Simon Rauber1, Hashem Mohammadian2, Chrstian Schmidkonz3, Armin Atzinger3, Maria Gabriella Raimondo1, Hannah Labinsky4, Christoph Treutlein2, Johannes Knitza1, Simone Maschauer2, Frank Roemer5, Olaf Prante2, Torsten Kuwert3, Juan Canete6, Georg Schett7 and Andreas Ramming1, 1Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany; Deutsches Zentrum Immuntherapie, Friedrich-Alexander-UniversityErlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany, 2Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Erlangen, Germany, 3Friedrich-Alexander University (FAU) Erlangen-Nuremberg, Erlangen, Germany, 4Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany; Deutsches Zentrum Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany, 5Friedrich-Alexander University Erlangen Nürnberg, Erlangen, Germany, 6Unidad de Artritis Hospital Clinic, Barcelona, Spain, 7Universitätsklinikum Erlangen, Erlangen, Germany
Background/Purpose: Psoriatic 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). In 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.
Methods: 123 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 and spinal 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 anti-TNF and anti-IL-17A (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.
Results: 68Ga-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 anti-IL-17A inhibitors significantly 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 high plasticity of FAP+ fibroblasts transdifferentiating from an highly active, damage associated into an inert subtype.
Conclusion: Our 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.
Disclosures: S. Rauber, None; H. Mohammadian, None; C. Schmidkonz, None; A. Atzinger, None; M. Raimondo, None; H. Labinsky, None; C. Treutlein, None; J. Knitza, AbbVie, Novartis, ThermoFisher, UCB, ABATON, Sanofi, Medac, Lilly, BMS, Gilead, GSK, Werfen, Vila Health, Böhringer Ingelheim, Janssen, Galapagos, Chugai; S. Maschauer, None; F. Roemer, Boston Imaging Core Lab (BICL) LLC., Grünenthal, Calibr; O. Prante, None; T. Kuwert, None; J. Canete, None; G. Schett, None; A. Ramming, Boehringer-Ingelheim, Janssen, Gilead, Novartis, Pfizer.
