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Rheumatoid Arthritis

Description

An in-depth report on the causes, diagnosis, treatment, and prevention of rheumatoid arthritis.

Alternative Names

Corticosteroids; Immunosuppressant Drugs; Nonsteroidal Anti-inflammatory Drugs, or NSAIDs

Causes

Although much has been learned about the process leading to rheumatoid arthritis, researchers have yet to uncover all the factors that lead to this devastating self-attack. One prevalent theory is that a combination of factors triggers rheumatoid arthritis, including an abnormal autoimmune response, genetic susceptibility, and some environmental or biologic trigger, such as a viral infection or hormonal changes.

The Immune Response and Inflammatory Process

The Normal Immune System Response. The inflammatory process is a byproduct of the activity of the body's immune system, which fights infection and heals wounds and injuries:

  • When an injury or an infection occurs, white blood cells are mobilized to rid the body of any foreign proteins, such as a virus.
  • The masses of blood cells that gather at the injured or infected site produce factors to repair wounds, clot the blood, and fight any infective agents.
  • In the process the surrounding area becomes inflamed and some healthy tissue is injured. The immune system is then called upon to repair wounds by clotting off any bleeding blood vessel and initiating fiber-like patches to the tissue.
  • Under normal conditions, the immune system has other special factors that control and limit this inflammatory process.

The Infection Fighters. Two important components of the immune system that play a role in the inflammation associated with rheumatoid arthritis are B cells and T cells, both of which belong to a family of immune cells called lymphocytes.

When macrophages recognize foreign particles entering the bloodstream, they are programmed to ingest them, split them into pieces, and bring specific sections of them (antigens) into contact with the surface of the T cell. These antigens are placed within specialized proteins on the surface of the T cell that signal to a T cell and begin a process of immune system inspection. This process involves the interaction of several proteins on B cells and T cells, which seem to signal back and forth. If the T cell recognizes an antigen as "non-self," then it will produce chemicals (cytokines) that cause B cells to multiply and release many immune proteins (antibodies). These antibodies circulate widely in the bloodstream, recognizing the foreign particles and triggering inflammation in order to rid the body of the invasion. T-cells can be further categorized as killer T-cells or helper T-cells. Killer T-cells directly attack antigens, such as viruses and tumor cells. Helper T-cells recognize antigens that are presented to them by macrophages (or other specialized cells), and can stimulate B cells to mount various kinds of attacks on the antigen. They also produce chemicals (cytokines) that can have a more direct role in the inflammatory process.

For reasons that are still not completely understood (and may be multi-factorial), both the T-cells and the B cells become overactive in certain ways in patients with RA. In an immune response it is normal for the antibody response to change over time, particularly if the first antibodies that are made do not eliminate the invading particles. Little by little, the types of antibodies being made undergo changes in an attempt to achieve better recognition and a stronger inflammatory response against a recalcitrant invader. In RA, a complex interaction between activated immune cells and an impaired antigen-elimination process leads to a greater than normal repertoire of what the antibodies recognize. Eventually, antibodies are made that recognize more of the bodys own tissues in a stronger or more persistent manner than is healthy, and inflammatory responses are mounted in these tissues.

Antigens
An antigen is a substance that can provoke an immune response. Typically antigens are substances not usually found in the body.

Cytokines. Most immune cells secrete or stimulate the production of powerful immune factors called cytokines. In small amounts, cytokines are indispensable for maintaining the balance of the body during immune responses, infections, injuries, tissue repair, blood clotting, clearing of debris from inflamed blood vessels, and other aspects of healing. If overproduced, however, they can cause serious damage, including dangerous levels of inflammation and cellular injury.Cytokines are very important in the destructive process of rheumatoid arthritis, particularly those known as interleukins (ILs)--notably IL1 and IL6--and tumor necrosis factor (TNF). TNF is now known to be the major cause of joint damage and various systemic manifestations of RA, including weight loss.

Leukocytes. The leukocytes, the other major white blood cells in the body, are also spurred into action by the over-zealous T-cells. Leukocytes stimulate the production of key players in the inflammatory process:

  • Leukotrienes, which attract even more white blood cells to the area.
  • Prostaglandins, which open blood vessels and increase blood flow.
  • Nitric Oxide. Nitric oxide is a gas that is important in blood vessel flexibility and dilation. In excessive amounts, however, it becomes a damaging substance that may play a major destructive role in RA.

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

Adrenal glands 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 would 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.

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 perpetuate the process. This defect would not be inherited but would occur overtime as the disease progressed:

  • 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, however, 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 perpetuate 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 ones.

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