Acral Hypopigmentation Associated with Ruxolitinib: A Novel Observation

Dear Editor, Ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, is being widely used in the management of myeloproliferative neoplasms and graft-versus-host disease (GVHD). Dermatologic adverse effects are known with JAK inhibitors. These include acneiform eruptions, infections, and rarely, hyperpigmentation.[1] However, hypopigmentation—especially acral hypopigmentation—has not been previously reported in association with ruxolitinib. We report a case of acral hypopigmentation in a patient receiving long-term oral ruxolitinib therapy, highlighting a possibly underrecognized cutaneous adverse effect. A 32-year-old man with a history of allogeneic hematopoietic stem cell transplantation for hypoplastic myelodysplastic syndrome presented with progressive, symmetrical hypopigmented patches on the dorsum of both hands and feet [Figures 1 and 2]. The lesions appeared approximately three months after initiation of oral ruxolitinib (10 mg twice daily) for chronic pulmonary GVHD. There was no history of topical or systemic corticosteroids use, phototherapy, or other medications known to affect pigmentation in the last 12 months. No other skin lesions, photosensitivity, or symptoms were present. There was no history of vitiligo, autoimmune disease, cutaneous GVHD, or occupational exposure to chemicals. No sensory loss or scaling was noted.Figure 1: Symmetrical bilateral hypopigmentation on dorsal hands in a patient on oral ruxolitinibFigure 2: Symmetrical bilateral hypopigmentation on dorsum of feet in a patient on oral ruxolitinibVitiligo-like cutaneous GVHD usually occurs independent of drug timing and typically presents as patchy, generalized, or segmental well-defined depigmented patches, which may be associated with poikiloderma, atrophy, and sclerosis. In contrast, our case demonstrated a symmetrical acral distribution, absence of interface changes, or sclerosis, which favored a drug-induced hypopigmentation rather than vitiligo-like depigmentation of chronic GVHD. The timing of onset and localization of lesions suggested a drug-related etiology. In particular, the temporal association with ruxolitinib initiation and the absence of other likely etiologies pointed toward a probable adverse drug reaction. Causality assessment (Naranjo score = 6) indicates a “probable” association between ruxolitinib and the observed acral hypopigmentation [Supplementary Table 1]. Although imatinib, a tyrosine kinase inhibitor, is known to cause hypopigmentation through KIT proto-oncogene receptor tyrosine kinase (c-KIT) inhibition,[2] ruxolitinib has not been reported to cause similar changes. Its mechanism does not directly involve c-KIT but interferes with the Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling pathway, interleukin (IL)-6, which plays a role in melanogenesis and melanocyte homeostasis via regulation of cytokines such as IL-6 and interferons.[3] A study by O’Sullivan et al. demonstrated the role of JAK inhibitors in reducing pigmentation in murine models by inhibiting the STAT-dependent microphthalmia-associated transcription factor, a key regulator of melanocyte differentiation and melanin production.[4] This suggests a biological plausibility for ruxolitinib-induced hypopigmentation. To our knowledge, there are no published clinical reports of ruxolitinib-induced hypopigmentation in humans. A search of the literature and pharmacovigilance databases revealed no prior documentation of this phenomenon. However, given the increasing use of JAK inhibitors across dermatology and oncology, such cutaneous side effects may be underreported or misattributed.[5] The hypopigmentation in our patient was localized to acral sites, which could be due to greater cumulative sun exposure or increased melanocyte sensitivity in these regions. The patient was counseled regarding the benign nature of the ruxolitinib adverse effect and opted to continue ruxolitinib due to its critical role in managing pulmonary GVHD. In conclusion, we present what may be the first clinical report of acral hypopigmentation associated with ruxolitinib therapy. This case adds to the evolving spectrum of dermatological manifestations of JAK inhibitors and underscores the need for vigilance when evaluating new pigmentary changes in patients on these agents. Further studies and pharmacovigilance data are needed to elucidate the incidence and mechanisms behind this observation. Authors’ contributions The manuscript has been read and approved by all authors. All authors meet authorship criteria and that the manuscript represents honest work. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Use of artificial intelligence (AI) The preparation of this manuscript was carried out entirely by the authors without the use of artificial intelligence technologies.Supplementary Table 1: Causality score (Naranjo adverse drug reaction probability score) for ruxolitinib