Crohn's Disease: The Pros and Cons of Current Treatment Options

RUSSELL D. COHEN, MD: Hello, and welcome to the program. Today, we will be focusing on the pros and cons of current treatment options for Crohn's disease.

I'm Dr. Russell Cohen, associate professor of medicine at the University of Chicago Medical Center and co-director of clinical IBD. Joining me today in the studio is Dr. Loftus, professor of medicine and associate director of the Inflammatory Bowel Disease Clinic at the Mayo Clinic College of Medicine in Rochester, Minnesota. And joining us from California is Dr. Marla Dubinsky, assistant professor of pediatrics at the David Geffen School of Medicine at UCLA and director of the Pediatric Inflammatory Bowel Disease Center at Cedars Sinai Medical Center.

Ed, what would you say would be the good layout for the treatment options for patients with mild to moderate Crohn's disease, the benefits and the risks of these therapies?

EDWARD V. LOFTUS, MD: Going way, way back in time, Russ, there was evidence that sulfasalazine had some efficacy in patients with mild to moderate Crohn's disease and it was hoped that, as the newer 5-ASA formulations were developed, that they would have similar efficacy in Crohn's disease. And, indeed, in the late '80s, early 1990s, there were several trials to suggest limited efficacy in patients with Crohn's disease for inducing and maintaining remission, but subsequent trials have yielded conflicting results and metaanalyses suggest that the non-sulfa 5-ASA agents have only a modest benefit at best in patients with Crohn's disease. If there is a benefit, it's probably limited to those patients with colonic Crohn's disease.

So we have that issue, just limited efficacy. The safety issues with 5-ASAs aren't as much of a concern.

So, moving on up the therapeutic pyramid, if you will, the next step would be oral budesonide, budesonide is a corticosteroid that has been modified such that it has high activity within the bowel, but then, due to first-pass hepatic metabolism, it has very low systemic bioavailability and, hence, fewer side effects than conventional corticosteroids. And there are trials to clearly show efficacy in patients with mildly to moderately active Crohn's disease, especially if they have ilial involvement or right colonic involvement.

There's even one head-to-head trial comparing budesonide to one of the mesalamine formulations and this showed that budesonide was superior to mesalamine for inducing remission in these patients. Don't get me wrong, budesonide still has potential for side effects. You can still see cushingoid-type side effects. You can still run into those issues, but it's not nearly as frequent as you would see with conventional corticosteroids. So I think, in selected patients with Crohn's disease, if it's the -- the right anatomic involvement (again, ilium and right colon), budesonide is a very reasonable option for first-line therapy.

Conventional corticosteroids are also a good option for patients that are on more the moderate end of the mild-to-moderate spectrum that we're talking about. Prednisone is typically administered and I think most of us use somewhere around 40 to 60 mg daily initially until the patient is seeing clearcut clinical improvement and then beginning a slow taper. The typical corticosteroid course might be anywhere between two to three months.

These are very effective drugs in the short term, 80% efficacy, but there's a problem with steroid dependence, as patients taper off of these medications. In other words, they begin to have flares as they're tapering down.

RUSSELL D. COHEN, MD: Well, Ed, that, I think, was very helpful. Marla, you know, Ed has really set us up here. He's explained that the mesalamine agents have some efficacy, but limited, and budesonide is helpful in some patients. Corticosteroids seem to be efficacious, but a lot of patients get stuck on them, either well or not-so-well. Can you perhaps let us know what the next step would be, in your practice or other practices as well, as far as agents to get patients off of the corticosteroids and keep them off of steroids?

MARLA D. DUBINSKY, MD: Sure. So, you know, Ed laid the groundwork, so to say, about the more mild to moderate approach first-line therapy. You're asking me to elaborate a little bit on the role of immunomodulators in Crohn's disease. Ed really highlighted the fact that steroid dependency, and even steroid-refractory patients have become very much an issue in our practice.

The key to the long-term treatment of patients is really the ability to get patients off of corticosteroids. There are that group of patients that respond well to 5-ASA's, and thankfully, may never see a corticosteroid. But once we get a patient onto a corticosteroid, often there is a limited and/or no exit strategy. Even budesonide, some would say, "What is the exit strategy?" So immunomodulators would fit perfectly in the next step of the therapy pyramid.

Essentially, we refer to immunomodulators, really, as two groups of drugs. One are the thiopurines, which include both 6-mercaptopurine and azathioprine, and also methotrexate.

When we look at 6-MP and azathioprine in Crohn's disease, we have really good evidence to supports its use mainly as a maintenance of remission therapy. There is some data from a metaanalysis published in 1995 by Pearson that actually also showed that there is a significant benefit over placebo, even for induction. But the main limiting factor to the use of 6-MP and azathioprine as induction therapy is really the later onset of action.

Originally, when 6-MP was first evaluated and published by Present in 1980, it was thought that it took almost three months for these drugs to really kick in. But then, when we reevaluated and looked at the IV azathioprine study that Bill Sandborn published, it looked to be that around six to eight weeks we may already see some benefit from these drugs when used at appropriate dosing.

Methotrexate, on the other hand, there's some data from Brian Feagan published in the New England Journal that it may have an induction role such that it may be effective at about four weeks of therapy, but may not actually take effect, also, until about eight. So you're looking at, for both of these therapies, from an induction perspective, of about four to eight weeks in terms of kicking in and having an antiinflammatory effect.

So a lot of patients view these drugs more as maintenance therapies. Thus, we've used things like 5-ASA's and, most notably, corticosteroids as a bridge to these immunomodulators, which will be the mainstay of treatment for these patients long term, or we hope will remain their therapy of maintenance choice for long term.

What limits a lot of times these uses, and not every patient responds to these drugs. I mean, not every patient responds to thiopurines, and not every patient responds to methotrexate. One, we discuss the limited onset of action for these drugs may take a little bit longer. But let's talk about the safety issue a little bit.

There's been some recent evidence that patients are asking questions about the role of lymphoma, most notably that we'll get into when we talk about biological therapies. But there's some recent evidence that even these drugs at this level on the pyramid actually are associated with lymphoma. So malignancy remains an important part of our conversation with our patients.

But as I tell my patients, this isn't the number-one side effect that we're worried about when we're using these drugs. I focus on, really, two broad categories. One is the immunosuppressive aspect of it. Even though we believe most patients do well, we monitor their blood counts very regularly on these medications so that we can maintain their white count at a normal count, try and make sure their lymphocyte count is at the lower limit of normal to try and make sure that they get their immune system down to be able to be susceptible to lots of infections.

So when you talk about the overall potential immunosuppressive role, we're talking about sustainability to infection. Often, patients are getting viruses such as EBV, CMV, other viral infections patients may be subjected to. And I explain to my patients that bacterial infections are important, but in the face of, usually, normal white counts when we employ these drugs, we're not as worried about it if our patients are properly monitored.

Other side effects, such as liver toxicity, is something that we typically talk more about when we're talking about methotrexate, but there's also some evidence that there may be some liver toxicity associated with the use of thiopurines, and therefore regular blood count monitoring as well as liver function test monitoring is important.

RUSSELL D. COHEN, MD: Well, Marla, I'd like to thank you. That was a terrific review of azathioprine, 6-mercaptopurine and methotrexate and their use for, hopefully, getting patients off of corticosteroids and keeping them off.

You know, turning to Ed, these medicines that Marla's discussed have been around for years and we've been using them for years and it's become apparent that there are still some patients who, despite our best intentions and efforts, are either allergic or intolerant or just nonresponsive to the medicines that we have discussed to date. Where do you see the role of infliximab? What are the benefits and risks of therapy with this agent?

EDWARD V. LOFTUS, MD: Infliximab is a monoclonal, chimeric antibody that's been commercially available in the United States since 1998. It's about 25% murine antibody and the remainder is human antibody. And this drug was actually approved on the basis of a relatively small phase II trial and the reason is, is that the effects of this medication were dramatic. It had significant efficacy in inducing remission in patients who had failed conventional therapy and significant benefit in healing fistulizing Crohn's disease. So when it was initially approved in '98, it was really more for induction than anything else. Later on, trials, namely ACCENT I and ACCENT II, showed that it also had a maintenance benefit, so the labeling was changed several years later to reflect that.

And, typically now, it's administered as a three-dose induction, so this is administered intravenously. Typically dosed by weight, the typical starting dose is 5 mg/kg body weight and this is given at zero, two and six weeks and then maintenance therapy is typically started at every eight weeks thereafter. These are, again, very efficacious drugs, dramatic effects in some patients in terms of symptoms, not only in terms of the gastrointestinal symptoms, but also in terms of their energy level.

And there are emerging data that maybe these drugs could be used earlier on more aggressively in patients to actually modify the natural history of the disease, although, again, that data is fairly preliminary and we don't want to make too much out of it.

Now, having said that, there are some drawbacks to these medications. If infliximab was perfectly safe, it would be obvious that we would have everybody with Crohn's disease on infliximab because of their high efficacy. There are some concerns about increasing infection risk and, particularly, infections that are granulomatous in nature; for example, tuberculosis, listeria, histoplasmosis, coccidioidomycosis, invasive fungal infections. And so, typically, when a patient is begun on one of these medications, you place a PPD, make sure the PPD's negative and also check a chest X-ray. But, also, counsel the patient to have a low threshold for seeking medical attention if they develop unexplained fever or unexplained pulmonary symptoms.

There's just a general sense that there's an increased risk of bacterial infections, although that isn't quite as well characterized as the risk with those granulomatous-type infections we just talked about.

There are also some concerns with infliximab with respect to neoplasm and it gets hard to tease out how much of that neoplasia risk is related to the Crohn's disease itself or the concomitant medications, namely thiopurines or methotrexate, or to the drug itself. And that's been difficult to tease out over the years.

There was particular concern early last year, in 2006, when the labeling of infliximab was changed to reflect the fact that, out of approximately 10,000 pediatric age patients treated, there were six patients that were either adolescents or young adults who had developed a particularly aggressive kind of T-cell lymphoma, hepatosplenic T-cell lymphoma. Interestingly, however, all of these patients were not only on infliximab, but also on a thiopurine, either azathioprine or mercaptopurine.

So, again, raises the issue that Marla referred to. Is this combination of the two medications contributing to some of these safety concerns? And I think there has been a reevaluation in the community, not quite a consensus yet, but you start seeing people moving more towards backing off on the immunosuppressive therapy a little bit and relying more on monotherapy.

One of the reasons why combination therapy has been employed is that because infliximab is chimeric, it's immunogenic. Patients, over time, especially if they received the infliximab episodically, can develop antibodies to infliximab and this can lead not only to infusion reactions but also to loss of efficacy over time. And it's thought that, at least for episodic treatment, using a concomitant immunosuppressive would actually mitigate or lower the risk of developing these antibodies to infliximab.

So there are, I think, evolving issues regarding how we use infliximab, especially with respect to some of these other medications and it's a continuing learning process.

RUSSELL D. COHEN, MD: Thank you, that's terrific.

So, Marla, you know, medicines only work if you take them and compliance with medications is an issue, particularly, I think, in the pediatric population but even for adults. What do you think about these different types of dosing protocols, pills, injections, infusions and tricks to ensure compliance?

MARLA D. DUBINSKY, MD: So, you know, both Ed and I just kind of listed a whole bunch of medications, and we didn't talk about even necessarily the frequency or how many pills. So you're right, Russ. I mean, I think if a patient's not going to take their medicines, the chances of the frequency of responsiveness and safety profile that we've talked about really wouldn't apply as much, and so our job as physicians is to try and explain to patients the importance of the therapies that we are prescribing.

One of the things we need to be up front about with the patients is more so on the education side. We need to explain to the patient why they're taking the medicine, why they're taking the amount of pills they're taking, and why they're taking it at the frequency that they have to.

I think the biggest compliance concern comes from the 5-ASA therapies, Russ. I mean, the reality is that the more pills, whether it's an adolescent or a young adult, or even somebody who's an older adult, really, it comes down to the fact that the more pills I need to take in a day, the more frequently I'm going to forget to take them. Especially if I have to take them more than twice a day. We have routines. Everybody has routines. So kind of when things interrupt you in the middle of the day, it's kind of hard to remember to take your pills, for example.

So if we would start with pill count being an issue, potentially, especially as you noted in the adolescent age group, and especially a three times for four times a day dosing regimen, you can imagine that when they're after school and they're running around and they're going from activity to activity, most notably they miss that third or fourth dose during the day. And as well, people have to think about, it's not really the coolest thing to go to the school nurse during the day, either, so there are also some psychosocial issues surrounding want to take your pills during the day.

So one way, whether it's for a child or an adult, would be to simplify the number of pills, or more so, really, the amount of times they take the pills. So typically, I think most of us are actually heading towards a twice-a-day dosing schedule with the 5-ASA's, for example, and going away from three or four times a day scheduling. And in the near future, we're going to be going to once-a-day dosing, as well. So I think limiting the frequency of how many times they have to take the pills is one area.

But the number of pills also is a significant impedance to adherence or compliance, and really, I think, if we can get more milligrams per capsule as we are heading towards the near future, as well, then we're going to be able to improve that.

RUSSELL D. COHEN, MD: Well, at this point, I'd like to thank my colleagues for such an interesting discussion pertaining to the risks and benefits of treatment of Crohn's disease as well as compliance. I'd also like to thank the AGA and you, the audience, for joining us as well. Thank you.