Vitiligo (overview) L80

Authors: Prof. Dr. med. Peter Altmeyer, Dr. med. Gerret Paulsen

All authors of this article

Last updated on: 14.01.2021

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Synonym(s)

Vitiligo generalized; Vitiligo localized; Vitiligo universal; White spot disease

Definition
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Chronic, localized or generalized disease of the skin, in which, under the influence of intrinsic or extrinsic factors, the melanocytes in the epidermis (and hair follicles) are destroyed, resulting in the loss of hereditary skin colour, which is clinically manifested by localized but also generalized patch-like depigmentation of the skin and/or mucous membranes.

Classification
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According to clinical distribution and localisation, a distinction is made between:

  • Vitiligo vulgaris (generalized vitiligo): In 78% of patients, the onset is usually symmetrical and perioriferal.
  • focal vitiligo: 14% of patients
  • Segmental Vitiligo: 5% of the pat (can be focal, unisegmental or bi- or multisegmental).
  • Acrofacial vitiligo: 2% of patients
  • Vitiligo of the mucous membrane: 0.5% of the patient
  • Vitiligo universalis: 0,5% of the patients

Depending on the beginning of the disease, a further subdivision of vitiligo can be made:

  • Type I (prepubertal vitiligo): Vitiligo begins before puberty. Familial accumulation of vitiligo, gray hair and other autoimmune diseases; more frequent atopic eczema and halo-naevi. Infestation of trunk and limbs.
  • Type II (post-pubertal vitiligo): Infestation of the acra and face.

The assessment of the clinical activity of vitiligo in the last 12 months is important for a decision on therapy:

  • Vitiligo with stable course
  • Vitiligo with continuous or intermittent progression
  • Inflammatory vitiligo (at the edge of the vitiligo, there is an increase in inflammation and a local inflammatory reaction)

Occurrence/Epidemiology
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Prevalence: 0.5-2.0% of the Caucasian population; 2-4% of the Indian, Arab, African and Asian populations. Familial clustering is observed in about 30% of cases. The disease has a "near-orphan status" in terms of treatment options.

Etiopathogenesis
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  • Unknown. Discussed is an immunological or autoimmunological pathogenesis.
  • There is evidence for a correlation between increased serum concentration of the chemokines CXCL9 and CXCL10 and a progression of vitiligo. CXCL10 may be a biomarker for the severity of vitiligo.
  • Hereditary disposition of the disease exists in up to 35% of patients.
  • Isomorphism(Koebner phenomenon) is detected in up to 40% of patients (sunburn, physical, chemical or mechanical trauma, topical application of diphencyprone, accidental skin contact with solvents or pesticides)
  • Other triggers: psychological stress, thyrotoxicosis.
  • Frequent and constant association with Hashimoto's thyroiditis.
  • Medicines: beta-blockers, statins, tetracyclines, hydroquinone
  • Random, non-constant associations exist with pernicious anemia, Addison's disease, alopecia areata, lupus erythematosus, autoantibodies against parietal cells of the stomach and adrenal cortex, malignant melanoma, pemphigus vulgaris, diabetes mellitus, myasthenia gravis, biliary cirrhosis, s.a. polyendocrinological syndrome, autoimmunological.
  • Genetic studies have revealed a number of polymorphisms in susceptibility genes of congenital (e.g. NLRP1 - is increasingly expressed in perilesional vitiligo skin - , CASP7) and adaptive immunity (e.g. HLA class I; IL2R, FOXP3) but also of melanogenesis (tyrosinase gene). This predisposition, coupled with other factors (e.g. cytokine growth factor hormone imbalance), results in increased melanocyte vulnerability, which leads to an immunological response (vitiligo melanocytes express the tyrosine-related protein-1, which induces autoimmunological reactions) and ultimately to melanocyte destruction.

Manifestation
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Mostly occurring between the 10th and 30th year of life (in half of the cases before the 20th year of life; in 25% of the cases before the 10th year of life). No sex preference. S.a. under classification (pre- and postpubertal)

Localization
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Especially face, capillitium(poliosis), neck region, hands, axillary region, nipples, navel as well as genito-anal region are affected.

Clinical features
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Differently sized, sharply defined, differently configured, white spots, often with hyperpigmented edges (pigment migration to the periphery). Especially in colored skin several color gradations become visible at the margins (trichrome vitiligo or multichrome vitiligo). There is an increase in number and size, also a confluence of white spots.

The hairs may be white (leukotrichia) in affected skin areas. Experience has shown that this infestation pattern is accompanied by resistance to theaphylaxis.

Around melanocytic nevi, perilesional depigmentation may occur(halo - or sutton nevus).

On the capillitium (also eyebrows and eyelashes), circumscribed, white tinted hair areas can occur (Poliosis circumscripta)

Depending on the distribution of the foci, a distinction is made between generalized, localized and universal vitiligo (see table); see also Uveomeningoencephalic syndrome.

Vitiligo is described as "stable" if no new foci occur; unstable = slow increase in size of existing foci, or the irregular intermittent occurrence of new foci; progressive = continuous progression of existing foci and occurrence of new foci (Meurer M et al. 2017).

Laboratory
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Determination of TSH as well as anti-TPO (elevated in 10%) and anti-thyroglobulin antibodies (elevated in 7.5%; see also under thyroglobulin). ANA are elevated in 5% of the patients. Relatively frequently (16.3%), eosinophilia is detected in the blood count. The relevance of elevated SOX10 serum levels in vitiligo remains to be seen. Further laboratory tests are not helpful.

Histology
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No or tyrosinase-negative melanocytes as well as melanin-free basal cells In the early phase of vitiligo development, a perivascular lymphocytic infiltrate is found, with melanocytes still preserved.

Differential diagnosis
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Kinisch:

Complication(s)
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In very rare cases, eye and inner ear involvement may occur (uveitis due to functional impairment of the melanocytes in the stria vascularis; mild sensineural hypoacusis is detectable in about 14% of patients and is usually ignored in everyday clinical practice).

Therapy
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Search for and treatment of any existing underlying disease. Therapy appropriate to the stage of the disease, see Table 1.

  • Glucocorticoids local/intralesional: Positive therapeutic effects with halogenated or fluorinated glucocorticoids (locally applied) such as betamethasone valerate (e.g. Betnesol V cream), clobetasol propionate (e.g. Dermoxin cream, R054 ) and hydrocortisone in creams or ointments R120. Successes have also been described with intralesional injections of triamcinolone acetonide (e.g. Volon A 10-40 mg) in various studies.
  • Pimecrolimus: A therapy attempt with topical calcineurin inhibitors (e.g. Elidel, Douglan) can be undertaken ( off-label-use). 2x per day over 6 months - study situation not secured -; strict indication because of unclear long-term side effects!) The level of the response rate is comparable with results of local glucocorticoid therapy. Some authors negate the effects of monotherapy with calcineurin inhibitors.
  • Tacrolimus: Good results were achieved in several pilot studies with topically applied tacrolimus (1-2 times/day) off-label-use. The effects are often only temporary. Larger controlled studies are missing. In a clinical study a comparably good effect could be achieved in comparison to clobetasol-17-propionate.
  • Tofacitinib: For this preparation, a selective JAH inhibitor, data are available on the potential efficacy of JAH inhibitors in vitiligo (Craiglow BG et al. 2015). JAK inhibitors are preferably used orally. However, there are studies that also prove the topical effectiveness of this group of drugs in vitiligo (Ciechanowicz P et al. 2018).

  • Symptomatic: Covering ( camouflage): Cosmetic covering of the depigmented areas (e.g. Dermacolor). Used dyes are eosin, rhodanine, naphto green B, sudan blue, chromium-3-oxide, bismuth oxide, titanium dioxide, various iron salts as well as different natural dyes, e.g. beta-carotene, canthaxanthin, carmine red, chlorophyll etc. R025. Cave! Consistent sun protection of these skin areas is additionally necessary! Notice! It is important to imitate the exact skin colour of the healthy areas!

  • Artificial tanning: For skin types II-III good results can be achieved with so-called "self-tanning". DHA ( dihydroxyacetone) can be used as a self-tanner (e.g. Delial Maxi-brown) or dyes (Tartrazine in Vitadye cream). The effect occurs 2-3 hours after application. Increased effects may occur on the knees and hands as the tanning effect depends on the thickness of the stratum corneum (e.g. Vitadye). Cave! Re-apply every 2-3 days, stain formation is not uncommon.
  • Bleaching agent: In case of pronounced vitiligo, the remaining pigmented skin can be bleached. Active ingredients are hydroquinone 5%, hydrocortisone 1% and tretinoin 0.1% (e.g. Pigmanorm Creme Widmer). Azelaic acid is less potent (e.g. Skinoren). NW: Irregular bleaching effects and staining may occur.
  • β-carotene, especially in cases of acral vitiligo (e.g. carotaben: initially 3-5 times 25 mg/day p.o. after approx. 5 weeks reduction to 1-2 times/day 25 mg p.o.).

    Cave! Liver and/or kidney dysfunctions are possible!

  • Substitution of vitamin C, B and folic acid are recommended by some authors, but their effectiveness is doubtful.
  • Combined therapy: see table 1 below.

General therapy
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Vitiligo is considered a purely cosmetic disorder, especially in regions of the world where a high proportion of the population has skin types IV - VI. The spectrum of therapeutic options has expanded significantly in the last 10 years. However, the expectations of a permanent and complete repigmentation can rarely be fulfilled.

Radiation therapy
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  • Narrow Spectrum UVB Therapy: 1st choice therapy for extensive or progressive vitiligo. UV-irradiation with narrow spectrum UVB, UVB 311 nm, if necessary limited to the focal area. Repigmentation in up to 75% of the patients. Therapy can also be carried out with handheld devices or as home therapy after appropriate instruction. UVB irradiation stimulates endothelin-1 (ET-1), a peptide secreted by keratinocytes, which promotes proliferation, chemotaxis and melanin production. Furthermore, an immunosuppressive effect of UV-B rays is expected.
  • Alternatively, in cases of moderately severe vitiligo (body surface area: 10-30%), treatment with an excimer laser can be carried out without and with only slight progression (therapy approach over 6-12 months!)
  • PUVA Therapy: Photochemotherapy with psoralens. Repigmentation in up to 60% of cases. Especially on face and neck for dark skin types. Systemic treatment usually with Methoxsalen (0.3-0.6 mg/kg bw p.o.). However, the systemic application of 5-methoxypsoralen (e.g. 5-MOP, Geralen) 0.6-1.2 mg/kg bw p.o. or trimethylpsoralen (TMP, Trisoralen) 0.6 mg/kg bw p.o. is also possible, in each case 2 hours before irradiation. Alternatively, perform PUVA bath therapy or cream PUVA therapy. Performance NW, AI see below. PUVA therapy. Treatment approx. 2-3 times/week over 1-3 years. If no repigmentation occurs after approx. 3 months (12-20 irradiations), a new change of the photosensitizer can be tried. Otherwise therapy is stopped after 4-6 months. Important: During the treatment and 12 hours afterwards, UVA-light impermeable glasses must be worn for systemic PUVA therapy (e.g. Clarlet from Zeiss).
  • PAUVA: Photochemotherapy with L-phenylalanine. 50-100 mg/kg bw 30-60 minutes before irradiation and then irradiate with UVA light. Average irradiation frequency 3 times/week with 60-70% of individual MED-UVA. Treatment duration 2 years and more. NW and AI see below. PUVA therapy. L-Phenylalanine is not officially approved as a photochemotherapeutic agent (off-label use!)
  • KUVA-Therapy: Photochemotherapy with Khellin. Take 1.0-2.0 mg/kg bw p.o. 2-3 hours before the start of UVA-irradiation. Repigmentation in 30-40% of cases. If the therapy responds within the first 6 months, continue treatment for about 2 years, otherwise discontinue. Do not use for acral vitiligo. NW and AI see below. PUVA therapy. Khellin is not officially approved as a photochemotherapeutic agent (off-label use)!
  • Experimental: Narrow spectrum UVB irradiation in combination with the melanocyte stimulant afamelantonide (dosage: 16mg implant s.c. every 4 weeks, over a period of 6 months) Results of a multicenter study (n= 53 patients) are available.

Internal therapy
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  • Glucocorticoids, oral: Especially in rapidly progressing vitiligo, oral minipulse therapy with a prednisolone equivalent(e.g. Decortin H) 20-40 mg/day p.o. or with dexamethasone (4-5mg, 2-3 times per week) can be performed. Due to the side effects, a long-term therapy > 12 weeks is controversial.
  • Anecdotally, healing of vitiligo has been described under therapy with TNF-alpha blockers. In a smaller application study, however, this approach proved to be unsuccessful (Rigopoulos D et al. 2007)
  • Experimental: Afamelanotide; there are several successful studies with the melanocortin afamelanotide for the indication Vitiligo. In a larger study (n=55) 16mg afamelanotides were applied once per month s.c., mostly in combination with UVB (3 x per week) (Lim HW et al. (2015)
  • Experimental: Use of the CD20 anitbody rituximab. This approach was successfully tested in a smaller study. (Ruiz-Arguelles A et al. 2013)
  • Alternatively "oral antixoydants": standardized extracts from the bark or leaves of Ginkgo biloba (e.g. Tebonin® forte) were successful in 2 placebo-controlled studies in patients with limited low progressive vitilgo (Parsad d et al. 2003).

Progression/forecast
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Often intermittent progression, rarely complete spontaneous regression.

The joint occurrence of vitiligo and malignant melanoma seems to be a prognostically favourable constellation (for the course of malignant melanoma).

Prognostically rather unfavourable with regard to the success of therapy, the following symptoms are to be evaluated:

  • early onset in childhood
  • Infestation of >30% of the body surface
  • progressive course within the last 6-12 months
  • Evidence of a Koebner phenomenon
  • White coloration of the body hairs in the vitiligo foci

The segmental (the midline is not crossed) vitiligo develops as an isolated spot, uni- or multilocular, shows a rapid progression to band-shaped white spot, but never leads to universal spread and comes to a halt after a few years.

Naturopathy
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Initial studies suggest that the vitiligo under ginkgo extract, 120 mg/day p.o. over 6 months, will regress. Analogous results are reported from the use of Polypodium leucotomos (see table).

Tables
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Determination of the extent of vitiligo after

Vitiligo European Task Force assessment (VETFa n. Taieb A et al. 2007)

Head/neck 9%
arms/hands 18%
Fuselage 36%
legs/feet 36%
Genital region 1%

Severity assessment of vitiligo

0-10% Limited Vitiligo
10-30% Medium Vitiligo
>30% Severe to generalized vitiligo
80-100% universal vitiligo

Treatment of Vitiligo according to its stage

Treatment I. Election

UVB 311 nm, therapy duration about 1 year, response rate: 75%.

Treatment II. Choice

PUVA systemic, over 2-3 months, with beginning follicular repigmentation continue for up to 2 years. Maintenance: Treatment once/7-14 days. In case of lack of repigmentation change of chemotherapeutic agent.

Treatment III. Choice

PAUVA or KUVA. External use of khellin/or phenylalanine and UVA irradiation. In case of lack of repigmentation, discontinuation of treatment after 3-4 months.

Alternative

External use of glucocorticoids, in the initial stage possibly short-term systemic therapy with glucocorticoids.

Alternative (experimental procedure)

Oral application of an extract of the fern plant "Polypodium leucotomos": 3 times/day 250 mg p.o. and narrow band UVB irradiation (Phillipps TL-01/initial dose between 210 and 360 mJ/cm2).

Localized vitiligo foci

calcineurin antagonists, e.g. Pimecrolimus (Elidel, Douglan); glucocorticoids locally (cream or intralesional Volon A injection). Alternatively PUVA locally (very phototoxic), KUVA or PAUVA locally.

Generalized Vitiligo

Depigmentation of the remaining pigmented areas with bleaching agents (Pigmanorm Widmer).

Accompanying measures

Camouflage (Dermacolor), self-tanner (Vitadye), light protection.

Accompanying medication

Vitamin B and C preparations and folic acid. Effectiveness controversial.

Application of photochemotherapy with oral chromophores and L-phenylalanine

Chromophore

Dosage [mg/kg bw].

Waiting time

Erythema

Repopulation

UVA Dose

Methoxsalen (8-MOP)

0,3-0,6

One hour.

++

+

60-70% of the MED

5-MOP

0,6-1,2

Two hours.

++

+

60-70% of the MED

TMP

0,6

Two hours.

+

+

60-70% of the MED

Khellin

1,0-2,0

2-3 hours.

-

+

60-70% of the MED

Phenylalanine

50-100

One hour.

+

60-70% of the MED

UVA dose, individual MED-UVA and treatment frequencies

Skin type

MED-UVA

[J/cm2]

Initial dose

[J/cm2]

Increase

[J/cm2]

Frequency

Maximum dose

[J/cm2]

I

0,5

0,3

0,25-0,5

3 times/week

8-10

II

1,0

0,6

0,25-0,5

3 times/week

8-10

III

1,5

1,0

0,25-0,5

3 times/week

8-10

IV

2,0

1,5

0,25-0,5

3 times/week

8-10

Literature
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  1. Antony F et al (2003) Vitiligo in association with human immunodeficiency virus infection. J Eur Acad Dermatol Venereol 17: 456-458
  2. Blokzijl A et al (2016) Elevated Levels of SOX10 in Serum from Vitiligo and Melanoma Patients, Analyzed by Proximity Ligation Assay. PLoS One 11:e0154214.
  3. Böhm M (2015) Differential diagnosis of hypomelanosis. dermatologist 66: 945-958
  4. Ciechanowicz P et al (2018) JAK inhibitors in dermatology. Current evidence and future applications. J Dermatolog Treat 15:1-22.

  5. Ezzedine K et al (2012) Halo nevi association in nonsegmental vitiligo affects age at onset and depigmentation pattern. Arch Dermatol 148:497-502

  6. Fain PR et al (2003) A genomewide screen for generalized vitiligo: confirmation of AIS1 on chromosome 1p31 and evidence for additional susceptibility loci. At J Hum Genet 72: 1560-1564
  7. Grimes PE et al (2013) The efficacy of afamelanotide and narrowband UV-B phototherapy for repigmentation of vitiligo. JAMA Dermatol 149:68-73
  8. Handa S et al (2003) Epidemiology of childhood vitiligo: A study of 625 patients from North India. Pediatric Dermatol 20: 207-210
  9. Hönigsmann H et al (1987) Oral Photochemotherapy with psoralens and UVA (PUVA): Principles and Practice. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedbberg IM, Austen KF (eds.) Dermatology in General Medicine. Mc Graw Hill, New York, pp. 1533-1558
  10. Jin Y et al (2016) Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants. Nat Genet 48:1418-1424.
  11. Kadono T (2017) Immune-related adverse events by immune checkpoint inhibitors. Nihon Rinsho Meneki Gakkai Kaishi 40:83-89.
  12. Langan EA et al (2011) Melanotropic peptides: what exactly is meant by "melanotan"? Acta Derm Venereol 91:377
  13. Lim HW et al (2015) Afamelanotide and narrowband UV-B phototherapy for the treatment of vitiligo:
    arandomized multicenter trial.JAMA Dermatol 151:42-50.
  14. Meurer M et al (2016) Therapy of vitiligo. dermatologist 67: 249-264
  15. Meurer M et al (2017) Systemic treatment of vitiligo: Balance and current developments.
    Dermatologist 68:876-884.
  16. Morohashi M et al (1977) Ultrastructural studies of vitiligo, Vogt-Koyanagi syndrome, and Incontinentia pigmenti achromians. Arch Dermatol 113: 755-766
  17. Ongenae K et al(2003) Evidence for an autoimmune pathogenesis of vitiligo. Pigment Cell Res 16:90-100
    .Scherschun L (2001) Narrow-band ultraviolet B is a useful and well-tolerated treatment for vitiligo. J Am Acad Dermatol 44: 999-1003
  18. Parsad D et al (2003) Effectiveness of oral Ginkgo biloba in treating limited, slowly spreadingvitiligo
    . Clin Exp Dermatol 28:285-287.
  19. Ruiz-Argüelles A et al (2013) Treatment of vitiligo with a chimeric monoclonal antibody to CD20: a pilot study.
    Clin Exp Immunol 174:229-236.
  20. Schild M et al (2016) Vitiligo, Clinical and Pathogenesis. Huatologist 67: 173-186
  21. Simon JA et al (2008) Vitiligo improvement in a patient with ankylosing spondylitis treated with infliximab. Dermatology 216: 234-235
  22. Rigopoulos D et al (2007) Etanercept in the treatment of vitiligo.
    Dermatology 215:84-85.
  23. Taïeb A et al (2007) The definition and assessment of vitiligo: a consensus report of the Vitiligo European Task Force. Pigment Cell Res 20:27-35.
  24. Taieb A et al (2013) Vitiligo European Task Force (VETF); European Academy of Dermatology and Venereology (EADV); Union Européenne des Médecins Spécialistes (UEMS). Guidelines for the management of vitiligo: the European Dermatology Forum consensus. Br J Dermatol 168:5-19
  25. Travis LB et al (2003) Successful treatment of vitiligo with 0.1% tacrolimus ointment. Arch Dermatol 139: 571-574
  26. Parsadet et al (2003) Effectiveness of oral gingko biloba in treating limites slowly spreading vitiligo. Clin Exp Dermatol 28: 285-287

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Authors

Last updated on: 14.01.2021