Anti-mycobacterial treatment and Crohn's Disease.

The rationale for antibiotic therapy of infectious bacterial disease is this. If the disease is caused by bacteria, then by eradicating the bacteria, the disease should end. Bacteria are "attacked" with a combination of drugs that are hopefully effective against them.

For more thorough discussions, please read the "Related info" links to the right of this page. It is important to bear in mind that both of the papers "Crohn's disease and the Mycobacterioses:- a review and comparison of two disease entities" (1989) and "Ruminant paratuberculosis:- current status and future prospects" (1984) were both written before the development of macrolide antibiotics, which have since been shown to be the most effective antibiotics against Mycobacterium paratuberculosis.

Conducting a clinical trial.

Clinical trials are designed to test whether a drug or combination of drugs is effective against any given disease. The test population in a clinical trial is divided into two groups, one of which receives the actual drug treatment under test and the other, known as the control group, which receives a "placebo" drug, which is known not to have any effect on the disease. If those taking the real drug treatment improve and the control group does not improve, then the trial is deemed to have proved that the drug treatment is successful at treating the disease.

It is difficult to judge the results of the trial if the people taking part in it are receiving other treatment for the same disease, but outside the trial. If patients are, for example, taking a course of drugs that maintains the disease, or are having surgery during the trial, it becomes difficult to judge improvements or lack of them.

This seems to be further complicated in the case of Crohn's Disease, since there are different views on what the disease actually is. Its symptoms vary widely from patient to patient, with treatment regimes differing greatly for each.

Choice of drugs.

All of the studies below have tested the use of antibiotic drugs for the treatment of Crohn's Disease. The drugs chosen are ones that are known to be effective against well known mycobacterial infections, such as tuberculosis or leprosy.

It is theorised that Crohn's disease is caused by mycobacteria that live inside host cells, i.e. they are intracellular mycobacteria. Hence, to be effective against them, the drugs chosen must have intracellular activity. Few antibiotics have intracellular activity. It is only in recent years that antibiotics have been developed that are active against intracellular mycobacteria. These antibiotics are known as macrolide antibiotics. One of these macrolide antibiotics is clarithromycin, which has been shown to be effective in treating Mycobacterium avium intracellulare, an intracellular mycobacterium that commonly infects immuno-compromised AIDS patients.

Multi-drug regimes.

When treating mycobacterial diseases, it is important to use multi-drug regimes. The reason for this is that mycobacteria have the ability to develop resistance to inividual drugs. If a single drug regime is used, then there is a possibility that the organism may become resistant to that one drug, and thus the treatment may fail.

Long treatment times.

Also, mycobacteria can exist in an inactive state, in which they do not metabolise. Antibiotics can only be effective against bacteria that are actively metabolising. Therefore, treatment duration must not only be long enough to destroy all active bacteria, but also long enough to destroy the inactive bacteria as they "re-activate". Since these periods of inactivity can be as long as many months, antibiotic treatment duration must be at least as long as this, and it is possible that the target mycobacteria may never be eradicated.

For more information on treating mycobacterial infections with antibiotics, see the page "Treating mycobacteria with antibiotics."

Polar manifestations of the disease.

Mycobacterial diseases present in two forms, the contained and aggressive forms. If it is not recognised that the population to be treated under a trial should be split between these two forms, the trial may yield incorrect results.

It is theorised that Crohn's disease may present in two "polar" forms. Individual patients usually do not suffer from the extremes mentioned below, but display symptoms that are somewhere between the two extremes. See the page "The polar manifestations of mycobacterial diseases and of Crohn's disease" for more details.

• The aggressive "perforating" form. This form of Crohn's is experienced by sufferers if they do not mount an immune response that is strong enough to control the Mycobacterium paratuberculosis infection. In this group, the population of infecting mycobacteria would be uncontrolled by the immune system, and would cause extensive damage to the intestines. The symptoms of this form are perforation of the intestinal wall and fistulisation, the formation of abnormal connections between the intestines and other internal organs. Crohn's patients with the aggressive perforating form would greatly benefit from treatment with antibiotics, since they are unable to control the bacterial infection by themselves.
• The contained "nonperforating" form. This form of Crohn's comes about when the immune system of the sufferer is strong enough to control the mycobacterial infection. However, this immune success comes at a high cost, since inflammation and granulomas are the result. Granulomas are formed when the immune system seals the mycobacteria inside hard shells. Over time, as the body is exposed to infection by Mycobacterium paratuberculosis again and again, more and more of these granulomas form in the intestines, eventually leading to obstruction (blockage) of the intestines. Crohn's patients with the contained nonperforating form of Crohn's disease may not benefit as much from treatment with antibiotics, since their infection may already be under control.

All of the studies listed below were complete or still in progress when attention was drawn, by Greenstein et al., to the possibility that Anti-mycobacterial treatment studies may fail if the study population is not first divided up into the perforating and nonperforating forms of Crohn's disease. This is because patients with the perforating form will show a strong improvement, whereas those with the nonperforating form will show less improvement. These two groups will be lumped together, leading to incorrect statistical analysis of the results.

Anti-mycobacterial treatment studies.

Since the success of these trials has increased through the years, the most important trials are the most recent, so I have listed these references in reverse chronological order.

• This paper was published in 1997, by Hermon-Taylor et al., the discoverers of the IS900 sequence. It describes the outcome of treating 52 patients with a combination of macrolide antibiotics (clarithromycin or azithromycin) and rifabutin. Six patients were excluded because of intolerance of the medication. Of the remaining forty-six, 93.5% achieved clinical remission, with a Harvey-Bradshaw Crohn's disease activity index of less than 5. I have included the full text of this paper. "Two-year outcomes analysis of Crohn's Disease treated with rifabutin and macrolide antibiotics."
• This paper was published in April 1994. It describes a controlled clinical trial using the drugs Ethambutol, Clofazimine, Dapsone and Rifampicin, but not macrolide antibiotics. It concludes that the regime chosen was effective in relieving symptoms and in maintaining remission in some Crohn's disease patients. "Antimycobacterial therapy in Crohn's disease: results of a controlled, double-blind trial with a multiple antibiotic regimen."
• This paper was published in March 1994. It describes a controlled clinical trial using the drugs Rifampicin, Isoniazid and Ethambutol, but not macrolide antibiotics. "Controlled trial of anti-tuberculous chemotherapy for two years in Crohn's disease."
• This paper was published in December 1992. It is the first to describe use of the macrolide antibiotic clarithromycin as a treatment for infection by Mycobacterium paratuberculosis, and concludes that it should be a highly effective drug for this use. "Activity of clarithromycin compared with those of other drugs against Mycobacterium paratuberculosis and further enhancement of its extracellular and intracellular activities by ethambutol."
• This paper was published in July 1992. It describes the use of Rifabutin and Ethambutol to treat Crohn's Disease. It concludes that the drugs are ineffective. For a comment on this work, see the abstract below. "Rifabutin and ethambutol do not help recurrent Crohn's disease in the neoterminal ileum."
• This editorial was published in July 1992, and is a comment on the use of Anti-mycobacterial treatment for Crohn's Disease, with particular reference to the study above. "The use of antimycobacterial agents in Crohn's disease"
• This paper was published in April 1991. It describes the use of a single drug regime in a controlled clinical trial. The drug is Clofazamine. It concludes that Clofazamine is ineffective as a treatment on its own, but that it may be effective as part of a multi-drug regime. "Controlled trial of antimycobacterial therapy in Crohn's disease. Clofazimine versus placebo."
• This paper was published in August 1989. It describes inducing remission in ten out of twenty Crohn's patients using a multi-drug, anti-tuberculosis regime. The drugs used were Rifampicin, Ethambutol, Isoniazid, and (Pyrazinamide or Clofazamine), all drugs commonly used against Mycobacterium tuberculosis. "Quadruple antimycobacterial chemotherapy in Crohn's disease: results at 9 months of a pilot study in 20 patients."
• This paper was published in 1989. It describes the successful cure of two out of five Crohn's patients, using a single drug regime. The drug used is Dapsone, the drug most commonly used against Mycobacterium leprae, the cause of leprosy. "Crohn's disease and mycobacteria: two cases of Crohn's disease with high anti-mycobacterial antibody levels cured by dapsone therapy."
• This letter was published in March 1988, in the Lancet. Since it is only a letter, no abstract text is available. "Antimycobacterial chemotherapy in two cases of inflammatory bowel disease."
• This letter was published in December 1987, in the Lancet. Since it is only a letter, no abstract text is available. "Remission of Crohn's disease with antimycobacterial chemotherapy."
• This letter was published in January 1986, in the New England Journal of medicine. Since it is only a letter, no abstract text is available. "Remission of Crohn's disease with tuberculosis chemotherapy."

Conclusion.

To date, no controlled drug trial has been conducted that uses a multi-drug anti-mycobacterial regime that includes macrolide antibiotics. Given the evidence of the studies quoted above, it is likely that such a trial would demonstrate that this is an effective method of treating Crohn's Disease.

Source: http://archive.crohn.ie/chemo.htm
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