Vitiligo: An In-Depth Review of Pathogenesis, Clinical Aspects, and Therapeutic Advances

Abstract

Vitiligo is a chronic, acquired pigmentary disorder distinguished by selective destruction of functional melanocytes resulting in depigmented macules and patches on skin and mucosa. Its pathogenesis implies intricate relationships of genetic predisposition, autoimmune reaction, and oxidative stress, and perhaps neural mechanism. Very recently, particularly with respect to immune dysregulation and cytokine signaling, advances have been made using molecular assays for understanding the pathways underlying vitiligo. Over these advances, Janus kinase (JAK) inhibitors have arisen as a significant clinical milestone, facilitating novel therapeutic pathways. This review highlights the advances between 2021 and 2024 on the epidemiology, pathogenesis, manifestations, diagnosis, psychosocial impact and evolving treatment landscape of vitiligo, particularly the emergence of JAK inhibitors as a new class of therapies.

Keywords

Vitiligo, autoimmune disease, melanocyte destruction, oxidative stress, JAK inhibitors, phototherapy, immune checkpoints, psychosocial impact, depigmentation therapy, pathogenesis, novel therapies

Introduction

Vitiligo presents with sharply defined, milky-white patches. Common sites include:

1. Face
2. Neck
3. Hands
4. Periorificial areas (mouth, eyes, genitals)

4.1 Types of Vitiligo

1. Non-segmental vitiligo (NSV): Symmetrical, progressive, most common form.
2. Segmental vitiligo (SV): Unilateral, often stabilizes after initial spread.
3. Mixed vitiligo: Features of both types.

5. Associated Disorders

Vitiligo frequently coexists with other autoimmune conditions, including:

1. Autoimmune thyroid disease
2. Type 1 diabetes mellitus
3. Alopecia areata
4. Pernicious anemia

6. Diagnostic Workup [456}

Vitiligo is predicated mostly on clinical diagnosis, but modern practice increasingly utilizes other tools to confirm diagnosis and assess disease activity, exclude differential entities, and individualize management strategies. Dermatologic imaging, histopathology, immunoassays, and newer molecular techniques have all advanced in the last five years to improve the diagnostic workup of vitiligo .A systematic evaluation yields proper definition, management, and teaching to the patients regarding differential diagnosis, considerably in discriminating between vitiligo and other hypopigmentary disorders.[4]

6.1 Clinical Evaluation

The cornerstone of diagnosis is a careful clinical examination:

• History-taking should cover:
  1. 1. Age at onset
     2. Progression speed
     3. Family history of vitiligo or other autoimmune diseases
     4. Triggers (stress, trauma, sunburn, chemical exposures)
     5. Symptoms of associated autoimmune conditions (e.g., thyroid dysfunction)

• Physical examination focuses on:
  1. 1. Distribution and pattern of lesions (segmental vs non-segmental)
     2. Signs of activity (Koebner phenomenon)
     3. Presence of leukotrichia (white hair within lesions)
     4. Mucosal involvement

6.2 Laboratory Testing

1. Thyroid function tests (T3, T4, TSH)
2. Antithyroid antibodies (e.g., anti-TPO, anti-thyroglobulin)
3. Blood glucose or HbA1c (screening for diabetes)
4. Vitamin B12 levels (especially if other autoimmune diseases are suspected) [5]

6.3 Disease Activity Scoring

• Vitiligo Disease Activity Score (VIDA):

A patient-reported scale assessing activity over the past 6–12 months:

1. VIDA +4 = activity in past 6 weeks
2. VIDA 0 = stable disease for 1 year

• Vitiligo Area Scoring Index (VASI):

1. Estimates body surface area involved and degree of depigmentation
2. Increasingly used in clinical trials

• Vitiligo Extent Score (VES):

Simplified alternative for clinical practice and research [6]

7. Treatment

7.1 Topical Therapies

1. Corticosteroids: Effective but may cause skin atrophy.
2. Calcineurin inhibitors (e.g., tacrolimus): Useful for facial lesions and sensitive areas.

7.2 Phototherapy

1. Narrowband UVB (NB-UVB): The current gold standard for widespread vitiligo.
2. Excimer laser: Useful for localized lesions.

Long-term phototherapy is often required, and repigmentation varies.

7.3 Systemic Therapies

1. Short-term oral corticosteroids help halt rapid progression.
2. Other systemic immunosuppressants are reserved for severe cases.

7.4 JAK Inhibitors

One of the most significant breakthroughs:

1. Ruxolitinib cream received FDA approval in 2022 for non-segmental vitiligo (Rodrigues et al., 2023).
2. Oral JAK inhibitors (e.g. tofacitinib, baricitinib) are under investigation.
3. They block cytokine signaling pathways (e.g. IFN-γ) critical in vitiligo pathogenesis.

Clinical trials report promising results, with significant repigmentation in many patients.

7.5 Surgical Techniques

1. For stable, treatment-resistant vitiligo:
2. Mini-punch grafting
3. Suction blister grafting
4. Cellular grafting (e.g. melanocyte-keratinocyte transplantation)

7.6 Camouflage and Depigmentation

1. Cosmetic camouflage improves appearance and self-esteem.
2. Depigmentation therapy (e.g. monobenzone) is considered for extensive disease.

8. Recent Advances and Future Directions [7891011]

Some advances in understanding vitiligo and even its treatment have been very significant in recent years, and the condition has emerged from being poorly understood into a condition that now serves as a model for targeted dermatologic therapeutic regimens. These advances are in the areas of molecular immunology, targeted pharmacotherapy, regenerative medicine, and artificial intelligence (AI). Here, we summarize the most promising developments and ongoing research that may define the future of vitiligo management.[7]

8.1 Janus Kinase (JAK) Inhibitors

The paradigm in vitiligo therapy is the clinical application of JAK inhibitors that inhibit the IFN-γ–CXCL10 axis, which is an important pathway for melanocyte destruction. In 2022, after promising results from the TRuE-V1 and TRuE-V2 trials, showing significant facial and total body repigmentation (Rosmarin et al., 2022), ruxolitinib cream 1.5% became the first FDA-approved topical medication for non-segmental vitiligo.[8]

Systemic JAK inhibitors such as tofacitinib and baricitinib are still being studied and preliminary trials show results, mainly in conjunction with phototherapy (Harris, 2022).

8.2 Targeted Cytokine Blockade and Immune Modulation

Besides inhibiting JAK, researchers investigate specific immune interventions to target specific mediating molecules in the cascade of vitiligo:[9]

CXCL10 is an upregulated chemokine by IFN-γ that induces elevation in lesional skin and serum. Blocking this chemokine or its receptor CXCR3 appears to be therapeutically promising in preclinical models (Zhang et al., 2022).[10] Immune checkpoint proteins such as PD-1/PD-L1 are viewed as contributions to pathogenesis and potential therapeutic targets.

8.3 Regenerative and Cell-Based Therapies

NCES and MKTP have undergone improvements whereby studies reported landscapes of repigmentation from 60% to 80% in stable lesions.

Tissue Engineering innovations are incorporated into the scaffold biomaterials/stem cells so that graft survival and pigmentation quality can be enhanced.[11]

REFERENCES

1. Ezzedine, K., Eleftheriadou, V., Whitton, M., & van Geel, N. (2021). Vitiligo. The Lancet, 397(10235), 613–627. https://doi.org/10.1016/S0140-6736(20)32335-0
2. Speeckaert, R., & van Geel, N. (2022). Vitiligo: An update on pathophysiology and treatment. Pigment Cell & Melanoma Research, 35(5), 486–502. https://doi.org/10.1111/pcmr.13015
3. Rodrigues, M., Ezzedine, K., Hamzavi, I., Pandya, A. G., & Harris, J. E. (2023). Vitiligo – Part I and II: Pathogenesis, clinical features, diagnosis, and treatment. Journal of the American Academy of Dermatology, 88(1), 1–26. https://doi.org/10.1016/j.jaad.2022.06.013
4. Harris, J. E. (2022). Advances in understanding and treating vitiligo. F1000Research, 11(F1000 Faculty Rev-109). https://doi.org/10.12688/f1000research.75237.1
5. Rodrigues, M., Ezzedine, K., Hamzavi, I., Pandya, A. G., & Harris, J. E. (2023). Vitiligo – Part I and II: Pathogenesis, clinical features, diagnosis, and treatment. Journal of the American Academy of Dermatology, 88(1), 1–26. https://doi.org/10.1016/j.jaad.2022.06.013
6. Speeckaert, R., & van Geel, N. (2022). Vitiligo: An update on pathophysiology and treatment. Pigment Cell & Melanoma Research, 35(5), 486–502. https://doi.org/10.1111/pcmr.13015
7. Harris, J. E. (2022). Advances in understanding and treating vitiligo. F1000Research, 11(F1000 Faculty Rev-109). https://doi.org/10.12688/f1000research.75237.1
8. Huggins, R. H., Somach, S. C., Kauffman, C. L., & Kerr, H. A. (2021). Melanocyte transplantation techniques for vitiligo: Current status and future directions. Dermatologic Surgery, 47(1), 35–43. https://doi.org/10.1097/DSS.0000000000002736
9. Rodrigues, M., Ezzedine, K., Hamzavi, I., Pandya, A. G., & Harris, J. E. (2023). Vitiligo—Pathogenesis and therapy. Journal of the American Academy of Dermatology, 88(1), 1–26. https://doi.org/10.1016/j.jaad.2022.06.013
10. Rosmarin, D., Pandya, A. G., Lebwohl, M., Grimes, P., Hamzavi, I., Harris, J. E., ... & Hordinsky, M. (2022). Ruxolitinib cream for the treatment of vitiligo: TRuE-V Phase 3 trials. New England Journal of Medicine, 387(16), 1445–1455. https://doi.org/10.1056/NEJMoa2202980
11. Zhang, C., Qiao, Q., Zhang, J., & Chen, L. (2022). Targeting CXCL10 in vitiligo: A review of recent progress. Autoimmunity Reviews, 21(5), 103038. https://doi.org/10.1016/j.autrev.2022.103038
12. Zhang, J., Li, X., Chen, Y., Wang, L., & Zhao, H. (2023). Deep learning for vitiligo lesion segmentation: A systematic review. Computers in Biology and Medicine, 158, Article 106846. https://doi.org/10.1016/j.compbiomed.2023.106846.