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STATEMENT OF DR. LAWRENCE D. SHULMAN

The National Institute of Arthritis and Musculoskeletal and Skin Diseases

(NIAMS) supports a broad range of basic and clinical research on many of the

most debilitating diseases affecting the health of the Nation.

I am privileged

to discuss with you some of the scientific advances that have been made this

past year in the disease areas under the mandate of the Institute, and to share

with you some of our future plans.

Osteoporosis, the leading cause of bone fractures both in postmenopausal

women and in the elderly, affects approximately twenty-four million Americans.

The NIAMS leads the federal research effort to conduct and support basic,

clinical, and epidemiologic investigations on osteoporosis through individual research grants and specialized research centers. In February 1990, the Institute cosponsored a highly successful International conference entitled "Research Advances in Osteoporosis." The latest findings were presented, and

recommendations for future research were developed.

A new treatment..

bisphosphonates--was shown to be very effective in combatting the bone loss of

osteoporosis.

The Institute continues to expand its research efforts in osteoporosis.

Two requests for applications (RFAs) for research on osteoporosis are being

issued.

One invites additional basic research on fundamental causes.

The

second invites more grant applications on clinical and epidemiological research

on osteoporosis.

The Institute is also stepping up its disease prevention and

health promotion efforts with regard to osteoporosis.

The NIAMS Information

Clearinghouse will expand its educational activities both for the public and for health professionals. Projects to inform consumers about risk factors,

preventive measures, and research results are being planned.

There are more than 100 kinds of arthritis, affecting not only the joints

but other connective tissues of the body including laportant supporting

structures such as muscles, tendons, and ligaments.

One of the most common is

rheumatoid arthritis, a chronic Inflammatory disease afflicting more than 2

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scientists have developed a T-cell vaccine that could ultimately lead to T-cell therapy and vaccination in humans. The Institute has also begun a clinical

trial in which an antibiotic is being tested as a treatment for rheumatoid

arthritis.

In other recent research, a dissimilarity in tissue type between

mother and fetus has been found in many women with rheumatoid arthritis who

improve during pregnancy.

This finding suggests that the aismatch induces an

immunologic reaction that suppresses the arthritis.

Lyme disease, which has both arthritis and skin disease among its major

manifestations, has become a national problem.

It is now the most common

insect-borne disease in the Nation, and its distribution is worldwide.

NIAMS

is giving high priority to both research and outreach programs for Lyme

disease.

The Institute has recently funded several new basic research grants

to increase understanding of how the infectious agent causes the disease, with

the hopes of improving diagnosis and treatment, and providing the foundation

for development of an effective vaccine.

NIAMS is also supporting a clinical

trial to determine if antibiotics can prevent Lyme disease from emerging in

people who have been bitten by the deer tick. Programs to better inform both

the public and health professionals about the dangers and prevention of Lyme

disease are under way.

A data base on educational materials was recently

completed; and in early March 1991, a workshop on Lyme disease will be held

with panels of experts to develop up-to-date vital Information for physicians

on both the diagnosis and treatment of Lyme disease.

One of the most exciting breakthroughs this year was the identification of a gene that causes a form of osteoarthritis, the most common form of arthritis,

a disease in which the cartilage that covers and cushions the joints breaks

down.

NIAMS - supported investigators at two different grantee institutions,

working together, isolated and characterized a faulty gene for collagen II, the

main structural protein that strengthens cartilage.

Another exciting breakthrough in arthritis this year was the successful

Induction, by transgenic transfer, into inbred rats of both the human gene

(HLA-B27) for spinal arthritis and the entire clinical spectrum of the group of

diseases (spondyloarthropathies) associated with spinal arthritis.

HLA-B27 is

found in over 90 percent of patients with spinal arthritis, and in only 8 percent of the general population. These diseases associated with spinal arthritis comprise the most common forms of arthritis in young men. The striking mimicry between the disease manifestations found in this animal model

and those found in humans opens avenues for research, including the testing of

innovative therapies, that were unimaginable just a few years ago. Ongoing

NIAMS epidemiological investigation of Native Americans in Alaska and Siberian

Eskimos --populations that have a high prevalence of spondylitis.-promises to

shed light on the roles of genetic factors and environmental triggers, such us

bacterial infections.

Systemic lupus erythematosus (lupus) is an immune -mediated Inflammatory

disease that afflicts numerous Americans, largely young women, especially black

wonen of child bearing age.

The disease affects the skin, joints, kidneys,

brain, and other organs. Recently, a new antibody was identified that is

clearly associated with psychiatric disorders due to lupus; this antibody will

make better diagnosis possible.

The Institute has set up a task force to study lupus in high-risk

populations.

With advice from the task force, NIAMS is developing instructive

kits that will help health care providers and community organizations conduct

health promotion programs targeted to young black women.

The Institute also

plans to sponsor an International workshop on systemic lupus erythematosus to

assess current knowledge and develop directions for future research.

Scleroderma is a serious disorder of connective tissue and the fine blood

vessels.

Besides damaging the skin, muscles, and joints, the disease may also

affect internal organs, such as the kidneys, heart, and lungs, making it life

threatening in some people.

Women are affected three times more often than

men.

The first symptom of scleroderma is usually Raynaud's phenomenon, wherein

blood vessels in the fingers narrow as the result of vasospasm, causing the

hands to become pale and cold.

There is also pathologic evidence of vascular

disease seen under the microscope. Accordingly, there is keen interest in exploring vascular abnormalities that may contribute to the etiology of the

disease.

NIAMS will issue a program announcement to stimulate more research on

causal mechanisms in scleroderma.

Over 100 different conditions are included among the horitable connective

tissue disorders, all of which sten fron abnormalities of connective tissue, the scaffolding that girds bone, skin, blood vessels, and the protective coverings of internal organs. Although the disorders are uncommon, they are

tremendously disabling. In April 1990, NIAMS cosponsored a multidisciplinary scientific workshop on heritable connective tissue disorders. Workshop

participants made it clear that sophisticated research methods are enabling

scientists to unravel the complex biology of connective tissue and to uncover

the several defects that cause the disorders.

The Institute is encouraging

additional research in this area, and is exploring the possibility of a patient

registry to facilitate progress against these diseases.

Reducing the risk of sports Injury is important to millions of Americans

who participate in exercise programs and athletics.

The Institute's mission

Includes responsibility for research on exercise physiology and sports

medicine.

Basic facts about how muscles function at the molecular level are

now being discovered.

Recent research has revealed a mechanism by which a

serious knee injury can destroy a joint. In April 1991, the Institute, in concert with the National Advisory Board, will hold a workshop on scholastic

sports Injuries to monitor the causes of athletic injuries and identify ways to

prevent them.

We are continuing to make progress in research on the nunerous skin

diseases that affect so many Americans.

In epidermolysis bullosa, a

devastating inherited blistering disease that affects the skin and mucous

membranes, researchers have found that the anchoring flbrils--which link the outer layer of the skin to the Inner layer--are conspicuously absent or

altered.

Recent investigations have also shown that type VII collagen, the

major structural protein of anchoring fibrils, can be broken down by both collagenase and gelatinase. Other research, utilizing patients assembled by

the National Epidermolysis Bullosa Registry, suggests that abnormal synthesis

of type VII collagen be responsible for the reduced number of anchoring fibrils.

Alopecia areata is a disease of the hair follicle that results in patchy

or total loss of hair.

The psychological impact of the disease can be

debilitating, especially in young people.

In October 1990, NIAMS and the

National Alopecia Areata Foundation sponsored a 2-day research workshop on the disease. Experts in a wide variety of areas were convened for an open exchange

of information on clinical and histopathologic features of alopecia areata,

factors controlling hair growth, autoimmune aspects of the disease,

pharmacologic Interventions, and animal models.

A new anatomic site that

controls hair growth has been discovered, and the ability to grow hair in a

test tube has been achieved.

These findings open new avenues of research that

will be pursued.

Psoriasis is a common chronic skin disease characterized by scaling and

redness produced by skin cells that divide rapidly. For many years, psoriasis

was treated with preparations of tars and chemotherapeutic agents, such as

methotrexate. Recently, clinical studies established the efficacy of

cyclosporine A, an immuno-suppressive drug in the treatment of psoriasis.

In

turn, this has led investigators to explore the role of Immune-mediated factors

in causing the disease and to search for alternative drugs that cause fewer

side effects than does cyclosporine A.

The NIAMS is encouraging further

exploration of molecular, immunologic, and pharmacologic aspects of psoriasis.

Significant strides have been made in the Institute's Intramural Program.

This past year two new laboratories were established to expand the scope of

research: the Laboratory of Skin Biology and the Laboratory of Structural

Biology Research.

Fundamental studies of proteins responsible for maturation

of the epidermis, the skin's outer layer, are the focus of research in the

Laboratory of Skin Biology.

In the Laboratory of Structural Biology Research,

new sophisticated instrumentation is facilitating analysis of extremely small

structures, including membrane-associated components of the AIDS virus.

In the area of orthopaedic research, Intramural scientists have identified

the various phases through which an injured bone must pass to heal properly.

They have detected the presence of a specific natural protein, transforming

growth factor-beta (TGF-beta), between and around the ends of fractured bone;

and determined that TGF-beta not only initiates a repair response, but also

controls the rate of fracture healing.

Another ground-breaking accomplishment achieved by Intramural scientists

was the development of an animal model for eosinophilia-myalgia syndrome (EMS).

a new epidemic inflammatory disease associated with ingestion of contaninated

L-tryptophan. Symptoms range from those of the flu, to severe rashes and

permanent nerve and muscle damage.

The new animal model provides the first

direct, experimental evidence linking EMS to contaminated batches of the

dietary supplement L-tryptophan.

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