To the Editor: Vitiligo is a cutaneous depigmenting autoimmune disorder with complex pathophysiology that can be genetic, immunological, and/or environmental in nature. Medications associated with vitiligo include imiquimod, interferons, and, more recently, anti- programmed cell death protein 1 (PD-1) agents.1Anthony N. Bourneau-Martin D. Ghamrawi S. Lagarce L. Babin M. Briet M. Drug-induced vitiligo: a case/non-case study in Vigibase®, the WHO pharmacovigilance database.Fundam Clin Pharmacol. 2020; 34: 736-742https://doi.org/10.1111/fcp.12558Google Scholar, 2Al-Dujaili Z. Hsu S. Imiquimod-induced vitiligo.Dermatol Online J. 2007; 13: 10Google Scholar, 3Hamadah I. Binamer Y. Sanai F.M. Abdo A.A. Alajlan A. Interferon-induced vitiligo in hepatitis C patients: a case series.Int J Dermatol. 2010; 49: 829-833https://doi.org/10.1111/j.1365-4632.2009.04443.xGoogle Scholar Systematic reviews of drug-associated vitiligo are lacking from the literature. Therefore, we evaluated all reports of medication-associated vitiligo in the US Food and Drug Administration’s Adverse Event Reporting System (FAERS) from January 1, 2016, to September 30, 2021. The medications most commonly reported for vitiligo adverse events were nivolumab, pembrolizumab, ipilimumab, and adalimumab, with 138, 110, 82, and 42 reports, respectively (Table I). Of all vitiligo reports since 2016, 77.84% came from health care professionals, 21.23% came from consumers, and 0.93% were not specified.Table IReports by year for the top 10 reported medications for vitiligo adverse events on the US Food and Drug Administration’s Adverse Event Reporting System since 2016∗2021 reports are only recorded up until September 30, 2021.RankMedication generic nameDrug classCases by yearTotal cases since 20162021202020192018201720161NivolumabAnti-PD-1232729311931382PembrolizumabAnti-PD-12216272310121103IpilimumabAnti-CTLA-413131820126824AdalimumabTNF-α inhibitor1396662425SecukinumabAnti-IL-17A3106353306TofacitinibJAK inhibitor2115371297AlemtuzumabAnti-CD-527211510268RibociclibAnti-CDK-4/61722100229EnteraceptTNF-α inhibitor195240219LenalidomideAnti-CD-283113220219InfliximabTNF-α inhibitor1142121219Sulfamethoxazole/trimethoprimAntibiotic11730002110LetrozoleAromatase inhibitor152110019CD, Cluster of differentiation; CDK, cyclin-dependent kinase; CTLA-4, T-lymphocyte-associated protein 4; IL-17A, interleukin 17A; JAK, Janus kinase; PD-1, programmed cell death protein 1; TNF, tumor necrosis factor.∗ 2021 reports are only recorded up until September 30, 2021. Open table in a new tab CD, Cluster of differentiation; CDK, cyclin-dependent kinase; CTLA-4, T-lymphocyte-associated protein 4; IL-17A, interleukin 17A; JAK, Janus kinase; PD-1, programmed cell death protein 1; TNF, tumor necrosis factor. Our results indicate that checkpoint inhibitors and anti-tumor necrosis factor (TNF) α agents remain some of the most commonly reported medications to be associated with vitiligo. They also highlight the importance of immunologic pathogenesis in vitiligo. A systematic review and meta-analysis from 2016 found that cutaneous toxicities are some of the most prevalent immune-related adverse events with both anti-PD-1 and anti-T-lymphocyte-associated protein 4 agents, and that of these cutaneous toxicities, vitiligo is one of the most prominent.4Belum V.R. Benhuri B. Postow M.A. et al.Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor.Eur J Cancer. 2016; 60: 12-25https://doi.org/10.1016/j.ejca.2016.02.010Google Scholar Induction of melanoma-associated vitiligo by immune checkpoint inhibitors can be a positive clinical marker for response and survival. Furthermore, anti-PD-1 and anti-T-lymphocyte-associated protein 4 agents in combination have been found to cause more frequent and severe cutaneous side effects than either medication alone. There are case reports of TNF-α inhibitors halting disease progression when used to treat vitiligo; however, they have also been seen to paradoxically cause de novo vitiligo when used to treat other autoimmune conditions.5Webb K.C. Tung R. Winterfield L.S. et al.Tumour necrosis factor-α inhibition can stabilize disease in progressive vitiligo.Br J Dermatol. 2015; 173: 641-650https://doi.org/10.1111/bjd.14016Google Scholar TNF-α inhibitors can also induce psoriasis via an elevation in type 1 interferons, even though this class of medicine is approved to treat plaque psoriasis. Reports for imiquimod and interferons were minimal in the FAERS database. There were 5 reports of imiquimod-associated vitiligo since 2016, while all subtypes of interferons were reported a combined total of 13 times. These results are in light of existing publications, which describe the significant association between imiquimod and vitiligo and case reports of interferon-induced vitiligo.1Anthony N. Bourneau-Martin D. Ghamrawi S. Lagarce L. Babin M. Briet M. Drug-induced vitiligo: a case/non-case study in Vigibase®, the WHO pharmacovigilance database.Fundam Clin Pharmacol. 2020; 34: 736-742https://doi.org/10.1111/fcp.12558Google Scholar,3Hamadah I. Binamer Y. Sanai F.M. Abdo A.A. Alajlan A. Interferon-induced vitiligo in hepatitis C patients: a case series.Int J Dermatol. 2010; 49: 829-833https://doi.org/10.1111/j.1365-4632.2009.04443.xGoogle Scholar The discrepancy could be due in part to under-reporting because vitiligo is a known side effect of interferons and imiquimod, as well as decreasing the use of these medications. A report from the World Health Organization showed that PD-1 inhibitors, imiquimod, and TNF-inhibitors are common drugs to induce vitiligo.1Anthony N. Bourneau-Martin D. Ghamrawi S. Lagarce L. Babin M. Briet M. Drug-induced vitiligo: a case/non-case study in Vigibase®, the WHO pharmacovigilance database.Fundam Clin Pharmacol. 2020; 34: 736-742https://doi.org/10.1111/fcp.12558Google Scholar While a useful tool for investigating current trends, there are several limitations of the FAERS database. These include that rate of occurrence cannot be established from this database, the presence of a report in the database cannot establish causation between the adverse event and reported drug, the data is subject to reporting bias, a diagnosis of vitiligo cannot be confirmed from these reports, and there is the potential for confounders. Overall, this study supports the association between immune-modulating therapies, including checkpoint inhibitors and TNF-α inhibitors, and vitiligo and serves as a reminder for providers to consider this adverse effect as the use of these therapies continues to grow. Dr Rosmarin has received honoraria as a consultant for AbbVie, Abcuro, AltruBio, Boehringer-Ingelheim, Bristol Meyers Squibb, Celgene, Concert, CSL Behring, Dermavant, Dermira, Incyte, Janssen, Kyowa Kirin, Lilly, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharmaceuticals, UCB, VielaBio; has received research support from AbbVie, Amgen, Bristol Meyers Squibb, Celgene, Dermira, Galderma, Incyte, Janssen, Lilly, Merck, Novartis, Pfizer, and Regeneron Pharmaceuticals Inc; and has served as a paid speaker for AbbVie, Amgen, Celgene, Janssen, Lilly, Novartis, Pfizer, Regeneron Pharmaceuticals Inc, and Sanofi.