Drug Therapy for Rheumatoid Arthritis in Adults

1073 Pages·2012·7.13 MB·English

Comparative Effectiveness Review
Number 55
Drug Therapy for
Rheumatoid Arthritis
in Adults: An Update
Comparative Effectiveness Review
Number 55

Drug Therapy for Rheumatoid Arthritis in Adults:
An Update

Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
540 Gaither Road
Rockville, MD 20850
www.ahrq.gov

Contract No. 290-2007-10056-I

Prepared by:
RTI International–University of North Carolina Evidence-based Practice Center
Research Triangle Park, NC

Investigators:
Katrina E. Donahue, M.D., M.P.H. Visali Peravali, M.S.
Dan E. Jonas, M.D., M.P.H. Shrikant I. Bangdiwala, Ph.D.
Richard A. Hansen, Ph.D. Andrea Yuen, B.S.
Robert Roubey, M.D. Patricia Thieda, M.A.
Beth Jonas, M.D., M.P.H. Laura C. Morgan, M.A.
Linda J. Lux, M.P.A. Karen Crotty, Ph.D.
Gerald Gartlehner, M.D., M.P.H. Rishi Desai, M.S.
Elizabeth Harden, M.P.H. Megan Van Noord, M.S.I.S.
Tania Wilkins, M.S.

Errata: Tables 2, 3, and 4 have been corrected.

AHRQ Publication No. 12-EHC025-EF
Updated June 2012
This report is based on research conducted by the RTI International–University of North
Carolina (RTI–UNC) Evidence-based Practice Center under contract to the Agency for
Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2007-10056-I).
The findings and conclusions in this document are those of the author(s), who are responsible for
its content; the findings and conclusions do not necessarily represent the views of AHRQ.
Therefore, no statement in this report should be construed as an official position of AHRQ or of
the U.S. Department of Health and Human Services.

The information in this report is intended to help healthcare decisionmakers—patients and
clinicians, health system leaders, and policymakers, among others—make well-informed
decisions and thereby improve the quality of health care services. This report is not intended to
be a substitute for the application of clinical judgment. Anyone who makes decisions concerning
the provision of clinical care should consider this report in the same way as any medical
reference and in conjunction with all other pertinent information, i.e., in the context of available
resources and circumstances presented by individual patients.

This report may be used, in whole or in part, as the basis for the development of clinical practice
guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage
policies. AHRQ or U.S. Department of Health and Human Services endorsement of such
derivative products may not be stated or implied.
This document is in the public domain and may be used and reprinted without permission except
those copyrighted materials that are clearly noted in the document. Further reproduction of those
copyrighted materials is prohibited without the specific permission of copyright holders.

Persons using assistive technology may not be able to fully access information in this report. For
assistance contact [email protected].

None of the investigators has any affiliations for financial involvement that conflicts with the
material presented in this report.

Suggested Citation:
Donahue KE, Jonas DE, Hansen RA, Roubey R, Jonas B, Lux LJ, Gartlehner G, Harden E,
Wilkins T, Peravali V, Bangdiwala SI, Yuen A, Thieda P, Morgan LC, Crotty K, Desai R, Van
Noord M. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative
Effectiveness Review No. 55. (Prepared by RTI-UNC Evidence-based Practice Center under
Contract No. 290-02-0016-I.) Rockville, MD: Agency for Healthcare Research and Quality.
April 2012. www.effectivehealthcare.ahrq.gov/reports/final.cfm.

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Preface
The Agency for Healthcare Research and Quality (AHRQ) conducts the Effective Health
Care Program as part of its mission to organize knowledge and make it available to inform
decisions about health care. As part of the Medicare Prescription Drug, Improvement, and
Modernization Act of 2003, Congress directed AHRQ to conduct and support research on the
comparative outcomes, clinical effectiveness, and appropriateness of pharmaceuticals, devices,
and health care services to meet the needs of Medicare, Medicaid, and the Children’s Health
Insurance Program (CHIP).
AHRQ has an established network of Evidence-based Practice Centers (EPCs) that produce
Evidence Reports/Technology Assessments to assist public- and private-sector organizations in
their efforts to improve the quality of health care. The EPCs now lend their expertise to the
Effective Health Care Program by conducting Comparative Effectiveness Reviews (CERs) of
medications, devices, and other relevant interventions, including strategies for how these items
and services can best be organized, managed, and delivered.
Systematic reviews are the building blocks underlying evidence-based practice; they focus
attention on the strength and limits of evidence from research studies about the effectiveness and
safety of a clinical intervention. In the context of developing recommendations for practice,
systematic reviews are useful because they define the strengths and limits of the evidence,
clarifying whether assertions about the value of the intervention are based on strong evidence
from clinical studies. For more information about systematic reviews, see
http://effectivehealthcare.ahrq.gov/reference/purpose.cfm.
AHRQ expects that CERs will be helpful to health plans, providers, purchasers, government
programs, and the health care system as a whole. In addition, AHRQ is committed to presenting
information in different formats so that consumers who make decisions about their own and their
family’s health can benefit from the evidence.
Transparency and stakeholder input are essential to the Effective Health Care Program.
Please visit the Web site (www.effectivehealthcare.ahrq.gov) to see draft research questions and
reports or to join an email list to learn about new program products and opportunities for input.
Comparative Effectiveness Reviews will be updated regularly.
We welcome comments on this CER. They may be sent by mail to the Task Order Officer
named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD
20850, or by email to [email protected].

Carolyn M. Clancy, M.D. Jean Slutsky, P.A., M.S.P.H.
Director Director, Centre for Outcomes and Evidence
Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality

Stephanie Chang, M.D., M.P.H. Carmen Kelly, Pharm.D., R.Ph.
Director, EPC Program EPC Program Task Order Officer
Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality

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Acknowledgements
We acknowledge the Director of the AHRQ Evidence-based Practice Center (EPC) Program,
Stephanie Chang, M.D., M.P.H., and Carmen Kelly, Pharm.D., the AHRQ Task Order Officer
for this project.
We extend our appreciation to our Technical Expert Panel. All provided thoughtful advice
and input during our research process.
The investigators deeply appreciate the considerable support, commitment, and contributions
of the EPC team staff at RTI International and the University of North Carolina at Chapel Hill.
We express our gratitude to research analysts: Tammeka Swinson Evans, M.O.P., Stacey Lloyd,
M.P.H., and Loraine Monroe, our EPC publications specialist.
Technical Expert Panel
Teresa J. Brady, Ph.D.
Patient Representative

Jeffrey R. Curtis, M.D., M.P.H.
Assistant Professor
Division of Clinical Immunology and Rheumatology
Associate Director
Center for Education and Research on Therapeutics of MSK disorders
University of Alabama at Birmingham
Birmingham, AL

Marion McDonagh, Pharm.D.
Assistant Professor
Informatics and Clinical Epidemiology
Oregon Health & Science University
Portland, OR

Christopher T. Ritchlin, M.D., M.P.H.
Internal Medicine, Rheumatology
School of Medicine and Dentistry
University of Rochester
Rochester, NY

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Peer Reviewers

Joan M. Bathon, M.D.
Professor of Medicine
Division of Rheumatology
Department of Medicine
Johns Hopkins University
Director, Johns Hopkins Arthritis Center
Co-Deputy Director, Division of Rheumatology
Bayview Medical Center
Baltimore, MD

Louis Bridges, Jr., M.D., Ph.D.
Professor of Medicine and Microbiology
Director of the Division of Clinical Immunology and Rheumatology
Deputy Director of the Comprehensive Arthritis, Musculoskeletal, and Autoimmunity Center
University of Alabama at Birmingham
Birmingham, AL

Marion McDonagh, Pharm.D.
Assistant Professor
Informatics and Clinical Epidemiology
Oregon Health & Science University
Portland, OR

James O’Dell, M.D.
Professor and Program Director
Department of Internal Medicine
University of Nebraska
Lincoln, NE

Nancy Olsen, M.D.
McGee Foundation Distinguished Professor in Arthritis Research
Internal Medicine – Rheumatic Diseases
UT Southwestern Medical School
Dallas, TX

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Drug Therapy for Rheumatoid Arthritis in Adults:
An Update
Structured Abstract
Objectives: Compare the benefits and harms of corticosteroids, oral and biologic disease-
modifying antirheumatic drugs (DMARDs) for adults with rheumatoid arthritis.

Data Sources: English-language articles from 1980 to February 2011 identified through
PubMed, Embase, Cochrane Library, and International Pharmaceutical Abstracts; unpublished
literature including dossiers from pharmaceutical companies.

Methods: Two people independently selected relevant head-to-head trials of any sample size,
prospective cohort studies with at least 100 participants, and relevant good- or fair-quality meta-
analyses that compared benefits or harms of 14 drug therapies. Retrospective cohort studies were
also included for harms. For biologic DMARDs, placebo-controlled, double-blind RCTs were
also included. We required trials and cohort studies to have a study duration of at least 12 weeks.
Literature was synthesized qualitatively within and between the two main drug classes (oral and
biologic DMARDs). Network meta-analysis also was performed to examine the relative efficacy
of biologic DMARDs and comparing withdrawal rates from placebo controlled trials.

Results: Head-to-head trials showed no clinically important differences in efficacy among oral
DMARD comparisons (methotrexate, sulfasalazine, leflunomide). The only head-to-head trial
comparing biologic DMARDs (abatacept vs. infliximab) found no clinically important
differences. Combination therapy of biologic DMARDs plus methotrexate improved clinical
response rates and functional capacity more than monotherapy with methotrexate. Network
meta-analyses found higher odds of reaching ACR 50 response for etanercept compared with
most other biologic DMARDs (abatacept, adalimumab, anakinra, infliximab, rituximab,
tocilizumab) for methotrexate-resistant patients with active rheumatoid arthritis. Similar overall
tolerability profiles were found among oral and biologic DMARDs, but short-term adverse
events were more common with biologic DMARDs. Adjusted indirect comparisons of biologic
DMARDs found that certolizumab had the most favorable overall withdrawal profile, followed
by etanercept and rituximab. Certolizumab had lower relative withdrawal rates due to lack of
efficacy than adalimumab, anakinra, and infliximab. Certolizumab and infliximab had more,
while etanercept had fewer withdrawals due to adverse events than most other drugs. Evidence
was insufficient to assess comparative risk of serious adverse events among biologic DMARDs.
Combinations of biologic DMARDs have higher rates of serious adverse events than biologic
DMARD monotherapy. Limited data existed for subgroups.

Conclusions: Limited head-to-head comparative evidence does not support one therapy over
another for adults with rheumatoid arthritis. Network meta-analyses from placebo-controlled
trials of biologics suggest some differences, including higher odds of reaching ACR 50 response,
but strength of evidence was low.

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Contents
Executive Summary ................................................................................................................ ES-1 

Introduction ................................................................................................................................... 1 
Causes and Diagnosis ............................................................................................................... 1 
Treatment of Rheumatoid Arthritis ........................................................................................... 2 
Treatment Strategies ................................................................................................................. 7 
Scope and Key Questions ......................................................................................................... 7 
Organization of the Report ........................................................................................................ 8 
Methods .......................................................................................................................................... 9 
Topic Development ................................................................................................................... 9 
Literature Search ....................................................................................................................... 9 
Study Selection ....................................................................................................................... 10 
Data Extraction ....................................................................................................................... 12 
Quality Assessment ................................................................................................................. 12 
Applicability Assessment........................................................................................................ 13 
Grading Strength of Evidence ................................................................................................. 13 
Data Synthesis ......................................................................................................................... 14 
Peer Review ............................................................................................................................ 16 
Results .......................................................................................................................................... 17 
Introduction ............................................................................................................................. 17 
Key Question 1: Reductions in Disease Activity, Limitations of Disease Progression, and
Maintenance of Remission ................................................................................................ 19 
Overview ........................................................................................................................... 20 
Rheumatoid Arthritis: Detailed Analysis .......................................................................... 22 
Key Question 2: Functional Capacity and Quality of Life ..................................................... 58 
Overview ........................................................................................................................... 58 
Detailed Analysis .............................................................................................................. 61 
Key Question 3: Harms, Tolerability, Adverse Effects, or Adherence .................................. 83 
Overview ........................................................................................................................... 84 
Rheumatoid Arthritis: Key Points ..................................................................................... 84 
Detailed Analysis .............................................................................................................. 89 
Key Question 4: Benefits and Harms for Selected Populations ........................................... 153
Overview ......................................................................................................................... 153
Detailed Analysis ............................................................................................................ 154
Discussion................................................................................................................................... 159 
Key Findings ......................................................................................................................... 163 
Applicability ......................................................................................................................... 165 
Conclusions ........................................................................................................................... 166 
Clinical Relevance ................................................................................................................ 166 
Future Research .................................................................................................................... 166 
References .................................................................................................................................. 168 

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Figures
Figure A. Analytic Framework for Treatment for Rheumatoid Arthritis ..................................ES-2
Figure 1. Disposition of Articles (PRISMA Figure) ......................................................................17
Figure 2. Evidence Network for ACR 50 Mixed Treatment Comparisons ...................................35
Figure 3. Relative Treatment Effect for ACR 50 Response for Biologics ....................................38
Figure 4. Meta-analysis of Overall Withdrawals From Randomized Controlled Trials of Biologic
DMARDs ...............................................................................................................................111
Figure 5. Meta-Analysis of Withdrawals Due To Lack of Efficacy in Randomized Controlled
Trials of Biologic DMARDs ..................................................................................................112
Figure 6. Meta-Analysis of Withdrawals Due To Adverse Events in Randomized Controlled
Trials of Biologic DMARDs ..................................................................................................114
Figure 7. Mixed Treatment Comparisons for Overall Withdrawals in Randomized Controlled
Trials of Biologic DMARDs ..................................................................................................115
Figure 8. Mixed Treatment Comparisons for Withdrawals Due To Lack of Efficacy in
Randomized Controlled Trials of Biologic DMARDs ..........................................................117
Figure 9. Mixed Treatment Comparisons for Withdrawals Due To Adverse Events in
Randomized Controlled Trials of Biologic DMARDs ..........................................................120

Tables
Table A. Summary of Findings With Strength of Evidence ......................................................ES-4
Table 1. ACR Criteria for the Diagnosis of Rheumatoid Arthritis ..................................................2
Table 2. Pharmaceutical Treatments for Rheumatoid Arthritis: Corticosteroids ............................4
Table 3. Pharmaceutical Treatments for Rheumatoid Arthritis: Oral DMARDs ............................5
Table 4. Pharmaceutical Treatments for Rheumatoid Arthritis: Biologic DMARDs ......................6
Table 5. Outcome Measures and Study Eligibility Criteria ...........................................................11
Table 6. Strength of Evidence Grades and Their Definitions ........................................................14
Table 7. Number of Head-To-Head Trials by Drug Comparison for Rheumatoid Arthritis .........18
Table 8. Disease Activity, Radiographic Progression, Functional Capacity, and Quality-of-Life
Measures ..................................................................................................................................19
Table 9. Disease Activity and Remission for Oral DMARD Versus Oral DMARD Studies ........24
Table 10. Radiographic Joint Damage in Oral DMARD Versus Oral DMARD ...........................25
Table 11. Disease Activity and Remission for Oral DMARD Combinations Versus
Monotherapy or Combinations With or Without Corticosteroid Studies ................................27
Table 12. Radiographic Joint Damage in Oral DMARD Combinations Versus Monotherapy
Combinations With or Without Corticosteroid Studies ...........................................................29
Table 13. Disease Activity and Remission for Biologic DMARD Versus Biologic DMARD
Studies ......................................................................................................................................30
Table 14. Summary of the 30 Studies Included in Mixed Treatment Comparison Meta-Analysis34
Table 15. Expected (Mean) ACR 50 Treatment Response of Biologic DMARDs .......................36
Table 16. Exclusion Criteria of MTC Meta-Analyses ...................................................................37
Table 17. Disease Activity and Remission for Biologic DMARD Versus Oral DMARD ............40
Table 18. Radiographic Joint Damage in Biologic DMARDs Versus Oral DMARD Studies......41
Table 19. Disease Activity and Remission for Biologic DMARD+Biologic DMARD Versus
Biologic DMARD Studies .......................................................................................................43
Table 20. Disease Activity and Remission for Biologic DMARD+Oral DMARD Versus
Biologic DMARD Studies .......................................................................................................45
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Table 21. Radiographic Joint Damage Biologic DMARD+Oral DMARD Versus Biologic
DMARD Studies ......................................................................................................................47
Table 22. Disease Activity and Remission for Biologic DMARD+Oral DMARD Versus Oral
DMARD ...................................................................................................................................49
Table 23. Radiographic Joint Damage of Biologic DMARD+Oral DMARD Versus Oral
DMARD ...................................................................................................................................51
Table 24. Disease Activity and Remission for Biologic DMARD+Oral DMARD Versus Biologic
DMARD+Oral DMARD .........................................................................................................53
Table 25. Radiographic Joint Damage for Biologic DMARD+Oral DMARD Versus Biologic
DMARD+Oral DMARD .........................................................................................................54
Table 26. Disease Activity and Remission for Early RA DMARD Strategies ..............................55
Table 27. Radiographic Joint Damage in Early RA Strategy Studies ...........................................56
Table 28. Oral DMARD Versus Oral DMARD Studies: Functional Capacity and Health-Related
Quality-of-Life Outcomes ........................................................................................................62
Table 29. Oral DMARD Combination Studies: Functional Capacity and Health-Related
Quality-of-Life Outcomes ........................................................................................................65
Table 30. Biologic DMARD Versus Biologic DMARD Studies: Functional Capacity and Health-
Related Quality-of-Life Outcomes ..........................................................................................68
Table 31. Biologic DMARD Versus Oral DMARD Studies: Functional Capacity and
Health-Related Quality-of-Life Outcomes ..............................................................................70
Table 32. Biologic DMARD Plus Biologic DMARD Versus Biologic DMARD Studies:
Functional Capacity and Health-Related Quality-of-Life Outcomes ......................................73
Table 33. Biologic DMARD Plus Oral DMARD Versus Biologic DMARD Studies: Functional
Capacity and Health-Related Quality-of-Life Outcomes ........................................................74
Table 34. Biologic DMARD Plus Oral DMARD Versus Oral DMARD Studies: Functional
Capacity and Health-Related Quality-of-Life Outcomes ........................................................76
Table 35. Biologic DMARD Plus Oral DMARD Versus Biologic DMARD Plus Oral DMARD
Studies: Functional Capacity and Health-Related Quality-of-Life Outcomes ........................81
Table 36. Early RA Strategies: Functional Capacity and Health-Related Quality-of-Life
Outcomes .................................................................................................................................82
Table 37. Overall Tolerability in Patients With Rheumatoid Arthritis Treated With
Corticosteroids .........................................................................................................................90
Table 38. Cardiovascular and Cerebrovascular Events in Patients With Rheumatoid Arthritis
Treated With Corticosteroids ...................................................................................................92
Table 39. Infection in Patients With Rheumatoid Arthritis Treated With Corticosteroids ...........93
Table 40. Other Specific Harms in Patients With Rheumatoid Arthritis Treated With
Corticosteroids .........................................................................................................................95
Table 41. Overall Tolerability in Patients With Rheumatoid Arthritis Treated With Oral
DMARDs .................................................................................................................................96
Table 42. Cardiovascular and Cerebrovascular Events in Patients With Rheumatoid Arthritis
Treated With Oral DMARDs .................................................................................................100
Table 43. Hepatic Events in Patients With Rheumatoid Arthritis Treated With Oral DMARDs101
Table 44. Infection in Patients With Rheumatoid Arthritis Treated With Oral DMARDs .........102
Table 45. Interstitial Lung Disease in Patients With Rheumatoid Arthritis Treated With Oral
DMARDs ...............................................................................................................................105
Table 46. Malignancies in Patients With Rheumatoid Arthritis Treated With Oral DMARDs ..105
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