Pathogenesis Of Hidradenitis Suppurativa Research Articles

The Skin and Gut Microbiome in Hidradenitis Suppurativa: Current Understanding and Future Considerations for Research and Treatment.

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease comprising painful abscesses, deep nodules, fistulas, and scarring predominantly in the axilla and groin. Bacterial colonization of HS lesions has been well characterized and may lead to chronic infection of lesions. While disease pathogenesis of HS is not fully understood, there is increasing evidence that microbial dysbiosis may be occurring in numerous locations, including the skin and gut. The skin-gut microbiome has been proposed as a mechanism by which inflammatory skin disorders, including HS, can be exacerbated. This is evidenced by HS patients being significantly more likely to develop inflammatory bowel disease as well as the well documented cutaneous manifestations in inflammatory bowel disease. In this review, we discuss the current literature regarding HS skin and gut microbiome research. Furthermore, we discuss further considerations for microbiome research in HS, including the potential role of bacterial metabolites in disease progression and future therapeutic avenues like probiotics.

Disease Association of Anti‒Carboxyethyl Lysine Autoantibodies in Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurring suppurating lesions of the intertriginous areas, resulting in a substantial impact on patients' QOL. HS pathogenesis remains poorly understood. An autoimmune component has been proposed, but disease-specific autoantibodies, autoantigens, or autoreactive T cells have yet to be described. In this study, we identify a high prevalence of IgM, IgG, and IgA antibodies directed against Nε-carboxyethyl lysine (CEL), a methylglyoxal-induced advanced glycation end-product, in the sera of patients with HS. Titers of anti-CEL IgG and IgA antibodies were highly elevated in HS compared with those in healthy controls and individuals with other inflammatory skin diseases. Strikingly, the majority of anti-CEL IgG was of the IgG2 subclass and correlated independently with both disease severity and duration. Both CEL and anti-CEL‒producing plasmablasts could be isolated directly from HS skin lesions, further confirming the disease relevance of this autoimmune response. Our data point to an aberration of the methylglyoxal pathway in HS and support an autoimmune axis in the pathogenesis of this debilitating disease.

33181 C5a and C5aR is prominently associated with tunnels in severe hidradenitis suppurativa

Complement dysregulation and neutrophil activation have been implicated in the pathogenesis of hidradenitis suppurativa (HS). The presence of tunnels (subcutaneous cavities lined with squamous epithelium) is a feature of the moderate and severe forms of HS. The complement 5a (C5a) receptor (C5aR) is highly expressed on neutrophils and is a major driver of the proinflammatory functions. Avacopan is a potent and specific inhibitor of human C5aR, and was shown to be efficacious and well tolerated in patients with severe HS in a recent phase 2 clinical trial.

Coexistence of pachyonychia congenita and hidradenitis suppurativa: more than a coincidence.

The coexistence of pachyonychia congenita (PC) and hidradenitis suppurativa (HS) has been described in case reports. However, the pathomechanism underlying this association and its true prevalence are unknown. To determine the genetic defect underlying the coexistence of PC and HS in a large kindred, to delineate a pathophysiological signalling defect jointly leading to both phenotypes, and to estimate the prevalence of HS in PC. We used direct sequencing and a NOTCH luciferase reporter assay to characterize the pathophysiological basis of the familial coexistence of HS and PC. A questionnaire was distributed to patients with PC registered with the International Pachyonychia Congenita Research Registry (IPCRR) to assess the prevalence of HS among patients with PC. Direct sequencing of DNA samples obtained from family members displaying both PC and HS demonstrated a missense variant (c.275A>G) in KRT17, encoding keratin 17. Abnormal NOTCH signalling has been suggested to contribute to HS pathogenesis. Accordingly, the KRT17 c.275A>G variant resulted in a significant decrease in NOTCH activity. To ascertain the clinical importance of the association of HS with PC, we distributed a questionnaire to all patients with PC registered with the IPCRR. Seventy-two of 278 responders reported HS-associated clinical features (25·9%). Disease-causing mutations in KRT17 were most prevalent among patients with a dual phenotype of PC and HS (43%). The coexistence of HS and KRT17-associated PC is more common than previously thought. Impaired NOTCH signalling as a result of KRT17 mutations may predispose patients with PC to HS. What is already known about this topic? The coexistence of pachyonychia congenita (PC) and hidradenitis suppurativa (HS) has been described in case reports. However, the pathomechanism underlying this association and its true prevalence are unknown. What does this study add? A dual phenotype consisting of PC and HS was found to be associated with a pathogenic variant in KRT17. This variant was found to affect NOTCH signalling, which has been previously implicated in HS pathogenesis. HS was found to be associated with PC in a large cohort of patients with PC, especially in patients carrying KRT17 variants, suggesting that KRT17 variants causing PC may also predispose to HS. What is the translational message? These findings suggest that patients with PC have a higher prevalence of HS than previously thought, and hence physicians should have a higher level of suspicion of HS diagnosis in patients with PC.

Recent advances in hidradenitis suppurativa: Role of race, genetics, and immunology.

Hidradenitis suppurativa (HS) is a multifactorial chronic skin disease characterized by inflammation around the hair follicles commonly affecting intertriginous areas. The underlying pathogenesis of HS and its molecular mechanisms are largely understudied. Genetic studies in families have identified variants within the γ-secretase complex associated with HS; however, no definitive genotype-phenotype correlations have been made. The lack of knowledge regarding the intersection of genetics, immunology and environmental risk factors is a major obstacle to improving treatment for patients with HS. This article provides an overview of the role of race, genetics, and immunology in HS to provide insight into the multiple factors influencing the pathophysiology of HS.

LB1037 Aberrant regulation of protein translation controlled by eukaryotic initiation factor 4F (eIF4F) in the pathogenesis of hidradenitis suppurativa (HS) and associated cutaneous squamous cell carcinoma (cSCC)

HS is a chronic inflammatory skin disorder and often associated with neoplastic growth of cSSC. Between 1%-3.2% of HS patients develop cSCC, however, the molecular pathogenesis of this disease remains undefined. Here, we demonstrate the pathogenic role for the 5’cap-binding protein complex eIF4F in HS and lesion-associated cSSC. This complex is composed of the scaffold protein eIF4G, the cap-binding protein eIF4E and a DEAD-box helicase eIF4A1. Employing confocal microscopy, we observed elevated expression of eIF4E, eIF4G, and eIF4A1 in HS skin that co-localized in hyperproliferative keratinocytes and associated with enhanced eIF4E translation targets, Cyclin D1 and c-Myc.

LB967 Monogenic mutations implicate STAT1 in hidradenitis suppurativa pathogenesis

Hidradenitis suppurativa (HS) is a prevalent and debilitating skin disease with many unmet needs. Genes that underlie rare monogenic etiologies demonstrate greater success as drug targets. HS gene discovery has been limited. Transcriptomic studies show that upregulated STAT1 has a prominent role in HS pathogenesis, supporting previous evidence implicating activators of STAT1 (TNFα, microbial signals, IFNγ). Patients with heterozygous STAT1 gain-of-function (GOF) mutations can develop clinical features that overlap with HS (abscesses, colitis, autoimmunity, SCC).

803 Epidermal inflammatory activity is an important driver of hidradenitis suppurativa lesions

Hidradenitis suppurativa (HS) is an inflammatory skin disorder of the pilosebaceous unit defined by painful nodules, tunnels, and scarring. Previous studies documented dermal cell infiltrate and the abundance of inflammatory cytokines in HS lesions, including TNFα, IL-17, and IL-1β. However, not much is currently known about the contribution of keratinocytes and immune cell activity within the epidermis in HS. We found that the degree of epidermal inflammation in HS lesions positively correlated with Hurley stage of disease (r =0.746; p=0), indicating the evolution of epidermal responses with disease severity. Keratinocytes were the primary producers of TNFα (p<0.05) and IL-6 (p<0.05) in HS lesions at all Hurley stages. Increased expression of CXCL3 (5-fold; p<0.01) in keratinocytes of stage III lesions positively correlated with increased recruitment of neutrophils to stage III lesional epidermis. Compared to healthy keratinocytes, enhanced production of chemokines from HS keratinocytes, including CCL22 (stage II 4-fold; p=0.09) and CCL3 (stages II and III p<0.05; 30-fold and 10-fold respectively), was associated with CD8 T cell infiltration and corresponding chemokine receptor expression in the epidermis. These recruited immune cells strongly produce or enable the production of IFNγ (>50 fold), IL-17A (500-fold), and IL-1β (5 to 10-fold), as well as IFNβ1, CXCL10, and STAT1 (HS II/III lesions; p<0.05 for all) by multiple cell types locally in the epidermis, likely generating positive feedback for increased inflammation. As epidermal inflammation evolves during disease progression and contributes to immune cell recruitment, our data suggest that topical therapeutics that block cytokine and chemokine production from the epidermis may be efficacious in HS. In all, our results collectively indicate that keratinocytes are not simply bystanders in HS inflammatory events, but rather actively contribute to HS pathogenesis.

Effects of NCSTN Mutation on Hair Follicle Components in Mice

Background and Objectives: Hidradenitis suppurativa (HS)/acne inversa is an intractable skin disease that is characterized by destructive lesions – primarily on the flexural areas. Although its etiology is unknown, genetics is considered to be a factor of its pathology – mutations in γ-secretase genes have been identified in certain familial HS patients, and follicular occlusion is widely accepted as the primary cause of HS. But, no relationship between these mutations and the components of hair follicles has been reported. Thus, we examined changes in these components in mice with a mutation in NCSTN (a γ-secretase gene). Methods: We generated C57BL/6 mice with an NCSTN mutation and examined their expression of hair cortex cytokeratin and trichohyalin by Western blot and immunohistochemistry, in addition to nicastrin, the product of NCSTN, and NICD compared with wild-type mice. The structure of hair follicles was analyzed by hematoxylin-eosin staining and transmission electron microscopy. Results: In mice with an NCSTN mutation, HS-like skin lesions appeared after age 6 months, the pathological manifestations of which were consistent with the features of human HS. The structure of hair follicles was abnormal in mice with an NCSTN mutation versus wild-type mice, and hair cortex cytokeratin, trichohyalin, nicastrin, and NICD were downregulated in these mice. Conclusions: This NCSTN mutant mouse model could be an improved model to study early lesion development aspects of human HS pathogenesis and could perhaps be a better alternative for evaluating early-acting and preventive therapeutics for HS experimentally before clinical trials in HS patients. NCSTN mutations disrupt the development of hair follicles, leading to abnormal hair follicle structures, perhaps resulting in the onset of HS.

State of the art of blue light effects on hidradenitis suppurativa: a concise systematic review

Introduction: In the setting of inflammatory diseases, hidradenitis suppurativa (HS), or acne inversa, is an immune-mediated skin disease with a prevalence of 0.1-1% and characterized by nodules and abscesses in the armpits, groin, and inframammary areas, which may evolve for fistulas and scars. Still, an update is needed on the recent understanding of the pathogenesis of HS, including the central role of inflammatory cytokines and other contributing factors such as genetics, hormones, and pathogenic microorganisms. As an innovative approach, antimicrobial blue light in the 400-470 nm spectrum has demonstrated its intrinsic antimicrobial properties resulting from the presence of endogenous photosensitizing chromophores in pathogenic microorganisms. Objective: To carry out a narrative and systematic review of the literature to explore the main clinical and experimental results of the use of photobiomodulation with blue light for the treatment of hidradenitis suppurativa by antibacterial action. Methods: The present study followed a model of narrative and systematic review, according to PRISMA rules, to gather the main information about the efficiency and safety of blue light in the treatment of HS. The research was carried out from January 2018 to May 2019 and developed based on Google Scholar, Scopus, PubMed, Scielo, and Cochrane Library. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results: Microorganisms are less able to develop resistance to antimicrobial blue light than to traditional antibiotics, due to the multi-targeting characteristics of antimicrobial blue light. Furthermore, it is well accepted that antimicrobial blue light is much less harmful to host cells than UV irradiation. Clinical studies have presented scientific evidence of treatment for HS with light-based therapy, showing efficacy and safety through articles published in quality journals in scientific evidence. A meta-analysis published in 2019, based on the quality of the evidence, showed that the most recommended treatments for HS include adalimumab and laser (blue light) therapy. For intense pulsed light with blue light, two RCTs reported improvements in HS-LASI scores and the Dermatology Quality of Life Index. Conclusion: The use of blue light for dermal treatments, particularly for HS, is finding an increasing role in dermatology. However, more robust and consistent studies are still needed to better demonstrate the antibacterial effects of blue light on HS.

Guselkumab effectiveness, and posology in patients with moderate to severe hidradenitis suppurativa: A retrospective bicentric experience.

Hidradenitis suppurativa (HS) is a chronic, inflammatory, and recalcitrant skin disease of the terminal hair follicle. Therapeutic alternatives in HS are limited nowadays. Adalimumab, is the only approved biological treatment for patients with moderate to severe HS, and some patients do not reach an optimal response, or experience a progressive response loss, needing therapeutic alternatives. IL-23 pathway is also involved in HS pathogenesis, so its blockade could contribute to reach disease control. Guselkumab is a monoclonal antibody targeting the p19 subunit of extracellular IL-23, currently approved for psoriasis in adults, and recently some authors have reported its effectiveness in patients with moderate to severe HS refractory to other systemic treatments, becoming a hope for some patients. However adequate dosing and intervals have not been determined yet, so in most published series, doses approved for psoriasis are commonly used. On this topic a retrospective bicentric study including HS patients treated with guselkumab in the dermatologic departments of university hospitals Puerta de Hierro of Majadahonda (Madrid, Spain) and Doctor Peset of Valencia (Valencia, Spain) was conducted. We reported effectiveness, dosage and frequency of administration in the cohort, in order to establish the most effective dosage regimen and to clarify the potential role of guselkumab for this disease.

New and Emerging Targeted Therapies for Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory skin disease deriving from the hair follicles. The formation of inflammatory nodules, abscesses, fistulas, and sinus tracts is characterized by a large inflow of key pro-inflammatory mediators, such as IFN-γ, TNF-α, IL-1, IL-17, and IL-12/23. Adalimumab is currently the only Food and Drug Administration (FDA)- and European Medicines Agency (EMA)-approved biologic therapy for moderate to severe HS in adults and adolescents. However, the long-term effectiveness of this TNF-α inhibitor in HS patients has shown to be highly variable. This review aims to review the evidence for emerging therapies that target the main pro-inflammatory cytokines in HS pathogenesis. A review of the literature was conducted, using the PubMed and Google Scholar repositories, as well as Clinicaltrials.gov. Presently, the most promising biologics in phase III trials are anti-IL-17 antibodies, secukinumab, and bimekizumab. Furthermore, an anti-IL-1 biologic, bermekimab, is currently in phase II trials, and shows encouraging results. Overall, the clinical efficacies of all new targeted therapies published up to this point are limited. More studies need to be performed to clarify the precise molecular pathology, and assess the efficacy of biological therapies for HS.

MicroRNA Cross-Involvement in Acne Vulgaris and Hidradenitis Suppurativa: A Literature Review.

Acne Vulgaris (AV) and Hidradenitis suppurativa (HS) are common chronic inflammatory skin conditions that affect the follicular units that often coexist or are involved in differential diagnoses. Inflammation in both these diseases may result from shared pathways, which may partially explain their frequent coexistence. MicroRNAs (miRNAs) are a class of endogenous, short, non-protein coding, gene-silencing or promoting RNAs that may promote various inflammatory diseases. This narrative review investigates the current knowledge regarding miRNAs and their link to AV and HS. The aim is to examine the role of these molecules in the pathogenesis of AV and HS and to identify possible common miRNAs that could explain the similar characteristics of these two diseases. Five miRNA (miR-155 miR-223-, miR-21, and miRNA-146a) levels were found to be altered in both HS and AV. These miRNAs are related to pathogenetic aspects common to both pathologies, such as the regulation of the innate immune response, regulation of the Th1/Th17 axis, and fibrosis processes that induce scar formation. This review provides a starting point for further studies aimed at investigating the role of miRNAs in AV and HS for their possible use as diagnostic-therapeutic targets.

The role of nutrition in acne vulgaris and hidradenitis suppurativa

Acne vulgaris and hidradenitis suppurativa (HS) are chronic inflammatory, multifactorial skin disorders that often develop in adolescence and young adulthood. Both acne vulgaris and HS can cause significant morbidity and psychologic distress, with a negative effect on the quality of life. The relationship among diet, acne, and HS remains somewhat controversial; however, there is increasing evidence that high-glycemic diets and consumption of milk and dairy products promote acne. Studies suggest that weight loss through dietary interventions or bariatric surgery and brewer's yeast exclusion diets have the potential to ameliorate the signs of HS. We review the role of diet in the pathogenesis, prevention, and treatment of HS and acne vulgaris.

Paradoxical Hidradenitis Suppurativa during Biologic Therapy, an Emerging Challenge: A Systematic Review.

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease usually occurring after puberty with painful, deep-seated, inflammatory lesions in the apocrine gland-bearing areas of the body. Although HS pathogenesis is still unproven, recent major research advantages have increased our knowledge of the mechanisms behind HS lesions. Particularly, follicular occlusion followed by follicular rupture has been shown to be crucial to HS development, leading to immune response activation, and resulting in typical clinical HS lesions. Moreover, an increased and imbalanced cytokine production, such as interleukin (IL) 17 and tumor necrosis factor (TNF) α, may play a role in HS. In recent years, paradoxical adverse events have been described during treatment. Since the recent increased use of biologic treatments in HS, an increased number of paradoxical HS occurrences have been reported. In this review, we analyzed all current data on paradoxical HS triggered by biological drugs.

Hidradenitis suppurativa: a review of current treatment options.

Hidradenitis suppurativa (HS) is a chronic, progressive, debilitating, recurrent inflammatory skin disease characterized by the occurrence of very severe, persistent, painful nodules, abscesses, and fistulas, most commonly found in the skin folds of the axilla, groin, gluteal, and perianal areas. The pathogenesis of HS is still not completely understood; currently, it is considered to be an immune-mediated inflammatory illness (IMID). Due to the significant decrease in the patients' quality of life and a delayed beginning of a treatment, the selection of the appropriate therapy is extremely important in these patients. Regardless of the fact that there are multiple treatment options for HS, no uniformly effective therapy has been found. All the guidelines underline the need for a multidisciplinary approach to the disease, which enables providers to create the right management of HS. This article aims to provide updates on the current treatment options of acne inversa to raise awareness and improve the management of the disease.

Hidradenitis Suppurativa: Consequences of Microbiome Dysbiosis on Immune Dysregulation and Disease Severity.

Hidradenitis suppurativa (HS) is a chronic inflammatory condition characterized by the formation of nodules, abscesses, and sinus tracts with tunnels that primarily involves the skin folds. HS affects approximately 1% of the population, but its pathogenesis is unclear. Dysbiosis of skin microbiome is a major cause of HS and alterations of microbiome composition and diversity can be seen in the skin of patients with HS. These disruptions may contribute to the immune dysfunction seen in HS. Understanding these alterations and their contributions to the pathogenesis of HS could help guide future treatment. In addition to dysbiosis promoting immune dysregulation, HS may promote dysbiosis via differences in expression of antimicrobial peptides (AMPs). In this review, we have discussed the role of skin and gut microbiome in manifestation of HS and the consequences of dysbiosis on the immune system.

Investigation of thiol-disulfide homeostasis and ischemia-modified albumin levels in patients with hidradenitis supurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease. The pathogenesis of HS is not clear, and the triggering mechanism for the initiation of the disease is still a controversy. The present study aims to investigate the relationship between thiol-disulfide homeostasis (TDH), ischemia-modified albumin (IMA), and HS. To our knowledge, this will be the first report evaluating TDH and IMA status in HS. The study included 30 patients with HS as the patient group and 30healthy individuals as the control group. For determination of HS severity, Hurley and Hidradenitis suppurativa physician global assessment (PGA) scores were used. One tube venous blood specimen from every participant was obtained. IMA and TDH tests were analyzed in sera of participants. The results were evaluated statistically. Disulfide (p<0.001), Index I (p=0.001), and Index II (p=0.001) levels in HS group were significantly higher than control group. IMA levels in patients with higher Hurley scores are significantly higher (p=0.032, r=0.39). A positive correlation was observed between IMA level and disease duration (p=0.021, r=0.42). The shift in thiol/disulfide balance toward disulfide and significant increase in IMA levels put out the importance of oxidation status in HS etiopathogenesis.

Increased Serum Levels of S100A4 and S100A15 in Individuals Suffering from Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease. Recently, some S100 proteins have been suggested to play an important role in the pathogenesis of chronic immune-mediated inflammatory diseases and they may constitute valuable biomarkers for these diseases’ diagnosis and monitoring. The objective of the current study was to investigate, for the first time, serum levels of S100A4 and S100A15 in individuals suffering from HS. Furthermore, we assessed the associations between S100A4 and S100A15 serum levels and the severity of disease, CRP serum concentration and some demographic and clinical data. Serum levels of S100A4 and S100A15 were evaluated with the commercially available ELISA kit according to the manufacturer’s instructions. The serum level of S100A4 in individuals with HS was significantly elevated as compared to controls, with the highest level found in the individuals in Hurley stage II. The S100A15 serum level was positively correlated with the CRP concentration and was associated with the severity of the disease. The serum level of S100A15 in the individuals in Hurley stage III was significantly elevated compared to that of the controls and the individuals with HS in Hurley stages I and II. S100A4 and S100A15 may be considered as new serum biomarkers for the monitoring of HS progression, and they may play a role in the pathogenesis of HS by promoting inflammatory process and fibrosis.

Antimicrobial peptides in hidradenitis suppurativa: a systematic review.

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease of the hair follicle defined by recurrent nodules, tunnels and scarring involving the intertriginous regions. HS is associated with microbial dysbiosis and immune dysregulation. In HS, an increasing number of studies have investigated antimicrobial peptides (AMPs). To provide an overview of the literature on AMPs in HS, and to discuss the potential role of AMPs in the pathogenesis of HS. PubMed, Embase and the Cochrane Library were searched. The titles, abstracts and full texts of all articles were manually screened. Additionally, the reference lists of the included articles were screened and hand searched for relevant studies. The final literature sample comprised 18 retrospective and prospective studies (no reviews or commentaries) published between 2009 and 2020. This review demonstrates the multitude of AMPs in HS. Although the methodology of the studies varied, the included studies indicate a consistent overexpression of human β-defensin (hBD)-2, S100A7, S100A8 and S100A9 at both the mRNA and protein levels, and a decreased expression of hBD-1. Overall, the studies point to a dysregulation of AMPs in both lesional and nonlesional HS skin.