Reprinted from the Los Angeles Times, Monday, September 18, 2000

Plenty of Relief ... and Skepticism

Increasing numbers of Crohn's sufferers are benefiting from antibiotics, but most scientists say there's not enough evidence to prove bacterial infection is the culprit.

By THOMAS H. MAUGH II, Times Medical Writer

Nine years ago, Barbara Perkins thought she had stomach cancer. She developed intestinal bleeding and diarrhea and lost 90 pounds from her 5-foot, 10-inch frame in six weeks.

"I was unable to get out of bed and could barely walk," said the 48-year-old homemaker from El Paso. "I was very, very sick."

Eventually, she was diagnosed with Crohn's disease, an intractable, debilitating condition that afflicts half a million Americans.

Though most people may be unfamiliar with it, Crohn's disease affects more people than multiple sclerosis, Duchenne muscular dystrophy and Huntington's disease combined. Resulting from an immune attack on the intestines, Crohn's is extremely painful, characterized initially by abdominal pain and disabling diarrhea, followed by loss of appetite and weight, joint pains and fever.

Crohn's is normally treated with drugs that suppress the immune system, but those have limited effectiveness. However, a new regimen of antibiotics--based on the revolutionary idea that Crohn's is caused by a bacterial infection--has Perkins and a growing number of others free of Crohn's symptoms for the first time in years.

In 1996, Perkins was hospitalized 23 times for kidney infections and intestinal blockages, among other problems, spending nearly a full nine months in confinement. Then she went to Dr. William Chamberlin of the William Beaumont Army Medical Center in El Paso, one of a small but increasing number of physicians who believe that Crohn's is caused by a microorganism called MAP.

He began her on a cocktail of antibiotics that targeted the bug.

Within 18 months, she was in complete remission, leading the active life she once thought was impossible. "I really think it saved my life," she said.

Perkins is one of perhaps 200 Crohn's sufferers around the world who have received a new antibiotic treatment that Chamberlin and others predict will revolutionize treatment of the disease.

Reports presented at a recent Digestive Diseases Week meeting in San Diego indicate the antibiotic cocktails have successfully induced long-term remissions in as many as two-thirds of those treated. Those preliminary studies have been so successful that researchers in Australia and the United States are gearing up for much larger trials.

"We've never had a treatment like this before," said Dr. Tom Borody of the Digestive Diseases Centre in Sydney, Australia. The patients not only stop having symptoms, he said, but their intestines heal--an unprecedented achievement. "If this were cancer, we would be calling these long remissions a cure."

Although the idea that MAP causes Crohn's is still highly controversial, the success of the treatment is making many critics take notice.

The successes are impressive, no matter what the cause of the disease, said Dennis Lang, a Crohn's expert at the National Institute of Allergy and Infectious Diseases in Bethesda, Md. "If I were a Crohn's patient, I would bring this information to my doctor," he said. The treatment "seems to be helping clinically -- and that's the important thing."

At the same time, the incidence of Crohn's is increasing, most researchers believe. Overall numbers are not available--Crohn's does not have to be reported--but some regional figures suggest an increase. The incidence of Crohn's went up 46% in Olmstead County, Minn., from 1980 to 1991, for example. In Spokane, Wash., it rose 49% between 1971 and 1981. Every day, an additional 55 people in the United States are diagnosed with the disease.

Many people with the illness are unable to leave their homes because of the diarrhea; others drive around in recreational vehicles and mobile homes to keep a bathroom handy.

Roughly half of Crohn's sufferers require one or more surgeries to remove affected areas of the bowel, but new problems almost always occur.

No one knows precisely what causes Crohn's, but MAP (for Mycobacterium avium subspecies paratuberculosis) has been a suspect for nearly a century. The purported link "has been out there for a long time, but the research to date is not clear-cut," said Dr. Charles O. Elson III of the University of Alabama, medical director of the Crohn's and Colitis Foundation.

"The bottom line is, their case is not proved," he said.

The drugs the researchers are using can kill a broad variety of bacteria in the gut, added Dr. R. Balfour Sartor of the University of North Carolina. "It's very difficult to say that response to these agents proves this mycobacterium is involved" in Crohn's, he said.

"Our critics outnumber us 99 to 1," conceded Dr. Ira Shafran of the University of Central Florida. "But our work shows that you can identify [a Crohn's patient with MAP] and put him on a treatment that is safe, effective and cheaper than existing therapies and that he will get better."

"We're really in the same position we were a few years ago with Helicobacter pylori and ulcers," Borody said. Although physicians had long believed that ulcers were caused by stress, Australian researchers demonstrated that 80% of cases were actually produced by H. pylori infections.

Doctors resisted that idea, even when it became clear that cocktails of antibiotics could eradicate ulcers, until Dr. Barry Marshall, then a physician in Perth, Australia, and now at the University of Virginia, intentionally swallowed a test tube full of the bacteria and promptly developed an ulcer.

No one is proposing to swallow a test tube of MAP--Crohn's is much worse than an ulcer. But Borody and others are hoping that their treatment successes and the earlier experience with ulcers will stimulate gastroenterologists to look at the new findings with an open mind.

MAP Difficult to Grow in a Laboratory

The case against MAP in Crohn's has been difficult to build because it is an elusive microorganism that is hard to identify in tissue and even harder to kill with conventional therapy. It is a close relative of Mycobacterium tuberculosis, which causes tuberculosis, and more distantly related to M. leprae, which causes leprosy. It normally grows very slowly--dividing only about once every 18 months or so--making it very difficult to grow in a laboratory and rendering it immune to most antibiotics.

Scientists originally suspected MAP in 1913 because it causes Johne's disease in cattle, a disorder whose symptoms are identical to those of Crohn's in humans. The microorganism produces similar diseases in many other animals, including four species of primates.

Early researchers were unable to isolate MAP from human patients and most came to consider the animal disease a red herring.

Those difficulties should not have been a surprise, Borody said. "We know without a doubt that M. leprae causes leprosy, but it is almost impossible to isolate it from patients with the disease. Why should MAP be any different?"

But most scientists have demanded that MAP be consistently isolated from Crohn's patients before they will even consider it as a potential cause.

The first step in that direction occurred in 1984, when microbiologist Roderick J. Chiodini, then at the University of Connecticut, successfully isolated MAP from the intestines of 11 people with Crohn's, a difficult process that took as long as 18 months for each specimen. Although other labs were eventually able to reproduce his findings, critics argued that identifying the bug in a handful of patients was a far cry from showing that the bug caused the disease.

More recently, microbiologist Saleh Naser of the University of Central Florida developed a technique in which MAP from patients' tissue can be grown and identified in the laboratory in as little as 10 weeks. He has found the microorganism in 83% of intestinal specimens from Crohn's patients. He even reported last year that he found it in the breast milk of two mothers with Crohn's, but not in milk from five healthy mothers.

More solid evidence has been provided by molecular biologists who have been able to identify DNA from MAP in Crohn's tissues. In 1991, for example, Dr. John Hermon-Taylor of St. George's Hospital Medical School in London identified a unique genetic sequence in MAP called IS900 and began looking for it in patients.

He found IS900 in 65% of bowel samples from Crohn's patients, but in only 4.3% of those with ulcerative colitis--a related condition that affects only the large intestine--and 12.5% of healthy people. The fact that MAP is present in a majority of Crohn's patients, but in few of those with a related bowel disease, strongly suggests that it is a causative agent, he said.

More recently, researchers have found evidence of an immune response to MAP in Crohn's patients, further strengthening the evidence of its role in the disease.

Last year, Naser and Dr. Fouad El-Zaatari of the Baylor College of Medicine in Houston independently identified antibodies directed against two proteins unique to MAP, called p35 and p36.

They found that antibodies against either p35 or p36 were present in 92% of 63 Crohn's patients, but in only 8% of patients with ulcerative colitis and 25% of healthy people.

Finally, Dr. Jonathan Braun of UCLA has identified antibodies against a mycobacterial protein called HubP in nine of 10 Crohn's patients he has studied.

"We're not saying that MAP is responsible for all cases of Crohn's," said Hermon-Taylor. "It's a question of: 'Does it cause 50% or 90%?' My hunch, based on the evidence that is available, is that it causes as much as 90%."

Even before this new evidence linking MAP to Crohn's came out, a few clinicians had begun treating Crohn's victims with a cocktail of antibiotics directed against the mycobacterium.

Hermon-Taylor studied 52 patients with Crohn's that had proved resistant to all other forms of therapy and began giving them a combination of the antibiotics rifabutin and either clarithromycin or azithromycin. He reported in 1997 that six of the patients could not tolerate the drugs, but two-thirds of the rest were in remission at the end of two years.

Some of those suffered relapses after the treatment was stopped, but restarting therapy pushed them back into remission.

Shafran enrolled 42 Crohn's patients who showed antibodies to p35 or p36 in a treatment program in which they were given a similar combination of drugs. He reported last month at the Digestive Diseases Week meeting in San Diego that 26 of the patients went into remission and were able to stop taking all other Crohn's drugs. Eight were unable to tolerate the therapy, four showed partial improvement and only four showed no benefit.

Borody reported at the same meeting on his studies of 12 patients who had failed all previous attempts at therapy. After as long as four years, six of them were in complete remission, including healing of their intestines, three were in remission but still showed signs of inflammation in their intestines and three did not respond to the drugs.

One of Borody's successes is Greg Portelli, a 28-year-old accountant in Sydney who was diagnosed with Crohn's at 16. He suffered gastrointestinal bleeding, weight loss, diarrhea and intense pain, as well as hair loss and allergies caused by the steroids used in his treatment. Hospitalized frequently, he struggled to get through his university courses. "I got so thin I could wear my girlfriend's jeans," he said.

Three years ago, doctors wanted to perform surgery, but Portelli decided to visit Borody, whose work he had read about. "My family doctor and the surgeon said, 'Don't [adopt Borody's regimen],' but I was at my final tether," he said.

Within a month, he stopped passing blood, could eat normal foods and began to keep weight on. He is still taking the drugs, but his intestines have healed. "To say it changed my life is a complete understatement."

Other physicians consider these results "anecdotal"--and rightly so, because they were not obtained in controlled trials. But that situation is already changing. Borody has organized a clinical trial on more than 200 patients that is now underway in Australia. Dr. David Graham of the Baylor College of Medicine is organizing one in this country that will be conducted under the auspices of the Department of Veterans Affairs.

"I've worked nonstop for three years," Shafran said. "I gave up my private practice to immerse myself in the field. These results have attracted Crohn's patients from all over the country, and I have 85 patients currently on treatment. But I underwrote the entire project myself. If I don't get some funding soon, this is going to bankrupt me."

Copyright © 2000, Los Angeles Times. Reprinted by permission.