AB0368 SAFETY OF COMBINATION THERAPY WITH TWO BIOLOGIC DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS IN PATIENTS WITH RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Gonçalo Boleto, Lukshe Kanagaratnam, Moustapha Dramé, Jean-Hugues Salmon
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> About 20% to 40% of patients with rheumatoid arthritis (RA) treated with biologic therapies fail to achieve remission consequently requiring additional treatment (1-4). Combining different biologic agents could be a promising therapeutic strategy. However, the safety and tolerability of combining different biologic agents is one of the major concerns of this treatment approach. <h3>Objectives</h3> We performed a systematic review and meta-analysis of the current literature to assess the safety of combining two bDMARDs (biologic disease-modifying anti-rheumatic drugs) in the treatment of patients with RA. <h3>Methods</h3> We searched PubMed, the Cochrane Library, Scopus, ClinicalTrials.gov, and the WHO International Clinical Trials Registry platform through 12/18/17. Our eligibility criteria included human RCTs or observational or non-randomized comparative studies in adults (≥ 18 years of age) that recorded safety of combination therapy with two bDMARDs in RA patients. We used R version 3.1.2 to perform meta-analysis between groups on combination therapy and placebo/single therapy alone using random effect model calculating odds ratio (OR) as well as 95% confidence interval (CI). Cochran Q statistic and I<sup>2</sup> statistic was used to identify heterogeneity between studies. The primary outcome was the rate of major serious events. Additional outcomes were the rate of total adverse events, total infectious events and major infectious events. <h3>Results</h3> Six studies with a total of 623 patients (410 on combination therapy and 213 on single therapy) were included for meta-analysis. 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<sup>2</sup>0%) as well as in total adverse events (94.6 vs 89.1%, OR 2.07, 95% CI 1.11-3.86, I<sup>2</sup>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<sup>2</sup>0%) and the risk of SAEs remained significantly higher (17.1 vs 6.2%, OR 2.72, 95% CI 1.30-5.69, I<sup>2</sup>0%). <h3>Conclusion</h3> Our findings suggest that combination therapy with two bDMARDs in RA patients appears to increase the risk of SAEs during the first twelve months of treatment. <h3>References</h3> [1] -Lipsky PE, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000Nov30;343(22):1594–602. [2] Weinblatt ME, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003Jan;48(1):35–45. [3] Keystone ECet al. Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2004 Feb;50(2):353–63. [4] Weinblatt ME, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999Jan28;340(4):253–9. <h3>Disclosure of Interests</h3> Gonçalo Boleto: None declared, Lukshe Kanagaratnam: None declared, Moustapha Dramé: None declared, Jean-Hugues Salmon Speakers bureau: Janssen Novartis