Kim, let's start with you. What are the goals of treatment of IBD today, and how have they changed?

Holly Atkinson MD

As we understand more of the biology of the disease, our goals have changed somewhat. We still want to control symptoms, but also, we want to try to change the natural history of the disease. We want to be able to see endoscopic decrease in inflammation. We want to prevent patients from going on to fibrosis. Whether we've attained all these goals, that's a matter of discussion, but that is now a good part of the goal of therapy.

Holly Atkinson MD: We're going to be talking about a lot of drugs. Give us an overview of the classification of the drugs, and how to think about where they interact in the process.

Kim Isaacs MD, PhD

James Marion MD: I think I need to preface any categorization of the medications that we're using with a warning to physicians that these categories are rather fluid at this point. I think at the speed with which some new agents are coming on to the scene, and being added to our armamentarium, there's a lot of discussion about where they fit exactly. But the basic rules, in terms of categories, I think, still largely apply.

There's a first level of therapy that we tend to institute in patients with inflammatory bowel disease, patients with milder, moderate forms, which would include the 5-ASA agents: medications like sulfasalazine, mesalamine, balsalazide or olsalazine. Antibiotics sometimes are squeezed into that first level, although that's a highly controversial area.

The second level includes corticosteroids. Corticosteroids have had a bit of a renaissance, given the nonsystemic budesonide, which has recently been made available for Crohn's ileitis. For maintenance, they don't really play a role. Infliximab occasionally gets squeezed into that category as well. The third level of therapy starts getting into immunomodulatory or immunosuppressive therapies, such as azathioprine, 6-mercaptopurine, methotrexate and cyclosporine and tacrolimus, in some cases. The biological therapy, really, at this point, is infliximab. On the horizon, I think, we'll be seeing many more. For example, natalizumab is on the horizon. A recent European study showed that it is quite effective. So, those are really the four basic categories, I think, that are still out there, but where they all fit, and how this pyramid needs to be approached when you're meeting a patient with inflammatory bowel disease is, I think, in flux at this point.

Holly Atkinson MD: Gary, why don't we start by talking about the use of these drugs for establishing and maintaining remission? Where do you begin, given the different grades of severity?

James Marion MD

If an individual is more on the moderate side, we might go to corticosteroids. If they have rather severe disease, we more think of the cyclosporine. Infliximab, although it has been used for moderate disease, it's more for those individuals that have higher disease activity, and it's that, plus the disease distribution that come into play when we look at the specific agents and how they'll be applied to treating patients that have active disease.

With maintenance therapy, we have just come, over the past several years, into the realization that we can maintain remission effectively with Crohn's disease. It had been known, and practiced, quite some years, with ulcerative colitis, but it's only recently that we've focused on that in our armamentarium of treatment regimes.

The maintenance of Crohn's has been looked at for several agents, and some are more effective than others. All of the agents, except for those of corticosteroids, have been looked at, and the immune modulators, such as mycophenolate or tacrolimus, have been shown to be somewhat effective to maintain remission. Cyclosporine, again, not something we should be using to maintain remission, either. But, that's a general approach that one might take when looking at induction and maintenance therapy directly.

Holly Atkinson MD: Kim, infliximab it's been mentioned several times. What's the mechanism of action?

Kim Isaacs MD, PhD: Infliximab is a monoclonal antibody directed at TNF, so it's an anti-TNF agent, and it binds TNF-both free TNF, and it also binds TNF, I think, more importantly, to TNF bound to cells, such as antigen-presenting cells and lymphocytes. And through its action on those cells, it actually can selectively destroy a certain population of cells. And I think that that aspect is exceedingly important in Crohn's Disease, as compared to maybe a little bit less important in rheumatoid arthritis.

Holly Atkinson MD: And what are the current indications right now?

Kim Isaacs MD, PhD: The indications for infliximab at this point are induction and maintenance of remission in patients with moderately to severely active Crohn's disease. Often, these are patients that have been medically refractory to some of our more standard medications. It's also indicated for initial fistula closure in patients with active fistulous disease related to Crohn's disease. It's now up for review for maintenance of fistula closure in patients who were initially treated with infliximab.

Holly Atkinson MD: Gary, concerns about using the drug?

Gary Lichtenstein MD: We now have had four years since it's been approved and on the market in the United States to observe, and it's a relatively safe medication. The main adverse events we see are that of infections, primarily. They can be anything from a sinusitis to a varicella infection, and often, are treated quite effectively. There's a 0.9% overall likelihood of having a severe adverse event, based on the recent ACCENT I data. The likelihood of stopping medication, due to adverse events, is less than 2%. So, given those numbers, and given the duration of trial of one year, that's important. Overall, we found it to be quite safe and quite effective, as Kim has suggested.

Kim Isaacs MD, PhD: Gary, what about infusion reactions?

Gary Lichtenstein MD: The infusion reactions are important, and the problem with infusion reactions is, if an individual has them, will they make it such that that individual is unable to receive future medication? And, that's something that occurs relatively infrequently, but it is something observed. There is some emerging information regarding that, and perhaps the future will be molded, based upon this directly, looking at antibodies directed against medication, in particular, against infliximab. The side effects that we're most concerned about are cardiorespiratory directly. Those people that have heart problems, shortness of breath, or an angio-like edema effect that might come about, and these are relatively uncommon, again. Most adverse events related to infusion are handled simply. Corticosteroids, diphenhydramine, acetaminophen are adequately available and easily used to treat these potential side effects that may develop, and once they do develop, they're handled easily.

Holly Atkinson MD: Kim, other anti-TNFs being studied?

Kim Isaacs MD, PhD: With the success of infliximab, there are a number of other anti-TNFs that have been studied. For example, fusion proteins that bind TNF, and these have been used in rheumatoid arthritis. They've had less effect in Crohn's disease. There are a variety of humanized anti-TNFs that are being looked at, and there are a number of other medications that are not biologics that have as an end result one of their components a blocking TNF, or affecting TNF. For example, there have been a few studies on thalidomide, which one of the mechanisms of action is the effects on TNF.

Holly Atkinson MD: Jim, you've already mentioned natalizumab. What's the mechanism of action?

James Marion MD: Natalizumab is another biological agent that I think there's a lot of interest in, maybe even some excitement about, in terms of potential use in Crohn's disease. Natalizumab is a humanized monoclonal antibody that's directed against a molecule called alpha-4 integrin. Alpha-4 integrin mediates the migration of leucocytes from the intravascular space into the surrounding tissues-presumably, one of the key steps in the inflammatory process of Crohn's disease. The antibody blocks the alpha-4 integrin and, again, blocks the migration of these leucocytes. It reduces the stick or the adhesiveness of the leukocyte in the endothelial lining. So, there was recently a published study in The New England Journal of Medicine that showed compared to placebo, that the natalizumab was more likely to induce a remission or a response in patients who received two infusions.

Now, there's a lot to be worked out here. The first is dose. There are some dosing questions raised by the study. And frequency. How often are we going to be using this medication in patients? Is this something that we'll be using in the acute setting, or is it something that's going to be used in the maintenance setting? These are questions that remain to be answered, but I think that the initial data is quite encouraging.

Holly Atkinson MD: Gary, other biologics?

Gary Lichtenstein MD: There's a whole host of other biologics, not necessarily focusing on TNF, but focusing on integrins and selectins. In other words, addressing antibodies that address where lymphocytes should attack, polymorphonuclear leucocytes. There's antagonist to various things, which are up-regulated in inflammatory bowel disease. A whole myriad of different agents are being looked at, some more proximal than others in the inflammatory cascade; others, more distal, thinking to block the common effect or target organ directly. So, we're uncertain as to where to go, but we know that we'd like to block the inflammation, and before we know the disease cause itself, this is the best we can do.

Holly Atkinson MD: Kim, other classes of drugs. We've mentioned thalidomide, but there's obviously a number of others.

Kim Isaacs MD, PhD: Again, if one looks at the inflammatory cascade, the inflammatory pathway, and different components of what contributes to inflammation, one can sort of piece out the different categories. For example, growth factors, growth hormone, in terms of restitution of the lining of the gut. There are cytokines that are thought to be pro-inflammatory and anti-inflammatory, so, if one gave an anti-inflammatory cytokine, one may reduce inflammation. IL-10 and IL-11 have been looked at with varying success.

There are also some proposals of increasing one's innate immunity by giving stimulating factors, like GM-CSF. And so, if you just take the inflammatory cascade, isolate each one of the steps, there are drugs directed at interfering or augmenting each one of the steps.

Holly Atkinson MD: Jim, obviously, patients are very interested in complementary medicine, alternative therapies. One of the ones that's received a lot of attention are the probiotics. Tell us where we stand on those.

James Marion MD: Well, I think one of my favorite slides that I've ever seen regarding probiotics is a slide that compared the number of reviews on probiotics, which is rather tall on a graph, compared to the number of randomized controlled trials that have looked at probiotics, which is, at this date, relatively few. I'm hoping that that's going to change.

There is intense excitement and interest in probiotics. There are, however, several stumbling blocks to their use. One, the data just isn't there yet, in many categories of treatment. The second is a standardized formulation is not there. Many of these studies involve using a probiotic soup or concoction that was made up specifically for that study, and you can't always make it to that soup for your own patient.

The other stumbling block has to do with what exactly are we accomplishing, when we give these organisms? What types of organisms ought to be included in these formulations? How many billions of organisms need to be put in? These are questions that at this point are really just wide open.

But, having said that, I prefer to act as a skeptic for my patients, so that they don't simply walk into a health food store, come home with bottles and bottles of probiotics, or gut flora-type dietary supplements or food supplements that are not regulated at all. I'd like to keep an eye out for them, and hopefully, guide them to probiotic therapy that one, is standardized and well-tested; and secondly, that works.

Holly Atkinson MD: Gary, what about fish oil?

Gary Lichtenstein MD: Well, we know it's been used in other areas. Cardiovascular-wise, it's been shown to be cardioprotective, but, more importantly, in inflammatory bowel disease. It's been shown to be effective in ulcerative colitis predominantly, but also there's a very nicely done trial looking at Crohn's disease. This, at present, is undergoing a multi-center trial to see if it can be reproduced.

The theory behind the use of fish oil is that leukotrienes are involved in the creation of inflammation in the bowel directly in patients with ulcerative colitis predominantly, as well Crohn's. Leukotriene B-4, in particular, has been shown to be a chemoattractant for polymorphonuclear leucocytes. The introduction of fish oil or icosapentaenoic acid, is perceived to be the active ingredient, shunts the leukotriene B-4 and produces more leukotriene B-5, which has less pro-inflammatory effects directly, hence not allowing the recruitment of the polymorphonuclear leucocytes into the lamina propria of the intestinal tract directly. And this is at least one of the perceived mechanisms, whereby it might function. It's relatively naturally occurring, and what can be wrong with eating fish?

Holly Atkinson MD: Before we close, do any of you have any final thoughts for the practicing physician?

James Marion MD: This isn't so controversial, but I think it's crucial for the practicing physician to truly understand the issue of inducing a remission and maintaining a remission, and that before you go to the second step of maintaining a remission, be absolutely certain that the patient has responded to the induction therapy.

If a patient is not in a remission from your initial intervention, your initial induction therapy, you are virtually doomed to fail in the maintenance step. So I always emphasize to my referring physicians that we need to get them better, initially, before we can keep them better in the long run.

Holly Atkinson MD: Kim, final thoughts?

Kim Isaacs MD, PhD: I think it's also very important in knowing where the disease is. In Crohn's disease, there are multiple potential locations that may affect therapy: where our drugs are released, if a person has more distal disease, they may respond very well to local therapy; and, the same for ulcerative colitis-we may be very effective with very aggressive local therapy in left-sided disease, where we can't really use that in pan colitis. So, I think in seeing a patient, one must be ready to reassess disease activity-how bad the disease activity is and where the location of the disease is at different intervals during their presentation and treatment course.

And one other aspect, and maybe Gary can address this a little bit more, is our status in terms of drug-monitoring, our ability to know whether the patient is getting enough drug, whether they're getting too much drug, whether the amount of drug that they are getting is going to be effective in treating their disease.

Gary Lichtenstein MD: Well, Kim brings up an excellent point. The area of pharmacogenomics is evolving. The particular metabolites looked at: azathioprine is nonenzymatically converted to 6-mercaptopurine, which then goes through several steps to be converted to what is perceived to be active metabolite, 6-thioguanine nucleotides. There is a perceived-to-be toxic metabolite produced as well: 6-methylmercaptopurine, or 6-MMP, for short. The use of these in predicting whether a person will develop a hepatotoxicity, as well the use of the 6-thioguanine nucleotides in the prediction of whether an individual will respond to an appropriate dose of medication or to an inappropriate dose of medication is currently evolving. And the use of prospective clinical trials is of paramount to better understand and define the usefulness or the efficacy of using these particular tests, which are now commonly used.

Holly Atkinson MD: Well, thank you all for joining me. I think it's been a great discussion for the practicing physician. And, thank you, for joining me. I'm Dr. Holly Atkinson.

Moderated panel discussion: IBD treatment overview

Gary Lichtenstein MD