ContextPretibial myxedema (PTM) is a refractory autoimmune dermopathy associated with Graves’ disease. Although metabolic dysregulation has been recognized in thyroid-associated disorders, the metabolic profile and its functional role in PTM remain unclear.ObjectiveTo characterize the metabolic landscape of PTM lesions and explore the contribution of fatty acids to fibroblast dysfunction and inflammation.MethodsWe performed untargeted metabolomic profiling of PTM skin lesions and healthy controls using LC-MS and GC-MS, integrated with spatial metabolomics to localize metabolic changes. Functional assays were conducted by stimulating human foreskin fibroblasts (HFFs) with palmitic acid (PA) and oleic acid (OA), followed by RNA sequencing, cytokine assays, and immunohistochemistry.ResultsPTM lesions exhibited substantial metabolic dysregulation, including accumulation of fatty acids and elevated tricarboxylic acid cycle intermediates. Spatial metabolomics confirmed pronounced lipid deposition in the dermis, the primary site of PTM pathology. RNA-seq of fibroblasts stimulated with PA and OA revealed enrichment of inflammatory pathways, including IL-17 and NF-κB signaling, and marked upregulation of IL-8 (CXCL8). Fatty acid stimulation induced robust IL-8 secretion, consistent with increased IL-8 expression in PTM lesions. Moreover, PA promoted α-SMA expression in fibroblasts, suggesting induction of myofibroblast differentiation.ConclusionsOur findings demonstrate that dermal fatty acid accumulation in PTM may contribute to fibroblast-mediated inflammation and fibrosis. This study provides novel insights into the metabolic-immunologic interface underlying PTM pathogenesis.

Background and Objective:Psychological stress and poor sleep quality are prevalent among urban adults and have been proposed to be associated with skin, scalp, and hair health through neuro-endocrine-immune pathways. However, evidence from large real-world cohorts under chronic, naturalistic conditions remains limited. The objective of this study was to characterize the associations of sleep quality and perceived stress with a range of dermatological outcomes under real-life conditions, including self-perceived concerns, expert-scored clinical signs, and objective instrumental measurement in healthy women. Methods:This cross-sectional observational study enrolled 1,017 healthy women aged 18-40 years in Shanghai, China. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and perceived stress with the Perceived Stress Scale (PSS-10). Dermatological outcomes were assessed through four modalities: validated psychometric questionnaires, self-perception surveys, expert clinical scoring, and objective instrumental measurements. Associations were investigated using generalized linear models (GLMs) adjusted for age and season (regression analytical sample: n=994 after exclusion of participants with BMI>30), with Benjamini-Hochberg correction for multiple comparisons. Results:Poor sleep quality (PSQI score ≥ 6) was identified in 60% of participants and elevated perceived stress (PSS-10 score ≥ 14) in 50%. Both factors were significantly associated with lower wellbeing, happiness, and higher fatigue scores. Poor sleep quality was associated with increased likelihood of reporting sensitive scalp (OR = 1.17 [95% CI:1.08-1.27], Adj-P = 0.004), skin fatigue appearance (OR = 1.11 [95% CI:1.06-1.17], Adj-P = 0.003), and self-perceived skin yellowness (OR = 1.10 [95% CI:1.04-1.15], Adj-P = 0.013), as well as a modest but significant increase in clinically graded dark eye circle severity (β = 0.028 [95% CI: 0.012-0.044], Adj-P = 0.014). Elevated perceived stress was associated with self-reported hair loss (OR = 1.04 [95% CI:1.01-1.06], Adj-P = 0.034) and itchy scalp (OR = 1.07 [95% CI:1.03-1.11], Adj-P = 0.035). In post-hoc exploratory age-stratified analyses, poor sleep was associated with higher acne severity exclusively in participants aged 18-25 years (p = 0.016). Conclusion:In this cross-sectional study of healthy urban women in Shanghai, poor sleep quality and elevated perceived stress were each associated with a range of self-perceived dermatological concerns and clinical signs. These findings are cross-sectional in nature and require longitudinal investigation to establish temporal directionality. The observed associations are consistent with the skin-brain axis hypothesis and support the relevance of sleep and stress assessment in dermatological research and practice.

BACKGROUND:Pemphigus is an autoimmune bullous disease primarily driven by anti-desmoglein (Dsg) autoantibodies. However, the disease pathogenesis beyond anti-Dsg autoantibodies remains unclear. OBJECTIVE:We sought to explore the pathogenic role of IFN-γ in pemphigus and to evaluate the therapeutic potential of targeting the IFN-γ-JAK pathway. METHODS:The pathogenetic effects of IFN-γ signaling in pemphigus were investigated by integrated single cell analysis, ex vivo human skin explants, and cocultures. Therapeutic efficacy of the JAK1 inhibitor abrocitinib was evaluated in a murine pemphigus model and in refractory pemphigus patients. RESULTS:IFN-γ-expressing T cells largely infiltrate pemphigus lesions and drive IFN-γ-dominant inflammation. IFN-γ-activated keratinocytes secrete C-X-C motif chemokines CXCL9/10/11 to recruit more CD8+ T cells. Notably, IFN-γ primes keratinocytes to become more susceptible to CD8+ T-cell-mediated cytotoxicity. Moreover, IFN-γ synergizes with anti-Dsg autoantibodies to induce keratinocyte dissociation through p38 activation and augments anti-Dsg autoantibody production. Oral JAK1 inhibitor abrocitinib effectively attenuated IFN-γ-dominant inflammation and improved skin lesions in a murine pemphigus model and in patients with refractory disease. CONCLUSION:A self-amplifying inflammatory circuit between IFN-γ+CD8+ T cells and keratinocytes acts as a key driver of pemphigus pathogenesis and provides a mechanistic rationale for targeting the IFN-γ-JAK pathway in its treatment.

This large-scale prospective study establishes the baseline homeostasis model assessment of insulin resistance (HOMA-IR) as a superior independent predictor of biologic response compared with triglyceride glucose-body mass index, resolving recent controversies regarding metabolic metrics in psoriasis. We identify an inflammation-associated metabolic phenotype characterized by compensatory hyperinsulinaemia and demonstrate that effective biologic therapy drives metabolic recalibration, supporting HOMA-IR profiling as a pragmatic tool for personalized management.

BACKGROUND:Prompt identification of rapidly progressive interstitial lung disease (RP-ILD) in dermatomyositis (DM) is crucial; however, reliable biomarkers remain lacking. OBJECTIVES:To evaluate the association between serum amyloid A (SAA) and RP-ILD in DM. METHODS:SAA levels were quantified via scattering turbidimetry. Spearman's correlation analyzed associations with serologic markers. Diagnostic thresholds were determined through ROC curve analysis, and independent markers associated with mortality were identified using Cox proportional hazards models. RESULTS:SAA levels were significantly higher in DM patients than in healthy controls (37.71 ± 6.93 vs 5.42 ± 0.30 mg/L; P < 0.0001) and were markedly elevated in those with RP-ILD (103.60 ± 18.02 mg/L). Elevated SAA was independently linked to RP-ILD. The combination of SAA and anti-MDA5 antibody provided the highest diagnostic accuracy (AUC = 0.950; 95% CI: 0.906-0.995). Patients with SAA >21.98 mg/L had significantly worse survival (P < 0.0001). SAA >21.98 mg/L independently implied mortality in multivariable analysis (HR = 14.12; 95% CI: 1.16-171.33; P = 0.038). LIMITATIONS:This was a retrospective, single-center cohort with a modest sample size. CONCLUSION:Elevated SAA is associated with increased frequency of RP-ILD and mortality. Combining SAA with anti-MDA5 antibody optimizes risk stratification and concurrent disease severity evaluation.

While there have been reports on the combined use of rituximab (RTX) and intravenous immunoglobulin (IVIg) for treating refractory pemphigus, there is a lack of extensive research affirming the value of adding IVIg to the current RTX regimen. In this retrospective cohort study of 76 patients with pemphigus treated with RTX and systemic corticosteroids, RTX + IVIg resulted in similar clinical efficacy, but with a potential reduction in risk of pneumonia. This suggests that IVIg might be a valuable adjuvant for RTX to be considered in certain cases of pemphigus, more to improve safety profile than to ameliorate clinical outcomes.

To our knowledge, this report describes the first documented case of PLEC-nEDD (formerly epidermolysis bullosa simplex-Ogna) in a Chinese patient. The case was characterized by an unusually late onset in the fourth decade of life and generalized skin lesions. Whole-exome sequencing identified the canonical PLEC c.5917C>T (p.Arg1973Trp) mutation, confirmed by Sanger sequencing, with immunofluorescence mapping revealing discontinuous plectin expression along the dermoepidermal junction. This case expands the phenotypic spectrum of PLEC-nEDD and underscores the importance of considering genetic testing in adults presenting with unexplained blistering disorders, even in the absence of family history.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug-induced hypersensitivity reaction often requiring prolonged corticosteroid (CS) treatment, yet tapering is challenging due to the risk of relapse. In this retrospective single-centre case series, we evaluated the effectiveness and safety of selective Janus kinase (JAK) inhibitors in facilitating CS tapering in patients with moderate-to-severe refractory DRESS and in ameliorating pruritus. Six patients (median age 35 years, range 9-70, five female) received baricitinib or abrocitinib with CS between July 2023 and June 2024. All achieved rapid clinical improvement, with generalized lesion resolution and a reduction in pruritus by > 3 points on the Worst Itch Numerical Rating Scale. Successful initial CS tapering occurred within 7-12 days. Four patients discontinued CS completely within 28-62 days, while two continued with low-dose CS due to primary autoimmune disease. Serum cytokines, particularly interleukin-5, decreased markedly following JAK inhibition. No severe adverse events occurred, including in patients with pancytopenia or hepatic dysfunction. JAK inhibitors appear to be effective and well-tolerated for promoting CS tapering in patients with refractory DRESS. Larger, controlled studies would be useful to confirm these findings.

BACKGROUND:The effectiveness of botulinum toxin A (BoNTA) in the treatment of Hailey-Hailey disease (HHD) has shown heterogeneity in recent studies. However, there is currently no research investigating the underlying mechanism behind the variability in patient response. OBJECTIVES:To identify potential biomarkers and elucidate the underlying mechanisms of the heterogeneity in efficacy of BoNTA treatment for HHD. METHODS:Twelve patients with HHD were administered standardized injections of BoNTA, with the primary endpoint being ≥ 75% improvement in Improvement Global Assessment(IGA) from baseline to month 6. A comprehensive multiomics approach, including whole-exome sequencing (WES), bulk RNA sequencing (RNAseq), single-cell RNAseq and immunohistochemistry (IHC) was used to investigate potential mechanisms underlying the heterogeneity of therapeutic efficacy. Additionally, an in vitro experiment was conducted to validate cellular responses to BoNTA, providing further insights into the biologic mechanisms involved. RESULTS:Ten of 12 patients (83%) achieved the primary endpoint with BoNTA treatment, while 2 patients (17%) showed no response at month 6. WES did not find a significant association between the type of mutation in ATP2C1 in patients with HHD and their response to BoNTA treatment. Transcriptomic analysis and IHC of baseline skin lesions revealed an overactivated store-operated calcium entry (SOCE) pathway involving genes such as ITPKC and ORAI1 in keratinocytes, accompanied by activation of the NOD-like-receptor containing a pyrin domain 1 (NLRP1)/interleukin (IL)-18/IL-1β inflammatory cascade in BoNTA-resistant patients. We confirmed that loss of ATP2C1 triggered inflammatory responses in HaCaT cells in vitro. BoNTA demonstrated potential anti-inflammatory effects as a calcium antagonist, while upregulation of ORAI1/SOCE contributed to a diminished response to BoNTA. CONCLUSIONS:BoNTA treatment in HHD exhibits interindividual variability. Although the type of ATP2C1 mutation has no direct association with patients' response, combined transcriptomic analysis and IHC indicate that upregulation of the ORAI1/SOCE pathway may contribute to treatment resistance and serve as biomarkers to predict patient responsiveness.

Pemphigus and bullous pemphigoid (BP) are both autoimmune bullous diseases (AIBD), but their clinical features and treatment strategies are different. Pemphigus is characterized by intraepidermal blisters mediated by antibodies against desmosomes, while BP is characterized by subepidermal blisters mediated by antibodies against epidermal-dermal junctions. Traditional therapy for pemphigus and BP is mainly composed of systemic glucocorticoid and immunosuppressant. Rituximab targeting CD20 on B lymphocytes has been approved for first-line treatment for pemphigus and significantly improved clinical outcomes. Type 2 inflammation also plays a key role in the pathogenesis of BP. Biologic agents such as dupilumab targeting the interleukin-4 receptor have demonstrated promising efficacy in treating refractory BP patients. Additionally, various immune-targeted therapies have been investigated for their efficacy and safety in managing pemphigus and BP. This review summarizes recent advances and clinical applications of immunotherapy in these two major AIBDs.