New director of Division of Rheumatology and Immunology continues a strong research and clinical care legacy
By Matthew Greseth
“The whole body becomes painful, the face in some becomes red, the pain rages especially about the joints, so that indeed neither the foot nor the hand, nor the finger can be moved without pain & outcry. Although the arthritis is in a certain part, this rheumatism itself is in the entire body.” —Guillaume de Baillou
Leading for more than 20 years
The Division of Rheumatology and Immunology was founded by E. Carwile LeRoy, M.D., in 1974. In 1981, he recruited Richard M. Silver, M.D., now Distinguished University Professor in the College of Medicine, following Silver’s fellowship at the University of California, San Diego. In 1995, when LeRoy stepped down, Silver became division chief and proceeded to lead the division for the next 23 years.
When Silver joined the division, there was a strong need to care for pediatric patients suffering from rheumatic diseases; however, South Carolina did not have any expertise in this field. Silver began seeing these individuals because of his experience caring for juvenile arthritis patients while studying in London with Barbara Ansell, CBE, FRCP, FRCS, the founder of pediatric rheumatology. He developed a program to care for these patients and eventually recruited the state’s first board-certified pediatric rheumatologist. One of his proudest achievements was helping the Department of Pediatrics develop its own Pediatric Rheumatology Division.
According to Silver, being a division director has its headaches but also can be very rewarding.
“I think one of the ideal attributes of being a division director is the ability to recruit people and build programs and I think we did that very successfully,” says Silver. “I’m also proud of the fact that we have trained so many rheumatology fellows who now practice throughout the U.S.”
Silver recruited many outstanding researchers to maintain the division’s strong national and international reputation in lupus and scleroderma research. He also developed a SmartState program—the South Carolina Inflammation and Fibrosis Center for Excellence. To create this program, he raised $5 million in large and small philanthropic donations that were matched by the state to fund critical research into lupus and scleroderma and to fund two endowed professorships.
Changing of the guard
In 2018, the Department of Medicine led a nationwide search for a new director after Silver decided to step down. At the end of the search, James C. Oates, M.D., now professor and director of the Division of Rheumatology and Immunology, was hired to head the division. Oates moved to MUSC in 1996 for a year-long research fellowship with Gary S. Gilkeson, M.D., and he joined the rheumatology faculty in 1997.
“I feel very good that Jim was selected,” says Silver. “I think he was clearly the best candidate, and he provides some continuity to the division as we move forward.”
Oates sees a lot of potential to advance the research and clinical care arms of the division.
“Key strengths of the division are the faculty, the culture and the national and international reputation in research and clinical care that Dr. Silver has built,” says Oates. “I’d like to maintain our strength in scleroderma and lupus clinical care and research.”
One way to maintain continuity with Silver’s tenure as director is to recruit new research faculty. Oates envisions recruiting a mid-level scleroderma physician scientist to maintain strong scleroderma research under the mentorship of excellent faculty such as Silver. Additionally, Oates would like to recruit a mid-level physician scientist to help develop an area of excellence for vasculitis, a related autoimmune disease.
Some new developments to the division include the formation of more formal centers that coordinate clinical care, research and education. For example, incorporating a care coordinator into the clinic to focus care on those at highest risk may reduce health disparities. Resources for that position are sometimes difficult to obtain, but Oates will work hard to bring such centers to fruition.
“With optimal patient care and reduction of health disparities as outcomes, I am hopeful that people will be on board for that type of initiative,” says Oates.
MUSC leads research into treatments for lupus and scleroderma
Autoimmune diseases are a result of the body’s immune system attacking and damaging its own tissues. There are more than 80 different types of autoimmune disease, and this group of researchers at MUSC are focused on better understanding two of them: lupus and scleroderma. While not very prevalent, they are very important diseases and serve as models for other, more prevalent diseases.
Systemic lupus erythematosus (the most common type of lupus and the one studied here at MUSC) is a systemic disease resulting in inflammation of vital organs. The Lupus Foundation estimates that 1.5 million Americans have lupus; 90 percent of diagnosed individuals are women, and women of color are two to three times more likely to be diagnosed. Scleroderma, or systemic sclerosis, is a chronic connective tissue disease that involves the hardening and tightening of skin and connective tissue. According to the American College of Rheumatology, 75,000 to 100,000 people in the U.S. are affected by scleroderma, with the highest incidence among women between the ages of 30 and 50.
In addition to running the Division of Rheumatology and Immunology, Oates also leads a strong research lab focused on lupus nephritis and lupus atherosclerosis. In work funded through a VA Merit Award, the Oates lab is studying how endothelial dysfunction may link the accelerated atherosclerosis seen in lupus patients with the process of immune cells becoming attracted to and migrating into kidney tissues to cause local inflammation. Nitric oxide, a potent vasodilator, is highly expressed in the kidney and may be a key mediator and modulator of disease.
To help guide therapy, the Oates lab is also looking at biomarkers at baseline that predict one-year outcomes. Furthermore, they are using a type of machine learning, random forest analysis, to assess variables that are already in the electronic health record in an attempt to model patients who are at risk for poor outcomes.
Another lab is taking a genetic approach to identify novel lupus biomarkers. Betty P. Tsao, Ph.D., professor and inaugural holder of the Richard M. Silver Endowed Chair for Inflammation Research in the Division of Rheumatology and Immunology, is analyzing patient genomes from different ethnic backgrounds to understand lupus risk variants, in both the coding and noncoding regions of the genome, which might reveal novel mechanisms underlying disease. Variants that appear in multiple major ethnic groups are more likely to be causal and may serve as novel drug targets.
“It seems so unfair that lupus affects young women,” says Tsao. “You want to be able to figure out something to help them.”
Indeed, her work has identified several interesting targets, including proteins involved in autophagy and the generation of reactive oxygen species. A better understanding of the pathways these proteins are involved in could aid in the development of more targeted therapies or personalized medications.
There is a large, multicenter clinical trial centered at MUSC that is using mesenchymal stem cells (MSCs) to treat patients with treatment-refractory lupus. The trial is headed by Gary S. Gilkeson, M.D., Distinguished University Professor in the College of Medicine and associate dean for faculty affairs and faculty development.
“The appeal of MSCs is their relative safety,” says Gilkeson. “They have been tried in other diseases, and there haven’t been reports of any major side effects. If they work, and if they work for a long period of time, that would be advantageous.”
Six patients were treated in the phase I trial. They were given a single infusion of MSCs and allowed to remain on their other medications. Five of the six patients met the response criteria, and some had remarkable responses to the treatment.
Trying to better understand the impact of MSCs on the immune system, Gilkeson and colleagues made a shocking observation. Infusion of the MSCs resulted in significant differences in the B cell compartment—the B cells that make autoantibodies and are increased in lupus patients returned to normal levels. Currently, they are unsure of the reason for these changes, but they hypothesize that transforming growth factor beta expressed from MSCs affects the B cell population.
Having retired from directing the division, Silver can now see more patients and focus on teaching and conducting cutting-edge scleroderma research. By examining data from scleroderma patients, he found that the level of thrombin, a coagulation factor, was elevated in the lung. In tissue culture models, addition of thrombin converted normal lung fibroblasts into myofibroblasts that exhibited all the hallmarks of fibrotic tissue.
Silver and his colleague, Galina S. Bogatkevitch, M.D., Ph.D., went on to show that an FDA-approved thrombin inhibitor was capable of transforming a scleroderma fibroblast back into a normal fibroblast. They then used an animal model of lung fibrosis to show that they could attenuate disease in animals that were given the thrombin inhibitor. Now they have found a natural antifibrotic peptide that is effective at blocking fibrosis in vitro and in animal models through a pathway distinct from the thrombin path.
Down the hall, Carol Feghali-Bostwick, Ph.D., professor and SmartState and Kitty Trask Holt Endowed Chair for Scleroderma Research in the Division of Rheumatology and Immunology, and members of her lab study the molecular differences that differentiate twins discordant for scleroderma. While trying to identify profibrotic factors, they realized that a fragment of collagen 18, endostatin, was induced.
Surprisingly, endostatin exhibited an antifibrotic effect. Subsequently, they chopped endostatin into smaller peptides to determine which region was antifibrotic. They identified a peptide that inhibits multiple pathways that have been implicated in fibrosis. This may be why it is more effective than other treatments and is likely to stop, even possibly reverse, fibrosis. The peptide has been licensed for cost-effective production in plants. Upon passing an investigative new drug approval by the FDA, this new peptide could be seen in the clinic in the near future.
“It looks promising so far,” says Feghali-Bostwick. “The encouraging part is that the parent molecule, endostatin, has been used in advanced clinical trials for its antiangiogenic activity in cancer and has shown no toxicity or drug resistance.”
Positive signs ahead for treating lupus and scleroderma
Currently, there is no cure for lupus or scleroderma. Treatments for this class of ailments can be toxic and focus on inhibiting immune system activity and reducing inflammation. Researchers at MUSC are pursuing several exciting research projects that aim to provide better alternatives.
“I think we are nicely integrating the clinical and research missions of the division, where both our clinicians and researchers are all focused on how to improve people’s lives,” says Oates.