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Testimony on National Institute of Arthritis and Musculoskeletal and Skin Diseases' FY 1998 Budget by Dr. Stephen I. Katz
Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institutes of Health
Accompanied by
Dr. Steven J. Hausman, Deputy Director, NIAMS
Ms. Margaret S. Kerza-Kwiatecki, Executive Officer, NIAMS
Ms. Robyn J. Strachan, Budget Officer, NIAMS
and
Dr. Harold Varmus, Director, NIH
Mr. Dennis P. Williams, Deputy Assistant Secretary, Budget, DHHS

U.S. Department of Health and Human Services

Before the House Appropriations Committee, Subcommittee on Labor, Health and Human Services, Education and Related Agencies
March 5, 1997

I am very pleased to have the honor of appearing before this Committee as the Director of the National Institutes of Arthritis and Musculoskeletal and Skin Diseases. I consider it a privilege to have the opportunity to represent the staff of the Institute and to tell you about the exciting science in our research areas. The diseases within our mission areas are common, costly, chronic, and crippling, and they compromise daily life for many Americans. Virtually every family in our country is affected in some way by diseases of muscles, bones, joints, and skin. We have made progress in our understanding of and approaches to these diseases and have launched promising initiatives to address research opportunities. I am delighted to share highlights of our research progress as well as our plans.

Osteoarthritis is the most prevalent disease of the joints. It takes a staggering toll in human suffering and economic costs. Osteoarthritis and related disorders accounted for more than half of all total hip replacements and 85 percent of all total knee replacements in the most recent analysis. We know that Americans over the age of 65 represent the fastest growing segment of the population, and it is predicted that osteoarthritis will affect at least 70 percent of this population, an astounding number of Americans. Despite its frequency, osteoarthritis remains a condition that is poorly understood and for which few treatments are available. The NIAMS has initiated a multi-pronged approach to understanding and treating osteoarthritis.

Osteoarthritis is characterized by progressive degeneration of the cartilage. It can affect any joint, but it primarily affects hip and knee joints. It can be caused by a variety of genetic, biochemical, and biomechanical factors, but the precise mechanisms by which these various factors cause the disease are unknown. Recent research results have provided some fascinating clues to help understand and develop approaches to the prevention and treatment of osteoarthritis. Highlights include the finding in elderly menopausal women that oral estrogen significantly reduced their risk of osteoarthritis of the hip, the report that the normal cellular compound nitric oxide may promote tissue damage in cartilage and that control of this compound may provide an opportunity for therapy, and the research indicating that dietary factors may play an important role in the treatment of osteoarthritis of the knee.

A major advance in the treatment of osteoarthritis is total joint replacement, in which the damaged joint surfaces are replaced with metal and/or plastic components. These joint replacement procedures have generally been regarded as an effective means of reducing the pain and functional limitation associated with severe osteoarthritis, the underlying cause of at least 60 percent of these surgeries. A NIAMS-supported study verified the cost effectiveness of total hip replacement for osteoarthritis. In addition to the actual cost savings, there is a marked improvement in functional abilities and quality of daily life in the people with total hip replacements. However, total joint replacements are not without their problems, including concerns for the effects of the implant on the body. There is concern that a patient may develop osteolysis, the virtual disappearance of bone around the implant, resulting in the need for costly revision surgery. The NIAMS is supporting research to understand why this happens in some individuals and to improve the design of the prostheses used in joint replacements. The NIAMS is also exploring the utility of nonsurgical approaches to osteoarthritis. Since previous studies indicated that certain antibiotics, such as doxycycline, inhibit the enzymes that degrade cartilage, the NIAMS is co-sponsoring an ongoing clinical trial on the effects of the antibiotic doxycycline on osteoarthritis.

The NIAMS continues our strong commitment to support studies on autoimmune diseases, including many arthritic and skin diseases. Genetic studies have provided important clues about systemic lupus erythematosus. Previously reported studies have identified genetic factors that predispose African-Americans to the severe kidney complications of systemic lupus erythematosus. During the last year, NIAMS-supported researchers identified, in mouse models of lupus, seven to ten regions in DNA that are linked to the disease. Some features of human lupus are readily apparent in these animal models. In addition, exciting new research findings indicate the first evidence linking a particular chromosomal region to systemic lupus erythematosus. The results to date suggest that systemic lupus erythematosus susceptibility genes are very similar in mice and humans, and that these same genes may be important in all racial groups. Building on these research opportunities, NIAMS-supported researchers have recently initiated further studies to locate the susceptibility genes in patients with systemic lupus erythematosus. The identification of these genes and their functions will provide a framework for understanding the basis of this disease as well as developing effective treatments. In another study initiated by the NIAMS, researchers are studying minority populations with systemic lupus erythematosus, including African-American and Hispanic people. Specifically, a number of factors -- including sociodemographic, psychosocial, immunologic, and immunogenetic -- are being investigated to determine their effect on the course and outcome of systemic lupus erythematosus in these minority populations. The results of this study will provide important insights into this disease and help reduce the morbidity and mortality associated with this disease, which disproportionately affects women, particularly African-American women.

To gain insights into possible causes of rheumatoid arthritis, researchers in the NIAMS intramural program and their colleagues studied rats with an autoimmune inflammatory arthritis that resembles human rheumatoid arthritis. Through genetic analyses of rats with different disease susceptibilities and severity, the researchers found that the genetic basis in the inflammatory arthritis bore a striking similarity to what is known about the genetics of rheumatoid arthritis. Multiple genes are involved in both diseases making it more complicated to discover the causes of the disease and to design effective therapies. The most significant aspect of the recent findings is that researchers have located several of the particular genes that affect arthritis susceptibility and severity in rats. Underscoring the significance of these research results, one of these genetic loci has been previously linked to other autoimmune diseases and may play a role in the phenomenon of autoimmunity. Future studies will focus on identifying the specific gene or genes in each of the regions that are involved in determining arthritis severity or susceptibility. Identifying these genes will provide important new information on the causes of inflammatory arthritis in rats and strong leads for identifying the genetic and biochemical bases of rheumatoid arthritis and other autoimmune diseases in humans. To provide a particular focus on the genetic aspects of rheumatoid arthritis, the NIAMS began support in FY 1997 for the newly formed North American Rheumatoid Arthritis Consortium. This Consortium will comprehensively study the genetic aspects of rheumatoid arthritis in a national project involving 800 sibling pairs affected with rheumatoid arthritis. This study is expected to provide important information about rheumatoid arthritis. Finally, the NIAMS has taken the initiative in developing a roundtable forum consisting of the major participants interested in rheumatoid arthritis and osteoarthritis -- the NIH, the FDA, and representatives from industry, academia, and voluntary and professional groups. The goal of this forum is to facilitate interactions among the diverse groups involved in rheumatoid arthritis research and to identify potential opportunities for therapeutic approaches to rheumatoid arthritis and osteoarthritis.

Osteoporosis is the leading cause of bone fractures in postmenopausal women and older people in general, and it is characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures of the hip, spine, and wrist. One reason that the condition is much more common in women is the decrease in estrogen levels following menopause. The clinical actions of estrogen in postmenopausal women and the mechanism of action of estrogen on bone cells have both been a major focus of NIAMS-supported research. The NIAMS was a co-sponsor of the NIH Postmenopausal Estrogen/Progestin Intervention trial which reported this year that postmenopausal women taking hormone replacement therapy gained significant amounts of bone mass at the hip and spine. Older women, women with low initial bone mineral density, and those with no previous hormone use gained the most bone. Since not all women are suitable candidates for estrogen replacement, it is important to determine the mechanism of estrogen action and to devise alternative therapies. The effects of estrogen are complex, and there is much to be learned about the biochemical pathways by which it acts. In recent research results, investigators have shown that estrogen induces "programmed cell death" in the cells (osteoclasts) that are responsible for the degradation of bone. This discovery opens up an exciting new avenue of research opportunities for investigators to discover whether other drugs can also affect the programmed cell death of osteoclasts, making them potentially useful as bone-protecting treatments.

Our understanding of many skin diseases is increasing significantly as their genetic bases are being identified. In a significant advance in our understanding and treatment of skin cancer, scientists have identified the gene involved in basal cell (skin) cancers, the most common human cancer. Specifically, scientists have discovered that mutations in the human version of a gene that controls growth and development of the 'skin' of fruit flies are the likely cause of both basal cell nevus syndrome (a rare inherited disorder that is accompanied by many, many skin cancers), and acquired basal cell carcinomas of the skin. This work in genetic medicine identifies a new gene that is important in human development as well as in tumor suppression, and may lead to novel, non-surgical treatments for basal cell carcinoma.

I would be remiss if I did not speak briefly about the extraordinarily stimulating environment in which the NIAMS operates. The NIH is a very collegial research enterprise where collaborations are encouraged. The NIAMS has been a partner with many institutes at the NIH as well as the Office of the Director components focused on women's health, minority health, behavioral sciences, and dietary supplements. This has increased our scientific and fiscal ability to undertake initiatives and has been a real benefit to our research portfolio.

Our research areas are broad and diverse. While that clearly presents a number of challenges for our Institute, I believe that there are many benefits. Progress in one research area serves to inform other areas as well. We have all witnessed the power of genetics to advance our understanding of fundamental biologic processes and their role in disease. The advances made in our understanding of bone and connective tissue hold analogous promise. Diseases that affect these tissues have the capacity to profoundly alter quality of life. Significant strides have been made in our understanding of diseases of bone, joints, muscles, and skin, and I am confident that the initiatives I have shared with you will do much to advance our knowledge of fundamental life processes and how they go awry in disease. The goal remains as always -- to improve the health of the American public -- to reduce the burden of disease and to enrich the quality of life for ALL Americans.