An inverse correlation between serum vitamin D levels and hidradenitis suppurativa (HS) severity is frequently reported, yet the causal nature and direction of this association remain unresolved. A systematic review was conducted following PRISMA guidelines, identifying 12 relevant studies. A two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW) method was subsequently performed using genetic instruments for vitamin D from the UK Biobank (n = 417,580) and HS summary statistics from FinnGen (n = 1420). The systematic review confirmed a high prevalence of vitamin D deficiency (<20 ng mL-1) among HS patients (weighted mean 17.90 ng mL-1) and identified inverse correlations between vitamin D levels and disease severity, active lesions, and C-reactive protein (CRP), while supplementation improved clinical outcomes. A null MR estimate consistent with the absence of a detectable average linear causal effect of lifelong genetically predicted 25(OH)D levels on HS risk in the analyzed population was observed. Sensitivity analyses yielded consistent null results with no significant horizontal pleiotropy. The results suggest that hypovitaminosis D is likely a marker of the systemic inflammatory state rather than a direct causative factor. The observed clinical benefits of vitamin D supplementation warrant further interventional studies to define its potential therapeutic role.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with significant diagnostic delays and impact on quality of life. Current guidelines prioritize antibiotics as first-line therapy, but experts increasingly recognize the need for earlier targeted therapy intervention to prevent irreversible scarring and tunnel formation. To establish consensus on clinical scenarios during the 14th European Hidradenitis Suppurativa Foundation Conference in February 2025, 54 HS experts participated in a Delphi consensus, using a Likert scale (−5 to +5) to vote on 16 statements concerning first-line therapy criteria with biologics and/or small molecules for eligible patients. Seventy-eight HS experts were invited, and 54 participated via hybrid onsite and electronic voting. Experts rated 16 pre-defined statements regarding first-line use of biologics and/or small molecules for HS using a Likert scale (−5 to +5). Agreement metrics were stratified as majority agreement (≥70%, median 3.0–3.5), consensus (≥75%, median 3.5–4.5), and strong consensus (≥90%, median ≥4.5). Statements were subsequently ranked for clinical relevance. Strong consensus was reached for patients contraindicated for antibiotics, rapid disease progressors and those with severe disease. Consensus also supported upgrading patients with moderate disease (IHS4 ≥ 4), frequent flares (≥3 in 12 weeks), multiple affected areas and specific phenotypes including anogenital involvement. Strong consensus emerged for syndromic HS and for patients with inflammatory comorbidities such as inflammatory bowel disease and arthritis. Paediatric patients with a positive family history and moderate disease were also considered candidates for first-line biologics or small molecules. This consensus provides evidence-based criteria for upgrading HS patients to first-line biologic therapy, reflecting expert practices across Europe aimed at preventing irreversible disease progression. The results support a ‘hit hard and early’ approach to minimize scarring and tunnel formation, although prospective studies are still needed to validate these expert-driven recommendations.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with significant diagnostic delays and impact on quality of life. Current guidelines prioritize antibiotics as first-line therapy, but experts increasingly recognize the need for earlier targeted therapy intervention to prevent irreversible scarring and tunnel formation. To establish consensus on clinical scenarios during the 14th European Hidradenitis Suppurativa Foundation Conference in February 2025, 54 HS experts participated in a Delphi consensus, using a Likert scale (-5 to +5) to vote on 16 statements concerning first-line therapy criteria with biologics and/or small molecules for eligible patients. Seventy-eight HS experts were invited, and 54 participated via hybrid onsite and electronic voting. Experts rated 16 pre-defined statements regarding first-line use of biologics and/or small molecules for HS using a Likert scale (-5 to +5). Agreement metrics were stratified as majority agreement (≥70%, median 3.0-3.5), consensus (≥75%, median 3.5-4.5), and strong consensus (≥90%, median ≥4.5). Statements were subsequently ranked for clinical relevance. Strong consensus was reached for patients contraindicated for antibiotics, rapid disease progressors and those with severe disease. Consensus also supported upgrading patients with moderate disease (IHS4 ≥ 4), frequent flares (≥3 in 12 weeks), multiple affected areas and specific phenotypes including anogenital involvement. Strong consensus emerged for syndromic HS and for patients with inflammatory comorbidities such as inflammatory bowel disease and arthritis. Paediatric patients with a positive family history and moderate disease were also considered candidates for first-line biologics or small molecules. This consensus provides evidence-based criteria for upgrading HS patients to first-line biologic therapy, reflecting expert practices across Europe aimed at preventing irreversible disease progression. The results support a 'hit hard and early' approach to minimize scarring and tunnel formation, although prospective studies are still needed to validate these expert-driven recommendations.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease primarily affecting intertriginous regions, and emerging evidence suggests that systemic autoinflammation (“metainflammation”) contributes to its clinical heterogeneity. We report two cases of HS in patients of Moroccan origin with overlapping autoinflammatory features. The first case involves a 42-year-old man with HS since 2012, Hurley stage II, treated with adalimumab since 2019 and achieving an IHS4-70, who developed Behçet’s disease-like systemic manifestations in 2025; genetic testing revealed a heterozygous MEFV variant, and HLA typing included A02, A68, B15, B45, C02, and C06. The second case involves a 40-year-old man with HS since age 22, Hurley stage II, with persistent oral aphthosis; he achieved IHS4-70 on secukinumab in 2025 and responded to adjunctive colchicine for mucosal lesions, with HLA typing showing B18, B51, C07, and C15. These cases illustrate the interplay between HLA subtypes, autoinflammatory gene variants, and systemic inflammation in HS, highlighting a potential autoinflammatory HS subtype. Population-specific genetic factors, particularly in North African populations, may influence disease severity, systemic manifestations, and therapeutic response. Taken together, these observations support the concept that HS, in certain genetically predisposed individuals, may represent a systemic autoinflammatory/metainflammatory disease, underscoring the relevance of personalized therapeutic strategies.

BACKGROUND:The identification of actionable secondary findings (SFs) through clinical exome sequencing has become increasingly relevant with the integration of genomics into routine healthcare. The frequency and spectrum of these findings vary across populations. METHODS:We analyzed exome sequencing data from 350 unrelated Maltese individuals, comprising 320 pseudonymised controls and 30 participants from the pilot sequencing phase of the national biobank DwarnaBio, to assess the prevalence of pathogenic or likely pathogenic (P/LP) variants in the ACMG SF v3.2 gene list. All samples underwent uniform sequencing, rigorous quality control, and variant interpretation according to ACMG/AMP guidelines. RESULTS:Actionable P/LP variants were identified in 12 individuals (3.4%) across autosomal dominant genes, predominantly associated with inherited cardiac conditions and cancer predisposition syndromes. These findings highlight the importance of including underrepresented populations in genomic research and emphasize the need to establish provisions for the return of clinically actionable results to biobank participants, supported by access to genetic counseling. CONCLUSION:Our results advocate for the integration of population-specific genomic data into national precision medicine frameworks, particularly for small or isolated populations where tailored approaches to variant curation and clinical translation are required. This study provides the first baseline estimate of actionable SFs in the Maltese population and offers insights for advancing precision medicine frameworks.

INTRODUCTION:The coexistence of multiple immune-mediated inflammatory diseases (IMIDs) in a single patient represents a growing clinical challenge, yet comprehensive data on patients with more than two IMIDs remain limited. The aim of this study was to characterize the clinical profiles, therapeutic responses, and quality of life outcomes in patients presenting with complex IMID associations involving cutaneous manifestations. METHODS:We established the CIMID-Skin registry, a prospective observational study enrolling adult patients with multiple IMIDs including at least one dermatological condition. Patients were stratified into control (2 IMIDs) and complex (>2 IMIDs) groups. Clinical data validated severity scores, and patient-reported outcomes were systematically collected. RESULTS:The cohort (n = 54) was predominantly female (77.8%), with a mean age of 45.4 years and overweight range body mass index (27.4 kg/m2). Patients frequently presented with multiple IMIDs, with 59.3% having ≥3 conditions. The most common diseases were psoriasis and hidradenitis suppurativa (42.6% each) and psoriatic arthritis (40.7%). Paradoxical reactions were observed in a significant proportion of patients, with paradoxical psoriasis reported in 24.1% of the cohort. Quality of life was markedly impaired, with 65.2% showing moderate-to-extreme DLQI impact, and 24.1% reaching the WHO-5 depression threshold. CONCLUSIONS:Patients with complex IMID associations demonstrate distinct clinical patterns and therapeutic challenges. The high prevalence of paradoxical reactions and the specific clustering of certain IMIDs suggest shared pathophysiological mechanisms that warrant further investigation.

BACKGROUND:Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized primarily by dysregulated innate immunity and abnormal keratinocyte differentiation. Over the past two decades, the treatment paradigm has evolved from antibiotics to targeted biologics, such as anti-TNF-α and anti-IL-17A/A-F inhibitors. However, antibiotic therapy remains a prerequisite for biologic initiation despite a lack of comparative studies evaluating their efficacy. OBJECTIVES:This study aimed to assess current prescription patterns for systemic HS therapies among European HS specialists, evaluate unmet needs in antibiotic and biologic use and explore expert opinions on criteria for biologic upgrade as a first-line therapy. METHODS:A structured questionnaire was distributed to 55 HS specialists, the majority of whom were members of the European Hidradenitis Suppurativa Foundation (EHSF), comprising HS experts and future opinion leaders. Responses underwent statistical analysis to assess trends in antibiotic versus biologic prescription, treatment efficacy and potential improvements in therapeutic decision-making. RESULTS:A total of 43 participants (76.6% of invited experts, 80% of invited opinion leaders) responded. While 95% adhered to licensing regulations mandating 10-12 weeks of antibiotics before biologics, 81% acknowledged prescribing antibiotics despite anticipating inadequate responses. More than half reported patient-reported flares during antibiotic treatment. The majority (77%) supported earlier biologic initiation in cases of persistent flares, and 79% favoured short-term biologic therapy over antibiotics for early-stage HS. Participants identified specific phenotypic attributes such as rapidly progressing disease, extensive involvement and comorbidities as factors warranting earlier biologic intervention. CONCLUSIONS:Current treatment practice may delay optimal intervention, potentially leading to missed therapeutic windows. A significant proportion of respondents expressed a preference for earlier biologic intervention, especially in cases of severe disease or frequent flares. The findings underscore the need for a consensus statement defining upgrade criteria for biologics as a first-line therapy, potentially improving patient outcomes and reducing healthcare burdens.

Hidradenitis suppurativa (HS) is a chronic, relapsing inflammatory dermatosis of the pilosebaceous unit characterized by nodules, abscesses, and dermal tunnels. Recent transcriptomic studies have implicated dysregulation of innate and adaptive immune responses, epidermal barrier dysfunction, and systemic metabolic alterations. This review synthesizes findings from 16 studies investigating the HS transcriptome using bulk and single-cell RNA sequencing. Differential gene expression analyses revealed extensive upregulation of inflammatory cytokines and chemokines, particularly in lesional and perilesional skin. These changes were also mirrored in non-lesional skin, suggesting diffuse immune dysregulation beyond visibly affected areas. Downregulated pathways include those involved in lipid metabolism, muscle contraction, and neuronal signaling, potentially linking HS to obesity, metabolic syndrome, and neuropsychiatric comorbidities. Single-cell transcriptomics confirmed the enrichment of keratinocytes and immune cells (B cells, plasma cells, M1 macrophages, and T cells) with proinflammatory profiles in HS lesions. Keratinocyte dysfunction further implicated a compromised epidermal barrier in disease pathogenesis. While transcriptomic studies have advanced mechanistic understanding and highlighted therapeutic targets—such as the IL-1β–TH17 axis and B cell signaling pathways—methodological heterogeneity limits cross-study comparisons. Integration of multi-omics data and standardized phenotyping will be essential to identify robust biomarkers, stratify HS subtypes, and guide personalized therapeutic approaches.

Importance Variation in nicastrin ( NCSTN ) is associated with a monogenic subtype of hidradenitis suppurativa. Dysregulation of humoral immunity has been suggested as a potential mechanistic link between NCSTN variation and hidradenitis suppurativa. There is a paucity of biomarkers that can predict disease-associated variation. Objective To investigate whether serum immunoglobulin levels, as a surrogate marker of humoral immunity, can identify individuals with hidradenitis suppurativa who have a specific disease-associated NCSTN variant. Design, Setting, and Participants Maltese individuals with hidradenitis suppurativa genotyped for a disease-associated NCSTN in-frame deletion prevalent in the local patient cohort were invited to participate in this cross-sectional study from January to July 2023. Participation was restricted to adult individuals with hidradenitis suppurativa without known or suspected pathologies that would be associated with serum immunoglobulin levels. Data were analyzed between October 2023 and December 2023. Exposure Serum immunoglobulin G levels and other hematological paraments were analyzed. Main Outcome and Measure Main outcomes were the associations between serum immunoglobulin levels and an underlying NCSTN variation in individuals with hidradenitis suppurativa. Results A total of 125 individuals (64 female individuals [51.2%]) with hidradenitis suppurativa of Maltese ethnicity were recruited in the study, of whom 17 (13.6%) who were from 7 genealogically unrelated families were heterozygous for the disease-associated NCSTN variant. Deletion carriers had a higher serum immunoglobulin G level (1370 mg/dL vs 1140 mg/dL [to convert to g/L, multiply by 0.01]; P < .001). The association between NCSTN variation and elevated immunoglobulin G levels retained significance despite adjusting for multiple confounders, including markers of disease severity, age of recruitment, age of disease onset, treatment with adalimumab, and liver transaminase levels. Serum immunoglobulin G demonstrated a strong discriminatory capacity in identifying patients who were heterozygous for the NCSTN variant. Conclusion and Relevance The results of this cross-sectional study suggest an altered humoral immune state in patients harboring a specific NCSTN variant and support the role of serum immunoglobulin G levels as a potential predictive biomarker of monogenic hidradenitis suppurativa. This may aid in identifying and prioritizing individuals with monogenic hidradenitis suppurativa.

Epidermal cysts, commonly seen in everyday practice, classically present with a readily identifiable central punctum. However, this is lacking in some patients, making diagnosis more difficult. We describe how to apply pressure between index finger and thumb to the cyst, thus revealing the punctum and enabling a definitive diagnosis.

INTRODUCTION:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common cause of chronic liver disease. Patients suffering from psoriasis are at an increased risk of developing MASLD. Psoriasis and MASLD share a pro-inflammatory cytokine milieu; however, it is still unclear whether these conditions are related through shared metainflammatory processes or shared comorbidities such as obesity, diabetes, insulin resistance, and metabolic syndrome. The aim of our study was to better characterize the anthropometric and metabolic profile of psoriatic patients with MASLD. METHODS:We conducted a prospective, single-center, cross-sectional study between June 2014 and August 2017. Recruitment was restricted to adult patients with psoriasis. Blood analysis, liver ultrasonography, and a FibroScan were performed. Blood investigations, baseline anthropometric measurements, and components of fatty liver disease (hepatic ultrasound, FibroScan) were assessed. RESULTS:A total of 100 patients were recruited, of which, 43% (65.1% men, n = 28) were diagnosed with MASLD. The mean BMI was significantly higher in MASLD than in non-MASLD (27.7 kg/m2 vs. 30.1 kg/m2, p =< 0.001). The mean waist circumference in MASLD patients was significantly higher than in non-MASLD patients (105.6 cm vs. 97.2 cm, p = 0.005). There was no significant difference between the mean age of both patient groups (50.4 vs. 47.3 years, p = 0.26). Psoriatic arthritis was more prevalent in MASLD than in the non-MASLD group (14.3% vs. 1.8%, p = 0.004). Biochemical analysis revealed significantly higher C-peptide level in patients with MASLD compared with patients without MASLD (2.5 vs. 1.6 ng/mL, p = 0.036). Moreover, MASLD patients were found to have a lower HDL level and higher glycemia, triglyceridemia, cholesterol, and LDL levels than non-MASLD patients. A total of 16.3% of patients with MASLD had fibrosis stage ranging from F2 to F4 based on liver stiffness measurement compared with only 10.6% of patients without MASLD. DISCUSSION:We identified parameters which were more prevalent in patients with psoriasis having MASLD, specifically a high BMI, elevated triglyceride levels, decreased HDL levels, and an elevated level of C-peptide. Patients with psoriasis and MASLD were more likely to suffer from comorbid psoriatic arthritis, despite having similar psoriasis disease severity as measured by PASI. CONCLUSION:This study highlights the importance of screening patients with psoriasis for MASLD to prevent the progression to liver fibrosis.

Hidradenitis suppurativa is a chronic, inflammatory condition of the pilosebaceous unit in which patients manifest multiple, painful cutaneous nodules, abscesses and tunnels. These lesions are described to affect the intertriginous zones, however, the condition exhibits significant phenotypic variability. Such variability is influenced by the patients lifestyle, genetic predisposition and sex. In this cross-sectional study, we investigate sex differences in patterns of hidradenitis suppurativa skin involvement, specifically at site of first involvement and most bothersome cutaneous site of involvement.

Hereditary Haemorrhagic Telangiectasia (HHT) is a rare autosomal dominant genodermatosis characterised by cutaneous and visceral telangiectasia, recurrent epistaxis, and Arterio-Venous Malformations (AVMs). In this manuscript, we describe two novel ENG variants in Maltese-Caucasian patients presenting with a variable inter- and intrafamilial clinical phenotypes. This report highlights the importance of diagnostic suspicion of HHT in the presence of cutaneous and/or mucosal telangiectasia and/or AVMs.

The data that support the findings of this study are available in GnomAD at https://gnomad.broadinstitute.org/. These data were derived from the following resources available in the public domain: PubMed, https://gnomad.broadinstitute.org/. Table S1: Summary of NOD2 variants identified in patients with hidradenitis suppurativa. Variant classification was interpreted using Varsome6 and Franklin (https://franklin.genoox.com). The impact of coding variants on protein structural conformation, stability and flexibility was predicted using DynaMut2,7 and Missense3D8 using the Alpha Fold Predicted Structure9 (accession code Q8K3Z0). Tolerance to variation was assessed using the MetaDome webserver.4 Further in silico prediction was carried out using MetaRNN, a recurrent neural network based ensemble prediction score, which incorporates 16 functional prediction scores (including SIFT), 8 conservation scores and allele frequency information. ACMG, American College of Medical Genetics; IBD, inflammatory bowel disease; PASH, pyoderma gangrenosum, acne, and hidradenitis suppurativa. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.