o We are in the planning stages of developing a national resource center on osteoporosis.

LYME DISEASE

Question. I was pleased to learn that the Institute will be sponsoring a conference in late March to educate physicians concerning proper diagnosis and treatment of Lyme disease.

The Committee has heard varying reports on the success of laboratory tests used to diagnose this chronic disease. Can you comment on the effectiveness of the tests that are currently available?

Answer. Laboratory tests currently available to aid in the diagnosis of Lyme disease consist largely of tests to identify antibodies to the causative bacteria in the blood. With recent infection, it often takes a few weeks for the antibody test to become positive. Once they develop, these antibodies tend to remain present for months or years thereafter. They may, therefore, indicate previous exposure but not necessarily current disease. Thus, there are many misdiagnoses based on both negative and positive tests. doctor's clinical judgement is, therefore, important in assessing both the clinical manifestations and the value of the tests in a given patient.

The

Last Fall, the Centers for Disease Control reported on an evaluation of seven selected commercially available Lyme disease serological test kits at the First National Conference on Lyme Disease Testing in Dearborn, Michigan. The evaluation was conducted at four state public health laboratories under contract with the Association of State and Territorial Public Health Laboratories Directors. The data presented at the conference suggest that the test kits evaluated do not meet sensitivity and specificity needs, and are not well standardized. The conference recognized the need for well-characterized, culture-confirmed sera from patients with and without Lyme disease, and the importance of establishing a spirochete repository for antigens to be used, as national standards, in test kit development and evaluation.

The NIAMS and the NIAID convened the first annual meeting of the 14 principal investigators who successfully competed for research grants under the joint NIAMS/NIAID Request for Applications to study the pathogenesis of Lyme borreliosis. Each investigator had the opportunity to present their research plans and, in some cases, preliminary results. Many of these research projects are addressing research questions that are directly relevant to the development of newer and better methods for diagnosing Lyme disease. These include some of the newer approaches that have been made possible by advances in molecular biology, such as the polymerase chain reaction technique for amplifying genetic material from specimens containing small amounts of genetic material from the causative spirochete.

The NIAMS and NIAID are also co-sponsoring a workshop in late March on the diagnosis and treatment of Lyme disease. National experts on these issues will discuss and assess both what is known and what is not known about the diagnosis and treatment of Lyme disease.

LUPUS

Question. Doctor, I have heard the statistic that women suffer from systemic lupus disease nine times more frequently than men.

What research is being done to locate the factors that "trigger" systemic lupus disease and address the high incidence of the disease among females, especially among minority women?

Answer. The reasons that women suffer lupus nine times more frequently than do men and the reasons that black women suffer three times more lupus than do white women are currently unknown. The NIAMS sponsors research grants that address these important questions. In addition, the NIAMS is developing new initiatives on minority and gender issues in lupus. These will include program announcements requesting applications to study the topic. The NIAMS is investigating high risk target populations and participating in a workshop in Barbados to look at the epidemiology of lupus in the special populations available in the Caribbean. The NIAMS recently convened a group of investigators interested in the genetics of SLE to plan for initiatives that would also involve these target populations.

CONNECTIVE TISSUE DISORDERS

Question. Doctor, I was delighted to learn that the

Epidermolysis Bullosa (EB) registry is now in its second generation and has been quite effective. Are there any plans to develop similar registries for other connective tissue diseases?

Answer. The National Epidermolysis Registry has been

particularly useful as a way to collect information about large numbers of patients for application in epidemiologic and treatment studies. Such data have already shown that EB is composed of a number of different conditions. While the EB registry has been beneficial, it needs to be employed within a framework of established investigators who can efficiently make use of the information produced. In addition, registries consume a relatively large amount of resources. The NIAMS is actively determining the most appropriate manner to facilitate research for several different connective tissue diseases. Decisions concerning registries for other connective tissue diseases will take into account the base of existing knowledge about the disease, investigators who could utilize such a facility, the research objectives to be achieved by a registry, other mechanisms to achieve these objectives, and the availability of funds.

Question. What initiatives are being undertaken to develop specialized centers for basic research and treatment of EB?

Answer. Epidermolysis Bullosa (EB) is a group of rare diseases. Very few, if any, single research institutions have a sufficiently large patient population necessary to assure the high quality clinical research component required in a SCOR. The clinical sites of the National Epidermolysis Bullosa Registry (NEBR) together have identified the majority of EB patients alive and diagnosed in the United States. Funds for clinical studies, including clinical trials, have been incorporated into the request for proposals for the

next five years of the NEBR. This was felt to be the best way to assure sufficient patients to make this type of research possible. The Skin Diseases research community, with whom we have consulted on several occasions, prefers core research centers, rather than specialized centers for research, as the most appropriate center mechanism at the present time for EB-related research.

It is, therefore, our objective that the Skin Diseases Core Centers Program be expanded by the addition of four centers to a total of six centers, as originally planned with the advice of national scientific leaders in the field, with the intent that one or two of the new centers would be on the subject of EB, blistering diseases, and the biology of the basement membrane zone of skin. The establishment of these Core Centers will provide for basic research on EB and the basement membrane zone that would complement support for large scale clinical research within the new NEBR. Clinical research supported through the NEBR will be of a larger and more significant scale than could be supported through a SCOR at a single institution. It allows the combining of the patient material from all of the clinical sites.

This combination of approaches and awards will provide more overall basic and clinical research on EB, as well as providing a wider geographic distribution of research locations facilitating the participation of greater numbers of EB patients than could be achieved by awarding a single SCOR.

RHEUMATOID ARTHRITIS

Question. The Committee has expressed interest in the use of antibiotics to treat rheumatoid arthritis. Doctor, can you please describe the status and progress of the clinical trials involving oral and intravenous antibiotics?

Answer. The contract to support the coordinating center for the clinical trial of minocycline treatment of rheumatoid arthritis will be awarded on or about March 1, 1991. Contracts for clinical centers to participate in the trial are expected to be awarded about the same time. Proposals for additional clinical centers needed to assure an adequate sample of patients are under review. The current design calls for a planning phase during which the protocol will be finalized, the procedures and data forms will be developed, and the staff at the clinical centers will be trained and certified to begin recruitment for the volunteers to participate in this trial.

SPORTS MEDICINE

Question. Doctor, there has been much publicity concerning sports related injuries. What are your plans for research in the study of sports medicine?

Answer. The Program Announcement on Musculoskeletal Fitness and Sports Medicine has been highly successful in generating applications and obtaining new funding related to this field. A book on inflammation and healing from sports injuries was published in 1990. The NIAMS is sponsoring two forthcoming workshops on sports related injury and has a current program announcement on this topic. The NIAMS will issue a new program announcement following the workshops.

SKIN DISEASE CENTERS

Question. There are now two core centers focused on skin disease research. In the past the Committee has heard about the need for a total of six of these centers. In your professional judgment are additional centers needed?

Answer. Yes. In 1988, the NIAMS established two Skin Diseases Core Centers to coordinate and foster interdisciplinary cooperation among investigators. The original plan, developed through consultation with our external advisors and the academic dermatology community, called for a total of six Skin Diseases Centers.

The NIAMS surveyed responsible members of the dermatology community and together with them decided that at least six centers would meet current needs at a minimal level. Funding was available to begin only two of these. Our opinion continues that six are needed.

RELATED BONE DISEASES

Question. I am also interested in the status of two other programs dealing with bone disease research.

First, has the Institute been successful in providing fellowships to attract and train postdoctoral fellows in the area of

bone research?

Answer. The NIAMS is issuing a program announcement for new research career awards in bone biology and bone diseases. This will request applications for clinical investigator awards, research career development awards, and physician scientist awards. This follows prior NIAMS announcements requesting additional research grants focusing on osteoporosis.

Question.

Also, I wonder if you could update us on the genetic cause of osteoarthritis and describe what further work has been done on the relationship between this "faulty" gene and the production of collagen?

Answer. In the fall of 1990, for the first time, a gene has been found that causes a form of osteoarthritis. Researchers led by NIAMS grantees Dr. Darwin J. Prockop at Thomas Jefferson University in Philadelphia, Pennsylvania, and Dr. Roland W. Moskowitz at Case Western Reserve University in Cleveland, Ohio, studied three generations of a family affected with a form of primary osteoarthritis. They pinpointed a gene defect in collagen II, a structural protein that strengthens cartilage. The researchers found a single gene mutation that directs the substitution of one amino acid, cysteine, for another, arginine, at one position in the chain of more than 1,000 amino acids that make up collagen II. This finding strongly supports the idea that a single genetic flaw can cause at least one form of osteoarthritis, and maybe others. Work is now in progress to determine whether this abnormality or similar ones are present in large numbers of patients with osteoarthritis.

INTRAMURAL RESEARCH

Question. Your intramural research program has grown to 7.5 percent of your overall budget, but this is still below the average for NIH as a whole. What plans to you have for your laboratory programs? Have you been given adequate space? What difficulties have you experienced in recruiting scientists for areas of your program that you would like to expand?

Answer. In 1990, the NIAMS established two new laboratories in its intramural research program: the Laboratory of Skin Biology and the Laboratory of Structural Biology Research. We are currently recruiting an individual to lead a Section on Genetics within the Laboratory on Skin Biology to study the genetic basis for a variety of heritable skin diseases. The Laboratory of Structural Biology Research is expanding its work with the Division of Computer Research and Technology in the area of image processing and analysis of macromolecules; it is also recruiting for a senior scientist to pursue x-ray diffraction analysis of proteins.

Establishment of a Laboratory of Bone and Connective Tissue Biology is the next step in expanding the Institute's intramural program in accordance with the plan submitted to Congress in 1988. The first director of the Orthopaedics Research Unit has recently accepted a position outside the NIH. A new director is being vigorously recruited with the advice of leaders in academic orthopaedics. We also have plans to recruit for a director of the Laboratory of Bone and Connective Tissue Biology.

Expansion of the Intramural Program depends upon space being vacated by other NIH Institutes that are moving to new quarters. We expect that some additional space will be available by the end of this fiscal year.

QUESTIONS SUBMITTTED BY SENATOR ARLEN SPECTER

SPORTS MEDICINE

Question. Dr. Shulman, much of the Nation's attention will be focused on sports this weekend as the NCAA Basketball Tournament gets underway. Let me note, for the record Mr. Chairman, that five Pennsylvania teams are participating in the tournament. There has been much publicity in recent years regarding sports related injuries. What are the Institute's plans for research in the study of sports injuries?

Answer. The NIAMS has organized and supported a Workshop on Sports Injuries in Youth: Surveillance Strategies to be held at the NIH on April 8-9, 1991. Speakers will discuss the background of existing surveillance systems and the scope of the problem, identify important data elements, and explore the resources needed to develop surveillance systems for sports injuries. Invited participants include orthopaedic surgeons, coaches, trainers, representatives from state health departments, epidemiologists, and other interested parties. The workshop and its written summary will encourage additional research applications in this field.