Technotes

Technotes

Rheumatoid Arthritis

Introduction


Rheumatoid arthritis (RA) is a systemic inflammatory disorder characterized by chronic inflammation of the synovium, which over time results in damage to the joints, leading to pain and disability. It occurs in approximately 1% of adults, and approximately 2.5 times more women than men are affected. Immune factors involved in the progression of RA are mainly manufactured by CD4+ T cells, monocytes, macrophages, or fibroblasts. Cytokines produced by these cells such as tumor necrosis f

actor α (TNF-α) and interleukin-1 are the keys to the damaging cascade that ultimately triggers the production of matrix metalloproteinases and osteoclasts resulting in irreversible damage to soft tissues and bones. 


Understanding of molecular pathogenesis of RA has enabled development ofinnovative agents to modulate specific components of the disease progress for early intervention or treatment. Various experimentally induced RA rodent models have been used extensively as the mainstay for evaluation of those therapeutic candidates.


PharmaLegacy Models and Research Tools


RA disease models:

* Type II collagen induced arthritis (CIA) in DBA/1 mice

* Type II collagen induced arthritis in Wistar / Lewis rats

* Adjuvant arthritis in Wistar / Lewis rats

* Streptococcal cell wall induced arthritis in Lewis rats)

Model characteristics:

* Symmetrical joint involvement, peripheral joints aff ected, persistent joint infl ammation

* Synovial hyperplasia, infl ammatory cell infiltration, marginal erosions

* Genetically regulated by MHC and non-MHC genes, responsive to most therapies effective in RA        

* Female rats have greater disease susceptibility to streptococcal cell wall induced arthritis, while male mice are more susceptible to CIA       

* Unlike other models, mouse CIA model is not responsive to non-steroidal anti-infl ammatory drugs        

* Diff erent from human RA, anti-collagen responses are not present in many cases of rat CIA, and rheumatoid factor is not present in neither CIA nor streptococcal cell wall-induced arthritis in rats

Measurement of bone destruction, infl ammatory responses, and molecular pharmacology:

* Bone mineral density (peripheral QCT), bone erosion, abnormal bone growth and joint space narrowing (X-rays, micro-CT)

* Antigen-specifi c T-cell and B-cell responses, cytokine and signal transduction levels, and cell function analysis (ELISA, RT-PCR, Western blot, flow cytometry)

Histopathology:

* Histomorphometry (bone destruction)

* Immunohistochemistry (cellular infi ltration in joint tissue)