Hidradenitis Suppurativa: A Perspective on Genetic Factors Involved in the Disease.

Hidradenitis Suppurativa (HS) is a chronic inflammatory skin disease of the pilosebaceous unit, clinically consisting of painful nodules, abscesses, and sinus tracts mostly in, but not limited to, intertriginous skin areas. HS can be defined as a complex skin disease with multifactorial etiologies, including-among others-genetic, immunologic, epigenetic, and environmental factors. Based on genetic heterogeneity and complexity, three different forms can be recognized and considered separately as sporadic, familial, and syndromic. To date, several genetic variants associated to disease susceptibility, disease-onset, and/or treatment response have been reported; some of these reside in genes encoding the gamma-secretase subunits whereas others involve autoinflammatory and/or keratinization genes. The aim of this perspective work is to provide an overview of the contribution of several genetic studies encompassing family linkage analyses, target candidate gene studies, and -omic studies in this field. In our viewpoint, we discuss the role of genetics in Hidradenitis suppurativa considering findings based on Sanger sequencing as well as the more recent Next Generation Sequencing (i.e., exome sequencing or RNA Sequencing) with the aim of better understanding the etio-pathogenesis of the disease as well as identifying novel therapeutic strategies.ThisworkwassupportedbyaBiomolecularAnalysesforTailoredMedicineinAcneiNversa (BATMAN)project, funded by ERA PerMed (JTC_2018) to A.V.M and S.C. and by a Starting Grant (SG-2019-12369421) funded by the Italian Ministry of Health to P.M.T

Characterisation of IL‐1 family members in Sweet syndrome highlights the overexpression of IL‐1β and IL‐1R3 as possible therapeutic targets

Sweet syndrome (SS) as a prototypic neutrophilic dermatosis (NDs) shares certain clinical and histologic features with monogenic auto-inflammatory disorders in which interleukin (IL)-1 cytokine family members play an important role. This has led to the proposal that NDs are polygenic auto-inflammatory diseases and has fuelled research to further understand the role of IL-1 family members in the pathogenesis of NDs. The aim of this study was to characterise the expression of the IL-1 family members IL-1β, IL-36γ, IL-33 and IL-1R3 (IL-1RaP) in SS. The expression profile of IL-1β, IL-33, IL-36γ and their common co-receptor IL-1R3 was analysed by immunohistochemistry, in situ hybridisation and double immunofluorescence (IF) in healthy control skin (HC) and lesional skin samples of SS. Marked overexpression of IL-1β in the dermis of SS (p < 0.001), and a non-significant increase in dermal (p = 0.087) and epidermal (p = 0.345) IL-36γ expression compared to HC was observed. Significantly increased IL-1R3 expression within the dermal infiltrate of SS skin samples (p = 0.02) was also observed, whereas no difference in IL-33 expression was found between SS and HC (p = 0.7139). In situ hybridisation revealed a good correlation between gene expression levels and the above protein expression levels. Double IF identifies neutrophils and macrophages as the predominant sources of IL-1β. This study shows that IL-1β produced by macrophages and neutrophils and IL-1R3 are significantly overexpressed in SS, thereby indicating a potential pathogenic role for this cytokine and receptor in SS

Unraveling the Epigenetic Tapestry: Decoding the Impact of Epigenetic Modifications in Hidradenitis Suppurativa Pathogenesis

Hidradenitis suppurativa (HS) is a chronic autoinflammatory skin disorder, which typically occurs during puberty or early adulthood. The pathogenesis of HS is complex and multifactorial; a close interaction between hormonal, genetic, epigenetics factors, host-specific aspects, and environmental influences contributes to the susceptibility, onset, severity, and clinical course of this disease, although the exact molecular mechanisms are still being explored. Epigenetics is currently emerging as an interesting field of investigation that could potentially shed light on the molecular intricacies underlying HS, but there is much still to uncover on the subject. The aim of this work is to provide an overview of the epigenetic landscape involved in HS. Specifically, in this in-depth review we provide a comprehensive overview of DNA methylation/hydroxymethylation, histone modifications, and non-coding RNAs (such as microRNA—miRNA-132, miRNA-200c, miRNA-30a-3p, miRNA-100-5b, miRNA-155-5p, miRNA-338-5p) dysregulation in HS patients. An interesting element of epigenetic regulation in HS is that the persistent inflammatory milieu observed in HS lesional skin could be exacerbated by an altered methylation profile and histone acetylation pattern associated with key inflammatory genes. Deepening our knowledge on the subject could enable the development of targeted epigenetic therapies to potentially restore normal gene expression patterns, and subsequentially ameliorate, or even reverse, the progression of the disease. By deciphering the epigenetic code governing HS, we strive to usher in a new era of personalized and effective interventions for this enigmatic dermatological condition

Clinical and molecular characterization of hidradenitis suppurativa: a practical framework for novel therapeutic targets.

Background: The pathophysiological picture underlying hidradenitis suppurativa (HS) and its syndromic forms is still patchy, thus presenting a great challenge for dermatologists and researchers since just by better understanding the pathogenesis of disease we could identify novel therapeutic targets. Methods: We propose a practical framework to improve subcategorization of HS patients and support the genotype-phenotype correlation, useful for endotype-directed therapies development. Results: This framework includes (i) clinical work-up that involves the collection of demographic, lifestyle, and clinical data as well as the collection of different biological samples; (ii) genetic-molecular work-up, based on multi-omics analysis in combination with bioinformatics pipelines to unravel the complex etiology of HS and its syndromic forms; (iii) functional studies, – represented by skin fibroblast cell cultures, reconstructed epidermal models (both 2D and 3D) and organoids –, of candidate biomarkers and genetic findings necessary to validate novel potential molecular mechanisms possibly involved and druggable in HS; (iv) genotype-phenotype correlation and clinical translation in tailored targeted therapies. Conclusion: Omic findings should be merged and integrated with clinical data; moreover, the skin-omic profiles from each HS patient should be matched and integrated with the ones already reported in public repositories, supporting the efforts of the researchers and clinicians to discover novel biomarkers and molecular pathways with the ultimate goal of providing faster development of novel patient-tailored therapeutic approaches.This work was supported by a Biomolecular Analyses for Tailored Medicine in AcneiNversa (BATMAN) project, funded by ERAPerMed, by Starting Grant (SG-2019-12369421) funded by the Italian Ministry of Health, by Grant (RC16/2018) from the Institute for Maternal and Child Health IRCCS “Burlo Garofolo” funded by the Italian Ministry of Health, and by a grant from Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan (protocol No. 487_2020). This work was also partially supported by Italian Ministry of Health (Ricerca Corrente 2023)/Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan, Italy

Biosensing circulating MicroRNAs in autoinflammatory skin diseases: Focus on Hidradenitis suppurativa

MicroRNAs (miRNAs) play a crucial role in the early diagnosis of autoinflammatory diseases, with Hidradenitis Suppurativa (HS) being a notable example. HS, an autoinflammatory skin disease affecting the pilosebaceous unit, profoundly impacts patients’ quality of life. Its hidden nature, with insidious initial symptoms and patient reluctance to seek medical consultation, often leads to a diagnostic delay of up to 7 years. Recognizing the urgency for early diagnostic tools, recent research identified significant differences in circulating miRNA expression, including miR-24-1-5p, miR-146a-5p, miR26a-5p, miR-206, miR338-3p, and miR-338-5p, between HS patients and healthy controls. These miRNAs serve as potential biomarkers for earlier disease detection. Traditional molecular biology techniques, like reverse transcription quantitative-polymerase chain reaction (RT-qPCR), are employed for their detection using specific primers and probes. Alternatively, short peptides offer a versatile and effective means for capturing miRNAs, providing specificity, ease of synthesis, stability, and multiplexing potential. In this context, we present a computational simulation pipeline designed for crafting peptide sequences that can capture circulating miRNAs in the blood of patients with autoinflammatory skin diseases, including HS. This innovative approach aims to expedite early diagnosis and enhance therapeutic follow-up, addressing the critical need for timely intervention in HS and similar conditions

Different molecular pathways are disrupted in Pyoderma gangrenosum patients and are associated with the severity of the disease.

Pyoderma gangrenosum (PG) is a rare inflammatory skin disease classified within the spectrum of neutrophilic dermatoses. The pathophysiology of PG is yet incompletely understood but a prominent role of genetics facilitating immune dysregulation has been proposed. This study investigated the potential contribution of disrupted molecular pathways in determining the susceptibility and clinical severity of PG. Variant Enrichment Analysis, a bioinformatic pipeline applicable for Whole Exome Sequencing data was performed in unrelated PG patients. Eleven patients were enrolled, including 5 with unilesional and 6 with multilesional PG. Fourteen pathways were exclusively enriched in the "multilesional" group, mainly related to immune system (i.e., type I interferon signaling pathway), cell metabolism and structural functions. In the "unilesional" group, nine pathways were found to be exclusively enriched, mostly related to cell signaling and cell metabolism. Genetically altered pathways involved in immune system biology and wound repair appear to be nodal pathogenic drivers in PG pathogenesis.This work was supported by a Biomolecular Analyses for Tailored Medicine in AcneiNversa (BATMAN) project, funded by ERA PerMed, by a grant from the Institute for Maternal and Child Health IRCCS ‘Burlo Garofolo/Italian Ministry of Health’ (RC16/2018), by a grant from Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan (Protocol No. 487_2020) and by Starting Grant (SG-2019- 12369421) founded by the Italian Ministry of Health

Pleiotropic role of notch signaling in human skin diseases

Notch signaling orchestrates the regulation of cell proliferation, differentiation, migration and apoptosis of epidermal cells by strictly interacting with other cellular pathways. Any disruption of Notch signaling, either due to direct mutations or to an aberrant regulation of genes involved in the signaling route, might lead to both hyper-or hypo-activation of Notch signaling molecules and of target genes, ultimately inducing the onset of skin diseases. The mechanisms through which Notch contributes to the pathogenesis of skin diseases are multiple and still not fully understood. So far, Notch signaling alterations have been reported for five human skin diseases, suggesting the involvement of Notch in their pathogenesis: Hidradenitis Suppurativa, Dowling Degos Disease, Adams–Oliver Syndrome, Psoriasis and Atopic Dermatitis. In this review, we aim at describing the role of Notch signaling in the skin, particularly focusing on the principal consequences associated with its alterations in these five human skin diseases, in order to reorganize the current knowledge and to identify potential cellular mechanisms in common between these pathologies.This work was supported by a Biomolecular Analyses for Tailored Medicine in AcneiNversa (BATMAN) project, funded by ERA PerMed and by a grant from the Institute for Maternal and Child Health IRCCS ‘Burlo Garofolo/Italian Ministry of Health’ (RC16/2018

A rare loss-of-function genetic mutation suggest a role of dermcidin deficiency in hidradenitis suppurativa pathogenesis

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a multifactorial aetiology that involves a strict interplay between genetic factors, immune dysregulation and lifestyle. Familial forms represent around 40% of total HS cases and show an autosomal dominant mode of inheritance of the disease. In this study, we conducted a whole-exome sequence analysis on an Italian family of 4 members encompassing a vertical transmission of HS. Focusing on rare damaging variants, we identified a rare insertion of one nucleotide (c.225dupA:p.A76Sfs*21) in the DCD gene encoding for the antimicrobial peptide dermcidin (DCD) that was shared by the proband, his affected father and his 11-years old daughter. Since several transcriptome studies have shown a significantly decreased expression of DCD in HS skin, we hypothesised that the identified frameshift insertion was a loss-of-function mutation that might be associated with HS susceptibility in this family. We thus confirmed by mass spectrometry that DCD levels were diminished in the affected members and showed that the antimicrobial activity of a synthetic DCD peptide resulting from the frameshift mutation was impaired. In order to define the consequences related to a decrease in DCD activity, skin microbiome analyses of different body sites were performed by comparing DCD mutant and wild type samples, and results highlighted significant differences between the groins of mutated and wild type groups. Starting from genetic analysis conducted on an HS family, our findings showed, confirming previous transcriptome results, the potential role of the antimicrobial DCD peptide as an actor playing a crucial part in the etio-pathogenesis of HS and in the maintenance of the skin’s physiological microbiome composition; so, we can hypothesise that DCD could be used as a novel target for personalised therapeutic approach

Clinical Features and Response to Treatment in Elderly Subjects Affected by Hidradenitis Suppurativa: A Cohort Study

hidradenitis suppurativa (HS) is a chronic-relapsing inflammatory skin disease. It usually appears in the second and third decades, but a smaller proportion of patients develop late-onset HS. geriatric HS, defined as the persistence or the development of HS after the age of 65 years, has been poorly explored. this study aimed to investigate the clinical features, treatment management and response to therapies of HS elderly subjects (&gt;= 65 years old). we designed a multicentric observational study, gathering data from seven Italian university hospitals. demographic and clinical data of HS patients aged over 65 years were collected at baseline, week 12 and week 24. overall, 57 elderly subjects suffering from HS were enrolled. at baseline, disease severity was predominantly moderate-to-severe, with 45.6% of patients classified as hurley III. the gluteal phenotype was the most frequently observed; it also appeared to affect patients' quality of life more than other phenotypes. gluteal involvement was detected in about half (49.1%) of cases and associated with severe stages of the disease. In terms of therapeutic response, hurley III patients showed the persistency of higher values of mean IHS4, DLQI, itch- and pain-NRS scores compared to hurley I/II. In conclusion, disease severity in this subpopulation appears high and treatment is often challenging

Holistic health record for Hidradenitis suppurativa patients.

Hidradenitis suppurativa (HS) is a recurrent inflammatory skin disease with a complex etiopathogenesis whose treatment poses a challenge in the clinical practice. Here, we present a novel integrated pipeline produced by the European consortium BATMAN (Biomolecular Analysis for Tailored Medicine in Acne iNversa) aimed at investigating the molecular pathways involved in HS by developing new diagnosis algorithms and building cellular models to pave the way for personalized treatments. The objectives of our european Consortium are the following: (1) identify genetic variants and alterations in biological pathways associated with HS susceptibility, severity and response to treatment; (2) design in vitro two-dimensional epithelial cell and tri-dimensional skin models to unravel the HS molecular mechanisms; and (3) produce holistic health records HHR to complement medical observations by developing a smartphone application to monitor patients remotely. Dermatologists, geneticists, immunologists, molecular cell biologists, and computer science experts constitute the BATMAN consortium. Using a highly integrated approach, the BATMAN international team will identify novel biomarkers for HS diagnosis and generate new biological and technological tools to be used by the clinical community to assess HS severity, choose the most suitable therapy and follow the outcome.This work was supported by a Biomolecular Analyses for Tailored Medicine in AcneiNversa (BATMAN) project, funded by ERA PerMed (JTC_2018) through the Italian Ministry of Health, the “Fondazione Regionale per la Ricerca Biomedica” (FRRB), the Slovenian Ministry of Education, Science, and Sport (MIZŠ), the Austrian Science fund (I 4229), the Federal Ministry of Education and Research Germany (BMBF), and ANR automate (ANR-20-CE15-0018-01). This work was also supported by and by a grant from the Institute for Maternal and Child Health IRCCS ‘Burlo Garofolo/Italian Ministry of Health (RC16/2018) and by a Starting Grant (SG-2019-12369421) founded by the Italian Ministry of Health. Figures were created with BioRender.com