Rheumatoid Arthritis

Animal models of rheumatoid arthritis (RA) with a proven track record of predictability for efficacy in humans include: rat adjuvant arthritis (AIA) , rat type II collagen arthritis (CIA), mouse type II collagen arthritis (CIA) and antigen- induced arthritis in several species. Agents currently in clinical use (or trials) that are active in these models include: corticosteroids, methotrexate, nonsteroidal anti-inflammatory drugs, cyclosporin A, leflunomide interleukin-1 receptor antagonist (IL-1ra) and soluble TNF receptors. For some of these agents, the models also predict that toxicities seen at higher doses for prolonged dosing periods would preclude dosing in humans at levels that might provide disease modifying effects.

In comparison to the osteoarthritis models, RA models are relatively easy to perform, have good reproducibility of data and are generally of short duration. Most of the RA models have some pathological features that are similar to those occurring in human disease. Important differences include 1) animal models of RA progress much more rapidly than human disease and thus are characterized by primarily acute inflammatory responses and 2) rodents have a tendency to have marked bone resorption and bone formation (especially periosteal/endosteal) in response to joint inflammation.

Ultimate selection of an animal model for studies on pathogenesis or effects of inhibitors of RA requires consideration of the purpose of the study. If the need is for rapid generation of preclinical efficacy/toxicity data to facilitate entry into clinical trials, selection of one of the induced (AIA, CIA) models is probably most appropriate. Generation of efficacy data in one of these models is procedurally straightforward and therefore should be reproducible. Test animals are readily available should the need for large-scale testing emerge. In addition, these models (AIA, CIA) have excellent track records for predicting activity and toxicity (at high doses of various agents) in humans. So comparative studies between older vs newer anti-arthritics can be done. Also, since these models are highly reproducible, examination of structure activity relationships between various molecules should be easily achievable.

Activity of commonly used small molecule anti-arthritic agents such as dexamethasone, indomethacin (and other NSAIDs, including cyclo-oxygenase 2 inhibitors) and methotrexate (adjuvant only) are predicted by the developing rat adjuvant and established rat type II collagen arthritis models.

Dexamethasone and other corticosteroids are used in the clinical treatment of RA but only at low doses because of the toxicities associated with chronic use. Both animal models predict that corticosteroids have the potential to beneficially affect all aspects of RA and that they have the potential to be disease modifying but that toxicities associated with chronic dosing preclude their use at these efficacious doses. So the models predict that only modest clinical responses could be expected with a non-toxic dosing regime.

References:

  1. Bendele AM. Animal Models of Rheumatoid Arthritis. J Musculoskel Interact 2001; 4: 377– 385.

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