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  • Drug Therapy for Rheumatoid Arthritis in AdultsThis slide set is based on a comparative effectiveness review (CER) Drug Therapy for Rheumatoid Arthritis in Adults: An Update,which was developed by the RTI International–University of North Carolina Evidence-based Practice Center for the Agency for Healthcare Research and Quality under Contract No. 290-2007-10056-I and is available online at http://www.effectivehealthcare.ahrq.gov/dmardsra.cfm.CERs are comprehensive systematic reviews of the literature that usually compare two or more types of treatment, such as different drugs or adding a second drug to usual care for the same disease. The literature included in this review was identified in searches for trials and studies that explicitly evaluated the use of drug treatments for rheumatoid arthritis in adults.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Outline of MaterialThis presentation is based on a comparative effectiveness review of the clinical study literature concerning the use of DMARDs in treating rheumatoid arthritis in adults. It includes an introduction to drug treatment 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; and suggestions of what to discuss with patients and their caregivers.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Health Impact of Rheumatoid ArthritisRheumatoid 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.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International―University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Treatment of Rheumatoid ArthritisThe goal of RA treatment is to control pain, control inflammation, limit progressive damage, and 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.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • DMARDs in Rheumatoid Arthritis Treatment (1 of 2)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, a oral DMARD, the first-line drug of choice for treating RA.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • DMARDs in Rheumatoid Arthritis Treatment (2 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. They include 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.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Oral DMARDs Included in the Comparative Effectiveness ReviewThe oral disease-modifying anti-rheumatic drugs that have been studied for treatment of rheumatoid arthritis and were included in the comparative effectiveness review are:Hydroxychloroquine: Its target of activity is uncertain but likely is T-lymphocytes.Leflunomide: Its target of activity is pyridine synthesis.Methotrexate: Its target of activity is dihydrofolate reductase and folate metabolism.Sulfasalazine: Its target of activity is uncertain but may be multifactorial, including impairment of lymphocyte function and cytokine synthesis.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Biologic DMARDs Included in the Comparative Effectiveness ReviewThe biologic disease-modifying anti-rheumatic drugs (DMARDs) that have been studied for treatment of rheumatoid arthritis and were included in the comparative effectiveness review are:The biologic DMARDs that target tumor necrosis factor-alpha (TNF-α) include adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi), and infliximab (Remicade).Other biologic DMARDs included in the review target immune system components other than TNF-α. They are:Abatacept (Orencia): Its target of activity is CD28.Anakinra (Kineret): Its target of activity is interleukin 1. Rituximab (Rituxan): Its target of activity is CD20.Tocilizumab (Actemra, RoActemra): Its target of activity is the interleukin-6 receptor.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) DevelopmentTopics 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.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Rating the Strength of Evidence From the Comparative Effectiveness ReviewThe Evidence-based Practice Center GRADE approach, based on the standard GRADE approach, was used to assess the quality of the body of evidence for each outcome. The overall strength of evidence was graded as high (further research is very unlikely to change the confidence in the estimate of effect), moderate (further research may change the confidence in the estimate of effect and may change the estimate), low (further research is likely to change the confidence in the estimate of effect and is likely to change the estimate), or insufficient (evidence either is unavailable or does not permit a conclusion). The authors also independently evaluated the applicability to real-world practice of the total body of evidence within a given clinical indication by using the PICOTS (population, intervention, comparator, outcome, timing, and setting) framework.References:Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 10(12)-EHC063-EF. Chapters available at www.effectivehealthcare.ahrq.gov/methodsguide.cfm.Brozek J, Oxman A, Schünemann H, for the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group. GRADEpro [computer program]. Version 3.2 for Windows. Available at www.ims.cochrane.org/revman/other-resources/gradepro/gradepro.
  • Clinical Questions Addressed by the Comparative Effectiveness ReviewThe comparative effectiveness review addressed several key clinical questions, including:- 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?Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Clinically Significant Outcomes of Interest in the Comparative Effectiveness ReviewIn analyzing the clinical study evidence, reviewers focused on these outcomes of benefit and corresponding assessment instruments or scoring indices: - Disease activity and symptoms were evaluated using American College of Rheumatology response scores (ACR 20/50/70) and DAS and DAS28 disease activity scores.- Radiographic changes were measured using the Sharp/van der Heijde Method (SHS) for scoring radiographs.- Functional capacity was evaluated by the Health Assessment Questionnaire (HAQ) and the disability index of HAQ (HAQ-DI).- Quality of life was measured using the SF-36 and EQ-5D questionnaires.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Adverse Effects of Interest in the Comparative Effectiveness ReviewFor analysis of the clinical study evidence, reviewers focused on these adverse effects measurements:- 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 hepatotoxicityReference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Summary of Study Characteristics Evaluated in the Comparative Effectiveness Review: PICOTSDevelopment of clinical studies of effectiveness of medical interventions is guided by the PICOTS (population, interventions, comparators, outcomes, timing, and setting) framework. These items are critical elements that will help to answer important clinical questions. In the comparative effectiveness review, the clinical study literature was reviewed and summarized by using the PICOTS framework. The evidence concerning the outcomes identified here was examined in:Population: AdultsInterventions: oral and biologic DMARDs and corticosteroidsComparators: Other DMARDs, other active interventions, placebo, or no active interventionOutcomes:- Symptom response and remission, general health and quality of life- Key adverse effects: mortality, infusion and injection reactions, infections, malignancy, and rare but serious eventsTiming: Any time point, ranging from 12 weeks to months/yearsSetting: All settingsReference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Summary of Studies Included in the Comparative Effectiveness ReviewThe 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 effectsReference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Analytic Methods Used in the Systematic ReviewTo compare study results systematically, the authors identified these minimally clinically important differences:- American College of Rheumatology 20-percent improvement criteria (ACR20): Finding a statistically significant difference in the proportion of patients achieving ACR20 between treatment and control groups- A disease activity score (DAS) of <2.6- Functional ability: Difference between treatment and control groups in Health Assessment Questionnaire score is ≥0.22- Health-related quality of life: The difference in the SF-36 (Medical Outcomes Study Short Form) is 2.6–4.4 for physical component score- A change in joint damage of 5.0 according to the Sharp/van de Heijde methodReference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Summary of Results: Head-to-Head Comparisons of Oral DMARDs for Rheumatoid ArthritisStudies of oral disease-modifying anti-rheumatic drugs (DMARDs) include head-to head-comparisons, but the number of studies and patients examined is limited and the strength of evidence in support of the findings is low or moderate. For some outcomes, the evidence is insufficient for a conclusion or the outcomes were not studied.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Summary of Benefits: Comparative Effectiveness of Oral DMARDs for Rheumatoid ArthritisThe comparative benefits of oral disease-modifying anti-rheumatic drugs (DMARDs) may be summarized as follows:- Leflunomide and methotrexate (MTX; 7.5 to 25 mg/week) have similar effects on symptom response, radiographic change, and functional capacity. The strength of evidence for this finding is low.- Leflunomide may be superior to sulfasalazine for improving functional capacity. The strength of evidence for this finding is 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). The strength of evidence for this finding is moderate.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Summary of Results: Head-to-head Comparisons of Combination Treatment With Oral DMARDsStudies of oral disease-modifying anti-rheumatic drugs (DMARDs) include head-to-head comparisons of DMARDs used in combination and compared with monotherapy or other DMARD combinations. Patient populations included those with early rheumatoid arthritis who had not been treated with DMARDs, and those patients with longstanding active rheumatoid arthritis and inadequate response to treatment. The number of studies and patients examined is limited, but where available, the strength of evidence in support of the findings is moderate. Some outcomes were not reported in all studies.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Summary of Benefits: Combination Treatments With Oral DMARDsThe comparative benefits of combination treatments with oral disease-modifying anti-rheumatic drugs (DMARDs) may be summarized as follows:- In patients with longstanding active rheumatoid arthritis (RA), combining up to three oral DMARDs (methotrexate [MTX], sulfasalazine, and hydroxychloroquine) produces greater improvements in disease activity than one or two oral DMARDs. The strength of evidence for this finding is 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. The strength of evidence for this finding is moderate.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm
  • Comparative Adverse Effects of Oral DMARDsOral disease-modifying anti-rheumatic drugs (DMARDs) used as monotherapies exhibit similar adverse event rates. The evidence included 3 randomized controlled trials (RCTs) with a total of 1,839 patients; 1 observational study with a total of 40,594 patients; and 3 meta-analyses with a total of 7,245 patients. The strength of evidence for this finding is moderate.Adding a corticosteroid to treatment with oral DMARDs does not increase treatment discontinuation rates and may delay discontinuation. The evidence included 4 RCTs with a total of 1,202 patients and 1 observational study with a total of 154 patients. The strength of evidence for this finding is moderate.Adding a corticosteroid may increase wound healing complications. The strength of evidence for this finding is low.Oral DMARDs do not appear to elevate the risk of lymphoma. The evidence includes 2 observational studies with a total of 16,545 patients. The strength of evidence for this finding is low.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Summary of Results: Head-to-Head Comparisons of Biologic DMARDsHead-to-head comparisons of biologic DMARDs were evaluated for the effectiveness review. Patient populations in the included studies were patients with active RA for longer than 3 years whose disease not did respond or inadequately responded to DMARDs but had not previously treated with an anti–TNF-α DMARD. This table presents a summary of the results of those studies, organized according to the interventions compared in each study. Disease activity and symptom response, functional status, and quality-of-life outcomes were reported. Radiographic evidence of progression was not reported in the studies. The evidence is limited for all comparisons; thus, the strength of evidence is low or insufficient.Abbreviations:ACR70 = American College of Rheumatology 70-percent improvement criteria; ACR20 = American College of Rheumatology 20-percent improvement criteria; DAS = Disease Activity Score; DMARD = disease-modifying anti-rheumatic drug; MCID = minimum clinically important difference; NSD = no statistically significant difference; RA = rheumatoid arthritis; SOE = strength of evidence; TNF-α = tumor necrosis factor-alphaReference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Comparisons of Biologic DMARDs Across Controlled Studies: Mixed Treatment ComparisonsThe authors of the comparative effectiveness review used data from placebo-controlled trials to compare biologic disease-modifying anti-rheumatic drugs (DMARDs) across studies, using an analytic method called a “mixed treatment comparison.” The patient populations in the studies had methotrexate-resistant rheumatoid arthritis. The outcome analyzed was the rate of achieving the American College of Rheumatology 50-percent response criteria (ACR50). Thirty placebo controlled trials with a total of 6,888 patients included the biologic DMARDs abatacept, adalimumab, anakinra, etanercept, golimumab, infliximab, rituximab, and tocilizumab. The analysis demonstrated that etanercept yields the greatest ACR50 response when compared with other biologics and that anakinra yields the lowest. However, the strength of evidence is low, as the comparisons are indirect.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Summary of Results: Comparative Benefits of Biologic DMARDs Used in CombinationTwo randomized controlled trials examined the benefits of combining two biologic DMARDs when compared with biologic DMARD monotherapy. The patient populations were those patients with longstanding active rheumatoid arthritis, rather than those with early disease. No statistically significant differences were noted in disease activity, function, or quality-of-life indices.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Summary of Results: Head-to-Head Comparisons of Oral and Biologic DMARDsThe reviewed studies included direct comparisons of oral and biologic disease-modifying anti-rheumatic drugs (DMARDs) used to treat patients with longstanding active rheumatoid arthritis who required a change in therapy. A retrospective cohort study of 1,083 patients found that as a class, biologic DMARDs resulted in more remissions when compared with oral DMARDs as a class. The systematic review found that biologic DMARDs achieved a higher response rate than oral DMARDs. The strength of evidence for this finding is moderate.Four randomized controlled trials and two retrospective cohort studies evaluated 3,696 patients in comparisons of biologic DMARDs with oral DMARDs. Higher symptom response rates were found with biologic DMARDs. The strength of the evidence for this conclusion is moderate.Radiographic evidence of progression was not reported in the studies presented here, and evidence for findings of effect on functional capacity was insufficient to permit conclusions.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Summary of Benefits: Biologic DMARDsConsidered as a class, for patients with longstanding active rheumatoid arthritis requiring a change in therapy, biologic disease-modifying anti-rheumatic drugs (DMARDs) provide greater symptom response and remission rate than do the oral DMARDs. The strength of evidence for this conclusion is moderate.Overall, the evidence about functional capacity and quality of life is insufficient to permit estimates of comparative effectiveness.Considered as a class, for patients with longstanding active disease requiring a change in therapy, biologic DMARDs provide greater symptom response and remission rate than do the oral DMARDs.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. The strength of evidence for this conclusion is low.Comparisons across studies of patients whose disease is resistant to methotrexate 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. The strength of evidence for this conclusion is low.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Comparative Adverse Effects of Biologic DMARDs (1 of 3)The systematic review investigated adverse effects associated with biologic DMARDs in the treatment of rheumatoid arthritis (RA). The risk of serious infections increases when patients with RA are treated with biologic DMARDs. Six randomized controlled trials with a total of 5,014 patients, 26 observational studies with a total of 391,403 patients, and 6 meta-analyses provided moderate evidence for this conclusion.Combining two biologic DMARDs leads to substantially higher rates of serious adverse events than monotherapy. Two studies with a total of 363 patients provided moderate evidence for this finding.The rate of adverse events did not increase over time in long-term studies of adalimumab, anakinra, etanercept, and infliximab. Nine studies with a total of 14,914 patients provided moderate evidence for this finding.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Comparative Adverse Effects of Biologic DMARDs (2 of 3)The systematic review investigated adverse effects associated with biologic disease-modifying anti-rheumatic drugs (DMARDs) in treatment of rheumatoid arthritis. Mixed treatment comparison analysis of data from placebo-controlled trials of biologic 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. The strength of evidence for this finding is low.- Withdrawal from treatment due to adverse events is more likely with certolizumab pegol and infliximab than with etanercept or rituximab. The strength of evidence for this finding is 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. The strength of evidence for these findings is low.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Comparative Adverse Effects of Biologic DMARDs (3 of 3)The systematic review investigated adverse effects associated with biologic DMARDs in treatment of RA.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). Six observational studies (N = 70,377), 4 meta-analyses, and 1 Adverse Event Reporting System (AERS) data review provided evidence of low strength in support of this finding.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)The strength of evidence for all these findings is low.Abbreviations:DMARD = disease-modifying anti-rheumatic drug; MTX = methotrexate; RA = rheumatoid arthritis; RCT = randomized controlled trialReference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Summary of Results: DMARD Combinations Versus MonotherapiesIn patients with longstanding active rheumatoid arthritis with inadequate disease control, head-to-head comparisons were made of combined DMARDs and DMARD monotherapy. Overall, combination treatment with biologic DMARDs and an oral DMARD is more effective than either used as monotherapy. Disease activity, radiographic progression, functional status, and quality of life all are greater improved with the combination therapy. The strength of evidence for these findings varies among the specific outcomes, with most supported by moderate or high strength of evidence.Abbreviations:DMARD = disease-modifying anti-rheumatic drug; MTX = methotrexate; RA = rheumatoid arthritis; RCT = randomized controlled trial; SOE = strength of evidence; SSZ = sulfasalazineReference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Summary of Results: 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. Combination therapy was more effective in achieving improvements in function and quality of life. The strength of evidence is moderate for functional status and low for quality of life.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Summary of Benefits: DMARD Combinations Versus Monotherapies (1 of 2)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) as well as in quality of life (Strength of Evidence = Moderate).Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Summary of Benefits: DMARD Combinations Versus Monotherapies (2 of 2)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. The strength of evidence for this finding is moderate.In MTX-naïve patients or those not taken MTX recently, combination therapy is superior to monotherapy with a biologic DMARD for functional capacity and quality of life. The strength of evidence for functional capacity is moderate and for quality of life is low.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Comparative Adverse Effects of Combining DMARDsCombining 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. The strength of evidence for this finding is low.Combining MTX and biologic DMARDs demonstrates a better tolerability profile than MTX alone. The strength of evidence for this finding is low.Evidence is insufficient to estimate differences in rates of specific adverse events between the biologic and oral DMARDs.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Summary of Results: Comparative Benefits of DMARDs for Patients With Early RASome clinical research has focused on treatment of patients with early rheumatoid arthritis, defined for this comparative effectiveness review as less than 3 years’ duration of disease. This table presents a summary of the results of those studies, organized according to the patient characteristics and by the interventions compared in the study. Disease activity and symptom response, radiographic evidence of progression, and functional status were reported. Quality-of-life outcomes were not reported in the studies. The strength of evidence is moderate for one conclusion, finding that methotrexate and adalimumab or etanercept produce similar effects on symptoms. The evidence is limited for all other comparisons, making the strength of evidence low.Abbreviations:DMARD = disease-modifying anti-rheumatic drug; MTX = methotrexate; NR = not reported; RA = rheumatoid arthritis; SOE = strength of evidenceReference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Summary of Benefits: DMARDs in the Treatment of Patients With Early Rheumatoid Arthritis (1 of 2)Combination strategies that use corticosteroids plus two or three oral DMARDs are more effective than oral DMARD monotherapy for improving symptom response, disease activity, and functional capacity in patients with rheumatoid arthritis 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.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Summary of Benefits: DMARDs in the Treatment of Patients With Early Rheumatoid Arthritis (2 of 2)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.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Comparative Adverse Effects of DMARDs for Patients With Early Rheumatoid ArthritisAdding 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). The strength of evidence for this finding is moderate.Combining oral DMARDs (sulfasalazine and methotrexate) increases withdrawal from treatment due to adverse events. The strength of evidence for this finding is low.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Other Findings: Influence of Patient Characteristics on Outcomes of DMARD TreatmentThe 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.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Conclusions (1 of 4)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.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Conclusions (2 of 4)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 or a biologic DMARD without increasing treatment discontinuation due to adverse effects.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Conclusions (3 of 4)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.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Conclusions (4 of 4)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.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • Gaps in KnowledgeApplicability 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.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
  • What To Discuss With Your Patients and Their CaregiversIn discussions with patients who have rheumatoid arthritis (RA) and their caregivers, topics related to the comparative effectiveness review evidence include the natural history of RA, 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 symptoms (e.g., diet and exercise), and patient and caregiver preferences and values regarding treatment.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.

Drug therapy for rheumatoid arthritis in adults ahrq Drug therapy for rheumatoid arthritis in adults ahrq Presentation Transcript

  • Drug Therapy for Rheumatoid Arthritis in Adults Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov
  • Outline of Material 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 caregiversDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Health Impact of Rheumatoid Arthritis 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.Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Treatment of Rheumatoid Arthritis  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.Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • DMARDs in Rheumatoid Arthritis Treatment (1 of 2) 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.Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • DMARDs in Rheumatoid Arthritis Treatment (2 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.Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Oral DMARDs Included in the Comparative Effectiveness Review 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 synthesisDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Biologic DMARDs Included in the Comparative Effectiveness Review Biologic Disease-Modifying anti-rheumatic Drugs Name Trade Name Target of Activity Adalimumab 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® IL-6 receptor RoActemra® Abbreviations: IL = interleukin; TNF-α = tumor necrosis factor-alphaDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development  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.Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Rating the Strength of Evidence From theComparative Effectiveness ReviewThe strength of evidence was classified into four broad categories: High Further research is very unlikely to change the confidence in the estimate of effect. Moderate Further research may change the confidence in the estimate of effect and may change the estimate. Low Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate. Insufficient Evidence either is unavailable or does not permit a conclusion.Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews.Available at www.effectivehealthcare.ahrq.gov/methodsguide.cfm.
  • Clinical Questions Addressed by the Comparative Effectiveness Review 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?Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Clinically Significant Outcomes of Interest in the Comparative Effectiveness Review  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-5DDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Adverse Effects of Interest in the Comparative Effectiveness Review 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 hepatotoxicityDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Summary of Study Characteristics Evaluated in the Comparative Effectiveness Review: PICOTS  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 settingsDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Summary of Studies Included in the Comparative Effectiveness Review  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 effectsDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Analytic Methods Used in the Systematic Review  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 methodDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Summary of Results: Head-to-Head Comparisons of Oral DMARDs for Rheumatoid Arthritis Comparison Reduced Limiting N Studies; Symptoms or Radiographic Improved Patients Disease Activity Progression Improved Function Quality of Life SSZ vs. MTX* NSD 3; 1,001 NSD (DAS) NSD (3 RCTs; 479 patients) NR (disease duration SOE = Moderate SOE = Moderate SOE = Moderate <3 years) Greater improvement Greater with LEF with LEF at 12 at 12 months LEF vs. MTX* NSD (ACR20 rates) NSD months (HAQ) but (SF-36 physical 2; 1,481 SOE = Low SOE = Low less than the MCID component ) SOE = Low SOE = Low Greater improvement LEF vs. SSZ NSD with LEF (HAQ) to 24 SOE = Insufficient NR 1; 358 SOE = Low months SOE =Low *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 = sulfasalazineDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Summary of Benefits: Comparative Effectiveness of Oral DMARDs for Rheumatoid Arthritis 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 = ModerateDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Summary of Results: Head-to-Head Comparisons of Combination Treatment With Oral DMARDs Intervention Reduced Limiting N Studies; Patient Symptoms or Radiographic Improved Patients Comparator Characteristics Disease Activity Progression Function‡ SSZ plus DMARD- SSZ or MTX* NSD NSD NSD MTX* naïve, early monotherapy SOE = Moderate SOE = Moderate SOE = Moderate 4; 709 RA† 2 or 3 oral 3 oral DMARDs DMARDs in Patients with are favored over Difference less than combination 1 or 2 oral longstanding 2 to improve NR MCID (MTX*, SSZ, DMARDs active RA disease activity. SOE = Moderate HCQ) SOE = Moderate 2; 273 * 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 = sulfasalazineDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Summary of Benefits: Combination Treatments With Oral DMARDs  „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 = ModerateDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Comparative Adverse Effects of Oral DMARDs  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 = 16,545Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • 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: Symptoms or Disease Activity* Function Quality of Life Intervention Comparator (N Studies; N Patients) (N Studies; N Patients) (N Studies; N Patients) Faster response with 2 of 3 studies reported etanercept, but NSD in the Etanercept Infliximab NSD Insufficient longer term (3; 2,239) Insufficient (6; 5,883) SOE = Low ACR70 at 6 months showed NSD NSD Etanercept Adalimumab NSD (1; 707) SOE = Low (1; 707) SOE = Low (1; 2,326) SOE = Low Symptom response (ACR20 Greater improvement at SF-36 physical component at at 6 months) and DAS at 1 12 months with 12 months favors Adalimumab Infliximab year greater with adalimumab but not adalimumab adalimumab greater than the MCID (1; 707) SOE = Insufficient (2; 3,033) SOE = Low (1; 707) SOE = Low Greater decrease in DAS and SF-36 physical component at greater remission rate, both at NSD at 1 year 1 year favors abatacept but Abatacept Infliximab 1 year, with abatacept. (1; 431) SOE = Low not greater than the MCID (3; 3,464) SOE = Low (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.
  • Comparisons of Biologic DMARDs Across Controlled Studies: Mixed Treatment Comparisons  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. Reduced Symptoms or Intervention Comparator Patient Characteristics Disease Activity Etanercept yields the greatest Biologic DMARDs Biologic DMARDs ACR50 response when Patients whose compared with other biologic rheumatoid arthritis is DMARDs, and anakinra resistant to MTX 30 placebo-controlled trials yields the lowest 6,888 patients SOE = Low Abbreviations: ACR50 = American College of Rheumatology 50-percent response criteria; DMARD = disease-modifying anti-rheumatic drug; MTX = methotrexate; SOE = strength of evidenceDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Summary of Results: Comparative Benefits of Biologic DMARDs Used in Combination Symptoms Patient or Disease Intervention Comparator Characteristics Activity* Function Quality of Life Combinations No Disease improve ClinicallyBiologic Biologic Patients with activity physical but SignificantDMARD DMARD longstanding, NSD not mental DifferenceCombinations Monotherapy active RA (2; 363) quality of life (1; 121) SOE = Low (1; 121) SOE = Low SOE = Low*Radiographic progression was not reported.DMARD = disease-modifying anti-rheumatic drug; NSD = no statistically significant difference;RA = rheumatoid arthritis; SOE = strength of evidenceDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Summary of Results: Head-to-Head Comparisons of Oral and Biologic DMARDs Intervention Radiographic (N Studies, Evidence of Functional N Patients) Comparator Symptoms or Disease Activity Progression Capacity In patients with longstanding active RA who required a change in therapy*: Biologic Oral DMARDs DMARDs Higher chance of remission with as a class as a class biologics than with oral NR Insufficient DMARDs 1 retrospective cohort study SOE = Moderate N = 1,083 Biologic Oral DMARDs DMARDs Higher response rates for biologic DMARDs NR Insufficient 4 RCTs, 2 cohort studies SOE = Moderate 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 evidenceDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Summary of Benefits: Biologic DMARDs  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 = LowDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Comparative Adverse Effects of Biologic DMARDs (1 of 3)  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 patientsDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Comparative Adverse Effects of Biologic DMARDs (2 of 3)  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 = LowDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Comparative Adverse Effects of Biologic DMARDs (3 of 3)  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 = LowDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Summary of Results: DMARD Combinations Versus MonotherapiesIn patients with longstanding active rheumatoid arthritis with inadequate disease control, head-to-headcomparisons of combined DMARDs and DMARD monotherapy were conducted. Symptoms or Radiographic Disease Activity Progression Function Quality of Life (N Studies; (N Studies; (N Studies; (N Studies;Intervention* Comparator N Participants) N Participants) N Participants) N Participants) (5 RCT, 4 cohort; (2; 1, 495) (2; 1,495) (2; 1,495) 9,804) Less change Combination CombinationBiologic Biologic Combination is with a treatment is treatment is moreDMARD DMARD more effective combination more effective effective.plus MTX Monotherapy SOE = Moderate SOE = Moderate SOE = Moderate SOE = Low (7; 4,482) (7; 4,482) (7 RCT, 1 cohort; (7 RCT, 1 cohort;Biologic Combination is Less change 7,516) 7, 516)DMARD MTX or SSZ more effective with Combination Combinationplus MTX or Monotherapy SOE = High combination treatment is treatment is moreSSZ SOE = Moderate more effective effective SOE = High 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.Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • 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. Function Quality of Life Patient (N Studies; (N Studies; Intervention Comparator Characteristics N Participants) N Participants) Early RA† (2; 1,495) (2; 1,495) Biologic MTX Naïve or not Combination is Combination is MTX* DMARD recently on MTX* more effective. more effective. monotherapy plus MTX* SOE = Moderate 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 evidenceDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Summary of Benefits: DMARD Combinations Versus Monotherapies (1 of 2)  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 = ModerateDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Summary of Benefits: DMARD Combinations Versus Monotherapies (2 of 2) 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 = LowDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Comparative Adverse Effects of Combining DMARDs 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.Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Summary of Results: Comparative Benefits of Oral and Biologic DMARDs for Patients With Early RA Reduced Limiting Patient Symptoms or Radiographic Improved Characteristics Intervention Comparator Disease Activity Progression Function Combination is Combination is Combination is 2 to 3 oral Patients with Oral DMARD more effective at 28 more effective more effective DMARDs plus early RA* Monotherapy but not 52 weeks. (2; 354) (2; 354) corticosteroids (2; 354) SOE = Low SOE = Low SOE = Low Results are Biologic similar with DMARD is more MTX-naïve MTX and Results are similar effective at patients with Adalimumab, adalimumab MTX‡ (2; 1,431) limiting aggressive early Etanercept (2; 1,431) SOE = Moderate progression. RA SOE = Low (2; 1,431) SOE = Low Combination is MTX-naïve Combination is more effective patients with MTX‡ plus Biologic DMARD more effective. (also improves NR aggressive early biologic DMARD Monotherapy (1; 799) remission rates) RA SOE = Low (1; 799) SOE = Low * 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.
  • Summary of Benefits: DMARDs in the Treatment of Patients With Early Rheumatoid Arthritis (1 of 2)  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. ˜™™Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Summary of Benefits: DMARDs in the Treatment of Patients With Early Rheumatoid Arthritis (2 of 2) 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. ˜™™Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Comparative Adverse Effects of DMARDs for Patients With Early Rheumatoid Arthritis 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 = LowDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Other Findings: Influence of Patient Characteristics on Outcomes of DMARD Treatment  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.Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Conclusions (1 of 4)  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.Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Conclusions (2 of 4) 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.Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Conclusions (3 of 4)  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.Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Conclusions (4 of 4) 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.Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • Gaps in Knowledge  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.Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
  • What To Discuss With Your Patients and Their Caregivers 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 treatmentDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.