These issues are discussed in Evans and Robbins (8), a copy of which is included 
in appendbc D. 
B. Rheumatoid Arthritis - Pathophysiology 
The essential anatomy common to all diarthrodial (moveable) joints is shown in 
figure 5. Smooth articulation is ensured by the unique macromolecular structure of 
articular cartilage, which covers the ends of the bones. The articular cartilages move 
against each within a cavity, the joint space, which is lined by a tissue known as the 
synovium. In normal joints, the joint space contains a small volume of synovial fluid 
which is involved in joint lubrication and nutrition of the cartilage. 
In normal joints the synovium is only 2-3 cell layers in depth. There are two types 
of synoviocytes: the type A cells which resemble macrophages, and the type B cells 
which are fibroblastic. It is the latter cells into which we will introduce genes as part of 
the present protocol. The synovium is underlain by a sparsely cellular sub-synovium, 
which, depending on the antatomical location, may be fibrous, adipose or areolar in 
nature. The anatomy and biology of the joint has been recently reviewed by Sledge (9). 
Two pathological processes predominate in the rheumatoid joint - inflammation 
and tissue destruction. The inflammatory component is largely seen as a synovitis with 
associated increase in the volume and cellularity of the synovial fluid. In the inflamed 
synovium the type B cells undergo considerable hyperplasia (10). In addition, the 
resident type A and type B synoviocytes are joined by a variety of leukocytes, 
predominantly lymphocytes, macrophages and mast cells. Most of the lymphocytes are 
CD4'^ helper cells which are thought to be activated by as yet unidentified intraarticular 
autoantigens. The predominant antigen presenting cell is the macrophage. B- 
lymphocytes within the synovium secrete immunoglobulins, in particular rheumatoid 
factor, which can form immune complexes and activate complement. (For a review of 
these matters, see reference 11). 
The major effector molecules in the inflamed joint are thought to be cytokines 
released from activated macrophages and synoviocytes (12-14). Analysis of rheumatoid 
synovial fluids reveals the presence of high levels of a number of their cytokines 
including interleukins-1,-6 and -8 (IL-1, IL-6, IL-8), tumor necrosis factor-a (TNF-a), 
granulocyte-macrophage colony stimulating factor, transforming growth factor (3 and 
others (12-14). Of these, IL-1 and TNF-a have attracted the most attention because they 
not only induce joint inflammation but also trigger loss of articular cartilage (15-17). 
Although a variety of pro-inflammatory cytokines exist in rheumatoid joints, IL-1 and 
TNF-a are the only well characterized cytokines known to cause cartilage loss. They do 
this in two ways. Firstly, they provoke chondrocyte-mediated breakdown of the 
extracellular matrix of cartilage; secondly, they suppress the synthesis of new matrix (18- 
20 ). 
Most new strategies to improve the treatment of RA are based upon manipulating 
(4281 
Recombinant DNA Research, Volume 19 
