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.

Pain perception in patients with hidradenitis suppurativa.

BACKGROUND: Pain is a prominent symptom of hidradenitis suppurativa (HS) and has been defined as a domain in the Core Outcome Set for the disease. Quality and intensity of pain is influenced by depression and anxiety, both of which are associated with HS. OBJECTIVES: To describe HS-related pain quantitatively and qualitatively; and to investigate how disease severity, depression and anxiety correlate with self-reported pain quality. METHODS: Pain perception was investigated using the McGill Pain Questionnaire. Symptoms of depression and anxiety were examined using the Hospital Anxiety and Depression Scale. Statistical analyses investigated differences in number of words chosen (NWC) and pain-rating index rank [PRI(R)] in patients with severe disease and in patients with depression/anxiety. RESULTS: A total of 138 patients with HS were recruited in an outpatient clinic (October 2017-March 2018). Patients presented a median NWC of 11·5 and a PRI(R) of 59·0%. Most common descriptors were 'shooting' (83%), 'itchy' (79%) and 'blinding' (75%). Patients with depression or anxiety presented significantly higher PRI(R)s [depressed 65% vs. non-depressed 57% (P = 0·015); anxious 65% vs. nonanxious 57% (P = 0·004)]. Patients with involvement of three or more HS regions vs. those with fewer than three involved regions exhibited a significantly higher NWC (13 vs. 8; P = 0·048). CONCLUSIONS: HS-related pain includes nociceptive and neuropathic pain, and perception appears to be influenced by disease severity, anxiety and depression. A multimodal pain management strategy may be the most appropriate; however, more detailed studies are necessary to define recommendations on pain management. What's already known about this topic? Pain is a core outcome domain hidradenitis suppurativa. Few studies have addressed this significant clinical problem. What does this study add? This study suggests that HS pain comprises both nociceptive and neuropathic pain. Pain appears associated to depression, anxiety and severity of the disease.

Prevalence of patients with self-reported hidradenitis suppurativa in a cohort of Danish blood donors: a cross-sectional study.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent inflamed nodules. No pathognomonic test is available for HS; hence the diagnosis is based on three clinical criteria. OBJECTIVES: To estimate the cross-sectional prevalence and characterize patients with HS in the Danish Blood Donor Study cohort. METHODS: A questionnaire previously developed containing HS screening questions, the Major Depression Inventory, the Short Form-12, as well as questions about height, weight and drinking habits was answered by 27 765 blood donors. RESULTS: The prevalence of HS was 1·8% [95% confidence interval (CI) 1·6-2·0%] in the cohort of Danish blood donors. Donors with HS were on average 4·7 years younger (P < 0·001), had 1·3 kg m-2 higher mean body mass index (BMI) (P < 0·001) and were significantly more likely to smoke [odds ratio (OR) 1·44, 17·9% vs. 13·1%, P = 0·002] compared with donors without HS. Furthermore, significantly more donors with HS were classified as having moderate depression (3·2% vs. 0·7%, P < 0·001). Also, significantly more patients with HS were apprenticeship educated, received educational support and sickness or cash benefits. CONCLUSIONS: The prevalence of HS in the cohort of blood donors was estimated to 1·8% (95% CI 1·6-2·0%). Donors with HS reported characteristics similar to those reported for hospital-based patients with HS such as higher BMI, smoking rates and lower socioeconomic status than donors without HS.

Pilonidal sinus disease: an intergluteal localization of hidradenitis suppurativa/acne inversa: a cross-sectional study among 2465 patients.

BACKGROUND: Hidradenitis suppurativa (HS), also referred to as acne inversa, is a debilitating skin disease characterized by inflammatory nodules, chronic abscesses and tunnels (fistulae and sinuses). The association with pilonidal sinus disease (PSD) is frequently reported but not well documented. OBJECTIVES: To determine the prevalence and characteristics of inflammatory skin lesions located in the intergluteal fold (IGF) of patients with HS. METHODS: This was an international multicentre retrospective cross-sectional study based on data collection from a large cohort of patients with HS with and without histopathology. Results From a total of 2465 patients with HS included in the study, 661 (27%) reported lesions in the IGF. These patients were significantly more often smokers and had more severe HS. Of the 238 patients with an available clinical diagnosis, intergluteal-HS (IG-HS) was diagnosed in 52 patients (22%) and PSD was diagnosed in 186 patients (78%). IG-HS was associated with the localization of HS in the proximity of the IGF, including the buttocks, genitals and the anus. There was a possibility of misclassification bias in this study as a clinical/image-based diagnosis or histopathology of the IGF lesions was not always available. CONCLUSIONS: The high prevalence of PSD suggests a strong link between both entities. Therefore, it may be useful to identify common pathophysiological mechanisms and develop common therapeutic strategies. What's already known about this topic? The occurrence of pilonidal sinus disease has not been clearly reported among patients with hidradenitis suppurativa/acne inversa. What does this study add? This is the first study that investigated the prevalence of pilonidal sinus disease among a large cohort of patients and identified the patient characteristics. Risk factors that might help to improve the management of patients were identified.

Severe hidradenitis suppurativa responding to treatment with secukinumab: a case report.

An inappropriate immunological response to an unknown antigen has been suggested to play a role in the pathogenesis of hidradenitis suppurativa (HS). Studies have identified elevated levels of several proinflammatory cytokines, including interleukin (IL)-17A and tumour necrosis factor-α, nominating these as possible therapeutic targets.1 Secukinumab is an IL-17A monoclonal antibody, which binds to IL-17A and inhibits the cytokine interaction with the IL-17 receptors, inhibiting the inflammatory cascade. Here we report a case of a 47-year-old man, with Hurley stage III lesions on the neck, axillae, breasts, genital skin and buttocks, who had experienced only temporary benefit from different medical treatments over several years. After 12 weeks of treatment with secukinumab, the number of lesions reported by the patient within the period of the last 4 weeks was reduced from 23 to seven, his pain visual analogue scale (VAS) score was reduced from 5 to 3 and pain/utility/handicap VAS score was reduced from 7 to 4. These results may be taken to imply that IL-17 blockade could provide a possible therapeutic approach in the treatment of HS.

Towards global consensus on core outcomes for hidradenitis suppurativa research: an update from the HISTORIC consensus meetings I and II.

BACKGROUND: A core outcomes set (COS) is an agreed minimum set of outcomes that should be measured and reported in all clinical trials for a specific condition. Hidradenitis suppurativa (HS) has no agreed-upon COS. A central aspect in the COS development process is to identify a set of candidate outcome domains from a long list of items. Our long list had been developed from patient interviews, a systematic review of the literature and a healthcare professional survey, and initial votes had been cast in two e-Delphi surveys. In this manuscript, we describe two in-person consensus meetings of Delphi participants designed to ensure an inclusive approach to generation of domains from related items. OBJECTIVES: To consider which items from a long list of candidate items to exclude and which to cluster into outcome domains. METHODS: The study used an international and multistakeholder approach, involving patients, dermatologists, surgeons, the pharmaceutical industry and medical regulators. The study format was a combination of formal presentations, small group work based on nominal group theory and a subsequent online confirmation survey. RESULTS: Forty-one individuals from 13 countries and four continents participated. Nine items were excluded and there was consensus to propose seven domains: disease course, physical signs, HS-specific quality of life, satisfaction, symptoms, pain and global assessments. CONCLUSIONS: The HISTORIC consensus meetings I and II will be followed by further e-Delphi rounds to finalize the core domain set, building on the work of the in-person consensus meetings.

In vivo measurements of blood vessels' distribution in non-melanoma skin cancer by dynamic optical coherence tomography - a new quantitative measure?

BACKGROUND: Skin biopsies only provide point-in-time data making longitudinal studies difficult. Using Dynamic optical coherence tomography (D-OCT) in vivo, non-invasive imaging of the microvasculature becomes possible. The current OCT literature is almost exclusively based on qualitative information but quantitative data may offer additional advantages, for example, by reducing observer variation. The objective of this study was to evaluate the in vivo superficial distribution of blood vessels, defined as the surface-to-first-vessel distance, in actinic keratosis, basal cell carcinoma, squamous cell carcinoma and normal skin. METHODS: D-OCT images of 52 histologically verified lesions and corresponding normal skin were included. The dataset consisted of 13 AK, 22 BCC and 17 SCC. No tumour sub-classification was done. RESULTS: The quantitative measurement of the surface-to-first-vessel distance showed a significant difference between NMSC and corresponding normal skin. Significant differences were also seen for BCC, and it is hypothesized that the measure may also be able to distinguish between AK and SCC (borderline significant differences). CONCLUSION: Our results could prove useful in discriminating between non-melanoma skin cancer lesions and healthy skin and in making a specific diagnosis. It is suggested that collecting different quantitative measurements increases the utility of D-OCT and makes the method less observer-dependent.

Factors predicting the self-evaluated health of hidradenitis suppurativa patients recruited from an outpatient clinic.

OBJECTIVES: In recent years, Hidradenitis suppurativa has received increased attention but still lack well-defined, robust patient-reported outcome measures. Such measures are likely to be influenced by contextual factors. We, therefore, aim to describe the association of biological and other factors with HS patient's self-evaluated health as reflected by the EQ5D VAS score. METHODS: This cross-sectional study measured basic information, Dermatology Life Quality Index, Major Depression Inventory and Euro-QoL-5D. Information obtained through questionnaires was used to create a model showing the relation between biological factors, questionnaire results and self-evaluated health using the stepwise method for linear regression. Patients with HS (n = 805) registered at our department were invited to participate. A total of 503 (62.5%) patients replied to this survey. There was no difference in basic demographics between responders and non-responders. RESULTS: Possible predictors for this study were DLQI, MDI, BMI, smoking, gender. A final model for correlation with self-evaluated health was obtained. Significant predictors for the model were DLQI (P < 0.05), BMI points above 25 and active smoking (both: P < 0.01) and MDI (P < 0.001). CONCLUSION: As this is a cross-sectional study, it reveals several clinically relevant correlations. Smoking appears to correlate with the highest change in VAS score, but an MDI of 10 (lower than study average) or a BMI of 40 influences the results more. This study provides an assessment of how much BMI and smoking, in relation to other factors, correlate to the self-evaluated health state of patients with HS. These may, therefore, be relevant contextual factors to the construction and interpretation of specific patient-reported outcome measures. To improve QoL, we advocate smoking cessation and weight loss, and advice active screening for depression as over 10% of our patients qualify for a depressive diagnosis according to ICD-10.

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.

Low and high body mass index in hidradenitis suppurativa patients-different subtypes?

INTRODUCTION: Overweight is a well-established risk factor for hidradenitis suppurativa (HS). In this cross-sectional study, we compare HS patients with a high body mass index (BMI) with HS patients with a low BMI to investigate differences in disease characteristics. MATERIALS AND METHOD: Patients were recruited from 17 dermatological centres from four continents. A total of 246 patients with a BMI below 25 were compared to 205 patients with a BMI of above 35. RESULTS: Patients with a high BMI suffered more severe disease (Hurley, physician global assessment, number of areas affected and patient-reported severity (PRS), P < 0.001 for all). There was no difference in smoking (P = 0.783) nor in family history (P = 0.088). In both low and high BMI patients, early onset of HS was a predictor of positive family history (P < 0.001, for each). For low BMI patients, an increase in BMI significantly increased PRS (P < 0.001). For patients with a high BMI, number of pack-years significantly increased PRS (P = 0.001). Cluster analysis of eruption patterns was location specific for low BMI patients but severity specific for high BMI patients. DISCUSSION: Patients with a low and high BMI could represent two clinically different subtypes. We suggest a non-linear relationship between BMI and impact of HS. As patients go from a low BMI patient to a high BMI patient (or from high to low), eruption patterns and risk factors may change.

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.

Recognizing syndromic hidradenitis suppurativa: a review of the literature.

Hidradenitis suppurativa (HS) is an inflammatory skin disease causing painful inflammation and suppuration. It may occur in rare syndromes: follicular occlusion, Bazex-Dupré-Christol, Down's, KID, PAPASH, PASS, PASH, and SAPHO syndromes, as well as Dowling-Degos disease. An overview of syndromic HS may inform the search for aetiological factors in HS. PubMed, Ovid and Web of Science were systematically searched using '(hidradenitis OR acne invers*) AND (syndrome OR KID OR PASS OR PAPA OR PASH OR SAPHO OR bazex-dupre OR 'dowling degos' OR triad OR tetrad)' and Cochrane Library using 'hidradenitis OR acne invers*'. A total of 82 articles were included in the final review. We summarize 134 cases collected from the 82 included articles. The syndromes are discussed, focusing on etiopathogenesis, clinical presentation and treatment. This study is based on case reports; therefore, conclusions may be subject to the selection bias. These syndromes are rare; however, it is important to recognize them, as treating them may require a different approach. Three subtypes of syndromic hidradenitis are suggested: syndromes with known genetic abnormalities, syndromes characterized by follicular plugging or structural defects, and syndromes with possible autoinflammatory pathogenesis. There was no universally effective treatment for syndromic HS, and treatment was individualized.