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

Educational Objective
To assess whether exposure to tumor necrosis factor inhibitors is associated with risk of inflammatory central nervous system events in patients with an autoimmune disease.
1 Credit CME
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.

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Article Information

Accepted for Publication: February 4, 2020.

Published Online: May 18, 2020. doi:10.1001/jamaneurol.2020.1162

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Kunchok A et al. JAMA Neurology.

Corresponding Author: Andrew McKeon, MD, Department of Neurology, Mayo Clinic, 200 1st St, Rochester, MN 55905 (mckeon.andrew@mayo.edu).

Author Contributions: Drs Kunchok and McKeon had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kunchok, McKeon.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Kunchok.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Kunchok.

Supervision: Aksamit, McKeon.

Other: Kantarci.

Conflict of Interest Disclosures: Dr Kunchok reported receiving research funding from Biogen outside the submitted work. Dr Kantarci reported receiving grants from Biogen outside the submitted work. Dr Davis reported receiving grants from Pfizer and Genentech as well as serving on advisory boards for both Abbvie and Sanofi-Genzyme. Dr Pittock reported receiving grants and personal fees from Alexion and Viela Bio, personal fees from Union Chimique Belge and Astellas, and grants from Griffols and Autoimmune Encephalitis Alliance outside the submitted work. Dr Weinshenker reported receiving personal fees from Viela Bio, Alexion, Chugai/Roche, Mitsubishi Tanabe, Novartis, Caladrius, Brainstorm Therapeutics, and Roivant outside the submitted work, as well as holding a patent to NMO-IgG for diagnosis of neuromyelitis optica that has been issued and licensed and with paid royalties. Dr McKeon reported receiving grants from Euroimmun and Medimmune outside the submitted work; being a member of the editorial board of Neurology: Neuroimmunology and Neuroinflammation; holding pending patent applications for Septin 5, GFAP, PDE10A, Kelch-11, and MAP1B IgGs as markers of neurological autoimmunity and paraneoplastic disorders; and receiving research support from Euroimmun, Grifols, and Alexion. No other disclosures were reported.

Funding/Support: This study was funded by grant UL1 TR002377 from the National Center for Advancing Translational Sciences.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentation: The results of this study were presented at the 71st annual meeting of the American Academy of Neurology; May 5, 2019, Philadelphia, Pennsylvania.

Disclaimer: The views expressed herein are those of the authors and do not necessarily represent the official policy or position of the National Institutes of Health.

Additional Contributions: Staff at the Mayo Clinic Center for Clinical and Translational Science and Terence Therneau, PhD, at the Mayo Clinic Department of Biostatistics, provided statistical advice. These individuals received no additional compensation, outside of their usual salary, for their contributions.

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Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

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