OP0326 ACPA-INDUCED PAIN-BEHAVIOR, BONE LOSS AND TENDON INFLAMMATION IN MICE: A NOVEL MODEL FOR THE PRE-DISEASE PHASES OF ACPA-POSITIVE RHEUMATOID ARTHRITIS
Authors: A. Krishnamurthy, Y. Kisten, A. Circiumaru, K. Sakurabas, P. Jarvolli, J. J. Jimenez Andrade, P. Damberg, H. Wähämaa, V. Malmström, L. Klareskog, C. Svensson, B. Réthi, A. Catrina
Journal: Annals of the Rheumatic Diseases (2020)

Background: In rheumatoid arthritis (RA), anti-citrullinated protein antibodies (ACPAs) are associated with bone loss and pain. Recently, tenosynovitis has been suggested as a predicting factor for arthritis progression in individuals at-risk for RA. Objectives: We aimed to investigate if transfer of human ACPAs into mice could induce tenosynovitis and/or subclinical inflammation. Methods: 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 (age 12-16 weeks) (n= 9). Pain-like behavior was monitored by measuring mechanical hypersensitivity using von Frey filaments every 3 days and estimation by up-down Dixon method. Bone morphometrics was analyzed 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 in a 9.4 T scanner and resulting T1-weighted images were evaluated for signs of soft tissue joint inflammation. The MRI images were scored for the presence of joint involvement and tendon inflammatory changes by 3 readers in a blinded manner. Figure 1. NAPA performed on healthy donor mo-DCs incubated with native, PAD2-citrullinated, and PAD4-citrullinated fibrinogen. Alpha, beta, and gamma chains of fibrinogen are shown separately. Each colored line represents a unique peptide. Nested peptides with a common core motif are shown in the same color. Grey bar denotes peptides with identical core motif between samples. Results: ACPAs (1325:04C03 and 1325:01B09) induced pain-like behavior (lasting for at least 4 weeks) and reduction of the trabecular and cortical bone thickness in the hind limbs as compared to control monoclonal antibodies (p&lt;0.05). While no macroscopic or MRI signs of synovial inflammation were detected, MRI subclinical inflammation of the tendon sheaths was present in mice injected with ACPAs, but not in those injected with control mAb. Semi-quantitative scoring of the inflammatory tendon changes showed significant higher values in mice injected with ACPA (median of 1, range 0 to 2) than those injected with control mAb (median of 0, range 0 to 1). Conclusion: We show that ACPA induces pain-like behavior, bone loss and tendon sheath inflammation in mice, a model that mimics the preclinical state of ACPA positive RA. References: [1]Harre, U. et al. J Clin Invest (2012) [2]Krishnamurthy, A. et al. Ann Rheum Dis (2016, 2019), JI 2019 [3]Wigerblad, G. et al. Ann Rheum Dis (2016, 2019) [4]KleyerA, Seminars in Arthritis and Rheumatism (2016) Disclosure of Interests: Akilan Krishnamurthy: None declared, Yogan Kisten: None declared, Alexandra Circiumaru: None declared, Koji Sakurabas: None declared, Patrik Jarvolli: None declared, Juan Jimenez Jimenez Andrade: None declared, Peter Damberg: None declared, Heidi Wähämaa: None declared, Vivianne Malmström Grant/research support from: VM has had research grants from Janssen Pharmaceutica, Lars Klareskog: None declared, Camilla Svensson: None declared, Bence Réthi: None declared, Anca Catrina: None declared