Assessing the dynamic changes in vitiligo: reliability and validity of the Vitiligo Disease Activity Score (VDAS) and Vitiligo Disease Improvement Score (VDIS).

BACKGROUND: The assessment of the individual evolution of vitiligo is important for therapeutic decision making in daily practice. A fast, simple and validated physician-reported score to assess clinical changes in depigmentation over time in separate parts (activity and improvement) is currently missing. OBJECTIVE: The main objective of the study was to develop and validate the Vitiligo Disease Activity Score (VDAS) and Vitiligo Disease Improvement Score (VDIS). METHODS: The Vitiligo Disease Activity Score (VDAS) and Vitiligo Disease Improvement Score (VDIS) were evaluated based on a photo set of 66 patients with two different time points. In the first (short) version, only the number of changing body regions was counted based on 15 predefined areas (VDAS15 and VDIS15 ), while in the second (extensive) version the degree of worsening or improvement from +4 to -4 for each body area was added for a more detailed assessment (VDAS60 and VDIS60 ). Content and construct validity were tested. In addition inter-, intrarater reliability and feasibility were evaluated by 7 (test) and 5 (retest) physicians. RESULTS: Evidence for content and construct validity was provided. Overall, VDAS15 , VDIS15 , VDAS60 and VDIS60 demonstrated good to excellent inter-rater reliability [intraclass correlation (ICC): VDAS: range = 0.797-0.900; VDIS: range = 0.726-0.798]. The intrarater reliability ICCs were 0.865 and 0.781 for the VDAS15 and VDIS15 , respectively. Similar results were obtained for the VDAS60 and VDIS60 (ICC = 0.913 and 0.800, respectively). Completion time was short (median: 122 s/patient (first round); 95 s/patient (second round)]. LIMITATIONS: Single tertiary centre mainly of skin phototype 2 to 3. CONCLUSION: The VDAS and VDIS appear to be valid, reliable and feasible instruments to score the evolution of vitiligo lesions. This accommodates the current urgent need for a simple, standardized and practical assessment of vitiligo activity and improvement over time.

The use of lasers in vitiligo, an overview.

Various types of lasers have been demonstrated to be effective in the treatment of vitiligo. The mode of action of these lasers is just as varied as the purpose of intervention. Many clinicians are not aware of the unique opportunity these lasers offer to improve the outcomes of vitiligo treatment. To date, no clear overview exists of the use of lasers in vitiligo treatment. Thus, the aim of this review is to discuss the various types of lasers and provide an overview of the evidence for their efficacy. We found good evidence from a systematic review that the excimer laser is effective, induces repigmentation rates comparable to NB-UVB and has improved outcomes when combined with calcineurin inhibitors. Ablative lasers are commonly used for tissue graft or melanocyte-keratinocyte cell graft transplantation. They provide safe, fast and uniform denudation of the epidermis with propitious repigmentation outcomes. We found conflicting evidence from two systematic reviews regarding the efficacy of fractional ablative lasers for improving outcomes of NB-UVB therapy, a systematic review including only fractional ablative lasers provided evidence for efficacy. Q-switched nanosecond lasers have shown to be safe and effective for inducing depigmentation, although recurrence is common, and most studies were small and retrospective. Despite proven efficacy and safety, laser treatments are relatively expensive and suited for limited body surface areas and selected cases. Each type of laser has benefits and risks associated and should, therefore, be individually chosen based on location, extent, activity and type of vitiligo.

Donor to recipient ratios in the surgical treatment of vitiligo and piebaldism: a systematic review.

Stabilized vitiligo resistant to conventional therapy (e.g. segmental vitiligo) and piebaldism lesions can be treated with autologous cellular grafting techniques, such as non-cultured cell suspension transplantation (NCST) and cultured melanocyte transplantation (CMT). These methods are preferred when treating larger surface areas due to the small amount of donor skin needed. However, the donor to recipient expansion ratios and outcomes reported in studies with cellular grafting vary widely, and to date, no overview or guideline exists on the optimal ratio. The aim of our study was to obtain an overview of the various expansion ratios used in cellular grafting and to identify whether expansion ratios affect repigmentation and colour match. We performed a systematic literature search in MEDLINE and EMBASE to review clinical studies that reported the expansion ratio and repigmentation after cellular grafting. We included 31 eligible clinical studies with 1591 patients in total. Our study provides an overview of various expansion ratios used in cellular grafting for vitiligo and piebaldism, which varied from 1:1 up to 1:100. We found expansion ratios between 1:1 and 1:10 for studies investigating NCST and from 1:20 to 1:100 in studies evaluating CMT. Pooled analyses of studies with the same expansion ratio and repigmentation thresholds showed that when using the lowest (1:3) expansion ratio, the proportion of lesions achieving >50% or >75% repigmentation after NCST was significantly better than when using the highest (1:10) expansion ratio (χ2 P = 0.000 and χ2 P = 0.006, respectively). Less than half of our included studies stated the colour match between different expansion ratios, and results were variable. In conclusion, the results of our study indicate that higher expansion ratios lead to lower repigmentation percentages after NCST treatment. This should be taken into consideration while determining which expansion ratio to use for treating a patient.

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.

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 0·87 in the first round and 0·90 in the second round. The intrarater reliability ICCs were all ≥ 0·86. The inter-rater reliabilities of the subscores were excellent for c-VSAS and fair for k-VSAS and h-VSAS (ICC 0·83, 0·51 and 0·53, respectively, in the first round). Evidence for construct validity was provided. The completion time by the raters (median 2·18 min per patient) improved during the second round (median 1·33 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. What are the clinical implications of this work? VSAS may be used for future trials that aim to establish the clinical significance of the specific visible clinical signs in vitiligo in a more controlled setting. Linked Comment: Eleftheriadou. Br J Dermatol 2020; 183:801-802.

Comparison of methods to estimate the affected body surface area and the dosage of topical treatments in psoriasis and atopic dermatitis: the advantage of a picture-based tool.

BACKGROUND: The accurate determination of the dosage of topical treatments is important given its repercussions on patient adherence and therapeutic efficacy. Up till now, the fingertip unit calculated by the rule of hands is considered the gold standard, although its use is associated with several drawbacks. OBJECTIVE: To compare different methods to estimate the affected body surface area (BSA) and dosage of topical treatments in atopic dermatitis and psoriasis and investigate its reliability, user-friendliness and timing. METHODS: In this study, we compared the reliability of three different methods: (i) the fingertip unit calculated by the 1% hand rule; (ii) a picture-based tool [termed Cutaneous Inflammatory Disease Extent Score (CIDES)]; and (iii) a digital drawing tool. Eleven observers scored 40 patients with psoriasis and eczema to assess the inter-rater and intrarater reliability. Timing was automatically recorded, and user-friendliness was investigated by a questionnaire. RESULTS: An excellent intraclass correlation (ICC) was found for both inter-rater agreement and intrarater agreement for the picture-based tool (ICC = 0.92 and ICC = 0.96, respectively). The ICCs for drawing the area of involvement on a silhouette were 0.89 and 0.93, respectively. Finally, the rule of hands was associated with an increased inter-rater variability although an excellent intrarater agreement was found (ICC = 0.79 and 0.95, respectively). Automated calculation of the amount of topical treatment improved reliability, and CIDES was associated with the least variation. CIDES was considered the preferred method by all observers and was fast to perform (median: 30 s). CONCLUSION: A picture-based method offered the most advantages (in terms of reliability, speed and user-friendliness) to estimate the affected BSA and calculate the dosage of topical treatments.

Clinical visible signs of disease activity in vitiligo: a systematic review and meta-analysis.

Vitiligo is an unpredictable depigmenting disorder for which a static method to assess disease activity is lacking. Presence of certain skin manifestations may be indicative of disease activity. Here, we evaluated the current evidence for an association between clinical signs and reported disease activity in vitiligo. A systematic review and meta-analysis was performed based on a search in PubMed, Embase and Cochrane Library. Literature reporting skin manifestations and disease activity was analysed based on descriptive analyses and, if applicable, odd ratios. Forty-six observational studies were selected and analysed, including 28 case reports. Reported clinical signs in relation to active vitiligo were as follows: Koebner's phenomenon, confetti-like depigmentations, tri- and hypochromic lesions (including poorly defined borders), inflammatory borders/areas, itch and leukotrichia. Based on this search, strong evidence was found for Koebner's phenomenon. Poorly defined borders and confetti lesions are potential markers, although more data are needed to confirm this. Evidence for other skin manifestations was inconclusive, whereas case reports on inflammatory borders were indicative of active disease. Limitations included the lack of randomized controlled trials, large-scale prospective studies and heterogeneity due to inconsistent definitions. This systematic review urges the vitiligo community to come forward with consensus-based definitions as well as a reliable scoring system to assess these clinical signs and to design optimal trials to investigate their true predictive value.

UV light set-ups for vitiligo photography, a comparative study on image quality and ease of use.

BACKGROUND: Ultraviolet (UV) light is an essential tool to assess the extent, spreading and staging of vitiligo. Different UV light set-ups are used for vitiligo photography, including the following: (i) hand-held Wood's lamps; (ii) soft boxes with UV lamps; (iii) UV flash attached to the camera; and (iv) high output UV flash. OBJECTIVE: Our objective was to compare UV light set-ups for vitiligo photography regarding image quality and ease of use. METHODS: Patients with vitiligo lesions with unclear borders were included. Two images were made with all four UV set-ups per patient, for a large and a small area. Image quality was scored separately by three blinded vitiligo experts on five criteria: overall quality, clearness of borders, contrast and sharpness and for larger areas the shadows. The two professional medical photographers were asked to score the ease of use for each set-up. RESULTS: A total of 88 photos were assessed from 11 patients. For larger areas, the frequency of a 'good' or 'very good' overall quality rating was 12.1% (Wood's), 6.1% (soft boxes), 15.2% (camera flash) and 78.8% (high output flash). For smaller areas, the score 'good' or 'very good' was given to 54.5%, 3%, 66.6% and 84.8% in the same order. For the shadow criteria, each set-up scored below 40% on a 'good' or 'very good' score. The high output flash was scored as most easy to use by the photographers. CONCLUSION: When comparing four different UV light set-ups for vitiligo photography, we concluded that the UV set-ups strongly influenced the quality scores of the obtained images. The high output flash scored best for both small and large areas and for ease of use. For small areas, Wood's lamp and camera flash were acceptable. All set-ups scored badly for shadows, and more research is needed to find the optimal exposure to avoid shadows.

Reference method for digital surface measurement of target lesions in vitiligo: a comparative analysis.

BACKGROUND: Objective measurement of target lesions in vitiligo is important for clinical practice and trials, yet no preferred tool has been defined. Reported digital tools have shortcomings related to feasibility aspects and often lack information on validity, reliability and responsiveness. Moreover, studies are not yet based on ultraviolet (UV) photography. OBJECTIVES: To assess the reliability, validity and feasibility of two functions in ImageJ for measurement of target lesions, based on three different types of images including UV pictures. METHODS: Planimetric measurements were performed on photographs with and without UV, and lesion contours on transparent sheets of 52 vitiligo lesions from 10 patients with vitiligo. The ImageJ functions 'wand' and 'threshold' were used by three and four assessors, respectively. Inter- and intrarater reliability, hypothesis testing for construct validity, and feasibility were evaluated. RESULTS: The inter- and intrarater reliability for the 'wand' and 'threshold' functions were excellent [intraclass correlation coefficient (ICC) > 0·9] for measurement on pictures (with or without UV). The highest agreement (ICC > 0·95) and lowest variance were obtained for measurements on transparent sheets. All four hypotheses for construct validity were confirmed for all measurements. Overall, all measurement methods scored satisfactorily for user-friendliness. However, measurements on transparent sheets were preferred and the completion time was significantly faster. CONCLUSIONS: This study confirmed the reliability, validity and feasibility of two functions in ImageJ to measure target lesions in vitiligo. Based on the feasibility and included three-dimensional aspects, transparent sheets measured with the ImageJ 'wand' function can be proposed for future trials as a reference method to investigate the criterion validity of other digital instruments.

Mapping widespread and increasing underwater noise pollution from acoustic deterrent devices.

Acoustic deterrent devices (ADDs) are used in attempts to mitigate pinniped depredation on aquaculture sites through the emission of loud and pervasive noise. This study quantified spatio-temporal changes in underwater ADD noise detections along western Scotland over 11 years. Acoustic point data ('listening events') collected during cetacean line-transect surveys were used to map ADD presence between 2006 and 2016. A total of 19,601 listening events occurred along the Scottish west coast, and ADD presence was recorded during 1371 listening events. Results indicated a steady increase in ADD detections from 2006 (0.05%) to 2016 (6.8%), with the highest number of detections in 2013 (12.6%), as well as substantial geographic expansion. This study demonstrates that ADDs are a significant and chronic source of underwater noise on the Scottish west coast with potential adverse impacts on target (pinniped) and non-target (e.g. cetaceans) species, which requires further study and improved monitoring and regulatory strategies.

Critical appraisal of the oxidative stress pathway in vitiligo: a systematic review and meta-analysis.

BACKGROUND: The pathogenesis of vitiligo remains a topic of extensive debate. This is partly due to the moderate efficacy of current treatments. The role of the oxidative stress pathway in vitiligo is a popular although controversial research topic. OBJECTIVE: To clarify the role of the oxidative stress pathway in vitiligo compared to other inflammatory skin disorders and to assess the therapeutic role of antioxidants. METHODS: We conducted a systematic search of the existing literature on the aberrancies of the oxidative stress pathway in vitiligo. Subsequently, the efficacy of both topical and oral antioxidants in clinical trials was investigated. RESULTS: A deregulated oxidative pathway is clearly evident with elevated superoxide dismutase, decreased catalase and increased lipid peroxidation. However, similar results have been obtained in other inflammatory skin diseases such as psoriasis, atopic dermatitis, lichen planus and urticaria. This questions the unique role of oxidative stress in the development of vitiligo. Some isolated successes have been reported with oral ginkgo biloba, polypodium leucotomos and vitamin C and E preparations, while other clinical trials have failed to show reproducible results. The use of topical antioxidants delivers in general no beneficial results. CONCLUSION: The oxidative pathway is affected in vitiligo, but its unique initiating or contributory role in the pathogenesis is less evident. Interesting data support the added value of oral antioxidants in vitiligo although confirmatory studies are missing.

Biomarkers of disease activity in vitiligo: A systematic review.

The pathophysiology of vitiligo is complex although recent research has discovered several markers which are linked to vitiligo and associated with disease activity. Besides providing insights into the driving mechanisms of vitiligo, these findings could reveal potential biomarkers. Activity markers can be used to monitor disease activity in clinical trials and may also be useful in daily practice. The aim of this systematic review was to document which factors have been associated with vitiligo activity in skin and blood. A second goal was to determine how well these factors are validated in terms of sensitivity and specificity as biomarkers to determine vitiligo activity. Both in skin (n=43) as in blood (n=66) an adequate number of studies fulfilled the predefined inclusion criteria. These studies used diverse methods and investigated a broad range of plausible biomarkers. Unfortunately, sensitivity and specificity analyses were scarce. In skin, simple histopathology with or without supplemental CD4 and CD8 stainings can still be considered as the gold standard, although more recently chemokine (C-X-C motif) ligand (CXCL) 9 and NLRP1 have demonstrated a good and possibly even better association with progressive disease. Regarding circulating biomarkers, cytokines (IL-1ß, IL-17, IFN-γ, TGF-ß), autoantibodies, oxidative stress markers, immune cells (Tregs), soluble CDs (sCD25, sCD27) and chemokines (CXCL9, CXCL10) are still competing. However, the two latter may be preferable as both chemokines and soluble CDs are easy to measure and the available studies display promising results. A large multicenter study could make more definitive statements regarding their sensitivity and specificity.

The many faces of interleukin-17 in inflammatory skin diseases.

Interleukin (IL)-17 is an emerging target for inflammatory skin disorders. Given the remarkable success of its therapeutic inhibition in psoriasis, the pathogenic role of this cytokine is being explored in other immune-mediated diseases. Interestingly, IL-17 is linked to particular skin conditions where its activation coincides with disease flares. The leading hypothesis for its contribution to proinflammatory signalling cascades is driving inflammasome activation. However, IL-17 stimulation also releases a range of noninflammasome-related cytokines from human skin. Furthermore, a role in cytotoxic responses and an important interplay with the microbiome is hypothesized. While treatment failure would be surprising in neutrophilic dermatoses, the picture might be more complex in lymphocyte-mediated conditions. Nonetheless, increasing insights into the pathogenesis suggest that beneficial responses are also probable in the latter conditions. Study of this pathway in the skin reveals some intriguing aspects of the IL-17-related immunological network.

Secukinumab: IL-17A inhibition to treat psoriatic arthritis.

Interleukin-17A is an important cytokine in the pathogenesis of psoriatic arthritis. Secukinumab is a recombinant, high-affinity, fully human immunoglobulin G1kappa monoclonal antibody with a selective binding and neutralization of interleukin-17A. By providing an alternative mechanism of action to current treatments, secukinumab has shown efficacy in the key clinical domains of psoriatic arthritis. In the present paper, we discuss the role of interleukin-17A as a clinically relevant target in the treatment of psoriatic arthritis, based on preclinical findings, dose-ranging and regimen-finding, randomized, placebo-controlled clinical trials.

Characterization of the in vivo immune network of IDO, tryptophan metabolism, PD-L1, and CTLA-4 in circulating immune cells in melanoma.

In melanoma, both the induction of immunosuppression by tumor cells and the inflammatory antitumor response can induce an upregulation of counter-regulatory mechanisms such as indoleamine 2,3-dioxygenase (IDO), programmed death-ligand 1 (PD-L1) and CTLA-4+ regulatory T-cells (Tregs) in the tumor microenvironment. Even though these immunosuppressive mediators are targets for immunotherapy, research investigating their expression in the peripheral blood is lacking. We therefore, performed flow cytometry on PBMCs of stage I-IV melanoma patients. IDO expression was detected in plasmacytoid dendritic cells (pDC) and monocytic myeloid-derived suppressor cells (mMDSC), and increased in advanced disease stage (p = 0.027). Tryptophan breakdown confirmed the functional activity of IDO and was linked with increased PD-L1+ cytotoxic T-cells (p = 0.009), relative lymphopenia (p = 0.036), and a higher mDC/pDC ratio (p = 0.002). High levels of circulating PD-L1+ cytotoxic T-cells were associated with increased CTLA-4 expression by Tregs (p = 0.005) and MDSC levels (p = 0.033). This illustrates that counter-regulatory immune mechanisms in melanoma should be considered as one interrelated signaling network. Moreover, both increased PD-L1+ T-cells and CTLA-4 expression in Tregs conferred a negative prognosis, indicating their in vivo relevance. Remarkably, circulating CTLA-4, IDO, and pDC levels were altered according to prior invasion of the sentinel lymph node and IDO expression in the sentinel was associated with more IDO+ PBMCs. We conclude that the expression of IDO, PD-L1, and CTLA-4 in the peripheral blood of melanoma patients is strongly interconnected, associated with advanced disease and negative outcome, independent of disease stage. Combination treatments targeting several of these markers are therefore likely to exert a synergistic response.

Relevance of congenital melanocytic naevi in vitiligo.

BACKGROUND: Some case reports concerning the concomitant presence of congenital melanocytic naevi (CMN), halo naevi and vitiligo have been published. However, their possible link has never been investigated in a large patient population. OBJECTIVES: To evaluate the relevance of CMN in patients with vitiligo with respect to the presence of halo naevi and some general clinical variables such as age of onset, Koebner phenomenon and body surface area (BSA) involvement. METHODS: In total, 1004 patients with vitiligo (nonsegmental) and 291 control patients were included in this observational study. CMN were scored in size, location and halo formation, and classified into clinical convincing or possible lesions. RESULTS: Convincing CMN were present in 3·3% of the patient population and in 1·0% of the control population. The presence of halo naevi was significantly higher (P = 0·01) and age of onset of vitiligo was significantly lower (P < 0·01) in the presence of CMN. Halo formation around the CMN, as observed in 30·3% of cases, was associated with a higher diameter of the CMN. Patients with congenital naevi had a particular predisposition to having lesions on joints/acral areas and reported more often signs of Koebner phenomenon (P = 0·01). No clear difference in disease activity, BSA involvement, associated autoimmune diseases or treatment response was observed in patients with vitiligo with or without congenital naevi. CONCLUSIONS: This study provides clinical evidence that CMN may influence the age of onset of vitiligo and trigger the development of halo naevi in patients with vitiligo.