Comparative efficacy of a secretory phospholipase A2 inhibitor with conventional anti-inflammatory agents in a rat model of antigen-induced arthritis

Introduction: Previously, secretory phospholipase A(2) (sPLA(2)) inhibition has been used as an adjunct to conventional rheumatoid arthritis therapy in human clinical trials without significant improvement of arthritic pathology. In this study, we compared the efficacy of a potent and orally active group IIa secretory phospholipase A(2) inhibitor (sPLA(2)I) to conventional anti-arthritic agents; infliximab, leflunomide and prednisolone, in a rat model of antigen-induced arthritis. Methods: Initially, to establish efficacy and dose-response, rats were orally dosed with the sPLA(2)I (1 and 5 mg/kg) two days prior to arthritis induction, and then daily throughout the 14-day study period. In the second trial, rats were orally dosed with the sPLA(2)I (5 and 10 mg/kg/day) beginning two days after the induction of arthritis, at the peak of joint swelling. Separate groups of rats were also dosed with the tumour necrosis factor-alpha (TNF-alpha) inhibitor infliximab (single 3 mg/kg i. v. injection), leflunomide (10 mg/kg/day, oral) or prednisolone (1 mg/kg/day, oral) at this same time point and used as comparative treatments. Results: In the pathology prevention trial, both 1 and 5 mg/kg dose groups of sPLA(2)I demonstrated a significant reduction in joint swelling and gait disturbances; however, only the higher 5 mg/kg dose resulted in significantly reduced histopathology scores. In the post-induction trial, rats dosed with sPLA(2)I showed a significant improvement in joint swelling and gait scoring, whereas none of the conventional therapeutics achieved a significant decrease in both of these two disease markers. Histopathological scoring at the end-point of the study demonstrated significantly reduced median scores in rats treated with 10 mg/kg sPLA(2)I and leflunomide. Conclusions: The results from this study suggest a pathogenic role for sPLA(2) enzymes in this model of arthritis in rats, and the potential clinical utility of sPLA(2) inhibition as a safer, and more effective, alternative to conventional anti-arthritic therapeutics.