Review: In rheumatoid arthritis, TNF- inhibitors do not differ from placebo or DMARDs for all-cause mortality

Question In adults with rheumatoid arthritis (RA), what is the effect of tumor necrosis factor (TNF)- inhibitors on all-cause mortality? Review scope Included English-language studies compared available TNF- inhibitors (adalimumab, etanercept, certolizumab, infliximab, or golimumab) with placebo or disease-modifying antirheumatic drugs (DMARDs) for 24 weeks in adults with RA. Primary outcome was all-cause mortality. Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane Library, Google Scholar (all Jan 2000 to Nov 2014), and reference lists were searched for randomized controlled trials (RCTs). 23 RCTs (n =10048, median follow-up 46 wk) met selection criteria; 14 were rated as high quality. TNF- inhibitors included adalimumab (8 RCTs), etanercept (3 RCTs), certolizumab (4 RCTs), infliximab (6 RCTs), and golimumab (2 RCTs). Comparators were placebo (3 RCTs), methotrexate monotherapy (17 RCTs), DMARDs (2 RCTs), and sulfasalazine (1 RCT). Main results TNF- inhibitors did not differ from placebo or DMARDs for all-cause mortality (Table). Similar results were found for TNF- inhibitor monotherapy vs placebo (odds ratio [OR] 1.0, 95% CI 0.2 to 5.3) and TNF- inhibitor combination therapy vs DMARDs (OR 1.4, CI 0.8 to 2.4). Conclusion In adults with rheumatoid arthritis, TNF- inhibitors do not differ from placebo or disease-modifying antirheumatic drugs for all-cause mortality. TNF- inhibitors vs placebo or disease-modifying antirheumatic drugs (control) in adults with rheumatoid arthritis* Outcomes TNF- inhibitor Number of trials (n) Weighted event rates At a median 46 wk TNF- inhibitor Control RRI (95% CI) All-cause mortality All 23 (10048) 0.37% 0.28% 32% (24 to 128) Adalimumab 8 {4011} 0.40% {0.18%} 117% (17 to 463) Etanercept 3 {1214} 0.27% {0.21%} 28% (77 to 616) Certolizumab 4 {2068} 0.21% {0.18%} 19% (73 to 414) Golimumab 2 {864} 0% {0} 102 (77 to 1719) RRR (CI) Infliximab 6 {1891} 0.62% {0.89%} 30% (80 to 73) *Abbreviations defined in Glossary. Weighted event rates, RRI, RRR, and CI calculated from control event rates and odds ratios in article using a fixed-effect model. Values provided by author. Commentary Based on evidence of efficacy, biological drugsand TNF- inhibitors in particularhave transformed care of patients with RA. Nonetheless, several treatment questions are unresolved (e.g., timing, choice of agent, dose, and combinations). Safety is a major concern and is addressed in the review by Poiroux and colleagues. What few similar studies that exist have provided conflicting results; in patients treated with TNF- inhibitors, meta-analyses have shown a somewhat increased risk for serious adverse events and serious infections (1). The findings of Poiroux and colleagues are robust due to the rigorous methodology, evaluation of 10048 patients, exclusion of RCTs <24 weeks in duration, and relative homogeneity of included trials. Mortality did not differ for TNF- inhibitors, used alone or combined with DMARDs, or across subgroups (high vs usual dose, high vs low quality of evidence, trials before vs after 2006). Mortality was not compared in patients with early vs longstanding RA, but 38 deaths among 6525 patients treated over a total of 243 months attests to the safety of TNF- inhibitors for most patients. However, generalizability is hampered by the inherent difference between the controlled setting of an RCT and daily clinical practice. Also, important long-term serious adverse events and mortality (e.g., related to serious infections and cancer) may occur beyond the limited double-blind period of the RCTs (median 46 wk), particularly because most patients continue to receive TNF- inhibitors after 5 years. RA registries are more suitable to address these issues. Since risk for mortality in patients with RA is increased and related to measures of disease activity, and early and persistent remission seems to be associated with reduced mortality (2), incorporating TNF- inhibitors may well lead to a reduction in RA mortality. Such expected beneficial long-term results have been suggested by data derived from patient cohorts followed prospectively in national registries (3).