Safety of combination therapy with two bDMARDs in patients with rheumatoid arthritis: A systematic review and meta-analysis

Objectives: We performed a systematic review and meta-analysis of the current literature to assess the safety of combining two biologic disease-modifying antirheumatic drugs (bDMARDs) in the treatment of rheumatoid arthritis (RA). Methods: We systematically searched for controlled studies evaluating safety in patients with RA treated with two bDMARDs independently of dose-regimen. Databases used were MEDLINE (via Pubmed), EMBase, Cochrane Library, Scopus, ClinicalTrials.gov, and the WHO International Clinical Trials Registry platform. A meta-analysis was performed between groups on combination therapy and patients on single therapy using random effects model calculating odds ratio (OR) as well as 95% confidence interval (CI). The primary outcome was the rate of serious adverse events (SAEs). Results: Six studies with a total of 623 patients (410 on combination therapy and 213 on single therapy) were included. Median follow-up was 9.5 months (range 6-12 months). There was a significant increase in SAEs in the combination group (14.9 vs 6.0%, OR 2.51, 95% CI 1.29-4.89, I-2 0%) as well as in total adverse events (94.6 vs 89.1%, OR 2.07, 95% CI 1.11-3.86, I-2 0%). When performing subgroup analysis in patients receiving only full-dose of both bDMARDs there was a significant increase in serious infections (6.7 vs 0.6%, OR 5.58, 95% CI 1.25-24.90, I-2 0%) and the risk of SAEs remained significantly higher (17.1 vs 6.2%, OR 2.72, 95% CI 130-5.69, I-2 0%). Conclusion: Our findings suggest that combination therapy with two bDMARDs in RA appears to increase the risk of SAEs during the first twelve months of treatment. (C) 2018 Elsevier Inc. All rights reserved.