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Congressional Justification Narrative
February 2006 (historical)
Authorizing Legislation: Section 301 of the Public Health Service Act, as amended.
|FY 2005 Actual||FY 2006 Appropriation||FY 2007 Estimate||Increase or Decrease|
This document provides justification for the Fiscal Year 2007 activities of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, including HIV/AIDS activities. A more detailed description of NIH-wide Fiscal Year 2007 HIV/AIDS activities can be found in the NIH section entitled "Office of AIDS Research (OAR)." Detailed information on the NIH Roadmap for Medical Research may be found in the Overview section.
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 of bones, muscles, joints, and skin affect people of all ages, racial and ethnic populations, and economic strata.
The NIH Roadmap for Medical Research: A major challenge in chronic diseases is the inability to really assess many dimensions of these diseases in objective ways. As part of the Re-Engineering the Clinical Research Enterprise component of the NIH Roadmap for Medical Research, the NIAMS is leading efforts to address this challenge. The NIH is funding six primary research sites and a statistical coordinating center for a network known as PROMIS - the Patient-Reported Outcomes Measurement Information System. The goal is to develop ways to measure patient-reported symptoms such as pain and fatigue and aspects of health-related quality of life across a wide variety of chronic diseases and conditions. Additional information on PROMIS can be found in the NIH Roadmap section of the Congressional Justification.
NIAMS Science Advances and New Initiatives
The NIAMS provides support for research across a broad spectrum of approaches, understanding that the ultimate conquest of diseases always involves basic, animal model, clinical, clinical trial, and prevention research. In most cases, the essential ingredient is the translation: taking the findings at the research bench and applying them to human disease, and taking observations from the bedside and using them to inform and guide basic research. We are proud of the stories of research progress from NIAMS-funded research, and we continually seek to identify areas of research opportunity and need. What follows are highlights of stories of progress and promise and new scientific initiatives.
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.
Barriers to Treatment Compliance in Economically Challenged Arthritis and Lupus Patients
Researchers supported by the NIAMS have identified some barriers that keep people who are economically disadvantaged as well as people from diverse ethnic backgrounds from complying with their prescribed medical treatments, including fear of side effects, belief that the medicines are not working, problems with the health system environment, and medication costs. Fear of side effects was the most often-mentioned factor - patients were concerned about long-term damage if they continued to take the medications. Some patients expressed concern that the prescribed drugs were not working - either the medications were not providing relief from symptoms or they were concerned because the drugs were not curing the disease. Problems with the health care system included navigating the requirements for Medicaid and the lack of continuity in seeing the same doctor. The financial costs of the medications meant that some people stopped taking their prescribed medications since many of them had little or no medical coverage. Other obstacles included language barriers for some Hispanic patients in this study and a shortage of translators; difficulties in scheduling appointments when patients had sporadic and unpredictable employment; financial difficulties in paying for the appointments; a lack of transportation to get to the appointments; and the severity of their illness on the day of the appointments often made the patients unable to keep appointments. Studies like this provide information on sensitivity to different populations, and are important as we continue to address the issues of health disparities - to identify the many, complex factors that make some populations more vulnerable to diseases within our mission areas.
Lupus Deaths in Minorities
Lupus is one of the many diseases within our mission areas that occurs in increased numbers and often greater severity in women and minorities, and recent reports suggest that lupus deaths may be underestimated in ethnic minorities with low education levels. In epidemiologic studies, higher socioeconomic status has been consistently coupled with lower overall mortality, and specifically with fewer deaths from cardiovascular and cerebrovascular diseases. In race-specific studies, similar associations have been found, but researchers have questioned whether the incidence of lupus-caused deaths follows the same pattern. An investigator in the NIAMS Intramural Research Program, drawing on data from the National Center for Health Statistics, recently studied U.S. deaths in people with lupus over a three-year period. It was determined that in whites of both genders, the incidence of lupus-caused deaths does decrease as socioeconomic status increases. However, in three minority categories -- African American men, African American women and Asian/Pacific Islander women -- the risk of death from lupus was lower among those with lower education levels. This study also compared the education/mortality link in lupus to that of other causes of death, and found that people with lower educational levels were underrepresented among deaths from lupus for the three minority categories. It is speculated that the under-representation was likely due to under-reporting and under-diagnosis.
Total Knee Replacement in Minorities
Researchers at a NIAMS-supported center undertook an analysis of the epidemiology of total knee replacement in the U.S. Medicare population. There is a real shortage of epidemiologic data in all of our mission areas, and this particular report described the rates of primary and revision total knee replacement and selected outcomes in people in the U.S. who were older than 65. Using Medicare claims and information on total knee replacements in the year 2000, the data showed that the rate of primary knee replacement was lower in African Americans than in whites. It was also lower in those qualifying for Medicaid supplementation than in those with higher incomes. Furthermore, African Americans had higher rates of mortality, readmission, and wound infection after primary knee replacements than whites. In addition, patients who qualified for Medicaid supplementation had high complication rates, particularly after primary knee replacement. While overall the rates of postoperative complications during the 90 days following total knee replacement are low, these data underscore the health disparity challenges that we face in many of our mission areas.
Bone Biology, Bone Diseases, and Orthopaedics
New Combinations and Sequential Use of Therapies for Osteoporosis
NIH-supported researchers reported seminal findings in 2003 on the use of combination therapies for the treatment of osteoporosis, and they have now taken the original studies to the next stage of investigation - with important results that provide good news for people with osteoporosis. The original study compared the effectiveness of combining the bone-building treatment of parathyroid hormone (PTH) with a drug that slows bone loss (alendronate). The results from two different studies demonstrated that combining injections of PTH with alendronate taken orally produced no significant improvement in bone mineral density compared to administering the drugs individually. In fact, PTH alone increased bone mineral density at least as well as or better than the combination therapy. In the latest study, women taking PTH alone in the first year were given either no drug in the second year or were switched to alendronate. The women receiving no drug after a year of PTH began to lose the bone they had gained during treatment. The women who switched to alendronate in the second year after taking PTH for the first year continued to gain bone, particularly in the spine. These studies demonstrate that the sequential use of PTH as a bone building drug followed by alendronate as an anti-resorptive (or bone conserving) drug maximized the bone gain as measured by bone mineral density.
In a related study in a different laboratory, researchers found that treatment with PTH does not need to be continuous throughout the year. In fact, cyclic treatment with PTH for three months followed by three months of alendronate alone was as effective in stimulating bone gain as the continuous use of PTH for 12 months. Taking 3-month breaks from PTH not only provides cost benefits, but also improves quality of life for patients who do not need to inject the drug every day. Physicians and patients can use the results of both of these studies to strategize for the best therapeutic benefit while minimizing drug use and cost.
In osteoporosis, bone strength is compromised and affected people have an increased risk of fractures. The term "bone quality" is not well defined, but it is used to describe the diverse factors influencing skeletal health and fracture risk that go beyond the measurement of bone mineral density. Although bone mineral density measurement is among the most useful clinical tools for diagnosing osteoporosis, its limitations have become apparent. Thus, bone quality and skeletal fragility have become critical topics for basic scientists, clinical investigators, and clinicians. The NIAMS partnered with the American Society for Bone and Mineral Research, the French Institute of Health and Medical Research (INSERM), and the NIH National Institute of Biomedical Imaging and Bioengineering, in sponsoring the meeting, "Bone Quality: What Is It and Can We Measure It?" on May 2-3, 2005. This scientific meeting brought together leading scientists from around the world to identify needs and future directions in bone quality research; highlighted basic science, clinical, regulatory (U.S. Food and Drug Administration), and pharmaceutical perspectives; assessed established and new methods for measuring bone quality and explored how to include them in clinical trials; and discussed novel mechanisms to bring together research efforts on bone quality to move this research field forward.
Markers of Fracture Risk in Older Persons
Elevated levels of the amino acid homocysteine have long been associated with an increased risk of cardiovascular disease, including heart attack and stroke. But a new research study suggests that high homocysteine levels also may be linked to the development of osteoporosis and related fractures. Investigators measured blood homocysteine levels and screened for hip fracture over a 16- to 19-year period in nearly 2,000 older (over 59) Framingham Osteoporosis Study participants. Analyses revealed that men and women with the highest homocysteine levels were at greater risk for hip fracture than those with the lowest levels. The risk was increased fourfold in men and twofold in women, and it was independent of other risk factors for fracture, such as age and weight. It is not clear from the study whether homocysteine has a direct effect on bone and fracture or whether it serves as a marker for something else. But this latest research shows that elevated homocysteine levels are emerging as an important risk factor for hip fractures in older persons. Since folic acid and other B vitamins in the diet can manipulate homocysteine, this may suggest a new therapeutic approach to reducing the risk of hip fractures in the elderly.
Basic Genetic Studies in Osteoporosis
Although scientists know that many genes influence bone mass and thus osteoporosis risk, identifying specific genes has been challenging - especially in humans, who are genetically diverse. By using laboratory mice, whose bone physiology is similar to humans, however, NIAMS-supported researchers have been able to locate a gene that not only influences bone density in mice, but also provides new insight into how to preserve bone mass in people. These researchers identified the gene, called alox15, while working with two strains of mice that have very different bone mineral densities. Variations in the gene, they discovered, account for a significant part of that difference. While scientists have known of the gene for some time, it was never recognized as important for the skeleton. Instead, it was known to be involved in the metabolism of certain fats and was believed to play a role in heart disease and other health problems. Because there are two genes in people with activities similar to that of alox15, scientists believe that one or both of these genes might be targets for treatment of osteoporosis. Also, the discovery of alox15's influence on bone mass suggests that a previously unsuspected metabolic pathway could be important for skeletal health. By further studying this pathway, scientists may find additional clues for preventing osteoporosis and the resulting fractures.
Progress in the Development of a Genetic Treatment for Osteogenesis Imperfecta
Scientists supported by the NIAMS have made an important step toward using gene therapy to treat severe cases of osteogenesis imperfecta (OI), a genetic disease in which bone is fragile and highly vulnerable to fracture. Severe cases of OI can lead to serious bone malformation and even death. Most cases of OI are due to mutations in the gene that produces a protein called type I collagen, which forms a network of fibers in bone and provides much of its strength. Everyone has two versions of the gene, so mutations that simply inactivate one version usually produce mild cases. But when mutations result in an abnormal collagen molecule, the mutant collagen can interact with normal collagens, disrupting the fiber network and drastically reducing the strength of bone. The scientists reasoned that by turning off the affected genes in these more severe patients, they could transform them into milder cases. They tested their theory in cultured cells from bone marrow, where bone-forming cells normally arise, by infecting the cells with harmless viruses specially modified to inactivate a gene. The greatest challenge in this process was to target the viruses to the collagen gene, avoiding the inactivation of normal genes with other functions. Using cells from OI patients with severe forms of the disease, the scientists were able to correctly target the collagen gene with the modified virus in 90 percent of the cells into which the viruses were inserted. Just as important, cells in which the mutant collagen gene was inactivated were shown to produce normal collagen and retain the ability to develop into mature bone-forming cells in culture. Although this approach to gene therapy is not yet ready for testing in humans, advances like this bring scientists closer to being able to repair genetic errors, not just for OI, but also for many other diseases that are due to the activity of abnormal genes. This may enable those born with genetic errors to escape lifelong and often devastating consequences.
Outcomes Following Severe Leg Injuries
Severe injuries of the legs as the result of pedestrian and motor vehicle accidents continue to be common, costly, and disabling public health problems. This is especially true for those leg injuries that put individuals at risk of losing their legs. A study conducted several years ago - the Lower Extremity Assessment Project (LEAP) -- provided prediction tools to be used by patients and providers in making treatment decisions, and demonstrated that patients treated with amputation and those treated with reconstruction had similar functional outcomes at two years following severe limb-threatening injuries. The most recent study assessed the functional outcomes 7 years following these treatments, and assessed whether previously determined risk factors had an impact on functional outcomes at 7 years. Patient characteristics that were significantly associated with poorer long term outcomes included: older age, female gender (physical functioning only), non-white race, lower education level, living in a poor household, current or previous smoking, low self-efficacy, and health status before the injury. The LEAP study is one of the first long-term, and largest prospective assessments of outcome following major lower leg injuries. These long-term results confirmed the investigative team's previous conclusions that efforts to improve the rate of successful reconstructions have merit. The long-term outcomes found in this study suggest that reconstruction of severe lower leg injuries below the knee joint is a goal for trauma centers. Regardless of the treatment option, however, long-term functional outcomes for both amputation and reconstruction groups are poor, underscoring the significant public-health impact of major leg trauma. Additional studies are needed on the post-acute-care services that address other conditions that affect optimal recovery. Clinical interventions that can reduce limb complications and the need for hospital readmission should also be determined.
Importance of Surgical Experience in the Outcomes of Total Knee Replacement
A research team analyzed almost 81,000 claims of Medicare patients who had primary or revision total knee replacement between January 1 and August 31, 2000. The results suggest a positive relationship between surgeons and hospitals performing a high volume of total knee replacements and the outcomes for these interventions. The study found that patients of surgeons who perform 50 or more total knee replacements per year had a lower incidence of morbidity and postoperative complications than those whose doctors do 12 or less. Also, hospitals in which 200 or more total knee replacements are performed per year demonstrated similar positive outcomes in contrast to facilities that do less than 25 of these procedures per year. The data were adjusted for age, gender, co-morbid conditions, Medicaid eligibility (which is a marker of low income) and arthritis diagnosis. The findings of this study are consistent with those reported previously on associations between procedure number and outcome for hip replacements. Arthritis is a major contributor to impairment of daily functions and disability in affected people, and it accounts for significant numbers of hospitalizations and health care costs in the elderly. Total joint replacements are a major advance in the treatment of joint deterioration and, if successful, make a significant difference in quality of life of patients. Studies like this most recent report on the positive relationship between outcome of total joint replacements performed by surgeons and in hospitals with high volumes of these procedures can help to guide patients in their decisions to undergo this life-changing surgery and improve overall costs and clinical outcomes.
Development of Promising New Polymers for Cartilage Repair
Cartilage is a tissue that lacks capacity for self repair. However, recent multidisciplinary studies by biologists, engineers, physicians, and other are providing new strategies for treating degenerative cartilage that may result in treatments for articular cartilage lesions. Researchers funded by the NIAMS have developed a class of injectable materials based on a biodegradable polymer OPF (oligo-polyethylene glycol fumarate) for cartilage tissue engineering. These are synthetic, biodegradable, and biocompatible polymers that can be injected into a site with a defect and crosslinked in situ under physiological conditions that eliminate the need for invasive surgery. Short-term studies in experimental animals demonstrated excellent tissue filling and integration resulting from implantation of these materials into cartilage defects. The polymers were also designed to deliver bioactive molecules, such as growth factors, as well as cells, such as chondrocytes or progenitor cells to cartilage lesions to enhance tissue repair. Early results show that chondrocytes remain viable, proliferate, and synthesize cartilage matrix components in these polymer gels. Taken together, these results indicate that OPF gels are promising materials for cell delivery in cartilage repair strategies.
The Osteoarthritis Initiative. The NIAMS partnered with the National Institute on Aging, several other NIH components, and three pharmaceutical companies in establishing 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. For the first time, a public-private partnership is bringing together new resources and commitments to help find biological markers for the onset and progression of osteoarthritis. Recruitment of participants is actively underway, and by the end of FY 2005, more than 3,800 participants have been recruited. One year follow-up measurements have been carried out on over 1,000 participants, and will continue for the next 4 years. All data and images collected will be available to researchers worldwide to help quicken the pace of scientific studies and biomarker identification. This consortium serves as a model for future endeavors that link the public and private sectors.
Mechanical Influences on the Induction of Osteoarthritis-related Biomarkers
The influences of biomechanical factors on biomarker production are not well understood, and two separate basic research laboratories explored these influences. The first study was on the role of mechanical stress on biomarker release from normal cartilage. It showed that mechanical stress in the ranges experienced from normal to intense physical activity increased the turnover of cartilage and the release of biomarkers from the tissue and varied with the magnitude of applied stress. This suggests that mechanical stress regulates turnover of molecules in the cartilage extracellular matrix. The second study examined release of cartilage- and bone-derived biomarkers in college athletes undergoing high-intensity training (rowers, cross-country runners, and swimmers) and in non-athlete controls. Analyses of urinary biomarkers suggest that rowers undergo the highest bone turnover and runners the highest cartilage turnover. These results suggest that biomarkers can vary between individuals involved in different types of physical activities. While the mechanisms involved in these processes are not fully understood, these studies indicate that mechanical stress is a variable that can increase the production and release of osteoarthritis-related biomarkers. This research has practical significance in that the interpretation of biomarker analyses from osteoarthritis patients will need to take into account the type and extent of physical activity of the patients.
The Importance of Self-management of Osteoarthritis
When patients understand and feel that they have some control over their chronic disease, the course of their disease is often improved. In this latest study, we learned that improvement can be made in the self-management of osteoarthritis when spouses provide help. The intervention that was tested used spouse-assisted coping skills training and exercise training to improve physical fitness, pain coping, and self-efficacy in patients with osteoarthritis of the knee. The results from this study suggest that a combination of both spouse-assisted pain coping skills training and exercise training leads to more improvements than could be achieved with either intervention alone.
Acupuncture and Knee Osteoarthritis
The NIAMS joined with the National Center for Complementary and Alternative Medicine in a study that revealed that acupuncture relieves pain and improves function in knee osteoarthritis, and it serves as an effective complement to standard care. This study is the longest and largest randomized, controlled phase 3 clinical trial of acupuncture ever conducted. This is the first time that a clinical trial with sufficient rigor, size, and duration has shown that acupuncture reduces the pain and functional impairment of osteoarthritis of the knee. These results also indicate that acupuncture can serve as an effective addition to a standard regimen of care and improve quality of life for knee osteoarthritis sufferers.
Rheumatoid Arthritis and Lupus Erythematosus
A Genetic Variation was Found to Double the Risk of Rheumatoid Arthritis
Scientists have long suspected that autoimmune diseases such as rheumatoid arthritis result from a combination of genetic and environmental factors. Now a NIAMS-funded research team has identified a specific genetic variation, called a single nucleotide polymorphism or SNP, that increases rheumatoid arthritis risk twofold. The SNP is located within a gene that codes for a particular enzyme that is known to be involved in controlling the activation of white blood cells called T cells that play an important role in the body's immune system. Under normal conditions, the enzyme works as a negative regulator: it inactivates a specific signaling molecule which, in turn, interrupts the communications and keeps immune cells from becoming overactive. However, in cases where the SNP is present in one or both copies of a person's genes for this enzyme, the team found that the negative regulation by the enzyme appears to be inefficient, allowing T cells and other immune cells to respond too vigorously, causing increased inflammation and tissue damage. The implications of this finding go beyond a better understanding of rheumatoid arthritis risk. It may also help explain why different autoimmune diseases tend to run in families, since this gene variant is also found in diabetes and lupus.
Increased Risk of Heart Disease in Rheumatoid Arthritis
Individuals with rheumatoid arthritis appear to have an increased risk of cardiovascular morbidity and mortality. A large, population-based study included individuals who first fulfilled diagnostic criteria for rheumatoid arthritis between 1955 and 1995, and age- and sex-matched controls who did not have rheumatoid arthritis. It was determined that patients with rheumatoid arthritis had a significantly higher risk of myocardial infarction ("heart attack") prior to meeting diagnostic criteria for rheumatoid arthritis than those without rheumatoid arthritis. Patients with rheumatoid arthritis were also less likely to have symptoms of angina, were likely to receive coronary artery bypass surgery, and had significantly higher risk of sudden cardiac death. Together, these findings indicate that the presentation of coronary heart disease differs markedly between those with rheumatoid arthritis and those without. In addition, patients with rheumatoid arthritis had twice the risk of developing congestive heart failure. These findings have implications for an inflammation-based etiology of heart disease, as well as implications for the detection and prevention of coronary heart disease and congestive heart failure in patients with rheumatoid arthritis.
A Cancer Drug Holds Promise as a Treatment for Lupus
Preliminary studies that were partly funded by the NIAMS show that the cancer medication rituximab may someday be an effective treatment for lupus. In a study of adults with lupus that was clinically active despite treatment, just one injection of rituximab eased symptoms for up to a year or more. Several participants were able to reduce or completely stop their regular lupus medications. Rituximab, which is FDA-approved for the treatment of patients with lymphoma, works by lowering the number of the immune system's B cells. In lymphoma, the body makes too many B cells. In lupus, there are usually lower-than-normal numbers of B cells, but the B cells that do exist overreact or react inappropriately toward the body's own tissues. As a result, the disease can damage many body organs and systems including the joints, skin, blood and blood vessels, kidney, lungs and brain. In this study, researchers reported that all of the lupus patient participants in whom rituximab reduced B cell levels experienced significant reduction in symptoms. Furthermore, the side effects from rituximab were minimal and even reactions to the infusion - a side effect of the drug seen in lymphoma - were not seen in the lupus patients. While current lupus treatments work by suppressing the entire immune system, rituximab selectively targets the B cells that are at the root of the problem. In doing so, it may not only be more effective than other medications, it may also be less toxic. But more studies are needed to better understand its effectiveness and safety and to better determine its role in lupus treatment. The researchers are currently planning another multicenter study that will help address those issues.
A Common Virus Can Trigger Lupus
For some time, scientists have suspected that the Epstein-Barr virus or EBV -- the virus that causes infectious mononucleosis -- may be related to the development of lupus in certain people. A recent study partly supported by the NIAMS helps confirm the connection. Researchers studied changes in the blood of people who later developed lupus, and were able to identify when people with lupus began to make the autoantibodies that damage target tissues. For many, the antibodies were first produced in response to EBV infection, as evidenced by antibodies to the virus. In genetically predisposed people, antibodies to a portion of the EBV protein cross-reacted with a piece of a protein in the body called Ro. Later studies showed that the same phenomenon occurred in rabbits injected with this same portion of the EBV protein. Although EBV infection has been implicated as a cause of lupus, proving an association has been difficult for a number of reasons. One reason is that most people are infected with EBV at some point and relatively few develop lupus. The Department of Defense repository that was used for this study allowed these researchers to identify military personnel who developed lupus and then look at their blood samples taken a decade or more before symptoms started. These researchers were able to identify the first changes in the blood that led to the disease. This study provides new insight into how lupus begins, and it also has implications for treating or even preventing the disease through vaccinations against EBV or other mechanisms that could prevent or block the autoimmune response.
Hormone Therapy is Not Associated with Severe Lupus Flares
Women with lupus may experience the benefits of postmenopausal hormone therapy (HT) without an increased risk of severe disease flares, according to a major study funded by the NIAMS. In a 16-center study of menopausal women, those taking a standard regimen of hormone therapy had no statistically significant increased risk of severe flares compared to those taking a placebo. Women in the HT group were, however, about 20 percent more likely to have a mild-to-moderate flare, which included new or worsening skin rashes, mouth ulcers, hair loss, aching or inflammation of the joints (arthritis), or fluid around the heart or lungs. None of these mild-to-moderate flares resulted in the need for high-dose steroids or hospitalizations. In recent years, long-term use of HT has been questioned because of risks of cardiovascular disease and some estrogen-dependent cancers. Yet short-term therapy is still widely used and beneficial for some of the unpleasant effects of menopause, as well as for preventing osteoporosis. Women with lupus who are taking cyclophosphamide (a drug that suppresses damaging inflammation of the disease) are especially prone to early and severe effects of menopause, and it may be that HT can provide a particular benefit for these women. Traditionally, doctors have not prescribed HT in women with lupus for fear that increasing the level of female hormones in the body might increase disease activity. This fear arose in part from the fact that lupus is far more common in women and that it typically begins during the childbearing years when female hormone levels are at their peak. This study provided important reassurances, but further investigation of HT is needed to determine the most appropriate candidates for therapy. Some women may be biologically predisposed to flares in response to hormones, and in the future there may be ways to determine who is at greatest risk of flares before initiating treatment. It is important for doctors and patients to carefully consider expected benefits balanced with possible risks in deciding whether to use HT in any women.
Muscle Biology and Muscle Diseases
Scientists Come a Step Closer to New Treatment for Muscular Dystrophy
One form of muscular dystrophy -- Duchenne muscular dystrophy (DMD) - is a severe form of the disease, and few people with DMD live past their early 20s. Researchers have recently shown that injecting a fragment of a protein called heregulin improves the structure and function of muscles of mice that develop a disease similar to DMD. After injecting these mice with the heregulin fragment for three months, the mechanical properties of their muscles were improved, and they showed fewer sites of muscle degeneration and less muscle inflammation than those injected with an inert saline solution alone. Previous research suggested that heregulin works by increasing the body's production of another muscle protein, utrophin, which is structurally and functionally similar to dystrophin. In laboratory animals, utrophin is produced in high levels before birth, but decreases to low levels by adulthood. By increasing utrophin production, scientists found they could halt muscle degeneration related to dystrophin deficiency in mice. It was suspected that utrophin would serve as a substitute for deficient dystrophin, and the latest research suggests that this is the case. Successful treatments for muscular dystrophy are being actively pursued through a number of research avenues, and additions to the candidate therapeutic approaches - such as this one - improve the chances of discovering ways to incrementally improve the lives of those affected by this devastating disease.
Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers
The NIAMS has teamed with the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Child Health and Human Development (NICHD), and the Muscular Dystrophy Association in funding a consortium of Centers of Excellence for research on muscular dystrophy. Three of these Centers were established in 2003, and - in addition to their research components -- they are required to make core resources or services available to the national muscular dystrophy research community. In FY 2005, 3 additional Centers were established, bringing the total number to 6. The interactions of the Centers and their service to the research and patient care communities are coordinated by a steering committee with representatives from each of the Centers, NIH program staff and a lay member who is a parent of a child with muscular dystrophy. The diseases studied by these Centers include Duchenne/Becker Muscular Dystrophy, Myotonic Dystrophy, Facioscapulohumeral Dystrophy, Limb-Girdle Muscular Dystrophy and others. Approaches at the Centers include basic and clinical studies of the mechanisms of the diseases, translational research on gene therapy, stem cell therapy, molecular and pharmacological treatments, as well as clinical studies of gene therapy and pharmacological treatments. These Centers are intended to serve as focal points of research, collaboration, and training for the MD scientific and patient care communities.
Postnatal Muscle-derived Stem Cells for Muscle Repair and Regeneration
The repair and regeneration of muscle due to injury, disease, or contraction-induced damage is an important public health issue. Fortunately, muscle contains cell types and cellular environments that contribute to the regenerative capacity of this tissue. The NIAMS is supporting a number of studies aimed at understanding the mechanisms by which these cells and environmental cues effect repair. Stem cells have been isolated and cloned from postnatal muscle (muscle-derived stem cells, MDSCs) and they exhibit the abilities to differentiate efficiently into muscle and other lineages. An important issue for researchers to consider is whether MDSCs have the capacity to proliferate to the levels necessary to regenerate muscle tissue with high mass. A NIAMS-supported laboratory has developed a method for isolating MDSCs from young mice. In recent work, these researchers tested the hypothesis that colonies of MDSCs could be expanded in tissue culture to create the number of cells that would be necessary for the treatment of muscle diseases. They also tested whether these cells retained the ability to form muscle tissue and did not give rise to tumors when reintroduced into the mice. These investigators found that colonies of MDSCs could be expanded for more than 200 doublings, which would theoretically provide enough cells for any clinical application. Furthermore, at up to about 200 doublings, the cells retained the ability to synthesize muscle-specific proteins and to develop muscle cell morphology, both in culture and when transplanted into mouse muscle tissue. The treatment of muscle diseases such as muscular dystrophies with stem cells will require several significant obstacles to be overcome. This NIAMS-funded work demonstrates that MDSCs can be expanded in culture to the level necessary, and a high percentage of the cells can become muscle. This level of expansion in culture, while maintaining the ability to differentiate, was previously attributed only to embryonic stem cells or cells in the bone marrow. While questions remain regarding the potential use of MDSCs for the treatment of diseased muscle, researchers are pursuing these promising findings from an animal model to determine if similar cells are present in human muscle.
Workshop on the Burden of Muscle Diseases.
The NIAMS and the NIH Office of Rare Diseases sponsored a workshop on the burden of muscle diseases on January 26-27, 2005. Speakers and attendees included muscle disease clinicians and researchers, health economists, epidemiologists, representatives of patient advocacy groups, and patients and their families. There were 100 registered attendees representing universities and institutions across the U.S., Canada and the United Kingdom. Also represented were several national and international voluntary health organizations and five agencies of the U.S. Government. The participants in this workshop identified existing data on the economic and psychosocial burdens of muscle diseases on patients, families, and societies, with a focus on the muscular dystrophies, and recommended strategies for developing new information sources.
Skin Biology and Skin Diseases
Advances in Understanding Psoriasis
Psoriasis is a chronic skin disease characterized by scaling and inflammation. It occurs when skin cells rapidly pass from their origin below the surface of the skin and pile up on the surface before they have a chance to mature. Usually this movement (also called turnover) takes about a month, but in psoriasis it may occur in only a few days. Three recent studies funded by the NIAMS are helping scientists and doctors to understand how the inflammatory skin disease psoriasis behaves at the molecular level, and what role genes play in predisposing people toward this disease. In the first study, researchers investigated the role of both genes and the environment in psoriasis, psoriatic arthritis and atopic dermatitis, another inflammatory skin condition. The researchers found some similarities in genetic susceptibility for psoriasis and atopic dermatitis. As for psoriatic arthritis - a condition in which inflamed joints produce symptoms of arthritis for patients who have or will develop psoriasis - they found that the presence of modifier genes can indicate which people with psoriasis are also at risk for psoriatic arthritis. Working at the molecular level, in the second study researchers developed an animal model to investigate the molecular basis of psoriasis. Psoriasis is a disorder of the immune system. Normally, a type of white blood cell called a T cell helps protect the body against infection and disease. However, in psoriasis, these T cells are put into action by mistake, and they become so active that they trigger other immune responses, which lead to inflammation and rapid turnover of skin cells. Using the model, the scientists were able to demonstrate how the proliferation of T cells is key to the formation of psoriatic lesions. They also demonstrated the role of a molecule known as "tumor necrosis factor-alpha" - a molecule that mediates the development of psoriatic lesions, and its production can result in T cell proliferation. In other research at the molecular level, the third team of researchers used psoriasis as a model disease to develop a way of identifying autoantigens for autoimmune diseases -- autoantigens are substances found naturally within the body and can trigger an immune response. Psoriasis is an ideal model disease for this kind of study because it is common, and because affected tissue is readily accessible. By studying the role of autoantigens in psoriasis, the researchers were able to better understand how autoantigens are recognized by T cells, and how autoreactive T cells give rise to autoimmune disease. The investigators found 11 potential autoantigens, but focused on 3 that were likely to be related to psoriasis and were associated with significant reactions in patients. Taken together, these three studies provide important information on what causes psoriasis, who gets it and how it can be treated.
Understanding the Nature of Regeneration and Stratification of the Epidermis
The outer layer of skin, the epidermis, provides the barrier function of the skin, excluding harmful microbes and retaining body fluids. NIH-funded basic researchers focused on asymmetric cell divisions that promote stratification and differentiation of mammalian skin, and gave us a new view of how skin is able to create layers of different cell types at the same time that it is forming a continuously self-renewing protective barrier. Working with genetically engineered mouse embryos, these researchers found that the epithelium starts as a single layer of dividing cells attached to a dense meshwork of proteins called the basement membrane. The basement membrane provides growth-signaling molecules to the dividing cells and separates the epidermis from the underlying tissue. As development proceeds, the epithelium begins to stratify to ultimately form a multilayered protective barrier through asymmetric cell division. This is a mechanism that can be described as one mother cell dividing into two distinctly different daughter cells. When these underlying skin cells divide, they actually divide both laterally and perpendicularly: one daughter cell remains attached to the basement membrane and the other daughter cell moves outward. During the course of division, the factors that promote cell growth are partitioned off in the cell that remains at the basement membrane. Other factors, which may be involved in the production of the barrier in skin, are confined to the outward-moving cells. These outward-moving cells eventually make it to the skin's surface where they provide a protective barrier until they are sloughed off or scraped off and replaced by new cells. During all of this development of the barrier dimension of the skin, the cells at the basement membrane continue to divide asymmetrically to form these two different daughter cells. Interestingly, this process continues in adult epidermis also. The next step in these studies is looking at which genes are necessary in the process. These fundamental studies of normal skin and the mechanisms by which cells form and rebuild tissue have significant implications for understanding the many different disorders of the skin that result when the normal mechanism goes awry -- with implications for skin cancer, psoriasis, and many other skin diseases.
Vitiligo Reveals Earlier Onset and Greater Risk for Other Autoimmune Diseases
Vitiligo is an autoimmune disease in which white patches develop on the skin because of the loss of pigment production within the skin. It can be psychologically devastating especially for people of color. The exact mechanism of pigment cell loss is still not completely clear. Statistically, vitiligo is associated with other autoimmune diseases including autoimmune thyroid disease, pernicious anemia, Addison's disease, and lupus. These other autoimmune diseases occur at greater frequency in relatives of patients with vitiligo even when those relatives do not have vitiligo. A NIAMS-supported research team has been studying familial vitiligo for a number of years. They have established a large cohort of patients and families and are investigating both the genetic basis for the disease and the genes associated with autoimmune disease predisposition as well. Using data from these studies in vitiligo families, the researchers were able to demonstrate not only the previously known association with autoimmune thyroid disease, pernicious anemia, Addison's disease and lupus but also the association within these families with rheumatoid arthritis, psoriasis and adult onset insulin-dependent diabetes mellitus. All of these diseases were found in greater frequency in the extended families of those with vitiligo. The form of vitiligo that demonstrated this association is generalized vitiligo with early onset as distinct from the other forms of vitiligo. The genetic basis for both vitiligo and the multiple autoimmune disease susceptibility continues to be investigated. The ability to recognize which subgroups of vitiligo may be associated with a higher incidence of a wide variety of autoimmune diseases in the family is an important finding that may allow for early diagnosis which can lead to better treatment. In addition, the further genetic analysis of these individuals and families should provide clues to the underlying susceptibility to these diseases, with the ultimate goal of being able to prevent and/or more effectively treat vitiligo and other autoimmune diseases.
Story of Discovery: The Genetic and Molecular Basis of Pseudoxanthoma Elasticum
Pseudoxanthoma Elasticum (PXE) is a systemic, inherited, connective tissue disease that involves the elastic tissue in the skin, eyes, and cardiovascular system. It can result in severe and even fatal health problems or may be much milder and more difficult to identify. It is often not visible early in life but, in more severe cases, may manifest in childhood. For a long time, PXE had been considered to be a genetic disorder of a structural component in elastic fibers. But with the discovery of the gene that is defective in the disease, it became apparent that PXE is actually a metabolic disorder in which the structural component is secondarily affected. A consortium of investigators worked together to uncover the gene underlying PXE several years ago. PXE was found to be caused by a mutation in a gene termed ABCC6, which encodes for a protein that underlies multiple drug resistance in microorganisms, but appears to have the function of transporting materials through the membrane of human cells. In other research, affected individuals from 4 families were studied to determine the specific genetic defects underlying the disease in each family. The 4 families were from different ethnic backgrounds, yet the specific defect in all 4 families was exactly the same. The fact that all 4 families had the identical defect implied that possibly the same mechanism of mutation leads to this uniformity of mutation in different families. The recognition that this is a metabolic disease offered new hope for the development of treatment based on metabolic modifications, potentially including such things as diet manipulation or drug therapy. The isolation of the gene and the cataloging of the gene defects underlying the disease enabled researchers to design studies aimed at the early identification of affected individuals. The goal is to be able to institute treatment before the development of signs or symptoms of the disease and, ultimately, early enough to prevent such signs and symptoms from ever developing.
In recent work reported in 2005, investigators applied the findings that identified the gene underlying PXE to create an animal model in which the ABCC6 gene was ablated. They demonstrated that these mice did not express the protein normally encoded for by the gene in the liver or kidney. At autopsy there was profound mineralization of several tissues in these animals including the skin, arterial blood vessels and the retina, which parallels the findings in the human disease. Only animals carrying 2 copies of the mutated gene showed these effects. Those animals having one normal and one abnormal gene were completely normal. This also parallels PXE in humans. Interestingly, the earliest abnormal finding in the animal model was in modified hair of the vibrissae (whiskers), where mineralization was noted as early as five weeks of age. There have been no systematic examinations of hair in PXE in humans, but this may provide an area of further investigation. If the human parallels the mouse in this area as well, it may provide an easier-to-obtain early indication of whether an individual in an affected family will develop the disease later in life. The availability of animal models allows researchers to undertake studies that reveal the mechanisms of disease in humans. It is anticipated that this animal model will be very useful in further investigation of the underlying disease mechanisms in PXE. This animal model provides a test bed for evaluating potential therapeutic interventions, and it also provides a general model for mineralization studies seen in other diseases with vascular and ocular degeneration.
An important dimension of our mission includes a comprehensive program of information dissemination to patients and to their health care providers. Research advances are of limited value if they never reach the arena of health care, and they miss the goal of improving public health for all Americans. We are also committed to making our information accessible to the vast and diverse populations affected by the diseases within our mandate.
Outreach to American Indian and Alaska Native Communities
The NIAMS, in an effort to expand its ability to reach out to the American Indian and Alaska Native communities, established a Trans-NIH Working Group comprised of representatives of the NIAMS, NIA, NICHD, and National Institute of Dental and Craniofacial Research (NIDCR). This Working Group determined that it was important to understand what the NIH community was doing to reach these populations. On November 1, 2005, these institutes held a workshop, "Taking Action: Health Promotion and Outreach with American Indians and Alaskan Natives," to provide a primer and "lessons learned" for NIH staff involved in health education, communications, and public liaison work. This workshop provided participants with a greater understanding of community analysis, including demographics, geography, and health status; influences on health behavior, including culture, values, and traditions; access, including health care providers and systems; and lessons learned from other NIH health promotion programs. This workshop was an initial step for the Working Group, and outcomes from the workshop may include collaborations between the Working Group members and a larger conference as well as publication opportunities.
Information in Spanish
The NIAMS has launched a new series of "fast facts" in Spanish called "Esenciales," meaning "essentials." This publication series is a transadaptation of the original English-language series developed for consumers using an easy-to-read format. The format uses plain-language techniques to deliver concise and easy-to-understand health information. In FY 2005, we have 10 Spanish fast facts in production: the subjects include gout, rheumatoid arthritis, acne, psoriasis, rosacea, vitiligo, scoliosis, growth plate injuries, fibromyalgia, and sprains and strains. In addition, the "Osteoartritis: Resumen" in Spanish was updated and reposted on the NIAMS website. The production of another Spanish-language publication was started in FY 2005: "Information for Patients About Paget's Disease of Bone."
Curriculum Supplement for Middle School Students
In collaboration with the NIH Office of Science Education, the NIAMS developed a curriculum supplement for middle school students called "Looking Good, Feeling Good: From the Inside Out," to be released in early 2006. The supplement highlights NIAMS scientific research on rheumatic, musculoskeletal, bone, and skin diseases, and provides students with the opportunity to learn how these systems contribute to health and well-being.
The stories above are by no means inclusive of all the progress that has been made through our investments in research. NIAMS-supported researchers are uncovering important pieces of the research puzzle and launching initiatives to take advantage of emerging areas of science. 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. We are investing in the future health of our nation, and American people of all ages and population groups will benefit from these investments.
The Fiscal Year 2007 budget request for the NIAMS is $504,533,000, a decrease of $3,399,000 and 0.7 percent over the FY 2006 Appropriation. Included in the FY 2007 request is NIAMS' support for the trans-NIH Roadmap initiatives, estimated at 1.2% of the FY 2007 budget request. 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 as the result of several administrative restructurings in recent years, FTE data is non-comparable.
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 pursuing new research opportunities. We estimate that the average cost of competing RPGs will be $306,000 in FY 2007. While no inflationary increases are provided for direct recurring costs in noncompeting RPGs, where the NIAMS has committed to a programmatic increase for an award, such increases will be provided.
NIH must nurture a vibrant, creative research workforce, including sufficient numbers of new investigators with new ideas and new skills. In the FY 2007 budget request for NIAMS, $360 thousand will be used to support 4 awards for the new K/R "Pathway to Independence" program.
NIAMS will also support the Genes, Environment, and Health Initiative (GEHI) to: 1) accelerate discovery of the major genetic factors associated with diseases that have a substantial public health impact; and 2) accelerate the development of innovative technologies and tools to measure dietary intake, physical activity, and environmental exposures, and to determine an individual's biological response to those influences. The FY 2007 request includes $866,000 to support this project.
In the FY 2007 request, stipend levels for trainees supported through the Ruth L. Kirschstein National Research Service Awards will remain at the FY 2006 levels.
The FY 2007 request includes funding for 38 research centers, 165 other research grants, including 137 career awards, and 68 R&D contracts. Intramural Research decreases by 0.5 percent. Research Management and Support increases by 1.5 percent.
The mechanism distribution by dollars and percent change are displayed below: