Immunology of Inflammatory Bowel Disease and Treatment with TNF-inhibitor

Interviews with Experts

Lloyd Mayer, MD
Professor of Medicine
Mount Sinai School of Medicine

Stephen Paget, MD: I am the physician and chief at the Hospital for Special Surgery and the Chairman of the Division of Rheumatology. We are particularly pleased today to introduce to you Dr. Lloyd Mayer who is a professor of microbiology, immunobiology and medicine at the Mt. Sinai Medical Center in New York. He has a particular interest in broad concepts of immunity and also the immunopathogenesis of inflammatory bowel disease. Dr. Mayer, thank you so much for coming today and talking to us.

Lloyd Mayer: My pleasure.

Stephen Paget: This is a musculoskeletal institute and a musculoskeletal web site. Why should the people joining us in this web site care about inflammatory bowel disease?

Lloyd Mayer: There are a lot of parallels between any of these chronic inflammatory diseases but it seems to be that through the years there has been a close link between rheumatoid arthritis and Crohn's disease. If you draw the long list of medications that have been used for rheumatoid arthritis you can essentially superimpose the list that has been used for Crohn's disease and vise versa. The newer agents which are being developed, have really been tested in both of these diseases. So, clearly the experience in one disease with some of these new agents is going to be directly applicable to the other.

Stephen Paget: So one may be a paradigm for understanding the other?

Lloyd Mayer: Absolutely. I think a lot of the disease mechanisms overlap as well so what we understand of the mechanisms in control of inflammation and of these inflammatory pathways they are going to provide new insight into both diseases.

Stephen Paget: What is inflammatory bowel disease?

Lloyd Mayer: Well it is actually a spectrum where there are two diseases on the polar ends. One is Crohn's disease, which is a disease, which affects any part of the bowel from the mouth all the way down to the anus and is a disease, which involves the full thickness of the bowel wall and involves segments of the ileum colon. In contrast ulcerative colitis is a disease, which is very superficial (mucosal), limited only to the colon and is a disease that is characterized more by a neutrophilic type of inflammation, mass cell infiltration, and a lot of mucosal injury and bleeding, etc.

Stephen Paget: What causes these diseases?

Lloyd Mayer: We do not know exactly what the cause is and probably there is not "the cause." We think that these are probably multiple diseases. What we do know is that there are at least three major components that contribute to pathogenesis. One is a genetic predisposition to inflammatory bowel disease in general or to specific forms of inflammatory bowel disease. The second is that there is some environmental trigger and we think that it is not one environmental trigger but there may be multiple environmental triggers. The third and probably the most important component is an immune response, which is abnormal in these diseases that allows you to react to things that normally you would not be reacting to.

Stephen Paget: These diseases in the past have been treated with medications such as steroids, which have there own potential side effects and you are always balancing cost and benefits. Are there newer therapies for these medications that are more effective?

Lloyd Mayer: I think the push in these diseases has been to get away from the use of corticosteroids because the long-term implications have been quite profound in terms of morbidity and even mortality. So some of the newer agents which have come out, have really come out based on our better understanding of the pathogenesis of these diseases. Agents which will interrupt some of these inflammatory pathways, agents such as Infliximab, anti-tumor necrosis factor, newer agents such as anti-interleukin 12 which are being developed by biotech companies, the use of interleukin 10 which unfortunately was not particularly helpful in either one of these diseases, agents which are more directed at these cytokine mediated inflammatory pathways have a lot of promise to interrupt some of the processes that are ongoing.

Stephen Paget: Since these newer biological modifiers are just the beginning of the beginning, like sulfur drugs were in antibiotics. Where do you see this going over the next five to ten years?

Lloyd Mayer: As I mentioned in the lecture, I think that we are making advances on all fronts and I think we really need in all of these chronic inflammatory diseases to understand differences in different patients. We need to be able to pigeonhole or categorize patients much better in terms of what the nature of the defect is in that patient. Then we could start pulling off the shelf either anti-cytokine therapies or cytokine therapies that will be specifically tailored for that patient and allow us to control the disease in that patient. I think that that is really around the corner.

Stephen Paget: Using the infection paradigm where you find a bacterium, you find its sensitivities, and the disease is over with. Do you see the future bringing specific patient profiles that include an equation of genetic clinical cytokine and immunological factors that will allow us to better fine-tune therapies to people like we do with infections.

Lloyd Mayer: I do believe that we will be able to keep patients under better control. I think though because there is not going to be a single trigger, we are not going to be able to completely eliminate all the triggers to these diseases and therefore we are never going to be able to "cure the disease." I think that we will largely be able to control of disease and control inflammation. With genetic manipulation there is a stronger possibility of cure especially since these are multigenic diseases, all of which modify the disease process. If you interrupt one pathway you have a greater potential for modifying the other pathway. So there is hope, although we are sorely lagging behind in terms of the gene therapeutic approaches. We are far behind where we had hoped we would be at this point in time.

Stephen Paget: Thank you very much.

Lloyd Mayer: Thank you. You had great questions.

Dr. Mayer was interviewed by Dr. Stephen A. Paget, Physician-in-Chief, Hospital for Special Surgery.


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