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Expert Critique
FROM THE ASCO Reading Room
MAP is widespread in dairy cattle. According to USDA estimates, the prevalence of MAP infection in U.S. dairy herds has increased from 21.6% in 1996 to 91.1% in 2007. MAP can be shed into the environment in a spore-like form which is able to survive heat. As a result, it is believed that humans are frequently exposed to MAP through contaminated food and milk.
MAP has been implicated in the development of Crohn鈥檚 disease given the clinical similarities to Johne鈥檚 disease. Studies have indicated that during the same time period when MAP prevalence increased in U.S. herds, Crohn鈥檚 disease likewise increased in the U.S. However, association does not prove causation. MAP can be cultured from the peripheral mononuclear cells from a subset of patients with Crohn's disease, which also supports this hypothesis. However, in human tissues, MAP is difficult or often impossible to identify microscopically, which makes identification difficult. Clinical trials have pointed to the potential for antimycobacterial antibiotic therapy to be beneficial in treating Crohn's disease, but this treatment has not been shown to be curative.
It is likely that a variety of factors influence whether an individual infected with MAP develops Crohn鈥檚 disease including age, sex, inoculum dose, and host genetics. It is also important to note that the antimycobacterial antibiotics may also alter levels of other intestinal microbes, including microbes which may contribute to the inflammation associated with Crohn's disease. As a result, findings should be interrupted with caution and further studies should be performed to define the role of MAP in Crohn's disease.
Mycobacterium avium subspecies paratuberculosis (MAP) is under investigation as a cause of the growing global prevalence of Crohn's disease (CD). Found in meat, milk, water, fruits and vegetables, pastures, and aerosols, this pathogen, which can exist only in mammalian cells, causes a similar to an intestinal tuberculosis known as Johne's disease in cattle and other ruminants.
Infected dairy and beef cattle shed more than a million infectious doses per day in their feces. One of off-the-shelf milk in three states found MAP in nearly 3% of the samples. "Up to 90% of cattle herds are infected with this pathogen, and you can find it in meat and milk at the grocery store, so many people are exposed," David Y. Graham, MD, a MAP researcher at Baylor College of Medicine in Houston, told the Reading Room.
"But only some humans are susceptible to chronic infection because they don't clear intracellular pathogens as readily as others. Genes associated with CD are also related to the ability to clear mycobacterium pathogens such as tuberculosis," he said.
Among an array of possible clearance genes are NOD2/CARD15, noted William Chamberlain, MD, a long-time MAP researcher and now retired gastroenterologist in Georgetown, Texas. "These genes basically cause immune dysregulation and impair clearance." In addition, the commensal bacteria of some patients could acquire virulence factors such as toxins or adherence and invasion properties that might cause chronic intestinal inflammation. "Map can also go dormant in the body, which makes it difficult to eradicate."
Graham noted that pasteurization does not kill MAP, and since it is not officially classified as a zoonotic pathogen, there are no regulations requiring its removal from the food supply. But if MAP is proven to cause CD, he said, major and costly changes in the cattle and dairy industries -- similar to those implemented to eradicate bovine tuberculosis -- will likely follow.
He said research in humans increasingly suggests a causative association between MAP and the chronic inflammation of CD, with viable MAP and its highly detectable in blood and tissue from CD patients. MAP was first experimentally implicated in the pathogenesis of Crohn's disease in 1984, when the organism was cultured from three resected intestinal specimens.
Evidence aside, a definitive causal role for MAP in CD remains elusive: "Until we can show that with anti-MAP treatment CD gets better and when MAP recurs, the inflammation recurs, MAP's role will remain debatable," Graham said. "We have the same problem with MAP that we had proving that Helicobacter pylori causes peptic ulcers." He pointed out that back in the 1980s when Barry Marshall, MD, first suggested H pylori as the cause of peptic ulcers, he was practically laughed off the stage, but subsequently, once the connection was proven, antibiotic-based eradication regimens became the norm.
MAP-specific treatments appear to promote resolution of symptoms and healing of mucosal damage. Non-controlled have reported that up to 84% of patients respond to treatment with combinations of antibiotics effective against MAP.
In 2005, preliminary results from a 2-year, blinded, placebo-controlled trial by Warwick Selby, MD, and colleagues were reported, showing a 33% response rate in patients treated with anti-MAP triple antibiotics versus 18% in controls (P<0.05), but there was an insignificant persistence of response 1 year after treatment (19% vs 12%).
And while adequate numbers of controlled trials remain to be done, Graham and colleagues recently reported positive from the MAP U.S. study, a phase III randomized double-blind placebo-controlled trial involving 92 global sites and more than 300 patients with moderate to severe CD. Significantly more patients receiving MAP-targeted antibiotics had clinical remission or response at 16, 26, and 52 weeks.
The researchers randomly assigned 331 patients with moderately to severely active Crohn's disease to receive either combination therapy with 95 mg of clarithromycin, 45 mg of rifabutin, and 10 mg of clofazimine, administered as five capsules twice daily for up to 52 weeks, or the same regimen of placebo pills. Patients maintained their regular CD medications during the trial.
Although in the absence of a definitive diagnostic assay, patients were not tested for MAP infection, they were assessed after 16, 26, and 52 weeks of treatment for clinical remission, defined as a Crohn's Disease Activity Index (CDAI) score <150. The patients were also evaluated for clinical response (a CDAI decrease of >100 points from baseline).
At 16 weeks, 42% of patients in the anti-MAP arm achieved clinical remission at week 16 versus 29% of placebo recipients (P=0.015). At 26 weeks, 37% and 23% of the two groups, respectively, were in clinical remission (P=0.007). By 26 weeks, 44% of patients in the anti-MAP arm achieved a clinical response as opposed to 31% in the placebo arm (P=0.017).
At 52 weeks, 25% of anti-MAP recipients were in clinical remission, compared with 12% of the placebo group (P=0.003).
The researchers concluded that the therapy was safe and well tolerated and could represent a new paradigm for treating a broad spectrum of CD disease patients: "RedHill Biopharma is currently negotiating with the FDA to do two more trials, and hopefully one may begin late this year or early next year," Graham said.
According to Ira Shafran, MD, however, a recently retired gastroenterologist in Orlando, Florida, and a proponent of anti-MAP therapy, the treatment effect might have been larger if all enrolled patients had assay-proven MAP infection.
In terms of definitive diagnosis, RedHill Biopharma's Ira Kalfus, MD, explained in a news release that detecting MAP via serological assays is challenging because commercially available tests have low sensitivity. Because MAP resides intracellularly within macrophages, serological antibody tests have limited utility, he said, adding that the company is researching whether a polymerase chain reaction can be used to detect the DNA of MAP in tissue samples and is also working on a diagnostic test for the pathogen in whole blood.
On the immunization front, British researchers such as John Hermon-Taylor and William Davis have been working on anti-MAP vaccines, and a of the vaccines ChAdOx2 HAV and MVA HAV is starting at the University of Oxford to test the safety and immunogenicity of two anti-MAP formulations.
Not waiting for such trials to be completed, some gastroenterologists have used anti-MAP antibiotic therapy in real-world practice. For example, in a to the Human Paratuberculosis Foundation, an organization dedicated to MAP research, Shafran reported on 11 patients who had deep mucosal healing and sustained remission when treated with anti-MAP therapy over an 18-year period.
Anticipating the launch of new trials, Graham and Chamberlain both expressed frustration at the reluctance of the broader medical community to accept MAP as a major cause of CD: "But the many labs that are doing the real research into MAP are taking it very seriously," Chamberlain said.
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