Single-cell sequencing reveals Hippo signaling as a driver of fibrosis in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by abscesses, nodules, dissecting/draining tunnels, and extensive fibrosis. Here, we integrate single-cell RNA sequencing, spatial transcriptomics, and immunostaining to provide an unprecedented view of the pathogenesis of chronic HS, characterizing the main cellular players and defining their interactions. We found a striking layering of the chronic HS infiltrate and identified the contribution of 2 fibroblast subtypes (SFRP4+ and CXCL13+) in orchestrating this compartmentalized immune response. We further demonstrated the central role of the Hippo pathway in promoting extensive fibrosis in HS and provided preclinical evidence that the profibrotic fibroblast response in HS can be modulated through inhibition of this pathway. These data provide insights into key aspects of HS pathogenesis with broad therapeutic implications.

Viewpoint on the evaluation of severity and treatment effects in mild hidradenitis suppurativa: the cumulative IHS4 (IHS4-C).

Hidradenitis suppurativa (HS) is a chronic, recurrent and debilitating inflammatory skin disease, characterized by painful inflamed nodules, abscesses and tunnels in the skin folds. Up to 66% of HS patients can be classified as having mild disease. However, currently, most clinical trials are focusing on patients with moderate to severe disease, resulting in more available treatment options for this smaller group of patients. This difference in treatment options and lack of clinical trials for patients with mild HS has been noticed and additional focus on milder HS cases is requested. However, an important hurdle to overcome studying treatment efficacy in mild HS is an adequate treatment outcome. Patients with mild HS sometimes have no lesions due to waxing and waning of the disease. Furthermore, the difference in aim of a clinical trial for patients with mild disease should be taken into consideration. Where treatment of moderate to severe patients focusses on lowering the number of draining tunnels, abscesses and inflammatory nodules, in patient with mild disease, we focus on prevention of new lesions and progression to moderate and severe disease. This clinical characteristic of mild HS and difference in aim of clinical trials are the key challenges for efficacy measurement in mild HS. To overcome these challenges, we propose to measure the continuous international hidradenitis suppurativa severity score (IHS4) monthly and use the cumulative IHS4 score (IHS4-C) over all these visits as a primary outcome in clinical trials in patients with mild HS, to increase the probability to detect the inflammatory lesions with a temporary nature. We argue that this novel application of the IHS4, has the potential to better facilitate assessment of treatments or interventions in patients with mild HS and should be tested in future studies.

Fibromyalgia in Patients With Hidradenitis Suppurativa.

This case-control study compares the prevalence of fibromyalgia between adults with hidradenitis suppurativa and adults with non­pain-related conditions.

Biology of Interleukin-17 and Novel Therapies for Hidradenitis Suppurativa.

Skin disorders affect ∼40% of the human population. One of the most debilitating cutaneous disorders is Hidradenitis suppurativa (HS), a noncommunicable chronic inflammatory disease with an estimated global prevalence of 0.4% to 2.5%. In January 2011, high levels of IL-17 were discovered in skin lesions of HS patients. In the following years, translational and clinical research led to a better understanding of the pathogenesis of HS. In June 2023, more than 12 years after the initial note, secukinumab, an anti-IL-17A monoclonal antibody, was approved for the treatment of moderate to severe HS. This is the next milestone in improving the treatment of these patients after the approval of the anti-TNF-α monoclonal antibody adalimumab in 2015. In this review article, we present the IL-17 pathway in HS and discuss the use of secukinumab as a therapeutic option for this disease. Our review starts with a description of the epidemiology, clinical features, etiology, and pathogenesis of HS. An overview of the IL-17/IL-17 receptor system in general and a detailed description of the known facts about the expression and action of IL-17 in HS follow. Afterward, we consider the results of clinical trials evaluating the safety and efficacy of IL-17 inhibitors in HS. Finally, a comparison is made between secukinumab and adalimumab and the characteristics of the patients that may be particularly suitable for each of these biologics are described.

Outcome Measures for the Evaluation of Treatment Response in Hidradenitis Suppurativa for Clinical Practice: A HiSTORIC Consensus Statement.

Importance: Although several clinician- and patient-reported outcome measures have been developed for trials in hidradenitis suppurativa (HS), there is currently no consensus on which measures are best suited for use in clinical practice. Identifying validated and feasible measures applicable to the practice setting has the potential to optimize treatment strategies and generate generalizable evidence that may inform treatment guidelines. Objective: To establish consensus on a core set of clinician- and patient-reported outcome measures recommended for use in clinical practice and to establish the appropriate interval within which these measures should be applied. Evidence Review: Clinician- and patient-reported HS measures and studies describing their psychometric properties were identified through literature reviews. Identified measures comprised an item reduction survey and subsequent electronic Delphi (e-Delphi) consensus rounds. In each consensus round, a summary of outcome measure components and scoring methods was provided to participants. Experts were provided with feasibility characteristics of clinician measures to aid selection. Consensus was achieved if at least 67% of respondents agreed with use of a measure in clinical practice. Findings: Among HS experts, response rates for item reduction, e-Delphi round 1, and e-Delphi round 2 surveys were 76.4% (42 of 55), 90.5% (38 of 42), and 92.9% (39 of 42), respectively; among patient research partners (PRPs), response rates were 70.8% (17 of 24), 100% (17 of 17), and 82.4% (14 of 17), respectively. The majority of experts across rounds were practicing dermatologists with 18 to 19 years of clinical experience. In the final e-Delphi round, most PRPs were female (12 [85.7%] vs 2 males [11.8%]) and aged 30 to 49 years. In the final e-Delphi round, HS experts and PRPs agreed with the use of the HS Investigator Global Assessment (28 [71.8%]) and HS Quality of Life score (13 [92.9%]), respectively. The most expert-preferred assessment interval in which to apply these measures was 3 months (27 [69.2%]). Conclusions and Relevance: An international group of HS experts and PRPs achieved consensus on a core set of HS measures suitable for use in clinical practice. Consistent use of these measures may lead to more accurate assessments of HS disease activity and life outcomes, facilitating shared treatment decision-making in the practice setting.

Adalimumab in conjunction with surgery compared with adalimumab monotherapy for hidradenitis suppurativa: A Randomized Controlled Trial in a real-world setting.

BACKGROUND: Adalimumab, the only biologic registered for hidradenitis suppurativa, shows clinical response in up to 60% of patients, leaving many patients in need for other treatment options such as surgery. OBJECTIVE: To compare the clinical effectiveness of adalimumab combined with surgery vs adalimumab monotherapy in patients with moderate to severe hidradenitis suppurativa. METHODS: A pragmatic Randomized Controlled Trial was performed from August 2018 to July 2022. Primary outcome was the difference in mean International Hidradenitis Suppurativa Severity Score System reduction after 12 months of treatment with the difference in mean Dermatology Life Quality Index reduction as a key secondary outcome. RESULTS: Thirty-one patients were included per arm. The mean International Hidradenitis Suppurativa Severity Score System at baseline was 23.9 ± 10.7 in the surgery group and 20.9 ± 16.4, in the monotherapy group. After 12 months of treatment the surgery group had a significantly greater reduction in International Hidradenitis Suppurativa Severity Score System compared with the monotherapy group (-19.1 ± 11.3 vs -7.8 ± 11.8, P < .001). Moreover, the surgery group showed a greater reduction in Dermatology Life Quality Index after treatment compared with the monotherapy group (-8.2 ± 6.2 vs -4 ± 7.7, P = .02). LIMITATIONS: The study follow-up was too short to assess surgical recurrence rates. DISCUSSION: Combining adalimumab with surgery resulted in greater clinical effectiveness and improved quality of life after 12 months in patients with moderate to severe hidradenitis suppurativa.

Guselkumab for hidradenitis suppurativa: a phase II, open-label, mode-of-action study.

BACKGROUND: The effectiveness of available biologics for the treatment of hidradenitis suppurativa (HS) is limited. Additional therapeutic options are needed. OBJECTIVES: To investigate the efficacy and mode of action of guselkumab [an anti-interleukin (IL)-23p19 monoclonal antibody] 200 mg subcutaneously every 4 weeks for 16 weeks in patients with HS. METHODS: An open-label, multicentre, phase IIa trial in patients with moderate-to-severe HS was carried out (NCT04061395). The pharmacodynamic response in skin and blood was measured after 16 weeks of treatment. Clinical efficacy was assessed using the Hidradenitis Suppurativa Clinical Response (HiSCR), the International Hidradenitis Suppurativa Severity Score System (IHS4), and the abscess and inflammatory nodule (AN) count. The protocol was reviewed and approved by the local institutional review board (METC 2018/694), and the study was conducted in accordance with good clinical practice guidelines and applicable regulatory requirements. RESULTS: Thirteen of 20 patients (65%) achieved HiSCR with a statistically significant decrease in median IHS4 score (from 8.5 to 5.0; P = 0.002) and median AN count (from 6.5 to 4.0; P = 0.002). The overall patient-reported outcomes did not show a similar trend. One serious adverse event, likely to be unrelated to guselkumab treatment, was observed. In lesional skin, transcriptomic analysis revealed the upregulation of various genes associated with inflammation, including immunoglobulins, S100, matrix metalloproteinases, keratin, B-cell and complement genes, which decreased in clinical responders after treatment. Immunohistochemistry revealed a marked decrease in inflammatory markers in clinical responders at week 16. CONCLUSIONS: Sixty-five per cent of patients with moderate-to-severe HS achieved HiSCR after 16 weeks of treatment with guselkumab. We could not demonstrate a consistent correlation between gene and protein expression and clinical responses. The main limitations of this study were the small sample size and absence of a placebo arm. The large placebo-controlled phase IIb NOVA trial for guselkumab in patients with HS reported a lower HiSCR response of 45.0-50.8% in the treatment group and 38.7% in the placebo group. Guselkumab seems only to be of benefit in a subgroup of patients with HS, indicating that the IL-23/T helper 17 axis is not central to the pathophysiology of HS.

External Validation of the IHS4-55 in a European Antibiotic-Treated Hidradenitis Suppurativa Cohort.

BACKGROUND: Previously, a new dichotomous outcome was developed, calculated as 55% reduction in the International Hidradenitis Suppurativa 4 (IHS4-55) score. It was validated in datasets of adalimumab and placebo-treated HS patients. External validation is an important aspect of clinical outcomes. OBJECTIVES: We aimed to externally validate the novel dichotomous IHS4-55 in a non-biologic treated dataset of HS patients. METHODS: Data from a previously published European-wide prospective clinical study of antibiotic treatment of HS patients were used to assess the association of IHS4-55 achievement with individual reduction in inflammatory nodules, abscesses, and draining tunnels. Moreover, the associations between IHS4-55 positivity and achievement of the minimal clinically important differences (MCIDs) for Dermatology Life Quality Index (DLQI), Numerical Rating Scale (NRS) Pain, and NRS Pruritus were analyzed. RESULTS: Data were obtained from 283 individual patients, of which 36.4% (103/283) were treated with clindamycin and rifampicin and 63.6% (180/283) with tetracyclines for 12 weeks. Achievers of the IHS4-55 demonstrated a significant reduction the counts of inflammatory nodules, abscesses, and draining tunnels (all p < 0.001). Additionally, IHS4-55 achievers had an odds ratio for achieving the MCID of DLQI, NRS Pain, and NRS Pruritus of 2.16 (95% CI 1.28-3.65, p < 0.01), 1.79 (95% CI 1.10-2.91, p < 0.05), and 1.95 (95% CI 1.18-3.22, p < 0.01), respectively. CONCLUSIONS: This study shows the external validity of the novel IHS4-55 by demonstrating a significant association between IHS4-55 achievement and a reduction in inflammatory lesion counts as well as achievement of MCIDs for DLQI, NRS Pain, and NRS Pruritus in an antibiotic-treated cohort. These findings support the use of the IHS4-55 as a novel primary outcome measure in clinical trials.

Development and validation of IHS4-55, an IHS4 dichotomous outcome to assess treatment effect for hidradenitis suppurativa.

BACKGROUND: Validated, inclusive and easy-to-use outcomes for hidradenitis suppurativa are essential both in the clinical trial setting and clinical practice. The continuous IHS4 is a validated tool that dynamically assesses nodules/abscesses/draining tunnels and classifies disease severity as mild/moderate/severe. However, dichotomous outcomes are often required for clinical trials reporting. OBJECTIVE: To develop and validate a dichotomous outcome based on IHS4 that can be used in clinical trial settings and day-to-day clinical practice. METHODS: De-identified data from the PIONEER-I and -II studies were accessed through Vivli. Potential IHS4 thresholds were analysed using baseline to Week 12 data from adalimumab- and placebo-treated hidradenitis suppurativa patients in the PIONEER-I trial. The final threshold was chosen based on its ability to discriminate between patients treated with adalimumab or placebo and its association with reduction in inflammatory lesions. The final threshold was validated using data from baseline to Week 12 from adalimumab- and placebo-treated hidradenitis suppurativa patients in both the PIONEER-II and the combined PIONEER-I and -II studies. RESULTS: The best performing cut-off for the IHS4 was a 55% reduction of the IHS4 score (IHS4-55). Patients who achieved the IHS4-55 had an odd's ratio of 2.00 [95%-CI 1.26-3.18, p = 0.003], 2.79 (95%-CI 1.76-4.43, p < 0.001) and 2.16 (95%-CI 1.43-3.29, p < 0.001) for being treated with adalimumab rather than placebo in PIONEER-I, PIONEER-II and the combined dataset, respectively. Additionally, the achievement of the IHS4-55 was associated with a significant reduction in inflammatory nodules, abscesses and draining tunnels in all analysed datasets. CONCLUSIONS: IHS4-55, a novel dichotomous IHS4 version, based on a 55% reduction of the total score was developed. The IHS4-55 performs similarly to the HiSCR in discriminating between adalimumab- and placebo-treated hidradenitis suppurativa patients and shows significant associations with reductions in lesion counts. Moreover, the IHS4-55 addresses some of the HiSCR drawbacks by dynamically including draining tunnels in a validated manner. By allowing the analysis of hidradenitis suppurativa patients with an abscess and nodule count below 3 but many draining tunnels, this outcome measure will improve inclusivity in clinical trials.

Drug Survival of Oral Retinoids in Hidradenitis Suppurativa: A Real-Life Cohort Study.

INTRODUCTION: Cohort studies on the use of retinoids for hidradenitis suppurativa (HS) have yielded contradicting results. As the clinical presentation of HS is heterogeneous, with different predilection sites and hallmark features, it can be hypothesized that HS phenotypes are associated with the effectiveness of specific retinoid treatments. OBJECTIVES: The aim of this study was to evaluate the drug survival of oral retinoids in the treatment of HS and to establish predictors for longer treatment duration. METHODS: A retrospective, dual-center study was conducted in the Netherlands in adult HS patients treated with oral retinoids between 2011 and 2021. Drug survival analyses were performed through Kaplan-Meier survival curves. Additionally, Cox regression models were used to determine predictors for a longer drug survival. RESULTS: In total, 102 patients were included. Overall drug survival of (low-dose) isotretinoin (n = 66) at 12 and 24 months was 44.2% and 15.5%, respectively. Termination of treatment was mostly due to ineffectiveness (26%). Presence of widespread comedones (p = 0.03) and the use of concomitant systemic medication (p = 0.04) were associated with a prolonged treatment duration. For acitretin (n = 36), the overall drug survival was 42.0% at 12 months and 37.4% at 24 months, and was also predominantly determined by ineffectiveness (28%). Interestingly, the scarring folliculitis phenotype (p < 0.05) was associated with prolonged drug survival time for acitretin treatment relative to the regular phenotype. CONCLUSION: Comparable drug survival rates at 12 months for isotretinoin and acitretin were found. HS patients with widespread comedones and the scarring folliculitis phenotype could benefit from treatment with isotretinoin or acitretin, respectively.

New treatments and new assessment instruments for Hidradenitis suppurativa.

Research interest in Hidradenitis Suppurativa (HS) has grown exponentially over the past decades. Several groups have worked to develop novel scores that address the drawbacks of existing investigator-assessed and patient-reported outcome measures currently used in HS trials, clinical practice and research. In clinical trial settings, the drawbacks of the HiSCR have become apparent; mainly, it is lack of a dynamic measurement of draining tunnels. The newly developed (dichotomous) IHS4 and HASI-R are backed up by adequate validation data and are good contenders to become the new primary outcome measure in HS clinical trials. Patient-reported outcomes, as well as physician reported measures, are being developed by the HIdradenitis SuppuraTiva cORe outcomes set International Collaboration (HISTORIC). For example, the Hidradenitis Suppurativa Quality of Life (HiSQOL) score is a validated measure of HS-specific quality of life and is already being used in many HS trials. Magnitude of pain measurement via a 0-10 numerical rating scale is well-established; however, consensus is still required to ensure consistent administration and interpretation of the instrument. A longitudinal measurement over multiple days rather than at one time point, such as for example the Pain Index could provide increased reliability and reduced recall bias. Ultimately, these newly developed scores and tools can be included in a standardized registry to be used in routine clinical practice.

Insights into hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic, debilitating, inflammatory skin disorder with a prevalence of around 1% and a profound impact on patients' quality of life. Characteristic lesions such as inflammatory nodules, abscesses, and sinus tracts develop in the axillae, inguinal, and gluteal areas, typically during or after puberty. A complex interplay of genetic predisposition, hormonal factors, obesity, and smoking contributes to development and maintenance of the disease. HS is considered to arise from an intrinsic defect within the hair follicle, leading to follicular plugging, cyst formation, and subsequent rupture that in turn induce an acute inflammatory response characterized by elevated levels of IL-1ß, IL-17, and TNF. Over time, acute lesions transition into chronic disease, with active draining sinus tracts accompanied by extensive fibrosis. HS is associated with other immune-mediated inflammatory diseases, metabolic and cardiovascular disorders, and psychiatric comorbidities. Treatment of HS often requires a combination of antibiotic or immunosuppressing therapies and surgical intervention. Nonetheless, the currently available treatments are not universally effective, and many drugs, which are often repurposed from other inflammatory diseases, are under investigation. Studies into the early stages of HS may yield treatments to prevent disease progression; yet, they are hampered by a lack of appropriate in vitro and animal models.

Prevalence of Central Sensitization in Patients With Hidradenitis Suppurativa.

Importance: Chronic pain is one of the most prominent symptoms of hidradenitis suppurativa (HS) and an independent domain in the core outcome set for HS. Previously, the chronic, recurrent, inflammatory nature of HS was hypothesized to induce central sensitization (CS; alteration and amplification of pain perception). However, evidence for this hypothesis is currently lacking. Objective: To determine the prevalence of CS in patients with HS compared with sex- and age-matched controls. Design, Setting, and Participants: This was a cross-sectional, survey-based, case-control study conducted from February to November 2020 that included all consecutive adult patients with HS attending the outpatient clinic of the Department of Dermatology of the Erasmus University Medical Center Rotterdam, in Rotterdam, the Netherlands. Age- and sex-matched controls without chronic inflammatory dermatologic diseases were recruited from the same department. Main Outcomes and Measures: The main outcome was the Central Sensitization Inventory (CSI) score (ranging from 0-100) as a screening tool for presence of CS. Based on current literature, a score of 40 or higher was deemed to indicate the presence of CS. Results: Overall, 100 patients with HS (median [IQR] age, 34.5 [27.3-47.0] years; 71 [71%] female) and 100 controls (median [IQR] age, 33.5 [27.0-48.8] years; 71 [71%] female) were included, of which 36% and 12%, respectively, had a CSI score of 40 or higher (P < .001). Multivariate logistic regression showed that patients with HS had 4.46 (95% CI, 1.89-10.52; P = .001) times the odds of having a positive CSI compared with controls. In addition, CS was significantly associated with previously diagnosed depression (odds ratio, 6.16; 95% CI, 2.81-13.54; P < .001). No association between CSI score and disease severity was found. Conclusions and Relevance: In this cross-sectional, case-control study, patients with HS had more than 4 times the odds of having CS, indicated by a positive CSI, compared with age- and sex-matched controls. This new insight in the presence of CS in patients with HS raises the question of whether we are adequately measuring and treating HS-associated pain. Active screening for CS and depressive symptoms in patients with a discrepant pain experience is recommended.

Clinical Implementation of Biologics and Small Molecules in the Treatment of Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic, recurrent, auto-inflammatory skin disease originating from the hair follicles. The typical inflammatory nodules, abscesses, and draining sinus tracts (tunnels) are characterized by a massive influx of neutrophils, macrophages, B-cells, plasma cells, T helper (Th)1, Th17 cells and upregulation of pro-inflammatory cytokines such as IL-1, IL-17, IL-12/23, and TNF-α. Over the last decades, several clinical trials evaluated the clinical efficacy of different biologics targeting these pro-inflammatory cytokines, in particular TNF-α and IL-1. However, adalimumab is still the only registered drug for HS. This review discusses biologics and small molecules with high level of evidence for their clinical application, provides guidance on when and how to use these biologics and small molecules in clinical practice, and elaborates on the combination with medical and surgical treatment options beyond the current guidelines. Furthermore this review provides an overview of potential biologics and small molecules currently under investigation for novel targets in HS such as IL-36, C5a, Janus kinase family members, CD-40, LTA4 and CXCR1/2.

The efficacy and tolerability of tetracyclines and clindamycin plus rifampicin for the treatment of hidradenitis suppurativa: Results of a prospective European cohort study.

BACKGROUND: Tetracyclines and clindamycin plus rifampicin combination therapy are both considered first-line therapy in current hidradenitis suppurativa guidelines. However, evidence for their efficacy is drawn from small studies, often without validated outcomes. OBJECTIVE: To assess the 12-week efficacy of oral tetracyclines and a combination of clindamycin and rifampicin. METHODS: A prospective, international cohort study performed between October 2018 and August 2019. RESULTS: In total, 63.6% of the included 283 patients received oral tetracyclines, and 36.4% were treated with clindamycin and rifampicin. Both groups showed a significant decrease in International Hidradenitis Suppurativa Severity Score System from baseline (both P < .001). The Hidradenitis Suppurativa Clinical Response (HiSCR) was achieved in 40.1% and 48.2% of patients, respectively (P = .26). Patient characteristics or disease severity were not associated with the attainment of HiSCR or the minimal clinically important differences for the Dermatology Life Quality Index and pain. LIMITATIONS: Cohort study. Respectively, 23.9% and 19.4% of patients had to be excluded from the HiSCR analysis for the tetracycline and combination therapy group because of a low abscess and nodule count at baseline. CONCLUSION: This study shows significant efficacy of both tetracycline treatment and clindamycin and rifampicin combination therapy after 12 weeks in patients with hidradenitis suppurativa. No significant differences in efficacy were observed between the 2 treatments, regardless of disease severity.