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Background: Vitiligo is a chronic autoimmune disease that causes skin depigmentation. A cream formulation of ruxolitinib (an inhibitor of Janus kinase 1 and 2) resulted in repigmentation in a phase 2 trial involving adults with vitiligo.Methods: We conducted two phase 3, double-blind, vehicle-controlled trials (Topical Ruxolitinib Evaluation in Vitiligo Study 1 [TRuE-V1] and 2 [TRuE-V2]) in North America and Europe that involved patients 12 years of age or older who had nonsegmental vitiligo with depigmentation covering 10% or less of total body-surface area. Patients were randomly assigned in a 2:1 ratio to apply 1.5% ruxolitinib cream or vehicle control twice daily for 24 weeks to all vitiligo areas on the face and body, after which all patients could apply 1.5% ruxolitinib cream through week 52. The primary end point was a decrease (improvement) of at least 75% from baseline in the facial Vitiligo Area Scoring Index (F-VASI; range, 0 to 3, with higher scores indicating a greater area of facial depigmentation), or F-VASI75 response, at week 24. There were five key secondary end points, including improved responses on the Vitiligo Noticeability Scale.Results: A total of 674 patients were enrolled, 330 in TRuE-V1 and 344 in TRuE-V2. In TRuE-V1, the percentage of patients with an F-VASI75 response at week 24 was 29.8% in the ruxolitinib-cream group and 7.4% in the vehicle group (relative risk, 4.0; 95% confidence interval [CI], 1.9 to 8.4; P<0.001). In TRuE-V2, the percentages were 30.9% and 11.4%, respectively (relative risk, 2.7; 95% CI, 1.5 to 4.9; P<0.001). The results for key secondary end points showed superiority of ruxolitinib cream over vehicle control. Among patients who applied ruxolitinib cream throughout 52 weeks, adverse events occurred in 54.8% in TRuE-V1 and 62.3% in TRuE-V2; the most common adverse events were application-site acne (6.3% and 6.6%, respectively), nasopharyngitis (5.4% and 6.1%), and application-site pruritus (5.4% and 5.3%).Conclusions: In two phase 3 trials, application of ruxolitinib cream resulted in greater repigmentation of vitiligo lesions than vehicle control through 52 weeks, but it was associated with acne and pruritus at the application site. Larger and longer trials are required to determine the effect and safety of ruxolitinib cream in patients with vitiligo. (Funded by Incyte; TRuE-V1 and TRuE-V2 ClinicalTrials.gov numbers, NCT04052425 and NCT04057573.). [ABSTRACT FROM AUTHOR]

Introduction & Objectives: Janus kinase (JAK) inhibition is a promising approach for the treatment of vitiligo. Here, we report the clinical efficacy and safety of upadacitinib (UPA), an oral JAK inhibitor, in a phase 2b multicenter, randomized, double-blind, placebo-controlled study of adults with extensive non-segmental vitiligo (NSV). Materials & Methods: Eligible patients were aged 18-65 years with NSV, a Facial Vitiligo Area Scoring Index (F-VASI) of ≥0.5, and a Total Vitiligo Area Scoring Index (T-VASI) of ≥5 at baseline. This 52-week study (NCT04927975) comprised 2 periods. In period 1, patients were randomly assigned to once daily UPA 22 mg (UPA22), UPA 11 mg (UPA11), UPA 6 mg (UPA6), or placebo (PBO) for 24 weeks of treatment. In a 28-week blinded extension (period 2), patients receiving UPA during period 1 continued their respective regimens; patients who received PBO in period 1 were pre-assigned to either UPA11 or UPA22. Clinical efficacy endpoints evaluated through week 36 included percent change from baseline (%CFB) in F-VASI (week 24, primary endpoint), reductions from baseline in F-VASI of ≥50% (F-VASI 50) and ≥75% (F-VASI 75), %CFB in T-VASI, and reduction from baseline in T-VASI of ≥50% (T-VASI 50). Safety data as of January 13, 2023 (data cutoff date) are presented. Results: Of the 185 patients enrolled in period 1, 165 (89.2%) continued to period 2. At baseline, 68% of patients had extensive vitiligo (T-VASI > 10), and 71% had active vitiligo. At week 24, the %CFB in F-VASI was greater with UPA11 (-35.6%) and UPA22 (-34.0%) vs PBO (-14.4%; nominal P = .005 and P = .013, respectively). A greater proportion of patients achieved F-VASI 50 and F-VASI 75 with UPA11 (38.3%, 19.1%) and UPA22 (39.5%, 14.0%) vs PBO (10.9%, 2.2%; nominal P < .05 for both doses and for both endpoints). Likewise, the %CFB in T-VASI was greater with UPA11 (-17.3%) and UPA22 (-20.7%) vs PBO (-6.4%; nominal P = .026 and P = .005, respectively). A higher percentage of patients achieved T-VASI 50 with UPA22 (11.6%) than with PBO (2.2%; nominal P = .027). UPA efficacy continued to improve through week 36, with %CFB in F-VASI for UPA6, UPA11, and UPA22 of -20.8%, -44.9% and -47.7%, respectively. At week 36, F-VASI 50 was achieved with UPA6, UPA11, and UPA22 by 34.2%, 54.3% and 61.5% of patients and F-VASI 75 by 15.8%, 40.0%, and 30.8%, respectively. At week 36, %CFB in T-VASI for UPA6, UPA11 and UPA22 were -24.3%, -32.0% and -37.6%, with 10.5%, 20.0% and 19.2% of patients, respectively, achieving T-VASI 50. Treatment-emergent adverse event (TEAE) rates were generally similar with UPA and PBO in period 1 (most common TEAEs: COVID-19, acne, fatigue, and headache) and were similar across treatment arms in period 2. One death adjudicated as undetermined/unknown cause and deemed by the investigator to have no reasonable possibility of being related to study drug occurred in the UPA22 group (period 1). One adjudicated event of nonfatal ischemic stroke occurred with UPA11 (period 2). There were no adjudicated events of venous thromboembolism, gastrointestinal perforation, or events of opportunistic infection, active tuberculosis, or malignancy. Conclusion: Treatment with UPA for 24 weeks resulted in greater improvements vs PBO in the clinical outcomes of adults with extensive NSV. Observed clinical efficacy continued to improve through week 36 with UPA treatment. UPA was generally well tolerated, with no new safety signals identified. [ABSTRACT FROM AUTHOR]

Highlights: [•] Melanocytes from vitiligo patients display features of elevated cellular stress. [•] Stressed cells produce damage-associated molecular patterns (DAMPs). [•] DAMPs activate innate immune cell populations through pattern recognition receptors. [•] Activated innate immune cells can promote adaptive immunity in vitiligo. [•] Activated stress pathways appear to play a role in organ-specific autoimmunity. [ABSTRACT FROM AUTHOR]

The article focuses on a study on melanocytes in psoriasis. Topics discussed include examination of T-cell clone-developed ADAMTSL5 autoantigen, existence of ADAMTSL5 in esophagus, heart and female reproductive tissues, and presence of ADAMTSL5 in skin fibroblasts and melanocytes. Other topics include psoriatic inflammation due to ADAMTSL5-T cells.

Background: Vitiligo is a chronic autoimmune disease resulting in skin depigmentation and reduced quality of life. There is no approved treatment for vitiligo repigmentation and current off-label therapies have limited efficacy, emphasising the need for improved treatment options. We investigated the therapeutic potential of ruxolitinib cream in patients with vitiligo and report the efficacy and safety results up to 52 weeks of double-blind treatment.Methods: We did a multicentre, randomised, double-blind, phase 2 study for adult patients with vitiligo in 26 US hospitals and medical centres in 18 states. Patients with depigmentation of 0·5% or more of their facial body surface area (BSA) and 3% or more of their non-facial BSA were randomly assigned (1:1:1:1:1) by use of an interactive response technology system to receive ruxolitinib cream (1·5% twice daily, 1·5% once daily, 0·5% once daily, or 0·15% once daily) or vehicle (control group) twice daily on lesions constituting 20% or less of their total BSA for 24 weeks. Patients in the control group in addition to patients in the 0·15% once daily group who did not show a 25% or higher improvement from baseline in facial Vitiligo Area Scoring Index (F-VASI) at week 24 were re-randomised to one of three higher ruxolitinib cream doses (0·5% once daily, 1·5% once daily, 1·5% twice daily). Patients in the 0·5% once daily, 1·5% once daily, or 1·5% twice daily groups remained at their original dose up to week 52. Patients, investigators, and the study sponsor (except members of the interim analysis and primary endpoint analysis data monitoring teams) remained masked to treatment assignment throughout the study. The primary endpoint was the proportion of patients achieving a 50% or higher improvement from baseline in F-VASI (F-VASI50) at week 24, assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03099304.Findings: Between June 7, 2017, and March 21, 2018, 205 patients were screened for eligibility, 48 were excluded and 157 patients (mean age, 48·3 years [SD 12·9]; 73 [46%] male and 84 [54%] female) were randomly assigned to either an intervention group or the control group. 32 (20%) of 157 were assigned to the control group, 31 (20%) to the 0·15% once daily group, 31 (20%) to the 0·5% once daily group, 30 (19%) to the 1·5% once daily group, and 33 (21%) to the 1·5% twice daily group. F-VASI50 at week 24 was reached by significantly more patients given ruxolitinib cream at 1·5% twice daily (15 [45%] of 33) and 1·5% once daily (15 [50%] of 30) than were treated with vehicle (one [3%] of 32). Four patients had serious treatment-emergent adverse events (one patient in the 1·5% twice daily group developed subdural haematoma; one patient in the 1·5% once daily group had a seizure; one patient in the 0·5% once daily group had coronary artery occlusion; and one patient in the 0·5% once daily group had oesophageal achalasia), all of which were unrelated to study treatment. Application site pruritus was the most common treatment-related adverse event among patients given ruxolitinib cream (one [3%] of 33 in the 1·5% twice daily group; three [10%] of 30 in the 1·5% once daily group; three [10%] of 31 in the 0·5% once daily group; and six [19%] of 31 in the 0·15% once daily group)with three [9%] of 32 patients showing application site pruritis in the control group. Acne was noted as a treatment-related adverse event in 13 (10%) of 125 patients who received ruxolitinib cream and one (3%) of 32 patients who received vehicle cream. All treatment-related adverse events were mild or moderate in severity and similar across treatment groups.Interpretation: Treatment with ruxolitinib cream was associated with substantial repigmentation of vitiligo lesions up to 52 weeks of treatment, and all doses were well tolerated. These data suggest that ruxolitinib cream might be an effective treatment option for patients with vitiligo.Funding: Incyte. [ABSTRACT FROM AUTHOR]

Toll-like receptors TLR7 and TLR9 are both implicated in the activation of autoreactive B cells and other cell types associated with systemic lupus erythematosus (SLE) pathogenesis. However, Tlr9-/- autoimmune-prone strains paradoxically develop more severe disease. We have now leveraged the negative regulatory role of TLR9 to develop an inducible rapid-onset murine model of systemic autoimmunity that depends on T cell detection of a membrane-bound OVA fusion protein expressed by MHC class II+ cells, expression of TLR7, expression of the type I IFN receptor, and loss of expression of TLR9. These mice are distinguished by a high frequency of OVA-specific Tbet+, IFN-γ+, and FasL-expressing Th1 cells as well as autoantibody-producing B cells. Unexpectedly, contrary to what occurs in most models of SLE, they also developed skin lesions that are very similar to those of human cutaneous lupus erythematosus (CLE) as far as clinical appearance, histological changes, and gene expression. FasL was a key effector mechanism in the skin, as the transfer of FasL-deficient DO11gld T cells completely failed to elicit overt skin lesions. FasL was also upregulated in human CLE biopsies. Overall, our model provides a relevant system for exploring the pathophysiology of CLE as well as the negative regulatory role of TLR9. [ABSTRACT FROM AUTHOR]

The skin, similar to most nonlymphoid tissues, contains substantial numbers of T cells. Among these, memory T cells serve a sentinel role to protect against pathogens, and regulatory T cells (Tregs) terminate immune responses as a check against unrestrained inflammation. Previously, we created conditional knockout mice with Treg-specific deletion of CD28. Although these mice have normal numbers of Tregs, these cells have lower levels of CTLA-4, PD-1, and CCR6, and the animals develop systemic autoimmunity characterized by prominent skin inflammation. In this study, we have performed a detailed analysis of the skin disease in these mice. Our data show that Treg-expressed CD28 is required for optimal maturation of CD44loCD62Lhi central Tregs into CD44hiCD62Llo effector Tregs (eTregs), as well as induction of CCR6 among the cells that do become eTregs. Although CD28-deficient Tregs are able to regulate inflammation normally when injected directly into the skin, they fail to home properly to inflamed skin. Collectively, these results suggest a key role for CD28 costimulation in promoting a central Treg to eTreg transition with appropriate upregulation of chemokine receptors such as CCR6 that are required for tissue homing. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented discussing the results of the authors' investigation aimed at addressing the hypothesis that the use of permanent hair dyes may be associated with an increased risk of vitiligo, using data from a large cohort in U.S. women, the Nurses' Health Study (NHS), which was established in 1976.

However, some patients may have treatment-related immunosuppression and some may have to access in-office narrow band ultraviolet light B (NB-UVB), which could increase their risk of developing COVID-19. Dear Editor, The World Health Organization declared a global pandemic on 12 March 2020 due to the worldwide spread of COVID-19, caused by SARS-CoV-2.1 Vitiligo is an autoimmune disease causing skin depigmentation affecting 0.5%-2% of the population. Pre-treatment symptom screening, increasing the time between consecutive patient treatments and cleaning all surfaces of phototherapy units between patients with a solution approved for use to combat COVID-19 is recommended.2 Discontinuing phototherapy for more than 2 weeks is not recommended, as the beneficial effect of phototherapy wanes quickly and the patient may plateau or relapse. [Extracted from the article]

Summary: How innate lymphoid cells (ILCs) in the thymus and gut become specialized effectors is unclear. The prototypic innate-like γδ T cells (Tγδ17) are a major source of interleukin-17 (IL-17). We demonstrate that Tγδ17 cells are programmed by a gene regulatory network consisting of a quartet of high-mobility group (HMG) box transcription factors, SOX4, SOX13, TCF1, and LEF1, and not by conventional TCR signaling. SOX4 and SOX13 directly regulated the two requisite Tγδ17 cell-specific genes, Rorc and Blk, whereas TCF1 and LEF1 countered the SOX proteins and induced genes of alternate effector subsets. The T cell lineage specification factor TCF1 was also indispensable for the generation of IL-22 producing gut NKp46+ ILCs and restrained cytokine production by lymphoid tissue inducer-like effectors. These results indicate that similar gene network architecture programs innate sources of IL-17, independent of anatomical origins. [ABSTRACT FROM AUTHOR]

Traditional skin sampling methods include punch or shave biopsies to produce a solid tissue sample for analysis. These biopsy procedures are painful, require anesthesia, and leave permanent scars. This unit describes a suction blister skin biopsy method that can be used in place of traditional biopsy methodologies as a minimally invasive, non-scarring skin sampling technique. The induction of suction blisters uses an instrument with a chamber that applies negative pressure and gentle heat to the skin. Blister formation occurs within 1 hr, producing up to five blisters, each 10 mm in diameter per biopsy site. Blister fluid can be extracted and centrifuged to retrieve cells from the epidermis and upper dermis for flow cytometry, single-cell RNA sequencing, cell culture, and more without the need for digestion protocols. In addition, the blister fluid can be used to measure soluble proteins and metabolites. This unit describes the preparation of supplies and subjects, the suction blister biopsy procedure and blister formation, fluid extraction, and post-blistering care. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Preparation of supplies and subject Basic Protocol 2: Suction blister biopsy procedure and formation Basic Protocol 3: Blister fluid extraction Basic Protocol 4: Post-blister care and clean up., (© 2024 Wiley Periodicals LLC.)

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., Competing Interests: TP is a consultant for AbbVie, Almirall, Amgen, Bristol Myers Squibb, Calypso, Galderma, Incyte Corporation, Janssen, Eli Lilly, Novartis, Pfizer, Roivant, UCB, and VYNE Therapeutics. He has received grants and/or honoraria from AbbVie, ACM Pharma, Almirall, Amgen, Astellas, Bristol Myers Squibb, Calypso, Celgene, Galderma, Genzyme/Sanofi, GlaxoSmithKline, Incyte Corporation, Janssen, LEO Pharma, Eli Lilly, Novartis, Pfizer, Roivant, Sun Pharmaceuticals, UCB, and VYNE Therapeutics. He is the cofounder of YUKIN Therapeutics; and has patents on WNT agonists or GSK3b antagonist for repigmentation of vitiligo and the use of CXCR3B blockers in vitiligo. KE is a consultant for AbbVie, Incyte Corporation, La Roche-Posay, Pfizer, Pierre Fabre, Sanofi, and Viela Bio. IH is a consultant for AbbVie, Almirall, Avita, Boehringer Ingelheim, Galderma, Incyte, Jansen, Novartis, Pfizer, Sonoma, UCB, and Union Therapeutics. He is an investigator for Avita, Incyte, Lenicura, L’Oréal/Laroche Posay, and Pfizer, and a board member and past president of the Hidradenitis Suppurativa Foundation and Global Vitiligo Foundation. NvG is a consultant and/or investigator for AbbVie, Pfizer, Incyte, MDS/Merck, and Sunpharma and has received grants from AbbVie, Incyte, Pfizer, and COURD-COUSIN Collaboration (C3). She is the chair of the Vitiligo International Task Force group. DR has served as a consultant, spoken for, or conducted trials for the following companies: AbbVie, Abcuro, AltruBio, Amgen, Boehringer Ingelheim, Bristol Meyers Squibb, Celgene, Concert, CSL Behring, Dermavant, Dermira, Galderma, Incyte, Janssen, Kyowa Kirin, Lilly, Merck, Nektar, Novartis, Pfizer, RAPT, Regeneron, Recludix, Revolo Biotherapeutics, Sanofi, Sun Pharmaceuticals, UCB, Viela Bio, and Zura Bio. JEH is a consultant for AbbVie, Aldena, Almiral, Avita, Biologics MD, Genzyme/Sanofi, Granular Therapeutics, Incyte, Klirna, LEO Pharma, Matchpoint Therapeutics, Merck, NIRA Biosciences, Pfizer, Sun Pharmaceuticals, Temprian Therapeutics, Vimela Therapeutics, and Vividion Therapeutics. He is an investigator for Genzyme/Sanofi, Incyte, LEO Pharma, Pfizer, and Sun Pharmaceuticals; and holds equity stock (founder) in Aldena, Klirna, NIRA Biosciences, and Vimela Therapeutics. AGP is a consultant for AbbVie, Arcutis, Avita, Immune Tolerance Network, Incyte, Pfizer, Thalocan, WCG/Trifecta, Twi Pharmaceuticals, Villaris, Vimela, and VYNE Therapeutics. He is an investigator for Incyte; and holds stock options in Tara Medical and Zerigo Health. BJS, XW, XH, AMS, and HSC are full-time employees of AbbVie and may own stock and/or options and patents., (© 2024 The Author(s).)

Competing Interests: None disclosed.

Identifying therapeutic oligonucleotides that are cross-reactive to experimental animal species can dramatically accelerate the process of preclinical development and clinical translation. Here, we identify fully chemically-modified small interfering RNAs (siRNAs) that are cross-reactive to Janus kinase 1 (JAK1) in humans and a large variety of other species. We validated the identified siRNAs in silencing JAK1 in cell lines and skin tissues of multiple species. JAK1 is one of the four members of the JAK family of tyrosine kinases that mediate the signaling transduction of many inflammatory cytokine pathways. Dysregulation of these pathways is often involved in the pathogenesis of various immune disorders, and modulation of JAK family enzymes is an effective strategy in the clinic. Thus, this work may open up unprecedented opportunities for evaluating the modulation of JAK1 in many animal models of human inflammatory skin diseases. Further chemical engineering of the optimized JAK1 siRNAs may expand the utility of these compounds for treating immune disorders in additional tissues., Competing Interests: A.K. is a founder of Atalanta Therapeutics and Comanche Biopharma; serves on the Scientific Advisory Board of Aldena Therapeutics, Prime Medicine, Alltrna, and Evox Therapeutics; and owns equities in RXi Pharmaceuticals and Advirna. J.E.H. owns equities in Rheos Medicines, and is a founder of Villaris Therapeutics, Aldena Therapeutics, NIRA Biosciences, Vimela Therapeutics, and Klirna Therapeutics. Q.T., H.H.F., K.Y.G., M.Z.U.I.A., K.R.M., J.E.H., A.K., and J.F.A. are listed as inventors of RNAi technology patents and patent applications. C.B., C.B.-P., and T.P. are executives of Aldena Therapeutics.

Inhibition of Janus kinase (JAK) family enzymes is a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting variable selectivity for JAK subtypes. Absolute JAK subtype selectivity has not yet been achieved. Here, we rationally design small interfering RNAs (siRNAs) that offer sequence-specific gene silencing of JAK1, narrowing the spectrum of action on JAK-dependent cytokine signaling to maintain efficacy and improve safety. Our fully chemically modified siRNA supports efficient silencing of JAK1 expression in human skin explant and modulation of JAK1-dependent inflammatory signaling. A single injection into mouse skin enables five weeks of duration of effect. In a mouse model of vitiligo, local administration of the JAK1 siRNA significantly reduces skin infiltration of autoreactive CD8 + T cells and prevents epidermal depigmentation. This work establishes a path toward siRNA treatments as a new class of therapeutic modality for inflammatory and autoimmune skin diseases., (© 2023. The Author(s).)

Background: The treatment of vitiligo can be challenging. Up-to-date agreed consensus recommendations on the use of topical and systemic therapies to facilitate the clinical management of vitiligo are currently lacking., Objectives: To develop internationally agreed-upon expert-based recommendations for the treatment of vitiligo., Methods: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in different online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence for different topics included in the algorithms. A survey was then given to a core group of eight experts to resolve the remaining issues. Subsequently, the recommendations were finalized and validated based on further input from the entire group during two live meetings., Results: The recommendations provided summarize the latest evidence regarding the use of topical therapies (steroids, calcineurin inhibitors and Jak-inhibitors) and systemic therapies, including steroids and other systemic immunomodulating or antioxidant agents. The different modalities of phototherapies (NB-UVB, photochemotherapy, excimer devices and home phototherapy), which are often combined with other therapies, are also summarized. Interventional approaches as well as depigmentation strategies are presented for specific indications. Finally, the status of innovative and targeted therapies under development is discussed., Conclusions: This international consensus statement culminated in expert-based clinical practice recommendations for the treatment of vitiligo. The development of new therapies is ongoing in vitiligo, and this will likely improve the future management of vitiligo, a disease that still has many unmet needs., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: The treatment of vitiligo can be challenging and depends on several factors such as the subtype, disease activity, vitiligo extent, and treatment goals. Vitiligo usually requires a long-term approach. To improve the management of vitiligo worldwide, a clear and up-to-date guide based on international consensus with uniform stepwise recommendations is needed., Objectives: To reach an international consensus on the nomenclature and to develop a management algorithm for the diagnosis, assessment, and treatment of vitiligo., Methods: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence of topics included in the algorithms. A survey was utilized to resolve remaining issues among a core group of eight experts. Subsequently, the unanimous recommendations were finalized and validated based on further input from the entire group during two live meetings., Results: The algorithms highlight the importance of shared decision-making. Dermatologists are encouraged to provide patients with detailed explanations of the prognosis and expected therapeutic outcomes based on clinical examination. The treatment goal should be discussed and clearly emphasized to patients given the different approaches for disease stabilization and repigmentation. The evaluation of disease activity remains a cornerstone in the tailor-made approach to vitiligo patients., Conclusions: These new treatment algorithms are intended to guide clinical decision-making in clinical practice. Promising novel therapies for vitiligo are on the horizon, further highlighting the need for reliable outcome measurement instruments and greater emphasis on shared decision-making., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

The melanocyte-keratinocyte transplantation procedure (MKTP) treats stable and recalcitrant vitiligo. Despite careful selection of candidates based on clinical stability, the success of the procedure is unpredictable. The aim of our study was to define the immunological profile of stable vitiligo lesions undergoing MKTP and correlate them with clinical outcomes. We included 20 MKTP candidates with vitiligo and a patient with piebaldism as a control. Prior to MKTP, T-cell subsets and chemokines in the recipient skin were measured by flow cytometry and ELISA. During MKTP, melanocytes in the donor skin were quantified by flow cytometry. After MKTP, patients were followed for 12 months and repigmentation was assessed clinically and by ImageJ analysis of clinical photographs. Baseline immunologic biomarkers, duration of clinical stability, and transplanted melanocyte number were correlated to postsurgical repigmentation scores. CD8+ T cells were elevated in 43% of the clinically stable vitiligo lesions. CD8+ T-cell number negatively correlated with postsurgical repigmentation scores (r = -0.635, P = 0.002). Duration of clinical stability, skin chemokines, and transplanted melanocyte number did not influence postsurgical repigmentation. This study demonstrates that CD8+ T-cell number correlates negatively with success of postsurgical repigmentation and can be a biomarker to identify ideal surgical candidates., (Copyright © 2023. Published by Elsevier Inc.)

Background: Vitiligo is a chronic autoimmune disease affecting melanocytes, resulting in skin depigmentation. Patients with vitiligo often have reduced quality of life and comorbid autoimmune conditions and have reported a lack of available treatments for their vitiligo., Objectives: The Vitiligo and Life Impact Among International Communities (VALIANT) study is the first global survey to explore the natural history and management of vitiligo from the perspectives of patients and healthcare professionals (HCPs)., Methods: The survey recruited adults (≥ 18 years) diagnosed with vitiligo and HCPs treating patients with vitiligo via an online panel in 17 countries. Patients were queried regarding clinical characteristics and vitiligo treatment. HCPs were queried regarding diagnosis and management of patients with vitiligo., Results: Included in the analysis were 3541 patients and 1203 HCPs. Nearly half (45.2%) of the patients had > 5% affected body surface area; 57.1% reported family history. Patients obtained formal diagnosis after a mean (SD) of 2.4 (4.1) years; 44.9% reported previous misdiagnosis. Many patients (56.7%) reported being told that vitiligo could not be treated; 53.9% of HCPs believed patients who never treated their vitiligo had been told that vitiligo could not be treated. One-quarter of HCPs (26.3%) did not believe that an effective therapy for vitiligo exists; 44.6% of patients reported giving up on finding an effective therapy. Top treatment goals for patients and HCPs, respectively, were reduction or cessation of spread (24.7% and 18.5%) and repigmentation (22.5% and 37.2%). Patient perception of effective care was similar for treatment by dermatologists (66.9%) and primary care HCPs (67.0%)., Conclusions: Patients with vitiligo and HCPs reported similar treatment goals and expressed frustration with the lack of effective therapies. Patients reported high rates of initial misdiagnosis; many ceased seeking healthcare because they perceived that vitiligo could not be treated. The findings highlight the need for earlier diagnosis and improved disease management for vitiligo., Competing Interests: Conflicts of interest: I.H.H. has served as an advisory board member for AbbVie; a consultant for Boehringer Ingelheim, Galderma Laboratories LP, Incyte, Pfizer and UCB; a principal investigator for Avita, Bayer, Estée Lauder, Ferndale Laboratories, Incyte Corporation, Lenicura, L’Oréal, Pfizer and Unigen; immediate past president of the HS Foundation; and a board member of the Global Vitiligo Foundation. K.B. was an employee and shareholder of Incyte at the time of the study. P.G. has served as a consultant for Aclaris Therapeutics, Clarify Medical, DermaForce, Incyte, Proctor & Gamble and Versicolor Technologies; and as a principal investigator for Aclaris Therapeutics, Allergan/SkinMedica, Clinuvel Pharmaceuticals, Incyte, Johnson & Johnson, L’Oreal, Merz Pharma, Pfizer, Thync Global Inc. and VT Cosmetics. J.E.H. has served as a consultant for AbbVie, Aclaris Therapeutics, BiologicsMD, EMD Serono, Genzyme/Sanofi, Janssen, Pfizer, Rheos Medicines, Sun Pharmaceuticals, TeVido BioDevices, The Expert Institute, 3rd Rock Ventures and Villaris Therapeutics; and as an investigator for Aclaris Therapeutics, Celgene, Dermira, EMD Serono, Genzyme/Sanofi, Incyte, LEO Pharma, Pfizer, Rheos Medicines, Stiefel/GlaxoSmithKline, Sun Pharmaceuticals, TeVido BioDevices and Villaris Therapeutics; holds equity in Aldena Therapeutics, NIRA Biosciences, Rheos Medicines, TeVido BioDevices and Villaris Therapeutics; is a scientific founder of Aldena Therapeutics, NIRA Biosciences and Villaris Therapeutics; and has patents pending for IL-15 blockade for treatment of vitiligo, JAK inhibition with light therapy for vitiligo and CXCR3 antibody depletion for treatment of vitiligo. N.v.G. is a consultant and/or investigator for AbbVie, Incyte, Merck/MSD, Pfizer and Sun Pharma; and is chair of the Vitiligo Task Force for the European Academy of Dermatology and Venereology. D.P. has served as an expert or primary investigator for Incyte, Pfizer and Sun Pharmaceuticals. M.T. has no conflicts of interest to disclose. J.G. has served as a consultant for AbbVie, Avita Medical, Concert Pharmaceuticals, Incyte, Mitsubishi Tanabe Pharma Corporation and Pfizer. Y.V. is CEO of the Vitiligo Research Foundation, has served as a scientific advisor at Temprian Therapeutics, and as an invited professor at Guglielmo Marconi University. G.T.M. is the founder of Beyond Vitiligo South Africa and cofounder of Beyond Vitiligo Botswana. C.L. is a co-owner of Envision Health Partners, who received funding for conducting this project from Incyte. H.R. is an employee and shareholder of Incyte. K.E. is a consultant for AbbVie, Incyte, La Roche-Posay, Pfizer, Pierre Fabre, Sanofi and Viela Bio., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Competing Interests: Conflicts of interest None disclosed.

Importance: Patients with vitiligo often have impaired quality of life (QOL) and experience substantial psychosocial burden., Objective: To explore the global association of vitiligo with QOL and mental health from the patient perspective., Design, Setting, and Participants: This qualitative study of the cross-sectional population-based Vitiligo and Life Impact Among International Communities (VALIANT) study was conducted from May 6, 2021, to June 21, 2021. Potential participants for this qualitative study were recruited from an online panel in 17 countries. Of 5859 surveyed adults (aged ≥18 years) who reported a vitiligo diagnosis, 3919 (66.9%) completed the survey, and 3541 (60.4%) were included in the analysis., Exposures: Patients were asked questions regarding their emotional well-being, including QOL and mental health., Main Outcomes and Measures: Reported analyses are descriptive and hypothesis generating. Vitiligo Impact Patient scale (VIPs) scores ranged from 0 to 60, with higher scores indicating more psychosocial burden., Results: The median age of the 3541 patients was 38 years (range, 18-95 years), and 1933 (54.6%) were male; 1602 patients (45.2%) had more than 5% affected body surface area (BSA; Self-Assessment Vitiligo Extent Score assessed), and 1445 patients (40.8%) had Fitzpatrick skin types IV to VI (ie, darker skin). The mean (SD) global short-form VIPs score was 27.3 (15.6) overall; patients from India (mean [SD], 40.2 [14.1]) reported the highest scores (ie, most burden). The QOL burden according to the scale was profound for patients with more than 5% affected BSA (mean [SD] score, 32.6 [14.2]), darker skin (mean [SD] score, 31.2 [15.6]), and lesions on the face (mean [SD] score, 30.0 [14.9]) or hands (mean [SD], 29.2 [15.2]). At least 40% of patients globally reported that vitiligo frequently affected aspects of their daily lives, including choosing clothes to wear (1956 of 3541 [55.2%]). Most patients (2103 of 3541 [59.4%]) reported concealing their vitiligo frequently. More than half of patients (2078 of 3541 [58.7%]) reported diagnosed mental health conditions, including anxiety (1019 of 3541 [28.8%]) and depression (866 of 3541 [24.5%]). The Patient Health Questionnaire-9 depression screener showed that 55.0% of patients (1948 of 3541) had moderate to severe depressive symptoms; the highest rates were in India (271 of 303 [89.4%]) and among patients with more than 5% affected BSA (1154 of 1602 [72.0%]) and darker skin (987 of 1445 [68.3%])., Conclusions and Relevance: This qualitative study found that, globally, patients with vitiligo reported being substantially affected in their emotional well-being, daily lives, and psychosocial health; the burden was typically greatest among patients with more than 5% affected BSA, darker skin types, and lesions on the face or hands. Survey findings suggest that patients reported having altered their behavior, expressed clear discontent, and have symptoms consistent with depression, which may be underdiagnosed.

Background: Efficacy of ruxolitinib cream, a topical Jak1/Jak2 inhibitor, was demonstrated in a phase 2 trial in patients with vitiligo., Objective: This study aimed to characterize circulating inflammatory biomarker profiles in patients who demonstrated ≥50% improvement in facial Vitiligo Area Scoring Index scores by week 24 (group 1) and those who did not (group 2)., Design: This was a posthoc analysis of a multicenter, randomized, double-blind, vehicle-controlled, phase 2 study in which screening was conducted between June 7, 2017 and March 21, 2018., Population: Patients aged between 18 and 75 years with vitiligo, including depigmentation affecting ≥0.5% of body surface area on the face and ≥3% of body surface area on nonfacial areas, were eligible., Intervention: Patients applied 1.5% ruxolitinib cream to lesions once or twice daily for 52 weeks., Main Outcomes and Measures: Patients were grouped by achievement of ≥50% improvement in facial Vitiligo Area Scoring Index at week 24. Proteomic analysis was performed on baseline serum samples., Results: Mean ± standard error facial Vitiligo Area Scoring Index in group 1 (n = 30) versus group 2 (n = 27) improved by 79.9 ± 4.0% versus 1.1 ± 7.3% and 91.9 ± 1.5% versus 25.1 ± 13.4% at weeks 24 and 52, respectively. Broad proteomic analysis revealed 76 proteins (of 1,104 tested) that were differentially expressed between groups 1 and 2 at baseline ( P < 0.05). Ten distinct proteins were upregulated in group 1; 64 were elevated in group 2., Conclusion: This analysis identified potential differences between patients who achieved ≥50% improvement in facial Vitiligo Area Scoring Index at 24 weeks and those who did not that require deeper scientific interrogation and may be important in stratifying therapeutic benefit for patients with vitiligo., Trial Registration: The original study was registered at ClinicalTrials.gov, NCT03099304., (© 2023 The Authors.)

Competing Interests: Conflicts of interest None declared.

Morphea is characterized by initial inflammation followed by fibrosis of the skin and soft tissue. Despite its substantial morbidity, the pathogenesis of morphea is poorly studied. Previous work showed that CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in the sera and lesional skin of patients with morphea. We found that an early inflammatory subcutaneous bleomycin mouse model of dermal fibrosis mirrors the clinical, histological, and immune dysregulation observed in human morphea. We used this model to examine the role of the CXCR3 chemokine axis in the pathogenesis of cutaneous fibrosis. Using the REX3 (Reporting the Expression of CXCR3 ligands) mice, we characterized which cells produce CXCR3 ligands over time. We found that fibroblasts contribute the bulk of CXCL9-RFP and CXCL10-BFP by percentage, whereas macrophages produce high amounts on a per-cell basis. To determine whether these chemokines are mechanistically involved in pathogenesis, we treated Cxcl9-, Cxcl10-, or Cxcr3-deficient mice with bleomycin and found that fibrosis is dependent on CXCL9 and CXCR3. Addition of recombinant CXCL9 but not CXCL10 to cultured mouse fibroblasts induced Col1a1 mRNA expression, indicating that the chemokine itself contributes to fibrosis. Taken together, our studies provide evidence that CXCL9 and its receptor CXCR3 are functionally required for inflammatory fibrosis., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Conflicts of interest KE declares acting as a consultant for Incyte, La Roche Posay, Pfizer, Pierre Fabre, Sanofi, and Viela Bio. EP, YY, LAC, AB, AS, DY, and MSV are employees of Pfizer and hold stock and/or stock options with Pfizer. KG was an employee of Pfizer at the time of the study and held stock and/or stock options with Pfizer. GH declares being an investigator for Amgen, Athenex, Boehringer Ingelheim, Bond Avillion, Bristol Myers Squibb, Celgene, Eli Lilly, Novartis, Janssen, MC2, PellePharm, Pfizer, and UCB; and a consultant, advisor, or speaker for AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Castle Biosciences, Dermavant, Dermtech, Eli Lilly, Janssen, LEO Pharma, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi Genzyme, SUN Pharmaceuticals, and UCB. IH declares being a consultant for Galderma Laboratories and UCB; an investigator for Arcutis, Avita, Bayer, Lenicura, L’Oréal, and Unigen; and a consultant and investigator for Incyte and Pfizer; serving on scientific advisory boards for AbbVie; and being co-chair of Global Vitiligo Foundation in a non-funded capacity. AKG declares being a consultant for AbbVie, Allergan Aesthetics, and Viela Bio. MP declares being a consultant, advisor, or speaker for Incyte, Pfizer, Pierre Fabre, and PPM. DT declares being a consultant, investigator, speaker, and participating in scientific advisory boards for AbbVie, Almirall, Amgen, Biogen Idec, BMS, Janssen-Cilag, LEO Pharma, Eli Lilly, Novartis, Pfizer, Regeneron, Samsung, Sanofi, and UCB; and research/educational grants from AbbVie, LEO Pharma, and Novartis. JEH declares acting as a consultant and investigator for Pfizer, Genzyme/Sanofi, Incyte, Rheos Medicines, Sun Pharmaceuticals, Leo Pharma, Villaris Therapeutics, Dermavant, and TeVido BioDevices; and a consultant for Temprian Therapeutics, AbbVie, Inc, Janssen, Almirall, Methuselah Health, Pandion, AnaptysBio, Avita, NIRA Biosciences, Admirx, Granular Therapeutics, Platelet BioGenesis, Inc; he has equity in TeVido Biodevices, Rheos, Villaris Therapeutics, Inc, and NIRA Biosciences; and is a founder of Villaris Therapeutics, Inc, and NIRA Biosciences. JMB declares acting as a consultant for Pfizer, AbbVie, LaserOptek, and Ilooda. KT declares being a speaker for AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi, and UCB. RS declares providing professional services to Amgen, Bayer, Boehringer Ingelheim, Celgene, Coherus Biosciences, Cutanea, Eli Lilly, GlaxoSmithKline, Janssen, LEO Pharma, MedImmune, Merck & Co, MSD, Novartis, Oncobiologics, Pfizer, Regeneron, Roche, Samson Clinical, and Sun Pharma. AGP declares acting as a consultant for AbbVie, Arcutis, Avita, Chromaderm, Immune Tolerance Network, Incyte, Pfizer, TWi, Viela Bio, and Villaris, and holds stock options with Tara Medical and Zerigo Health. BK declares receiving honoraria and/or consultation fees from Aclaris Therapeutics, Arena Therapeutics, Bristol-Myers Squibb, Concert Pharmaceuticals, Dermavant Sciences, Eli Lilly, Pfizer, Regeneron, and Viela Bio, and serving on a speakers bureau for Pfizer. The other authors have no conflicts of interest to declare., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Vitiligo is an autoimmune skin disease caused by melanocyte-targeting autoreactive CD8+ T cells. Regulatory T cells (Tregs) have been implicated in restraining vitiligo severity in both mouse models and human patients; however, whether they must be present in the skin for their suppressive function is still unclear. We observed uneven distribution of Tregs within different anatomical locations of mouse skin, which correlated with reduced depigmentation after vitiligo induction. We specifically depleted Tregs in our mouse model of vitiligo and observed increased disease. Next, we found that Tregs contact CD8+ T effector cells in vitiligo lesional skin and that Treg recruitment to the skin inversely correlated with disease severity, suggesting a critical role for Treg suppression within the skin. When we investigated the signals facilitating Treg migration to the skin, we found that although CXCR3 was dispensable for Treg migration and function in vitiligo, Tregs lacking CCR6 exhibited a reduced capacity to migrate to the skin and suppress depigmentation, despite normal systemic numbers in the skin-draining lymph nodes. Our observations highlight a key role for cutaneous Tregs in disease suppression during vitiligo and identify CCR6 as a chemokine receptor that contributes to Treg migration to the skin., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite the central role of IFN-γ in vitiligo pathogenesis, systemic IFN-γ neutralization is an impractical treatment option owing to strong immunosuppression. However, most patients with vitiligo present with <20% affected body surface area, which provides an opportunity for localized treatments that avoid systemic side effects. After identifying keratinocytes as key cells that amplify IFN-γ signaling during vitiligo, we hypothesized that tethering an IFN-γ‒neutralizing antibody to keratinocytes would limit anti‒IFN-γ effects on the treated skin for the localized treatment. To that end, we developed a bispecific antibody capable of blocking IFN-γ signaling while binding to desmoglein expressed by keratinocytes. We characterized the effect of the bispecific antibody in vitro, ex vivo, and in a mouse model of vitiligo. Single-photon emission computed tomography/computed tomography biodistribution and serum assays after local footpad injection revealed that the bispecific antibody had improved skin retention, faster elimination from the blood, and less systemic IFN-γ inhibition than the nontethered version. Furthermore, the bispecific antibody conferred localized protection almost exclusively to the treated footpad during vitiligo, which was not possible by local injection of the nontethered anti‒IFN-γ antibody. Thus, keratinocyte tethering proved effective while significantly diminishing the off-tissue effects of IFN-γ blockade, offering a safer treatment strategy for localized skin diseases, including vitiligo., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aberrant activation of interferon (IFN)-γ signaling plays a key role in several autoimmune skin diseases, including lupus erythematosus, alopecia areata, vitiligo, and lichen planus. Here, we identify fully chemically modified small interfering RNAs (siRNAs) that silence the ligand binding chain of the IFN-γ receptor (IFNGR1), for the modulation of IFN-γ signaling. Conjugating these siRNAs to docosanoic acid (DCA) enables productive delivery to all major skin cell types local to the injection site, with a single dose of injection supporting effective IFNGR1 protein reduction for at least 1 month in mice. In an ex vivo model of IFN-γ signaling, DCA-siRNA efficiently inhibits the induction of IFN-γ-inducible chemokines, CXCL9 and CXCL10, in skin biopsies from the injection site. Our data demonstrate that DCA-siRNAs can be engineered for functional gene silencing in skin and establish a path toward siRNA treatment of autoimmune skin diseases., Competing Interests: Declaration of interests A.K., J.E.H., and Q.T. have filed a patent that covers the abovementioned IFNGR1 and other (JAK1, JAK2, and STAT1) identified siRNA oligonucleotides for the modulation of IFN-γ signaling pathway. A.K. discloses ownership of stock in RXi Pharmaceuticals and Advirna and is a founder of Atalanta Therapeutics. J.E.H holds equity in Rheos Medicines, TeVido BioDevices and is a founder of Villaris Therapeutics, Aldena Therapeutics, NIRA Biosciences, and Vimela Therapeutics., (Published by Elsevier Inc.)

Competing Interests: Conflicts of interest Dr Hamzavi has served as an advisory board member for AbbVie; a consultant for Incyte Corporation, Pfizer, and UCB; a principal investigator for AbbVie, Allergan, Bayer, Clinuvel Pharmaceuticals, Estée Lauder, Ferndale Laboratories, Galderma Laboratories LP, GE Healthcare, Incyte Corporation, Janssen, Janssen Biotech, Johnson & Johnson, Lenicura, LEO Pharma, Pfizer, and Unigen; a subinvestigator for Amgen, Bristol Myers Squibb, Foamix Pharmaceuticals, and Janssen; president of the HS Foundation; and cochair of the Global Vitiligo Foundation. Dr Rosmarin has received honoraria as a consultant for AbbVie, Celgene, Dermavant Sciences, Dermira, Eli Lilly and Company, Janssen, Kyowa Kirin, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi, Sun Pharmaceuticals, UCB, and VielaBio; research support from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Dermira, Eli Lilly and Company, Incyte Corporation, Janssen, Merck, Novartis, Pfizer, and Regeneron Pharmaceuticals; and has served as a paid speaker for AbbVie, Celgene, Eli Lilly and Company, Janssen, Novartis, Pfizer, Regeneron Pharmaceuticals, and Sanofi. Dr Harris has served as a consultant for AbbVie, Aclaris Therapeutics, BiologicsMD, EMD Serono, Genzyme/Sanofi, Janssen, Pfizer, Rheos Medicines, Sun Pharmaceuticals, TeVido BioDevices, The Expert Institute, 3rd Rock Ventures, and Villaris Therapeutics; has served as an investigator for Aclaris Therapeutics, Celgene, Dermira, EMD Serono, Genzyme/Sanofi, Incyte Corporation, LEO Pharma, Pfizer, Rheos Medicines, Stiefel/GSK, Sun Pharmaceuticals, TeVido BioDevices, and Villaris Therapeutics; holds equity in Rheos Medicines, TeVido BioDevices, and Villaris Therapeutics; is a scientific founder of Villaris Therapeutics; and has patents pending for IL-15 blockade for treating vitiligo, JAK inhibition with light therapy for vitiligo, and CXCR3 antibody depletion for the treatment of vitiligo. Dr Pandya has served as an investigator for Aclaris Therapeutics, Immune Tolerance Network, Incyte Corporation, and Pfizer; a consultant for Arcutis, Avita Medical, Chromaderm, Immune Tolerance Network, Incyte Corporation, Pfizer, Viela Bio, and Villaris; and a board member who also holds stock options for Clarify Medical and Tara Medical. Dr Lebwohl is an employee of Mount Sinai Hospital, which receives research funds from AbbVie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Dermavant, Eli Lilly, Incyte Corporation, Janssen Research & Development, LLC, Ortho Dermatologics, Regeneron, and UCB, Inc; and is a consultant for Aditum Bio, Almirall, AnaptysBio, Arcutis, Aristea, Arrive Technology, Avotres Therapeutics, BioMX, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Dr. Reddy's Laboratories, Evelo, Evommune, Facilitate International Dermatologic Education, Forte, Foundation for Research and Education in Dermatology, Helsinn, LEO Pharma, Meiji Seika Pharma, Mindera, Pfizer, and Verrica. Dr Gottlieb has received honoraria as an advisory board member and consultant for AnaptysBio, Avotres Therapeutics, Beiersdorf, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Incyte Corporation, Janssen, LEO Pharma, Novartis, Sun Pharmaceuticals, and UCB; has stock options in Xbiotech; and has received institutional research/educational grants from Boehringer Ingelheim, Incyte Corporation, Janssen, Novartis, UCB, Xbiotech, and Sun Pharmaceuticals to Mount Sinai School of Medicine. Drs Butler, Kuo, and Sun are employees and shareholders of Incyte Corporation. Dr Grimes has served as a consultant for Aclaris Therapeutics, Clarify Medical, DermaForce, Incyte Corporation, Proctor & Gamble, and Versicolor Technologies and a principal investigator for Aclaris Therapeutics, Allergan/SkinMedica, Clinuvel Pharmaceuticals, Incyte Corporation, Johnson & Johnson, L'Oreal, Merz Pharma, Pfizer, Thync Global Inc, and VT Cosmetics.

Vitiligo is an autoimmune skin disease characterized by the targeted destruction of melanocytes by T cells. Cytokine signaling between keratinocytes and T cells results in CD8 + T cell infiltration of vitiligo lesions, but the full scope of signals required to coordinate autoimmune responses is not completely understood. We performed single-cell RNA sequencing on affected and unaffected skin from patients with vitiligo, as well as healthy controls, to define the role of each cell type in coordinating autoimmunity during disease progression. We confirmed that type 1 cytokine signaling occupied a central role in disease, but we also found that this pathway was used by regulatory T cells (T regs ) to restrain disease progression in nonlesional skin. We determined that CCL5-CCR5 signaling served as a chemokine circuit between effector CD8 + T cells and T regs , and mechanistic studies in a mouse model of vitiligo revealed that CCR5 expression on T regs was required to suppress disease in vivo but not in vitro. CCR5 was not required for T reg recruitment to skin but appeared to facilitate T reg function by properly positioning these cells within the skin. Our data provide critical insights into the pathogenesis of vitiligo and uncover potential opportunities for therapeutic interventions.