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Focus OnDear Reader:
Welcome to the Crohn's Disease Information Center. Our goal is to find a cause and cure for Crohn's Disease. This site is a work in progress so please contact us with any suggestions or comments you may have.
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Where we are and where we are going
The role of Mycobacterium avium paratuberculosis in Crohn's disease has been debated for the past several decades. Our work has shown a significant serologic response of Crohn's patients to recombinant cloned antigens as compared with non-IBD controls. We have also documented the organism in cultures from surgically acquired tissue using special media confirmed by PCR. Our open clinical trial has shown the combination of Rifabutin and Clarithromycin effective in achieving remission in 80% of treated patients to date with elimination of corticosteroids, significant reduction of Crohn's Disease Activity Index and improvement of quality of life. Correlating with clinical response is endoscopic healing and return to normal histology in the majority (75%) of patients in remission at one year. The benefit of probiotics in the induction and maintenance of remission is being evaluated in our open trial, using a combination of naturally occurring bacteria, amino acids, and antioxidants. Studies using probiotics have suggested the mechanism of action to be the up regulation of anti-inflammatory cytokines(IL10) and reduction of the most widely known proinfammatory cytokine(alpha-tumor necrosis factor,TNF). The recent report by our group of fistula closure in serologically positive patients adds further support to a bacterial etiology and the role of antibiotics in the treatment of this subset of patients.
Recent discovery of the Nod-2 gene on chromosome 16, suggests the important role of the monocyte in the detection of cell wall lipopolysaccharides of a variety of bacteria. This gene, which is an important determinant of innate immunity, is defective in as many as 15% of patients with Crohn's disease. The unique cell wall features of Mycobacterial species and their interaction with receptors on the human intestinal epithelial cell fit well with a possible role of this organism in the pathogenesis of this disease.
Since 1998, infliximab has been used extensively in the treatment of Crohn's disease. This monoclonal chimeric antibody to alpha-tumor necrosis factor (TNF) has proven beneficial to chronic steroid dependent Crohn's disease patients. Several groups have published the benefit in fistula closure. The preliminary results of the ACCENT I trial showed the benefit of every eight-week administration of infliximab with maintenance of remission and improved quality of life in over 500 patients with Crohn's. Safety concerns have not been sufficiently addressed with regard to complications of the immunosuppressive effects of this therapy. Recent reports of neoplasms and disseminated infection raise concerns for our patients. Documented miliary tuberculosis, aspergillosis and other opportunistic infections have all been reported in patients treated for Crohn's and Rheumatoid arthritis treated with immunotherapy.
Our group is studying the effect of immunotherapy in patients serologically positive for Mycobacterium avium paratuberculosis. Our preliminary results show the elimination of antibody markers after treatment with infliximab in patients known previously positive. The loss of humoral antibody as a result of infliximab and the known protective role of TNF in the recruitment of macrophages may in fact be harmful to those patients with underlying bacterial infection. The identification of these patients and eradication of infection prior to using immunotherapy may prove safer for these patients. We are currently studying serology and its role in selecting the best therapy for these patients.
Further work is needed to evaluate the role of microbes in inflammatory bowel disease. Animal models of IL 10 knockout mice, using artificial methods to induce colitis shed little information on human Crohn's disease, where these models may not explain the complex interactions of microbes and the human intestine. The role of bacteria, the balance between harmless commensals and potential pathogens should be studied using molecular diagnostic techniques. The response of the bacteria and the human immune system (innate and adaptive), the genes, which predetermine these responses, will all be critical in our understanding of this complex disease. Antibiotic treatment has not been sufficiently studied in large multicentered double blind studies. The opportunity to understand the cause of Crohn's disease has never been so exciting.
Ira Shafran, MD
