Purpose of Review

Compare benefits and harms of drug therapies for adults with early rheumatoid arthritis (RA) within 1 year of diagnosis.

Key Messages

• Conclusions are based on studies that enrolled patients with moderate to high disease activity at baseline as measured with Disease Activity 28 Scores and may not apply to the general RA population.
• Corticosteroids in combination with methotrexate (MTX) may improve remission rates more than MTX alone (difference range, 2.1% to 42.8%), but they 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 treatment with MTX monotherapy or any biologic monotherapy (range of American College of Rheumatology response differences, 1.2% to 25.6%).
• Rates of serious adverse events and discontinuations because of adverse events may not differ between any disease-modifying antirheumatic drugs (DMARDs).
• Insufficient information was available about treatment options for patient subgroups, such as disease activity, prior therapy, demographics, and the presence of other serious conditions.
• Future research should address the (1) assessment of long-term comparative benefits and harms of DMARDs, (2) determination of treatment decisions 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 findings on early RA from 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 from January 2011 to October 5, 2017.

Review methods. Literature was synthesized qualitatively in narrative form and summary tables within and between corticosteroids and classes of disease-modifying antirheumatic drugs (DMARDs). Additionally, combination treatment strategies were examined. We conducted network meta-analysis for five outcomes: American College of Rheumatology 50-percent improvement (ACR50), remission based on Disease Activity Score (DAS), radiographic joint damage, all discontinuations, and discontinuations due to adverse events. Eligibility for network meta-analyses required the following: (1) patients with early RA had not attempted prior treatment with methotrexate (MTX), (2) doses of treatments were within ranges approved by the Food and Drug Administration (FDA), (3) length of followup was similar, and (4) studies were double-blinded randomized controlled trials of low or medium risk of bias.

Results. We analyzed 49 studies: 41 RCTs and 8 observational studies reported in 124 published articles. All included studies enrolled patients with moderate to high disease activity at baseline as measured with mean or median DAS 28 scores. A combination of corticosteroids plus MTX achieved higher remission rates than with MTX monotherapy (low strength of evidence [SOE]). Combination therapy with TNF (tumor necrosis factor) or non-TNF biologics plus MTX improved disease control, remission, and functional capacity compared with monotherapy with 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 MTX monotherapy (range of relative risk, 1.20 [95% confidence interval (CI), 1.04 to 1.38] to 1.57 [95% CI, 1.30 to 1.88]). In available data, consisting mostly of clinical trials, no significant differences emerged between any DMARDs for rates of discontinuation attributable to adverse events or serious adverse events (low SOE for adalimumab, certolizumab pegol, etanercept, infliximab, or abatacept with MTX, and moderate SOE for rituximab or tocilizumab with MTX). Data about subgroups (based on disease activity, prior therapy, demographics, and the presence of other serious conditions) were insufficient. No difference in findings were noted in MTX naïve and resistant populations. We found no studies of biosimilars for patients with early RA.

Conclusions. Qualitative synthesis and network meta-analyses suggest that the combination of MTX with TNF or non-TNF biologics improves disease activity and remission when compared with biologic monotherapy or a conventional synthetic DMARD (csDMARD) monotherapy in patients with moderate to high disease activity at baseline as measured with mean or median DAS 28 scores. Overall rates of adverse events and discontinuation were similar among patients given csDMARDs, TNF biologics, and non-TNF biologics. We did not find eligible studies of biosimilars.

Journal Citation

Donahue KE, Schulman ER, Gartlehner G, et al. Comparative Effectiveness of Combining MTX with Biologic Drug Therapy Versus Either MTX or Biologics Alone for Early Rheumatoid Arthritis in Adults: A Systematic Review and Network Meta-analysis. J Gen Internal Med. 2019 Aug 6 (Epub ahead of print). DOI: 10.1007/s11606-019-05230-0.

Citation

Suggested citation: Donahue KE, Gartlehner G, Schulman ER, Jonas B, Coker-Schwimmer E, Patel SV, Weber RP, Lohr KN, Bann C, Viswanathan M. Drug Therapy for Early Rheumatoid Arthritis: A Systematic Review Update. Comparative Effectiveness Review No. 211. (Prepared by the RTI International–University of North Carolina at Chapel Hill Evidence-based Practice Center under Contract No. 290-2015-00011-I for AHRQ and PCORI.) AHRQ Publication No. 18-EHC015-EF. PCORI Publication No. 2018-SR-02. Rockville, MD: Agency for Healthcare Research and Quality; July 2018. Posted final reports are located on the Effective Healthcare Program search page. https://doi.org/10.23970/AHRQEPCCER211.