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Effective Health Care Program

Drug Therapy for Early Rheumatoid Arthritis: A Systematic Review Update

Systematic Review Draft

Open for comment through Feb 10, 2018

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Related Activities include: PCORI Evidence Synthesis Program Stakeholder Workshop

Purpose of This Review

Compare benefits and harms of drug therapies for adults with early rheumatoid arthritis (RA).

Key Messages

  • All included studies enrolled patients with moderate to high disease activity at baseline as measured with mean or median Disease Activity Score (DAS) 28 scores
  • Corticosteroids in combination with methotrexate (MTX) may improve remission rates more than MTX alone but did not differ significantly in disease activity in the long term (up to 5 years).
  • Two-agent treatments with MTX and tumor necrosis factor (TNF) biologics or non-TNF biologics most likely yield higher treatment response rates than MTX monotherapy treatment or any biologic monotherapy.
  • Rates of serious adverse events and discontinuations because of serious adverse events do not differ between all disease-modifying antirheumatic drugs (DMARDs).
  • Patients older than 65 years had higher rates of serious adverse events when treated with etanercept or MTX monotherapy than younger patients.
  • Only limited information was available for treatment options for patient subgroups.
  • Future research should address (1) long-term comparative benefits and harms of DMARDs, (2) treatment based on disease activity severity in early RA, and (3) timing of initiation of biologic medications.

Structured Abstract

Objectives. Compare the benefits and harms of drug therapies for adults with early rheumatoid arthritis (RA) within 1 year of diagnosis, updating the 2012 review.

Data sources. English language articles identified through MEDLINE®, Cochrane Library, Embase, International Pharmaceutical Abstracts, gray literature, the previous 2012 review, expert recommendations, reference lists of published literature, and supplemental evidence data requests.

Review methods. Two researchers independently selected relevant randomized controlled trials (RCTs) of any sample size and observational studies that assessed outcomes of at least 12 weeks’ duration. Literature was synthesized qualitatively within and between corticosteroids and classes of disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic (cs) DMARDs, targeted synthetic (ts) DMARDS, tumor necrosis factor (TNF) and non-TNF biologics, and biosimilars. Additionally, combination treatment strategies were examined. We conducted network meta-analysis for five outcomes: American College of Rheumatology 50% improvement (ACR50), Disease Activity Score, radiographic joint damage, all withdrawals, and withdrawals attributable to adverse events.

Results. We analyzed 46 studies: 37 RCTs and 9 observational studies. All included studies enrolled patients moderate to high disease activity at baseline as measured with mean or median Disease Activity Score (DAS) 28 scores. Higher remission rates were achieved with a combination of corticosteroids plus MTX than with MTX monotherapy (low strength of evidence [SOE]). Combination therapy involving the TNF or non-TNF biologics plus MTX improved disease activity, remission, and functional capacity compared with monotherapy of either MTX or a biologic (low to moderate SOE). Network meta-analyses found higher ACR50 response for combination therapy of biologics plus MTX than for biologic DMARD monotherapy (abatacept, adalimumab, etanercept, infliximab, tocilizumab) or MTX monotherapy (range of relative risk 1.34 [95% confidence interval (CI), 1.16 to 1.54] to 1.73 [95% CI, 1.34 to 2.27]). No significant differences emerged between any DMARDs for rates of discontinuation attributable to adverse events or serious adverse events (low to moderate SOE). Data about subgroups (based on disease activity, prior therapy, demographics, and the presence of other serious conditions) were quite limited. Patients older than 65 years of age had higher rates of serious adverse events when treated with etanercept or MTX monotherapy than younger patients (low SOE). We found no studies of biosimilars for patients with early RA.

Conclusions. Qualitative and network meta-analyses suggest that combination of MTX with TNF or non-TNF biologics improve disease activity and remission when compared with a biologic monotherapy or a csDMARD monotherapy. Overall rates of adverse events and discontinuation rates were similar among patients given csDMARDs, TNF biologics, and non-TNF biologics. Compared with younger patients, older populations had higher rates of serious adverse events when treated with etanercept or MTX monotherapy.