by Seema Kumar
Every Thursday morning for the past month, Ralph Schumacher, Acting Chief of the Division of Rheumatology at the University of Pennsylvania, has been taking the 6:24 from Philadelphia's 30th Street Station to participate in an new experiment that NIAMS launched last month -- a minisabbatical to foster clinical research collaboration with the extramural community. And already, says John Klippel, NIAMS's Clinical Director, the experiment is proving that intramural-extramural collaborations are not just convenient ways to share expertise and resources -- they can yield impressive results.
"Our sabbatical is only in its first month, but we are confident it will be a great success," says Klippel. "Many cutting-edge advances from the extramural program [can benefit from] the unique resources we have here at NIH, and we should...provide extramural investigators the opportunity to use these facilities and collaborate with scientists on campus."
Extramural-intramural collaborations are also high on NIH Director Harold Varmus' agenda, and his endorsement has provided renewed vigor to the idea of establishing a formal sabbatical-at-NIH program for extramural investigators. Klippel says the minisabbatical experiment started by NIAMS's Arthritis and Rheumatism Branch might serve as a prototype for NIH and provide a good model, albeit not the only one, of how formal intramural-extramural collaborations can be established.
During his sabbatical, Schumacher is studying patients in the early stages of arthritis to find out whether external factors, particularly infectious agents, trigger the disease. The idea that infectious agents can cause difficult to diagnose arthritis is not new: Lyme disease, caused by the spirochete Borrelia burgdorferi, is a well-known example. What is new, says Schumacher, are the methods he will use to investigate the idea. Schumacher is looking for evidence of infectious agents in biopsies of joint tissues and by using electron microscopy, immunoelectron microscopy, polymerase chain reaction (PCR), and in situ hybridization -- techniques that have been perfected in the past few years but not yet applied systematically to the study of potential infectious agents in arthritis.
Schumacher is pretty sure that he is going to find something. In similar studies on patients with Reiter's syndrome, a type of arthritis associated with urethritis or cervicitis, conjunctivitis, and mucocutaneous lesions, he and his colleagues found evidence of Chlamydia and Ureaplasma in joint tissues. They also found these agents in joint biopsies from patients with early unexplained arthritis and, tantalizingly, in a few patients with early rheumatoid arthritis. Schumacher says a key to the success was the use of newer laboratory techniques. "We think there may be hidden infections in other diseases that these techniques might be able to pick up, where in the past, routine cultures did not," says Schumacher.
"Chlamydia, Borrelia, and Ureaplasma are probably much more common than we realize and may cause not only some of the yet-unclassified arthritis, but also recognized syndromes and even some of what we currently call rheumatoid arthritis," says Schumacher. Although these agents are the most likely culprits in arthritis in general, scientists have also speculated that other agents, such as mycobacteria, gram-positive bacteria, and even viruses may be implicated in rheumatoid arthritis. Although the big payoff in Schumacher's study would be finding one or more pathogenic organisms responsible for rheumatoid arthritis, the success he has already had finding bacteria in unclassified arthritis guarantees that his NIH work will yield clinical rewards. "Even if we don't find [a pathogenic organism] for rheumatoid arthritis, many of the other people who have unclassified synovitis or arthritis can probably be treated better if we prove what the cause of their arthritis is."
Many of the current treatments for arthritis, which affects an estimated 1% - 2% of adults, are immunosuppressive, blocking the body's immune response, and "it may, in fact, be that in some of these cases, we need to stimulate the body's immune response, and so [this research] may make some very dramatic changes in the way we think about the disease," says Schumacher.
Although the current NIH protocol does not include treatment, if an infectious agent is proved to be the cause, Schumacher, Klippel, and their colleagues plan to develop clinical trials to evaluate the role of antibiotics. So far, such treatment has only been partially successful perhaps because the organisms have developed survival strategies, as with the Lyme disease spirochete, which makes it impossible to eradicate the organisms completely.
The search for infectious triggers is the main emphasis of Schumacher's studies, but he also plans to collaborate with Daniel Kastner at NIAMS in immunogenetic studies of early-arthritis patients to see what genes influence the type of arthritis people get. Schumacher and his collaborators plan to do immunologic studies in these patients to determine how differences in their immune systems affect the way their bodies respond to infection. "There are a lot of good immunologists, cell biologists, and molecular biologists at NIH who might like to get specimens from patients with very early arthritis and look at whether the system that they are interested in is turned on very early in the disease and thus is important, or whether it is just a late manifestation of the disease," says Schumacher. "So we would like to get people who are studying growth factors and cell differentiation and various aspects of cell and humoral immunity [to come] out of the woodwork and see if they would be interested in looking at patients with us."
Schumacher also has many other collaborations lined up. Ronald Wilder at NIAMS, with whom Schumacher has collaborated in the past, is studying hormonal aspects of the disease; Mark Ghourley, an investigator at NIAMS, is studying the status of bone -- which the synovitis eventually eats into, thus crippling patients -- in early disease to determine whether changes at that stage can be used to predict the course of the disease. Social worker Louise Meister will be studying whether patients' social and economic support and resources can influence their prognosis. Finally, Lynn Gerber, a rehabilitation specialist, will be looking at whether a patient's level of physical activity can determine their prognosis.
By the end of his sabbatical next August, Schumacher hopes to have studied 100 patients and accumulated valuable research material in the form of joint tissues. "We are going to prepare cDNA libraries from all of these [tissues] and will be able to share that with other researchers. We are also talking to people in other institutes to see if they are interested in possibly applying some of their techniques," says Schumacher.
Schumacher, Klippel, and colleagues are looking not only for collaborators but also for patients who have had one or more swollen painful joints for less than one year, but preferably less -- even for as little as a week. Patients who are interested in participating in this study should call Cheryl Yarboro, Study Nurse Coordinator, at 402-6409.
"It is great to work here at NIH," says Schumacher. "Everyone seems enthusiastic, and the staff is very cooperative. But the beauty of this arrangement is the combination of the expertise and facilities from Penn and NIH."