Sustained Macrophage Infiltration upon Multiple Intra-Articular Injections: An Improved Rat Model of Rheumatoid Arthritis for PET Guided Therapy Evaluation

To widen the therapeutic window for PET guided evaluation of novel anti-RA agents, modifications were made in a rat model of rheumatoid arthritis (RA). Arthritis was induced in the right knee of Wistar rats with repeated boosting to prolong articular inflammation. The contralateral knee served as control. After immunization with methylated bovine serum albumin (mBSA) in complete Freund's adjuvant and custom Bordetella pertussis antigen, one or more intra-articular (i.a.) mBSA injections were given over time in the right knee. Serum anti-mBSA antibodies, DTH response, knee thickness, motion, and synovial macrophages were analyzed and [18F]FDG(-general inflammation) and (R)-[11C]PK11195 (macrophages-)PET was performed followed by ex vivo tissue distribution. Significant anti-mBSA levels, DTH, swelling of arthritic knee, and sustained and prolonged macrophage infiltration in synovial tissue were found, especially using multiple i.a. injections. Increased [18F]FDG and (R)-[11C]PK11195 accumulation was demonstrated in arthritic knees as compared to contralateral knees, which was confirmed in ex vivo tissue distribution studies. Boosting proved advantageous for achieving a chronic model without remission. The model will offer excellent opportunities for repeated PET studies to monitor progression of disease and efficacy of novel therapeutic agents for RA in the same animal.