Drug-induced skin ulcers: A disproportionality analysis from the WHO pharmacovigilance database

To the Editor: Skin ulcerations have occasionally been reported as adverse drug reactions.1D'Epiro S. Salvi M. Luzi A. et al.Drug cutaneous side effect: focus on skin ulceration.Clin Ter. 2014; 165: e323-329PubMed Google Scholar However, to our knowledge, no pharmacovigilance study has performed, and little is known about drug-related ulcers.We therefore performed combined disproportionality analyses using data from VigiBase, World Health Organization's database, biomedical literature through MEDLINE, identify pharmacologic classes suspected of inducing ulcers.2Bate Lindquist Edwards I.R. al.A Bayesian neural network method for reaction signal generation.Eur J Clin Pharmacol. 1998; 54: 315-321Crossref PubMed Scopus (665) Scholar,3Xu R. Wang Q. Large-scale combining signals both FDA Adverse Event Reporting System (FAERS) improve post-marketing safety detection.BMC Bioinformatics. 15: 17Crossref (60) Then, all were independently reviewed by a committee experts in pharmacology dermatology, selected according their clinical relevance, strength evidence, previous knowledge possible associations (Supplemental methods available via Mendeley at 10.17632/sgnzg8k9tt.1).4European Medicines Agency (EMA). Guideline good practices (GVP) - Module IX – Signal management (Rev 1). Accessed April 26, 2021. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-gvp-module-ix-signal-management-rev-1_en.pdfGoogle ScholarFrom 21,421,352 cases extraction (March 3, 2020), we identified 19,887 reports “skin ulcer,” 4440 “decubitus 596 “diabetic 103 “varicose ulceration,” 79 “ischemic ulcer.” Sixty-one drugs displayed ulcer” least 1 other specific ulcer term Fig Among 814 records chemically induced ulcers after screening titles abstracts, 241 regarding 59 selected, among which 10 had signal.Among 61 validation, 22 excluded obvious indication or protopathic bias, substances Table I). retrieval references databases, Food Drug Administration European labels, alerts, 21 considered “already known” plausibility remaining 19 was assessed discussion during expert meetings based analyses, potential mechanisms Tables II III). Finally, 13 having ulcer: 3 protein kinase inhibitors (afatinib, ibrutinib, tofacitinib), 2 immunomodulators (thalidomide lenalidomide), interferons (alfa beta), bisphosphonate (alendronic acid), leflunomide, rofecoxib, mitomycin, ocrelizumab, digoxin (Table I Supplemental IV).Table IResults analysesDrug classesDrugsSDR WHO databaseSDR MEDLINEKnown associationsProtein inhibitorsSorafenib2.19Ulceration∗Food summary product characteristics.Sunitinib1.99Cracking skin∗Food characteristics.Afatinib†New signals.1.02Erlotinib2.12Skin fissure∗Food characteristics.Ibrutinib†New signals.2.10Cabozantinib4.63Skin ulcer‡EMA characteristics.Lenvatinib2.56Impaired wound healing§Micromedex database.Pazopanib1.10Skin ulcer∗Food characteristics.Tofacitinib†New signals.0.51Regorafenib0.97Impaired database.Ponatinib0.77Skin painmTOR inhibitorsEverolimus1.15Impaired database.Sirolimus1.66Impairment healing∗Food characteristics.AntimetabolitesMethotrexate1.521.84Skin characteristics.Hydroxycarbamide5.855.95Leg characteristics.Teriflunomide†New signals.0.02Calcineurin inhibitorTacrolimus0.16Skin characteristics.ImmunomodulatorsLenalidomide†New signals.0.19Thalidomide†New signals.0.15Antitumor antibioticMitomycin†New signals.2.520.39CD-20 antibodyOcrelizumab†New signals.0.12BisphosphonatesAlendronic acid†New signals.1.49VEGF inhibitorsBevacizumab1.33Wound healing complications∗Food characteristics.TNF-α inhibitorsAdalimumab0.65Signal ulcerPharmacovigilance Risk Assessment Committee (PRAC) assessment.Etanercept1.11Leg characteristics.InterferonsInterferon beta†New signals.0.141.59Interferon alfa†New signals.0.990.81Cardiac glycosidesDigoxin†New signals.0.77Nonopioid analgesicZiconotide0.06Skin characteristics.COX-2 inhibitorsRofecoxib†New signals.0.96GlucocorticoidsPrednisone1.38Impairs characteristics.SGLT-2 inhibitorsCanagliflozin4.41Ulcers lower limbs∗Food characteristics.Potassium-channel activatorsNicorandil5.024.85Skin ulceration∗Food characteristics.Opiate analgesicsPentazocine1.133.75Ulceration characteristics.The boundary Information Component (IC025) Organization database MEDLINE (if significant) provided each drug. Warnings ulcers, retrieved EMA, characteristics, are indicated.COX, Cyclooxygenase; SDR, disproportionate reporting; SGLT, sodium-glucose cotransporter; TNF, tumor necrosis factor; VEGF, vascular endothelial growth WHO, Organization.∗ characteristics.† New signals.‡ EMA characteristics.§ Micromedex database.|| Pharmacovigilance assessment. Open table new tab Four main proposed being implicated pathogenesis iatrogenic ulcers: angiogenesis inhibition, direct toxicity, decreased perfusion vasoconstriction, increased blood viscosity.1D'Epiro Except did not find any hypothesis, could be related these (Fig V).This limitations. First, selective reporting reactions inherent spontaneous nature notifications, may distort found this study.5Bate Evans S.J.W. Quantitative detection ADR reporting.Pharmacoepidemiol Saf. 2009; 18: 427-436Crossref (430) In addition, development often multifactorial, clear causality with exposure might difficult assess, given high rate missing data.To best first identifying etiologies ulcers. The represent plausible considering understanding biological activity, case characteristics. they yet evaluated purpose-designed epidemiologic studies. We From signal. IV). indicated. COX, Organization. V). This data. thank VigiBase giving us access also Alison Foote (Grenoble Alpes University Hospital) critically editing manuscript.