Vitiligo

Definition

• Dermatology 2-Volume Set 5e, p. 1307
• Andrews' Diseases of the Skin, p. 1001

Epidemiology

• Prevalence: ~0.5-1% globally
• Peak onset: ages 10-30; ~50% of cases begin before age 20
• No definitive sex predilection, though females are over-represented in clinical populations (possibly due to greater healthcare-seeking behavior)
• Up to 30% of patients have an affected first-degree relative; 7% of first-degree relatives of probands have vitiligo
• Monozygotic twin concordance ~23%, confirming additional environmental contribution
• Fitzpatrick's Dermatology, p. 1360; Dermatology 2-Volume Set 5e, p. 1307

Pathogenesis

Key Pathway (IFN-γ → JAK-STAT → CXCL9/10 Axis)

1. Genetic risk + environmental triggers (oxidative stress, chemical exposures such as MBEH or 4-tertiary butyl phenol) cause melanocyte stress - including ER stress, ROS generation, and tyrosinase/TYRP-1 abnormalities
2. Stressed melanocytes release DAMPs (HSP-70, HMGB1, exosomes) into the skin
3. DAMPs activate plasmacytoid dendritic cells and innate lymphoid cells, which secrete IFN-α and IFN-γ
4. IFN-γ signals through its receptor (IFN-γR) on keratinocytes via JAK1/JAK2 → STAT1 phosphorylation
5. Phosphorylated STAT1 drives transcription of CXCL9 and CXCL10
6. CXCL9/10 recruit autoreactive CD8+ T cells expressing CXCR3 to the skin
7. These T cells kill melanocytes through direct cytotoxicity
8. Resident memory T cells (CD69+, CD103+, CD49a+) persist in lesional skin, explaining disease relapse at the same sites after treatment

• Impaired WNT/β-catenin signaling reduces melanocyte precursor differentiation, limiting repigmentation
• Regulatory T cells (Tregs) appear insufficient to suppress the autoreactive response
• Dermatology 2-Volume Set 5e, p. 1307-1308

Clinical Features

Lesion Characteristics

• Well-defined, milky-white macules with smooth, convex margins
• Surrounding skin may be normal or hyperpigmented
• Trichrome vitiligo: three zones - depigmented, intermediate tan, and normal - seen in early disease
• Inflammatory border (red): rare, indicates active disease
• Poliosis: white hairs within lesions (follicular melanocyte loss)
• Depigmented lesions are chalk-white under Wood's lamp (fluoresce bright white), which helps distinguish from hypopigmentation

Subtypes and Distribution

Markers of Active Disease (Important for Treatment Timing)

• Confetti lesions: small guttate white spots - indicate rapid spread
• Koebner phenomenon: new lesions at sites of trauma
• Trichrome lesions: intermediate pigmentation zones
• Inflammatory/erythematous border
• Fitzpatrick's Dermatology, p. 1361

Histopathology

• Complete absence of melanocytes (confirmed by S100 or MART-1/Melan-A staining)
• Usually no inflammatory infiltrate in established lesions
• Lichenoid or spongiotic inflammation at the margins of active lesions
• This explains the occasional scaling or hyperpigmentation around lesion borders
• Andrews' Diseases of the Skin, p. 1001

Differential Diagnosis

• Andrews' Diseases of the Skin, p. 1001

Associations

• Other autoimmune diseases: thyroid disease (Hashimoto's thyroiditis, Graves'), alopecia areata, rheumatoid arthritis, pernicious anemia, type 1 diabetes, lupus, Addison's disease
• Decreased risk of skin cancer (melanoma and keratinocyte cancers) - a protective immune surveillance effect
• Psychiatric comorbidity: anxiety, depression, significant impairment in quality of life; should be assessed and documented at every visit
• Up to 65% of patients in Europe have been told their disease is untreatable - a major management gap
• Fitzpatrick's Dermatology; Andrews' Diseases of the Skin

Treatment

Predictors of Response

• Favorable: face, trunk, areas with high follicular density, pigmented hairs still present in lesional skin, early/active disease
• Unfavorable: hands/feet (acral), mucosae, leukotrichia (white hairs), long-standing disease, segmental vitiligo

1. Topical Corticosteroids

• First-line for localized disease
• Mid- to high-potency agents (e.g., mometasone, clobetasol)
• Risk: skin atrophy, telangiectasias with prolonged use
• Useful for stopping progression

2. Topical Calcineurin Inhibitors (TCIs)

• Tacrolimus 0.1% or pimecrolimus 1% cream
• Preferred for face and flexural areas (fewer atrophy concerns than steroids)
• Effective for halting progression and some repigmentation
• Often combined with phototherapy

3. JAK Inhibitors (emerging/approved)

• Ruxolitinib cream 1.5% (topical JAK1/JAK2 inhibitor): FDA-approved (2022) for non-segmental vitiligo in patients ≥12 years old; first and only FDA-approved topical treatment specifically for vitiligo
• Targets the IFN-γ-JAK-STAT-CXCL9/10 axis directly
• Enhanced repigmentation reported with ruxolitinib cream + NB-UVB combination
• Oral JAK inhibitors (e.g., ritlecitinib, baricitinib) under investigation
• Dermatology 2-Volume Set 5e, p. 2810; off-label ruxolitinib systematic review PMID 40192197

4. Narrowband UVB Phototherapy (NB-UVB)

• Now the gold standard phototherapy for generalized/widespread vitiligo
• Superior to oral PUVA in efficacy and side-effect profile; better color matching of repigmented skin
• Typically 2-3 sessions/week; response assessed after 3-6 months
• Initial dose: 70% of the MED in lesional (depigmented) skin; increase carefully by 5-20% weekly based on barely perceptible erythema
• Important: depigmented skin has increased photosensitivity - dosing must be careful to avoid Koebner phenomenon from burns
• Dermatology 2-Volume Set 5e, p. 2809-2810

5. PUVA (Psoralen + UVA)

• Oral or topical psoralen followed by UVA
• More side effects than NB-UVB (nausea, photocarcinogenesis risk, cataract risk)
• Reserved for cases unresponsive to NB-UVB or where NB-UVB is unavailable

6. Systemic Corticosteroids

• Short pulse courses for rapidly progressive, generalized vitiligo to halt progression
• Not for long-term use

7. Afamelanotide + NB-UVB

• Afamelanotide (α-MSH analogue, subcutaneous implant) + NB-UVB: significantly superior and faster repigmentation vs. NB-UVB alone in RCT
• Effect more pronounced in Fitzpatrick skin types IV-VI
• Dermatology 2-Volume Set 5e, p. 2810

8. Surgical Options

• For stable vitiligo (no progression for ≥1 year)
• Autologous skin grafting (split-thickness, punch grafting, suction blister grafting)
• Melanocyte-keratinocyte transplantation procedure (MKTP)
• Segmental vitiligo often responds well to surgery due to its stability

9. Depigmentation

• For patients with near-universal vitiligo (>80% BSA), depigmentation of remaining skin with monobenzyl ether of hydroquinone (MBEH) or Q-switched laser can achieve a uniform appearance
• Irreversible

Monitoring and Investigations

• TSH, anti-TPO antibodies: screen for thyroid disease at diagnosis and periodically
• Fasting blood glucose: screen for type 1 diabetes
• CBC: screen for pernicious anemia (if suspected)
• ANA: if systemic autoimmune features present
• Psychological assessment: quality of life tools (VASI, SAVES, VIP/VIS scales)
• EADV 2025 Global Guidelines recommend formal QoL assessment at every visit, given the significant psychosocial burden

Key Points Summary