Tape strips detect molecular alterations and cutaneous biomarkers in skin of patients with hidradenitis suppurativa.

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-α pathways were highly correlated between tape strips and biopsies. HS clinical severity was significantly associated with expression of biomarkers (eg tumor necrosis factor-α , 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.

A phase 2a trial of brepocitinib for cicatricial alopecia.

BACKGROUND: Cicatricial alopecias (CA) are chronic, progressive scarring hair-loss conditions. Molecular dysregulation is not fully understood, hindering treatment development. Th1/IFNγ signaling and JAK dysregulation has shown involvement, providing rationale for this phase 2a trial with TYK2/JAK1 inhibitor brepocitinib. METHODS: Randomized, placebo-controlled phase 2a trial spanning 52 weeks. Adults (18≥years of age) with lichen planopilaris, frontal fibrosing alopecia, or central centrifugal cicatricial alopecia diagnosis were randomized 3:1 to brepocitinib 45mg daily or placebo for 24 weeks, after which all patients received brepocitinib for another 24 weeks, with a safety follow up 4 weeks later. Lesional scalp biopsies were collected at baseline, week 24, and week 48. Co-primary endpoints were changes in lesional expression of CCL5, changes in lesional expression of fibrosis-related markers, and safety at week 24. RESULTS: Patients receiving brepocitinib showed significant downregulation in CCL5 expression at week 24 (p=0.004). Enrichment analysis of a subset of fibrosis markers showed trending upregulation in placebo patients (p<0.1). Brepocitinib was well tolerated and improved clinical severity scores. LIMITATIONS: Single-dose regimen, small placebo group. CONCLUSION: Brepocitinib significantly reduces CCL5 expression and was well tolerated at week 24, meeting co-primary endpoints. Brepocitinib reduces inflammatory biomarker expression and improves clinical severity, while maintaining favorable safety profile.

Dupilumab induces hair regrowth in pediatric alopecia areata: a real-world, single-center observational study.

Alopecia areata (AA) is nonscarring hair loss characterized by Th1 and concomitant Th2 skewing, particularly in atopic patients. Despite novel developments for adult AA, safe and effective treatments for pediatric patients remain limited. Dupilumab, with a well-studied safety profile, may have therapeutic potential for atopic pediatric AA. To evaluate the ability of dupilumab to regrow hair in pediatric AA patients. We conducted a single-center, retrospective, observational study to evaluate hair regrowth [using Severity of Alopecia Tool (SALT)] with dupilumab in 20 children with both AD and AA (age range 5-16 years, mean 10.8 years; baseline SALT range 3-100, mean 54.4). Patient demographics, atopic history, IgE and SALT scores were collected at 12wk follow-up visits, up to > 72wks, to evaluate hair regrowth. Spearman correlations with clinical data were performed. Patients showed clinical improvement over the follow-up period (range 24 to > 72wks, mean 67.6wks) with significant mean(± SD) reduction in SALT at 48wks versus baseline [20.4(± 35.1) vs 54.4(± 37.6), respectively; p < 0.01] and continued improvement up to > 72wks [2.2(± 4.9), p < 0.01]. Baseline SALT positively correlated with disease duration (r = 0.54, p < 0.01), and negatively correlated with improvement in SALT at weeks 24, 36, and 48 (|r|≥ 0.65, p < 0.01 for all comparisons). Baseline IgE positively correlated with improvement in SALT at week 36 (r > 0.60, p < 0.05). Dupilumab was well-tolerated, with no new safety concerns. These real-world data support the utility of dupilumab to safely treat pediatric AA patients, corroborating the role of Th2 skewing in children with AA and associated atopy, warranting larger clinical trials.

Sclerotic-Type Cutaneous Chronic Graft-Versus-Host Disease Exhibits Activation of T Helper 1 and OX40 Cytokines.

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-γ, 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.