Statement to the Senate Appropriations Subcommittee

May 11, 2011 (historical)

Stephen I. Katz, M.D., Ph.D., Director
National Institute of Arthritis and Musculoskeletal and Skin Diseases
_______________________________________

Mr. Chairman and Members of the Committee:

I am pleased to present the President’s Fiscal Year 2012 Budget for the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH). The FY 2012 budget includes $547,891,000 which is $14,002,000 more than the comparable FY 2011 appropriation of $533,889,000.

Introduction

NIAMS addresses diseases that affect individuals of all ages, of all racial and ethnic backgrounds, and across all economic strata; many disproportionately affect women and minorities. Some are rare disorders, but many are very common, and all have a major impact on the quality of people's lives. Twenty-five years of NIAMS-funded research has contributed greatly to a variety of new treatment and prevention strategies that are reducing the burden the diseases place on individuals, their families, and society.

Leveraging Basic Science to Improve Patient Care

NIAMS research has been the basis for the development and testing of many new medications, including biologic therapies for autoimmune diseases. The newly approved drug belimumab, the first lupus treatment to receive U.S. Food and Drug Administration approval in over fifty years, interferes with a molecule that NIAMS-funded researchers showed to be involved in the immune dysfunction that characterizes this disorder. Other, more recent basic research results suggest another existing drug, omalizumab, may prevent lupus-associated kidney damage. NIAMS investigators in Bethesda, MD, are planning to start testing the drug’s safety for lupus patients soon.

Basic research into disease mechanisms also is explaining why some therapies do not work as well as expected. In 2003, investigators were baffled when two NIAMS-funded clinical trials showed that combining two medications (a bisphosphonate and parathyroid hormone) that each improve bone mass and prevent fractures did not help people any more than either drug did individually. Eight years later, research into the mechanisms by which bisphosphonates preserve bone revealed that they interfere with parathyroid hormone’s bone-forming activity. This discovery can help physicians choose drug regimens that are best for their patients.

Developing Tools to Diagnose and Monitor Disease

Improvements in bone health have underscored the importance of identifying which of the 40 million Americans1 who have low bone mass are most likely to break a bone. Several large, NIAMS-funded studies have indicated that spine fractures predict both future spine fractures and debilitating hip fractures. Researchers recently published evidence that women who have mild spine defects may also be at risk of hip fractures and could benefit from lifestyle changes or drugs that prevent bone deterioration. However, the ability to distinguish between deformities related to fragile bones and those from other causes is critical. If imaging tools that are under development can make this distinction, clinicians will be better able to predict patients’ risk and monitor responses to therapies. Also, the new tools potentially could reduce the cost of clinical trials by allowing investigators to assess a medication’s effects relatively quickly.

Other researchers are testing whether a specific type of magnetic resonance imaging can predict worsening of knee arthritis. Preliminary work—using images that are available to the research community through a public-private partnership supported by the NIH and various companies—is promising. If confirmed, clinicians could use the technology to identify patients whose knee cartilage is likely to rapidly deteriorate due to osteoarthritis. Moreover, like the imaging tools mentioned above, the discovery and validation of structural changes that researchers can visualize could lead to shorter, more efficient trials of promising disease-modifying agents that may help the more than 27 million Americans2 who have osteoarthritis pain in their knees or other joints.

1 Looker AC, et al. J Bone Miner Res. 2010 Jan;25(1):64-71. PMID: 19580459
2 Lawrence RC, et al. Arthritis Rheum. 2008 Jan;58(1):26-35. PMID: 18163497

Many diseases within the NIAMS mission involve pain, fatigue, and other difficult-to-measure symptoms. A test to quantify changes in these parameters could enhance clinical outcomes research and, ultimately, clinical practice. NIAMS is one of several NIH components engaged in the Patient-Reported Outcomes Measurement Information System (PROMIS) initiative to develop such a tool. In addition to managing PROMIS on behalf of the NIH, NIAMS encourages researchers to use the resource. For example, NIAMS is funding a study to test questions for fibromyalgia patients, along with information collected through PROMIS, for development of disease-specific measures that allow investigators and health care providers to monitor patients more effectively.

Applying Genetics, Genomics, and Other Cutting-Edge Research to New Treatments

Researchers have been trying to determine for decades if pain and itch send different signals to the brain. Difficulties distinguishing the two symptoms at molecular and cellular levels had hindered this effort, but a group of NIAMS investigators finally identified an itch-specific molecule. Their work also illuminated a previously elusive mechanism by which the itch message travels through the spinal cord to be perceived by the brain. Such a discovery should pave the way for studies into how chronic itch develops, and make it possible, for the first time, to design better treatments.

Research is providing hope to patients with epidermolysis bullosa (EB), a group of rare, inherited blistering skin conditions. When investigators repaired the genetic defect in an EB patient, NIAMS-funded scientists wondered if gene therapy might also work for another form of the disease. The strategy seemed promising in a mouse model of recessive dystrophic EB (characterized by large, painful blisters, open wounds, and early death due to cancer). A first-in-human clinical trial will begin this year.

NIAMS also is funding a Phase I clinical trial that suggests that a different gene transfer approach may correct the molecular defect underlying type-2 limb-girdle muscular dystrophy (LGMD-2D). The study, supported through one of the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers, demonstrated that the procedure could safely produce the corrected protein for at least six months. The data provide a framework that investigators can use when designing subsequent LGMD-2D clinical trials. Furthermore, researchers can leverage the study’s findings about immune responses as they develop gene-based therapies for other diseases.

In the past twelve months, muscular dystrophy researchers also have made considerable progress toward understanding the genetic underpinnings of facioscapulohumeral muscular dystrophy (FSHD). Prior findings from an NIH-funded FSHD patient registry showed that the disease is associated with a shorter-than-normal series of repeated genetic sequences. Recent technologic advances enabled researchers to identify a genetic pattern within these sequences in FSHD patients. This discovery, combined with findings that the defects cause FSHD by activating a gene and allowing its product to accumulate in muscle, are enabling new directions that will accelerate progress. For example, researchers can now engineer animal models of the disease, something that they could not do without a basic understanding of the genes involved.

Like FSHD, many health problems are influenced by complex genetic factors. Over the last few years, the ability of genome-wide association (GWAS) approaches to identify gene variants related to disease risk has matured from an intriguing concept to a widely used scientific tool. These analyses can require thousands of patients, and often entail data sharing among NIAMS-funded researchers and scientists around the globe.

An international GWAS team including researchers at the NIH Clinical Center showed that a gene involved in the body's immune response underlies a person’s susceptibility to a painful, inflammatory condition called Behcet's disease, which primarily affects people of Asian, Middle Eastern, Turkish, or European descent. The gene linked to Behcet’s disease is associated with other conditions for which treatments exist or are being developed. Because of this connection, therapies might be available sooner than if the investigators had found a completely new disease mechanism.

In the past year, other genetic studies uncovered additional, shared links among diseases. Investigators discovered that rare variants of a gene encoding the enzyme sialic acid acetylesterase are associated with rheumatoid arthritis and type 1 diabetes, and may play a role in other autoimmune diseases. Likewise, researchers leveraging the NIAMS-sponsored National Alopecia Areata Registry found that genes associated with rheumatoid arthritis and type 1 diabetes are linked to the development of alopecia areata, a disease in which the body's immune system attacks the hair follicles and causes hair loss. As with Behcet’s disease, the possibility of a common mechanism is particularly exciting because drugs under development for other diseases might also be effective against alopecia areata.

GWAS also holds promise for understanding the genetic differences that give rise to more common diseases, such as osteoporosis. The NIAMS dedicated funds from the American Recovery and Reinvestment Act of 2009 toward developing a resource that investigators can use to identify molecular changes that influence bone health. The discovery of gene variants that protect against osteoporosis or increase a person’s risk of having low bone mass is likely to suggest targets that researchers can pursue when exploring new ways to prevent fragility fractures. Moreover, investigators could use genetic markers to identify appropriate participants for clinical trials. Data from this effort is likely to be available to the wider research community at the end of this year.

Conclusion

Twenty-five years ago, a few months after Congress passed the Health Research Extension Act of 1985 (P.L. 99-158), the NIH established the NIAMS. Over the past two-and-a-half decades, the increased emphasis on research on arthritis and musculoskeletal and skin disorders has benefited nearly every household in our Nation. We are proud of the scientific advances that our researchers have made toward helping people who have diseases of the bones, joints, muscles, and skin, and are excitedly looking forward to the discoveries they will make in the future.