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

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

Human Dermal Fibroblast Subpopulations and Epithelial Mesenchymal Transition Signals in Hidradenitis Suppurativa Tunnels are Normalized by Spleen Tyrosine Kinase Antagonism in Vivo

ABSTRACTHidradenitis 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.</jats:p