Maristella Vezzù

Synovial effusion and synovial fluid biomarkers in psoriatic arthritis to assess intraarticular tumor necrosis factor-α blockade in the knee joint.

IntroductionThe purpose of this study was theevaluation of synovial effusion (SE), synovial fluid (SF) and synovial tissue (ST) biomarkers in relation to disease activity indexes to assess the response to intraarticular (IA) tumor necrosis factor (TNF)-α blockers in psoriatic arthritis (PsA).MethodsSystemic and local disease activity indexes (disease activity score (DAS); the Ritchie articular index (mRAI), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP); Thompson articular (THOMP) and joint articular (KJAI)-Index ) and ST samples were assessed at baseline, throughout treatment, and during the follow-up in 14 patients affected with PsA who underwent IA injections (0.5 ml to 12.5 mg) in the knee joint of etanercept (E) or placebo (P) once every two weeks for a 10-week period. Total SF white blood cell (WBC) counts (WBC/μl) and SF cytokine/chemokine (CK/CCK) levels were measured before IA-E at baseline, after IA-E, and as long as there were adequate amounts of SF for knee aspiration (post). Characterization of synovial mononuclear cell infiltration and synovial vessels was carried out in 8 out of 14 knees by staining serial sections of synovial tissue biopsies for CD45, CD3, CD68, CD31 and CD105.ResultsAt baseline, CRP and/or ESR were significantly correlated with SF-CK (interleukin- (IL-)1β, IL-1Ra, IL-6, IL-8) and CCK (CCL3). Post-IA injections, there was a decrease in SE in the knees in which aspiration following IA-E injection was possible as well as a significant reduction in SF WBC/μl and in SF-CK (IL-1β, IL-1Ra, IL-6 and IL-22). Pre- and post-IA-E injections, there were significant correlations between ST markers and SF-CK (IL-1β with CD45; IL-1β and IL-6 with CD31) and between SF-CCK (CCL4 and CCL3 with CD3). At the end of the study, there was a significant reduction in disease activity indexes (CRP, DAS, RAI, THOMP, KJAI) as well as in the ST markers (CD45; CD3).ConclusionsSynovial effusion regression is a reliable indicator of the response to IA TNF-α blockers in PsA patients as it is confirmed by the correlation between SF biomarkers to disease activity and synovial tissue inflammation.

Molecular pathways involved in synovial cell inflammation and tumoral proliferation in diffuse pigmented villonodular synovitis.

Diffuse-type tenosynovial giant cell tumors, also known as pigmented villonodular synovitis, are unique mesenchymal lesions that arise from the synovial tissue of the joints. They are predominantly intraarticular, aggressive, infiltrative processes, characterized by both inflammatory or neoplastic properties and local destructive progression. The pattern of synovial gene and protein expressions in pigmented villonodular synovitis, similar to those in activated macrophages in rheumatoid arthritis, and the phenotype of multinucleated giant cells, characteristic of osteoclasts, suggest that there is a common autocrine mechanism in osteoclast differentiation in both diseases and indicate the potential utility of tumor necrosis factor (TNF)-alpha blockade. High synovial colony stimulating factor 1 (CSF1) messenger RNA (m RNA) expression in pigmented villonodular synovitis, unrelated to a chromosomal translocation involving CSF1 locus, may indicate that there is a synergic paracrine loop mediated by TNF-alpha and CSF1, as shown in both inflammatory and neoplastic conditions. The effects of a new therapeutic approach consisting in intraarticular TNF-alpha blockade were studied in four pigmented villonodular synovitis knees. Knee injections produced a rapid reduction in clinical and sonographic indexes and immunohistological alterations, confirmed by arthroscopic synovectomy. A delayed relapse in one of the four knees and unaltered synovial CSF1 expression were other important findings. In the light of these observations, CSF1/CSF1R interaction probably represents a more sensible therapeutic target than TNF-alpha blockade in the diffuse form of pigmented villonodular synovitis.

Quantitative imaging by pixel-based contrast-enhanced ultrasound reveals a linear relationship between synovial vascular perfusion and the recruitment of pathogenic IL-17A-F + IL-23 + CD161 + CD4 + T helper cells in psoriatic arthritis joints

To develop quantitative imaging biomarkers of synovial tissue perfusion by pixel-based contrast-enhanced ultrasound (CEUS), we studied the relationship between CEUS synovial vascular perfusion and the frequencies of pathogenic T helper (Th)-17 cells in psoriatic arthritis (PsA) joints. Eight consecutive patients with PsA were enrolled in this study. Gray scale CEUS evaluation was performed on the same joint immediately after joint aspiration, by automatic assessment perfusion data, using a new quantification approach of pixel-based analysis and the gamma-variate model. The set of perfusional parameters considered by the time intensity curve includes the maximum value (peak) of the signal intensity curve, the blood volume index or area under the curve, (BVI, AUC) and the contrast mean transit time (MTT). The direct ex vivo analysis of the frequencies of SF IL17A-F+CD161+IL23+ CD4+ T cells subsets were quantified by fluorescence-activated cell sorter (FACS). In cross-sectional analyses, when tested for multiple comparison setting, a false discovery rate at 10%, a common pattern of correlations between CEUS Peak, AUC (BVI) and MTT parameters with the IL17A-F+IL23+ - IL17A-F+CD161+ - and IL17A-F+CD161+IL23+ CD4+ T cells subsets, as well as lack of correlation between both peak and AUC values and both CD4+T and CD4+IL23+ T cells, was observed. The pixel-based CEUS assessment is a truly measure synovial inflammation, as a useful tool to develop quantitative imaging biomarker for monitoring target therapeutics in PsA.

AB0518 Synovial biomarkers in peripheral spondyloarthritis.

Objectives To analyse a panel of synovial fluid (SF) and synovial tissue (ST) biological markers expression at single joint level to find candidate biomarkers in resistant peripheral spondyloarthritis (SpA). Methods Twenty seven resistant SpA patients with knee joint synovitis, included in an Intra-articular (IA) TNF alpha blocking open-label study1, were treated with biweekly four IA Etanercept injections (12.5 mg) in a single knee joint. The primary outcome (Thompson’s knee index: THOMP) and secondary outcomes were assessed at baseline and at week 8 of the study. The secondary outcomes are: C-reactive protein; Knee Joint Articular Index (KJAI), Health Assessment Questionnaire disability index (HAQ-DI), maximal synovial thickness by gray-scale ultrasonography (US-MST), synovial tissue cluster differentiation CD45+ mononuclear cell (ST-CD45+), synovial tissue-CD31+ vessels (ST-CD31+), and along with levels of synovial fluid (SF) soluble inflammation makers such as Interleukin 1ß (SF-IL 1ß), Interleukin 1 Receptor antagonist (SF-IL 1Ra) and Interleukin 6 (SF-IL 6). Results At the end of the study, composite clinical indexes, US-MST, ST and SF biological markers were significantly reduced compared to baseline. There was a significant correlation between CRP and THOMP, or KJAI, or HAQ-DI, or SF-IL 1Ra; between KJAI and THOMP or US-MST; between ST-CD45+ and THOMP, or KJAI or ST-CD31+, or SF-IL 1ß; between SF-IL 6 and THOMP, or KJAI, or SF-IL 1ß, or SF-IL 1Ra; between SF-IL 1 Ra and SF-IL 1ß. Comparing pre- versus post-IA Etanercept injection changes (Δ), we found a significant correlation between ΔCRP with ΔSF-IL 1ß, ΔKJAI with ΔTHOMP and ΔSF-IL 6; Δ HAQ with ΔSF-IL 6; ΔST-CD-45+ with ΔSF-IL 1ß; ΔSF-IL 6 and ΔSF-IL 1ß; ΔSF-IL 1Ra with ΔSF-IL 1ß and ΔSF-IL 6. Conclusions The significant association at single joint level of composite clinical indexes to inflammatory soluble markers and to synovial tissue marker expression, as well as between clinical and synovial biomarkers changes following IA-anti TNF-alpha blockers treatment, suggest that CD45+ in synovial tissue and IL-6 and IL-1β in SF may be considered potential biomarkers of the peripheral SpA response to IA TNF- alpha blocking. References Fiocco U. et al: Synovial Biomarkers in Psoriatic Arthritis. J Rheumatol Suppl. 2012 Jul;89:61-4. doi: 10.3899/jrheum.120246 Disclosure of Interest None Declared