Tumor Necrosis Factor-α Inhibition and the Unmasking of CNS Demyelination across a Large United States Health Research Network

PURPOSE: To evaluate the risk of demyelinating disease and optic neuritis among patients treated with tumor necrosis factor (TNF)-α inhibitors using a large, nationwide electronic health record database.

DESIGN: Retrospective, propensity score-matched cohort study.

PARTICIPANTS: A total of 283 760 patients with newly initiated autoimmune disease (excluding CNS demyelination) receiving TNF-α therapy were matched 1:1 to 283 760 control participants with similar diagnoses who did not receive TNF-α inhibitors.

METHODS: Electronic health records from the TriNetX network (70 United States health care organizations) were analyzed from 2010 through 2025. Demographics and comorbidities (including vitamin D deficiency, obesity, thyroid disease, mononucleosis, and smoking) were balanced using propensity score matching. Time-to-event analysis was performed to estimate hazard ratios (HRs) for demyelinating disease and optic neuritis.

MAIN OUTCOME MEASURES: Incidence and HRs of demyelinating disease and optic neuritis at 1 year, 1 to 3 years, and 3 to 5 years after initiation of TNF-α inhibitor therapy.

RESULTS: Across all TNF-α inhibitors, exposure was associated with a modest increase in the risk of demyelinating disease or optic neuritis at 1 to 3 years (HR, 1.237; 95% CI, 1.081-1.415) and 3 to 5 years (HR, 1.201; 95% CI, 1.003-1.438). However, the absolute incidence of these events remained notably low (all < 1%). These signals were not uniform across the drug class. Although an increased 5-year risk was observed with infliximab (0.531% vs. 0.244% in control participants; HR, 1.983), other agents such as etanercept, certolizumab, and golimumab did not show statistically significant increases for the combined outcome. Furthermore, adalimumab showed a significant association specifically with optic neuritis (HR, 1.278; 95% CI, 1.013-1.613), but not with the combined outcome or demyelinating disease alone.

CONCLUSIONS: Exposure to TNF-α inhibitors was associated with a small and statistically significant increase in the risk of demyelinating events, although the absolute risk remained very low. The variability in risk signals across different inhibitors and the low overall incidence suggest that although clinical awareness is appropriate, these findings should be viewed within the context of the established benefits of these therapies.

FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.