Gastroenterology Nursing

A nurse-driven outpatient clinic for thiopurine-treated inflammatory bowel diseasepatients reduces physician visits and increases follow-up efficiency.

--Manuscript Draft--

Manuscript Number: GNJ-D-13-00057

Full Title: A nurse-driven outpatient clinic for thiopurine-treated inflammatory bowel diseasepatients reduces physician visits and increases follow-up efficiency.

Article Type: Research Study

Corresponding Author: xavier calvet, MD; PhDServei Aparell Digestiu, Hospital de Sabadell.Sabadell, SPAIN

Corresponding Author SecondaryInformation:

Corresponding Author's Institution: Servei Aparell Digestiu, Hospital de Sabadell.

Corresponding Author's SecondaryInstitution:

First Author: María López, MsC

First Author Secondary Information:

Order of Authors: María López, MsC

Angelina Dosal, RN

Albert Villoria, PhD

Laura Moreno, RN

xavier calvet, MD; PhD

Order of Authors Secondary Information:

Manuscript Region of Origin: SPAIN

Abstract: Patients on thiopurine therapy need frequent monitoring to prevent drug adverseevents.To describe the structure and main results of a nurse-driven outpatient clinic (NDOC)programme for the follow-up of patients receiving treatment with thiopurineimmunosuppressants.We retrospectively reviewed patient´s clinical charts on thiopurine drugs, azathioprine(AZA) and 6-Mercaptopurine (6-MP). We evaluated the efficacy of the NDOC bycomparing the number of physician visits and the adequacy of laboratory controls foreach patient before and after inclusion in the programme.From January 2006 to December 2008, 179 patients were included. Of these, 102 hadreceived thiopurines for at least one year before the start of the NDOC. Mean age was42±15; 83% were female. In all, 137/179 (76%) of the patients had Crohn disease(CD); AZA was the most frequently drug used (97%). Mean time of follow-up was 2.03± 0.9 years. Implementation of this programme decreased the number of physicianvisits per year - from 4.6 ± 1.9 to 2.4±1.3 (p< 0.001) - and the number of periods longerthan four months without laboratory control (68% to 45%, p= 0.01). Leucopeniaepisodes and complications did not differ significantly before and after the start of theNDOC.Nurse-driven follow up of these patients reduces physician visits while improvingtightness of the follow-up.

Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation

Kathy A. Baker Editor-in-Chief Gastroenterology Nursing Please find enclosed the manuscript “A nurse-driven outpatient clinic for thiopurine-treated inflammatory bowel disease patients reduces physician visits and increases follow-up efficiency.” for evaluation and possible publication in Gastroenterology Nursing I confirm, on behalf of all the authors, that the work has not been published and is not being considered for publication elsewhere. Statement of Autorship: All authors have made substantial contributions to all of the following: the conception and design of the study, or acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; final approval of the version to be submitted. Conflict of Interest: The authors have no conflicts of interest that are directly relevant to the contents of this manuscript. Ethical Adherence: This study has been approved by the Ethic Committee at the Corporació Sanitària Parc Taulí, Sabadell, Spain.

Yours faithfully,

Dr. Xavier Calvet, MD Digestive Diseases Unit. Hospital de Sabadell Institut Universitari Parc Taulí, Universitat Autónoma de Barcelona CIBEREHD – Instituto de Salud Carlos III Parc Taulí, 1 08208 Sabadell (Barcelona). Spain Phone: +34 937231010 (extension 29801) Fax: +34 937160646 E-mail: xcalvet@tauli.cat

Cover Letter

A nurse-driven outpatient clinic for thiopurine-treated

inflammatory bowel disease patients reduces physician

visits and increases follow-up efficiency.

María López MsC1, Angelina Dosal RN 1, Albert Villoria PhD, MD 2, 3, Laura

Moreno RN 1, Xavier Calvet PhD, MD 2, 3

Infermeria, Hospital de Sabadell 1, Servei Aparell Digestiu2, Hospital de Sabadell.

Institut Universitari Parc Taulí. Universitat Autònoma de Barcelona. CIBERehd,

Instituto de Salud Carlos III3.

Conflicts of interest and Source of Funding: No conflict of interest has been declared by the authors. This study has been funded by grants from the Hospital de Sabadell Research Committe nº 2009058 and Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III nº PI10/02650 Corresponding author: Xavier Calvet, MD, PhD

Unitat de Malalties Digestives Departament de Medicina. Universitat Autònoma de Barcelona. Centro de Investigación Biomédica En Red de enfermedades hepáticas y digestivas. Instituto de Salud Carlos III Parc Taulí, 1 08208 SABADELL (BARCELONA) SPAIN Phone: + 34. 937231010 (29805) Fax: + 34. 937160646 e-mail: xcalvet@tauli.cat

*Title Page

A nurse-driven outpatient clinic for thiopurine-treated

inflammatory bowel disease patients reduces

physician visits and increases follow-up efficiency.

Manuscript (NO AUTHOR INFORMATION)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Patients on thiopurine therapy need frequent monitoring to prevent drug adverse events.

To describe the structure and main results of a nurse-driven outpatient clinic (NDOC)

programme for the follow-up of patients receiving treatment with thiopurine

immunosuppressants. We retrospectively reviewed patient´s clinical charts on thiopurine

drugs, azathioprine (AZA) and 6-Mercaptopurine (6-MP). We evaluated the efficacy of

the NDOC by comparing the number of physician visits and the adequacy of laboratory

controls for each patient before and after inclusion in the programme. From January

2006 to December 2008, 179 patients were included. Of these, 102 had received

thiopurines for at least one year before the start of the NDOC. Mean age was 42±15;

83% were female. In all, 137/179 (76%) of the patients had Crohn disease (CD); AZA

was the most frequently drug used (97%). Mean time of follow-up was 2.03 ± 0.9 years.

Implementation of this programme decreased the number of physician visits per year –

from 4.6 ± 1.9 to 2.4±1.3 (p< 0.001) – and the number of periods longer than four months

without laboratory control (68% to 45%, p= 0.01). Leucopenia episodes and

complications did not differ significantly before and after the start of the NDOC. Nurse-

driven follow up of these patients reduces physician visits while improving tightness of

the follow-up.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Background:

One of the most important goals in the treatment of Inflammatory bowel disease (IBD) is

to keep the disease in remission, as this normalizes the quality of life of the patients

(Calvet X, Gallardo O, Coronas R et al., 2006). Evidence from controlled trials supports

the use of the thiopurine immunosuppressive drugs, Azathioprine (AZA) and 6-

Mercaptopurine (6-MP), to maintain Crohn's disease (CD) remission (Pearson DC, 2000;

Sandborn W, 2000). Thiopurines are also effective for maintaining remission in patients

with steroid-dependent or steroid-refractory UC and after cyclosporine treatment(Kirk AP,

1982; Hawthorne AB, 1992; Ardizzone S, 2006; Travis SP, 2008). Unfortunately,

however, up to 20% of the IBD patients treated with AZA/6-MP had to discontinue these

drugs because of adverse events (Present DH, 1989; Connell WR, 1993)

Thiopurine-induced adverse events can be divided into dose-dependent (Type A) and

dose-independent idiosyncratic reactions (Type B). Type A adverse events include

malaise and nausea (11%), infectious complications (7.4%), hepatitis (0.3–1.3%) and

bone marrow suppression (1.4–5%) (Ardizzone S, 2006; Travis SP, 2008; Present DH,

1989). The percentage of leucopenia varies depending on its definition, but it has been

reported to be as high as 11%10. Type B adverse events, including fever, pancreatitis,

rash, and arthralgia (Korelitz BI, Zlatanic J, Goel F et al, 1999), occur in 2% of the

patients and appear more often at the beginning of the treatment. Pancreatitis is one of

the most frequent idiosyncratic reactions (1.4–5 %) and generally appears in the first

three to four weeks (Weersma RK, Peters FT, Oostenbrug LE et al., 2004); it is usually

mild and improves after discontinuation of the drug.

Routine white-cell count is recommended after starting thiopurine therapy for early

detection of bone marrow toxicity. However, at present, there is no consensus on the

ideal monitoring schedule. Although less strict monitoring schedules have been

advocated, manufacturers of AZA and 6-MP recommend complete blood counts (CBC)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

weekly up to eight weeks after the initiation of treatment, followed by blood tests at least

every two to three months (Carter MJ, 2004; Wallace TM, 2001)..

Monitoring blood counts of all IBD patients receiving thiopurines represents a substantial

commitment for the IBD specialist, and timely follow-up in busy outpatient clinics may be

difficult. With the aim of improving follow-up efficiency and reducing medical workload,

we set up a multidisciplinary, nurse-driven outpatient clinic (N-DOC) for the management

of IBD patients treated with AZA/ 6-MP, which has been operational since 2006.

The aim of the present study is to describe our N-DOC and to evaluate its potential for

reducing physician visits and improving control of IBD-patients treated with AZA/ 6-MP.

We compared these parameters before and after the start of N-DOC follow-up in patients

who were already on thiopurines, using the patients themselves as their own controls.

Patients and methods:

Description of the follow-up protocol:

At our multidisciplinary IBD day care unit, we set up a specific N-DOC for follow-up of

IBD patients on thiopurinic drugs in February 2006. The N-DOC worked in conjunction

with other facilities such as vaccine administration and an open-access outpatient clinic

for IBD patients developing flares or complications. All patients who were being treated

with AZA or 6-MP at the day care unit of the Hospital of Sabadell were followed up

according to a pre-established protocol. Blood count was performed one, two and six

weeks after starting AZA/6-MP and every three months thereafter. At each visit, the N-

DOC nurses performed a brief interview and a blood extraction. Analytical controls

included a blood count every three months plus liver and renal function every six months.

Other analytical parameters (iron, ferritin, vitamin B12 and folic acid levels) were

obtained when necessary. The day after the control, the nurse team reviewed the

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

analytical parameters and discussed any relevant abnormalities with the IBD medical

staff. When the neutrophil count was below 2000 x109/L, the thiopurine dose was

decreased by 25% to 50%, according to medical criteria. Thiopurines were temporally

stopped when the neutrophil count fell below 1500 x109/L and resumed at a 50% dose

when it returned to 2000 x109/L or more. Additional measures, such as follow-up at

shorter intervals, were also undertaken when necessary. Patients were informed that

they would be contacted by phone only when modifications of the treatment or a further

procedure were required. A medical visit was performed when necessary.

Patients who did not comply with follow-up were contacted by phone and re-scheduled.

In order to avoid work absenteeism and to increase adherence, clinical controls and

blood sampling were scheduled both in the morning and in the afternoon.

The study was reviewed and approved by the Ethics Committee of the Hospital de Sabadell.

Description of the series

We retrospectively reviewed the medical records of all patients on thiopurinic

immunomodulators controlled at the N-DOC of the IBD day care unit at the Hospital of

Sabadell between February 2006 and January 2009. Demographic variables, type of

IBD, drug dose, number of outpatient physician visits, blood count and medical

interventions were recorded.

Comparative study:

For the evaluation of the effect of the N-DOC, all patients followed up for at least one

year before and one year after inclusion in the N-DOC were selected from the whole

series. Baseline characteristics of these patients were similar to those of the whole group

included in the N-DOC (table 1).

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

To perform the comparative study, each patient was his/her own control. We selected

two equal periods of follow-up for each patient. The index period was the one after

inclusion in the N-DOC. The control period was calculated as the same period prior to

inclusion as the patient had spent on the N-DOC program. We compared the number of

physician visits and the number of periods of insufficient follow-up (arbitrarily defined as

an interval between blood counts of four months or more). Secondary variables were the

number of analytical controls and the number of determinations with a neutrophil count

below 1500 x109/L. We also determined the number of treatment complications and

specifically the number of episodes of severe neutropenia (neutrophils <1000 x109/L).

Statistics

Data were expressed as means ± standard deviation for quantitative variables and as

percentages for qualitative variables. The Kolmogorov-Smirnov test was used to check

the normality of data distribution. Paired analysis was used for within-group

comparisons, that is, the number of physician visits before and after inclusion in the N-

DOC. For comparisons between groups, an unpaired analysis was performed. Normally

distributed data were compared by the Student’s t-test for paired or unpaired data;

otherwise, the Wilcoxon signed-rank test was used for paired data, and the Mann-

Whitney U-test for unpaired data. Statistical analysis was performed by SPSS 18, HP, IL,

USA.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Results

Description of the whole series

From February 2006 to January 2009, 179 patients initiated follow-up in the N-DOC.

Mean age at inclusion was 42 ± 15 years. Eighty-three patients were female. Most of the

patients included in the study had CD (137/179, 76%). Locations according to the

Montreal Classification were: L1: ileal 35%, L2: colonic 25%, L3: ileocolic 35%, and L4:

upper digestive tract 5%. The remaining 42 patients (24%) had UC.

AZA was the most frequently used drug in our patients (97%). Mean dose was 145 ± 33

mg; 6-Mercaptopurine was prescribed in the remaining 3% at an initial dose of 95 ± 41

mg. Indications for thiopurinic immunosuppressive drugs were steroid-dependent or

steroid-refractory CD or UC and maintenance of cyclosporine-induced remission after a

severe UC flare.

In CD, AZA/6-MP was given alone in 33% of cases, associated with 5-Aminosalicylic

acid (5-ASA) in 47% of patients, and associated with anti-TNF drugs in the remaining

30%. Immunosuppressive drugs in UC were associated with 5-ASA in 86% of cases and

with anti-TNF drugs in 20%. Only 4% received the immunosuppressive drug alone. Mean

time from diagnosis to the beginning of AZA/6-MP was 2.2 ±3.4 years in CD, and 3.0

±4.4 years in UC.

Total mean time of follow-up was 2.03 ± 0.9 years. During this time, ten patients dropped

out of the program after a mean follow-up of 3.8 ± 3.4 years. Reasons for drop-out were:

death in three patients – two of causes unrelated to their IBD and one of complications of

the CD – loss to follow-up in two patients and hospital change in two others. The

treatment was stopped in three patients: one after surgery, one with a severe herpetic

dermatological infection and one who developed breast cancer.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Effect of the nurse-driven clinic on patient control and physician visits

A hundred and two patients received the immunosuppressive drug for at least one year

before starting the N-DOC. The clinical and demographic characteristics of these

patients were similar to those of the whole group (table 1). The total number of patient-

years of follow-up in the 102-patient comparison group was 236 before and 236 after the

creation of the nurse-driven outpatient clinic.

a) Physician visits and procedures:

The mean number of physician visits per year decreased from 4.6 ± 1.9 to 2.4±1.3 (p<

0.001) after inclusion in the N-DOC (table 2). However, counting the multiple physician

visits required by patients with active disease at the start of the thiopurine period may

have biased the results by increasing the number of visits during the pre-N-DOC period.

To control for this bias we also compared physician visits pre and post N-DOC in the

patients (n=45) who started immunosuppressive therapy before the beginning of the

control period – that is, before 2003. The differences were similar in this subgroup (3.8

±1.2 pre-NDOC vs. 2.4±1.3 post-NDOC group, p< 0.001).

The number of patients requiring dose modifications and the number of changes in the

thiopurine dose in the follow-up schedule fell slightly after the creation of the N-DOC,

although the differences were not statistically significant (21 vs. 12 patients; p= ns (non-

significant) and 28 vs. 16 interventions, p= ns). The most frequent measures were the

reduction in the immunosuppressive dose and the increase in the frequency of blood

test. In two patients – one before and one after the start of the N-DOC – the drug was

withdrawn due to a recurrent low neutrophil count.

b) Blood analysis:

The number of total analyses per year fell slightly after implementation of the N-DOC

(3.97±3 vs. 3.5±2.2, p=0.03) (table 2). However, when the patients initiating AZA/6-MP in

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

the pre-NDOC period (the 45 who initiated thiopurines before 2003) were analyzed

separately, no differences were found (3.7±1.9 vs 3.5±2.2; p=0.63).

After the creation of the N-DOC, the number of periods with insufficient control fell (see

table 2) as did the proportion of patients with at least one period of insufficient control

(68% to 45%, p= 0.01). In contrast, the number of patients re-scheduled because of a

missed analysis increased after the introduction of the N-DOC.

The number of patients in whom a low neutrophil count was detected (<2000 x109/L) did

not change significantly before and after the onset of N-DOC (21.5% vs. 14.7%, p=0.20).

The lowest mean leukocyte count was similar in the two periods (see table 2). The

number of patients with at least one neutrophil count below 1500 x109/L was higher in

the pre-N-DOC period: seven (6%) vs. two (2%), although this difference did not reach

significance (p= 0.067). Finally, only two patients had a neutrophil count lower than 1000

x109/L, both in the pre N-DOC period and both without severe complications. There was

no correlation between thiopurinic drug dose and the development of neutropenia (r=

0.03, p=0.7).

Discussion

Our study shows that the N-DOC was suitable for the follow-up of IBD patients on

immunosuppressive treatment. N-DOC almost halved the number of physician visits

compared to the period prior to nurse-led follow-up. Taking into account the large

number of IBD patients treated with thiopurines, the program proved its ability to reduce

medical workload in IBD units. Although no specific cost analysis was performed, this

strategy has a potential for saving costs while improving the quality of care. Additional

advantages of this strategy that have not been measured in the present report include a

more flexible (and therefore more convenient) schedule for control and closer monitoring

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

by the nursing team complementing medical follow-up. Although this aspect was not

formally analyzed, most patients reported high satisfaction with the quality of the care.

As expected, the number of blood tests per year did not differ significantly between

groups. By contrast, the number of re-scheduled blood tests was significantly higher in

the nursing follow-up period. So, N-DOC seems to allow closer monitoring and early

detection of non-adherence.

In addition, before the start of the follow-up program, the intervals between blood tests

and physician visits were often considerable. This increased the risk of missing a low

leukocyte count for a long period of time. Under the current policy, the blood count was

reviewed by the nurse team the day after sampling, thus shortening the time for medical

intervention. The quicker response may well have accounted for the reduction observed

in the proportion of patients showing a neutrophil count below 1500 x109/L.

However, despite closer control, the number of severe leucopenia episodes and

complications was not significantly different before and after the start of the N-DOC. This

finding suggests that thiopurinic drugs are reasonably safe and corroborates the low rate

of severe leucopenia reported in the literature15.

The main limitation of this study was its retrospective design. However, as endpoints we

measured objective variables that were routinely collected and reflected in the medical

records. As very few patients were lost to follow-up, we believe that the results are

reliable. Another limitation of the study is that CD is still active at the beginning of

immunosuppressive treatment, and therefore requires more visits and analytical blood

tests. For this reason, to evaluate whether including the patients who began AZA during

the follow-up prior to the beginning of the N-DOC might have biased the results, we

performed a sub-analysis including only the patients who initiated AZA before 2003. As

shown in the results, the sub-analysis in this group also showed a significant reduction in

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

the number of physician visits and an increase in the effectiveness of the control which

was numerically very similar to those observed in the whole group.

In conclusion, our study strongly suggests that following up IBD patients on AZA/6-MP

treatment in a nurse-driven outpatient clinic decreases the need for physician visits and

increases the effectiveness of follow-up.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Table 1: Characteristics of patients

On AZA/6-MP before 2006

n = 102

Started AZA/6-MP after 2006

n = 77

P-value

Age (years) 42.3±15 40.7±14 0.49

Gender (M/F) 57/45 39/38 0.23

EC/CU (n) 81/21 56/21 0.29

AZA / 6-MP (n) 101 / 1 73 / 4 0.09

AZA dose (mg) 142±38 143±28 0.82

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Table 2: Comparison of the main outcomes before and after N-DOC follow-up.

Pre- NDOC n = 102

Post- NDOC n = 102

p-value

Physician visits/ year * (n) 4.6 ± 1.9 2.4±1.3 < 0.001

Blood test / year * (n) 3.97±3 3.5±2.2 0.03

Lowest leukocyte count * (x 109) 2940±1200 2840±800 0.67

Leukocyte count < 1500 x 109 (n) 7 (6%) 2 (2%) 0.067

Periods > 4 months without follow-

up/ patient * 1.1±1.1 0.7 ±0.9 < 0.001

Blood test rescheduled / patient-

year * 0.4±1.2 0.8±1.0 < 0.002

* Data are expressed as means± standard deviation (SD).

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

References:

Ardizzone S, Maconi G, Russo A, Imbesi V, Colombo E, Bianchi PG. (2006). Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis. Gut, 55 (1), 47-53. Calvet X, Gallardo O, Coronas R, Casellas F, Montserrat A, Torrejon A, Vergara M, Campo R, Brullet E. (2006). Remission on thiopurinic immunomodulators normalizes quality of life and psychological status in patients with Crohn's disease. Inflammatory Bowel Diseases, 12 (8), 692-696.

Carter MJ, Lobo AJ, Travis SP. (2004). Guidelines for the management of inflammatory bowel disease in adults. Gut, 53 Suppl 5, V1-16. Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE. (1993). Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut, 34 (8), 1081-1085.

de Jong DJ, Derijks LJ, Naber AH, Hooymans PM, Mulder CJ. (2003). Safety of thiopurines in the treatment of inflammatory bowel disease. Scandinavian Journal of Gastroenterology Suppl, 69-72. Gisbert JP, Gomollon F. (2008). Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. American Journal of Gastroenterology, 103 (7), 1783-1800.

Hawthorne AB, Logan RF, Hawkey CJ, Foster PN, Axon AT, Swarbrick ET, Scott BB, Lennard-Jones JE. (1992). Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. British Medical Journal, 305 (6844), 20-22. Kirk AP, Lennard-Jones JE. (1982). Controlled trial of azathioprine in chronic ulcerative colitis. British Medical Journal (Clin Res Ed), 284 (6325), 1291-1292.

Korelitz BI, Zlatanic J, Goel F, Fuller S. (1999). Allergic reactions to 6-mercaptopurine during treatment of inflammatory bowel disease. Journal of Clinical Gastroenterology, 28 (4), 341-344. Pearson DC, May GR, Fick G, Sutherland LR. (2000). Azathioprine for maintaining remission of Crohn's disease. Cochrane Database Systematic Reviews, CD000067.

Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI. (1989). 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Annals of Internal Medicine, 111 (8), 641-649.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Sandborn W, Sutherland L, Pearson D, May G, Modigliani R, Prantera C. (2000). Azathioprine or 6-mercaptopurine for inducing remission of Crohn's disease. Cochrane Database Systematic Reviews, CD000545.

Travis SP, Stange EF, Lemann M, Oresland T, Bemelman WA, Chowers Y, Colombel JF, D'Haens G, Ghosh S, Marteau P, Kruis W, Mortensen NJ, Penninckx F, Gassull M. (2008). European evidence-based Consensus on the management of ulcerative colitis: Current management. Journal of Crohns & Colitis, 2 (1), 24-62. Wallace TM, Veldhuyzen van Zanten SJ. (2001). Frequency of use and standards of care for the use of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease: a systematic review of the literature and a survey of Canadian gastroenterologists. Canadian Journal of Gastroenterology, 15 (1), 21-28.

Weersma RK, Peters FT, Oostenbrug LE, van den Berg AP, van HM, Ploeg RJ, Posthumus MD, Homan van der Heide JJ, Jansen PL, Van Dullemen HM. (2004). Increased incidence of azathioprine-induced pancreatitis in Crohn's disease compared with other diseases. Alimentary Pharmacology and Therapeutics, 20 (8), 843-850.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

LWW Copyright and Disclosure FormClick here to download LWW Copyright and Disclosure Form: renamed_2f66d.pdf

LWW Copyright and Disclosure FormClick here to download LWW Copyright and Disclosure Form: copyrightTransfer Angelina Dosal.pdf

LWW Copyright and Disclosure FormClick here to download LWW Copyright and Disclosure Form: copyrightTransfer Albert Villoria.pdf

LWW Copyright and Disclosure FormClick here to download LWW Copyright and Disclosure Form: copyrightTransferLaura Moreno.pdf

LWW Copyright and Disclosure FormClick here to download LWW Copyright and Disclosure Form: copyrightTransfer Xavier Calvet.pdf