Testimony

June 8, 2004

Good morning Mr. Chairman and Members of the Subcommittee. I am Dr. Susana Serrate-Sztein, Chief of the Rheumatic Diseases Branch in the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes of Health (NIH). The NIAMS is the lead Institute at the NIH for research on arthritis and related diseases, though 18 other agency components also support research in this area. I am pleased to have this opportunity to testify before you today to highlight recent research advances and new NIH initiatives in the field of arthritis research. While the public health burden of arthritis and related conditions is significant - at the personal, community, and societal levels - we have made notable progress in understanding these diseases and how best to diagnose, treat, and ultimately prevent them. Indeed, as the number of Americans affected by arthritis increases with the aging of the population, the research community is faced with growing challenges as well. The NIH is fully committed to meeting these new challenges, and to pursuing the many promising scientific opportunities in this area of research.

Introduction

Arthritis and related rheumatic diseases are characterized by inflammation and loss of function in one or more connecting or supporting structures of the body. These disorders especially affect the joints, tendons, ligaments, bones, and muscles. Common symptoms include pain, swelling, and stiffness that can be debilitating. Some rheumatic diseases also involve the internal organs. There are over 100 forms of arthritis and related conditions, and many of them can affect both children and adults. Research has shown that a number of these disorders are autoimmune in nature, and affect women and minorities disproportionately. Some of the more common forms include osteoarthritis (OA), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), scleroderma, and fibromyalgia.

Recent Advances

Arthritis research supported by the NIH covers a broad spectrum of basic, translational, and clinical studies, and includes funding for major research centers and research registries which serve as a national resource. By way of example, in the pediatric arena, the NIAMS funds a Multidisciplinary Clinical Research Center at the Children's Hospital Medical Center in Cincinnati which focuses on diseases such as juvenile rheumatoid arthritis (JRA), juvenile fibromyalgia, and juvenile dermatomyositis. The Institute also supports a Core Center on pediatric rheumatic diseases, and a research registry on JRA, at the Cincinnati Children's Hospital. At the Hospital for Joint Diseases in New York, the NIAMS is funding a research registry for neonatal lupus. Both the centers and the registries strengthen the overall foundation for rheumatology research across the country, and provide training opportunities for scientists who are interested in studying these often devastating diseases.

In recent years, a number of important advances have been made as a result of NIH-supported research. Highlights of these advances include:

• A better understanding of the genetics of RA, including the role of inflammation in cells lining the joints, and how these inflammatory processes contribute to joint destruction.

• The identification of biological markers that can predict rapid progression of RA, allowing physicians to develop treatment strategies based on the likely course of disease in affected patients.

• The discovery that a variation within the interleukin-6 (IL-6) gene increases susceptibility to systemic juvenile rheumatoid arthritis, the most severe type of this pediatric disease. Progress in uncovering such disease-associated genes may lead to clinically useful subgroupings for affected patients.

• New insights into the role that increased anxiety - rather than depressed mood - plays in heightening the fatigue and pain associated with juvenile arthritis. Researchers found that a comprehensive treatment approach that addresses pain and fatigue can optimize affected children's participation in school and social activities.

• A better understanding of the bone and cardiovascular changes experienced by young women with lupus. New findings indicate that women with lupus are at increased risk for both clinical osteoporosis and cardiovascular complications at a much younger age, suggesting that more aggressive treatments are needed for this population.

• The identification of a genetic "signature" in some patients with lupus who develop such life-threatening complications as blood disorders, central nervous system damage, and kidney failure.

• The discovery that scleroderma cells are resistant to factors that can normally regulate the production of collagen, a major protein component of the skin and connective tissue. The results suggest that, by targeting these factors, new therapeutics could be developed to restore a balanced collagen synthesis in scleroderma cells.

• The finding that the drug etanercept - one of the new "biologic" therapies that are designed to interfere with specific biological processes associated with rheumatic disease - alleviates the pain and stiffness associated with ankylosing spondylitis (spinal arthritis). This type of arthritis typically strikes adolescent and young adult males.

While this is by no means a comprehensive listing of critical advances, it paints a clear picture of the considerable progress that has been made through NIH's investments in this area of research.

New Initiatives

There are many exciting initiatives across the NIH in arthritis research that are building on our growing understanding of the underlying mechanisms of disease, as well as the cellular, genetic, and environmental factors involved. I will cite three examples that illustrate the promise of such initiatives to improve public health.

The Osteoarthritis Initiative

Osteoarthritis (OA) is a degenerative condition whose hallmarks are joint pain and limited movement resulting from progressive loss of cartilage. OA is the most common type of arthritis, especially among older people. Currently, there are no treatments, other than surgical joint replacement, that significantly change the course of this disease. Clinical trials for new therapies are long, difficult, and expensive.

In an effort to hasten the discovery of new biological markers for OA which can be used in clinical studies of potential treatments, the NIH launched a public-private partnership known as the Osteoarthritis Initiative (OAI). This collaboration - which includes several NIH components as well as three private sector partners - is supporting four clinical sites around the country, and a data coordinating center. These sites will recruit a total of 5,000 men and women age 45 and older and follow them for 5 years. Through the collection and analysis of biological specimens, images, and clinical data, the researchers leading the OAI hope to find markers that will, ultimately, enable doctors to identify individuals at risk for OA and people with OA at risk for disease progression.

In a related effort, the NIAMS is also supporting a new OA biomarkers network to bring together researchers to share clinical, biological, and human resources. Through this novel network, scientists will learn more about joint destruction by identifying and monitoring biomarkers in joint, bone, and synovial tissues. These efforts could provide the clues needed to better define the stages of OA on a more consistent and reliable basis.

The APPLE Trial

Systemic lupus erythematosus (SLE) is a chronic, inflammatory, autoimmune disease that can cause damage to various body tissues, including the joints, skin, kidneys, heart, lungs, blood vessels, and the brain. Studies have shown that women are much more likely to have the disease than men, and that it affects African Americans, Asians, and Native Americans more commonly than Caucasians. Children who have lupus are at higher risk for cardiovascular disease, due to the buildup of fat in the blood vessels.

To better understand this potentially life-threatening complication of lupus in pediatric patients, NIAMS is funding a study of statins - drugs used to lower "bad" cholesterol levels - to test their effects against fat buildup in the blood vessels of these children. This 5 year study, the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, will involve 280 children diagnosed with SLE. Recruitment will be facilitated by the Childhood Arthritis and Rheumatology Research Alliance (CARRA), a national network designed to enhance pediatric rheumatology studies. Researchers will use a double-blind, placebo-controlled approach to randomize patients to receive either statins or a placebo for 36 months. Atherosclerosis will be measured at baseline and at 6 month intervals using ultrasound imaging. Ultimately, the scientists hope that the statin treatment will have preventive effects on the arterial fat buildup that occurs in these young patients.

The NIH Pediatric Rheumatology Clinic

NIH's Pediatric Rheumatology Clinic, a component of our intramural research program, is a specialty-care medical facility dedicated to evaluating and treating children with pediatric rheumatic diseases who are enrolled in clinical trials. These trials may be studies of the natural history, signs, and symptoms of disease when standard treatment is given, or can include experimental treatment or diagnostic tests.

Current studies at the Pediatric Rheumatology Clinic include:

• An investigation of the most effective dosing regime of the drug infliximab, one of the new biologic agents, for children with juvenile rheumatoid arthritis. The trial will look at the safety and effectiveness of a stepwise dosing regime, rather than a fixed dose, for eligible children between the ages of 4 and 17 with active JRA who do not respond to standard therapy. The drug's effects on bone and cartilage, and whether it can improve abnormal growth, metabolism, and hormones, will also be examined.

• A pilot trial to evaluate the safety and effectiveness of the drug anakinra, another novel biologic therapy, for treating patients with neonatal-onset multisystem inflammatory disease (NOMID). This disease can cause rash, joint deformities, brain inflammation, eye problems, and learning difficulties. Immune-suppressing medicines commonly used to treat NOMID do not completely control disease symptoms and, if used for a long time in high doses, can cause harmful side effects.

Conclusion

In summary, the NIH is committed to supporting arthritis research across a broad spectrum: from basic and animal studies, to clinical trials, to prevention and behavioral investigations. We are proud of the progress that has been made since the Institute was formed in 1986, and are poised to take advantage of emerging areas of science for the benefit of affected patients.

I would be happy to answer any questions you may have about arthritis research at the NIH.