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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/transfer-of-monoclonal-acpas-induces-pain-bone-loss-and-tenosynovitis-in-mice-in-a-peptidyl-arginine-deiminase-4-dependent-manner/