Crohn's disease and MAP

[Mike Bartolatz]

crohns disease
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Saturday Evening Post

By THOMAS H. MAUGH II, Times Medical Writer

"I really think it saved my life," Crohn's sufferer Barbara Perkins says of
an antibiotics regimen.
AP

RELATED STORY

Milk May Be the Carrier of Crohn's

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 recur.

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."
Further information is available at http://www.crohns.org,
paratuberculosis.org and http://www.ccfa.org.








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