TNFalpha inhibitors and amyotrophic lateral sclerosis: a risk factor ?

Abstract

Introduction: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neurone disease leading to amyotrophy and paralysis, with a median survival of 3 years after diagnosis. ALS is multifactorial, involving both genetic and environmental risk factors. TNFalpha inhibitors (TNFi) (infliximab, etanercept, adalimumab, certolizumab, golimumab and biosimilars) 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 [1,2]. Material(s) and Method(s): All cases of drug-induced ALS registered in the French Pharmacovigilance Database between 1/01/1999 and 17/07/2017 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), considering non-cases either as all other adverse reactions or as all other neurological adverse reactions. Result(s): A total of 35 cases were collected among which 5 were currently exposed to TNFi and one to tocilizumab preceded by 7 years of TNFi exposure. 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 methotrexate 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 TNFi (or tocilizumab in one case) was withdrawn and riluzole was introduced in all patients.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] vs. all adverse reactions and ROR = 18.3; 95% [7.6-44.2] vs. all other neurological adverse reactions. Discussion/Conclusion: To our knowledge, this is the first case series of druginduced 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.