New faculty join Kellogg colleagues in planning a unique research and treatment center
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Graves' eye disease, also called thyroid-associated ophthalmopathy, remains poorly understood, according to the two newest faculty members at the U-M Kellogg Eye Center. They are shedding new light on the disorder through their research and an initiative to standardize the evaluation of treatment. These advances should one day help patients, chiefly women, who experience its painful manifestations — bulging eyes, double vision, and, in severe cases, vision loss.
Even before settling into their new laboratory, Terry J. Smith, M.D., and Raymond S. Douglas, M.D., Ph.D., are discussing several promising therapeutic agents that may soon be ready for clinical trials. And they are keen to join forces with other U-M specialists in developing a major research and treatment program for Graves' eye disease and other autoimmune conditions.
Dr. Smith, the Frederick G.L. Huetwell Professor of Ophthalmology and Visual Sciences, is a renowned endocrinologist who has studied Graves' disease, its eye manifestations, and related autoimmune diseases for over 20 years. His laboratory was first to describe the unique molecular attributes of tissue surrounding the eye that make it susceptible to inflammation in Graves' disease. The discovery came as he questioned why a systemic disease associated with thyroid overactivity would single out the orbit as a site of involvement.
From these findings, Dr. Smith went on to identify a receptor that binds to antibodies and sets off a series of events resulting in inflammation and fibrosis—excessive scar-like tissue that pushes the eye outward and disrupts its function. Currently, he is mapping a signaling pathway where "cross talk" between cells and small molecules may provide a therapeutic target that allows interruption of the immune system's assault on orbital tissue.
As he notes these successes, Dr. Smith observes that the biggest impediment in understanding Graves' disease is lack of access to tissue early in the process. "It is generally later, when surgery is indicated, that we can access and analyze the tissue. But by then we may be looking at secondary reactions that are entirely different from those initiating the pathology," he says. "It's like looking at a scar that has formed over a wound. The scar is the reaction to the injury, not the cause of it."
Developing treatments and a standard to measure their effectiveness Dr. Douglas echoes these concerns, adding that he and Dr. Smith have taken a broad view of the disease process rather than searching for a "magic bullet." Says Dr. Douglas, "As in other autoimmune diseases, there are multiple factors, no less than four or five things that go awry. If we can describe the factors affecting a particular patient—how much inflammation vs. fibrosis—we could design treatments to respond to specific characteristics."
In one very promising study, Dr. Douglas has shown that B-cells, the body's normal antibody-producing cells, play a pivotal role in the inflammatory process in Graves' eye disease. He found that patients with severe inflammation responded to a treatment that depleted the B-cells and, remarkably, reduced activity of the disease. Conventional treatment with steroids did not help these patients.
Dr. Douglas was also instrumental in forming an international group to develop standard language and a scale for measuring the effectiveness of treatments. Through the International Thyroid Eye Disease Society (ITEDS), Dr. Douglas has collected data from ophthalmologists and endocrinologists worldwide to gain consensus regarding common indicators of disease activity and progression. The group now has recruited nearly 200 participants and Dr. Douglas believes a reliable rating index will soon be developed.
While they search for novel therapies, these researchers do not dismiss therapies that have been effective in allied diseases like rheumatoid arthritis. "Some of these therapies have cleared safety hurdles and they address processes common to both diseases," says Dr. Douglas. Similarly, discoveries concerning therapy for Graves' disease may have implications for other diseases, including rheumatoid arthritis, Crohn's disease, and juvenile-onset diabetes.
Establishing an international center for the treatment and investigation of Graves' disease Kellogg's new clinician–scientists envision a comprehensive research and treatment program here, drawing on resources within the Eye Center and the U-M Health System. One of their chief collaborators is Ravitz Foundation Professor Victor M. Elner, M.D., Ph.D., who served with Dr. Douglas on the ITEDS Steering Committee." The Department has had a strong emphasis on Graves' eye disease as well as a history of significant research in the inflammatory mechanisms of ocular disease in general," says Dr. Elner, an oculoplastic surgeon and pathologist. "We know that many other diseases causing blindness, such as age-related macular degeneration and diabetes, have inflammatory components."
Then, too, there is the prospect of collaborating with scientists studying diabetes when the Eye Center expansion and Brehm Center—with laboratories on adjacent floors—open in early 2010. In Type 1 diabetes, the focus of the Brehm Center, autoimmune destruction of pancreatic cells occurs by processes similar to those in Graves' disease.
As Dr. Douglas sees it, the U-M is likely to become the "central proving ground" for research and treatment of Graves' eye disease—a site for testing tissue and blood samples, for finalizing the Graves' eye disease index, and for launching clinical trials.
"It always comes back to the patients," says Dr. Douglas. "Graves' eye disease affects them in the prime of their lives, causes emotional and physical pain, and challenges their quality of life. We plan to solve the mysteries of this disease with our new colleagues at the University of Michigan."
Dr. Smith will see patients in the Department of Internal Medicine and he and Dr. Douglas will see patients in Kellogg's Eye Plastic, Orbital and Facial Cosmetic Surgery Service.
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