July 1996
LONDON — Recent study findings suggest that antibiotics may have a role in treating Crohn's disease, a serious illness characterized by chronically inflamed bowels.
Acting on DNA evidence that implicates Mycobacterium paratuberculosis as a possible cause of Crohn's disease, a team led by John Hermon-Taylor, MD, a Crohn's disease researcher here, used a combination of rifabutin and clarithromycin (Biaxin, Abbott) to treat 46 patients with Crohn's disease. The investigators did not determine whether patients were infected with M. paratuberculosis.
After patients started antibiotic treatment, they continued to take steroids, a conventional treatment, at their usual dosages for four to six weeks. After that, they gradually reduced the steroids until they were off them completely. Data from this uncontrolled study suggest that patients who took the antibiotics had a much longer remission than patients who received conventional treatment alone. About 80% of the patients who could take the treatment had "a profound and lasting remission" of their illness, said Hermon-Taylor, who is professor of surgery at St. George's Hospital Medical School, London.
The outcomes analysis of this group justifies a larger and controlled trial of this treatment approach, according to Hermon-Taylor.
Hermon-Taylor and his colleagues are not the only investigators who have tested antibiotics as a treatment for Crohn's disease. David Graham, MD, of Houston, and colleagues conducted a placebo-controlled trial looking at the efficacy of clarithromycin as a treatment for Crohn's disease. They randomly assigned 17 people with severe Crohn's disease to receive either conventional therapy plus a placebo or conventional therapy plus clarithromycin. They did not determine whether the patients harbored M. paratuberculosis.
Forty percent of the patients in the antibiotic arm became well and stayed well for up to three years, said Graham, who is chief of gastroenterology at the Veterans Administration Medical Center in Houston. In contrast, one person in the placebo arm became well but did not remain well. To confirm their findings, Graham and colleagues are conducting a larger placebo-controlled study looking at the efficacy of clarithromycin plus ethambutol.
In the United States, from 500,000 to 1 million people have Crohn's disease, according to the Crohn's and Colitis Foundation of America (CCFA). Precise prevalence figures are difficult to determine in part because many people put off seeking treatment and physicians frequently misdiagnose the illness, said a foundation spokesperson.
Crohn's disease varies widely in its clinical features and no definitive test exists for diagnosing the illness. The foundation estimates that 15,000 new cases of Crohn's disease are diagnosed each year in the United States.
"People who have Crohn's disease most frequently have initial onset of the illness between the ages of 12 and 35 years," said Richard P. MacDermott, MD, a gastroenterologist at Lahey Clinic, Boston, who chairs CCFA's National Scientific Advisory Committee.
Although researchers have yet to do a definitive study to prove that M. paratuberculosis or any microbe causes Crohn's disease, "Crohn's disease specialists believe that scientific evidence supports a role for an infectious agent," MacDermott said. "Crohn's has every feature of a chronic, long-term disease process stimulated or mediated by infection."
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Researchers have considered M. paratuberculosis a possible cause of Crohn's disease for two decades, largely on the basis of circumstantial evidence. The bacterium causes chronic inflammation of the intestines in many different animals, including primates, Hermon-Taylor said. The bacterium causes an illness in cattle and other animals called Johne's disease, some forms of which are similar to Crohn's disease in humans. In addition, intestinal tuberculosis in humans caused by Mycobacterium tuberculosis, a related bacterium, also can be similar to Crohn's disease.
Using polymerase chain reaction (PCR) tests, researchers have detected M. paratuberculosis DNA more frequently in intestinal tissue from people with Crohn's disease than in intestinal tissue from people with ulcerative colitis or from people who do not suffer from inflammatory bowel disease.
Using PCR to test full-thickness samples of intestinal tissue, Hermon-Taylor and colleagues identified M. paratuberculosis DNA in 26 (65%) of 40 people with Crohn's disease, one (4.3%) of 23 people with ulcerative colitis and five (12.5%) of 40 people without inflammatory bowel disease (controls). They published their findings in a 1992 article in Gut.
In another study, investigators used PCR to detect M. paratuberculosis DNA in tissue samples from 53 children with various gastrointestinal (GI) diseases and disorders. The investigators found DNA sequences of the bacterium in 13 (72%) of 18 samples from children with Crohn's disease, compared with one (20%) of five children with ulcerative colitis, two (33%) of six children with severe "unclassified" colitis and seven (29%) of 24 children with other GI illnesses. The difference in detection rates between the children with and without Crohn's disease was statistically significant, according to the investigators.
"These results appear to support the hypothesis that M. paratuberculosis is involved in the pathogenesis of Crohn's disease," the investigators said in The Journal of Infectious Diseases.
Some studies produced contradictory findings. For example, a team of researchers in Brussels reported in 1996 that they used PCR to detect DNA from M. paratuberculosis and other mycobacteria in intestinal biopsy samples from 36 patients with Crohn's disease, 13 patients with ulcerative colitis and 23 controls. The researchers detected no M. paratuberculosis DNA in any sample, but detected other mycobacteria in 17 (47%) of the Crohn's disease samples, six (46%) of the ulcerative colitis samples and 13 (57%) of the control samples.
Another research team used PCR to test intestinal samples from 68 patients with Crohn's disease, 49 patients with ulcerative colitis and 26 controls who did not have inflammatory bowel disease. The researchers detected no M. paratuberculosis DNA in any sample from patients with Crohn's disease or ulcerative colitis. They detected the DNA in one sample from a patient without inflammatory bowel disease.
Hermon-Taylor said he believes the researchers who conducted these studies made methodologic errors that prevented them from finding M. paratuberculosis DNA.
Investigators have had to rely on DNA evidence to demonstrate the presence of M. paratuberculosis because the bacterium can be extremely difficult or impossible to grow in culture. In 1985, Hermon-Taylor and colleagues examined samples of material that grew on culture medium up to 2½ years after investigators inoculated the medium with extracts of intestinal tissue from three patients with Crohn's disease. DNA analysis showed that the three samples demonstrated the same DNA fingerprint and that the fingerprint matched that of M. paratuberculosis, Hermon-Taylor said.
"To provide strong evidence that M. paratuberculosis is a cause of Crohn's disease," MacDermott said, "researchers should show that people with Crohn's disease test positive for the bacterium prior to antibiotic treatment, test negative for the bacterium when the illness goes into remission and test positive for the bacterium when the illness recurs or relapses. It is very possible that we may ultimately find more than one infectious agent as causative or inflammatory-inducing in Crohn's disease."
Hermon-Taylor acknowledged the need to monitor specifically for the organism in intestinal biopsy samples before and throughout treatment. This approach should be part of a prospective, randomized and controlled trial, he said, adding, "Our attempts to get this funded here [in the UK] have all been unsuccessful, so far."
In Graham's view, the notion that M. paratuberculosis causes at least some cases of Crohn's disease is plausible. If antibiotics effective against M. paratuberculosis prove to be a good treatment for Crohn's disease clinicians should wait until the optimal antibiotic regimen is worked out before prescribing antibiotics for Crohn's disease. Otherwise, clinicians may contribute to a growing problem of drug-resistant bacterial strains, Graham said.
Hermon-Taylor pointed out that M. paratuberculosis is difficult to eradicate because the bacterium lives within host cells in a form that has no cell wall and it occurs in low abundance and replicates quite slowly. "Single-agent therapies are almost all certain to fail and should be avoided," he said.
Patients must take the antibiotics for at least 2½ years to have long-term remission, Hermon-Taylor said. Among patients who respond to treatment, remission occurs slowly over the first three to six months of treatment. Symptoms often get worse before they get better, as in the drug treatment of leprosy, he said.
Hermon-Taylor noted that tM. paratuberculosis is endemic in dairy herds throughout Europe as well as in North America, Australia, New Zealand and South Africa. In the United Kingdom, at least 3.5% of cattle harbor the bacterium, as determined by PCR analysis of intestinal tissues. M. paratuberculosis can exist in apparently healthy animals for years without the animals showing signs of clinical disease. These animals shed the bacterium in their milk.
In fact, Hermon-Taylor and colleagues recently completed a 4½-year study throughout central and southern England that showed that intact M. paratuberculosis bacteria are present in an overall 7% of retail supplies of pasteurized cow's milk, especially from January to March and from September to November. Hermon-Taylor and his collaborators do not know whether these surges are important for human infection. People might contract M. paratuberculosis infection by drinking milk. Hermon-Taylor presented these findings recently at the European Congress of Microbial Chemotherapy in Glasgow, Scotland.
Unlike M. tuberculosis, M. paratuberculosis can survive pasteurization. Laboratory tests have shown that some M. paratuberculosis bacteria remain active even after heating at 71.6° C for 15 seconds, the conditions of a method of commercial pasteurization.
Crohn's disease in the UK emerged "perceptibly" in the mid-1940s and the incidence of the disease has been rising. In the UK, up to 80,000 people suffer from the illness, Hermon-Taylor said. The rising incidence may be related to changes in farming practices.
For more information, see:
- Dumonceau JM, Van Gossum A, Adler M, et al. No Mycobacterium paratuberculosis found in Crohn's disease using polymerase chain reactions. Dig Dis Sci.1996;41:421-6.
- Sanderson JD, Moss MT, Tizard MLV, Hermon-Taylor. Mycobacterium paratuberculosis DNA in Crohn's disease tissue. Gut. 1992;33:890-6.
- Dell'Isola B, Poyart C, Govlet O, et al. Detection of Mycobacterium paratuberculosis by polymerase chain reaction in children with Crohn's disease. J Infect Dis. 1994; 169:449-51.
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