Dr. Dana Ascherman, Assistant Professor of Medicine, has recently been awarded a grant from the Arthritis Foundation, Western PA Chapter, for research on Sjögren's syndrome. His Co-investigator on this project is Dr. William Ridgway, also Assistant Professor of Medicine. In the competition, Dr. Ascherman's was the highest ranked proposal, earning it the title of the 1999 H. M. Margolis Research Grant (see article on page 7 on Dr. Margolis). The Newsletter interviewed Dr. Ascherman about this project.

What is Sjögren's Syndrome?
Dr. Ascherman: Sjögren's syndrome is a disease in which the immune system "attacks" different tissues in the body, particularly the glands responsible for producing tears and saliva. As a result, patients with Sjögren's syndrome have dry eyes, dry mouth, mouth ulcers and increased tooth decay. It can also result in arthritis, circulatory problems (Raynaud's phenomenon), nerve damage, or breathingj difficulty. Rarely, Sjögren's syndrome may even evolve into a form of malignancy affecting the lymphocyte cells of the immune system, called lymphoma.

Tell us what you plan to study?
Dr. Ascherman: Sjögren's syndrome involves interactions between abnormally activated cells of the immune system (T cells and B cells), both of which are forms of white blood cells. If we could find a way to target and eliminate these cells the disease could be halted. The "overactive" cells in Sjögren's syndrome have on their surfaces unique molecules or proteins which are different from those on normal" cells of the immune system. One such protein is called CD40 ligand and is important in the ability of these cells to bind to and influence other cells. Using antibodies against CD40 ligand is one strategy for blocking damage to tissues. We will test this treatment in a particular strain of mice that naturally develop a Sjögren's-like disease.

How did you get interested in this type of research?
Dr. Ascherman: Sjögren's syndrome is a disorder in which no specific treatment exists, so there is real opportunity to help patients with gland dysfunction. Also, exploring the reasons for autoimmune disease has been one of my long-standing interests. Although this research will focus on Sjögren's syndrome, the information that we gain may provide insight into abnormal immune responses in general.

If successful, how might your results help patients with Sjögren's syndrome in the future?
Dr. Ascherman: Previous research on anti-CD40 ligand antibody treatment of different autoimmune diseases affecting particular strains of mice has been encouraging. If the mice with Sjögren's-like disease respont to anti-CD40 ligand antibody therapy, treating human patients would be the next step. Ultimately, the key is to find a treatment that will not only improve gland malfunction but also treat or prevent more serious complications of the disease. If successful, this treatment approach also might eliminate the need for medications which generally suppress the immune system, such as Prednisone and Cytoxan.

Arthritis Network physicians have begun a project to examine the effect of a videotape on exercise, quality of life, and confidence in ability to exercise. Patients diagnosed with osteoarthritis of the knee who are being treated by rheumatologists are qualified to participate. The 14-minute videotape was developed by the University of Pittsburgh Medical Center (UPMC) with input from physicians, physical therapists, and video production specialists. The videotape provides general information about osteoarthritis of the knee and the importance of exercise and illustrates range of motion, stretching, strengthening, and a variety of low-impact fitness activities to educate patients on how to effectively perform exercise. A written summary guide accompanies the videotape; it repeats information on how to do the leg exercise simply and painlessly, building patient confidence.

Patients participating in the project complete short questionnaires and exercise diaries during an office appointment and two more times after watching the videotape. The information gained from the project will guide the investigators in developing a second generation videotape to improve the ability of osteoarthritis and other chronic disease patients to perform therapeutic exercises easily and effectively. The project is funded by the Center for Research in Chronic Disorders at the University of Pittsburgh School of Nursing.

Patients are being recruited from the practices of Arthritis & Internal Medical Associates - UPMC (Dr. Terence W. Starz, contact) and the Margolis Rheumatology Associates - UPMC Dr. Thaddeus A. Osial, Jr., contact).

The University of Pittsburgh Medical Center, in affiliation with Stanford University, is participating in a multi-site research study to determine the long-term outcome of rheumatoid arthritis and osteoarthritis. The study is geared to determine the impact that rheumatoid arthritis and osteoarthritis have on everyday life. The investigators use the term ARAMIS (Arthritis, Rheumatism and Aging Medical Information System) to describe their research team.

Participants in ARAMIS receive a questionaire to complete twice each year regarding their disease and the effects it has upon them. This questionnaire is called a Health Assessment Questionnaire (HAQ); it contains questions about many different aspects of daily life. Some of the areas of interest include the medications that one is taking, any side effects experienced, hospitalizations and oupatient medical or surgical procedures that patients have had. Due to the fact that rheumatoid arthritis and osteoarthritis can be costly diseases, participants are asked to answer questions regarding their health insurance, employment status and ability to complete non-employment activities.

Included with the questionnaire is an ARAMIS newsletter. In this newsletter you will find helpful hints on dealing with your disease, answers to some of the most frequently asked questions about arthritis and articles that relate to arthritis.

If you are interested in participating or would like to receive more information on the ARAMIS rheumatoid arthritis and osteoarthritis research study, please contact Amy Cunningham, Study Coordinator at (412) 383-8903.

The physicians in the UPMC Arthritis Network are developing an Arthritis Network Registry to aid investigators in arthritis research. The purpose of this Registry is to develop a list of patients who have rheumatic diseases and who are interested in hearing about research studies for which they may be eligible to participate. The Registry was described in detail in the last Newsletter. The Registry is generously funded by the St. Margaret Memorial Hospital Foundation.

The first step in developing this Registry was to recruit patients with rheumatoid arthritis. We mailed 2000 invitation letters to Network rheumatoid arthritis patients in May, 1999 and as of now 596 patients have enrolled in the UPMC Arthritis Network Registry. This is a tremendous response; it indicates the strong interest of patients in research involving their disease! Rheumatoid Arthritis patients can still sign up for the Registry. Appropriate information is in each of the Network practice offices.

How Does the Registry Work?

Once a person has agreed to participate in the Registry, his/her name, address, date of birth, and diagnosis are entered into a computer database. When a researcher decides that he or she would like to conduct a study on patients with a particular rheumatic disease, such as rheumatoid arthritis, the researcher can apply to the Network Research Committee for permission to use the Registry. If the investigator has secured University approval and the Research Committee agrees that the research is scientifically sound, the investigator would receive a list of the Registry patients' names and addresses. Then either the researcher or a member of the research team would contact the Registry patients with the specific details about that study.

As a participant in the UPMC Arthritis Network Registry, you are under no obligation to participate in any of the studies that you are contacted about. When agreeing to participate in the Registry you are consenting only to being contacted with information about upcoming research studies. You may remain a member of the Registry and receive study announcements and newsletters even if you have decided not to participate in a study in which you were invited to enroll.

The Next Step

Due to the success in recruitment of rheumatoid arthritis patients, we will begin to recruit patients with osteoarthritis beginning in October, 1999. If you have osteoarthritis, you will receive a letter of invitation from your rheumatologist. This letter will contain information regarding the Registry and a "consent form". In order to participate in the Registry, a consent form must be signed and returned, as directed. Again, signing this consent form simply means that you are giving researchers authorized by the Network Research Committee consent to contact you regarding specific research opportunities.

Joining the Registry

The Registry is open to all rheumatoid arthritis patients. For questions or an invitation to join, contact the Registry Coordinator at 412-383-8000.

Although systemic lupus erythematosus (lupus) may affect virtually any organ, involvement of the kidney (nephritis) is responsible for much of the disability and many deaths related to lupus. Several different forms of lupus nephritis exist, ranging from mild disease to severe, destructive inflammation that can result in kidney failure and necessitate transplantation. Over the last 20 years, treatment routines have developed for nephritis which have resulted in improved kidney function in many patients. Unfortunately, such treatments involve considerable suppression of the immune system with high doses of cortisone and "cytotoxic" (cell killing) drugs such as cyclophosphamide (Cytoxan). The use of these drugs may lead to serious infections as well as other side effects including weight gain, poor wound healing, osteoporosis, and malignancy.

Because these drugs are potentially toxic, researchers have been searching for safer, more effective treatments in lupus nephritis. One new approach involves using antibodies directed against proteins on the surfaces of activated immune cells. This treatment has been used in several types of mice which develop lupus with resulting improvement in nephritis. Based in part on these animal data, investigators at the University of Pittsburgh will be participating in a multi-center study designed to examine the effect of these antibodies in a group of human patients with lupus nephritis. If this initial trial produces the beneficial response seen in mice, larger trials would then be needed to confirm the positive results and identify other categories of patients who might respond to this treatment.

Drs. Susan Manzi and Dana Ascherman will be directing the treatment of those patients enrolled through the University of Pittsburgh.

Acute low back pain (<3 months duration) is one of the most common musculoskeletal disorders, affecting 70-90% of persons during their lifetime. In addition to the physical setbacks associated with this problem, acute low back pain presents an enormous economic burden in terms of diagnosis, treatment and loss of work.

Twenty million women and 5 million men in the U.S. have osteoporosis and many of them don't even know it! By definition, osteoporosis means porous or thin bones. These bones have lost enough strength to become soft and fragile and therefore break easily. Most of the structure of the skeleton is in place before the age of 20 years. Remodeling or rebuilding of bones takes place throughout life. Factors such as female sex, smoking, low calcium intake, and reduced exposure to sunlight all contribute to osteoporosis. In addition, small-boned, thin build, early menopause, sedentary life style, excessive caffeine, prolonged cortisone therapy and certain medications are risk factors. Post-menpausal women are at greatest risk. Osteoporosis can also be seen in association with rheumatic diseases, such as rheumatoid arthritis, most likely because of inability to be physically active and cortisone treatment.

The standard test for osteoporosis is the DEXA scan which measures bone density with reasonable accuracy. It is a modified x-ray technique that can be ordered by your doctor. Detection of osteoporosis is important since effective treatment is now available. Earlier detection and treatment of osteoporosis may prevent fractures and their complications. All arthritis patients should discuss whether they have, or are at risk for, osteoporosis with their primary care physician or rheumatologist.

Adequate intake of calcium and Vitamin D are difficult to achieve, but very necessary and may delay osteoporosis. Current recommendations are that all persons have a minimum of 1000mg of calcium daily. However, post-menopausal women require 1500mg per day. Hormone replacement therapy, with estrogen and newer medications such as Fosamax, Evista and Miacalcin nasal spray have been reported to improve bone density and reduce fracture rates in patients with osteoporosis.

In future editions of the Newsletter we will examine each of the new treatments for osteoporosis in detail and describe a study at the University on osteoporosis in elderly men.

Recently the Food and Drug Administration (FDA) has approved 2 new drugs for the treatment of arthritis: Celebrex and Vioxx. Celebrex was introduced in Febryary, 1999 and Vioxx in May, 1999.

These drugs belong to a new group of anti-inflammatory medications called COX2 (inhibitors) blockers. The older anti-inflammatories block two proteins (enzymes), COX1 and COX2. COX1 is important in the normal function of different body organs and cells, including the stomach, kidneys and platelets. On the other hand, COX2 is a substance which causes inflammation, perhaps for the body's protection in times of stress. The advantage of a COX2 is to decrease inflammation without interfering with other body functions. The greatest benefit of COX2 inhibitors at this time is that they are much better tolerated as far as the stomach is concerned compared to the older anti-inflammatories.

Comparing Celebrex and Vioxx, there are far greater similarities than differences. Because they do not influence platelets, both medications can be taken up until the day of surgery. In the past, anti-inflammatory drugs had to be stopped one week before an elective surgical procedure. Celebrex can't be taken by patients with sulfa allergy, but Vioxx can. In contrast to Celebrex, there is some concertn about the use of Vioxx with methotrexate. Both medications are expensive. Some medical insurance and prescription plans require your physician to justify why you cannot take other anti-inflammatory drugs. Valid reasons might be a history of bleeding ulcer, intolerance of or allergy to these drugs, or failure of these drugs to adequately control your arthritis.

I take coumadin to prevent blood clots. If I have pain from my osteoarthritis, which medications are safe to take?

Coumadin is a medication that thins the blood and by doing so prevents blood clots. Unfortunately, most of the arthritis medications in the anti-inflammatory class, e.g. Advil, Aleve, etc. can also thin the blood by affecting the function of one of the blood elements called the platelet. Physicians usually avoid combining these drugs for fear of excessive bleeding. Any medication for pain that does not contain aspirin or anti-inflammatories can be used safely with coumadin; for example, cortisone is safe in this respect. Standard practice is to start with plain Tylenol and if that alone is not enough, stronger prescription pain medications can be prescribed. As a reminder, patients should not forget other simple measures that can relieve pain such as applying moist heat, doing proper exercises, applying topical creams, or possibly getting a joint injection from their doctor, which often helps for several weeks or months.

Please explain why it is not wise to take anti-inflammatory drugs if you have kidney disease.

A variety of side effects from anti-inflammatory drugs on the kidneys have been reported. Some of these problems occur because these drugs block the action of a substance called cyclooxygenase (COX) which is important in maintaining normal blood supply to the kidneys. Fortunately, the effects of anti-inflammatory drugs on the kidneys are usually reversible (the kidneys will recover completely if the drug is stopped). However, if your kidneys are already functioning at a low level from a disease, their ability to recover from an insult is compromised, leading to further deterioration of kidney function. Therefore, patients with pre-existing kidney malfunction should not take anti-inflammatory medications. Cortisone, in contrast, is safe for the kidneys.

There have been some concerns about the safety of Celebrex now that it is on the market. Who should be concerned?

Celebrex is a new arthritis medication released to the public in February, 1999 after FDA approval. There have been some reports of deaths in patients who were taking Celebrex. Our review of the available data so far does not suggest any direct relationship of these fatalities to Celebrex. Overall, rheumatologists consider Celebrex to be a very safe drug. As a reminder, when you hear or read in the news that a drug has been released that is 100% helpful with absolutely no side effects, this is usually not a true statement. Any time a patient takes a drug there is some risk of some side effects, many of which cannot be predicted beforehand.

Can Enbrel and Arava be used with other strong medications such as methotrexate or cyclosporin?

Methotrexate is currently considered the "backbone" of rheumatoid arthritis treatment. Other medications can be added for more complete control of the disease, including Enbrel, Arava or cyclosporin. In many instances, two drugs used in combination are superior to one drug. For example, some rheumatologists prescribe the combination of Plaquenil, Methotrexate and Sulfasalazine. However, when a second or third medication is added the dose of one of the other drugs could conceivably be reduced. Therefore when Enbrel is added to methotrexate, the patient may do so well that the dose of methotrexate may be reduced without loss of effectiveness.

Dr. Harry Margolis spent his entire medical career provinding care and help to patients with arthritis. He received his medical degree from the University of Pittsburgh and then went to Mayo Clinic for further training where he studied under Dr. Philip Hench, a University of Pittsburgh graduate, who eventually became a Nobel Prize winner for his discovery of the action of cortisone in rheumatoid arthritis.

Dr. Margolis returned to Pittsburgh to concentrate on the diagnosis and treatment of patients with arthritis and the education of physicians regarding the plight of these patients. He was the founder of the Western Pennsylvania Chapter of the Arthritis Foundation and was its first Director. He attracted corporate heads, professionals and educators to become board members to help in the operation of the organization. Dr. Margolis initiated Chapter support of local research, which provided seed money for young investigators embarking on arthritis research careers. Their research studies were done in local hospitals and the University of Pittsburgh. The Chapter has continued this practice and has over the years funded many young investigators who have gone on to become senior scientists, both at the University of Pittsburgh and other academic institutions. Dr. Margolis also developed a program which partially supported the salary of physicians in training at the University of Pittsburgh to become rheumatologists. Many trainees supported by this program have entered the practice of rheumatology in the greater Pittsburgh area, providing help and medical care for patients with arthritis.

Editor's Note: In recognition of Dr. Margolis' contributions, the Arthritis Foundation, Western PA Chapter has designated the highest ranking research grant funded by the Chapter each year as he Harry M. Margolis Research Grant (see article on page 1 about the grant and its first recipient, Dr. Dana Ascherman).

During the past year, two physicians have joined the Network.

Noah Bass, M.D. is the newest member of Arthritis and Internal Medicine Associates. Dr. Bass attended Emory University School of Medicine. He subsequently completed his residency in internal medicine at Montefiore Hospital and his rheumatology fellowship at Emory University Affiliated Hospitals. Currently, Dr. Bass is a Clinical Instructor in Medicine at the University of Pittsburgh. He joins Arthritis and Internal Medicine Associates after eighteen years of private practice in western Pennsylvania.