Pathogenesis Of Hidradenitis Suppurativa Research Articles

Hidradenitis Suppurativa: A Review of the Biologic and Small Molecule Immunomodulatory Treatments.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that presents as painful, deep-seated nodules, sinus tracts, and abscesses in about 1% of the population. Although the pathogenesis of HS is not perfectly understood, it is generally recognized to be caused by a combination of genetic, endocrine, environmental, and microbiological factors. The treatment principles of HS focus on decreasing the microbial load with antibiotics and/or modulating the host immune response to reduce inflammation. The treatment of adults with moderate-to-severe HS has significantly changed recently with the development of new biological medications and immunomodulators. While previously the mainstay of treatment of moderate-to-severe HS was adalimumab, a biologic tumour necrosis factor α inhibitor, the evidence for the use of other treatment classes such as interleukin (IL)-17 inhibitors, IL-1 inhibitors, and Janus kinase inhibitors has been growing. The goal of this review article is to review the available evidence that supports the efficacy and safety of biologics and small molecule immunomodulator treatments to treat adults with moderate-to-severe HS.

The roles of IL-17A and IL-17F in hidradenitis suppurativa pathogenesis: evidence from human in vitro preclinical experiments and clinical samples.

Hidradenitis suppurativa (HS) is a chronic, relapsing inflammatory skin disease associated with significant comorbidities and poor quality of life. Despite uncertainty about pathways driving inflammation in HS lesions, the cytokines IL-17A and IL-17F have been shown to be upregulated in patients with HS. Previous studies demonstrated that the monoclonal IgG1 antibody bimekizumab selectively inhibits IL-17F in addition to IL-17A. To further investigate the roles of IL-17A and IL-17F in HS pathogenesis. RNA sequencing was conducted on skin biopsies taken at baseline and after treatment at Week 12 of the phase 2 proof of concept study of bimekizumab in patients with moderate to severe HS. Differentially expressed genes were identified between baseline lesional and non-lesional samples and between lesional samples before and after bimekizumab treatment to describe molecular disease mechanisms and treatment effect.Human hair follicular keratinocytes (HHFK) were cultured and treated with the supernatant of stimulated Th17 cells in combination with anti-IL-17A, anti-IL-17F, anti-IL-17A and anti-IL-17F, or IgG control antibodies. Total mRNA was analysed by RNA sequencing (RNAseq). Cellular supernatants from the stimulated HHFKs were used as a source of Th17-induced chemoattractants in neutrophil chemotaxis assays. RNAseq revealed that the most prominently upregulated genes within HS lesions included those associated with neutrophil biology. Bimekizumab treatment resulted in reduced expression of these genes. Extent of reduction in gene expression was dependent on HiSCR50 fulfilment. In vitro, dual inhibition of IL-17A and IL-17F had greater attenuation of Th17-induced HS-associated genes and neutrophil migration in HHFKs compared to IL-17A or IL-17F inhibition alone. In situ hybridisation revealed IL-17A and IL-17F producing cells in HS lesions can lack IL-23R and IL-1β could induce IL-23-independent IL-17F expression in vitro. Furthermore, mucosal-associated invariant cells in HS tunnels expressed IL-17F and IL-1R1. IL-1β, IL-17A and IL-17F expressing cells were found to be co-localised in HS lesions. These data support the hypothesis that IL-17A and IL-17F play central roles in HS, a neutrophilic dermatosis. The presence of IL-1β may partly explain the high expression of IL-17F in lesional HS tissue.

Apocrine Gland Damage and the Release of Specific Keratins in Early Stage Indicate the Crucial Involvement of Apocrine Glands in Hidradenitis Suppurativa

The apocrine glands (AGs) are not considered to be primarily involved in hidradenitis suppurativa (HS). This study investigated the potential role of AGs in HS pathogenesis using immunohistochemistry and single-cell sequencing of nonlesional skin (NLS) and early lesional skin (LS) from patients with HS (n = 12) and healthy controls (HC, n = 8). AG cell destruction was more frequent and AG size was significantly reduced in the NLS and LS. Barrier-related genes (e.g., claudin 1 and E-cadherin) were downregulated in the AGs of the NLS and LS. Damaged AGs in the LS primarily recruit and activate neutrophils via the CXCL-CXCR and SAA1-FPR2 pathways. Elevated levels of specific keratins (KRT18 and KRT19) released from damaged AGs were observed on the skin surface of patients and were associated with disease severity. KRT19 was also detected in the dermis of the NLS and LS and was surrounded by neutrophils and macrophages. Moreover, serum KRT19 levels in patients (n = 20) were significantly negatively correlated with the age at HS onset. Collectively, our findings provide previously unreported evidence that the AGs are damaged and release specific keratins in early HS lesions, indicating a crucial role of the AGs in HS pathogenesis.

Human papillomavirus infection is associated with increased risk of new-onset hidradenitis suppurativa: a population-based cohort study

BackgroundThe exact cause of hidradenitis suppurativa (HS) remains unclear, though emerging research suggests a link between infectious agents and inflammatory skin diseases. The association between human papillomavirus (HPV) infection and HS development, however, has not been studied. ObjectiveTo evaluate the risk of incident HS in HPV infection patients. MethodsUsing the TriNetX research network, we conducted a retrospective cohort study of patients diagnosed with HPV and matched controls. Propensity score matching adjusted for variables like age, sex, race, BMI, comorbidities, and lifestyle factors. The primary outcome was new-onset HS, analyzed across demographic and clinical factors. Hazard ratios with 95% confidence intervals (95% CI) were calculated to assess risk. ResultsAfter matching, both the HPV and control cohorts included 582,007 patients. HPV-infected individuals had a significantly higher risk of developing HS (HR: 1.356, 95% CI: 1.290-1.427). This increased risk was consistent across various demographic and clinical groups. Sensitivity analyses confirmed the robustness of these findings. LimitationsRetrospective cohort design. ConclusionsHPV infection is linked to a higher risk of HS, suggesting a potential association. Further research is required to validate these results and assess their impact in different populations and clinical settings but could also elucidate a potential impact of other infections involved in the pathogenesis of HS.

Upregulation of TLR2 in keratinocytes activates the MAPK pathway and plays a role in the pathogenesis of FHS

BackgroundMutations in gamma-secretase complex (GSC) genes are associated with hidradenitis suppurativa (HS), and toll-like receptor (TLR) 2 is elevated in HS lesions. However, it remains unclear whether TLR2 is upregulated in the skin lesions of patients with HS with GSC gene variants, and the role of its upregulation in the pathogenesis of this disease are unknown. ObjectiveTo investigate the role of TLR2 upregulation in NCSTN and PSENEN knockdown keratinocytes. MethodsHuman immortalized keratinocyte line (HaCaTs) was treated with potent short-hairpin RNA targeting NCSTN or PSENEN. RNA sequencing was used to assess the effects of PAM2CSK4 treatment on gene expression in HaCaT cells. Altered signaling pathways were confirmed in both HaCaT cells, as well as in skin lesions from patients with HS and in Ncstn keratinocyte-specific knockout (NcstnΔKC) mice. ResultsTLR2 agonist stimulation exacerbated the increased phosphorylation levels of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase (MAPK) in NCSTN- and PSENEN- knockdown keratinocytes. Similar findings were observed in skin lesions from patients with HS and NcstnΔKC mice. ConclusionNovel variations were identified within the GSC gene in Chinese patients with HS. Moreover, our study indicates that TLR2/MAPK signaling pathways play a key role in the pathogenesis of HS associated with GSC gene mutations and represent a crucial therapeutic target.

Expanding the frontiers of therapeutic options in hidradenitis suppurativa: The valid contribution of bimekizumab

Hidradenitis suppurativa (HS) is a chronic inflammatory cutaneous disorder with a significant negative impact on quality of life. Th17 axis has a central role in the pathogenesis of HS. Kimball etal. demonstrated the efficacy and safety of bimekizumab in two double-blind, placebo-controlled phase 3 studies (BE HEARD I-II), adding a new targeting option to the therapeutic armamentarium of HS.1.

A Review of Hidradenitis Suppurativa (HS)

Background: Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease of the hair follicle, affecting intertriginous areas such as the axillae, perianal, and inguinal regions. It is more prevalent in females, with peak onset between ages 18 and 29. Specific Background: HS, characterized by nodules, abscesses, and sinus tract scarring, uses the Hurley staging system for disease severity classification, but its limitations exist due to its static clinical features. Knowledge Gap: Although several treatment modalities exist, ranging from antibiotics to surgery, there is no definitive therapy, and the pathogenesis remains poorly understood, complicating early diagnosis and management. Moreover, international diagnostic delays of 8-12 years further hinder patient outcomes. Aims: This study aims to explore the limitations of current classification and treatment approaches, while emphasizing the importance of prevention strategies and timely diagnosis to mitigate HS severity. Results: The Hurley classification, though widely used, fails to account for disease progression or quality of life. Current treatment options depend on disease severity, including topical and systemic antibiotics, hormonal therapies, biologics, and surgical interventions. Prevention strategies, such as laser hair removal and lifestyle modifications (e.g., smoking cessation, weight management), are essential to reducing disease impact. Novelty: This research highlights the under-explored role of early prevention and lifestyle interventions in managing HS and reducing progression through Hurley stages. Implications: Enhanced diagnostic tools, combined with early intervention strategies and a holistic approach to patient care, are necessary to improve clinical outcomes, reduce diagnostic delays, and minimize HS-related morbidity. Further research is needed to better understand the genetic and environmental factors contributing to HS pathogenesis. Highlights: HS peaks in females aged 18-29 with chronic skin inflammation. 8-12 years diagnostic delay worsens disease severity and treatment. Prevention: laser hair removal, lifestyle changes reduce HS progression. Keywords: Hidradenitis suppurativa, Hurley staging, inflammatory skin disease, prevention, diagnostic delays

Cellular indexing of transcriptomes and epitopes (CITE-Seq) in hidradenitis suppurativa identifies dysregulated cell types in peripheral blood and facilitates diagnosis via machine learning.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful nodules, abscesses, and scarring, predominantly affecting intertriginous regions and it is often underdiagnosed. This study aimed to utilize single cell RNA and cell-surface protein sequencing (CITE-Seq) to delineate the immune composition of circulating cells in Hidradenitis suppurativa (HS) peripheral blood compared to healthy controls. CITE-Seq was used to analyze the gene and protein expression profiles of peripheral blood mononuclear cells (PBMCs) from 9 HS and 29 healthy controls. The study identified significant differences cell composition between HS patients and healthy controls, including increased proportions of CD14+ and CD16+ monocytes, cDC2, plasmablasts, and proliferating CD4+ T cells in HS patients. Differential expression analysis revealed upregulation of inflammatory markers such as TNF, IL1B, and NF-κB in monocytes, as well as chemokines and cell adhesion molecules involved in immune cell recruitment and tissue infiltration. Pathway enrichment analysis highlighted the involvement of IL-17, IL-26 and TNF signaling pathways in HS pathogenesis. Machine learning identified key markers for diagnostics and therapeutic development. The findings also support the potential for machine learning models to aid in the diagnosis of HS based on immune cell markers. These insights may inform future therapeutic strategies targeting specific immune pathways in HS.

Evidence on Hidradenitis Suppurativa as an Autoinflammatory Skin Disease.

Hidradenitis suppurativa (HS) is a chronic and debilitating inflammatory skin disease that often exhibits heterogeneity in its clinical presentation, especially in the context of its rare syndromic forms. The pathogenesis of HS results from a complex interplay of genetic predisposition, innate and adaptive immunity dysregulation, smoking, obesity and environmental factors. In the early phase of the disease, the innate immune system is hyperactivated, contributing to tissue damage and triggering the activation and amplification of the adaptive immune response, which plays a pivotal role in the chronic stages of the disease. Recent studies focused on elucidating the importance of innate immunity impairment and autoinflammation in HS and increasing evidence has emerged on the occurrence of the disease in the context of well-known monogenic and polygenic autoinflammatory syndromes (AIDs). This review provides a comprehensive examination of the current scientific background supporting the contribution of autoinflammation to HS etiology, including genetic data, molecular studies and clinical evidence, as well as the association between HS and AIDs. However, further research is needed to shed light on the pathogenic mechanism of this challenging condition and to identify potential perspectives for future therapeutic approaches.

GUT AND SKIN MICROBIOME IN PATIENTS WITH HIDRADENITIS SUPPURATIVA

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that profoundly diminishes the quality of life for the affected patients, and is characterized by persistent purulent lesions in anatomical areas prone to constant skin friction, such as the armpits, groin, buttocks and breasts. The HS pathophysiology encompasses an array of factors, such as inflammation, genetics, the microbiome of the patient, and environmental components to name a few. Although it has been implicated that the patient microbiome is one of the factors in the pathogenesis of HS, the precise connection between the commensals and the host still remains to be fully researched. The studies examined in this review note that Porphyromonas, Peptoniphilus and Prevotella spp were observed in the skin microbiome of the patients with hidradenitis suppurativa, along with the decrease in Cutibacterium. The increase of certain bacterial species, such as Robinsoniella peoriensis, Bilophila, Holdemania, and Ruminococcus callidus was also observed when comparing gut microbiomes of the healthy subjects to those with hidradenitis suppurativa, suggesting that these microorganisms may be involved in the pathophysiology of HS. However, the specific mechanisms that regulate the interaction between the gut and skin microorganisms remain unclear. Therefore, the purpose of this review is to analyze the recent results from skin and microbiome studies related to hidradenitis suppurativa.

IRAK4 Is Overexpressed in Hidradenitis Suppurativa Skin and Correlates with Inflammatory Biomarkers

Hidradenitis suppurativa (HS) is a chronic inflammatory disease manifesting as painful dermal nodules, abscesses, and tunnels. Activation of the IL-1R/toll-like receptor (TLR) pathway is strongly implicated in the pathogenesis of HS; thus, the role of a key signaling node, IL-1R-associated kinase 4 (IRAK4), was investigated in a noninterventional study (NCT04440410) that enrolled 30 patients with HS. IRAK4 expression was evaluated in blood and lesional, perilesional, and nonlesional skin biopsies. Peripheral blood mononuclear cells (PBMCs) expressed IRAK4, with significantly higher levels in monocytes (P ≤ 0.0001). Ex vivo treatment of PBMCs with KT-474, a targeted degrader of IRAK4, robustly decreased IRAK4 in all immune cell types from healthy volunteers and patients with HS. Ex vivo treatment of TLR-stimulated healthy donor monocytes with KT-474 decreased IRAK4 protein levels and inhibited inflammatory cytokine production. In HS skin samples, IRAK4 protein levels were significantly higher in lesional versus nonlesional tissue (P ≤ 0.0001), and IRAK4-positive immune infiltrate increased with greater disease severity. Multiple inflammatory mediators were upregulated in HS lesional skin, correlating with IRAK4 overexpression. These data confirm the significance of the IL-1R/TLR pathway in the pathogenesis of HS and provide support for ongoing clinical studies evaluating KT-474 in the treatment of HS.

A Novel Whole Tissue Explant Model of Hidradenitis Suppurativa.

Hidradenitis Suppurativa (HS) is a relatively common and highly morbid inflammatory skin disease. Due to our relatively limited understanding of HS's pathogenesis, there are currently insufficient treatment options available, and many patients' medical needs are not being met. This is partly due to a scarcity of ex vivo human assays and animal models that accurately recapitulate the disease. To address this deficit, we have developed a whole-tissue explant model of HS to examine its pathogenic mechanisms and the efficacy of potential treatments within intact human tissue. We measured cytokine protein and RNA within whole tissue maintained in an agar-media solution, finding that IL-6 and IL-8 concentrations trended upwards in both HS explants and healthy controls, while IL-17A, IL-1β, and TNF-α exhibited increases in HS tissue alone. We also show that the explants were responsive to treatment with both dexamethasone and IL-2. Not only do our results show that this model effectively delivers treatments throughout the explants, but they also elucidate which cytokines are related to the explant process regardless of tissue state and which are related to HS tissue specifically, laying the groundwork for future implementations of this model.

Eosinophils in hidradenitis suppurativa patients exhibit pro-inflammatory traits, implicating a potential pathogenic role in the disease.

Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful nodules, abscesses and purulent secretions in intertriginous regions. Intense pruritus frequently accompanies HS lesions, adding further discomfort for patients. While Th17 pathway activation is implicated in HS pathogenesis, disease mechanisms are still not fully understood, and therapeutics are lacking. Previous reports raise a potential role for eosinophils in HS, showing a strong association of eosinophil levels with disease severity. To investigate eosinophils in HS, we recruited patients and matched healthy controls and then performed flow-cytometry studies, eosinophil stimulation assays, and lesional skin staining for eosinophils. We found that HS patients reported similar levels of pain and itch. Compared to matched controls, HS blood exhibited decreased mature eosinophils and increased numbers of immature eosinophils, coupled with a significant increase in dermal eosinophilic infiltrates. Additionally, IL-17RA+ eosinophils were highly and significantly correlated with multiple HS-related clinical scores. In both stimulated and unstimulated conditions, HS eosinophils showed an inflammatory phenotype versus controls, including an increase in costimulatory T- and B-cell markers (e.g. CD5 and CD40) following all stimulations (TNFα/IL-17A/IL-17F). These findings highlight the significance of pruritus in HS and suggest a higher turnover of eosinophils in HS blood, potentially due to the consumption of eosinophils in skin lesions. Our data delineate the features and functions of eosinophils in HS and suggest that eosinophils participate in disease pathogenesis, advancing Th17-related inflammation. Further studies are needed to investigate eosinophils' response to current HS treatments and their potential as a therapeutic target in the disease.

Inflammasomes: emerging therapeutic targets in hidradenitis suppurativa?

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent inflammatory lesions, which affect skin and hair follicles in intertriginous areas. HS has a multifactorial aetiology resulting in barrier dysfunction associated with aberrant immune activation. There is increased evidence for the role of inflammasomes in the pathophysiology of inflammatory skin diseases, including HS. Inflammasomes are multiprotein complexes activated following exposure to danger signals, including microbial ligands and components of damaged host cells. Inflammasome activation induces many signalling cascades and subsequent cleavage of proinflammatory cytokines- most notably interleukin (IL)-1β - which have a role in HS pathogenesis. Limited immunotherapies are approved for treating moderate-to-severe HS, with variable response rates influenced by disease heterogeneity. Inflammasomes represent attractive targets to suppress multiple inflammatory pathways in HS, including IL-1β and IL-17. This review aims to summarize the role of inflammasomes in HS and to evaluate evidence for inflammasomes as therapeutic targets for HS treatment.

Genetic factors associated with hidradenitis suppurativa, a literature review.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by deep-seated, painful lesions most frequently occurring in intertriginous areas of the skin. HS leads to poor quality of life in affected individuals and is difficult to diagnose and treat. Understanding the genetics associated with familial inheritance may lead to a better understanding of the pathogenesis of this debilitating disease. Articles published until March 9, 2023, were identified in PubMed using the following search terms: hidradenitis suppurativa and gene* or acne inversa and gene*. The rate of monogenic mutations associated with HS is less than 7%, with the most common genetic mutations reported in sporadic and familial HS cases being in NCSTN and less frequently in PSENEN. Individuals with mutations in the gamma-secretase complex tended to have more severe HS and an early age of onset. This study was limited to the case studies available in PubMed, the majority of which used targeted gene panels to detect genetic mutations. Approximately 30% of individuals diagnosed with HS report having a positive family history; however, very few studies demonstrate monogenic familial transmission of HS. The case studies of syndromic HS reported a variety of genetic mutations associated with HS, some of which were familial, while others were sporadic, suggesting that other pathways may be involved in the pathogenesis of HS and other potential mutations that have yet to be evaluated. More research is needed to understand the genetic mutations in HS.

Hidradenitis suppurativa: definition, epidemiology, etiology, diagnosis (part 1)

Hidradenitis suppurativa (HS) is a chronic recurrent skin disease characterized by development of autoimmune inflammation in the infundibulum of the hair follicle and apocrine sweat glands located in the axillary, inguinal, anogenital regions, submammary folds, near the areola of mammary glands and the umbilical region. HS is difficult to treat and has an extremely negative impact on the quality of life. HS is separated into a distinct clinical entity fundamentally different in etiopathogenesis from acute bacterial hidradenitis. The exact prevalence of HS is unknown, it varies greatly in different studies ranging from 0.03 to 4% in general population. The detection of IL-1β, IL-23, and IL-17 in the lesions indicates the key role of autoimmune inflammation involving Th17-lymphocytes in the pathogenesis of HS. Risk factors include smoking, obesity, mechanical friction, genetic predisposition. The diagnosis of HS relies on three obligatory criteria: characteristic distribution, typical morphology of the lesions and relapsing, chronic disease course. There is no “gold standard” in assessing the severity of the disease, since all available scoring systems have many limitations, therefore many questions regarding this disease remain unsolved at present — from terminology and clear and most objective assessment criteria for the severity of the process to the development of native clinical guidelines.

Deregulated Long Non-Coding RNAs (lncRNA) as Promising Biomarkers in Hidradenitis Suppurativa.

Background/Objectives: In recent times, epigenetics alterations in Hidradenitis suppurativa (HS) have been explored and exploited translationally to guide investigation of new therapeutic approaches. On the other hand, long noncoding RNAs (LncRNAs), main regulators of the epigenetic status of the human genome, have been scarcely investigated, notwithstanding their potential relevance in broad pathogenesis comprehension. Here, we aim to explore the methylation pattern of lncRNAs in HS. Methods: In this case-control study, 24 HS patients and age-, sex- and BMI-matched controls were analyzed to characterize the methylome of lncRNA genes in peripheral blood cells. Gene ontology analysis (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein interaction (PPI) network, and MCODE analysis were performed. Results: A set of fifteen lncRNA genes exhibited significantly differential methylation patterns, with ten of them showing hypomethylation and five displaying hypermethylation at specific CpG sites. The hypomethylated lncRNA genes were DLEU2, MESTIT1, CASC2, TUG1, KCNQ1DN, PSORS1C3, PCA3, DSCR8, RFPL1S, and PVT1, while the hypermethylated ones were HAR1A, FAM66B, SNHG9, HCG9, and HCP5. These lncRNA genes have been linked to various important biological processes, including cell proliferation, apoptosis, inflammation, chronic inflammatory skin diseases, and wound healing. Their altered methylation status suggests potential roles in regulating these processes, and may contribute to HS pathogenesis and healing mechanisms. Conclusions: This study revealed an interesting dysregulation pattern of definite lncRNAs in the methylome which is linked to both the development of HS and its comorbidities. Epigenetically altered lncRNAs genes could represent useful biomarkers, and could help in guiding innovative treatment strategies.

Gram-negative anaerobes elicit a robust keratinocytes immune response with potential insights into HS pathogenesis.

Hidradenitis Suppurativa (HS) is a chronic autoinflammatory skin disease with activated keratinocytes, tunnel formation and a complex immune infiltrate in tissue. The HS microbiome is polymicrobial with an abundance of commensal gram-positive facultative (GPs) Staphylococcus species and gram-negative anaerobic (GNA) bacteria like Prevotella, Fusobacterium and Porphyromonas with increasing predominance of GNAs with disease severity. We sought to define the keratinocyte response to bacteria commonly isolated from HS lesions to probe pathogenic relationships between HS and the microbiome. Type strains of Prevotella nigrescens, Prevotella melaninogenica, Prevotella intermedia, Prevotella asaccharolytica, Fusobacterium nucleatum, as well as Staphylococcus aureus and the normal skin commensal Staphylococcus epidermidis were heat-killed and co-incubated with normal human keratinocytes. RNA was collected and analysed using RNAseq and RT-qPCR. The supernatant was collected from cell culture for protein quantification. Transcriptomic profiles between HS clinical samples and stimulated keratinocytes were compared. Co-staining of patient HS frozen sections was used to localize bacteria in lesions. A mouse intradermal injection model was used to investigate early immune recruitment. TLR4 and JAK inhibitors were used to investigate mechanistic avenues of bacterial response inhibition. GNAs, especially F. nucleatum, stimulated vastly higher CXCL8, IL17C, CCL20, IL6, TNF and IL36γ transcription in normal skin keratinocytes than the GPs S. epidermidis and S. aureus. Using RNAseq, we found that F. nucleatum (and Prevotella) strongly induced the IL-17 pathway in keratinocytes and overlapped with transcriptome profiles of HS patient clinical samples. Bacteria were juxtaposed to activated keratinocytes invivo, and F. nucleatum strongly recruited murine neutrophil and macrophage migration. Both the TLR4 and pan-JAK inhibitors reduced cytokine production. Detailed transcriptomic profiling of healthy skin keratinocytes exposed to GNAs prevalent in HS revealed a potent, extensive inflammatory response vastly stronger than GPs. GNAs stimulated HS-relevant genes, including many genes in the IL-17 response pathway, and were significantly associated with HS tissue transcriptomes. The close association of activated keratinocytes with bacteria in HS lesions and innate infiltration in murine skin cemented GNA pathogenic potential. These novel mechanistic insights could drive future targeted therapies.

Brodalumab for moderate-severe hidradenitis suppurativa: An open-label multicentric cohort study in real clinical practice.

The use of biological therapy is becoming increasingly common in patients with hidradenitis suppurativa (HS). Levels of serum TNF-alfa and IL17 support the role of an immune system dysregulation in the pathogenesis of HS. Brodalumab targets the receptor A of IL-17, thus having a promising role in the treatment of HS. A multicenter retrospective observational open-label study was conducted in two tertiary hospitals. Adults with moderate to severe HS under treatment with brodalumab 210 mg at week 0, 1, 2 and then every 2 weeks were included and assessed at weeks 0 and 16 which was the median follow-up time. Demographic and disease-related variables as well as response parameters (HiSCR and IHS4) and safety data were recorded and analysed. A total of 16 patients (75% males) were included in our study. 50% of patients presented an inflammatory phenotype and mean BMI was 28.37. HiSCR was achieved in 50% of patients and mean IHS4 decreased from 24.13 to 16.81 (p = 0.002). No differences were found between those who achieved HiSCR and those who did not. Grade 2 adverse events were reported in three patients with no fatal outcomes and treatment discontinuation was advised in four patients. Brodalumab seems to be effective and safe in patients with moderate to severe HS, even in those that did not respond to adalimumab, which, at the moment, is the only widely approved biologic for this indication. Thus, it stands as an interesting option for the treatment of HS.

Macrophage Polarization and Crosstalk between Macrophages and Other Cells in Hidradenitis Suppurativa

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic inflammatory disease characterized by the development of inflammatory nodules, abscesses, and pus-discharging tunnels in areas such as the axillary, inguinal, gluteal, and perianal regions. The pathogenesis of HS remains unclear, but it is being increasingly recognized to rely on the dysregulation of inflammatory responses. Central to this process are macrophages, which have emerged as key players in the inflammatory milieu of HS. These cells orchestrate inflammation via polarization and significantly influence the functions of neighboring cells. This review briefly describes macrophage polarization and crosstalk between macrophages and other cells in patients with HS with the aim of providing new therapeutic strategies for the clinical management of HS.