Janus Kinase Inhibitors in the Treatment of Vitiligo: A Review

Abstract

Vitiligo is a multifactorial reversible skin disorder characterized by distinct white patches that result from melanocyte destruction. Activated CXCR3⁺ CD8⁺ T cells promote melanocyte detachment and apoptosis through interferon-gamma (IFN-γ secretion and chemokines secreted by keratinocytes through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT)-1 signaling pathway results in further recruitment of CXCR3⁺ CD8⁺ T cells and the formation of a positive-feedback loop. JAK inhibitors target the JAK/STAT pathway and are now approved to treat many immune-related diseases. In the treatment of vitiligo, JAK inhibitors, including ruxolitinib, baricitinib, and tofacitinib, are effective, supporting the implication of the IFN-γ-chemokine signaling axis in the pathogenesis of vitiligo. However, more studies are required to determine the ideal dosage of JAK inhibitors for the treatment of vitiligo, and to identify other inflammatory pathways that may be implicated in the pathogenesis of this condition.

Keywords: IFN - interferon; JAK inhibitors; JAK/STAT-1 signaling pathway; chemokines; vitiligo.

Figure 1

(A) IFN- γ signaling and the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in vitiligo. (B) The secretion of MMP-9 by keratinocytes, in response to IFN-γ and TNF-α, induced melanocytes detachment through E-cadherin disruption and released its soluble form, in the vitiligo skin comparing with the normal skin. (C) Illustrates the vitiligo pathogenesis: the IFN-γ-chemokine axis, with its associated positive-feedback loop: the autoreactive CD8+ T cells produce IFN-γ, which promotes depigmentation; IFN-γ simultaneously stimulates keratinocytes to express CXCR3 that binds to CXCL9 to recruit more melanocyte-reactive T cells. In addition, CXCL10 recruits T cells within the skin through the CXCR3 receptor, which prolongs and exacerbates the established vitiligo lesion. (D) The potential target for JAK inhibitors to treat vitiligo.