Rheumatoid Arthritis (cont.)

What Research Is Being Done on Rheumatoid Arthritis?

Over the last several decades, research has greatly increased our understanding of the immune system, genetics, and biology. This research is now showing results in several areas important to rheumatoid arthritis. Scientists are thinking about rheumatoid arthritis in exciting ways that were not possible even 10 years ago.

The National Institutes of Health (NIH) funds a wide variety of medical research at its headquarters in Bethesda, MD, and at universities and medical centers across the United States. One of the NIH institutes, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), is a major supporter of research and research training in rheumatoid arthritis through grants to individual scientists, Specialized Centers of Research, Multidisciplinary Clinical Research Centers, and Multipurpose Arthritis and Musculoskeletal Diseases Centers.

Following are examples of current research directions in rheumatoid arthritis supported by the Federal Government through the NIAMS and other parts of NIH.

Genetics

Researchers are studying genetic factors that predispose some people to developing rheumatoid arthritis, as well as factors connected with disease severity. In recent years, NIAMS-supported research in this area has led to several important genetic discoveries including the following:

Variation in a gene involved in controlling T-cell activation doubles rheumatoid arthritis risk: The variation -- called a single nucleotide polymorphism (SNP) -- is located within a gene that codes for PTPN22, an enzyme known to be involved in controlling the activation of white blood cells called T cells that play an important role in the body's immune system. Where the SNP is present in one or both copies of a person's genes for this enzyme, T cells and other immune cells respond too vigorously, causing increased inflammation and tissue damage. Scientists say the implications of this finding go beyond a better understanding of rheumatoid arthritis risk; it may also help explain why different autoimmune diseases tend to run in families. Other studies have the same SNP with type-1 diabetes and juvenile arthritis.

Genetic variation increases risk of rheumatoid arthritis and lupus: Separate research found a SNP in a large segment of the STAT4 gene increases the risk of both rheumatoid arthritis and another autoimmune disease, systemic lupus erythematosus (lupus). The STAT4 gene encodes a protein that plays an important role in the regulation and activation of certain cells of the immune system. One variant form of the gene was present at a significantly higher frequency in rheumatoid arthritis patient samples from the North American Rheumatoid Arthritis Consortium (NARAC) -- a consortium formed to collect, analyze, and make available clinical and genetic data on 1,000 sibling pairs with rheumatoid arthritis -- as compared with controls. Scientists replicated that result in two independent collections of rheumatoid arthritis cases and controls.

Twin study shows genetic differences in rheumatoid arthritis: Because identical twins have the exact same genes at conception, scientists believe that changes in the genes after the genome is constructed may account for why one of a twin pair can have rheumatoid arthritis while the other does not. To better understand what those changes might be, scientists have used a sophisticated technique called microarray to examine the expression of more than 20,000 genes at a time in 11 pairs of disease-discordant identical twins (meaning one twin had the disease, the other did not). The examination led to the detection of differences in expression of 827 genes. The most significantly overexpressed gene was laeverin, an enzyme that breaks down certain types of proteins; second was 11-hydroxysteroid dehydrogenase type 2 (11-HSD2), important in a steroid pathway linked to inflammation and bone erosion; and third was cysteine-rich angiogenic inducer 61 (Cyr61), which is known for its role in angiogenesis, the formation of new blood vessels. The scientists say their findings are exciting because they offer new insights into the mechanisms by which rheumatoid arthritis is mediated.

Genetic region associated with rheumatoid arthritis risk: Using the relatively new genome-wide association approach, which makes it possible to analyze between 300,000 and 500,000 single nucleotide polymorphisms, researchers in the United States and Sweden identified a region of chromosome 9 containing two genes relevant to chronic inflammation: TRAF1 (encoding tumor necrosis factor receptor-associated factor 1) and C5 (encoding complement component 5). Scientists say it is not yet known how the genes in the TRAF1-C5 region influence rheumatoid arthritis risk, but they hope that by learning more about the genes and their role in the disease, they may find clues to influencing treatment of the disease.

Rheumatoid Arthritis and Disability

During the past 20 years, significant changes in managing rheumatoid arthritis, including new and more powerful drugs and more aggressive treatment, have improved both shortand long-term disability outcomes. Using data from 3,035 patients enrolled in the ARAMIS (Arthritis, Rheumatism, and Aging Medical Information System) data bank -- a large data bank with treatment history for a broad range of patients, and containing widely accepted disability measurements -- NIAMS-supported researchers found that average disability levels in patients with rheumatoid arthritis have declined by 40 percent since 1977 at a rate of about 2 percent a year.

Despite recent improvements in treatment and disability outcomes, women with rheumatoid arthritis may have difficulty maintaining jobs, one NIAMS-supported study shows. Researchers who followed two groups of women with rheumatoid arthritis 11 years apart -- the first group beginning in 1987, the second in 1998 -- found the rate at which women left the workforce did not fall significantly. They found that more than a quarter of the women in both groups stopped working within 4 years after being diagnosed with rheumatoid arthritis.

Researchers cited several possible reasons to explain why the rate of stopping work did not decline, even while disease activity did. They concluded that patients' reasons for leaving work had changed between the time the 1987 and 1998 groups were studied, and that more women were leaving work in 1998 for reasons other than increased disease activity.

Potential Treatments

Researchers continue to identify molecules that appear to play a role in rheumatoid arthritis and thus are potential targets for new treatments. The path between identifying the molecule and developing a drug that targets it is long and difficult. Fortunately, this path has been successfully negotiated and new drugs have emerged that successfully reduce symptoms and damage in rheumatoid arthritis. Researchers continue to identify more candidate drugs, with hopes that these will have fewer side effects or will cure more patients.

Understanding Joint Destruction

Advances in understanding the processes that lead to joint destruction are bringing NIAMS-supported researchers a step closer to new therapies to stop the destructive process. In one NIAMS study researchers found a factor they suspect plays a crucial role in joint destruction: an adhesion molecule on cells of the synovium called cadherin-11. Adhesion molecules allow individual cells to stick together to form tissues. At normal levels, cadherin-11 enables the cells (synoviocytes) to adhere together to form the lining layer of the synovium. But when overgrowth of the synovium occurs, cadherin plays a key role in the destructive behavior of the synovium; namely, eroding the cartilage, which causes permanent destruction to the joint. In studies of mice prone to a disease similar to human rheumatoid arthritis, blocking cadherin-11 prevented cartilage destruction. The next step is to determine whether an agent to block an excess of the molecule has the same beneficial effect in people with rheumatoid arthritis.

In other research scientists found that a lack of apoptosis (programmed cell death) contributes to a proliferation of cells in the joint lining and the failure to eliminate immune cells that react against self. In animal studies, mice lacking two proteins that mediate the process of apoptosis developed arthritis.

Preventing Related Problems

Having rheumatoid arthritis does not make people immune to other medical problems. Thus, reducing the risk of problems that can be associated with rheumatoid arthritis is a focus of NIAMS research. One recent study showed that treatment with hydroxychloroquine, a medication used to treat rheumatic diseases and malaria, reduced the incidence of diabetes in people with rheumatoid arthritis. People with rheumatoid arthritis who took the medication for more than 4 years showed a reduction in risk of diabetes of up to 77 percent.