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    Original Investigation
    May 18, 2020

    Association Between Tumor Necrosis Factor Inhibitor Exposure and Inflammatory Central Nervous System Events

    Author Affiliations
    • 1Department of Neurology, Mayo Clinic, Rochester, Minnesota
    • 2Division of Rheumatology, Mayo Clinic, Rochester, Minnesota
    • 3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
    JAMA Neurol. Published online May 18, 2020. doi:10.1001/jamaneurol.2020.1162
    Key Points

    Question  Is exposure to tumor necrosis factor inhibitors associated with risk of inflammatory demyelinating and nondemyelinating central nervous system events in patients with an autoimmune disease?

    Findings  In this case-control study of 212 patients with or without inflammatory CNS events, exposure to tumor necrosis factor inhibitors was associated with an increased risk of inflammatory central nervous system events. The association was similar for both inflammatory demyelinating and nondemyelinating central nervous system events.

    Meaning  The association observed between exposure to tumor necrosis factor inhibitor and increased risk of inflammatory demyelinating and nondemyelinating central nervous system events warrants future research to ascertain whether the association may indicate de novo inflammation or exacerbation of already aberrant inflammatory pathways.


    Importance  Tumor necrosis factor (TNF) inhibitors are common therapies for certain autoimmune diseases, such as rheumatoid arthritis. An association between TNF inhibitor exposure and inflammatory central nervous system (CNS) events has been postulated but is poorly understood.

    Objective  To evaluate whether TNF inhibitor exposure is associated with inflammatory demyelinating and nondemyelinating CNS events in patients with an indication for TNF inhibitor use and to describe the spectrum of those CNS events.

    Design, Setting, and Participants  A nested case-control study was conducted using the medical records of patients with autoimmune diseases treated at 3 Mayo Clinic locations (Rochester, Minnesota; Scottsdale, Arizona; and Jacksonville, Florida) between January 1, 2003, and February 20, 2019. Patients were included if their records reported International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnostic codes for US Food and Drug Administration–approved autoimmune disease indication for TNF inhibitor use (ie, rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, Crohn disease, and ulcerative colitis) and diagnostic codes for inflammatory CNS events of interest. Patients were matched 1:1 with control participants by year of birth, type of autoimmune disease, and sex.

    Exposures  TNF inhibitor exposure data were derived from the medical records along with type of TNF inhibitor, cumulative duration of exposure, and time of exposure.

    Main Outcomes and Measures  The main outcome was either inflammatory demyelinating (multiple sclerosis and other diseases such as optic neuritis) or nondemyelinating (meningitis, meningoencephalitis, encephalitis, neurosarcoidosis, and CNS vasculitis) CNS event. Association with TNF inhibitor was evaluated with conditional logistic regression and adjusted for disease duration to determine the odds ratios (ORs) and 95% CIs. Secondary analyses included stratification of outcome by inflammatory demyelinating and nondemyelinating CNS events and by autoimmune disease (rheumatoid arthritis and non–rheumatoid arthritis).

    Results  A total of 212 individuals were included: 106 patients with inflammatory CNS events and 106 control participants without such events. Of this total, 136 were female (64%); the median (interquartile range) age at disease onset for patients was 52 (43-62) years. Exposure to TNF inhibitors occurred in 64 patients (60%) and 42 control participants (40%) and was associated with an increased risk of any inflammatory CNS event (adjusted OR, 3.01; 95% CI, 1.55-5.82; P = .001). These results were similar when the outcome was stratified by demyelinating and nondemyelinating CNS events. Secondary analyses found the association was predominantly observed in patients with rheumatoid arthritis (adjusted OR, 4.82; 95% CI, 1.62-14.36; P = .005).

    Conclusions and Relevance  This study found that exposure to TNF inhibitors in patients with autoimmune diseases appeared to be associated with increased risk for inflammatory CNS events. Whether this association represents de novo or exacerbated inflammatory pathways requires further research.