SCIENTIST AT WORK:CREATIVE DISCOVERIES ARE MORE THAN A GUT REACTION

Call it serendipity or a touch of brilliance. The doctor says it's simply a result of "keeping an open mind and thinking ahead." Or maybe this is the usual pace of science and medicine – a slow jog forward with an occasional skyward leap. This is an account of how a physician made an observation that dramatically impacted one woman's life, and consequently may change the treatment for a chronic and debilitating disease affecting more than six million in the U.S.

Inflammatory bowel disease – specifically Crohn's disease and ulcerative colitis – is Kiron Das's specialty. But when the severe psoriasis plaguing one of his Crohn's disease patients dramatically improved, a lightbulb switched on. Could this be mere coincidence? Or might the Crohn's drug also be potent in halting the buildup of skin plaques which is the hallmark of psoriasis? Das was treating the patient with Remicade (Infliximab), a monoclonal antibody that blocks the action of a natural protein involved in inflammation. Remicade had not been used before to treat an inflammatory skin disease, explains Das, although about 10 percent of Crohn's patients suffer from related skin disorders.

The question drove the gastroenterologist to call colleague Alice Gottlieb, MD, PhD, a psoriasis expert, to evaluate the patient and corroborate the findings. The two doctors agreed to pursue the answer. Their excitement propelled them to propose the initiation of clinical trials of Remicade for psoriasis patients to Johnson & Johnson, the drug's manufacturer. The pharmaceutical company signed on; and early results of the trials are in. The data, recently published in The Lancet (Vol. 357, 2001), is extremely positive.

According to Gottlieb, who authored the article and is director of the Clinical Research Center at UMDNJ-Robert Wood Johnson Medical School, 20 of the 22 patients with moderate to severe psoriasis (covering more than 10 percent of the body) treated with Remicade reported good or excellent results, and the larger the dose they were given, the more effective the therapy. None reported serious side effects associated with other treatments for the disease. While further studies are planned to establish the safety and effectiveness of the drug, especially for long-term use, the outlook is excellent.

"An observation made on this one case led to a discovery that may ultimately prove quite important," says Das modestly.

The breakthrough seems so simple. But it's predicated on years of research that have yielded insights into autoimmunity and the spectrum of diseases it can cause. The immune system generally produces controlled inflammation in response to an invasion of viruses or bacteria. But sometimes the body's defense system turns against its own tissue. This doesn't always cause disease. But sometimes, the autoimmune response is unpredictable and exaggerated, resulting in damage to the body.

There are roughly 80 chronic diseases currently identified as autoimmune. These diseases attack different organs and body systems (skin, joints, intestinal tract, respiratory system, heart, etc.); are triggered by different agents; and produce a broad variety of symptoms. What they share is a similar disease process. It was a leap, but not one without foundation, to consider that Remicade, which is effective for Crohn's disease, and also works for rheumatoid arthritis, might clear psoriasis, a disfiguring skin disorder.

Until quite recently, psoriasis was not counted among the autoimmune diseases. But Gottlieb was among the first to demonstrate that treating the scaly clumps of excess skin cells does not begin to touch the actual underlying disease process. Immunosuppressive drugs, such as cyclosporine, dampen the immune system and work for psoriasis 90 percent of the time. Unfortunately, they often have serious side effects and even patients who do well on cyclosporine must be taken off the drug within one year.

A Cascade of Challenges

Das, a professor of medicine and chief of the division of gastroenterology at UMDNJ-Robert Wood Johnson Medical School, may have hit the jackpot for psoriasis sufferers, but inflammatory bowel disease (IBD) is his research and clinical focus. His primary goal in the lab is to identify the triggers that set up a cascade of events resulting in ulcerative colitis (UC). Finding a means to block the disease process or discovering a cure is truly a matter of some urgency. Ulcerative colitis lasting longer than 8 to 10 years is a known precursor for colon cancer; and since many patients first experience symptoms in their teens and 20s, major surgery to head off cancer looms on the horizon for them during their 20s and 30s. About one third of those affected will eventually require surgery either to prevent cancer, or because of massive bleeding, rupture of the colon or serious illness no longer responsive to drugs.

Inflammation and ulcers in the innermost layer of the lining of the large intestine are the hallmarks of this disease, which affects about one million Americans. (Crohn's disease also strikes roughly one million in this country.) Das says that 10 percent of those affected by ulcerative colitis are children, with the disease striking as young as 2. The inflammation provokes the colon to empty more frequently and also causes ulcers that can bleed, and produce pus and mucous. Sometimes, the inflammation is limited to the rectum and lower part of the colon, but more commonly it affects the entire colon.

The most common symptoms are abdominal pain, diarrhea and rectal bleeding. "This is a lifelong disease," says Das. "If you stop the medication because the symptoms have disappeared, it will almost always recur."

About half have mild disease, but the others are often far sicker and may require periodic hospital stays when the disease flares up. The symptoms take their toll, making it difficult for some to work, or even leave the house and carry on ordinary daily activities. Because it can be difficult to maintain adequate nutrient and fluid intake, the disease can cause growth retardation in children and adolescents. In addition, ulcerative colitis sometimes triggers other inflammatory conditions, such as arthritis, skin and eye problems, and liver disease.

Das tells the story of a young, fit pizza parlor owner in New Brunswick who could no longer manage his business because of uncontrolled symptoms. He lost 60 pounds and was admitted to the hospital frequently before he was correctly diagnosed as having colitis and the right combination of drugs was prescribed.

Drugs to counteract the inflammation are the first line of treatment. For many, a 5-ASA agent (or the parent compound sulfonamide, sulfapyridine and salicylate) will work. There are also some new 5-ASA agents currently available. "Ninety percent of those affected can be kept in remission if they get the right treatment," says Das. The key is a correct diagnosis, and a treatment plan tailored to the patient. The physician says that at least 30 percent of those with UC either get an incorrect diagnosis or do not get the right therapies.

For severe disease, or when a patient does not respond to a 5-ASA agent, steroids often work, but come with a price. "You have to know the limits of the drugs," he says, "and you have to recognize when the time is right for surgery." This means a physician needs to be more watchful, assessing objectively with colonoscopies and multiple biopsies. He explains that increasing the doses of steroids to offset worsening symptoms can be extremely dangerous, building toxicity in other tissues.

Even when the drugs work, the disease is not cured. Only surgery is a cure. Surgery always consists of removal of the colon and rectum, after which a J-pouch reservoir is usually created out of a portion of the small intestine, allowing bowel function to continue. This eliminates the need for a "bag" or permanent ileostomy, although the majority of patients will need this for two to three months. Das says that anyone under age 65 is a candidate for the pouch procedure.

While advances in treatment make life better for UC patients, Das continues to study the basic biology of this disease, and he has discovered some important clues. His team has identified two proteins in the lining of the epithelium of the colon that seem to act as triggers to the autoimmune response in ulcerative colitis. Blocking one or both proteins may halt that response. The researchers are currently developing a monoclonal antibody therapy for UC directed against one of the antigens. In addition, they have also identified a cytoskeletal protein that is expressed in colon cancer cells, but not in normal counterparts. This may provide an important early detection tool for colon cancer. The group is also investigating the possibility of an oral vaccine therapy using animal models of colitis.

The researcher has also discovered a novel biomarker – dubbed 7E12H12 – for Barrett's epithelium (a precancerous condition of the esophagus) and other precancerous conditions of the stomach and small intestine. The antibody, recently featured on the cover of the American Journal of Gastro- enterology (August 2001, Vol 96), can be used for early detection of these diseases. And in much the same way as city officials name buildings after innovative architects and designers, this marker was fondly renamed Das1 monoclonal antibody by the researcher's fellow investigators in this field.

Das's research has been funded continuously for more than 20 years by the NIH, and in 1998 he received a $1.6 million NIH grant to continue his investigations into the autoimmune mechanism in ulcerative colitis and to develop a new diagnostic test for the disease. While understanding the cellular and molecular immune processes underlying UC are a prime focus of his work, taking care of patients at the Crohn's and Colitis Center of New Jersey, which he founded in 1998, is equally high on his priority list. The newest drug therapies, clinical trials for medications not yet available to the general public, as well as fresh findings right out of the laboratory are all integrated into each patient's care. And there have been several important discoveries made here over the last five years!

Of course, most patients appreciate the expert care, but many don't realize that the opportunity to be cared for by the real Das#1 is nothing to sneeze at.