Remicade for Crohn's Disease: Drug May Help When Others Fail

by Carol Lewis

Thirty-two years ago Ginger Gray walked into her doctor's office complaining of abdominal pain, diarrhea, severe weight loss, and overwhelming joint pain. At 19, she hadn't grown an inch since the sixth grade. But her doctor said there was nothing physically wrong with her, and even suggested she seek psychiatric counseling. Fortunately for Gray, she sought another physician's opinion. Based on tests he conducted, the doctor recommended the 4-foot-11-inch Pennsylvania resident begin full-time treatment for Crohn's disease.

"Crohn's disease robbed me of my stamina," Gray says. "It took two years for me to fully regain m y strength and weight so that I could begin working again."

Until now, treatment for Crohn's has relied on surgery and anti-inflammatory and other drugs also used to treat other conditions. In August 1998, the Food and Drug Administration licensed the first treatment specifically for Crohn's disease, an incurable and sometimes debilitating inflammation of the bowel.

Remicade (infliximab) is a genetically engineered antibody that blocks inflammation caused by a protein called tumor necrosis factor. After clinical trials showed benefit from Remicade treatment within a two-to-four week period following a single dose, FDA approved the drug for patients with moderate to severe Crohn's disease who have not found relief with other treatments.

"We recognized that [Remicade] had such a dramatic effect on patients," says Barbara Matthews, M.D., a medical officer in FDA's Center for Biologics Evaluation and Research, "that it was given accelerated approval."

Remicade, which is taken intravenously, can decrease the amount of inflammation along the lining of the intestine. Clinical trials also show that Remicade is effective in closing fistulas (abnormal passages or sores between the bowel and skin). Although not a cure, the drug reduces the symptoms in patients who have not responded well to traditional treatments.

"This is an exciting development for two reasons," says R. Balfour Sartor, M.D., professor of medicine, microbiology and immunology at the University of North Carolina, and chairman of the National Scientific Advisory Committee for the Crohn's & Colitis Foundation of America (CCFA). "It is the first therapy for Crohn's disease derived by molecular techniques, and it has the possibility of improving the quality of life for [Crohn's] patients."

But Sartor also cautions that the long-term toxic effects of Remicade are unknown and that the drug is not needed by every Crohn's disease patient. "Two-thirds of the people will have near immediate results," he says, "but only those patients who do not respond to other therapies" are eligible to take the drug. The next step is to maintain a patient's remission after the drug's initial effect has worn off.

Currently, studies are being done to better define the risks and longer-term benefits of Remicade because drug reactions and potential adverse effects from suppressing tumor necrosis factor require further clarification.

Understanding Crohn's Disease

Crohn's disease is one of two major types of inflammatory bowel diseases (IBD)--the general term for diseases that cause inflammation in the intestines--and has no cure and a high rate of recurrence following treatment. It usually occurs in the lowest portion of the small intestine (ileum), and the large intestine (colon or bowel), but it can occur in other parts of the digestive tract. Crohn's usually involves all layers of the intestinal wall. The disease can be difficult to diagnose because its symptoms, which include chronic diarrhea, crampy abdominal pain, loss of appetite, and weight loss, often mimic those of the other IBD type--ulcerative colitis--which affects only the colon.

"Both illnesses are chronic," says David S. Kaminstein, M.D., former chief of gastroenterology at The Chester County Hospital in West Chester, Pa. "But Crohn's disease often leads to other complications that are less often seen in ulcerative colitis, such as intestinal obstruction."

CCFA estimates that the incidence of Crohn's disease is from 1.2 to 15 cases per 100,000 people in the United States. While it can affect any age group, the onset of the disease most commonly occurs between ages 15 and 30, and between ages 60 and 80.

Kaminstein adds that IBD symptoms are similar to and often mistaken for irritable bowel syndrome. However, in contrast to IBD, the bowel syndrome does not cause inflammation in the intestines.

Researchers believe that Crohn's disease has a genetic basis but does not appear until triggered by an environmental agent such as bacteria or virus. The trigger causes an abnormal activation of the immune system.

According to CCFA, people who have a relative with the disease have at least a 10 times greater risk of developing Crohn's than that of the general population. If the relative is a sibling, the risk is 30 times greater. CCFA says that new technologies are helping researchers close in on the genes that predispose people to IBD.

"There are stories of obstructed bowel and bowel surgery back to my great-great grandfather on my mother's side of the family," Gray recalls, "but they didn't have the sophisticated tools for diagnosing Crohn's back then." Gray's second cousin and a nephew also have the disease.

Diagnosis Tests and Tools

A doctor may suspect Crohn's disease in anyone with recurring, crampy abdominal pain or diarrhea, particularly if the person has weight loss, fever or inflammation in the joints, eyes, and skin. No laboratory test specifically identifies Crohn's disease, but blood tests may show anemia (low red blood cell count), abnormally high numbers of white blood cells, low albumin levels, and other indications of inflammation.

According to Brian E. Harvey, M.D., Ph.D., a medical officer with FDA's Center for Devices and Radiological Health, "Barium enema x-rays have traditionally revealed the characteristic appearance of Crohn's disease in the colon, and barium upper GI with small bowel follow-through for abnormalities in the small intestine." Today, however, a procedure that examines the large intestine with a flexible viewing tube, known as a colonoscopy, along with a biopsy (removal of a tissue specimen for microscopic examination), most commonly confirms the diagnosis.

Another diagnostic tool, computed tomography (CT) or CAT scan, being used more now than previously, shows changes in the wall of the entire intestine and can identify complications such as intestinal obstruction, abscesses, and fistula formation.

Treating the Symptoms

Since there is no cure for Crohn's disease, the goals of treatment are to control inflammation, relieve symptoms, and correct nutritional deficiencies. Treatment depends on which part and how much of the intestine is affected.

Most people with Crohn's disease are first treated with drugs containing 5-aminosalicylates (5-ASA), which help control inflammation. Sulfasalazine (azulfidine) was traditionally the drug of choice until later evidence showed that newer ASA-containing medications were more effective at higher doses and presented fewer side effects.

Corticosteroids such as prednisone can control inflammation as well. These drugs are the most effective for active Crohn's disease, rather than for remission maintenance, but they can cause serious side effects, including greater susceptibility to infection, weight gain, increased blood sugar levels, thinning of the bones, elevated blood pressure, and personality disorder. Both corticosteroids and 5-ASAs are not approved specifically for Crohn's disease. Use of approved drugs for unapproved indications is commonly referred to as "off-label."

Drugs that suppress the immune system are reserved for patients who do not respond to less toxic forms of therapy because "they carry an increased chance of infection," says Kaminstein. The most commonly prescribed, Purinethol (mercaptopurine) and Imuran (azathioprine), also not specifically FDA-approved for this indication, work by blocking the immune reaction that contributes to inflammation, and are particularly effective for maintaining long periods of remission.

Antibiotics such as Flagyl (metronidazole), which are effective against many types of bacteria, are often prescribed "off-label" to help relieve symptoms of Crohn's disease, especially when it affects the large intestine or causes abscesses and fistulas around the anus. Other "off-label" medication use includes antidiarrheal drugs such as Lomotil (diphenoxylate) and Imodium (loperamide), which may relieve cramps and diarrhea.

Many Crohn's disease patients require surgery to relieve chronic symptoms that do not respond to drug treatment or, like Gray, to correct complications such as an abscess that has begun to perforate. The bowel is cut above and below the diseased area and reconnected. But since Crohn's disease often recurs after surgery, it is very important, according to Kaminstein, for the individual and doctor to consider carefully the benefits, risks and costs of surgery compared with other treatments. He says surgery should be used only after attempts at other forms of therapy have failed.

"It's been 14 years since my last bowel surgery," says Gray, who has had four resections in 23 years. Presently in remission, she is being maintained on low-dose prednisone and 4,000 milligrams of mesalamine (5-ASA) daily. She also receives a monthly injection of vitamin B-12 (cyanocobalamin) since her entire ileum was removed. According to Kaminstein, B-12 is absorbed by receptors located in the last 100 centimeters of the ileum, and removal can lead to B-12 deficiency within five years.

Patients may have areas of narrowing in the small intestine (strictures) that can cause obstruction. These can be surgically widened or stretched to relieve the obstruction.

Some people have long periods of remission, sometimes for years, when they are free of symptoms. However, CCFA says the disease can recur at various times over a person's lifetime. This changing pattern of the disease means a person cannot always tell when treatment has helped.

Controlling Crohn's with Diet

No special diet has been proven effective for preventing or treating Crohn's disease, but during a severe attack, Kaminstein says it is important to eat well to replace lost nutrients. And while there are a number of theories as to the role of "antigens" or other products in the diet that may cause IBD flare-ups, "we do know that we can sometimes decrease symptoms of Crohn's disease by placing the bowel at rest," he says. "In other words, by avoiding certain foods."

Renée Gordon of Montgomery Village, Md., agrees. She says that after 30 years of living with Crohn's disease, she knows exactly what foods trigger her symptoms or make them worse.

"I don't eat rich or spicy foods or those with sauces," she explains. "A bland diet is just the one thing that makes me feel great."

Kaminstein adds that fats may not be digested or absorbed in some Crohn's sufferers who have had a large portion of the small intestine removed. This can increase diarrhea and cramps.

But Kaminstein also warns that IBD patients should not restrict themselves from eating one food or another "unless they find it repeatedly bothers them," and have consulted with their physicians. In some cases, he recommends patients seek the advice of a registered dietitian or nutritionist, who can suggest changes that will conform to their overall nutritional needs.

"Arbitrarily removing certain food groups from the diet can only impair nutrition and should be avoided."

People with Crohn's disease may feel well and be free of symptoms for substantial periods, but there is no way to predict when symptoms may return. Maintenance of remission, according to Kaminstein, involves appropriate medical treatment, monitoring patients for adverse effects and disease complications, and screening for cancer, which can occur in some instances. People with long-term IBD (more than eight to ten years), for example, face a somewhat higher risk of getting colon cancer.

But although there may be long-term needs for medicine and even periods of hospitalization, most individuals, like Gordon, are able to hold productive jobs and function successfully at home and in society.

When to Call Your Doctor

People with Crohn's disease frequently need medical advice. It is important to know whether the matter requires immediate attention, or whether it should be considered routine. The Crohn's & Colitis Foundation of America recommends that you call your physician immediately if you notice any dramatic change in the illness such as:

• a sudden high fever, which might be accompanied by chills
• a sudden weight loss of more than 5 pounds in a few days
• the onset of significant or new rectal bleeding
• any severe abdominal pain that persists for more than an hour
• persistent vomiting accompanied by cessation of bowel movements
• a drastic change in bowel movements without passing gas.

Carol Lewis is a staff writer for FDA Consumer. This article originally appeared in the FDA Consumer magazine, published by the U.S. Food and Drug Administration, in the September-October 1999 issue.