Drug Therapy for Early Rheumatoid Arthritis

127 Pages·2017·4.74 MB·English

Drug Therapy for Early Rheumatoid
Arthritis in Adults: A Systematic Review
Update

Authors

Publication Date

Agency for Healthcare Research and Quality Patient-Centered Outcomes Research Institute
U.S. Department of Health and Human Services 1828 L Street NW
5600 Fishers Lane Suite 900
Rockville, MD 20857 Washington, DC 20036
www.ahrq.gov www.pcori.org
Draft Comparative Effectiveness Review
Number xx

Drug Therapy for Early Rheumatoid Arthritis:
A Systematic Review Update

Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
5600 Fishers Lane
Rockville, MD 20857
www.ahrq.gov

and

Patient-Centered Outcomes Research Institute
1828 L Street, NW, Ste 900
Washington, DC 20036
www.pcori.org

This information is distributed solely for the purposes of pre-dissemination peer review. It has not
been formally disseminated by the Agency for Healthcare Research and Quality or the Patient-
Centered Outcomes Research Institute (PCORI). The findings are subject to change based on the
literature identified in the interim and peer-review/public comments and should not be referenced as
definitive. It does not represent and should not be construed to represent an Agency for Healthcare
Research and Quality or Department of Health and Human Services (AHRQ) determination or policy.

Contract No.

Prepared by:
<EPC> Evidence-based Practice Center

AHRQ Publication No. xx-EHCxxx PCORI Publication No. xxx
This report is based on research conducted by the <EPC> Evidence-based Practice Center (EPC)
under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD
(Contract No.<#>). The Patient-Centered Outcomes Research Institute (PCORI) funded the
report (PCORI publication No. <X>). The findings and conclusions in this document are those of
the authors, who are responsible for its contents; the findings and conclusions do not necessarily
represent the views of AHRQ or PCORI. Therefore, no statement in this report should be
construed as an official position of PCORI, AHRQ, or of the U.S. Department of Health and
Human Services.

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

The information in this report is intended to help health care decision makers—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 is made available to the public under the terms of a licensing agreement between the
author and AHRQ. This report may be used and reprinted without permission except those
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PCORI, AHRQ, or U.S. Department of Health and Human Services endorsement of any
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This report may periodically be assessed for the currency of conclusions. If an assessment is
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Persons using assistive technology may not be able to fully access information in this report. For
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Suggested citation:
<Authors>. Drug Therapy for Early Rheumatoid Arthritis-A Systematic Review Update.
Comparative Effectiveness Review No. X. (Prepared by the XXX Evidence-based Practice
Center under Contract No. XXX for AHRQ and PCORI) AHRQ Publication No. XX-EHCXXX-
EF. Rockville, MD: Agency for Healthcare Research and Quality. 2018.
www.effectivehealthcare.ahrq.gov/reports/final.cfm.
ii
Preface
The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based
Practice Centers (EPCs), sponsors the development of evidence reports and technology
assessments to assist public- and private-sector organizations in their efforts to improve the
quality of health care in the United States.
The Patient-Centered Research Outcomes Institute (PCORI) was established to fund research
that can help patients and those who care for them make better-informed decisions about the
health care choices they face every day. PCORI partnered with AHRQ to help fulfill PCORI’s
authorizing mandate to engage in evidence synthesis and make information from comparative
effectiveness research more available to patients and providers. PCORI identifies topics for
review based on broad stakeholder interest. After identifying specific topics, multistakeholder
virtual workshops are held by PCORI to inform the individual research protocols.
The reports and assessments provide organizations, patients, clinicians, and caregivers with
comprehensive, evidence-based information on common medical conditions and new health care
technologies and strategies. They also identify research gaps in the selected scientific area,
identify methodological and scientific weaknesses, suggest research needs, and move the field
forward through an unbiased, evidence-based assessment of the available literature. The EPCs
systematically review the relevant scientific literature on topics assigned to them by AHRQ, and
conduct additional analyses when appropriate prior to developing their reports and assessments.
To bring the broadest range of experts into the development of evidence reports and health
technology assessments, AHRQ encourages the EPCs to form partnerships and enter into
collaborations with other medical and research organizations. The EPCs work with these partner
organizations to ensure that the evidence reports and technology assessments they produce will
become building blocks for health care quality improvement projects throughout the Nation. The
reports undergo peer review and public comment prior to their release as a final report.
AHRQ expects that the EPC evidence reports and technology assessments, when appropriate,
will inform patients and caregivers, individual health plans, providers, and purchasers as well as
the health care system as a whole by providing important information to help improve health
care quality.
If you have comments on this evidence report, they may be sent by mail to the Task Order
Officer named below at: Agency for Healthcare Research and Quality, 5600 Fishers Lane,
Rockville, MD 20857, or by email to [email protected].

Gopal Khanna M.B.A. Arlene Bierman, M.D., M.S.
Director Director
Agency for Healthcare Research and Quality Center for Evidence and Practice
Improvement
Agency for Healthcare Research and Quality

Joe V. Selby, M.D., M.P.H. Evelyn P. Whitlock, M.D., M.P.H.
Executive Director Chief Science Officer
PCORI PCORI
iii
Acknowledgments
The authors gratefully acknowledge the following individuals for their contributions to this
project and deeply appreciate their considerable support, commitment, and contributions:

iv
Contents

Evidence Summary ................................................................................................................. ES-1
Introduction ................................................................................................................................... 1
Condition..................................................................................................................................... 1
Etiology ................................................................................................................................... 1
Burden of Disease ................................................................................................................... 1
Definitions of Early RA and Challenges with the Definitions ............................................... 1
Current Practice and Treatment Strategies ............................................................................. 2
Scope and Key Questions ............................................................................................................ 4
Scope of the Review ............................................................................................................... 4
Key Questions ......................................................................................................................... 4
Contextual Questions .............................................................................................................. 5
Analytic Framework ................................................................................................................... 5
Organization of This Report ....................................................................................................... 5
Methods .......................................................................................................................................... 6
Criteria for Inclusion/Exclusion of Studies in the Review ......................................................... 6
Searching for the Evidence: Literature Search Strategies for Identification of Relevant Studies
to Answer the Key Questions ..................................................................................................... 7
Literature Review, Data Abstraction, and Data Management .................................................... 8
Assessment of Methodological Risk of Bias of Individual Studies .......................................... 10
Data Synthesis ........................................................................................................................... 10
Grading the Strength of Evidence for Major Comparisons and Outcomes .............................. 11
Assessing Applicability ............................................................................................................ 12
Peer Review and Public Commentary ...................................................................................... 12
Results .......................................................................................................................................... 13
Organization of the Results ....................................................................................................... 13
Search Results ........................................................................................................................... 13
Characteristics of Included Studies ....................................................................................... 13
Corticosteroids ...................................................................................................................... 17
csDMARD Studies ................................................................................................................ 18
Biologics ............................................................................................................................... 20
KQ 1: For patients with early RA, do drug therapies differ in their ability to reduce disease
activity, slow or limit the progression of radiographic joint damage, or induce remission? .... 23
Key Points ............................................................................................................................. 23
Detailed Synthesis ................................................................................................................. 23
KQ 2: For patients with early RA, do drug therapies differ in their ability to improve patient-
reported symptoms, functional capacity, or quality of life? ..................................................... 46
Key Points ............................................................................................................................. 46
Detailed Synthesis ................................................................................................................. 46
KQ 3: For patients with early RA, do drug therapies differ in harms, tolerability, patient
adherence, or adverse effects? .................................................................................................. 60
Key Points ............................................................................................................................. 61
Detailed Synthesis ................................................................................................................. 61
KQ 4: Comparative Benefits and Harms in Subgroups of Patients .......................................... 79
Key Points ............................................................................................................................. 79
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Detailed Synthesis ................................................................................................................. 79
Discussion..................................................................................................................................... 81
Overview of Key Findings ........................................................................................................ 81
Findings in Relationship to What Is Already Known ............................................................... 86
Applicability ............................................................................................................................. 87
Contextual Questions ................................................................................................................ 87
Contextual Question 1: Does treatment of early RA improve disease trajectory and disease
outcomes compared with the trajectory or outcomes of treatment of established RA? ........ 87
Contextual Question 2: What barriers prevent individuals with early RA from obtaining
access to indicated drug therapies? ....................................................................................... 88
Limitations ................................................................................................................................ 88
Research Needs ......................................................................................................................... 89
Conclusions ............................................................................................................................... 90
References .................................................................................................................................... 91

Tables
Table ES-1. Summary of characteristics of this systematic review on treatment of patients
with early rheumatoid arthritis .................................................................................................. ES-2
Table ES-2. Benefits and harms of csDMARDs and tsDMARDs for treatment of patients
with early rheumatoid arthritis .................................................................................................. ES-4
Table ES-3. Benefits and harms of biologic DMARDs for early RA treatment ...................... ES-5

Table 1. Disease-modifying antirheumatic drugs approved by the U.S. Food and Drug
Administration ................................................................................................................................ 3
Table 2. Eligibility criteria for review of treatments for early rheumatoid arthritis ....................... 6
Table 3. Outcomes and hierarchy of preferred measures for data abstraction ................................ 9
Table 4. Definitions of the grades of overall strength of evidence ............................................... 12
Table 5. Number of studies included for each key question, by drug therapy group, comparison
type, and study design ................................................................................................................... 15
Table 6. Characteristics of included studies ................................................................................. 16
Table 7. Disease activity, response, and radiographic progression .............................................. 39
Table 8. Results for patient-reported outcomes, functional status, and quality of life ................. 53
Table 9. Discontinuation rates and adverse events ....................................................................... 72
Table 10. Summary of findings about benefits and harms of treatments for early rheumatoid
arthritis with strength of evidence grades ..................................................................................... 81

Figures
Figure 1. Analytic framework for drug therapy for early rheumatoid arthritis .............................. 5
Figure 2. Summary of literature search flow and yield for early rheumatoid arthritis ................. 14
Figure 3. Network diagram for network meta-analysis: ACR50 response rates .......................... 26
Figure 4. Forest plot for network meta-analysis: ACR50 response rates ..................................... 27
Figure 5. Network diagram for network meta-analysis: change from baseline in
radiographic joint damage score ................................................................................................... 29
Figure 6. Forest plots for network meta-analysis: change from baseline in radiographic
joint damage score ........................................................................................................................ 30
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Figure 7. Network diagram for network meta-analysis: remission according to Disease
Activity Score ............................................................................................................................... 37
Figure 8. Forest plots for network meta-analysis: remission according to Disease Activity
Score ............................................................................................................................................. 38
Figure 9. Network diagram for network meta-analysis: All withdrawals and withdrawals
due to adverse events .................................................................................................................... 64
Figure 10. Forest plots for network meta-analysis: All withdrawals ............................................ 65
Figure 11. Forest plot for network meta-analysis: Withdrawals attributable to adverse
events ............................................................................................................................................ 67

Appendixes
Appendix A. Search Strings ........................................................................................................ A-1
Appendix B. Excluded Articles .................................................................................................. B-1
Appendix C. Detailed Evidence Tables ...................................................................................... C-1
Appendix D. Risk of Bias Ratings and Rationales for Included Studies .................................... D-1
Appendix E. Strength of Evidence for Key Questions 1-4 Outcomes ......................................... E-1
Appendix F. Eligible Clinical and Self-Reported Scales and Instruments Commonly
Used in Eligible Studies of Drug Therapy for Rheumatoid Arthritis .......................................... F-1
Appendix G. Tests of Consistency for Main Network Meta-Analyses ..................................... G-1
Appendix H. Sensitivity Analyses for Network Meta-Analyses ................................................ H-1
Appendix I. Stakeholder Input in Formulating the Research Protocol ......................................... I-1
Appendix J. Peer Reviewers ........................................................................................................ J-1
Appendix K. PCORI Methodology Standards Checklist ............................................................ K-1

vii
Drug Therapy for Early Rheumatoid Arthritis: A
Systematic Review Update
Evidence Summary
Introduction
This systematic review updates a 2012 report that evaluated the benefits and harms of drug
therapies for adults with rheumatoid arthritis (RA).1 This updated review, however, has a
targeted scope focusing solely on patients with early RA. Early RA has no formal consensus
definition. Based on guidance from a recent task force of experts, we define early RA as no more
than 1 year of diagnosed disease. Our findings should be considered applicable only to patients
with early RA.
The U.S. Food and Drug Administration (FDA) has approved several drug therapy groups for
treating patients with RA. Corticosteroids have been prescribed the longest; targeted synthetic
disease-modifying antirheumatic drugs (tsDMARDs) and biosimilars were approved more
recently. The majority of trials or observational studies in this review evaluated mainly FDA-
approved conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and
biologic drugs (both tumor necrosis factor [TNF] and non-TNF drugs). FDA has approved
numerous biosimilars. However, because they have not been studied specifically among early
RA patients, we had no studies about them to include in this review.
Many challenges arise in evaluating pharmacological treatments for RA in the literature.
These include the appropriate use and order or combination of different therapeutic options, the
optimal approach for patients with coexisting and chronic conditions, severity of RA, and the
role of newer drugs in treatment strategies that compare csDMARDs.
We evaluated the benefits and harms of multiple drug monotherapies, combination therapies,
and different treatment strategies to determine whether therapeutic approaches differ in their
ability to affect important outcomes for patients with early RA. The benefits and harms included
(1) reduced disease activity, decreased progression of joint damage, or remission; (2) improved
functional capacity or quality of life; (3) harms such as tolerability, serious adverse events, and
adverse effects; and (4) benefits and harms among patient subgroups (based on disease activity,
prior RA therapy, demographics, or presence of other diseases with or without treatment).
Additional details about this systematic review are described in Table ES-1. Two contextual
Questions were also examined: (1) Does treatment of early RA improve disease trajectory and
disease outcomes compared with the trajectory or outcomes of treatment of established RA? and
(2) What barriers prevent individuals with early RA from obtaining access to indicated drug
therapies?

ES-1
Table ES-1. Summary of characteristics of this systematic review on treatment of patients with
early rheumatoid arthritis
Population Included in the Review
Key Inclusion Criteria Adult outpatients, 19 years of age or older, with an early RA diagnosis,
defined as 1 year or less from disease diagnosis
Key Exclusion Criteria Adolescents and adults with RA greater than 1 year from diagnosis
Drug Therapies Approved by FDA for RA, Included in the Review
Corticosteroid Methylprednisone, prednisone (PRED), prednisolone (PNL)
Conventional synthetic DMARD Hydroxychloroquine (HCQ), leflunomide (LEF), methotrexate (MTX),
(csDMARD) sulfasalazine (SSZ)
Tumor necrosis factor (TNF) biologic Adalimumab (ADA), certolizumab pegol (CZP), etanercept (ETN),
DMARD golimumab (GOL), infliximab (IFX)
Non-TNF biologic DMARD Abatacept (ABA), rituximab (RIT), tocilizumab (TCZ), sarilumab (SAR)a
Targeted synthetic DMARD (tsDMARD) Tofacitinib (TOF)a
Biosimilars ADA-atto,a IFX-dyyb,a IFX-abda,a ETN-szzsa
Key Questions Covered by the Review
1. Benefits of drug therapies including Clinical tools including:
reducing disease activity, slowing or  ACR 20/50/70
limiting the progression of joint damage,  DAS
or inducing remission  Sharp Scoreb
2. Benefits of drug therapies including Clinical tools including:
improving patient-reported symptoms,  HAQ
functional capacity, or quality of life  SF-36
3. Harms of drug therapies including Harms including:
tolerability, patient adherence, and  Overall discontinuations
adverse effects  Discontinuations attributable to AEs
 Seriousc AEs
 Specificd AEs
4. Benefits and harms of drug therapies Subgroups of patients defined by:
in subgroups of patients  Age
 Sex
 Race or ethnicity
 Disease activity
 Prior treatment
 Concomitant therapies
 Coexisting conditions
a New medications that FDA has approved since the prior report
b Sharp-van der Heijde method for scoring radiographs
c As defined by FDA: Life-threatening, requires hospitalization, leads to lasting disability or congenital anomaly, or jeopardizes
the patient in any serious way
d Rash, upper respiratory tract infection, nausea, pruritus, headache, diarrhea, dizziness, abdominal pain, bronchitis, leukopenia,
injection site reactions
ACR 20/50/70 = American College of Rheumatology 20/50/70% improvement from baseline; AE = adverse event; DAS =
Disease Activity Score; DMARD = disease-modifying antirheumatic drug; FDA = U.S. Food and Drug Administration; HAQ =
Health Assessment Questionnaire; SF-36 = Medical Outcomes Study Short Form 36 Health Survey.
Results and Key Findings
We included 46 studies (reported in 113 published articles) that provided data on at least one
of the review’s Key Questions. Of these studies, 37 were randomized controlled trials (RCTs), 5
were observational studies with control groups, and 4 were single-arm observational studies that
we included only for evaluating harms of treatment.
We rated a majority of these studies as low or medium risk of bias. We rated 14 studies as
high risk of bias for at least some of the eligible outcomes they reported. Studies rated high risk
ES-2