A Pain in the Mouth

A dental researcher finds causes of an elusive oral ailment that afflicts mostly middle-aged women
Lynn Solomon suspects there are many more cases of chronic ulcerative stomatitis (CUS) than the handful documented in the medical literature. Photo: Kelvin Ma
August 2, 2011

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A Tufts dental researcher is shedding light on a difficult-to-diagnose disorder and is finding evidence to suggest the condition, which afflicts mostly middle-aged women and leaves its sufferers with painful mouth sores, is in fact an autoimmune disease.

With just 39 documented cases of chronic ulcerative stomatitis (CUS) documented in the English-speaking medical literature, a dentist could be forgiven for not recognizing it in a patient presenting with the painful mouth lesions that characterize the condition.

CUS is easily confused with lichen planus, a more common ulcerative disorder that can be triggered by allergies or ailments, including hepatitis C. And since the definitive test for the rarely seen CUS is elaborate and can take up to 10 days between biopsy and diagnosis, most dentists start patients on the treatment for lichen planus, namely topical or oral steroids. But those medications are not effective for CUS.

“Then the clinicians are puzzled because the lesions are not responding to the usual treatments,” says Lynn Solomon, an associate professor in the department of oral and maxillofacial pathology at the School of Dental Medicine, whose research into the underlying causes of CUS could open the door to speedier diagnosis. Her most recent study, published in the April 4 issue of Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology, classifies CUS as an autoimmune disorder caused by the body launching an inappropriate attack on its own tissues.

Which Came First?

Researchers already had circumstantial evidence that CUS belongs to that group of ailments. Like better-known autoimmune disorders such as rheumatoid arthritis and lupus, CUS most frequently afflicts middle-aged women. More telling, CUS patients test positive for specific antibodies; detecting these antibodies in tissue biopsies is the current, if unwieldy, method of diagnosing the disease. But until now, the antibodies represented a chicken-and-egg problem; no one knew if they caused the ulcerations that characterize CUS or if they were simply the body’s immune response to the disorder.

In her recent study, Solomon and her colleagues, Jonathan Garlick, director of the Center for Integrated Tissue Engineering, and postdoctoral researcher Mark Carlson, demonstrate that the antibodies indeed play a role in causing the ulcers. The team treated three-dimensional tissue models with various concentrations of the antibodies in question derived from the blood of known CUS patients. Grown from human skin cells, the tissue models are stratified into several layers that are anchored to a base membrane just like in our own skin.

Sure enough, the tissue models treated with the antibody began to fray, with the upper layers of skin pulling away from the base layers, mimicking the way CUS-related ulcers form. More damning, the tissue samples treated with a higher concentration of antibodies fared far worse than the models treated with the lower concentration. “Whole sections are losing their connections, weakening the tissue,” says Solomon.

What’s going on? These CUS antibodies bind with a key cellular protein that acts as a genetic switch. Under normal conditions, this switch regulates the expression of integrins, cellular structures that Solomon calls “the little molecular hooks” that hold cells and tissues together. But in Solomon’s study, the tissue models treated with the CUS antibodies produced fewer integrins than the untreated control samples. That evidence suggests that the CUS antibodies interfere with the genetic switch, which in turn decreases integrin production, and the tissue loses its structural integrity as a result.

Solomon suspects there are many more cases of CUS than the handful documented in the medical literature. “Some argue that people with lichen planus also have [these] antibodies,” says Solomon. “My stance is ‘Gee, maybe it’s the same disease.’ ”

To know for sure, Solomon is also working to develop better diagnostic tools for CUS. In a 2010 study with colleagues from Tufts and SUNY Buffalo, Solomon demonstrated that an already widely available lab test known as ELISA (enzyme-linked immunosorbent assay) could reliably detect CUS. That’s an advantage because the ELISA test requires only a blood sample, while the current gold-standard CUS test requires a biopsy, which dentists may be reluctant to perform.

Future studies will investigate the feasibility of using saliva rather than blood. “Blood isn’t a dentist’s medium,” Solomon says. “But saliva is.” And faster diagnosis means patients could be treated with the proper medication right off the bat, rather than waiting for the treatment for lichen planus to fail first.

 That’s good news for CUS sufferers.  “It can be miserable to live with a sore mouth,” says Solomon. 

Jacqueline Mitchell can be reached at jacqueline.mitchell@tufts.edu.