0399: Differential Synovial Tissue Enrichment of Oxylipins and Their Mediators Across Rheumatoid Arthritis Trajectory

Simone Perniola¹, Jessica Murillo-Saich², Barbara Tolusso³, Clara Di Mario³, Marco Gessi⁴, Dario Bruno⁵, Luca Petricca⁶, Maria Rita Gigante⁶, Elisa Gremese⁵, Monica Guma⁷ and Stefano Alivernini⁸, ¹Division of Clinical Immunology – Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy, ²Department of Medicine, University of California San Diego, La Jolla, CA, ³Immunology Research Core Facility – Gemelli Science and Technology Park (GSTeP) - Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy, ⁴Division of Pathology - Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy, ⁵Division of Rheumatology, Institute of Rheumatology and Affine Sciences, School of Medicine, Catholic University of the Sacred Heart, Roma, Italy, ⁶Division of Rheumatology - Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy, ⁷University of California San Diego, La Jolla, CA, ⁸Immunology Research Core Facility, Gemelli Science and Technology Park, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Division of Rheumatology - Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore, Rome, Italy

Background/Purpose: Synovial membrane represents the target tissue of Rheumatoid Arthritis (RA) inflammation. Our study aimed to perform a comprehensive quantification of oxylipins and their precursors in synovial tissue specimens of RA patients across disease trajectory.

Methods: 32 patients fulfilling the ACR/EULAR 2010 classification criteria underwent US-guided minimally invasive synovial tissue biopsy of the knee [n=16 patients with DAS28≥4.2 and n=16 patients in sustained (≥12 months) clinical (DAS28≤2.6) and ultrasound remission (Power Doppler negative)]. Oxylipins in synovial tissue were determined by liquid chromatography with tandem mass spectrometry (LC-MS-MS) and were classified into groups according to their precursor: arachidonic acid (AA), LA, ALA, DHA, EPA and DGLA. Moreover, each sample was processed for histology and the synovitis degree was assessed using H&E-based scoring by pathologist blinded on clinical characteristics. Statistical analysis was performed using MetaboAnalyst 5.0 and SPSS software v27.

Results: Among the general panel, 84 different oxylipins were detected in at least one sample and 55 oxylipins remained after eliminating those with less than 50% across the samples (Figure 1). Stratifying RA patients based on the disease status, synovial tissue of active RA was significantly enriched of distinct specialized pro-resolving lipid mediators (SPMs) precursors such as free AA (p=0.0045), free adrenic acid (p=0.0080) and free docosahexaenoic acid (p=0.012) compared to synovial tissue of RA patients in sustained remission. Moreover, considering a threshold ≥4 of oxylipins expression, synovial tissue of active RA showed an 5LOX-derived oxylipins enrichment of 16.087 folds of 5,12-diHETE, 5.7419 folds of LTB4, TXA-derived 34.259 folds of 2,3 dinor TXB2, non-enzymatic -derived 6.192 folds of 16-HDoHE, 5.5097 folds of 9-HETE and, COX-derived oxylipins 4.8275 folds of 11-HETE compared to synovial tissue of RA patients in sustained clinical and ultrasound remission which was enriched 5.1589 folds of PGD3. Finally, the enrichment of pro-inflammatory SPMs was directly correlated with the histological synovitis degree (R²=0.473, p=0.006) particularly with the score of synovial hyperplasia (R²=0.472, p=0.006) and inflammatory infiltrate (R²=0.466, p=0.007).

Conclusion: Synovial tissue of RA patients shows a differential enrichment of oxylipins and their precursors which is contingent with the disease status directly mirroring the synovitis degree in terms of synovial hyperplasia and inflammatory infiltrate.




S. Perniola: None; J. Murillo-Saich: None; B. Tolusso: None; C. Di Mario: None; M. Gessi: None; D. Bruno: None; L. Petricca: None; M. Gigante: None; E. Gremese: None; M. Guma: None; S. Alivernini: None.