Rheumatoid arthritis and the pharmaceutical industry

Stages in the progression of rheumatoid arthritis

In general terms, the development of RA joint symptoms can be divided into three overlapping stages.

• The inflammatory stage, lasting a few months to a few years and characterised by pain, swelling, stiffness, and early bone loss.
• The proliferative stage, in which the tissues around the joint (synovium and tendons) thicken and form what are known as invasive pannus.
• The destructive stage, in which cartilage and bone are eroded and the joints become unstable and may dislocate, giving the characteristic hand and foot deformities of RA.

The inflammatory stage

Acute inflammation is a normal and necessary response to injury or infection. Its purpose is to minimise damage to the tissue and to eliminate its cause (e.g. an infecting organism). It is self-limiting and the affected tissue returns to normal, usually after a few hours or days.

Inflammatory symptoms arise because the small blood vessels in the area respond by becoming leaky, thus allowing fluid, inflammatory chemicals and specialised blood cells to enter the tissues and collect there. One especially important group of substances, prostaglandins, are formed and released into the tissues. By reducing or stopping their formation, inflammation and swelling can be controlled.

This discovery more than any other led to the development of a large family of anti-inflammatory compounds which affect the formation of prostaglandins – the NSAIDs.

The proliferative stage

The body responds to infection or injury by producing cells that attack invading germs or damaged cells. Normally, when the infection has been overcome or the damage has been repaired through the response of the immune system in this way, the body returns to normal. However, if the infection or injury is severe and long-lasting, inflammation can lead to long-term changes (the proliferative stage of RA). In particular, this may include the thickening of the synovium and the growth of pannus tissue.

The established disease-modifying medicines (DMARDs) reduce this proliferative stage, but it has proved impossible to improve on them to any marked extent. However, since the early 1980s, the growth of genetic engineering has brought new treatments that have made it possible to harness some of the body’s own natural defence mechanisms, which help regulate the proliferative stage and which may lead to new biologically active agents.

The destructive stage

By the time the pannus has developed and the synovium thickened, inflammation is no longer the driving force. Under the microscope, pannus tissue and synovium can be seen to contain a great variety of different cell types. These cells release several kinds of digestive enzyme that are capable of breaking down the molecular building blocks out of which cartilage and bone are made, ultimately leading to the loss of function and the joint deformities which are typical of RA.

By identifying the digestive enzymes involved in this process, researchers have been able to develop experimental medicines which may help to control the final destructive stage. Each of the above stages offers targets for medicines discovery and continue to be the subject of intensive research.