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Synovitis was induced in rabbits sensitized to bovine serum albumin (BSA) by a modification of the method of Dumonde and Glynn. Agents were administered starting on the day of initial BSA joint challenge and every weekday (14-17 doses) for 17 to 21 day periods. Synovial tissues were then excised and evaluated either (1) histologically for inflammatory cell infiltration, or (2) both histologically and for total IgG, anti-BSA, and beta-glucuronidase levels in homogenates of portions of the same tissues. By the intraperitoneal and oral routes, methylprednisolone (1 mg/kg/day), azathioprine (25-40 mg/kg/day) and cyclophosphamide (10 mg/kg/day) produced significantly decreases of 40-100% in some or all of the parameters measured. Non-steroidal anti-inflammatory drugs, including phenylbutazone, ibuprofen and acetylsalicylic acid at oral doses of 75 or 100 mg/kg/day, were ineffective as were colchicine at 1 mg/kg/day and indomethacin at 5 mg/kg/day. Thus, as we have measured it, this model of rheumatoid arthritis is not affected by those agents considered to be of limited effectiveness in this chronic disease, but is ameliorated by corticoids and some slow acting agents.

The immune complex-induced reversed passive Arthus (RPA) reaction in the rabbit has been investigated as a screening test for detecting anti-inflammatory agents potentially more effective in the treatment of rheumatoid arthritis than those presently available. RPA lesions, characterized by edema, erythema, and hemorrhage, were elicited by intravenous injections of bovine serum albumin (BSA) followed by intradermal injections of rabbit anti-BSA antiserum. The anti-edema activities of compounds (mg quantities required for testing) were evaluated after their administration by the intradermal route (compounds admixed with antiserum) as well as by the intraperitoneal route. Of 14 reference anti-inflammatory agents tested by the intradermal screening procedure, only aurothioglucose and chloroquine were inactive. Other pharmacologically active compounds (e.g. antihistamines, anti-complement agents, cytotoxic-immunosuppressives) were also evaluated after their intradermal administration. Protoporphyrin, phloretin, and hexadimethrine bromide (Polybrene) were active. When whole antiserum, or the antibody fraction of the serum, was used to eliminate nonspecific edema, intraperitoneally administered reference agents were found to be effective in the RPA test.

Immunoglobulin and beta-glucuronidase levels in joint exudates and homogenates of synovial tissues were measured during the course of bovine serum albumin (BSA) antigen-induced synovitis in rabbits. After intra-articular BSA challenge, the anti BSA hemagglutinating antibody in tissue homogenates increased with time up to 14 days. Results obtained indicated relatively greater increases in specific anti-BSA activity compared with total IgG and are compatible with in vivo antibody synthesis by inflamed synovial tissue. beta-Glucuronidase was measured as a reflection of phagocytic cell activity. Tissue enzyme levels increased to a maximum at 1 day and this level persisted up to at least 7 days, despite the fact that exudate enzyme levels reached a maximum at 1 day and then declined significantly over the next 2-3 weeks. These observations reinforce the view that inflamed synovial tissue possesses a substantial potential for perpetuating joint destruction by producing increased levels of inflammatory mediators.