Combination therapy in rheumatoid arthritis: the animal model perspective

Attempts to improve antirheumatic agent efficacy have resulted in exploration of treatment protocols with combinations of 2 or more agents. Hypothetically, an ideal combination therapy would have greater efficacy and less toxicity than any of its component agents used individually. However, even a limited number of available drugs can produce a daunting number of possible combination protocols, each requiring clinical evaluation. Intelligent selection of combination protocols, based on a firm understanding of each agent's specific mechanism(s) of action, may help identify potentially useful regimens. Autoimmune animal models of inflammatory synovitis provide a unique opportunity to study the etiology, pathophysiology, and treatment of rheumatoid arthritis (RA). Induction of chronic inflammatory synovitis in susceptible inbred strains can allow for in vivo study under reproducible controlled conditions, using experimental protocols not possible in humans. Although animal models can only approximate human rheumatic disease in its complete form, they are nonetheless important for developing new therapeutic strategies. We review the 3 most common animal models of RA, the streptococcal cell wall, adjuvant, and collagen arthritis rat models. Surprisingly, few published studies evaluate combination therapy in RA animal models. We discuss these investigations, which use interventions aimed at angiogenesis, microtubule function, and immune regulation, as examples of animal models to assess and develop effective therapeutic combinations of antirheumatic agents.