Vitiligo

Etiology

• • Acquired destruction of melanocytes with chronic and progressive melanocyte depletion from the epidermis.
  • Non-segmental vitiligo (NSV)
    • Autoimmune mediated depigmentation.
      • There is a strong association between NSV and a personal or family history of autoimmune disease.
      • Autoimmune thyroid disease coexists in approximately 25% of NSV cases (Taïeb, 2007).
      • Other associated autoimmune diseases include: autoimmune adrenal insufficiency, diabetes mellitus, psoriasis, alopecia areata, rheumatoid arthritis and pernicious anemia.
    • Based on current evidence, it is likely that NSV is a melanocytorrhagic disorder (melanocytes have an inappropriate response to a stressor (i.e. oxidative) which leads to melanocyte dysfunction and apoptosis).
      • Genetic predisposition
      • May relate to an initial oxidative stress event with inappropriate initial and subsequent response (innate and adaptive immune responses)
    • The inappropriate melanocyte response is likely due to:
      • Genetic polymorphisms in genes involved in melanogenesis and immunity.
        • The TYR gene, which encodes for the key melanocyte enzyme tyrosinase, has been implicated in disease.
      • Environmental factors.
      • Metabolic alterations that facilitate increased generation of reactive oxygen species as well as heightened susceptibility to mild epidermal insults (i.e. friction).
  • Segmental vitiligo (SV)
    • Due to somatic mosaicism.
    • This mosaicism leads to a population of cutaneous cells failing to express some genes responsible for a normal skin phenotype.
    • This mosaicism hypothesis may also be responsible for pathogenesis in mixed vitiligo (MV), a term used to describe rare cases in which individuals are afflicted with both NSV and SV.
  • Mixed NSV and SV: Initially presenting with SV, later developing bilateral NSV
  • Unclassified: i.e. Multifocal asymmetrical nonsegmental, punctate, single-site mucosal

Epidemiology

• Estimated prevalence: 0.5-2% of the population (Ezzedine, 2015).
  • Prevalence varies significantly by geographic region.
    • Vitiligo afflicts up to 9% of the population in India, but less than 1% of the population in the Shaanxi province of China (Bergqvist, 2020).
• Approximately 50% of cases develop before age 20, with 80% of cases presenting by age 30 (Taïeb, 2009).
• There are equal rates of disease in both sexes.
  • Women and girls are more likely to seek treatment.
• NSV is the overwhelmingly most common form, accounting for up to 90% of cases (Taïeb, 2009).
• SV has an earlier age of onset and accounts for up to 30% of pediatric cases (Taïeb, 2009).
• In a 19 patient retrospective case series of MV, the majority of patients developed SV in childhood followed by development of NSV within 24 months (Ezzedine, 2011).
• Patients at high risk of developing vitiligo:
  • Individuals who have received a stem cell transplant or allogenic bone marrow transplant are three times more likely to develop vitiligo than healthy individuals.
  • Nota bene metastatic melanoma and certain drugs used to treat metastatic melanoma (i.e. immune checkpoint inhibitors and BRAF inhibitors) can lead to a vitiligo-like whitening of the skin (leukoderma).
    • Leukoderma as a side effect of immunotherapy is associated with a favorable prognosis because it indicates destruction of neoplastic melanocytes.
• Individuals with vitiligo have been demonstrated in clinical trials to have a significantly lower risk of developing cutaneous or internal malignancies than those without vitiligo (Paradisi, 2004 & Bae, 2019).

Clinical features

• Non-segmental vitiligo (NSV)
  • Well demarcated white macules that may present around the eyelids (Figure 1).
    • The boarders of the lesions are usually the color of normal skin, but may be hyperpigmented or erythematous.
  • Symmetric and bilateral.
• Segmental vitiligo (SV)
  • Well demarcated white, band-shaped macules.
  • Appear in a dermatomal distribution.
    • Most commonly involves the trigeminal nerve.
    • More likely than NSV to involve the face.
  • Poliosis (eyebrow and eyelash whitening).
  • A unilateral, solitary lesion occurs in 75% of cases (Hann, 1996).
• Ocular involvement
  • Vitiligo can lead to hypopigmentation of the retinal pigment epithelium. However, it does not cause a change in iris pigmentation.
  • Vogt-Koyanagi-Harada syndrome (VKH) is a multisystem disease defined by bilateral granulomatous panuveitis. Vitiligo, poliosis, alopecia areata and neurological findings are also often present.
• Triggers:
  • Emotional stress may trigger new-onset vitiligo.
  • Koebner’s phenomenon (KP)
    • Patients with cutaneous skin disease develop lesions at sites of skin trauma that were not previously involved.
    • Sites of relapse may therefore be related to occupation, clothing, personal hygiene, or daily habits (i.e. eye rubbing).
    • KP occurs in higher rates in NSV than in SV; an observational study analyzing the factors associated with KP demonstrated it occurring at a rate of 31% in NSV and 5% in SV (Khurrum, 2017).
• Other diagnostic tests (when diagnosis is unclear based on history and physical exam):
  • Woods lamp examination
  • Dermoscopy (vitiligo macules will demonstrate a white glow)
  • Skin biopsy (only required to exclude other disorders)
    • Absence of melanocytes and epidermal pigment
    • A lymphocytic infiltrate may be present
• Severity scoring (not routinely assessed but can be particularly helpful in monitoring disease progression):
  • Vitiligo Area Scoring Index (VASI)
    • Measures the degree and extent of depigmentation on the head and neck, upper extremities, hands, trunk, lower extremities and feet.
    • Based on the Psoriasis Area and Severity Index.
  • Vitiligo European Task Force (VETF) system
    • Assesses five sites using a scale from 0 (normal pigmentation) to 4 (complete whitening).
    • Additionally assesses spreading of disease as -1 (regressing), 0 (stable disease), or +1 (spreading disease).
    • Based on the SCORing Atopic Dermatitis (SCORAD) system.

• Pityriasis versicolor
• Nevus depigmentosus
• Idiopathic guttate hypomelanosis
• Melanoma associated leukoderma
• Drug induced leukoderma
• Post inflammatory hypopigmentation (may be seen in the setting of atopic dermatitis, contact dermatitis, psoriasis, drug reactions, phototherapy or radiotherapy)
• Infection related hypomelanoses
• Hypomelanosis of Ito

An underlying principal of management is avoidance of any form of skin injury (i.e. cuts, abrasions, sunburn) as injury can lead to new vitiligo lesions (consistent with Koebner’s phenomenon).

• Medical therapy: Current available therapies may slow rapidly spreading disease and may stimulate repigmentation, but are not curative and have variable efficacy.
• Oral corticosteroids are efficacious for stabilizing rapidly progressive disease.
• Moderate dose oral dexamethasone administered twice per week (mini-pulse therapy) was demonstrated to halt disease progression after 18 weeks in 88% of patients (Radakovic-Fijan, 2001).
• Topical calcineurin inhibitors
• Topical corticosteroids
• In the periocular region, topical corticosteroids can increase intraocular pressure and cause dermal atrophy, making calcineurin inhibitors a preferred option.  
• Phototherapy (most efficacious if initiated early)     
• Narrow band ultraviolet B therapy (NBUVB)          
• Preferred for widespread disease.
• Combination therapy with NBUVB plus topical immunomodulators and topical corticosteroids has been demonstrated to increase rates of repigmentation.
• Excimer
  • A type of targeted phototherapy preferred for local disease.
• Psoralen and ultraviolet A therapy
  • No longer commonly used as NBUVB is safer and more efficacious.
• Oral antioxidants may be beneficial in combination with phototherapy.
• Systemic corticosteroids
• α-melanocyte-stimulating hormone analogues 
• Refractory disease
• Skin graft
• Melanocyte transplantation with engineered or autologous epidermal skin cells
• Total body depigmentation
• When vitiligo covers more than 50-60% of total body surface area, depigmentation using cryotherapy, laser therapy, or bleaching creams can be implemented.
• Natural history:
• NSV
• Highly unpredictable
• Depigmentation followed by spontaneous repigmentation
• Relapse is common
• SV
• Rapid spread of depigmentation over 3-24 months
• Depigmentation may persist or spontaneous repigmentation may occur
• Relapse is uncommon
• In cases in which mini-pulse steroid therapy and/or NBUVB therapy is not feasible, there is some demonstrated success using afamelanotide, methotrexate, minocycline, and ginko biloba; polypodium leucotomas may help when combined with NBUVB
• Janus kinase inhibitors have demonstrated mixed results and, given carcinogenicity, are not typically pursued
• The FDA has approved 1.5% ruxolitinib (topical) for nonsegmental vitiligo, and this proved successful in a case report of eyelid vitiligo (OPRS 2024:40:p e70).
• 30% trichloroacetic acid (TCA) also demonstrated benefit in vitiligo of the eyelid in a clinical trial that included 10 eyelids; all eyelids demonstrated good (20%) or excellent (80%) response. Care was taken to avoid intraocular exposure (Derm Surg 2021: 47:p e 53).

• Psychiatric morbidity
• In one study of 520 individuals, 56% reported that their disease moderately to significantly impacted their quality of life, using a validated questionnaire (Talsania, 2009).
• These individuals most often reported feels of social stigma from disfigurement and low self-esteem.
• Notably, nearly 80% of these individuals had disease involving their face.


Photograph courtesy of Roman Shinder, MD.

Figure 1. Bilateral depigmentation involving the lower eyelid and lid margin in NSV.

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