Once-daily upadacitinib versus placebo in adults with extensive non-segmental vitiligo: a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-ranging study.

Background: Janus kinase (JAK) inhibition is a promising approach for treating vitiligo. We aimed to assess the efficacy and safety of upadacitinib, an oral selective JAK inhibitor, in adults with non-segmental vitiligo. Methods: This was a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-ranging study completed at 33 clinical centres in the United States, Canada, France, and Japan. Eligible patients were aged 18-65 years with non-segmental vitiligo and had a Facial Vitiligo Area Scoring Index (F-VASI) ≥0.5 and a Total Vitiligo Area Scoring Index (T-VASI) ≥5. Patients were randomly assigned (2:2:2:1:1) using an interactive response technology to receive upadacitinib 6 mg (UPA6), upadacitinib 11 mg (UPA11), upadacitinib 22 mg (UPA22), or placebo (PBO; preassigned to switch to either UPA11 or UPA22 in period 2) once daily for 24 weeks (period 1). For weeks 24-52 (period 2), patients randomly assigned to upadacitinib continued their treatment, and patients receiving PBO switched to their preassigned upadacitinib dose in a blinded fashion. The primary endpoint was the percent change from baseline in F-VASI at week 24. Efficacy was analysed in the intention-to-treat population, and safety was examined in all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT04927975. Findings: Between June 16, 2021, and June 27, 2022, 185 patients (including 115 [62%] who were female and 70 [38%] who were male) were randomly assigned to UPA6 (n = 49), UPA11 (n = 47), UPA22 (n = 43), or PBO (n = 46). At week 24, the LS mean difference versus PBO in the percent change from baseline in F-VASI was -7.60 (95% CI -22.18 to 6.97; p = 0.3037) for UPA6, -21.27 (95% CI -36.02 to -6.52; p = 0.0051) for UPA11, and -19.60 (95% CI -35.04 to -4.16; p = 0.0132) for UPA22. The LS mean difference versus PBO in the percent change from baseline in T-VASI was -7.45 (95% CI -16.86 to 1.96; p = 0.1198) for UPA6, -10.84 (95% CI -20.37 to -1.32; p = 0.0259) for UPA11 and -14.27 (95% CI -24.24 to -4.30; p = 0.0053) for UPA22. Ongoing treatment with upadacitinib induced continuous skin repigmentation over time without reaching a plateau through week 52. The rates for study drug discontinuation and serious treatment-emergent adverse events (TEAEs) were higher in the UPA22 group than in the UPA11 and UPA6 groups. Eight serious TEAEs, including one death of unknown cause and one case of infiltrating lobular breast carcinoma, were reported through 52 weeks; only two serious TEAEs (coronary artery arteriosclerosis [UPA6 (n = 1)] and non-fatal ischemic stroke [UPA11 (n = 1)]) were deemed by the investigator to have a reasonable possibility of being related to study drug. The one case of breast cancer in the UPA11 group was deemed unrelated to study drug, and the one death of unknown cause in the UPA22 group was reviewed and adjudicated and was deemed to be unrelated to study drug. The most common TEAEs were COVID-19, headache, acne, and fatigue. No new safety signals were observed. Interpretation: Upadacitinib monotherapy led to substantial repigmentation of both facial and total body vitiligo lesions and may offer an effective treatment option for adults with extensive non-segmental vitiligo. Based on these findings, upadacitinib 15 mg is being investigated in adults and adolescents with non-segmental vitiligo in an ongoing phase 3 randomised controlled trial. Funding: AbbVie Inc.

Integrating skin color assessments into clinical practice and research: A review of current approaches.

Skin color classification can have importance in skin health, pigmentary disorders, and oncologic condition assessments. It is also critical for evaluating disease course and response to a variety of therapeutic interventions and aids in accurate classification of participants in clinical research studies. A panel of dermatologists conducted a literature review to assess the strengths and limitations of existing classification scales, as well as to compare their preferences and utilities. We identified 17 skin classification systems utilized in dermatologic settings. These systems include a range of parameters such as UV light reactivity, race, ethnicity, and degree of pigmentation. The Fitzpatrick skin type classification is most widely used and validated. However it has numerous limitations including its conflation with race, ethnicity, and skin color. There is a lack of validation data available for the remaining scales. There are significant deficiencies in current skin classification instruments. Consensus-based initiatives to drive the development of validated and reliable tools are critically needed.

Practical guidelines for the treatment of vitiligo with the melanocyte-keratinocyte transplantation procedure.

Vitiligo manifests as depigmented macules and patches on the skin and can significantly impact a patient's quality of life. Despite the availability of several treatment modalities, rates of repigmentation can vary widely among individuals and disease subtypes. For patients with stable vitiligo who have not achieved satisfactory results with medical treatments, the melanocyte-keratinocyte transplantation procedure (MKTP) is a viable option. While variations of this autologous non-cultured cellular grafting procedure are performed by dermatologic surgeons worldwide and has shown good tolerability and effectiveness, it remains under utilized in the United States. We present a comprehensive overview of MKTP, highlighting evidence-based and practical techniques to enhance patient outcomes. By serving as a valuable resource, this review aims to support dermatologic surgeons seeking to incorporate MKTP into their practice and promote awareness regarding its benefits, ultimately fostering a more comprehensive approach to vitiligo care.

Optimisation of skin phototype classification.

Understanding individuals' skin pigmentation and photosensitivity is important in judging risk of skin cancer and response to certain treatment modalities. However, individuals with darkly pigmented skin are poorly represented in the widely used Fitzpatrick skin phototype (FST) system. Moreover, the FST system is prone to misuse, as it relies on subjective patient and clinician assessment of skin type, and does not clearly differentiate pigmentation from photosensitivity. By evaluating the key literature surrounding the FST system, its criticisms and proposed alternatives, this review serves to understand how skin phototype classification can be optimised.

Diagnosing Disorders of Hypopigmentation and Depigmentation in Patients with Skin of Color.

Skin hypopigmentation and depigmentation disorders are a top concern for patients with skin of color seeking care from a dermatologist. The visual contrast between involved and uninvolved skin in these disorders makes them particularly burdensome for patients with skin of color. These disorders may have a wide differential of diagnosis, as patients with skin of color may present differently or more frequently than White patients for certain conditions. Clues from a comprehensive history and physical examination with standard lighting and a Wood's light are essential for clinching the diagnosis, although a biopsy may be warranted in special cases.

Surgical Procedural Definitions for Hidradenitis Suppurativa Developed by Expert Delphi Consensus.

Importance: Various surgical approaches for hidradenitis suppurativa (HS) have been described in the literature, but the nomenclature is inconsistent. Excisions have been described as wide, local, radical, and regional with variable descriptions of margins. Deroofing procedures have been described with various approaches though descriptions of the approach are generally more uniform. No international consensus has been formed to globally standardize terminology for HS surgical procedures. Lack of such agreement may contribute to misunderstanding or misclassification in HS procedural research studies and impair clear communication among clinicians or between clinicians and patients. Objective: To create a set of standard definitions for HS surgical procedures. Design, Setting, and Participants: This consensus agreement study was conducted from January to May 2021 using the modified Delphi consensus method to reach agreement among a group of international HS experts regarding standardized definitions for an initial set of HS surgical terms, including "incision and drainage," "deroofing/unroofing," "excision," "lesional excision," and "regional excision," ultimately expanded to 10 terms. Provisional definitions were drafted based on existing literature and discussion among an expert 8-member steering committee. Online surveys were disseminated to members of the HS Foundation, direct contacts of the expert panel, and the HSPlace listserv to reach physicians with considerable experience with HS surgery. Consensus was defined as greater than 70% agreement to accept a definition. Results: In the first and second modified Delphi round, 50 and 33 experts participated, respectively. Ten surgical procedural terms and definitions reached consensus with greater than 80% agreement. Overall, the term "local" excision was abandoned and replaced with the descriptors "lesional" or "regional" excision. Of note, "regional" replaced the terms "wide" and "radical" excision. Furthermore, modifiers such as "partial" vs "complete" should also be included when describing surgical procedures. A combination of these terms helped formulate the final glossary of HS surgical procedural definitions. Conclusion and Relevance: An international group of HS experts agreed on a set of definitions describing surgical procedures frequently used by clinicians and in the literature. The standardization and application of such definitions are vital to allow for accurate communication, reporting consistency, and uniform data collection and study design in the future.

Cutaneous interaction with visible light: What do we know?

Visible light has been used therapeutically in dermatology for years for a variety of cosmetic and medical indications, including skin rejuvenation and the treatment of inflammatory and neoplastic conditions, among others. Until recently, visible light was thought to be relatively inert compared to its spectral neighbors, ultraviolet and infrared radiation. However, recent literature has described the ability of visible light to cause erythema in light skin and pigmentary changes in individuals with darker skin types. Concern surrounding its potentially damaging cutaneous effects has been raised in both the medical community and social media outlets. In this article, we provide an evidenced-based review describing what is currently known about visible light, focusing on its role in dermatologic diseases including disorders of hyperpigmentation such as melasma and postinflammatory hyperpigmentation.

Systematic review of photodynamic therapy for the treatment of hidradenitis suppurativa.

OBJECTIVE: To perform a systematic review of available literature regarding the use of 5-aminolevulinic acid (ALA) and ALA derivative photodynamic therapy (PDT) in the treatment of hidradenitis suppurativa (HS) and provide recommendations on its use. METHODS: A systematic review was performed of all published studies up to September 1, 2019 from nine databases, including PubMed, that evaluated PDT in the treatment of HS. For each study, quality of evidence and risk of bias was evaluated. Recommendations from the body of evidence were created based on Strength of Recommendation and Taxonomy (SORT) criteria. RESULTS: Eighteen studies met inclusion criteria. The majority of studies had a high risk of bias. Blue light PDT with 20% ALA and red light PDT with 16% methyl aminolevulinate (MAL) demonstrated some benefit based on a small number of poor-quality studies with a high risk of bias (Grade C, level III evidence). The most promising results were for 1%-5% ALA with intralesional diode, with good to complete response in 78%-94% of anatomic sites treated (Grade B, level II evidence). LIMITATIONS: The majority of studies contained high levels of bias, with significant heterogeneity between studies. Conclusions are limited by small samples sizes, lack of randomized controlled trials, and differing protocols. CONCLUSION: Further studies are needed to determine the clinical efficacy of 20% ALA with blue light and MAL with red light. Intralesional diode PDT shows the most promise and warrants further investigation in larger, randomized controlled trials.

Efficacy and safety of oral ritlecitinib for the treatment of active nonsegmental vitiligo: A randomized phase 2b clinical trial.

BACKGROUND: Vitiligo is a chronic autoimmune disorder characterized by depigmented patches of the skin. OBJECTIVE: To evaluate the efficacy and safety of ritlecitinib, an oral JAK3 (Janus kinase)/TEC (tyrosine kinase expressed in hepatocelluar carcinoma) inhibitor, in patients with active nonsegmental vitiligo in a phase 2b trial (NCT03715829). METHODS: Patients were randomized to once-daily oral ritlecitinib ± 4-week loading dose (200/50 mg, 100/50 mg, 30 mg, or 10 mg) or placebo for 24 weeks (dose-ranging period). Patients subsequently received ritlecitinib 200/50 mg daily in a 24-week extension period. The primary efficacy endpoint was percent change from baseline in Facial-Vitiligo Area Scoring Index at week 24. RESULTS: A total of 364 patients were treated in the dose-ranging period. Significant differences from placebo in percent change from baseline in Facial-Vitiligo Area Scoring Index were observed for the ritlecitinib 50 mg groups with (-21.2 vs 2.1; P < .001) or without (-18.5 vs 2.1; P < .001) a loading dose and ritlecitinib 30 mg group (-14.6 vs 2.1; P = .01). Accelerated improvement was observed after treatment with ritlecitinib 200/50 mg in the extension period (n = 187). No dose-dependent trends in treatment-emergent or serious adverse events were observed across the 48-week treatment. LIMITATIONS: Patients with stable vitiligo only were excluded. CONCLUSIONS: Oral ritlecitinib was effective and well tolerated over 48 weeks in patients with active nonsegmental vitiligo.

Factors associated with treatment satisfaction in patients with hidradenitis suppurativa: results from the Global VOICE project.

BACKGROUND: Nearly half of patients with hidradenitis suppurativa (HS) report dissatisfaction with their treatment. However, factors related to treatment satisfaction have not been explored. OBJECTIVES: To measure associations between treatment satisfaction and clinical and treatment-related characteristics among patients with HS. METHODS: Treatment satisfaction was evaluated utilizing data from a cross-sectional global survey of patients with HS recruited from 27 institutions, mainly HS referral centres, in 14 different countries from October 2017 to July 2018. The primary outcome was patients' self-reported overall satisfaction with their current treatments for HS, rated on a five-point scale from 'very dissatisfied' to 'very satisfied'. RESULTS: The final analysis cohort comprised 1418 patients with HS, most of whom were European (55%, 780 of 1418) or North American (38%, 542 of 1418), and female (85%, 1210 of 1418). Overall, 45% (640 of 1418) of participants were either dissatisfied or very dissatisfied with their current medical treatment. In adjusted analysis, patients primarily treated by a dermatologist for HS had 1·99 [95% confidence interval (CI) 1·62-2·44, P < 0·001] times the odds of being satisfied with current treatment than participants not primarily treated by a dermatologist. Treatment with biologics was associated with higher satisfaction [odds ratio (OR) 2·36, 95% CI 1·74-3·19, P < 0·001] relative to treatment with nonbiologic systemic medications. Factors associated with lower treatment satisfaction included smoking (OR 0·78, 95% CI 0·62-0·99; active vs. never), depression (OR 0·69, 95% CI 0·54-0·87), increasing number of comorbidities (OR 0·88 per comorbidity, 95% CI 0·81-0·96) and increasing flare frequency. CONCLUSIONS: There are several factors that appear to positively influence satisfaction with treatment among patients with HS, including treatment by a dermatologist and treatment with a biologic medication. Factors that appear to lower treatment satisfaction include active smoking, depression, accumulation of comorbid conditions and increasing flare frequency. Awareness of these factors may support partnered decision making with the goal of improving treatment outcomes. What is already known about this topic? Nearly half of patients with hidradenitis suppurativa report dissatisfaction with their treatments. What does this study add? Satisfaction with treatment is increased by receiving care from a dermatologist and treatment with biologics. Satisfaction with treatment is decreased by tobacco smoking, accumulation of comorbid conditions including depression, and higher flare frequency. What are the clinical implications of this work? Awareness of the identified factors associated with poor treatment satisfaction may support partnered decision making and improve treatment outcomes.

A Focused review on the pathophysiology of post-inflammatory hyperpigmentation.

Post-inflammatory hyperpigmentation (PIH) is one of the most common disorders of acquired hyperpigmentation. It often develops following cutaneous inflammation and is triggered by various stimuli, from inflammatory and autoimmune conditions to iatrogenic causes and mechanical injuries. While it is well established that an increase in melanin production and distribution within the epidermis and dermis is a hallmark feature of this condition, the exact mechanisms underlying PIH are not completely understood. This article aims to review the current evidence on the pathophysiology of PIH as the cellular and molecular mechanism of PIH represents a promising avenue for the development of novel, targeted therapies.

Comorbidity screening in hidradenitis suppurativa: Evidence-based recommendations from the US and Canadian Hidradenitis Suppurativa Foundations.

BACKGROUND: Hidradenitis suppurativa (HS) is associated with comorbidities that contribute to poor health, impaired life quality, and mortality risk. OBJECTIVE: To provide evidence-based screening recommendations for comorbidities linked to HS. METHODS: Systematic reviews were performed to summarize evidence on the prevalence and incidence of 30 comorbidities in patients with HS relative to the general population. The screening recommendation for each comorbidity was informed by the consistency and quality of existing studies, disease prevalence, and magnitude of association, as well as benefits, harms, and feasibility of screening. The level of evidence and strength of corresponding screening recommendation were graded by using the Strength of Recommendation Taxonomy (SORT) criteria. RESULTS: Screening is recommended for the following comorbidities: acne, dissecting cellulitis of the scalp, pilonidal disease, pyoderma gangrenosum, depression, generalized anxiety disorder, suicide, smoking, substance use disorder, polycystic ovary syndrome, obesity, dyslipidemia, diabetes mellitus, metabolic syndrome, hypertension, cardiovascular disease, inflammatory bowel disease, spondyloarthritis, and sexual dysfunction. It is also recommended to screen patients with Down syndrome for HS. The decision to screen for specific comorbidities may vary with patient risk factors. The role of the dermatologist in screening varies according to comorbidity. LIMITATIONS: Screening recommendations represent one component of a comprehensive care strategy. CONCLUSIONS: Dermatologists should support screening efforts to identify comorbid conditions in HS.

The value of photomedicine in a global health crisis: Utilizing ultraviolet C to decontaminate N95 respirators during the COVID-19 pandemic.

One early problem during the height of the COVID-19 global pandemic, caused by severe acute respiratory syndrome 2 (SARS-CoV-2), was the shortage of personal protective equipment donned by healthcare workers, particularly N95 respirators. Given the known virucidal, bactericidal, and fungicidal properties of ultraviolet irradiation, in particular ultraviolet C (UVC) radiation, our photomedicine and photobiology unit explored the role of ultraviolet germicidal irradiation (UVGI) using UVC in effectively decontaminating N95 respirators. The review highlights the important role of photobiology and photomedicine in this pandemic. Namely, the goals of this review were to highlight: UVGI as a method of respirator disinfection-specifically against SARS-CoV-2, adverse reactions to UVC and precautions to protect against exposure, other methods of decontamination of respirators, and the importance of respirator fit testing.

Mitigating Visible Light and Long Wavelength UVA1-induced Effects with Topical Antioxidants.

The role of topical antioxidants (AOs) on visible light plus ultraviolet A1 (VL+UVA1)-induced skin changes were evaluated. Twenty subjects with skin phototypes (SPTs) I-VI had placebo and concentrations of an AO blend applied to their back (AO 0.5%, 1.0% and 2.0%). Treated and control sites were irradiated with VL+UVA1. Colorimetric and diffuse reflectance spectroscopy (DRS) assessments were performed immediately, 24 h and 7 days after irradiation. Subjects with SPT I-III had erythema that faded within 24 h, while SPT IV-VI had persistent pigmentation. SPT I-III demonstrated significantly less erythema at the 2% AO site while SPT IV-VI demonstrated significantly less immediate pigmentation at 2% AO site and less pigmentation (approaching significance, P = 0.07) on day 7 compared with control. Immunohistochemistry from biopsies of 2% AO and placebo at 24 h did not demonstrate a significant change in COX-2 or MART-1 for any SPT. There was a decrease in cyclin D1 for SPT IV-VI which was approaching significance (P = 0.06) but not for SPT I-III. The results indicate that topical AO inhibits erythema in SPT I-III and reduces pigmentation in SPT IV-VI caused by VL+UVA1. AO may help prevent worsening of pigmentary disorders and should be incorporated into photoprotection.

Impact of visible light on skin health: The role of antioxidants and free radical quenchers in skin protection.

Until recently, the primary focus of photobiology has centered on the impact of UV radiation on skin health, including DNA damage and oncogenesis; however, the significant effects of visible light (VL) on skin remain grossly underreported. VL has been reported to cause erythema in individuals with light skin (Fitzpatrick skin types [FSTs] I-III) and pigmentary changes in individuals with dark skin types (FSTs IV-VI). These effects have importance in dermatologic diseases and potentially play a role in conditions aggravated by sun exposure, including phototoxicity in patients with FSTs I to III and post-inflammatory hyperpigmentation and melasma in patients with FSTs IV to VI. The induction of free radicals, leading to the generation of reactive species, is one driving mechanism of VL-induced skin pathologies, leading to the induction of melanogenesis and hyperpigmentation. Initial clinical studies have demonstrated the effectiveness of topical sunscreen with antioxidant combinations in inhibiting VL + UV-A1-induced erythema in FSTs I to III and reducing pigmentation in FSTs IV to VI. Antioxidants may help prevent the worsening of pigmentary disorders and can be incorporated into photoprotective strategies. It is essential that dermatologists and the public are aware of the impact of VL on skin, especially in patients with skin of color, and understand the available options for VL protection.

The potential effect of Polypodium leucotomos extract on ultraviolet- and visible light-induced photoaging.

Photoaging induced by both ultraviolet and visible light has been shown to lead to increased inflammation and dysregulation of the extracellular matrix. Standardized extract of the Polypodium leucotomos fern, PLE, possesses anti-inflammatory and antioxidant properties, and has been shown to potentially mitigate photoaging through various mechanisms. This comprehensive review presents the data available on the effects of P. leucotomos extract on UV and VL-induced photoaging in vitro as well as in vivo in murine and human models.

Surgical Interventions for Patients With Vitiligo: A Systematic Review and Meta-analysis.

Importance: Surgical interventions are a key part of the therapeutic arsenal, especially in refractory and stable vitiligo. Comparison of treatment outcomes between the different surgical procedures and their respective adverse effects has not been adequately studied. Objective: To investigate the reported treatment response following different surgical modalities in patients with vitiligo. Data Sources: A comprehensive search of the MEDLINE, Embase, Web of Science, and Cochrane Library databases from the date of database inception to April 18, 2020, was conducted. The key search terms used were vitiligo, surgery, autologous, transplantation, punch, suction blister, and graft. Study Selection: Of 1365 studies initially identified, the full texts of 358 articles were assessed for eligibility. A total of 117 studies were identified in which punch grafting (n = 19), thin skin grafting (n = 10), suction blister grafting (n = 29), noncultured epidermal cell suspension (n = 45), follicular cell suspension (n = 9), and cultured epidermal cell suspension (n = 17) were used. Data Extraction and Synthesis: Three reviewers independently extracted data on study design, patients, intervention characteristics, and outcomes. Random effects meta-analyses using generic inverse-variance weighting were performed. Main Outcomes and Measures: The primary outcomes were the rates of greater than 90%, 75%, and 50% repigmentation response. These rates were calculated by dividing the number of participants in an individual study who showed the corresponding repigmentation by the total number of participants who completed the study. The secondary outcomes were the factors associated with treatment response to the surgical intervention. Results: Among the 117 unique studies and 8776 unique patients included in the analysis, rate of repigmentation of greater than 90% for surgical interventions was 52.69% (95% CI, 46.87%-58.50%) and 45.76% (95% CI, 30.67%-60.85%) for punch grafting, 72.08% (95% CI, 54.26%-89.89%) for thin skin grafting, 61.68% (95% CI, 47.44%-75.92%) for suction blister grafting, 47.51% (95% CI, 37.00%-58.03%) for noncultured epidermal cell suspension, 36.24% (95% CI, 18.92%-53.57%) for noncultured follicular cell suspension, and 56.82% (95% CI, 48.93%-64.71%) for cultured epidermal cell suspension. The rate of repigmentation of greater than 50% after any surgical intervention was 81.01% (95% CI, 78.18%-83.84%). In meta-regression analyses, the treatment response was associated with patient age (estimated slope, -1.1418), subtype of vitiligo (estimated slope, 0.3047), and anatomical sites (estimated slope, -0.4050). Conclusions and Relevance: The findings of this systematic review and meta-analysis suggest that surgical intervention can be an effective option for refractory stable vitiligo. An appropriate procedure should be recommended based on patient age, site and size of the lesion, and costs.