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Hidradenitis suppurativa is a disease in great need of novel therapies. Given the heterogeneous nature of the disease and the variable response to therapies, biomarkers are essential to predict response to therapies and increase our understanding of disease pathogenesis. Our recent phase 2 clinical trial of spleen tyrosine kinase antagonism using fostamatinib in hidradenitis suppurativa demonstrated a 75% clinical response, with the greatest benefit in individuals with elevated serum inflammation and IgG. In this study, we present results of an in-depth serum proteomic analysis in this patient cohort identifying downregulation of IL-12B as well as B-cell-associated proteins CCL19 and CCL20 and IFN-γ-mediated proteins CXCL10 and CX3CL1. Clinical responders demonstrated greater reduction in serum IL-17A, IL-6, IL-8, and CX3CL1 compared with clinical nonresponders. Baseline levels of CCL28 were associated with clinical response to fostamatinib therapy at week 12. Overall, this suggests that fostamatinib, by targeting B-cell receptor and Fc receptor activity in B cells, monocytes, and macrophages, has a significant molecular impact on the inflammatory serum proteome of hidradenitis suppurativa. In addition, potential therapeutic biomarkers may aid in patient selection for targeted therapy., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Association between Hidradenitis Suppurativa (HS) and Inflammatory Bowel Disease (IBD) has been suggested., Aims: To assess characteristics of HS and IBD in patients with or without concomitant IBD., Methods: In a prospective, nested case-control study, each IBD patient with concomitant HS (Case) was retrospectively matched with 4 patients with HS and no IBD (Controls) for gender and age (±5 years).HS was classified according to the Hurley score and the International Hidradenitis Suppurativa Severity Score System (IHS4). Data were expressed as mean (Standard Deviation). Statistical analysis included Student-t Test or Mann-Whitney Test, χ2 test, univariate and multivariate logistic regression., Results: The study population included 125 patients with HS: 25 with IBD, 100 matched Controls with no IBD. IBD group included 19 (76%) Crohn's disease and 6 (24%) Ulcerative Colitis patients. Obesity, familial HS and perianal HS were less frequent in Cases than in Controls (1[4%] vs 25(25%];p = 0.02; 1[4%] vs 21(21%];p = 0.04; 1[4%] vs 31(31%];p = 0.005, respectively).HS was less severe in Cases when assessed by the IHS4 (5.9 ± 4 vs 9 ± 6.7;p = 0.04).Complete drug-induced response for HS was more frequent in IBD (13[53%] vs28 (28%]; p = 0.04)., Conclusion: Clinical characteristics of HS and of patients differed between Cases and Controls. Present findings suggest the need to appropriately search and assess skin lesions compatible with HS in IBD., Competing Interests: Conflict of interest All authors declare no disclosures specifically related to the study. Biancone L: speaker fee from Takeda, Janssen, ViforPharma, Celltrion; Monteleone G: consultant for First Wave BioPharma and filed a patent related to the treatment of inflammatory bowel diseases with Smad7 antisense oligonucleotides; Calabrese E: speaker fee from Takeda, Janssen, MSD; Bianchi L: speaker or board member for Abbvie, Amgen, Novartis, Almirall, Sunpharma, Sanofi Genzyme, Biogen, Eli Lilly, Janssen, Leo Pharma; Campione E: advisory boards, lectures lee and research grants from Amgen, Almirall, Leo Pharma, UCB., (Copyright © 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Hidradenitis suppurativa (HS) is a chronic inflammatory condition of the apocrine glands primarily affecting the axillae, perineum, and inframammary regions. It is characterized by painful, inflamed cutaneous lesions causing nodules, sinus tracts, and abscesses. Cervicofacial HS is an atypical presentation of HS in the head and neck region and is scarcely reported in the literature. We present a 34-year-old male who developed a large facial swelling overlying the left inferior mandibular border. Management included surgical incision and drainage, antibiotic therapy, followed by infliximab (Remicade). The purpose of this case report was to highlight the presentation, pathophysiology, interdisciplinary approach to treatment and follow-up of patients with cervicofacial HS, and finally, review the cervicofacial HS literature., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by the formation of nodules, abscesses, and fistulae at intertriginous sites. The skin-gut axis is an area of emerging research in inflammatory skin disease and is a potential contributory factor to the pathogenesis of HS. A total of 59 patients with HS provided fecal samples and nasal and skin swabs of affected sites for analysis. A total of 30 healthy controls provided fecal samples, and 20 healthy controls provided nasal and skin swabs. We performed bacterial 16S ribosomal RNA gene amplicon sequencing on total DNA derived from the samples. Microbiome alpha diversity was significantly lower in the fecal, skin, and nasal samples of individuals with HS, which may be secondary to disease biology or related to antibiotic usage. Ruminococcus gnavus was more abundant in the fecal microbiome of individuals with HS, which is also reported in Crohn's disease, suggesting comorbidity due to shared gut microbiota alterations. Finegoldia magna was overabundant in HS skin samples relative to that in the healthy controls. It is possible that local inflammation is driven by F. magna by promoting the formation of neutrophil extracellular traps. These alterations in both the gut and skin microbiome in HS warrant further exploration, and therapeutic strategies, including fecal microbiota transplant or bacteriotherapy, could be of benefit., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Hidradenitis suppurativa (HS) is a chronic, recurring inflammatory dermatosis characterized by abscesses, deep-seated nodules, sinus tracts, and fibrosis in skin lesions around hair follicles of the axillary, inguinal, and anogenital regions. Whereas the exact pathogenesis remains poorly defined, clear evidence suggests that HS is a multifactorial inflammatory disease characterized by innate and adaptive immune components. Bioactive lipids are important regulators of cutaneous homeostasis, inflammation, and resolution of inflammation. Alterations in the lipid mediator profile can lead to malfunction and cutaneous inflammation. We used targeted lipidomics to analyze selected omega-3 and omega-6 polyunsaturated fatty acids in skin of patients with HS and of healthy volunteers. Lesional HS skin displayed enrichment of 5-lipoxygenase (LO)‒derived metabolites, especially leukotriene B4. In addition, 15-LO‒derived metabolites were underrepresented in HS lesions. Changes in the lipid mediator profile were accompanied by transcriptomic dysregulation of the 5-LO and 15-LO pathways. Hyperactivation of the 5-LO pathway in lesional macrophages identified these cells as potential sources of leukotriene B4, which may cause neutrophil influx and activation. Furthermore, leukotriene B4-induced mediators and pathways were elevated in HS lesions, suggesting a contribution of this proinflammatory lipid meditator to the pathophysiology of HS., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Diagnosis of pyoderma gangrenosum, acne and hidradenitis suppurativa (PASH) and pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PAPASH) patients, in spite of recently identified genetic variations, is just clinical, since most patients do not share the same mutations, and the mutations themselves are not informative of the biological pathways commonly disrupted in these patients., Objective: To reveal genetic changes more closely related to PASH and PAPASH etiopathogenesis, identifying novel common pathways involved in these diseases., Methods: Cohort study on PASH (n = 4) and PAPASH (n = 1) patients conducted using whole exome sequencing (WES) approach and a novel bioinformatic pipeline aimed at discovering potentially candidate genes selected from density mutations and involved in pathways relevant to the disease., Results: WES results showed that patients presented 90 genes carrying mutations with deleterious and/or damage impact: 12 genes were in common among the 5 patients and bared 237 ns ExonVar (54 and 183 in homozygosis and heterozygosis, respectively). In the pathway enrichment analysis, only 10 genes were included, allowing us to retrieve 4 pathways shared by all patients: (1) Vitamin D metabolism, (2) keratinization, (3) formation of the cornified envelope and (4) steroid metabolism. Interestingly, all patients had vitamin D levels lower than normal, with a mean value of 10 ng/mL., Conclusion: Our findings, through a novel strategy for analysing the genetic background of syndromic HS patients, suggested that vitamin D metabolism dysfunctions seem to be crucial in PASH and PAPASH pathogenesis. Based on low vitamin D serum levels, its supplementation is envisaged., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare, (Copyright © 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Although the role of immune dysregulation in hidradenitis suppurativa (HS) has yet to be elucidated, recent studies identified several complement abnormalities in patients with HS. The complement system serves a critical role in the modulation of immune response and regulation of cutaneous commensal bacteria. Complement is implicated in several inflammatory skin diseases including systemic lupus erythematosus, angioedema, pemphigus, bullous pemphigoid, and HS. A model of HS pathogenesis is proposed, integrating the role of commensal bacteria, cutaneous immune responses, and complement dysregulation. The role of complement in disease pathogenesis has led to the development of novel anticomplement agents and clinical trials investigating the efficacy of such treatments in HS., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Hidradenitis suppurativa is a chronic skin disease with a significant genetic component and prevalence from 0.5% to 4%. Adalimumab is the only treatment approved by either the European Medicines Agency or the U.S. Food and Drug Administration for the management of moderate to severe hidradenitis suppurativa. To identify genetic variants associated with adalimumab response, we performed a genome-wide association study (GWAS) from the most extensive two phase 3 hidradenitis suppurativa clinical trials (PIONEER I and II) to date. Through direct genotyping and imputation, we tested almost 7 million genetic variants with minor allele frequency > 5% and identified one single linkage disequilibrium block, located in the intron of the BCL2 gene, which reached genome-wide significance (lead single-nucleotide polymorphism, rs59532114; P = 2.35E-08). Bioinformatic analysis and functional genomics experiments suggested a correlation of the most strongly associated single-nucleotide polymorphism minor allele with increased BCL2 gene and protein expressions in hair follicle tissues. In reciprocal knockdown experiments, we found that BCL2 is down-regulated by TNF inhibition. These results highlight a pathway that involves BCL2 in response to adalimumab. Further work is required to determine how this pathway influences adalimumab effectiveness in patients with hidradenitis suppurativa., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Hidradenitis suppurativa (HS) (also designated acne inversa) is a chronic inflammatory disease characterized by painful purulent skin lesions and progressive destruction of skin architecture. Despite the high burden for the patients, pathogenetic pathways underlying HS alterations remain obscure. When we examined the HS cytokine pattern, IL-1β turned out to be a highly prominent cytokine, overexpressed even compared with psoriatic lesions. Analyses of IL-1β-induced transcriptome in various cell types showed overlapping profiles, with upregulations of molecules causing immune cell infiltration and extracellular matrix degradation, and of specific cytokines including IL-6, IL-32, and IL-36. Matching cellular IL-1 receptor levels, dermal fibroblasts showed both the strongest and broadest IL-1β response, which was not clearly shared or strengthened by other cytokines. The IL-1β signature was specifically present in HS lesions and could be reversed by application of IL-1 receptor antagonist. Search for blood parameters associated with IL-1β pathway activity in HS identified serum amyloid A, which was synergistically induced by IL-1β and IL-6 in hepatocytes. Consequently, strongly elevated blood serum amyloid A levels in HS correlated positively with the extent of inflammatory skin alterations. In summary, the IL-1β pathway represents a pathogenetic cascade, whose activity may be therapeutically targeted and monitored by blood SAA levels., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Nicastrin (NCSTN) mutations are associated with familial acne inversa (AI), and emerging evidence suggests that microRNAs (miRNAs) are involved in various skin diseases. However, whether NCSTN mutations affect miRNA levels and their subsequent signaling pathways in familial AI patients has not been studied. We aimed to elucidate the relationship between NCSTN mutations and familial AI pathogenesis by investigating differential miRNA expression and their related pathways. Combined with miRNA microarray data from familial AI patients, Ncstn keratinocyte-specific-knockout (Ncstn ΔKC ) mice and bioinformatics predictions showed that NCSTN mutations led to decreased miR-30a-3p levels, which negatively regulated RAB31 expression. Moreover, enhanced RAB31 levels accelerated degradation of activated EGFR, leading to abnormal differentiation in keratinocytes. The impaired EGFR signaling and its effects on epidermal differentiation were also observed in familial AI patients and Ncstn ΔKC mice. Thus, our study showed that miR-30a-3p/RAB31/EGFR signaling pathway may play a key role in the pathogenesis of familial AI with NCSTN mutations., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Hidradenitis suppurativa (HS) is a chronic, inflammatory, and debilitating disease of hair follicles with 1-4% prevalence and high morbidity. There is a dearth of information on the pathogenesis and immune dysregulation underlying HS; therefore, we carried out a detailed analysis of skin-infiltrating T cells. Cells isolated from skin biopsy samples and blood from HS patients and healthy control subjects were analyzed by 16-parameter flow cytometry to provide detailed profiles of CD4 T-cell subsets. We observed substantial infiltration of inflammatory T cells with a striking T helper (Th) type 17-skewed cytokine profile in HS skin; these cells expressed the Th17 lineage marker CD161 and IL-17, as well as proinflammatory cytokines GM-CSF, IL-22, IFN-γ, and tumor necrosis factor. Regulatory T cells were also enriched in HS lesional skin; however, the ratio of Th17 to regulatory T cells was nonetheless highly dysregulated in favor of Th17 cells. In contrast, lesional skin from anti-tumor necrosis factor-treated HS patients who showed substantial clinical improvement exhibited a significant reduction in the frequency of Th17 cells and normalization of the Th17 to regulatory T cell ratio. These data suggest that inhibition of pathogenic IL-17 via tumor necrosis factor blockade is associated with improvement in immune dysregulation in HS and may provide a rationale for targeting IL-17 in the disease., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The reused skin-graft technique can be used to treat chronic gluteal hidradenitis suppurativa, but long-term outcomes and the reliability of the technique have not been reported., Methods: In a retrospective review of 18 men with chronic gluteal hidradenitis suppurativa (age range, 18-68 years) treated with a reused skin graft between June 2004 and March 2012, we evaluated disease severity (Hurley classification system), skin-graft thickness, the need for an additional normal skin graft, histological findings and recurrence rate at the surgical site., Results: The mean duration of follow-up was 61.3 months (range, 17-113 months). Five cases were classified into severity group I, 12 cases into severity group II and one case into severity group III. The range of skin-graft thicknesses was 0.013-0.020 inches. An additional donor site was unnecessary in 10 cases (three cases in group I (60%) and seven cases in group II (58.3%)). Histological examination indicated that a buried epidermal cyst could cause chronic gluteal hidradenitis suppurativa recurrence, although none of the patients experienced recurrence at the surgical site during follow-up., Conclusion: The reused skin-graft technique is reliable for chronic gluteal hidradenitis suppurativa resection, and it shows promising long-term outcomes., (Copyright © 2015 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

To identify the underlying subtypes of hidradenitis suppurativa (HS), we performed latent class analysis on prospective clinical data of 618 consecutive patients seen between 2002 and 2010. The median patient age was 31 years (Q1=26; Q3=38), median age at HS onset was 20 years (16-25), and median Sartorius score was 18 (11-19); 34.4% of patients were of Hurley stage II or III. A three-class model showed the best fit. Latent class 1 (LC1) patients (48%) had a high probability of breast and armpit lesions (0.74) and hypertrophic scars (0.41). LC2 patients (26%) had a high probability not only of breast and armpit lesions (0.96) but also of lesions in the ears, chest, back, or legs (0.55); follicular lesions (pilonidal sinus: 0.48; comedones: 0.74); severe acne (0.47); and a family history of HS (0.44). Compared with LC1 patients, LC2 patients were more often male (odds ratio, 4.6; 95% confidence interval, 3-7; P<0.001) and current smokers (2.2; 1.3-3.9; P=0.005), and had greater disease severity (odds ratio, 1.6; 1.3-1.9; P<0.001). LC3 was characterized by gluteal involvement (0.54), papules, and folliculitis (0.71). LC3 patients were less often obese (0.6; 0.3-0.95; P=0.03) and had less severe disease (0.9; 0.7-1.1; P<0.001). These three phenotypes ("axillary-mammary", "follicular", and "gluteal") may help stratify patients for clinical trials.

Awareness is increasing that there is phenotypic heterogeneity within the hidradenitis suppurativa (HS) disease spectrum. However, the few randomized HS trials that are available have not distinguished between the subtypes of the disease. In this issue, Canoui-Poitrine et al. used latent class (LC) analysis of the largest HS cohort described to date to generate three phenotypic subtypes. LC 1 correlates with "typical" European HS, mainly involving the axilla, groin, and, in women, the inframammary region. "Atypical" HS, which may be linked to γ-secretase gene mutations, was subdivided further into LC2 and LC3 subtypes.

In recent years, the physiological role of non-neuronal acetylcholine (ACh) and its receptors (AChR) in epidermal physiology has been under intense investigation. However, little is known about the role of the non-neuronal cholinergic system in inflammatory skin diseases. We chose the clinically nicotine-dependent skin disease hidradenitis suppurativa (HS) as model to study the influence of long term nicotine ingestion on epidermal morphology and AChR expression. HS is a chronic inflammatory, disabling disease of unknown pathogenesis emerging from the pilosebaceous unit of the intertriginous areas. In order to correlate our findings to specific nicotine effects, we used the organotypical coculture system (OTC) and raised artificial epidermis in the presence of nicotine. After 12 days in culture control OTC showed a mature epithelium, while nicotine treated OTCs were significantly thicker. Using immunofluorescence analysis, nicotine treated OTCs produced significantly stronger immunoreactivity (IR) for the alpha3, M(3) and M(5) AChR antisera than control. In contrast, the alpha7 nAChR antiserum showed a slightly reduced IR in the granular layer and the alpha9 nAChR IR retracted to the lower suprabasal layers. In HS epidermis we found the strongest IR for all AChR around the follicular infundibulum while in the sinus epithelia it was only weak. In contrast to the nicotine treated OTC, the alpha7 nAChR IR in the hyperplastic HS epidermis was clearly extended to all living layers. Altogether we provide first hints for a causative role of the non-neuronal cholinergic system in the pathogenesis of HS by promoting infundibular epithelial hyperplasia and thus follicular plugging.

Acne inversa (hidradenitis suppurativa) is a chronic relapsing inflammatory skin disease characterized by recurrent draining sinuses and abscesses, predominantly in skin folds that carry terminal hairs and apocrine glands. The genetic basis for this disease is unknown. In this study, we performed a genome-wide scan in a four-generation Chinese family to map the chromosome location of the responsible gene. We first identified a locus at chromosome 1p21.1-1q25.3 with the maximum logarithm of odds (LOD) score of 3.26 at the marker D1S2624 (at recombination fraction=0.00). The other two-point LOD scores >/=3 were observed at markers D1S2695, D1S2726, D1S252, and D1S2777. Haplotype analysis localized this locus to a 76 Mb region flanked by D1S248 and D1S2711. This is the first locus for the inversa acne and will be a starting point towards understanding the molecular mechanisms of this disease.

Hidradenitis suppurativa is a chronic, suppurative and scarring disease characterized by painful, inflamed lesions in the axillae, perineum, groin, scrotum and other parts of the body with apocrine-bearing skin including genital skin. Appropriate medical treatment alone appears to be insufficient for managing most patients with severe lesions. In the vast majority of cases, surgery consists in complete excision of the lesions with primary closure or healing by secondary intention. In severe cases, radical excision of all diseased apocrine-bearing skin is mandatory and the resulting defects are generally repaired by mesh skin grafts. In the most severe cases it may be necessary to realize loco-regional flaps. Generally we reconstruct the perineal region with bilateral fasciocutaneous thigh flaps. We report a case of hidradenitis suppurativa where the lesions were so extensive from penis to anus we had to imagine a tailor-made flap based on the abdominoplasty techniques.

Squamous cell carcinoma is a rare complication of chronic, severe, hidradenitis suppurativa. We describe a patient with a 20-year history of extensive perineal hidradenitis suppurativa who presented with subacute muscle weakness and sensory symptoms. He was subsequently diagnosed with squamous cell carcinoma arising in the area of hidradenitis. The neurologic symptoms and signs resolved after complete excision of the tumor. This presentation is consistent with a paraneoplastic neuropathy, which has not been reported previously in patients with squamous cell carcinoma arising in patients with hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic disease manifested by recurrent abscesses, sinus tracts and scarring. It arises most commonly, however, not exclusive from apocrine gland bearing skin. This review article sets out to clarify the importance of early diagnosis, the pathogenesis and aetiology of HS, and evidence for medical and surgical therapies for this debilitating disease.HS is caused primarily by follicular occlusion with secondary involvement of the apocrine glands. The aetiology is still poorly understood. There is a genetic component with probable hormonal influence on gene expression. Shearing forces from obesity and tight clothing contribute to its development. Management should be appropriately tailored for the severity and distribution of HS as well as quality of life of the patient. Medical management with appropriate antibiotics, if initiated early, can be successful in mild to moderate severity HS as well as improving disease control prior to attempted curative surgery in severe HS. Other helpful measures include advice on lifestyle changes, intralesional steroids, systemic retinoids, hormonal manipulation, and a revival of interest in the use of radiotherapy for HS. While there is a place for 'conservative' surgical procedures (including CO(2) laser) in selected cases of mild to moderate HS, radical excision of all apocrine-bearing tissue is the definitive treatment. We advocate close interdisciplinary collaboration as well as a cautionary approach to timing and planning of surgery to minimise recurrence rates.

Although a number of different reconstructive techniques have been described for the treatment of axillary skin defects, split-thickness skin grafting continues to be the most common surgical modality. Here, we present our recent experience of using split-thickness skin grafts together with negative-pressure dressings for the management of defects following wide surgical excision of severe hidradenitis suppurativa. This technique ensures complete skin-graft take whilst allowing full shoulder mobility, thereby minimising the undesirable sequelae associated with split-thickness skin grafting alone.

Background: Two patients with bilateral Mooren-type ulcers had underlying chronic hepatitis C virus (HCV) infection. Both patients also had chronic, pruritic dermatitis, which in one patient was diagnosed as hidradenitis suppurativa., Methods: Serum from the first patient and serum, conjunctiva, and liver from the second patient were analyzed for HCV genomic RNA using the reverse transcriptase-polymerase chain reaction. Serum anti-HCV antibodies were monitored with a commercially available second-generation test. Liver and conjunctival biopsies were evaluated histopathologically., Results: Liver biopsy showed severe hepatitis in the first patient, but normal liver tissue in the second. Hepatitis C virus genomic RNA was detected in the serum of both patients. In the first patient, the virus was detected 4 months after completion of interferon alfa-2b treatment for chronic active hepatitis. In the second patient, HCV genomic RNA was detected in serum, but not in conjunctiva or liver tissue. Hepatitis C virus could not be detected in the serum of the second patient after 2 weeks of interferon alfa-2b treatment. Both patients had serum anti-HCV antibodies. In case 1, there was a marked improvement in the corneal disease during and after 6 months of interferon alfa-2b treatment for chronic active hepatitis that paralleled a return of serum liver enzyme levels to the normal range. In the second patient, the corneal disease improved after 6 weeks of interferon alfa-2b treatment, but abruptly worsened when the patient discontinued therapy. The corneal disease improved again after interferon alfa-2b was reinstituted., Conclusions: Chronic HCV virus infection is associated with Mooren-type peripheral ulcerative keratitis. All patients with Mooren-type ulcers should be tested for evidence of HCV infection in consultation with a liver specialist. Even when improvement is obtained with interferon alfa-2b treatment, however, continued follow-up is important because relapse is common and repeat treatment may be effective.