Therapy-Associated Vitiligo: Hypopigmentation Secondary to Programmed Cell Death Protein 1 Inhibitors, Interferon Alfa-2b, Cytotoxic T-Lymphocyte-Associated Protein 4 Inhibitors, and B-Raf/Mitogen-Activated Protein Kinase Kinase Inhibitors

Background Malignant melanoma (MM) arises from melanocytes, and vitiligo is an autoimmune condition targeting these cells. Although an association between MM and vitiligo has been proposed, underlying mechanisms remain unclear. Because several melanoma treatments modulate immune responses, this study evaluated the relationship between MM and vitiligo across commonly used systemic therapies. Methods In September 2025, using the TriNetX network, patients with MM receiving programmed cell death protein 1 (PD-1) inhibitors, interferon alpha-2b (IFN-α2b), B-Raf serine/threonine kinases (BRAF)/ mitogen-activated protein kinase kinases (MEK) inhibitors, or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors were identified and 1:1 propensity score-matched to patients without MM receiving the same therapy. Demographics and vitiligo incidence were analyzed using risk ratios (RRs) and 95% confidence intervals (CIs) via Wald’s method. Counts <10 were suppressed per platform guidelines. Results Baseline demographics were well balanced between MM and matched non-MM patients. MM was significantly associated with higher vitiligo risk among those treated with PD-1 inhibitors (RR: 24.84; 95% CI: 16.92-36.45), IFN-α2b (RR: 3.10; 95% CI: 1.53-6.30), and CTLA-4 inhibitors (RR: 32.04; 95% CI: 18.05-56.88). In the BRAF/MEK cohort, vitiligo occurred only in patients with MM, preventing RR calculation. Conclusions Across multiple therapeutic classes, MM consistently conferred a greater risk of developing vitiligo compared with matched non-MM patients. The strong associations observed with immune-modulating agents support vitiligo as a potential marker of antitumor immune activation rather than a coincidental adverse event. Even rare cases in BRAF/MEK-treated patients suggest that targeted therapy may also influence melanocyte-directed immunity. Further prospective studies are needed to characterize the clinical and immunologic significance of treatment-associated vitiligo.