Very low-calorie ketogenic diet (VLCKD) in the management of hidradenitis suppurativa (Acne Inversa): an effective and safe tool for improvement of the clinical severity of disease. Results of a pilot study.

BACKGROUND: Hidradenitis suppurativa (HS), an inflammatory-based dermatological condition often associated with obesity, poses significant challenges in management. The very low-calorie ketogenic diet (VLCKD) has shown efficacy in addressing obesity, related metabolic disorders, and reducing chronic inflammation. However, its effects on HS remain underexplored. In this prospective pilot study, we aimed to investigate the impact of a 28-day active phase of VLCKD on HS in a sample of treatment-naive women with HS and excess weight. METHODS: Twelve women with HS and overweight or obesity (BMI 27.03 to 50.14 kg/m2), aged 21 to 54 years, meeting inclusion/exclusion criteria and agreeing to adhere to VLCKD, were included. Baseline lifestyle habits were assessed. The Sartorius score was used to evaluate the clinical severity of HS. Anthropometric parameters (waist circumference, weight, height, and body mass index), body composition via bioelectrical impedance analysis, levels of trimethylamine N-oxide (TMAO), oxidized low-density lipoprotein (oxLDL), and derivatives of reactive oxygen metabolites (dROMs) were assessed at baseline and after 28 days of the active phase of VLCKD. RESULTS: VLCKD led to general improvements in anthropometric parameters and body composition. Notably, a significant reduction in the Sartorius score was observed after the intervention (Δ%: - 24.37 ± 16.64, p < 0.001). This reduction coincided with significant decreases in TMAO (p < 0.001), dROMs (p = 0.001), and oxLDL (p < 0.001) levels. Changes in the Sartorius score exhibited positive correlations with changes in TMAO (p < 0.001), dROMs (p < 0.001), and oxLDL (p = 0.002). CONCLUSION: The 28-day active phase of VLCKD demonstrated notable improvements in HS severity and associated metabolic markers, highlighting the potential utility of VLCKD in managing HS and its association with metabolic derangements in women with overweight or obesity.

Detection of native, activated Notch receptors in normal human apocrine-bearing skin and in hidradenitis suppurativa.

Notch signalling has generated considerable interest as a pathogenetic factor and a drug target in a range of human diseases. The gamma-secretase complex is crucial in the activation of Notch receptors by cleaving the intracellular domain allowing nuclear translocation. In recent years several mutations in gamma-secretase components have been discovered in patients with familial hidradenitis suppurativa (HS). This has led to hypotheses that impaired Notch signalling could be an important driver for HS in general, not only in the monogenic variants. However, no study has examined in situ Notch activation per se in HS, and some reports with conflicting results have instead been based on expression of Notch receptors or indirect measures of Notch target gene expression. In this study we established immunostaining protocols to identify native, activated Notch receptors in human skin tissue. The ability to detect changes in Notch activation was confirmed with an ex vivo skin organ model in which signal was reduced or obliterated in tissue exposed to a gamma-secretase inhibitor. Using these methods on skin biopsies from healthy volunteers and a general HS cohort we demonstrated for the first time the distribution of active Notch signalling in human apocrine-bearing skin. Quantification of activated NOTCH1 & NOTCH2 revealed similar levels in non-lesional and peri-lesional HS to that of healthy controls, thus ruling out a general defect in Notch activation in HS patients. We did find a variable but significant reduction of activated Notch in epidermis of lesional HS with a distribution that appeared related to the extent of surrounding tissue inflammation.

Mast cells are upregulated in hidradenitis suppurativa tissue, associated with epithelialized tunnels and normalized by spleen tyrosine kinase antagonism.

Mast cells have traditionally been associated with allergic inflammatory responses; however, they play important roles in cutaneous innate immunity and wound healing. The Hidradenitis Suppurativa tissue transcriptome is associated with alterations in innate immunity and wound healing-associated pathways; however, the role of mast cells in the disease is unexplored. We demonstrate that mast cell-associated gene expression (using whole tissue RNAseq) is upregulated, and in-silico cellular deconvolution identifies activated mast cells upregulated and resting mast cells downregulated in lesional tissue. Tryptase/Chymase positive mast cells (identified using IHC) localize adjacent to epithelialized tunnels, fibrotic regions of the dermis and at perivascular sites associated with Neutrophil Extracellular Trap formation and TNF-alpha production. Treatment with Spleen Tyrosine Kinase antagonist (Fostamatinib) reduces the expression of mast cell-associated gene transcripts, associated biochemical pathways and the number of tryptase/chymase positive mast cells in lesional hidradenitis suppurativa tissue. This data indicates that although mast cells are not the most abundant cell type in Hidradenitis Suppurativa tissue, the dysregulation of mast cells is paralleled with B cell/plasma cell inflammation, inflammatory epithelialized tunnels and epithelial budding. This provides an explanation as to the mixed inflammatory activation signature seen in HS, the correlation with dysregulated wound healing and potential pathways involved in the development of epithelialized tunnels.

Correlation between PainDETECT Questionnaire and Quantitative Sensory Testing for the Detection of Neuropathic Pain in Hidradenitis Suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that is often severely painful due to nociceptive mechanisms (i.e., stimulation of cutaneous nociceptors). However, patient-reported pain character suggests that neuropathy may also drive HS pain in a subset of patients. Quantitative sensory testing (QST) can help identify neuropathic pain by testing for heightened and paradoxical pain responses in patients, but it is less feasible for routine clinical use compared with brief questionnaires. We therefore tested the suitability of a standardized neuropathic questionnaire (PainDETECT; PD-Q) for use as a surrogate clinical measure by directly comparing it with QST-identified neuropathic pain in HS. METHODS: This observational, cross-sectional study included 22 adults with painful HS lesions who completed the PD-Q and underwent QST. A receiver operating characteristic curve was generated and Cohen's Kappa, sensitivity, and specificity were examined at three scoring thresholds. RESULTS: Of the 22 participants, 14 (64%) exhibited dynamic mechanical allodynia and/or paradoxical thermal sensations in QST, which are characteristically found in neuropathic pain. According to the PD-Q, 8 participants (36%) were unlikely, 8 (36%) were possible, and 6 (27%) were likely to have neuropathic pain. A PD-Q Score indicating possible or likely neuropathic pain (i.e., ≥13) demonstrated 82% agreement with QST-determined neuropathic pain (Cohen's Kappa = 0.61 [p = 0.004]; sensitivity = 86%; specificity = 75%). CONCLUSION: The PD-Q demonstrates moderate agreement with QST in screening for neuropathic pain in HS and may be a helpful clinical tool.

Discovery and Potential Functional Characterization of Long Noncoding RNAs Associated with Familial Acne Inversa with NCSTN Mutation.

BACKGROUND: Long noncoding RNAs (lncRNAs) are associated with many dermatologic diseases. However, little is known about the regulatory function of lncRNAs in familial acne inversa (AI) patients with nicastrin (NCSTN) mutation. OBJECTIVES: The aim of this study was to explore the regulatory function of lncRNAs in familial AI patients with NCSTN mutation. METHODS: The expression profiles of lncRNAs and mRNAs in skin tissues from familial AI patients with NCSTN mutation and healthy individuals were analysed in this study via RNA sequencing (RNA-seq). RESULTS: In total, 359 lncRNAs and 1,863 mRNAs were differentially expressed between the two groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the dysregulated mRNAs targeted by lncRNAs were mainly associated with the immune regulation, Staphylococcus aureus infection and B cell receptor signalling pathways. The lncRNA-miRNA-mRNA coexpression network contained 265 network pairs comprising 55 dysregulated lncRNAs, 11 miRNAs, and 74 mRNAs. Conservation analysis of the differentially expressed lncRNAs between familial AI patients with NCSTN mutation and Ncstn keratinocyte-specific knockout (NcstnΔKC) mice identified 6 lncRNAs with sequence conservation; these lncRNAs may participate in apoptosis, proliferation, and skin barrier function. CONCLUSIONS: These findings provide a direction for exploring the regulatory mechanisms underlying the progression of familial AI patients with NCSTN mutation.

Response to adalimumab in Caucasian and Asian patients with hidradenitis suppurativa: A retrospective cohort study of an Australian cohort stratified by patient-reported ethnicity.

BACKGROUND/OBJECTIVES: Caucasian and Asian patients with hidradenitis suppurativa demonstrate significant differences with regard to age, gender and body mass index. Demographic characteristics are known to influence the efficacy and drug survival of hidradenitis suppurativa therapeutics including biologic therapies. What remains unknown is the impact of ethnicity upon the efficacy of therapeutics once demographic and disease characteristics have been taken into account. This is an important question given the expansion of biologic therapies for HS into the global patient community. METHODS: We assessed 170 patients from a single HS specialist centre in Australia stratified by patient-identified ethnicity including those identifying as either Caucasian or Asian. RESULTS: Asian patients demonstrated lower BMI, higher rates of smoking and greater odds of Hurley stage 3 disease with tunnels than Caucasian patients in line with the reported literature. There was no significant difference between percentage of individuals achieving HiSCR50 or IHS4-55 at Week 16. Significant differences were seen in median time to secondary loss of response, and Kaplan-Meier curve analysis showed a significant difference between curves when stratified by patient-reported ethnicity. Cox regression analysis demonstrated after accounting for age, gender, BMI, smoking and Hurley stage, the significance of ethnicity in influencing time to secondary loss of response disappears. CONCLUSIONS: Caucasian or Asian ethnicity does not influence response to adalimumab treatment on patients with hidradenitis suppurativa.

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.

Real-world effectiveness and safety of the LAight-therapy in patients with hidradenitis suppurativa.

BACKGROUND AND OBJECTIVES: Hidradenitis suppurativa (HS)/Acne inversa (Ai) is a chronic debilitating disease with limited therapy options. The device-based LAight therapy was approved in Europe in 2017. The aim of this study was to evaluate the effect of real-world care with at least one treatment with LAight therapy on disease activity and burden in 3,437 patients. PATIENTS AND METHODS: Patients were included in the analysis if they had a diagnosis of HS and received at least one treatment. The endpoints Hidradenitis Suppurativa Severity Score System (IHS4), pain on the numeric rating scale (pain-NRS) and Dermatology Life Quality Index (DLQI) were analyzed using a linear mixed model for repeated measures (MMRM) over 26 weeks of care with LAight therapy. Furthermore, responder rates were calculated for all endpoints, and the therapy's safety profile and patient satisfaction were thoroughly examined. RESULTS: A significant decrease in IHS4, pain-NRS, and DLQI was achieved during 26 weeks of care with LAight. The BMI at baseline had a significant negative effect on therapy response for pain-NRS and DLQI. CONCLUSIONS: This study confirms that LAight therapy leads to satisfactory disease control in all stages of severity and is a valuable addition to the therapeutic repertoire of HS.

S2k guideline for the treatment of hidradenitis suppurativa / acne inversa - Short version.

The S2k guideline on hidradenitis suppurativa/acne inversa (HS/AI) aims to provide an accepted decision aid for the selection/implementation of appropriate/sufficient therapy. HS/AI is a chronic recurrent, inflammatory, potentially mutilating skin disease of the terminal hair follicle-glandular apparatus, with painful, inflammatory lesions in the apocrine gland-rich regions of the body. Its point prevalence in Germany is 0.3%, it is diagnosed with a delay of 10.0 ± 9.6 years. Abnormal differentiation of the keratinocytes of the hair follicle-gland apparatus and accompanying inflammation form the central pathogenetic basis. Primary HS/AI lesions are inflammatory nodules, abscesses and draining tunnels. Recurrences in the last 6 months with at least 2 lesions at the predilection sites point to HS/AI with a 97% accuracy. HS/AI patients suffer from a significant reduction in quality of life. For correct treatment decisions, classification and activity assessment should be done with a validated tool, such as the International Hidradenitis Suppurativa Severity Scoring System (IHS4). HS/AI is classified into two forms according to the degree of detectable inflammation: active, inflammatory (mild, moderate, and severe according to IHS4) and predominantly inactive, non-inflammatory (Hurley grade I, II and III) HS/AI. Oral tetracyclines or 5-day intravenous therapy with clindamycin are equal to the effectiveness of clindamycin/rifampicin. Subcutaneously administered adalimumab, secukinumab and bimekizumab are approved for the therapy of HS/AI. Various surgical procedures are available for the predominantly non-inflammatory disease form. Drug/surgical combinations are considered a holistic therapy method.

Gluteal Hidradenitis Suppurativa: Analysis of 83 Patients.

BACKGROUND: In 2013, Canoui-Poitrine et al. identified three hidradenitis suppurativa (HS) phenotypes by a latent class (LC) analysis, based on anatomical sites of involvement. OBJECTIVE: To improve the classification of the gluteal phenotype (LC3) patients given their diverse lesion types and differences in clinical profile. MATERIAL AND METHODS: We designed a bicentric study gathering all LC3 patients (n=83) from two hospitals. We conducted a two-step cluster analysis among them and also compared their characteristics with the rest of the HS patients (n=661). RESULTS: Compared with global HS series, LC3 patients were more frequently non-obese men, with smoking habit, an associated arthropathy, and a more frequent history of pilonidal sinus. The analysis of LC3 patients yielded two clusters: cluster 1 (38.3%) included elderly female patients, with later diagnosis of the disease and more sinus tracts; cluster 2 (61.7%) encompassed more men with earlier disease onset and more nodules and folliculitis lesions. LIMITATIONS: The study's limitations include its retrospective nature, bicentric design, and small sample size. CONCLUSION: The heterogeneous clinical presentation of HS makes it essential to have a good classification of the patients. Gluteal phenotype could actually be classified into two "subphenotypes" with a different clinical profiles and management.

Gluteal Hidradenitis Suppurativa: Analysis of 83 Patients. / [Artículo traducido] Hidradenitis supurativa con afectación glútea: análisis de 83 pacientes.

BACKGROUND: In 2013, Canoui-Poitrine et al. identified three hidradenitis suppurativa (HS) phenotypes by a latent class (LC) analysis, based on anatomical sites of involvement. OBJECTIVE: To improve the classification of the gluteal phenotype (LC3) patients given their diverse lesion types and differences in clinical profile. MATERIAL AND METHODS: We designed a bicentric study gathering all LC3 patients (n=83) from two hospitals. We conducted a two-step cluster analysis among them and also compared their characteristics with the rest of the HS patients (n=661). RESULTS: Compared with global HS series, LC3 patients were more frequently non-obese men, with smoking habit, an associated arthropathy, and a more frequent history of pilonidal sinus. The analysis of LC3 patients yielded two clusters: cluster 1 (38.3%) included elderly female patients, with later diagnosis of the disease and more sinus tracts; cluster 2 (61.7%) encompassed more men with earlier disease onset and more nodules and folliculitis lesions. LIMITATIONS: The study's limitations include its retrospective nature, bicentric design, and small sample size. CONCLUSION: The heterogeneous clinical presentation of HS makes it essential to have a good classification of the patients. Gluteal phenotype could actually be classified into two "subphenotypes" with a different clinical profiles and management.

Hidradenitis Suppurativa: Molecular Etiology, Pathophysiology, and Management-A Systematic Review.

Hidradenitis suppurativa is a chronic inflammatory skin condition that affects the hair follicles in areas of the body with apocrine glands. The condition is characterized by recurrent, painful nodules, abscesses, and draining sinuses that can lead to scarring and disfigurement. In this present study, we provide a focused evaluation of recent developments in hidradenitis suppurativa research, including novel therapeutics and promising biomarkers that may facilitate clinical diagnosis and treatment. We conducted a systematic review of controlled trials, randomized controlled trials, meta-analyses, case reports, and Cochrane Review articles in accordance with the PRISMA guidelines. The Cochrane Library, PubMed, EMBASE, and Epistemonikos databases were queried via Title/Abstract screen. Eligibility criteria included the following: (1) has a primary focus on hidradenitis suppurativa, (2) includes measurable outcomes data with robust comparators, (3) details the sample population, (4) English language, and (5) archived as full-text journal articles. A total of 42 eligible articles were selected for review. Qualitative evaluation identified numerous developments in our understanding of the disease's multiple potential etiologies, pathophysiology, and treatment options. It is important for individuals with hidradenitis suppurativa to work closely with a healthcare provider to develop a comprehensive treatment plan that addresses their individual needs and goals. To meet this objective, providers must keep current with developments in the genetic, immunological, microbiological, and environmental factors contributing to the disease's development and progression.

Inborn Errors of Immunity in Hidradenitis Suppurativa Pathogenesis and Disease Burden.

Hidradenitis suppurativa (HS), also known as Verneuil's disease and acne inversa, is a prevalent, debilitating, and understudied inflammatory skin disease. It is marked by repeated bouts of pathological inflammation causing pain, hyperplasia, aberrant healing, and fibrosis. HS is difficult to manage and has many unmet medical needs. There is clinical and pharmacological evidence for extensive etiological heterogeneity with HS, suggesting that this clinical diagnosis is capturing a spectrum of disease entities. Human genetic studies provide robust insight into disease pathogenesis. They also can be used to resolve etiological heterogeneity and to identify drug targets. However, HS has not been extensively investigated with well-powered genetic studies. Here, we review what is known about its genetic architecture. We identify overlap in molecular, cellular, and clinical features between HS and inborn errors of immunity (IEI). This evidence indicates that HS may be an underrecognized component of IEI and suggests that undiagnosed IEI are present in HS cohorts. Inborn errors of immunity represent a salient opportunity for rapidly resolving the immunological landscape of HS pathogenesis, for prioritizing drug repurposing studies, and for improving the clinical management of HS.

A proof-of-concept open-label clinical trial of spleen tyrosine kinase antagonism using fostamatinib in moderate-to-severe hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is an autoinflammatory disorder of keratinization with a prominence of B cells and plasma cells. Fostamatinib is a spleen tyrosine kinase inhibitor targeting B cells and plasma cells. OBJECTIVES: To assess the safety, tolerability, and clinical response at week 4 and week 12 of fostamatinib in moderate-to-severe HS. METHODS: Twenty participants were administered fostamatinib 100 mg twice a day for 4 weeks, escalating to 150 mg twice a day thereafter until week 12. Participants were assessed for adverse events and clinical response assessed by HiSCR (Hidradenitis Suppurativa Clinical Response Score) and IHS4 (International Hidradenitis Suppurativa Severity Score) as well as other outcomes including DLQI (Dermatology Life Quality Index), visual analog scale, and physician global assessment. RESULTS: All 20 participants completed the week 4 and week 12 endpoints. Fostamatinib was well tolerated in this cohort with no grade 2/3 adverse events reported. A total of 85% achieved HiSCR at week 4 and 85% at week 12. The greatest reduction in disease activity was seen at weeks 4/5 with worsening in a proportion of patients thereafter. Significant improvements were seen in pain, itch, and quality of life. CONCLUSIONS: Fostamatinib was well tolerated in this HS cohort with no serious adverse events and improvement in clinical outcomes. Targeting B cells/plasma cells may be a viable therapeutic strategy in HS and requires further exploration.

Patterns of Surgical Recurrence in Patients with Hidradenitis Suppurativa.

BACKGROUND: Surgery is an essential part of hidradenitis suppurativa (HS) treatment. Understanding and reducing surgical recurrence are crucial to obtaining the best results in patients' treatment. OBJECTIVE: The aim of the study was to characterize surgical recurrences in a cohort of patients with HS treated with wide excision and second-intention healing. METHODS: A prospective nested case-control study was conducted. A cohort of patients with HS treated with wide excision and second-intention healing was monitored for 68 weeks. The surgical procedure was classified as case (recurrence) or control (no recurrence). The type of recurrence was classified according to the elementary lesion in tunnel or abscess and inflammatory nodule (AN) recurrence. Sociodemographic and clinical data likely related to recurrence and the type of recurrence were evaluated. RESULTS: Sixty-three patients were included, receiving a total of 82 surgical procedures. The mean age of the patients was 36.18 years, and the surgical site presented a Hurley stage II severity in 79.26% (65/82) of the interventions. Tunnel recurrence was observed in 8.5% (7/82) and AN recurrence in 15.85% (13/82) of the interventions. Obesity was associated with a higher risk of recurrence, for both tunnel and AN recurrence. Hurley III at the surgical site, a history of pilonidal sinus, and higher International Hidradenitis Suppurativa Severity Score System (IHS4) after surgery and at week 68 increased the risk of tunnel recurrence. CONCLUSION: We propose classifying surgical recurrence based on the elemental type of lesion. Tunnel recurrence could originate in the depth of the surgical scar and could be associated with both surgical site factors and inflammatory load. AN recurrence could originate in the borders of the surgical scar and may particularly benefit from preoperative ultrasound.

Prevalence of Hidradenitis Suppurativa in an African Population: Validation of a Screening Questionnaire in Lagos, Nigeria.

BACKGROUND: Epidemiologic hidradenitis suppurativa (HS) studies from Africa are lacking. This study aimed at uncovering the prevalence of HS in Lagos, Nigeria, to validate an HS screening questionnaire, and to contribute to the Global Hidradenitis Suppurativa Atlas (GHiSA). METHODS: This was a cross-sectional study of 802 healthy adults accompanying their relations to the outpatient clinic of Family Medicine and Ophthalmology at the Lagos State University Teaching Hospital in Lagos, Nigeria, following ethical approval. Verbal and written consents were obtained prior to inclusion of study participants. The study was conducted using a validated screening questionnaire. Screen-positive and randomly selected screen-negative participants were clinically examined. Severity was categorized using the Hurley score. RESULTS: The prevalence of HS in the sample was 2.2% (18/802; 95% CI: 1.4-3.5%) with no gender predominance. The mean age in the HS group was 34 years (IQR 28-42) and the median body mass index (BMI) of the HS patients was 27.0 (IQR 21.4-28.6). There was no significant difference in BMI between the HS and control group. The screening questionnaire had a sensitivity of 1 (18/18), specificity of 0.8 (20/25), positive predictive value of 0.8 (18/23), and a negative predictive value of 1 (20/20). The axilla was the predominant site of affection (66.7%), and all HS patients were classified as mild disease (Hurley score 1). CONCLUSION: The prevalence of HS in Lagos, Nigeria, was 2.2% and, in this population, BMI did not appear to be a risk factor. The axilla was the most affected site, and all patients had a mild disease severity (Hurley score 1). Finally, the HS screening questionnaire is a suitable tool in population surveys.

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.

Demographic Gaps and Requirements for Participation: A Systematic Review of Clinical Trial Designs in Hidradenitis Suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease that disproportionally affects women, as well as Black and biracial individuals. While adalimumab remains the only therapy approved by the Food and Drug Administration for HS, many HS clinical trials for novel and re-tasked therapies are ongoing or upcoming. To optimize treatment equity, reflect the patient population, and facilitate trial participation, it is important to elucidate aspects of clinical trial protocols that may systematically exclude specific patient groups or impose hardships. OBJECTIVE: The study aimed to systematically review inclusion and exclusion criteria as well as participant demographics in HS clinical trials. METHODS: A literature search of PubMed, Embase, Cochrane Central, and Web of Science databases was conducted. Peer-reviewed publications of randomized controlled trials that were written in English and had at least 10 participants were included. Title and abstract screening and data extraction were completed by two independent reviewers, with disagreements resolved by a third. RESULTS: Twenty-three studies totaling 1,496 adult participants met the inclusion criteria. Race and ethnicity were not reported in 473/1,496 (31.6%) and 1,420/1,496 (94.9%) trial participants, respectively. Trial participants were predominantly white (811/1,023, 79.3%) and female (1,057/1,457, 72.5%). The median of each study's average age was 35.7 years (IQR 33.5-38.0), and 17/23 (73.9%) trials excluded pediatric patients. Nearly all participants had Hurley Stage II (499/958, 52.0%) or Hurley Stage III (385/958, 40.2%) disease. Many trials excluded patients who were pregnant (19/23, 82.6%) and breastfeeding (13/23, 56.5%), or who had HS that was "too severe" (8/23, 34.8%) or "too mild" (16/23, 70.0%). Frequently, trial protocols required prolonged washout periods from HS therapies, relatively long duration in the study's placebo arm, and prohibited concurrent analgesic use. CONCLUSIONS: This systematic review of 23 HS clinical trials totaling 1,496 participants identified substantial hardships imposed by trial participation, high rates of missing race and ethnicity data, and low representation of key patient groups, including those who identify as Black. Future trials with pragmatic study designs, broader inclusion criteria, and study sites in diverse communities may alleviate burdens of trial participation and improve enrollment of diverse patient groups.

Can Ultrasound Examinations Generate Pain in Hidradenitis Suppurativa Patients? Results from a Multicentric Cross-Sectional Study.

BACKGROUND: Pain is not a trivial issue for hidradenitis suppurativa (HS) patients and has been considered a domain in the Core Outcome Set. To date, there is no evidence about pain caused by the ultrasound examinations. OBJECTIVE: The aim of the study was to assess the presence of pain generated by the ultrasound examinations of HS patients. METHODS: A multicentric cross-sectional study for detecting pain during the ultrasound examinations of HS patients using a validated verbal questionnaire immediately after the imaging studies. Statistical analysis included demographic data and possible associations with sex, age, location, clinical (Hurley), and ultrasonographic scoring (SOS-HS). The statistical tests were two proportions Z test, χ2 test, Student's t test, and ANOVA. A p < 0.05 was considered significant. RESULTS: 317 patients met the criteria. 77.3% of them did not present pain. Of cases with pain, 59.8% were mild, 16.7% moderate, and 23.6% severe. No significant association was found with sex, age, staging, location, or the number of affected regions. Although nonsignificant, severe pain cases were more frequent in the clinical Hurley III and ultrasonographic SOS-HS III stages. CONCLUSION: Pain generated by the ultrasound examination of HS patients is infrequent.

Validity and Reliability of Two Digital Wound Measurement Tools after Surgery in Patients with Hidradenitis Suppurativa.

BACKGROUND: After excision surgery in patients with hidradenitis suppurativa (HS), wounds are usually left open for secondary intention healing. To evaluate wound healing, reliable wound measurement is important. However, digital wound measurement tools for measuring the surface area are validated for small wounds located on flat or mildly convex body surfaces in studies, often powered inadequately. Up until now, a validated digital measurement tool to accurately measure wounds on all body surfaces, including the intertriginous areas, was not available. OBJECTIVES: The aim of this study was to validate two digital wound measurement tools for the measurement of the surface area of larger and concave wounds, using surgical wounds in patients with HS. METHODS: This prospective observational validation study included consecutive patients with HS undergoing excision surgery in the Department of Dermatology of the Erasmus University Medical Center, Rotterdam. Wound measurements using a ruler, the tracing method, the inSight® 3-dimensional (3D) device, and the ImitoWound app were performed by three investigators. The intraclass correlation coefficients (ICCs) for concurrent validity and the intra- and inter-rater reliability were analyzed. The standard error of measurement (SEm) and minimal detectable change were calculated, and Bland-Altman plots were constructed to determine the limits of agreement. RESULTS: Twenty patients with a total of 52 wounds were included. The wounds had a mean surface of 18.7 cm2. The inSight® 3D device showed an ICC of 0.987 for concurrent validity, 0.998 for intra-rater reliability, and 0.997 for inter-rater reliability. The ICCs from the ImitoWound application were 0.974, 0.978, and 0.964 for concurrent validity, intra-rater reliability, and inter-rater reliability, respectively. The SEms for intra- and inter-rater reliability were 0.95 cm2 and 1.11 cm2 for the inSight® 3D device and 3.33 cm2 and 3.51 cm2 for the ImitoWound app, respectively. CONCLUSION: Both the inSight® 3D device and the ImitoWound app demonstrated excellent concurrent validity and reliability for the surface measurements of concave wound, enabling these tools to be used reliably in clinical research and daily practice. Furthermore, it paves the way for broader application, such as telemonitoring of wound care at home.