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Congressional Justification Narrative
February 2003 (historical)
Authorizing Legislation: Section 301 of the Public Health Service Act, as amended. Reauthorizing legislation will be submitted.
|FY2002 Actual||FY2003 Amended President's Budget||FY2004 Estimate||Increase or Decrease|
This document provides justification for the Fiscal Year 2004 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 2004 HIV/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 (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 and disfigurement. These diseases include the many different forms of arthritis and other rheumatic diseases and numerous disorders 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 the mission of the NIAMS have a disproportionate impact on women and minorities. The NIAMS is committed to uncovering the bases of these gender, racial, and ethnic disparities and to devising effective strategies to treat or prevent them.
A Focus on Research Progress
The budget increases provided by Congress over the last few years have made a tremendous difference in the studies we have been able to launch, particularly clinical research and clinical trials addressing complex biological issues as well as the expansion of vital scientific infrastructure in a creative way. As stewards of these funds, we have worked with a wide range of advisers, both from the scientific community as well as from the lay public, to ensure that we were targeting areas of greatest scientific opportunity. In addition, we worked to undertake studies that could either be done solely or better by the Federal government. Examples of these investments include: (1) launching a large multicenter study of the epidemiology of osteoporosis in men; (2) initiating a study of combination therapies for the treatment of osteoporosis; (3) embarking on a large controlled study comparing surgical and nonsurgical treatments for various forms of back pain; (4) starting the Spondylitis Consortium to assess the complex genetics of spondyloarthropathies; (5) creating and funding the Osteoarthritis Initiative, a large public-private partnership to develop a research resource for the study of osteoarthritis; (6) initiating a large controlled study to assess the ability of statins to alter the course of cardiovascular disease in children with lupus; (7) launching studies of the genetics of complex diseases including a number of skin diseases, rheumatoid arthritis, lupus, and many others; and (8) initiating a number of strategies to stimulate increased research focus on the muscular dystrophies.
Within our Intramural Research Program, we have created and are developing a new Cartilage Biology and Orthopaedics Branch as well as a trans-NIH collaboration in musculoskeletal medicine that will be located at the National Naval Medical Center. We are also focusing more of our intramural efforts on autoimmune diseases like lupus erythematosus and various forms of arthritis in children. While we know that the results of some of these studies may not be known for several years, if we look at research progress today we see the yield from investments made over the last several years. Assessing progress over this time continuum reveals the value of long-term investments in science with the constant and overarching goal of improving public health. We are proud of the stories of research progress that we have the opportunity to present below, and we are pleased to highlight some of the research opportunities and areas of need that we have identified. We have targeted special initiatives to send a signal to the scientific community that there are both particular needs and scientific opportunities in these areas. Many of the targeted areas are described below. What follows are highlights of stories of progress and promise and new scientific initiatives.
Arthritis and Other Rheumatic Diseases
The NIAMS and the National Institute on Aging have joined with several other institutes and centers, and four pharmaceutical companies in launching the Osteoarthritis Initiative, a public-private partnership aimed at developing clinical research resources that support the discovery and evaluation of biomarkers and surrogate endpoints for osteoarthritis clinical trials. This is a seven-year project that will recruit 5,000 men and women aged 50 and above who are at high risk for developing symptomatic knee osteoarthritis. Four clinical sites and one data coordinating center have been selected to establish and maintain a natural history database 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. It is expected that this consortium can serve as a model for future endeavors that link the public and private sectors.
Among the many mysteries of health disparities is the fact that no one knows exactly why more African Americans die of systemic lupus erythematosus (or lupus) and develop more severe complications, such as kidney failure, compared with people of European descent. NIAMS-supported researchers are studying the inherited component of lupus in order to identify the specific genes that predispose African Americans to develop lupus. Using DNA, researchers have investigated the linkage patterns in African American and European American families, and have determined that African Americans have different genetic risks for developing lupus - a region of chromosome 1 is associated with the development of lupus in African American families. They also identified two regions of chromosome 11 associated with lupus in subsets of the African American families. In European American families, researchers found a genetic linkage near the top of chromosome 4 that contributes to lupus. These results suggest that the genetic origins of lupus may differ in African Americans and European Americans, and may help explain why sometimes the disease has a more severe prognosis in African Americans.
In other news related to lupus, the NIAMS recently launched a prevention trial in cardiovascular lupus in children. We know that women with lupus have a significantly increased risk for cardiovascular complications, and children do as well. We have funded researchers to uncover the bases for these life-threatening complications. In addition, we have launched a study that will evaluate whether the long-term complications of cardiovascular disease in childhood lupus can be prevented. The data on cardiovascular and lipid abnormalities in children with lupus implicate atherosclerosis as an important potential source of long-term morbidity and mortality. The trial is designed to test the efficacy of statins (cholesterol-lowering agents) in delaying progression of atherosclerotic arterial thickening in children with lupus. Not only do statins decrease mortality and morbidity from coronary artery disease in adults, but they also have intrinsic anti-inflammatory properties, which may be especially beneficial in lupus. This is a multicenter, prospective, randomized, double-blinded, interventional study for children with lupus. Over 12 months, 20 centers from the Pediatric Rheumatology Research Network will enroll 250 children with recent onset lupus who will be treated with the medication atorvastatin for 36 months, establishing the largest cohort of pediatric lupus patients ever prospectively studied.
Scleroderma (or systemic sclerosis) is a disease that involves the abnormal growth of connective tissue which supports the skin and internal organs. In some forms of scleroderma, hard, tight skin is the extent of the disease. In other forms, however, the problem goes much deeper, affecting internal organs, such as heart, lungs, and kidneys. In scleroderma, the immune system is thought to stimulate cells called fibroblasts to produce excess collagen. Currently, there is no treatment that controls or stops the underlying problem: the overproduction of collagen. Little is known about the cellular changes that cause the skin and organs to harden, and the disease may be difficult to diagnose. Understanding the early cellular and molecular changes in scleroderma will help scientists develop more effective treatments. Ten new research grants on scleroderma have recently been funded by the NIAMS (with co-funding from the NIH Office of Research on Women's Health on two of these grants) that include both basic and clinical research studies. The NIAMS has already supported a broad portfolio of research in this area, and the new grants will enhance research into our understanding of the causes of scleroderma and bring us closer to finding treatments.
Relief for Patients with A Disorder of the Spine
NIAMS-supported researchers have determined that the drug etanercept (EnbrelŪ) alleviates the pain and stiffness associated with ankylosing spondylitis, a chronic inflammatory arthritis characterized by joint stiffness, pain and extra bone growth that can result in partial or complete fusion of the spine. Ankylosing spondylitis typically strikes adolescent and young adult males. Currently there is no cure, and treatments have not been shown to affect spinal symptoms of the disease. Etanercept belongs to a class of drugs called "biologic agents" that are designed to interfere with the biological disease process. Etanercept is a tumor necrosis factor (TNF) antagonist, a substance that blocks the action of TNF, a naturally occurring protein in the body that contributes to the inflammation found in ankylosing spondylitis. In a small clinical trial, some patients received twice-weekly injections of etanercept and other patients received a placebo for four months. At the end of the trial, 80 percent of the patients taking the drug reported less morning stiffness, spinal pain, and joint swelling, compared with 30 percent in the placebo group. All patients continued to take their pretrial medications for ankylosing spondylitis, including nonsteroidal anti-inflammatory drugs, oral corticosteroids, and disease-modifying antirheumatic drugs, during the trial. Results from the trial suggest that etanercept can be used safely in combination with other anti-inflammatory and immunosuppressive drugs.
Genetic Regions Linked to Inherited Hand Osteoarthritis
Specific chromosomal areas are likely to play a role in the inheritance of hand osteoarthritis, a form of degenerative joint disease that is a major cause of disability in people age 65 and over. NIAMS-supported researchers have reported the first large-scale study of hand osteoarthritis in the general U.S. population. The project was a search for genetic markers that are linked to the amount of hand osteoarthritis in parents and children participating in the Framingham Heart Study. Half of the participants and 30 percent of their children had at least one joint affected by osteoarthritis. Results suggest eight genetic regions may be linked to susceptibility for hand osteoarthritis. In the future, a test to determine who carries osteoarthritis susceptibility genes could help people reduce their risk for osteoarthritis with lifestyle adjustments. In addition, an understanding of how genes cause osteoarthritis could enhance the development of new treatments.
Studies of the role of behavior in disease onset and progression are important across all areas of the Institute. One particular area of focus in FY 2002 was to attract researchers working in other disciplines to bring their expertise and skills to address the challenges in arthritis and skin research. To this end, the Institute issued a Request for Applications for Multidisciplinary Biobehavioral Rheumatic Diseases Workshops. This solicitation was developed to encourage researchers to organize and design workshops that will gather biobehavioral scientists, clinicians, and basic scientists with shared or overlapping interests to discuss the biobehavioral aspects of rheumatic disease. The NIAMS also sponsored a meeting in September 2002 to assess the NIAMS program in fibromyalgia, and we are considering how to pursue the opportunities and new directions for research that were identified at this meeting.
Bone Biology and Bone Diseases
Musculoskeletal diseases such as post-menopausal osteoporosis take a tremendous personal and societal toll. By predisposing people to bone fractures, osteoporosis compromises the quality of life of affected individuals. Thus, translating the results of basic biological research into therapies that prevent or treat osteoporosis can have a very significant impact on public health.
Menopausal Hormone Therapy
For a number of years, hormone therapy has been recognized as effective in preventing postmenopausal bone loss. However, recent developments underscore the importance of balancing the beneficial effects of therapy for one organ or tissue with concerns about possible harmful effects elsewhere in the body. In October 2002, the NIAMS participated in an NIH scientific workshop, entitled Menopausal Hormone Therapy, to review the results from a critical portion of the Women's Health Initiative (WHI). The WHI includes an exceptionally large-scale clinical trial of the effects of hormone therapy and calcium and vitamin D supplementation in postmenopausal women. One portion of the WHI, focused on therapy with a combination of the hormones estrogen and progestin, was recently stopped when it was shown that the treatment resulted in increased risks for heart attacks, strokes, blood clots, and breast cancer. Although the trial confirmed that estrogen/progestin therapy reduced the risk for osteoporotic fracture, it was judged that this benefit is outweighed for most women by the increased risk for the other health problems.
The Menopausal Hormone Therapy scientific workshop placed these studies in the context of other research on hormone therapy, and helped clinicians and patients understand the implications of the new information for individual decisions about the use of hormone therapy. In addition, the workshop provided information about currently available alternatives to hormone therapy for the treatment of osteoporosis and the symptoms of menopause itself. Finally, workshop participants discussed recent scientific advances that suggest routes to new treatments for postmenopausal osteoporosis. Most intriguing, in light of the WHI results, are the results of work jointly supported by the NIAMS and the National Institute on Aging (NIA) on the molecular mechanisms of estrogen action. This work suggests that the beneficial effects of estrogen on bone occur via a pathway that is fundamentally different from the one that mediates effects on reproductive tissues. Thus, it may be possible to develop estrogen-like drugs that protect bone without having undesirable side effects such as the increased risk of breast cancer. In fact, investigators have already shown that a compound called estren has just this sort of action when tested in mice.
Other recent advances emphasize that we still have much to learn about bone biology, and that new knowledge often opens doors to new therapies. A variety of pharmacological agents and biochemical factors, some already familiar in other contexts, has been found to have unexpected effects on bone mass. For example, the actions of the cholesterol-lowering drugs called statins, the hormone leptin (originally identified as important for controlling obesity), and nitric oxide (best known for its effects on the heart and blood vessels) all provide clues to ways that new therapies might improve bone health.
Genetics of Bone Mass.
Studies of the genetics of bone mass are increasingly productive, as new genomic resources become available. Continued effort in this area seems likely to identify still more new targets for development of osteoporosis therapies. For example, in work that drew together the efforts of many scientists, including researchers at one of the NIAMS Core Centers for Musculoskeletal Disorders, a gene that was previously unsuspected of playing any role in bone has emerged as a possible key to restoring bone in cases of osteoporosis. Studying families in which people have unusually dense, strong bones, has revealed that an abnormality in a gene called LRP5 is responsible for the extra bone growth. Future work will focus on understanding how LRP5 functions, with the goal of using its action to stimulate new bone growth.
Bone and Joint Decade.
The NIAMS is pleased to participate in the celebration of the Bone and Joint Decade, from 2002 to 2011, as proclaimed by President George W. Bush on March 21, 2002. We joined with other components of the NIH in a meeting with leaders of a variety of organizations that are involved in this effort. Together, we began the process of trying to define opportunities to enhance information dissemination, as well as to identify opportunities to capitalize on this international collaboration. The goals of the Bone and Joint Decade include raising the awareness of the American people to the growing burden of musculoskeletal disorders on society; promoting prevention of musculoskeletal disorders and empowering patients through educational programs; advancing research in the prevention, diagnosis, and treatment of musculoskeletal disorders; and improving the diagnosis and treatment of musculoskeletal disorders.
A large United States/Canada cooperative project is just underway to resolve differences of opinion on the best way to repair the most common long bone fracture in the human body. The three-year study of the repair of fractures of the tibia (the larger of the two lower leg bones) will enroll 900 patients at 10 centers in the United States, 10 centers in Canada, and 1 center in Europe. Co-funding the project are the NIAMS and two institutes of the Canadian Institutes of Health Research: the Institute of Musculoskeletal Health and Arthritis and the Institute of Health Services and Policy Research. Surgeons agree that repair of serious tibial fractures should include the insertion of a nail into the canal within the central marrow cavity of the bone. They disagree, however, on whether it is better to enlarge (ream) the canal before inserting the nail. Proponents of reaming believe that reaming increases blood flow to the hard bone at the outer surface of the fracture site, thus increasing fracture stability. They also believe reaming provides a natural graft of the patient's own bone tissue at the fracture site. Opponents believe that reaming damages the blood supply to the tissue lining the canal, impairing fracture healing. During the study, patients who have a tibial fracture will be randomly assigned to either a reaming or nonreaming surgical group. At six weeks, three months, six months, nine months, and one year, surgeons will examine participants to determine whether the operation was successful or whether they require additional surgery to promote fracture healing. These operations would include a bone graft, exchange or removal of the nail, removal of the locking screws, or procedures to treat soft tissue infections or defects. Other factors will be considered in determining which group has a more successful outcome, including how soon patients return to work and their general health status and quality of life.
In a significant advance in the field of orthopaedics, needle irrigation for the treatment of osteoarthritis of the knee was shown to be safe and feasible. Women rather than men, patients with more limited osteoarthritis of the knee, and patients with a shorter duration of symptoms were found to have a more favorable response to treatment. These findings may be useful for patients and their health care providers as they consider treatment options for the nonsurgical management of knee osteoarthritis.
Consensus Development Conference on Primary Knee Replacement.
Approximately 300,000 total knee replacements are performed each year in the United States for end-stage arthritis of the knee joint, and reports in the orthopaedic literature indicate that total knee replacements have shown outstanding success. Despite this success, some controversies exist. To address these controversies, to review the current state of the science, and to identify directions for future research, the NIH (with the NIAMS as the sponsoring Institute) will hold a Consensus Development Conference on Primary Total Knee Replacement on December 8-10, 2003. Six questions will form the basis of the panel's deliberations: (1) What are the current indications and outcomes for primary total knee replacement? (2) How do specific characteristics of the patient, material, and design of the prosthesis and surgical factors affect the short-term and long-term outcomes of primary total knee replacement? (3) Are there important perioperative interventions that influence outcomes? (4) What are the indications, approaches, and outcomes for revision total knee replacement? (5) What factors explain disparities in the utilization of total knee replacement in different populations? and (6) What are the directions for future research?
Muscle Biology and Muscle Diseases
Muscular dystrophy refers to a group of genetic diseases characterized by progressive weakness and degeneration of the skeletal or voluntary muscles which control movement. The muscles of the heart and some other involuntary muscles are also affected in some forms of muscular dystrophy, and a few forms involve other organs as well. Duchenne muscular dystrophy is the most common form of muscular dystrophy to affect children. It is caused by mutations in the dystrophin gene and results in repeated cycles of muscle damage and insufficient muscle regeneration, leading to gradual replacement of muscle by fibrous tissue.
Muscle Stem Cells Show Promise Against Muscular Dystrophy.
Recently, scientists have isolated muscle-generating stem cells that can improve muscle regeneration and deliver the missing protein dystrophin to damaged muscles in a mouse muscular dystrophy model. The research involves the isolation of a subpopulation of muscle stem cells that grow and reproduce over many generations while maintaining their essential character through multiple generations. Importantly, they can differentiate into muscle as well as other kinds of cells needed to regenerate muscle tissue, and they resist immune rejection. When these cells were transplanted into an animal model of muscular dystrophy, the mdx mouse, numerous muscle fibers developed containing normal dystrophin, suggesting that transplanting these cells into dystrophic muscle could potentially help restore function. Results of the study signal that some of the major obstacles to stem cell transplantation - low cell survival rate, poor spreading of cells, and cell rejection by the immune system - may be overcome. Advances of this nature could make treatments for muscular dystrophy and other muscle-related diseases more effective.
Other research relevant to the muscular dystrophies relates to muscle stamina and a newly created "marathon mouse." This new mouse model expresses a particular energy-metabolizing protein that increases the proportion of "slow-twitch" muscle fibers - the kind that give distance runners their muscular stamina. Muscle fibers treated this way have fewer of the "fast-twitch" fibers coveted by sprint runners. These findings have caused some to speculate that further work in this area could benefit from research efforts against muscle-wasting diseases like the muscular dystrophies.
In an additional finding, a mouse model of Duchenne muscular dystrophy, altered to develop high levels of insulin-like growth factor I (IGF-I), has shown increases in muscle mass of at least 40 percent and other changes that could herald a possible treatment for secondary symptoms of the disease in humans. The new dystrophic mouse model also has reduced amounts of muscle-replacing fibrous tissue and enhanced biological pathways associated with muscle regeneration. The new mouse model offers an additional potential benefit: the combination of better muscle regeneration and less muscle wasting could lead to a better muscle capacity over time. Less muscle effort would be needed to produce a required force, so muscle would be less likely to be damaged by normal activity.
Muscular Dystrophy Initiatives
This has been a particularly active time for research progress related to the muscular dystrophies, as the advances above demonstrate. It has also been a very active time for launching initiatives. The NIAMS continues to work closely with other NIH components, including the NINDS and the NICHD, to implement the provisions of the Muscular Dystrophy Community Assistance, Research, and Education Act of 2001 (the MD-CARE Act). Specifically, we jointly developed initiatives to fund muscular dystrophy cooperative research centers, and to support planning grants for future research centers. Both of these initiatives were Requests for Applications and they were issued in the fall of 2002. We are also working on an initiative to enhance the training of muscular dystrophy researchers. To help guide our efforts in this area, the NIH recently established a muscular dystrophy research task force. In addition, the NIH is assisting the DHHS in establishing an interagency muscular dystrophy coordinating committee, as called for in the MD-CARE Act. The NIAMS is pleased to participate in all of these initiatives, and we look forward to the many ways in which they will advance the field of research on the muscular dystrophies.
Skin Biology and Skin Diseases
Genetic Correction of Inherited Skin Disease
Among the most devastating skin diseases are the various forms of epidermolysis bullosa (EB). EB represents a group of inherited childhood skin diseases that typically result either in death or a very difficult life for many patients. The manifestations of these diseases include extremely fragile skin on which even the slightest friction can cause painful blistering. In some severe forms of EB, blisters can cover most of the body. Often, patients with severe EB have wounds that resemble serious burns. Affected children typically face physical, emotional, and financial hardships for themselves and their families. Researchers have been focused on determining strategies to correct the genetic defect, but all of the current gene-transfer technologies have limitations in their effectiveness to deliver the required gene. These limitations include difficulties in stably integrating large corrective sequences into the genomes of long-lived skin stem cell populations. Larger capacity viral vectors that are currently available are associated with biosafety concerns, and plasmid-based approaches have poor efficiency of stable gene transfer. These are significant barriers to the scientific efforts to correct the genes involved in inherited diseases. NIAMS-supported researchers recently reported exciting and promising results from their work in the recessive form of dystrophic epidermolysis bullosa that is caused by the absence of a particular gene (COL7A1). The approach in these studies was to use a particular enzyme, a bacteriophage integrase, as the base for gene transfer, and researchers were successful in stably integrating the COL7A1 cDNA into genomes of primary cultured epidermal cells from four patients with this inherited, blistering skin disease. The skin that was developed using these cells displayed stable correction of the hallmark features of this disease. These results establish a potential practical approach to nonviral genetic correction of severe human genetic disorders that require stable genomic integration of large DNA sequences.
Burden of Skin Disease
In response to FY 2002 Congressional language, the NIAMS sponsored the "Workshop on the Burden of Skin Disease" in September 2002. A diverse group of investigators and patients discussed the elements that comprise the burden of skin diseases and their impact on public health and daily living; current knowledge and data-collection instruments, and how to access the data more effectively; and future data needs and instruments for facilitating the collection of the data. The recommendations from this workshop are being reviewed by the Institute to determine the need for and path of future initiatives in this area. The lessons learned from this workshop can serve as a paradigm for other areas - all of which share the challenge of defining the burden of a disease on an individual, the family, the workplace, and society as a whole.
The NIAMS teamed with the National Alopecia Areata Foundation in sponsoring the Fourth International Research Workshop on Alopecia Areata in November 2002. Alopecia areata is an autoimmune disease that causes hair loss. This workshop brought together investigators from around the country for an exchange of recent findings in alopecia areata and related fields of hair biology. Topics included immunology, immunogenetics, hair cycle controls, gene profiling, animal models, and gene arrays. Results of this workshop will serve to guide future research in this field.
Immune Modulation of Skin Diseases.
The NIAMS is planning a workshop on immune modulation in the treatment of skin diseases, which will include new treatments for psoriasis, atopic dermatitis, autoimmune bullous diseases, and other skin diseases. The workshop will focus on trying to understand how some new treatments are actually working so that we may better understand the mechanisms underlying these diseases.
Chronic wounds are a major health problem, particularly among the elderly, diabetics, and those with disabilities. The development of artificial skin substitutes has improved the healing of many of these wounds. The mechanism by which this improved wound healing occurs is being investigated to design better treatments of chronic wounds. One study determined that a skin substitute applied to the legs of patients with chronic ulcers and followed using molecular genetic techniques resulted in the DNA from the graft persisting for less than a month in most of the patients. This means that the wound healing induced by these grafts is not due to the persistence of the cells that are applied to the wound, but rather to some other mechanism of improved wound healing, possibly due to the placement of the graft. Other studies in this field focused on the changes that occur within the first few days after the placement of bioengineered skin. These investigations demonstrated that the bioengineered skin was capable of responding to injuries and would allow the migration of skin cells and other biologic evidence of active responses to wounding. This means that the bioengineered skin is behaving like a living tissue during the initial few days that it is used on the wound. These studies improve both our understanding of the process involved in wound healing and our ability to create ever more effective strategies for healing chronic wounds.
Health Partnership Program
The NIAMS continues to support the diversity initiative it has created and developed over the last few years - the Health Partnership Program. This is a collaborative community-based effort directed at developing research programs to understand and address health disparities in rheumatic diseases. This program is aimed at reducing the morbidity and mortality associated with rheumatic diseases and their complications, which disproportionately affect African Americans and Hispanic/Latinos in addition to other minority groups. The Institute convened a meeting to foster information sharing among the community partners, academic and community experts from a variety of geographic areas, and NIAMS staff involved in the Health Partnership Program. The goals of this meeting were to review the current state of the Partnership; to learn about other programs and experiences that are relevant; and to begin to formulate 5- and 10- year program goals in the Health Partnership Program areas of public health education, patient care, access to clinical studies, and recruitment to research careers. As part of the Health Partnership Program, the NIAMS opened a Community Health Center in a medically underserved area of Washington, DC, which focuses on outreach to African American and Hispanic/Latino communities. The Center celebrated its first anniversary in July 2002, and there was much to celebrate, as increasing numbers of patients are being seen at the Center.
Other Research on Health Disparities
Lupus is one of the diseases within the NIAMS portfolio that disproportionately affects both women and minorities. Because survival rates of people with lupus have improved over the last two decades, investigators are now paying increasing attention to the complications leading to mortality later in life as well as progressive morbidity. Increasing numbers of young women with lupus are experiencing fractures, strokes, and heart attacks, complications that are typically associated with aging in women without lupus. In recent studies, investigators have demonstrated an association between decreased bone mineral density and both an increased carotid plaque index and the presence of coronary artery calcification in a cohort of young women with lupus. These findings indicate that women with lupus are at increased risk for both clinical osteoporosis and cardiovascular complications at a much younger age, and suggest that more aggressive control of the risk factors for atherosclerosis and osteoporosis are needed to prevent these conditions in women with lupus. This is one of the reasons we launched the previously mentioned clinical intervention trial in which statins are to be tested for their effect in preventing atherosclerosis in children with lupus.
Researchers have documented differences in the damage caused by lupus in studies of Hispanic, African American, and Caucasian individuals with this disease. Patients from these three populations had similar disease duration, but the proportion of patients accruing any organ damage was higher among Hispanics than among the other two groups, confirming the greater negative impact of lupus among members of this ethnic group. The association of damage with poor coping skills was reported for the first time, and it suggests that approaches designed to modify patients' behaviors and attitudes to their illness could reduce the damage to the body caused by lupus.
Additional insights into health disparities came from a recent report from an NIAMS-supported, long-term study of patients with lupus known as LUMINA (Lupus in Minority Populations: Nature versus Nurture). In this report, researchers compared the patient's and the physician's assessment of disease activity in a multiethnic (Hispanic, African American, and Caucasian) group of patients with lupus. Researchers in this study reported that a discrepancy was exhibited by 58 percent of the patients - meaning that patients and their physicians rate disease activity in lupus differently. Physicians appear to place more emphasis on laboratory features, while patients place more emphasis on function. Ethnicity did not account for the discrepancies in perception of disease activity.
The Institute also provided support for a study of the racial differences in social network experience and perceptions of the benefit of arthritis treatments among a group of New York City Medicare beneficiaries with self-reported hip and knee pain. The goal of the study was to determine whether social network experience and perceptions of benefit of arthritis treatments influence the decision to seek diagnosis and treatment in this group. The results reported were that 42 percent of African Americans and 31 percent of whites reported hip or knee pain. In addition, 42 percent of African Americans and 65 percent of whites reported knowing someone who had surgery for hip or knee pain. African Americans were less likely than whites to report that surgery had helped someone they knew with hip or knee pain, and they appeared less likely to perceive that this form of treatment is beneficial.
In other related studies, the NIAMS joined with the Agency for Healthcare Research and Quality and the DHHS Centers for Medicare and Medicaid Services in funding a study of hip replacement in elderly Hispanics. The results indicated that, despite the fact that surgical costs would be covered, many Hispanic Medicare beneficiaries who suffer from arthritis that is debilitating may not be getting hip replacement surgery that could both relieve their pain and keep them from becoming disabled. Specifically, Hispanics aged 65 and older that were included in this study were less than one-third as likely as non-Hispanic whites of the same age to undergo total hip replacement - an operation that can alleviate pain and improve physical function and quality of life in patients with severe osteoarthritis. It has been suggested that this underuse among older Hispanics may be due to some degree to the lack of experience of their friends and family with total hip replacement, so that there is less first-hand experience about the value of the surgery. It is possible that language may serve as a barrier as well.
1 Alarcon, GS, et.al., Systemic Lupus Erythematosus in Three Ethnic Groups. XI. Sources of Discrepancy in Perception of Disease Activity: A Comparison of Physician and Patient Visual Analog Scale Scores, Arthritis & Rheumatism 47, pp 408-413, 2002.
2 "Disparity in Total Hip Replacement Affecting Hispanic Medicare Beneficiaries," Medical Care, June 2002.
Intramural Research Program
Alternative Therapy for Rheumatoid Arthritis.
The roots of Thunder God Vine, a plant whose leaves and flowers are highly toxic, have been used medicinally in China for over 400 years. A root extract of this plant was shown to safely and effectively reduce pain and inflammation in a small group of people with treatment-resistant rheumatoid arthritis, according to a study supported in the Intramural Research Program of the NIAMS. This randomized, double-blind, placebo-controlled trial is the first to test the use of an extract of this vine in rheumatoid arthritis patients in the United States. Twenty-one rheumatoid arthritis patients completed a 20-week clinical trial of the ethanol/ethyl acetate extract. Patients were randomly assigned to one of three treatment groups: placebo, low-dose extract, or high-dose extract. After four weeks, 80 percent of patients in the high-dose group and 40 percent in the low-dose group showed rapid improvement in symptoms compared with no improvement in the placebo group. Side effects were minor for all three treatment groups. Longer term studies with larger numbers of patients are needed to confirm the safety and benefits of the treatment, but this extract is a promising treatment for rheumatoid arthritis. It is unique, because it slows down the overactive immune system, reduces inflammation by turning off genes that encode inflammatory molecules like tumor necrosis factor, and reduces the activity of B and T cells (immune cells). Researchers believe that this plant extract has the potential to treat other immune diseases such as lupus, and they are planning further studies.
Trans-NIH Collaboration in Musculoskeletal Medicine
A new trans-NIH collaboration in musculoskeletal medicine has been initiated and is intended to serve as a national resource that will bring together unique partnerships and long-term investments that could only be done at the NIH. The NIAMS is leading the effort and has been joined by the NICHD, NINDS, and NCCAM in developing this program at the NIH that will be physically located at the National Naval Medical Center and is expected to be fully operational by FY 2005. In addition to becoming a central focus for clinical and basic research in musculoskeletal medicine, it will provide an excellent training environment for the next generation of investigators in musculoskeletal research and medicine.
Story of Discovery: New Treatment Brings New Hope for Patients with Rheumatoid Arthritis
Doctors who are treating patients with rheumatoid arthritis today remember all too well how challenging treatment was not so long ago. Within the last two decades, there has been a major transformation in the treatments that are available to people with rheumatoid arthritis. But as we look back over time, the constant in this story is the insidious nature of rheumatoid arthritis and the challenge it presents to patients, their families, and their health care providers. Rheumatoid arthritis is a chronic, inflammatory disease of the joint lining, and it often results in pain, stiffness, swelling, and loss of joint function. It occurs two to three times more often in women than in men, and it is widely considered to be the prototype of an autoimmune joint disease. In the case of rheumatoid arthritis, the patient's own immune and inflammatory cells mistakenly attack and destroy the joints.
If we look back to the early 1980s, when a patient with rheumatoid arthritis went to the doctor looking for help, the doctor knew that the options were rather limited and the prognosis unpredictable, but pretty grim. Treatment would be initiated in what was known as a therapeutic pyramid. Patients would first be given a course of aspirin or another non-steroidal anti-inflammatory drug (known as NSAIDs), and they would be followed to see if erosions occurred in the bone. If erosions did occur or if the patients did not respond to the NSAIDs, the next course was disease-modifying anti-rheumatic drugs that were added one-by-one as the disease progressed. Gold therapy would frequently be added, but the frustration for the doctors was that disease-modifying therapy was initiated after the patient was already on the road to disability. Whether the gold therapy was supplemented or replaced with penicillamine and whether corticosteroids had to be given during periods of disease worsening, the reality was that all of the joint swelling was rarely completely eradicated. While disease-modifying anti-rheumatic drugs did improve inflammatory symptoms or slowed the progression of joint erosion in some patients, they were less effective and had significant side effects when used long term. In addition, patients on these forms of therapy had to have frequent monitoring of blood and physical examinations for toxic effects. Furthermore, while the markers of inflammation decreased in patients taking these therapies, most of the patients continued to have progression of irreversible joint destruction.
Moving on to the late 1980s, the first use of relatively low doses of methotrexate (used also for chemotherapy in cancer) began in the U.S. in patients with rheumatoid arthritis, and doctors and patients were pleased by the noticeable improvements in a short amount of time. But doctors recognized that the improvements were still not all that they hoped to be able to offer to their patients.
Just before the turn of the century, treatment of rheumatoid arthritis underwent a revolution. Entirely new disease-modifying antirheumatic drugs were approved for the treatment of rheumatoid arthritis, beginning with the drugs etanercept and infliximab as the first biological-response modifying drugs. The speed with which these new drugs were developed was remarkable.
Etanercept and infliximab are produced through biotechnology and they interfere with the specific inflammatory processes of the disease. These biologicals behave as tumor necrosis factor (TNF) antagonists, meaning that they work by blocking the action and decreasing the availability of TNF, a naturally occurring protein in the body that mediates inflammation.
TNF is one member of a family of molecules known as cytokines, small soluble proteins that mediate communication between cells that are involved in the immune responses. Tumor necrosis factor is one cytokine that was originally identified in tumor systems and only later was found to be present in large quantities in the synovial fluid and synovial tissue in rheumatoid arthritis. Work in animal models revealed that TNF plays a central role in the process of synovitis and joint destruction, and when TNF is added into experimental models of arthritis, it induces or exacerbates synovitis. When animal models of arthritis are treated with antibodies against TNF, the disease is improved.
These studies in the laboratory were translated to clinical research, and clinical trials of these new biologicals showed substantial efficacy in people with rheumatoid arthritis who had not previously responded to other treatments. The treatments are generally well tolerated. Other studies reported that infliximab and methotrexate used in combination significantly reduced the symptoms of rheumatoid arthritis and halted the progression of joint damage when compared to the use of only methotrexate. In fact, X-ray examination showed that joint damage was halted in those given the drug combination, and in 40 to 55 percent of patients, joint damage decreased, implying that some damage had been repaired. The combination treatment was well-tolerated and it also significantly improved quality of life. Scientists involved in this study observed that in the last 2 years, rheumatoid arthritis research has moved further than in the last 30 years, and that a wealth of new treatments are now (or will soon become) available that have the potential to prevent and heal structural damage to the joints of people with rheumatoid arthritis. Additional studies determined that these treatments are safe and effective in the treatment of children and teenagers with juvenile rheumatoid arthritis. For those children given etanercept in a clinical trial, all measures of arthritis impact - symptoms, joint abnormalities, ability to perform daily functions, and laboratory tests - were dramatically improved, and the drug was well tolerated.
The success of the story of biologic agents that work to reduce or eliminate the deleterious effects of TNF was the culmination of many years of basic research supported by the NIAMS and other NIH components. The foundation was laid by basic scientists, and it was through years of research - many years of concentrated effort in academia, government, and industry - that we now know much more about what causes joint inflammation and destruction in rheumatoid arthritis. Some very effective medications have been developed by drug companies from this research foundation, and these new medications change everyday life for hundreds of thousands of Americans. This is all the more remarkable because the base of this investment comes from early studies of cancer and TNF as an anti-tumor molecule.
This revolution in the treatment of patients with rheumatoid arthritis - targeting antibodies to molecules that cause rheumatoid arthritis and documenting the ability of the new anti-TNF biological response modifiers to alter the disease process - has made doctors and their patients enthusiastic to use them. This, in turn, has stimulated researchers to refine their studies and work to develop additional drugs in the future that target individual inflammatory pathways. Finally, we see that through NIH investments years ago, the molecules that are now being targeted for rheumatoid arthritis were identified from studies across many scientific disciplines, and pharmaceutical efforts are now focused on developing drugs that will target these molecules in even more precise ways.
The stories above are by no means inclusive of all the progress that has been made through our investments in research. While we would hope to see immediate rewards from our investments, we know that that is not the nature of research. But there are several indications that we need to stay the course and continue the investments. Ask a patient today with a chronic disease that is within our mission if they are grateful for the Federal investment in research to date, and they are likely to answer in the affirmative and note their improved quality of life in particular. While our view is certainly on the long term, we also concentrate on what can be done to advance science and improve public health right now. Our goal is to expand and enhance research so that benefits are realized by all Americans. We are striving to improve our understanding of the fundamental biology of bones, joints, muscles, and skin; determine the changes that cause these life processes to go awry in diseases; improve diagnosis and treatments; and ultimately, prevent the extensive and diverse array of diseases within our mission. Medical research has already made a genuine difference in the length and quality of life, and the investments we are making in research today will have a significant effect on our generation and generations that follow.
The Fiscal Year 2004 budget request for the NIAMS is $502,778,000, including AIDS, an increase of $17,297,000 and 3.6 percent over the FY 2003 amended President's Budget Request. A five year history of FTEs and Funding Levels for NIAMS is shown in the graphs on the following page. Note that Fiscal Years 2001 and 2000 FTEs are not comparable for the NIH Human Resources functional consolidation.
NIH's highest priority 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 FY 2004 request will provide an increase of approximately 5 percent in average cost for research project grants. Also in FY 2004, NIAMS will fully fund 4 grants. It is planned that these grants will be a combination of Academic Research Enhancement Awards (AREA) and Shannon Awards.
Promises for advancement in medical research are dependent on maintaining the supply of new investigators with new ideas. In the Fiscal Year 2004 request, NIAMS will support 289 pre- and postdoctoral trainees in full-time training positions, the same number as in FY 2003. Stipend levels for NRSA trainees will increase by 4 percent over Fiscal Year 2003 levels for predoctoral fellows, and from 4-1 percent, based on years of experience, for postdoctoral fellows.
The Fiscal Year 2004 request includes funding for 40 research centers and 174 other research grants, including 15 new clinical career awards. The request will also provide funds for 67 R&D contracts, including $260,000 for the Best Pharmaceuticals for Children Act initiative. Intramural Research and Research Management and Support receive increases of 1.8 percent over FY 2003.
The mechanism distributions by dollars and percent change are displayed on the following page.