In previous linkage and genome-wide association studies we identified 17 susceptibility loci for generalized vitiligo. By a second genome-wide association study, meta-analysis, and independent replication study, we have now identified 13 additional vitiligo-associated loci, including OCA2-HERC2, a region of 16q24.3 containing MC1R, a region of chromosome 11q21 near TYR, several immunoregulatory loci including IFIH1, CD80, CLNK, BACH2, SLA, CASP7, CD44, IKZF4, SH2B3, and a region of 22q13.2 where the causal gene remains uncertain. Functional pathway analysis shows that most vitiligo susceptibility loci encode immunoregulatory proteins or melanocyte components that likely mediate immune targeting and genetic relationships among vitiligo, malignant melanoma, and normal variation of eye, skin, and hair color.

Vitiligo is an autoimmune disease in which depigmented skin results from destruction of melanocytes1, with epidemiologic association with other autoimmune diseases2. In previous linkage and genome-wide association studies (GWAS1, GWAS2), we identified 27 vitiligo susceptibility loci in patients of European (EUR) ancestry. We carried out a third GWAS (GWAS3) in EUR subjects, with augmented GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three GWAS, followed by an independent replication. The combined analyses, with 4,680 cases and 39,586 controls, identified 23 new loci and 7 suggestive loci, most encoding immune and apoptotic regulators, some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some corresponding to eQTL at these loci. Together, the identified genes provide a framework for vitiligo genetic architecture and pathobiology, highlight relationships to other autoimmune diseases and melanoma, and offer potential targets for treatment.

In contrast to other mid-infrared lasers tested, the 2940-nm Erbium:YAG laser thus provides a potential instrument for future applications in skin surgery, especially when aiming at a careful ablative removal of delicate superficial lesions with maximum sparing of adjacent tissue structures. However, in the purely incisional application mode pulsed mid-infrared lasers, though of potential usefulness in microsurgical indications (eg, surgery of the cornea), do not offer a suggestive alternative to simple scalpel surgery of the skin.

Besides its proinflammatory properties, interleukin-8 (IL-8) has been suggested as an important promoter for melanoma growth. To study the role of IL-8 in melanoma biology, we determined the in vivo expression of IL-8 mRNA by in situ hybridization in primary melanoma lesions and metastases. High levels of melanoma cell-associated IL-8-specific transcripts were exclusively detected in close vicinity of necrotic/hypoxic areas of melanoma metastases, whereas both in primary melanomas and in non-necrotic metastases IL-8 expression was low or absent. To analyze further the up-regulation of IL-8 mRNA expression in necrotic/hypoxic tumor areas, human melanoma cell lines of different aggressiveness exposed to severe hypoxic stress (anoxia) were used as an in vitro model. Anoxia induced IL-8 mRNA and protein expression in the highly aggressive/metastatic cell lines MV3 and BLM but not in the low aggressive cell lines IF6 and 530. As shown by IL-8 promoter-dependent reporter gene analysis and mRNA stability assays, elevated mRNA levels in melanoma cells were due to both enhanced transcriptional activation and enhanced IL-8 mRNA stability. Interestingly, transcriptional activation was abolished by mutations in the AP-1 and the NF-kappaB-like binding motifs, indicating that both sites are critical for IL-8 induction. Concomitantly, anoxia induced an enhanced binding activity of AP-1 and NF-kappaB transcription factors only in the highly aggressive cells. From our in vitro and in vivo data we suggest that anoxia-induced regulation of IL-8 might be a characteristic feature of aggressive tumor cells, thus indicating that IL-8 might play a critical role for tumor progression in human malignant melanoma.

After 7-16 weeks, six of the nine patients showed initial repigmentation on the side treated with UVB311 nm. After 6 months of treatment, none of the patients showed repigmentation on the areas treated with broad-band UVB, which prompted us to apply UVB311 nm all over the body. At the end of 12 months, two patients showed > 75% repigmentation, two showed 51-75%, two showed 26-50%, and three showed 0-25%. In all patients with progressive vitiligo (seven of the nine patients), disease activity was stopped. Remarkably, vitiligo lesions treated with calcipotriol initially showed delayed repigmentation compared with control areas; however, there was no therapeutic difference between calcipotriol and placebo, both in combination with UVB311 nm, by the end of the study. The DLQI score improved significantly by an average of 28%. Conclusion UVB311 nm therapy was effective in the treatment of vitiligo, whereas broad-band UVB had no effect. Combination with calcipotriol ointment was not superior to UVB311 nm monotherapy. The quality of life significantly improved with narrow-band UVB311 nm phototherapy.

Topical tacrolimus was recently introduced as a novel therapeutic option in vitiligo. Excellent results were seen mainly on the face and neck areas. We treated 30 adult vitiligo patients with tacrolimus 0.1% ointment twice daily, and compared the results with those of placebo ointment. In 20 patients, defined areas on the right arm or leg were occluded overnight with 3 different dressings. Repigmentation was evaluated quantitatively and qualitatively. Quality of life changes were assessed with the Dermatology Life Quality Index. After 6 months, treatment was stopped in 7 of 30 patients as they did not show any repigmentation, 5 of them had no occlusive therapy. After 12 months, 17 of 21 patients (81%) with facial involvement showed repigmentation of the face. Although no or minimal repigmentation occurred on the extremities when using tacrolimus ointment alone, 80% of the patients showed repigmentation on the arms when using additional occlusive, especially hydrocolloid dressings. Hands, feet and lower legs were unresponsive. The best results were obtained in patients with long-standing vitiligo. Only minimal side-effects were noted. There was no significant elevation in tacrolimus blood levels, taking into account that occlusion was performed only on limited parts of the body. In conclusion, tacrolimus 0.1% ointment proved an effective and safe treatment option for adult patients with vitiligo. Beyond the face and neck areas, repigmentation could be achieved only by additional occlusion.

Whereas differences exist concerning associated autoimmune diseases, MAH and vitiligo shared many common clinical and histological features. Further studies are needed to assess the clinical relevance of vitiligo-like alterations in melanoma patients.

In a multicenter trial, the effect of a commercially available combination of autologous keratinocytes (3-6 x 10(6)/mL) with fibrin sealant (Tissucol Duo S Immuno, Baxter Hyland Immuno) on the healing of recalcitrant venous leg ulcers (duration >3 months) was compared with standard care. The primary endpoint was time to healing, and the secondary endpoint was number of healed ulcers in both groups. Both groups received compression therapy with short-stretch bandages. Forty-four (38.3%) of the 116 patients who had BioSeed-S treatment achieved complete healing of the target ulcer compared with 24 (22.4%) of 109 patients who received standard treatment. The advantage for treatment with BioSeed-S over standard treatment was statistically significant (chi-square test: p=0.0106). Time to complete healing of ulcers: the log-rank test for equality over strata revealed a superiority of treatment with BioSeed-S+compression (median: 176 days) over compression+standard care (median >201 days) (p<0.0001). This study, to date the largest multicenter study with autologous keratinocytes, provides evidence for its efficacy in the treatment of patients with therapy-resistant chronic venous leg ulcers.