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BackgroundPsoriatic arthritis (PsA) is characterized by substantial mesenchymal tissue activation in the context of inflammation leading to structural damage. Measuring mesenchymal tissue activation in humans in vivo is challenging but may represent a possibility to detect regions at risk for structural damage. Recently, theranostic ligands have been developed that selectively bind Fibroblast Activation Protein (FAP) and allow recognition of activated mesenchymal cells in vivo. Accumulation of such FAP-based tracers can be visualized by positron-emission tomography (PET) (1).ObjectivesIn this study, we analyzed whether FAP tracer-based PET-CT can detect mesenchymal tissue activation in patients with PsA and whether this signal is associated with joint damage.Methods120 consecutive PsA patients fulfilling CASPAR criteria and 100 healthy controls without musculoskeletal disease received full-body PET-CT investigation using a 68Ga-labelled FAP inhibitor (68Ga-FAPI-04) tracer, specifically binding FAP. For all visually identified pathological tracer-positive lesions the mean and maximum standardized uptake value (SUV mean, SUV max) was assessed. Tracer uptake was quantified in peripheral and axial joints and correlated to various composite scores of PsA. Hand MRI scans were performed in parallel to assess inflammation and structural lesions. Follow-up 68Ga-FAPI-04 PET-CT scans were obtained in a subset of patients treated with cytokine inhibitors (follow-up between 3-6 months) to assess joint damage over time. In addition, FAP related tissue responses in synovial biopsy samples were evaluated on a molecular level by high-resolution slide RNA-sequencing in a subset of patients.Results68Ga-FAPI-04 accumulated at synovial and enthesial sites in patients with PsA compared to healthy controls (p < 0.0001). Active pain in peripheral as well as axial joints as measured on a visual analogue scale highly correlated with an increased 68Ga-FAPI-04 uptake (peripheral pain: R = 0.718, p < 0.0001; back pain: R = 0.875, p < 0.0001). Disease Activity in PSoriatic Arthritis (DAPSA) score also correlated with the SUV mean and SUV max of FAP expression (R = 0.774; p = 0.0001). Increased 68Ga-FAPI-04 uptake at baseline was associated with progression of joint damage 3-6 months later as assessed by PsAMRIS score (R = 0.778, p < 0.0001). Treatment with cytokine inhibitors partially reduced FAP expression which was associated with arrest of joint damage in MRI. In contrast, persistent FAP expression was associated with a rapid progression of joint damage in MRI. Molecular analysis of synovial biopsy samples from FAP+ lesions revealed interactions between FAP+ fibroblasts and T cells, innate lymphoid cells and macrophages, which was correlated to a strong upregulation of NF-kB related pathways fostering cartilage and bone destruction.ConclusionOur study presents the first in-human evidence that fibroblast activation correlates with disease progression and joint damage in patients with PsA. FAP related imaging might therefore improve the risk assessment of rapidly emerging joint damage in PsA and open new options of treat-to-target strategies in PsA.References[1]Schmidkonz C, Rauber S, Atzinger A, Agarwal R, Gotz TI, Soare A, Cordes M, Prante O, Bergmann C, Kleyer A, Agaimy A, Kuwert T, Schett G, Ramming A, Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging. Ann. Rheum. Dis. 79 (2020), 1485-1491.Disclosure of InterestsNone declared

BackgroundSpreading of inflammation from skin to joint is a key question behind the pathogenesis of psoriatic arthritis (PsA). Psoriasis (PsO), being one of the most prevalent skin diseases, usually anticipates joint manifestations, suggesting spreading of skin to joint disease, which happens in about 30% of the patients with psoriasis.1 To date, it is still obscure why the inflammatory process in some patients with PsO remains restrained to the skin, whereas in other patients it extents to tendons and joints.ObjectivesUsing a pre-clinical model of PsA, we aimed to unveil the skin-joint axis, i.e. the spreading of psoriatic inflammation from the skin to the joints.MethodsKAEDE transgenic mice expressing a photo-convertible fluorescent reporter were used to assess cell trafficking from inflamed skin to other organs in the mouse model of IL-23 overexpression (IL-23OE) induced PsA. Psoriatic skin lesions were irradiated with UV light to trigger the photoswitch from KAEDEGREEN to KAEDERED. Migration to different organs was determined by flow cytometry. Imaging flow cytometry was used to characterize the type of cells migrating from the skin to the joints. Migrating cells were further characterized by single-cell RNA-sequencing (scRNAseq) and functional analyses.ResultsMRI imaging and histological evaluation of IL-23OE mice revealed skin inflammation preceding joint inflammation in both wild-type and KAEDE-transgenic mice. Specific leukocyte migration from the skin to the joints started shortly after the onset of skin inflammation and before onset of inflammation within the joints of KAEDE transgenic mice. No migration was observed in healthy control animals. Other organs such as spleen or lymph nodes showed no model-dependent migration. Imaging flow cytometry revealed that the cells migrating to the joints were predominantly CD45+ CD11b+ cells. ScRNAseq analysis of sorted KAEDERED cells from inflamed joints confirmed that approximately 80% of the migrating cells were macrophages. Differential gene expression and pathway analysis revealed an imbalance between pro- and anti-inflammatory macrophages in the joints of experimental psoriatic arthritis.ConclusionWe describe IL-23-mediated migration of skin-derived macrophages from the skin to the joints during the onset of experimental psoriatic arthritis. This process may explain the spreading from psoriatic skin to joint disease as these cells foster the development by local cytokine production once arrived in the joints.References[1]Veale, D.J. & Fearon, U. The pathogenesis of psoriatic arthritis. Lancet391, 2273-2284 (2018).Disclosure of InterestsNone declared.

BackgroundEnthesitis represents a hallmark feature of spondyloarthritis, including psoriatic arthritis (PsA).1 So far, most of the data on enthesitis in PsA are based on clinical assessment of tenderness as well as MRI or ultrasound examinations.2 These approaches, however, do not allow molecular analysis of entheses, which will require acquisition of entheseal tissue. Up today, it is unknown, which entheseal structure in humans would qualify for a feasible biopsy and how correct sampling of entheseal structures could be ascertained within such biopsy material. These technical challenges have led to substantial lack of knowledge on human entheseal tissues.ObjectivesTo establish a minimally invasive biopsy technique of human entheses for the analysis of entheseal tissue in patients with PsA.MethodsHuman cadavers were used for establishing the technique to retrieve tissue from the lateral humeral epicondyle enthesis (cadaveric biopsies). After biopsy, the entire entheses was surgically resected (cadaveric resections). Biopsies and resections were assessed by label-free second-harmonic-generation (SHG) microscopy. The same biopsy technique was then applied in PsA patients with subsequent definition of entheseal tissue by SHG.ResultsEntheseal biopsies were performed in five cadavers and allowed the retrieval of entheseal tissue, validated by analysis of the resection material. Thus, microscopy of biopsy and resection sections allowed differentiation of entheseal, tendon and muscle tissue by SHG and definition of specific intensity thresholds for entheseal tissue. The same method was then successfully applied to 10 PsA patients. Hence, the fraction of entheseal tissue within the PsA biopsy specimens was high (65%) and comparable to the fraction retrieved in cadaveric biospies (68%) as assessed by SHG microscopy.ConclusionEntheseal biopsy of the tendon plate of the lateral epicondyle is feasible in PsA patients allowing reliable retrieval of entheseal tissue and its identification by SHG microscopy.References[1]Schett, G, Lories D, D´Agostino MA, Elewaut E, Kirkham B, Soriano ER, McGonagle D. Enthesitis: from pathophysiology to treatment Nat Rev Rheumatol 2017 Nov 21;13(12):731-741.[2]Groves C, Chandramohan M, Chew NS, et al. Clinical Examination, Ultrasound and MRI Imaging of The Painful Elbow in Psoriatic Arthritis and Rheumatoid Arthritis: Which is Better, Ultrasound or MR, for Imaging Enthesitis? Rheumatol Ther 2017;4:71-84.Disclosure of InterestsNone declared

Background Antiphospholipid antibodies (aPL) are risk factors for Adverse Pregnancy Outcome (APO). In particular, for aPL carriers (patients with aPL positivity with no thrombotic or obstetric history) pregnancy outcome and treatment are still undefined. Objectives To review pregnancy outcome in a large multicenter cohort of aPL carriers patients, according to different serological profile and treatment protocols. Methods We reviewed 69 pregnancies in 61 patients, prospectively followed in 3 Italian centers (1994–2015). Patients with any complication in previous pregnancies or concomitant autoimmune diseases were excluded. aPL profile was defined as the combination of the 3 criteria tests for aPL (Lupus Anticoagulant, anti-cardiolipin, anti-Beta2 Glycoprotein I). APO was defined as: miscarriage ( Results Regarding aPL profile: 44 (64%) were single positive, 16 (23%) were double and 9 (13%) were triple. aPL non-criteria manifestations were present in 6 (9%) and lupus-like manifestations in 5 (7%). Eight pregnancies had a combination treatment with prophylactic low molecular weight heparin (LMWH) plus low dose aspirin (LDA), 37 had LDA alone and 24 had no treatment. We observed 2 thrombotic events (3%, 1 deep venous thrombosis and 1 ischemic stroke) and 6 APO (9%): 3 fetal deaths and 3 pre-term birth ≤34w with PE. We compared 8 complicated (6 APO,2 thrombosis) with 61 non-complicated pregnancies (Table 1). Acquired risk factors (p:0.006), non-criteria aPL (p:0.018) and lupus-like manifestation (p:0.010), triple positive aPL profile (p:0.001) were associated with APO. The combination treatment was also more frequent in APO pregnancies (p:0.005). Conclusions Acquired risk factors,aPL profile (triple positivity), lupus-like and non-criteria aPL manifestations could represent risk factors for pregnancy complications and could determine failure to conventional treatment.These patients may deserve additional treatment, for example LMWH at higher/anti-coagulant dose or immunomodulatory treatment (e.g.hydroxychloroquine, also considering its anti-platelet/anti-thrombotic effects). Disclosure of Interest None declared