Human dermal fibroblast subpopulations and epithelial mesenchymal transition signals in hidradenitis suppurativa tunnels are normalized by spleen tyrosine kinase antagonism in vivo.

Hidradenitis Suppurativa is a chronic inflammatory disease of which the pathogenesis is incompletely understood. Dermal fibroblasts have been previously identified as a major source of inflammatory cytokines, however information pertaining to the characteristics of subpopulations of fibroblasts in HS remains unexplored. Using in silico-deconvolution of whole-tissue RNAseq, Nanostring gene expression panels and confirmatory immunohistochemistry we identified fibroblast subpopulations in HS tissue and their relationship to disease severity and lesion morphology. Gene signatures of SFRP2+ fibroblast subsets were increased in lesional tissue, with gene signatures of SFRP1+ fibroblast subsets decreased. SFRP2+ and CXCL12+ fibroblast numbers, measured by IHC, were increased in HS tissue, with greater numbers associated with epithelialized tunnels and Hurley Stage 3 disease. Pro-inflammatory CXCL12+ fibroblasts were also increased, with reductions in SFRP1+ fibroblasts compared to healthy controls. Evidence of Epithelial Mesenchymal Transition was seen via altered gene expression of SNAI2 and altered protein expression of ZEB1, TWIST1, Snail/Slug, E-Cadherin and N-Cadherin in HS lesional tissue. The greatest dysregulation of EMT associated proteins was seen in biopsies containing epithelialized tunnels. The use of the oral Spleen tyrosine Kinase inhibitor Fostamatinib significantly reduced expression of genes associated with chronic inflammation, fibroblast proliferation and migration suggesting a potential role for targeting fibroblast activity in HS.

Adalimumab therapy is associated with increased faecal short chain fatty acids in hidradenitis suppurativa.

Altered gut microbiota composition has been observed in individuals with hidradenitis suppurutiva (HS) and many other inflammatory diseases, including obesity, type 1 and type 2 diabetes. Here, we addressed whether adalimumab, a systemic anti-inflammatory therapy, may impact the microbiota biochemical profile, particularly on beneficial metabolites such as short-chain fatty acids (SCFAs). We conducted an observational single-arm pilot trial to assess gut microbiota composition by 16S rRNA gene sequence analysis and to detect metabolite signatures by gas chromatography in stool samples from participants with HS prior to and 12 weeks after commencing adalimumab therapy. HS individuals that better responded to adalimumab treatment showed a shift in the composition and function of the gut microbiota with significantly increased SCFA acetate and propionate compared to age, gender and BMI-matched healthy controls. A positive correlation was observed between propionate with Prevotella sp and Faecalibacterium prausnitsii. Increased SCFAs, changes in gut microbiota composition, function and metabolic profile following 12 weeks of adalimumab suggest that targeting SCFAs may be considered a potential biomarker to be evaluated as a complementary protective factor or as a diagnostically relevant signal in HS.

Secukinumab treatment demonstrated high drug survival and sustained effectiveness in patients with severe chronic plaque psoriasis: 21-month analysis in Australian routine clinical practice (SUSTAIN study).

BACKGROUND: Drug survival measures the rate and duration of adherence to a given therapeutic agent and evaluates its long-term effectiveness, safety, and real-world utility. The SUSTAIN study sought to establish the drug survival and effectiveness of secukinumab for patients with severe chronic plaque psoriasis (CPP) in the Australian clinical setting. METHODS: Data of all patients (aged ≥18 years) from Australasian Psoriasis Registry (APR) treated with secukinumab were analysed. The primary objective was to describe the drug survival of secukinumab at 9 months. Key secondary objectives included drug survival of secukinumab at 3, 6, 15, and 21 months, stratified by biologic-naïve vs biologic-experienced patients; proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75/90/100 responses; and changes in health-related quality of life over time utilising the Dermatology Life Quality Index (DLQI). RESULTS: Of 294 patients included in this analysis, 110 (37.4%) were biologic-naïve and 184 (62.6%) biologic-experienced. Kaplan-Meїer drug survival rates in biologic-naïve vs biologic-experienced patients were 0.92 vs. 0.86 (9 months) and 0.82 vs. 0.68 (21 months), respectively. The proportion of patients with PASI 75/90/100 responses for biologic-naïve vs. biologic-experienced was 100/87.7/38.4 vs 98.5/61.5/27.2 (9 months) and 100/81.0/41.7 vs. 98.4/62.0/24.2 (21 months), respectively. The mean (standard deviation [SD]) DLQI in biologic-naïve vs. experienced patients was 2.2 (4.1) vs. 3.1 (5.2) (9 months) and 1.4 (2.5) vs. 3.1 (5.3) (21 months). No new safety signals were observed. CONCLUSIONS: Secukinumab demonstrated high drug survival and sustained effectiveness in Australian real-world setting, in biologic-naïve and biologic-experienced patients with severe CPP.

Treatment modalities and risk of adverse events associated with biologic therapy: A 10-year observational review of the Australasian Psoriasis Registry.

BACKGROUND: Psoriasis is a chronic inflammatory disease affecting ~2-3% of the Australasian population. Therapeutic options include topical agents, phototherapy, systemic immunomodulators and biologic agents. Biologics present an acceptable short- and medium-term safety profile, derived mainly from randomised controlled trials (RCTs) and, however, may not represent real-world rates of adverse events (AEs). METHODS: A retrospective, observational study of patients enrolled in The Australasian Psoriasis Registry from April 2008 to October 2018 was conducted. Data were collected from 104 sites in Australia and New Zealand. Patient characteristics, treatments and AE data were collected. AEs were classified by MedDRA System events. RESULTS: 2094 patients were included (3765 patient-treatments), comprising; 1110 phototherapy, 1280 systemic and 1375 biologic therapy patient-treatments. Treatment arms were not mutually exclusive. The mean ± SD from date of diagnosis of psoriasis to commencement of biologic therapy was 8.9 ± 12.3 years. Methotrexate had the longest exposure time (3740.3 patient-years), and ustekinumab had the longest median (95% CI) time on treatment, 4.3 years (2.2, 6.6). AE differences on biologic treatment were present between patients who would have been eligible or ineligible for RCTs. Approximately 29% of registry patients would have been excluded from clinical trials enrolment. Patients ineligible for RCTs had increased adjusted hazard ratios (95% CI) of: infections and infestations (2.3, 1.7-3.1; P < 0.001), cardiac (8.2, 3.5-25.6; P < 0.001), gastrointestinal (3.5, 1.52-8.0; P < 0.001), hepatobiliary (5.6 1.7-19.1; P < 0.001), psychiatric (4.7, 1.5-14.1; P = 0.006) and eye disorders (4.8 1.5-15.6; P = 0.008), compared to those eligible for RCTs. Incidence rates in the trial eligible patients were similar to those reported from RCT rates. CONCLUSIONS: This study establishes treatment modalities in use for severe psoriasis and the clinical rates of AEs associated with biologic therapy.

The Microbiome in Hidradenitis Suppurativa: A Review.

INTRODUCTION: Hidradenitis suppurativa (HS) is a chronic autoinflammatory skin disease. It is characterised by the development of abscesses and nodules in intertriginous anatomical sites. Whilst it is now recognised as an autoinflammatory condition rather than an infective disease, bacteria are implicated in disease pathogenesis. METHODS: We performed a search of the literature from inception to 12 August 2020 using the search terms "hidradenitis suppurativa", "Verneuil's disease", "acne inversa", "microbiome", "bacteriology" and "microbiology". Studies were included if they assessed the cutaneous, gut or oral bacteria, bacteriology or microbiome in hidradenitis suppurativa. RESULTS: Twenty-one studies examining the cutaneous microbiome and two studies examining the gastrointestinal microbiome in HS were identified. No studies examining the oral microbiome in HS were identified. A total of 972 patients and 46 healthy controls were included across studies examining the cutaneous microbiome. A total of 100 patients and 36 controls were included across both gut microbiome studies. Coagulase-negative Staphylococcus, anaerobes such as Porphyromonas and Prevotella, and Staphylococcus aureus species were commonly encountered organisms across the included cutaneous microbiome studies. The studies examining the gut microbiome were limited, with one small study demonstrating an alteration in the gut microbiome composition compared to controls. The other study found no alteration to the gut microbiome in patients with HS compared to those with inflammatory bowel disease (IBD) and HS, and IBD and/or psoriasis. CONCLUSION: Research should be undertaken into the oral microbiome in HS. Further research should be undertaken examining the cutaneous and gut microbiome in HS, and its relationship with documented co-morbidities. Additionally, metagenomics-focused studies may help identify the relationship between microorganisms and host, and this may shed light on new pathways of disease pathogenesis. This may help identify potential future therapeutic targets.

Prevalence of inflammatory bowel disease (IBD) in hidradenitis suppurativa (HS): systematic review and adjusted meta-analysis.

BACKGROUND: Several case reports and case series have recently explored the association between hidradenitis suppurativa (HS) and inflammatory bowel disease (IBD). OBJECTIVE: We performed a systematic review and meta-analysis of case-control studies to determine  (i) the pooled prevalence of IBD in HS cohorts, and (ii) whether HS is more strongly associated with Crohn's disease or ulcerative colitis. METHODS: Electronic searches were performed using five databases, from their inception to August 2018. Case-control studies reporting the proportion of IBD cases in HS cohorts were included and meta-analysis performed. RESULTS: From six included studies, a significant association between HS and IBD after pooling of adjusted effect sizes was identified (OR 2.12; 95% CI 1.62-2.77; P = 0.03). Subgroup analysis demonstrated a significant association between HS and Crohn's disease (OR 2.25; 95% CI 1.52-3.32; P < 0.0001, I2  = 92%) and with ulcerative colitis (OR 1.56; 95% CI 1.26-1.94; P < 0.0001; I2  = 36%). LIMITATIONS: Studies reviewed were observational by design which are susceptible to bias and lack of randomization. CONCLUSIONS: Our results indicate a statistically significant association between HS and IBD. Our results highlight that all patients with HS should be clinically screened for symptoms of IBD and symptomatic patients referred for further investigations.

Hidradenitis suppurativa, a review of pathogenesis, associations and management. Part 2.

Hidradenitis suppurativa is a chronic, painful, autoinflammatory condition resulting in nodules, abscesses and sinus tracts. We present an evidence-based review providing new understanding of the pathogenesis of hidradenitis suppurativa and associated comorbidities. By the nature of their speciality, dermatologists are uniquely positioned to investigate and treat patients.

Hidradenitis suppurativa, a review of pathogenesis, associations and management. Part 1.

Hidradenitis suppurativa is a chronic, painful, autoinflammatory condition resulting in nodules, abscesses and sinus tracts. We present an evidence-based review providing new understanding of the pathogenesis of hidradenitis suppurativa and associated comorbidities. By the nature of their speciality, dermatologists are uniquely positioned to investigate and treat patients with this condition. Data collected from a subspecialty hidradenitis suppurativa clinic (N = 106) and experiences thereof are discussed in this review.

SAPHO syndrome associated with hidradenitis suppurativa and pyoderma gangrenosum successfully treated with adalimumab and methotrexate: a case report and review of the literature.

SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome is a rare inflammatory condition describing the combination of skin, bone, and joint manifestations that has a heterogeneous presentation. We report a case of severe SAPHO syndrome in association with hidradenitis suppurativa and pyoderma gangrenosum in a 27-year-old male. The patient had an initial migratory arthritis affecting the knees, ankles, metacarpophalangeal joints, proximal interphalangeal joints, wrists, shoulder, and lower back, which progressed to a persistent arthritis and swelling at the sternum, shoulders, wrists, hands, feet, and lower back. Radiographic changes were consistent with the diagnosis of SAPHO syndrome. Serum proinflammatory cytokine levels were significantly elevated and improved substantially after 3 months of therapy. Rationale for therapy in this patient was the observation that tumor necrosis alpha antagonists have been successfully used in SAPHO syndrome, and since arthropathy was so prominent in our patient, we elected to use adalimumab combined with methotrexate.

Hidradenitis suppurativa: A neglected disease in Indigenous Australians.

We report the first case series of hidradenitis suppurativa in patients of Indigenous Australian heritage. The incidence and ethnicity of populations affected by this condition are not known. The high comorbid disease burden and socioeconomic disadvantage that is well recognised in the Indigenous Australian population poses significant challenges to therapeutic outcomes.

Hidradenitis suppurativa - Management, comorbidities and monitoring.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease presenting in intertriginous areas. HS is associated with a number of disease-modifying comorbidities, including metabolic syndrome and androgen dysfunction, and smoking. OBJECTIVE: This review provides a synopsis of the aetiology and diagnosis of HS, and an overview of management for this often devastating disease. DISCUSSION: The clinical course and disease severity of HS are variable among patients. HS has profound physical and psychological consequences that affect patients' quality of life. Effective treatment is now a realistic goal, but needs to be combined with treatment of the comorbidities and psyche. Evidence-based management guidelines have been established for the management of this disease. General practitioners play a pivotal role in the holistic treatment of this disease.

Inter-observer reliability of the PASI in a clinical setting.

BACKGROUND: With the evolving emphasis on evidence-based practice, the use of reliable clinical scales forms an important foundation for clinical assessment. The psoriasis area and severity index (PASI) is the most widely used tool for the measurement of psoriasis severity; however, there has been some debate over the potential reproducibility of PASI scoring. OBJECTIVES: To determine the inter-observer reliability of the PASI at a large tertiary hospital with a psoriasis treatment centre. METHODS: In total, 34 patients who were due for their 3-monthly follow up at a psoriasis treatment centre were independently evaluated by five clinical staff (observers) from the Department of Dermatology. Each observer independently determined the PASI score of each patient and the inter-observer reliability coefficient was determined by employing intra-class correlation coefficients (ICC). RESULTS: There was a significant degree of concordance among the PASI scoring of observers (ICC = 0.804; CI 95%: 0.706-0.883). CONCLUSIONS: Our cross-sectional study suggests that the PASI provides a reproducible method of assessing psoriasis severity among patients seen in a busy dermatology clinic at a large tertiary hospital.

Moderate to severe hidradenitis suppurativa treated with biological therapies.

Hidradenitis suppurativa is a debilitating disorder that can be difficult to manage with current conventional treatment strategies. Given its association with proinflammatory cytokines there has been interest in the use of novel biological monoclonal antibodies. We describe our experience with the use of these agents in six patients in whom conventional treatment had failed, with promising response noted in some patients. A growing number of studies now highlight the efficacy of these agents.