Vitiligo (overview) L80

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

All authors of this article

Last updated on: 22.11.2021

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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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A distinction is made according to clinical distribution and localization:

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

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

  • Type I (prepubertal vitiligo): onset of vitiligo before puberty. Familial accumulation of vitiligo, grey hair, as well as other autoimmune diseases; frequent atopic eczema and halo-nevi. Infestation of trunk and limbs.
  • Type II (postpubertal vitiligo): Affection of the acra and face.

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

  • Vitiligo with stable course
  • Vitiligo with continuous or relapsing progression
  • Inflammatory vitiligo (erythema formation at the edge of the vitiligo due to 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 demarcated, differently configured, white patches often with hyperpigmented margins (pigment evasion into the periphery). Particularly in coloured skin, several colour gradations become visible at the edges (trichrome vitiligo or multichrome vitiligo). There is an increase in number and size, also confluence of white patches.

The hair may be white (leukotrichia) in affected skin areas. In our experience, this pattern of infestation is associated with resistance to theapier.

Perilesional depigmentation may occur around melanocytic nevi(halo or Sutton nevus). In the area of alopecia areata, there may be two-dimensional or reticular depigmentation (see figure).

At the capillitium (also eyebrows and eyelashes) circumscribed, white coloured hair areas may occur (poliosis circumscripta).

Depending on the distribution of the foci, generalized, localized and universal vitiligo are distinguished (see table); see also Uveomeningoencephalic syndrome.

Vitiligo is described as "stable" if no new foci appear; unstable = slow increase in the size of existing foci, or the irregular episodic appearance of new foci; progressive = continuous progression of existing and appearance of new foci (n. 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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Kinic:

  • Pityriasis versicolor alba: scaling, confetti-like, affection of seborrheic zones, recurrent course.
  • Pityriasis alba: skin dryness, scaling, atopic signs
  • Naevus anaemicus: localized, no irritative reddening of the focal area after scratch irritation
  • Piebaldism: congential, white forelock
  • Circumscribed scleroderma: no spot, planar tissue induration. Histology is diagnostic
  • Lichen sclerosus et atrophicus: no spot, extensive tissue induration. Mostly involvement of the genito-anal area. Itching, burning. Histology is diagnostic
  • Nevus depigmentosus: congenital, recognizable as cutaneous mosaic
  • Hypomelanosis Ito: congenital,running in the Blaschko lines,
  • Leukoderm: condition after previous diseases, often also hyperpigmentation
  • Leprosy (rarity in Europe): white spot with hypo- or anaesthesia. Histology is diagnostic
  • Hypomelanosis guttata: occurring only in areas of skin exposed to UV radiation. In individuals > 50 years of age.

  • Blaschko-linear vitiligo: special form of vitiligo; late-maifesting hamartoma of the skin.

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 according to stage, see Tab. 1.

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

  • Symptomatic: Covering ( camouflage): Cosmetic covering of depigmented areas (e.g. Dermacolor). Dyes used include eosin, rhodanine, naphto green B, sudan blue, chromium 3-oxide, bismuth oxide, titanium dioxide, various iron salts, and various natural dyes, e.g., beta-carotene, canthaxanthin, crimson, chlorophyll, etc. R025. Cave. Consistent light protection of these skin areas is additionally necessary! Notice! The exact imitation of the skin colour of the healthy areas is important!

  • Artificial tanning: In case of skin type II-III good results can be achieved with so-called "self-tanning agents". DHA ( dihydroxyacetone) as a self-tanning agent (e.g. Delial Maxi-brown) or dyes (tartrazine in Vitadye cream) are possible. The effect appears 2-3 hours after application. Enhanced effects may occur on knees and hands as the tanning effect depends on the thickness of the stratum corneum (e.g. Vitadye). Caution. Reapply every 2-3 days, spotting is not uncommon.
  • Bleaching agents: In cases 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). Less potent is azelaic acid (e.g. Skinoren). NW: Irregular bleaching effects and spotting may occur.
  • β-Carotene, especially in acral accentuated 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.).

    Caution. 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: Therapy of first choice for extensive or progressive vitiligo. UV irradiation with narrow spectrum UVB, UVB 311 nm, if necessary focally limited. Repigmentation in up to 75% of patients. Therapy can also be carried out with hand-held devices or after appropriate instruction as home therapy. UVB irradiation stimulates endothelin-1 (ET-1), a peptide secreted by keratinocytes, which promotes proliferation, chemotaxis and melanin production. Furthermore, UV-B rays are expected to have an immunosuppressive effect.

Alternatively, in the case of moderately severe vitiligo (body surface area: 10-30%) without and only with slight progression, treatment with an excimer laser can be carried out (therapy approach over 6-12 months!).

PUVA therapy: photochemotherapy with psoralenes. Repigmentation in up to 60% of cases. Especially effective on the face and neck of dark skin types. Systemic application usually with methoxsalen (0.3-0.6 mg/kg bw p.o.). However, 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, to be taken 2 hours before irradiation in each case. Alternatively, PUVA bath therapy or cream PUVA therapy can be administered. Implementation NW, KI see below. PUVA therapy. Treatment approx. 2-3 times/week for 1-3 years. If no repigmentation occurs after approx. 3 months (12-20 irradiations), a renewed change of the photosensitizer can be attempted. Otherwise discontinuation of the therapy after 4-6 months. Important: During the treatment and for 12 hours afterwards, UVA light-impermeable glasses (e.g. Clarlet from Zeiss) must be worn for systemic PUVA therapy.

PAUVA: Photochemotherapy with L-phenylalanine. Take 50-100 mg/kg bw 30-60 min. before irradiation and then irradiate with UVA light. Average irradiation frequency 3 times/week with 60-70% of the individual MED-UVA. Duration of treatment 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. 1.0-2.0 mg/kg bw p.o. to be taken 2-3 hours before start of UVA irradiation. Repigmentation in 30-40% of cases. If response to therapy within the first 6 months, continue treatment for the period of about 2 years, otherwise discontinue. Do not use in acral accentuated 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 hypomelanoses. 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. Am 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: a
  14. randomized multicenter trial.JAMA Dermatol 151:42-50.
  15. Meurer M et al (2016) Therapy of vitiligo. Dermatologist 67: 249-264
  16. Meurer M et al. (2017) Systemic treatment of vitiligo: balance and current developments.
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  18. Morohashi M et al (1977) Ultrastructural studies of vitiligo, Vogt-Koyanagi syndrome, and Incontinentia pigmenti achromians. Arch Dermatol 113: 755-766
  19. Ongenae K et al.(2003) Evidence for an autoimmune pathogenesis of vitiligo. Pigment Cell Res 16:90-100.
  20. Scherschun L (2001) Narrow-band ultraviolet B is a useful and well-tolerated treatment for vitiligo. J Am Acad Dermatol 44: 999-1003
  21. Parsad D et al. (2003) Effectiveness of oral Ginkgo biloba in treating limited, slowly spreading
  22. vitiligo. Clin Exp Dermatol 28:285-287.
  23. Park JH et al (2014) Clinical course of segmental vitiligo: a retrospective study of eighty-seven patients. Ann Dermatol 26:61-65.
  24. Ruiz-Argüelles A et al (2013) Treatment of vitiligo with a chimeric monoclonal antibody to CD20: a pilot study.
  25. Clin Exp Immunol 174:229-236.
  26. Schild M et al (2016) Vitiligo, clinic and pathogenesis. Huatarzt 67: 173-186
  27. Simon JA et al (2008) Vitiligo improvement in a patient with ankylosing spondylitis treated with infliximab. Dermatology 216: 234-235
  28. Rigopoulos D et al (2007) Etanercept in the treatment of vitiligo.
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  31. 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
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  33. Parsadet et al (2003) Effectiveness of oral gingko biloba in treating limiting slowly spreading vitiligo. Clin Exp Dermatol 28: 285-287

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Authors

Last updated on: 22.11.2021