TNFαi-Associated CNS Demyelination Persists After Treatment Discontinuation

Spencer K. Hutto, MD

Data from a retrospective analysis cohort of individuals with neurologic dysfunction suggest that central nervous system (CNS) demyelination persists in prolonged follow-up despite tumor necrosis factor alpha inhibitor (TNFαi) treatment discontinuation.

The study’s findings were presented virtually at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2021, February 25-27, by Spencer K. Hutto, MD, clinical fellow, Advanced General and Autoimmune Neurology, Massachusetts General Hospital, and colleagues.

“TNFαi have a recognized association with [CNS] demyelination since the lenercept trial for the treatment of multiple sclerosis (MS). It remains unclear if the relationship is causal or related to unmasking of an underlying risk,” Hutto and coauthors wrote.

The group analyzed data from 21 patients evaluated for neurologic dysfunction during TNFαi use from the Mass General Brigham Research Patient Data registry from January 1998 to August 2020. Patients with a previous CNS inflammatory disorder were not included. 

The patients included had a mean age of 44 years (range, 16-68) at first demyelinating event. Most patients were women (n = 20; 95%), 90% (n = 19) were White, 5% (n = 1) were Black, and 5% (n = 1) Hispanic/Latinx. The patients had a median rheumatologic illness duration of 102 months and a mean TNFαi use of 11 months. TNFαis used were adalimumab (n = 10; 48%), etanercept (n = 6; 28%), and infliximab (n = 5; 24%). 

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Over half of the patients (n = 12; 57%) had new disease activity over time. Clinical relapse was experienced by 48% (n = 10), with a median of 41 months to first relapse (range, 12-80). Magnetic resonance imaging (MRI) lesion accrual was experienced by 47% (n = 10), with a median of 28 months to new lesion or lesions (range, 3-139).

TNFαi were discontinued at the onset of demyelinating events in 86% (n = 18) of patients, and 69% (n = 14) were treated acutely with steroids. Ultimately, 42% (n = 9) of patients used MS disease modifying therapies (DMTs). Hutto and colleagues found that participants in the study had risk factors for MS including obesity (n = 3; 16%), tobacco use (n = 11; 52%), vitamin D deficiency (n = 11; 50%), and family history of autoimmunity (systemic, n = 15; 71%; CNS demyelination, n = 4; 17%).

Hutto and colleagues also found that retrospectively, 19% (n = 4) of patients had remote transient neurologic dysfunction, and 10% (n = 2) had prior MRI scans consistent with radiologically isolated syndrome. MRI surveillance was continued for a median of 26 months (range, 0-147), with 52% (n = 11) of patients surveilled for over 2 years. Average follow-up duration was 28 months (range, 0-71).

Cerebrospinal fluid (CSF) pleocytosis was present in 22% (n = 5), elevated protein in 33% (n = 7), and oligoclonal bands in 43% (n = 9). The authors found that tests for antibodies against myelin oligodendrocyte glycoprotein in 1% (n = 2) of patients and against aquaporin in 38% (n = 8) of patients were all negative. 

All told, 22% (n = 5) of patients made a complete recovery, while 67% (n = 14) made a partial recovery, 5% (n = 1) had no recovery, and 5% (n = 1) experienced disease progression. One death (5%) occurred, unrelated to demyelination. The median modified Rankin score (mRS) at last follow-up was 1 (range, 0-6), with 79% (n = 17) of patients achieving an mRS score less than 2. Ultimately, 50% (n = 11) of patients were diagnosed with MS, 40% (n = 8) with TNFαi-induced demyelination, and 10% (n = 2) with "possibly either” diagnosis. Revised 2017 McDonald criteria were met by 65% (n = 14) of patients at onset and by 75% (n = 16) by last follow-up. 

Hutto and colleagues analyzed subgroups and found that 75% (n = 16) of patients that re-challenged or continued on TNFαi relapsed. Of those starting a DMT after the index event, 50% (n = 11) had evidence of continued disease activity, with 33% (n = 7) experiencing clinical relapses, and 50% (n = 11) having MRI accrual. Over half (n = 12; 56%) of patients off medications from onset, either by discontinuing TNFαi or not starting DMTs, had subsequent evidence of continued disease activity, with 44% (n = 9) experienced relapses and 44% (n = 9) having MRI lesions.

“In patients with CNS demyelination while on TNFαi, continued evidence of disease activity was common despite TNFαi discontinuation over a period of prolonged follow-up,” Hutto and colleagues concluded.

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REFERENCE

Hutto SK, Rice DR, Mateen FJ. Long-term outcomes of CNS demyelination associated with exposure to TNFaInhibitors: A Retrospective cohort analysis. Presented at ACTRIMS Annual Forum; February 25-27, 2021. Abstract P165