Caio Cesar Silva de Castro

Developing core outcome set for vitiligo clinical trials: international e‐Delphi consensus

1 Centre of Evidence Based Dermatology, University of Nottingham, Nottingham,UK 2 Department of Dermatology, Ghent University Hospital, Ghent, Belgium3 Department of Dermatology, Henry Ford Hospital, Detroit, MI, USA4 Department of Dermatology, Yamagata University School of Medicine,Yamagata, Japan 5 Department of Dermatology, Osaka University, Osaka, Japan6 Dermatology Department, Al-Minya University, Al-Minya, Egypt 7 Departmentof Dermatology and Venereology, Ain Shams University, Cairo, Egypt8 Department of Dermatology, Ibn Sina University Hospital, Rabat, Morocco9 Mohammed V Souissi University, Rabat, Morocco 10 Department ofDermatology, University of Bordeaux National Reference Centre for Rare SkinDiseases H^opital St-Andr e, Bordeaux, France 11 Department of Medicine,Division of Dermatology, University of Massachusetts Medical School,Worcester, MA, USA 12 Department of Dermatology, Pontifcia UniversidadeCatœlica do Paranffi, Curitiba, Brazil 13 Department of Dermatology, University ofTexas Southwestern Medical Center, Dallas, TX, USA 14 National Skin Centre,Singapore City, Singapore 15 Department of Dermatology, Kaohsiung MedicalUniversity, Kaohsiung City, Taiwan 16 Department of Dermatology, KinkiUniversity Faculty of Medicine, Osaka-Sayama, Japan 17 Vitiligo Light Clinic,Riyadh, Saudi Arabia 18 Department of Dermatology, Cairo University, Kasr AlAiny Hospital, Cairo, Egypt 19 Departments of Pathology, Microbiology andImmunology/Oncology Institute, Loyola University Chicago, Chicago, IL, USA20 Department of Dermatology, Dongguk University Ilsan Hospital, Gyeonggi-do,Korea 21 Department of Dermatology, PGIMER, Chandigarh, India 22 Departmentof Dermatology, San Gallicano Dermatologic Institute IRCCS, Roma, ItalyCORRESPONDENCE Khaled Ezzedine and Viktoria Eleftheriadou, e-mails: khaled.ezzedine@chu-bordeaux.fr; viktoria.eleftheriadou@nottingham.ac.uk

Genetic Variants of the DDR1 Gene Are Associated with Vitiligo in Two Independent Brazilian Population Samples

Vitiligo is a chronic disease characterized by macules devoid of melanin and identifiable melanocytes. Adhesion of melanocytes to the basement membrane by integrin CCN3 is mediated through collagen IV receptor DDR1. We hypothesize that genetic variants of the DDR1 gene are associated with the occurrence of vitiligo. To test this hypothesis, we genotyped 10 DDR1 tag single-nucleotide polymorphisms (SNPs) in 212 trios composed of an affected child and both parents. Associated markers were then genotyped in 134 independent, unrelated individuals with vitiligo and 134 unrelated controls. Allele T of tag SNP rs4618569 was associated with an increased risk for vitiligo in the family trios (P=0.002, odds ratio (OR)=5.27; 95% confidence interval (CI)=1.59-17.40), whereas allele C of tag SNP rs2267641 was associated with an increased risk for vitiligo in both family-based and case-control populations (P=0.01, OR=3.47; 95% CI=1.22-9.17; P=0.04, OR=6.00; 95% CI=1.73-52.33, respectively). The best evidence for association in the trios was obtained for a haplotype composed of risk alleles of markers rs4618569 and rs2267641 (P=0.0006). There was an age-dependent enrichment of rs4618569 T allele and rs2267641 C allele in early-onset affected individuals. In conclusion, we propose DDR1 as a susceptibility gene for vitiligo, possibly implicating a defective cell adhesion in vitiligo pathogenesis.

Vitiligo - Part 1

Vitiligo is a chronic stigmatizing disease, already known for millennia, which mainly affects melanocytes from epidermis basal layer, leading to the development of hypochromic and achromic patches. Its estimated prevalence is 0.5% worldwide. The involvement of genetic factors controlling susceptibility to vitiligo has been studied over the last decades, and results of previous studies present vitiligo as a complex, multifactorial and polygenic disease. In this context, a few genes, including DDR1, XBP1 and NLRP1 have been consistently and functionally associated with the disease. Notwithstanding, environmental factors that precipitate or maintain the disease are yet to be described. The pathogenesis of vitiligo has not been totally clarified until now and many theories have been proposed. Of these, the autoimmune hypothesis is now the most cited and studied among experts. Dysfunction in metabolic pathways, which could lead to production of toxic metabolites causing damage to melanocytes, has also been investigated. Melanocytes adhesion deficit in patients with vitiligo is mainly speculated by the appearance of Köebner phenomenon, recently, new genes and proteins involved in this deficit have been found.

Vitiligo - Part 2 - classification, histopathology and treatment

In an unprecedented effort in the field of vitiligo, a global consensus resulted on a suggested new classification protocol for the disease. The main histopathological finding in vitiligo is the total absence of functioning melanocytes in the lesions, while the inflammatory cells most commonly found on the edges of the lesions are CD4+ and CD8+ T lymphocytes. Physical and pharmacological treatment strategies aim to control the autoimmune damage and stimulate melanocyte migration from the unaffected edges of lesions and the outer hair follicle root sheath to the affected skin; moreover, surgical treatments can be combined with topical and physical treatments.

Prevalência de psoríase em estudo de 261 pacientes com vitiligo

FUNDAMENTOS: O estudo da associacao de psoriase e vitiligo e necessario em razao das provaveis origens imunologicas dessas enfermidades e da proximidade de loci encontrados no cromossomo 1p31. OBJETIVO: O proposito principal foi determinar a prevalencia de psoriase em pacientes com vitiligo em amostra de 740 pacientes submetidos a fototerapia em Curitiba, PR e descrever suas caracteristicas clinicas. METODOS: Dos 740, foram estudados retrospectivamente 261 pacientes com diagnostico de vitiligo, e analisados aqueles com associacao de vitiligo e psoriase no periodo entre 2000 e 2004. RESULTADOS: A prevalencia dessa associacao neste trabalho foi de 3,06%; semelhante a de outras pesquisas anteriores. Foram identificados dois casos dos quais nao se encontrou relato em revisao da literatura: a) a associacao de vitiligo, psoriase e halo nevo; b) a associacao de vitiligo segmentar e psoriase. CONCLUSOES: A associacao de vitiligo e psoriase tem sido raramente relatada, sendo ainda necessarios estudos sobre a fisiopatologia e a genetica dessa associacao.

A pattern of association between clinical form of vitiligo and disease-related variables in a Brazilian population.

BACKGROUND Vitiligo classification systems are often based exclusively on the number and distribution of the white patches. To what extend these classification protocols reflect possible different pathophysiological basis for vitiligo or carry any prognostic value is currently unknown. OBJECTIVE To investigate patterns of association between type of vitiligo and common disease-related variables, in order to advance on the understanding of the exact nature of different clinical forms of disease, as well as to identify features with prognostic value for clinical progression of early diagnosed vitiligo. MATERIALS AND METHODS This is a cross-sectional study of a population sample from south of Brazil composed of 586 independent vitiligo-affected individuals. Different strategies of case-control analysis were employed to test for association between the three most common vitiligo clinical types and age of onset, family history of vitiligo, occurrence of Köebner phenomenon (KP) and presence of autoimmune co-morbidity. RESULTS Individuals affected by segmental vitiligo showed lower average age of onset (16 years) when compared with vulgaris (23.9 years) and acrofacial cases (29 years) (p<0.001). The distribution of occurrence of KP, family history of vitiligo and co-occurrence of autoimmune disease followed a gradient pattern, with high, intermediate and low chance of occurrence of all three variables observed for vulgaris, acrofacial and segmental vitiligo, respectively (p<0.001 for overall distribution). CONCLUSION Results indicate a uniform pattern of association between vitiligo clinical forms and KP, positive vitiligo family history and occurrence of co-morbidity autoimmune. The impact of the observed pattern of association over disease prognosis and classification is discussed.

Repigmentation in vitiligo: position paper of the Vitiligo Global Issues Consensus Conference

The Vitiligo Global Issues Consensus Conference (VGICC), through an international e‐Delphi consensus, concluded that ‘repigmentation’ and ‘maintenance of gained repigmentation’ are essential core outcome measures in future vitiligo trials. This VGICC position paper addresses these core topics in two sections and includes an atlas depicting vitiligo repigmentation patterns and color match. The first section delineates mechanisms and characteristics of vitiligo repigmentation, and the second section summarizes the outcomes of international meeting discussions and two e‐surveys on vitiligo repigmentation, which had been carried out over 3 yr. Treatment is defined as successful if repigmentation exceeds 80% and at least 80% of the gained repigmentation is maintained for over 6 months. No agreement was found on the best outcome measure for assessing target or global repigmentation, therefore highlighting the limitations of e‐surveys in addressing clinical measurements. Until there is a clear consensus, existing tools should be selected according to the specific needs of each study. A workshop will be conducted to address the remaining issues so as to achieve a consensus.

Reduced immunohistochemical expression of adhesion molecules in vitiligo skin biopsies

Because defects in adhesion impairment seem to be involved in the etiopathogenesis of vitiligo, this study aimed to compare the immunohistochemical expression of several adhesion molecules in the epidermis of vitiligo and non lesional vitiligo skin. Sixty-six specimens of lesional and non lesional skin from 33 volunteers with vitiligo were evaluated by immunohistochemistry using anti-beta-catenin, anti-E-cadherin, anti-laminin, anti-beta1 integrin, anti-collagen IV, anti-ICAM-1 and anti-VCAM-1 antibodies. Biopsies of vitiligo skin demonstrated a significant reduction in the expression of laminin and integrin. The average value of the immunohistochemically positive reaction area of the vitiligo specimens was 3053.2μm2, compared with the observed value of 3431.8μm2 in non vitiligo skin (p=0.003) for laminin. The immuno-positive area was 7174.6μm2 (vitiligo) and 8966.7μm2 (non lesional skin) for integrin (p=0.042). A reduction in ICAM-1 and VCAM-1 expression in the basal layer of the epidermis in vitiligo samples was also observed (p=0.001 and p<0.001, respectively). However, no significant differences were observed with respect to the expression of beta-catenin, E-cadherin, and collagen IV between vitiligo and non lesional skin. Our results suggest that an impairment in adhesion exists in vitiligo skin, which is supported by the diminished immunohistochemical expression of laminin, beta1 integrin, ICAM-1 and VCAM-1.

Safety of ustekinumab in severe psoriasis with chronic hepatitis B.

Only a few previous cases of drug reaction with eosinophilia and systemic symptoms syndrome have been reported following exposure to a calcium channel blocker. Diltiazem was the most frequently incriminated calcium channel blocker agent.[3] The onset of the eruption occurred 2–10 days after starting diltiazem. Liver involvement occurred in the majority of the cases. Recently, Moriya et al. presented a case of drug reaction with eosinophilia and systemic symptoms syndrome, which occured 19 months after initiating azelnidipine and verapamil hydrochloride, which appears to be a very long delay in the onset of the syndrome.[4] Our patient’s symptoms started 3 weeks after lercanidipine initiation. It was classified as a definitive case of drug reaction with eosinophilia and systemic symptoms according to the RegiSCAR scoring system.[5] According to the Naranjo probability scale, the adverse drug reaction was considered probable.[6]

Scientific output of Brazilian dermatologists during the last 25 years in the five highest impact factor journals in dermatology.

BACKGROUND The qualitative and quantitative scientific output of Brazilian dermatologists in journals of high impact factor is little known. OBJECTIVE To describe the scientific output of dermatologists from Brazilian institutions in journals of high impact factor. METHODS The five journals with the highest impact factor in dermatology were analyzed. All articles produced from Brazilian institutions between 1986 and 2010 were compiled and the following aspects were analyzed: position of Brazilian researchers in the list of authors, selected theme, experimental design, studied disease, area of interest and year of publication. RESULTS Seventy-four articles written with the participation of Brazilian dermatologists have been identified. Upon grouping the articles in five-year periods, an important increase was observed in the Brazilian production from the year 2006 onwards. The dermatologists were placed as second authors in the majority of cases (53.66%). According to the selected theme to be studied, the majority of the articles had a laboratory focus (45.95%). The majority of the articles reported cross-sectional studies or non-controlled clinical trials (both at 17.57%), and pemphigus foliaceus was the most studied disease (29.73%). CONCLUSION The increase in the number of publications by Brazilian dermatologists over the last years is encouraging, but it is still small in comparison to the total number of articles published in these five periodicals.