By Liz Finch

Crohn’s, an autoimmune disease, poses a challenge to both patient and practitioner. A type of inflammatory bowel disease (IBD) similar to ulcerative colitis, Crohn’s is particularly difficult to diagnose because its symptoms are so similar to other intestinal disorders. In addition, Crohn’s is frustrating to treat. Current methods may help control the disease, but there is no cure, and the disease usually recurs at various times over a person’s lifetime.

“Many report frustration with being misdiagnosed and rediagnosed, and with the constant testing,” says Laura Hitchens, a medical writer for the Crohn’s & Colitis Foundation of America, headquartered in New York. “The symptoms resemble so many other types of digestive diseases that accurate diagnosis is difficult.”

This frustration has led to scientific efforts at creating more precise testing methods and more effective medications for symptomatic control in the 500,000 Americans currently diagnosed with the disease. Crohn’s disease affects men and women equally and seems to run in some families. Among those with Crohn’s, about 20% have a blood relative with some form of IBD.

The classic symptoms of Crohn’s disease are abdominal pain, diarrhea, and vomiting, but more subtle symptoms may appear years earlier, including prolonged and unexplained fever, joint pain, eye pain, mouth ulcers, or skin rashes. Children with Crohn’s disease may suffer delayed development and stunted growth. Those with Crohn’s disease have inflammation that extends deeper into the intestinal wall and can also involve the small and large intestines.

While theories abound as to what causes Crohn’s disease, none has been proven. However, researchers from the University of Toronto have found that two genetic variations on chromosome 5 increase susceptibilty to the disease.

The most popular theory on the cause of Crohn’s disease is that the body’s immune system reacts to a virus or a bacterium by causing ongoing inflammation in the intestine. People with Crohn’s disease tend to have abnormalities of the immune system, but doctors do not know whether these abnormalities are a cause or result of the disease.

Diagnosis therefore starts with the most noninvasive test first. Blood tests may be done to check for anemia, which could indicate bleeding in the intestines, or a high white blood cell count, which is a sign of inflammation. A stool sample can determine if there is bleeding or infection in the intestines.

Additional studies should include serum proteins and micronutrients, as hypoalbuminemia, iron, and vitamin deficiencies are commonly found in patients with Crohn’s. Acute phase reactants erythrocyte sedimentation rate and C-reactive protein are elevated in 90% of patients with the disorder.

More advanced testing methods look at particular antibodies, which have been shown to be highly specific to Crohn’s and ulcerative colitis. Specifically, the combination of a positive anti-Saccharomyces cerevisiae antibodies (ASCA) test and a negative perinuclear antineutrophil cytoplasmic antibody (pANCA) test yields a sensitivity of 49%, a specificity of 97%, and a positive predictive value of 96% for Crohn’s disease, according to R. L. Young, MD.1 Another study, which found ASCA in 20% of healthy first degree relatives of patients with Crohn’s disease, suggests that these antibodies might be a subclinical marker for Crohn’s disease in families. The ASCA and pANCA assays therefore assist clinicians in diagnosing and categorizing patients with IBD, and may be useful in making therapeutic decisions as well.

“Unfortunately, some patients don’t test positive for either,” Hitchens says. “So when physicians are trying to differentiate between the diseases, it can be hard to clarify.”

Additionally, patients may undergo an upper gastrointestinal series, a sigmoidoscopy or a colonoscopy to assist in the differential diagnosis. Magnetic resonance imaging (MRI) coupled with the use of the contrast dye gadolinium, also may help pediatricians better diagnose children with ulcerative colitis and Crohn’s disease, according to a study by researchers at the Johns Hopkins Children’s Center. Results of the study, published in the March issue of Inflammatory Bowel Diseases, showed that the gadolinium-enhanced MRI confirmed these diagnoses in more than 90% of the children in the study who had IBD.

Prognosis and Treatment
Once the disease is properly identified, the challenge shifts to dealing with the many complications of Crohn’s, including blockage of the intestine, fistulas, and nutritional complications of proteins, calories, and vitamins. Other complications associated with Crohn’s disease include arthritis, skin problems, inflammation in the eyes or mouth, kidney stones, gallstones, or other diseases of the liver and biliary system.

Treatment is therefore multifaceted, focusing on controlling inflammation, correcting nutritional deficiencies, and relieving symptoms. A combination of drugs, nutrition supplements, and surgery are often likely, and the evolutionary nature of the disease means one cannot always tell when a treatment has helped. Predicting when a remission may occur or when symptoms will return is not possible.

Most patients are first treated with drugs containing mesalamine, a substance that helps control inflammation. Sulfasalazine is the most commonly used of these drugs, but patients who do not benefit from it or who cannot tolerate it may be put on other mesalamine-containing drugs, generally known as 5-ASA agents. To control inflammation, some patients take corticosteroids, which, though effective, are also linked to serious side effects that increase susceptibility to infection.

Drugs that suppress the immune system may likewise be used to treat Crohn’s disease. The most commonly prescribed are mercaptopurine (6-MP) and azathioprine. Some studies suggest that immunosuppressive drugs may enhance the effectiveness of corticosteroids.

As in diagnostics, research is uncovering more promising medications for Crohn’s patients.

“The latest treatment with any significance involves tumor necrosis factor (TNF) inhibitors like infliximab (Remicade), which has been used in rheumatoid arthritis cases and is now being looked at for Crohn’s disease,” says Virginia Ladd, president and executive director of the American Autoimmune-Related Diseases Association. “Infliximab is FDA-approved for the treatment of moderate to severe Crohn’s disease that has failed to respond to standard therapies.”

TNF is a protein produced by the immune system that may cause the inflammation associated with Crohn’s disease. Anti-TNF works by locating TNF in the bloodstream, binding to it, and removing it before it can reach the intestines and cause inflammation. In studies, anti-TNF seems particularly helpful in closing fistulas.

In addition, infliximab was approved by the FDA in June 2002 for maintaining remission of Crohn’s. The ACCENT I trial, a 54-week study with more than 545 patients, demonstrated that treatment with infliximab is an effective strategy for tapering patients off steroids; and is it also a useful option for maintaining remission. In April 2003, infliximab also received supplemental approval for maintaining remission in fistulizing Crohn’s disease.

Another promising treatment option may be anti-interleukin (IL-12) therapy, which focuses on eliminating the cause of Crohn’s rather than simply suppressing symptoms. The National Institutes of Health has licensed a patent for anti-IL-12 therapy to the pharmaceutical company Genetics Institute. IL-12 is known to help stimulate inactive T cells to become an aggressive form of T cells known as Th1 cells. In Crohn’s disease, Th1 cells damage the digestive tract and show up as elevated IL-12 levels in tests. Researchers are looking at whether locking the IL-12 signal with a synthetic antibody might reduce the number of Th1 cells and prevent the harmful effects of Crohn’s disease. So far, studies have found that not only did it prevent the disease from occurring, it also healed active disease.

According to Hitchens, there are other biologic drugs in the pipeline as well, including Humira from Abbott Laboratories. Humira is a human monoclonal antibody that resembles antibodies normally found in the body, and it works by specifically blocking TNF-a. A phase III study is currently under way that will evaluate the safety and efficacy of Humira in the induction and maintenance of clinical remission in subjects with moderately to severely active Crohn’s disease. Elan’s drug Antegren also has gone through a phase III trial in which Crohn’s patients showed no recurrence of the disease during a 6-month course of the drug.

Medical therapy becomes less effective with time, and surgery for underlying complications is required in nearly two thirds of patients at some point in their lives. Surgery to remove part of the intestine can help those with Crohn’s disease, but it too is not a cure, as the inflammation tends to return adjacent to the area of intestine that has been removed. Some who have Crohn’s disease in the large intestine need to have a colectomy instead.

Although Crohn’s disease is chronic with recurrent relapses, appropriate medical and surgical therapy have helped patients have a reasonable quality of life. Those with Crohn’s disease may feel well and be free of symptoms for substantial spans of time when the disease is not active. It is the increasing length of those times, thanks to medical developments, that lessen the challenge of living with Crohn’s.

Reference
1. Young RL. ASCA-New marker for Crohn’s disease? Am J Gastroenterol. 1998;93:2020.

Liz Finch is a contributing writer for Clinical Lab Products.