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This document provides information about a study on the effectiveness of ruxolitinib cream in treating vitiligo, a chronic autoimmune disease that causes depigmentation on the skin. The study found that repigmentation varied across different body regions, with the face, trunk, and proximal extremities showing better response than bony prominences, hands, and feet. Patients treated with ruxolitinib cream showed improvement in repigmentation over a 52-week period, with the head/neck and trunk responding the best. However, repigmentation of the hands and feet was more challenging. The study suggests that longer-term treatment and combination therapies may be helpful for achieving optimal repigmentation in difficult-to-treat areas. The document also provides information about the authors and their affiliations, as well as potential conflicts of interest. It includes a statement about data availability and an ethics statement regarding the trials conducted. [Extracted from the article]

This article explores the advancements in targeted therapies for vitiligo, a skin condition that causes depigmentation. It emphasizes the importance of equity in drug development, particularly for individuals with skin of color who may experience more severe disfigurement. The US FDA has approved a topical JAK inhibitor called ruxolitinib as a treatment for vitiligo, but there is a lack of diversity in the study populations for these inhibitors. The article highlights the need for more inclusive clinical trials and discusses the racial disparities in these trials. It also suggests a multifaceted approach to address these disparities, including increasing awareness, improving access, and promoting diversity in clinical trial teams. [Extracted from the article]

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.sup.-/-] 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.sup.+] 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.sup.+], [IFN-[gamma].sup.+], 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 [DO11.sup.gld] 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., Introduction Cutaneous lupus erythematosus (CLE) refers to dermatologic features of systemic lupus erythematosus (SLE) that may or may not be associated with more systemic manifestations, such as arthritis, nephritis, or [...]

Introduction/Background Vitiligo is a chronic autoimmune disease characterized by melanocyte destruction, leading to skin depigmentation. Limited data are available regarding the efficacy of long-term topical vitiligo treatment. In 2 randomized, double-blinded, vehicle-controlled phase 3 studies in adults and adolescents (aged ≥12 y) with nonsegmental vitiligo (TRuE-V1 [NCT04052425]; TRuE-V2 [NCT04057573]), ruxolitinib cream application resulted in statistically superior improvements in repigmentation versus vehicle in the primary and all key secondary endpoints at Week 24 and was well tolerated. In the open-label period of TRuE-V1/TRuE-V2 (Weeks 24-52) and the TRuE-V long-term extension (LTE; Weeks 52-104) study (NCT04530344), further improvements in facial and body repigmentation (as assessed by Vitiligo Area Scoring Index [VASI] responses) were observed through Week 104 among patients who continued to apply ruxolitinib cream. Objectives: In this pooled analysis, we evaluated shifts in facial and total body VASI (F-VASI/T-VASI) responses among patients with vitiligo who had limited or no repigmentation at Week 24 and who continued to apply ruxolitinib cream for an additional 80 weeks. Methods: In TRuE-V1/TRuE-V2, patients were randomized 2:1 to apply twice-daily 1.5% ruxolitinib cream or vehicle for 24 weeks, after which all patients could apply 1.5% ruxolitinib cream through Week 52. Patients who completed TRuE-V1/TRuE-V2 were eligible to enroll in the TRuE-V LTE. Patients who did not achieve ≥90% improvement in F-VASI at Week 52 continued to apply open-label 1.5% ruxolitinib cream until Week 104. Patients initially randomized to apply ruxolitinib cream who had <25% improvement from baseline in F-VASI or T-VASI at Week 24 and had non-missing VASI assessments at the evaluated time points were included in this analysis. Shifts in F-VASI and T-VASI were assessed among patients with no facial/body repigmentation or worsening depigmentation (≤0% improvement in F-VASI/T-VASI) and patients with limited facial/body repigmentation (>0%- <25% improvement in F-VASI/T-VASI) at Week 24. Results: Among patients with no facial repigmentation at Week 24, improvements in F-VASI at Weeks 52 and 104 were observed in 77.8% (49/63) and 97.1% (34/35) of patients, respectively. Among patients with limited facial repigmentation at Week 24, F-VASI improvements at Weeks 52 and 104 were observed in 64.0% (32/50) and 83.3% (30/36) of patients, respectively. Across both groups, 54.9% (39/71) of patients achieved =75% improvement from baseline in F-VASI (F-VASI75) at Week 104. Among those with no body repigmentation at Week 24, T-VASI improvements at Weeks 52 and 104 were observed in 79.6% (39/49) and 93.3% (28/30) of patients, respectively. For those with limited body repigmentation at Week 24, T-VASI improvements at Weeks 52 and 104 were observed in 64.5% (80/124) and 81.6% (62/76) of patients, respectively. Across both groups who had <25% improvement in total body repigmentation at Week 24, 50.0% (53/106) of patients achieved ≥50% improvement in T-VASI (T-VASI50) at Week 104. Conclusions: In the TRuE-V studies, ruxolitinib cream application for an additional 80 weeks resulted in improved repigmentation among patients with nonsegmental vitiligo who had limited or no repigmentation at Week 24. These 2-year TRuE-V results highlight the importance of prolonged treatment in patients with vitiligo, even when minimal or no repigmentation is achieved after 6 months of treatment. [ABSTRACT FROM AUTHOR]

Two adolescent females presented to outpatient clinic with isolated, non‐scaly, asymptomatic hypopigmented macules and patches on the arm(s). Both cases had Wood's lamp exams notable for extralesional punctiform coral‐red perifollicular fluorescence on the back and faint intralesional enhancement. In one case, biopsy was performed and deemed consistent with progressive macular hypomelanosis. The patient had complete response to antimicrobial therapy and sun exposure. [ABSTRACT FROM AUTHOR]

New-onset vitiligo and progression of pre-existing vitiligo during treatment with biological agents in chronic inflammatory diseases. Four patients (57.1%) noted new onset vitiligo, while three (42.8%) had a past history of stable vitiligo despite no treatment (i.e. no reported new or enlarging lesions) and presented with worsening vitiligo after dupilumab (Figure 1). [Extracted from the article]

Vitiligo is characterized by the development of depigmented macules and patches. Autoimmunity has been established as a factor in disease pathogenesis, leading to utilization of immunosuppressive agents. Topical immunosuppressants are commonly used; however, this treatment modality is often cumbersome and inefficient, as many patients have active disease with extensive body surface area involvement. Prompt and aggressive treatment of vitiligo is important, as this may prevent progression and improve quality of life. To meet these challenges and improve patient outcomes, interest in systemic therapies has grown. Currently, oral therapies are rarely prescribed, likely due to concerns with systemic side effects and unclear efficacy. This article provides a brief overview on the use of systemic agents in treating vitiligo in order to provide additional therapeutic options to clinicians. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The accrual of cytosolic DNA leads to transcription of type I IFNs, proteolytic maturation of the IL-1 family of cytokines, and pyroptotic cell death. Caspase-1 cleaves pro-IL1β to generate mature bioactive cytokine and gasdermin D which facilitates IL-1 release and pyroptotic cell death. Absent in melanoma-2 (AIM2) is a sensor of dsDNA leading to caspase-1 activation, although in human monocytes, cGAS-STING acting upstream of NLRP3 mediates the dsDNA-activated inflammasome response. In healthy human keratinocytes, AIM2 is not expressed yet caspase-1 is activated by the synthetic dsDNA mimetic poly(dA:dT). Here, we show that this response is not mediated by either AIM2 or the cGAS-STING-NLRP3 pathway and is instead dependent on NLRP1. Poly(dA:dT) is unique in its ability to activate NLRP1, as conventional linear dsDNAs fail to elicit NLRP1 activation. DsRNA was recently shown to activate NLRP1 and prior work has shown that poly(dA:dT) is transcribed into an RNA intermediate that stimulates the RNA sensor RIG-I. However, poly(dA:dT)-dependent RNA intermediates are insufficient to activate NLRP1. Instead, poly(dA:dT) results in oxidative nucleic acid damage and cellular stress, events which activate MAP3 kinases including ZAKα that converge on p38 to activate NLRP1. Collectively, this work defines a new activator of NLRP1, broadening our understanding of sensors that recognize poly(dA:dT) and advances the understanding of the immunostimulatory potential of this potent adjuvant. [ABSTRACT FROM AUTHOR]

Introduction I. The North Carolina Attorney General: An "ANCIENT AND HONORABLE OFFICE" A. Historical Development B. The North Carolina Attorney General II. To Defend or Not to Defend? A. The [...]

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]

Vitiligo allies and villains: Vitiligo is an autoimmune skin disease defined by T cell–mediated destruction of melanocytes. Gellatly et al. (p. 0000) used single-cell RNA sequencing (scRNA-seq) to characterize immune cell subsets that are associated with skin lesions in vitiligo. Type 1 cytokine signaling is a key driver of disease progression, and this signaling pathway was also used by regulatory T cells (Tregs) to limit disease in nonlesional skin. CCR5-CCL5 signaling was critical to effector CD8+ T cell and Treg function, and mouse studies showed that disease suppression required CCR5 expression on Tregs. These studies reveal the complex interactions between immune cell subsets that are involved in vitiligo progression and containment. 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 (Tregs) to restrain disease progression in nonlesional skin. We determined that CCL5-CCR5 signaling served as a chemokine circuit between effector CD8+ T cells and Tregs, and mechanistic studies in a mouse model of vitiligo revealed that CCR5 expression on Tregs was required to suppress disease in vivo but not in vitro. CCR5 was not required for Treg recruitment to skin but appeared to facilitate Treg 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. [ABSTRACT FROM AUTHOR]

Vitiligo is an autoimmune skin disease in which epidermal melanocytes are targeted for destruction by CD8+ T cells specific for melanocyte/melanoma‐shared antigens. IFNγ is the central cytokine driving disease, but the role of type I IFN in vitiligo remains unclear. We investigated the functional role of type I IFN during vitiligo progression using two different mouse models: one induced with a vaccinia virus (VV) vaccine and one induced with dendritic cells to prime autoimmune T cells. Induction of vitiligo by VV in IFNaR‐deficient mice led to the development of severe vitiligo compared with wild‐type (WT) mice and was characterized by a significantly enhanced effector CD8+ T‐cell response. Severe vitiligo in this model was a result of VV persistence, because exacerbation of disease in IFNaR‐deficient mice was not observed when antigen‐pulsed dendritic cells were used to induce vitiligo instead of virus. Treatment of B16F10 melanoma‐inoculated mice with VV vaccine therapy also induced a significantly enhanced anti‐tumor response in IFNaR‐deficient mice compared with WT. These results not only help define the pathways responsible for vitiligo progression but also suggest that blockade of type I IFNs following administration of a VV vaccine may provide increased immunogenicity and efficacy for melanoma immunotherapy. [ABSTRACT FROM AUTHOR]

The committee for the 1994 series of theater shows in New York theaters had subpar choices for the Best Musical category. New musicals featured included 'Cyrano' and 'Red Shoes.'