J.P. Wietze van der Veen

Autoimmune Destruction of Skin Melanocytes by Perilesional T Cells from Vitiligo Patients

In vitiligo, cytotoxic T cells infiltrating the perilesional margin are suspected to be involved in the pathogenesis of the disease. However, it remains to be elucidated whether these T cells are a cause or a consequence of the depigmentation process. T cells we obtained from perilesional skin biopsies, were significantly enriched for melanocyte antigen recognition, compared with healthy skin-infiltrating T cells, and were reactive to melanocyte antigen-specific stimulation. Using a skin explant model, we were able to dissect the in situ activities of perilesional T cells in the effector phase of depigmentation. We show that these T cells could infiltrate autologous normally pigmented skin explants and efficiently kill melanocytes within this microenvironment. Interestingly, melanocyte apoptosis was accompanied by suprabasal keratinocyte apoptosis. Perilesional T cells did, however, not induce apoptosis in lesional skin, which is devoid of melanocytes, indicating the melanocyte-specific cytotoxic activity of these cells. Melanocyte killing correlated to local infiltration of perilesional T cells. Our data show that perilesional cytotoxic T cells eradicate pigment cells, the characteristic hallmark of vitiligo, thereby providing evidence of T cells being able to mediate targeted autoimmune tissue destruction.

Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo

We previously reported a genome-wide association study (GWAS) identifying 14 susceptibility loci for generalized vitiligo. We report here a second GWAS (450 individuals with vitiligo (cases) and 3,182 controls), an independent replication study (1,440 cases and 1,316 controls) and a meta-analysis (3,187 cases and 6,723 controls) identifying 13 additional vitiligo-associated loci. These include OCA2-HERC2 (combined P = 3.80 × 10−8), MC1R (P = 1.82 × 10−13), a region near TYR (P = 1.57 × 10−13), IFIH1 (P = 4.91 × 10−15), CD80 (P = 3.78 × 10−10), CLNK (P = 1.56 × 10−8), BACH2 (P = 2.53 × 10−8), SLA (P = 1.58 × 10−8), CASP7 (P = 3.56 × 10−8), CD44 (P = 1.78 × 10−9), IKZF4 (P = 2.75 × 10−14), SH2B3 (P = 3.54 × 10−18) and TOB2 (P = 6.81 × 10−10). Most vitiligo susceptibility loci encode immunoregulatory proteins or melanocyte components that likely mediate immune targeting and the relationships among vitiligo, melanoma, and eye, skin and hair coloration.

The burden of vitiligo: patient characteristics associated with quality of life.

BACKGROUND Vitiligo is commonly regarded as a harmless cosmetic skin problem in Western societies, and the importance of treating patients with vitiligo is often underestimated. OBJECTIVE We sought to determine the clinical and sociodemographic variables that adversely affect the quality of life in adult patients with generalized vitiligo so that these variables can be considered in the treatment and care. METHODS A total of 245 adult patients with generalized vitiligo completed two quality-of-life questionnaires (the Medical Outcomes Study 36-Item Short-form General Health Survey and the Skindex-29). Physicians assessed sociodemographic and clinical characteristics of these patients. RESULTS Dark skin type, vitiligo located on the chest, and treatment in the past appeared to have an adverse impact on the psychosocial domains of quality of life. Moreover, itch was reported by 20% of the patients in this study. LIMITATIONS Psychiatric comorbidity was not evaluated in the analyses. CONCLUSION Generalized vitiligo is a serious skin disorder with an adverse impact on the emotional state, comparable with that of other major skin diseases.

Non-ablative 1,550 nm fractional laser therapy versus triple topical therapy for the treatment of melasma: A randomized controlled split-face study†‡

Melasma is a uichronic, often relapsing skin disorder, with poor long‐term results from all current therapies.

Nonablative 1550-nm fractional laser therapy versus triple topical therapy for the treatment of melasma: A randomized controlled pilot study

BACKGROUND Various treatments are currently available for melasma. However, results are often disappointing. OBJECTIVE We sought to assess the efficacy and safety of nonablative 1550-nm fractional laser therapy and compare results with those obtained with triple topical therapy (the gold standard). METHODS Twenty female patients with moderate to severe melasma and Fitzpatrick skin types II to V were treated either with nonablative fractional laser therapy or triple topical therapy (hydroquinone 5%, tretinoin 0.05%, and triamcinolone acetonide 0.1% cream) once daily for 8 weeks in a randomized controlled observer-blinded study. Laser treatment was performed every 2 weeks for a total of 4 times. Physician Global Assessment was assessed at 3 weeks, 3 months, and 6 months after the last treatment. RESULTS Physician Global Assessment improved (P < .001) in both groups at 3 weeks. There was no difference in Physician Global Assessment between the two groups. Mean treatment satisfaction and recommendation were significantly higher in the laser group at 3 weeks (P < .05). However, melasma recurred in 5 patients in both groups after 6 months. Side effects in the laser group were erythema, burning sensation, facial edema, and pain; in the triple group side effects were erythema, burning, and scaling. LIMITATIONS Limitations were: small number of patients; only one set of laser parameters; and a possible difference in motivation between groups. CONCLUSIONS Nonablative fractional laser therapy is safe and comparable in efficacy and recurrence rate with triple topical therapy. It may be a useful alternative treatment option for melasma when topical bleaching is ineffective or not tolerated. Different laser settings and long-term maintenance treatment should be tested in future studies.

Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants

Vitiligo is an autoimmune disease in which depigmented skin results from the destruction of melanocytes, with epidemiological association with other autoimmune diseases. In previous linkage and genome-wide association studies (GWAS1 and GWAS2), we identified 27 vitiligo susceptibility loci in patients of European ancestry. We carried out a third GWAS (GWAS3) in European-ancestry 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 significantly associated loci and 7 suggestive loci. Most encode immune and apoptotic regulators, with some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some of which corresponds to expression quantitative trait loci (eQTLs) at these loci. Together, the identified genes provide a framework for the genetic architecture and pathobiology of vitiligo, highlight relationships with other autoimmune diseases and melanoma, and offer potential targets for treatment.

Hypertrophy in port-wine stains: prevalence and patient characteristics in a large patient cohort.

BACKGROUND Port-wine stains (PWS) may thicken and darken with age. Little is known about the pathogenesis and epidemiology of PWS hypertrophy because of the lack of large studies. OBJECTIVE We sought to assess the prevalence and characteristics of patients with hypertrophic PWS. METHODS Medical records and clinical photographs of all patients with PWS visiting our clinic between 2005 and 2009 were examined to identify hypertrophy. Patients were sent questionnaires regarding their hypertrophic PWS. RESULTS In all, 335 patients (age 0-81 years; 69% female) with PWS were included. Hypertrophy was found in 68 patients (20%; 32 male, 36 female) and classified as thickened (5%), nodular (8%), or both (7%). Color of hypertrophic PWS was mainly red (50%) or purple (44%). Patients with hypertrophy in their PWS were mostly (68%) older than 40 years, and rarely (7%) younger than 20 years. When older than 50 years, 71% of all patients had hypertrophy in their PWS. Median age of onset of PWS hypertrophy was 31 years (12 years for thickened, 39 years for nodular). LIMITATIONS This was a retrospective study in a selected population. CONCLUSION Hypertrophy is an important feature in the development of PWS and affects a majority of patients older than 50 years. Depth of color of the PWS is associated with hypertrophy, whereas location and size appear not to be related. More attention should be drawn to therapy and prevention of hypertrophic PWS. Diffuse thickening and nodules should be distinguished, as a different age of onset may indicate different pathomechanisms.

Effective Melanoma Immunotherapy in Mice by the Skin-Depigmenting Agent Monobenzone and the Adjuvants Imiquimod and CpG

Background Presently melanoma still lacks adequate treatment options for metastatic disease. While melanoma is exceptionally challenging to standard regimens, it is suited for treatment with immunotherapy based on its immunogenicity. Since treatment-related skin depigmentation is considered a favourable prognostic sign during melanoma intervention, we here aimed at the reverse approach of directly inducing vitiligo as a shortcut to effective anti-melanoma immunity. Methodology and Principal Findings We developed an effective and simple to use form of immunotherapy by combining the topical skin-bleaching agent monobenzone with immune-stimulatory imiquimod cream and cytosine-guanine oligodeoxynucleotides (CpG) injections (MIC therapy). This powerful new approach promptly induced a melanoma antigen-specific immune response, which abolished subcutaneous B16.F10 melanoma growth in up to 85% of C57BL/6 mice. Importantly, this regimen induced over 100 days of tumor-free survival in up to 60% of the mice, and forcefully suppressed tumor growth upon re-challenge either 65- or 165 days after MIC treatment cessation. Conclusions MIC therapy is effective in eradicating melanoma, by vigilantly incorporating NK-, B- and T cells in its therapeutic effect. Based on these results, the MIC regimen presents a high-yield, low-cost and simple therapy, readily applicable in the clinic.

Melanocyte antigen‐specific antibodies cannot be used as markers for recent disease activity in patients with vitiligo

Background  Objective parameters to assess disease activity in non‐segmental vitiligo are lacking. Melanocyte antigen‐specific antibodies are frequently found in the sera of patients with vitiligo and the presence of these antibodies may correlate with disease activity.

Non-ablative 1550 nm fractional laser therapy not effective for erythema dyschromicum perstans and postinflammatory hyperpigmentation: a pilot study

Abstract Background: Erythema dyschromicum perstans and postinflammatory hyperpigmentation (PIH) are characterized by papillary dermal pigmentation or pigment incontinence. To date, no standard treatment is available. Fractional laser therapy (FLT) was recently reported to improve different pigment disorders. Objectives: To assess the efficacy and safety of non-ablative FLT in the treatment of erythema dyschromicum perstans and PIH. Methods: Eight patients with erythema dyschromicum perstans and six patients with PIH were included. In each patient, two similar test regions were randomized to receive either five fractional laser treatments in combination with intermittent daily topical bleaching or the same intermittent regimen of topical bleaching alone. Three months after the last treatment, improvement of hyperpigmentation was assessed by melanin index, reflectance spectroscopy, physicians assessment, patients assessment and patients satisfaction. In addition, a biopsy of both laser treated and control site was evaluated by an independent blinded pathologist. Results: No clinical improvement of hyperpigmentation was observed. Reflectance spectroscopy, melanin index, number of melanocytes and amount of dermal melanin did not significantly differ. Patients considered FLT unsatisfactory. Moreover, three patients developed laser-induced PIH. Conclusions: With these specific laser settings, non-ablative FLT was not effective for the treatment of erythema dyschromicum perstans and PIH.