Efficacy and safety of bimekizumab in patients with moderate-to-severe hidradenitis suppurativa (BE HEARD I and BE HEARD II): two 48-week, randomised, double-blind, placebo-controlled, multicentre phase 3 trials.

BACKGROUND: Patients with hidradenitis suppurativa have substantial unmet clinical needs and scarce therapeutic options. We aimed to assess the efficacy and safety of bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F and IL-17A, in patients with moderate-to-severe hidradenitis suppurativa. METHODS: BE HEARD I and II were two identically designed, 48-week randomised, double-blind, placebo-controlled, multicentre phase 3 trials. Patients aged 18 years or older with moderate-to-severe hidradenitis suppurativa were randomly assigned 2:2:2:1 using interactive response technology (stratified by worst Hurley Stage at baseline and baseline systemic antibiotic use) to receive subcutaneous bimekizumab 320 mg every 2 weeks; bimekizumab 320 mg every 2 weeks to week 16, then every 4 weeks to week 48; bimekizumab 320 mg every 4 weeks to week 48; or placebo to week 16, then bimekizumab 320 mg every 2 weeks. The primary outcome was an hidradenitis suppurativa clinical response of at least 50%, defined as a reduction in total abscess and inflammatory nodule count of at least 50% from baseline with no increase from baseline in abscess or draining tunnel count (HiSCR50) at week 16. Efficacy analyses included all randomly assigned study patients (intention-to-treat population). Safety analyses included all patients who received at least one full or partial dose of study treatment in the safety set, and of bimekizumab in the active-medication set. These trials are registered at ClinicalTrials.gov, NCT04242446 and NCT04242498, and both are completed. FINDINGS: Patients for BE HEARD I were recruited from Feb 19, 2020, to Oct 27, 2021, and 505 patients were enrolled and randomly assigned. Patients for BE HEARD II were recruited from March 2, 2020, to July 28, 2021, and 509 patients were enrolled and randomly assigned. The primary outcome at week 16 was met in the group who received bimekizumab every 2 weeks using modified non-responder imputation; higher responder rates were observed with bimekizumab versus placebo in both trials: 138 (48%) of 289 patients versus 21 (29%) of 72 patients in BE HEARD I (odds ratio [OR] 2·23 [97·5% CI 1·16-4·31]; p=0·0060) and 151 (52%) of 291 patients versus 24 (32%) of 74 patients in BE HEARD II (2·29 [1·22-4·29]; p=0·0032). In BE HEARD II, HiSCR50 was also met in the group who were administered bimekizumab every 4 weeks (77 [54%] of 144 vs 24 [32%] of 74 with placebo; 2·42 [1·22-4·80]; p=0·0038). Responses were maintained or increased to week 48. Serious treatment-emergent adverse events were reported in 40 (8%) patients in BE HEARD I and in 24 (5%) patients in BE HEARD II treated with bimekizumab over 48 weeks. The most frequently reported treatment-emergent adverse events to week 48 were hidradenitis in both trials, in addition to coronavirus infection and diarrhoea in BE HEARD I, and oral candidiasis and headache in BE HEARD II. One death was reported across the two trials, and was due to congestive heart failure in a patient with substantial cardiovascular history treated with bimekizumab every 2 weeks in BE HEARD I (considered unrelated to bimekizumab treatment by the investigator). No new safety signals were observed. INTERPRETATION: Bimekizumab was well tolerated by patients with hidradenitis suppurativa and produced rapid and deep clinically meaningful responses that were maintained up to 48 weeks. Data from these two trials support the use of bimekizumab for the treatment of patients with moderate-to-severe hidradenitis suppurativa. FUNDING: UCB Pharma.

Secukinumab in moderate-to-severe hidradenitis suppurativa (SUNSHINE and SUNRISE): week 16 and week 52 results of two identical, multicentre, randomised, placebo-controlled, double-blind phase 3 trials.

BACKGROUND: Few therapeutic options are available for patients with moderate-to-severe hidradenitis suppurativa. We aimed to assess the efficacy of secukinumab in patients with moderate-to-severe hidradenitis suppurativa in two randomised trials. METHODS: SUNSHINE and SUNRISE were identical, multicentre, randomised, placebo-controlled, double-blind phase 3 trials done in 219 primary sites in 40 countries. Patients aged 18 years old or older with the capacity to provide written informed consent and with moderate-to-severe hidradenitis suppurativa (defined as a total of ≥5 inflammatory lesions affecting ≥2 distinct anatomical areas) for at least 1 year were eligible for inclusion. Included patients also agreed to daily use of topical over-the-counter antiseptics on the areas affected by hidradenitis suppurativa lesions while on study treatment. Patients were excluded if they had 20 or more fistulae at baseline, had ongoing active conditions requiring treatment with prohibited medication (eg, systemic biological immunomodulating treatment, live vaccines, or other investigational treatments), or met other exclusion criteria. In both trials, patients were randomly assigned (1:1:1) by means of interactive response technology to receive subcutaneous secukinumab 300 mg every 2 weeks, subcutaneous secukinumab 300 mg every 4 weeks, or subcutaneous placebo all via a 2 mL prefilled syringe in a double-dummy method as per treatment assignment. The primary endpoint was the proportion of patients with a hidradenitis suppurativa clinical response, defined as a decrease in abscess and inflammatory nodule count by 50% or more with no increase in the number of abscesses or in the number of draining fistulae compared with baseline, at week 16, assessed in the overall population. Hidradenitis suppurativa clinical response was calculated based on the number of abscesses, inflammatory nodules, draining fistulae, total fistulae, and other lesions in the hidradenitis suppurativa affected areas. Safety was assessed by evaluating the presence of adverse events and serious adverse events according to common terminology criteria for adverse events, which were coded using Medical Dictionary for Regulatory Activities terminology. Both the SUNSHINE, NCT03713619, and SUNRISE, NCT03713632, trials are registered with ClinicalTrials.gov. FINDINGS: Between Jan 31, 2019, and June 7, 2021, 676 patients were screened for inclusion in the SUNSHINE trial, of whom 541 (80%; 304 [56%] women and 237 [44%] men; mean age 36·1 years [SD 11·7]) were included in the analysis (181 [33%] in the secukinumab every 2 weeks group, 180 [33%] in the secukinumab every 4 weeks group, and 180 [33%] in the placebo group). Between the same recruitment dates, 687 patients were screened for inclusion in the SUNRISE trial, of whom 543 (79%; 306 [56%] women and 237 [44%] men; mean age 36·3 [11·4] years) were included in the analysis (180 [33%] in the secukinumab every 2 weeks group, 180 [33%] in the secukinumab every 4 weeks group, and 183 [34%] in the placebo group). In the SUNSHINE trial, significantly more patients in the secukinumab every 2 weeks group had a hidradenitis suppurativa clinical response (rounded average number of patients with response in 100 imputations, 81·5 [45%] of 181 patients) compared with the placebo group (60·7 [34%] of 180 patients; odds ratio 1·8 [95% CI 1·1-2·7]; p=0·0070). However, there was no significant difference between the number of patients in the secukinumab every 4 weeks group (75·2 [42%] of 180 patients) and the placebo group (1·5 [1·0-2·3]; p=0·042). Compared with the placebo group (57·1 [31%] of 183 patients), significantly more patients in the secukinumab every 2 weeks group (76·2 [42%] of 180 patients; 1·6 [1·1-2·6]; p=0·015) and the secukinumab every 4 weeks group (83·1 [46%] of 180 patients; 1·9 [1·2-3·0]; p=0·0022) had a hidradenitis suppurativa clinical response in the SUNRISE trial. Patient responses were sustained up to the end of the trials at week 52. The most common adverse event by preferred term up to week 16 was headache in both the SUNSHINE (17 [9%] patients in the secukinumab every 2 weeks group, 20 [11%] in the secukinumab every 4 weeks group, and 14 [8%] in the placebo group) and SUNRISE (21 [12%] patients in the secukinumab every 2 weeks group, 17 [9%] in the secukinumab every 4 weeks group, and 15 [8%] in the placebo group) trials. No study-related deaths were reported up to week 16. The safety profile of secukinumab in both trials was consistent with that previously reported, with no new or unexpected safety findings detected. INTERPRETATION: When given every 2 weeks, secukinumab was clinically effective at rapidly improving signs and symptoms of hidradenitis suppurativa with a favourable safety profile and with sustained response up to 52 weeks of treatment. FUNDING: Novartis Pharma.

Alpha-1 antitrypsin deficiency associated with increased risks of skin cancer, leukemia, and hepatic cancer: A nationwide cohort study.

BACKGROUND: α1-Antitrypsin deficiency is characterized by elevated elastase activity and excessive elastin degradation, which may impact cancer development and progression. We tested the hypothesis that individuals with α1-antitrypsin deficiency have increased susceptibility to cancer in the Danish population. METHODS: In a nationwide nested study, we identified 2702 individuals with α1-antitrypsin deficiency and 26,750 control subjects without α1-antitrypsin deficiency matched on age, sex, and municipality. We recorded admissions due to cancer as outcomes during a median follow-up of 62 years. RESULTS: Individuals with α1-antitrypsin deficiency versus control subjects had an increased hazard of skin cancer (2.18, 95%CI: 1.81-2.63), leukemia (1.76, 1.12-2.79), liver cancer (3.91, 2.23-6.85), and cancer overall (1.25, 1.13-1.38). Corresponding hazard ratios when the entire Danish population was used as control group were 3.02 (2.55-3.58), 1.83 (1.19-2.81), 4.46 (2.74-7.28), and 1.45 (1.31-1.59). When the analysis was stratified according to comorbidities, the hazard for skin cancer was higher in those with chronic obstructive pulmonary disease (COPD) (3.59, 2.60-4.95) and skin disease (2.93, 2.19-3.92) but remained elevated in those without any of these diseases. Hazards for skin cancer in individuals with α1-antitrypsin deficiency were similar when stratified by liver cirrhosis and ischemic heart disease (ps for interaction: ≥0.76). Hazards for liver cancer in individuals with α1-antitrypsin deficiency versus control subjects were similar when stratified according to liver cirrhosis, COPD, skin disease, and ischemic heart disease (ps for interaction: ≥0.13). CONCLUSION: Individuals with α1-antitrypsin deficiency have increased risks of skin cancer, leukemia, and liver cancer in the Danish population.

Hidradenitis suppurativa: new insights into disease mechanisms and an evolving treatment landscape.

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic disabling and debilitating inflammatory disease with a high unmet medical need. The prevalence of HS reported in most studies is 1-2%, although it is likely to be under-reported and estimates vary globally owing to variance in data collection methods, ethnicity, geographical location and under-diagnosis. HS is characterized by persistent, painful cutaneous nodules, abscesses and draining tunnels commonly affecting the axillary, anogenital, inguinal and perianal/gluteal areas. Over time, chronic uncontrolled inflammation results in irreversible tissue destruction and scarring. Although the pathophysiology of HS has not been fully elucidated, the tumour necrosis factor (TNF)-α and interleukin (IL)-17 pathways have an important role, involving multiple cytokines. Currently, treatment options include topical medications; systemic therapies, including repeated and/or rotational courses of systemic antibiotics, retinoids and hormonal therapies; and various surgical procedures. The anti-TNF-α antibody adalimumab is currently the only biologic approved by both the US Food and Drug Administration and the European Medicines Agency for HS; however, its efficacy varies, with a clinical response reported in approximately 50% of patients in phase III trials. HS is a rapidly evolving field of discovery, with a diverse range of agents with distinct mechanisms of action currently being explored in clinical trials. Several other promising therapeutic targets have recently emerged, and agents targeting the IL-17 and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways are the most advanced in ongoing or completed phase III clinical trials. Alongside limited therapeutic options, significant challenges remain in terms of diagnosis and disease management, with a need for better treatment outcomes. Other unmet needs include significant diagnostic delays, thus missing the therapeutic 'window of opportunity'; the lack of standardized outcome measures in clinical trials; and the lack of established, well-defined disease phenotypes and biomarkers.

Hidradenitis suppurativa prevalence in Algeria: A multicenter cross-sectional study.

Introduction Although there has been an expansion of knowledge on hidradenitis suppurativa (HS), data about the disease is largely based on Western population and no relevant African or Asian studies are available. Methods We conducted a descriptive, cross-sectional, multicenter study, as part of GHiSA (Global HS Atlas) initiative, to assess the epidemiologic profile of HS in Algerian population. Healthy adults accompanying patients undergoing care in a non-dermatological wards were approached and invited to complete a self-administered questionnaire. Subsequently, a clinical assessment was performed by an in-person dermatologists for all screen-positive participants and ten percent of the screen-negative ones. Results A total of 1434 participants were included in this study. The prevalence of HS among Algerian adults was 0.78%. Compared to non HS group, no significant difference was found regarding gender, age, body mass index and smoker status. Both the sensitivity (100%) and the specificity (97%) of the HS screening questionnaire were excellent. Conclusion The prevalence of HS in Algeria is very close to that of Australia (0.8%) and Europe (0.7%) and almost the same prevalence found by Ghanaian study (other GHiSA study from Africa). The results of this study demonstrate also the reliability and validity of GHiSA questionnaire as HS data collection instrument.

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.

The Global Hidradenitis Suppurativa Atlas Methodology: Combining Global Proportions in a Pooled Analysis.

INTRODUCTION: Data concerning the global burden of hidradenitis suppurativa (HS) are limited. Reported prevalence estimates vary between 0.0003% and 4.1%, and data from various geographical regions are still to be collected. Previously reported prevalences have been limited by the methodological approach and source of data. This has resulted in great heterogeneity as prevalence data from physician-diagnosed cases poorly match those of self-reported apparent HS disease. METHODS: The Global Hidradenitis Suppurativa Atlas (GHiSA) introduces an innovative approach to determine the global prevalence of HS. This approach involves using a previously validated questionnaire to screen apparently healthy adults accompanying a patient to a non-dermatological outpatient clinic visit in a hospital or a private/family medicine clinic. The screening questionnaire (i.e., the index test) is combined with a subsequent physician-based in-person validation (i.e., the reference standard) of the participants who screen positive. Approximately ten percent of the screen-negative participants are also clinically assessed to verify the diagnostic precision of the test. The local prevalence (pi) will be estimated from each country that submits the number of patients who are HS positive according to the index test and clinical examination (n), and the corresponding total number of observations (N). CONCLUSION: The GHiSA Global Prevalence studies are currently running simultaneously in 58 countries across six continents (Africa, Europe, Australia, North America, South America, and Asia). The goal of the combined global proportion is the generation of a single summary (i.e., proportional meta-analysis), which will be done after a logit transformation and synthesized using a random-effects model. The novel standardization of the Global Prevalence Studies conducted through GHiSA enables direct international comparisons, which were previously not possible due to substantial heterogeneity in past HS prevalence studies.

Sex-related Variations in Comorbidities in Lichen Sclerosus: A Systematic Review and Meta-Analysis.

The comorbidities of lichen sclerosus (LS) are presumed but have not been analysed in detail. The purpose of this review was to identify evidence-based associated diseases in patients with LS and explore the potential need for sex-dependent screening protocols. A comprehensive search of the MEDLINE, Embase, and PsycINFO databases from inception to 29 February 2024 was conducted using the key search terms LS and all its synonyms. Pooled odds ratios and 95% confidence intervals of comorbidities were generated using the DerSimonian and Laird random-effects model. A total of 21 case-control studies met the inclusion criteria. Of the 75 comorbidities analysed, only 16 (21.3%) were studied in both sexes, revealing no contrasting associations based on sex. Both female and male LS patients showed significantly increased odds of common dermatological conditions (i.e., lichen planus, vitiligo, alopecia areata, atopic dermatitis, and psoriasis), various cardiovascular risk factors (i.e., essential hypertension, obesity, dyslipidaemia, diabetes mellitus, and diabetes mellitus type 2), genital warts, and hypothyroidism compared with controls. Overall, the scarcity of data currently does not support the implementation of sex-dependent screening strategies. The findings do, however, present significant associations with a range of potentially serious comorbidities, which warrants further elucidation and clinical vigilance.

Professional Cleaners' and Healthcare Workers' Ability to Recognize Hand Eczema.

Timely intervention reduces the risk of a poor prognosis in hand eczema, making early recognition of symptoms important in high-risk professions. However, limited data exist regarding the ability of cleaners and healthcare workers to recognize hand eczema. The aim of this study was to examine cleaners' and healthcare workers' ability to recognize hand eczema in clinical photographs and to assess the severity of the disease. Cleaners and healthcare workers completed a questionnaire consisting of 16 questions and participated in a structured interview referring to a validated photographic severity guide for chronic hand eczema, which comprised clinical photographs of hand eczema at varying levels of severity. Eighty cleaners and 201 healthcare workers (total N = 281) participated in the study. The rates of correctly identified hand eczema in clinical photographs (cleaners/ healthcare workers) were: 41.2%/57.7% (mild hand eczema), 81.2%/92.0% (moderate hand eczema), 85.0%/94.5% (severe hand eczema) and 82.5%/97.0% (very severe hand eczema). The proficiency of healthcare workers in recognizing hand eczema was significantly higher than that of cleaners. The results indicate that a large proportion of cleaners and healthcare workers fail to recognize mild hand eczema in clinical photographs. Healthcare workers had higher success rates in recognizing hand eczema in all severity categories. Symptom underestimation may lead to under-reporting of the true prevalence of hand eczema, with consequent loss of opportunities for prevention.

An Explorative Study on Calcium Electroporation for Low-risk Basal Cell Carcinoma.

In electrochemotherapy, permeabilization of the cell membrane by electric pulses increases the anti-tumour effect of chemotherapeutics. In calcium electroporation, chemotherapy is replaced by calcium chloride with obvious benefits. This study explores the effect and underlying mechanisms of calcium electroporation on basal cell carcinomas using either high- or low-frequency electroporation. Low-risk primary basal cell carcinomas were treated in local anaesthesia with intratumoral calcium chloride followed by electroporation with high (167 kHz) or low (5 kHz) frequencies. Non-complete responders were retreated after 3 months. The primary endpoint was tumour response 3 months after last calcium electroporation. Plasma membrane calcium ATPase was examined in various cell lines as plasma membrane calcium ATPase levels have been associated with calcium electroporation efficacy. Twenty-two out of 25 included patients complete the study and 7 of these (32%) achieved complete response at 3 months with no difference in efficacy between high- and low-frequency pulses. High-frequency calcium electroporation was significantly less painful (p=0.03). Plasma membrane calcium ATPase was increased 16-32-fold in basal cell carcinoma cell lines compared with 4 other cancer cell lines. Calcium electroporation for low-risk basal cell carcinomas does not fulfil the requirements of a new dermatological basal cell carcinoma treatment but may be useful as adjuvant treatment to surgery in more advanced basal cell carcinomas. The elevated PMCA levels in basal cell carcinomas may contribute to low efficacy.

A systematic review and meta-analysis of psychiatric diseases in individuals with primary hyperhidrosis.

Primary hyperhidrosis is associated with a substantial mental burden. In this study, the objective was to compare the occurrence of psychiatric diseases in individuals with and without primary hyperhidrosis by systematically reviewing the literature and conducting a meta-analysis. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the Meta-analysis Of Observational Studies in Epidemiology checklist were employed. Cochrane Library, Embase, and PubMed were searched. The risk of bias was determined by the Newcastle-Ottawa Scale. A random effects model was employed in the meta-analysis. Fifteen studies met the eligibility criteria encompassing 50,429 participants with hyperhidrosis and 182,464 control participants. Hyperhidrosis was associated with increased odds of anxiety (odds ratio 3.5 [95% confidence interval 1.0, 11.8]) and depression (odds ratio 2.4 [95% confidence interval 1.4, 4.0]). Studies using outcome definitions for anxiety and depression, which not were included in the meta-analysis, showed similar results. Studies reporting on other morbidities (i.e., body dysmorphic disorder, social phobia and stress) found a higher occurrence of these outcomes in the individuals with hyperhidrosis than in the control participants. Primary hyperhidrosis is associated with anxiety and depression. These results acknowledge the psychiatric burden patients with primary hyperhidrosis experience.

Pharmacies Counselling of Patients in the Era of Antifungal Resistance.

BACKGROUND: Tinea pedis is one of the most prevalent superficial fungal infections. Initial antifungal treatment is often acquired over-the-counter (OTC) without previous consultation with a physician. OBJECTIVE: Lately, increasing antifungal terbinafine resistance has been documented in Denmark and globally and it is therefore of interest to assess how Danish pharmacies advise customers with tinea pedis. METHODS: One hundred Danish pharmacies were randomly selected and an employee interviewed from each. A structured question guide was followed, with the possibility to add further comments. RESULTS: Interviews of 94 pharmacies were conducted. Six pharmacies never replied. Terbinafine as standard dose or cutaneous solution terbinafine one time application (Lamisil Once (R)) were recommended by 99% of the pharmacy employees as first-line treatment. The customer was advised to seek medical attention when tinea pedis was recurring (93%), or when treatment duration was > 2 weeks (77%). The majority (88%) of the pharmacy employees had no knowledge about antifungal resistance. CONCLUSION: Only few pharmacy employees were aware of the current problem of antifungal resistance and the majority advised costumers to initiate treatment using OTC topical terbinafine. The problem of emerging antifungal resistance requires attention in order to provide customers with tinea pedis effective treatment and prevent further societal spread of resistance to antifungals.

Hidradenitis suppurativa associated telomere-methylome dysregulations in blood.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic debilitating disease with a significant burden of both organic and psychological comorbidities. It has been shown that certain telomere-related genes (TRGs) affect a wide range of diseases, including HS and its associated comorbidities, but their exact role in HS pathogenesis is still unknown. OBJECTIVES: To determine whether TRG methylomes can be used as biomarkers in HS. METHODS: Using the Illumina HumanMethylation450 BeadChip array, we examined methylation variations associated with TRGs in HS cases and age-, sex- and ethnicity-matched healthy controls. The study utilized integrated bioinformatics statistical methods, such as a false discovery rate (FDR), the area under the receiver operating characteristic curve (AUC) and principal component analysis. RESULTS: There were a total of 585 different differentially methylated CpG sites identified in 585 TRGs associated with HS (474 hypomethylated and 111 hypermethylated) (FDR p-value < 0.05). A number of these CpGs have been identified as being involved in increased pain sensitivity including EPAS1, AHR, CSNK1D, DNMT1, IKBKAP, NOS3, PLCB1 and PRDM16 genes; GABRB3 as a potential alcohol addiction marker; DDB1, NSMCE2 and HNRNPA2B1 associated with cancers. Pathway analysis identified 67 statistically significant pathways, including DNA repair, telomere maintenance, mismatch repair and cell cycle control (p < 0.001). CONCLUSION: The disruption of TRGs leads to the shortening of telomeres, which is associated with HS progression, ageing, cellular senescence and an increased risk of various diseases, including cancer and associated comorbidities, such as metabolic syndrome, cardiovascular disease and inflammatory disorders. Further research is necessary to better understand the underlying mechanisms and establish causal links between TRGs and HS. The present study is the first effort to comprehend potential pathomechanisms of sporadic HS cases concentrating on PBMC methylome since ours.

New insights on hidradenitis suppurativa phenotypes and treatment response: An exploratory automated analysis of the SUNSHINE and SUNRISE trials.

BACKGROUND: Defining hidradenitis suppurativa (HS) subtypes was previously limited by small sample sizes and poor interrater reliability; no study has investigated subtype treatment responses. The objective of this analysis was to characterize HS clusters in adult patients with moderate to severe HS and evaluate secukinumab treatment responses between clusters. METHODS: Clusters were identified via an unsupervised machine learning clustering analysis using baseline data from the randomized, placebo-controlled SUNSHINE (NCT03713619) and SUNRISE (NCT03713632) phase 3 trials. To assess treatment responses, patients received secukinumab every 2 (SECQ2W) or 4 weeks (SECQ4W) or placebo, for 16 weeks, after which, placebo patients randomly switched to SECQ2W/SECQ4W, and SECQ2W/SECQ4W patients maintained their original treatment, until week 52. Baseline outcomes included patient characteristics, disease characteristics and severity, HS-associated comorbidities and previous treatment exposures. Treatment response was assessed via the HS clinical response (HiSCR), abscess and inflammatory nodule (AN) count, flares and NRS30 (skin pain). RESULTS: Based on baseline data, three clusters were identified from 1084 patients (Cluster 1: 54.1%, Cluster 2: 17.8%, Cluster 3: 28.1%). Cluster 1 was predominantly female (65.4%) and was characterized by milder HS. Cluster 2 had more patients from the Asia Pacific, Middle East and Africa region (58.5%) and was characterized by moderate HS. Cluster 3 had the highest rates of previous exposure to biologics (45.9%) and prior HS-related surgeries (47.5%) and was characterized by severe HS. SECQ2W and SECQ4W demonstrated efficacy versus placebo in all clusters at week 16; SECQ2W and SECQ4W efficacy was maintained to week 52. SECQ2W treatment showed a trend for greater efficacy versus SECQ4W in Cluster 3 through week 52. CONCLUSIONS: Three HS clusters were identified. Secukinumab demonstrated benefit over placebo in all clusters. However, patients with more severe disease may take longer to respond and more frequent secukinumab dosing may be required for these patients. TRIAL REGISTRATION: SUNSHINE (NCT03713619) and SUNRISE (NCT03713632).

Secukinumab efficacy in patients with hidradenitis suppurativa assessed by the International Hidradenitis Suppurativa Severity Score System (IHS4): A post hoc analysis of the SUNSHINE and SUNRISE trials.

INTRODUCTION: The International Hidradenitis Suppurativa Severity Score System (IHS4) is a validated tool that measures inflammatory lesions, including draining tunnels, in hidradenitis suppurativa (HS). OBJECTIVE: To evaluate secukinumab efficacy using IHS4 in patients with moderate to severe HS. METHODS: Data from the SUNSHINE and SUNRISE trials, which assessed subcutaneous secukinumab 300 mg every 2 (SECQ2W) and 4 (SECQ4W) weeks in adults with moderate to severe HS, were analyzed. Assessments included changes from baseline in IHS4 and severity classification up to Week 52; IHS4-55, IHS4-75, IHS4-90 responses (55%, 75% and 90% reduction in IHS4) and concordance between IHS4-55 and HS clinical response (HiSCR), at Weeks 16 and 52. RESULTS: In total, 1084 patients (SECQ2W = 361; SECQ4W = 360; placebo = 363) were analyzed. At Week 16, SECQ2W and SECQ4W demonstrated a numerically higher reduction in IHS4 from baseline versus placebo (adjusted mean [95% CI]: -10.80 [-12.30 to -9.30] and -9.46 [-10.96 to -7.96] vs. -4.92 [-6.43 to -3.41]); the reduction was maintained until Week 52 in both dose regimens. A greater proportion of patients achieved IHS4-55 with SECQ2W (43.4%) and SECQ4W (39.5%) versus placebo (31.5%) at Week 16, with further improvement at Week 52. Similar trends were observed for IHS4-75 and IHS4-90 responses. While no patients had mild disease based on IHS4 (80.7% had severe and 19.3% had moderate HS) at baseline, a greater proportion of patients were categorized as having mild disease at Week 16 in the SECQ2W (25.9%) and SECQ4W (24.0%) groups versus placebo (16.4%); this trend continued up to Week 52 in both dose regimens. Strong concordance (>85%) was observed between IHS4-55 and HiSCR. CONCLUSIONS: Both SECQ2W and SECQ4W demonstrated efficacy in improving treatment response as measured by IHS4 and reducing disease severity versus placebo at Week 16 and these improvements were sustained through Week 52. These findings support that the dynamic and dichotomous IHS4 can efficiently detect treatment response changes in clinical trial settings.

Cluster Analysis Identifies Clinical Phenotypes of Primary Hyperhidrosis.

INTRODUCTION: Identifying subgroups of patients with primary hyperhidrosis (PHH) can improve the understanding of the disease pathophysiology. The study objective was to determine the naturally occurring subgroups of patients with PHH based on clinical characteristics. METHODS: In this retrospective cohort study, data were collected from participants included in a clinical trial. The data were collected between January 2020 and June 2021 from outpatients with PHH attending a dermatologic department in Denmark. Overall, 84 patients with PHH were screened for inclusion in the clinical trial. Of these, 41 met the eligibility criteria. Four participants were excluded because of missing data. The main outcome was the identification of subgroups of patients with PHH using an unsupervised hierarchical cluster analysis. RESULTS: Overall, 37 patients were included {28 (76.7%) females; median age at inclusion 28.0 (interquartile range [IQR] 24.0-38.3); median body mass index 24.9 (IQR 20.9-27.4); median age of onset 13.0 (IQR 9.5-18.5); and 26 (70.3%) had a familial disposition toward PHH}. Two clusters of 18 and 17 patients were identified. The first cluster had, when compared to the second, a younger age of onset (median age 11.0 [IQR 0-13.0] vs. 17.0 [IQR 15.0-21.0], p = 0.003) and higher sweat rates on gravimetry (median 175.0 [IQR 121.2-252.5] vs. 40.0 [IQR 20.0-60.0] milligrams of sweat/5 min, p < 0.001) and transepidermal water loss (median 93.7 [IQR 91.2-97.8] vs. 59.0 [IQR 44.4-73.2] g/m2/h, p < 0.001). No differences were observed for the other variables. CONCLUSIONS: This study identifies 2 subgroups of patients with PHH. The patients with an onset of PHH during childhood had a substantially higher sweat and evaporation rate in adulthood than those with an onset during adolescence. These findings may imply a changed understanding of the pathophysiology of PHH, by indicating that an early disease onset can lead to a worse disease course.

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.

Quality of life in individuals with primary hyperhidrosis: a systematic review and meta-analysis.

PURPOSE: Hyperhidrosis can be a debilitating disease that leads to the deterioration of well-being. In this study, the objective was to compare the health-related quality of life (HRQOL) in individuals with and without hyperhidrosis by conducting a systematic review and meta-analysis. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the Meta-analysis Of Observational Studies in Epidemiology checklist were employed. We systematically searched Cochrane Library, Embase and PubMed. Two authors independently assessed the literature and extracted the data. The risk of bias was assessed using the Newcastle-Ottawa Scale. A random-effects model was employed. The heterogeneity was determined using I2. RESULTS: Eleven studies met the eligibility criteria comprising 4297 and 147,604 participants with and without hyperhidrosis, respectively. The risk of bias ranged from high quality to very high risk of bias. The individuals with hyperhidrosis had a higher Dermatology Life Quality Index (mean difference 8.53; 95% confidence interval 3.47, 13.58; p = 0.0009) and a lower mental component summary of the short form-12 or -36 (mean difference -6.15; 95% confidence interval -9.00, -3.30; p < 0.0001) than the control individuals. No difference was found for the physical component summary score of the short form-12 or -36 (mean difference -0.88; 95% confidence interval -1.88, 0.12; p = 0.085). Studies using patient-reported outcomes, not included in the meta-analysis, showed similar results. CONCLUSION: Individuals with hyperhidrosis experience a reduced HRQOL that is clinically meaningful and leads to perceivable deteriorations in their well-being. The evidence shows a high degree of heterogeneity, which warrants additional studies.

Hidradenitis suppurativa presents a methylome dysregulation capable to explain the pro-inflammatory microenvironment: Are these DNA methylations potential therapeutic targets?

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, systemic, inflammatory skin condition with elusive pathogenesis that affects therapeutic intervention directly. OBJECTIVE: To characterize epigenetic variations in cytokines genes contributing to HS. METHODS: Epigenome-wide DNA methylation profiling with the Illumina Epic array was performed on blood DNA samples from 24 HS patients and 24 age- and sex-matched controls to explore DNA methylation changes in cytokine genes. RESULTS: We identified 170 cytokine genes including 27 hypermethylated CpG sites and 143 genes with hypomethylated sites respectively. Hypermethylated genes, including LIF, HLA-DRB1, HLA-G, MTOR, FADD, TGFB3, MALAT1 and CCL28; hypomethylated genes, including NCSTN, SMAD3, IGF1R, IL1F9, NOD2, NOD1, YY1, DLL1 and BCL2 may contribute to the pathogenesis of HS. These genes were enriched in the 117 different pathways (FDR p-values ≤ 0.05), including IL-4/IL-13 pathways and Wnt/ß-catenin signalling. CONCLUSIONS: The lack of wound healing, microbiome dysbiosis and increased tumour susceptibility are all sustained by these dysfunctional methylomes, hopefully, capable to be targeted in the next future. Since methylome describes and summarizes genetic and environmental contributions, these data may represent a further step towards a feasible precision medicine also for HS patients.