Risk of Malignancies in Patients With Rheumatoid Arthritis Treated With Biologic Therapy: A Meta-analysis
Question: What is the risk of malignant disease in patients with rheumatoid arthritis (RA) treated with biologic response modifiers (BRMs)?
Data Sources: Cochrane Collaboration methods were followed. Randomized controlled trials (RCTs) examining the role of abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab in rheumatoid arthritis were identified from comprehensive literatures searches of electronic databases, conference proceedings, and regulatory agency websites. All studies of human subjects published in English, French, or Spanish from inception through July 9, 2012, were identified.
Study Selection: Four pairs of independent reviewers identified randomized controlled trials that met the following inclusion criteria: (1) compared the safety of any BRM against placebo or any disease-modifying antirheumatic drug (DMARD); (2) included only patients with RA; and (3) reported a minimum of 24 weeks of follow-up.
Data Extraction: A total of 63 distinct trials with 29 423 patients met inclusion criteria, including 5991 patients from 20 studies of BRM monotherapy. Two independent reviewers extracted general information and characteristics of the study, population, and intervention from each selected trial. Two additional reviewers cross-checked the data. Primary outcome data of interest included overall number and type of malignant diseases developed by study participants. Authors of trials that did not report on number of malignant diseases were contacted for the specific data. Risk of bias of included studies was also appraised by the reviewers with each study ascribed a low, unclear, or high risk of bias score.
Data Synthesis: Data from the included studies were pooled, and Peto odds ratios (ORs) and relative risks with associated 95% confidence intervals were calculated for each BRM as well as for the subset of BRMs comprising tumor necrosis factor (TNF) inhibitors. Continuity correction estimates of the Peto ORs were generated to account for trials with no malignant diseases reported in either the intervention or control group (zero-total-event trials). Subgroup analyses were conducted to assess the impact of BRM monotherapy vs combination therapy with traditional DMARDs, as well as the impact of follow-up length, on malignant diseases development. Results were analyzed both at a 2-sided α level of significance of .05 and with a Bonferroni correction to control for multiple dosing regimens of each BRM.
Results: A total of 211 patients out of the 29 423 analyzed developed a malignant disease during the course of the trials (0.72%; 95% CI, 0.63%-0.82%), including 118 solid tumors, 48 skin cancers, 14 lymphomas, 5 nonlymphoma hematologic malignant diseases, and 26 unspecified cancers. No significantly increased risk of malignant disease was seen with any BRM monotherapy. Statistically significant increases in the risk of malignant diseases were seen in individuals treated with TNF inhibitors in combination with methotrexate compared with controls at 52 weeks (Peto OR, 2.1; 95% CI, 1.1-3.9) but not at other time points. Statistically significant lower odds of malignant disease were noted in patients treated with anakinra plus methotrexate compared with methotrexate alone at 24 weeks (Peto OR, 0.11; 95% CI, 0.03-0.45). Patients treated with anakinra also had significantly lower odds of developing nonmelanoma skin cancer (Peto OR, 0.06; 95% CI, 0.00-0.94).
Authors’ Conclusions: The authors conclude that the available data seem to suggest that there is no cumulative risk for the development of malignant diseases in patients with RA treated with BRMs.