Congressional Justification Narrative
FY 2005

February 2004 (historical)

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

Budget Authority:

  FY2003 Actual FY2004 Final Conference FY2005 Estimate Increase or Decrease
BA $485,611,000 $500,908,000 $515,378,000 +$14,470,000
FTE 250 236 236 -

This document provides justification for the Fiscal Year 2005 activities of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), including HIV/AIDS activities. Justification of the National Institutes of Health (NIH)-wide FY 2005 AIDS activities can be found in the NIH section entitled "Office of AIDS Research (OAR)."

Introduction

Improving daily life is the driving force for the research that we support and conduct at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Virtually every home in America is touched by diseases affecting bones, joints, muscles, and skin. We are committed to advancing understanding, diagnosis, treatment, and prevention of these diseases and disorders that are often chronic and disabling, many of which disproportionately affect women and minority populations.

The stories of research progress and promise below illustrate that support for research across a broad spectrum is essential - basic research at the laboratory bench needs to be translated through clinical research to benefit patients. The converse is equally true - we count on clinical researchers to stimulate basic studies that will ultimately yield information useful to patient care and disease prevention. The budget increases over the last several years have made a real difference in the research that the NIAMS has been able to support in that we have significantly expanded our support of clinical research and clinical trials. Some of these investments have already borne fruit while others will take several years before we can determine their outcome. Highlights of some recent research advances as well as of ongoing and new initiatives in areas of scientific opportunity follow.

The NIH Roadmap. The NIAMS is an enthusiastic partner in all dimensions of the newly-released NIH Roadmap. We believe much of the basic research our investigators conduct will be greatly facilitated by the focus on basic science in the "Pathways to Discovery" initiatives. Further, because the NIAMS supports research on complex chronic diseases, many initiatives within the "Research Teams of the Future," theme are very relevant to our mission. Specifically, facilitation of interdisciplinary research can only enhance progress in arthritis, musculoskeletal, and skin research. Finally, we are most enthusiastic about the promise of the multidimensional approach to "Re-engineering the Clinical Research Enterprise." The initiatives in this area will provide many clinical researchers studying diseases of the bones, muscles, joints, and skin access to advanced and novel infrastructure, eliminating the need to create new infrastructure every time a new clinical study is initiated. We expect to enjoy more efficient use of resources and an increased pace of scientific discovery in our clinical research as a result.

NIAMS Science Advances and New Initiatives

An Illustration of Effective Translational Research - NIH Researchers Collaborate to Produce a Targeted Immunosuppressive Drug. Ten years ago, researchers in an NIAMS Intramural Research Program laboratory discovered a particular protein, an enzyme known as JAK3, and determined that it is found only in immune system cells. This finding now holds great promise for people undergoing organ transplants as well as for people with the wide range of autoimmune diseases. The importance of JAK3 comes from a long process of research and discovery by the NIH team and their collaborators engaged in basic research that included not only the actual discovery of JAK3, but also demonstrating that this protein was critical for cell signaling resulting in the development of infection-fighting white blood cells. Further research revealed that mutations of the gene that encodes JAK3 in humans is responsible for a form of severe combined immunodeficiency disease (SCID). Researchers then looked to translate these seminal discoveries in basic research to benefit patients with improved, targeted therapies. Because JAK3 is essential for immune cell function, and because its expression is limited to blood cells, researchers predicted that inhibiting JAK3 might be the basis for a new class of drugs that could suppress the immune system. While suppression of the immune system is problematic for most people and results in a whole host of potentially devastating side effects, suppression of the immune system is actually desirable for people who have had organ transplants as well as people who have autoimmune diseases. The researchers then entered into a collaborative research and development agreement with Pfizer in a partnership that enabled Pfizer to develop a new drug. This partnership, involving researchers in the NIAMS Intramural Program, in academia, and at Pfizer, is studying a new immunosuppressive drug, CP-690,550, that holds the promise of avoiding some of the common side effects associated with other currently available medications that curb the immune system. This new drug was tested in mice that had heart transplants and in monkeys that had kidney transplants and, in both cases, animals treated with CP-690,550 survived much longer than untreated animals. None of the treated animals showed signs of typical, serious immunosuppressive side effects. An analysis of the mechanism of action of this new drug revealed that it specifically inhibits the enzyme JAK3, and that inhibiting this enzyme has the effect of suppressing the immune system, while not affecting other systems of the body. This is in contrast to many of the current immunosuppressive drugs that target enzymes found in cells throughout the body, resulting in toxic side effects. This is an illustration of translational research at its best - with research findings from basic to clinical investigations. These studies have enabled researchers to design more focused basic research as well as offered the promise of improved, targeted patient care. CP-690,550 is the first protein tyrosine kinase inhibitor to show positive results in primates with respect to regulating immune response. Further animal studies are being conducted to determine if this drug could be used successfully and safely in humans to prevent the body from rejecting transplanted organs, as well as to treat autoimmune diseases such as lupus, rheumatoid arthritis, and psoriasis.

Arthritis and Other Rheumatic Diseases

Progress in Research on Lupus: Serum Antibodies Precede Clinical Findings in Lupus by Many Years

Systemic lupus erythematosus (SLE), or lupus, is a chronic and potentially fatal autoimmune disease, often occurring in women of child-bearing age. It can affect many parts of the body, including the joints, skin, kidneys, heart, lungs, blood vessels, and brain. People of all races have lupus; however, African American women are three times more likely to have lupus and are more likely to die from lupus than are white women. African American women also tend to develop the disease at a younger age than white women and develop more serious complications. Lupus is also more common in women of Hispanic, Asian, and Native American descent. Women are nine times more likely to have lupus than are men. Lupus is often difficult to diagnose because of its highly varied and often serious insidious clinical manifestations. A new study funded by the NIH revealed that people diagnosed with lupus have autoantibodies (antibodies against their bodies' own tissues) in their blood years before the symptoms of lupus appear. The early detection of these autoantibodies may help in recognizing those who will develop the disease and allow physicians to monitor them before they might otherwise be diagnosed. Lupus and other autoimmune diseases often go untreated for years and are diagnosed only after damage to the body tissues has occurred. Findings such as these, which will help to identify and monitor people who may develop these diseases, are extremely valuable.

Researchers Uncover a Genetic "Signature" for Lupus

A team of scientists supported by the NIH and the private sector have discovered a genetic "signature" present in some patients with lupus who develop such life-threatening complications as blood disorders, central nervous system damage, and kidney failure. Researchers analyzed thousands of genes in the blood cells of lupus patients and healthy controls. Interestingly, 14 of the thousands of genes studied were linked to a subset of lupus patients with severe disease. These 14 genes, referred to collectively as the IFN (interferon) expression signature, are turned on by the activity of interferon, a complex family of proteins involved in the regulation of immune responses. Patients with severe lupus consistently showed higher expression levels of this IFN signature. Identifying lupus patients at particular risk for severe disease before serious complications arise has enormous implications for the early diagnosis and treatment of this potentially devastating disease. These research results provide strong support for developing new therapies to block IFN pathways in patients with severe lupus, and the pattern of gene expression in blood cells may be useful in identifying patients most likely to benefit from these new therapies. Gene expression profiling in blood cells may also be useful in identifying disease pathways in other autoimmune and inflammatory disorders. The NIAMS partnered with the National Center on Minority Health and Health Disparities, the NIH Office of Research on Women's Health, the Minnesota Lupus Foundation, and the Alliance for Lupus Research in this research.

Genetic Differences Found in African American, European American Lupus Families

After 10 years of collecting genetic information on families with lupus, researchers have found different genetic regions linked to lupus in African Americans and European Americans. This genetic linkage study may one day help to explain why more African Americans die of lupus and develop more serious complications such as nephritis (kidney failure) compared with people of European descent. These researchers identified a region on chromosome 1 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, they found a genetic linkage to chromosome 4 that contributes to lupus. These results suggest that the genetic origins of lupus may differ in African Americans and European Americans.

Federal Working Group on Lupus

In other news related to lupus, the first meeting of the Federal Working Group on Lupus was held in October 2003. The conference report for the FY 2003 appropriations included language calling on the Office of the Secretary to establish this new group. This working group was established under the leadership of the NIAMS, and it includes representatives from seven NIH components as well as all relevant DHHS agencies and other federal departments having an interest in lupus. The working group will provide a forum for representatives of federal agencies and non-federal organizations with an active interest in lupus research, training, and education to share ideas and information, to identify promising scientific opportunities, and to facilitate novel collaborations. In addition, liaison members from interested health voluntary organizations will be participating in working group meetings and activities, to ensure that broad input and diverse perspectives are incorporated into the working group's deliberations. We will make every effort to harmonize the activities of this working group with the work of existing groups, such as the NIH Autoimmune Diseases Coordinating Committee, to be sure that the new working group complements on-going efforts to promote collaborations relevant to lupus.

Pain and Social Activity in Children with Juvenile Arthritis

Using diary analysis in conjunction with standard clinical testing, researchers have shown that increased anxiety - and, surprisingly, not depressed mood - was significantly associated with increased fatigue and pain frequency and intensity. In addition, the research team found - not surprisingly - that increased pain and fatigue are linked to reduced participation in school and social activities. Children with juvenile arthritis may have pain that can be intense and disabling, and comprehensive treatment optimizes their ability to fully participate in these activities. In addition to being more aggressive in treating pain with traditional pharmacological therapies, the researchers also recommend including behavior-altering medication and cognitive-behavioral therapy to treat associated anxiety in children with juvenile arthritis. While arthritis pain has been the focus of much research in adults, there is an increasing awareness of the need to focus on pain in children. This study, supported by NIAMS, the Office of Research on Women's Health, and the private sector, has shed new light on this important research topic.

Identification of Pain-Signaling Pathways

Chronic pain is a debilitating feature of fibromyalgia and other musculoskeletal diseases of concern to the NIAMS. A recent study, partly funded by the NIAMS, suggests that a pain-signaling pathway in the brain, modulated by the neurotransmitter GABA, could be a target for a potential therapy for controlling chronic pain. The work showed that signals from the insular cortex (a small region in the forebrain), to the amygdala (a brain area involved in pain, fear and attention) - facilitated by GABA - may be involved in chronic pain. When the insular cortex sends signals to the amygdala, pain is experienced; equally, communication between the insular cortex and the locus coeruleus (an area in the hindbrain involved in the stress response) increases pain. The insular cortex uses two different forms of the neurotransmitter GABA - GABAA and GABAB - to communicate with the locus coeruleus and the amygdala, respectively. Thus, it might be possible to inhibit the signals from the insular cortex to the amygdala by manipulating GABAB levels in the insular cortex, which might benefit patients who experience chronic pain. Most current therapies work "from the bottom up," focusing on peripheral areas where the pain is experienced. This research points toward an approach "from the top down": blocking the signals from the brain to the peripheral areas affected by pain.

Two New Initiatives in Osteoarthritis

Osteoarthritis is the most common form of arthritis, and it not only affects millions of Americans today, but it is expected to affect many more people in the future as the number of elderly in our country increases. The NIAMS supports a broad and diverse portfolio of basic and clinical research to improve our understanding of the underlying causes of osteoarthritis, improve the diagnosis and treatment of osteoarthritis, and improve quality of life for affected individuals. This year the NIAMS has targeted two particular areas of opportunity in research on osteoarthritis. The first is the recent launch of a collaborative osteoarthritis biomarkers research network that is currently made up of five grant awardees. This network is structured to facilitate the discovery and development of osteoarthritis biomarkers. Investigators in the network will work collaboratively and share resources for the development, evaluation, and validation of biochemical markers for osteoarthritis onset, severity, progression, and response to treatment. When the NIAMS has sought the advice of leading researchers and professional and lay organizations, there has been widespread support for research that would identify biomarkers of disease for osteoarthritis - biological clues to increased susceptibility, early stages of disease, the course of the disease, and the response of people with osteoarthritis to various therapies. The hope is that this collaborative network of leading investigators will speed the process for identifying these critically needed biomarkers so that people at various stages of the disease can be identified before they progress to significant symptoms of pain and joint deterioration.

The second new NIAMS initiative is focused on determining the influences of biomechanics in osteoarthritis. A team of scientists is now conducting three interrelated studies of biomechanical factors that influence cartilage breakdown and inflammation in osteoarthritis. The work is interdisciplinary, involving such disciplines as orthopaedic surgery, immunology, biomedical engineering, and behavioral science. This multidisciplinary approach promotes the exchange of expertise and research findings, and promises a more rapid translation of basic science to clinical therapies and screening and diagnostic techniques. One project will involve laboratory experiments to examine the roles of biomechanical factors on cells and tissue within joints affected by osteoarthritis. A second study will examine the effects of biomechanical factors in a mouse model of osteoarthritis. A third component will seek to develop more effective exercise and weight loss therapies to reduce pain and disability for patients with knee osteoarthritis.

Gout

Gout is one of the most painful rheumatic diseases. It results from deposits of needle-like crystals of uric acid in connective tissue and in the joint space. These deposits lead to inflammatory arthritis, which causes swelling, redness, heat, pain, and stiffness in the joints. A number of risk factors, including genetics and age, are related to the development of gout. It is more common in men than in women and more common in adults than in children. Because research on gout has not progressed much in the past several years, the NIAMS sponsored a scientific meeting last April on gout and other articular crystal deposition diseases. Scientific opportunities and research gaps were identified and we anticipate releasing a solicitation for research in targeted areas.

Additional areas related to rheumatic diseases that we have targeted for research emphasis include the study of the microcirculation and target organ damage in rheumatic and skin diseases; gene expression studies in arthritis and other areas; high risk research in arthritis and other areas; the role of innate immunity in autoimmune rheumatic diseases; clinical trial outcomes instrument development; and translational cooperative research on pediatric rheumatic and skin immunomodulatory diseases.

Musculoskeletal Biology and Musculoskeletal Diseases

Story of Discovery: Important New Information in the Treatment of Osteoporosis

From its inception almost two decades ago, the NIAMS has committed a significant portion of its budget to bone research - including seminal studies on bone biology and ground-breaking research on bone diseases that laid the foundation for understanding normal bone biology as well as determining what goes awry in bone diseases. Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing affected people to an increased risk of fracture. Bone strength reflects the integration of two main features: bone density and bone quality. Osteoporosis is the most common of the bone diseases that affect Americans. Although it is the underlying cause of most fractures in older people, the condition is silent and undetected in many cases until a fracture occurs.

With the significant budget increases of the last few years, the Institute was able to launch a study of combination therapies in osteoporosis - a study that industry would never undertake. Patients with osteoporosis may be given therapy to slow down the breakdown of bone or therapy to enhance the bone building process - both with the goal of building up bone mass before fractures occur. The NIAMS undertook studies combining the bone-building treatment parathyroid hormone (PTH) with a drug that slows bone loss (alendronate). The design of these studies is such that the drugs are compared as single treatments as well as in combination, and the head to head comparison is something that the companies who make the drugs would be less inclined to support. The hope was that the combination of these two therapies with different targets of action would optimize osteoporosis treatment and increase bone density more than either therapy would alone. The results of two independent studies (one at an NIAMS Specialized Center of Research) testing bone density in the spine and the hip of postmenopausal women and men with low bone mineral density determined, however, that combining PTH with alendronate actually produced no significant improvement in bone mineral density beyond that produced by the individual drugs. In fact, PTH alone increased bone mineral density at least as well as or better than combination therapy. It is thought now that alendronate, given concurrently with PTH, may reduce the bone-building effects of PTH, and the therapeutic effect of PTH is somewhat diminished when the two agents are combined. Both patients and physicians benefit from knowing how the combination compares to single drug treatment.

These findings could offer important clinical guidance to people at high risk for fractures and to those who treat them. People with osteoporosis have had their treatment options diminished by reports in recent years that the negative consequences of long-term estrogen therapy out-weigh the positive effects on bone. We need more information on safe and effective alternatives for treating osteoporosis. Both of the drugs tested in this project are an important part of the arsenal to treat patients with osteoporosis. NIAMS-supported researchers are pursuing additional research to determine if the optimal effects of these drugs might be achieved by sequential or cyclic therapy, rather than by combining them at the same time. In addition, a comparative study of fracture rates will also be initiated to assess drug effectiveness. The NIAMS is continuing its strong commitment to identifying the most beneficial and best tolerated therapies for osteoporosis, and these recent research studies have provided important information on osteoporosis treatment to affected people and their health care providers.

Bone Quality

To date, the best surrogate of bone quality is the measurement of bone mineral density by DXA (dual energy x-ray absorptiometry). However, it is generally agreed that DXA does not really adequately assess bone quality. As a consequence, the NIAMS sponsored a meeting to encourage new approaches to studying and assessing bone quality. One of our goals for this meeting was to stimulate cross-disciplinary collaborations among investigators in the areas of bone mechanics, bone imaging, and clinical medicine. We were pleased to have the participation of so many representatives from the pharmaceutical and imaging companies at this meeting. We plan to foster research and new technology in this area so that better tools can be developed to assess fracture risk. The NIAMS is very interested in stimulating the development of public-private partnerships and initiatives in this important area of bone quality assessment.

In other research related to bone mineral density, a study by an interdisciplinary team of researchers determined that the combination of supervised aerobic, weight-bearing and weight-lifting exercises, three times per week for a year, provided significant improvement in the bone mineral density of postmenopausal women at specific bone sites. The key to reaching the goal of improved bone health is in the intensity of the weight-bearing workout. It is especially noteworthy that this benefit was found for women not taking hormone replacement therapy as well as for women who were taking hormone replacement therapy.

Other researchers in this field have studied bone mineral content and size in young children and determined that the effect of physical activity is amplified by calcium supplementation. This determination that calcium intake can modify the response of bones to exercise holds promise for the ability to create effective exercise programs that include not only exercise, but also optimal calcium intake. Research has demonstrated the importance of building bone mass in young children and adolescents, and this study in young children provides important information on the interaction between calcium and exercise that will be useful to parents, schools, and sports programs for young children.

Similar Outcomes for Limb Reconstruction and Amputation After Trauma

For years it was not known whether amputation or limb reconstruction provided a better outcome for patients who suffered severe trauma to the leg. Recent research reports indicate that individuals who undergo limb reconstruction or amputation following severe trauma to the lower leg fare about the same functionally. The NIAMS-supported study, Lower Extremity Assessment Project (LEAP), is a multicenter initiative that was intended to: (1) compare clinical and functional outcomes for those undergoing amputation versus reconstruction, (2) identify early clinical predictors of successful limb salvage and good functional outcomes, and (3) identify characteristics of the patient and environment that affect functional outcomes and well-being. Despite medical and surgical advances in reconstruction of severely injured legs, patients undergoing this procedure were more likely than those who had amputations followed by a well-fit prosthesis to experience serious complications requiring re-hospitalization for additional surgery. However, when overall functional outcome was determined by the Sickness Impact Profile (a measure of self-reported health status), there was very little difference between patients in the reconstruction and amputation groups. Fifty-three percent of patients in the amputation group and 49.4 percent of those in the reconstruction group returned to work within two years of their procedure. Neither the severity of fracture and soft-tissue injury nor the presence of other injuries in the same or opposite leg significantly affected the functional outcome. The findings of this study should help surgeons and patients make better-informed decisions when choosing between reconstruction or amputation of a limb that has been severely damaged.

Quality of Life for People with Low Back Pain

Participation in a self-management program decreases symptoms associated with low back pain and increases confidence in managing low back pain symptoms for inner city patients, according to a recent study funded by NIAMS and the Department of Veteran Affairs. Researchers followed inner city patients participating in either a self-management program or in standard care. The researchers found that those individuals participating in the self-management program reported less anxiety and depression, less low back pain, less fear of physical activity and movement, and more confidence in managing back pain symptoms. There is a high prevalence of back pain in the United States, and additional research on reducing back pain disability - especially in socioeconomically vulnerable patients - is needed. Self-management strategies show promise as a tool to improve the quality of life for selected individuals who experience acute low back pain.

Insights into the Interaction of Bone and the Immune System

Many bones in the skeleton are partially hollow, and are filled with marrow. The marrow is the source of the many types of infection-fighting cells of the immune system, and also of the cells that produce and break down or resorb bone. In spite of this close relationship between bone and the immune system, much is still unknown about the nature of bone/immune interactions. Evidence is accumulating that similar biochemical signals are important in both bone and the immune system. Under certain conditions, cells of the immune system can influence the activities of bone cells. However, it remains unclear how important such interactions are for skeletal health and disease. Several avenues of study have revealed significant parallels and interactions between bone and the immune system. One group discovered that bone cells have a particular protein called CD40 on their surfaces. This suggested that the bone cells might interact with CD40's partner protein, called CD40L, which is known to prevent the death of immune cells called dendritic cells. In experiments, investigators found that CD40L did prevent the death of bone cells that normally occurs in the presence of a drug used to suppress the immune system. This is potentially important because increased cell death rates among bone cells are observed under a variety of conditions that lead to bone loss. A second research group focused on a particular protein called RANKL, which is important for both bone and the immune system. Mice that lack RANKL have both immune defects and a condition called osteopetrosis, caused by an absence of bone-resorbing cells, called osteoclasts. Osteopetrotic bones lack a marrow space, and grow slowly. Using genetic engineering techniques, investigators created a mouse in which RANKL was produced only by immune cells. In these mice, osteoclasts were present and the marrow space was restored, but the growth defects persisted. Thus, immune cells can provide the RANKL necessary for osteoclast development, but only in certain parts of the skeleton. Finally, researchers have identified new factors in the complex chain of events that links estrogen deficiency with bone loss. In mice, estrogen deficiency leads to a stimulation of immune cells, increasing production of several proteins that promote bone resorption. Similar events may contribute to post-menopausal bone loss in women, leading to osteoporosis. Taken together, these studies provide a growing body of evidence that suggests that bone/immune interactions must be taken into account in the design of therapies. For example, bone loss induced by immuno-suppressive drugs (used in organ transplantation, and to treat some rheumatic diseases) is a serious clinical problem. Targeting drugs to CD40 on bone cells could prevent the death of these cells, preventing bone loss. Conversely, if immune cells are involved in bone loss, targeting drugs to specific immune functions may provide new preventive therapies for osteoporosis arising from a variety of causes.

Total Joint Replacement

Researchers have reported significant progress in the whole field of joint replacement, including three recent findings: The first study focused on the long-term results of total hip replacement performed in young adults. Total hip replacement has been previously shown to be a highly successful treatment for end-stage arthritis in older adults with severe pain and limited functions. With this success has come the gradual expansion of the indications for total hip replacement to younger adults (50 years old and younger). Unlike older adults, the indications for total hip replacement in these younger patients is usually arthritis that results from hip dysplasia, trauma or infection. Because of their age and greater activity level, this group of patients places unique stresses on these artificial joints, which may predispose such patients to increased wear and premature artificial joint failure. To alleviate this concern, porous coated implants have been designed, in which the patient's own bone grows into pores (holes) in the surface of the implant to hold it in place. Conventional total hip replacements have implants that are cemented into the end of the femur and into the pelvis. The NIAMS supported a 25 to 35-year follow-up of patients who received conventional total hip replacements that were cemented. All individuals were less than 50 years old when surgery was performed, and all surgeries were performed by the same surgeon in the same hospital. The results from this study were that less than one-third of the original total hip replacements had to be revised or removed, while more than two-thirds of the original group who had a total hip replacement were functioning well at the latest follow-up. This study confirms that a well performed conventional total hip replacement (cemented) provides excellent results in patients less than 50 years old with isolated disease in one or both hips. Additional research is needed to further compare the results of cemented versus porous coat implant total hip replacements.

The second study in this area determined that the timing of total joint replacement affects clinical outcomes among patients with osteoarthritis of the hip or knee. While analyses have established that total hip replacement and total knee replacement are both highly successful and cost-effective procedures for end-stage joint disease, the influence of the timing of these two procedures on patient outcomes had not been previously examined. Researchers at an NIAMS-supported Multidisciplinary Clinical Research Center studied patients undergoing elective total hip replacement or total knee replacement for osteoarthritis and followed them for 2 years postoperatively. Patients were characterized as high function or low function before surgery. Improvements in pain and function were constant after six months. However, patients who were in the low function group before surgery had a higher level of pain and lower level of function than patients who were in the high function group before surgery. So although the surgery reduced pain and improved function, these were not improved to the same degree as those in the pre-operative high function group. This study suggests that patients operated upon earlier in the course of functional decline have better outcomes. The improvements in functional status are seen in six months and persist through 24 months. This observation supports a strategy to intervene earlier with total joint replacement in patients with lower extremity osteoarthritis.

The third study identified risk factors for hip replacement in women. Using information from participants enrolled in the Nurses Health Study who received a hip replacement to treat hip osteoarthritis, researchers examined several risk factors including body mass index, use of hormone therapy after menopause, age, alcohol consumption, physical activity and cigarette smoking. Of these potential risk factors, only body mass index and age were associated with needing hip replacement. Participants with a high body mass index showed double the risk for having a hip replacement compared with low body mass index participants. Those individuals who had a high body mass index at age 18 had five times the risk for receiving a hip replacement while those women age 70 and older were nine times more likely to have a hip replacement compared with those under age 55. This is one of the first long-term prospective studies to show an association between a modifiable risk factor and osteoarthritis. Results suggest that reducing weight may improve quality of life and decrease health care costs related to osteoarthritis. The NIAMS partnered with the National Cancer Institute and the Arthritis Foundation in supporting this study.

In other news related to joint replacements, 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) held a Consensus Development Conference on Primary Total Knee Replacement on December 8-10, 2003. Six questions formed 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? We look forward to the report from this meeting and the recommendations it will provide for the best ways to address areas of research opportunity.

Muscle Biology and Muscle Diseases

Reversing Muscle Degeneration

The broad fields of muscle biology and muscle diseases are active areas of research, and there are many exciting advances to highlight in these areas. One example is the recent report from scientists who have discovered how to reverse muscle degeneration in a mouse model of Duchenne muscular dystrophy. Researchers devised a way to revitalize wasting muscle by using a special carrier to introduce the missing dystrophin gene into the diseased muscle tissue. Using a strain of mouse that lacks the dystrophin gene, researchers injected affected muscles with the missing gene, using a special adenovirus vector, or carrier. The muscles became more able to resist injury and muscle function was restored. Such techniques could eventually lead to gene therapies for patients with Duchenne muscular dystrophy once it is possible to provide gene delivery to all of the muscles in the body.

Faulty Gene is Key to Understanding Myotonic Dystrophy

Researchers have succeeded in linking the gene defect in myotonic dystrophy to its biological malfunction. Their findings emphasize how misreading of a gene can lead to improper conduction of electrical impulses in skeletal muscle. Two different studies were completed. The first examined tissue samples from skeletal muscle in patients with myotonic dystrophy, and the results revealed that extra genetic material caused by the defect in the DNA sequence affects the chloride channels that control muscle relaxation. The second study measured electrochemical muscle impulses in a mouse model of the disease. The results indicated that the genetic defect affects the conductance of electrical signals, resulting in delayed muscle control. People with myotonic dystrophy have the normal gene with additional information that interferes with the translation of proteins. While further study still needs to be done, these findings are a key step in understanding the causes of this type of muscular dystrophy.

Facioscapulohumeral Muscular Dystrophy Study Shows Chromosomal Variation

NIAMS-supported scientists have found that people with facioscapulohumeral muscular dystrophy (FSHD) have an exclusive association with one of the two different forms, or alleles, of the chromosomal region linked to the disease. Scientists examined the alleles 4qA and 4qB in people with FSHD and in controls. The alleles occurred with roughly equal frequency in the control group, but in the FSHD group, the affected allele was always of the 4qA type. This research may lead to a better understanding of the role of genetics in people with FSHD.

NIAMS Scientists Find Biochemical "Switch" Directs Muscle Building

Scientists may soon be able to influence muscle formation more easily as a result of research conducted in the NIAMS Intramural Research Program. These researchers along with collaborators in California and Italy have found that inhibitors of the enzyme deacetylase can switch the pathway of muscle precursor cells (myoblasts) from simply reproducing themselves to becoming mature cells that form muscle fibers (myotubules). It has been known for some time that deacetylase prevents the skeletal muscle gene from being expressed, and inhibits myoblasts from forming muscle. This research team has found that under certain conditions, deacetylase inhibitors (DIs) in myoblasts enhance muscle gene expression and muscle fiber formation. Knowledge of how DIs act against deacetylase is providing important insights on potential ways to correct problems that occur during embryonic muscle development. This research may also lead to methods to induce muscle growth, regeneration, and repair in adults.

Muscular Dystrophy Initiatives

The NIH has been actively engaged in implementing the Muscular Dystrophy Community Assistance, Research, and Education Amendments of 2001 (the MD-CARE Act), to boost research and training related to all forms of muscular dystrophy. In September 2002, NIH issued a Request for Applications (RFA) entitled "Muscular Dystrophy Cooperative Research Centers," and in October 2003, following peer review of the submitted applications, NIH announced plans to establish three new centers. The NIAMS, the National Institute of Child Health and Human Development (NICHD), and the National Institute of Neurological Disorders and Stroke (NINDS) are each funding one center at up to $1 million in direct costs per center per year for five years. The centers are based at the University of Pittsburgh (funded by NIAMS); the University of Washington, Seattle (funded by NICHD); and the University of Rochester, New York (funded by NINDS). Researchers at the three centers will conduct studies on Duchenne, myotonic, and facioscapulohumeral muscular dystrophies, and will investigate therapeutic approaches including stem cell and gene therapy.

In a novel collaboration, the Muscular Dystrophy Association (MDA) has agreed to commit up to $1.5 million to enhance research activities at each of the three Centers funded by NIH ($500,000 per center per year for three years). The NIAMS, NINDS, and NICHD signed a Memorandum of Understanding (MOU) with the MDA in May 2003 to formalize this partnership. The principal investigators of each center have been invited by the MDA to apply for these supplemental funds, and the MDA expects to make awards in early January 2004.

The NIAMS will continue to work collaboratively with NINDS and NICHD on the Centers program. As required in the "Muscular Dystrophy Cooperative Research Centers" solicitation, a steering committee to ensure overall coordination of the program is being formed, and will include the scientific program officers from NIAMS, NINDS, and NICHD, the principal investigators of each center, a bioethicist, and a lay member. However, the Centers program is only one of the many ways that NIH is working to further MD research and training. All three institutes are represented on the Muscular Dystrophy Coordinating Committee (MDCC), which held its first meeting in July 2003, and the group is currently in the process of developing a research and education plan for MD. The plan will highlight opportunities for future research and training initiatives, and identify road blocks to progress in this area. In recent years, the three institutes have worked together to co-sponsor initiatives and workshops on MD. All three institutes also participate in the NIH MD Research Task Force to help guide efforts to intensify research and training related to muscular dystrophy. It is important that NIH use its resources to support a wide range of activities on MD, including support for the new centers program. Such a multi-faceted approach will likely yield the most significant advances in understanding and treating the muscular dystrophies.

Skin Biology and Skin Diseases

Identification of the Genetic Basis of Predisposition for Vitiligo and Other Autoimmune Diseases

Generalized vitiligo is a common autoimmune disorder characterized by loss of pigment in patches on the skin and hair. It often clusters in families allowing for genetic analysis. In addition, vitiligo is often seen in individuals who have multiple autoimmune diseases. It is a potentially socially devastating disease particularly in more darkly pigmented individuals and races. Thus, an understanding of the susceptibility and the mechanism for the development of vitiligo should facilitate research into prevention and treatment. A group of investigators studied families gathered from both the United States and the United Kingdom, and analyzed multiple family members who were affected by vitiligo. Linkage to a particular location on chromosome 1 established this as the major susceptibility site for vitiligo. The same investigators also used their large population base to look at the coexistence of other autoimmune diseases and vitiligo in these families. They demonstrated that within the same family there were likely to be multiple members with vitiligo as well as other individuals with autoimmune thyroid disease, pernicious anemia, Addison's disease, systemic lupus erythematosus, and inflammatory bowel disease. Many of these autoimmune diseases can be severe both in terms of the general health of the individual and in terms of psychological and social impact. Understanding the genetic basis as well as the environmental triggers that may lead to the development of vitiligo is important in prevention and treatment.

Understanding the Molecular Events in the Development and Progression of Melanoma

Melanoma is the most severe skin disease with regard to mortality, accounting for approximately half of all deaths from skin disease. Scientists are striving to understand the molecular events involved in the transformation of normal pigment cells of the skin to melanoma cells and the early progression of melanoma. A group of investigators, recognizing that certain atypical moles predisposed individuals to the development of melanoma, studied these cells in culture and added genes to turn on a particular protein (MAPK). The introduction of this activated gene resulted in the development of factors involved in melanoma invasion and metastasis, indicating that this pathway is probably important in melanoma development. This new understanding may facilitate the design of therapeutic interventions to suppress this pathway. Recognition of the molecular pathways that result in malignant transformation of melanocytes into melanoma cells and the spread of melanoma should facilitate the design of better methods for identifying the disease in its earliest stages as well as the design of better therapeutic interventions.

Gene Therapy of Epidermolysis Bullosa

Epidermolysis Bullosa (EB) is a group of severe hereditary blistering skin diseases. Many of them are fatal either early in infancy or in childhood or young adulthood, and the less severe forms may be disabling for affected individuals. Gene therapy for permanent correction of various forms of EB is the ultimate goal. One challenge is the potential complications of viral based DNA transfer. A new method of nonviral transfer of normal genes to correct the EB defect has been investigated by NIAMS-supported researchers. They have been able to demonstrate sustained correction of the abnormality in affected cells that demonstrate the defect. Thus, this potentially safer form of gene transfer may eventually result in genetically based treatments for these affected children. Another research group was also able to demonstrate the use of genetically corrected cells to facilitate the healing of wounds in one form of severe EB (recessive dystrophic EB) that usually results in severe deformity and death in early adulthood. In this particular strategy the cells providing the normal gene and gene product were fibroblasts (cells normally present in the deeper layers of skin) rather than the cells of the epidermis (the outer layer of skin) that are usually thought to be the prime target of the disease. This methodology potentially provides a better way to heal the wounds of EB of this type, although it is not a permanent or long lasting cure. These studies indicate progress in providing potential treatments, both curative very early in life or palliative to reverse the major skin defects later in life in different forms of Epidermolysis Bullosa. They also provide evidence for the success of potentially safer methods of gene therapy in the treatment of skin and other diseases.

The Genetic Basis of Psoriasis

Psoriasis is one of the most common skin diseases. It can be mild or quite severe. When severe, it has a major adverse impact on an individual's ability to conduct the normal activities of daily living and can be disabling. There are many treatments for psoriasis, but none of them is without significant risks. Many new treatments are becoming available, particularly for more severe disease. An improved understanding of the molecular and genetic basis of the disease would allow more rational treatments to be designed. One of the major thrusts in understanding psoriasis is looking for genes common to multiple members of the same family in whom psoriasis is prevalent. Using familial clusters of psoriasis, a group of investigators has demonstrated that a particular area of human chromosome 17 is where susceptibility for psoriasis exists, at least in some families. This study needs to be confirmed in other larger groups before it can be determined whether it is a common or major susceptibility determinant for the disease. Using gene arrays, a multicenter clinical study was undertaken to demonstrate which mediators and markers were activated in diseased skin as compared to normal skin of people with psoriasis and normal controls. The results indicate that immune T-cells, as well as other immunologic cells that reside in the skin called dendritic cells, demonstrate a pattern of inflammatory mediators that sustain the psoriatic skin type. It appears that multiple components of the immune system are activated in developing the disease pattern that we recognize as psoriasis. Once we understand the genes that are involved, we will have a better idea of the gene products that drive the skin to produce psoriasis. This will give us a better approach to designing specific therapeutic interventions that will minimize or eliminate the abnormal skin appearance, but are less detrimental to the overall immune system.

Information Dissemination

The NIAMS remains committed to a comprehensive program of information dissemination to patients and to their health care providers. We work closely with our many voluntary and professional societies to both learn their needs and views and to disseminate our research findings to them. We have also targeted our information to particular areas of need (including "Lupus: A Patient Care Guide for Nurses and Other Health Professionals" and "The Many Shades of Lupus") and to diverse populations (including printed information and our toll-free information line in Spanish). We will continue to build and strengthen these relationships with the community and will strive to make our information accessible to the vast and diverse populations affected by the diseases within our scientific mission. We are very proud of the new arm of our information dissemination efforts - the NIAMS Spanish-language home page. A new Spanish-language Web site has been launched to provide information about research and health education on diseases of bones, muscles, joints, and skin. The NIAMS has developed En Espaņol (In Spanish) as a tool to reach out to the growing Hispanic/Latino population through the Institute's home page. En Espaņol, launched during Hispanic Heritage Month, provides vital information about health, research, grants, and available clinical trials on the NIAMS Web site as well as information about the Institute's leadership and budget. The new Web site offers an opportunity to learn more about the NIAMS mission and how it is implemented through research and other initiatives to improve the health of the nation.

Conclusion

The 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 of bones, muscles, joints, and skin are chronic and many cause life-long pain, disability, or disfigurement. They afflict millions of Americans, cause tremendous human suffering, and cost the United States economy billions of dollars in health care and lost productivity. These diseases affect people of all ages, racial and ethnic populations, and economic strata. Researchers supported by the NIAMS are using powerful research tools to acquire and apply new knowledge to studies of some of the most challenging diseases affecting Americans today. Many of these diseases have troubled patients for decades, but each year significant discoveries bring researchers closer to fully understanding, diagnosing, treating, and ultimately preventing these common, disabling, costly, and chronic diseases, which greatly compromise quality of life. This was a productive year for NIAMS-supported investigators who reported significant progress in their research studies. In the future, the Institute plans to build on these advances and launch initiatives to pursue the most promising research opportunities and needs with the continuing goal of advancing the scientific enterprise and improving public health.

Budget Policy

The Fiscal Year 2005 budget request for the NIAMS is $515,378,000, an increase of $14,470,000 and 2.9 percent over the FY 2004 Final Conference Level. Also included in the FY 2005 request, is NIAMS's support for the trans-NIH Roadmap initiatives, estimated at 0.63% of the FY 2005 budget request. This Roadmap funding is distributed through the mechanisms of support, consistent with the anticipated funding for the Roadmap initiatives. A full description of this trans-NIH program may be found in the NIH Overview.

A five year history of FTEs and Funding Levels for NIAMS are shown in the graphs below. Note that the Fiscal Year 2001 FTE figure is not comparable to the figures in the succeeding years due to NIH's consolidation of its Human Resources function in FY 2003.

FTEs by Fiscal Year. In 2001, 209 FTEs. In 2002, 245 FTEs. In 2003, 250 FTEs. In 2004, 236 FTEs. In 2004, 236 FTEs
Funding Levels by Fiscal Year. In 2001, $396.3 million. In 2002, $447.8 million. In 2003, $486.6 million. In 2004, $501.1 million. In 2005, $515.4 million.

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 2005 NIH request provides for an aggregate 1.3 percent increase in average cost for Research Project Grants, consistent with the Gross Domestic Product deflator. The NIAMS is providing an average cost increase of 1.9 percent for direct recurring costs in noncompeting continuation awards. Competing RPGs are based on an average cost increase of 1 percent.

Advancement in medical research is dependent on maintaining the supply of new investigators with new ideas. In the Fiscal Year 2005 request, NIAMS will support 296 pre- and postdoctoral trainees in full-time training positions. Stipend levels for pre-doctoral and post-doctoral recipients supported through the Ruth L. Kirschstein National Research Service Awards will remain at FY 2004 levels.

The Fiscal Year 2005 request includes funding for 38 research centers, 174 other research grants, including 56 clinical career awards, and 67 R&D contracts. Intramural Research and Research Management and Support receive increases to support increased pay and estimated inflationary increases in FY 2005.

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

FY 2005 Budget Mechanism pie chart. Research management and support, $21.6 million. Intramural research, $50.8 million. R and D contracts, $29.5 million. Research training, $15.3 million. Other research, $21.9 million. Research centers, $42.6 million. Research project grants, $333.3 million.
Bar chart showing FY 2005 Estimate Percent Change from FY 2004 by Mechanism. Research management and support, 2.8 percent. Intramural research, 2.9 percent. R and D contracts, 31.1 percent. Research training, 3 percent. Other research, 3.7 percent. Research centers, 3.8 percent. Research project grants, .8 percent.