PPMS onset upon adalimumab treatment extends the spectrum of anti-TNF-α therapy-associated demyelinating disorders

Abstract

Since their introduction in 1999, anti-tumour necrosis factor-α (anti-TNF-α) therapies have been suspected repeatedly to be associated with the occurrence of central nervous system (CNS) demyelinating disorders, including multiple sclerosis (MS). However, recent publications were restricted to descriptions of monophasic demyelinating events or cases of relapsing–remitting MS (RRMS). We here provide the first case report of primary progressive MS (PPMS) onset upon anti-TNF-α therapy as well as a literature review of previously published cases of anti-TNF-α therapy-associated MS onset. The 51-year old male patient was treated with adalimumab due to psoriasis arthritis. About 18 months after treatment initiation, he developed slowly progressing neurological deficits including gait impairment, paraesthesia of the lower limbs, strangury and visual impairment, which led to the discontinuation of adalimumab therapy. Magnetic resonance imaging of the brain and the spinal cord revealed multiple inflammatory lesions and cerebrospinal fluid examination showed slight pleocytosis and positive oligoclonal bands. Thus, PPMS was diagnosed according to the 2017 revision of the McDonald criteria. As PPMS often causes only subtle symptoms in the beginning and early treatment discontinuation of anti-TNF-α therapy seems essential to improve the patient’s outcome, we think that it is important to increase the awareness of slowly progressing neurological deficits as a potential adverse event of anti-TNF-α therapy among all clinicians involved in the initiation and monitoring of these drugs. In addition, the occurrence of both RRMS and progressive MS upon anti-TNF-α therapy might suggest a shared TNF-α-mediated pathophysiological mechanism in the evolution of all MS subtypes.

Re-Examining the Role of TNF in MS Pathogenesis and Therapy

“…Based on current knowledge of TNF biology, a possible explanation for these results, which at that time were quite unexpected, could be linked to the pleiotropic actions of TNF, including both pro- and anti-inflammatory functions as well as the almost ubiquitous expression and action of such cytokine. Moreover, the relationship between nonselective TNF inhibitors and MS is further supported by several cases of MS onset observed in patients with other diseases [ 192 , 193 ]. Patients with rheumatoid arthritis treated with either etanercept or infliximab showed new-onset neurologic signs and symptoms, associated with demyelinating lesions of the CNS [ 194 ] or symptoms fulfilling the criteria for clinically definite RRMS [ 195 ].…”

“…Patients with rheumatoid arthritis treated with either etanercept or infliximab showed new-onset neurologic signs and symptoms, associated with demyelinating lesions of the CNS [ 194 ] or symptoms fulfilling the criteria for clinically definite RRMS [ 195 ]. More recently, a case report showed a 51-year old male patient treated for a psoriasis arthritis with an anti-TNF agent, adalimumab, developed slowly progressing neurological deficits about 18 months after treatment initiation [ 192 ]. Overall these studies suggested that nonselective inhibition of TNF is harmful both in MS and in other inflammatory disease, but at the same time highlight the relevance of TNF in the pathophysiology of MS. Current guidelines suggest to avoid the use of anti-TNF drugs in individuals with a history of MS or demyelinating disease and patients with inflammatory disease should be carefully monitored with frequent MRI regardless of their clinical status in order to prevent the occurrence of MS.…”

Improved Glucocorticoid Receptor Ligands: Fantastic Beasts, but How to Find Them?

“…For one, anti-TNF therapy has been associated with a 250% increase in the occurrence of tuberculosis (46). Furthermore, these therapies have been reported to trigger multiple sclerosis (MS) and other demyelinating conditions (47)(48)(49)(50). This is in line with the reported disease worsening in patients with pre-existing MS in clinical trials for Lenercept and cA2, two types of anti-TNF therapy (51,52).…”

Primary Progressive Multiple Sclerosis Under Anti-TNFα Treatment: A Case Report

“…4 Until now, about 20 MS case reports have been related to anti-TNFa treatment and Engel et al described the first case of PPMS under adalimumab treatment. 10 Actually, several hypotheses have been proposed to explain a potential biological relationship between TNFα blockers and demyelinating disease. TNFα blockers can exacerbate CNS demyelination by decreasing TNFR2 receptors, which are necessary for the proliferation of immature oligodendrocytes and myelin repair.…”

“… 15 On the other hand, growing clinical reported evidence, and recently, a link between the development of MS and the presence of the single nucleotide polymorphism (SNP), suggest an etiological role of anti-TNF drugs in. 10 …”