Amyotrophic Lateral Sclerosis as an Adverse Drug Reaction: A Disproportionality Analysis of the Food and Drug Administration Adverse Event Reporting System

Anna Gaimari, Michele Fusaroli, Emanuel Raschi, Elisa Baldin, Luca Vignatelli, Francesco Nonino, Fabrizio Ponti, Jessica Mandrioli () and Elisabetta Poluzzi
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Anna Gaimari: University of Bologna
Michele Fusaroli: University of Bologna
Emanuel Raschi: University of Bologna
Elisa Baldin: IRCCS Istituto delle Scienze Neurologiche di Bologna, Epidemiology and Statistics Unit
Luca Vignatelli: IRCCS Istituto delle Scienze Neurologiche di Bologna, Epidemiology and Statistics Unit
Francesco Nonino: IRCCS Istituto delle Scienze Neurologiche di Bologna, Epidemiology and Statistics Unit
Fabrizio Ponti: University of Bologna
Jessica Mandrioli: Neurology Unit, Azienda Ospedaliero-Universitaria di Modena
Elisabetta Poluzzi: University of Bologna

Drug Safety, 2022, vol. 45, issue 6, No 6, 663-673

Abstract: Abstract Introduction Amyotrophic lateral sclerosis is a fatal progressive disease with a still unclear multi-factorial etiology. This study focused on the potential relationship between drug exposure and the development of amyotrophic lateral sclerosis by performing a detailed analysis of events reported in the FDA Adverse Event Reporting System database. Methods The FDA Adverse Event Reporting System quarterly data (January 2004–June 2020) were downloaded and deduplicated. The reporting odds ratios and their 95% confidence intervals were calculated as a disproportionality measure. The robustness of the disproportion was assessed accounting for major confounders (i.e., using a broader query, restricting to suspect drugs, and excluding reports with amyotrophic lateral sclerosis as an indication). Disproportionality signals were prioritized based on their consistency across analyses (reporting odds ratio stability). Results We retained 1188 amyotrophic lateral sclerosis cases. Sixty-two drugs showed significant disproportionality for amyotrophic lateral sclerosis onset in at least one analysis, and 31 had consistent reporting odds ratio stability, including tumor necrosis factor-alpha inhibitors and statins. Disproportionality signals from ustekinumab, an immunomodulator against interleukins 12–23 used in autoimmune diseases, and the anti-IgE omalizumab were consistent among analyses and unexpected. Conclusions For each drug emerging as possibly associated with amyotrophic lateral sclerosis onset, biological plausibility, underlying disease, and reverse causality could be argued. Our findings strengthened the plausibility of a precipitating role of drugs primarily through immunomodulation (e.g., tumor necrosis factor-alpha, ustekinumab, and omalizumab), but also by impacting metabolism and the musculoskeletal integrity (e.g., statins and bisphosphonates). Complement and NF-kB dysregulation could represent interesting topics for planning translational mechanistic studies on amyotrophic lateral sclerosis as an adverse drug effect. Graphical abstract

Date: 2022
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DOI: 10.1007/s40264-022-01184-1

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