Animal models of rheumatoid arthritis (RA) are widely used for testing potential new therapies for RA. However, the question of which animal model is most predictive of therapeutic efficacy in human RA commonly arises in data evaluation. A retrospective review of the animal models used to evaluate approved, pending RA therapies, and compounds that were discontinued during phase II or III clinical trials found that the three most commonly used models were adjuvant-induced arthritis (AIA) in rats and collagen-induced arthritis (CIA) in rats and mice. Limited data were found for more recently developed genetically modified animal models. Examination of the efficacy of various compounds in these animal models revealed that a compound's therapeutic efficacy, rather than prophylactic efficacy, in AIA and CIA models was more predictive of clinical efficacy in human RA than data from either model alone.

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Utility of animal models for identification of potential therapeutics for rheumatoid arthritis

The resolution of inflammation is central to the maintenance of good health and immune homeostasis. Recently, several intracellular stress proteins have been described as having extracellular properties that are anti-inflammatory or favour the resolution of inflammation. We propose that these molecules should be defined as resolution-associated molecular patterns (RAMPs). RAMPs are released at times of cellular stress and help to counterbalance the inflammatory effects of pathogen-associated (PAMPs) and damage-associated (DAMPs) molecular patterns. We propose that heat shock protein 10 (HSP10), αB-crystallin (αBC), HSP27 and binding immunoglobulin protein (BiP) should be considered founding members of the RAMP family. A greater understanding of RAMP biology may herald the development of novel immunotherapies.

Resolution‐associated molecular patterns (RAMP): RAMParts defending immunological homeostasis?

Development of novel drugs for treatment of chronic inflammatory diseases is to a large extent dependent on the availability of good experimental in vivo models in order to perform preclinical tests of new drugs and for the identification of novel drug targets. Here, we review a number of existing rodent models for Rheumatoid Arthritis in the context of how these models have been utilized for developing established therapy in Rheumatoid Arthritis and, furthermore, the present use of animal models for studies of novel drug candidates. We have studied the literature in the field for the use of in vivo models during development of anti-rheumatic drugs; from Methotrexate to various antibody treatments, to novel drugs that are, or have recently been, in clinical trials. For novel drugs, we have explored websites for clinical trials. Although a single Rheumatoid Arthritis in vivo model cannot mirror the complexity of disease development, there exist a number of good animal models for Rheumatoid Arthriti...

Old and new therapeutics for Rheumatoid Arthritis: in vivo models and drug development.

We previously demonstrated that treatments with rIL-1B accelerated the onset and progression of CIA in mice. In the present study, it was observed that IL-1 also enhanced the development of CIA in rats. Like the mouse model, maximal incidence (80–100%) of arthritis occurred within 7 days after the first treatment with IL-1 in rats. Thus, the acceleration of CIA by IL-1 (IL-1 CIA) may be an improved model for the rapid screening of anti-inflammatory and/or anti-arthritic drugs. As a first step to determining the utility of the IL-1 CIA model as a drug screen, we examined the ability of various known anti-inflammatory and anti-arthritic drugs to modify the IL-1 mediated enhancement of CIA in both rats and mice. The results of these studies showed that when analyzed in the IL-1 CIA model, rats and mice exhibited differences in their responses to several of these drugs. For example, dexamethasone, cyclophosphamide, azathioprine, various non-steroidal anti-inflammatory drugs (NSAIDs) as well as methotrexate were found active in the IL-1 CIA of rats. By contrast, the NSAIDs were found to be less effective in suppressing the IL-1 accelerated disease in mice. In both rats and mice, cyclosporine A and several disease modifying anti-arthritic drugs failed to the prevent the development of CIA that was potentiated by IL-1. Thus, in the IL-1 CIA model NSAIDs appeared to be less active in mice than rats. In conclusion, because of the shorter latent period required for the development of arthritis in the IL-1 treated animals, the IL-1 accelerated CIA model in both mice and rats may be useful for screening anti-inflammatory or anti-arthritic compounds.

Interleukin 1 mediated acceleration of type II collagen-induced arthritis: effects of anti-inflammatory or anti-arthritic drugs.

Immunopharmacological studies on collagen-induced arthritis in dark Agouti (DA) rats.

The effects of steroidal and non-steroidal anti-inflammatory drugs on the established lesion of type II collagen induced arthritis in rats were evaluated by measuring the hind paw oedema and anti-type II collagen antibody titre. Dexamethasone, a steroidal anti-inflammatory drug, reduced the anti-type II collagen antibody titre and markedly suppressed the established lesion of type II collagen induced arthritis in rats. A rebound of the arthritis, i.e., a rapid recovery of the hind paw swelling took place after withdrawal of the treatment with steroidal anti-inflammatory drugs, including dexamethasone, prednisolone, and hydrocortisone. On the other hand, indomethacin, benoxaprofen, piroxicam, and tiflamizole, which are cyclo-oxygenase inhibitors in prostaglandin synthesis, had no effect on anti-type II collagen antibody titre, but suppressed the established lesion of the arthritis without causing an apparent rebound of the arthritis after withdrawal of the drug treatment. These results suggest that the level of anti-type II collagen antibodies has no relation to the intensity of hind paw swelling in the established lesion of the arthritis, though the antibodies contribute to the incidence of the arthritis. It also indicates that non-steroidal anti-inflammatory drugs having inhibitory action on cyclo-oxygenase are useful antiarthritic drugs without causing the rebound phenomenon, an untoward side effect after withdrawal of steroidal anti-inflammatory drugs.

https://ard.bmj.com/content/annrheumdis/46/7/543.full.pdf

H Nakagawa

Papers

Inhibitory effects of anti-inflammatory drugs on type II collagen induced arthritis in rats.