Causes

The Hypothalamic-Pituitary-Adrenal Axis and Stress Hormones. Some research suggests that abnormalities in the hypothalamic-pituitary-adrenal axis (HPA axis) may contribute to RA. The HPA system includes two parts of the brain (the hypothalamus and the pituitary) and the adrenal gland.

Click the icon to see an image of the adrenal glands.

The HPA axis regulates a person's response to stress, which includes the release of cortisol (an important stress hormones) and DHEA (a weak male hormone). The cytokines interleukin-6 and TNF-alpha normally stimulate a surge in these hormones, which then block further release of the cytokines. Research suggests, however, that in RA, a defective HPA axis responds to the cytokines with a lower-than-normal release of cortisol and DHEA. Without a strong stress response, the cytokine levels remain high and become destructive, causing inflammation.

Genetic Factors

Genetic factors play some role in RA, but some twin studies suggest that it is not very important in most cases. The presence of certain genetic mutations, however, may worsen the disease process. It should be pointed out that defective genes not only can be inherited but they may be changed and mutated by environmental or other factors. More research is needed to determine the specific genetic contributions to this disease.

HLA. HLA (human leukocyte antigen) is a genetically regulated molecule that traps part of antigens and presents them on the surface of cells for destruction by antibodies and T cells. It is designed to recognize self- from non-self cells. Researchers have identified a number of HLA genetic forms called HLA-DRB1 alleles, which are referred to as the RA-shared epitope because of their association with rheumatoid arthritis. These genetic factors do not cause RA, though they may make the disease more severe once it has developed. A 2004 study suggested that genetic variations in the HLA region may also predict drug treatment response. In this study, researchers found that genetics determined how well a patient responded to treatment with the anti-TNF blocker etanercept. Similarly, particular HLA genes determined response to the disease-modifying anti-rheumatic drug methotrexate.