We present data from the Topical Ruxolitinib Evaluation in Vitiligo (TRuE-V) long-term extension (LTE) study evaluating repigmentation outcomes with continued 1.5% ruxolitinib cream treatment in patients who did not achieve near-complete facial repigmentation in TRuE-V1/TRuE-V2. Among patients in the TRuE-V1/TRuE-V2 trials who applied ruxolitinib cream from day 1, approximately 66% achieved F-VASI 75 (indicative of treatment success) at week 104, increasing from nearly 31% at week 52 (TRuE-V LTE baseline); similar repigmentation improvements were reported in patients who switched from vehicle to ruxolitinib cream after TRuE-V1/TRuE-V2 at week 24, albeit with lower overall response rates due to the shorter duration of ruxolitinib cream application. These findings indicate that continued ruxolitinib cream treatment allows further repigmentation in many patients.

Photosensitivity is central to cutaneous lupus erythematosus and dermatomyositis (DM), but the mechanisms linking UVB exposure to tissue-specific autoimmunity are poorly defined. Using single-cell RNA sequencing, spatial transcriptomics, proteomics, UVB provocation and in vitro modeling, we identify MMP9+CD14+ myeloid cells as critical mediators of photosensitivity. These cells expand significantly in lesional skin, produce interferon-β (IFNβ) and colocalize with cytotoxic CD4+ T cells at the dermal-epidermal junction. Keratinocytes activate fibroblasts in the superficial dermis, prompting them to release chemokines (CCL2, CCL19, CCL7, CCL8) that recruit MMP9+CD14+ cells. In vitro, type I interferon-primed keratinocytes exposed to UVB release cytokines activating dendritic cells, mirroring in vivo responses. UVB irradiation of non-lesional skin of patients with DM rapidly recruits these myeloid cells. In a clinical proof-of-concept study, anti-type I interferon treatment with anifrolumab prevented UVB-induced myeloid infiltration and reduced photosensitivity. Therefore, targeting MMP9+CD14+ cells may offer therapeutic potential for managing photosensitive autoimmune skin conditions.

T cells initiate targeted immune responses using T cell receptors (TCRs) to recognize specific antigens. Mapping TCRs to antigens at scale remains a major challenge. Here, we developed an approach to synthesize and functionally screen tens of thousands of TCRs simultaneously. TCR rapid assembly for functional testing (TCRAFT) uses a modular strategy to rapidly and inexpensively construct large pools of TCRs from sequences while maintaining TCRα/β pairing. We applied TCRAFT to reconstruct over 3,800 TCRs from vitiligo blister fluid and mapped these TCRs to specific peptide-major histocompatibility complexes using RAPTR, an activation-based library-on-library screening approach. Vitiligo antigen-specific T cells displayed pronounced clonal expansion and transcriptomic signatures similar to antigen-specific T cells in melanoma, pointing to shared features of disease-relevant T cells in autoimmunity and cancer. Demonstrating scalability, we synthesized and screened over 30,800 TCRs from donors with pancreatic ductal adenocarcinoma to capture antigen-reactive TCRs. Our approach expands the scale and accessibility of TCR-antigen screening, which is critical to understanding immunity and developing new immunotherapies.

Cutaneous gene therapy has the potential to treat a wide range of skin disorders, but effective delivery remains limited by the barrier properties and immune surveillance of the skin. Here, we identify AAVrh32.33 as a potent vector for targeting dermal stromal compartments. Following systemic administration in mice, AAVrh32.33 mediated robust and durable transgene expression, with preferential targeting of dermal fibroblasts and hair follicle bulge cells. Expression peaked at 1 month and persisted for up to 2 years, highlighting its suitability for chronic conditions. To reduce immunogenicity, a dominant CD8+ T cell epitope was disrupted, generating the IDPΔ variant. This modification attenuated peptide-specific T cell responses while preserving stromal transduction. In human skin explants, IDPΔ achieved high levels of gene expression, primarily in dermal fibroblasts and precursors, confirming translational relevance. Finally, vectors encoding CCL17, CCL20, and CCL22 demonstrated localized targeted therapeutic gene delivery in both healthy and inflamed skin, underscoring the feasibility of using this platform to reshape local immune responses. Together, these findings establish AAVrh32.33 and IDPΔ as promising platforms for durable cutaneous gene therapy, with direct applications in diseases such as vitiligo, where long-term modulation of the dermal microenvironment is essential.

We present data from the TRuE-V1/TRuE-V2 rollover TRuE-V long-term extension study evaluating withdrawal and continuation of ruxolitinib cream treatment. Among patients with near-complete facial repigmentation in TRuE-V1/TRuE-V2, approximately 70% of those randomized to treatment continuation and approximately 40% of those randomized to treatment withdrawal maintained facial repigmentation indicative of treatment success (i.e. >= F-VASI 75). Lost repigmentation could be regained in a timely manner following reinitiation of open-label active treatment.

Chemokines play critical roles in the recruitment and activation of immune cells in both homeostatic and pathologic conditions. Here, we examined chemokine ligand-receptor pairs to better understand the immunopathogenesis of cutaneous lupus erythematosus (CLE), a complex autoimmune connective tissue disorder. Our objectives were to investigate the immunopathogenesis and therapeutic targets of interface dermatitis in patients with cutaneous lupus erythematosus. Four subacute cutaneous lupus erythematosus (SCLE), 4 discoid lupus erythematosus (DLE) and 3 healthy margin controls were enrolled for archival tissue sampling for spatial transcriptomics and proteomics. Seven CLE (4 SCLE, 3 DLE) patients and 3 healthy controls were enrolled for fresh tissue blister biopsy sampling of 184 protein analytes in interstitial skin fluid and serum using targeted proteomics, as well as spectral flow cytometry analysis for interface dermatitis cells. An additional 6 CLE and 6 healthy blood donors were enrolled for functional chemotaxis assays. Spatial and targeted proteomics data confirmed elevation of interferon (IFN) and IFN-inducible CXCR3 chemokine ligands. Comparing involved to uninvolved epidermal keratinocytes in CLE samples revealed upregulation of essential inflammatory response genes in areas near interface dermatitis, including AIM2. Targeted proteomics data confirmed upregulation of Caspase 8, IL-18 which is the final product of AIM2 activation, and induced chemokines including CCL8 and CXCL6 in CLE lesional samples. Chemotaxis assays using peripheral blood mononuclear cells (PBMCs) from healthy and lupus donors revealed that T cells respond to CXCL9 and CXCL11, whereas CD14+CD16+ monocyte populations are more sensitive to CXCL6 via CXCR1 and CD14+ monocytes are more sensitive to CCL8 via CCR2. Furthermore, in vitro blocking assays revealed that hydroxychloroquine blocks CCL8 driven CD14+ monocyte migration, whereas reparixin blocks CXCL6 driven CD14+CD16+ monocyte migration. Taken together, our data map a pathway from keratinocyte injury to lymphocyte recruitment in CLE via AIM2-Casp8-IL-18-CXCL6-CXCR1 CD14+CD16+ monocyte recruitment, CCL8-CCR2 CD14+ monocyte recruitment, and IFNG/IFNL1-CXCL9/CXCL11-CXCR3 T cell recruitment, and suggest a mechanism by which hydroxychloroquine blocks CCR2+ CD14+ monocyte migration. We also identify reparixin and its derivatives as potential novel inhibitors of CXCR1+ CD14+CD16+ monocyte migration.

Small interfering RNAs (siRNAs) offer significant therapeutic potential; however, extrahepatic applications, particularly to the skin, remain a challenge. Limited work has explored siRNA therapies for the skin, the largest organ in the human body, where dermatological conditions affect over one-third of the population worldwide. The skin's external location makes it easily accessible for direct, local administration. Here, we present the in vivo intradermal delivery of therapeutic siRNAs into a porcine model whose skin structure most closely resembles that of human skin, demonstrating functional, and sustained gene silencing. We characterize two siRNA conjugates in human ex vivo and porcine in vivo skin models, showing that increased hydrophobicity significantly enhances skin retention and efficacy of siRNAs. Using a validated JAK1-targeting compound, we demonstrate that local delivery of siRNA enables accumulation across multiple cell types and suppression of JAK1-dependent inflammatory pathway in human skin ex vivo. In porcine models, intradermal injections result in prolonged skin siRNA retention for more than eight weeks, limited systemic tissue exposure, and sustained gene silencing for at least one month. These results underscore the importance of tailored siRNA conjugate design for achieving optimal skin biodistribution and therapeutic efficacy, providing a foundation for siRNA-based treatments for a broad range of dermatological conditions.

ImportanceThere is no international consensus on defining vitiligo severity or relapse. Current measures (such as body surface area) quantify depigmentation but do not fully capture the broader clinical and psychosocial effects of the disease.ObjectiveTo develop internationally agreed-upon definitions and criteria for vitiligo severity and relapse as part of the International Consensus on Definition of Severity and Relapse in Vitiligo study.Evidence ReviewThis global, mixed-methods consensus study used a multistep approach, including comprehensive literature review, qualitative study, 2 rounds of electronic Delphi surveys, and a final consensus meeting. To ensure adequate diversity and inclusivity and to capture a broad range of experiences, perspectives, social contexts, and representation, a recruitment framework (encompassing variation in age, sex, and skin phototypes) was predefined.FindingsIn total, 91 people from 5 continents expressed interest in participating. Experts (dermatologists, trialists, methodologists, nurses, psychologists, journal editors, and researchers) and people with vitiligo from diverse ethnic backgrounds and skin phototypes took part. During the first electronic Delphi survey round, 85 people participated and 81 participated in round 2 (response rate of 95% in each survey round). Consensus was reached that even though measurement of body surface area remains a necessary and adequate starting point for assessing vitiligo severity, this measure alone is insufficient to capture disease burden. The final consensus meeting included 44 participants (response rate of 54%). Twelve criteria for upgrading severity were recommended, encompassing both clinical aspects of vitiligo and its psychosocial effects. The major criteria for vitiligo include spread or active disease, involvement of highly visible or high-impact areas, psychological distress, stigmatization, lack of self-acceptance, and overall burden. The minor criteria for vitiligo include darker skin tones, younger age, involvement of scalp/facial hair, increased risk of sunburn, impact on career or school, and perceived loss of personal or cultural identity. No consensus was reached on the extent of pigment loss. Relapse was defined as loss of pigmentation in previously repigmented lesions (repigmentation had occurred either spontaneously or with treatment).Conclusion and RelevanceThis global, mixed-methods consensus study established internationally agreed-upon severity criteria for vitiligo. This consensus aims to bridge the gap between physician assessment and patient experience; improve the relevance and consistency of the severity classification in clinical care, research, and regulatory frameworks; and help close the remaining gaps in the diagnosis and classification of vitiligo. This consensus statement presents internationally agreed-upon definitions and criteria for vitiligo severity and relapse as part of the International Consensus on Definition of Severity and Relapse in Vitiligo study.

Importance:There is no international consensus on defining vitiligo severity or relapse. Current measures (such as body surface area) quantify depigmentation but do not fully capture the broader clinical and psychosocial effects of the disease. Objective:To develop internationally agreed-upon definitions and criteria for vitiligo severity and relapse as part of the International Consensus on Definition of Severity and Relapse in Vitiligo study. Evidence Review:This global, mixed-methods consensus study used a multistep approach, including comprehensive literature review, qualitative study, 2 rounds of electronic Delphi surveys, and a final consensus meeting. To ensure adequate diversity and inclusivity and to capture a broad range of experiences, perspectives, social contexts, and representation, a recruitment framework (encompassing variation in age, sex, and skin phototypes) was predefined. Findings:In total, 91 people from 5 continents expressed interest in participating. Experts (dermatologists, trialists, methodologists, nurses, psychologists, journal editors, and researchers) and people with vitiligo from diverse ethnic backgrounds and skin phototypes took part. During the first electronic Delphi survey round, 85 people participated and 81 participated in round 2 (response rate of 95% in each survey round). Consensus was reached that even though measurement of body surface area remains a necessary and adequate starting point for assessing vitiligo severity, this measure alone is insufficient to capture disease burden. The final consensus meeting included 44 participants (response rate of 54%). Twelve criteria for upgrading severity were recommended, encompassing both clinical aspects of vitiligo and its psychosocial effects. The major criteria for vitiligo include spread or active disease, involvement of highly visible or high-impact areas, psychological distress, stigmatization, lack of self-acceptance, and overall burden. The minor criteria for vitiligo include darker skin tones, younger age, involvement of scalp/facial hair, increased risk of sunburn, impact on career or school, and perceived loss of personal or cultural identity. No consensus was reached on the extent of pigment loss. Relapse was defined as loss of pigmentation in previously repigmented lesions (repigmentation had occurred either spontaneously or with treatment). Conclusion and Relevance:This global, mixed-methods consensus study established internationally agreed-upon severity criteria for vitiligo. This consensus aims to bridge the gap between physician assessment and patient experience; improve the relevance and consistency of the severity classification in clinical care, research, and regulatory frameworks; and help close the remaining gaps in the diagnosis and classification of vitiligo.

Detecting antigen-specific lymphocytes is crucial for immune monitoring in vaccination, infection, cancer and autoimmunity. However, their low frequency and dispersed distribution make reliable detection challenging. We developed a strategy exploiting the functions of tissue-resident memory T cells (TRMs) to locally concentrate target circulating immune cells in the skin, enabling their non-invasive sampling using a microneedle (MN) skin patch. TRMs were first induced by antigen sensitization and subsequently restimulated by intradermal inoculation of the same antigen to trigger the 'alarm' and immune recruitment functions of these cells, leading to accumulation of antigen-specific T cells from the circulation over several days. In mouse vaccination models, MN patches with optimized hydrogel coatings effectively isolated thousands of live antigen-specific lymphocytes and innate immune cells. In a human participant with allergic contact dermatitis, allergen-induced TRM stimulation followed by MN application recovered diverse lymphocyte populations absent from untreated skin sites. These results establish TRM restimulation coupled with MN sampling as a non-invasive platform to monitor both local and systemic antigen-specific immune responses across disease or vaccination settings.

Our study demonstrated that adults with vitiligo had a 1.5-unit lower BMI [mean (SD) 27.8 (6.1) vs. 29.3 (7.2) kg m-2; P = 0.001], but higher risk of hyperlipidaemia [aOR 1.40, 95% CI (1.12-1.70)] and hypercholesterolaemia [aOR 1.44, 95% CI (1.10-1.90)] compared with age-, sex- and race-matched subjects without vitiligo. The inverse association between BMI and vitiligo was independent of the presence of concomitant cardiometabolic diseases. Additionally, we contextualized these findings in relation to other immune-mediated skin disorders, including alopecia areata and psoriasis, to explore underlying pathogenesis and guide the development of appropriate screening criteria.

Inflammatory cytokine signaling pathways share notable similarities between humans and dogs. Janus kinase (JAK) family enzymesJAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) are popular therapeutic targets for inflammatory diseases in human clinics. While more than a dozen JAK inhibitors are available for human use, the only FDA-approved JAK inhibitor for dogs is oclacitinib. Oclacitinib targets multiple JAK subtypes (i.e., JAK1/2/3 and TYK2) and requires daily oral administration, raising concerns about its long-term safety. There is a growing demand for safer and longer-lasting JAK inhibitors to improve the treatment of dog inflammatory diseases. Small-interfering RNAs (siRNAs) are an emerging class of medicines that offer mRNA sequence-specific target selectivity and sustained durability. In this work, we developed a fully chemically modified siRNA that supports efficient gene silencing of dog JAK1. We show that dog JAK1 siRNA offers more than 90% target silencing in vitro. The partial homology of the siRNA targeting site between dog and mouse mRNAs allowed us to validate the compound's preclinical in vivo activity in mouse skin and muscle tissues. In ex vivo models using surgically discarded dog tissues from veterinary clinics, we show that dog JAK1 siRNA supports approximately 65% JAK1 silencing in the skin after intradermal injection and about 51% silencing in the muscle after intramuscular injection. This siRNA potentiates the treatment of inflammatory skin conditions and myopathies in dogs. Further engineering of siRNA may extend its utility to additional tissues, opening up new avenues for the development of immunomodulatory therapies for dogs.

Background:Chemokines play critical roles in the recruitment and activation of immune cells in both homeostatic and pathologic conditions. Here, we examined chemokine ligand-receptor pairs to better understand the immunopathogenesis of cutaneous lupus erythematosus (CLE), a complex autoimmune connective tissue disorder. Objectives:Our objectives were to (1) characterize the cellular and proteomic constitution of interface dermatitis in CLE using blister biopsies, (2) map chemokine:ligand receptor pairs that govern recruitment of immune cells to form interface dermatitis in CLE, and (3) perform unbiased analyses in tandem on different clinical subtypes to identify novel genes and proteins underlying discoid versus subacute CLE. Methods:We used suction blister biopsies to measure cellular infiltrates with spectral flow cytometry in the interface dermatitis reaction, as well as 184 protein analytes in interstitial skin fluid using 96-plex immunoassay targeted proteomics. Flow and 96-plex immunoassay data concordantly demonstrated significant increases in T cells and antigen presenting cells (APCs). We also performed spatial transcriptomics and spatial proteomics of punch biopsies using digital spatial profiling (DSP) technology on CLE skin and healthy margin controls to examine discreet locations within the tissue. Results:Spatial and 96-plex immunoassay data confirmed elevation of interferon (IFN) and IFN-inducible CXCR3 chemokine ligands. Comparing involved versus uninvolved keratinocytes in CLE samples revealed upregulation of essential inflammatory response genes in areas near interface dermatitis, including AIM2. 96-plex immunoassay data confirmed upregulation of Caspase 8, IL-18 which is the final product of AIM2 activation, and induced chemokines including CCL8 and CXCL6 in CLE lesional samples. Chemotaxis assays using PBMCs from healthy and CLE donors revealed that T cells are equally poised to respond to CXCR3 ligands, whereas CD14+CD16+ APC populations are more sensitive to CXCL6 via CXCR1 and CD14+ are more sensitive to CCL8 via CCR2. Conclusions:Taken together, our data map a pathway from keratinocyte injury to lymphocyte recruitment in CLE via AIM2-Casp8-IL-18-CXCL6/CXCR1 and CCL8/CCR2, and IFNG/IFNL1-CXCL9/CXCL11-CXCR3, and identify potential novel biomarkers of disease.

Allergic contact dermatitis (ACD) is a pruritic skin disease caused by environmental chemicals that induce cell-mediated skin inflammation within susceptible individuals. Irritant contact dermatitis (ICD) is caused by direct damage to the skin barrier by environmental insults. Diagnosis can be challenging because both types of contact dermatitis can appear similar by visual examination, and histopathological analysis does not reliably distinguish ACD from ICD. To discover specific biomarkers of ACD and ICD, we characterized the transcriptomic and proteomic changes that occur within the skin during each type of contact dermatitis. We induced ACD and ICD in healthy human volunteers and sampled skin using a nonscarring suction blister biopsy method that collects interstitial fluid and cellular infiltrate. Single-cell RNA sequencing analysis revealed that cell-specific transcriptome differences rather than cell-type proportions best distinguished ACD from ICD. Allergy-specific genes were associated with upregulation of IFNG, and cell signaling network analysis implicated several other genes such as IL4, despite their low expression levels. We validated transcriptomic differences with proteomic assays on blister fluid and trained a logistic regression model on skin interstitial fluid proteins that could distinguish ACD from ICD and healthy control skin with 93% sensitivity and 93% specificity.

This cohort study analyzed the association of pediatric vitiligo with auditory and ocular manifestations.

Vitiligo is an acquired autoimmune depigmenting disorder that affects approximately 0.36% of the global population and presents in three forms based on lesion distribution: non-segmental, segmental and mixed vitiligo. Beyond its visible impact on the skin, vitiligo deeply affects mental well-being and quality of life. The pathogenesis of non-segmental vitiligo is influenced by genetic polymorphisms that are linked to immune response and melanogenesis pathways, whereas environmental factors contribute to disease onset. Diagnosis is generally clinical, with laboratory tests or biopsies rarely required. Melanocyte loss involves mechanisms, such as cellular stress, innate immune activation and adaptive immune responses, that specifically target melanocytes, with a central role for tissue-resident memory T cells. This cascade ultimately leads to the depletion of epidermal melanocytes and impairs melanocyte stem cell regeneration. Clinical management emphasizes shared decision-making with three primary objectives: halting depigmentation, initiating repigmentation and sustaining pigment restoration. Signs of active disease help clinicians to identify patients in need of intervention. Treatments approved in the past 2 years offer potential for reversing disease progression, and emerging therapies targeting key pathways to modulate immune activation and stimulate melanocyte regeneration and differentiation are being tested in clinical trials. Vitiligo is a chronic, autoimmune, depigmenting disorder that has both physiological and psychological effects on affected individuals. In this Primer, Seneschal and colleagues provide an overview of the epidemiology, pathogenesis, diagnosis and management of the condition as well as of its effect on quality of life, and highlight current and emerging treatments.