line of address – free text. No lookup

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21.10. ......................................................................................................................................................... 4th line of address – free text. No lookup

21.11. ......................................................................................................................................................... Postcode – free text. No lookup.

22. Cancel button – will return the user to the search screen without saving changes

23. Save button – will save the provider, when all fields are completed.

23.1. Validation will check that a Provider with this domain does not already exist

23.2. Save Successful confirmation message. The modal window will confirm successful creation of the New provider and in addition feature two buttons:

• Close

• Create New User

UI / UX guidance if appropriate

23.2.1. ........................................................................................................................................................ The Provider cannot be used with a User. Therefore, the system will attempt to guide the System Administrator to complete the process correctly by taking them to the User Editor to create a User under this Provider. It is important to note that the first User added to a newly created provider will always system default to be a Super User role, whilst allowing for other roles to be added too. This will ensure a Provider can always be self-maintained

23.3. Close – User routed back to “Provider Editor” Search screen.

23.4. Create New User – User routed to the “User Editor” screen. See User Editor

302


24. Clicking into the User Editor will allow the System Administrator to search for an existing User or create a new User.

25. Search – The system will perform a text match search based on the entered string compared with the entered text.

25.1. There will be validation to ensure a minimum of 3 characters are entered

25.2. The user will be required to click / touch the search button to initiate the search

26. Search results will appear in the table below, detailing:

• Name

• Provider

• Role

26.1. Pagination controls will be presented at the bottom of the screen to limit the number of results per ‘page’

27. The user will be able to click / touch a search result to navigate through to the details of that particular Provider, providing options to Edit or Delete.

UI guidance required by Hitachi – Will use a link, a row select, a dedicated button, etc

28. When viewing an individual User, it will initially be displayed in read only mode. The available action buttons on this screen will include:

29. “Cancel” button – return to User Search screen without saving

30. “Edit” button – Makes fields editable and presents “Save” and “Cancel” buttons

31. “Delete” button – Deletes the User from visible view (deactivates) but not from the database for reporting purposes

31.1. It will not be possible to delete a User if they are associated to patients

31.1.1. ........................................................................................................................................................ A administrative function will be available to bulk move patients from one clinician to another See Admin Functions

31.2. “Delete” – Modal window for user to confirm if they wish to delete record. “Yes” – Record deleted and will no longer be available. “No” – Return to provider overview page.

31.3. The system will not allow the User to be deleted if there are patients associated to it

32. “Edit” – Selecting edit will enable changes to be made to all fields

32.1. When ”Edit” is selected the action buttons options will become available:

32.1.1. ........................................................................................................................................................ “Save” – All changes made to record will be saved, overwriting original information.

32.1.2. ........................................................................................................................................................ “Cancel”- Return to “User” page in read only view

33. System Administrators will have the ability to view the global user list. However, Super Users will only have the ability to view and search local users within their own Provider

34. New – The New button will initiate the creation of a new User in a dedicated screen

303


35. System Administrators and Super Users can create New Users through the “User Editor” tile within the VasCot settings screen.

36. Selecting “User Editor” will route the user to the “User Search” screen. This screen gives the user the functionality to search for an existing patient or select the “New” button to create a new user.

Search functionality will follow the same conventions as Provider Search.

37. Selecting “New” will route the user to “User Editor” screen.

38. Creating a new user will require the following information to be completed:

38.1. Account enabled – Selecting this option will activate the account and send the user an email to create a password. Tick box. Not mandatory.

This will be actioned at the point of selecting “Save”

38.1.1. ........................................................................................................................................................ If the Account is disabled, it will not be possible to create / associate Patients to this user as a named Clinician

38.1.2. ........................................................................................................................................................ It will not be possible to disable the User if there are Patients associated with it.

38.1.3. ........................................................................................................................................................ This field is of particular use when a user attempts self-registration and the User is unknown by VasCOT. The system will populate the User information but will not enable it, so that the System Admin can review and enable once verified as a true User

See Self-Registration

38.2. Account locked – Selecting this option will add the account details to the VasCOT database but upon login attempt, the user will be informed that the Account is locked.

38.2.1. ........................................................................................................................................................ The account will be locked by the System automatically if the number of login attempts is surpassed

38.2.2. ........................................................................................................................................................ Can also be manually set by a Super User to restrict access to the account without needing to disable.

38.3. Force Password Reset – If selected, a password reset email with a secure link will be sent to the User. Tick box.

This will be actioned at the point of selecting “Save”

38.3.1. ........................................................................................................................................................ User will not be able to sign in until they change their password

38.4. Role – Role(s) will be set for the user. It will be possible to assign a user to multiple roles Multi-select combo box used in wireframes to facilitate many roles being available in the future

38.5. Provider – Combo box. The Provider to which the user belongs. System Administrators will be able to select from the full list. Super Users will be restricted to their own Provider and will not be able to change this.

May require a search and suggest type implementation if there is large number of Providers

38.6. Title – combo box. Containing: o Mr o Miss o Mrs o Ms o Dr

304

o Prof

38.7. Forename – free text field. Mandatory.

38.8. Surname – free text field. Mandatory.

38.9. Email – free text field. Validation required to ensure the domain used matches the domain of the Provider

38.10. ......................................................................................................................................................... Telephone number – number field

38.11. ......................................................................................................................................................... 1st Line of Address – free text. No lookup.

38.12. ......................................................................................................................................................... 2nd Line of Address – free text. No lookup.

38.13. ......................................................................................................................................................... 3rd Line of Address – free text. No lookup.

38.14. ......................................................................................................................................................... 4th Line of Address – free text. No lookup.

38.15. ......................................................................................................................................................... Post code – free text. No lookup.

38.16. ......................................................................................................................................................... Secretary / team email – Free text field Requires review for notifications

39. Cancel – will return the user to the search screen without saving changes

40. Save – will save the provider, if all mandatory fields are completed.

40.1. Save Successful confirmation message UI / UX guidance if appropriate

40.2. If the User has had their account enabled, the “Successful Save” will trigger the sending of an email to the User for them verify registration and create their password.

See User Verification

305

ID Requirement

41. Patient creation will not be completed from the User editor and instead will be completed from within the “Patient Folder” screen, which means the user creating the patient will need to have access to patient data – likely to be a clinician but to be determined by Role.

42. Patient entries will be selectable. Selecting a patient will route User to “Patient Overview”

43. The Patient Folder offers the ability to search for a patient. In the event of the patient not being found, the system will suggest that the patient can be created, using a dedicated “Create New Patient” button.

44. “Create New Patient” will route the User to “Patient Folder – Editor”

45. “Patient Folder – Editor” will be displayed in tab format:

• Patient – Patient details

• Provider – Provider details

45.1. User will be required to input the below information on the “Patient” tab:

• NHS Number – Number field. Mandatory.

• Title – Drop down menu (Miss, Ms, Mrs, Mr, Dr). Mandatory.

• Forename – Free text field. Mandatory. Middle Name(s) – Free text field Surname – Free text field. Mandatory.

• Date of Birth – Date Picker. Mandatory.

• Email Address – Free text field. Mandatory.

• Telephone Number – Number Field. Mandatory.

• 1st Line of Address – Free test field. Mandatory.

• 2nd Line of Address – Free test Field. Mandatory.

• 3rd Line of Address – Free text Field

• 4th Line of Address – Free text Field. Mandatory.

• Preferred Method of Communication – Tick box (Email, Post). Mandatory.

• Consent – The Consent field will be disabled during Patient creation as the Patient will need to provide this when they verify and login.

45.1.1. ........................................................................................................................................................ NHS Number validation algorithm will check that the NHS number is in the correct format and a valid number but will not check that this number belongs to the created patient unless otherwise specified.

45.1.2. ........................................................................................................................................................ Without consent, users of the creating Provider can begin to populate patient data but it will not be shared with the wider VasCOT community (users associated to providers other than the creating Provider) until consent is provided by the patient. If this consent is removed only the Lead Provider will have access until Consent is granted again.

45.2. Cancel – Returns user to “Patient Folder” without saving

45.3. Next Button – Will route the user to the “Providers” tab in a wizard style approach

306

46. On the Providers tab, the patient will need to be associated with:

46.1. A Lead Provider – The user will select from a list of currently existing Providers of Types “Hospital” or “Clinic”. Mandatory.

46.1.1. ........................................................................................................................................................ The “Lead Provider” will automatically populate the details of the Provider associated with the currently logged in User.

46.1.2. ........................................................................................................................................................ When Lead Provided is inputted the “Clinician” field will be enabled for the user to select a user associated to this Provider. Optional.

46.2. GP Practice – The user will select from a list of currently existing Providers of Type “Practice”. Optional.

46.2.1. ........................................................................................................................................................ When GP Practice is inputted the “GP” field will be enabled for the user to select a user associated to this Provider. Optional.

46.3. Satellite Clinic – The user will select from a list of currently existing Providers of Types “Hospital” or “Clinic”. Optional.

46.3.1. ........................................................................................................................................................ When Satellite Clinic is inputted the “Clinician” field will be enabled for the user to select a user associated to this Provider. Optional.

46.4. All of these Providers will already need to exist in the system in order to associate them to a patient using the combo boxes.

47. There will be controls to add / remove multiple satellite sites, as required.

48. Cancel Button – Will return to the search screen without saving

49. Back Button – Will move the user back to the “Patient” tab / wizard screen.

50. Save Button – Will save the patient (subject to mandatory fields being completed correctly)

51. Selecting “Save” will trigger the Patient verification email.

52. A “Save Successful” message will be presented in a modal window.

53. “OK” Button – Route user back to “Patient Folder” with the patient present in the Patient Queues

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ID Requirement

54. Enabling a new User will trigger the sending of a verification email to the email address inputted.

54.1. The email will contain instructions and a secure VasCOT URL which allows the user to create a password for their account

54.1.1. ........................................................................................................................................................ The URL will only be valid for ‘x’ amount of time (will need to be defined as a variable / config setting for flexible changes in the future)

54.1.2. ........................................................................................................................................................ If this time elapses before the user has verified their email, the URL should present a screen informing the user of this fact and provide the ability for the user to request a new URL, which will trigger the same verification email but with a new URL, to be delivered to their registered email address

55. Upon accessing the verification email (within the allowed time limit) and following the URL link provided, the User will have the ability to create a password.

56. The User will be required to input:

• Email – Free text field

• Create Password – Free text field

• Re-enter Password – Free text field

56.1. Password will be entered twice so that matching validation can confirm that the password was entered the same on both occasions.

56.1.1. ........................................................................................................................................................ Password criteria validation will also be enforced (E.g. min characters, upper case, etc)

57. Depending on whether the user verifying their account is a Patient or not, the screen will either a present Disclaimer information (not a patient) or Consent information (patient).

57.1. It will be a mandatory requirement that the user confirms that they either give consent or acknowledge the disclaimer before they can submit to verify their account.

57.2. Guidance and wording to be provided for Disclaimer

57.3. Guidance and wording to be provided for Consent

57.3.1. ........................................................................................................................................................ Consent can later be revoked by the Patient within their own Patient Details section

58. “Submit” – Selecting submit will validate the details entered

58.1. If the details are correct a modal window will appear confirming successful registration. Close – Routes User to the Login page

58.2. If the details are incorrect, the fields will be cleared and the User instructed to re-enter.

308

ID Requirement

59. The system will offer the ability for new users to register directly from the home screen of the solution via the “Register” button.

60. If the user enters an email address with a domain already belonging to a Provider, the request will be sent to the Provider Super User(s) and the “Provider” details on the right hand side of the registration screen will be hidden.

61. If the user enters an email address with a domain which does not belong to a known Provider, the “Provider” details on the right of the screen will be shown and made mandatory. The request will be sent to the System Administrator for review and for a Provider to be setup.

62. To register, the user will complete the below mandatory fields:

63. Title – Drop down menu

• Miss

• Mrs

• Ms

• Mr

• Dr

• Other

64. Forename – Free text field

65. Surname – Free text field

66. Email Address – Free Text field

67. Domain checking will be performed on the email address to show / hide the Provider details as required

68. Unique ID – string

69. Telephone Number – Number field

70. Reason for access request – Free text field

71. If the email domain is unrecognised, the following mandatory information will be completed:

72. Provider type: Drop down menu

• Trust / Hospital

• GP Practice

• Clinic

73. Code – String

74. Provider Name – Free text field

75. 1st Line of Address – Free text field

76. 2nd Line of Address – Free text field

77. 3rd Line of Address – Free text field

78. 4th Line of Address – Free text field

79. Postcode – Free text field

80. Telephone Number – Number field

81. “Cancel” button will not commit the information inputted and route the user back to the VasCOT landing page.

309

82. “Submit” button will register details to the system and a modal window will appear explaining the next steps.

83. The submission will trigger a notification to the relevant VasCOT Users to authorise the request.

ID Requirement

84. The Dashboard will provide full visibility across all Providers to System Administrators.

85. The Dashboard will display Provider Specific information to Super Users of that Provider.

86. The Dashboard will display KPI information in the main body of the screen. This will include:

• No. of user login in the last 24 hours

• No. of hits the website received in 24 hours

• No. of users online

87. The VasCOT dashboard will include a fixed toolbar that will feature across the top of the screen.

88. The toolbar will display user credentials with a “User Profile” button.

89. “Logout” button when selected will end the Users current session and route back to “Login” screen.

90. “Settings” button will direct users to the “Settings” page. From this page four options will be available:

• User Editor

• Role Editor

• Provider Editor

• Notification Settings

ID Requirement

91. Clinical Users will be routed to “Patients” screen upon login (as defined by Role)

92. The main body of the screen will be split into two tabs listing patients

92.1. • My Patients: List of patients associated with the User identified as the Named Clinician

• Our Patients: List of patients associated with the Provider

92.2. Each tab header will contain:

• Tab Title

• A Patient Count: This is the number of patients on that list.

• Notification Count: This is the total number of notifications awaiting acknowledgement from that Provider, on that list.

93. Patient information will be displayed in a table including the following columns:

93.1. • Patient Name

• Date of Birth

• NHS number

• Last Patient Update (Date / Time)

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• Next Appointment

• Lead Clinician (Named clinician of lead Provider)

• Consent (Yes / No)

• Notification Count

94. Users will be able to navigate between the tabs freely

95. Selecting a patient row from the list will route the User to the “Patient Overview”.

ID Requirement

96. If the User belongs to a Provider which is not associated to any patients, then the Patient Queues will be empty with a count of zero.

97. The system will provide a search feature from the Patient Folder, for the user to find patients using a combination of names or NHS Number.

98. The system will return results based on the search or offer to create a new patient, depending on Role.

99. Upon selecting a patient from the search results, the system will determine whether the current User’s Provider is associated to the patient or not.

99.1. If it is, the user will be able to access the Patient Overview information.

99.2. If it is not, all clinical information will be hidden and the user will be informed that they do not currently have access but may request it

100. The user will be required to select how they would like to be associated to the Patient from a drop down menu, consisting of:

• Lead Provider

• GP Practice

• Satellite Clinic

100.1. ......................................................................................................................................................... The available options in the dropdown will intelligently be restricted based on the current user. If the user belongs to a GP Practice, then the option will default and be restricted to “GP Practice”. If the user belongs to any other type of Provider, they will have the options to select “Lead Provider” or “Satellite Clinic”

100.2. ......................................................................................................................................................... If “Lead Provider” is selected, a warning will appear under the field informing the user that if they are granted access, they will replace the current Lead Provider for that patient, as only one Provider can be identified as the Lead.

100.3. ......................................................................................................................................................... If “GP Practice” is selected, a warning will appear under the field informing the user that if they are granted access, they will replace the current GP Practice for that patient, as only one GP Practice can be associated to the patient.

100.4. ......................................................................................................................................................... If “Satellite” is selected, a note will appear under the field informing the user that if they are granted access, they will be added as another satellite provider without replacing any of the other providers.

101. The User will be required to select who they are requesting access on behalf of, from a drop down list. The list should contain all of the Users for their Provider with the current user defaulted into the box.

102. The system will offer a mandatory dropdown menu of coded reasons

102.1. ......................................................................................................................................................... The system will also offer a supplementary but optional free text box to capture additional information for requesting access.

103. The Request Access screen will offer two control buttons:

• Request Access

• Cancel

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103.1. ......................................................................................................................................................... “Request Access” – Will present a “Submission Success” message.

103.1.1........................................................................................................................................................ This will also trigger a notification to the Lead Provider in order for them to approve or reject the request

Requirement

104. To request a change to Provider Type, a User will need existing access to patient data (via their Provider asscociated), in order to access the “Edit Patient Details” Screen from the “Patient Overview”.

105. “Edit Patient Details” will feature:

• Patient Tab – Patient details

• Provider Tab – Provider details

106. The Provider tab will display all current provider information (Lead, Satelite, GP etc.)

107. If the logged in user is not the current Lead Provider and is not a GP Practice a check box should be displayed labelled “Send request to become Lead Provider”.

107.1. ......................................................................................................................................................... Checking this box and saving the changes will trigger a notification to the current Lead Provider for review.

107.2. ......................................................................................................................................................... No changes in Provider Type will take effect until the request has been “Accepted”

108. Within the Patient Editor, Satellite Providers will also have the ability to relinquish access to the patient, using the same add / remove controls available to the Super User but restricted by RBAC to only allow removal of themselves.

ID Requirement

109. To request a change to Provider Type, a User will need existing access to patient data (via their Provider asscociated), in order to access the “Edit Patient Details” Screen from the “Patient Overview”.

110. “Edit Patient Details” will feature:

• Patient Tab – Patient details

• Provider Tab – Provider details

111. The Provider tab will display all current provider information (Lead, Satelite, GP etc.)

112. If the logged in user is not the current Lead Provider and is not a GP Practice a check box should be displayed labelled “Send request to become Lead Provider”.

112.1. Checking this box and saving the changes will trigger a notification to the current Lead Provider for review.

112.2. No changes in Provider Type will take effect until the request has been “Accepted”

113. Within the Patient Editor, Satellite Providers will also have the ability to relinquish access to the patient, using the same add / remove controls available to the Super User but restricted by RBAC to only allow removal of themselves.

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ID Requirement

114. The notification will route the user to Patient Editor upon selection. However, the user can also access the Patient Editor manually, via the Patient Overview screen.

115. Requested Provider changes will present themselves next to the current Provider information for easy comparison

115.1. ......................................................................................................................................................... In some instances the current Provider information will be blank for GP Practices and Satellite Clinics, if they have not been previously set.

116. A dedicated control container will surround the current provider and the requested changes with two action buttons:

• Approve

• Reject

116.1. ......................................................................................................................................................... “Reject” button. Rejecting the change would trigger a notification to the satellite clinic and provider status would remain the same.

116.2. ......................................................................................................................................................... “Accept” button - Accepting the change will populate the fields in the “Provider” tab accordingly by updating the current Provider information with the requested Provider information.

116.2.1........................................................................................................................................................ A notification will be triggered to the requesting Provider to confirm the change.

117. The system will still require the user to Save the changes by using the dedicated Patient Editor Controls:

117.1. ......................................................................................................................................................... Cancel – Route back to “Notifications”

117.2. ......................................................................................................................................................... Save – Save will open a modal window asking user if they wish to become a satellite provider:

117.2.1........................................................................................................................................................ If the request was to change the Lead Provider and the Lead Provider approves this change, they will effectively be removing their own association to the patient and will no longer have the ability to contribute to the patient record – although they will have access to any past information they have been responsible for. Therefore, in this scenario, an additional check should prompt the user with a modal window with two actions buttons.

117.2.2........................................................................................................................................................ The modal should ask the user : “Do you also wish to set the previous Lead Provider as a Satellite Provider now? This will ensure that this Provider can still contribute to the Patient Record. Yes – Provider details will automatically set as Satellite for this patient No – Provider details will be removed from the patient record and the ability to contribute will be removed

117.2.3........................................................................................................................................................ Any current workflows, data input or record contributions will be completed prior to the Lead Provider before accepting another Provider as the Lead. Incomplete workflow / information will be attributed to the new Provider under their responsibility.

118. “Patient folder” will be displayed in read only again to reflect the change in Providers agreed.

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ID Requirement

119. The notification will route the user to Patient Editor upon selection. However, the user can also access the Patient Editor manually, via the Patient Overview screen.

120. Requested Provider changes will present themselves next to the current Provider information for easy comparison

120.1. ......................................................................................................................................................... In some instances the current Provider information will be blank for GP Practices and Satellite Clinics, if they have not been previously set.

121. A dedicated control container will surround the current provider and the requested changes with two action buttons:

• Approve

• Reject

121.1. ......................................................................................................................................................... “Reject” button. Rejecting the change would trigger a notification to the satellite clinic and provider status would remain the same.

121.2. ......................................................................................................................................................... “Accept” button - Accepting the change will populate the fields in the “Provider” tab accordingly by updating the current Provider information with the requested Provider information.

121.2.1........................................................................................................................................................ A notification will be triggered to the requesting Provider to confirm the change.

122. The system will still require the user to Save the changes by using the dedicated Patient Editor Controls:

122.1. ......................................................................................................................................................... Cancel – Route back to “Notifications”

122.2. ......................................................................................................................................................... Save – Save will open a modal window asking user if they wish to become a satellite provider:

122.2.1........................................................................................................................................................ If the request was to change the Lead Provider and the Lead Provider approves this change, they will effectively be removing their own association to the patient and will no longer have the ability to contribute to the patient record – although they will have access to any past information they have been responsible for. Therefore, in this scenario, an additional check should prompt the user with a modal window with two actions buttons.

122.2.2........................................................................................................................................................ The modal should ask the user : “Do you also wish to set the previous Lead Provider as a Satellite Provider now? This will ensure that this Provider can still contribute to the Patient Record. Yes – Provider details will automatically set as Satellite for this patient No – Provider details will be removed from the patient record and the ability to contribute will be removed

122.2.3........................................................................................................................................................ Any current workflows, data input or record contributions will be completed prior to the Lead Provider before accepting another Provider as the Lead. Incomplete workflow / information will be attributed to the new Provider under their responsibility.

123. “Patient folder” will be displayed in read only again to reflect the change in Providers agreed.

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ID Requirement

124. “Notifications Settings” will only be available for System Administrators.

125. System Administrators will use notification settings to define role types.

126. The screen will detail the “Notification Type” and the recipient of such notification type.

127. All recipient types will be listed in a dropdown/tick box menu:

• Patient

• Clinical User

• Receiving Provider

• Super User

• System Administrator

• Administrator

128. Several recipient types can be selected per notification type.

129. Users will access this screen from the Patient Overview.

130. As per the other editors, the fields will be first displayed as read-only with the following actions:

131. Cancel – Returns to the Patient Overview

132. Edit – Enables the fields for editing (Role dependant)

133. Replaces the current action buttons with just two: Save – Save changes and return to read only view of the Patient Editor Cancel – Do not save any changes and return to read only view of the Patient Editor

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8 DISCUSSION

Although mortality from ANCA associated vasculitis itself is improving, this body of work

looks beyond treating the disease, to managing the patient in the longer-term through

acknowledging the morbidity that may accrue through chronic disease and

immunosuppression exposure. Identification of potential factors contributing towards

current morbidity in this population was undertaken through an initial literature review

followed by the broad patient questionnaire study. This study highlighted that there are

several hurdles patients face on their route through diagnosis, initial treatment and long

term management that must be overcome to optimise their outcomes.

8.1 RECOGNITION AND IDENTIFICATION OF DISEASE

One of the major challenges for patients with vasculitis is correct and timely identification

of the disease. Data from the patient questionnaire study has shown there is often

substantial delay to diagnosis with this likely to translate into accrual of organ damage. This

is more prominent in patients presenting with more unusual disease manifestations

perhaps highlighting the need for increased awareness of the disease and its spectrum in

the wider clinical community. The majority of patients surveyed were diagnosed from the

year 2000 onwards (59%) meaning that this data reflects relatively recent patient

experience. This is supported by data from the combined EUVAS studies reporting that

34.5% of patients had more than one item of damage, as identified through the Vasculitis

Damage Index, at baseline (being enrolment to clinical trial)205.

The Chapel Hill group conducted a study with some parallels, examining the pathway to

renal biopsy of patients with small vessel vasculitis diagnosed in the United States. They

identified that contributory factors to delay to biopsy (and therefore usually definitive

diagnosis) included a delay from the patient in seeking care, and those presenting with

upper respiratory tract involvement or ‘flu like prodrome66.

One approach to improving the patient’s pathway to diagnosis will be in having clearer

diagnostic and classification criteria for vasculitis. This will be provided by the previously

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mentioned DCVAS study which has so far recruited around 4000 patients worldwide,

aiming to not only revise the classification criteria for vasculitis but for the first time to

provide diagnostic criteria.

The questionnaire study novelly reports diagnoses that patients had their vasculitis

symptoms attributed to prior to receiving their diagnosis of vasculitis. Understandably,

patients were assigned commoner diagnoses, usually in primary care, initially.

Education and raising awareness of vasculitis is undoubtedly part of the challenge to

improve routes to diagnosis. However, due to the rarity of the disease it is not appropriate

to focus these efforts on primary care as predominantly the patients presenting with

symptoms of nasal congestion or arthralgia will not have vasculitis.

Equally with an increasing burden on primary care, it is not reasonable to expect primary

care physicians to not only be aware of the full spectrum of vasculitis disorders, but also to

dedicate their time and resources to defining and diagnosing these rare and challenging

conditions. One approach however, may be to examine constellations of presenting

symptoms and to use this to develop algorithms to allow generation of red flags for ANCA

testing and secondary care referral should these arise within a certain time period in a

patient. In order to inform this sort of algorithm large numbers of well phenotyped patients

are required. Once again, this is something that may be supported by the DCVAS data set

following completion of this study.

Another possible source of data to contribute to such a development would be the Clinical

Practice Research Datalink (CPRD). This is a resource with over 11 million UK patient

primary care records, including around 6.9% of the population337. This dataset provides

complete primary care records, allowing identification of the most common initial

presenting complaints to primary care, prior to the diagnosis of AAV. This would also allow

the findings of the most frequent “misdiagnoses” in AAV to be validated using a different

approach.

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8.2 INITIAL MANAGEMENT

For patients for whom the suspicion of disease has been raised the next step is ensuring

that patients are rapidly referred to a centre with the capacity and experience to facilitate

timely and appropriate therapy. The way care is delivered within the NHS is evolving. Finite

resources and increasing patient numbers means that the structure of care is changing to

ensure the most efficient models are used. For many specialties this is resulting in “centres

of expertise” being formed to concentrate both resources and clinicians with the

knowledge and experience in these particular areas. With regards to provision of vasculitis

care, current recommendations are that patients should be managed “by a nominated

clinician within clinical networks linked with centres of expertise and other specialities

within the local organisation”83. One way of defining these “centres of expertise” is through

the designation of “Specialised Centres” through Specialised Service Commissioning.

However, these services are provided through individual clinical disciplines, being

Rheumatology for vasculitis care. Patients with vasculitis clearly can have multi- organ

involvement and as such may need clinical input from multiple disciplines. This can make

planning for delivery of care to these patients challenging.

However, through close collaboration and establishment of networks of care involving the

relevant clinicians across a region, these challenges can be overcome. In the case of the

patient with life- threatening disease, initial care needs to be provided in a centre with

critical care support and plasma exchange facilities. For patients who require treatment

with Rituximab as opposed to cyclophosphamide, current NHS England commissioning

requires patients to be entered onto the UKIVAS national disease registry. Therefore,

although patients do not necessarily need to be managed in UKIVAS registered centres,

they will need to be managed in collaboration with such a centre to enable registry entry if

NHS England criteria is to be met.

8.3 LONGER TERM MANAGEMENT

Once initial therapy has been decided upon and arranged then the longer-term treatment

strategy becomes important. It is important for patients with vasculitis to remain under

life-long follow-up due to the risk of future disease relapse, or complications that may arise

from the disease or the therapy. Currently, that long-term surveillance is usually carried out

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in secondary or tertiary centres. However, the questionnaire study and the Delphi results

suggest there is a role for primary care in the long-term management of this patient group.

Indeed, the population appears to have confidence in their GP, seeing them as the first

point of contact for scenarios including infection but also clinical manifestations that could

represent vasculitis disease activity.

Equally, one of the major parts of managing this condition long-term is managing the risks

associated with damage and therapy. There are none better placed than primary care to

undertake cardiovascular risk assessment, ensure vaccination uptake and cancer

surveillance.

What is vital, is to provide the support and education to facilitate this. Primary care need to

be empowered with the information regarding the augmented risk of cardiovascular

disease, infection, and cancer amongst others, in order to provide appropriate screening

and prophylaxis.

However, prospectively collected data would provide a much more valid way of answering

these questions. Within the UK and Ireland, the national vasculitis registry (UKIVAS) aims to

eventually provide a comprehensive repository for longitudinal data on all patient within

these countries. There are also well established disease registries in Poland and

Germany338 amongst other countries . In the future, combination of these large datasets

may allow us better information to inform our patients of their likely outcomes.

In addition, a tool such as VasCOT has a role, through providing prompts to secondary care

to evaluate for risk factors, through improving two- way communication with primary care,

and in addition providing an educational resource, both for the patient, but also for other

clinicians. The principle of VasCOT fits well within the “5 year forward view” of NHS

England336 which focuses in part on emerging models of care with creating integrated

networks of care a key principle. This report outlines the concept of patients having access

to specialist centres at pivotal points in their management but in parallel acknowledging

that creation and maintenance of care networks for conditions will enable a significant

proportion of patient care to be delivered closer to their home.

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8.4 FURTHER WORK

Following publication of the ADAPTIV guidelines it is hoped that these will provide a

valuable resource for all clinicians involved in the care of this patient group. The idea is that

these guidelines will provide a comprehensive point of reference to allow safe and holistic

management of the patient, without clinicians having to access multiple documents to

guide them in the different facets of long-term vasculitis care. The guidelines will in

addition, provide standards against which care can be audited to ensure ongoing

improvement of quality.

The major section of this work which is ongoing, is that of VasCOT. Initial development (of

the stages so far outlined within this thesis) was undertaken with resource support from

Hitachi Europe. There has been subsequent interest from other software developers, with

discussions underway as to how to best move this project forward. The next step, following

development, is clinical testing in a single centre, for user acceptability. This will include

detailed feedback from both clinicians and patients to ensure that the data input

requirements are sustainable and will not lead to user fatigue and that the outputs are

valid and relevant. This project is fully supported by the UK and Ireland Rare Disease Group

for Vasculitis and with collaboration with the leading vasculitis centres across the UK

already, this secures participation in more wide scale testing to allow initial outcome and

health economic data to be collected. Alongside this, there is substantial interest in

developing this product for the monitoring of other populations requiring long-term

immunosuppression. The initial plan is to, in conjunction with developing the vasculitis

software, adapt and pilot this tool for patients with Systemic Lupus Erythematosus. These

are patients with many parallels with vasculitis. Not only is lupus an autoimmune disease

with the ability to affect multiple systems, but in addition, these patients may receive

similar induction therapy (in the form of cyclophosphamide or Rituximab and steroids) and

continue to need long-term immunosuppression. This is a population for whom the major

causes of morbidity and mortality include infection, VTE, CVD and bone disease339,

therefore there is significant reason to think that a similar approach will translate well.

In addition to lupus, other conditions requiring long-term immunosuppression, including

immune mediated renal and rheumatological conditions, inflammatory bowel disease and

the transplant population would be suitable to consider adaptation of this software.

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As electronic health records continue to develop across the UK, this will in turn improve the

functionality of VasCOT and the possible scope for future use. Once there is a validated

method for patients to perform their own disease activity scoring, then VasCOT could aid in

distance monitoring of patients, allowing self- reporting of symptoms and prioritisation of

those to be seen in specialist centres. Other possible opportunities include testing of

VasCOT in a different healthcare setting overseas, with initial steps towards future

collaboration with the Monash Institute in Melbourne, Australia, already taken.

It is hoped that with the approaches outlined in this thesis, the major complications of

infection, cardiovascular disease, and osteoporosis can be raised in the conscious level of

the community, and hopefully diminished. In addition, the longer-term cancer risks seen in

this population will hopefully continue to dwindle with more controlled, and evidence

based, use of cyclophosphamide.

8.5 FUTURE THERAPIES

However, moving forwards, better future outcomes for these patients will largely depend

on more targeted and steroid sparing immunosuppressive regimes. The PEXIVAS study340,

which evaluates the role of plasma exchange for those with moderate renal impairment

secondary to AAV, in addition randomises patients to receive a modified steroid protocol

equating to approximately half that prescribed by “standard” protocols340. This will allow

better definition of both the sub population of vasculitis patients who may benefit from

PLEX whilst hopefully allowing patients to be exposed to fewer steroids, with an evidence

base to support this.

One of the most promising new therapeutic agents currently undergoing clinical trials is the

C5a receptor inhibitor, CCX168. In a Phase II randomised controlled trial of this agent

compared 1) standard care (cyclophosphamide or rituximab) and prednisolone starting at

60mg a day, 2) CCX168 plus CYC or RTX and prednisolone starting at 20 mg a day with 3)

CCX168 and CYC or RTX plus no prednisolone. At week 12, the patients who received the

study drug had better outcomes, in terms of a reduction in disease activity and patient

reported outcomes, than those on standard therapy35. This therapeutic agent shows great

promise, with Phase III trials now underway.

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8.6 EPIGENETICS

Another strategy which will allow us to provide more personalised medicine to our

patients, therefore hopefully reducing unnecessary immunosuppression exposure, is the

field of epigenetics. Epigenetics can be defined as “mechanisms that register, signal or

perpetuate gene activity states”341. Essentially epigenetic processes affect gene expression

without affecting gene sequences. It is thought that these processes of epigenetic

modification occur in response to environmental changes, either the environment of the

cell, or the entire organism. Therefore, it is thought that this may be the missing link that

explains why there is significant disconcordance, even amongst genetically identical twins,

in patterns of disease development. Epigenetics has started to explain the “two-hit” model

of autoimmune disease with regards to the interaction between genetic predisposition and

environmental trigger in other conditions such as Inflammatory Bowel Disease and Lupus.

Although there is limited data regarding the epigenetics of AAV so far, there is some

suggestion that it will aid with allowing distinction early on between those patients who

will relapse and those who will attain drug free remission342. This will allow

immunosuppression strategies to be more commensurate with the risk of future disease

activity. In addition, it is likely that the study of epigenetics will enable us to further

understand this complex disease pathogenesis and identify new therapeutic targets.

8.7 SUMMARY

In summary, the landscape of care for those with vasculitis has and is undergoing some

significant changes. As clinicians, we must remain focused on optimising outcomes for our

patients despite increasing financial constraints and evolving models of care. Although this

will be challenging, the vasculitis community continues to work together, with

collaboration bringing the possibility of more robust longitudinal data for outcomes in this

population. In addition, this collaboration increases the power for meaningful clinical trial

data.

Therefore, despite tough times ahead for the healthcare system in this country, the

ongoing enthusiasm and drive of both the clinical and patient communities promise that

outcomes for patients with ANCA associated vasculitis can, and will, continue to improve.

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9 PUBLICATIONS

328

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