Relief in sight?
Daniel GRAY’S stomach tells a story.
The gnarled lines across his abdomen are the mementos of three major surgeries on his digestive system. The slashes along each side are reminders of the time the stitches broke and the doctors put him into a drug-induced coma for seven weeks, keeping his abdomen open for repeated washes. The doctors made the slits so that they would have enough skin to stretch over the opening when they finally sewed him together.
Gray, 46, was diagnosed 24 years ago with Crohn’s disease, a chronic inflammation of the bowel and intestines that afflicts nearly 1 million people worldwide. Crohn’s patients suffer from diarrhea and abdominal pain, and 80% will eventually face the surgeon’s knife to remove damaged portions of bowel.
Gray, who lives in Long Beach, is nearly 6 feet tall but weighs only 125 pounds -- yet his situation is better than it used to be. Lately, scientific research has started catching up with the disease, and modern treatments -- notably, anti-inflammatory medications called TNF blockers -- work for many patients.
With two new drugs poised to hit the market, and if all goes well, things should soon improve further for Crohn’s patients.
On July 31, a Food and Drug Administration advisory committee recommended approval of the drug Tysabri as a medication for Crohn’s. Tysabri is already in use for treatment of about 14,000 patients with multiple sclerosis, another autoimmune disease in which the body attacks the sheath surrounding nerve cells. Although the committee’s decision is nonbinding, it will allow the FDA to move toward approval of Tysabri for Crohn’s.
And in two studies published in the July 19 issue of the New England Journal of Medicine, researchers reported that another drug, Cimzia, was effective at treating about one-third of the studies’ 1,330 patients with moderate to severe Crohn’s. In addition, 62% of patients who responded to Cimzia continued to benefit from the treatment after six months.
UCB, the Belgium-based company that makes Cimzia, has begun filing paperwork with the FDA and plans to seek formal approval soon.
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Blocking the inflammation
In Crohn’s disease, the immune system attacks the digestive system, most commonly the end of the small intestine and the beginning of the colon.
The inflammation can cause ulcers or swelling, damaging the walls of the digestive tract and ultimately narrowing the passageway. Sometimes, ulcers can extend through the intestinal wall, forming abnormal tunnels between the bowels and other organs or the skin.
The exact cause of Crohn’s disease is unclear, but there appears to be a genetic link. A person is 10 times more likely to have Crohn’s if a relative has it.
Symptoms include diarrhea, abdominal pain and bloody stool. Patients with severe Crohn’s disease have to do “bathroom mapping,” identifying nearby restrooms whenever they plan to go out.
In treating Crohn’s, doctors and patients consider a variety of medications. Patients frequently start out with anti-inflammatory drugs such as Azulfidine and Rowasa, then progress to steroids, which are stronger but toxic and can be taken only for a short time. The long-term solution is often to suppress the immune system even further.
Since 1998, many Crohn’s patients have been helped by medications called TNF blockers, which stymie the action of a molecule called TNF. TNF is produced by immune cells and activates further inflammation.
Two of these drugs, Remicade and Humira, are antibodies that bind to TNF, interfering with its function and helping to prevent symptoms.
Remicade and Humira are the first drugs to make a noticeable dent in the rates of hospitalization and surgery for Crohn’s patients, says Dr. Stephen Hanauer, chief of gastroenterology at the University of Chicago.
But they don’t work for everyone. Although the antibodies block TNF, they can induce a damaging immune response of their own. Some patients are allergic to them.
For others, the drugs work for a while, and then stop.
Cimzia is also a TNF blocker, but unlike the others it contains only part of the antibody -- the portion that recognizes TNF. The rest of the antibody -- the part that can induce its own immune response -- is replaced with a compound called PEG.
This PEG tail stabilizes the drug, allowing it to stay in the patient’s body much longer, explains Hanauer, who was a coauthor on one of the recently published Cymzia studies.
That means patients would only require treatment every other month, as opposed to every other week with Humira.
Many of the patients in the two trials had nearly exhausted their treatment options, says Dr. William Sandborn, a gastroenterologist at the Mayo Clinic in Minnesota, who oversaw one of the studies.
“Gains that you see in those patients are particularly important and interesting,” he says.
Ongoing studies are assessing Cimzia’s efficacy over a longer period of time than six months, and preliminary data indicate that it can remain effective for at least 18 months.
Tysabri, the second new approach to Crohn’s, works by interfering with a different part of the immune response.
During inflammation, infection-fighting white blood cells of the immune system cruise through capillaries, searching for infection. When tissues are infected, they put out signals to slow down the blood cells and coax them to enter the tissue. “They’re kind of like the exit signs on the expressway,” Hanauer says.
Tysabri binds to those exit signs -- blocking them from recognition by the immune cells that are causing the Crohn’s. So the white blood cells keep on moving, and the course of inflammation is stopped.
Two clinical trials involving 848 patients published in the New England Journal of Medicine in 2005 and 2007 reported that Tysabri was effective for about one-third of Crohn’s patients, and 59% of those patients continued to see benefits after one year.
However, three patients out of 3,000 in clinical trials for Crohn’s or MS, developed a viral infection in the brain -- and two died. Because of this, Tysabri use is closely monitored.
Lars Ekman, president of global research and development at Elan Pharmaceuticals, which markets Tysabri, noted that the viral infections occurred when Tysabri was used with other immunosuppressants. He recommends that Tysabri be taken only on its own.
“With multiple sclerosis, we have been very successful in screening out the patients that are at risk,” he says.
Gray no longer has to worry about mapping bathrooms -- by 2001 his condition had become so serious that surgeons had to remove his colon and rectum. Instead, waste drains into a pouch he wears on the front of his abdomen.
With Remicade, his condition is more manageable than it has been in years. Although he has been on disability for a decade, he hopes to return to work soon.
“It’s much better to get Crohn’s disease in 2007 than 1987,” Sandborn says. “I think the future looks very different for these groups of patients.”
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The history of Crohn’s
By the time Dr. Burrill Crohn officially described the disease that bears his name in 1932, inflammatory bowel disease -- an umbrella term for Crohn’s disease and the related condition known as ulcerative colitis -- had afflicted sufferers for centuries.
Alfred the Great, considered the first king of England, ascended the throne in 871 and defeated the occupying Danes more than once, demanding equal rights for English citizens of Danish territory. He built towns and schools and was an accomplished diplomat who put limits on blood feuds and upheld strict penalties for oath-breakers.
And, if the suspicions are true, he had Crohn’s. A contemporary biographer reported that he suffered a chronic illness that caused him discomfort and embarrassment and pain when he ate. Ninth century explanations for what Alfred had included the curses of witches or divine punishment for his philandering.
President Dwight D. Eisenhower had Crohn’s, and his physicians prescribed a bland diet. But sometimes Eisenhower couldn’t resist forbidden foods such as pig knuckles and sauerkraut. He had surgery for bowel obstruction in 1956, months before winning his second term in office.
During the second half of the 20th century, understanding and treatment of inflammatory bowel disease has advanced considerably:
Until the 1950s, doctors thought it was psychological and, accordingly, treatment focused on psychoanalysis.
It wasn’t until the 1960s that scientists started to consider the immune system as a source for the disease.
Before the 1970s, doctors dismissed the fact that it runs in families as mere coincidence.
For decades, Crohn’s and colitis research was stymied by the lack of an animal model. Scientists tried, and failed, to induce colitis in animals with vitamin deficiencies and bacterial toxins.
Then, in 1981, scientists identified an animal that naturally develops human-like colitis: the cotton-top tamarin, a monkey found in Colombia. The first mouse model was developed in the 1990s, allowing research to progress at a faster rate.
-- Amber Dance
