5. PROTOCOL 
Protocol 
A. Rheumatoid Arthritis - The Clinical Problem 
Arthritis is the most prevalent condition among those over 65 years of age 
(1,2), with over 30 million Americans suffering from the various arthritides. Of these, 
rheumatoid arthritis (RA) accounts for approximately 5 million individuals; around 
150,000 new cases of RA are diagnosed each year in the USA (3). The prevalence of RA 
is greater in females than males, and increases with age; 5% of women aged 65 or more 
have RA. The lifetime costs of RA have been estimated as more than $29,000 per case 
in 1990 dollars (3). The cost in human suffering is impossible to quantify. 
RA is a chronic, progressive inflammatory disorder which primarily affects joints. 
Associated with the disease is erosion of the soft tissues within the joint, particularly the 
articular cartilages. These pathophysiological changes lead to pain and functional failure 
of the joint. As such, RA is an agent of considerable human suffering which, if it affects 
the weight bearing joints, can lead to confinement to a wheelchair. Furthermore, 
patients with severe RA have a shortened life expectancy (4). Some of this is due to the 
toxicity of anti-arthritic drugs. 
Despite a sizeable pharmacologic armamentarium, RA remains incurable. Most 
treatment protocols are based upon the traditional therapeutic pyramid (fig. 4). The first 
line of pharmacologic defense is usually administration of a non-steroidal 
antiinflammatory drug (NSAID); aspirin is one such drug. Although NSAJDs often 
produce some measure of symptomatic relief, they neither prevent loss of the articular 
cartilage, nor interfere with the underlying disease process. Furthermore, they have such 
high incidence of undesirable side effects, such as peptic ulcers, hypertension and 
hyperkalemia, that about 50% of patients taking any one NSAID discontinue its use 
within a year (5). 
The next level of drugs contains the so-called "disease modifying anti-rheumatic 
drugs" (DMARDs), which include gold drugs, penicillamine and antimalarials (fig. 4). 
Although DMARDs are thought to slow the progression of RA, they are unpredictable 
in their effects and all have severe side effects. After 5 years of initiating DMARD 
therapy only 5-15% of patients persist with the drug (6). This leaves cytotoxic drugs and 
various experimental agents as the only remaining therapeutic options. 
When all pharmacologic methods have been exhausted, the only recourse for the 
severely diseased, rheumatoid joint is the surgical insertion of a prosthetic replacement. 
A measure of the inability of existing drugs to combat RA may be gathered from the 
statistic that, in 1988, 190,000 artificial joints were implanted because of RA. This 
accounted for nearly 12% of all artificial joints inserted that year (7). Against such 
daunting statistics, the pursuit of novel therapies, such as gene therapy, would seem to be 
required. 
Recombinant DNA Research, Volume 19 
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