Psoriatic arthritis (PsA) is classified as a member of the spondyloarthropathy family and may be defined as an inflammatory arthropathy associated with psoriasis (PsO) and usually negative for rheumatoid factor (RF). Primarily characterized by musculoskeletal and skin inflammation, PsA is nowadays considered a systemic immune disease, with a wide spectrum of clinical manifestations which can occur. PsA immunopathogenesis is still a matter of debate, as probably different pathologic events occur in different disease sites, such as synovium, spine, enthesis and skin. Due to these extremely complex pathogenic mechanisms, despite new available therapies still limited rate of treated PsA patients achieve a sustained clinical low disease activity/remission (LDA/Rem) status. Since the synovium is the principal target of inflammatory arthritis, one promising approach in the research for biomarkers of treatment response may be the study of the PsA synovitis by novel highthroughput technologies with the capability of transcriptomic and proteomic in-depth analysis. Moreover, the transition from PsO to PsA and its early diagnosis is of considerable scientific and clinical interest for the prevention and prompt interception of the disease, being the topic largely discussed among rheumatologists due to the lack of valuable soluble as well as tissue biomarkers capable of interrupting this transition. It is well established that the clinical onset of inflammatory arthritis, in the context of chronic skin disease, is usually preceded by a preclinical phase encompassing immunological abnormalities, arthralgia and imaging abnormalities. Following on this, the aims of the current proposal are (I) to assess the diagnostic value of the Krenn Synovitis Score (KSS) on synovial tissue (ST) samples obtained from minimally invasive ultrasound (US)-guided biopsies in a large bio-samples dataset of PsA patients across different disease phases and (II) to provide a comprehensive atlas of immune and stromal cellular and transcriptomic composition of synovial membrane across PsA disease phases including PsO patients at risk (PsO at risk) of arthritis onset, with the secondary intention to identify both novel biomarkers of transition towards inflamed joint status and the pathogenic mechanisms underlying both poor outcome/no treatment response across different domains of disease and maintenance of clinical low disease activity/remission status. To do this, we consecutively enrolled 411 patients with an established diagnosis of PsA across disease phases and 84 individuals PsO at risk. All the enrolled cohort underwent US-guided ST biopsy at baseline within the SYNGem cohort (Division of Clinical Immunology and Division of Rheumatology, Fondazione Policlinico Universitario IRCCS A. Gemelli). Biological samples have been processed and analyzed at Immunology Research Core Facility – Gemelli Science and Technology Park (GSTeP), Fondazione Policlinico Universitario IRCCS A. Gemelli) for the histological analysis and at School of Infection & Immunity, University of Glasgow, for the omics technologies. Each patient was treated according to the current EULAR/GRAPPA recommendations in the outpatients clinic and for naïve to treatment PsA patients the 6-month clinical outcome was recorded. The distribution of KSS was significantly different across the different PsA phases (ANOVA p<0.001), being significantly higher in treatment-resistant patients compared to naïve PsA and PsA in LDA/Rem. Regardless to the disease phase, KSS directly correlated to disease activity in terms of DAPSA score. Considering the cellular composition of synovitis, ST lymphocytic infiltrates were significantly more common in active PsA than in the PsO group. Similarly, plasma cells were more prevalent in active phases, particularly in the csDMARDs-IR and bDMARDs-IR cohorts, compared to LDA/Rem. Considering naïve PsA patients, those who achieved Rem/LDA at 6-month follow-up showed, at baseline, significantly lower KSS as well as lower plasma cell infiltrate rate compared to those not achieving this clinical outcome. From single-cell RNA sequencing analysis, we obtained transcriptomic profiles for 406,648 synovial tissue-derived cells from 58 patients across different disease phases, including PsO at risk. The in-depth omics analysis enabled the comprehensive identification of all immune and stromal cell populations within psoriatic synovitis and facilitated the detailed characterization of how each distinct cellular subset defines the various stages of disease progression. In conclusion, the primary aim of this study was to advance the personalized medicine approach, which is pivotal for enhancing the management of PsA by improving patient stratification and optimizing therapeutic strategies.

Multiparametric assessment of synovial tissue inflammation in psoriatic arthritis across clinical disease phases

Bruno, Dario;Tolusso, Barbara;Kurowska-Stolarska, Mariola;ALIVERNINI, Stefano;Gremese, Elisa
In corso di stampa

Abstract

Psoriatic arthritis (PsA) is classified as a member of the spondyloarthropathy family and may be defined as an inflammatory arthropathy associated with psoriasis (PsO) and usually negative for rheumatoid factor (RF). Primarily characterized by musculoskeletal and skin inflammation, PsA is nowadays considered a systemic immune disease, with a wide spectrum of clinical manifestations which can occur. PsA immunopathogenesis is still a matter of debate, as probably different pathologic events occur in different disease sites, such as synovium, spine, enthesis and skin. Due to these extremely complex pathogenic mechanisms, despite new available therapies still limited rate of treated PsA patients achieve a sustained clinical low disease activity/remission (LDA/Rem) status. Since the synovium is the principal target of inflammatory arthritis, one promising approach in the research for biomarkers of treatment response may be the study of the PsA synovitis by novel highthroughput technologies with the capability of transcriptomic and proteomic in-depth analysis. Moreover, the transition from PsO to PsA and its early diagnosis is of considerable scientific and clinical interest for the prevention and prompt interception of the disease, being the topic largely discussed among rheumatologists due to the lack of valuable soluble as well as tissue biomarkers capable of interrupting this transition. It is well established that the clinical onset of inflammatory arthritis, in the context of chronic skin disease, is usually preceded by a preclinical phase encompassing immunological abnormalities, arthralgia and imaging abnormalities. Following on this, the aims of the current proposal are (I) to assess the diagnostic value of the Krenn Synovitis Score (KSS) on synovial tissue (ST) samples obtained from minimally invasive ultrasound (US)-guided biopsies in a large bio-samples dataset of PsA patients across different disease phases and (II) to provide a comprehensive atlas of immune and stromal cellular and transcriptomic composition of synovial membrane across PsA disease phases including PsO patients at risk (PsO at risk) of arthritis onset, with the secondary intention to identify both novel biomarkers of transition towards inflamed joint status and the pathogenic mechanisms underlying both poor outcome/no treatment response across different domains of disease and maintenance of clinical low disease activity/remission status. To do this, we consecutively enrolled 411 patients with an established diagnosis of PsA across disease phases and 84 individuals PsO at risk. All the enrolled cohort underwent US-guided ST biopsy at baseline within the SYNGem cohort (Division of Clinical Immunology and Division of Rheumatology, Fondazione Policlinico Universitario IRCCS A. Gemelli). Biological samples have been processed and analyzed at Immunology Research Core Facility – Gemelli Science and Technology Park (GSTeP), Fondazione Policlinico Universitario IRCCS A. Gemelli) for the histological analysis and at School of Infection & Immunity, University of Glasgow, for the omics technologies. Each patient was treated according to the current EULAR/GRAPPA recommendations in the outpatients clinic and for naïve to treatment PsA patients the 6-month clinical outcome was recorded. The distribution of KSS was significantly different across the different PsA phases (ANOVA p<0.001), being significantly higher in treatment-resistant patients compared to naïve PsA and PsA in LDA/Rem. Regardless to the disease phase, KSS directly correlated to disease activity in terms of DAPSA score. Considering the cellular composition of synovitis, ST lymphocytic infiltrates were significantly more common in active PsA than in the PsO group. Similarly, plasma cells were more prevalent in active phases, particularly in the csDMARDs-IR and bDMARDs-IR cohorts, compared to LDA/Rem. Considering naïve PsA patients, those who achieved Rem/LDA at 6-month follow-up showed, at baseline, significantly lower KSS as well as lower plasma cell infiltrate rate compared to those not achieving this clinical outcome. From single-cell RNA sequencing analysis, we obtained transcriptomic profiles for 406,648 synovial tissue-derived cells from 58 patients across different disease phases, including PsO at risk. The in-depth omics analysis enabled the comprehensive identification of all immune and stromal cell populations within psoriatic synovitis and facilitated the detailed characterization of how each distinct cellular subset defines the various stages of disease progression. In conclusion, the primary aim of this study was to advance the personalized medicine approach, which is pivotal for enhancing the management of PsA by improving patient stratification and optimizing therapeutic strategies.
In corso di stampa
Inglese
58
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.14242/203086
Il codice NBN di questa tesi è URN:NBN:IT:UNIVR-203086