Advances in molecular pathogenesis of hidradenitis suppurativa: Dysregulated keratins and ECM signaling.

Hidradenitis suppurativa (HS) is characterized by deep-seated, highly inflamed, and painful lumps/abscesses, fistulae, and sinus tracts that grow extensively deep in the dermis and are highly immunogenic in nature. In about one-third of the HS patients there is strong evidence for the role of γ-secretase mutations along with dysregulated Notch signaling. However, the contribution of dysregulated Notch signaling in HS pathogenesis in relation to hair follicle alterations and hyper-activation of the immune system remains undefined. A genome-wide association study (GWAS), proteomic data and functional investigations of identified sequence variants in HS pathology are not fully revealing. The disease initiation or progression may involve bacterial infection besides intrinsic functional defects in keratinocytes, which may be key to further exacerbate immune cell infiltration and cytokine production in and around the lesional tissue. The absence of a suitable animal model that could fully recapitulate the pathogenesis of HS is a major impediment for proper understanding the underlying mechanisms and development of effective treatments. The presence of extracellular matrix (ECM) degradation products along with dysregulation in keratinocytes and, dermal fibroblasts ultimately affect immune regulation and are various components of HS pathogenesis. Bacterial infection further exacerbates the complexity of the disease progression. While anti-TNFα therapy shows partial efficacy, treatment to cure HS is absent. Multiple clinical trials targeting various cytokines, complement C5a and ECM products are in progress. This review provides state-of-the-art information on these aspects with a focus on dysregulated keratinocyte and immune cells; and role of ECM, and Keratin functions in this regard.

Dysregulation of Aquaporin-3 and Glyceryl Glucoside Restoring Action in Hidradenitis Suppurativa in Vitro Models.

BACKGROUND/AIMS: Aquaporin-3 (AQP3) is an aquaglyceroporin and peroxiporin that plays a crucial role in skin barrier homeostasis. Dysregulated AQP3 expression has been observed in different inflammatory skin conditions. Hidradenitis Suppurativa (HS) is an autoinflammatory keratinization disease that typically appears between 10 and 21 years of age, characterized by alteration of skin barrier homeostasis. METHODS: To evaluate in vitro the role of AQP3 in the development of HS, we performed real-time PCR and Western blot to analyze gene and protein levels in human keratinocyte cell lines knock-out (KO) for NCSTN and PSENEN genes, simulating genetic-associated HS. Additionally, we investigated the impact of Glyceryl Glucoside (GG) on biological processes by performing MTT, scratch, proliferation assays and proteome studies. RESULTS: We detected a significant decrease of the levels of AQP3 gene and protein in KO cell lines. GG effectively elevated the levels of mRNA and protein, significantly decreased the hyperproliferation rate, and enhanced cell migration in our in vitro model of genetic Hidradenitis Suppurativa. Pathway enrichment analysis further confirmed GG's role in the migration and proliferation pathways of keratinocytes. CONCLUSION: Our results suggest that AQP3 may act as a new novel actor in HS etio-pathogenesis, and GG could be further explored as potential treatment option for managing HS in patients.

Initial steps towards developing a predictive algorithm of disease progression for hidradenitis suppurativa (HS): results from a Cox proportional hazard regression analysis on disease progression among a cohort of 335 Danish patients with HS.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory and scarring disease with a wide spectrum of disease severity. The amount of scarring is proportional to the preceding tissue damage and poses a challenge to patients. Severe HS is most often treatment recalcitrant, but hypothetically avoidable through early biologic treatment. Early prediction of individual risk of disease progression is therefore essential for patient management. OBJECTIVES: To investigate risk factors associated with disease progression and to design an algorithm capable of predicting disease -progression. METHODS: A prospective cohort study of 335 Hurley III-naïve patients with HS, not treated with biologics, was followed for a median of 2 years. Potential risk factors covered basic demographics, HS anamnestic factors and clinical HS factors collected during physical examination. Two separate Cox proportional hazard regression (CPHR) analyses were conducted. A summated 'progression score' was calculated and used in the predictive algorithm of severe disease. Subsequent bootstrap sampling was used to validate the predictability of the predictive algorithm. RESULTS: The CPHR analysis of Transition to severe disease found that active smoking [hazard ratio (HR) 4.01, 95% confidence interval (CI) 1.71-9.40, P = 0.001]; body mass index (BMI) points > 25 at baseline (each point: HR 1.06, 95% CI 1.02-1.09, P < 0.001); active disease in 2 (HR 4.26, 95% CI 1.23-14.84, P = 0.02) and ≥ 3 areas (HR 6.54, 95% CI 1.89-22.72, P = 0.003) all constituted substantial risk factors. Conversely, the CPHR analysis of Disease progression did not yield results of clinical relevance. A 'progression score' of 3.04 was used as a threshold in the predictive algorithm of Transition to severe disease and achieved the following test specifics: sensitivity = 0.51, specificity = 0.86, positive predictive value = 0.50, negative predictive value = 0.86. CONCLUSIONS: We found a disparity between factors increasing the risk of simple Disease progression and those increasing the risk of Transition to severe disease. For the latter, active smoking, BMI points > 25, active disease in 2 or ≥ 3 areas were all shown to be the clinically relevant factors that could be used to construct an algorithm that correctly predicted progression to severe HS in more than half of all instances.

Neutrophilic granulocyte-derived B-cell activating factor supports B cells in skin lesions in hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by painful inflamed nodules, abscesses, and pus-draining tunnels appearing in axillary, inguinal, and perianal skin areas. HS lesions contain various types of immigrated immune cells. OBJECTIVE: This study aimed to characterize mediators that support lesional B/plasma cell persistence in HS. METHODS: Skin samples from several cohorts of HS patients and control cohorts were assessed by mRNA sequencing, quantitative PCR on reverse-transcribed RNA, flow cytometry, and immunohistofluorescence. Blood plasma and cultured skin biopsy samples, keratinocytes, dermal fibroblasts, neutrophilic granulocytes (neutrophils), monocytes, and B cells were analyzed. Complex systems biology approaches were used to evaluate bulk and single-cell RNA sequencing data. RESULTS: Proportions of B/plasma cells, neutrophils, CD8+ T cells, and M0 and M1 macrophages were elevated in HS lesions compared to skin of healthy and perilesional intertriginous areas. There was an association between B/plasma cells, neutrophils, and B-cell activating factor (BAFF, aka TNFSF13B). BAFF was abundant in HS lesions, particularly in nodules and abscesses. Among the cell types present in HS lesions, myeloid cells were the main BAFF producers. Mechanistically, granulocyte colony-stimulating factor in the presence of bacterial products was the major stimulus for neutrophils' BAFF secretion. Lesional upregulation of BAFF receptors was attributed to B cells (TNFRSF13C/BAFFR and TNFRSF13B/TACI) and plasma cells (TNFRSF17/BCMA). Characterization of the lesional BAFF pathway revealed molecules involved in migration/adhesion (eg, CXCR4, CD37, CD53, SELL), proliferation/survival (eg, BST2), activation (eg, KLF2, PRKCB), and reactive oxygen species production (eg, NCF1, CYBC1) of B/plasma cells. CONCLUSION: Neutrophil-derived BAFF supports B/plasma cell persistence and function in HS lesions.

A centre-based ambulatory care concept for hidradenitis suppurativa improves disease activity, disease burden and patient satisfaction: results from the randomized controlled EsmAiL trial.

BACKGROUND: Hidradenitis suppurativa (HS) is an inflammatory disease of the inverse skin regions that occurs in young women, in particular, and affects approximately 1% of the population. Outpatient care is often inadequate and usually cannot prevent progression. OBJECTIVES: To evaluate in the EsmAiL ('Evaluation eines strukturierten und leitlinienbasierten multmodalen Versorgungskonzepts für Menschen mit Akne inversa') trial whether an innovative care concept can decrease disease activity and burden, and improve patient satisfaction. METHODS: EsmAiL was conducted as a two-arm, multicentre, prospective, randomized controlled trial that included 553 adults with HS. Inclusion criteria were a minimum of three inflammatory lesions and at least a moderate impact of the disease on quality of life. The control group (CG) remained under standard care, while patients in the intervention group (IG) were treated according to a trial-specific, multimodal concept. The primary endpoint was the absolute change in International Hidradenitis Suppurativa Severity Score System (IHS4). RESULTS: In total, 274 patients were randomized to the IG and 279 to the CG. Altogether, 377 attended the final assessment after 12 months of intervention. Participants in the IG (n = 203) achieved a mean improvement in IHS4 of 9.3 points, while the average decrease in IHS4 in patients in the CG (n = 174) was 5.7 points (P = 0.003). Patients treated under the new care concept also reported a statistically significantly higher decrease in pain, Dermatology Life Quality Index and Hospital Anxiety and Depression Scale scores compared with those in the CG (P < 0.001). Patient satisfaction was also statistically significantly higher in the IG compared with the CG (P < 0.001). CONCLUSIONS: The establishment of standardized treatment algorithms in so-called 'acne inversa centres' in the ambulatory setting has a substantial, positive impact on the course of HS and significantly improves patient satisfaction.

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.

Adalimumab-Induced Paradoxical Psoriasis Treated with Biologics Targeting the IL-17/IL-23 Axis in Patients with Hidradenitis Suppurativa.

BACKGROUND: Paradoxical psoriasis (PP) has been mainly described in patients receiving tumor necrosis factor-α (TNFα) inhibitors for inflammatory bowel disease or psoriasis vulgaris, while such data in the context of hidradenitis suppurativa (HS) are scarce. The purpose of this study was to demonstrate the course of PP and the underlying HS upon switching from adalimumab to a biologic agent targeting the interleukin (IL)-17/IL-23 axis. METHODS: The electronic medical database of the outpatient department for HS of a tertiary hospital for skin diseases was searched to identify patients with moderate-to-severe HS under treatment with adalimumab, who developed PP and were switched to biological therapy with an IL-17 or IL-23 inhibitor between February 2016 and January 2022. Disease assessment scores were evaluated at baseline, at time of PP development, as well as six and 12 months thereafter. RESULTS: Among the 83 patients who received adalimumab for the treatment of HS between February 2016 and January 2022, 10 patients (12%) developed paradoxical psoriasiform skin reactions after a median time of seven (range, 2-48) months. There were four females (40%) and six males (60%) with a median age of 42.5 (range, 33-56) years. Five patients presented with plaque psoriasis and five with palmoplantar pustulosis, while four had intertriginous and three nail involvement. In most of the patients, HS responded well to adalimumab at onset of PP. Eight patients were changed to secukinumab, one to ustekinumab, and one to risankizumab. HS further improved in all but 2 patients, one receiving secukinumab and one receiving risankizumab. In addition, all patients achieved improvement of PP. CONCLUSION: Despite the small number of patients, this study provides support that patients with adalimumab-induced PP may benefit from biologics targeting the IL-17/IL-23 axis. Further studies are needed to establish the optimal therapeutic strategy of the anti-TNFα-induced PP in the context of HS.

Association between Hidradenitis Suppurativa and Abnormalities in Semen Parameters and Sexual Function: A Pilot Study.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease affecting patients of reproductive age. Although HS shares risk factors with male infertility, only 1 epidemiological study has evaluated this association. To further evaluate this potential association, findings on semen and hormonal analysis, testicular ultrasound, and the International Index of Erectile Function (IIEF-15) were compared between 28 men attending a tertiary HS clinic during the period April 2019 to April 2021, and 44 healthy controls, spouses of infertile women undergoing semen evaluation before in vitro fertilization. Patients with HS were divided based on the absence or presence of gluteal and genital lesions. Patients with HS were younger than controls (median 27 vs 34 years, p < 0.0004) and had a higher proportion of smokers (86% vs 33%, p < 0.0001). Semen parameters in patients with gluteal-genital lesions, specifically those with severe scrotal involvement necessitating surgery, were lower than the WHO reference values and significantly lower than in patients without gluteal-genital lesions and controls. Erectile dysfunction was reported by 93% of patients with HS. These findings suggest that spermatogenesis and sexual function may be impaired in young men with HS. Therefore, multidisciplinary management of HS should include their evaluation to identify patients who might benefit from semen cryopreservation and sexual treatment.

High inflammation in hidradenitis suppurativa extends to perilesional skin and can be subdivided by lipocalin-2 expression.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease presenting with diverse manifestations ranging from nodules and abscesses to draining tunnels. Whether the underlying inflammation from lesions extends to relatively healthy-appearing adjacent perilesional and distant nonlesional skin has not been systematically evaluated. OBJECTIVE: We sought to characterize lesional, perilesional, and nonlesional skin in patients with HS. METHODS: Skin biopsy samples were collected under ultrasound guidance from patients with active, untreated moderate-to-severe HS. Site-matched control biopsy samples from healthy volunteers were used for comparison. RESULTS: RNA sequencing demonstrated that HS skin clustered separately from healthy control skin, with perilesional and lesion skin clustering together and away from nonlesional skin. Immunohistochemistry analysis identified psoriasiform hyperplasia with keratin 16 positivity in both perilesional and lesional skin, with comparable levels of CD3+, CD11c+, and neutrophil elastase-positive cellular infiltration. There was a marked upregulation of IL-17 signaling in perilesional and lesional skin. HS samples clustered on the basis of expression of lipocalin-2 (LCN2), with samples characterized by high LCN2 expression in the skin exhibiting a differing transcriptomic profile with significantly higher overall inflammation than that of skin characterized by low LCN2 levels. CONCLUSIONS: Perilesional HS skin has a transcriptomic and molecular profile comparable to that of lesional skin. HS can be grouped into 2 distinct subtypes based on molecular levels of LCN2 in the skin, with the LCN2-high subtype exhibiting an overall higher inflammatory burden and an upregulation of targetable cytokines. To our knowledge, this is the first study to characterize a unique HS subtype (and a potential endotype) that may guide future therapeutic targets.

Blood T Helper Memory Cells: A Tool for Studying Skin Inflammation in HS?

Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful lesions on intertriginous body areas such as the axillary, inguinal, and perianal sites. Given the limited treatment options for HS, expanding our knowledge of its pathogenetic mechanisms is a prerequisite for novel therapeutic developments. T cells are assumed to play a crucial role in HS pathogenesis. However, it is currently unknown whether blood T cells show specific molecular alterations in HS. To address this, we studied the molecular profile of CD4+ memory T (Thmem) cells purified from the blood of patients with HS and matched healthy participants. About 2.0% and 1.9% of protein-coding transcripts were found to be up- and down-regulated in blood HS Thmem cells, respectively. These differentially expressed transcripts (DETs) are known to be involved in nucleoside triphosphate/nucleotide metabolic processes, mitochondrion organization, and oxidative phosphorylation. The detected down-regulation of transcripts involved in oxidative phosphorylation suggest a metabolic shift of HS Thmem cells towards glycolysis. The inclusion of transcriptome data from skin from HS patients and healthy participants in the analyses revealed that in HS skin lesions, the expression pattern of transcripts identified as DETs in blood HS Thmem cells was very similar to the expression pattern of the totality of protein-coding transcripts. Furthermore, there was no significant association between the extent of the expressional changes in the DETs of blood HS Thmem cells and the extent of the expressional changes in these transcripts in HS skin lesions compared to healthy donor skin. Additionally, a gene ontology enrichment analysis did not demonstrate any association of the DETs of blood HS Thmem cells with skin disorders. Instead, there were associations with different neurological diseases, non-alcoholic fatty liver disease, and thermogenesis. The levels of most DETs linked to neurological diseases showed a positive correlation to each other, suggesting common regulatory mechanisms. In summary, the transcriptomic changes in blood Thmem cells observed in patients with manifest cutaneous HS lesions do not appear to be characteristic of the molecular changes in the skin. Instead, they could be useful for studying comorbidities and identifying corresponding blood biomarkers in these patients.

The Essential Role of microRNAs in Inflammatory and Autoimmune Skin Diseases-A Review.

The etiopathogenesis of autoimmune skin diseases is complex and still not fully understood. The role of epigenetic factors is emphasized in the development of such diseases. MicroRNAs (miRNAs), a group of non-coding RNAs (ncRNAs-non-coding RNAs), are one of the important post-transcriptional epigenetic factors. miRNAs have a significant role in the regulation of the immune response by participating in the process of the differentiation and activation of B and T lymphocytes, macrophages, and dendritic cells. Recent advances in research on epigenetic factors have provided new insights into the pathogenesis and potential diagnostic and therapeutic targets of many pathologies. Numerous studies revealed a change in the expression of some microRNAs in inflammatory skin disorders, and the regulation of miRNA expression is a promising therapeutic goal. This review presents the state of the art regarding changes in the expression and role of miRNAs in inflammatory and autoimmune skin diseases, including psoriasis, atopic dermatitis, vitiligo, lichen planus, hidradenitis suppurativa, and autoimmune blistering diseases.

Modulation of Disease-Associated Pathways in Hidradenitis Suppurativa by the Janus Kinase 1 Inhibitor Povorcitinib: Transcriptomic and Proteomic Analyses of Two Phase 2 Studies.

Janus kinase (JAK)/signal transducer and activator of transcription signaling (STAT) has been implicated in the pathophysiology of hidradenitis suppurativa (HS). This study evaluated treatment-related transcriptomic and proteomic changes in patients with moderate-to-severe HS treated with the investigational oral JAK1-selective inhibitor povorcitinib (INCB054707) in two phase 2 trials. Lesional skin punch biopsies (baseline and Week 8) were taken from active HS lesions of patients receiving povorcitinib (15 or 30 mg) once daily (QD) or a placebo. RNA-seq and gene set enrichment analyses were used to evaluate the effects of povorcitinib on differential gene expression among previously reported gene signatures from HS and wounded skin. The number of differentially expressed genes was the greatest in the 30 mg povorcitinib QD dose group, consistent with the published efficacy results. Notably, the genes impacted reflected JAK/STAT signaling transcripts downstream of TNF-α signaling, or those regulated by TGF-ß. Proteomic analyses were conducted on blood samples obtained at baseline and Weeks 4 and 8 from patients receiving povorcitinib (15, 30, 60, or 90 mg) QD or placebo. Povorcitinib was associated with transcriptomic downregulation of multiple HS and inflammatory signaling markers as well as the reversal of gene expression previously associated with HS lesional and wounded skin. Povorcitinib also demonstrated dose-dependent modulation of several proteins implicated in HS pathophysiology, with changes observed by Week 4. The reversal of HS lesional gene signatures and rapid, dose-dependent protein regulation highlight the potential of JAK1 inhibition to modulate underlying disease pathology in HS.

The Effectiveness of Guselkumab in Patients With Hidradenitis Suppurativa Under Clinical Practice Conditions: A Spanish Multicentre Retrospective Study.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic skin condition causing lesions in which high levels of interleukin (IL)-23 and T-helper 17 cells are found. Adalimumab remains the only approved treatment. Guselkumab, an antibody targeting the p19 protein subunit of extracellular IL-23, is approved for the treatment of moderate-severe psoriasis, but evidence on its efficacy in treating HS is limited. OBJECTIVES: To assess the effectiveness and safety of guselkumab in treating moderate-severe HS under clinical practice conditions. METHODS: A multicentre retrospective observational study was carried out in 13 Spanish Hospitals including adult HS patients treated with guselkumab within a compassionate use programme (March 2020-March 2022). Data referred to patient demographic and clinical characteristics at treatment initiation (baseline), patient-reported outcomes (Numerical Pain Rating Scale [NPRS] and Dermatology Life Quality Index [DLQI]), physician scores (International Hidradenitis Suppurativa Severity Score System [IHS4], HS Physical Global Score [HS-PGA] and Hidradenitis Suppurativa Clinical Response [HiSCR]) were recorded at baseline and at 16, 24, and 48 weeks of treatment. RESULTS: A total of 69 patients were included. Most (84.10%) had severe HS (Hurley III) and had been diagnosed for over ten years (58.80%). The patients had been subjected to multiple non-biological (mean 3.56) or biological (mean 1.78) therapies, and almost 90% of those treated with biologics had received adalimumab. A significant decrease in IHS4, HS-PGA, NPRS, and DLQI scores was observed from baseline to 48 weeks of guselkumab treatment (all p<0.01). HiSCR was achieved in 58.33% and 56.52% of the patients at 16 and 24 weeks, respectively. Overall, 16 patients discontinued treatment, mostly due to inefficacy (n=7) or loss of efficacy (n=3). No serious adverse events were observed. CONCLUSIONS: Our results indicate that guselkumab may be a safe and effective therapeutic alternative for patients with severe HS that fail to respond to other biologics.

The Effectiveness of Guselkumab in Patients With Hidradenitis Suppurativa Under Clinical Practice Conditions: A Spanish Multicentre Retrospective Study. / [Artículo traducido] Efectividad de guselkumab en pacientes con hidradenitis supurativa en condiciones de práctica clínica: estudio retrospectivo y multicéntrico en España.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic skin condition causing lesions in which high levels of interleukin (IL)-23 and T-helper17 cells are found. Adalimumab remains the only approved treatment. Guselkumab, an antibody targeting the p19 protein subunit of extracellular IL-23, is approved for the treatment of moderate-severe psoriasis, but evidence on its efficacy in treating HS is limited. OBJECTIVES: To assess the effectiveness and safety of guselkumab in treating moderate-severe HS under clinical practice conditions. METHODS: A multicentre retrospective observational study was carried out in 13 Spanish hospitals including adult HS patients treated with guselkumab within a compassionate use programme (March 2020-March 2022). Data referred to patient demographic and clinical characteristics at treatment initiation (baseline), patient-reported outcomes (Numerical Pain Rating Scale [NPRS] and Dermatology Life Quality Index [DLQI]), physician scores (International Hidradenitis Suppurativa Severity Score System [IHS4], HS Physical Global Score [HS-PGA] and Hidradenitis Suppurativa Clinical Response [HiSCR]) were recorded at baseline and at 16, 24, and 48weeks of treatment. RESULTS: A total of 69 patients were included. Most (84.10%) had severe HS (HurleyIII) and had been diagnosed for over ten years (58.80%). The patients had been subjected to multiple non-biological (mean: 3.56) or biological (mean: 1.78) therapies, and almost 90% of those treated with biologics had received adalimumab. A significant decrease in IHS4, HS-PGA, NPRS, and DLQI scores was observed from baseline to 48weeks of guselkumab treatment (all P<.01). HiSCR was achieved in 58.33% and 56.52% of the patients at 16 and 24weeks, respectively. Overall, 16 patients discontinued treatment, mostly due to inefficacy (n=7) or loss of efficacy (n=3). No serious adverse events were observed. CONCLUSIONS: Our results indicate that guselkumab may be a safe and effective therapeutic alternative for patients with severe HS that fail to respond to other biologics.

Hidradenitis Suppurativa: Absence of Hyperhidrosis but Presence of a Proinflammatory Signature in Patients' Sweat.

The role of sweat glands in hidradenitis suppurativa has been largely neglected, despite the fact that its original designation, as "hidrosadénite phlegmoneuse", implied an inflammatory malfunction of the apocrine sweat glands as the underlying pathogenic driver. The aim of this study was to evaluate the role of apocrine sweat glands with respect to the proinflammatory environment of hidradenitis suppurativa. Therefore, gravimetric assessment and multiplex cytokine assays from sweat obtained from patients with hidradenitis suppurativa along with immunofluorescence cytokine/chemokine analysis of lesional apocrine glands- bearing hidradenitis suppurativa skin were performed. Gravimetric assessment of 17 patients with hidradenitis suppurativa revealed that the condition is not associated with hyperhidrosis. However, patients seem to be more affected by subjective sweating. The current data identified a complex proinflammatory signature in hidradenitis suppurativa sweat characterized by a significant upregulation of monocyte chemoattractant protein-1, interleukin-8 (CXCL8), and interferon-γ. In agreement with this, a strong in situ expression of these mediators could be observed in apocrine glands of lesional hidradenitis suppurativa skin. These data shed new light on the proinflammatory capacity of apocrine sweat glands in hidradenitis suppurativa, which may lead to reconsideration of the role of sweat glands in hidradenitis suppurativa pathology.

Pilot study of fractional microneedling radiofrequency for hidradenitis suppurativa assessed by clinical response and histology.

BACKGROUND: Hidradenitis suppurativa (HS) is a devastating chronic inflammatory skin disease with frequent recurrences. Various systemic treatments and procedures have been used but the efficacy of fractional microneedling radiofrequency (FMR) has not been reported. AIM: To evaluate the clinical and histological efficacy of FMR in the treatment of HS lesions. METHODS: An 8-week, prospective, split-body, unblinded study was conducted, which enrolled 10 adult patients with mild to moderate HS to receive 3 sessions of FMR treatment biweekly. HS severity was assessed using the number and type of lesions, HS Physician Global Assessment (HS-PGA) and the modified Sartorius score (mSS). Skin biopsies were performed on participants to assess change in inflammation before and after FMR. RESULTS: Severity of HS was significantly reduced on the FMR-treated side of the body, but not on the control side. Inflammatory HS lesions were significantly reduced after 4 weeks, while HS-PGA and mSS were significantly decreased after 6 weeks. Immunohistochemistry staining showed decreased expression of inflammatory markers including neutrophil elastases, interleukin (IL)-8 and IL-17, tumour necrosis factor-α, transforming growth factor-ß1 and matrix metalloproteinases. CONCLUSION: FMR may be a viable treatment option for mild to moderate HS.

Stress signalling and STAT1 activation characterize the keratinocytic gene expression pattern in Hidradenitis suppurativa.

BACKGROUND: The pathogenetic factors generating the innate immune signal necessary for T-cell activation, initiation and chronification of Hidradenitis suppurativa (HS, also known as Acne inversa) are still poorly understood. Emerging evidence suggests that a defective keratinocyte function critically contributes to HS disease development and progression. OBJECTIVES: To elucidate the role of keratinocytes in HS lesion formation, we compared the transcriptomes of lesional and perilesional epidermis isolated from HS patients by RNA sequencing (RNA Seq). METHODS: Pairwise-matched lesional and perilesional HS skin samples of five different donors were obtained and epidermal keratinocytes freshly isolated and processed for RNA extraction and RNA seq. Lesionally regulated genes were analysed by large-scale promoter analysis and functional annotation clustering to identify epidermally overrepresented transcription factor binding sites and functionally related gene groups. Results were experimentally validated with independent epidermal isolates of patient-matched lesional and perilesional HS skin employing qRT-PCR, cell culture, immunoblot and immunostaining. RESULTS: We show that HS is characterized by a strong epidermal stress state evident by a significant overrepresentation of an AP-1-driven gene signature and a substantial activation of the stress-activated cJun N-terminal kinase (JNK) pathway in lesional epidermis. Additionally, our data reveal a strong induction of STAT1 activation in lesional HS epidermis that likely results from IFNγ production and triggered expression of key inflammatory genes coordinating innate immune activation and the adaptive T-cell response in HS. CONCLUSIONS: Our data implicate a key role of stress signalling and JAK/STAT1 activation in disease progression of HS and suggest interference with JAK/STAT1 signalling as a potentially promising therapeutic approach for HS.

Does SAPHO syndrome exist in dermatology?

In the late 1960s, palmoplantar pustulosis (PPP) with sternocostoclavicular arthropathy was first described in Japan, predominantly affecting women in the perimenopausal age. In the 1970s, the chronic non-bacterial osteomyelitis and chronic recurrent multifocal osteomyelitis were initially observed in paediatric patients with approximately 70% girls. Acne fulminans accompanied by polyarthralgia have been observed since early 1970s, which almost exclusively occurs in adolescent boys. Report on spondyloarthropathy associated with hidradenitis suppurativa can be traced back to 1982. The SAPHO syndrome was coined in 1987 to lump together synovitis, acne, pustulosis, hyperostosis and osteitis to conceptualize a group of inflammatory osteocutaneous diseases of unclear etiopathogenesis and ill-defined associations spanning disparate age and gender groups. From historical view, Sasaki syndrome is proposed to replace SAPHO syndrome to represent PPP with sternocostoclavicular arthropathy in the absence of other skin manifestations. Hidradenitis suppurativa is folliculitis in pathogenesis and no longer classified as acne. PPP accompanied by psoriasis vulgaris is more likely psoriasis pustulosa palmoplantaris in dermatological aspect, and the associated arthritis is part of psoriatic arthropathy. Pathophysiology of these disorders is incompletely understood. To echo the advancement of high-throughput sequencing, splitting but not lumping of clinical findings would be a better strategy to decipher these multigenic complex inflammatory disorders.

Microbiome in Hidradenitis Suppurativa-What We Know and Where We Are Heading.

Recently, interest in the microbiome of cutaneous diseases has increased tremendously. Of particular interest is the gut-brain-skin axis proposed by Stokes and Pillsbury in 1930. The microbiome has been suggested in the pathogenesis of hidradenitis suppurativa, however the link between the commensals and the host is yet to be established. Across all studies, the increased abundance of Porphyromonas, Peptoniphilus, and Prevotella spp., and a loss of skin commensal species, such as Cutibacterium in HS lesions, is a consistent finding. The role of gut and blood microbiome in hidradenitis suppurativa has not been fully elucidated. According to studies, the main link with the intestine is based on the increased risk of developing Crohn's disease and ulcerative colitis, however, further research is highly needed in this area. Lifestyle, dietary approaches, and probiotics all seem to influence the microbiome, hence being a promising modality as adjuvant therapy. The aim of this review was to present the latest reports in the field of research on skin, blood, and gut microbiome in terms of hidradenitis suppurativa.