Vitiligo (overview) L80

Chronic, localized or generalized skin disease in which intrinsic or extrinsic factors lead to the destruction of melanocytes in the epidermis (and hair follicles) and thus to the loss of hereditary skin color, which manifests clinically as localized, but also generalized, patchy depigmentation of the skin and/or mucous membranes.

A distinction is made according to clinical distribution and localization:

• Vitiligo vulgaris (generalized vitiligo): In 78% of patients the onset is usually symmetrical and periorificial.
• Focal vitiligo: 14% of patients
• Segmental vitiligo: 5% of patients (usually unisegmental, more rarely bi- or multisegmental - probably with segmental but cutaneous mosaic dermatosis).
• 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, gray hair and other autoimmune diseases; frequent atopic eczema and halo nevi. Infestation of the trunk and limbs.
• Type II (post-pubertal vitiligo): Infestation of the acra and face.

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

• Vitiligo with a stable course
• Vitiligo with continuous or relapsing progression
• Inflammatory vitiligo (erythema forms at the edge of the vitiligo due to a local inflammatory reaction)

Prevalence: 0.5-2.0% of the Caucasian population; 2-4% of the Indian, Arab, African and Asian population. Familial clustering is observed in about 30% of cases.

Vitiligo can also occur as part of complex syndromes:

• Vogt-Koyanagi-Harada syndrome(segmental vitiligo)
• Alezzandrini syndrome (segmentalvitiligo)

• Autoimmune polyglandular syndromes (APS)

Unknown.

An immunological or autoimmunological pathogenesis is being discussed. It is assumed that overactivity of the JAK signaling pathway promotes inflammatory processes, which in turn are involved in the development and progression of vitiligo.

There is evidence of a correlation between increased serum concentrations of the chemokines CXCL9 and CXCL10 and the progression of vitiligo. CXCL10 may be a biomarker for the severity of vitiligo.

A hereditary disposition to the disease exists in up to 35% of patients.

Isomorphism(Köbner phenomenon) is detected in up to 40% of patients (sunburns, physical, chemical or mechanical trauma, topical application of diphencyprones, accidental skin contact with solvents or pesticides)

Other triggers: psychological stress, thyrotoxicosis.

Frequent, constant association with Hashimoto's thyroiditis.

Medication: beta-blockers, statins, tetracyclines, hydroquinone

Random, inconstant 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, see also 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) as well as melanogenesis (tyrosinase gene). This predisposition, coupled with other factors (e.g. cytokine growth factor hormone imbalance), results in an increased vulnerability of the melanocytes, which leads to an immunological response (vitiligo melanocytes express tyrosine-related protein-1, which induces autoimmunological reactions) and ultimately to the destruction of the melanocytes.

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)

The face, capillitium(poliosis), neck region, hands, axillary region, nipples, navel and genito-anal region are particularly affected.

Differently sized, sharply defined, differently configured, white patches, often with hyperpigmented edges (pigment flight into the periphery). In dark skin in particular, several color gradations become visible at the edges (trichrome vitiligo or multichrome vitiligo). There is an increase in the number and size of the white patches, as well as their confluence.

The hair may be white (leukotrichia) in affected areas of the skin. Experience has shown that this pattern of infestation is associated with resistance to theapia.

Perilesional depigmentation may occur around melanocytic nevi(halo or Sutton nevus). In the area of alopecia areata, flat or reticular depigmentation may occur (see illustration).

Circumscribed, white-colored areas of hair may appear on the capillitium (also eyebrows and eyelashes)(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. The so-called "segmental vitiligo", which many authors interpret as a cutaneous mosaic, requires special interpretation (Dellatorre G et al. 2023).

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

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.

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.

Clinical:

• Pityriasis versicolor alba: scaling, confetti-like, involvement of seborrheic zones, recurrent course.
• Pityriasis alba: skin dryness, scaling, atopic signs
• Nevus anaemicus: localized, no irritative redness 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, planar tissue induration. Mostly involvement of the genito anal area. Itching, burning sensation. Histology is diagnostic
• Nevus depigmentosus: congenital, recognizable as a cutaneous mosaic
• Hypomelanosis Ito: congenital,running in the Blaschko lines,
• Leukoderm: condition after previous diseases, often also hyperpigmentation
• Leprosy (rarity in Europe): white mottling with hyp- or anesthesia. Histology is diagnostic

• Hypomelanosis guttata: occurring only in UV-exposed skin areas. In individuals > 50 years of age.

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

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).

Search for and treatment of any existing underlying disease. Stage-appropriate therapy, see Table 1.

• Glucocorticoids local/intralesional: Positive therapeutic effects with halogenated or fluorinated glucocorticoids (applied locally) 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 trial with topical calcineurin inhibitors (e.g. Elidel) can be undertaken ( off-label use). 2x per day over 6 months - study situation not confirmed; strict indication due to unclear long-term side effects). The response rate is comparable with the 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 lacking. In a clinical study, a comparably good effect was achieved in comparison with clobetasol-17-propionate.

• Tofacitinib: Data on the potential efficacy of JAK inhibitors in vitiligo are available for this preparation, a selective JAK inhibitor (Craiglow BG et al. 2015). JAK inhibitors are preferably used orally. However, there are studies that also demonstrate the topical efficacy of this group of drugs in vitiligo (Ciechanowicz P et al. 2018).

• Ruxolitinib: topical JAK inhibitor, indicated for facial involvement with good study results for repigmentation (Rosmarin D et al. 2020/Tavoletti G et al. 2023). Since May 2023, the active ingredient has also been available on the German market in the form of a cream (^Opzelura®) to support repigmentation in non-segmental vitiligo.

• Symptomatic: Covering ( camouflage): Cosmetic covering of the depigmented areas (e.g. Dermacolor). Dyes used include eosin, rhodanine, naphtho green B, Sudan blue, chromium-3-oxide, bismuth oxide, titanium dioxide, various iron salts and various natural dyes, e.g. beta-carotene, canthaxanthin, carmine red, chlorophyll etc. R025. Caution! Consistent light protection of these skin areas is also necessary! Remember! It is important to imitate the exact skin color of the healthy areas!

• Artificial tanning: For skin types II-III, good results can be achieved with so-called "self-tanners". These include DHA ( dihydroxyacetone) as a self-tanning agent (e.g. Delial Maxi-brown) or colorants (tartrazine in Vitadye cream). The effect occurs 2-3 hours after application. Increased effects can occur on the 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 the 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 cream Widmer). Less potent is azelaic acid (e.g. Skinoren). NW: Irregular bleaching effects and spotting may occur.
• β-Carotene, especially for 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.)

  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.

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.

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.

Glucocorticoids, oral: Especially in cases of rapidly progressing vitiligo, oral mini-pulse therapy with a prednisolone equivalent(e.g. Decortin H) 20-40 mg/day p.o. or with dexamethasone (4-5mg, 2-3x per week) can be carried out. Due to the side effects, 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 unsuccessful (Rigopoulos D et al. 2007)

Experimental: Afamelanotide; several successful studies with the melanocortin afamelanotide are available for the indication vitiligo. In a larger study (n=55), 16mg afamelanotide was applied s.c. once a month, mostly in combination with UVB (3 x per week) (Lim HW et al. (2015)

Experimental: Use of the CD20 antibody rituximab. This approach was successfully tested in a smaller study. (Ruiz-Arguelles A et al. 2013)

Alternative "oral antioxidants": 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, less progressive vitiligo (Parsad d et al. 2003).

Often relapsing progression, rarely complete spontaneous regression.

The joint occurrence of vitiligo and malignant melanoma appears to represent a prognostically favorable constellation (for the course of malignant melanoma).

Prognostically rather unfavorable with regard to a successful therapy are the following symptoms:

• Early onset in childhood
• Infestation of >30% of the body surface
• Progressive course within the last 6-12 months
• Indications of a Köbner phenomenon
• White coloration of the body hair in the vitiligo foci

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

Stage-specific therapy of vitiligo

Application of photochemotherapy with oral chromophores and L-phenylalanine

UVA dose, individual MED UVA and treatment frequencies

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