The JAK/STAT pathway is an intracellular signal transduction pathway expressed in all cell types. It is responsible for broad biological processes, including proliferation, differentiation, apoptosis, and immune system regulation through cytokine-mediated signaling, with the JAK family consisting of four main members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) (62, 63). Upon activation by an associated receptor chain cytokine, members of the JAK family become phosphorylated, initiating a signaling cascade that results in the translocation of phosphorylated STAT protein dimers to the nucleus and transcriptional changes that further activate the immune response (64–66).

JAK1, JAK2, and TYK2 are expressed in all tissues (64–66). JAK1 can be phosphorylated by the γc receptors (such as IL-2, IL-7, and IL-15 receptors), class II cytokine receptors (such as IFN-α/β/γ receptors), and gp130 subunit receptors (such as IL-16 receptor and leukemia inhibitory factor receptor) (67, 68). JAK2 can be phosphorylated by class II cytokine and gp130 subunit receptors, but also participates in IL-3 receptor signaling (69). Knockout of either Jak1 or Jak2 is embryonically lethal in mice (67, 70). TYK2 participates in IFN-α/β, IL-6, IL-10, IL-12, IL-13, and IL-23 signaling (66, 71). Unlike mice lacking Jak1 or Jak2, Tyk2 deficiency is not embryonically lethal; these mice display dysfunction in T helper type 1 (Th1) and Th2 cell signaling instead (72). Humans lacking TYK2 display severe allergies (73). In vitiligo, JAK1 and 2 are activated directly by IFN-γ, leading to CD8+ T cell recruitment (63, 74). TYK2, through regulation of Th1 cells and IL-12, can also create an elevated type 1 immune response in vitiligo (75, 76). Several type 1 IFN, regulated in part by TYK2, have also been implicated in vitiligo pathogenesis (77).

Unlike other JAK family members, which are ubiquitously expressed and associated with many receptor chains, JAK3 is primarily found in hematopoietic cells and is associated with the γc receptor. This receptor is shared by 6 cytokines, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 (64–66).

In vitiligo, IFN-γ and other vitiligo pathogenesis-associated cytokines, including IL-2 and IL-15, drive increased chemokine production, recruitment of melanocyte-reactive immune cells, reduced melanocyte adhesion, enhanced melanocyte apoptosis, and disease reactivation through the JAK/STAT pathway and TEC pathways (63, 78, 79).

In vitiligo, CD4⁺ and CD8⁺ T-cells induce the expression of cytokines associated with γc receptor chains (Figure 1). The IL-2 family cytokines, consisting of IL-2, IL-7, and IL-15, while not directly affecting melanocytes or keratinocytes, subsequently activate CD49a⁺/CD8⁺ tissue-resident memory T cells. These cytokines influence multiple aspects of tissue-resident memory T cell behavior, promoting melanocyte apoptosis and maintaining disease activity (46, 47, 58, 79, 80). IL-2, produced by CD4⁺ T-cells, stimulates CD8⁺ tissue-resident memory T cell proliferation (81, 82). As discussed earlier, IL-7 and IL-15 activate and maintain tissue-resident memory T cells (42, 58).

Outside of T cell activation, JAK3 also plays a role in other immune system functions, including NK cells and ILCs. Through activation of IL-2 expression, JAK3 can lead to higher levels of IFN-γ and NK-cell expansion (with constitutional JAK3 expression playing a role in certain oncogenic events) (83). Through IL-15, STAT5 signaling leads to maturation of NK cells and maintenance of higher levels of NK cells (84). Jak3 deficiency in mice blocks ILC differentiation, which may abrogate the secretion of IFN-γ by these cells, leading to induction of melanocyte apoptosis and activation of T-cell melanocyte auto-immunity activation (23, 85).

The TEC family kinase members are cytoplasmic tyrosine kinases involved in many intracellular signaling processes in hematopoietic cells (86–88). The five members include TEC, Bruton’s tyrosine kinase (BTK), IL-2–inducible T-cell kinase (ITK), Resting lymphocyte kinase (RLK/TXK), and Bone-marrow tyrosine kinase gene on chromosome X (BMX) (86–88). TEC, BTK, and BMX are expressed highly in myeloid cells (89), while ITK, RLK, and TEC are important for CD4⁺ and CD8⁺ T-cell development (90).

In vitiligo, ITK (a TEC member), may play a role in maturation of CD8⁺ T-cells (91). APCs when sensing autoantigens take up and process them into autoantigenic peptide:MHC-I complexes. These complexes are presented on the cell surface and recognized by TCRs (24, 36), leading to ITK activation, recruitment to the cell surface, and subsequent T-cell maturation, differentiation, and proliferation (Figure 1). Additionally, inhibition of ITK has been shown in vitro to disrupt CD8⁺ T-cell-induced IFN-γ secretion (92). In Itk knockout mice, Th2 and T helper type 17 (Th17) cell differentiation and functioning are impacted, leading to dysregulation of regulatory T-cells (Tregs) (93). Also via IFN-γ secretion, ITK plays a role in NK cell activity (94–96). These NK cells secrete cytokines such as IFN-γ, contributing to further immune recruitment.

The involvement of the TCR in recognition of autoantigenic peptide:MHC-I complexes suggests that TEC kinase family members, such as ITK, contribute to the development of vitiligo. This is supported by evidence implicating a role for ITK in other T-cell-mediated autoimmune disorders, including rheumatoid arthritis, psoriasis, and atopic dermatitis (91). RLK and TEC also act downstream of TCR, and may affect IFN-γ secretion from NK cells. RLK, alongside ITK, mediates T-cell and NK cell activation and proliferation (94, 95). T cells that are deficient in ITK and RLK show little expression of IL-2, and following activation show a reduction in proliferation (97). In some cases, RLK and ITK also induce expression of “natural killer T-cells”, which express characteristics of both T-cells and NK cells, and secrete IFN-γ in large quantities rapidly (94). Disruption of RLK and ITK also disrupts Th1 and Th2 cell signaling, respectively (98). Increased RLK expression is also found in patients with the inflammatory disorder Behcet disease, which is characterized by increased inflammation and Th1 cytokines (99). However, RLK and ITK may serve similar functions in the immune system. In some instances, selective disruption of RLK expression was found to have little effect on immune system regulation unless ITK expression was also disrupted (95, 100). RLK may function somewhat independently in chemokine receptor signaling, as in murine models, Itk-/Rlk-deficient T cells showed defective responses to various chemokines (101). Collectively, this supports a role for ITK and RLK in vitiligo pathogenesis, with ITK contributing via IFN-γ signaling and RLK contributing via chemokine-induction of Th1 signaling alone, and through IL-2 induced activation of resident memory T cells in combination.

TEC, expressed at lower levels than ITK, BTK, or BMX in T- and B-cells, also shares a role with ITK and BTK, with Tec knockout mice showing no defects in lymphocyte functioning (102). However, it is upregulated at T-cell activation following stimulation with anti-CD3/CD28, and in Th1 and Th2 cells following stimulation with IL-4, IL-12, and IFN-γ, and induces activation of nuclear factor of activated T cell transcription factors (103). This suggests that it may increase the sensitivity of effector or resident memory T-cells.

Additionally, BTK, ITK, RLK, and TEC are expressed in mast cells, which serve as effectors for allergic responses, and innate and adaptive immune responses (104). In mast cells, BTK is thought to be involved in c-kit specific signaling, with other TEC family kinase members potentially serving redundant or regulatory roles (104). BTK, through IL-15-activated STAT5 signaling, also plays a role in the development, maturation, and function of B-cells, CD8⁺ T cells, and NK cells (105–108). BTK expression, when disrupted, also reduces expression of Ifn-γ in animal models (108). Emerging evidence suggests that BMX may contribute to the pathogenesis of inflammatory disorders (such as vitiligo) through TNF-α and IL-1β signaling to IL-8 (109).

Dual JAK3 and TEC family kinase inhibition with ritlecitinib was shown to decrease certain biomarkers associated with vitiligo pathogenesis in blood samples taken from patients with NSV, including NK and T-cell activation (NCR1, IL-2, IL-15), Th1 activation (TNFSR10B, CXCR3, CCL5, IL-23a, IL-12b), and oxidative stress (NOS3) (76). Other biomarkers expressed in the skin affected include those related to Th2, Th17, and Th22 activation (including IL-13, CCL13, CCL18, IL-17a, and IL-22), and regulatory markers such as CTLA4 and PD1 (76).

Collectively, these studies highlight the importance of both JAK3 and the TEC family kinases in immune cell-signaling and vitiligo pathogenesis and suggest that targeting of these pathways may be a viable therapy option for patients with vitiligo.

Ruxolitinib cream, a topical JAK1/2 inhibitor previously approved for the treatment of atopic dermatitis, was approved by the FDA to treat NSV in July 2022 and by the EC in April 2023 for the treatment of patients with NSV including facial involvement aged ≥12 years (116, 120–122); however, two phase 3 clinical trials (NCT04052425 and NCT04057573) limited topical application to ≤10% of the body surface area (120–122).

Other targeted therapies are currently under development for the treatment of vitiligo (Table 2). Ritlecitinib is an oral, selective dual inhibitor of JAK3 and the TEC family kinases and is approved to treat severe alopecia areata (123). Through blocking the adenosine triphosphate binding site on these proteins, ritlecitinib irreversibly and selectively inhibits JAK3 and the TEC family kinases (92). In cellular settings, ritlecitinib inhibits signaling of the JAK3-dependent common γ-chain cytokines (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21). It has high selectivity over the other three JAK isoforms (JAK1, JAK2, and TYK2) as well as over the broader human kinome (65, 92).

Ritlecitinib is also under investigation for the systemic treatment of NSV (124). In a phase 2b clinical trial (NCT03715829), ritlecitinib demonstrated significant improvement on the centrally read Facial Vitiligo Area Scoring Index (crF-VASI) at Week 24 in patients with active NSV at 50 mg daily with or without a loading dose (100 or 200 mg daily for 4 weeks), with further improvement in the crF-VASI observed up to Week 48 (124). A substudy of the phase 2b trial found that treatment with ritlecitinib significantly reduced biomarkers associated with immune signaling and inflammation in skin and blood of patients with active NSV, and upregulated melanocyte-specific markers; this correlated with clinical improvements (76). Three phase 3 clinical trials assessing ritlecitinib treatment for vitiligo in adults and adolescents aged ≥12 years are ongoing (NCT05583526, NCT06072183 [assessing adults only], and NCT06163326).

Upadacitinib is an oral JAK1 inhibitor and is approved to treat rheumatoid arthritis, atopic dermatitis, ulcerative colitis, psoriatic arthritis, ankylosing spondylitis, and Crohn’s disease (125, 126). In a phase 2 clinical trial (NCT04927975), upadacitinib monotherapy led to repigmentation of facial and body lesions, with significant improvement on the F-VASI and total-VASI (T-VASI) at Week 24 in adults with NSV at 11 mg or 22 mg daily, with further improvement observed up to Week 52 (127). A phase 3 clinical trial in adults and adolescents is ongoing (NCT06118411).

Povorcitinib, an oral selective JAK1 inhibitor, is under investigation for treatment of hidradenitis suppurativa, vitiligo, prurigo nodularis, asthma, and chronic spontaneous urticaria (128). In a phase 2b clinical trial (NCT04818346), once-daily 15 mg, 45 mg, and 75 mg povorcitinib demonstrated significant improvement in T-VASI in patients with NSV at Week 24, with continued improvement up to Week 52 (129). Two phase 3 clinical trials (NCT06113445 and NCT06113471) in adults are ongoing.

Baricitinib, an oral JAK1/2 inhibitor, is approved to treat rheumatoid arthritis, atopic dermatitis, and alopecia areata (130). In a prospective randomized phase 2 clinical trial (NCT04822584), baricitinib combined with narrowband UVB has demonstrated significant superior improvement in F-VASI and T-VASI compared to placebo and narrowband UVB in patients with active NSV at Week 36 (131).

Deucravacitinib, an oral TYK2 inhibitor that inhibits IFN type 1 responses and IL-12 amongst others, is approved to treat plaque psoriasis (75). It is being investigated in an ongoing phase 2 clinical trial (NCT06327321) in patients with NSV.

Other treatments targeting cytokines associated with the JAK/STAT pathway under investigation as treatments for vitiligo include SYHX1901, an oral pan-JAK inhibitor (which is currently recruiting for a phase 2 clinical trial [NCT06511739] in adults with NSV), the intravenous IL-15 inhibitor AMG 714 (currently being investigated in a completed phase 2a clinical trial [NCT04338581] in adults with vitiligo), the subcutaneous IL-15 inhibitor TEV-53408 (currently recruiting for a phase 1b clinical trial [NCT06625177] in adults with vitiligo), and anifrolumab, an intravenous type I interferon inhibitor (currently being investigated in an ongoing phase 2 clinical trial [NCT05917561] in adults with nonsegmental progressive vitiligo).

Several of the treatments discussed above have also seen approvals in other autoimmune inflammatory dermatological diseases, such as alopecia areata and atopic dermatitis, which share some overlapping pathogenesis with vitiligo, particularly in activation of the JAK/STAT pathway (17, 66, 132–140).

As is the case for autoimmune diseases such as alopecia areata or atopic dermatitis, vitiligo may require long-term treatment due to the underlying pathology and unpredictable course of the disease. As new treatments for vitiligo targeting the JAK/STAT and TEC family kinase pathways are developed and evaluated, the need to address knowledge gaps also arises.

Of note, potential safety concerns associated with long-term usage should be addressed specifically within the vitiligo treatment population. Based on studies of JAK inhibitors in patients with rheumatoid arthritis, the FDA and other regulatory bodies have issued warnings that JAK inhibition may be associated with increased risks of infection, malignancies, thromboembolic events, and lipid levels, and changes in hematologic parameters (141–146). However, differences between those autoimmune skin diseases (such as vitiligo, alopecia areata, or atopic dermatitis), and those with other autoimmune diseases, such as rheumatoid arthritis, including differences in clinical manifestations, underlying pathophysiology, associated comorbidities and risk of adverse events, concomitant treatments, and age, as well as the specific kinases being targeted, may change the safety profile of the JAK inhibitor. Notably, in two phase 3 clinical trials of patients 12 years and older spanning 52 weeks, treatment with topical ruxolitinib cream was not associated with any serious treatment-emergent adverse events (120), and a long-term safety study evaluating ruxolitinib over 104 weeks reported no serious treatment-related adverse events (147). Additionally, short- and long-term systemic JAK and TEC family kinase inhibition has been evaluated in patients with alopecia areata and atopic dermatitis, where these therapies were generally well tolerated and not associated with increased rates of adverse events such as infections or thromboembolic events compared with the general population of patients with alopecia areata or atopic dermatitis (146, 148–153). Ongoing and future studies evaluating long-term treatment with oral/systemic JAK or TEC family kinase inhibition will shed further light on the safety profile specifically in patients with vitiligo.

Studies evaluating long-term treatment efficacy in individuals with vitiligo who receive targeted therapies will also provide evidence on other knowledge gaps currently lacking, such as durability, while evaluations of patients outside of clinical trials will allow health care providers to understand the impact of stopping and restarting treatments.