WHAT CAUSES RHEUMATOID ARTHRITIS?

Rheumatoid arthritis is unlikely to be due to a single cause, but rather a combination of genetic and environmental factors that trigger an abnormal immune response.
 
The Inflammatory Process and Rheumatoid Arthritis
The Normal Immune System Response. The inflammatory process is a byproduct 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.
 
Under normal conditions, the immune system has other factors that control and limit this inflammatory process.
 
The Infection Fighters. The primary infection-fighting units are two types of white blood cells: lymphocytes and leukocytes.
 
Lymphocytes include two subtypes known as T-cell s and B-cells. Both types of cells are designed to recognize foreign invaders (antigens) and to launch an offensive or defensive action against them:
 
B-cells produce antibodies, which are separate agents that can either ride along with a B-cell or travel on their own to attack the antigen.
 
T-cells have special receptors attached to their surface that recognize the specific antigen.
 
T-cells are further categorized as killer T-cells or helper T-cells (TH cells).
Killer T-cells directly attack antigens that occur in any cells that contain a nucleus.
 
Helper T-cells also recognize antigens, but their role is two fold. They stimulate B-cells and other white cells to attack the antigen. They also produce cytokines, powerful immune factors that have an important role in the inflammatory process .
 
Helper T-Cells and Rheumatoid Arthritis. The actions of the helper T-cells are of special interest in rheumatoid arthritis. For some unknown reason, the T-cells become overactive in rheumatoid arthritis and mistake the body's own collagen as an antigen and trigger a series of immune responses to destroy the false enemy:
 
TH-cells stimulate B-cells to produce antibodies. In this case, however, they appear to direct the B-cells to produce autoantibodies, which are directed against the body's own cells. Antibodies come in five types: IgM, IgG, IgA, IgD or IgE. The autoantibody in rheumatoid arthritis appears to be derived from IgG.
 
TH-cells also secrete or stimulate the production of powerful immune factors called cytokines. In small amounts, cytokines are indispensable for healing. If overproduced, however, they can cause serious damage, including inflammation and injury in the joints during the rheumatoid arthritis process. They may even be responsible for inflammation that occurs in parts of the body beyond the joints, including fever, shock, and even damage to organs, such as the liver.
 
Cytokines. Important cytokines in the process of rheumatoid arthritis are those known as interleukins (ILs) and tumor necrosis factor (TNF). (Levels of TNF soar in the synovial fluid during arthritic flare-ups.) Some cytokines play a role in releasing enzymes, such as those known as collagenase and cathepsin L, which destroy collagen. Other cytokines under study are interferon, GM-CSF, and interleukins 1,6, 9, 10, 11, 15, and 17.
 
Leukocytes. The leukocytes are the other major white blood cells. They are also spurred into action by the over-zealous T-cells. Leukocytes stimulate the production of two 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.
 
Other Factors. Excessive amounts of nitric oxide, a substance important in blood vessel flexibility and dilation, may also play a major destructive role in RA.

Genetic Factors

Although much has been learned about the inflammatory process leading to rheumatoid arthritis, researchers have yet to uncover the factors that lead to this devastating self-attack. One prevalent theory is that a combination of factors trigger rheumatoid arthritis, including genetic susceptibility, an abnormal autoimmune response, and a viral infection.
 
HLA-DR4. 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 molecule called HLA-DR4, which is present in many patients with autoimmune conditions. This HLA molecule may be responsible for the confusion between collagen and an actual foreign antigen in people with rheumatoid arthritis. HLA-DR4, however, is also present in many people who do not contract RA, and many experts believe that more than one gene must be involved in order for the disease to develop.
 
Lack of Corticotropin-Releasing Hormone. Some people 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 the inflammation does not completely prevent further joint destruction. Research has found the presence of a mutated gene known as p53 in synovial tissue obtained from a group of patients. This mutation does not appear to be inherited but to develop as part of the disease process:
 
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.

Infectious Triggers
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, which some experts think may stimulate the immune system to perpetuate RA once the disease has been triggered by some other initial infection.
 
Hormonal Triggers
Hormonal imbalances may contribute to the processes leading to RA. People with RA appear to have lower than normal levels of certain hormones secreted by the adrenal gland, including the following:
 
Cortical, a stress hormone.
 
In women, dehydroepiandrosterone (DHEA), a weak androgen (male hormone).
 
WHO GETS RHEUMATOID ARTHRITIS? 
Rheumatoid arthritis (RA) is an ancient disease. Bone changes indicating the condition have been identified in skeletons thousands of years old. RA affects an estimated 2.1 million Americans, or 1% of the US population.
 
Age
Although the disease can occur at any age from childhood to old age, it usually starts in young adulthood, with age of onset peaking between 20 and 45. Still, about 50,000 children may be afflicted with the juvenile rheumatoid arthritis.
 
Gender
Up to three quarters of rheumatoid arthritis sufferers are women. (The risk for women is slightly lower if they have been pregnant.) Women are also at higher risk for the severe type 2 rheumatoid arthritis.
 
Family History
The risk increases in those with relatives who have rheumatoid arthritis.
 
Other Risk Factors
Other factors may place certain susceptible individuals at higher risk for developing RA:
 
Long-Term Smoking.
 
History of Blood Transfusions.
 
Obesity.
 
Coffee Consumption.
A 2000 Finnish study reported a direct association between coffee consumption and an increased risk for RA, possibly because coffee's effect on rheumatoid factor. The study did not account for other factors, however, such as other behaviors or habits, or the way coffee is prepared (typically without filters in Finland). Further investigation is needed.
 
Silicone Implants.
Most studies are not finding any association between silicone breast implants and rheumatoid arthritis or other autoimmune disease (except possibly Sjögren's syndrome).
 
The Role of Allergies
Reports from a Dutch study suggest that hay fever sufferers have a reduced risk of developing rheumatoid arthritis, and, conversely, arthritis patients are less likely to have hay fever.

WHAT ARE THE SYMPTOMS OF RHEUMATOID ARTHRITIS?

Morning Stiffness in the Joints
The hallmark symptom of rheumatoid arthritis is morning stiffness that lasts for at least an hour. (Stiffness from osteoarthritis, for instance, usually clears up within half an hour.) Even after remaining motionless for a few moments, the body can stiffen. Movement becomes easier again after loosening up.
 
Swelling and Pain
Swelling and pain in the joints must occur for at least six weeks before a diagnosis of rheumatoid arthritis is considered. The inflamed joints are usually swollen and often feel warm and "boggy" when touched. The pain often occurs symmetrically but may be more severe on one side of the body, depending on which hand the person uses more often.
 
Specific Joints Affected
Although rheumatoid arthritis almost always develops in the wrists and knuckles, the knees and joints of the ball of the foot are often affected as well. Indeed, many joints may be involved, even causing the spine to become misaligned. It does not usually show up in the fingertips, where osteoarthritis is common, but joints at the base of the fingers are often painful.
 
Nodules
In about 20% of people with RA, inflammation of small blood vessels can cause nodules, or lumps, under the skin. They are about the size of a pea or slightly larger, and are often located near the elbow, although they can show up anywhere. Nodules can occur throughout the course of the disease. Rarely, nodules may become sore and infected, particularly if they are in locations where stress occurs, such as the ankles. On rare occasions, nodules can reflect the presence of rheumatoid vasculitis, a condition that can affect blood vessels in the lungs, kidneys, or other organs.