Role of TNF-alpha Inhibitors in Crohn's Disease

Marla Dubinsky, MD: When we think about overall treatment goals, I think all of us similarly want our patients to have no disability and to have a normal quality of life. That is something we all agree on. The question is, are the treatments that are out there now good enough to actually change the natural history of the disease and also limit disability and improve quality of life? I think when the first anti-TNF therapy, infliximab, was brought to us in 1998 for Crohn’s disease, there was a lot of excitement around the idea that we finally have a drug that targets the biology of Crohn’s disease.

The drugs we were using before were somewhat anti-inflammatory or masked lymphocyte proliferation inhibiting with thiopurines, which was our classic story from 1980 until the TNF boom in 1998. And at first, the way that this drug came to market was, did it actually make a patient feel better? There was no discussion of, does it actually heal the lining? There was a picture on the front of our Journal of Gastroenterology that showed a before and after shot. We’re not used to seeing before and after shots on a medical journal, but it was that dramatic to say you took someone with deep ulcerations and normalized their mucosa. That, to me, finally has caught on now, because we’re now saying that our therapies need to achieve mucosal healing. Why? Because it will implicate on a drug’s ability to reduce the endpoint, which we all want, patients and physicians, which is disability and quality of life.

We had our first entity, infliximab, and then in 2007 we had adalimumab approved for Crohn’s disease. And then in 2008, we had certolizumab approved for Crohn’s disease. So, there are 3 agents being used specifically for Crohn’s disease and approved for Crohn’s disease. There are others also approved for ulcerative colitis. But if we focus purely on Crohn’s disease, we know that we’ve had almost 20 years of experience with infliximab, we have a decade of experience with adalimumab, and we have almost a decade with certolizumab. We know for a fact that if used early enough, meaning not when bowel wall damage has already occurred, circling back to the discussions we’ve had so far, not waiting for a complication, these drugs work so well at getting the outcome of mucosal healing. We know that our goal is to induce remission and then maintain remission. And so, we figured out that we can’t induce or maintain remission in someone who already has bowel wall damage that has passed the point of no return.

One of the most important things that goes along with TNF use is that you need to use it early. We’ve seen that in cohort studies, some people would say TNF hasn’t changed the natural history. That’s because the average time to first see a TNF was around 5, 7 years into disease—too late. The action is upfront.

The question on how to best use anti-TNF therapy, with a particular emphasis on monotherapy versus combination therapy, gives you this historical pendulum of IBD (inflammatory bowel disease) and us switching our minds and our guidance. I think the people who listen to us at meetings or in scenarios like this can’t keep up with how much we swing from monotherapy to combination, back from combination to monotherapy.

If we start from the beginning when these drugs were first approved, they were approved on the background of failing conventional therapy, which meant thiopurines. That’s what we’ll talk mainly about when it comes to combination. Methotrexate is another option, but that came into our story a little bit later. We followed the rheumatoid doctors a little bit later, when we started having issues with combination therapy of an anti-TNF with thiopurine, such as 6-MP (mercaptopurine) or azathioprine.

In 2006, there were the first cases of something called hepatosplenic T-cell lymphoma, which was essentially universally fatal and typically in adolescent males. There were the first 6 cases in 2006. Oddly enough, it was basically in the same month that infliximab was approved for pediatric patients despite these first 6 cases, because there was no denying that anti-TNF therapy works extremely well in pediatrics as well as adults. If anything, in pediatric patients it may work a little better, because the disease duration is shorter, which speaks to the fact that if you use it earlier you get better outcomes.

The discussions at that time went from “Use it together,” to “Oh, maybe you should use infliximab without thiopurine.” The fear was that people were going to develop antibodies against the TNF, because the thought process was that the immunomodulator was protecting the body from rejecting or developing an antibody to the TNF. Then this fear of combination therapy happened. People thought it mainly affected adolescents or below, so the adult practice didn’t change as much as the pediatric practice maybe. And 2 years after that, there was a publication called the SONIC study that said combination therapy is better than monotherapy. So, people said, “Oh, no, do I now really need to go back to combination therapy? And if I am, I’ll maybe use methotrexate instead of thiopurines, because the RA (rheumatoid arthritis) folks weren’t seeing this type of malignancy.”

And then came the understanding of therapeutic drug monitoring. We understood that maybe it has nothing to do with 2 drugs being better than 1, or that the thiopurine or methotrexate is protecting antibodies. Maybe what it’s doing is giving you enough drug level and increasing the actual drug concentration, which will then decrease the amount of antibodies for the drug.

We figured out just recently, there was now an update on the whole SONIC story, that in the end, it didn’t matter whether you were on combination therapy or not. You just needed a good drug level to protect yourself against antibodies. So, I think now we’re understanding that if we do very tight control of the drug monitoring, you can use monotherapy, I’d call that optimized monotherapy, versus combination therapy, but just knowing the risk factors that come along with it.

We just recently published in the Gastroenterology journal the developed registry, which is a large pediatric study. Over 5000 children were followed: 2500 were on infliximab or on a TNF agent, and 2500 were never exposed. We actually showed that the risk of malignancy, which is what we’re really focused on, was not increased in children with infliximab monotherapy, but was increased when using combination therapy or even thiopurines alone. So, in the pediatric age group where there is that higher risk, we’re advising that you use optimized monotherapy or substitute thiopurines and stop using thiopurines in pediatric patients.

Transcript edited for clarity.