Measuring the Impact of Vitiligo: Behind the White Spots

The impact of vitiligo is generally believed to be underestimated. Salzes et al. propose a questionnaire to measure the actual burden of vitiligo. Using a stepwise approach they constructed and validated this instrument taking into account the differences between fair and dark skin phototypes. It is a promising approach that can be implemented on an international scale

Learning from success and failure: biologics for non-approved skin diseases

The impressive potential of biologics has been demonstrated in psoriasis, hidradenitis suppurativa, and urticaria. Numerous biologicals are entering the field for a restricted number of skin disorders. Off-label use of biologics in other recalcitrant skin diseases has increased. Mounting data point to the potential of already existing biologics acting on the IL-17/IL-23 pathway in skin disorders with epidermal hyperkeratosis (e.g., pityriasis rubra pilaris), acneiform inflammation (e.g., hidradenitis suppurativa), and loss of mucosal integrity (e.g., aphthosis). TNF-alpha blockers are also effective in the latter conditions but seem of particular value in granulomatous (e.g., granuloma annulare) and neutrophilic disorders (e.g., pyoderma gangrenosum). Failure of IL-17 blockade in skin diseases resulting from immune-mediated cell destruction (e.g., alopecia areata and vitiligo) illustrates its limited involvement in Th1-dependent skin immunology. Overall, disappointing results of TNF-alpha blockers in alopecia areata and vitiligo point to the same conclusion although promising results in toxic epidermal necrolysis suggest TNF-alpha exerts at least some in vivo Th1-related activities. Acting on both the Th1 and Th17 pathway, ustekinumab has a rather broad potential with interesting results in lupus and alopecia areata. The efficacy of omalizumab in bullous pemphigoid has revealed an IgE-mediated recruitment of eosinophils leading to bullae formation. Reconsidering reimbursement criteria for less common but severe diseases seems appropriate if substantial evidence is available (e.g., pityriasis rubra pilaris). For other disorders, investigator-and industry-initiated randomized clinical trials should be stimulated. They are likely to improve patient outcome and advance our understanding of challenging skin disorders

Reliability and validity of the vitiligo signs of activity score (VSAS)

Background The associations between disease activity and several clinical signs in vitiligo have been described, but a widely accepted and validated scoring system is lacking. Objectives To validate the Vitiligo Signs of Activity Score (VSAS) for physicians. Methods Three visible clinical signs were scored on 15 body locations: confetti-like depigmentation (c), Koebner phenomenon (k) and hypochromic areas/borders (h). The inter- and intrarater reliability of the global VSAS and VSAS subscores (c-VSAS, k-VSAS and h-VSAS) were tested by four and three raters (physicians), respectively. Construct validity and feasibility were evaluated. Results The VSAS demonstrated good inter-rater reliability, with an intraclass correlation coefficient (ICC) of 0 center dot 87 in the first round and 0 center dot 90 in the second round. The intrarater reliability ICCs were all >= 0 center dot 86. The inter-rater reliabilities of the subscores were excellent for c-VSAS and fair for k-VSAS and h-VSAS (ICC 0 center dot 83, 0 center dot 51 and 0 center dot 53, respectively, in the first round). Evidence for construct validity was provided. The completion time by the raters (median 2 center dot 18 min per patient) improved during the second round (median 1 center dot 33 min per patient). A limitation of the study is the low number of patients, mainly of skin phototypes II-III, from a single tertiary centre. Conclusions The VSAS appears to be a valid and reliable instrument to score visible clinical signs linked to disease activity in a standardized way. What is already known about this topic? Evidence exists for a possible link between several visible clinical signs in vitiligo and disease activity. A widely accepted and validated scoring system to quantify these clinical signs is lacking. What does this study add? The Vitiligo Signs of Activity Score (VSAS) underwent preliminary validation and may assist quantification of visible clinical signs linked to disease activity in a standardized way in clinical practice and trials

From IL-17 to IFN-γ in inflammatory skin disorders: Is transdifferentiation a potential treatment target?

The targeted inhibition of effector cytokines such as interleukin 17 (IL-17) in psoriasis and IL-13 in atopic dermatitis offers impressive efficacy with a favorable side effect profile. In contrast, the downregulation of interferon gamma (IFN-γ) in T helper (Th) 1-dominant skin disorders may lead to more adverse events, given the crucial role of IFN-γ in antiviral and antitumoral immunity. Modulating Th17 and Th2 cell differentiation is performed by blocking IL-23 and IL-4, respectively, whereas anti-IL-12 antibodies are only moderately effective in downregulating Th1 lymphocyte differentiation. Therefore, a targeted approach of IFN-γ-driven disorders remains challenging. Recent literature suggests that certain pathogenic Th17 cell subsets with Th1 characteristics, such as CD4+CD161+CCR6+CXCR3+IL-17+IFN-y+ (Th17.1) and CD4+CD161+CCR6+CXCR3+IL-17-IFN-y+ (exTh17), are important contributors in Th1-mediated autoimmunity. Differentiation to a Th17.1 or exTh17 profile results in the upregulation of IFN-y. Remarkably, these pathogenic Th17 cell subsets are resistant to glucocorticoid therapy and the dampening effect of regulatory T cells (Treg). The identification of Th17.1/exTh17 cells in auto-immune disorders may explain the frequent treatment failure of conventional immunosuppressants. In this review, we summarize the current evidence regarding the cellular plasticity of Th17 cells in inflammatory skin disorders. A deeper understanding of this phenomenon may lead to better insights into the pathogenesis of various skin diseases and the discovery of a potential new treatment target

Clinical significance of plasmacytoid dendritic cells and myeloid-derived suppressor cells in melanoma

Background: Immune markers in the peripheral blood of melanoma patients could provide prognostic information. However, there is currently no consensus on which circulating cell types have more clinical impact. We therefore evaluated myeloid-derived suppressor cells (MDSC), dendritic cells (DC), cytotoxic T-cells and regulatory T-cells (Treg) in a series of blood samples of melanoma patients in different stages of disease. Methods: Flow cytometry was performed on peripheral blood mononuclear cells of 69 stage I to IV melanoma patients with a median follow-up of 39 months after diagnosis to measure the percentage of monocytic MDSCs (mMDSCs), polymorphonuclear MDSCs (pmnMDSCs), myeloid DCs (mDCs), plasmacytoid DCs (pDCs), cytotoxic T-cells and Tregs. We also assessed the expression of PD-L1 and CTLA-4 in cytotoxic T-cells and Tregs respectively. The impact of cell frequencies on prognosis was tested with multivariate Cox regression modelling. Results: Circulating pDC levels were decreased in patients with advanced (P = 0.001) or active (P = 0.002) disease. Low pDC levels conferred an independent negative impact on overall (P = 0.025) and progression-free survival (P = 0.036). Even before relapse, a decrease in pDC levels was observed (P = 0.002, correlation coefficient 0.898). High levels of circulating MDSCs (>4.13%) have an independent negative prognostic impact on OS (P = 0.012). MDSC levels were associated with decreased CD3+ (P < 0.001) and CD3 + CD8+ (P = 0.017) T-cell levels. Conversely, patients with high MDSC levels had more PD-L1+ T-cells (P = 0.033) and more CTLA-4 expression by Tregs (P = 0.003). pDCs and MDSCs were inversely correlated (P = 0.004). The impact of pDC levels on prognosis and prediction of the presence of systemic disease was stronger than that of MDSC levels. Conclusion: We demonstrated that circulating pDC and MDSC levels are inversely correlated but have an independent prognostic value in melanoma patients. These cell types represent a single immunologic system and should be evaluated together. Both are key players in the immunological climate in melanoma patients, as they are correlated with circulating cytotoxic and regulatory T-cells. Circulating pDC and MDSC levels should be considered in future immunoprofiling efforts as they could impact disease management

Autoimmunity in segmental vitiligo

The autoimmune basis of segmental vitiligo (SV) has only recently been recognized. Systemic autoimmune diseases are less frequently associated compared to non-segmental vitiligo (NSV), but localized skin disorders - in particular linear morphea - have been repeatedly observed in patients with SV. The inflammatory response is documented on a clinical level with cases displaying erythematous borders or a hypochromic stage, on a histopathological level with predominantly CD8 lymphocytes migrating toward the basal layer and by flow cytometry demonstrating the antimelanocyte specificity of these cytotoxic T cells. The increased risk for halo naevi and NSV in these patients further underline the immune-mediated mechanisms of SV. Nonetheless, the localized and unique distribution pattern points to somatic mosaicism. This places SV in a category of similar diseases such as lichen striatus, blaschkitis, linear lupus erythematosus, and linear scleroderma where an immune reaction against genetically mutated skin cells is believed to be the underlying cause. All these disorders are characterized by a young age of onset, a temporary disease activity with spontaneous resolution, limited response to treatment, and often long-term sequelae. Although challenging, genetic research proving this genetic mosaicism could offer crucial insights into the pathogenesis of both segmental and non-segmental vitiligo

Vaccinations in Patients Receiving Systemic Drugs for Skin Disorders : What Can We Learn for SARS-Cov-2 Vaccination Strategies?

Large-scale vaccination strategies are currently being deployed against severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2). Whether systemic medication for skin diseases affects the efficacy of vaccination and whether temporary interruption or extension of the dosing interval is necessary is under debate. Most immunomodulating/immunosuppressive drugs only affect vaccine-induced immune responses to a limited or moderate extent, preserving sufficient immunity in most patients. Mycophenolate mofetil, Janus kinase inhibitors, and rituximab require a more cautious approach, and judicious timing of vaccination might be appropriate in patients receiving these treatments. It should be noted that, for most drugs except methotrexate, data on the length of the interruption period to restore vaccine-induced immune responses to normal levels are either very limited or absent. In these cases, only the drug half-life can be used as a practical guideline. In most patients, systemic medication can be continued through the vaccination process, although case-by-case decisions can be considered

Validation of a Patient Global Assessment for extent, severity and impact to define the severity strata for the Self Assessment Vitiligo Extent Score (SA-VES)

Background: The Self Assessment Vitiligo Extent Score (SA‐VES) is a validated, patient‐reported outcome measure to assess the body surface area affected with vitiligo. Information on how to translate the obtained score into extent, severity and impact strata (mild–moderate–severe) is still lacking. Stratification is helpful to define inclusion criteria for trials, enables comparison and pooling of trial results and can be used for epidemiological research. Objectives: The aim was to develop extent, severity and impact strata for the SA‐VES based on validated anchor‐based questions. Methods: In total, 315 patients with vitiligo (non‐segmental; age ≥ 16) recruited at the Ghent University Hospital (Belgium) completed a questionnaire that was conducted in cooperation with the Dutch Society for vitiligo patients to ensure content validity. First three anchor questions included in the questionnaire [Patient Global Assessment (PtGA) for vitiligo extent, severity and impact] were assessed for content validity, construct validity and intrarater reliability. Subsequently, the PtGAs were used to stratify the SA‐VES based on ROC analysis. Results: For all PtGAs (PtGA extent, PtGA severity, PtGA impact), at least 75% of hypotheses evaluated for construct validity were confirmed. Intrarater reliability of all PtGAs was good to excellent (ICCs PtGA extent: 0.623; PtGA severity: 0.828; PtGA impact: 0.851). The optimal cut‐off values of the SA‐VES between the three global categories (mild/limited – moderate – severe/extensive) were 1.05% and 6.45% based on PtGA extent, 2.07% and 4.8% based on PtGA severity and 2% and 3.35% based on PtGA impact. Conclusion: This study provides the first guide for the interpretation of the numerical output obtained by the SA‐VES (vitiligo extent) and enables the translation into a global vitiligo grading for extent, severity and impact. As patients’ interpretation of vitiligo extent, severity and impact may vary amongst patients worldwide, future international studies will be required