Michael Chiorean, MD, on Stopping or De-escalating IBD Therapy

In this podcast Dr Chiorean reviews his presentation at the recent Advances in Inflammatory Bowel Diseases virtual meeting about the risks and reasons for de-escalating or stopping therapy for IBD.

Michael Chiorean, MD, is director of the IBD Center for Excellence at Virginia Mason Medical Center in Seattle, Washington.

TRANSCRIPT

GASTROENTEROLOGY LEARNING NETWORK:  Hello everyone, and thanks for joining us again for another podcast from Gastroenterology Learning Network. I'm your moderator, Rebecca Mashaw.

Today, we have Dr. Michael Chiorean here with us. He's with the Virginia Mason Medical Center in Seattle, Washington where he is a gastroenterologist and specialist in the treatment of inflammatory bowel disease.

He's going to discuss some reasons patients may have for wanting to discontinue or de-escalate their therapy, the risks of these steps, and how he manages these situations in his own practice.

DR CHIOREAN:  Hello, Rebecca.

GASTROENTEROLOGY LEARNING NETWORK:  It's good to have you here with us today, Dr. Chiorean, and I appreciate you taking the time. Today, we're going to be talking about when and if you should discontinue or de-escalate therapy for inflammatory bowel diseases.

The first question is, because both Crohn's and ulcerative colitis are chronic illnesses, when would you ever consider stopping therapy and why?

DR CHIOREAN:  That question actually comes up in our practice more often than you think, and we distinguish between two types of treatment de-escalation or discontinuation: proactive, which is typically elective. This is decided by the patient or the provider in a situation of calm with no clear trigger, or reactive when there is a specified trigger, such as an adverse event, an infection, pregnancy, or unforeseen circumstances, such as loss of insurance and similar situations that represent a hurdle or mandates changes in treatment.

Now, as far as the former is concerned, as you would imagine, it's a major decision which carries the weight, essentially, as big as starting therapy for Crohn's disease and ulcerative colitis, because as you pointed out, these are chronic immune-mediated conditions.

The common sense there is that there is a tendency for them to flare the moment we take the foot off the brake. In essence, we distinguish 4 instances where this is something that is entertained or relatively safe. The more clear situations here are treatment de-escalation, not treatment discontinuation.

Treatment de-escalation for patients who for instance are in deep remission, especially ulcerative colitis, but also sometimes patients with Crohn's disease are in deep remission on a biologic, and they have mesalamine as cotherapy to their prescription regimen.

Post hoc analysis of randomized trials have shown that stopping the mesalamine at that point in patients with ulcerative colitis certainly seems to be safe without the risk of disease exacerbations. Anecdotally, I can tell you from my experience that occasionally, you will have a patient that will experience a mild flare, but those tend to resolve with reinitiating the mesalamine.

The other two situations where treatment de-escalation is relatively safe is combination therapy with an anti-TNF agent and immunomodulator in both Crohn's disease and ulcerative colitis patients who are in deep remissions. When we have clear evidence that the inflammatory bowel disease is under excellent control by endoscopic and biochemical criteria, oftentimes, the immunomodulator can be either dose-reduced or discontinued, and the patients usually will remain in remission on biologic therapy alone.

A third situation also pertains to biologic agents that are or have been used at very high doses for induction, so atypical doses for induction. This also has to do mostly with anti-TNF drugs. From a subgroup of patients in the TAXIT study or TAXIT trial, that's spelled T-A-X-I-T, we learned that, based on pharmacokinetics, there is a subgroup of patients, about a quarter, whose drug level is above the optimal range or what we call the optimal range at least for infliximab. When those investigators reduced the dose of infliximab to relocate these patients within that optimal drug window, they remained in remission. Dose reduction in patients who are in remission is also possible in selected cases, this time using therapeutic drug monitoring of drug levels.

Then, lastly, with the new kids on the block, with JAK inhibitor, tofacitinib in particular, we have evidence that a subgroup of patients can be dose-reduced during maintenance from 10 to 5 milligrams twice daily if they are in deep remission for a certain length of time.

That has been shown both in post hoc analysis of the OCTAVE clinical trial, as well as in a separate clinical trial call called RIVETING, R-I-V-E-T-I-N-G. Those are the four scenarios where treatment de-escalation makes sense.

Going back to the original question, does stopping therapy ever make sense? It's a much more difficult conversation. It's a much more difficult question. You always have to ask yourself why are you doing this when you talk about stopping therapy, and what are the risks.

Again, it bears the same weight as when you start somebody with inflammatory bowel disease on any specific treatment.

GLN:  So what are the risks? If a patient is in real deep remission, they don't have any clinical symptoms, the colonoscopy is normal, their biomarkers are normal, all the indicators are that the disease is fully controlled, what are the risks that the patient will relapse if you take them off of a therapeutic?

DR CHIOREAN:  If you end up discontinuing a treatment altogether, a lot of times, it depends on their disease behavior and the type of treatment they were on to maintain remission.

From the observation standpoint, it appears that the highest risk is discontinuing an advanced therapeutic in patients who are in remission—a biologic drug, especially anti-TNF agents, and there is data now with JAK inhibitors, again from post hoc analysis of randomized trials.

Generally speaking, the more effective the drug is that was used to induce remission, the higher the risk of relapse after that drug is discontinued. Other predictors of risk include the disease severity, the presence of complications, in Crohn's disease, penetrating complications or strictures, the age of the patients. The same risk factors that basically drive us towards more effective therapies are the risk factors that generally predict relapse after treatment discontinuations—a young age of diagnosis, previous complications, previous surgeries, previous failure of other therapeutics, whether within the same class or other classes of therapeutic agents, are risk factors for relapse after treatment discontinuation.

GLN:  If you have a patient who has decided for whatever reason, that they're going to stop their treatment—perhaps it is a financial issue, as you mentioned, sometimes, loss of insurance may be one of the issues and they do relapse—and then they decide that, "OK, now I've got a new job. I've got insurance again. I would like to start therapy again." Can treatment be restarted with the same agents? What are the risks or challenges? How would you approach that situation?

DR CHIOREAN:  This is an excellent point, and it depends on how you laid the path when you stop the drug. Essentially, treatment discontinuation, or the preparations for treatment discontinuation, start before you stop the medication. When you verify that the patient is in remission using, as you pointed out, not just clinical symptoms, but also biomarkers in endoscopy, and it continues with the plan. The de-escalation plan oftentimes involves not just stopping therapy, but sometimes stepping down.

I'll give you an example. If a patient is in remission on biologic therapy, whether it's an anti-TNF drug, anti-integrin, or interleukin, rather than stopping cold and going to nothing, we oftentimes prefer to step down to an immunomodulator.

We consider that as intermediate therapy, these drugs being less expensive. They can be continued even in situations of financial strength. A thiopurine or methotrexate would be the way to go depending on the disease state, depending on the condition. Then, resuming therapy after a longer or shorter drug holiday becomes a relatively easier feat.

Data has shown that in these situations, the recapture rate, meaning regaining response or even remission, is fairly high short term, but long term, it appears that a substantial number of these patients will lose response eventually after this therapeutic exercise.

We don't know yet what happens with small molecules such as JAK inhibitors or tofacitinib, but this clearly has some advantages in that it lacks the risk of immunogenicity. Therefore, in theory, aside from the risks incurred by the disease flare itself, the risk of stopping and restarting tofacitinib for elective or nonelective reasons seems to be lower compared to biologic drugs.

Having said that, again, from subanalysis of larger clinical trials, we realize that not every patient that does this can be recaptured. There's always a risk of long-term loss of response to a drug that initially worked, and it worked very well.

GLN:  In those cases, say it's an anti-TNF, do you try to change that patient to a therapeutic agent out of that class to see if you can recapture response?

DR CHIOREAN:  Yes. If the first drug that was effective doesn't work or doesn't work any longer, we switch to a different drug within the same class if available. Of course, that applies primarily to anti-TNF agents. We don't yet have competitors to the other 2 classes of biologics or to JAK inhibitors.

The future will be different, but for now, if a patient has lost response to an anti-TNF drug after a drug holiday, we generally tend to return to the same class or to anti-TNF drugs. For anti-TNF agents, you certainly can consider either biologic drugs or a JAK inhibitor.

GLN:  Are those safe to use episodically?

DR CHIOREAN:  Nothing is safe to use episodically because the risk of the disease is what comes into play. The major risk of episodic therapy is letting the disease run out of control resulting in a flare which may be difficult to control or nearly impossible to control.

Time and again, we have seen this in the past with the biologic agents, and I don't expect things to be different with JAK inhibitors. There is a risk of treatment discontinuation regardless.

But having said that, yes, theoretically, and likely practically, JAK inhibitors have a lower risk of secondary loss of response owing to the fact that they are not immunogenic. There's no antibody development, and thus, you prevent a very important mechanism for loss of response to therapeutic drugs.

GLN:  If a patient came to you and said, "I'm tired of getting these infusions or being on this treatment regimen," and really wanted to stop, what do you say to that patient?

DR CHIOREANYou're trying to get to the reason why the patient is truly interested in stopping a medication that's working. By that, as you mentioned, it's convenience. Now, again, the trade-off there is effectiveness. So if we do these "healthy switches," which means switching a patient from a treatment within the class of a medication that works — examples here would be an anti-TNF drug or switching from an infusional drug to a subcutaneous drug —carries some risk. Because we really don't know if all the drugs in that class or outside of that class will be equally effective for that patient. We don't have enough comparative trials, or certainly don't have switching studies, except for between originators and biosimilars, which is a no-brainer. But it doesn't provide the advantage that you mentioned earlier, switching from an infusion to a subcutaneous drug or a pill.

We're inferring from meta-analysis and other types of indirect studies comparing therapeutics that Therapeutic B will be as effective as Therapeutic A, whereas we don't have a very accurate way of predicting how Drug B will behave compared to Drug A at controlling this patient's condition.

So as much as we can, with the exception of very special circumstances—a particular job, particular profession, you have for instance, flight attendants or pilots who are traveling all over the world, and for whom infusions may truly be a hindrance or a problem for their job, in that situation, we sometimes consider these healthy transition switches from one drug to the other for convenience—but generally speaking, we try to talk our patients out of this because we don't know how well the next drug is going to do compared to the current drug.

GLN:  Adverse events, of course, would also be a factor.

DR CHIOREAN:  Correct. That would be the reactive discontinuation, but in that case, it's a transition. It's a transition that outside of class because of class-dependent side effects, or sometimes even drug-specific drug effects within the same class.

Yes, that is more of an event-driven therapeutic change. But the same risk applies as with elective therapeutic exchanges where you don't know if the next drug, which hopefully will avoid the side effect that the patient experiences with the first drug, will have the same efficacy as the initial drug.

However, there you have more in the balance to help you make a decision, and a shared decision, hopefully, about changing therapies.

GLN:  Thank you very much.

DR CHIOREAN:  Thank you very much, Rebecca, for having me.