1. Drug Therapy for Rheumatoid Arthritis in Adults Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov

2.  Introduction to drug treatment of rheumatoid arthritis and disease-modifying anti-rheumatic drugs (DMARDs)  Systematic review methods  The clinical questions addressed by the comparative effectiveness review  Modes of statistical analysis and results reporting in the comparative effectiveness review  Results of studies and evidence-based conclusions about the effectiveness and adverse effects of DMARDs  Gaps in knowledge  What to discuss with patients and their caregivers Outline of Material Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

3.  Rheumatoid arthritis (RA) is an autoimmune disease that causes joint inflammation and progressive erosion of bone, leading to joint misalignment, loss of function, and disability.  RA affects 1.3 million American 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.

4.  The goal of RA treatment is to:  Control pain  Control inflammation  Limit progressive damage  Reduce disease activity or induce remission  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.  Corticosteroids — both low-dose systemic and intra-articular formulations — are used as adjuncts to DMARD treatment. Treatment of Rheumatoid Arthritis Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

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

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

7. Oral Disease-Modifying anti-rheumatic Drugs NameTarget of Activity HydroxychloroquineT-lymphocytes (?) LeflunomidePyridine synthesis MethotrexateDihydrofolate reductase; folate metabolism SulfasalazineUncertain; multifactorial, including impairment of lymphocyte function and cytokine synthesis Oral DMARDs Included in the Comparative Effectiveness Review Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

8. Biologic DMARDs Included in the Comparative Effectiveness Review Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm. Biologic Disease-Modifying anti-rheumatic Drugs NameTrade NameTarget of Activity AdalimumabHumira ® TNF-α Certolizumab pegolCimzia ® TNF-α EtanerceptEnbrel ® TNF-α GolimumabSimponi ® TNF-α InfliximabRemicade ® TNF-α AbataceptOrencia ® CD28 AnakinraKineret ® IL-1 RituximabRituxan ® CD20 TocilizumabActemra ® RoActemra ® IL-6 receptor Abbreviations: IL = interleukin; TNF- α = tumor necrosis factor-alpha

9.  Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others.  A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment.  The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The Research Summaries and the full report, with references for included and excluded studies, are available at www.effectivehealthcare.ahrq.gov/dmardsra. Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

10.  The strength of evidence was classified into four broad categories: Rating the Strength of Evidence From the Comparative Effectiveness Review Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Available at www.effectivehealthcare.ahrq.gov/methodsguide.cfm.

11.  Clinical questions addressed by the comparative effectiveness review include:  Do drug therapies for rheumatoid arthritis (RA) differ in their ability to reduce disease activity, to slow or limit the progression of joint damage, or to maintain remission?  Do drug therapies for RA differ in their ability to improve patient- reported symptoms, functional capacity, or quality of life?  Do drug therapies for RA differ in harms, tolerability, patient adherence, or adverse effects?  What are the comparative benefits and harms of drug therapies for RA in subgroups of patients, based on stage of disease, prior therapy, demographics, concomitant therapies, or comorbidities? Clinical Questions Addressed by the Comparative Effectiveness Review Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

12.  In analyzing the clinical study evidence, reviewers focused on these outcomes of benefit:  Disease activity and symptoms  ACR 20/50/70: American College of Rheumatology response scores  DAS and DAS28: disease activity score  Radiographic changes  Sharp/van der Heijde Method (SHS) for scoring radiographs  Functional capacity  HAQ: Health Assessment Questionnaire  HAQ-DI: disability index of the Health Assessment Questionnaire  Quality of life  SF-36  EQ-5D Clinically Significant Outcomes of Interest in the Comparative Effectiveness Review Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

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

14.  Population: Adults 19 years and older  Interventions: Oral and biologic disease-modifying anti- rheumatic drugs (DMARDs); corticosteroids  Comparators: Other DMARDs  Outcomes:  Symptom response and remission; general health and quality of life  Key adverse effects: mortality, infusion and injection reactions, infections, malignancy, and rare but serious events  Timing: minimum 12 weeks, up to months/years  Setting: All settings Summary of Study Characteristics Evaluated in the Comparative Effectiveness Review: PICOTS Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

15.  The analysis included 258 published articles reporting on 211 studies:  31 head-to-head randomized controlled trials  1 head-to-head nonrandomized controlled trial  44 placebo-controlled trials  28 meta-analyses or systematic reviews  107 observational studies  30 studies for quantitative synthesis for analysis of effects on disease activity and joint damage  42 studies for quantitative syntheses for analysis of adverse effects Summary of Studies Included in the Comparative Effectiveness Review Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

16.  To compare study results systematically, the authors identified these minimal clinically important differences:  American College of Rheumatology 20-percent improvement criteria (ACR20): Statistically significant difference in the proportion of patients achieving ACR20 between treatment and control groups  Disease Activity Score (DAS): A DAS of <1.6 correlates with remission; a DAS28 (short form) of <2.6 correlates with remission  Functional ability: Difference in Health Assessment Questionnaire score ≥0.22  Health-related quality of life: An SF-36 (Medical Outcomes Study Short Form) physical or mental component change of 2.6 – 4.4 for physical component score  A change in joint damage of 5.0 according to the Sharp/van de Heijde method Analytic Methods Used in the Systematic Review Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

17. Summary of Results: Head-to-Head Comparisons of Oral DMARDs for Rheumatoid Arthritis Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm. Comparison N Studies; Patients Reduced Symptoms or Disease Activity Limiting Radiographic ProgressionImproved Function Improved Quality of Life SSZ vs. MTX* 3; 1,001 (disease duration <3 years) NSD (DAS) SOE = Moderate NSD SOE = 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 MCID SOE = Low Greater with LEF at 12 months (SF-36 physical component ) SOE = Low LEF vs. SSZ 1; 358 SOE = Insufficient NSD SOE = Low Greater improvement with LEF (HAQ) to 24 months SOE =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

18.  Leflunomide and methotrexate (MTX; 7.5 to 25 mg/week) have similar effects on symptom response, radiographic change, and functional capacity.  Strength of Evidence = Low  Leflunomide may be superior to sulfasalazine for improving functional capacity. ˜™™  Strength of Evidence = Low  Sulfasalazine and MTX (7.5 to 25 mg/week) have similar effects on symptoms, disease activity, functional capacity, and limiting radiographic changes (in patients with rheumatoid arthritis for <3 years). ˜˜™  Strength of Evidence = Moderate Summary of Benefits: Comparative Effectiveness of Oral DMARDs for Rheumatoid Arthritis Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

19. Summary of Results: Head-to-Head Comparisons of Combination Treatment With Oral DMARDs Intervention N Studies; PatientsComparator Patient Characteristics Reduced Symptoms or Disease Activity Limiting Radiographic 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 NR Difference less than MCID SOE = 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 Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

20.  „In patients with longstanding active rheumatoid arthritis (RA), combining up to three oral disease-modifying anti- rheumatic drugs (DMARDs; methotrexate [MTX], sulfasalazine, and hydroxychloroquine) produces greater improvements in disease activity than one or two oral DMARDs. ˜˜™  Strength of Evidence = Moderate  For patients with early RA who have not previously been treated with oral DMARDs, combining oral DMARDs (sulfasalazine and MTX) does not improve symptom response, radiographic progression, or functional capacity more than monotherapy. ˜˜  Strength of Evidence = Moderate Summary of Benefits: Combination Treatments With Oral DMARDs Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

21.  Oral disease-modifying anti-rheumatic drugs (DMARDs) used as monotherapies exhibit similar adverse event rates.  Strength of Evidence = Moderate  3 randomized controlled trials (RCTs), N= 1,839  1 observational study, N = 40,594  3 meta-analyses, N = 7,245  Adding a corticosteroid to treatment with oral DMARDs does not increase treatment discontinuation rates and may delay discontinuation.  Strength of Evidence = Moderate  4 RCT, N = 1,202  1 observational study, N = 154  Adding a corticosteroid to may increase wound healing complications.  Strength of Evidence = Low  Oral DMARDs do not appear to elevate the risk of lymphoma.  Strength of Evidence = Low  2 observational studies, N = 16,545 Comparative Adverse Effects of Oral DMARDs Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

22. Summary of Results: Head-to-Head Comparisons of Biologic DMARDs In 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: InterventionComparator Symptoms or Disease Activity* (N Studies; N Patients) Function (N Studies; N Patients) Quality of Life (N Studies; N Patients) EtanerceptInfliximab Faster 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 EtanerceptAdalimumab ACR70 at 6 months showed NSD (1; 2,326) SOE = Low NSD (1; 707) SOE = Low NSD (1; 707) SOE = Low AdalimumabInfliximab Symptom 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 AbataceptInfliximab Greater 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. Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

23. Comparisons of Biologic DMARDs Across Controlled Studies: Mixed Treatment Comparisons InterventionComparatorPatient Characteristics Reduced Symptoms or Disease Activity Biologic DMARDs Patients whose rheumatoid arthritis is resistant to MTX Etanercept yields the greatest ACR50 response when compared with other biologic DMARDs, and anakinra yields the lowest SOE = Low 30 placebo-controlled trials 6,888 patients The authors of the comparative effectiveness review used data from placebo- controlled trials to compare biologic DMARDs across studies, using an analytic method called “mixed treatment comparison.” The patient populations in the studies had MTX- resistant rheumatoid arthritis. The outcome analyzed was the rate of achieving an ACR50 response to treatment. The studies included the biologic DMARDs abatacept, adalimumab, anakinra, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm. Abbreviations: ACR50 = American College of Rheumatology 50-percent response criteria; DMARD = disease-modifying anti-rheumatic drug; MTX = methotrexate; SOE = strength of evidence

24. Summary of Results: Comparative Benefits of Biologic DMARDs Used in Combination InterventionComparator Patient Characteristics Symptoms or Disease Activity*FunctionQuality of Life Biologic DMARD Combinations Biologic DMARD Monotherapy Patients with longstanding, active RA Disease activity NSD (2; 363) SOE = Low No Clinically Significant Difference (1; 121) SOE = Low Combinations improve physical but not mental quality of life (1; 121) SOE = Low *Radiographic progression was not reported. DMARD = disease-modifying anti-rheumatic drug; NSD = no statistically significant difference; RA = rheumatoid arthritis; SOE = strength of evidence Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

25. Summary of Results: Head-to-Head Comparisons of Oral and Biologic DMARDs Intervention (N Studies, N Patients)ComparatorSymptoms 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 DMARDs SOE = Moderate NRInsufficient 1 retrospective cohort study N = 1,083 Biologic DMARDs Oral DMARDs Higher response rates for biologic DMARDs SOE = Moderate NRInsufficient 4 RCTs, 2 cohort studies N = 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 Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

26.  Considered as a class, for patients with longstanding active rheumatoid arthritis requiring a change in therapy, biologic disease-modifying anti-rheumatic drugs (DMARDs) provide a greater symptom response and remission rate than do the oral DMARDs. ˜˜™  Strength of Evidence = Moderate  †Overall, the evidence about functional capacity and quality of life is insufficient to permit estimates of comparative effectiveness.  Strength of Evidence = Insufficient  „Combining two biologic DMARDs (etanercept with abatacept or anakinra) does not add to improvement in disease activity, functional capacity, or symptom response more than one biologic DMARD and increases the risk of serious adverse effects.  Strength of Evidence = Low  „„Comparisons across studies of patients whose disease is resistant to suggest that there may be clinically observable differences in the efficacy of the biologic DMARDs. Evidence from head-to-head comparisons is too limited to provide guidance for clinical decisionmaking.  Strength of Evidence = Low Summary of Benefits: Biologic DMARDs Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

27.  The risk of serious infections increases when patients with rheumatoid arthritis are treated with biologic disease-modifying anti-rheumatic drugs (DMARDs).  Strength of Evidence = Moderate  6 randomized controlled trials (RCTs), N = 5,014  26 observational studies, N = 391,403  6 meta-analyses  Combining two biologic DMARDs leads to substantially higher rates of serious adverse events than monotherapy.  Strength of Evidence = Moderate  2 RCTs, N = 363  The rate of adverse events did not increase over time in long-term studies of adalimumab, anakinra, etanercept, and infliximab.  Strength of Evidence = Moderate  9 studies, N = 14,914 patients Comparative Adverse Effects of Biologic DMARDs (1 of 3) Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

28.  Mixed treatment comparison analysis of data from placebo-controlled trials of biologic disease-modifying anti-rheumatic drugs (DMARDs; 43 trials, 19,413 patients) provided the basis for the following conclusions:  Certolizumab pegol, etanercept, and rituximab have more favorable overall treatment withdrawal profiles than other biologic DMARDs.  Strength of Evidence = Low  Withdrawal from treatment due to adverse events is more likely with certolizumab pegol and infliximab than with etanercept or rituximab.  Strength of Evidence = Low  Withdrawals from treatment due to injection site reactions are more likely with anakinra, and infliximab is associated with a higher rate of infusion reactions.  Strength of Evidence = Low Comparative Adverse Effects of Biologic DMARDs (2 of 3) Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

29.  Studies present no consistent evidence of elevated risk of lymphoma or other cancer types associated with biologic DMARDs (relative to either oral DMARDs or placebo), and the actual risk to patients with RA is not clear (study durations range from 3 months to 5 years).  Strength of Evidence = Low  6 observational studies, N = 70,377  4 meta-analyses  1 Adverse Event Reporting System (AERS) data review  For biologics, the likelihood of withdrawals from trials, when compared with placebo or MTX, was:  Overall, about half that of the MTX and placebo groups (41 RCTs, N = 18,029)  Due to adverse events, 1.4-fold more likely than with placebo or MTX (43 RCTs, N = 11,243)  Due to lack of efficacy, about one-fifth (0.2x the rate) as likely as MTX or placebo (34 RCTs, N = 13,079)  Strength of Evidence = Low Comparative Adverse Effects of Biologic DMARDs (3 of 3) Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

30. Summary of Results: 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 DMARD Monotherapy (5 RCT, 4 cohort; 9,804) Combination is more effective SOE = Moderate (2; 1, 495) Less change with a combination SOE = Moderate (2; 1,495) Combination treatment is more effective SOE = Moderate (2; 1,495) Combination treatment is more effective. SOE = Low Biologic DMARD plus MTX or SSZ MTX † or SSZ Monotherapy (7; 4,482) Combination is more effective SOE = High (7; 4,482) Less change with combination SOE = Moderate (7 RCT, 1 cohort; 7,516) Combination treatment is more effective SOE = High (7 RCT, 1 cohort; 7, 516) Combination treatment is more effective SOE = 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. Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

31. Summary of Results: DMARD Combinations Versus Monotherapies In 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. InterventionComparator Patient 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 Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

32.  In patients with rheumatoid arthritis who had inadequate disease control and required a change in treatment, combination therapy with a biologic disease-modifying anti-rheumatic drug (DMARD) and methotrexate (MTX) achieved greater improvements in some outcomes than either a biologic DMARD or MTX alone.  Combination therapy achieves greater improvement than biologics alone in:  Disease activity and radiographic progression  Strength of Evidence = Moderate  Combination therapy achieves greater improvement than MTX alone in:  Clinical response and functional capacity ˜˜˜  Strength of Evidence = High  Quality of life  Strength of Evidence = Moderate Summary of Benefits: DMARD Combinations Versus Monotherapies (1 of 2) Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

33.  In patients whose rheumatoid arthritis failed to respond to methotrexate (MTX), combination therapy with MTX and a biologic disease-modifying anti-rheumatic drug (DMARD) was not more successful than monotherapy with a biologic DMARD. ˜˜™  Strength of Evidence = Moderate  In MTX-naïve patients or those had not taken MTX recently, combination therapy is superior to monotherapy with a biologic DMARD for functional capacity and quality of life. ˜™™  Strength of Evidence for Functional Capacity = Moderate  Strength of Evidence for Quality of Life = Low Summary of Benefits: DMARD Combinations Versus Monotherapies (2 of 2) Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

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

35. Summary of Results: Comparative Benefits of Oral and Biologic DMARDs for Patients With Early RA Patient CharacteristicsInterventionComparator Reduced Symptoms or Disease Activity Limiting Radiographic Progression Improved Function Patients with early RA* 2 to 3 oral DMARDs plus corticosteroids Oral DMARD Monotherapy 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. Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

36.  Combination strategies that use corticosteroids plus two or three oral disease-modifying anti-rheumatic drugs (DMARDs) are more effective than oral DMARD monotherapy for improving symptom response, disease activity, and functional capacity in patients with rheumatoid arthritis (RA) in the short term and reducing radiographic evidence of progression and joint erosion in the longer term (≥1 year). ˜™™„  Combining one oral DMARD with prednisone reduces radiographic progression and joint erosion more than the DMARD alone. ˜™  For patients with early RA who have not been treated with methotrexate (MTX):  Effects on symptom response are similar when MTX is compared with adalimumab or etanercept. ˜˜™  Effects on functional capacity are similar with MTX and adalimumab. ˜™™ Summary of Benefits: DMARDs in the Treatment of Patients With Early Rheumatoid Arthritis (1 of 2) Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

37.  Biologic disease-modifying anti-rheumatic drugs (DMARDs) more effectively limit radiographic evidence of progression than do oral DMARDs. ˜˜™  For methotrexate (MTX)-naïve patients with aggressive early rheumatoid arthritis, combining MTX with a biologic DMARD (abatacept, adalimumab, etanercept, or infliximab) provides greater improvement than biologic DMARD monotherapy for symptom response, clinical remission rates, and radiographic progression. ˜™™ Summary of Benefits: DMARDs in the Treatment of Patients With Early Rheumatoid Arthritis (2 of 2) Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

38.  Adding prednisone to treatment with one or multiple oral disease-modifying anti-rheumatic drugs (DMARDs) does not increase treatment discontinuation rates (treatment durations spanned 2 months to 5 years).  Strength of Evidence = Moderate  Combining oral DMARDs (sulfasalazine and methotrexate) increases withdrawal from treatment due to adverse effects.  Strength of Evidence = Low Comparative Adverse Effects of DMARDs for Patients With Early Rheumatoid Arthritis Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

39.  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.  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 anakinra.  Concomitant antidiabetic, antihypertensive, or statin medications given to patients treated with anakinra did not increase the risk of adverse events. Other Findings: Influence of Patient Characteristics on Outcomes of DMARD Treatment Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

40.  For patients with early rheumatoid arthritis (RA)who have not been treated with methotrexate (MTX), treatment with either MTX or a biologic disease-modifying anti-rheumatic drug (DMARD) provides similar benefits for symptoms and function. However, biologic DMARDs are more effective at limiting radiographic evidence of progression.  The evidence is too limited to permit conclusions about whether one combination strategy is better than another in treating early RA (<3 years’ duration).  Evidence is accumulating that biologic DMARDs as a class offer greater likelihood of remission in patients with longstanding active disease than do oral ones. Conclusions (1 of 4) Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

41.  Indirect comparisons reveal potential differences in effectiveness of the biologic disease-modifying anti- rheumatic drugs (DMARDs) in treating rheumatoid arthritis, but the analysis should be interpreted with caution.  Combining biologic DMARDs provides no additional benefits and increases the risk of serious adverse effects.  In patients with inadequate disease control, biologic DMARDs used in combination with methotrexate (MTX) offer greater relief than monotherapy with either MTX of a biologic DMARD without increasing treatment discontinuation due to adverse effects. Conclusions (2 of 4) Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

42.  The oral disease-modifying anti-rheumatic drugs (DMARDS), particularly methotrexate (MTX), remain effective first-line treatments for rheumatoid arthritis (RA).  MTX (at a dose of 7.5 to 25 mg per week) and sulfasalazine are similarly effective for patients with early RA, and leflunomide may provide comparable results.  Adding prednisone to treatment with oral DMARDs improves function and may limit radiographic progression, although there is evidence that the combination increases the risks of adverse effects.  For patients with longstanding active disease, two or three oral DMARDs in combination can provide more improvement than monotherapy. Conclusions (3 of 4) Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

43.  Disease-modifying anti-rheumatic drugs (DMARDs) of both classes are associated with well-known adverse effects (toxicity of oral DMARDs, serious infections with biologic DMARDs), but the comparative risks are not known.  Overall tolerability is similar between DMARDs of both classes. The evidence about cancer risk is limited, but the risk for patients with rheumatoid arthritis does not appear to be elevated by DMARDs of either class. Conclusions (4 of 4) Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

44.  Applicability of the conclusions is limited, as most evidence comes from efficacy trials that exclude many typical patients with rheumatoid arthritis and are conducted in ideal settings.  The evidence about the effects of disease stage, age, concomitant therapies, and comorbidities is limited and is derived from single studies that address these potential modifiers of effectiveness and safety.  Evidence about response of subgroups defined by health status, age, coexisting conditions, comorbidities, concurrent treatments, sociodemographics, or other variables is inadequate to understand the effects of these characteristics.  The effect of timing of initiation and duration of treatment, especially whether early use of biologic disease-modifying anti-rheumatic drugs (DMARDs) is beneficial, is not well understood.  Future studies should include measurements of patient-centered, quality-of-life outcomes.  Head-to-head comparisons of DMARDs and studies that focus on different combination strategies are needed. Gaps in Knowledge Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

45.  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 caregiver preferences and values regarding treatment What To Discuss With Your Patients and Their Caregivers Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.