Holly Atkinson MD: How does medical therapy differ between adults and children?

Holly Atkinson MD

Marla Dubinsky MD: I think that the therapeutic approach is not dissimilar between adults and children. I think our objectives are clear. We want to induce remission in the patient, regardless of age, and we want to maintain remission. I think that the therapeutic pyramid in terms of starting with your milder therapies and going up to your more potent paralleling disease activity, I think similarly stays the same, regardless of age group.

But I think there are two areas that may be a little bit different in children. One is we as pediatricians may use nutritional therapy a little bit more than the adult population, given the effect on growth of the disease, particular Crohn's disease. And the evidence shows that it may be similar to, or as effective as, some of the more potent steroids that we're using.

The other important point is when it does come to choosing steroids and if we are about to embark on a steroid, such that the patient's gone beyond mild therapy or has failed mild therapy and we're moving up on the pyramid to our next approach. It could be that we're going to be thinking, the back of our mind, "Well, where is this child in their phase of growth? And if they are growth-stunted, are steroids going to have a significant impact on the growth?" And so there's been some theory to suggest and some studies that have suggested that if you're about to embark on steroids, you may want to think automatically about partnering or bridging this with other, more potent immunomodulators. So that children aren't becoming steroid-dependent and don't run the risk of having prolonged courses of steroids, therefore affecting their growth. And similarly, their bones, because you need good strong bones in order to grow. So the effects of steroid may,you know, dampen the effect on bone density and growth.

Holly Atkinson MD: Athos, what's you're thinking on steroids? Similar approach?

Marla Dubinsky MD

Secondly, they work quickly and I think that's very important. Very few of our other agents work as quickly as steroids. They can both get the disease under control and promote some short-term weight gain.

The problem with steroids is that when patients come off of corticosteroids, they frequently tend to relapse. And then you're stuck in a situation where you end up-if you're going to use steroids-using them for a long time. And then you do get the effects of growth and the untoward side effects that Marla was talking about. Therefore, my rule is if you're going to use steroids, use them for as short a time as possible. And as Marla was saying, use them as a bridge to another maintenance agent.

And the main maintenance agent we tend to utilize in children with significant growth failure would be 6-mercaptopurine. We do use aminosalicylates also, but the problem with aminosalicylates is that the likelihood of relapse is quite high. Whereas if you can get someone from a steroid onto 6-mercaptopurine, they're much more likely to stay in remission. And hopefully, you can spare their growth-stunting affects of steroids.

Nutritional therapy has never really caught on in the United States quite as much, I think because of the psychological impact. Nutritional therapy involves basically a child off of all food and either having them drink about eight cans of elemental or polymeric formula a day or administering it through a nasogastric tube. And that's a very commonly used and effective therapy in Canada and England, but I think in the States it's just been a harder sell to our patients. Most of our teenagers really do not want to do a tube, unless their backs are up against the wall. So we tend to save that.

Athos Bousvaros MD

Kim Isaacs MD, PhD: I wonder about how much are you using budesonide in children. I mean, that may be-at least in ileal disease-may spare you some of the steroid side effects. Are you using that much in children right now?

Marla Dubinsky MD: Yes. For patients that clearly have right-side or ileocecal disease, where its location is conducive to using a locally-acting steroid, absolutely. I would use that before I would use prednisone.

However, I'll say that the 9 mg dosage that we use for adults, 9 mg in children is very different. And so trying to gauge whether or not truly 9 mg maybe is like 40 mg of prednisone in children. I can say that I have had a number of children who have developed cushingoid and who have gotten the increase appetite that you would see per se with prednisone. So I think finding the right dose for children is critical. And deciding what age cutoff do you use to decide 9 versus 6 mg and the theory, do you wean Entocort in children. People have suggested that because the dose is a little bit higher, you may want to wean.

So I think people are still trying to figure out, number one, its role, but also in children, what is the appropriate dose, and I do use it in the right patient. And I think that that has given pediatricians a kind of a level in between 5-ASA and prednisone when it comes to concern about growth. However, we don't have any great studies in children to look at bone-even though they may have some in the adult population-to look at the effect on bone density and truly long-term growth in children. So I think until those are available, I'm not 100% convinced that we're avoiding the things we're trying to avoid long-term, which is growth and bone density.

Athos Bousvaros MD: There was a study by Ann Griffiths looking at approximately 35 children that had been treated with budesonide for as long as a year for ileocecal Crohn's disease. And unfortunately, during this period of treatment, these children did develop growth failure. That could be due to two things. One is it's possible that budesonide did not adequately control their disease. And if you're on the 3 mg dose, you still may have problems. The other, more likely possibility, however, is that the budesonide itself probably does suppress growth. So, while budesonide is out there, I think that it also should be used as an induction treatment, not a long-term or maintenance treatment, so you still need to bridge to something else, either ASA or 6-MP probably.

Holly Atkinson MD: What about the biologics? What's your experience been, Marla, with those and side effects in kids versus adults?

Marla Dubinsky MD: Some of our larger IBD centers across the country have accumulated great numbers of experience. And from these centers, it truly does not appear to be that biologics-number one, from an efficacy perspectives-are any different from the adult population. And from a safety perspective, it looks like there's similarly the same degree of safety concerns. The serious infection rates are similar between adults and pediatrics so far, based on the limited data we have. The risk of infusion reactions appear to be similar between the two populations.

So biologic, the one we're talking about is infliximab. Clearly, as new biologics come on board and there's already biologics that are being tested in adolescent population that clearly answering safety and efficacy in children-or less than 18, however we're going to define the pediatric age group-is going to be critical. And the way to do that is to talk and collaborate in terms of experiences across the nation in terms of what are people's experiences.

Athos Bousvaros MD: Infliximab has helped a lot of our Crohn's patients that have not responded to other drugs, particularly those with refractory fistulizing disease. And fortunately, I'd say 95% of children tolerate the drug well. The one thing that worries me about it in terms of use in children is we've been using steroids for 50 years, so we know that they can do. We've been using 6-MP and azathioprine for 25 years, so we've got a good idea of the long-term side effects. Infliximab we've really only had for about three years and there are a few case reports coming out of opportunistic infections, tuberculosis, aseptic meningitis. So I'm really reluctant to use it as a first-line drug at this time.

Holly Atkinson MD: Let's talk about a different population here. Kim, you work a lot with women who are pregnant who have IBD. What's the basic approach to therapy?

Kim Isaacs MD, PhD: The basics of therapy is keeping mother healthy. That's the bottom line in treating pregnant IBD patients. Most of the patients that I treat with IBD and are pregnant actually get pregnant after I've started taking care of them for their IBD. But I think one of the key things is that a woman who is in remission at the time of the onset of their pregnancy, they're going to fare much better overall than a woman who's not in remission.

So one of the worst things that can happen is for a woman to get pregnant or find out that they're pregnant and then stop all their drugs. And we see this. We see people who've been in remission for years on sulfasalazine or another 5-ASA, get pregnant, worry about the effect of the drug on the pregnancy, stop it, flare, and the outcome is poor.

Holly Atkinson MD: Athos, what's the effect that you see of IBD on pregnancy? I mean, it can go both ways; IBD can affect pregnancy and pregnancy affecting IBD. What's the effect of IBD on the pregnancy?

Athos Bousvaros MD: I think patients with inactive disease who become pregnant-as Kim was saying-tend to do just fine. Usually they stay in remission, their IBD doesn't flare. And assuming they take their prenatal vitamins and watch everything, they should have a healthy baby.

The concern is with patients who have active inflammatory bowel disease. You know, because if you feel sick, you may not eat. If you don't eat, you may not gain enough weight, you might be at risk for a premature delivery. If your disease were to unfortunately flare to the point that you would need surgery, operating on a pregnant IBD patient can be particularly risky.

Holly Atkinson MD: Well, Kim, let's talk about the medications, those that are safe to continue to use and those that are not.

Kim Isaacs MD, PhD: Many of our standard medicines are very safe to use during pregnancy. The 5-aminosalicylates are safe during pregnancy. The one caveat to that is sulfasalazine. It affects folate metabolism and decreased folate levels are associated with neural tube defects. So in general, with the patients who are on sulfasalazine, we'll push up the amount of folate supplementation that we give them during pregnancy. But mesalamine, the whole range of 5-ASAs is actually very, very safe. And if you have a patient with ulcerative colitis who becomes pregnant, they absolutely should stay on their 5-ASA agent.

Steroids in very high doses in rats has been associated with some developmental abnormalities, including cleft palate. But this really has not been borne out in, in the human population. I don't hesitate at all if I have a patient who's flaring to have them on steroids. Again, the goal is to have them on the lowest dose needed to control their symptoms and control their flare. But, as I said earlier, if you have a healthy mother, the outcome is much better for the baby.

There are certain antibiotics that can be used during pregnancy. And there is limited, very limited, data available on some of our newer therapies, including infliximab; we just don't have a lot of data on pregnancies on infliximab. I wouldn't start a person on that, but if they had received a dose and didn't know they were pregnant, I would certainly not recommend that they do something to terminate the pregnancy.

Cyclosporine, there's a little bit of data on. And if you have a patient with very fulminant colitis when the option is surgical therapy, there may be a higher fetal loss rate with surgical therapy; one may consider cyclosporine.

But the two safest agents during pregnancy are the class of drugs of the 5-ASAs and steroids.

Holly Atkinson MD: Athos, what's absolutely contraindicated?

Athos Bousvaros MD: Absolutely contraindicated, I would say thalidomide is number one. Fortunately, this drug is not used very often in inflammatory bowel disease, though there are some reports in severely refractory Crohn's. But a mother who were to conceive on thalidomide runs a risk of having a baby born with no arms and no legs. So that's a severe teratogen that should not be used under any circumstances.

I think methotrexate would be another drug that should be probably terminated if possible, though I would defer to Kim on that one.

Kim Isaacs MD, PhD: If we have concerns about a young woman, in terms of their contraception, we will try to avoid using methotrexate. We consider that an absolute contraindication.

Athos Bousvaros MD: Metronidazole, ciprofloxacin are two antibiotics that have potentially birth defect-causing effects and, again, are generally not recommended. Cipro is a drug that we've been using for years now in IBD. But in kids, it was used very carefully in the beginning, because it can affect developing cartilage.

Holly Atkinson MD: What about washout periods on these drugs? If you have been using them and a woman wants to plan a pregnancy. How long do you wait before you say, "It's okay. Go ahead"?

Kim Isaacs MD, PhD: It depends on the drug. For example, we feel that there's beginning to be a reasonable amount of data on azathioprine and 6-MP in terms of its safety in pregnancy. And if a patient really needs to be on it, I will keep a patient on that during pregnancy. But if they did want to wash out, if they had been doing really well, they had other maintenance agents and they felt real strongly about not being on it. Then I would probably use about three months in terms of washout for that particular drug.

For the other agents, like methotrexate and some of the antibiotics, I would probably-with methotrexate, maybe a month. And many of these people have been on contraceptives like birth control pills and they're using that washout period anyway for their birth control pills before trying to conceive and so would be stopping a medication like that. But again, most of the people that are on standard maintenance therapy, like the 5-ASAs, that I certainly wouldn't have any washout period; I would keep them on that drug.

Holly Atkinson MD: Marla, what about breast-feeding? The effect upon the infant, the use of these agents.

Marla Dubinsky MD: I think there's even less information on breast-feeding than there is on pregnancy. If you talk about absolute contraindications, methotrexate and cyclosporine are absolute contraindications. The jury is still out on the use of 6-MP, 6-mercaptopurine or azathioprine. We do know that there are levels of these drugs in breast milk. We do know that they've been measured. If you look at The Physician Desk Reference it is suggested that patients are removed from these drugs.

Infliximab is newish in regards in the pregnancy data to-it's category B-which means that, you know, until proven otherwise, the benefits outweigh the risks. But however, breast-feeding again, there's little information on that, whether or not there's levels of the drug in breast milk.

Ciprofloxacin and metronidazole again are controversial in terms of their use.

Corticosteroids and 5-ASA products are safe and patients are recommended to continue. The only caveat to the sulfasalazine, which Kim already mentioned in terms of folate and needing folate supplementation, in newborns, patients are at risk with the sulfa component of actually getting increased jaundice, because it displaces the bilirubin. So in terms of whether or not they could be using another 5-ASA other than sulfasalazine, it may be recommended for breast-feeding mothers.

Holly Atkinson MD: Kim, what do you see as the effect of pregnancy on IBD?

Kim Isaacs MD, PhD: You need to know whether the person is coming into the pregnancy with active or inactive disease. If we look at patients, for example, with Crohn's disease who go into their pregnancy with active disease, about a third of patients will actually get better during the pregnancy, about a third of the patients will stay the same level activity and about a third of the patients will actually get worse during pregnancy. If you go in to a pregnancy with inactive disease, about two-thirds of the people will stay inactive.

Holly Atkinson MD: If you're going to see a flare, do you see it at a particular time during pregnancy?

Kim Isaacs MD, PhD: There's not a lot of data, but there is some thought that during the first and the third trimesters you're more likely to flare. And I've actually seen some of these patients who've done much better during pregnancy than in the postpartum period, where there are huge hormonal shifts; that's when they have their flare. So I think the bottom line is you can flare any time. The second trimester is a little bit less likely than the first and the third.

Holly Atkinson MD: Let's talk about the elderly. Kim, drugs you would use in the elderly?

Kim Isaacs MD, PhD: We use the same drugs, for the most part, in the elderly that we do in a younger population, with a couple of things that we need to think about a little bit differently. Elderly patients may likely have more comorbid disease. They may have more heart disease, they may have more hypertension, they may have cataracts. And so they may be on medications for these, such as diuretics for hypertension. They may be on warfarin for blood-thinning effects related to vascular disease. So what we need to take into consideration is how the medicines that we're using for inflammatory bowel disease are going to impact on their other medications.

We need to worry, many elderly women especially have fairly significant osteopenia or osteoporosis. And steroids are going to make those situations worse. I feel very badly seeing an 80-year-old who already has fairly significant osteoporosis, and then putting that person on steroids. As a turnaround on that, because we're talking about advanced age in some of these patients, I feel a little bit more comfortable using some of our immunosuppressant agents. In that some of these drugs, we worry about their long-term effects and if I'm dealing with an 80-year-old and placing them on something like 6-mercaptopurine, I'm not worried about having them on that drug for 40 years. So I think that we need to worry mainly about drug interactions and comorbid disease.

Holly Atkinson MD: What about cancer risk?

Kim Isaacs MD, PhD: We certainly need to be concerned about it. It depends on when the patient developed their inflammatory bowel disease. And if they developed their inflammatory bowel disease in their 40s, and they're now 80, and they've had ulcerative colitis for forty years, we have to worry significantly about their colon cancer risk. And make sure that they're embarked upon a screening program for assessing that. It's not clear when to stop doing the screening.

And in addition, the other thing that we need to worry about is that if some of these drugs are associated with increasing cancer risk. Or not necessarily the risk, but once a cancer cell is there, and say the person has a lung nodule. Then by starting the immunosuppressant, are we then allowing that cancer to grow and get out of control? I think we do need to be concerned about that in the elderly population. It's a balancing act as it is with younger children and younger adults, is risk and benefit and the risks and benefit are going to be a little bit different in the older individual than in, in the child.

Holly Atkinson MD: Just some final thoughts, Kim, about treating pregnant women. Take-home point?

Kim Isaacs MD, PhD: Take-home point in treating pregnant women is to: If a patient is in remission, keep them on their medications to maintain that remission. And if a flare should occur during pregnancy, to treat that flare aggressively and early to get the patient back into remission with a goal of being in remission. Because if you can maintain remission or get a patient into remission, the pregnancy outcome is going to fare much better, and that's really the bottom line.

Holly Atkinson MD: Athos? Children?

Athos Bousvaros MD: Children, to get them to grow do three things. One is control their disease activity. The second is minimize corticosteroid use and the third is maximize nutrition. And then make sure you support them psychologically if necessary.

Holly Atkinson MD: Marla? Final word? Take-home point?

Marla Dubinsky MD: Take-home point is just to recognize that IBD can affect anyone from the young to the old. And recognize that the therapeutic approach seems similar, but for us to be educated and aware of the little idiosyncrasies or the things we need to be careful about in both the young and the elderly.

Holly Atkinson MD: Wonderful. Thank you all for joining me. Just a marvelous conversation. And thank you for joining me. I'm Dr. Holly Atkinson.

Moderated panel discussion: treatment of special populations

Kim Isaacs MD, PhD