SAT0054 INVESTIGATING MECHANISMS OF AUTOANTIBODY INDUCED PAIN, BONE LOSS AND ARTHRITIS DEVELOPMENT
Authors: Akilan Krishnamurthy, Yogan Kisten, Katalin Sandor, Alexandra Circiumaru, Gustaf Wigerblad, Peter Damberg, Koji Sakurabas, Heidi Wähämaa, Patrik Jarvolli, Juan Jimenez Jimenez Andrade, Vivianne Malmström, Lars Klareskog, Camilla Svensson, Bence Réthi, Anca Catrina
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> In rheumatoid arthritis (RA), autoantibodies against citrullinated proteins (ACPAs) have been reported to be associated with bone loss, pain and tenosynovitis prior to disease onset. <h3>Objectives:</h3> We aimed to investigate if transfer of human ACPAs into mice could reproduce these clinical observations. <h3>Methods:</h3> Monoclonal ACPA (1325:04C03 and 1325:01B09) and control (1362:01E02) antibodies (mAbs) were generated from synovial plasma or memory B cells of RA patients. 2mg of combination of monoclonal ACPAs or control antibody were injected in BALB/c female mice (12-16 Weeks) with or without a consecutive intra-articular injection of LPS after 8 days. Pain-like behavior was monitored by measuring mechanical hypersensitivity using von Frey filaments every 3 days and estimation by up-down Dixon method. Bone mineral density was measured by micro-CT. Using specially designed mobilization casts, dedicated mouse MRI coils, and gadolinium enhanced contrast medium, the hind limbs of these mice were scanned and evaluated for any signs of soft tissue joint inflammation. Blinded to ACPA and controls, the MRI images were scored for the presence of synovial thickening, effusion and tendon inflammatory changes by 3 readers in consensus. <h3>Results:</h3> ACPAs (1325:04C03 and 1325:01B09) induced significantly more pronounced pain-like behavior (lasting for at least 4 weeks) and reduction of the trabecular bone thickness in the hind limbs, whereas no such effect was seen with the control mabs generated in the same way as the monoclonal ACPAs. While no macroscopic sign of joint inflammation could be detected, preliminary MRI data shows that sub-clinical joint inflammation (such as tenosynovitis) in mice injected with ACPAs but not those injected with control mAb. Intra-articular LPS injection resulted in significantly increased prolonged mechanical hypersensitivity in mice initially receiving sub-optimal doses of monoclonal ACPA as compared to those receiving control mAb. This was associated with higher levels of sub-clinical inflammation (as shown by MRI scans) in ACPA injected mice. <h3>Conclusion:</h3> We show that ACPA induces pain-like behavior, bone loss and sub-clinical inflammation in mice, a model that mimics the pre-clinical state of ACPA positive RA. <h3>References</h3> [1] Harre, U. et al. J Clin Invest (2012) [2] Krishnamurthy, A. et al. Ann Rheum Dis (2016) [3] Wigerblad, G. et al. Ann Rheum Dis (2016) [4] KleyerA, Seminars in Arthritis and Rheumatism (2016) <h3>Disclosure of Interests:</h3> Akilan Krishnamurthy: None declared, Yogan Kisten: None declared, Katalin Sandor: None declared, Alexandra Circiumaru: None declared, Gustaf Wigerblad: None declared, Peter Damberg: None declared, Koji Sakurabas: None declared, Heidi Wähämaa: None declared, Patrik Jarvolli: None declared, Juan Jimenez Jimenez Andrade: None declared, Vivianne Malmström: None declared, Lars Klareskog Grant/research support from: Yes, but not for the presented study., Camilla Svensson: None declared, Bence Réthi: None declared, Anca Catrina Grant/research support from: Yes, but not for the presented study.