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Disease-Modifying Antirheumatic Drugs in Children With Juvenile Idiopathic Arthritis

Disease-Modifying Antirheumatic Drugs in Children With Juvenile Idiopathic Arthritis. Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov. Outline of Material. Introduction to the health impact and medical treatment of juvenile idiopathic arthritis (JIA)

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Disease-Modifying Antirheumatic Drugs in Children With Juvenile Idiopathic Arthritis

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  1. Disease-Modifying Antirheumatic Drugs in Children With JuvenileIdiopathic Arthritis Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov

  2. Outline of Material • Introduction to the health impact and medical treatment of juvenile idiopathic arthritis (JIA) • Systematic review methods used to create the comparative effectiveness review • The clinical questions addressed by the comparative effectiveness review • Results of studies and evidence-based conclusions about effectiveness and safety of disease-modifying antirheumatic drugs (DMARDs) to treat JIA • Gaps in knowledge and future research needs • What to discuss with patients and their caregivers . Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm

  3. Health Impact of Juvenile Idiopathic Arthritis • JIA is the most common rheumatic disease of childhood. • Prevalence of the disease is estimated to be between 7 to 400 per 100,000 children. • As a chronic, disabling disease, JIA interferes with growth and development and causes psychological distress. • Left unchecked, the course of disease results in irreversible joint damage and life-long disability. • There is no cure for JIA. Helmick CG, Felson DT, Lawrence RC, et al. Arthritis Rheum 2088;58(1):15-25. PMID: 18163481. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm. Manners PJ, Bower C. J Rheumatol 2002;29(7):1520-30. PMID: 12136914.

  4. Characteristics of JIA • To be considered JIA, onset must occur before 16 years of age. • JIA is heterogeneous: the presentation of the disease and its natural history vary among individuals and over time. • The disease is typically classified into categories based on the symptoms displayed and their severity. • Systemic arthritis • Oligoarthritis • Rheumatoid-factor positive (RF+) polyarthritis • Rheumatoid-factor negative (RF-) polyarthritis • Enthesitis-related arthritis • Psoriatic arthritis • Undifferentiated Goldmuntz EA, Echite PH. Pediatr Rev 2005;27(4):324-5. PMID: 16581950. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  5. Treatment of JIA (1 of 2) • Understanding both the circumstances in which DMARDs should be used and which DMARD should be selected is challenging because of the heterogeneity of the disease and response to treatment. • The approach to treatment is based on the severity of symptoms. • The goal of treatment is to reduce pain, swelling, and joint damage. Treatment typically includes: • Nonsteroidal anti-inflammatory drugs • Corticosteroids: intra-articular injections or rarely, oral • This approach does not cure the disease but may significantly reduce symptoms. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  6. Treatment of JIA (2 of 2) • Steroidal and nonsteroidal anti-inflammatory drugs alone are often inadequate to relieve symptoms and limit progression of disease. • DMARDs are now in common use for JIA, and several have been approved by the U.S. Food and Drug Administration for this indication. • DMARDs inhibit the immune cells and mechanisms underlying the symptoms of rheumatic disease. • There are two classes of DMARDs: biologic and nonbiologic. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  7. DMARDs for Treating JIA (1 of 2) • Nonbiologic, synthetic 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 (TNF-α) blockers are the most typical members of this drug class. • Other targets are interleukins 1 and 6 and the transmembrane proteins CD20 and CD28. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  8. DMARDs for Treating JIA (2 of 2) • Methotrexate, a nonbiologic DMARD, is widely used and is considered by many to be essential to the treatment of JIA. • Although studies in pediatric populations have been performed, the evidence base regarding DMARDs for treatment of JIA is more limited compared with the wider experience and clinical evidence base in adult rheumatoid arthritis. • Long-term safety of the DMARDs used in children with JIA is not well understood. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  9. DMARDs Included in the Comparative Effectiveness Review • Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm • Abbreviations: IL = interleukin; IVIG = intravenous immunoglobulin; TNF-α = tumor necrosis factor-alpha

  10. 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 Summaries and the full report, with references for included and excluded studies, are available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  11. Rating the Strength of Evidence From the CER The strength of evidence was classified into four broad categories: Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  12. Clinical Questions Addressed by the CER (1 of 2) • Despite being widely used, there are still unanswered questions about the effectiveness and safety of DMARDs when used to treat JIA, including: • What is the effectiveness of DMARDs when compared with conventional anti-inflammatory/anti-immune treatments? • What is the comparative effectiveness of DMARDs, both within a drug class and between drug classes? • What is the long-term safety of the DMARDs? • Drugs in both categories carry safety warnings. • Anti–TNF-α DMARDs are associated with increased risk of cancer (lymphoma) and serious infections. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  13. Clinical Questions Addressed by the CER (2 of 2) • What is the influence of disease category on effectiveness? • Many assessment instruments are available to evaluate treatment effects, disease progression, health status, and overall well-being of children with JIA. • What is the reliability, validity, and responsiveness of these instruments? Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at: www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  14. Clinically Significant Outcomes of Interest (1 of 2) • For analysis of the clinical study evidence, reviewers focused on these outcomes: • Intermediate Outcomes • Disease activity, symptoms • Physician global assessment of disease activity (PGA) • Symptom response* (e.g., 20%, 30%, or 50% from baseline) • Parent/patient global assessments of well-being • Active joint count; joints with limited range of motion • Laboratory measures of inflammation • Erythrocyte sedimentation rate (ESR) • Radiographic evidence of progression *American College of Rheumatology Pediatric (ACR Ped) Improvement Score Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  15. Clinically Significant Outcomes of Interest (2 of 2) • Long-term outcomes • Pain control • Clinical remission • Quality of life (QoL) • Growth and development • Health Status • Child Health Assessment Questionnaire (CHAQ), for example • Joint function • Functional ability • Mortality Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  16. Adverse Effects • Known risks associated with DMARDs • Lymphoma • Infections • Other adverse effects of interest: • Mortality • Hepatitis • Bone marrow suppression • Nausea or vomiting • Risks to the fetus or pregnant mother Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  17. Summary of Study Characteristics Evaluated in the Effectiveness Review: PICOTS • Population: Individuals 18 years of age or younger with a diagnosis of juvenile idiopathic (JIA), rheumatoid (JRA), or chronic (JCA) arthritis, as defined by these organizations: • JIA: International League of Associations for Rheumatology (ILAR) • JRA: American College of Rheumatology (ACR) • JCA: European League Against Rheumatism (EULAR) • Interventions: Biologic and nonbiologic DMARDs added to conventional anti-inflammatory treatment (NSAIDs and intra-articular or oral corticosteroids) • Comparators: (1) Baseline treatment (NSAIDs and intra-articular corticosteroids) with or without methotrexate or (2) another DMARD • Outcomes: Intermediate and long-term disease status, health status, inflammation markers, and radiographic progression • Timing: Intervention period of at least 3 months • Setting: Any setting for treatment of JIA Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  18. Controlled Studies in This CER: Combining Nonbiologic DMARDs and Conventional Anti-inflammatory Drugs (1 of 2) Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  19. Controlled Studies in This CER: Combining Nonbiologic DMARDs and non-DMARD Anti-inflammatory Drugs (2 of 2) Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  20. Results: Combining Nonbiologic DMARDs and Conventional Anti-inflammatory Drugs Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  21. Summary of Results: Adding Nonbiologic DMARDs to JIA Treatment • Adding methotrexate to anti-inflammatory treatments improves disease activity, as scored by physicians. • Strength of Evidence = Moderate • The results for other nonbiologic DMARDs are inconsistent and often statistically nonsignificant. For many outcomes, no observations are available. The evidence is insufficient to permit conclusions about benefits of nonbiologic DMARDs other than methotrexate. • Strength of Evidence = Insufficient Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  22. Controlled Studies in This CER: Adding Biologic DMARDs to JIA Treatment (1 of 2) Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  23. Controlled Studies in This CER: Adding Biologic DMARDs to JIA Treatment (2 of 2) Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at: www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  24. Results: Adding Biologic DMARDs to JIA Treatment (Methotrexate Permitted) Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  25. Summary of Results: Adding Biologic DMARDs to JIA Treatment (Methotrexate Permitted) • Health status improved when biologic DMARDs were added to treatment. • Strength of Evidence = Low • Improvements in a measure of inflammation, ESR, were inconsistent across studies. • Strength of Evidence = Insufficient • Radiographic evidence of progression was not reported. • Strength of Evidence = Insufficient Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  26. Meta-analysis of Discontinuation Trials ofBiologic DMARDs • Randomized discontinuation trials include only patients who respond to a treatment during a run-in phase. These studies evaluate the sustainability of treatment effects. • Data from four discontinuation trials were combined in a meta-analysis to determine the risk of a disease flare for patients receiving biologic DMARDs when compared to those who discontinued treatment. • The trials included only patients who failed to improve with methotrexate therapy. Study durations were 2 months to 4 years. • Result: The risk of a flare in patients who continued treatment was half that of those who discontinued treatment (relative risk = 0.46, 95% confidence interval = 0.36, 0.63). • NNT = 3 (the number needed to treat [NNT] to see this effect in one patient more than in untreated patients is three) • Strength of Evidence = Moderate Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  27. Summary: Nonbiologic and Biologic DMARDs Compared With Conventional Anti-inflammatory Treatments (1 of 2) • Improved ESR is inconsistently associated with treatment, and the evidence is insufficient to estimate treatment effects. • ESR is influenced by factors that may be unrelated to treatment. • Strength of Evidence = Insufficient • The evidence about how both biologic and nonbiologic DMARDs affect radiographic evidence of disease progression is insufficient to permit a conclusion about treatment effects. • Strength of Evidence = Insufficient Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  28. Summary: Nonbiologic and Biologic DMARDs Compared With Conventional Anti-inflammatory Treatments (2 of 2) • Health status improves with treatment by both classes of DMARDs, but statistically significant differences from controls are not consistent. • Strength of Evidence = Low • Overall, the evidence indicates that when compared with conventional anti-inflammatory treatment alone, adding methotrexate provides more consistent improvement in disease activity as assessed by physicians. • Strength of Evidence = Moderate • For patients whose disease responds to a biologic DMARD after inadequate response to methotrexate, the risk of a flare is reduced by 54% while treatment with the biologic DMARD continues. • Strength of Evidence = Moderate Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  29. Head-to-Head Studies of DMARDs in This Review Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm

  30. Results: Head-to-Head Comparisons of DMARDs Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  31. Summary of Results: Head-to-Head Comparisons of DMARDs • In the few head-to-head comparisons to date, disease activity and health status improve to a similar degree in both treatment arms. • Nonbiologics: D-penicillamine or sulfasalazine versus hydroxychloroquine; leflunomide versus methotrexate • Biologics: Etanercept versus infliximab • Strength of Evidence = Low • Larger studies and more precise outcome assessments are needed to reveal any statistically significant differences that may exist. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  32. Studies Reporting Adverse Effects Associated With DMARDs • 13 randomized controlled trials describing 14 DMARD interventions included a placebo comparison and reported adverse effects. • 914 unique patients were included. • 151 other publications reported adverse effects in patients with JIA treated with DMARDs. • 4,344 patients were included. • Patient populations in the reports may overlap with randomized controlled trials and with each other. • 2 studies reported cases of malignancies in children undergoing DMARD treatment for JIA. • Patient populations were not identified. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  33. Adverse Effects Associated With DMARDs • Both nonbiologic and biologic DMARDs are associated with increased risks for adverse effects, for example: • Nonbiologic DMARDs: • Nausea, other gastrointestinal upset • Skin rashes • Kidney, liver, and other organ toxicity • Serious infections • Biologic DMARDs: • Serious infections • Allergic and hypersensitivity reactions • TNF-alpha blockers may increase the risk of lymphoma and other malignancies Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  34. General Findings of Adverse Event Reports • There are few direct comparisons of DMARDs in children with JIA, and the evidence is insufficient to determine if there are differential rates of adverse effects between drugs or drug classes. • Adverse event rates may be underestimated by clinical trials that exclude patients because of adverse effects in a run-in phase. • The evidence about adverse effects in patients with JIA has not been collected or reported systematically in patients with JIA. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  35. Specific Findings About Adverse Effects • Methotrexate is associated with more laboratory abnormalities than are other DMARDs. • Combination therapy with infliximab and methotrexate is associated with more serious adverse effects and infections than are other DMARDs. • Two publications that surveyed the world literature identified 66 cases of malignancy in children with JIA who were treated with TNF-α–blocking DMARDs. • In this effectiveness review, 11 cases of malignancy were identified in more than 4,000 patient reports. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  36. Evaluating JIA Assessment Instruments (1 of 3) • For this review, seven individual outcomes instruments that are used in composite assessments were evaluated. They measure: • Disease activity • Active joint count (AJC) • Physician global assessment of disease activity (PGA) • Parent global assessment of well-being (PGW) • Functional Status and Disability • CHAQ • Health-Related Quality of Life (QoL) • Child Health Questionnaire (CHQ) • Pediatric Quality of Life Inventory (PedsQL) • Pediatric Quality of Life Inventory–Rheumatology Module (PedsQL-RM) Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  37. Evaluating JIA Assessment Instruments (2 of 3) • Composite assessments combine results from multiple outcome measures to describe disease status. • These assessments are used in both clinical research and patient care settings. • Examples are: • ACR Pediatric response criteria (Peds 30, 50, 70, 90, etc.) • This assessment reports the degree of improvement from baseline status as a percentage. • Flare • A consensus-based definition of remission • Minimal disease activity Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  38. Evaluating JIA Assessment Instruments (3 of 3) • There are three test characteristics that are used to describe outcome assessment tools. They are: • Validity: How well an instrument measures what it claims to measure; examined in comparison to other measurements. • Reliability: The consistency of the instrument in measuring the construct of interest. • Reproducibility is the test–retest reliability. • Responsiveness: Determined by two properties: (1) reproducibility and (2) the ability to register changes in scores when a patient’s symptom status shows clinically important improvement or deterioration. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  39. Results From Evaluation of JIA Assessment Instruments (1 of 2) Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  40. Results From Evaluation of JIA Assessment Instruments (2 of 2) Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  41. Evaluating JIA Assessment Instruments:Conclusions (1 of 2) • No one instrument or outcomes measure appears to be superior in measuring disease activity or functional status. • Reliability and validity are moderate for the physical scales of most measures examined but are poor in the psychosocial domains. • The CHAQ is the most frequently studied instrument for assessing health/disease status for patients with JIA. It shows moderate to high validity and reliability. • CHAQ responsiveness appears to be affected by disease subtype and baseline severity. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  42. Evaluating JIA Assessment Instruments:Conclusions (2 of 2) • Current evidence is inadequate to fully understand the validity, reliability, and responsiveness of the clinical outcomes measures that are used in composite assessments of JIA (such as the ACR Pediatric). • An outcome instrument that accurately describes all aspects of JIA—including disease activity, functional status, and quality of life—is needed to improve both comparative effectiveness research and understanding of the overall impact of JIA. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  43. Conclusions About Benefits and Adverse Effects of DMARDs (1 of 2) • Adding methotrexate to treatment with anti-inflammatory drugs improves disease activity, as scored by physicians. • Strength of Evidence = Moderate • For children who respond to a biologic DMARD, continuing treatment reduces the risk of a flare by 56% (NNT = 3). • Strength of Evidence = Moderate • Health status improves with treatment with both biologic and nonbiologic DMARDs, but statistically significant differences from controls are not consistent. • Strength of Evidence = Low • Evidence is insufficient to state how DMARDs affect markers of inflammation and radiographic progression of disease. • Strength of Evidence = Insufficient Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  44. Conclusions About Benefits and Adverse Effectsof DMARDs (2 of 2) • Few studies of sufficient size make direct comparisons of DMARDs in well-characterized patient populations; thus, it is not clear in which circumstances one DMARD will yield better outcomes than another. • No one instrument for measuring disease activity or functional status has been identified as clearly superior. • Evidence about the rate, types, and severity of adverse effects is too limited to permit conclusions about specific risks to patients with JIA. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  45. Knowledge Gaps and Future Research Needs • The systematic review identified areas where evidence about the use of DMARDs to treat JIA is limited or absent, including: • The comparative effectiveness of DMARDs for JIA has rarely been examined in direct, head-to-head studies. • The effects of DMARDs on measures of inflammation and radiographic progression are not established in the literature; their impact on JIA-associated conditions, such as uveitis and macrophage activation syndrome, has not been examined. • The evidence is too limited to understand how patient characteristics, disease subtype, and variability in the disease process affect response to treatment. • There are few high-quality data about the safety of DMARDs. Standardized definitions, measurement, and reporting of the adverse effects associated with DMARDs are needed, together with long-term data collection. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

  46. What To Discuss With Your Patients andTheir Caregivers • The role of DMARDs for reducing JIA-related symptoms. • The natural history of JIA and the potential benefits and adverse effects of DMARDs. • The importance of communicating symptoms to you and completing any assessment questionnaires you use. • Patient and caregiver preferences and values regarding treatment. Kemper A, Coeytaux, R, Sanders G, et al. Comparative Effectiveness Review No. 28. Available at www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

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