Orismilast for the treatment of mild to severe hidradenitis suppurativa: Week 16 data from OSIRIS, a Phase 2a, open-label, single-centre, single-arm, dose-finding clinical trial.

BACKGROUND: Hidradenitis suppurativa (HS) is a disease with an unmet need for treatment. OBJECTIVE: To examine tolerability, safety and efficacy of oral phosphodiesterase-4 (PDE4) inhibitior orismilast 10-40 mg twice daily (BID) in HS. METHODS: A Phase 2a, single-arm, single-centre, open-label, 16-week trial in HS patients. Adjustments in maximal dose and titration were allowed, to improve tolerability, dividing the study population in two groups who completed and discontinued 16 weeks of treatment. Descriptive statistics were applied to efficacy data from patients who completed treatment and patients who discontinued treatment prematurely. A last-observation-carried-forward (LOCF) approach was used for patients who discontinued treatment. The primary endpoint was percent change in the total number of abscesses and nodules (AN-count) at Week 16, with the HS Clinical Response with a 50% reduction in the AN-count (HiSCR50) as key secondary endpoint. RESULTS: Of the 20 patients included, 9 completed 16 weeks of treatment and 11 discontinued treatment prematurely. The mean AN-count was reduced with 33.1% in patients who completed treatment and with 12.0% in patients who discontinued. HiSCR50 was achieved by 67.0% and 27.0% of patients who completed and discontinued treatment, respectively. Most adverse events were mild to moderate. CONCLUSIONS: Oral orismilast demonstrated a dose-dependent tolerability, with mild to moderate adverse effects. Further, the results of this exploratory trial indicate that orismilast may lead to clinical improvements in HS. However, larger trials with tolerable dose ranges are warranted. The Trial is registered at Clinicaltrials.gov (UNI50007201) and EudraCT.ema.europa.eu (2021-000049-42).

Position statement: Recommendations on the diagnosis and treatment of Malassezia folliculitis.

Malassezia is a lipophilic yeast that is a part of the human mycobiome. Malassezia folliculitis appears when the benign colonization of the hair follicles, by the Malassezia yeasts, becomes symptomatic with pruritic papules and pustules. Although Malassezia folliculitis is common in hospital departments, diagnosing and treating it varies among dermatologists and countries. The European Academy of Dermatology and Venereology Mycology Task Force Malassezia folliculitis working group has, therefore, sought to develop these recommendations for the diagnosis and management of Malassezia folliculitis. Recommendations comprise methods for diagnosing Malassezia folliculitis, required positive findings before starting therapies and specific treatment algorithms for individuals who are immunocompetent, immunocompromised or who have compromised liver function. In conclusion, this study provides a clinical strategy for diagnosing and managing Malassezia folliculitis.

Human leukocyte antigen system associations in Malassezia-related skin diseases.

BACKGROUND: The human leukocyte antigen system (HLA) is divided into two classes involved in antigen presentation: class I presenting intracellular antigens and class II presenting extracellular antigens. While susceptibility to infections is correlated with the HLA system, data on associations between HLA genotypes and Malassezia-related skin diseases (MRSD) are lacking. Thus, the objective of this study was to investigate associations between HLA alleles and MRSD. MATERIALS AND METHODS: Participants in The Danish Blood Donor Study (2010-2018) provided questionnaire data on life style, anthropometric measures, and registry data on filled prescriptions. Genotyping was done using Illumina Infinium Global Screening Array, and HLA alleles were imputed using the HIBAG algorithm. Cases and controls were defined using filled prescriptions on topical ketoconazole 2% as a proxy of MRSD. Logistic regressions assessed associations between HLA alleles and MRSD adjusted for confounders and Bonferroni corrected for multiple tests. RESULTS: A total of 9455 participants were considered MRSD cases and 24,144 participants as controls. We identified four risk alleles B*57:01, OR 1.19 (95% CI: 1.09-1.31), C*01:02, OR 1.19 (95% CI: 1.08-1.32), C*06:02, OR 1.14 (95% CI: 1.08-1.22), and DRB1*01:01, OR 1.10 (95% CI: 1.04-1.17), and two protective alleles, DQB1*02:01, OR 0.89 (95% CI: 0.85-0.94), and DRB1*03:01, OR 0.89 (95% CI: 0.85-0.94). CONCLUSION: Five novel associations between HLA alleles and MRSD were identified in our cohort, and one previous association was confirmed. Future studies should assess the correlation between Malassezia antigens and antigen-binding properties of the associated HLA alleles.

Incidence and remission rates of self-reported hidradenitis suppurativa - A prospective cohort study conducted in Danish blood donors.

BACKGROUND: A large discrepancy between physician-diagnosed and self-reported Hidradenitis suppurativa (HS) exists. Knowledge regarding incidence and remission rates of self-reported HS is missing, but may help bridge the gap in understanding between these two phenotypes. OBJECTIVES: To determine the incidence and remission rates of self-reported HS, and to what degree these are affected by sex, smoking and BMI. METHODS: A prospective cohort of 23 930 Danish blood donors. Information on self-reported HS, symptom-localisation, sex, age, BMI and smoking status was collected at baseline and study termination. Self-reported HS fulfilled clinical obligatory diagnostic criteria. Cox proportional hazards regression analyses were conducted for both incidence and remission rates providing a hazard ratio (HR) of risk for each variable in the regression. RESULTS: Incidence rate of self-reported HS was 10.8/1000 person-years (95% confidence interval (CI): 9.9-11.7), decreasing as a function of numbers of areas affected. Female BMI points above 25 (HR = 1.11, 95% CI: 1.09-1.13), male BMI points above 25 (HR = 1.07, 95% CI: 1.04-1.11), active smoking (HR = 1.72, 95% CI: 1.15-2.57), male sex (HR = 0.55, 95% CI: 0.45-0.67) and years of age above 25 (HR = 0.97, 95% CI: 0.96-0.97) were all statistically associated with the development of self-reported HS. Remission rate of self-reported HS was 256.7/1000 person-years (95% CI: 223.9-292.6), decreasing as a function of numbers of affected areas. Symptoms in ≥3 areas (HR = 0.54, 95% CI: 0.34-0.85), active smoking (HR = 0.49, 95% CI: 0.32-0.76) and female weight loss (every percentage drop in BMI: HR = 1.07, 95% CI: 1.05-1.11) all significantly affected the remission rate. CONCLUSIONS: Both incidence and remission rates of self-reported HS are high, indicating that many with self-reported HS are unlikely to be diagnosed, as they to a higher degree experience mild transient HS symptoms.

Tinea capitis asymptomatic carriers: what is the evidence behind treatment?

Tinea capitis is a fungal infection mostly affecting children. Epidemiology is changing over time due to migration, and it has been estimated that up to 40% of children from certain developing countries are affected. The mechanism of transmission is still unclear although asymptomatic carriage seems to have an influence in establishing persistent reservoirs that can cause or fuel epidemics. Screening and prophylactic treatment of close contacts of tinea capitis patients are therefore recommended by several international guidelines, but vaguely and not consistent. The treatments involved can be expensive, hard to integrate in everyday life, have well-known side effects and some are not approved for the treatment of children. The aim of this review was to clarify the evidence behind treatment of human asymptomatic carriers of tinea capitis. Databases were searched for the 'tinea capitis', 'carriers' and 'treatment'. Inclusion criteria were clinical trials, observational and interventional studies including case series (10+ cases) and case reports in English, Danish, Swedish, Norwegian and French. Reviews, guidelines, unclear reports and in vitro trials were excluded. A systematic review identified 10 studies with low to moderate evidence levels. The topical treatments ketoconazole, povidone-iodine, miconazole and the systemic antifungals terbinafine and itraconazole have all shown significant effects in the mycological eradication of fungal conidia. General prophylactic hygienic measures may have a benefit. The scientific evidence behind the treatment of asymptomatic carriage of scalp dermatophytes is sparse and not of high quality. Yet, both topical and systemic antifungal agents show treatment efficacy. Considering the possible adverse effects, topical agents are preferable, but with necessary attention to the compliance of asymptomatic contacts with treatment.

Emerging antifungal treatment failure of dermatophytosis in Europe: take care or it may become endemic.

BACKGROUND: Dermatophytosis is a world-wide distributed common infection. Antifungal drug resistance in dermatophytosis used to be rare, but unfortunately the current Indian epidemic of atypical widespread recalcitrant and terbinafine-resistant dermatophytosis is spreading and has sporadically been reported in Europe. OBJECTIVES: To explore the occurrence of clinical and mycological proven antifungal drug resistance in dermatophytes in Europe. METHODS: A standardized questionnaire was distributed through the EADV Task Force of Mycology network to dermatologists in Europe. RESULTS: Representatives from 20 countries completed the questionnaires of which 17 (85 %) had observed clinical and/or mycological confirmed antifungal resistance, two countries published cases of antifungal resistance and one country had no known cases. CONCLUSIONS: This pilot study confirms that both clinical and mycological antifungal resistance exist in Europe.

Convergent Validity of Suffering and Quality of Life as Measured by The Hidradenitis Suppurativa Quality of Life.

BACKGROUND: Hidradenitis suppurativa (HS) is a painful chronic, recurrent inflammatory skin disease with great impact on health-related quality of life (HRQOL). Recently, Hidradenitis SuppuraTiva cORe outcomes set International Collaboration (HISTORIC) established HRQOL as a core domain set for HS clinical trials and developed the Hidradenitis Suppurativa Quality of Life (HiSQOL) as a validated outcome measurement instrument. OBJECTIVES: To provide further convergent validity of HiSQOL by comparing it to Dermatology Life Quality Index (DLQI) and Pictorial Representation of Illness and Self Measure-Revised 2 (PRISM-R2). METHODS: In this cross-sectional study, 103 participants completed HiSQOL, PRISM-R2 and DLQI. PRISM-R2 is an instrument designed to measure suffering and reports the two measures, Illness Perception Measure (IPM) and Self-Illness Separation (SIS). Correlation analyses were performed including a sub-analysis for a subgroup of patients with high scores in the HS-specific domains of HiSQOL. RESULTS: A very strong correlation was found between HiSQOL and DLQI (ρ = 0.93, P < 2.2 × 10-16 , (95% CI: 0.89;0.95)), and moderately strong correlations were found between HiSQOL and SIS (ρ = -0.73, P < 2.2 × 10-16 , (95% CI: -0.81; -0.62)) and DLQI and SIS (ρ = -0.70, P < 2.2 × 10-16 , (95% CI: -0.79; -0.59)). IPM was positively associated with HiSQOL and DLQI and negatively with SIS. CONCLUSIONS: HiSQOL is a valid measure of quality of life for HS patients, and we suggest that HiSQOL can be used as a measure of suffering as well.

A systematic review of worldwide data on tinea capitis: analysis of the last 20 years.

Dermatophyte infections are the most common fungal infections in humans; among them, tinea capitis (TC) - the most contagious fungal infection - is caused by anthropophilic, zoophilic and geophilic dermatophytes. The purpose of this systematic review was to determine the different aetiological variants involved in TC and the overall epidemiology of the causes of this infection in the last two decades. We searched the MEDLINE (PubMed) and Embase databases for articles published from July 2000 to August 2019 using the following search terms: 'Tinea capitis', 'Africa', 'America', 'Asia', 'Europe', 'Oceania', and the names of the countries on each continent. The flow of information through the different phases in this systematic review was depicted using a PRISMA flow diagram, which mapped the number of records identified, included and excluded, and the reasons for exclusion. Our findings indicate that the frequency of different aetiologic agents of TC in the reported studies varied globally, from 0.4-87.7% in Africa, 0.2-74.0% in North America, 0.0-91.2% in Eastern Asia, 0.0-69.0% in Eastern Europe and 2.9-86.4% in Oceania. Microsporum canis is the most frequent reported zoophilic agent worldwide, while Trichophyton violaceum and Trichophyton tonsurans are the predominant anthropophilic agents. Over time, the frequency of these latter fungal infections has increased globally, and these fungi have become the major species globally. Anthropophilic transmission - the most prevalent type of transmission - could be explained by two factors: (i) the socioeconomic status of affected countries and population groups with associated risk factors and (ii) movement of populations importing new causes of infection to areas where they had not been encountered previously. We observed that intercontinental migration and travel; globalization; environmental, climatic and ecological changes; and accelerated evolution of health technologies may influence the observed epidemiological changes and, consequently, contributed to the variations in the global status of TC.

Full exome sequencing of 11 families with Hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is not a well-studied or easily treated disease. Genetic information is essential for advances in the understanding and treatment of HS. This study aims to examine mutations in the gamma-secretase complex, the Notch signalling pathway and to perform a Mendelian analysis of genetic variants that segregated with disease in a full exome sequencing of 11 families with HS. METHOD: Whole-exome sequencing and Mendelian analysis of 11 families with HS from Denmark. Patients with a clinical diagnosis of active HS and a positive family history of HS were recruited. Consenting family members were enrolled and examined for HS as well. We included 11 families, with a total of 51 participants, 24 with HS and 27 without. Whole-exome sequencing using HiSeq platform as paired-end 2 × 150 bases was used. RESULTS: We found mutations in the Notch pathway for all families. We found mutations in the PSENEN and APH1B of the gamma-secretase genes. We also report 161 variants of unknown significance that segregated with the disease within these families. CONCLUSIONS: We did not find causative mutation for each family in this study, supporting the theory that HS is rarely caused by single-gene mutations. We suggest that future genetic studies should be focused on genome-wide association with thousands of cases, as this technique is better suited for suspected polygenic diseases.

Critical synthesis of available data in Malassezia folliculitis and a systematic review of treatments.

Folliculitis is an inflammatory process involving the hair follicle, frequently attributed to infectious causes. Malassezia, an established symbiotic yeast that can evolve to a skin pathogen with opportunistic attributes, is a common source of folliculitis, especially when intrinsic (e.g. immunosuppression) or extrinsic (high ambient temperature and humidity, clothing) impact on the hair follicle and the overlying skin microenvironment. Our aim was to critically review the pathophysiology and clinical characteristics of Malassezia folliculitis, to describe laboratory methods that facilitate diagnosis and to systematically review treatment options. Malassezia folliculitis manifests as a pruritic, follicular papulopustular eruption distributed on the upper trunk. It commonly affects young to middle-aged adults and immunosuppressed individuals. Inclusion into the differential diagnosis of folliculitis is regularly oversighted, and the prerequisite-targeted diagnostic procedures are not always performed. Sampling by tape stripping or comedo extractor and microscopic examination of the sample usually identifies the monopolar budding yeast cells of Malassezia without the presence of hyphae. However, confirmation of the diagnosis with anatomical association with the hair follicle is performed by biopsy. For systematic review of therapies, PubMed was searched using the search string "(malassezia" [MeSH Terms] OR "malassezia" [All Fields] OR pityrosporum [All Fields]) AND "folliculitis" [MeSH Terms] and EMBASE was searched using the search string: 'malassezia folliculitis.mp OR pityrosporum folliculitis.mp'. In total, 28 full-length studies were assessed for eligibility and 21 were selected for inclusion in therapy evaluation. Conclusively Malassezia folliculitis should be considered in the assessment of truncal, follicular skin lesions. Patient's history, comorbidities and clinical presentation are usually indicative, but microscopically and histological examination is needed to confirm the diagnosis. Adequate samples obtained with comedo extractor and serial sections in the histological material are critical for proper diagnosis. Therapy should include systemic or topical measures for the control of the inflammation, as well as the prevention of recurrences.

Cutaneous candidiasis - an evidence-based review of topical and systemic treatments to inform clinical practice.

Cutaneous candidiasis is a common skin disease, and several treatments have been investigated within the last fifty years. Yet, systematic reviews are lacking, and evidence-based topical and systemic treatment strategies remain unclear. Thus, the aim of this review was to summarize efficacy and adverse effects of topical and oral therapies for cutaneous candidiasis in all age groups. Two individual researchers searched PubMed and EMBASE for 'cutaneous candidiasis' and 'cutaneous candidiasis treatment', 'intertrigo', 'diaper dermatitis' and 'cheilitis'. Searches were limited to 'English language', 'clinical trials' and 'human subjects', and prospective clinical trials published in abstracts or articles were included. In total, 149 studies were identified, of which 44 were eligible, comprising 41 studies of 19 topical therapies and four studies of three systemic therapies for cutaneous candidiasis. Topical therapies were investigated in infants, children, adolescents, adults and elderly, while studies of systemic therapies were limited to adolescents and adults. Clotrimazole, nystatin and miconazole were the most studied topical drugs and demonstrated similar efficacy with complete cure rates of 73%-100%. Single-drug therapy was as effective as combinations of antifungal, antibacterial and topical corticosteroid. Four studies investigated systemic therapy, and oral fluconazole demonstrated similar efficacy to oral ketoconazole and topical clotrimazole. Limitations to this review were mainly that heterogeneity of studies hindered meta-analyses. In conclusions, clotrimazole, nystatin and miconazole were the most studied topical drugs and demonstrated equal good efficacy and mild adverse effects similar to combinations of antifungal, antibacterial and topical corticosteroids. Oral fluconazole was as effective as topical clotrimazole and is the only commercially available evidence-based option for systemic treatment of cutaneous candidiasis.

The microbiome of tunnels in hidradenitis suppurativa patients.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease defined by recurrent nodules, tunnels and scarring involving the intertriginous regions. Recent next-generation sequencing (NGS) studies suggest genera such as Prevotella spp., Peptoniphilus spp. and Porphyromonas spp. are associated with chronic and early HS lesions. However, a systematic investigation of the bacterial microbiome in HS tunnels remains unexplored using NGS. OBJECTIVE: We aimed to investigate the bacterial composition of the luminal white gelatinous material found in HS tunnels using NGS. METHODS: An exploratory study of patients with diagnosis of HS (n = 32) with tunnels. The tunnels were present either in the groin (n = 17) or in the axilla (n = 15). During deroofing of the tunnels, a sterile E-swab was taken of the luminal gelatinous material. The samples were investigated using NGS targeting 16S ribosomal RNA. RESULTS: The skin microbiome was characterized in 32 HS patients. Overall, five microbiome types were identified: Porphyromonas spp. (type I), Corynebacterium spp., (type II), Staphylococcus spp. (type III), Prevotella spp. (type IV) and Acinetobacter spp (type V). Porphyromonas spp. (type I) and Prevotella spp. (IV) were the most frequent genera found the tunnels. CONCLUSION: This study points to a potential association between the presence of certain anaerobic bacteria (Porphyromonas spp., Prevotella spp.) and HS tunnels. It may be speculated that these two genera are associated with the pathogenesis in HS either as drivers or as biomarkers.

Inter-rater agreement and reliability of outcome measurement instruments and staging systems used in hidradenitis suppurativa.

BACKGROUND: Monitoring disease activity over time is a prerequisite for clinical practice and research. Valid and reliable outcome measurement instruments (OMIs) and staging systems provide researchers and clinicians with benchmark tools to assess the primary and secondary outcomes of interventional trials and to guide treatment selection properly. OBJECTIVES: To investigate inter-rater reliability and agreement in instruments currently used in hidradenitis suppurativa (HS), with dermatologists experienced in HS as the rater population of interest. METHODS: In a prospective completely balanced design, 24 patients with HS underwent a physical examination by 12 raters (288 assessments) using nine instruments. The results were analysed using generalized linear mixed models. RESULTS: For the staging systems, the study found good inter-rater reliability for Hurley staging in the axillae and gluteal region, moderate inter-rater reliability for Hurley staging in the groin and for Physician's Global Assessment, and fair inter-rater reliability for refined Hurley staging and the International HS Severity Scoring System. For all the tested OMIs, the observed intervals for limits of agreement were very wide relative to the ranges of the scales. CONCLUSIONS: The very wide intervals for limits of agreement imply that substantial changes are needed in clinical research in order to rule out measurement error. The results illustrate a difficulty, even for experienced HS experts, to agree on the type and number of lesions when evaluating disease severity. The apparent caveats call for global efforts, such as the HIdradenitis SuppuraTiva cORe outcomes set International Collaboration (HISTORIC) to reach consensus on how best to measure physical signs of HS reliably in randomized trials. What's already known about this topic? Without valid and reliable instruments to measure outcomes, researchers and clinicians lack the necessary benchmarks to assess primary and secondary end points of interventional trials properly. Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease. Several outcome measure instruments exist for HS, but their validation is generally incomplete or of relatively low methodological quality. What does this study add? Using a prospective completely balanced design this study examined inter-rater reliability with HS-experienced dermatologists as the rater population of interest. The study did not find very good reliability for any included instrument or lesion counts. This study illustrates the difficulty in finding agreement on the type and number of HS lesions, even among experts. The results question whether physical signs are best measured by a traditional physician lesion count instrument. What are the clinical implications of this work? For staging, Hurley staging and physician global visual analogue scale proved to be acceptable instruments in terms of inter-rater reliability. For the instruments designed to measure changes in health status, our study illustrates how difficult it is, even for experts, to measure the physical signs of HS using a simple rater counting. Consequently, other assessment methods of physicals signs, such as ultrasound evaluation, require consideration.

A survey among dermatologists: diagnostics of superficial fungal infections - what is used and what is needed to initiate therapy and assess efficacy?

BACKGROUND: Superficial fungal infections are common. It is important to confirm the clinical diagnosis by mycological laboratory methods before initiating systemic antifungal treatment, especially as antifungal sensitivity and in vitro susceptibility may differ between different genera and species. For many years, the gold standard for diagnosis of superficial fungal infections has been direct fungal detection in the clinical specimen (microscopy) supplemented by culturing. Lately, newer molecular based methods for fungal identification have been developed. OBJECTIVE: This study was initiated to focus on the current usage of mycological diagnostics for superficial fungal infections by dermatologists. It was designed to investigate whether it was necessary to differentiate between initial diagnostic tests and those used at treatment follow-up in specific superficial fungal infections. METHODS: An online questionnaire was distributed among members of the EADV mycology Task Force and other dermatologists with a special interest in mycology and nail disease. RESULTS: The survey was distributed to 62 dermatologists of whom 38 (61%) completed the whole survey, 7 (11%) partially completed and 17 (27%) did not respond. Nearly, all respondents (82-100%) said that ideally they would use the result of direct microscopy (or histology) combined with a genus/species directed treatment of onychomycosis, dermatophytosis, Candida- and Malassezia-related infections. The majority of the dermatologists used a combination of clinical assessment and direct microscopy for treatment assessment and the viability of the fungus was considered more important at this visit than when initiating the treatment. Molecular based methods were not available for all responders. CONCLUSION: The available diagnostic methods are heterogeneous and their usage differs between different practices as well as between countries. The survey confirmed that dermatologists find it important to make a mycological diagnosis, particularly prior to starting oral antifungal treatment in order to confirm the diagnose and target the therapy according to genus and species.