Drugs induced Raynaud's phenomenon and underlying mechanism: a disproportionality analysis from the WHO pharmacovigilance database

Objectives The aim of this study is to generate hypotheses about unknown drugs associated with the onset or worsening of Raynaud's Phenomenon (RP) and to explore their potential pathophysiological mechanisms through a mixed disproportionality/clustering analysis from the WHO pharmacovigilance database. Methods Using the WHO Pharmacovigilance database, we identified cases using the Preferred Term “Raynaud's phenomenon” and we excluded all Individual Case Safety Reports (ICSRs) associated with at least one drug used in RP treatment. To estimate signals of disproportionate reporting (SDR) we calculated Information Component (IC) values (IC LB >0 deemed significant). We performed several sensitivity analyses to assess the robustness of the results. We evaluated and prioritized the plausibility of signals according to expert review of cases characteristics, robustness of results, and pharmacological hypotheses. Lastly, to explore pathophysiological mechanisms, we used drug target extraction from DrugBank and a clustering method to identify similar patterns of adverse events reporting. Results We included 4,430 ICSRs of Raynaud's phenomenon in our analysis. We found 124 significant SDRs in the primary analysis, of which 52 SDRs were consistent across all sensitivity analyses, and 16 were considered probable after signal evaluation and prioritization; including amphetamine‐like, antimigraine drugs, antineoplastics drugs and dopaminergic agonists. Most of the targets involved were 5‐HT1A‐R, sodium‐dependent noradrenaline transporter, and beta‐1 and beta‐2 adrenergic receptors. Cluster analyses yielded inconsistent results according to the method used. Conclusion This study allowed us to identify robust safety signals (such as solriamfetol, tyrosine kinase inhibitors and CGRP inhibitors) for drugs associated with RP and potential implicated pathophysiological mechanisms.