Vitiligo is a chronic skin disease characterized by loss of pigmentation due to the destruction of melanocytes. An autoimmune mechanism is thought to play a key role in developing vitiligo, with T-cells and cytokines activated, causing melanocyte death. Oxidative stress, genetic predisposition, and immune response dysfunction are important pathogenesis factors [1].

Current methods of vitiligo treatment and their limitations

Classical approaches to the treatment of vitiligo include the following modalities:

1. Topical corticosteroids and calcineurin inhibitors. These drugs suppress localized inflammation, but their long-term use can cause side effects such as skin atrophy and risk of infections [1].
2. Phototherapy. Narrowband UV-B (311 nm) therapy stimulates melanocyte proliferation but requires long courses of treatment and may also be inconvenient for patients due to frequent clinic visits [2].
3. Melanocyte and keratinocyte transplantation. It is used for limited forms of vitiligo but is not available to all patients and involves a high technical difficulty [3].

Despite the effectiveness of these methods in several patients, none provides complete and long-term pigmentation restoration. This stimulates searching for new, more effective approaches, including topical agents, to modulate the immune response. One promising approach is the inhibition of Janus kinases, intracellular non-receptor enzymes of the tyrosinase family that transmit cytokine-mediated signals via the JAK-STAT pathway.

Role of Janus kinases in vitiligo development and target cells for inhibition

Basics of the JAK/STAT signaling pathway

Janus kinases (JAK) are a family of enzymes consisting of four members: JAK1, JAK2, JAK3, and TYK2. They play a key role in cytokine receptor signaling by activating transcription factors of STAT (Signal Transducer and Activator of Transcription). This pathway regulates the expression of genes associated with cell proliferation, survival, differentiation, and inflammation.

In the context of vitiligo, the JAK/STAT pathway is activated due to an excess of cytokines, especially interferon-gamma (IFN-γ) and interleukins (IL-15) [4]. This causes:

1. Chronic inflammation in the skin.
2. Increased migration and activation of cytotoxic T cells (CD8+) directed against melanocytes.
3. Production of molecules such as CXCL9 and CXCL10 that increase autoimmune inflammation.

The role of JAK in the autoimmune attack on melanocytes

The primary pathologic process in vitiligo is the destruction of melanocytes, the cells responsible for melanin synthesis. The autoimmune attack on melanocytes is initiated by cytotoxic T lymphocytes (CD8+) infiltrating the affected areas of the skin. These T cells produce IFN-γ, which triggers the JAK1/JAK2 signaling pathway in skin cells, including keratinocytes and melanocytes.

The cytokine cascade leads to:

1. Increased expression of the chemoattractants CXCL9 and CXCL10, which recruit additional T cells, increasing inflammation.
2. Induction of melanocyte apoptosis through the direct action of IFN-γ and related mechanisms, including activation of oxidative stress and impairment of melanocyte antioxidant defense systems.

Thus, the JAK/STAT pathway connects cytokine activation, inflammation, and melanocyte destruction.

Target cells for JAK inhibition

Effective treatment of vitiligo requires inhibition of JAK in several cell types:

1. Keratinocytes. In keratinocytes, JAK/STAT activation leads to increased expression of CXCL9 and CXCL10, contributing to the chronicization of inflammation. Inhibition of JAK in these cells reduces local inflammation and decreases the influx of new T cells into affected skin areas.
2. Cytotoxic T lymphocytes (CD8+).Activation of JAK/STAT in T cells enhances their cytotoxic activity and resistance to apoptosis. Inhibiting JAK in these cells may reduce their activity and aggression against melanocytes.
    When exposed to IFN-γ and other proinflammatory signals, melanocytes activate their own stress and apoptosis mechanisms via JAK/STAT. Suppression of JAK in melanocytes may protect them from destruction, setting the stage for repigmentation.
3. Dendritic cells and macrophages.These cells are involved in antigen presentation and the production of pro-inflammatory cytokines. Inhibition of JAK in these cells may reduce the overall activity of the autoimmune response.

Prospects for JAK inhibition in the treatment of vitiligo

Topical JAK inhibitors, such as ruxolitinib, act locally by inhibiting JAK1/JAK2 in the skin. This reduces inflammation and limits the autoimmune destruction of melanocytes. Local application has advantages over systemic therapy because it minimizes the risks of side effects and allows focus on the affected areas.

Thus, JAK inhibition represents a promising approach that targets several key links in the pathogenesis of vitiligo, including chronic inflammation, autoimmune response, and melanocyte death [4].

Topical JAK inhibitors, such as ruxolitinib, act locally by inhibiting the activity of cytokines involved in the immune response. Their advantages include a low risk of systemic side effects and the ability to target affected skin areas [5].

One of the most significant advances in this field was the development of Opzelura cream (ruxolitinib 1.5%). The drug is approved for treating non-segmented vitiligo in patients over 12. Its efficacy and safety have been confirmed in two significant phase 3 clinical trials — TRuE-V1 and TRuE-V2.

The TRuE-V1 and TRuE-V2 studies examined the efficacy of ruxolitinib over 24 weeks. The primary efficacy measure, 75% or more significant improvement on the Facial Vitiligo Area Scoring Index (F-VASI75), was achieved in 29.8-52.6% of patients receiving Opzelura, compared to 7.4-12.6% in the placebo group. Side effects were rare, including mild local reactions such as skin irritation [5].

Opzelura demonstrates the ability to suppress inflammation and promote repigmentation, making it the first drug with proven efficacy in this category.

Conclusion

Using JAK inhibitors in topical form represents a promising direction in treating vitiligo. Opzelura was the first drug of this class approved for clinical use, confirming its efficacy and safety. These data open new horizons for the therapy of vitiligo, especially in patients with limited forms of the disease.

References

1. Ezzedine K., Eleftheriadou V., Whitton M., Van Geel N. Vitiligo. Lancet 2015; 386(9988): 74–84.
2. Almutairi N., AlKhawajah N.M. Phototherapy for vitiligo: a systematic review and meta-analysis. J Dermatol 2019; 46(9): 764–770.
3. Mulekar S., Al Issa A., Al Eisa A. Surgical treatment of vitiligo: current status. Clin Dermatol 2019; 37(6):747–755.
4. Harris J.E., Rashighi M. Mechanisms of disease: pathogenesis of vitiligo. J Am Acad Dermatol. 2020; 82(1): 1–11.
5. Kang C. Ruxolitinib Cream 1.5%: A review in non-segmental vitiligo. Drugs. 2024; 84(5): 579–586.