TNFalpha inhibitors and amyotrophic lateral sclerosis: a risk factor ?

[Speaker] Antoine Coquerel:1
[Co-author] Nadine Petitpain:2, David Devos:3, Haleh Bagheri:4, Fanny Rocher:5, Kamel Masmoudi:6
1:Regional Pharmacovigilance Center of Caen, UMR University of Caen Normandie, Inserm U1075, France, 2:Clinical Pharmacology, Toxicology, University Hospital of Nancy, Regional Pharmacovigilance Center, France, 3:Department of Medical Pharmacology and Department of Neurology, ALS center Lille University, INSERM UMRS_1171, University Hospital Center, LICEND COEN Center, Lille, France, 4:Department of clinical and medical pharmacology, Midi-Pyrenees Pharmacovigilance and pharmacoepidemiology center, INSERM, UMR 1027, University hospital of Toulouse, France, 5:Regional Pharmacovigilance center of Nice, University hospital of Nice, France, 6:Regional Pharmacovigilance center of Amiens, University hospital of Amiens, France

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neurone disease, with a median survival of 3 years after diagnosis. ALS is multifactorial, involving both genetic and environmental risk factors. TNFalpha inhibitors (TNFi) drugs (infliximab, etanercept, adalimumab, certolizumab and golimumab) are currently largely prescribed in chronic inflammatory rheumatic diseases, psoriasis and inflammatory bowel diseases. TNFi-induced neurological adverse reactions (AR) are mainly demyelinating neuropathies. Very rare cases of ALS have been reported.
All cases of drug-induced ALS registered in the French Pharmacovigilance Database (FPvD) between 1/01/1999 and 31/07/2017 were reviewed by 3 neurologists to perform i) a descriptive analysis of cases with TNFi exposure and ii) disproportionality analysis by case/non-case method with the calculation of Reporting Odd Ratio (ROR), non-cases being all other adverse reactions, or all other neurological adverse reactions.
Among the 35 reviewed cases, 5 had current TNFi exposure and 1 had tocilizumab exposure preceded by 7 years of TNFi. Patients were 4 females and 2 males, aged from 43 to 75 years old, mainly treated for inflammatory rheumatism (n=5). ALS had a bulbar onset in 2 patients and limb onset in 4, without familial history. Cumulated TNFi exposure before the diagnosis ranged from 7 to 96 months. Concomitant or previous MTX exposure was present in 5 patients. The median onset delay of first symptoms of ALS was 75 months [min: 12; max: 108]. TNFi (or tocilizumab in one case) was withdrawn and riluzole was introduced in all patients. According to last data, 3 patients died within 12 to 20 months after ALS diagnosis.
The disproportionality analysis found a significant association with TNFi exposure, whatever the choice of non-cases: ROR = 11.9; 95% [4.9-28.8] versus all adverse reactions and ROR = 18.3; 95% [7.6-44.2] versus all other neurological adverse reactions.
To our knowledge, this is the first case series of drug-induced ALS suggesting the role of TNFi, monoclonal antibodies or soluble receptors, as a potential risk factor of this rare disease. Further analyses at larger scales are warranted, including ALS incidence in patients with chronic inflammatory disease and preclinical mechanistic analysis.

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