Anna Gaimari1, Michele Fusaroli1, Emanuel Raschi1, Elisa Baldin2, Luca Vignatelli2, Francesco Nonino2, Fabrizio De Ponti1, Jessica Mandrioli3,4, Elisabetta Poluzzi1. 1. Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy. 2. IRCCS Istituto delle Scienze Neurologiche di Bologna, Epidemiology and Statistics Unit, Bologna, Italy. 3. Neurology Unit, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy. jessica.mandrioli@unimore.it. 4. Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy. jessica.mandrioli@unimore.it.
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.
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.
Authors: J Sun; Y Zhan; D Mariosa; H Larsson; C Almqvist; C Ingre; U Zagai; Y Pawitan; F Fang Journal: Eur J Neurol Date: 2019-06-07 Impact factor: 6.089