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The exact cause of rheumatoid arthritis is not known. Most likely, RA is caused by some combination of factors, possibly including any or all of these: a genetic susceptibility to RA, exposure to environmental factors, hormonal influences or exposure to infectious agents. While the underlying cause of RA has not been determined, research has revealed many things about how the immune system becomes overactive, creating the symptoms we recognize as rheumatoid arthritis.

A healthy immune system is designed to protect the body from harmful invaders like bacteria and viruses. When invaders are present, two kinds of infection-fighting white blood cells go into action. These white blood cells are called lymphocytes and leukocytes. Lymphocytes are either T-cells or B-cells. T-cells detect the invaders and tell the B-cells to attack and destroy them. In rheumatoid arthritis, the T-cells become overactive. They also mistake the body's own tissues for invaders and instruct the B-cells to attack them.

The T-cells also alert the leukocytes, the other type of specialized white blood cells. Leukocytes produce chemicals that attract additional white blood cells to the area and widen the blood vessels so that more blood floods in. Normally, the inflammation caused by these chemicals facilitates healing, then stops when the mission has been accomplished. In RA, however, the inflammatory process continues on, creating excessive inflammation that can cause damage. One of the mysteries of RA is why this process spins out of control.

Researchers are investigating each of these factors to determine what role they play in the development of rheumatoid arthritis.

Genetics

Scientists are sure that a person's genetic makeup plays a role in the development of rheumatoid arthritis, and that more than one gene is probably involved. Certain genes are found in many -- but not all -- people with RA. One, known as HLA-DR4, tricks the immune system into attacking the body's joint linings. However, many people with this gene type never develop RA, so it is evident that other factors or genes are also important.

Gene Mutation

A mutated gene known as p53 is sometimes found in the synovial tissues of RA patients. This gene's mutation occurs as part of the disease course, not as an error of heredity. Once mutated, p53 allows joint destruction to continue even after a patient's inflammation has been successfully treated. A normal p53 gene is known as a tumor suppressor gene. Its role is to cause cells to self-destruct. The mutated version allows cells to keep growing, and this mutated gene is found in many cancers. The role of this gene in RA is not understood, nor is it clear whether p53 causes the increased risk that RA patients have for certain cancers.

Environmental Factors

People who have a genetic predisposition for RA may actually get the disease only after exposure to some environmental trigger. There are many speculations about what such a trigger might be.

Recent studies have identified three significant risk factors for RA:

A history of smoking. Long-term smoking increases the risk of RA for women. Women who have relatives with RA can reduce their risk for this disease by not smoking.

A history of blood transfusions.

Obesity (defined as a body mass index* of 30 or more ).

Although more research is needed, what is already known is sufficient to establish that environmental factors do play a role in RA.

Infectious Agents

The body normally responds to infection by activating the immune system. One theory about the cause of RA suggests that perhaps the disease is triggered by an infection that stimulates the immune system, which then fails to return to normal.

One reason for this theory is that the flu-like symptoms of RA are often also experienced with infection -- fatigue, low-grade fever, lack of appetite, and achiness. Another reason for this theory is that the synovial fluid of RA patients sometimes contains high levels of an antibody that the body produces against E. coli bacteria. Other microorganisms such as chalamydia and gonococci have also been found in the joints of RA patients. Researchers have suspected numerous viruses, bacteria and fungi, but decades of research have been unable to prove that any infectious agent is responsible for triggering RA.

Even if RA is triggered by infection, RA is not a contagious disease; people cannot "catch" it from others. This is demonstrated by the demographics of RA, which do not match those of a disease spread by infection. There are no documented reports of any RA epidemic, and the disease does not follow any seasonal or latitudinal pattern anywhere in the world.

Hormonal Influences

It is possible that a genetically susceptible person may be more sensitive to hormonal changes or deficiencies. Perhaps genetic susceptibility plus an environmental agent combine with hormonal changes to trigger RA. No one is sure.

Some people may have a genetic deficiency of Corticotropin-Releasing Hormone, or CRH. CRH produces other hormones (corticosteroids) that help suppress inflammation. Perhaps a lack of sufficient CRH plays a role in RA's out of control immune response.

Hormones are also suspect because three times more women than men get RA. RA appears linked to female hormones because the incidence of RA in women declines after age 50, presumably due to menopause. Hormones are also implicated because women are more prone to get RA during the first three months after giving birth. This is because the lactation (milk secreting) hormone, prolactin, binds to the receptors on T-cells and stimulates T-cell activity.

*Body mass index uses height and weight to calculate nutritional status. An acceptable range for men is between 22 and 24; for women between 21 and 23. Obesity begins at 30.

References

First published September 1, 1999
Last updated December 16, 2002
Copyright © 1999 Accordant Health Services, Inc. All Rights Reserved.

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