Systematic Review and Meta-Analysis on Central and/or Peripheral Nervous System Demyelination in Patients Treated With Tumor Necrosis Factor Alpha (TNF-α) Inhibitors.

Tumor necrosis factor alpha inhibitors (TNFi) are widely used for autoimmune diseases, but concerns exist regarding their association with demyelinating disorders affecting the central nervous system (CNS) and peripheral nervous system (PNS). The objective is to systematically evaluate the association between TNF inhibitor exposure and the risk of CNS and PNS demyelination. A systematic review and meta-analysis was conducted following PRISMA 2020 guidelines. PubMed, Scopus, Embase, and the Cochrane Library were searched for studies published between January 2000 and February 2026. Observational cohort and case-control studies reporting TNFi exposure and demyelinating outcomes were included. Risk of bias was assessed using the Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) tool and visualized using robvis (Luke A. McGuinness, Bristol, UK). Random-effects meta-analysis was performed using the metafor package (Wolfgang Viechtbauer, Maastricht University, Maastricht, Netherlands). Subgroup analyses were conducted for CNS and PNS outcomes. Publication bias was evaluated using funnel plots and Egger's regression test. Thirteen studies were included in the systematic review, with 11 eligible for meta-analysis. TNFi exposure was associated with an increased risk of demyelinating disorders affecting both CNS and PNS, with pooled random-effects estimates of RR 1.46 (95% CI 1.09-1.95) for CNS demyelination and RR 2.00 (95% CI 1.19-3.38) for PNS demyelination. Moderate heterogeneity was observed overall (I² = 54.2%), with subgroup heterogeneity of 50.4% for CNS and 47.4% for PNS outcomes. Subgroup analysis showed no significant difference between CNS and PNS risk (p = 0.334). Risk-of-bias assessment demonstrated predominantly low-to-moderate risk of bias, though three single-arm studies without a comparator group were judged to have serious risk of bias; Egger's test showed no significant publication bias. TNFi therapy is associated with increased risk of CNS and PNS demyelinating disorders. Clinicians should monitor neurological symptoms during treatment. Further prospective studies are needed to clarify mechanisms and identify high-risk populations.