About Us

Congressional Justification Narrative
FY 2001

February 2000 (historical)

Authorizing Legislation: Section 301 and Title IV of the Public Health Service Act, as amended. Reauthorizing legislation will be submitted.

Budget Authority:

  FY 1999 Actual FY 2000 Estimate FY 2001 Estimate Increase or Decrease
BA $301,293,000 $344,458,000 $363,479,000 +$19,021,000
FTE 174 187 200 +13

Introduction

This document provides justification for FY 2001 Non-AIDS activities of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Justification of NIH-wide FY 2001 AIDS activities can be found in the NIH section entitled, "Office of AIDS Research (OAR)."

The National Institute of Arthritis and Musculoskeletal and Skin Diseases supports basic, clinical, and epidemiologic research, research training, and information programs on many of the more debilitating diseases affecting the American people. Most of these diseases are chronic and many cause life-long pain, disability, or disfigurement. They afflict millions of Americans, cause tremendous human suffering, and cost the United States economy billions of dollars in health care and lost productivity. These diseases include the many different forms of arthritis and numerous diseases of the musculoskeletal system and the skin that affect people of all ages, racial and ethnic populations, and economic strata. Many of the diseases within our mandate disproportionately affect women and minorities, who, in many cases, also suffer worse outcomes. We are committed to uncovering the bases of these gender, racial, and ethnic disparities and to devising effective strategies to treat or prevent them. Almost every household in America is affected in some way by arthritis, musculoskeletal diseases, or skin diseases.

In addition to the many studies supported by the NIAMS, we have also implemented a number of creative approaches to enhance collaborations beyond the Institute. We have leveraged our funds by teaming with other components of the NIH as well as with many voluntary and professional organizations. This has both budget and scientific implications -- not only are we able to support more research projects, but such collaborations provide the expertise and public involvement of the patient and professional groups with whom we partner. In addition, we often team with our colleagues in other institutes of the NIH to issue research solicitations -- sending signals to the scientific community of areas of particular opportunity and need, and encouraging them to develop research proposals to address these areas. We are also active participants in a number of NIH-wide initiatives, such as the BECON (the NIH bioengineering consortium), as bioengineering has significant implications for a number of areas within our mission.

Finally, we are committed to a comprehensive program of information dissemination to patients and to their health care providers. Research advances are of limited value if they never reach the arena of health care, and they miss the goal of improving public health for all Americans. The NIAMS supports information dissemination through three primary means: the Institute's Office of Communications and Public Liaison in the Office of the Director, the National Institute of Arthritis and Musculoskeletal and Skin Diseases Information Clearinghouse, and the NIH Osteoporosis and Related Bone Diseases ~ National Resource Center. In addition, we work closely with many voluntary and professional societies to both learn their needs and views and to disseminate our research findings to them. We have also targeted our information to particular areas of need (including "Lupus: A Patient Care Guide for Nurses and Other Health Professionals" and "What Black Women Should Know About Lupus") and to diverse populations (including printed information and our toll-free information line in English and in Spanish). We will continue to build and strengthen these relationships with the community and will strive to make our information accessible to the vast and diverse populations affected by the diseases within our mandate.

Science Advances and Initiatives

A Focus On Clinical Research

The promise of improved understanding, diagnosis, treatment, and prevention of diseases is based on the ability of scientists to translate basic research and apply the findings to improving health. Highlights of some of these translational research efforts in bone, muscle, joints, and skin follow. For example, we have learned that doses of estrogen that are lower than ordinarily prescribed can be effective in preventing osteoporosis, that proteins essential for normal muscle formation can be produced by injecting genes into muscles containing defective proteins, that new treatments for rheumatoid arthritis can be directed at disease-causing targets that were identified in basic and animal studies of rheumatoid arthritis, and that normal hair growth is under the control of genes that encode proteins that can be targets for new therapeutic developments.

With the generous increases in our appropriation, the NIAMS has been able to support more clinical research in all of its scientific areas. Highlights of five significant clinical research initiatives include (1) pilot studies in rheumatic diseases and skin diseases: these innovative studies include expanded research on some of the most difficult challenges in public health, including leg ulcers, rheumatoid arthritis, scleroderma, lupus, spondylitis, and others where new research approaches are being developed; (2) osteoporosis in men: a seven-year study that will enroll and then follow 5,700 men 65 years and older for an average of 4 to 5 years, and will determine the extent to which the risk of fracture in men is related to bone mass and structure, biochemistry, lifestyle, tendency to fall, and other factors. The study will also try to determine if bone mass is associated with an increased risk of prostate cancer; (3) combination therapies for osteoporosis: we are supporting research to determine whether combinations of the drugs (such as bisphosphonates, parathyroid hormone, and estrogen) available for osteoporosis will be more effective and have fewer side effects than any of the drugs alone; (4) treatment of back pain: surgical versus nonsurgical treatment of three back disorders will be studied in 1,450 patients at 11 medical centers in a 5-year study. Researchers at these centers will compare the two treatment approaches in patients who have a herniated (bulging) lumbar disc, spinal stenosis (narrowing of the canal through which the spinal cord passes) or degenerative spondylolisthesis, where a vertebra in the spine slips forward out of place. This project is expected to have a major impact on clinical practice and on the cost of medical services for persons with one of these three back disorders; and (5) the Spondylitis Consortium: The NIAMS has established the North American Spondylitis Consortium to search for genes that determine susceptibility to ankylosing spondylitis, a painful inflammatory disease of the spine. Ankylosing spondylitis is also known as arthritis of the spine, and it causes inflammation of the tendons and ligaments around the bones and joints in the spine. The result is pain and stiffness, especially in the lower back. The consortium is made up of researchers from 10 research centers and staff from the Spondylitis Association of America with a background in clinical and genetic research in ankylosing spondylitis. They hope to learn more about genes that play a role in the disease, and plan to collect medical information and genetic material (DNA) from 400 families nationwide. The goal is to develop new approaches for the diagnosis and treatment of ankylosing spondylitis as a result of identifying the genes that make people susceptible to this disease.

As the above examples illustrate, clinical research has significantly improved public health and holds the promise to enhance quality of life even more. We will also continue our commitment to clinical research training to ensure a solid pipeline of investigators trained to conduct these studies.

Muscle Diseases

Profound changes and challenges are faced by the people affected by muscle diseases. Many of these diseases have their bases in genetic alterations, and NIAMS-supported scientists are actively striving to overcome the barriers to effective gene therapy of muscle diseases. It is important to target gene delivery to muscle and control its expression. Such manipulation in skeletal muscle should aid therapy for muscle diseases (for example, Duchenne muscular dystrophy and Facioscapulohumeral muscular dystrophy). In a recent advance in muscle gene therapy, researchers have reported that gene therapy restored muscle mass in aging mice. We already know that muscle strength decreases up to one-third in humans between ages 30 and 80. The risk for falls increases with age, and with less muscle cushioning the vertebrae and the hip area, the impact of a fall is taken much more directly by the bones that might fracture. Researchers supported by the NIAMS are using gene therapy to help the body fight the seemingly inevitable effects of aging or to give it a hand in repairing the damage caused by injury or muscle-wasting disorders like muscular dystrophy. These findings have potential applicability for a broad range of people including those who have suffered a bad burn or severe muscle tears from sports injuries, those on missions in space or immobilized for an extended period because of an accident, and those who have particular muscular dystrophies because it may lead to better treatments for these disorders.

In another study, gene therapy has been shown to restore muscle function in limb-girdle muscular dystrophy. Limb-girdle muscular dystrophies are caused by genetic mutations that disrupt a critical protein complex on muscle membranes called the sarcoglycan complex. The sarcoglycan complex links components of the extracellular matrix to the inside of the muscle cell. Limb- girdle muscular dystrophy is recognized as a group of conditions distinct from Duchenne muscular dystrophy (characterized by mutations in the dystrophin gene), but because the genes for the sarcoglycans are considerably smaller than those for dystrophin, researchers have considered them as a test case for gene therapy in muscle. Researchers have developed a technique that successfully produces widespread transfer of corrective genetic material into muscle cells throughout an entire limb. Using hamsters with a naturally occurring form of limb- girdle muscular dystrophy caused by a defective sarcoglycan subunit, the researchers were able to deliver viruses carrying a normal gene for the defective subunit. The result was stable supranormal expression of the sarcoglycan subunit gene, and muscles that expressed the replacement gene were fivefold less likely to be damaged during forceful contractions than the original defective cells. Successful stable gene transfer after either intramuscular or intravascular administration in mature hamsters provides a strong rationale for using virus-derived vectors to treat genetic muscular diseases.

In other research results related to muscular dystrophy, a commonly used antibiotic restored normal protein production in a mouse model of muscular dystrophy. NIAMS-funded scientists (co-funded by the Muscular Dystrophy Association) have successfully used the antibiotic gentamicin to restore the function of the protein dystrophin in mouse models of Duchenne muscular dystrophy. It is the absence of dystrophin which is responsible for this genetic muscle-wasting disease that affects 1 in 3,500 boys1. The result of this study was that dystrophin was restored to the cell membranes of all the striated mouse muscles they examined. Furthermore, the treatment afforded the muscles protection against injury. This discovery may pave the way for a treatment in some patients with Duchenne muscular dystrophy. To further advance our understanding of the pathology, diagnosis, and treatment of patients with muscular dystrophies, we are planning to support workshops in Duchenne muscular dystrophy and Facioscapulohumeral dystrophy in FY 2000, and to identify areas of scientific opportunity in the study of these diseases.

Osteoarthritis

Osteoarthritis is the most common disease of joints. Also known as degenerative joint disease, osteoarthritis occurs when cartilage begins to fray, wear, and decay causing joint pain, reduced joint motion, and loss of function and disability. As the number of older people in our population continues to grow, osteoarthritis can be expected to affect more of the American public. Scientific opportunities to prevent OA are increasing as more modifiable risk factors are being identified. The NIAMS has taken a multi-pronged approach to addressing the many facets of osteoarthritis, including (1) Assessing the role of physical activity in the development of osteoarthritis: Known as a "wear-and-tear" disease, osteoarthritis is associated with physically demanding activity. Researchers using participants in the Framingham Study found that individuals who engaged in more than 4 hours of heavy physical activity per day were 7 times more likely (13 times, if obese) to develop knee osteoarthritis than individuals who did no heavy physical activity. Fortunately, walking and light physical activities, usually recommended for older individuals, did not contribute to increased risk of osteoarthritis. The finding suggests that excess force on otherwise normal joints contributes to the cartilage degradation characteristic of osteoarthritis and could lead to better exercise recommendations for those suffering from osteoarthritis. (2) Studies on grip strength and hand osteoarthritis: Investigators examining the association between the occurrence of hand osteoarthritis and maximal grip strength found that women are two times more likely to have hand osteoarthritis than men. Because hand osteoarthritis is common in older Americans, research on risk factors could have preventive implications. and (3) Support for a major conference in July 1999 of scientists and patients with osteoarthritis: The conference participants reviewed the current state of the science regarding the prevention of onset and progression of osteoarthritis and the disability it causes, and received critical input from experts currently working in the field; examined various prevention interventions targeted to the general public, to people who have osteoarthritis, and to those at higher-than-average risk of developing osteoarthritis; identified promising opportunities for further investigation; and stimulated scientific collaboration, as well as provided public information on treatment and prevention strategies for osteoarthritis. This was a true multidisciplinary conference and was of interest to researchers and practitioners in orthopaedics, rheumatology, epidemiology, rehabilitation, prevention, and health education, as well as patients and their families. (4) The NIAMS has joined with the National Institute on Aging in attempting to create a public-private partnership to identify biomarkers for osteoarthritis. We have been joined by other NIH components, the Food and Drug Administration, pharmaceutical companies, and medical organizations in constructing this partnership. The goal is to support clinical and laboratory evaluations of biomarkers and imaging techniques as potential surrogate endpoints for clinical trials that assess the efficacy of osteoarthritis disease-modifying interventions.

Joint Replacements

Over 241,000 hip replacements and over 245,000 knee replacements2 are performed each year in the United States for end-stage arthritis, usually osteoarthritis. A complication of total joint replacement can be osteolysis, the disappearance of bone around the implant in response to the presence of microscopic wear particles. In a living mouse model, researchers demonstrated that tumor necrosis factor (TNF), a substance that modulates cell functions, is essential to development of wear particle-induced osteolysis. This finding sets the stage for development of pharmacologic or biologic treatments that target TNF and thus prevent the disappearance of bone around orthopaedic implants.

Imaging Technologies

In other research in orthopaedics, researchers are using a novel imaging technology to identify joint disorders and assess their progression. Optical coherence tomography is a new method of imaging capable of detecting small structural changes that occur in tissues during the earliest stages of disease. The resolution of the optical coherence tomography system is nearly tenfold greater than the resolution of any available clinical technology. In addition to its high resolution, several features make optical coherence tomography attractive for joint imaging: it is optical fiber based, allowing easy integration with an arthroscope, an instrument for the examination of the interior of a joint; it is compact and portable, making it well suited for an outpatient setting; it is "noncontact," allowing imaging to be performed through air or a transparent medium; it can be performed at high speeds, allowing information at the cellular level to be obtained from throughout the joint; and it can be used in combination with other techniques, providing biochemical and structural information from tissue. Using normal and osteoarthritic cartilage specimens, investigators demonstrated the usefulness of this technology to detect structural abnormalities in cartilage, including changes early in the pathogenesis of osteoarthritis and before loss of cartilage thickness (narrowing of the joint space, as seen by radiography). Optical coherence tomography represents a promising new technology for detecting cartilage abnormalities through ultrahigh-resolution joint imaging. Refinement of this technology and its ultimate clinical use may permit early diagnosis of degenerative joint disorders, evaluation of disease severity and progression, and enhanced understanding of pathological processes within joints.

Osteoporosis

Osteoporosis, a major threat for 28 million Americans3, is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures-especially of the hip, spine, and wrist. It is the most prevalent of the bone diseases that affect Americans. Although American women are four times as likely to develop osteoporosis as men, an estimated one-third of hip fractures worldwide occur in men. Men tend to develop osteoporosis about 10 years later in life than women. This difference has been attributed to a higher peak bone mass at maturity and to a more gradual reduction in sex steroid influence in aging men. As noted earlier in the section on Clinical Research, the NIAMS has launched a major study of osteoporosis in men. The lifetime risk of older men for fractures of the hip, spine, or wrist is considerable, and the Institute is committed to providing a particular focus on osteoporosis in men, in addition to its extensive portfolio of research on osteoporosis in women.

In other exciting reports from clinical research, we learned from a clinical trial testing the efficacy of daily low-dose estrogen plus progesterone in older women (over the age of 65), that significant increases in spine, forearm, and total body bone mineral density were found in the women on low-dose estrogen. Because estrogen is currently the first line of defense for osteoporosis and has known side effects, it is critical to use the lowest effective dose that will preserve and even add bone. This study provides important proof of the concept that low-dose estrogen can be an effective preventive and therapeutic option.

Researchers have also conducted studies of hormone therapy in men, including testosterone supplements in older men. Circulating levels of testosterone are known to decline in older men as they age, leading to bone loss. A recent clinical trial of testosterone supplementation in a group of older men with low natural hormone levels revealed very little difference in bone mineral density between the placebo- or testosterone-treated men when the groups were compared as a whole. Only men with the lowest initial testosterone levels increased their bone density by 5 percent, indicating that hormone therapy to replace bone mass is not necessary for most older men.

Osteoporosis is known to have a genetic component, but genes associated with fractures themselves had not previously been found. Osteoporotic hip and wrist fractures may be partially rooted in a gene on chromosome 19, according to a study funded by the NIAMS and other NIH components. Scientists have found that older women with the gene for apolipoprotein E (APOE*4) are at increased risk for hip and wrist fractures. Previous studies of this gene have also shown its association with common, late-onset forms of Alzheimer's disease and with osteoporosis in patients on dialysis. The study showed that the risk of hip and wrist fractures for women age 65 and over with the APOE*4 gene was nearly twice that of those without the gene, even after making adjustments for bone density, cognitive level, or tendency to fall. Women with at least one APOE*4 gene were more likely to have a maternal history of fracture after age 50. Scientists have long suspected that these types of fractures are due to more than a single factor, and this finding provides evidence of a specific genetic influence at work even when weak bones and balance problems are not at issue. The APOE*4 gene might involve the following factors in increasing risk for hip and wrist fractures: (1) Vitamin K: People with the gene may have reduced levels of this substance, which stimulates bone formation and reduces bone-cell loss; (2) Alzheimer's disease: People with this disease have a higher risk of hip fracture, and the APOE*4 gene has now been found to have connections to both; (3) Weight loss: Women with the gene experience greater weight loss than those who do not have it. Weight loss contributes to bone loss, which could affect fracture risk.

To bring a focus to the research needs and opportunities in bone diseases, the NIAMS sponsored two scientific workshops in September 1999: (1) on osteogenesis imperfecta; and (2) to explore the relationship between osteoporosis and vascular calcification, following up on the research findings that osteoporosis assessed around the time of menopause was associated with a higher risk of cardiovascular disease in later years. In March 2000 the NIAMS and other NIH components will hold a Consensus Development Conference on Osteoporosis that will address five key questions: what is osteoporosis and what are its consequences; how do risks vary among different segments of the population; what factors are involved in building and maintaining skeletal health throughout life; what is the optimal evaluation and treatment of osteoporosis and fractures; and what are the directions for future research. The goal of these conferences is to bring a focus to scientific opportunities that can be pursued in bone biology and bone diseases.

Exercise and Sports

Along with the tremendous growth in women's participation in sports and other fitness activities has come an increase in female sports injuries. The NIAMS is working to raise awareness of the need for greater attention to women's health in sports and exercise, and shed light on future directions for research and sports injury prevention. A scientific workshop was held in June 1999, cosponsored by the NIAMS and the American Academy of Orthopaedic Surgeons, with participation by the Women's Sports Foundation. The objectives of this workshop were to define the current knowledge base concerning the involvement of women in sports and fitness activities at all ages, to profile the injuries that are prevalent in women, to highlight the most fruitful areas for research on the prevention and treatment of such injuries, and to attract new investigators to research on women's health in sports and exercise. Among the key points from the meeting was the report that injury rates tend to be sports specific, and some injuries such as anterior cruciate ligament injuries are more common in women than in men. According to the National Collegiate Athletic Association injury surveillance system, soccer and basketball have the highest game injury rates among female sports and a higher risk of serious injury relative to men playing these sports. Gender differences were apparent in knee injuries, anterior cruciate ligament injuries, and stress fractures. Following this workshop, the Institute conducted a briefing for members of Congress, the media, and the American public in the summer of 1999, timed to coincide with the Women's World Cup Soccer events in Washington, DC, and with the first month of the season of the Women's National Basketball Association. Cosponsors of the briefing were the NIH Office of Research on Women's Health, the Office on Women's Health of the Department of Health and Human Services, the President's Council on Physical Fitness and Sports, the Centers for Disease Control and Prevention, the National Osteoporosis Foundation, and the Arthritis Foundation.

Skin Diseases

Skin gene therapy is an area of great promise. The skin is unique in its accessibility for gene therapy approaches, both for skin diseases and for the use of the skin as a factory for the production of molecules in the treatment of systemic diseases including hormones such as insulin and human growth hormone. Skin provides a number of advantages, including the ability to remove genetically altered skin by simple excision if problems develop. Some particularly promising areas of research include development of gene therapy-based interventions. The NIAMS is supporting a conference in March 2000 to increase the level of interest in the field of gene therapy using skin and to identify scientific opportunities and needs in this area.

Epidermolysis bullosa and other blistering skin diseases

The physical connection between the epidermis and dermis (the two outermost living layers of skin) is mediated by a large number of molecules interacting in the basement membrane zone (the area between these two layers) of skin. Some of these molecules are within the basal cell layer of the epidermis, some are within the electron microscopic basement membrane zone, and others are in the upper dermis. In a recent study, researchers used a molecular genetic approach to isolate a molecule implicated in blistering skin diseases, studying how it interacts with other molecules and functions as an attachment molecule. Understanding the interactions that underlie the physical connection between epidermis and dermis could lead to design of therapeutic interventions for autoimmune blistering skin diseases such as bullous pemphigoid and genetic diseases such as epidermolysis bullosa.

Alopecia areata

Alopecia areata is an autoimmune disease, and it is one of the most common forms of acquired hair disease (excluding male pattern baldness). There has been a vast increase in scientific findings related to the normal structure and function of hair, its embryologic development, its cycling (moving between growing and resting phases), and defects in both genetic and acquired diseases. This knowledge has derived from the many advances in the molecular biology of the keratins (structural proteins of the hair), and, somewhat unexpectedly, from information concerning adhesion molecules in the skin (molecules that are involved in the attachment of the layers of skin to one another), as well as from a variety of other basic research findings in both human biology and in naturally occurring and transgenic (genetically altered) mouse model systems. Recent research reveals that a molecule that functions as an intracellular adhesion molecule, beta-catenin, also functions in a signaling process involved in the development of hair follicles. When this beta-catenin was inserted into epidermal cells, the genetically altered mouse skin in adult animals underwent a process resembling new hair development. The follicles, however, were disoriented and defective in certain signaling and polarization processes (which ensure normal hair cycling and the hair shaft pointing in the right direction), and proliferation continued unchecked, resulting in tumors that look like hair-follicle tumors seen in humans. These findings indicate that it may be possible to initiate new hair formation in adult animals.

Autoimmunity

Basic research has tremendously improved our understanding of what factors - both within and outside the body - trigger the body to recognize parts of itself as foreign. Clinical research has dramatically improved our ability to treat people with these puzzling diseases. The NIAMS has a broad portfolio of grants in autoimmunity, including studies in rheumatoid arthritis, scleroderma, lupus, vitiligo, and many other diseases. As a result of additional funds that were provided by Congress in FY 1999 for autoimmunity research, the Institute was able to initiate several new research projects including (1) pilot trials on innovative therapies for rheumatic and skin diseases, including a multicenter clinical trial involving oral administration of a small peptide in treating rheumatoid arthritis, and a multicenter clinical trial testing the ability of a fibrous protein collagen to induce tolerance in patients with scleroderma; (2) target organ damage in autoimmune diseases, including a study of abnormalities in connective tissue fibers of people with scleroderma; a project looking at why certain anti-inflammatory signaling proteins do not reduce inflammation of the joint lining in rheumatoid arthritis; an investigation of the roles that blood vessel malfunction, cell death, and autoimmunity play in scleroderma; and a study of mechanisms that lead to growth malfunction in cells lining the joints of people with rheumatoid arthritis; (3) an autoimmune rat repository and transgenic resource -- a central NIH resource and development center for rat models of autoimmune disorders affecting many organ systems; and (4) NIAMS data registries that will collect information on neonatal lupus and expand our juvenile rheumatoid arthritis registry to pursue genetic susceptibility studies. We were pleased to participate in the autoimmunity initiative and look forward to the research findings from these new studies that will benefit the many patients with autoimmune diseases.

Lupus

Systemic lupus erythematosus (SLE) or lupus is a multisystem autoimmune disease primarily affecting women of childbearing age. Many organs can be involved, including skin, joints, heart, lungs, the nervous system, and kidneys. Symptoms wax and wane, and range in severity from mild to life-threatening. Antibodies that recognize various parts of the cellular machinery are found in patients with lupus. Such autoantibodies are markers of lupus and may be involved in causing specific organ damage. Therapeutic interventions in lupus are generally directed toward nonspecific immune suppression and are associated with significant morbidity and toxicity. In an exciting advance in basic research on treatments for lupus, mice treated with short peptides (protein fragments) derived from nucleosomes (a component of cells and a common target for lupus autoantibodies) prior to the development of signs of lupus had delayed onset of lupus kidney disease and lower urinary protein excretion. Animals treated with peptides once kidney disease was already established showed prolonged survival and halting of the progression of their renal disease. It appears that the mechanism responsible for the effectiveness of this treatment rests in preventing B cells from making antibodies. The antibodies made to nucleosomes and other host molecules are thought to be important in the development of the kidney failure that occurs in lupus. The implications of this work are novel and important in that they may serve as a therapeutic option to treat patients with established lupus, especially those with lupus nephritis (kidney disease). Lupus nephritis is among the most severe, life- and livelihood-threatening manifestations of this disease. Therapies for lupus nephritis are currently limited in scope, nonspecific in targeting, and associated with significant toxicity and morbidity. Autoantigen-derived peptide therapy may prove to be a specific, targeted, and relatively less toxic therapy.

In genetic studies of lupus, researchers have found an association between the disease and a region on chromosome 1. Fine mapping of this region has identified another candidate gene involved in immune function, specifically in the processes of DNA repair and cell death-both of which have been reported to be abnormal in lupus. Studies of the genetics of lupus allow identification of at-risk individuals prior to development of disease, potential therapeutic strategies targeting the involved genes or gene products, and the possibility of developing markers of disease activity and/or response to treatment. In addition to the many body systems involved, patients with lupus also have a higher risk of neuropsychiatric manifestations and accelerated atherosclerosis. In FY 1999 the NIAMS sponsored workshops in both of these areas and we intend to follow-up on the recommendations from these two meetings.

Fibromyalgia

The NIAMS has targeted fibromyalgia as a priority area for the past several years. In FY 1999 the Institute and several other components of the NIH funded a number of new clinical and basic research grants in fibromyalgia. The new NIAMS-funded studies include: (1) insomnia behavioral therapy for fibromyalgia patients, a prospective, randomized clinical trial to test whether cognitive behavioral therapy will improve insomnia in patients with fibromyalgia; (2) employment and health status among women with fibromyalgia, exploring the relationships among paid work, family work, daily stress and psychological health among women with fibromyalgia; (3) noradrenergic dysfunction: a model of fibromyalgia pain, to develop a rat model of fibromyalgia pain by manipulating the release of substance P, a chemical involved in the transmission of pain signals via the nervous system; (4) chronic low back pain as a model of fibromyalgia, examining the relationship of pain sensitivity to clinical outcome and physiological and psychosocial factors in both fibromyalgia and low back pain; (5) exercise-induced changes in hypothalamic-pituitary axis activity in fibromyalgia, a clinical project that will attempt to determine whether aerobic exercise benefits patients with fibromyalgia by enhancing the hypothalamic stimulus of pituitary and adrenal gland function; (6) outcomes in young women with fibromyalgia, a pilot project to develop a model to plan early intervention strategies that minimize disabilities and maximize health status in young women with fibromyalgia; and (7) a controlled family study in patients with fibromyalgia, to determine the prevalence of irritable bowel syndrome, migraines, chronic fatigue syndrome and mood disorders in first-degree relatives of patients with fibromyalgia. It will explore whether a common risk factor or pathophysiologic mechanism exists among affected family members. The study will compare the results with those obtained in families of people with rheumatoid arthritis.

The NIAMS currently supports a broad portfolio of research on fibromyalgia. Research ranges from efforts examining hormonal abnormalities associated with fibromyalgia, to projects on how specific brain structures are involved in the painful symptoms of the disease, to investigations of the causes of a post-Lyme disease syndrome as a model for fibromyalgia. Both the ongoing and the new research studies were designed to increase understanding of the specific abnormalities that cause and accompany fibromyalgia, with the hope of developing better ways to diagnose, treat, and prevent this disorder.

Intramural Research Program

The NIAMS is at a particularly exciting juncture in the life of its Intramural Research Program. With the appointment of a new Scientific Director and the recruitment underway for a new Clinical Director, we are planning to enhance the strong programs already established in our intramural program and to develop new programs. One example of a strong and productive research program is the work on Familial Hibernian Fever. NIH intramural scientists had previously led an international consortium in cloning the gene for Familial Mediterranean fever (FMF), a hereditary disorder of fever and inflammation common among people of Jewish, Arab, Armenian, and Turkish ancestry. After the FMF gene was identified, it became clear that some families with the characteristic periodic fevers did not have FMF mutations. NIAMS intramural researchers and their collaborators from around the world have discovered genetic mutations on chromosome 12 underlying a newly recognized group of inherited inflammatory disorders that includes Familial Hibernian Fever. The disorders, collectively known as TRAPS (TNF Receptor-Associated Periodic Syndrome), are characterized by long, dramatic, episodes of high fever; severe pain in the abdomen, chest, or joints; skin rash; and inflammation in or around the eyes. Mutations involving a cell surface receptor for the inflammatory protein tumor necrosis factor have been identified in these patients. These results mark the first time that TNF receptor mutations have been tied to an inherited disease. This discovery may lead to additional treatments, targeted at the cellular level, for many immune-related and inflammatory disorders. Researchers are now studying the potential usefulness of synthetic forms of the TNF receptor in suppressing inflammation in affected patients. Fortuitously, a drug recently approved for the treatment of rheumatoid arthritis is in fact the soluble form of a related TNF receptor. Researchers will now determine the potential usefulness of this drug in treating patients with TRAPS. Currently, many patients are treated with high doses of corticosteroids, which can have serious side effects and are not completely effective. Researchers are hopeful that the discovery of TNF receptor mutations will help provide more specific direction to the treatment of these patients.

With regard to new areas to be developed, the NIAMS Intramural Research Program will be significantly enhanced by the planned additions of a new focus on autoimmunity and by a new laboratory in cartilage biology and osteoarthritis. These will be important additions to work underway on the NIH campus and are meant to serve as resources for scientists across the country. We also anticipate that the intramural program will continue to serve as a strong training ground for the next generation of scientists.

Health Disparities

Many of the diseases within the mission of the NIAMS affect minorities and women disproportionately - both in increased numbers and increased severity of the diseases. We are committed to finding and addressing the factors that account for these disparities. Four examples will be cited of diseases that account for health disparities: lupus, scleroderma, osteoarthritis, and vitiligo. Nine times more women than men have lupus. It is also three times more common in African American women than in white women, and is more common in women of Hispanic, Asian, and Native American descent. Considerable research has been focused on addressing the relationship of socioeconomic, demographic, cultural, immunogenetic, and clinical variables to the course of disease and outcome in Hispanic, African-American, and Caucasian lupus patients. A study supported by the NIAMS since 1993, Lupus in Minority Populations: Nature vs. Nurture, demonstrated that Hispanic and African-American lupus patients have more severe disease at the time of presentation than Caucasian patients. The study also found that genetic and ethnic factors appear to be more important than socioeconomic determinants in influencing disease activity at the onset of disease.

Scleroderma is an autoimmune disorder that occurs much more frequently in women than in men. The hallmark of scleroderma is widespread hardening of the skin. In addition, many forms of scleroderma involve tissues in the lungs, heart, kidneys, intestinal tract, muscles, and joints. In severe cases, scleroderma can be fatal. Although the cause is unknown, researchers believe that both environmental and genetic factors play a role in scleroderma. While scleroderma affects members of all ethnic groups, it is particularly prevalent in certain Native American people.

Osteoarthritis is another disease in which ethnic differences have been noted -- African Americans have a higher risk of both bilateral radiographic knee osteoarthritis and hip osteoarthritis than Caucasians. Obesity is associated with bilateral knee and hip osteoarthritis and is a more important risk factor for bilateral knee osteoarthritis in African-Americans than in Caucasians. In addition, studies have shown that African-Americans have much lower rates of total knee replacement than Caucasians, even when adjusted for age, sex, and insurance coverage. The NIAMS is encouraging research studies to evaluate risk factors for the development and progression of osteoarthritis in vulnerable populations. Furthermore, the Institute recently sponsored a workshop on the prevention of onset, progression, and disability of osteoarthritis, with sessions aimed at researchers and clinicians, as well as health educators and patients with osteoarthritis. Information and insights from these efforts may lead to the identification and development of potential interventions to treat or prevent osteoarthritis.

Vitiligo is a disease of the skin that is characterized by a loss of pigment in all people who are affected. The psychological and social consequences are particularly profound in people of color who are affected.

The NIAMS is expanding its commitment to better understanding health disparities. The objectives of this initiative are: (1) to understand the genetic and non-genetic factors related to susceptibility and severity of disease in especially vulnerable populations, and (2) to develop new approaches to understanding the epidemiology and prevention of rheumatic and skin diseases, especially as they affect minority populations. Plans are underway for a workshop to address these and other opportunities for research in this area.

Alternative Medicines

There is substantial interest on the part of the American public in alternative therapies, particularly for people suffering with chronic diseases of bones, muscles, joints, and skin. The first U.S. multicenter study to investigate the dietary supplements glucosamine and chondroitin sulfate for knee osteoarthritis has been awarded by the National Center for Complementary and Alternative Medicine (NCCAM) in collaboration with the NIAMS. A 4-year research contract was awarded to coordinate a nine-center effort to study the effectiveness of glucosamine and chondroitin sulfate, two natural substances found in and around the cells of cartilage, in over 1,000 patients with osteoarthritis of the knee. The goal is to determine the effectiveness of glucosamine and chondroitin sulfate in reducing pain and improving knee function in patients with osteoarthritis of the knee, and the hope is that the results will provide solid evidence of the benefits and safety of this treatment and help to expand health care options for patients affected by this major public health challenge.

In other research on alternative medicines, researchers have reported that green tea products show anti-inflammatory activity in mouse models. Rheumatoid arthritis is an example of an inflammatory condition affecting joints, resulting in pain and, over time, destruction of joints. In a recent study, investigators fed an antioxidant-rich organic fraction isolated from green tea to mice before inducing an inflammatory arthritis in the mice. They found that mice fed green tea products were significantly less susceptible to the development of inflammatory arthritis when compared to mice not fed these products. This research suggests that identification of common dietary substances capable of affording protection or modulating the onset and severity of arthritis may be used in the future to treat or prevent rheumatoid arthritis.

Story of Discovery

A Brighter Future for People with Lupus as a Result of Medical Research

When patients hear a diagnosis, the reaction is typically a mix of relief and anxiety. The relief comes as the symptoms they have been experiencing finally have a name. The anxiety comes as they explore the implications of the diagnosis and look to the future. Twenty-five years ago, women - and it usually is women - who were diagnosed with systemic lupus erythematosus (SLE) or lupus faced a future that was uncertain, but clouded. Today, a patient with lupus faces an altogether different prognosis for a whole variety of reasons. The underpinning for all of those reasons is advances through medical research. The story of discovery in lupus is one of the most exciting stories from a patient perspective, as the following highlights illustrate.

Lupus is an autoimmune disease that can affect many parts of the body, including the joints, skin, kidneys, heart, lungs, blood vessels, and brain; it is a serious public health problem that mainly affects young women. The disease often starts between the ages of 15 and 44. Nine times more women than men have the disease. It is also three times more common in African American women than in Caucasian women, and is more common in women of Hispanic, Asian, and Native American descent. African-American women tend to develop the disease at a younger age than Caucasian women and to develop more serious complications.

The primary reason for the optimism for the future of lupus patients comes from seminal studies from the NIAMS Intramural Research Program that determined that treatment with immunosuppressive drugs (cyclophosphamide and prednisone) can prevent or delay kidney failure due to nephritis, one of the most serious common complication of this disease. NIAMS clinical investigators continue to study and refine treatment regimens for lupus nephritis.

Although the cause of lupus is unknown, applied genetics have dramatically improved the pace of research by NIAMS-supported investigators for discovering the genes that contribute to lupus susceptibility, severity, and mortality. Using experimental animal models of lupus, investigators are uncovering the genetic factors involved. NIAMS-supported researchers identified, in mouse models of lupus, 7 to 10 gene regions that are linked to the disease. Some features of human lupus are readily apparent in these animal models. Recently, researchers have found an association between lupus and a region on chromosome 1. Fine mapping of this region has identified another candidate gene involved in immune function, specifically in the processes of DNA repair and cell death-both of which have been reported to be abnormal in lupus. The results to date suggest that lupus susceptibility genes are very similar in mice and humans, and that these same genes may be important in all racial groups. In addition, the identification of genetic risk factors in lupus could indicate which patients may potentially develop severe disease and therefore merit early, aggressive treatment. Recent studies yielded two such risk factors--absence of the C4a gene and changes in the Fc receptor gene. C4a and the Fc receptor are involved in the removal of proteins known as immune complexes, which, if not removed, stay in the body and cause tissue injury.

In other approaches to lupus, the NIAMS, the NIH Office of Research on Women's Health, and the NIH Office of Research on Minority Health are co-funding the first clinical trial on the safety of estrogens for women with lupus. At the present time, women with lupus are usually advised not to take any medications that contain estrogen in the belief that it will worsen their disease or cause problems with blood clotting. This leaves women limited options for contraception during child-bearing years and for hormone replacement therapy during postmenopausal years. These studies will focus on the effects of oral contraceptives on disease activity in women with lupus and on the effects of hormone replacement therapy with estrogen and cyclic low-dose progestins in postmenopausal women with lupus. Many of the patients recruited for this trial are minority women. The outcomes of this trial are expected to have a major impact on the treatment options, health, and quality of life for patients with lupus.

With regard to modifiable risk factors for health outcomes in patients with lupus, we know that patients with chronic diseases have poorer outcomes when they have low socioeconomic status. Socioeconomic status includes such factors as education, employment, occupation, income, insurance, and access to medical care. Several studies have found an association between lower socioeconomic status and higher morbidity or mortality in black patients with lupus. In a large multicenter study, lupus disease activity and health status were most strongly associated with potentially modifiable psychosocial factors such as self-efficacy for disease management. Cumulative organ damage was most highly associated with clinical factors such as age and duration of disease. None of the outcomes measured was associated with race. These results indicate that education and counseling, coordinated with medical care, might improve outcomes in patients with lupus. Psychosocial interventions were also suggested whereby patients could increase their role as self-advocates in the management of their lupus.

Information dissemination is a vital dimension to the work of the NIAMS. We have recently joined with NIH and health voluntary partners in publishing "Lupus: A Patient Care Guide for Nurses and Other Health Professionals," that will be a valuable tool and resource for nurses and all health professionals who work with lupus patients. We have also targeted our information to particular areas of need and to diverse populations (including printed information and our toll-free information line in Spanish and in English). We will continue to strive to make our information accessible to the vast and diverse populations affected by lupus and other chronic diseases.

In summary, the NIAMS has undertaken research on multiple fronts. Our long-term investment in research has meant that a young person who has lupus today faces a much brighter future than even 25 years ago. Significant progress has been realized over even the last decade from the investment in research on lupus. Through research, we have learned much more about the causes of lupus, we have improved diagnostic abilities, the treatments are significantly better than in the past, and newer treatments are on the horizon, taking advantage of emerging areas of science.


Conclusion

Bones, muscles, joints, and skin are central components of the human body. We now understand better how they develop and function normally, and how they are altered in disease. We now know much more about the roles of genetics, the environment, diet, and behavior in disease. Perhaps most noteworthy, we are making significant progress in our efforts to prevent disease in the first place. The ultimate conquest of diseases always involves research across a broad spectrum -- from basic to animal models to clinical trials to prevention research. In most cases, the essential ingredient is the translation: clinical research without the basic foundation is very limited in scope and effectiveness, and basic research that is not translated into clinical studies misses the opportunity to improve public health. Stories of the interplay of research across many disciplines, across the full spectrum -- stories of progress and promise supported by the NIAMS are stories of which we are proud.

For years, people have believed that chronic disease was an inevitable companion to many lives and could not really be prevented. We now know that neither of these beliefs is necessarily true. The NIAMS supports scientists who are making significant inroads in developing strategies for chronic disease prevention, and Americans are claiming the expectation and promise of good health and quality of life. In addition, as people are living longer lives, they are seeking strategies to maximize their quality of life and minimize the impact of the many chronic diseases that can compromise that quality of life. The research stories that have been told give testimony to a central truth: medical research has made a genuine difference in the lives of all Americans. Considerable progress has been made in alleviating many of the physical and social consequences of chronic diseases, and the investigations underway and planned promise to continue to improve life.

Since the NIAMS was established, significant progress has been realized from the investment in research on arthritis and musculoskeletal and skin diseases. We are on the brink of discoveries that can revolutionize health care and the treatment of chronic illnesses. NIAMS-supported researchers are today uncovering important pieces of the research puzzle and are launching initiatives to take advantage of emerging areas of science. NIAMS research has ramifications for this generation and generations to come. We are investing in the future health of our nation, and American people of all ages and population groups will benefit from these investments.

Budget Policy

The Fiscal Year 2001 budget request for the NIAMS is $363,479,000, excluding AIDS, an increase of $19,021,000 and 5.5 percent over the FY 2000 level. Included in this total is $9,500,000 for the following NIH Areas of Special Emphasis: New Approaches to Pathogenesis --$5,000,000; New Avenues for the Development of Therapeutics-$2,500,000; Genetic Medicine-$1,000,000; and Health Disparities-$1,000,000.

A five year history of FTEs and Funding Levels for NIAMS are shown in the graphs below:

FTEs by Fiscal Year.
Funding Levels by Fiscal Year.

One of NIH's highest priorities is the funding of medical research through research project grants (RPGs). Support for RPGs allows NIH to sustain the scientific momentum of investigator-initiated research while providing new research opportunities. To control the growth of continuing commitments and support planned new and expanded initiatives, the Fiscal Year 2001 request provides average cost increases of 2 percent over Fiscal Year 2000 for competing RPGs. Noncompeting RPGs will receive increases of 2 percent on average for recurring costs. This strategy will ensure that NIH can maintain a healthy number of new awards, especially for first time researchers.

Promises for advancement in medical research are dependent on a continuing supply of new investigators with new ideas. In the Fiscal Year 2001 request, NIAMS will support 252 pre- and postdoctoral trainees in full-time training positions. Stipends will increase by 2.2 percent over Fiscal Year 2000 levels.

The Fiscal Year 2001 request includes funding for 36 research centers, 121 other research grants, including 28 total clinical career awards, and 33 R&D contracts.

The mechanism distribution by dollars and percent change are displayed below:

FY 2001 Budget Mechanism pie chart.
Bar chart showing FY 2001 Estimate Percent Change from FY 2000 by Mechanism.

# # #

1Emery, AE. Population frequencies of inherited neuromuscular diseases-a world survey, Neuromuscular Disorders 1991; 1(1):19-29

2American Academy of Orthopaedic Surgeons: Musculoskeletal Conditions in the United States, Second Edition, 1999.

3National Osteoporosis Foundation: 1996 and 2015 Osteoporosis Prevalence Figures. Washington, DC: National Osteoporosis Foundation, January 1997.