Anti-Melanoma immunity and local regression of cutaneous metastases in melanoma patients treated with monobenzone and imiquimod; a phase 2 a trial.

Vitiligo development in melanoma patients during immunotherapy is a favorable prognostic sign and indicates breakage of tolerance against melanocytic/melanoma antigens. We investigated a novel immunotherapeutic approach of the skin-depigmenting compound monobenzone synergizing with imiquimod in inducing antimelanoma immunity and melanoma regression. Stage III-IV melanoma patients with non-resectable cutaneous melanoma metastases were treated with monobenzone and imiquimod (MI) therapy applied locally to cutaneous metastases and adjacent skin during 12 weeks, or longer. Twenty-one of 25 enrolled patients were evaluable for clinical assessment at 12 weeks. MI therapy was well-tolerated. Partial regression of cutaneous metastases was observed in 8 patients and stable disease in 1 patient, reaching the statistical endpoint of treatment efficacy. Continued treatment induced clinical response in 11 patients, including complete responses in three patients. Seven patients developed vitiligo-like depigmentation on areas of skin that were not treated with MI therapy, indicating a systemic effect of MI therapy. Melanoma-specific antibody responses were induced in 7 of 17 patients tested and melanoma-specific CD8+T-cell responses in 11 of 15 patients tested. These systemic immune responses were significantly increased during therapy as compared to baseline in responding patients. This study shows that MI therapy induces local and systemic anti-melanoma immunity and local regression of cutaneous metastases in 38% of patients, or 52% during prolonged therapy. This study provides proof-of-concept of MI therapy, a low-cost, broadly applicable and well-tolerated treatment for cutaneous melanoma metastases, attractive for further clinical investigation.

Optimising size and depth of punch grafts in autologous transplantation of vitiligo and piebaldism: a randomised controlled trial.

BACKGROUND: To date, autologous punch grafting appears to be the easiest and least expensive surgical technique for stable vitiligo and piebaldism. Punch grafting is available worldwide, with no need for specialised instruments. However, no reliable data on efficacy and safety of different punch depths and punch sizes are available. OBJECTIVE/METHODS: To compare the efficacy and safety of different punch depths and punch sizes in autologous punch grafting, a randomised controlled trial was performed in 33 patients with vitiligo or piebaldism. In each patient, four depigmented regions were allocated to: 1.5 mm deep grafts, 1.5 mm superficial grafts, 1.0 mm deep grafts, and 1.0 mm superficial grafts. Primary outcome was the total pigmented surface area. Secondary outcomes were Patients' Global Assessment (PGA) and side effects. RESULTS: Six months after grafting, 1.5 mm grafts showed a significantly larger pigmented surface area compared to 1.0-mm grafts (p < 0.001), though more side effects as well. No significant differences in the total pigmented surface between different punch depths were found. Deep grafts showed more erythema compared to superficial grafts. CONCLUSION: We recommend 1.5 mm superficial grafts in autologous punch grafting for trunk and proximal extremities in patients with stable vitiligo and piebaldism.

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.

The validity, reliability and acceptability of the SAVASI; a new self-assessment score in vitiligo.

BACKGROUND: Vitiligo is a common depigmenting skin disorder that can influence a patient's quality of life. Although patient-orientated medicine is an emerging concept, a self-assessment tool to assess the degree of depigmentation in vitiligo is not yet available. Therefore, we developed the SAVASI, a self-assessment tool that uses the same basic principles as the VASI. OBJECTIVE: To assess the validity, reliability and acceptability of the SAVASI. METHODS: To assess the validity of the SAVASI, we compared the scores assessed by the patient with the scores of the VASI assessed by the physician. To assess the intra-rater reliability, the correlation between the baseline SAVASI and the SAVASI after 2 weeks was calculated. To assess the acceptability, patients indicated the time needed to complete the SAVASI and the patient assessed the difficulty of the questionnaire on a five-point scale. The Skindex-29 was used to determine the quality of life. The overestimation of the SAVASI compared to the VASI was calculated by subtracting the VASI scores off from the SAVASI scores. RESULTS: A high correlation between the VASI and the SAVASI (ICC 0.97, 95% CI: 0.95-0.98) was found in 60 patients. The intra-rater reliability of the SAVASI (ICC 0.75, 95% CI 0.54-0.87) was adequate in 31 patients. Fifty (83%) of the patients completed the questionnaire within 10 min and only five (8%) of the patients considered the SAVASI hard. We found no correlation between overestimation of the SAVASI score and the Skindex-29 score. CONCLUSION: The SAVASI is a valid, reliable and acceptable self-assessment tool to measure the degree of depigmentation in vitiligo. With the SAVASI the degree of depigmentation can reliably be assessed by the patient themselves which can be useful in large (epidemiological) studies. Furthermore, this could contribute to the patient's disease insight and therapy loyalty.

Vitiligo Area Scoring Index and Vitiligo European Task Force assessment: reliable and responsive instruments to measure the degree of depigmentation in vitiligo.

BACKGROUND: Vitiligo is a common skin disorder causing depigmented macules that can impair a patient's quality of life. Currently, there are no standardized outcome measures to assess the degree of depigmentation. Moreover, there is limited knowledge on the measurement properties of outcome measures in vitiligo. OBJECTIVES: To assess the reliability and responsiveness of the Vitiligo Area Scoring Index (VASI) and the Vitiligo European Task Force assessment (VETFa), two well-described clinician-reported outcomes. METHODS: We included three vitiligo patient groups. In one group of 31 patients, the interobserver reliability was assessed by three observers. In 27 patients the intraobserver reliability was assessed by two repeated measures by one of the observers. To assess the responsiveness the repigmentation was calculated after 6 months of phototherapy in 33 patients and tested against hypotheses. RESULTS: The interobserver reliability was high for VASI [intraclass correlation coefficient (ICC) 0·93] and VETFa depigmentation (ICC 0·88). The intraobserver reliability was high for VASI (ICC 0·93) and VETFa depigmentation (ICC 0·97). The smallest detectable changes (SDCs) were 7·1% and 10·4% for interobserver reliability and 4·7% and 2·9% for intraobserver reliability in VASI and VETFa depigmentation, respectively. All four responsiveness hypotheses formulated a priori were confirmed. CONCLUSIONS: VASI and VETFa are reliable and responsive instruments to assess the degree of depigmentation in vitiligo. VASI and VETFa for depigmentation are potential instruments for vitiligo research in the future. However, for use in individual patient care, caution is needed when interpreting score changes in individual patients because of the relatively large SDC.

The antibody response against MART-1 differs in patients with melanoma-associated leucoderma and vitiligo.

Patients with melanoma may develop skin depigmentation spontaneously or following therapy, referred to as melanoma-associated leucoderma (MAL). As clinical presentation of MAL may precede primary/metastatic melanoma detection, recognition of MAL is important to prevent its misdiagnosis as vitiligo and the subsequent application of immunosuppressive treatment. To reveal the immunity involved in MAL development, we investigated the presence of antibody and T-cell immune responses directed against the melanocyte-differentiation-antigens MART-1 (Melan-A), tyrosinase and gp100 in patients with MAL, as compared to patients with vitiligo. Autoantibodies to gp100 and tyrosinase were commonly found in both diseases. Interestingly, MART-1 antibodies were only present in patients with MAL. Melanocyte antigen-specific T cells were found in all patients, with relatively more specific T cells in patients with active vitiligo. Although MAL and vitiligo may appear clinically similar, our results indicate that the humoral immune responses against MART-1 differ between these diseases, which can help to differentiate MAL from vitiligo.

Long-term remission of folliculitis decalvans after treatment with the long-pulsed Nd:YAG laser.

Folliculitis decalvans (FD) is a rare inflammatory scalp disorder presenting with tufted folliculitis, follicular papules and pustules, progressing to cicatricial alopecia. Current treatments mainly consist of antibiotic and immunomodulatory therapies and are often disappointing. FD has previously shown to respond to treatment with neodymium:yttrium aluminium garnet (Nd:YAG) laser in one case. We present a case of recalcitrant FD, successfully treated with a long-pulsed Nd:YAG laser.

Q-switched laser depigmentation in vitiligo, most effective in active disease.

BACKGROUND: In widespread vitiligo, when repigmentation therapies are no longer feasible, Q-switched lasers can be used to remove the remaining disfiguring pigmentation. However, little literature is available on the long-term effects of Q-switched laser treatment in patients with vitiligo, and the variables influencing the effect of treatment are unknown. OBJECTIVE: To evaluate retrospectively the effectiveness, safety and patient satisfaction of Q-switched ruby (QSR) laser-induced depigmentation in widespread vitiligo. METHODS: We performed a retrospective study on well-documented patients with vitiligo with widespread lesions who received depigmentation therapy with the QSR laser between 2000 and 2012 in our institute. Eligible patients were asked to visit our institute for assessment of depigmentation and to fill in a questionnaire on patient satisfaction and disease variables. RESULTS: After a mean follow-up of 13 months, 48% of the 27 included patients showed > 75% depigmentation. Patients with active disease at the time of treatment had significantly better results than patients with stable disease (P < 0·05). Twenty-three (85%) patients were satisfied after treatment. Eighteen patients (67%) reported temporary side-effects after treatment. None of the patients reported adverse effects, such as scars or infections. CONCLUSION: Q-switched ruby laser therapy is effective in approximately half of patients treated; it is a safe treatment with a high patient satisfaction. Patients with active vitiligo show better results after treatment than patients with stable vitiligo. Therefore, in patients with stable vitiligo resistant to trial treatment, we advise postponing treatment until their vitiligo becomes active.

High prevalence of autoimmune thyroiditis in children and adolescents with vitiligo.

BACKGROUND/AIMS: Vitiligo is considered to be an autoimmune disease and is known to be associated with other autoimmune diseases, particularly affecting the thyroid. In children and adolescents this association has been reported in only a few studies, with varying results. The aim of this study was to examine thyroid function and prevalence of thyroid autoimmunity in children and adolescents with vitiligo and to investigate the utility of screening. METHODS: Two hundred and sixty patients with vitiligo were enrolled. Plasma TSH, FT4 and anti-thyroid peroxidase (TPO) antibody concentrations were measured. The prevalence of thyroid dysfunction and autoimmunity were compared to the general healthy paediatric population. RESULTS: Autoimmune thyroiditis (AIT) with thyroid hormone disturbances was diagnosed in 16 patients (6.2%). This is significantly higher than the prevalence reported in the general healthy paediatric population. Increased levels of anti-TPO antibodies (= 30 kU/l), without thyroid hormone disturbances, were found in 27 patients (10.5%). CONCLUSION: The prevalence of AIT in children and adolescents with vitiligo is significantly higher than in the general population. It may be advantageous to screen thyroid function and antibody levels in all paediatric patients with non-segmental vitiligo. To strengthen recommendations on screening, research on the burden for patients and cost-effectiveness is needed.

Radiation-induced melanoma-associated leucoderma, systemic antimelanoma immunity and disease-free survival in a patient with advanced-stage melanoma: a case report and immunological analysis.

BACKGROUND: Melanoma is an immunogenic tumour. The development of skin depigmentation or melanoma-associated leucoderma (MAL) has been associated with favourable clinical outcome in patients with metastatic melanoma, especially after immunotherapy. Evidence for clinically meaningful enhancement of melanoma-directed autoimmunity, as indicated by MAL, after radiotherapy without immunotherapy has not yet been published. OBJECTIVES: We investigated whether a patient with stage IV melanoma, who developed leucoderma in the irradiated skin areas following radiotherapy and experienced exceptional disease-free survival of 3 years despite brain metastasis, possessed antimelanoma immunity that could be linked to the favourable disease course. METHODS: A detailed immunological analysis was performed consisting of immunohistochemistry of several melanoma tissues, and analyses of T cells isolated from the blood and MAL skin tissue for melanocyte/melanoma specificity and functionality, as well as the presence of a melanoma-specific antibody response. RESULTS: Immunological analyses showed the presence of CD8+ T cells and antibody responses directed against melanocyte differentiation antigens expressed in the primary tumour, lymph node and brain metastasis, indicating adequate tumour recognition by activated T cells. CONCLUSION: The immune responses found in this patient, probably enhanced by radiotherapy, are thought to have contributed to his favourable clinical course. Radiotherapy may act as local immunotherapy in patients with melanoma by destroying melanocytes, leading to the induction, or enhancement, of already existent antimelanoma immunity. As in patients treated with immunotherapy, this may lead to MAL, also at distant sites from the treated area. This patient is a clear example of the positive prognostic value of MAL, which is possibly induced by radiotherapy, for patients with melanoma.

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. OBJECTIVE: To investigate the relationship between melanocyte antigen-specific antibodies and recent disease activity in patients with vitiligo and to evaluate the potential usefulness of this objective parameter in daily clinical practice. METHODS: The prevalence of tyrosinase, melanoma antigen recognized by T-cells-1 (MART1), melanin-concentrating hormone receptor-1 (MCHR1), gp100 and tyrosine hydroxylase (TH) antibodies was evaluated in 21 patients with non-segmental vitiligo and in 20 healthy controls. RESULTS: In 21 patients, nine (42.8%) showed antibody responses against tyrosinase, MART1, MCHR1, gp100 or TH. No antibody responses were found in the 20 controls. No correlation was found between the presence of antibodies and recent disease activity or other clinical characteristics such as age, gender, extension and duration of vitiligo. CONCLUSIONS: In this study, 42.8% of the vitiligo patients showed an antibody response to melanocyte antigen-specific antigens. However, the presence of antibodies against melanocytes did not correlate with recent disease activity or other relevant disease parameters, and for the moment screening for these antibodies in individual patients does not appear to be clinically relevant.

Digital image analysis vs. clinical assessment to evaluate repigmentation after punch grafting in vitiligo.

BACKGROUND: Repigmentation as a treatment outcome in vitiligo is not assessed in a standard way, making results of clinical trials hard to compare. Different types of repigmentation assessments after punch grafting have not been compared so far. OBJECTIVE: To compare assessments of repigmentation by a digital image analysis system (DIAS) with those of clinical observers and patients after punch grafting for vitiligo. METHODS: One vitiligo patch was selected in each patient (n = 21). This patch was treated with the punch grafting technique. The grade of repigmentation (%) after 3 months was assessed by: (i) DIAS; (ii) 3 clinical observers ; and (iii) the patient, scoring the grade of repigmentation on photographs. Physicians and patients also evaluated the global result on a 7-point scale. RESULTS: There was an almost perfect agreement between the three clinical observers and the DIAS (ICC 0.83). As expected, variation was found between the clinical observers. Patients' scores showed a moderate agreement with the DIAS (ICC 0.49) and a poor agreement with the physicians (ICC 0.28). Overall, the patients were more satisfied with the results than the physicians. CONCLUSIONS: Whereas the results of the digital and clinical assessments were comparable, patients' ratings diverged. The DIAS can overcome the inevitable differences between observers, which are intrinsic to a visual grading method, and is advisable for clinical trials on vitiligo to objectively assess repigmentation in limited lesions.

Long-pulsed 1064 nm Nd:YAG laser improves hypertrophic port-wine stains.

BACKGROUND: Hypertrophic port-wine stains (PWS) usually respond poorly to pulsed dye laser treatment. The long-pulsed 1064 nm Nd:YAG laser can target deeper situated vessels and may therefore be more effective. OBJECTIVE: To evaluate the efficacy and safety of the Nd:YAG laser for the treatment of hypertrophic PWS. METHODS: In a retrospective cohort study, all hypertrophic PWS patients treated with the Nd:YAG laser between 2005 and 2011 were invited for follow-up. Clinical improvement was assessed using Physician Global Assessment (PhGA) and Patient Global Assessment (PGA). RESULTS: Assessment was obtained in 32 of 44 eligible patients (mean age 51.4 years), after a mean of 2.8 (SD ± 2.1) Nd:YAG laser treatments. Good or excellent improvement of hypertrophy was found in a majority of patients, both by PhGA (91%) and PGA (93%). Good or excellent improvement of colour was found in 63% of patients by PhGA, and in 87% by PGA. Recurrence of hypertrophy was seen in three patients. All but two patients would recommend Nd:YAG treatment to other patients. Mild to moderate scars were seen in seven patients, hypopigmentation in 14 patients. CONCLUSION: The 1064 nm Nd:YAG laser is highly effective in the treatment of hypertrophic PWS with only a few treatments needed. Mostly mild side effects were seen in half of all patients. Hypertrophy seems to respond better than colour. To further improve colour, a combination with pulsed dye laser treatment is advisory. Observation of immediate clinical endpoints is important when using the Nd:YAG laser, to optimize outcomes and reduce side effects.

Decreased risk of melanoma and nonmelanoma skin cancer in patients with vitiligo: a survey among 1307 patients and their partners.

BACKGROUND: Vitiligo is a common skin disease characterized by autoimmune melanocyte destruction. Recent genetic studies suggest a lower susceptibility to melanoma in patients with vitiligo; however, lifetime melanoma prevalence in patients with vitiligo has not previously been studied. Nonmelanoma skin cancer (NMSC) prevalence has been studied, but only in small studies and with contradictory results. OBJECTIVES: This retrospective, comparative cohort survey was designed to assess lifetime prevalences of melanoma and NMSC in patients with vitiligo compared with nonvitiligo controls. METHODS: Patients with nonsegmental vitiligo, who visited our clinic between January 1995 and September 2010, and were aged 50 years or older at the time of the study, were invited to participate in a postal survey. The questions regarded demographics, vitiligo characteristics, phototherapy history, skin cancer risk factors and the number of skin cancers experienced during the patient's lifetime. Patients were asked to have their partner fill in a control questionnaire. All skin cancers were validated by a pathology report. In total 2635 invitations were sent and 1307 eligible questionnaires were returned (50%). Multivariate logistic regression models were used to quantify adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between vitiligo and lifetime prevalences of melanoma and NMSC. RESULTS: Adjusted for confounders, patients with vitiligo had a threefold lower probability of developing melanoma (adjusted OR 0·32; 95% CI 0·12-0·88) and NMSC (adjusted OR 0·28; 95% CI 0·16-0·50). Subgroup analyses of patients treated with narrowband ultraviolet (UV) B, and psoralen and UVA did not show dose-related trends of increased age-adjusted lifetime prevalence of melanoma or NMSC. CONCLUSIONS: Our findings suggest that patients with vitiligo have a decreased risk of both melanoma and NMSC.

Provoking factors, including chemicals, in Dutch patients with vitiligo.

BACKGROUND: In vitiligo, many provoking factors have been described, but epidemiological data, especially on the role of contact with chemicals, are scarce. OBJECTIVE: To obtain an insight into the patient-reported factors provoking vitiligo, including contact with chemicals. METHODS: A retrospective cohort study was conducted on all 1264 patients with vitiligo who visited the Netherlands Institute for Pigment disorders from January 2003 to December 2007. Patients for whom an exogenous provoking factor was recorded were sent a questionnaire. Subsequently, patients who mentioned a chemical provoking factor were contacted to elucidate the alleged causal relationship between exposure to the chemical and the onset of vitiligo. RESULTS: A total of 300 out of the 1264 patients indicated that provoking factors had played a role in their disease. Two hundred and forty-six patients were sent a questionnaire, which was returned by 177 (response rate of 72%). Emotional stress was indicated as a provoking factor in 98 patients (55.4%), 51 patients (28.8%) recorded sunburn, 34 patients (19.2%) recorded mechanical factors and 20 patients (11.3%) other factors. Of 29 patients (16.4%) who indicated a chemical factor, a presumed causal relationship could be corroborated in four. The chemicals involved were para-tertiary butylphenol (n = 2), captan (n = 1) and diphencyprone (n = 1). CONCLUSION: The majority of the patients with vitiligo from this study did not mention provoking factors, but the ones who did point to emotional stress in more than half of the cases. Of the 29 patients who assigned chemical provoking factors, solvents were mainly indicated. However, a presumed relationship with the chemical could be corroborated in only four patients.