The safety and efficacy of combining conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) with other advanced therapies for the treatment of rheumatoid arthritis (RA) is confirmed, according to results from a systematic literature review published in Arthritis Care & Research.

Investigators conducted a systematic search of MEDLINE, PubMed, EMBase, and databases from the American College of Rheumatology and the European League Against Rheumatism (EULAR) annual meetings.

Eligible studies reported the efficacy and safety of methotrexate (MTX) vs non-MTX csDMARDs in combination with other advanced therapy modalities in adults (≥18 years) with RA. Observational cohort studies and randomized clinical trials were included whereas case reports and reviews were excluded. Relevant advanced therapies included tumor necrosis factor inhibitors (TNFi), abatacept, rituximab, tocilizumab, and Janus kinase (JAK) inhibitors. Efficacy outcomes of interest were remission or low disease activity per the disease activity score in 28 joints (DAS28); remission per EULAR response criteria; improvement in Health Assessment Questionnaire-Disability Index; slowed radiographic progression; and therapy retention. Trials were also assessed for all treatment-emergent adverse events. The meta-analysis utilized an inverse variance approach with fixed or random effects models, depending on the level of between-study heterogeneity. Pooled efficacy estimates were expressed as risk ratios (RRs).

From 3842 relevant articles identified in the database search, 41 were included in the systematic literature review and 21 in the meta-analysis. Of the 21 meta-analysis articles, 13 concerned TNFi, 3 concerned abatacept, and 5 concerned rituximab. Not enough studies were available to perform meta-analysis for tocilizumab or JAK inhibitors. Relative risk for good and moderate EULAR response at 6 months was significantly lower among patients receiving non-MTX csDMARDs combined with TNFi vs patients receiving MTX with TNFi (RR, 0.93; 95% confidence interval [CI], 0.87-1.0; P =.04). The majority of patients with non-MTX csDMARDs received leflunomide (87.3% across 4 studies). Among patients receiving rituximab, good EULAR response was more likely among patients given concurrent leflunomide vs MTX (RR, 1.38; 95% CI, 1.13-1.68; P =.001). For abatacept, efficacy appeared similar between patients with MTX vs non-MTX csDMARDs. Adverse events generally occurred with similar frequency between MTX and non-MTX regimens. However, non-MTX csDMARDs had lower retention at 12 months vs MTX (RR, 0.91; 95% CI, 0.88-0.95; P <.0001). Systematic review results corroborated these findings. Per these data, MTX may perform better with concurrent TNFi than other csDMARDs. However, leflunomide appeared superior to MTX in combination with rituximab.

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As study limitations, investigators noted that MTX is often prescribed as a first line csDMARD; patients typically use non-MTX csDMARDs when MTX has failed. As such, the efficacy of non-MTX csDMARDs may have been inflated relative to MTX.

Even so, review results support the safety of MTX and other csDMARDs in combination with other advanced therapies for RA treatment. Additional randomized clinical trials are necessary to confirm the relatively efficacies of each regimen.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Decarriere G, Barnetche T, Combe B, et al. The most appropriate conventional DMARD to combine with different advanced therapies in rheumatoid arthritis: a systematic literature review with meta-analysis [published online March 26, 2020]. Arthritis Care Res (Hoboken). doi: 10.1002/acr.24195