TNF Inhibitors Linked to Inflammatory
CNS Events

Deborah Brauser

August 21, 2020

Use of tumor necrosis factor (TNF) inhibitors in patients with autoimmune diseases may increase risk for inflammatory central nervous system (CNS) outcomes, new research suggests

The nested case-control study included more than 200 participants with diseases such as rheumatoid arthritis, psoriasis, and Crohn's disease. Results showed that exposure to TNF inhibitors was significantly associated with increased risk for demyelinating CNS events, such as multiple sclerosis, and non-demyelinating events, such as meningitis and encephalitis.

Interestingly, disease-specific secondary analyses showed that the strongest association for inflammatory events was in patients with rheumatoid arthritis.

Lead author Amy Kunchok, MD, autoimmune, neurology, and MS fellow at Mayo Clinic, Rochester, Minnesota, noted that "these are highly effective therapies for patients" and that these CNS events are likely uncommon.

Dr Amy Kunchok

"Our study has observed an association, but this does not imply causality. Therefore, we are not cautioning against using these therapies in appropriate patients," Kunchok told Medscape Medical News.

"Rather, we recommend that clinicians assessing patients with both inflammatory demyelinating and non-demyelinating CNS events consider a detailed evaluation of the medication history, particularly in patients with coexistent autoimmune diseases who may have a current or past history of biological therapies," she said.

The findings were published in the August issue of JAMA Neurology.

Poorly Understood

TNF inhibitors "are common therapies for certain autoimmune diseases," the investigators note.

Previously, a link between exposure to these inhibitors and inflammatory CNS events "has been postulated but is poorly understood," they write.

In the current study, they examined records for 106 patients who were treated at Mayo clinics in Minnesota, Arizona, or Florida from January 2003 through February 2019.

All participants had been diagnosed with an autoimmune disease that the US Food and Drug Administration (FDA) has listed as an indication for TNF inhibitor use. This included rheumatoid arthritis (n = 48), ankylosing spondylitis (n = 4), psoriasis and psoriatic arthritis (n = 21), Crohn's disease (n = 27), and ulcerative colitis (n = 6).

Their records also showed diagnostic codes for the inflammatory demyelinating CNS events of relapsing-remitting or primary progressive MS, clinically isolated syndrome, radiologically isolated syndrome, neuromyelitis optica spectrum disorder, and transverse myelitis; or for the inflammatory non-demyelinating CNS events of meningitis, meningoencephalitis, encephalitis, neurosarcoidosis, and CNS vasculitis.  

The investigators also included 106 age-, sex-, and autoimmune disease-matched participants 1:1 to act as the control group.

In the total study population, 64% were women and the median age at disease onset was 52 years. In addition, 60% of the patient group and 40% of the control group were exposed to TNF inhibitors.

Novel Finding?

Results showed that TNF inhibitor exposure was significantly linked to increased risk for developing any inflammatory CNS event (adjusted odds ratio [aOR], 3.01; 95% CI, 1.55 – 5.82; P = .001).

When the outcomes were stratified by class of inflammatory event, these results were similar. The aOR was 3.09 (95% CI, 1.19 – 8.04; P = .02) for inflammatory demyelinating CNS events and was 2.97 (95% CI, 1.15 – 7.65; P = .02) for inflammatory nondemyelinating events.

Kunchok noted that the association between the inhibitors and non-demyelinating events was "a novel finding from this study."

In secondary analyses, patients with rheumatoid arthritis and exposure to TNF inhibitors had the strongest association with any inflammatory CNS event (aOR, 4.82; 95% CI, 1.62 – 14.36; P = .005).

A pooled cohort comprising only the participants with the other autoimmune diseases did not show a significant association between exposure to TNF inhibitors and development of CNS events (P = .09).

"Because of the lack of power, further stratification by individual autoimmune diseases was not analyzed," the investigators report.

Although the overall findings showed that exposure to TNF inhibitors was linked to increased risk for inflammatory events, whether this association "represents de novo or exacerbated inflammatory pathways requires further research," the authors write.

Kunchok added that more research, especially population-based studies, is also needed to examine the incidence of these inflammatory CNS events in patients exposed to TNF alpha inhibitors.

Adds to the Literature

In an accompanying editorial, Jeffrey M. Gelfand, MD, Department of Neurology at the University of California, San Francisco, and Jinoos Yazdany, MD, Zuckerberg San Francisco General Hospital at UCSF, note that although the study adds to the literature, the magnitude of the risk found "remains unclear."

"Randomized clinical trials are not suited to the study of rare adverse events," Gelfand and Yazdany write. They agree with Kunchok that "next steps should include population-based observational studies that control for disease severity."

Still, the current study provides additional evidence of rare adverse events in patients receiving TNF inhibitors, they note. So how should prescribers proceed?

"As with all treatments, the risk–benefit ratio for the individual patient's situation must be weighed and appropriate counseling must be given to facilitate shared decision-making discussions," write the editorialists.

"Given what is known about the risk of harm, avoiding TNF inhibitors is advisable in patients with known MS," they write.

In addition, neurologic consultation can be helpful for clarifying diagnoses and providing advice on monitoring strategies for TNF inhibitor treatment in those with possible MS or other demyelinating conditions, note the editorialists.

"In patients who develop new concerning neurological symptoms while receiving TNF inhibitor treatment, timely evaluation is indicated, including consideration of neuroinflammatory, infectious, and neurological diagnoses that may be unrelated to treatment," they add.

"Broader awareness of risks that studies such as this one by Kunchok et al provide can…encourage timelier recognition of potential TNF inhibitor-associated neuroinflammatory events and may improve outcomes for patients," Gelfand and Yazdany conclude.

The study was funded by a grant from the National Center for Advancing Translational Sciences. Kunchok reports having received research funding from Biogen outside this study. A full list of disclosures for the other study authors is in the original article. Gelfand reports having received g rants for a clinical trial from Genentech and consulting fees from Biogen, Alexion, Theranica, Impel Neuropharma, Advanced Clinical, Biohaven, and Satsuma. Yazdany reports having received grants from Pfizer and consulting fees from AstraZeneca and Eli Lilly outside the submitted work.

JAMA Neurol. Published August 2020 issue. Full text, Editorial

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