Abstract
Background and Objectives: Anti-tumor necrosis factor-alpha (TNF-α) agents are effective in treating rheumatoid arthritis (RA) but may entail a risk of lymphoma due to TNF-α's role in immune surveillance. This systematic review and meta-analysis assesses the risk of lymphoma in patients with RA treated with anti-TNF agents versus patients treated with methotrexate and/or a placebo. Materials and Methods: The Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Embase, PubMed, and Google Scholar were systematically searched for relevant literature. Data were extracted and analyzed to determine risk ratios (RRs) and 95% confidence intervals (CIs), with heterogeneity assessed using I(2) statistics. Methodological quality and risk of bias were assessed using the Cochrane Risk of Bias tool for randomized controlled trials (RCTs) and the Newcastle-Ottawa Scale for observational studies. Results: The search yielded 932 articles, 13 of which were retained for qualitative review and 12 for quantitative synthesis. Overall, the studies reviewed included 181,735 participants: 3772 from six RCTs and 177,963 from seven observational studies. The meta-analysis of RCTs revealed no significant difference in the risk of lymphoma between patients receiving anti-TNF-α therapy and patients on conventional treatments, with an overall RR of 1.43 (95% CI: 0.32-5.16) and I(2) of 0%. Conversely, observational studies showed some variability, with an overall RR of 1.43 (95% CI: 0.59-3.47) and significant heterogeneity (I(2) = 95%), whereas others indicated a potentially elevated risk of lymphoma in specific subgroups but had inconsistent results. Conclusions: The systematic and meta-analysis revealed no significant difference in the risk of lymphoma for patients with RA treated with anti-TNF-α agents versus conventional therapies. However, given the limitations of the studies included, additional research is needed to validate the results and explore potential risk factors contributing to the development of lymphoma in patients with RA.