About Us

Congressional Justification Narrative
FY 2003

February 2002 (historical)

This document provides justification for the Fiscal Year 2003 activities of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), including HIV/AIDS activities. A more detailed description of NIH-wide Fiscal Year 2003 HIV/AIDS activities can be found in the NIH section entitled "Office of AIDS Research (OAR)."

The President's appropriations request of $488,228,000 for this account includes current law adjusted by assuming Congressional action on the proposed Managerial Flexibility Act of 2001.

Introduction

The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) 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. Almost every household in America is affected in some way by diseases of bones, muscles, joints, and skin. These diseases 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. In addition, many of the diseases within our mission areas are autoimmune in nature. 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 autoimmune diseases. The NIAMS has a broad portfolio of grants in autoimmunity and many other diseases. An important dimension of our mission includes 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. We are also committed to making our information accessible to the vast and diverse populations affected by the diseases within our mandate.

Science Advances and Initiatives

A Focus on Research in Children

While diseases of bones, muscles, joints, and skin affect people of all ages, the impact of chronic diseases is even more profound in children. We have much to learn about the risk factors for diseases in children as well as effective treatments for chronic rheumatic and musculoskeletal and skin diseases in children. The Institute has undertaken a number of initiatives to address these research gaps and opportunities. Highlights include:

Molecular Causes of Painful Joints in Juvenile Rheumatoid Arthritis

One of the hallmarks of rheumatoid arthritis in both juveniles and adults is the tumor-like expansion of inflamed synovial tissue, called pannus, which causes much of the joint damage in this disease. The synovial tissue is normally a thin coating on joints, but in rheumatoid arthritis the synovial cells undergo significant proliferation and inflammatory cells are brought in from the general circulation. This expansion is also supported by extensive formation of new blood vessels, which provide not only a source of nutrients for the growing pannus, but also increased access for inflammatory cells to infiltrate the synovial tissue. The molecular entities supporting this process have not been determined. Researchers at an NIH-supported Center have used an animal model that does not have a functioning immune system to detect the molecular entities in inflamed synovial tissue. Small pieces of human tissue can be grafted into these animals without rejection of the tissue. This allows the human tissue to continue functioning but in the absence of an immune response. The researchers found that synovial tissue from patients with juvenile rheumatoid arthritis readily developed new blood vessels from cells of human origin when grafted into the mice. Several key protein receptors that are associated with promotion of new blood vessels were identified. The utilization of human synovial tissue grafted into a mouse will allow the assessment of various agents to block the growth of new blood cells and to determine their effect on inflamed synovial tissue. These studies offer a new model for assessing novel treatments for rheumatoid arthritis.

Jumping Improves Hip and Spine Bone Mass in Prepubescent Children: A Randomized Controlled Trial

Developing a stronger skeleton in childhood is an important mechanism to prevent osteoporosis in later life. Exercises that produce an impact on bone have been shown to be more effective in increasing bone mass than other types of low-impact activity. For example, there is good evidence in the literature that gymnasts exhibit higher levels of bone density compared with age-matched controls. Gymnastic activities often expose the athlete to ground reaction forces of 10-15 times body weight. NIAMS-supported investigators designed a 7-month high-intensity jumping regimen that could be implemented in a regular elementary school curriculum and developed ground reaction forces of eight times body weight. The effect of jumping on hip and spine bone mass was investigated in prepubertal children between the ages of 6 and 10 years. Male and female subjects were randomized into either a jumping group or control group. The exercise involved participation during the school day 3 times per week and involved 100 two-footed jumps off 61-cm-high boxes at each session. The control group participated in nonimpact stretching exercises. Investigators determined that the jumping group had a significantly greater 7-month change in bone mineral content in both the hip and spine than controls, and positive differences in bone mineral density and bone area were observed in the jumping group as well. This study has potentially important public health implications with respect to optimizing peak bone mass attainment in young individuals. A simple jumping program offered in the prepubertal years may increase peak bone mass at 2 clinically relevant sites, the hip and spine. Such a regimen appeared both safe and effective and clearly is a program of exercise that could be incorporated into physical education programs of primary and secondary schools.

Stimulating Multidisciplinary Research

The Institute is developing an initiative that will focus on multidisciplinary translational research projects in rheumatic and immuno-inflammatory skin and muscle diseases of children. This initiative will incorporate the areas of opportunity that have been identified in research on diseases of bones, muscles, joints, and skin that present special challenges in children.

Lupus: Molecular Mechanisms of Brain Changes Revealed

Lupus is a serious and potentially fatal autoimmune disease, often occurring in women of child-bearing age. People of all races can have lupus; however, African American women have a three times higher incidence (number of new cases) and mortality than white women. They tend to develop the disease at a younger age than white women and to develop more serious complications. Nine times more women than men have lupus, and it is also more common in women of Hispanic, Asian, and Native American descent. The manifestations of lupus are diverse - it can affect many parts of the body, including the joints, skin, kidneys, heart, lungs, blood vessels, and brain. Researchers supported by the NIAMS have focused on the involvement of the nervous system in some people with lupus, and have reported significant advances in our understanding of the molecular mechanisms involved in changes that can occur in the brains of people with lupus. These researchers reported that the antibodies that attack the DNA of people with lupus can also attack molecules that bind a particular neurotransmitter (glutamate) involved in nerve cell activity. These same antibodies can cause death of the nerve cells, and they are present in the fluid of the brain and spinal cord (cerebrospinal fluid), possibly affecting brain function. While researchers had previously documented cognitive dysfunction in some patients with lupus, it was not clear what mechanism was involved in this dysfunction. This new research finding not only helps us to understand the nervous system complications in lupus, with also provides some new therapeutic possibilities for these aspects of lupus that can be quite challenging for patients, their families, and their health care providers. These researchers who were funded through our extramural program have recently come to the NIH to utilize the state-of-the-art imaging and other facilities on the NIH campus to pursue related avenues of research in brain changes in lupus. To further stimulate research in this area, the Institute recently released a solicitation for applications on neuropsychiatric lupus, in an effort to stimulate additional study of the neurological and psychiatric syndromes associated with this chronic disease, including cognitive, behavioral, affective and motor manifestations. Finally, in January 2002, the NIAMS sponsored a scientific conference on new targets for lupus therapeutics. The conference encouraged the exchange and integration of scientific information among scientists working in disparate areas of lupus and helped identify novel strategies for clinical intervention.

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. The NIAMS is encouraging research studies to evaluate risk factors for the development and progression of osteoarthritis in vulnerable populations. In addition, basic research is focusing on the development of agents that can block the degradation of cartilage cells, caused by various inflammation producing enzymes or cell-death producing enzymes. The identification of these agents as potential cartilage protective agents in cell culture will hopefully lead to their safe and efficacious use in humans.

In addition, the Institute partnered with the National Institute on Aging (NIA) in establishing a public-private partnership to develop clinical research resources that support discovery and evaluation of biomarkers and surrogate endpoints for osteoarthritis clinical trials. Following several years of effort, the NIAMS and NIA recently joined with other NIH components, including the National Institute of Dental and Craniofacial Research, the National Center for Complementary and Alternative Medicine, the Office of Research on Women's Health, and the National Center on Minority Health and Health Disparities; other Federal agencies; and four pharmaceutical companies in funding the newly launched Osteoarthritis Initiative. For the first time, a public-private partnership will bring together new resources and commitment to help find biological markers for the progression of osteoarthritis. The Osteoarthritis Initiative will fund from four to six clinical research centers to establish and maintain a natural history database for osteoarthritis that will include clinical evaluation data and radiological images, and a biospecimen repository. All data and images collected will be available to researchers worldwide to help quicken the pace of scientific studies and biomarker identification.

Osteoporosis

Osteoporosis continues to be a significant public health challenge for women and men, particularly the elderly. Reports from the Framingham Osteoporosis Study recently provided important new information on the effect of dietary protein on bone loss in elderly men and women. The role of protein in bone metabolism is an area of some controversy. Dietary protein can cause an increased acid load, which results in the transfer of calcium from bone to maintain acid-base balance. Many laboratory studies have shown that high protein intake is an important and powerful determinant of urinary calcium loss, which can in turn cause negative calcium balance and hence an increase in bone loss. However, other studies have shown that protein under-nutrition is associated with osteoporosis and that low protein intake or even protein "insufficiency" is particularly associated with frailty and fracture in the elderly population. The Framingham Osteoporosis Study recently reported on the relationship between dietary protein intake and the 4-year change in lumbar spine, femoral neck, and radial shaft bone mineral density in this population-based study. Subjects included 391 women and 224 men, and the mean age at baseline was 75 years. Results indicated that lower protein intake was significantly associated with greater bone loss at the spine and femur skeletal sites but not the radial shaft (leg), with subjects having the lowest levels of protein intake showing the highest level of bone loss. Results were consistent after adjustment for important confounding factors, which included body weight loss. The two key findings from this study were, first, that protein intake was found to be important in maintaining skeletal health in the elderly population, and second, a higher intake of animal protein did not appear to have any detrimental effects on skeletal integrity. This is an important study concerning the role of diet (particularly protein nutrition) on bone health maintenance of the aging population. The results of this study should encourage an adequate consumption of dietary protein in the elderly population and point to the potential benefits of this dietary change on skeletal health.

In addition, basic researchers have reported new insights into the complex effects of estrogen on bone. Bone breakdown, or resorption, is a normal part of bone remodeling, in which old or damaged bone is replaced with new bone. Net loss of bone, leading to osteoporosis, occurs when bone resorption exceeds new bone formation. The most common cause of bone loss is the decline in the female sex hormone, estrogen, in women after menopause. Estrogen also seems to be important for the maintenance of bone mass in men, although men have much less estrogen than the male sex hormone androgen. Yet it remains unclear just how sex hormones influence bone remodeling. It is known that many types of cells have proteins on their surfaces called receptors, which enable the cells to respond to estrogen and the male sex hormone androgen. But it is not clear just which cells are responsible for the effects of estrogen on bone, or even whether estrogen receptors are necessary for estrogen's effects. Two recent reports from NIAMS-supported researchers have provided important clues to the complex relationship between estrogen and bone, and have demonstrated that there is still much to be learned about the action of estrogen and the function of estrogen receptors. In the most surprising development, investigators have extended earlier work showing that estrogen decreases rates of controlled cell death (called apoptosis) among bone-forming cells (osteoblasts), thus increasing bone formation and preventing net bone loss. Now they find that either estrogen or androgen can have this anti-apoptotic effect, and that it can be mediated by either estrogen receptors or androgen receptors, regardless of which sex hormone is present. It appears that the effects of sex hormones on bone reflect a previously unrecognized function of the estrogen and androgen receptors, which is distinct from their familiar action on reproductive tissues. In a second report, investigators have shown that immune cells called T cells can contribute to the bone loss that occurs when estrogen levels are low through the stimulation of osteoclasts that resorb bone and thereby enhance the susceptibility to fractures.

Scientists have also continued to identify, through epidemiologic studies and through imaging studies, factors that can better predict increased fracture susceptibility. Using data from the Study of Osteoporotic Fractures (in which 7782 women were studied), a clinical assessment tool was developed that can be used by women or their physicians to assess the risk of fracture. The variables that were used to develop the tool are: age, fracture after 50 years, maternal hip fracture after age 50, weight of less than 125 pounds, smoking status, use of arms to stand up from a chair, and bone mineral density. This assessment tool now needs to be validated in additional studies. In other studies it was shown that imaging, using an MRI scan of bone, in combination with the bone mineral density determination, can enhance the prediction for fracture risk.

Progress in Research on Osteogenesis Imperfecta and Other Genetic Diseases of Bone

Genetic diseases are caused by mutated genes that either fail to produce any protein at all, or produce abnormal proteins. Osteogenesis imperfecta, one of the most common genetic diseases of bone, is caused by mutations in the gene for a protein called type I collagen. Often, an abnormal collagen protein causes more severe disease than the simple absence of the protein. In order to correct mutations that result in a deficiency of collagen, it is necessary to develop methods of introducing normal collagen genes into cells that can be permanently established in bone by transplantation. Correction of mutations that produce abnormal proteins requires the development of molecular agents that can inactivate the mutant gene. In either case, it is important that production of the introduced molecule is efficient, but restricted to bone cells. NIAMS-supported investigators have recently reported progress in both the controlled introduction of genes into bone cells and the design of agents for inactivating disease-causing mutant genes. First, they have shown that a genetically modified virus can carry a special version of the type I collagen gene into bone cells of mice. Importantly, the virus-borne gene was incorporated into the genetic material of bone cells such that it was passed on when the cells divided. Also, the protein specified by the introduced gene was produced in bone cells but not other cells, just as a normal collagen is. In a second line of work, investigators have shown that it is possible to block the production of a protein specified by a particular gene, by introducing a modified version of a naturally occurring molecule called U1 snRNA. Normally, U1 snRNA participates in the processing of messenger RNAs, which are necessary intermediates in the production of a protein. But with specific modifications of its structure, U1 snRNA instead interferes with messenger RNA processing, reducing the amount of protein produced. Most importantly, this effect can be targeted to a particular gene. In the reported work, using genes chosen for easy measurement of their protein products, investigators showed better than 90% reduction in protein production by the target genes. These results show that it is possible to introduce a gene such that its specified protein is produced only in bone cells, and that it is possible to block the production of proteins specified by genes already present in the cells. Some genetic diseases may be treated simply by introducing a gene for a missing protein. Further, by combining these techniques, it may be possible eventually to block the production of the abnormal proteins specified by some mutant genes. These approaches could apply to many genetic diseases of bone, including osteogenesis imperfecta.

The NIAMS has undertaken a number of initiatives in osteogenesis imperfecta recently. In FY 2001, the NIAMS issued a request for applications targeting new research strategies in osteogenesis imperfecta. This solicitation built on recommendations that were made at the scientific meeting in September of 1999 that was co-sponsored by the NIAMS, the NIH Office of Rare Diseases, the Osteogenesis Imperfecta Foundation, and the Children's Brittle Bone Foundation, to identify ways to expand the scope of research on OI. As a result of the request for applications, the NIAMS funded five new grants to support research activities ranging from cutting-edge gene and cell therapies to testing drug treatments in animal models.

New Insights into the Development of Arthritis

Both rheumatoid arthritis and osteoarthritis are characterized by inflammation of the joints and destruction of the cartilage in those joints. A particular enzyme (Cyclooxygenase-2 or Cox-2) is involved in the production of inflammatory molecules. The expression of this enzyme is increased in the synovial tissue in the joints of rheumatoid arthritis patients and in the affected cartilage in osteoarthritis patients. Consequently, Cox-2 has become a major target for the treatment of inflammatory diseases such as rheumatoid and osteoarthritis. However, the full physiological role of Cox-2 in the development of these diseases remains unclear. A model for rheumatoid arthritis has been developed by injecting normal mice with collagen, a major component of cartilage. These mice develop an arthritis characterized by the development of antibodies to collagen. Antibodies become deposited in the joints resulting in inflammation and swelling of the joints followed by increased numbers of lymphocytes in the joint tissue and cartilage destruction. In addition, normal mice develop arthritis when injected with antibodies against collagen from arthritic mice. To understand the role of Cox-2 in the pathogenesis of arthritis, researchers injected mice that lack Cox-2 with collagen. These animals did not produce antibodies against collagen and showed no inflammation or cartilage destruction in their joints. In addition, arthritis could not be induced in the Cox-2 deficient mice by the injection of antibodies from normal arthritic mice. In looking at the public health implications of these studies, we know that osteoarthritis and rheumatoid arthritis are common afflictions of the adult population, and that therapeutic agents alleviate discomfort and maintain function for those affected. However, the pathogenesis of these diseases remains unclear. These recent studies shed new light on the role of Cox-2 in arthritis by showing that Cox-2 is essential for the production of antibodies as well as inflammatory molecules involved in collagen-induced arthritis. Furthermore, the presence of antibodies against collagen alone does not induce arthritis. Rather, the inflammatory products of Cox-2 are also essential for the induction of arthritis.

Improved Understanding of the Muscular Dystrophies

In May 2000, the NIAMS sponsored two scientific workshops to lay the groundwork for research into the muscular dystrophies. The first workshop, sponsored by the NIAMS together with the National Institute of Neurological Disorders and Stroke (NINDS), the NIH Office of Rare Diseases, the FSH Society, Inc., and the Muscular Dystrophy Association of America, focused on the cause and treatment of Facioscapulohumeral Muscular Dystrophy (FSHD). The NIAMS and the NINDS used the recommendations from this meeting in developing and issuing a request for applications in FSHD in November 2000. As a result of this solicitation, the NIAMS and the NINDS funded six new research grants to support both basic and clinical research studies in FSHD, including studies using new genomic approaches to understand the underlying causes of FSHD as well as studies of the cellular and molecular processes that are altered in this form of muscular dystrophy. The second workshop focused on therapeutic approaches for Duchenne Muscular Dystrophy, and the NIAMS and the NINDS subsequently issued a Program Announcement, "Therapeutic and Pathogenic Approaches for the Muscular Dystrophies" in January 2001. This PA uses set-aside funds for FY 2002-2004. The Institute recently awarded several new grants that were submitted in response to this solicitation.

In other initiatives in the muscular dystrophies, the NIAMS and the NINDS continue to support a new national research registry for people with myotonic dystrophy (DM) and FSHD and their families. Registry scientists seek out and classify patients with clinically diagnosed forms of DM and FSHD, and store their medical and family history data. The registry is also a central information source where researchers can obtain data for analysis associated with these diseases. This national registry is an important resource for scientists to collect and analyze new research data for better treatments for these two diseases, as well as hasten the course of research for more in-depth answers to what causes the muscular dystrophies.

Skin Biology and Diseases

Skin research has lagged behind in two key areas - common vocabulary to describe skin diseases and a sufficient cadre of clinical investigators being trained in dermatology. The Institute has partnered with the Herzog Foundation to address both of these areas of need. We recently awarded a contract to develop a national and international dermatology lexicon for use by the entire research community, and have also developed a fellowship program in epidemiology and health services research and outcomes research in skin diseases. Finally, we have broadened our Multidisciplinary Clinical Research Centers so that they may include studies in skin.

Genetic and Molecular Basis of Pseudoxanthoma Elasticum

Pseudoxanthoma Elasticum (PXE) is a systemic inherited disorder that involves the elastic tissue in the skin, eyes and cardiovascular system. It can result in severe and even fatal health problems or may be much milder and clinically difficult to identify unless suspected and pursued vigorously. It is often not visible early in life but, in more severe cases, may manifest in childhood. It had been classically considered a genetic disorder of a structural component, but with the discovery of the gene that is defective in the disease, it is now becoming apparent that this disease actually is a metabolic disorder in which the structural component is secondarily affected. A consortium of investigators localized the gene underlying PXE a little over a year ago. This gene encodes for a protein that underlies multiple drug resistance in microorganisms but appears to have the function of transporting materials through the membrane of human cells. In a recent study, affected individuals from four families were investigated to determine the specific genetic defects underlying the disease in that family. The four families were from different ethnic backgrounds, yet the specific defect in all four families was exactly the same. The fact that all four families had the identical defect implies that this is a genetic "hot spot" and possibly that the same mechanism of mutation leads to this uniformity of mutation in different families. The recognition that this is a metabolic disease offers new hope for the development of treatment based on metabolic modifications potentially including such things as diet manipulation or drug therapy. The isolation of the gene and the cataloging of the gene defects underlying the disease, particularly in families where there has been one identified member, will allow the early identification of affected individuals so that treatment can be instituted before the development of signs or symptoms of the disease and, hopefully, early enough to prevent such signs and symptoms from ever developing.

Chronic Wounds: Epidemiology and Treatment

Chronic wounds are a major public health problem. They particularly affect the elderly and people with certain predisposing diseases, such as diabetes mellitus. Studies of drugs meant to influence and improve wound healing are difficult to do because the FDA requires complete wound closure as the endpoint. This is not only often difficult to achieve but also can take many months. Validation of markers that appear earlier in the course of wound treatment and correlate with an eventual successful result would improve our ability to conduct such studies. Similarly, epidemiologic studies of chronic wounds that identify predisposing factors would allow identification of higher risk individuals. Changes in routine care for these individuals could prevent the development of some of these chronic wounds and, therefore, prevent this major health problem. A meta-analysis (an analysis of a number of already published articles in which the data are combined to produce more statistically significant results) of diabetic foot ulcers and a multicenter study of venous leg ulcers demonstrated that standard care would result in wound healing if the wounds were small or of brief duration. Large or long standing wounds were not likely to heal within the twenty week time period. In another study of diabetic foot ulcers, individuals treated with a living skin substitute, Graftskin, showed a significant increase in wound healing and decrease in time to complete closure as compared to control-treated wounds. Adverse reactions were similar in both groups except that osteomyelitis (infection of the underlying bone) and lower-limb amputation, major adverse results of chronic ulcers, were less frequent in the Graftskin group. In a preclinical study, the use of gene transfer of growth factors incorporated into viral vectors (modified viruses used to carry the gene into the skin) increased granulation tissue (the first tissue response in the wound healing process), blood vessel formation and skin covering of the wound, all indications of enhanced wound healing. These large scale clinical trials and meta-analyses of prior trials indicate that it should be possible to predict the outcome of wound healing studies without waiting for complete closure of the wounds. This should shorten the trials and save money. In addition, they demonstrate the importance of selection of patients when trying to distinguish between those individuals who can be put on standard conservative therapy and those for whom newer or more aggressive treatments should be considered. Newer technologies such as artificial skin equivalent systems can improve the success rate and the rate of healing of existing wounds and minimize or reduce the incidence of severe complications.

Story of Discovery: Medical Research Changed Lives for Pemphigus Patients

It would be difficult to overstate the importance of our skin in our lives. It keeps vital organs and life-sustaining fluids inside our bodies and environmental toxins outside our bodies and works continuously to regulate body temperature on hot and cold days. Our skin is also the first thing people notice when they meet us, so blistering and other changes in our skin can have devastating psychological consequences. As well, a number of skin diseases can be fatal. While there are thousands of skin diseases catalogued to date, one of the most clinically challenging is pemphigus - challenging both for patients and for the doctors who treat them. Research over a number of years has resulted in a better understanding of the underlying causes of pemphigus, improved diagnosis, and more effective treatments. Medical research has also resulted in a dramatic reversal in the view of a patient diagnosed with pemphigus. A few decades ago, in the era before corticosteroids and immunosuppressive agents were used, the diagnosis of pemphigus meant facing the grim reality that this disease was fatal in the vast majority of affected people. Today, with the advent of more selective drug treatments, pemphigus is fatal in less than 10 percent of affected people. The intervening years were filled with stories of basic, clinical, and translational research studies that have laid the foundation for the much more optimistic view for people affected by pemphigus. The following overview highlights some of these stories of progress.

Pemphigus is a group of blistering diseases of the skin and mucous membranes. Left untreated, the disease is usually fatal. If we begin the story of progress in 1964, researchers successfully applied a new technique called immunofluorescence to the study of pemphigus. Their results provided the first suggestion that pemphigus is an autoimmune disease, a category of puzzling diseases in which the body comes to recognize some of its own components as foreign, and launches an attack on those components. Having the information that pemphigus is part of the constellation of diseases that are autoimmune in nature has enabled researchers to target their laboratory studies on immune function as well as to apply research advances in other autoimmune diseases to pemphigus.

Research on pemphigus has been multi-pronged. Basic research has included studies of the structure and function of the molecules in the skin that are the actual target of the autoantibody attack in this disease. Research into the underlying causes of pemphigus was initially limited by the lack of an animal model of this disease. NIAMS grantees addressed and overcame this limitation with the development of an animal model created by the injection of antibodies from human patients with pemphigus into newborn mice. The mice then developed blisters that were indistinguishable from those seen in people with pemphigus. This model system was valuable both in establishing that the antibodies could cause the blisters as well as providing a model system for better understanding of the disease itself.

Once researchers knew that antibodies are the likely cause of this disease, they then focused their studies on the particular molecules in the skin that were the target for these antibodies. Researchers were able to identify that two particular molecules - desmoglein 1 and 3 - are the ones attacked by antibodies in different forms of pemphigus. Functionally, these molecules are part of the structure that works to keep skin cells attached to each other. When these molecules are disrupted, skin cells lose their attachment to each other, intact skin is disrupted, and blisters characteristic of pemphigus develop.

With the isolation and proof of the specific molecules that were the target of the antibodies, a kit was devised in which isolated and purified molecules are directly reacted with blood specimens from the patient to provide a simple, rapid and sensitive test for pemphigus. This rapid diagnosis can be performed in almost any commercial laboratory and replaces the previous specialized, expensive, and relatively slow tissue-based diagnostic procedures that had been the standard for many years.

Research has also shown that certain ethnic groups are more susceptible to pemphigus, and studies have focused on what other factors are related to disease occurrence beyond the molecules in the skin that have been identified. A particular type of pemphigus that occurs in high frequency in the rain forests of Brazil has provided valuable information on the potential role of environmental agents as the trigger for the development of pemphigus in genetically susceptible populations. This is one of the first lines of evidence implicating a specific environmental factor as the trigger of an autoimmune disease.

Finally, looking to treatment implications of research, we know that treatment is primarily based on suppressing the immune system. This is a risky and potentially dangerous course for patients. Not infrequently in the past, patients had such serious side effects from immunosuppression that they died of complications from the treatment rather than from the disease itself. Now that we have a better understanding of the immune system as well as of the specific targets in this disease, newer treatment modalities have been introduced into clinical practice with the promise of better control of disease with fewer adverse side effects. A key area of current research is to refine these treatment modalities even more to target the particular molecules involved in the disease process.

Forty years ago, a person diagnosed with pemphigus faced the reality that they had a disease that was rare, usually fatal, poorly understood, and for which there were no good treatment options. Through medical research supported by the NIH, the picture is dramatically different today. We know the targeted molecules in pemphigus, we can much more easily and effectively diagnose patients at a substantially reduced cost, and we have far better treatment options to offer affected people. As with almost all research stories, this one also is a work in progress. The promise of research being conducted today is that each aspect of the disease - understanding, diagnosis, and treatment - will be even more improved in the future. Each of these dimensions is the focus of active research supported by the NIH today. The powerful tools that are the outcome of the molecular genetic revolution hold promise for even more effective treatment in the near future, and the identification of environmental triggers may eventually allow primary prevention of some or even many cases of pemphigus even in people who are genetically predisposed. This continuum of studies provides a fascinating story of discovery, as well as hope and benefit for affected people - medical research at its best.

Intramural Research Program

There has been exciting growth in the Intramural Research Program of the NIAMS recently and we are launching promising initiatives in a number of key areas. Highlights include:

Trans-NIH Collaboration in Musculoskeletal Medicine

The NIAMS recognized the opportunity we have to make a significant difference in the field of musculoskeletal medicine. In the spirit of focusing expertise in bone and cartilage biology, the NIAMS joined with our colleagues in the National Institute of Dental and Craniofacial Research, the National Institute of Child Health and Human Development, and the National Institute on Aging in focusing resources in this area. This trans-NIH effort will build on the strengths that are already present and are beginning to be coordinated, enhance research productivity through synergy of the programs, develop new programs, recruit new investigators, coordinate with existing and newly developed clinical programs, and make it possible to create a national resource in this critical and under-served area of research.

This collaborative effort will encompass state-of-the-art and innovative fundamental science, clinical studies, and translational research. It will provide a focus for a wide array of basic and clinical research on bone and cartilage medicine, development, genetics, and musculoskeletal disease. In addition, NIH scientists will explore and advance the application of the emerging discipline of tissue engineering for reconstituting damaged skeletal components; establish a facility that would serve as a scientific resource for a broad spectrum of investigators on the NIH campus, around the country, and around the world; and provide leadership in both research training and education in the full array of basic, clinical, and translational research related to the musculoskeletal system.

There are many disciplines that are currently involved with musculoskeletal research, as well as numerous others that have the potential to make contributions in this area. Examples of these disciplines include cellular and molecular biology, biochemistry, genetics, cell and tissue engineering, bioengineering, biology, developmental biology, morphology, signal transduction, muscle biology, orthopaedics, rheumatology, endocrinology, immunology, biological imaging, protein structure and proteomics, protein function, electron microscopy, biomechanics, pathology, research training, clinical applications, and translational studies. Currently there is no forum at the NIH for scientists from these many disciplines to come together and focus their skill and expertise on the myriad unsolved questions in research on the musculoskeletal system. Diseases to be addressed include: osteoarthritis, osteoporosis, fibrous dysplasia, osteogenesis imperfecta, low back pain, temporomandibular joint disorder, and genetic diseases of cartilage and bone, among others.

Creation of the New Cartilage Biology and Orthopaedics Branch

The NIAMS is very pleased to have recruited an internationally recognized scientist in cartilage research to head this new Branch. We are currently recruiting a scientist to head our orthopaedic program, recognizing that there is a need for new orthopaedic interventions in clinical care and currently there is no orthopaedics program on the NIH campus. As protocols for tissue regeneration and for skeletal gene therapy and other areas are developed, it is essential that there be an established orthopaedic program and active involvement of orthopaedic surgeons in these protocols, to facilitate tissue harvesting, clinical evaluation of the efficacy of candidate tissue-engineered cartilage products, and most importantly, the translation of laboratory findings to clinical applications. The orthopaedic program will interface with our colleagues in the greater Washington D.C. area, including those at the National Naval Medical Center. This arrangement should lead to the amplification and enhancement of these existing programs. The intention is also to create a training environment for orthopaedic surgeons that would serve as a strong attractant for outstanding individuals to the field of orthopaedic surgery as well as provide them with high quality research training.

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.

Health Partnership Program

One unique strategy that the NIAMS devised and implemented to address health disparities is the Health Partnership Program. In the first phase of this program, we implemented a model community-based research program to study rheumatic diseases in the African American and Hispanic/Latino communities in the metropolitan, Washington, D.C. area.

In addition, through collaborations with community leaders, we have created and opened the new NIAMS Community Health Center in a medically under-served area of Washington, DC. This new Center provides researchers with the opportunity to (1) increase understanding of health disparities in rheumatic diseases, (2) provide health care to the community, (3) increase participation of minorities in research studies, (4) increase the number of underrepresented biomedical researchers, and (5) train NIAMS rheumatology fellows to care for patients from minority communities. The health center opened in July 2001. Patients are seen under the Natural History of Rheumatic Diseases protocol, which is conducted by investigators from the Institute's Intramural Research Program. Researchers expect to develop related health disparities studies based on outcomes of the Natural History protocol. In addition, health education is an important component of the program that includes developing brochures and factsheets and conducting arthritis education seminars.

The goals for the first phase of the HPP are to (1) increase awareness and understanding of rheumatic diseases and the importance of early detection and treatment in preventing complications and chronic disabilities associated with these diseases, (2) increase awareness of and access to clinical investigations on rheumatic diseases, (3) increase the number of underrepresented minority investigators at the NIAMS and in the biomedical research fields related to rheumatic diseases, and (4) evaluate the impact of providing access to and medical care for patients who have rheumatic diseases.

Initiating a Program in Clinical Research Training at Minority Serving Institutions

Minority institutions have had difficulties developing and sustaining independent clinical research, and there is a shortage of ethnic minority clinical researchers who are pursuing successful clinical research careers. The NIAMS, in partnership with several other NIH components, created a new strategy for enhancing clinical research training in minority-serving institutions. The first phase, funded in FY 2001, was a solicitation for a one-year planning grant, and the second phase is a 5-year grant to assist in the actual development of the clinical research curriculum, with funding in FY 2002 and beyond. A successful program will produce well-trained clinical researchers who can lead clinical research projects.

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 2003 budget request for the NIAMS is $488,228,000, including AIDS, an increase of $37,988,000 and 8.4 percent over the FY 2002 level.

A five year history of FTEs and Funding Levels for NIAMS are shown in the graphs below. Note that Fiscal Years 2000 and 1999 are not comparable for the Managerial Flexibility Act of 2001 legislative proposal.

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. The Fiscal Year 2003 request provides average cost increases for competing RPGs equal to the Biomedical Research and Development Price Index (BRDPI), estimated at 4.0 percent. Noncompeting RPGs will be funded at committed levels which include increases of 3 percent on average for recurring direct costs.

Future promises for advancement in medical research rest in part with new investigators with new ideas. In the Fiscal Year 2003 request, NIAMS will support 270 pre- and postdoctoral trainees in full-time training positions, the same number as in FY 2002. Stipend levels for NRSA trainees will increase by 4 percent over Fiscal Year 2002 levels.

The Fiscal Year 2003 request includes funding for 37 research centers, 183 other research grants, including 60 clinical career awards, and 39 R&D contracts. The R&D contracts mechanism also includes support for 9 contracts for the Extramural Clinical Loan Repayment Program. Intramural Research and Research Management and Support receive increases of 9 percent over FY 2002.

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

FY 2003 Budget Mechanism pie chart.
Bar chart showing FY 2003 Estimate Percent Change from FY 2002 by Mechanism.