Genetic Variants Associated With Hidradenitis Suppurativa.

Importance: Hidradenitis suppurativa (HS) is a common and severely morbid chronic inflammatory skin disease that is reported to be highly heritable. However, the genetic understanding of HS is insufficient, and limited genome-wide association studies (GWASs) have been performed for HS, which have not identified significant risk loci. Objective: To identify genetic variants associated with HS and to shed light on the underlying genes and genetic mechanisms. Design, Setting, and Participants: This genetic association study recruited 753 patients with HS in the HS Program for Research and Care Excellence (HS ProCARE) at the University of North Carolina Department of Dermatology from August 2018 to July 2021. A GWAS was performed for 720 patients (after quality control) with controls from the Add Health study and then meta-analyzed with 2 large biobanks, UK Biobank (247 cases) and FinnGen (673 cases). Variants at 3 loci were tested for replication in the BioVU biobank (290 cases). Data analysis was performed from September 2021 to December 2022. Main Outcomes and Measures: Main outcome measures are loci identified, with association of P < 1 × 10-8 considered significant. Results: A total of 753 patients were recruited, with 720 included in the analysis. Mean (SD) age at symptom onset was 20.3 (10.57) years and at enrollment was 35.3 (13.52) years; 360 (50.0%) patients were Black, and 575 (79.7%) were female. In a meta-analysis of the 4 studies, 2 HS-associated loci were identified and replicated, with lead variants rs10512572 (P = 2.3 × 10-11) and rs17090189 (P = 2.1 × 10-8) near the SOX9 and KLF5 genes, respectively. Variants at these loci are located in enhancer regulatory elements detected in skin tissue. Conclusions and Relevance: In this genetic association study, common variants associated with HS located near the SOX9 and KLF5 genes were associated with risk of HS. These or other nearby genes may be associated with genetic risk of disease and the development of clinical features, such as cysts, comedones, and inflammatory tunnels, that are unique to HS. New insights into disease pathogenesis related to these genes may help predict disease progression and novel treatment approaches in the future.

Surgical Procedural Definitions for Hidradenitis Suppurativa Developed by Expert Delphi Consensus.

Importance: Various surgical approaches for hidradenitis suppurativa (HS) have been described in the literature, but the nomenclature is inconsistent. Excisions have been described as wide, local, radical, and regional with variable descriptions of margins. Deroofing procedures have been described with various approaches though descriptions of the approach are generally more uniform. No international consensus has been formed to globally standardize terminology for HS surgical procedures. Lack of such agreement may contribute to misunderstanding or misclassification in HS procedural research studies and impair clear communication among clinicians or between clinicians and patients. Objective: To create a set of standard definitions for HS surgical procedures. Design, Setting, and Participants: This consensus agreement study was conducted from January to May 2021 using the modified Delphi consensus method to reach agreement among a group of international HS experts regarding standardized definitions for an initial set of HS surgical terms, including "incision and drainage," "deroofing/unroofing," "excision," "lesional excision," and "regional excision," ultimately expanded to 10 terms. Provisional definitions were drafted based on existing literature and discussion among an expert 8-member steering committee. Online surveys were disseminated to members of the HS Foundation, direct contacts of the expert panel, and the HSPlace listserv to reach physicians with considerable experience with HS surgery. Consensus was defined as greater than 70% agreement to accept a definition. Results: In the first and second modified Delphi round, 50 and 33 experts participated, respectively. Ten surgical procedural terms and definitions reached consensus with greater than 80% agreement. Overall, the term "local" excision was abandoned and replaced with the descriptors "lesional" or "regional" excision. Of note, "regional" replaced the terms "wide" and "radical" excision. Furthermore, modifiers such as "partial" vs "complete" should also be included when describing surgical procedures. A combination of these terms helped formulate the final glossary of HS surgical procedural definitions. Conclusion and Relevance: An international group of HS experts agreed on a set of definitions describing surgical procedures frequently used by clinicians and in the literature. The standardization and application of such definitions are vital to allow for accurate communication, reporting consistency, and uniform data collection and study design in the future.

Patient Impressions and Outcomes After Clinic-Based Hidradenitis Suppurativa Surgery.

IMPORTANCE: Surgical intervention is frequently needed to treat hidradenitis suppurativa (HS). Patient satisfaction is high based on previous studies, but reports of patient impressions of clinic-based operative experiences and postoperative recovery are limited. OBJECTIVE: To characterize patient impressions, outcomes, and recovery time after clinic-based surgical treatment of HS and examine patient characteristics associated with outcomes. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included patients 12 years or older who underwent clinic-based surgical procedures for treatment of HS at a single subspecialty HS clinic at the University of North Carolina Department of Dermatology from April 2014 to December 2018. Data analysis was performed from January to September 2021. EXPOSURES: Clinic-based deroofing and excisional procedures performed as part of routine care. MAIN OUTCOMES AND MEASURES: The primary outcomes were patient-reported recurrence of HS at the site of surgery, patient satisfaction with the procedures and outcomes, and patient-reported pain and recovery associated with surgery obtained from electronic medical record review and patient questionnaires. RESULTS: Outcomes of 194 procedures for 78 patients (65 [83%] female; mean [SD] age, 35.1 [12.1] years) were analyzed. Self-reported rate of recurrence was 41% (79 procedures). Despite recurrence, most patients (148 procedures [76%]) were very satisfied with their surgical results. The median number of missed days of work or school was 2 (IQR, 1-7 days), and the median number of days until return to normal activity was 10 (IQR, 3-14 days). In addition, for 126 of the 194 procedures (65%), patients stated that pain during an HS flare was worse than pain during surgical recovery. CONCLUSIONS AND RELEVANCE: In this cohort study, patients reported high rates of satisfaction with clinic-based HS surgery. Recovery was typically rapid, with most patients rating postsurgical pain as less severe than their HS pain.

Vulvoperineal Hidradenitis Suppurativa: Diagnosis, Treatment, and Management of Deformities.

IMPORTANCE: Hidradenitis suppurativa (HS) is a chronic, inflammatory disorder affecting skin of intertriginous areas that is often encountered and treated by nondermatologic specialists. OBJECTIVE: The purpose of this literature review is to provide a comprehensive, clinical source of information on HS as it relates to incidence of disease, pathophysiology, diagnosis, and overall management of this condition. EVIDENCE ACQUISITION: Sources were obtained through a comprehensive literature search using PubMed and PMC. Various terms were used to query the database, including "hidradenitis suppurativa," "pathogenesis," "prevalence," "management," "surgery," "perineal," and "vulva." RESULTS: Underreported prevalence and unknown pathogenesis have subsequently led to variable approaches in clinical management, often employing a combination of medical and surgical management. CONCLUSIONS: Early diagnosis and treatment of HS may lead to better disease control and minimize patients' associated morbidity related to disease. RELEVANCE: Knowledge of vulvoperineal hidradenitis is necessary for gynecologists and primary care physicians to ensure early diagnosis, management, and referral for optimal patient outcomes.

Target molecules for future hidradenitis suppurativa treatment.

The registration of the tumour necrosis factor-α inhibitor adalimumab in 2015 was a major step forward in the treatment of hidradenitis suppurativa/acne inversa (HS). However, it soon became evident that the effectiveness of adalimumab in daily practice was highly variable. A significant unmet medical need of HS patients remained, and the search for novel therapeutic targets was intensified. During the 10th European Hidradenitis Suppurativa Foundation (EHSF) e.V. Conference, reknown international HS investigators virtually presented and discussed the published data on these potential target molecules for future HS treatment. This article addresses the most promising molecules currently under investigation from a pathophysiological and clinical point of view. With phase III trials ongoing, the anti- interleukin (IL)-17 biologics bimekizumab and secukinumab are in the most advanced stage of clinical development showing promising results. In addition, targeting IL-1α with bermekimab has shown encouraging results in two clinical trials. Directing treatment at neutrophil recruitment and activation by targeting IL-36 with spesolimab fits well in the pathogenic concept of HS and clinical phase II trial results are pending. In contrast to in situ evidence, Complement 5a (C5a) and C5a receptor blockade have only shown greater clinical benefit in patients with severe HS. Inhibition of Janus kinase (JAK) 1 signalling in HS showed clinical efficacy only in the highest dosage, highlighting that careful surveillance of the balance between safety and efficacy of JAK inhibition is warranted. Overall, clinical efficacies of all novel treatments reported so far are modest. To guide drug development, more and better-defined translational data on the pathogenesis of this severe and enigmatic inflammatory skin disease are required.

Multidisciplinary Update on Genital Hidradenitis Suppurativa: A Review.

Importance: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a predilection for the genital region. Genital HS requires medical and surgical management as well as close collaboration among a multidisciplinary team. Observations: Hidradenitis suppurativa is a disease of the hair follicles that results in recurrent nodules, abscesses, and tunneling sinus tracts. Medical treatment mainstays include antibiotics and retinoids, but the evolving class of biologic medications has gained traction in the treatment of moderate and severe disease. Many of the medical therapies come with adverse effects requiring clinical and laboratory monitoring over the course of treatment. When lesions are refractory to therapy or are too large for medical therapy alone, surgical intervention is required. Surgical procedures can include treatment of affected areas with deroofing or excision of affected skin. When large portions of genital skin are removed, reconstruction is necessary to restore function and aesthetics of the genitals. We describe a variety of reconstructive techniques based on the size and location of the skin deficiency. Conclusions and Relevance: Effective management of genital hidradenitis suppurativa requires a thorough understanding of medical and surgical techniques for prevention, treatment, and reconstruction of genital defects.

PD-L1 and LAG-3 expression in advanced cutaneous squamous cell carcinomas.

BACKGROUND: Expression of programmed death ligand 1 (PD-L1) by cutaneous squamous cell carcinomas has been shown to correlate with advanced disease and risk of metastasis. Lymphocyte activation gene 3 (LAG-3, or CD223) is an inhibitory receptor that interacts with the PD-L1 axis, which has been shown to be a marker of immune exhaustion and a potential immunotherapy target. However, the role of LAG-3 in cutaneous squamous cell carcinoma has not been established. METHODS: We reviewed 18 cases of locally advanced and/or metastatic cutaneous squamous cell carcinomas and assessed for PD-L1 expression, presence or absence of tumor-infiltrating lymphocytes (TILs), and expression of LAG-3 by TILs. RESULTS: PD-L1 expression was present in 11 of 13 locally advanced primary tumors and 5 of 5 metastases. TILs were present in all 18 tumors, of which 14 cases were positive for LAG-3 expression. In positive cases, LAG-3 was expressed on average by 32% of TILs. CONCLUSIONS: Advanced cutaneous squamous cell carcinomas frequently express PD-L1 and are associated with an inflammatory response. LAG-3 expression by TILs was identified in a majority of cases. Our findings suggest that LAG-3 positive tumor-associated inflammatory cells may play a role in the development of advanced disease and offer another potential target for drug therapy.