Risk of active tuberculosis and herpes zoster with tumor necrosis factor inhibitor treatment in adults with autoimmune disease conditions: a systematic trial sequential analysis of randomized placebo-controlled clinical trials

Introduction To thoroughly examine the risk of active tuberculosis and herpes zoster infections with tumor necrosis factor (TNF) inhibitor treatment in adults (≥18-year-olds) with autoimmune disease conditions. Methods A trial sequential analysis (TSA) informed by a high-quality systematic review and meta-analysis of evidence from published randomized placebo-controlled trials. We pooled appropriate trial data using an inverse variance, random-effects model and expressed the results as relative risk and associated 95% confidence intervals. Statistical heterogeneity was calculated using the I2 statistic. Further, we assessed the strength/quality of the pooled evidence. Results We included 49 trials. Irrespective of autoimmune disease condition type and TNF inhibitor treatment dosage, while we observed a marginally increased risk of active tuberculosis with infliximab (3.66 [1.13-11.90], I2 = 0%, 7 pooled estimates, moderate certainty), there was no increased risk of active tuberculosis or herpes zoster with other evaluated TNF inhibitors. However, TSA suggested that pooled sample sizes were not enough to support definitive conclusions on all the analyses. Conclusions The available evidence from randomized placebo-controlled clinical trials in adults with autoimmune disease conditions does not support the risk of active tuberculosis or herpes zoster with TNF inhibitors. However, the evidence is insufficient for strong conclusions. Protocol registration www.crd.york.ac.uk/prospero identifier is CRD42024614017.