The exact cause of rheumatoid arthritis is not clear. It is known that it is an autoimmune disease – that is, a disease caused when the immune system malfunctions and attacks healthy tissues in the body – but exactly what triggers this malfunction has not been identified. Most likely it is a combination of several factors.

Infection
Infections trigger the body’s immune system to produce antibodies (specialised proteins that bind to infectious agents in the body and help to destroy them). Antibodies are individually shaped to bind to a specific target, called an antigen, so that a particular antibody should react only with the particular virus or bacteria it is intended to destroy – like a key that only fits into only one lock. In rheumatoid arthritis, it is thought that antibodies designed to eliminate a virus or bacteria may ‘cross react’ with a protein found on the membranes’ lining joints – like a key that can open a different lock due to its similarity in shape. The binding of an antibody to an antigen triggers an inflammatory response and this could be what causes rheumatoid arthritis.

Infections that have been proposed as potential triggers for rheumatoid arthritis include Epstein Barr virus (the virus that causes glandular fever), certain types of herpes virus, the rubella virus, and the bacteria Mycoplasma (which can cause lung infections), Proteus (which can cause urine infections) and Mycobacteria (which can cause TB).

Hormonal factors
Rheumatoid arthritis often develops in women at around the time of the menopause and it has been suggested that this may be due to a fall in the level of the female hormone oestrogen. Oestrogen reduces the production of inflammatory chemicals in the body, helping to keep inflammation in check. Oestrogen deficiency may therefore be associated with the development of inflammation.
This theory is supported by the fact that the oral contraceptive pill, which contains oestrogen, appears to protect against the development of rheumatoid arthritis; and that the symptoms of rheumatoid arthritis often improve during pregnancy, when oestrogen levels are high. However, the effects of hormone replacement therapy on rheumatoid arthritis are unclear.

Genetic factors
No one gene causes rheumatoid arthritis but certain genes have been identified that can make a person more susceptible to it. It is thought that these genes lower the threshold that must be reached for an inflammatory reaction to be triggered.

Pathophysiology of RA

Autoimmunity
Rheumatoid arthritis develops when the body’s own immune system attacks the joints. This is known as autoimmunity.
The immune system is designed to detect foreign material (for example, bacteria, viruses or toxins) in the body and react by eliminating it. In autoimmune diseases, the body mistakenly identifies a component of the body as foreign and mounts an immune response against it. This results in inflammation.

Inflammation
Inflammation is the body’s way of healing when it is injured, infected or, in the case of autoimmune disease, when an immune response has been inappropriately stimulated. When an immune response is triggered, immune cells are activated and begin to secrete inflammatory chemicals. These chemicals cause nearby blood vessels to dilate and become leaky, to increase the blood flow to the target area and allow more immune cells and immune proteins to enter. These responses cause the characteristic signs of inflammation:

• heat and redness (from the increased flow of blood)
• pain (due to the irritation of nerve endings by inflammatory chemicals)
• swelling (from the accumulation of blood, fluid and immune cells and proteins at the site of injury)

In effect, the purpose of the inflammatory response is to concentrate the components of the immune system around a site of injury or infection so the tissues have all the cells, proteins and chemicals they need to destroy any foreign material and heal effectively. Under normal circumstances, once the trigger of the process has been eliminated, the inflammatory response abates.

The inflammatory process in rheumatoid arthritis

A healthy joint contains bone, cartilage (a spongy pad at the end of bones acting as a shock absorber) and ligaments (tough sheets of fibrous tissues that ‘strap’ the two bones of the joint together) enclosed in a thin membrane known as synovium. This membrane secretes a liquid called synovial fluid, which lubricates the joint like oil in a car, helping it to move smoothly.

In rheumatoid arthritis, the immune response is mistakenly directed at the synovium. An inflammatory reaction is triggered and immune cells flood to the joint, causing it to become swollen, painful and stiff. The immune cells release inflammatory chemicals and enzymes that:

• irritate nerve endings, aggravating the pain
• cause the synovial membrane to thicken and swell into the joint space, making the joint stiff
• increase the production of synovial fluid, compounding the swelling and stretching the joint membrane, which causes further pain
• destroy cartilage, making the joint painful and difficult to move
• stimulate the production of inflammatory tissue that invades the joint space, limiting the movement of the joint
• eventually, destroy the bone itself

These effects also cause the muscles around the joint to become weak and loosen the ligaments connecting the bones, leading to progressive destruction, deformity and instability of the joint.

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