Nanny van Geel

Variant of TYR and Autoimmunity Susceptibility Loci in Generalized Vitiligo

BACKGROUND Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases. METHODS To identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families. RESULTS We detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility-complex class I molecules (P=9.05x10(-23)) and class II molecules (P=4.50x10(-34)), PTPN22 (P=1.31x10(-7)), LPP (P=1.01x10(-11)), IL2RA (P=2.78x10(-9)), UBASH3A (P=1.26x10(-9)), and C1QTNF6 (P=2.21x10(-16)). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07x10(-15)) and GZMB (P=3.44x10(-8)), and in a locus containing TYR (P=1.60x10(-18)), encoding tyrosinase. CONCLUSIONS We observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma.

Common variants in FOXP1 are associated with generalized vitiligo

In a recent genome-wide association study of generalized vitiligo, we identified ten confirmed susceptibility loci. By testing additional loci that showed suggestive association in the genome-wide study, using two replication cohorts of European descent, we observed replicated association of generalized vitiligo with variants at 3p13 encompassing FOXP1 (rs17008723, combined P = 1.04 × 10−8) and with variants at 6q27 encompassing CCR6 (rs6902119, combined P = 3.94 × 10−7).

Modified technique of autologous noncultured epidermal cell transplantation for repigmenting vitiligo: A pilot study.

BACKGROUND Several reports have demonstrated that grafting of autologous melanocytes from normally pigmented donor skin can be used for repigmentation of achromic macules in vitiligo. OBJECTIVE To investigate a modified approach in which noncultured autologous melanocytes and keratinocytes are grafted on superficially laser dermabraded vitiligo lesions in a suspension enriched with hyaluronic acid. METHODS Four patients with stable vitiligo were treated using a noncultured melanocyte-keratinocyte suspension. The cellular suspension was grafted on vitiliginous lesions previously dermabraded with a CO2 laser. To improve the viscosity and fixation of the cellular suspension hyaluronic acid was added. Three weeks after grafting, psoralen plus ultraviolet A (PUVA) or ultraviolet B (UVB) therapy was started. Residual leukodermic areas were subsequently retreated. RESULTS Repigmentation was observed within 2–4 weeks and continued to increase for 3 months after treatment. In all patients, 85–100% repigmentation was achieved. A temporary slight color mismatch was visible in all patients. The most homogeneous repigmentation was obtained 5 months after treatment. CONCLUSION This modified procedure seems to be a simple and promising treatment for larger vitiliginous areas.

Genome-Wide Analysis Identifies a Quantitative Trait Locus in the MHC Class II Region Associated with Generalized Vitiligo Age of Onset

Generalized vitiligo is a common autoimmune disease in which acquired patchy depigmentation of skin, hair, and mucous membranes results from loss of melanocytes from involved areas. Previous genetic analyses have focused on vitiligo susceptibility, and have identified a number of genes involved in disease risk. Age of onset of generalized vitiligo also involves a substantial genetic component, but has not previously been studied systematically. In this study, we report a genome-wide association study of vitiligo age of onset in 1,339 generalized vitiligo patients, with replication in an independent cohort of 677 cases. We identified a quantitative trait locus for vitiligo age of onset in the major histocompatibility complex (MHC) class II region, located near c6orf10-BTNL2 (rs7758128; P=8.14 × 10(-11)), a region that is also associated with generalized vitiligo susceptibility. In contrast, there was no association of vitiligo age of onset with any other MHC or non-MHC loci that are associated with vitiligo susceptibility. These findings highlight the differing roles played by genes involved in vitiligo susceptibility versus vitiligo age of onset, and illustrate that genome-wide analyses can be used to identify genes involved in quantitative aspects of disease natural history, as well as disease susceptibility per se.

Subjective and Objective Evaluation of Noncultured Epidermal Cellular Grafting for Repigmenting Vitiligo

Background: Noncultured epidermal cell transplantation in vitiligo permits the coverage of relatively large areas without culturing cells. Objective: To investigate the effectiveness of noncultured epidermal cell transplantation in treating stabilized vitiligo using objective and subjective evaluation methods. Methods: Noncultured autologous melanocytes and keratinocytes were grafted in a hyaluronic-acid-enriched suspension on superficially laser-abraded vitiligo lesions in 40 patients with refractory stable vitiligo (30 with generalized and 10 with localized vitiligo). The repigmentation was evaluated 3–12 months after grafting using a digital image analysis system. Furthermore the treatment was evaluated from the patients’ point of view with the DLQI (Dermatology Life Quality Index) and a ‘global assessment’. Results: The mean percentage of repigmentation, evaluated at the last follow-up visit, was 72% (median 84%), and a repigmentation of ≧70% was observed in 62% of patients. The best results were achieved in the neck and the presternal region. A subjective evaluation was performed in half of the subjects. The mean DLQI score at inclusion (6.95, SD = 6.68, n = 20) was significantly decreased after treatment (p = 0.013, mean 3.85, SD = 4.13, n = 20). The patients were satisfied with the achieved result, found it worthwhile to undergo the treatment and would choose it again. Conclusion: According to both subjective and objective evaluation methods, noncultured epidermal cell transplantation is promising in patients with stable vitiligo.

Current and emerging therapy for the management of vitiligo

Vitiligo is an acquired cutaneous disorder of pigmentation, with an incidence of 0.5% to 2% worldwide. There are three major hypotheses for the pathogenesis of vitiligo that are not exclusive of each other: biochemical/cytotoxic, neural and autoimmune. Recent data provide strong evidence supporting an autoimmune pathogenesis of vitiligo. As vitiligo can have a major effect on quality of life, treatment can be considered and should preferably begin early when the disease is active. Current treatment modalities are directed towards stopping progression of the disease and achieving repigmentation. Therapies include corticosteroids, topical immunomodulators, photo(chemo)therapy, surgery, combination therapies and depigmentation of normally pigmented skin. Topical class 3 corticosteroids can be used for localized vitiligo. The use of topical immunomodulators (TIMs) in vitiligo seems to be equally effective as topical steroids, especially when used in the face and neck region. In photo(chemo)therapy, narrowband ultraviolet-B therapy (NB-UVB) seems to be superior to psoralen ultraviolet-A therapy (PUVA) and broadband UVB. In surgical techniques, split-thickness grafting and epidermal blister grafting were shown to be effective methods, although the non-cultured epidermal suspension technique has many advantages and seems to be a promising development. Depigmentation therapy can be considered if vitiligo affects more than 60% to 80% of the body. Complementary therapies such as Polypodium leucotomos show promising results in combination with UVB therapy. No causative treatment for vitiligo is currently available. More randomized controlled trials on the treatment of vitiligo are necessary.

Simplified cellular grafting for treatment of vitiligo and piebaldism: the '6-well plate' technique

BACKGROUND Vitiligo is a disfiguring depigmenting dermatosis that affects approximately 0.5% to 1% of the general population regardless of race and sex. In patients with stable vitiligo who fail conventional therapies, surgical transplant offers a viable alternative. Noncultured cellular grafting offers the advantage of repigmenting vitiligo 5 to 10 times the size of the donor skin and can be completed on the same day on an outpatient basis. In recent years, ways to simplify this procedure have been explored, including the use of commercially available kits. OBJECTIVES To simplify the extraction of epidermal cells from donor skin using a 6‐well plate and to evaluate the clinical efficacy of this simplified technique in repigmenting stable vitiligo and piebaldism. METHODS Four patients with focal or segmental vitiligo and one with piebaldism were treated using the simplified noncultured cellular grafting protocol. Percentage of repigmentation 6 months after grafting was objectively measured using digital contour mapping. RESULTS Patients with stable segmental or focal vitiligo achieved 65% to 92% repigmentation 6 months after grafting; the treated sites involved face or limbs. The patient with piebaldism achieved 86% repigmentation. One year after grafting, the extent of repigmentation remained for all patients. CONCLUSION This set‐up is simple and inexpensive; it reduces cell preparation time, amount of reagents used, and costs, and obviates the need of a laboratory for extraction of epidermal cells. The authors have indicated no significant interest with commercial supporters.

Autoimmune/Inflammatory and Other Diseases Associated with Vitiligo

Although the exact aetiology of vitiligo remains unclear, vitiligo is widely considered to have an autoimmune component in its pathogenesis based on disease associations. According to ethnic background, large variations exist in association with autoinflamma-tory/autoimmune disorders. Some reported associations may reflect a simple coexistence of two disorders, and the repertoire of associations may help to detect shared heritable predispositions for inflamma-tion and autoimmunity. Thyroid disorders are the most commonly associated to vitiligo in Caucasian populations, alopecia areata in Chinese populations, rheumatoid arthritis (RA) being more rarely associated in both.