Antimicrobial peptides in hidradenitis suppurativa: a systematic review.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease of the hair follicle defined by recurrent nodules, tunnels and scarring involving the intertriginous regions. HS is associated with microbial dysbiosis and immune dysregulation. In HS, an increasing number of studies have investigated antimicrobial peptides (AMPs). OBJECTIVES: To provide an overview of the literature on AMPs in HS, and to discuss the potential role of AMPs in the pathogenesis of HS. METHODS: PubMed, Embase and the Cochrane Library were searched. The titles, abstracts and full texts of all articles were manually screened. Additionally, the reference lists of the included articles were screened and hand searched for relevant studies. RESULTS: The final literature sample comprised 18 retrospective and prospective studies (no reviews or commentaries) published between 2009 and 2020. CONCLUSIONS: This review demonstrates the multitude of AMPs in HS. Although the methodology of the studies varied, the included studies indicate a consistent overexpression of human ß-defensin (hBD)-2, S100A7, S100A8 and S100A9 at both the mRNA and protein levels, and a decreased expression of hBD-1. Overall, the studies point to a dysregulation of AMPs in both lesional and nonlesional HS skin.

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.

Burden, predictors and temporal relationships of comorbidities in patients with hidradenitis suppurativa: a hospital-based cohort study.

AIM: To examine the burden, predictors and temporal relationships of comorbidities in patients with hidradenitis suppurativa (HS). METHODS: Information on HS and ten systemic comorbidities was obtained by interview and clinical examination, including blood pressure, body mass index (BMI) and blood samples, in a cohort of consecutive HS outpatients. RESULTS: A total of 302 patients were included. About 86.6% had at least one comorbidity. The mean number of comorbidities per patient was 2.1. One or more cardiovascular comorbidities were observed in 76.5% with evidence of substantial unawareness and undertreatment; 48.4% had hypertension, 9.3% had diabetes, 57.7% had dyslipidaemia and 36.7% were obese. About 6.6% had inflammatory bowel disease, 6.3% had arthritis, 29.5% had a psychiatric diagnosis, 5.6% had psoriasis, 7.9% had obstructive lung disease, and 6.6% had polycystic ovary syndrome. These comorbidities occurred at different time points in relation to the onset of HS with evidence of shared as well as differential risk factors. Age (per year), HR = 0.87 (0.79-0.96), P < 0.006, age of onset of HS (per year), HR = 1.26 (1.14-1.40), P < 0.001, male sex, HR = 2.51 (0.88-7.16), P = 0.086, Hurley stage III (vs. Hurley I + II), HR = 3.46 (1.25-9.58), P = 0.017, BMI (per unit), HR = 1.12 (1.04-1.20), P = 0.002, and blood glucose (per unit), HR = 1.27 (1.16-1.39), P < 0.001 were significant predictors for onset of diabetes. CONCLUSION: There is a substantial burden, unawareness and undertreatment of several systemic comorbidities in patients with HS. Comorbidities occur at different time points in relation to the onset of HS. This should lead to higher awareness among treating specialists.

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.

Hidradenitis suppurativa/acne inversa: a practical framework for treatment optimization - systematic review and recommendations from the HS ALLIANCE working group.

Hidradenitis suppurativa (HS)/acne inversa is a debilitating chronic disease that remains poorly understood and difficult to manage. Clinical practice is variable, and there is a need for international, evidence-based and easily applicable consensus on HS management. We report here the findings of a systematic literature review, which were subsequently used as a basis for the development of international consensus recommendations for the management of patients with HS. A systematic literature review was performed for each of nine clinical questions in HS (defined by an expert steering committee), covering comorbidity assessment, therapy (medical, surgical and combinations) and response to treatment. Included articles underwent data extraction and were graded according to the Oxford Centre for Evidence-based Medicine criteria. Evidence-based recommendations were then drafted, refined and voted upon, using a modified Delphi process. Overall, 5310 articles were screened, 171 articles were analysed, and 65 were used to derive recommendations. These articles included six randomized controlled trials plus cohort studies and case series. The highest level of evidence concerned dosing recommendations for topical clindamycin in mild disease (with systemic tetracyclines for more frequent/widespread lesions) and biologic therapy (especially adalimumab) as second-line agents (following conventional therapy failure). Good-quality evidence was available for the hidradenitis suppurativa clinical response (HiSCR) as a dichotomous outcome measure in inflammatory areas under treatment. Lower-level evidence supported recommendations for topical triclosan and oral zinc in mild-to-moderate HS, systemic clindamycin and rifampicin in moderate HS and intravenous ertapenem in selected patients with more severe disease. Intralesional or systemic steroids may also be considered. Local surgical excision is suggested for mild-to-moderate HS, with wide excision for more extensive disease. Despite a paucity of good-quality data on management decisions in HS, this systematic review has enabled the development of robust and easily applicable clinical recommendations for international physicians based on graded evidence.

Moderate to severe hidradenitis suppurativa patients do not have an altered bacterial composition in peripheral blood compared to healthy controls.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease defined by recurrent nodules, tunnels and scarring involving the intertriginous skin. Patients with HS often report an array of systemic symptoms such as fatigue and malaise. The aetiology of these symptoms remains unclear. Previously, various bacteria have been associated with mature HS lesions, and bacteraemia has been reported in patients with HS using traditional culturing methods. Thus, we hypothesized that a low-grade bacteraemia contributes to the symptomatology in patients with HS. OBJECTIVE: To explore the potential presence of bacteraemia in patients with HS and healthy controls. METHOD: A case-control study. Compositions of bacteria in the blood of 27 moderate to severe HS patients and 26 healthy controls were investigated using next-generation 16S ribosomal RNA gene sequencing (NGS) and routine anaerobic and aerobic blood culturing. None of the participants received any antibiotics (systemic or topical therapy) within 1 month prior to the study. HS patients with a recent flare were randomly selected by consecutive recruitment of eligible patients from the Department of Dermatology, Zealand University Hospital, Denmark. Healthy controls were recruited from the University of Copenhagen as well as from the healthcare staff. RESULTS: The different bacterial compositions were investigated using NGS and traditional anaerobic and aerobic blood culturing. Our NGS analysis provided a previously unreported characterization of the bacterial composition in peripheral blood from patients with HS and healthy controls. Overall, our data demonstrated that patients with HS do not have a different bacterial composition in their peripheral blood than healthy controls. CONCLUSION: The study suggests that the self-reported symptoms in HS such as malaise and fatigue may not be linked to bacteraemia.

Self-reported minor infections in patients with hidradenitis suppurativa and healthy controls.

BACKGROUND: Patients with hidradenitis suppurativa (HS) often report opportunistic infections such as herpes and urinary tract infections. AIM: To compare opportunistic infections in patients with HS against a group of healthy controls (HCs). METHODS: In total, 99 patients with HS and 109 HCs were recruited at random to this retrospective case-control study. We devised a questionnaire to explore the frequency of minor infections, general practitioner (GP) visits and sick days experienced during the past 6 months. Additionally, participants were asked if they felt unwell more often compared with their peers. RESULTS: Patients with HS felt unwell more often than did HCs (26.3% vs. 7.3%, P < 0.001). Although there was no difference between the groups in five of the seven diseases studied, patients with HS had a higher frequency of the common cold (P < 0.01) and genital herpes (P < 0.01). Number of pack-years of smoking did not affect risk of infections (Pearson correlation, P = 0.51). Subgroup analysis of nonsmokers found the same differences in frequency of minor infections, common cold and genital herpes between patients with HS and controls. CONCLUSIONS: Patients with HS appear to experience more frequently symptoms compatible with minor infections in general, and the common cold and genital herpes specifically. This results in more GP visits and more sick days. Further research is needed to determine if this is caused by an immunological hyper-reactive state in these patients or a reduced threshold for minor infections.

Prodromal symptoms in hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease, which presents as recurrent nodules and sinus tracts (tunnels) with subsequent scarring, predominantly involving the intertriginous regions. Although prodromal symptoms (i.e. various symptoms preceding the eruption of the HS lesions) are often mentioned, there have been no formal investigations into this aspect. Insight into prodromal symptoms may enable patients with HS or dermatologists in choosing a more targeted treatment at a much earlier stage, potentially increasing treatment efficacy and quality of life. AIM: To characterize the spectrum of prodromes in patients with HS. METHODS: An extensive questionnaire that explored the frequency, type and time of occurrence of the prodromal symptom(s) and the degree of certainty of the perceived association was administered to 72 patients. RESULTS: The majority of the 72 patients (83.3%; n = 60) confirmed that they experienced one or more symptom(s) prior to the development of inflamed nodules or abscesses. These included: fatigue (32%), malaise (defined as a fever-like sensation) (23%), headache (11%) and nausea (2%). Localized symptoms included skin erythema (75%), paraesthesia (63%) and itching (20%). the majority of the patients stated that the prodromes usually occurred > 24 h (45%) or 12-24 h (20%) before the eruption. CONCLUSION: Our data suggest that the majority of patients with HS experience prodromal symptoms, heralding a flare of their HS. The findings may give rise to important new treatment approaches for the management of HS.

Bacterial biofilm in chronic lesions of hidradenitis suppurativa.

BACKGROUND: Chronic nonhealing or recurrent inflammatory lesions, reminiscent of infection but recalcitrant to antibiotic therapy, generally characterize biofilm-driven diseases. Chronic lesions of hidradenitis suppurativa (HS) exhibit several characteristics, which are compatible with well-known biofilm infections. OBJECTIVES: To determine and quantify the potential presence of bacterial aggregates in chronic HS lesions. METHODS: In 42 consecutive patients with HS suffering from chronic lesions, biopsies were obtained from lesional as well as from perilesional skin. Samples were investigated using peptide nucleic acid-fluorescence in situ hybridization in combination with confocal laser scanning microscopy. In addition, corresponding histopathological analysis on haematoxylin and eosin slides was performed. RESULTS: Biofilms were seen in 67% of the samples of chronic lesions and in 75% of the perilesional samples. The mean diameter of aggregates in lesional skin was significantly greater than in perilesional skin (P = 0·01). Large biofilms (aggregates > 50 µm in diameter) were found in 42% of lesional samples and in only 5% of the perilesional samples (P = 0·009). The majority of the large biofilms were situated in sinus tracts (63%) or in the infundibulum (37%). The majority of the sinus tract samples (73%) contained active bacterial cells, which were associated with inflammation. CONCLUSIONS: This study suggests that biofilm formation is associated with inflammation of chronic HS lesions. The aggregates most likely occur as a secondary event, possibly due to predisposing local anatomical changes such as sinus tracts (tunnels), keratinous detritus and dilated hair follicles.

Body composition and basal metabolic rate in Hidradenitis Suppurativa: a Danish population-based and hospital-based cross-sectional study.

BACKGROUND: Several studies have suggested an association between Hidradenitis Suppurativa (HS) and obesity. Obesity is often expressed as Body Mass Index (BMI). However, BMI lacks information on body composition. General obesity is a predictor of health status and cardiovascular risk, but body composition (e.g. abdominal fat) may be more so. Basal metabolic rate (BMR) is an expression of resting metabolism and may serve as a complementary tool when assessing the possibly underlying metabolism behind a persons' body composition. OBJECTIVE: To investigate the body composition and basal metabolic rate in individuals with HS compared with healthy controls. METHODS: We performed a cross-sectional study on both a hospital-based and population-based HS group and compared with controls using Bioelectrical Impedance Analysis to assess body composition. RESULTS: We identified a hospital-based HS group of 32 hospital HS patients, a population-based HS group of 430 population HS patients, and 20 780 controls. Age- and sex-adjusted analyses showed a 10.12% (P < 0.0001) significantly higher fat percentage in the hospital-based HS group and 3.11% (P < 0.0001) significantly higher fat percentage for the population-based HS group compared to controls. Correspondingly, the HS groups had a lower muscle percentage (P < 0.0001) and lower bone mass percentage (P < 0.0001). Furthermore, visceral fat rating (P < 0.0001), Body Mass Index (P < 0.0001), waist circumference (P < 0.0001), and Waist/Hip Ratio (P < 0.0001) was significantly higher in HS patients compared with controls. Additionally, age and sex-adjusted analyses showed a higher predicted estimate of BMR for the HS groups compared with controls (154.56 kcal/day (95% CI 54.96-254.16) (P = 0.0031) for the hospital-based HS group, and 82.63 kcal/day (95%CI 59.70-105.56) (P < 0.0001) for the population-based HS group). CONCLUSION: Hidradenitis Suppurativa is associated with a high fat percentage, high visceral fat, and low muscle percentage adding to the morbidity of HS. The higher predicted estimate of basal metabolic rate (BMR) in HS patients may reflect a dysfunctional metabolism contributing to the high-fat-body composition.