Treatment & diagnosis of Crohn's Disease

Treatment of Crohn's Disease

Diagnosis of MAP infection

Antibiotic Clinical Trial

Vaccine Research

An Interview with TJ Borody

Anti-MAP treatment for Crohn's Disease

Introduction

A limited summary of the history and background information regarding anti-mycobacterial treatment for Crohn's disease is detailed below.  It should be noted that there is considerable overlapping subject matter in terms of research.  Therefore, we would urge you to visit the Research section of this website for additional information.

History of anti-mycobacterial treatment for Crohn's disease

Since Crohn's disease bears significant similarities to known mycobacterial diseases, clinicians have been attempting to treat Crohn's disease with anti-mycobacterial drugs since 1975. Early treatment regimes were composed of antibiotics chosen for their activity against Mycobacterium tuberculosis (MTB), although both in-vitro and in-vivo data for these antibiotics showed that they had little effect against Mycobacterium paratuberculosis, as Mycobacterium avium subspecies paratuberculosis (MAP) was known at that time. If cases of Crohn's disease were caused by infection with MAP, then it is not surprising that these early treatment regimes were, in general, failures. For a full review of this early work, please read Chiodini 98: Antimicrobial Agents and Crohn's disease.

In the 1980's, disease caused by Mycobacterium Avium Complex (MAC) became prevalent. During the 1980's, MAC became the leading cause of lethal infection in patients with Acquired Immune Deficiency Syndrome (AIDS). Clinicians attempted to treat these MAC infections with the only anti-mycobacterial drugs available, namely drugs active against Mycobacterium tuberculosis. Successes with these early regimes were rare, since MAC bacteria were either resistant to anti-MTB drugs, or quickly developed resistance.

The advent of macrolides

The outlook for patients with MAC disease improved greatly in the late 1980's, with the development of a new class of antibiotics, known as macrolides. Two of these macrolides, Clarithromycin and Azithromycin, were highly effective against MAC bacteria, and revolutionized the treatment of MAC infections. Although they were unable to eradicate MAC infections, they had such a strong inhibitory effect that the chances of the host's own immune system bringing the infection under control were greatly enhanced. However, development of macrolide resistance is a common problem, and there are still no antibiotics regimes available which are guaranteed to eradicate a MAC infection. For a thorough review of antibiotic treatment for MAC disease, please read Heifets 96: Clarithromycin against Mycobacterium avium complex infections.

In the 1990's, a group of clinicians in England began treating Crohn's disease patients with anti-mycobacteria regimes which included macrolide antibiotics. The results of their work are discussed below.

Work to date

To date, three groups of investigators have published results of open trials of anti-MAP treatment which includes macrolide antibiotics. These are:

1. Gui et al published in 1997 their paper "Two year outcomes analysis of Crohn's disease treated with Rifabutin and macrolide antibiotics". They treated 52 patients with a combination of Rifabutin and Clarithromycin/Azithromycin for between 6 and 35 months. They documented remission in 43 out of 52 patients studied, as measured by the Harvey Bradshaw Crohn's disease activity index. Of the 9 patients not in remission, 6 patients withdrew because of the severity of side effects, and 3 patients experienced no improvement.
   
   
2. Borody et al published in 2002 (Digest Liver Dis 2002; 34:29-38) their paper "Treatment of Severe Crohn's Disease Using Antimycobacterial Triple Therapy - Approaching a Cure?"  They treated 12 patients with a combination of Rifabutin, Clarithromycin and Clofazimine.  Their conclusion:  "Reversal of severe Crohn's disease has been achieved in 6/12 patients using prolonged combination anti-MAP therapy alone.  Three patients remain in long-term remission with no detectable Crohn's disease off all therapy.  These results support a causal role for MAP in Crohn's disease while also suggesting that a cure may become possible."
   
   
3. A trial conducted by Shafran et al. in Orlando, Florida, treated 29 Crohn's disease patients with a combination of Rifabutin and Clarithromycin. After three months of treatment, the investigators found that 8 of the 29 patients were in clinical remission, 9 of the 29 patients experienced marked improvement, 8 of the 29 patients experienced minor improvement, and 4 of the 29 patients had to be taken off the medication, due to intolerance of side-effects.
   

 For a discussion of anti-MAP treatment for Crohn's disease, please read An interview with Dr. T. J. Borody.

We would encourage you to visit Dr. Shafran's Crohn's Disease Info Center  for extensive information about RMAT treatment. 

Endoscopic photos of responses to RMAT

Dr. Ira Shafran has graciously provided endoscopic photographs of intestinal condition before and after Rifabutin and Macrolide Antibiotics Treatment (RMAT) from an award-winning report presented at the Digestive Disease Workshop in San Diego, May 2000. To see a portion of that report and the accompanying photographs click here.

Dr. Thomas Borody has also graciously provided "before" and "after" endoscopic photographs of intestinal condition of patients treated with antimycobacterial therapy.  To see those photographs, click here.   These photographs are in conjunction with an interim report published by Borody et al in 1998 of their Phase 2 trial, entitled "Treatment of Severe Crohn's Disease (CD) Using Rifabutin-Macrolide-Clofazimine Combination."  See the section below entitled "Work to Date" for details about  publication of this study in 2002.

Trial structures

Open trials, regardless of the results obtained, do not provide sufficient evidence to recommend the treatment which is being tested. In order for the treatment in question to be proven to be an effective treatment, it must be subjected to a double-blind, placebo-controlled, and preferably multi-center clinical trial, for the following reasons.

• Double-blind. When the patients in the trial are unaware whether they are in the active or placebo arm of the trial, the trial is said to be blind. In a trial where the doctors administering the trial are also not aware which arm the patient is in, the trial is said to be double-blind. A double-blind trial greatly reduces the possibility of investigator bias during the trial.
  
  
• Placebo controlled. In order to obtain objective data on the effectiveness of the treatment under trial, patients in the trial are divided into two groups. One group receives the treatment under trial, and is said to be in the active arm of the trial. The other group receives treatment which they are told is the active drug, but is in fact an ineffective substitute which is known not to have activity in the disease condition being treated.
  
  
• Multi-center. To increase diversity and eliminate regional bias of the study, a multi-center trial is conducted by several independent groups of investigators at several locations.
  
  

Existing clinical trials

A double-blind, multi-center, controlled clinical trial of combination anti-MAP treatment is underway in Australia. For full details see the report on the Antibiotic Clinical Trial section of this site.

Known side effects of treatment

Among the side effects noted with existing anti-MAP treatment regimes are:

• Stricture formation. Some patients experienced a narrowing of the intestines which seemed to be caused by a build-up of fibrotic tissue (fibrostenosis). The formation of this tissue appeared to be related to scarring which takes place as a result of healing of the severely inflamed and structurally damaged tissue which is associated with chronic Crohn's disease. The probability of such stricturing may be related to the length of disease involvement in the patient.
  
  
• Leucopenia. A shortage of white blood cells occurred in some patients who were treated with Rifabutin. The level of white blood cells in many patients treated with anti-MAP treatment fell during treatment, as a natural consequence of the reduction of inflammation in the body. However, in some patients the levels of such white blood cells was sufficient to be classified as a severe deficiency, and warranted modification of the treatment regime or even withdrawal from treatment.
  
  
• Uveitis. Some patients taking Rifabutin-based therapy for Crohn's disease experienced ocular inflammation. This is thought to be an immune-mediated phenomenon, since similar symptoms do not occur in immuno-compromised AIDS patients who are being treated for mycobacterial infections with Rifabutin.
  
  
• Flu-like syndrome. A flu-like syndrome appeared in some patients after one week of anti-MAP treatment, and lasted for between 3 and 8 weeks. Up to 50% of patients treated experienced such symptoms. Up to 50% of patients who experienced the flu-like syndrome experienced a severe form of the symptoms.
  
  

Treatment failures

In recent years, a number of investigators have conducted studies of anti-MAP treatment for Crohn's disease. Their results are largely unpublished. They have reported treatment failures in between 16% and 33% of patients, i.e. that a subgroup of patients has experienced little or no improvement in their condition. The reasons for such failures may include

• Multiple diseases. There is growing support for the belief that Crohn's disease may not be a single disease, but is more than one disease that manifest symptoms that are sufficiently similar as to be diagnosed as being the same condition. Although MAP may be the cause of some cases of Crohn's disease, it is highly unlikely to be the cause of all cases. Therefore, not all patients treated with anti-MAP treatment would experience improvement.
  
  
• Insufficient activity of antibiotics. Infections by all species of Mycobacterium avium, including Mycobacterium avium subspecies paratuberculosis, are extremely difficult to eradicate with antibiotic treatment. Treatment failure of Mycobacterium avium infections is frequent, for a variety of reasons, including the ability of these bacteria to rapidly develop resistance to antibiotics.
  
  
• Existence of antibiotic resistance prior to treatment. Before anti-MAP treatment begins, some patients may have been treated with macrolide antibiotics, which are an essential element of all existing anti-MAP treatment regimes. Experience with Mycobacterium avium infections has shown that treatment of such infections with a single macrolide antibiotic, administered alone, results in a high risk that macrolide-resistance will develop. The mathematical probability of resistance is a function of how long monotherapy lasted, the number of separate treatment periods, and the number of infecting mycobacteria. Thus, there is a possibility that some Crohn's disease patients treated with anti-MAP treatment may have harbored macrolide-resistant MAP due to previous treatment with Clarithromycin, Azithromycin, or related antibiotics.