BACKGROUND:Atopic dermatitis (AD) is a common inflammatory skin disease associated with Th2, Th9, and Th22 skewing. Recent studies have implicated various lipid mediators in modulating T helper cell responses. However, the relationship between lipid mediators and Th skewing in AD is not fully understood. OBJECTIVE:We sought to identify lipid mediators that modulate cytokine production involved in Th skewing in AD. METHODS:RNA-sequencing was performed in CD3+ T cells and CD3- non-T cells from AD patients and healthy subjects. Differentially expressed genes were analyzed to detect candidate lipid mediators. Intracellular cytokine staining (ICS) was used to evaluate production of polarizing cytokines in CD4+ T cells cultured in vitro with various lipid mediators. RESULTS:Several lipid mediator-related genes, including sphingosine 1-phosphate receptor 5 (S1PR5), were differentially expressed in CD3+ and CD3- cells from AD patients. ICS revealed markedly increased IL-13 and IL-9 production in the presence of S1P, with AD patients expressing higher levels of S1P in serum compared to healthy controls. Further mechanistic studies using siRNA knockdown for S1PR5 and S1PR1 revealed that IL-13 and IL-9 production are suppressed via S1PR5 and enhanced via S1PR1 signaling. CONCLUSIONS:S1P signaling contributes to Th2/Th9-driven inflammation in AD by reciprocally regulating IL-13 and IL-9 production via S1PR5 and S1PR1.

Alopecia areata is a common cause of non-scaring autoimmune hair loss, associated with substantial psychosocial burden. Alopecia areata is an autoimmune disease in which loss of immune privilege in hair follicles leads to local hair follicle-associated inflammation. A chronic disease with uncertain course that is estimated to affect 2% of people over their lifetime, alopecia areata can present with a range of clinical features, from a single small round patch of hair loss to full scalp and body hair loss, and is associated with atopic, autoimmune and psychological comorbidities. Alopecia areata also has a major negative impact on quality of life, with a greater mental burden than physical burden. Since the 2010s, advances in understanding of disease pathogenesis have led to the identification of inflammatory pathways that can be successfully inhibited to produce substantial clinical responses. The therapeutic landscape has been transformed, with FDA approval of the first treatment for adults with severe alopecia areata in 2022 and for adolescents with severe alopecia areata in 2023, with multiple investigational treatments currently in phase II and phase III clinical trials. This Primer by Guttman-Yassky and colleagues reviews the epidemiology, pathophysiology, diagnosis and treatment of alopecia areata. This Primer also discusses the quality of life issues faced by patients and future research avenues.

BACKGROUND:Vitiligo is a chronic autoimmune skin depigmenting disorder, with a major impact on quality of life. Therapeutic options are still limited, with only one topical JAK inhibitor being approved by the US Food and Drug Administration. Although vitiligo is primarily regarded as a TH1/interferon-driven disease, emerging evidence suggests the involvement of additional immune axes, but their relevance to disease pathogenesis remains unclear. OBJECTIVE:We sought to obtain a global cutaneous transcriptomic profile of lesional and nonlesional vitiligo. METHODS:We performed bulk RNA sequencing combined with real-time PCR and immunohistochemistry of skin biopsy samples from 15 lesional and nonlesional vitiligo samples and compared them to 14 matched healthy controls. Results were corroborated by single-cell RNA sequencing. RESULTS:Robust inflammatory dysregulation was captured not only in lesional but also nonlesional vitiligo skin relative to healthy controls. Lesional samples demonstrated upregulation of TH1 (OASL, CXCL9, CXCL10), TH2 (IL4, IL4R, CCL13, CCL17, CCL22, CCL26), and TH17/22 (IL20, S100A7, S100A8, S100A9, PI3) related markers. Similarly, nonlesional samples demonstrated activation of TH1 (CXCL9, OASL), TH2 (IL4R, IL10, CCL13, CCL17, CCL22), and TH17/22 (PI3, DEFB4A) associated markers. Clinical severity scores (Vitiligo Area Scoring Index and/or Vitiligo Disease Activity Index) significantly and positively correlated with multiple inflammatory mediators (ie, CXCL14, IL25, IL17RC) in lesional and/or nonlesional vitiligo skin. On a single-cell level, IL13 and IFNG expression were primarily found in nonlesional helper T cells and in lesional proliferating T cells, respectively. CONCLUSIONS:Our findings show that immune dysregulation in vitiligo involves immune axes beyond TH1/Tc1, with particular upregulation of type 2 markers already observed in nonlesional skin, suggesting a role during early lesion formation.

Atopic dermatitis is the most common chronic inflammatory skin disease globally. Key features include an eczematous eruption accompanied by intense itch, which can have an enormous negative effect on patients’ quality of life, especially in those with moderate-to-severe disease. Atopic dermatitis is part of a spectrum of atopic conditions that can also include several non-cutaneous organs such as respiratory (eg, allergic rhinitis and asthma) and gastrointestinal (eg, food allergy) systems. For decades, long-term disease control and maintenance were particularly challenging given that treatment options were limited to broad topical and systemic immunosuppressive agents. However, better insights into the pathophysiology of this condition over the past decade have led to the development and approval of safe and efficacious novel targeted treatment approaches. The updated pathophysiological understanding and the evolving therapeutic landscape of atopic dermatitis are discussed in this Seminar.

Atopic dermatitis is the most common chronic inflammatory skin disease globally. Key features include an eczematous eruption accompanied by intense itch, which can have an enormous negative effect on patients' quality of life, especially in those with moderate-to-severe disease. Atopic dermatitis is part of a spectrum of atopic conditions that can also include several non-cutaneous organs such as respiratory (eg, allergic rhinitis and asthma) and gastrointestinal (eg, food allergy) systems. For decades, long-term disease control and maintenance were particularly challenging given that treatment options were limited to broad topical and systemic immunosuppressive agents. However, better insights into the pathophysiology of this condition over the past decade have led to the development and approval of safe and efficacious novel targeted treatment approaches. The updated pathophysiological understanding and the evolving therapeutic landscape of atopic dermatitis are discussed in this Seminar.

Alopecia areata is a common cause of non-scaring autoimmune hair loss, associated with substantial psychosocial burden. Alopecia areata is an autoimmune disease in which loss of immune privilege in hair follicles leads to local hair follicle-associated inflammation. A chronic disease with uncertain course that is estimated to affect 2% of people over their lifetime, alopecia areata can present with a range of clinical features, from a single small round patch of hair loss to full scalp and body hair loss, and is associated with atopic, autoimmune and psychological comorbidities. Alopecia areata also has a major negative impact on quality of life, with a greater mental burden than physical burden. Since the 2010s, advances in understanding of disease pathogenesis have led to the identification of inflammatory pathways that can be successfully inhibited to produce substantial clinical responses. The therapeutic landscape has been transformed, with FDA approval of the first treatment for adults with severe alopecia areata in 2022 and for adolescents with severe alopecia areata in 2023, with multiple investigational treatments currently in phase II and phase III clinical trials.

Alopecia areata is a common cause of non-scaring autoimmune hair loss, associated with substantial psychosocial burden. Alopecia areata is an autoimmune disease in which loss of immune privilege in hair follicles leads to local hair follicle-associated inflammation. A chronic disease with uncertain course that is estimated to affect 2

Anti TNFα agents can induce cutaneous adverse events in both adults and children. While drug-related alopecia was reported in adults treated with TNFα inhibitors for various indications, pediatric data are scarce. To describe clinical characteristics and outcomes in pediatric patients with TNFα inhibitor-induced alopecia we conducted a single center retrospective study (0748-21-RMC, retrospectively registered on January 2nd 2022) including all patients aged < 18 years who were treated with TNFα inhibitors for any indication and developed drug-induced alopecia between the years 2018–2023. A comprehensive literature review was also performed. Twenty patients were included (mean age 12.9 ± 3.1 years, male:female ratio 1:1.4). Fourteen were diagnosed with Crohn’s disease, three with ulcerative colitis, and three with juvenile idiopathic arthritis. Half of the patients were treated with adalimumab and half with infliximab. Overall, alopecia was observed after 14.8 ± 10.8 months of treatment. Eighteen (90.0

BACKGROUND:Pediatric pemphigus is a rare bullous disease that represents a diagnostic and therapeutic challenge;  evidence on patients' response to various treatments and long-term surveillance data are lacking. We aimed to investigate pediatric pemphigus patients' characteristics, diagnosis, therapeutics, response, and long-term follow-up. METHODS:This is a retrospective study of all pemphigus patients aged <18 years, diagnosed between 2000 and 2023, from three tertiary medical centers in Israel. The diagnosis was confirmed by positive immunofluorescence. RESULTS:Twelve pediatric pemphigus patients were included (mean age 10.7 ± 4.3 years, male:female ratio 1:1). Mean diagnostic delay was 11.1 ± 12.6 months (range 1.8-36 months). Most patients had pemphigus vulgaris with mucosal involvement (58.3%). First-line treatment for all patients included systemic corticosteroids (sCS), with a treatment duration (including tapering down) of 28 ± 18.4 months. Hospitalization did not yield better outcomes. Only three patients achieved sustained complete response with sCS treatment (25.0%), and the rest required additional therapeutics, most commonly rituximab. Rituximab showed a good safety profile and therapeutic response. Follow-up was recorded up to 18.1 years after diagnosis (mean: 5.6 years). Three of five patients with information available more than 5 years after the pemphigus diagnosis still exhibited disease symptoms. CONCLUSIONS:Pediatric pemphigus is associated with a significant diagnostic delay. While sCS can induce remission in most patients as a first-line treatment, long-term disease control requires additional immunomodulators. Long-term follow-up reveals a chronic yet mostly benign disease course in this population and advocates for the use of rituximab in pediatric pemphigus patients.

Atopic dermatitis (AD) is a complex and heterogeneous skin disease where achieving complete clinical clearance for most patients has proven challenging through single cytokine inhibition. Current studies integrate biomarkers and evaluate their role in AD, aiming to advance our understanding of the diverse molecular profiles implicated. While traditionally characterized as a Th2-driven disease, extensive research has recently revealed the involvement of Th1, Th17, and Th22 immune pathways, as well as the interplay of pivotal immune molecules, such as OX40, OX40 ligand (OX40L), thymic stromal lymphopoietin (TSLP), and IL-33. This review will explore the mechanistic effect of treatments for AD, focusing on monoclonal antibodies and JAK inhibitors. It will describe how these treatments modulate immune pathways, and examine their impact on key inflammatory and barrier biomarkers.

Background: Hidradenitis suppurativa (HS) has a high unmet need for better treatments. Biopsies are considered the gold standard for studying molecular alterations in skin. A reproducible, minimally invasive approach is needed for longitudinal monitoring in trials and in pediatric populations. Objective: To determine whether skin tape strips can detect molecular alterations in HS and identify biomarkers of disease activity. Methods: We performed RNA sequencing on tape strips collected from lesional and healthy-appearing (nonlesional) HS skin ( n = 22) and healthy controls ( n = 21). We correlated the expression of skin biomarkers between tape strips and a previously published gene-signature of HS biopsies. Results: Tape strips detected upregulation of known HS biomarkers (eg, Interleukin[IL]-17A) in nonlesional and/or lesional skin and also identified novel clinically actionable targets, including OX40 and JAK3. The expression of Th17 and tumor necrosis factor - a pathways were highly correlated between tape strips and biopsies. HS clinical severity was significantly associated with expression of biomarkers (eg tumor necrosis factor - a , IL -17 A/F, OX40, JAK1-3, IL -4R) in HS lesional and/or nonlesional skin. Limitations: Sample size. Tape stripping is limited in depth. Conclusion: This study validates tape strips as a minimally-invasive approach to identify cutaneous biomarkers in HS. This provides a novel avenue for monitoring treatment efficacy and a potential step toward individualized therapy in HS. ( J Am Acad Dermatol 2024;90:749-58.)

Sclerotic -type cutaneous chronic graft -versus -host disease is a severe complication of allogeneic hematopoietic stem cell transplantation, with profound morbidity. A dearth of effective, targeted treatment options necessitates further investigation into the molecular mechanisms underlying this T -cell -mediated disease. In this study, we compared the transcriptome in skin biopsies from pediatric and young adult (aged <25 years) patients with sclerotic -type cutaneous chronic graft -versus -host disease (n = 7) with that in demographically matched healthy controls (n = 8) and patients with atopic dermatitis (n = 10) using RNA sequencing with RT-PCR and immunohistochemistry validation. Differential expression was defined as fold change > 1.5 and false discovery rate < 0.05. Sclerotic -type cutaneous chronic graft -versus -host disease exhibited strong and significant T helper (Th)1 skewing through key related cytokines and chemokines (CXCL9/10/11, IFNG/IFN-g, STAT1/signal transducer and activator of transcription 1). Several markers related to the TSLP-OX40 axis were significantly upregulated relative to those in both controls and lesional atopic dermatitis, including TNFSF4/OX40L, TSLP, and IL33, as well as fibroinflammatory signatures characterized in a prior study in systemic sclerosis. Gene set variation analysis reflected marker -level findings, showing the greatest enrichment of the Th1 and fibroinflammatory pathways, with no global activation identified in Th2 or Th17/Th22. Cell -type deconvolution revealed a significant representation of macrophages and vascular endothelial cells. Sclerotic -type cutaneous chronic graft -versus -host disease in young patients may therefore be characterized by strong Th1-related upregulation with a unique TSLP-OX40 signature, suggesting new therapeutic avenues for this devastating disease.

The literature on vitiligo is extremely heterogeneous with limited standardization in vitiligo disease severity reporting. The IDEOM Vitiligo Workgroup initiated a project to develop an improved understanding of clinical reporting of vitiligo severity and extent. A medical librarian-developed literature review identified 51 English-language clinical trials treating vitiligo topically using topical corticosteroids or topical tacrolimus that included adult and paediatric patients, with 10 or more patients. Grading of studies was performed using SORT criteria. The grading systems used included three studies reporting overall improvement: one as absolute Improvement vs. did not improve (B2), one as marked improvement (C3) and one as improvement, no change or worse (A2). Severity was reported as straight body surface area scoring (BSA) in five trials with grades of (A1, A1, B1, C2 and C3), and two via photography and mapping (A1, A2). Many studies report success as meeting the metric of 50% improvement or clearance (C3). Kanwar et al. further subdivides this into 50% to <75% or >75% (C3). Three studies add the complete clearance metric (A1, A1, B1), with some adding worsening categories. Most studies create a grading system including G0- no change (A1, A1, A2, A2< B2, B2, B3, B3), G1- 1–25%, G2- 26–50%, G3- 51–75%, G4- 75–99% (one study by Lepe et al. reports this as >75%) and G5- 100% re-pigmentation [Bae et al. (C2) report these numbers as 0, 1–24%, 25–49%, 50–74%, 75–99%, 100%]. Variations in response include the meta-analysis by Lee et al. reporting >25%, >50% and >75% re-pigmentation and the combination of G0 and G1 as < or = 25% re-pigmentation, considered a failure (A1, A1, A2. B2, C3, C3, C3). Koopmans-VanDorp (B2) and Kandil (B2) break down re-pigmentation as none, beginning (<25%), good (25–90%) or complete or almost complete (90–100%) or spontaneous re-pigmentation. Success can be defined as G3–G5 or G4–G5. Kathuria classifies <50% as failure (A1). Hu and Farajzadeh (A2) classify >50% as success, Bae (C2) classifies >75% and Kumari (B2) as >90% improvement. Majid further subdivides the score into six subdivisions (A1). Abd-Elazim (A2) reports VASI and Baldo reports DLQI. Sach (C1) and Batchelor (A1) use the vitiligo noticeability scale Baldo, with target patches reported as ‘a lot less noticeable’ or ‘no longer noticeable’ being successful. Ibrahim (A2) uses Patient-Expressed Satisfaction, reporting ‘not satisfied’, ‘slightly satisfied’, ‘satisfied’ or ‘very satisfied’. Batchelor (A1) report percentage re-pigmentation, onset and maintenance of response, treatment burden, QoL, side effects and cost-effectiveness. Body surface area total and quartiles of improvement are the most commonly reported metrics in studies with high-level evidence. The addition of categories of no improvement, complete clearance, spontaneous improvement and worsening appears to enhance information collection. Collection of data using photographs or computer-assisted BSA monitoring enhances data reproducibility. Using 50%, 75% and 90% as thresholds for success appears to be standardized, with a rarer inclusion of 100%. Validated scores like VASI represent a validated alternative collection method, which can be modified to address the 50%, 75% and 90% thresholds. Quality of life has not per se been correlated to clinical response to topical therapeutics, and current scores including patient expression of satisfaction, vitiligo noticeability and satisfaction are not known to reflect topical response at this time.

ImportanceEvidence-based recommendations for the treatment of vitiligo in pediatric, adolescent, and young adult patients in the US are needed.ObjectiveTo develop evidence- and consensus-based expert recommendations on the diagnosis and treatment of vitiligo in young patients.Evidence ReviewA process was developed to produce consensus recommendations addressing questions regarding pediatric vitiligo. A librarian-conducted literature review was performed using articles that met the inclusion criteria: published in English, containing primary data (including meta-analysis) and pediatric-specific data, and analysis of 6 or more patients. Included articles were graded by the Strength of Recommendation Taxonomy criteria and Oxford Centre for Evidence-based Medicine’s Levels of Evidence and Grades of Recommendation. Research questions were reviewed on May 9, 2022, through a video conference. One month after the conference, participants participated in an online survey documenting their level of agreement with the generated statements, using a 5-point Likert scale.FindingsArticles on topical corticosteroids and/or topical calcineurin inhibitors (n = 50), topical Janus kinase inhibitors (n = 5), pseudocatalase (n = 2), and microdermabrasion (n = 2) met inclusion criteria. Forty-two recommendations were made on the diagnosis of vitiligo and optimal topical therapeutics, with 33 recommendations obtaining a 70% or greater composite agreement and strong agreement. Topical calcineurin inhibitors twice daily, topical corticosteroids with time limitation due to atrophy risk, and topical ruxolitinib, 1.5%, cream—used off-label for patients younger than 12 years and limited to nonsegmental vitiligo—were identified as evidence-based first-line therapies in the management of pediatric and adolescent patients, with specific guidance on age-based data, minimum therapeutic trial of 6 months or greater, prolonged therapy to prevent recurrence, and the positive benefit of coordinated use of UV therapeutic sources.Conclusions and RelevanceEvidence supports the use of topical calcineurin inhibitors, topical corticosteroids, and topical Janus kinase inhibitors as effective therapeutics for vitiligo in pediatric, adolescent, and young adult patients, with specific decisions on choice of agent based on factors such as site location, body surface area, and age.

BACKGROUND:Janus kinase inhibitors (JAKi) have the potential to alter the landscape of atopic dermatitis (AD) management dramatically, owing to promising efficacy results from phase III trials and their rapid onset of action. However, JAKi are not without risk, and their use is not appropriate for all patients with AD, making this a medication class that dermatologists should understand and consider when treating patients with moderate-to-severe AD. OBJECTIVES:To provide a consensus expert opinion statement from the International Eczema Council (IEC) that provides a pragmatic approach to prescribing JAKi, including choosing appropriate patients and dosing, clinical and laboratory monitoring and advice about long-term use. METHODS:An international cohort of authors from the IEC with expertise in JAKi selected topics of interest were placed into authorship groups covering 10 subsections. The groups performed topic-specific literature reviews, consulted up-to-date adverse event (AE) data, referred to product labels and provided analysis and expert opinion. The manuscript guidance and recommendations were reviewed by all authors, as well as the IEC Research Committee. RESULTS:We recommend that JAKi be considered for patients with moderate-to-severe AD seeking the benefits of a rapid reduction in disease burden and itch, oral administration and the potential for flexible dosing. Baseline risk factors should be assessed prior to prescribing JAKi, including increasing age, venous thromboembolisms, malignancy, cardiovascular health, kidney/liver function, pregnancy and lactation, and immunocompetence. Patients being considered for JAKi treatment should be current on vaccinations and we provide a generalized framework for laboratory monitoring, although clinicians should consult individual product labels for recommendations as there are variations among the different JAKi. Patients who achieve disease control should be maintained on the lowest possible dose, as many of the observed AEs occurred in a dose-dependent manner. Future studies are needed in patients with AD to assess the durability and safety of continuous long-term JAKi use, combination medication regimens and the effects of flexible, episodic treatment over time. CONCLUSIONS:The decision to initiate JAKi treatment should be shared between the patient and provider, accounting for AD severity and personal risk-benefit assessment, including consideration of baseline health risk factors, monitoring requirements and treatment costs.