Nanja van Geel

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.

Psychosocial effects of vitiligo

A limited number of studies have paid attention to the psychosocial well‐being of patients affected with vitiligo. We review the psychosocial effects of vitiligo, how patients deal with them and the psychiatric morbidity in vitiligo patients. Given the appreciable comorbidity, it is important to consider these observations in the management of patients, for example in patient–physician interaction but also in treatment strategies and evaluation of treatments. The effects of the psychological state on the disease itself together with the potential therapeutic implications are reviewed. Based on these data, we suggest how to further improve patients management.

Comprehensive Association Analysis of Candidate Genes for Generalized Vitiligo Supports XBP1, FOXP3, and TSLP

We previously carried out a genome-wide association study of generalized vitiligo (GV) in non-Hispanic whites, identifying 13 confirmed susceptibility loci. In this study, we re-analyzed the genome-wide data set (comprising 1,392 cases and 2,629 controls) to specifically test association of all 33 GV candidate genes that have previously been suggested for GV, followed by meta-analysis incorporating both current and previously published data. We detected association of three of the candidate genes tested: TSLP (rs764916, P=3.0E-04, odds ratio (OR)=1.60; meta-P for rs3806933=3.1E-03), XBP1 (rs6005863, P=3.6E-04, OR=1.17; meta-P for rs2269577=9.5E-09), and FOXP3 (rs11798415, P=5.8E-04, OR=1.19). Association of GV with CTLA4 (rs12992492, P=5.9E-05, OR=1.20; meta-P for rs231775=1.0E-04) seems to be secondary to epidemiological association with other concomitant autoimmune diseases. Within the major histocompatibility complex (MHC), at 6p21.33, association with TAP1-PSMB8 (rs3819721, P=5.2E-06) seems to derive from linkage disequilibrium with major primary signals in the MHC class I and class II regions.

First histopathological and immunophenotypic analysis of early dynamic events in a patient with segmental vitiligo associated with halo nevi

Segmental vitiligo is often ascribed to the neurogenic theory of melanocyte destruction, although data about the initial etiopathological events are scarce. Clinical, histopathological and T‐cell phenotypic analyses were performed during the early onset of a segmental vitiligo lesion in a patient with associated halo nevi. Histopathological analysis revealed a lymphocytic infiltrate, mainly composed of CD8+ T‐cells and some CD4+ T‐cells around the dermo–epidermal junction. Flow cytometry analysis of resident T‐cells revealed a clear enrichment of pro‐inflammatory IFN‐γ producing CD8+ T‐cells in lesional skin compared to the non‐lesional skin. Using human leukocyte antigen‐peptide tetramers (MART‐1, tyrosinase, gp100), increased numbers of T cells, recognizing melanocyte antigens were found in segmental vitiligo lesional skin, as compared with the non‐lesional skin and the blood. Our findings indicate that a CD8+ melanocyte specific T cell‐mediated immune response, as observed in generalized vitiligo, also plays a role in segmental vitiligo with associated halo nevi.

Indoleamine 2,3-dioxygenase, a new prognostic marker in sentinel lymph nodes of melanoma patients

BACKGROUND Indoleamine 2,3-dioxygenase (IDO), an enzyme with immunosuppressive properties is considered as a factor that impairs the antitumour immune response in melanoma. In this study, we investigated the expression of IDO in sentinel nodes of melanoma patients to determine its prognostic relevance. PATIENTS AND METHODS One hundred and sixteen melanoma patients were enrolled in this study with a median follow-up time after diagnosis of 71 months. The expression of IDO and forkhead box P3 (Foxp3) in the sentinel lymph nodes was determined by immunohistochemistry and correlated with progression-free survival and overall survival. In 42 patients, regulatory T cells were investigated by flow cytometry. RESULTS Cox regression survival analysis showed a significant negative effect of IDO expression on progression-free survival (p = 0.015) and overall survival (p = 0.010). High IDO expression was correlated with a significant higher frequency of Foxp3-positive cells in uninvaded lymph nodes (p = 0.016). The presence of IDO expression in the sentinel nodes was not associated with an increased frequency of circulating regulatory T cells (Tregs) but was significantly correlated with an increased mean fluorescence intensity of Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) in Tregs (p = 0.019). After CD3CD28 stimulation, peripheral blood mononuclear cells of patients with high IDO expression showed a lower production of interferon-gamma (IFN-γ) (p = 0.025). CONCLUSIONS This study points to an independent predictive role of IDO on survival, especially in melanoma patients with uninvolved sentinel nodes. Investigating IDO expression in the sentinel nodes of melanoma patients may be a useful marker to pre-identify patients with a less favourable prognosis in stage I and II disease.

Why treatments do(n't) work in vitiligo: An autoinflammatory perspective.

Vitiligo is a recalcitrant depigmentary skin disorder with significant effects on the quality of life and a frequent association with other autoimmune disorders. The results of the current therapeutic options remain variable and treatment resistance is often encountered. The mainstay of treatment remains topical corticosteroids, topical calcineurin inhibitors and UVB therapy. In more extensive or progressive cases, systemic corticosteroids are effective although their prolonged use is hampered due to safety concerns. A lot of topical and systemic treatments have been investigated during the last decades. Given the elevated TNF-α levels in vitiligo lesions, the failure and even paradoxal effects of TNF-α inhibitors were highly remarkable. Nonetheless, a lot of progress has been made to unravel the pathophysiology of vitiligo. In this review, we provide an overview of the currently known underlying mechanisms leading to vitiligo and link this to the success or failure of treatments that have been used in clinical trials. We believe that this overview can direct future vitiligo research and rationalise the treatment options.

Koebner's phenomenon in vitiligo: European position paper.

Koebner’s phenomenon (KP) has been observed in a number of skin diseases, including vitiligo. Its clinical significance in vitiligo with respect to disease activity and course is still debatable, while its relevance for surgical techniques has been demonstrated in some reports. We present a literature review on the currently known facts about KP in vitiligo, including details of clinical, experimental, and histopathological changes. The consensus view is that there are still no methods to define and assess KP in vitiligo. A new classification is proposed to allow an evaluation of KP in daily practice or in experimental studies. However, many unanswered questions still remain after redefining KP in patients with vitiligo. Active research focusing on KP in vitiligo may not only provide unexpected clues in the pathogenesis of vitiligo but also help to tailor novel therapies against this chronic and often psychologically devastating skin disease.

Vitamin D binding protein: a multifunctional protein of clinical importance.

Since the discovery of group-specific component and its polymorphism by Hirschfeld in 1959, research has put spotlight on this multifunctional transport protein (vitamin D binding protein, DBP). Besides the transport of vitamin D metabolites, DBP is a plasma glycoprotein with many important functions, including sequestration of actin, modulation of immune and inflammatory responses, binding of fatty acids, and control of bone development. A considerable DBP polymorphism has been described with a specific allele distribution in different geographic area. Multiple studies have shed light on the interesting relationship between polymorphisms of the DBP gene and the susceptibility to diseases. In this review, we give an overview of the multifunctional character of DBP and describe the clinical importance of DBP and its polymorphisms. Finally, we discuss the possibilities to use DBP as a novel therapeutic agent.

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

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.