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Drug-Induced Raynaud's Phenomenon and Underlying Mechanism: A Disproportionality Analysis From the World Health
Alex Hlavaty1,2, Loubna Dari3,4, Jean-Luc Cracowski1,2
1Pharmacovigilance Unit, Grenoble Alpes University Hospital, University Grenoble Alpes, F-38000, Grenoble, France.
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 pathophysiologic mechanisms through a mixed disproportionality/clustering analysis from the World Health Organization (WHO) pharmacovigilance database.
Methods:
Using the WHO pharmacovigilance database, we identified cases using the Medical Dictionary for Regulatory Activities 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 (ICLB >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 pathophysiologic 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 RP 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 receptors, sodium-dependent noradrenaline transporters, 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 calcitonin gene-related peptide inhibitors) for drugs associated with RP and potential implicated pathophysiologic mechanisms.
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