Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that principally attacks the joints (but may affect many tissues and organs), producing an inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints. There are a number of animal models in both mice and rats that are used to screen compounds against the effects of RA.
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Collagen-Induced Arthritis (CIA)
Collagen-induced arthritis (CIA) is a preclinical animal inflammation model of rheumatoid arthritis (RA) that is widely used to address questions of disease pathogenesis and to validate therapeutic targets. Collagen-induced arthritis models can be performed in mice or rats by immunization with heterologous type II collagen in adjuvant. Susceptibility to collagen-induced rheumatoid arthritis is strongly associated with major histocompatibility complex class II genes, and the development of rheumatoid arthritis is accompanied by a robust T-cell and B-cell inflammation response to type II collagen.
The chief pathological features of collagen-induced arthritis include a proliferative synovitis with infiltration of polymorphonuclear and mononuclear cells, pannus formation, cartilage degradation, erosion of bone, and fibrosis. As in human rheumatoid arthritis, pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-a), interleukin-1b (IL-1b) and IL-6 are increased in collagen-induced arthritis. Biological therapies designed to interfere with these mediators are active in these models.
Disease activity is assessed by measuring inflammation swelling in the affected joints (paw volume or thickness) over time. Treatments can be assessed in either prophylactic or therapeutic testing paradigms. Additional measures of disease activity include evaluation of serum IL-1b, IL-6, C-reactive protein (CRP) or serum amyloid A (SAA) and erythrocyte sedimentation rate. Bone lesion scoring is conducted by preclinical Positron Emission Tomography (preclinical PET). Charles River typically measures all four paws for thickness and gives an average paw thickness for each animal at each time point. Animal body weights are typically taken 2 times per week.
Hind Limb Swelling in Rat CIA
Collagen Antibody-Induced Arthritis
Collagen antibody-induced arthritis is a model of human rheumatoid arthritis. This model has the advantage of inducing disease in many strains of mice that are resistant to the traditional collagen-induced arthritis methods. Collagen antibody-induced arthritis relies on the injection of a cocktail of monoclonal antibodies directed against type II collagen (C-II), followed by a single injection of LPS. In animals, a significant part of the inflammatory attack on the joints is mediated by pathogenic antibodies directed against C-II. An advantage of this model is that compound assessment can be completed in a relatively short period of time. In standard collagen-induced arthritis protocols, disease doesn’t begin to appear until 3 – 4 weeks and a typical study might last 6 – 8 weeks. In collagen antibody-induced arthritis, the disease appears within 7- 8 days and studies can be completed within 18 days. An additional 7 days can be added to assess the effects of agents on the resolution phase of the disease. Collagen antibody-induced arthritis is dependent on IL-1β and TNF-α, but is independent of the effects of IL-6. The model is quite robust and produces disease in virtually 100% of the injected animals.
Injected animals develop rapid and severe arthritis within 2 – 3 days following LPS injection. Swelling develops in all limbs (hind and fore paws). Published literature suggests that histologic changes can be observed in the joints after 18 days on study.
Footpad thickness, measured in mm via digital vernier calipers and clinical score. Clinical scoring is accomplished by awarding a score of 1 for each swollen digit, a score of 5 for a swollen footpad, and a score of 5 for a swollen wrist or ankle. These are added together to give a maximal score of 60 for each animal.
Histology from mouse CAIA (Day 21), vehicle control tibiotarsal joint.
H&E Staining
Toulidine Blue - Collagen and connective tissue
Mac2 macrophages
Effects of Standard DMARD Agents in Mouse CAIA
Total Clinical Score in Mouse CAIA
Adjuvant-Induced Arthritis (model under development)
Adjuvant-induced arthritis (AIA) is one of the oldest animal models used to recapitulate human RA. Inoculation of animals with complete Freund’s adjuvant (CFA) containing Mycobacterium butyricum produces a profound systemic inflammation resulting in severe joint swelling and remodeling. Unlike the collagen-induced arthritis models, the AIA induces rather sustained serum elevations of certain cytokines. The model is dependent upon a T-cell component. The model is quite robust and can be completed in about 30 days. The elevation in serum cytokines provides an additional readout of efficacy. Historically, this model has been used extensively in the pursuit of anti-arthritic agents. It can be inhibited (some say easily) by NSAIDs, which make its translatability to human disease suspect. Nonetheless, the model is useful in studying T-cell-dependent articulopathies.
Animals develop arthritis within 10 – 14 days following CFA injection. Swelling develops in all limbs (hind and fore paws). Swelling persists for 30 days. Female Lewis rats are inoculated with CFA containing M. butyricum at the base of the tail. Animals are monitored for disease development. Treatment begins once initial symptoms are manifested. Lewis and Dark Agouti rats seem to be standard. Reports exist claiming the model can be performed with SD rats. Footpad thickness, measured in mm via digital vernier calipers and clinical score. Clinical scoring is accomplished by awarding a score of 1 for each swollen digit, a score of 5 for a swollen footpad, and a score of 5 for a swollen wrist or ankle. These are added together to give a maximal score of 60 for each animal.
For more information about our models of rheumatoid arthritis, please contact us at askcharlesriver@crl.com.