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, I² 0%) as well as in total adverse events (94.6 vs 89.1%, OR 2.07, 95% CI 1.11-3.86, I² 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, I² 0%) and the risk of SAEs remained significantly higher (17.1 vs 6.2%, OR 2.72, 95% CI 1.30-5.69, I² 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.