Although the core pathophysiological pathways of chronic urticaria (CU) are increasingly understood, the upstream triggers and factors contributing to disease chronicity remain poorly understood. Emerging evidence suggests that gut microbiota dysbiosis represents a potentially modifiable upstream factor, which has been predominantly investigated in patients with chronic spontaneous urticaria (CSU). Multi-omics and Mendelian randomization studies have provided convergent evidence linking gut dysbiosis to systemic inflammation and mast cell instability. This is characterized primarily by the depletion of short-chain fatty acid (SCFA)-producing taxa (e.g., Faecalibacterium, Roseburia and Bifidobacterium) and the relative enrichment of pro-inflammatory Proteobacteria (particularly Enterobacteriaceae). Mechanistically, these alterations may lower the mast cell activation threshold and promote systemic immune dysregulation through specific metabolic shifts, such as the depletion of SCFAs and unsaturated fatty acids, and the translocation of endotoxins (e.g., lipopolysaccharide) due to compromised intestinal barrier function. In this review, we discuss how the use of Mendelian randomization (MR) and germ-free mouse models can advance the gut-urticaria axis (with a primary focus on CSU) from mere correlation to causation, while highlighting the crucial need to account for clinical confounders. Finally, we evaluate the clinical translational potential and associated challenges of microbiome-targeted interventions (e.g., probiotics, faecal microbiota transplantation) as novel adjuvant therapies.

Autoinflammatory diseases (AIDs) are characterized by abnormal responses of the innate immune system, accompanied by elevations in inflammatory biomarkers, in the absence of a physiologic crisis or infection. Certain monogenic AIDs may present with acneiform or hidradenitis suppurativa-like cutaneous manifestations. In contrast, acne vulgaris, plaque psoriasis and hidradenitis suppurativa are complex, multifactorial inflammatory dermatoses situated along an autoinflammation-associated immunologic spectrum, involving both innate and adaptive immune pathways. There is a growing sphere of research dedicated to exploring dietary patterns as modifiable factors associated with inflammatory disease activity. The Mediterranean diet (MD)-which includes a high consumption of vegetables, whole grains, legumes, fruits, nuts, seeds, fish, wine and extra-virgin olive oil (EVOO)-has gained attention for its potential to modulate pathogenic inflammatory mechanisms. In this review, we summarize the current evidence examining associations between MD adherence and three autoinflammation-associated skin conditions: acne vulgaris, psoriasis and hidradenitis suppurativa. We highlight shared and disease-specific inflammatory pathways while emphasizing the predominance of observational data and the need for further interventional studies to clarify clinical implications.

Genetic studies mutations (IL36RN, CARD14 and AP1S3) account for only 28.6% of generalised pustular psoriasis (GPP) leaving much of its pathogenesis remained to be elucidated. Emerging evidence suggests Th17-mediated inflammation, potentially driven by specific HLA class alleles, may underlie dysregulated IL-36 signalling. This study explores the genotypic and phenotypic features of autochthonous GPP in Sarawak. A cross-sectional case-control study was conducted in Sarawak's three main dermatology centres. GPP patients (n = 43) fulfilling ERASPEN criteria between 1997 and June 2024 were included (23 with GPP alone); 20 with concomitant psoriasis vulgaris. HLA genotyping (HLA-A, -B, -C, -DR) was performed via polymerase chain reaction and sequence-specific oligonucleotide probe hybridisation (PCR-SSO) methods at the Institute of Medical Research (IMR). HLA frequencies were compared to 90 Sarawakian controls from Malaysian Stem Cell Registry. Female predominance was noted (1:4.4). Median age at GPP onset was 29 years. Family history of psoriasis was reported in 30.2%, with 16% females developing GPP during pregnancy. Treatment responses: corticosteroids (100%), ciclosporin (82.1%), acitretin (60%) and methotrexate (50%). While biologics were effective in 10 patients. Common alleles included HLA-DRB1*12:02, HLA-A*11:01 and HLA-C*07:02 while HLA-C06:02 was not observed. HLA-A*02:07 and HLA-B*46:01 were observed only in concomitant psoriasis patients. HLA-A*11:02 was seen in patients with ciclosporin non-response, HLA-A*24:02 in those with poorer responses to acitretin and methotrexate and HLA-B*38:02 in psoriatic arthritis. Lower frequencies of HLA-B*35:05 and HLA-C*04:01 were observed among Dayak patients. The absence of HLA-C*06:02 and variation in allele frequencies in this cohort may reflect population-specific patterns but require validation in larger studies.

Chronic hand eczema (CHE) is associated with substantial functional impairment and reduced quality of life. Delgocitinib, a pan-Janus kinase (JAK) inhibitor, has emerged as a promising topical treatment for CHE. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to assess the efficacy and safety of topical delgocitinib 20-30 mg/g compared with vehicle in patients with CHE. PubMed, Embase, Cochrane Library, ClinicalTrials.gov, EU CTR, and WHO ICTRP were searched up to 15 February 2026. The primary outcome was treatment success at week 16, defined as clear or almost clear skin with a ≥ 2-point improvement on the Investigator's or Physician's Global Assessment (IGA/PGA). Secondary outcomes included treatment success at weeks 4 and 8, changes in Hand Eczema Symptom Diary (HESD) itch and pain scores, and safety outcomes. Relative risks (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were calculated using random-effects models. Three publications reporting four RCTs involving 1154 patients were included, with 752 receiving delgocitinib and 402 receiving vehicle. At week 16, treatment success was significantly higher with delgocitinib (RR 3.17; 95% CI 1.78-5.65; p < 0.01), corresponding to an absolute risk difference of 16.9% and a number needed to treat (NNT) of 6 (95% CI 3-16). Similar results at weeks 4 and 8. Delgocitinib also led to significantly greater improvements in HESD itch and pain scores. No significant differences were found in overall adverse events (AEs), treatment-related AEs, or serious AEs. Discontinuation due to AEs was lower in the delgocitinib group. Delgocitinib 20-30 mg/g demonstrated greater efficacy than vehicle and a favourable safety profile, supporting its use as a topical treatment for CHE.

The human gut microbiota is involved in immune regulation, metabolism, and skin homeostasis. In recent years, gut microbiota alterations have been linked with several inflammatory skin disorders, such as atopic dermatitis (AD), psoriasis, and hidradenitis suppurativa (HS). This systematic review synthesises current evidence on gut microbiota composition and functional alterations in these dermatoses. A comprehensive literature search was conducted in the PubMed database, identifying studies from inception to January 2025. Eligible studies included human observational, interventional, and genetic studies investigating gut microbiota alterations in AD, psoriasis, or HS, using microbiome profiling or genetic causal-inference approaches. Studies lacking control groups or relying on culture-based techniques were excluded. Sixty-two studies were included: 38 on AD, 22 on psoriasis and 5 on HS, with three addressing more than one disease. In AD, most studies focused on paediatric populations, leaving a knowledge gap regarding adult-specific data. Reduced alpha-diversity and decreased abundance of Faecalibacterium prausnitzii, Bifidobacterium spp., and Akkermansia muciniphila were recurrent findings. In psoriasis, in addition to dysbiosis, microbial metabolic pathways were also found to be altered. In HS, data remain limited, but increased Ruminococcus gnavus and reduced alpha-diversity have been reported, mirroring findings in inflammatory bowel diseases. Gut microbiota has been increasingly implicated in skin inflammation. Despite advances in microbiota analysis, significant gaps remain-especially in adult AD and HS. Future research should prioritize standardised methodologies, larger and more diverse cohorts, and leverage emerging tools such as Mendelian randomization and AI-based models to develop precision medicine interventions.

The extracellular matrix (ECM) plays a pivotal role in determining the structure and function of the skin. Collagen and elastin, in particular, are responsible for providing tensile strength and elasticity, respectively. However, imbalances in the components of the extracellular matrix (ECM) during tissue engineering often result in the deterioration of the mechanical properties and physiological relevance of dermal substitutes, in part due to the detrimental effect of ascorbic acid (AA) on elastic fibre biosynthesis. The objective of this study is to investigate the potential of a synthetic elastic protein (SEP) to improve ECM remodelling and to restore the equilibrium between collagen and elastin in reconstructed dermal tissues. Primary fibroblasts monolayers were treated with increasing concentrations of SEP in the presence or not of AA without affecting cytotoxicity. Western blot and immunofluorescence analyses showed that in the presence of AA - which typically reduced elastin synthesis- SEP improved elastic fibre formation without affecting type I collagen assembly. Additionally, 3D dermal substitutes treated with SEP and AA were analysed at the ultrastructural scale showing a specific colocalization of SEP with fibrillin-rich fibrils. Finally, dynamic mechanical analyses were conducted to measure mechanical properties of decellularized ECM. In the presence of SEP, we observed an increase of 46% and 40% of elastic and Young's moduli respectively. By restoring ECM integrity, SEP is emerging as a promising biomimetic tool for the development of 3D skin substitutes. Its application has the potential to improve the physiological relevance and therapeutic value of engineered skin tissues.

Systemic lupus erythematosus (SLE) is a chronic, heterogeneous autoimmune disease influenced by various genetic and environmental factors, and recent advances have established type I interferons (IFN-I) as pivotal drivers. This study comprehensively characterises IFN-I risk gene signatures in SLE. The IFN-I-related genes were obtained from GSE185047, and then Mendelian randomisation analysis using data from the FinnGen cohort (705 SLE cases, 385 509 controls) was utilised as a discovery set to identify IFN-I related risk genes. Single-cell RNA sequencing (scRNA-seq) and external cohorts were used to validate the four key signatures. Univariate and multivariate linear regression models assessed associations between gene expression and clinical parameters. DNA methylation analysis further evaluated epigenetic dysregulation in SLE immune subsets. Thirty-eight IFN-I-related genes were identified, and Mendelian randomisation analysis revealed robust causal associations between four genes (HERC5, IFIT3, IFI44L and IFI6) and SLE risk, with no heterogeneity or pleiotropy. ScRNA-seq demonstrated significant upregulation of these gene signatures in SLE PBMCs and monocytes (except IFIT3 in monocytes), along with altered immune cell proportions-specifically, increased monocytes and decreased T cells. External validation confirmed elevated expression of all four genes in SLE, with high diagnostic accuracy. Clinically, increased expression of these genes correlated with SLEDAI, reduced lymphocyte counts and lower complement C4 levels. Furthermore, DNA hypomethylation of IFI44L was observed across multiple SLE immune subsets, indicating epigenetic dysregulation. This study establishes HERC5, IFIT3, IFI44L and IFI6 as causal IFN-I risk genes in SLE and identifies IFI44L hypomethylation as a key epigenetic driver of IFN-I pathway activation. These findings offer new insights into SLE pathogenesis and highlight potential diagnostic biomarkers and therapeutic targets.