Inflammatory demyelinating CNS events seen with TNF inhibitors

Multiple sclerosis

By Michael Woodhead

20 May 2020

TNF inhibitor exposure in patients with autoimmune diseases such as RA appears to be associated with an increased risk of inflammatory demyelinating CNS events such as optic neuritis, a new study has shown.

The US nested case control study also found that TNF inhibitors were associated with non-demyelinating CNS events such as meningitis and meningoencephalitis.

However the study authors cautioned that the events were uncommon and the association did not necessarily represent causality.

Published in JAMA Neurology, the study conducted at three Mayo Clinic sites in the US compared TNFi exposures in 106 patients with inflammatory CNS events and 106 control participants without such events.

Exposure to TNF inhibitors occurred in 60% of CNS inflammatory event patients and 40% of control participants and was associated with a three-fold increased risk of any inflammatory CNS event (adjusted Odds Ratio 3.01).

The associations were similar for both demyelinating CNS events such as MS, and non-demyelinating CNS events such as neurosarcoidosis.

Of the individuals who had inflammatory demyelinating CNS events, 33 of 48 patients (69%) and 6 of 8 patients with optic neuritis (75%) were exposed to TNF inhibitors

Of those who had inflammatory non-demyelinating CNS events, exposure to TNF inhibitors occurred in 7 of 8 patients with neurosarcoidosis (88%), 3 of 4 patients with meningoencephalitis (75%), 9 of 15 patients with lepto-pachymeningitis (60%), 3 of 7 patients with encephalitis (43%), and 3 of 8 patients with aseptic meningitis (38%)

Secondary analyses found the association was predominantly observed in patients with rheumatoid arthritis, in whom the adjusted Odds Ratio was 4.82.

Most patients with inflammatory CNS disorders (90%) were exposed to a TNF inhibitor within the previous 12 months.

The researchers said their findings conformed observations about CNS inflammatory events  in case studies of patients exposed to TNF inhibitors, but they stressed that they were unable to ascertain whether this association indicates de novo inflammation.

They hypothesised that TNF inhibitors may further dysregulate already aberrant immune responses, triggering inflammatory CNS events in patients with certain autoimmune diseases.

“Proposed mechanisms for the paradoxical development of inflammatory CNS events in association with TNF inhibitor exposure include immune dysregulation from the inhibition of apoptosis of autoreactive T cells, which may then enter the CNS and cause demyelination,” they wrote.

TNF inhibition may result in upregulation of TNF expression, and because TNF inhibitors cannot cross the blood brain barrier, a paradoxical increase in TNF within the CNS may occur, they said.

In an editorial comment, other neurologists said the risk of an uncommon CNS event had to be weighed against the substantial benefits of TNF inhibitor therapy in autoimmune diseases.

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

“In patients with possible MS or other inflammatory demyelinating diseases such as myelitis or optic neuritis, neurological consultation can help to clarify diagnoses and can provide advice about risks of TNF inhibitor treatment or strategies for close monitoring. 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.”

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