Oxidative stress in refractory and recurrent vitiligo: from immune amplification mechanisms to potential stratified antioxidant combination therapy

Vitiligo is an acquired depigmenting disorder characterized by destruction of epidermal melanocytes and skin depigmentation. Although treatments have developed substantially, there is still a considerable proportion of vitiligo patients fail to achieve satisfactory repigmentation or experience disease recurrence after treatment withdrawal. Vitiligo treatment failure involves heterogeneous clinical states, including persistent disease activity, treatment resistance, site-related limitations, and disease recurrence. Importantly, refractory and recurrent vitiligo are heterogeneous and partially overlapping clinical issues rather than a single biological damage requiring a uniform management strategy. Oxidative stress serves as a critical factor in the pathogenesis of vitiligo, linking melanocyte injury, release of danger-associated molecular patterns (DAMPs), innate immune activation, and IFN-γ driven adaptive immune amplification, associated with active and refractory disease. Interleukin (IL)-15-dependent tissue-resident memory T (TRM) cells provide a mechanism for local immune reactivation and recurrence. However, the role of oxidative stress in treatment resistance and recurrence remains incompletely defined. Importantly, available studies of antioxidant therapy are heterogeneous, with no evidence demonstrates that antioxidant therapy eliminates TRM cells or prevents recurrence. In this review, we propose a hypothesis-generating clinical framework that distinguishes refractory and recurrent vitiligo based on disease activity, IFN-γ signaling, anatomical sites, phototherapy responses and recurrence risk. Currently, antioxidant therapy should be considered as an investigational adjunctive therapy. The review investigates the relationship between oxidative stress and antioxidant therapy in refractory and recurrent vitiligo, and evaluates the role of antioxidant therapy in the management of vitiligo. In the future, it will be essential to conduct prospective biomarker based stratified clinical trials to define the targeted vitiligo patients for antioxidant combination therapies, as well as to continuously develop novel antioxidant-based anti-inflammatory therapeutic approaches for refractory and recurrent vitiligo.