Akilan Krishnamurthy1, Jitong Sun2, Alexandra Circiumaru1, Yogan Kisten1, Koji Sakuraba3, Thuy Tran1, Peter Damberg1, Patrik Jarvoll1, Li Lu1, Katalin Sándor1, Tunhe Zhou4, vivianne malmström1, Camilla I. Svensson1, Aase Hensvold1, Anca Catrina1, Lars Klareskog1 and Bence Réthi1, 1Karolinska Institutet, Stockholm, Sweden, 2Karolinska Institutet, Solna, Sweden, 3Karolinska Institutet and Karolinska University Hospital, Fukuoka, Japan, 4Stockholm University, Stockholm, Sweden
Background/Purpose: The appearance of anti-citrullinated protein antibodies (ACPAs) in the circulation represents a major risk factor for developing rheumatoid arthritis (RA). Here we studied whether a combination of two monoclonal ACPAs could induce pain, bone erosion and tenosynovitis in mice, i.e. symptoms that often precede disease onset in ACPA-positive individuals at risk of developing RA. ACPAs often cross-react with other types of protein-modifications and therefore we evaluated the role of protein citrullination, mediated by peptidyl arginine deiminase (PAD4), in the symptoms observed in ACPA-injected mice.
Methods: Monoclonal ACPAs (1325:04C03 and 1325:01B09), generated from plasma cells of RA patients, were transferred to wildtype and PAD4-deficient mice. ACPA distribution was studied by using positron emission tomography (PET). Pain-like behavior and macroscopic inflammation were monitored for a period of four weeks, followed by the analyses of tenosynovitis in the ankle joints using 9.4T magnetic resonance imaging (MRI) and bone micro-architecture in the tibia using X-ray microscope. Microscopic changes in the tendon sheath were analyzed in decalcified ankle joint sections.
Results: Clone 1325:04C03 accumulated in the smaller joints at higher levels as compared to 1325:01B09 or to control antibodies, in line with the different fine-specificity pattern of the two ACPAs and the preferential targeting of osteoclasts and their precursors by 1325:04C03. The combination of the two ACPA clones induced long-lasting pain-like behavior and trabecular bone loss in mice. Although no synovitis was observed macroscopically, we detected tenosynovitis in the ACPA-injected mice by MRI. Microscopic analyses of the joints revealed a cellular hyperplasia and a consequent enlargement of the tendon sheath in the ACPA-treated group. In PAD4-deficient mice the effects of ACPAs on pain-like behavior, tenosynovitis and bone loss were significantly reduced.
Conclusion: Monoclonal ACPAs can reach the joints from the circulation and induce pain, bone erosion and tenosynovitis via mechanisms dependent on PAD4-mediated citrullination. ACPAs might thus directly contribute to early symptoms preceding the onset of RA.
Disclosures: A. Krishnamurthy, None; J. Sun, None; A. Circiumaru, None; Y. Kisten, None; K. Sakuraba, None; T. Tran, None; P. Damberg, None; P. Jarvoll, None; L. Lu, None; K. Sándor, None; T. Zhou, None; v. malmström, Eli Lilly, Pfizer, Janssen; C. Svensson, Eli Lilly, AstraZeneca, Novartis, UCB, Oblique, Cellectricon; A. Hensvold, None; A. Catrina, Bristol-Myers Squibb, Pfizer; L. Klareskog, None; B. Réthi, None.
