Causes

Lack of Corticotropin-Releasing Hormone. Some people with RA may have a genetic deficiency of a hormone known as corticotropin-releasing hormone (CRH), which produces corticosteroids, hormones that suppress the inflammatory process.

Mutation of P53 Gene. Even successful treatment of inflammation in RA does not completely prevent further joint destruction. Research has suggested that a mutation of the gene known as p53 may prolong the process. This defect is inherited but occurs over time as the disease progresses. In its normal state, the p53 gene is known as a tumor suppressor gene and causes apoptosis, a natural process by which cells self-destruct. When the p53 gene is defective, cells do not die but continue to reproduce. The actions of a defective p53 gene may help explain several processes associated with RA:

• The development of a pannus, the growth composed of thickened synovial tissue.
• The progressive destruction of cartilage and bone that occurs even after the inflammation has been treated.
• A higher than normal risk for certain cancers. A p53 mutation is found in many cancers. Although the defective p53 gene behaves differently in RA than in cancer, researchers are investigating whether it may play some role in this higher risk.

Environmental Triggers

Infections. Although many bacteria and viruses have been studied, no single organism has been proven to be the primary trigger for the autoimmune response and subsequent damaging inflammation. Higher than average levels of antibodies that react with the common intestinal bacteria E. coli have appeared in the synovial fluid of people with RA. Some experts think they may stimulate the immune system to prolong RA once the disease has been triggered by some other initial infection.

Chemicals. A number of chemicals are being investigated as triggers of rheumatoid arthritis. For example, exposure to silica was associated with RA in a 2003 study. A number of other chemicals are under investigation but it is very difficult to determine causal effects of any specific one.