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What role do genetic factors play in rheumatoid arthritis (RA)? Which proteins involved in RA's chronic, destructive inflammation might be appropriate targets for new therapies? What progress is being made to help those with cartilage damage? In this issue of Research Update, you'll learn how researchers funded by the Arthritis Foundation are helping to address these and other important questions and in so doing, are moving us closer to the prevention, control and eventual cure of arthritis and related diseases. Please join us in congratulating these researchers for their exciting accomplishments!

Progress in RA genetics

What problem was studied?

Previous research has confirmed an association between the development of rheumatoid arthritis (RA) and a cluster of genes involved in immune function called the human leukocyte antigen (HLA) complex. Studies of twins and families have shown that non-HLA genes are also likely to play a role in RA. Identifying and learning more about other genes involved in RA will shed new light on what causes the disease.

Arthritis Foundation-funded researchers involved in the study: Peter K. Gregersen MD, Center for Genomics and Human Genetics, Manhasset, N.Y. and Lindsey A. Criswell, MD, MPH, University of California at San Francisco, supported by an Arthritis Foundation grant to the North American Rheumatoid Arthritis Consortium.

What was done in the study?

The North American Rheumatoid Arthritis Consortium (NARAC) is a unique, multi-million dollar collaboration of the Arthritis Foundation and the National Institutes of Health designed to learn more about genetic factors that contribute to RA. Under the auspices of NARAC, twelve research centers recruited 512 families with two or more siblings with RA. A previous screening of the genetic information from 256 of the families showed several genetic regions outside the HLA complex that appeared more often in affected families. In the current study, the researchers screened the genetic information from an additional 256 families, and then pooled the data from all 512 families.

What were the study results?

In addition to confirming an association between RA and HLA genes, the study found that other genetic regions on chromosomes 1 and 18 are likely to contain genes involved in RA. Many of these regions have also been linked to an increased risk of other autoimmune diseases, such as lupus and diabetes, suggesting that these diseases may share a common set of genetic factors.

What's the relevance to people with arthritis?

This study allows researchers to narrow down their search for specific genes involved in RA. For instance, one gene on chromosome 18 affects cells that break down bone. Understanding how this gene is involved in RA would allow for the development of new treatments to block the effects of the gene and prevent joint damage.

Source: Arthritis and Rheumatism, April 2003 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12687532&dopt=Abstract

Identifying new therapeutic targets

What problem was studied?

Breakthrough biologic response modifier drugs that block the action of the molecule, tumor necrosis factor alpha (TNFá) have been shown to reduce inflammation and joint damage in RA. However these drugs don’t work for everyone and often do not completely eliminate joint symptoms even when effective. Therefore, researchers continue to look for other molecules involved in RA that could be the target for new, improved therapies.

A recent focus of research has been on the TNF family member, “TWEAK” and its cell surface receptor, “Fn14,” which appear to stimulate the growth of new blood vessels. In RA, new blood vessel formation within the membrane lining the joint (the synovium) allows inflammatory cells and chemicals to accumulate in, and destroy joint tissues.

Arthritis Foundation-funded researcher involved in the study: Patrick J. Donohue, PhD, American Red Cross, Rockville, MD, supported by an Arthritis Foundation career development grant.

What was done in the study?

The researchers grew human blood vessel cells (called endothelial cells) in the laboratory, and analyzed what happened when TWEAK was added to the cells. Then they created a decoy receptor for Fn14 ("dFN14" which contains only the part of Fn14 that interacts with TWEAK) and tested whether this type of biologic agent could block the effects of TWEAK.

What were the study results?

The study showed that TWEAK can stimulate endothelial cell growth. The Fn14 decoy agent significantly inhibited TWEAK's ability to increase endothelial cell growth in cell culture.

What's the relevance to people with arthritis?

This study suggests that agents that block TWEAK have the potential to reduce new blood vessel formation and suppress disease progression in RA. Adds Dr. Donohue, "Our plan is to assess TWEAK expression in both normal and RA joint tissue. If TWEAK expression is higher in the RA samples, we will test the ability of dFN14 to block TWEAK function and lessen the severity of RA."

Source: Arteriosclerosis, Thrombosis and Vascular Biology, April 2003 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12615668&dopt=Abstract

Biotechnology advances provide hope in osteoarthritis

What problem was studied?

Osteoarthritis (OA) is often not diagnosed until it begins to cause pain, at which point irreversible cartilage damage is usually already present. For those who already have severe joint damage, a promising alternative to joint replacement surgery are innovative “tissue engineering” techniques to grow cartilage for transplanting into damaged joints. It is hoped that this transplant approach will soon become a reality for millions of people. However, in order for this to happen, optimal conditions for growing cartilage tissue must be further studied.

Arthritis Foundation-funded researcher involved in the study: Walter E. Horton Jr., Ph.D., Northeastern Ohio Universities College of Medicine, supported by an Arthritis Foundation biomedical grant and a grant from the Northeastern Ohio chapter.

What was done in the study?

Cartilage cells were grown within a special device called a hollow fiber bioreactor. Magnetic resonance imaging was used to evaluate a protein in cartilage with a strong negative charge (the "fixed charge density"), which is a measure of the biomechanical properties of cartilage. Additional tests were done on a section of the newly formed cartilage to determine other mechanical and chemical features.

Then an enzyme was added to the new cartilage to simulate the degenerative changes seen in early OA and the MRI and other tests were repeated.

What were the study results?

The study showed that MRI successfully detected changes in cartilage fixed charge density. These changes correlated with other measures of cartilage mechanics and biochemistry in situations when the cartilage was undergoing rapid changes- such as during development and breakdown. The study also demonstrated that the hollow fiber system was an effective model for growing and studying the formation of cartilage under a variety of conditions.

What's the relevance to people with arthritis?

This study provides further evidence that MRI could be useful in the early detection of OA. This sensitive technique may also be useful for monitoring disease progression and for evaluating response to treatments--which will make it easier to evaluate new experimental therapies. In addition, the use of the new model system for growing cartilage has moved us closer to the practical use of transplanting tissue-engineered cartilage. "With this study, we've taken a major step forward in understanding how we might use MRI to determine the health of cartilage and in the evaluation of current treatments. The study also highlights a unique bioreactor system for the tissue engineering of cartilage," Dr. Horton said.

Source: Arthritis and Rheumatism, April 2003 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12687548&dopt=Abstract

Low vitamin B6 levels associated with severe RA

What problem was studied?

People with rheumatoid arthritis (RA) have low vitamin B6 levels but why this abnormality occurs is unclear. People with vitamin B6 deficiency do not adequately break down an amino acid in the blood called homocysteine which can result in a heart attack or stroke. This study focused on whether the abnormal vitamin B6 levels are related to RA disease status.

Arthritis Foundation-funded researchers involved in the study: En-Pei I. Chiang, PhD, supported by an Arthritis Foundation training grant and Ronenn Roubenoff, MD, MHS, supported by an Arthritis Foundation clinical grant, Tufts University, Boston, MA.

What was done in the study?

Thirty-seven persons with RA completed surveys, physical examinations and laboratory tests to assess their pain and fatigue, disability status, number of tender and swollen joints, vitamin B6 and homocysteine levels, as well as markers of inflammation.

What were the study results?

Low vitamin B6 levels in people with RA were associated with signs of more severe disease, including higher disability score, number of swollen joints and increased signs of inflammation. These results provide evidence that the low vitamin B6 levels result from inflammation, rather than lower intake or higher breakdown of the vitamin. The researchers further concluded that the combination of chronic inflammation, low vitamin B6 and elevated homocysteine could contribute to an increased risk of heart disease in people with RA.

What's the relevance to people with arthritis?

This study suggests that people with severe RA may need more vitamin B6 to help prevent vitamin deficiency. There are no guidelines yet for how much vitamin B supplement should be taken to decrease homocysteine levels and taking too much can result in nerve damage. However, eating foods rich in this vitamin, such as whole grain cereals, fish, bananas and beans, could be beneficial.

Source: American Journal of Medicine, March 2003 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12681455&dopt=Abstract

Benefits of exercise targeted to functional limitations

What problem was studied?

Knee osteoarthritis (OA) can result in impairments such as pain, limited mobility and muscle weakness, and ultimately can affect walking and other functions. Traditional rehabilitation programs are aimed at reducing the impairments, e.g., increasing knee flexibility and strength, with the hope that improved walking ability will follow.

Nevertheless, it is unclear how traditional exercises result in improved function or why some people do not improve their function even when they do have positive changes in mobility and strength. One hypothesis is that people with knee OA develop functional limitations because they use inefficient body movements to compensate for their weakness and other impairments. This study was designed to help identify how people compensate and whether it is more effective to aim a rehabilitation program at the impaired muscle strength or the functional problem.

Arthritis Foundation-funded researcher involved in the study: David E. Krebs, DPT, PhD, Massachusetts General Hospital and Harvard Medical School, Boston, supported by an Arthritis Foundation clinical grant.

What was done in the study?

Fifteen older adults were randomly assigned to one of two 6-week intervention programs--either a muscle strength training program that included exercises done with resistance elastic bands, or a "functional training" program in which the participants simulated activities of daily living (such as gait, rising from a chair, and stepping) at different speeds and levels of difficulty.

Explains co-author, Donna Moxley Scarborough, MS, PT, (shown in photo), "Functional training of common daily activities aims to improve neuromuscular control of the whole body with specific focus on the individual's abilities and safety limits. Ultimately, we are hopeful that this novel approach will allow individuals to transfer newly acquired strategies of whole body movement control to other 'real life' activities." Before and after training, the researchers tested the study participants' muscle strength, gait, and energy used while walking.

What were the study results?

Both study groups had positive increases in their leg muscle strength and gait stability although the functional training group had marginally greater improvements in their muscle strength, and significant improvements in gait speed and amount of energy used. It appeared that the functional training group modified their gait to a healthier, coordinated pattern, while the strength training group simply exaggerated their maladaptive compensatory style.

What's the relevance to people with arthritis?

The study suggests that functional training not only increases muscle strength but may also improve other factors that increase a person's ability to perform tasks, e.g. balance, coordination of muscle power and control of movement. Therefore, individualized rehabilitation programs that target the person's functional limitations appear to provide greater benefit than targeting the strength impairment alone.

"Our study suggests that neuromuscular adaptations to lower extremity pathology, such as knee OA, are more complicated than traditional impairment-based 'strengthening interventions' can address. A functional-training intervention may better ameliorate the compensatory biomechanical demands placed on other joints, such as the hip," said lead author, Chris McGibbon, PhD.

Source: Arthritis & Rheumatism (Arthritis Care and Research), April 2003, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12687518&dopt=Abstract

Arthritis Foundation Researchers in the News

Thigh Muscle Strength and Knee Osteoarthritis

A recent population study suggests that strong thigh muscles may not protect and may actually worsen knee osteoarthritis (OA) in people with malaligned or lax knee joints. These results do not negate the importance of exercise for people with knee OA but do suggest the need for further research to evaluate the impact of muscle strengthening exercise programs in persons with OA and unstable knee joints, reports lead author, Leena Sharma, MD of Northwestern University, Chicago.

http://www.arthritis.org/research/summaries/quad_strength_knee_OA.asp

Staph Protein May Help Lupus

In a study funded by the Alliance for Lupus Research, Gregg Silverman, MD, at the University of California at San Diego showed that a protein produced by the Staphylococcus aureus (staph) bacteria inactivated the immune system in animals by causing specialized immune cells called B cells to commit suicide. This study suggests the potential for using the staph protein to eliminate B cells that are believed to play a major role in diseases such as lupus.

http://www.arthritis.org/research/summaries/staph_protein_lupus.asp

Impact of Pain on Children with Arthritis

Using data from daily diaries completed by children with juvenile arthritis, Laura Schanberg, MD (Duke University, Durham, NC) and colleagues found that pain was a frequent occurrence and was associated with anxiety and reduced school and social activities.

These findings suggest the need for more aggressive treatment of pain and anxiety in children to improve their function and quality of life. http://www.arthritis.org/Resources/DisplayScreamingNews.asp?id=317 Research Update is compiled by Michele Boutaugh, BSN, MPH, Medical and Scientific Affairs Department, National Office.

Source: http://www.arthritis.org/research/ResearchUpdate/03July_Aug/Printable.htm