Adalimumab Treatment Effects on Inflammation and Adipose Tissue Mitochondrial Respiration in Hidradenitis Suppurativa.

OBJECTIVE: Tumour necrosis factor (TNF)-α is a proinflammatory marker and has been shown to affect mitochondrial function in different tissues. We investigated the effect on adipose tissue (AT) inflammation and mitochondrial respiration in patients with hidradenitis suppurativa (HS) after 12 weeks of treatment with adalimumab, a TNF-α inhibitor. METHODS: We sampled blood and an AT biopsy from 13 patients with HS and 10 control subjects after an overnight fast. The patients were retested after at least 12 weeks of treatment with adalimumab (40 mg/week). We measured macrophage content and mitochondrial respiration in the AT and interleukin (IL)-1ß, IL-6, IL-10, high-sensitivity C-reactive protein (hsCRP), interferon-γ, TNF-α, adiponectin and leptin in plasma. Clinical scores and Dermatology Quality of Life Index (DLQI) were assessed. RESULTS: We found a higher anti-inflammatory macrophage content (CD206+) in the patient group compared with the control group, but no differences between before and after the intervention. No difference in mitochondrial respiration was observed. We observed higher plasma IL-6 and hsCRP concentrations in patients with HS compared to controls, with no differences before and after the intervention. The difference between controls and HS patients was abolished after the intervention. HS patients improved their DLQI after the intervention with no change in clinical scores. CONCLUSION: Treatment with adalimumab in patients with HS does not alter AT inflammation or mitochondrial respiratory capacity; however, we did see a higher content of anti-inflammatory macrophages in the patient group compared with the control group.

Exploring the Association Between Hidradenitis Suppurativa and Hyperthyroidism.

PURPOSE: Hidradenitis suppurativa (HS) is an inflammatory disease affecting the pilosebaceous skin units and is linked to several autoimmune conditions. An area of exploration includes the connection between hyperthyroidism and HS. This study aims to investigate and establish the relationship between HS and hyperthyroidism. METHODS: The relationship between hyperthyroidism and HS was evaluated using data from the National Institute of Health (NIH) All of Us Researcher Program. A cross-sectional study was performed to assess the prevalence of HS in individuals with and without a history of hyperthyroidism matched by age ranges and health surveys. Relative risk and significance were determined by using standard statistical methods. RESULTS: A total of 407,333 patients were matched by health surveys and age ranges in the control and experimental groups. Among patients with a history of hyperthyroidism, the prevalence of HS was 1.40% compared to 0.38% in the control group. This difference was statistically significant (p < 0.0001 with an OR = 3.717, 95% CI 3.038-4.548). CONCLUSION: This study demonstrates a statistically significant correlation between hyperthyroidism and increased prevalence of HS. These results justify the need for further research regarding hyperthyroidism's role in HS and the potential screening tools and lifestyle management techniques that may be prevalent for both conditions.

Spesolimab, the first-in-class anti-IL-36R antibody: From bench to clinic.

Inflammatory diseases that are driven by several pro-inflammatory cytokines has resulted in in the development of targeted therapies across different disease settings. Interleukin (IL)-36 cytokines have been implicated in several inflammatory diseases. In this review we describe the scientific evidence surrounding the use of the IL-36 receptor (IL-36R)-targeting antibody, spesolimab, in IL-36-mediated skin diseases: generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), hidradenitis suppurativa, and Netherton syndrome (NS). Spesolimab, a high affinity, specific, humanized, antagonistic immunoglobulin G1 antibody, targets the IL-36R at a binding site distinct from its agonists, IL-36α/ß/γ, and at least one endogenous antagonist, IL-36R antagonist. In vitro and in vivo data for spesolimab show effective inhibition of IL-36R-mediated signaling pathways, and six Phase I studies in healthy volunteers presented a favorable safety and pharmacokinetic (PK) profile, leading to the development of a clinical trial program to evaluate spesolimab in the treatment of IL-36R-mediated diseases. Six studies (including an expanded access program) have evaluated the efficacy, safety, PKs, and pharmacogenomics of spesolimab in patients with GPP flares. Spesolimab treatment of GPP flares resulted in rapid and sustained improvements in pustular and skin clearance, and clinically significant improvements in patient-reported symptoms and quality of life. Spesolimab also significantly reduces the risk of GPP flares and flare occurrence, preventing disease worsening and has a favorable safety profile. There have been three trials of spesolimab in PPP; further evaluation is needed to better define those patients who might benefit from the treatment. A trial of spesolimab in NS is ongoing, while other spesolimab trials suggest that IL-36 may only play a secondary role in the pathogenesis of atopic dermatitis. In conclusion, research into spesolimab has provided much needed insight into the role of IL-36 in the human immune system and the mechanism behind IL-36-mediated inflammatory diseases. Spesolimab provides an efficacious targeted treatment for GPP, a disease with a high unmet medical need.

Exploring racial and ethnic disparities in the hidradenitis suppurativa patient disease journey: Results from a real-world study in Europe and the USA.

Hidradenitis suppurativa (HS) is an inflammatory skin disease associated with high morbidity and disability that has limited treatment options. People from racial and ethnic minority groups may experience greater disease severity and delay to diagnosis. This study assessed the impact of race/ethnicity on HS diagnosis and management in real-world clinical settings. Data were derived from the Adelphi Real World Hidradenitis Suppurativa Disease Specific Programme, a survey of dermatologists and their consulting HS patients in five European countries and the USA in 2020/2021. Dermatologists returned demographic and clinical data, and treatment goals and satisfaction for their next five to seven consulting patients. Patients completed a questionnaire on disease history and diagnosis, disease burden, and treatment satisfaction. Groups were compared with bivariate tests. In total, 312 physicians returned data on 1787 patients; 57.6% were female and 77.7% White. People from racial and ethnic minority groups were younger than White patients (32.9 ± 11.6 vs. 34.9 ± 12.4, mean ± standard deviation) and reported symptoms at a younger age (23.3 ± 10.8 vs. 26.2 ± 11.1), but their time to first consultation was longer than for White patients (2.6 ± 5.7 vs. 1.2 ± 2.5 years). People from racial and ethnic minority groups took longer to receive a correct diagnosis following first consultation (2.7 ± 5.3 vs. 1.5 ± 4.1 years) and were more likely to be misdiagnosed with boils (73.5% vs. 40.4%). People from racial and ethnic minority groups had a greater disease awareness at diagnosis and reported wanting greater support. People from racial and ethnic minority groups reported a greater impact on life, more severe pain, and a greater level of activity impairment in the Work Productivity and Activity Impairment: General Health (27.0 ± 25.2 vs. 20.0 ± 20.6). All P values were ≤0.05. These data show evidence of delayed diagnosis and higher HS symptom burden amongst people from racial and ethnic minority groups, highlighting health disparities in HS.

Quality-of-life evaluation in hidradenitis suppurativa in Australia: Validation and outcomes of the HiSQOL questionnaire.

BACKGROUND: Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory disease with significant impact upon quality of life. Generic quality-of-life measures suffer from decreased face validity and content validity, leading to the development of disease-specific quality-of-life measures such as the Hidradenitis Suppurativa Quality of Life (HiSQOL) outcome measure. The aim of this study was to validate the use of the HiSQOL in the Australian population and evaluate the quality-of-life impact in HS patients in Australia. METHODS: A total of 301 patients were recruited and consented to be involved in this study. All participants were invited to complete the HiSQOL questionnaire along with basic demographic and disease information, the DLQI and HADS anxiety and depression scale. Participants were then asked to repeat the questionnaires 14 days later to assess test-retest reliability. RESULTS: The mean HiSQOL score was 46.5 out of a possible total score of 76 (SD = 24.2) indicating a very large impact on quality of life. Based upon the published validity bands this corresponds to a very large impact on quality of life. Validation statistics indicated a high degree of internal consistency (Cronbach's alpha = 0.956) with expected levels of convergent validity and excellent test-retest reliability (p = 0.95). Multiple regression analysis indicated individuals with a younger age of onset and positive family history had significantly greater quality-of-life impact as measured by the HiSQOL. CONCLUSIONS: The HiSQOL is a valid, reliable measure for assessing the quality-of-life impact of HS. Significant factors influencing quality of life include age of onset and family history. Longitudinal measurements will enable evaluation of the impact of therapy upon QOL in the Australian context.

Determinant Factors of Disease Severity for Patients With Hidradenitis Suppurativa Evaluated in a Spanish Hospital Over a 5-Year Period.

It is necessary to identify which factors or comorbidities are associated with more severe hidradenitis suppurativa, aiming to identify which patients may benefit more from early systemic treatment or a more aggressive approach. A retrospective study was conducted, including patients diagnosed with HS at the dermatology department of a Spanish hospital over a 5-year period. A total of 322 patients were included. A relationship was found between diagnostic delay, the presence of acne conglobata, pilonidal sinus, cardiovascular risk factors (hypertension, dyslipidemia, and/or diabetes mellitus) and more severe HS. No significant relationship was found between psychiatric comorbidities and the severity of the HS. The presence of perianal or truncal involvement was significantly associated with severe HS. Female sex and the presence of a family history of HS were associated with an earlier onset of the disease.

Prevalence and Predictors of Inflammatory Arthritis in Hidradenitis Suppurativa.

Hidradenitis Suppurativa (HS) is a chronic, debilitating, auto-inflammatory condition often associated with inflammatory arthritis, significantly impacting patients' quality of life. Early diagnosis of both conditions is crucial for optimal management. The objective of this study was to determine the prevalence and factors associated with the development of inflammatory arthritis among HS patients. A cross-sectional study was conducted between November 2021 and February 2023 at an academic dermatology centre in Canada. Adult patients with HS were consecutively sampled, and 52 patients consented to participate and completed assessments. Variables examined included age, sex, HS severity, treatment, ethnicity, family history, lifestyle factors and comorbidities. The main outcomes were rheumatologist-confirmed inflammatory arthritis diagnosis and associated risk factors. Among 52 patients (24 males, 28 females; mean age: 37.4 years), 12 had inflammatory arthritis. Multivariate analysis revealed that Blacks (OR = 0.10, p < 0.001, CI: 0.026-0.343) and Asians (OR = 0.02, p < 0.001, CI: 0.005-0.109) had lower inflammatory arthritis odds compared to Whites. Every 1-year increase in age at HS onset correlated with a 1.17-fold increase in the odds of developing inflammatory arthritis (OR: 1.17, p < 0.001, CI: 1.12-1.24). Smoking (OR = 0.01, p < 0.001, CI: 0.002-0.49), hypertension (OR: 0.23, p = 0.04, CI: 0.057-0.930) and depression (OR: 0.12, p < 0.001, CI: 0.041-0.330) reduced inflammatory arthritis odds. White ethnicity and older age at HS onset were positively associated with inflammatory arthritis, while smoking, hypertension and depression were negatively associated. These findings suggest a distinct subset of HS patients with inflammatory arthritis that warrant further prospective studies. This study contributes to the understanding of inflammatory arthritis in HS patients and emphasises the importance of rheumatology referral during dermatologic clinic visits.

Therapeutic burden in hidradenitis suppurativa: a cross-sectional study of 557 patients.

INTRODUCTION: Therapeutic burden (TB) has been identified as a potential predictor of response to biologic therapy in hidradenitis suppurativa (HS). We aim to analyze the determinants of TB in real-world clinical settings among HS patients to explain this concept and its utility as an additional tool for guiding therapeutic decision-making. METHODS: We conducted a cross-sectional study including all consecutive HS patients attending a specialized HS clinic between 2017 and 2024. The primary variable was TB, defined as the cumulative sum of prior systemic treatment cycles and surgical interventions for HS. We analyzed whether sociodemographic or clinical factors were associated with a higher TB. RESULTS: We included 557 HS patients. Of these, 50.81% were women, and the mean age was 41.87 (14.19) years. Most patients (62.30%) were referred from general dermatology consultations. The mean disease duration was 17.52 (11.51) years. Regarding disease severity, 46.50% presented with Hurley II, and 42.19% had an IHS-4 score between 4 and 10. Before their baseline visit, 9.70% of patients had received biological therapy, mostly adalimumab (88.89%). The mean TB was 2.42 (2.25) systemic medical and/or surgical interventions. Referral from general dermatology or other hospital departments, older age, longer disease duration, greater HS severity, presence of pilonidal sinus, and prior biological therapy were significantly associated with higher TB. CONCLUSIONS: Our findings suggest that TB comprehensively captures HS severity and progression factors. This metric could prove valuable in aiding decision-making for HS patients by indicating when a change in therapy might be necessary.

Identification of Novel Genetic Risk Variants Associated with Hidradenitis Suppurativa in an Exome Sequencing Cohort of 92,455 Individuals.

INTRODUCTION: Hidradenitis suppurativa (HS) is a prevalent and persistent inflammatory skin disorder, lacking a known cure or effective biomarkers for early diagnosis at present. The genetic determinants of HS have not been fully documented, but it is believed to result from a combination of genetic and environmental factors. METHODS: To identify relevant HS gene variants in sporadic HS patients, this study utilized longitudinal electronic health records (EHRs) and whole-exome sequencing. DNA exome sequencing data from 92,455 participant samples in the MyCode biobank, linked to Geisinger's EHR, were analyzed. This cohort included 1,092 HS cases and 91,363 healthy controls. The MyCode EHR has a median longitudinal follow-up of 15 years per participant, with an average of 87 clinical encounters, 687 laboratory tests, and 7 procedures. RESULTS: There were 1,092 (901 females and 191 males) participants aged 14-89 years (median 47 years) with HS (L73.2), indicating a 1.18% prevalence and accounting for a 4.7:1 female-to-male ratio among the individuals presenting for clinical care. γ-secretase complex, syndromic, and autoinflammatory gene variants were assessed. Potential pathogenic variants were identified among 66 individuals in the HS genes studied. Molecularly, the estimated HS variant prevalence was 1:1,400 in the cohort, 12.3% of variant carriers had HS diagnosis in EHR. CONCLUSIONS: Using longitudinal EHR data, genomic screening identified HS-associated gene variants in a defined group of sporadic HS patients to augment the clinical diagnosis, particularly in cases of ambiguity. Based on this study, the field of skin disorders can benefit from a personalized approach to HS diagnosis using large-scale sequencing.

Factors Associated with Severe Hidradenitis Suppurativa, Using Hurley Staging and Metascore.

INTRODUCTION: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease for which certain risk factors are well known: obesity and smoking (in particular). However, the factors associated with more severe conditions, and therefore potential aggravators of the disease, remain a matter of debate. Our study aims to determine the clinical factors associated with severe HS using several severity scores. METHODS: The data were obtained via the ERHS questionnaire from patients exclusively recruited at Erasme Hospital in Brussels. The severity of HS was firstly estimated by the Hurley score, and secondly by a metascore, a system combining the iHS4, HS-PGA, SAHS, and DLQI. Univariable and multivariable analyses were performed. RESULTS: Six hundred and forty-seven patients were included in the Hurley analysis, and 456 patients in the metascore analysis. In multivariable analysis, men have a more severe metascore than women (odds ratio [OR] = 1.89, p = 0.022), smoking was associated with a more severe disease according to metascore, especially in mild cases (OR = 0.76, p = 0.043), and an elevated body mass index was associated with having Hurley stage III disease compared to Hurley I or II disease (OR = 1.09, p = 0.001). A significant association is also shown between blood pressure and Hurley stage (OR = 0.97, p = 0.025). Self-reports of nonsteroidal anti-inflammatory drugs aggravating the disease is also a factor associated with greater severity according to the metascore (OR = 0.12, p = 0.008). Finally, several locations of HS lesions were associated with greater severity, in particular the armpits according to the metascore (OR = 0.29, p < 0.001), and the perianal area according to the Hurley score (OR = 0.15, p < 0.001). CONCLUSION: HS seems to be more severe in men; smoking seems to aggravate mild cases of HS, while increased body mass index plays a major role in the transition from Hurley II to Hurley III.

Comprehensive Catalog of Variants Potentially Associated with Hidradenitis Suppurativa, Including Newly Identified Variants from a Cohort of 100 Patients.

Hidradenitis suppurativa (HS) is a chronic skin disease characterized by painful, recurrent abscesses, nodules, and scarring, primarily in skin folds. The exact causes of HS are multifactorial, involving genetic, hormonal, and environmental factors. It is associated with systemic diseases such as metabolic syndrome and inflammatory bowel disease. Genetic studies have identified mutations in the γ-secretase complex that affect Notch signaling pathways critical for skin cell regulation. Despite its high heritability, most reported HS cases do not follow a simple genetic pattern. In this article, we performed whole-exome sequencing (WES) on a cohort of 100 individuals with HS, and we provide a comprehensive review of the variants known to be described or associated with HS. 91 variants were associated with the γ-secretase complex, and 78 variants were associated with other genes involved in the Notch pathway, keratinization, or immune response. Through this new genetic analysis, we have added ten new variants to the existing catalogs. All variants are available in a .vcf file and are provided as a resource for future studies.

Neutrophil extracellular traps activate Notch-γ-secretase signaling in hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is an inflammatory chronic skin disorder of unknown etiology characterized by inflamed abscess-like nodules and boils resulting in sinus tract formation, tissue scarring, and massive infiltration of neutrophils. Multiple lines of evidence have highlighted the potential association between alterations in the Notch pathway and HS pathogenesis, but the mechanisms remain incompletely characterized. OBJECTIVE: We aimed to elucidate the role of neutrophil extracellular traps in Notch-γ-secretase signaling. METHODS: Twenty-six HS lesional tissues, primary HS macrophages, and skin fibroblasts were interrogated by quantitative PCR, Western blot, and ELISA analyses. γ-Secretase and TNF-α converting enzyme activities were measured in HS skin lesions, macrophages, and skin fibroblasts. Immunofluorescence and RNAscope analyses were performed in HS and control skin. RESULTS: A prominent presence of Notch ligands, Delta-like ligand 4 (DLL4), and Jagged (JAG) 2 were detected at the protein and mRNA levels in HS skin lesion compared to control. Levels of DLL4, JAG1, citrullinated histone H3 DNA, and γ-secretase activity correlated with HS disease severity. Additionally, significantly elevated levels of Notch ligands and γ-secretase activity were found in dissected sinus tracts compared to the rest of HS tissue. Immunofluorescence microscopy of HS skin lesions revealed activation of Notch-1 signaling in macrophages and skin fibroblasts. Neutrophil extracellular traps (NETs) purified from HS patients displayed elevated levels of DLL4. HS NETs activated the Notch pathway in macrophages and dermal fibroblasts isolated from HS patients. HS skin fibroblasts displayed elevated levels of CD90 and DPP4 in association with increased migratory capacity and Notch activation. Inhibition of Notch decreased migratory capacity and profibrotic markers in HS fibroblasts. CONCLUSION: These data support a pathogenic connection between NETs, Notch-γ-secretase activation, and the release of profibrotic molecules that promote dysregulation of macrophages and skin fibroblasts in HS. Unveiling the relevance of these molecular events not only expands our understanding of HS but also opens new venues for the development of targeted therapies to address the fibrotic complications of advanced stages of HS.

Hidradenitis Suppurativa in Elderly Patients: Clinical and Therapeutical Outcomes-A Review of the Literature.

The management of hidradenitis suppurativa (HS) in elderly patients presents unique challenges due to its chronic inflammatory nature, heterogeneous clinical presentation and comorbidities. While HS typically affects the anogenital and intertriginous regions, elderly patients may exhibit atypical features such as the involvement of the neck, mammary area and gluteal region. The prevalence of HS in the elderly population is lower and the average age of disease onset is higher than in patients under 65. In contrast, it is unclear whether HS in the elderly has different clinical features. The elderly frequently present multiple comorbidities, including obesity, diabetes, and heart disease, which further complicate management decisions. Therapeutic interventions must consider the frailty and increased risk of multimorbidity and adverse events in elderly patients. While systemic antibiotics remain a mainstay of HS treatment, biologic agents such as TNFα inhibitors and secukinumab offer promising options for refractory cases. However, their safety and efficacy in elderly patients, particularly those with multiple comorbidities, require careful consideration. A comprehensive approach to managing HS in elderly patients involves not only pharmacological interventions but also lifestyle modifications and surgical options where appropriate. Multidisciplinary collaboration between dermatologists, geriatricians and other specialists is essential for tailoring treatment strategies and optimizing long-term outcomes and quality of life in special population.

Factors Affecting Wound Healing after the Wide Surgical Excision of Hidradenitis Suppurativa Lesions.

Background: Hidradenitis suppurativa (HS) is a chronic and inflammatory disease. Its management depends on the stage and extent of the disease. Surgery plays an important role in treatment options. This study explores the factors influencing healing after wide excision. Methods: This study analyzed data from patients who underwent wide excision for HS between 2016 and 2021. Results: A total of 160 patients (64.4% women) were included, with surgeries performed in the axillae (70), inguinal-ano-genital (73), and other locations (17, including gluteal). The mean TTWC was 74 ± 6 days, varying from 11 to 445 days. Factors negatively influencing TTWC included axillary localization (p < 0.001) and the presence of another inflammatory disease (p = 0.017). Factors positively influencing healing were smoking (<0.001) and previous or ongoing medical treatment (antibiotherapy or biologics) (p = 0.011). Obesity or being overweight did not impact the TTWC in multivariate analysis, although overweight was significant in univariate analysis. Conclusions: While smoking cessation remains important in the management of HS, it does not appear to be a prerequisite for successful surgical treatment. Conversely, patients with an inflammatory disease or those undergoing surgery for an axillary lesion exhibit slower healing and should be informed of potential healing delays before surgery.