Vitiligo Trials Research Articles

Phosphodiesterase-4 Inhibitors Increase Pigment Cell Proliferation and Melanization in Cultured Melanocytes and within a 3-Dimensional Skin Equivalent Model

Vitiligo is a common chronic autoimmune disease characterized by white macules and patches of the skin, having a negative impact on patients' life, and without any definitive cure at present. Identification of new compounds to reverse depigmentation is therefore a pressing need for this disease. The pharmacologic compounds phosphodiesterase-4 inhibitors (PDE4i) are small molecules with immunomodulatory properties, used for treatment of inflammatory dermatoses. PDE4i have shown repigmentation effects in vitiligo patients, in some case reports. We characterized the proliferative and melanogenic potential of two known PDE4i, crisaborole and roflumilast, and of a more recently designed compound, PF-07038124. We used two in vitro model systems, the primary human melanocyte culture and a 3D co-cultured skin model (MelanoDermTM), with an exploratory testing platform composed of complementary assays (spectrophotometry, melanin and proliferation assays, immunostaining, Fontana-Masson staining, qRT-PCR, western blot and whole transcriptome RNA-Sequencing). We identified that the treatment with PDE4i was associated with increased melanocyte proliferation and melanization in both in vitro models, and with increase in the melanogenic genes and proteins expression in cultured melanocytes. These effects were found to be enhanced by addition of α-MSH. Our findings support the further evaluation of PDE4i with or without α-MSH agonists in vitiligo trials.

Psychometric Evaluation of the Facial and Total Vitiligo Area Scoring Index Instruments in the TRuE-V Phase 3 Studies.

This study reports psychometric testing of the facial and total Vitiligo Area Scoring Index quantitative clinical instruments (F-VASI [range: 0-3], T-VASI [range: 0-100], respectively) using data from two phase 3 randomized, vehicle-controlled studies of ruxolitinib cream (TRuE-V1/TRuE-V2), the largest vitiligo trials conducted to date. Because VASI assessment is required by regulatory authorities, we evaluated the psychometric properties of the VASI instruments and confirmed thresholds for clinically meaningful change. The TRuE-V1/TRuE-V2 full analysis set population included 652 patients (≥ 12years old with nonsegmental vitiligo affecting ≤ 10% total body surface area, F-VASI ≥ 0.5, and T-VASI ≥ 3 at baseline). Data collected using the facial and total Patient Global Impression of Change-Vitiligo (PaGIC-V) and Physician's Global Vitiligo Assessment (PhGVA) scales were used as anchors to assess F-VASI and T-VASI for reliability, validity, sensitivity to change, and clinically meaningful change. Median F-VASI and T-VASI scores were 0.70 and 6.76, respectively, at baseline, decreasing to 0.48 and 4.80 at week 24. Test-retest reliability was excellent between screening and baseline for F-VASI (intraclass correlation coefficient [ICC]: 0.943) and T-VASI (ICC: 0.945). Among stable patients per PaGIC-V and PhGVA, reliability was moderate to good for both F-VASI (ICC: 0.891 and 0.739, respectively) and T-VASI (ICC: 0.768 and 0.686). F-VASI and T-VASI differentiated well among PhGVA categories mild/moderate/severe at baseline and week 24. Both VASI instruments detected changes assessed by correlations with PaGIC-V scores at week 24 (F-VASI, r = 0.610; T-VASI, r = 0.512) and changes in PhGVA scores from baseline to week 24 (F-VASI, r = 0.501; T-VASI, r = 0.344). Thresholds for clinically meaningful improvement per PaGIC-V and PhGVA were 0.38-0.60 for F-VASI and 1.69-3.88 for T-VASI. Data from the TRuE-V1/TRuE-V2 studies confirmed that F-VASI and T-VASI are reliable, valid, and responsive to change, with defined clinically meaningful change from baseline in patients with nonsegmental vitiligo. The original studies were registered at ClinicalTrials.gov: NCT04052425/NCT04057573.

A meta-analysis of the placebo response in vitiligo: Causes and consequences for the interpretation of clinical trials.

The current understanding of the placebo response in vitiligo is limited. Nonetheless, it is difficult to compare the outcomes of vitiligo trials if the repigmentation rates in placebo patients vary significantly. We conducted a meta-analysis of the placebo response in vitiligo trials. Overall, repigmentation rates in patients receiving placebo were 22%, ranging substantially from 0 to 60%. Repigmentation (>25%) was still relatively common for placebo (9.35%), but fell to 5% when >50% improvement was analyzed. Higher frequencies of placebo responses correlated with more repigmentation in the intervention groups. Facial vitiligo and sunlight exposure was linked to higher placebo responses. Roughly estimating the amount of improvement using quartiles (0-25, 25%-50%, 50%-75%, 75%-100% repigmentation) resulted in higher placebo rates compared to other assessment methods. In clinical studies with older patients, the ratio of placebo reactions to treatment responses was higher. This is likely because clinical trials with older patients reported less repigmentation after treatment than studies with younger patients. The percentual difference in affected body surface area during the study period ranged from 6.2% worsening to 17.6% improvement in the placebo groups. This high variability in placebo responses illustrates the need for standardized outcome measures and more head-to-head trials in vitiligo.

Reliability and agreement testing of a new automated measurement method to determine facial vitiligo extent using standardized ultraviolet images and a dedicated algorithm.

Facial repigmentation is the primary outcome measure for most vitiligo trials. The Facial Vitiligo Area Scoring Index (F-VASI) score is often chosen as the primary outcome measure to assess the efficacy of treatments for facial vitiligo. Although useful, this scoring system remains subjective and has several limitations. To assess the agreement and reliability of an algorithmic method to measure the percentage depigmentation of vitiligo on the face. We developed a dedicated algorithm called Vitil-IA® to assess depigmentation on standardized facial ultraviolet (UV) pictures. We then conducted a cross-sectional study using the framework of the ERASE trial (NCT04843059) in 22 consecutive patients attending a tertiary care centre for vitiligo. Depigmentation was analysed before any treatment and, for 7 of them, after 3 and 6 months of narrowband UVB treatment combined with 16 mg methylprednisolone, both used twice weekly. Interoperator and interacquisition repeatability measures were assessed for the algorithm. The results of the algorithmic measurement were then compared with the F-VASI and the percentage of depigmented skin scores assessed by 13 raters, including 7 experts in the grading of vitiligo lesions. Thirty-one sets of pictures were analysed with the algorithmic method. Internal validation showed excellent reproducibility, with a variation of < 3%. The percentage of depigmentation assessed by the system showed high agreement with the percentage of depigmentation assessed by raters [mean error (ME) -11.94 and mean absolute error (MAE) 12.71 for the nonexpert group; ME 0.43 and MAE 5.57 for the expert group]. The intraclass correlation coefficient (ICC) for F-VASI was 0.45 [95% confidence interval (CI) 0.29-0.62] and 0.52 (95% CI 0.37-0.68) for nonexperts and experts, respectively. When the results were analysed separately for homogeneous and heterogeneous depigmentation, the ICC for homogeneous depigmentation was 0.47 (95% CI 0.31-0.77) and 0.85 (95% CI 0.72-0.94) for nonexperts and experts, respectively. When grading heterogeneous depigmentation, the ICC was 0.19 (95% CI 0.05-0.43) and 0.38 (95% CI 0.20-0.62) for nonexperts and experts, respectively. We demonstrated that the Vitil-IA algorithm provides a reliable assessment of facial involvement in vitiligo. The study underlines the limitations of the F-VASI score when performed by nonexperts for homogeneous vitiligo depigmentation, and in all raters when depigmentation is heterogeneous.

Quality of Life Assessments Utilized in Vitiligo Clinical Trials

Introduction. Vitiligo is an acquired autoimmune disease associated with high psychosocial burden. As novel treatments are being developed in clinical trials, assessing vitiligo disease burden extends beyond physical manifestations. Including quality of life (QoL) measures in vitiligo clinical trials can better capture disease‐specific psychosocial concerns and facilitate cross comparisons amongst interventions. Objective. To determine the frequency and types of QoL measures utilized in vitiligo clinical trials and comment on how this has changed longitudinally. Methods. A search of vitiligo clinical trials using clinicaltrials.gov was conducted. Phase 2 and phase 3 trials published in English from January 2000 to July 2023 were eligible for this review. Characteristics of clinical trial parameters were compared to those of non‐QoL reporting clinical trials using Pearson’s χ2 tests (or Fisher’s if low n). Results. A total of 60 clinical trials were eligible for this review, of which 40% included a QoL measure in their study design. Phase 3 clinical trials (p = 0.002), larger (100+ participants) trials (p = 0.063), U.S. trials (p = 0.029), and pharmaceutical interventions (p = 0.022) were more likely to include QoL measures in their design. The number of clinical trials has been increasing over time, with 8 trials from 2000 to 2010, 32 total trials from 2011 to 2020, and 20 trials from 2021 to 2023. The most commonly used QoL measures were the Dermatology Life Quality Index (DLQI, 55.2%), Children′s Dermatology Life Quality Index (CDLQI, 13.8%), and Vitiligo‐specific quality of life instrument (VitiQoL, 13.8%). Over time, the VitiQoL and CDLQI have been used more frequently. Conclusion. Although vitiligo is associated with high psychological and emotional burden, less than half of vitiligo trials utilize QoL measures. The general dermatology QoL measures, namely the DLQI and CDLQI, are the most commonly used QoL assessments. As the number of clinical trials is increasing, vitiligo‐specific questionnaires may better capture unique vitiligo‐specific concerns. Standardizing the types of and implementation of QoL questionnaires in clinical trials can aid in assessing outcome measures across clinical trials worldwide and allow for better data interpretation, comparability, and clinical application of results.

Using the Vitiligo Noticeability Scale in clinical trials: construct validity, interpretability, reliability and acceptability.

Validated outcome measures are needed for vitiligo trials. To assess construct validity, interpretability, reliability and acceptability of the Vitiligo Noticeability Scale (VNS). We used images of vitiligo before and after treatment, plus outcome data, from the HI-Light Vitiligo trial. We compared outcome assessments made by trial participants with assessments of images by clinicians and people with vitiligo who were not trial participants [Patient and Public Involvement (PPI) panel]. Hypothesis testing assessed psychometric properties of the VNS, with κ statistics to assess agreement between outcomes. Three focus groups and two online discussion groups provided insight into the use of VNS by people with vitiligo. Our hypothesis of a positive association between VNS and participant-reported global treatment success was supported for trial participants (κ = 0·41 if VNS success was defined as ≥ 4; κ = 0·71 if VNS success was defined as ≥ 3), but not for the blinded PPI panel (κ = 0·28). As hypothesized, the association with participant-reported global success was higher for VNS (κ = 0·41) than for clinician-reported percentage repigmentation (κ = 0·17). Seventy-five per cent of trial participants valued a VNS of 3 (partial response) as a treatment success. Test-retest reliability was good: κ = 0·69 (95% confidence interval 0·63-0·74). Age and skin phototype did not influence interpretation of the VNS scores. To people with vitiligo, the VNS is an acceptable and meaningful patient-reported outcome measure. Trial participants may assess their vitiligo differently compared with blinded assessors. A VNS score of 3 may be more highly valued by people undergoing vitiligo treatment than was previously thought. What is already known about this topic? Vitiligo is a common condition, and can have a considerable psychological impact. A Vitiligo Core Outcome Set is being developed, to enable the results of vitiligo trials to be compared and combined more easily. The Vitiligo Noticeability Scale (VNS) is a patient-reported outcome measure (PROM) developed in partnership with people with vitiligo; initial validation studies have been promising. What does this study add? The VNS shows good construct validity, reliability and acceptability; it can be used in all ages and skin phototypes. All five levels of the VNS scale should be reported for transparency, to aid interpretation of trial findings, and to facilitate meta-analysis in systematic reviews. VNS assessments made by trial participants and independent observers are likely to be qualitatively different, making blinded assessment of VNS by independent observers difficult to interpret. Blinding of participants to trial interventions is recommended whenever possible. What are the clinical implications of the work? The VNS can be used as a PROM to assess the cosmetic acceptability of repigmentation at individual patches of vitiligo. A VNS score of 3 or more is likely to be valued by patients as a treatment success.

P95: Update of a systematic review on outcomes in vitiligo trials: international implementation of core outcomes set and recommendations on its further development

P95: Update of a systematic review on outcomes in vitiligo trials: international implementation of core outcomes set and recommendations on its further development

International Initiative for Outcomes for vitiligo trials (INFO)

International Initiative for Outcomes for vitiligo trials (INFO)

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 3yr. Treatment is defined as successful if repigmentation exceeds 80% and at least 80% of the gained repigmentation is maintained for over 6months. 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.

A programme of research to set priorities and reduce uncertainties for the prevention and treatment of skin disease

BackgroundSkin diseases are very common and can have a large impact on the quality of life of patients and caregivers. This programme addressed four diseases: (1) eczema, (2) vitiligo, (3) squamous cell skin cancer (SCC) and (4) pyoderma gangrenosum (PG).ObjectiveTo set priorities and reduce uncertainties for the treatment and prevention of skin disease in our four chosen diseases.DesignMixed methods including eight systematic reviews, three prioritisation exercises, two pilot randomised controlled trials (RCTs), three feasibility studies, two core outcome initiatives, four funding proposals for national RCTs and one completed national RCT.SettingSecondary care, primary care and the general population.ParticipantsPatients (and their caregivers) with eczema, vitiligo, SCC and PG, plus health-care professionals with an interest in skin disease.InterventionsOur three intervention studies included (1) barrier enhancement using emollients from birth to prevent eczema (pilot RCT); (2) handheld narrowband ultraviolet light B therapy for treating vitiligo (pilot RCT); and (3) oral ciclosporin (Neoral®, Novartis Pharmaceuticals) compared with oral prednisolone for managing PG (pragmatic national RCT).ResultsSystematic reviews included two overarching systematic reviews of RCTs of treatments for eczema and vitiligo, an umbrella review of systematic reviews of interventions for the prevention of eczema, two reviews of treatments for SCC (one included RCTs and the second included observational studies), and three reviews of outcome measures and outcome reporting. Three prioritisation partnership exercises identified 26 priority areas for future research in eczema, vitiligo and SCC. Two international consensus initiatives identified four core domains for future eczema trials and seven core domains for vitiligo trials. Two pilot RCTs and three feasibility studies critically informed development of four trial proposals for external funding, three of which are now funded and one is pending consideration by funders. Our pragmatic RCT tested the two commonly used systemic treatments for PG (prednisolone vs. ciclosporin) and found no difference in their clinical effectiveness or cost-effectiveness. Both drugs showed limited benefit. Only half of the participants’ ulcers had healed by 6 months. For those with healed ulcers, recurrence was common (30%). Different side effect profiles were noted for each drug, which can inform clinical decisions on an individual patient basis. Three researchers were trained to PhD level and a dermatology patient panel was established to ensure patient involvement in all aspects of the programme.ConclusionsFindings from this programme of work have already informed clinical guidelines and patient information resources. Feasibility studies have ensured that large national pragmatic trials will now be conducted on important areas of treatment uncertainty that address the needs of patients and the NHS. There is scope for considerable improvement in terms of trial design, conduct and reporting for RCTs of skin disease, which can be improved through wider collaboration, registration of trial protocols and complete reporting and international consensus over core outcome sets. Three national trials have now been funded as a result of this work. Two international initiatives to establish how best to measure the core outcome domains for eczema and vitiligo are ongoing.Trial registrationCurrent Controlled Trials Barrier Enhancement for Eczema Prevention (BEEP) (ISRCTN84854178 and NCT01142999), Study of Treatments fOr Pyoderma GAngrenosum Patients (STOP GAP) (ISRCTN35898459) and Hand Held NB-UVB for Early or Focal Vitiligo at Home (HI-Light Pilot Trial) (NCT01478945).FundingThis project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full inProgramme Grants for Applied Research; Vol. 4, No. 18. See the NIHR Journals Library website for further project information.

Validation of the Vitiligo noticeability scale: a patient-reported outcome measure of Vitiligo treatment success

Background: Patient-reported outcome measures are rarely used in vitiligo trials. The Vitiligo Noticeability Scale (VNS) is a new patient-reported outcome measure assessing how ‘noticeable’ the vitiligo patches are after treatment. The noticeability of vitiligo after treatment is an important indicator of treatment success from the patient’s perspective. Objectives: This study aimed to evaluate the construct validity, acceptability and interpretability of the VNS. Our main hypothesis was that the VNS would be a better and more consistent indicator of treatment success than percentage repigmentation. Methods: Clinicians (n=33) and patients with vitiligo (n=101) examined 39 image pairs, each depicting a vitiligo lesion pre- and post-treatment. Using an online questionnaire, respondents gave a global assessment of treatment success and a VNS score for treatment response. Clinicians also estimated percentage repigmentation of lesions ( 75). Treatment success was defined as ‘Yes’ on global assessment, a VNS score of 4 or 5, and more than 75% repigmentation. Agreement between respondents and the different scales was assessed using kappa statistics. Results: VNS scores were associated with both patient- and clinician-reported global treatment success (κ = 0.54 and κ = 0.47, respectively). Percentage repigmentation showed a weaker association with patient- and clinician-reported global treatment success (κ = 0.39 and κ = 0.29, respectively). VNS scores of 4 or 5 can be interpreted as representing treatment success. Images depicting post-treatment hyperpigmentation were less likely to be rated as successful. Conclusions: The VNS is a valid patient-reported measure of vitiligo treatment success. Further validation of the VNS is required, using larger sets of clinical pre- and post-treatment images, affecting a wider range of anatomical sites.

Living with vitiligo: development of a new vitiligo burden questionnaire is a step forward for outcomes consensus.

ORIGINAL ARTICLE, p 607 Vitiligo is the most common depigmentation disorder, affecting around 0·5% of the population worldwide.1 It is a cosmetically and psychologically devastating disease.2 Therefore, one would expect that patients' views on the effectiveness of a treatment would be considered important. However, patient‐centred outcomes have rarely been measured in vitiligo trials, despite previous recommendations.1 3 4 In this issue of the BJD, Ezzedine et al.5 report a cross‐sectional study with the aim of developing a new questionnaire specific to vitiligo burden. The burden of vitiligo was evaluated in 300 patients, using the new conceptual vitiligo‐burden‐specific questionnaire alongside several validated assessment tools including the Dermatology Life Quality Index.6 The study demonstrated that regardless of skin phototype, patients with vitiligo experience disease‐related burden and self‐perceived stress. This new questionnaire identified several factors that occurred more or less frequently in patients with dark skin types than in fair‐skinned individuals. In particular, patients with fair skin types were more worried about skin cancer than patients with dark skin types, who were more worried about the visibility and burden of vitiligo.

Survey and online discussion groups to develop a patient-rated outcome measure on acceptability of treatment response in vitiligo.

BackgroundVitiligo is a chronic depigmenting skin disorder which affects around 0.5-1% of the world’s population. The outcome measures used most commonly in trials to judge treatment success focus on repigmentation. Patient-reported outcome measures of treatment success are rarely used, although recommendations have been made for their inclusion in vitiligo trials. This study aimed to evaluate the face validity of a new patient-reported outcome measure of treatment response, for use in future trials and clinical practice.MethodAn online survey to gather initial views on what constitutes treatment success for people with vitiligo or their parents/carers, followed by online discussion groups with patients to reach consensus on what constitutes treatment success for individuals with vitiligo, and how this can be assessed in the context of trials. Participants were recruited from an existing database of vitiligo patients and through posts on the social network sites Facebook and Twitter.ResultsA total of 202 survey responses were received, of which 37 were excluded and 165 analysed. Three main themes emerged as important in assessing treatment response: a) the match between vitiligo and normal skin (how well it blends in); b) how noticeable the vitiligo is and c) a reduction in the size of the white patches. The majority of respondents said they would consider 80% or more repigmentation to be a worthwhile treatment response after 9 months of treatment. Three online discussion groups involving 12 participants led to consensus that treatment success is best measured by asking patients how noticeable their vitiligo is after treatment. This was judged to be best answered using a 5-point Likert scale, on which a score of 4 or 5 represents treatment success.ConclusionsThis study represents the first step in developing a patient reported measure of treatment success in vitiligo trials. Further work is now needed to assess its construct validity and responsiveness to change.

Core outcomes in vitiligo trials: progress and challenges

Vitiligo is the most common depigmentation disorder, affecting 0.5% of the population worldwide. It has a major negative impact on the quality of life of patients [1,2]. Vitiligo that begins in childhood can be associated with significant psychological trauma that may have a long-lasting effect on personal self esteem [3]. However, vitiligo is still largely perceived as a cosmetic disorder and the only intervention licensed for vitiligo in the UK is cosmetic camouflage [4].

Which outcomes should we measure in vitiligo? Results of a systematic review and a survey among patients and clinicians on outcomes in vitiligo trials

Relevant and reliable outcomes play a crucial role in the correct interpretation and comparison of the results of clinical trials. There is a lack of consensus around methods of assessment and outcome measures for vitiligo, which makes it difficult to compare results of randomized controlled trials (RCTs) and perform meta-analysis. To describe the heterogeneity in outcome measures used in published RCTs of vitiligo treatments, and to report the most desirable outcomes from patients' and clinicians' perspectives. We conducted a systematic review of outcome measures used in RCTs as well as a survey of the most desirable outcomes identified by patients and clinicians as part of a Vitiligo Priority Setting Partnership. Outcomes from 54 eligible trials were analysed and compared with outcomes suggested by patients and clinicians. In the systematic review, 25 different outcomes were reported. Only 22% of trials had clearly stated primary outcome measures. Repigmentation was the most frequently reported outcome in 96% of trials and was measured using 48 different scales. Only 9% of trials assessed quality of life. Thirteen per cent measured cessation of spreading of the disease and 17% of studies reported patients' opinions and satisfaction with the treatment. In contrast, out of 438 suggestions made by patients and clinicians, cosmetically acceptable repigmentation (rather than percentage of repigmentation) was the most desirable outcome (68%), followed by cessation of spread of vitiligo (15%), quality of life (8%) and maintenance of repigmentation (4%). We propose that future vitiligo trials should include repigmentation, cosmetic acceptability of results, global assessment of the disease, quality of life, maintenance of repigmentation, stabilization of vitiligo and side-effects. International consensus among clinicians, researchers and patients is needed to establish an agreed core outcome set for future vitiligo trials.