Challenges and gaps in RA goals and management

Challenges and Gaps in RA Goals and Management

(Guideline Implementation)

• Patients journey (apa saja hambatan pasien untuk bisa mendapatkan pengobatan yang sesuai, terkecuali masalah harga)

• Implementasi guideline (apakah kita mengimplementasi guideline yang ada, jika iya/tidak alasannya kenapa, guideline mana yang kita ikuti, berapa banyak dokter yang mengikuti guideline)

• Apa saja tantangan/hambatan yang dijumpai dalam penerapan guideline untuk tatalaksana AR ?

• Apa yang menjadi pertimbangan utama dalam menentukan tatalaksana pasien AR ?

• Apakah nyeri yang berkurang atau membaik menjadi poin yang paling utama dalam pencapaian goal of treatment di AR ?

Our topic

Rheumatoid arthritis (RA) is a systemic autoimmune disease that causes joint inflammation and progressive erosion of bone, leading to joint misalignment, loss of function, and disability.

RA affects more 600.000 than million Indonesian adults. Onset occurs most often between the ages of 30 and 50 years. Women and older adults are more commonly affected.

Health Impact of Rheumatoid Arthritis

Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

The goal of RA treatment is to: Control pain & inflammation Limit progressive damage Reduce disease activity or induce remission Maintain function

Treatment of Rheumatoid Arthritis


Disease-modifying anti-rheumatic drugs (DMARDs) interfere with rheumatoid disease processes by blocking the production or activity of the immune cells and their products that cause inflammation and damage.

Treatment with DMARDs is increasing with the expectation that they will lead to better disease control and more remissions.

Steroids—both low-dose systemic and intra-articular formulations—are used as adjuncts to DMARD treatment.

DMARDs

Disease-modifying anti-rheumatic drugs (DMARDs) are in common use for rheumatoid arthritis (RA), and several have been approved by the U.S. Food and Drug Administration for this indication.

DMARDs may be oral or biologic drugs. The consensus of clinical experience has made methotrexate, an oral DMARD, the first-line drug of choice for treating RA.

DMARDs in Rheumatoid Arthritis Treatment (1 of 2)


Oral disease-modifying anti-rheumatic drugs (DMARDs) are small-molecule chemical drugs. The mechanism of action of each of these drugs is not well defined and is unknown in some cases.

Biologic DMARDs block the activity of immunostimulatory cytokines and other cell-signaling molecules. Biologic DMARDs are genetically engineered antibodies and proteins. Tumor necrosis factor-alpha blockers are the most typical members of this drug class.

Other targets are interleukins 1 and 6 and the transmembrane proteins CD20 and CD28.

DMARDs in Rheumatoid Arthritis Treatment (2 of 2)


Patients journey • Apa saja hambatan pasien untuk bisa mendapatkan pengobatan yang sesuai ? • Keterlambatan diagnosis

• Keragaman pengetahuan dan kompetensi• Akses ke fasilitas kesehatan yang tersedia KR• Sistim rujukan

• Keterlambatan memulai DMARDs• Pengetahuan dokter• Ketersediaan DMARDs di faskes

• Kelemahan dalam follow up• Timing• Eskalasi• Treat to target

Oral Disease-Modifying anti-rheumatic Drugs

Name Target of Activity

Hydroxychloroquine T-lymphocytes (?)

Leflunomide Pyridine synthesis

Methotrexate Dihydrofolate reductase; folate metabolism

Sulfasalazine Uncertain; multifactorial, including impairment of lymphocyte function and cytokine synthesis

Oral DMARDs Included in the Comparative Effectiveness Review


Biologic DMARDs Included in the Comparative Effectiveness Review


Biologic Disease-Modifying anti-rheumatic Drugs

Name Trade Name Target of ActivityAdalimumab Humira® TNF-α

Certolizumab pegol Cimzia® TNF-α

Etanercept Enbrel® TNF-α

Golimumab Simponi® TNF-α

Infliximab Remicade® TNF-α

Abatacept Orencia® CD28

Anakinra Kineret® IL-1

Rituximab Rituxan® CD20

Tocilizumab Actemra®

RoActemra®IL-6 receptor

Abbreviations: IL = interleukin; TNF-α = tumor necrosis factor-alpha

Implementasi guideline • Apakah kita mengimplementasi guideline yang ada?

• Ya sebagian kecil

• Jika iya/tidak alasannya kenapa• Akses terhadap update guideline

• Guideline mana yang kita ikuti• IRA. EULAR, ACR, ARA ?, CRA ?

• Berapa banyak dokter yang mengikuti guideline?• Belum ada survey. • Rheumatologist umumnya sesuai

EULAR RECOMMENDATION FOR THE MANAGEMENT OF RA

(Phase 1)

Smolen JS, et al. Ann Rheum Dis 2013;0:1-18


(Phase 2)



(Phase 3)


2012 ACR Update

Tantangan•Hambatan yang dijumpai dalam penerapan guideline untuk tatalaksana AR ?

• Ketersediaan guideline• Aksesibilitas• Ketersediaan obat yang dianjurkandalam guideline

Apa yang menjadi pertimbangan utama dalam menentukan tatalaksana pasien AR ?

• Kondisi pasien :• Disease activity• Disease damage• Comorbidity

• Aspek DMARDs• Efficacy, safety profile, drug interaction• Ketersediaan obat dalam formularium:

• FORNAS• Formularium Rumah Sakit

• Dukungan finansial / insurance

The strength of evidence for each of the following findings is low: Patients with moderate rheumatoid arthritis (RA) had better overall improvement and better functional status than patients with severe RA. However, patients with severe RA had the greatest degree of improvement from baseline.

In treatment with methotrexate (MTX), as the age of patients increased, the likelihood of major clinical improvement decreased slightly; however, overall age did not affect efficacy or risk of adverse effects.

Patient Characteristics on Outcomes of DMARD Treatment


Biologics showed no apparent influence on the risk of cardiovascular events in the elderly (≥65 years of age).

Toxicity of MTX was more likely in patients with greater renal impairment. High-risk comorbidities (cardiovascular disease, diabetes, malignancies, and renal impairment) did not increase the risk of serious adverse events or infections in patients treated with b-DMARDs.

Concomitant antidiabetic, antihypertensive, or statin medications given to patients treated with b-DMARDs did not increase the risk of adverse events.

Head-to-Head Comparisons of Oral DMARDs for Rheumatoid Arthritis


ComparisonN Studies; Patients

Reduced Symptoms or Disease Activity

Limiting Radiographic Progression Improved Function

Improved Quality of Life

SSZ vs. MTX*3; 1,001(disease duration <3 years)

NSD (DAS)SOE = Moderate

NSDSOE = Moderate

NSD(3 RCTs; 479 patients)SOE = Moderate

NR

LEF vs. MTX*2; 1,481

NSD (ACR20 rates)SOE = Low

NSD SOE = Low

Greater improvement with LEF at 12 months (HAQ) but less than the MCIDSOE = Low

Greater with LEF at 12 months(SF-36 physical component )SOE = Low

LEF vs. SSZ1; 358 SOE = Insufficient NSD

SOE = LowGreater improvement with LEF (HAQ) to 24 monthsSOE =Low

NR

*Methotrexate was used at 7.5 to 25 mg per week in the reported studies.ACR20 = American College of Rheumatology 20-percent improvement criteria; DAS = disease activity score; HAQ = Health Assessment Questionnaire; LEF = leflunomide; MCID = minimum clinically important difference; MTX = methotrexate; NR = not reported; NSD = no statistically significant difference; RCT = randomized controlled trial; SOE = strength of evidence; SSZ = sulfasalazine

Head-to-Head Comparisons of Combination Treatment With Oral DMARDs

InterventionN Studies; Patients Comparator

Patient Characteristics


LimitingRadiographic Progression

Improved Function‡

SSZ plus MTX*4; 709

SSZ or MTX*monotherapy

DMARD-naïve, early RA†

NSD SOE = Moderate

NSD SOE = Moderate

NSD SOE = Moderate

2 or 3 oral DMARDs in combination(MTX*, SSZ, HCQ)2; 273

1 or 2 oral DMARDs

Patients with longstanding active RA

3 oral DMARDs are favored over 2 to improve disease activity.SOE = Moderate

NRDifference less than MCIDSOE = Moderate

* Methotrexate was used at 7.5 to 25mg per week in the reported studies.† Early rheumatoid arthritis is defined as <3 years.‡ Health-related quality of life was not reported.DMARD = disease-modifying anti-rheumatic drug; HCQ = hydroxychloroquine; LEF = leflunomide; MCID = minimum clinically important difference; MTX = methotrexate; NR = not reported; NSD = no statistically significant difference; RA = rheumatoid arthritis; SOE = strength of evidence; SSZ = sulfasalazine


Head-to-Head Comparisons of Biologic DMARDsIn patients with active RA (>3 years), with failed or inadequate disease response to DMARDs who did not receive an anti–TNF-α DMARD, head-to-head comparisons of DMARDs produced the following results:

Intervention Comparator

Symptoms or Disease Activity* (N Studies; N Patients)

Function(N Studies; N Patients)

Quality of Life(N Studies; N Patients)

Etanercept InfliximabFaster response with etanercept, but NSD in the longer term(6; 5,883) SOE = Low

2 of 3 studies reported NSD(3; 2,239) Insufficient Insufficient

Etanercept Adalimumab ACR70 at 6 months showed NSD (1; 2,326) SOE = Low

NSD(1; 707) SOE = Low

NSD(1; 707) SOE = Low

Adalimumab InfliximabSymptom response (ACR20 at 6 months) and DAS at 1 year greater with adalimumab(2; 3,033) SOE = Low

Greater improvement at 12 months with adalimumab but not greater than the MCID(1; 707) SOE = Low

SF-36 physical component at 12 months favors adalimumab(1; 707) SOE = Insufficient

Abatacept InfliximabGreater decrease in DAS and greater remission rate, both at 1 year, with abatacept. (3; 3,464) SOE = Low

NSD at 1 year(1; 431) SOE = Low

SF-36 physical component at 1 year favors abatacept but not greater than the MCID (1; 431) SOE = Low

*Radiographic progression not reported.


Head-to-Head Comparisons of Oral and Biologic DMARDs

Intervention(N Studies,N Patients) Comparator Symptoms or Disease Activity

Radiographic Evidence of Progression Functional Capacity

In patients with longstanding active RA who required a change in therapy*:

Biologic DMARDs as a class

Oral DMARDs as a class Higher chance of remission with biologics

than with oral DMARDsSOE = Moderate

NR Insufficient

1 retrospective cohort studyN = 1,083

Biologic DMARDs Oral DMARDsHigher response rates for biologic DMARDs SOE = Moderate NR Insufficient

4 RCTs, 2 cohort studiesN = 3,696

* Health-related quality of life was not reported.DMARD = disease-modifying anti-rheumatic drug; NR = not reported; RA = rheumatoid arthritis; RCT = randomized controlled trial; SOE = strength of evidence


DMARD Combinations Versus Monotherapies

Intervention* Comparator

Symptoms or Disease Activity(N Studies; N Participants)

Radiographic Progression(N Studies;N Participants)

Function(N Studies; N Participants)

Quality of Life(N Studies; N Participants)

Biologic DMARD plus MTX†

Biologic DMARDMonotherapy

(5 RCT, 4 cohort; 9,804)Combination is more effectiveSOE = Moderate

(2; 1, 495)Less change with a combinationSOE = Moderate

(2; 1,495)Combination treatment is more effectiveSOE = Moderate

(2; 1,495)Combination treatment is more effective.SOE = Low

Biologic DMARD plus MTX or SSZ

MTX† or SSZMonotherapy

(7; 4,482)Combination is more effectiveSOE = High

(7; 4,482)Less change with combinationSOE = Moderate

(7 RCT, 1 cohort; 7,516)Combination treatment is more effectiveSOE = High

(7 RCT, 1 cohort; 7, 516)Combination treatment is more effectiveSOE = Moderate

* Patients with active disease whose disease did not respond to an oral DMARD did not benefit from including that oral DMARD in combination with a biologic DMARD.† MTX was used at a dose of 7.5 to 25mg per week in the reported studies.

In patients with longstanding active rheumatoid arthritis with inadequate disease control, head-to-head comparisons of combined DMARDs and DMARD monotherapy were conducted.


DMARD Combinations Versus MonotherapiesIn patients with early rheumatoid arthritis who had not been treated with methotrexate (MTX), or who had not received MTX in the previous 3 months, head–to–head comparisons of combination therapy and MTX monotherapy were examined for effects on function and quality of life.

Intervention ComparatorPatient Characteristics

Function(N Studies; N Participants)

Quality of Life(N Studies; N Participants)

Biologic DMARD plus MTX*

MTX* monotherapy

Early RA† MTX Naïve or not recently on MTX*

(2; 1,495)Combination is more effective.SOE = Moderate

(2; 1,495)Combination is more effective.SOE = Low

* Methotrexate was used at 7.5 to 25mg per week in the reported studies. † Early RA is defined as disease of as less than 3 years’ duration.DMARD = disease-modifying anti-rheumatic drug; MTX = methotrexate; RA = rheumatoid arthritis; SOE = strength of evidence


Comparative Benefits of Oral and Biologic DMARDs in Early RA

Patient Characteristics Intervention Comparator


Limiting Radiographic Progression

Improved Function

Patients with early RA*

2 to 3 oral DMARDs plus corticosteroids

Oral DMARDMonotherapy

Combination is more effective at 28 but not 52 weeks.(2; 354) SOE = Low

Combination is more effective(2; 354)SOE = Low

Combination is more effective†

(2; 354)SOE = Low

MTX-naïve patients with aggressive early RA

MTX‡ Adalimumab, Etanercept

Results are similar(2; 1,431)SOE = Moderate

Biologic DMARD is more effective at limiting progression.(2; 1,431)SOE = Low

Results are similar with MTX and adalimumab§

(2; 1,431)SOE = Low

MTX-naïve patients with aggressive early RA

MTX‡ plus biologic DMARD

Biologic DMARD Monotherapy

Combination is more effective(also improves remission rates)(1; 799) SOE = Low

Combination is more effective.(1; 799) SOE = Low

NR§

* Early RA is disease of less than 3 years’ duration.† Combination treatment is also more effective at improving quality of life. ‡ Methotrexate was used at a dose of 7.5 to 25mg per week in the reported studies.§ Quality-of-life outcomes were not reported.


Combining methotrexate (MTX) or other oral disease-modifying anti-rheumatic drugs (DMARDs) with a biologic DMARD does not alter the adverse event rate found with the biologic DMARD alone. Strength of Evidence = Low

Combining MTX and biologic DMARDs demonstrates a better tolerability profile than MTX alone. Strength of Evidence = Low

Evidence is insufficient to estimate differences in rates of specific adverse events between the biologic and oral DMARDs.

Comparative Adverse Effects of Combining DMARDs


Withdrawal due to adverse events Time to withdrawal Infusion and injection-site reactions Infections Malignancy Mortality Cardiovascular and cerebrovascular events Rare but serious adverse events: demyelination, autoimmunity, pancytopenia, and hepatotoxicity

Adverse Effects of Interest in the Comparative Effectiveness Review


Apakah nyeri yang berkurang atau membaik menjadi poin yang paling utama dalam pencapaian goal of treatment di AR ? • Dari sisi pasien jawabannya: YA

• NYERI merupakan KELUHAN UTAMA disamping STIFFNESS pada pasien dengan RA

• Dari sisi dokter : disease control• Disease activity (inflammation)• Function• Disease damage

The natural history of rheumatoid arthritis (RA) and the role of disease-modifying anti-rheumatic drugs (DMARDs) in reducing symptoms and improving disease control

The potential benefits and adverse effects of DMARDs Changes in lifestyle that can help relieve RA symptoms, such as diet and exercise

Patient and family preferences and values regarding treatment

What To Discuss With Your Patients and Their Family


How to monitor Tt in RA?• Disease activity is assessed by several parameters…• Duration of morning stiffness• Tender joints count• Swollen joints count• Observer global assessment• Patient global assessment• Visual analogue scale for pain• Health assessment questionnaire• ESR• NSAID pill count etc

• Patient on MTX, SSZ or leflunamide show clinical improvement in 6-8 wks.• Patient should be observed for 6 months before declaring a DMARD ineffective.

How long should Tt. be continued?• Once remission is achieved , maintenance dose for long period is recommended.• Relapse occurs in 3-5 months (1-2 months in case of MTX) if drug is discontinued in most instances.

• DMARDs are discontinued by patients because of toxicity or secondary failure(common after 1-2 yrs) and such patients might have to shift over different DMARDs over 5-10 yrs.

• Disease flare may require escalation of DMARD dose with short course of steroids.

Thank you.

Challenges and gaps in RA goals and management

Health & Medicine

Transcript of Challenges and gaps in RA goals and management