Adam Cheifetz, MD, and Konstantinos Papamichail, MD, on Therapeutic Drug Monitoring in Fistulizing Crohn Disease

In this podcast, Adam Cheifetz, MD, and Konstantinos Papamichail, M.D., Ph.D., discuss the use of reactive and proactive therapeutic drug monitoring in the treatment of patients with fistulizing perianal Crohn disease.

Adam Cheifetz, MD, is director of the Center for Inflammatory Bowel Disease at Beth Israel Deaconess Medical Center in Boston, Massachusetts and associate professor at Harvard Medical School. Konstantinos Papamichail, M.D., Ph.D., is an instructor in medicine at Harvard Medical School and gastroenterologist at Beth Israel Deaconess Medical Center.

TRANSCRIPT

Gastroenterology Learning Network:  Hello, and welcome to another podcast from the Gastroenterology Learning Network. I'm your moderator, Rebecca Mashaw.

We're happy today to have with us Dr Adam Cheifetz and Dr. Konstantinos Papamichail from Beth Israel Deaconess Medical Center and Harvard University in Boston. They're going to be talking about therapeutic drug monitoring in the management of Crohn's disease.

Dr. Adam Cheifetz:  Thank you. I am Adam Cheifetz. I'm a professor of medicine at Harvard Medical School and head up the Inflammatory Bowel Disease Center. It is my pleasure to be here with Kostas Papamichael who is undoubtedly one of the world's leading experts on therapeutic drug monitoring.

We're here not just to discuss his recent publication in the Red Journal but also TDM in general. Kostas, welcome.

Dr. Konstantinos Papamichail:  Thank you very much for the nice words. I'd like to thank you for giving us the opportunity to present the results of our study and discuss the role of therapeutic drug monitoring of biological therapy in patients with perianal fistulizing Crohn's disease and in general IBD patients.

Dr. Cheifetz:  Fantastic. Let's get started. First question, how prevalent is perianal fistulizing disease amongst patients with Crohn's disease—but not just how widespread is the problem, but how can this really impact patients' lives?

Dr. Papamichail:  Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract that is characterized by transmural inflammation that can disrupt the mucosal integrity of the gut and the anal canal. This can lead to complications such as fistulas, abscesses, and infection.

Fistula is a common and severe complication of Crohn's disease that affects up to 50% of patients within 20 years of initial diagnosis. Regarding now how fistulizing Crohn's disease impacts patients' lives, I would like to highlight that fistulizing Crohn's disease is a morbid phenotype of Crohn's disease that often leads to hospitalization and surgeries.

As you can imagine, this has a negative impact on the patient's quality of life. The treatment of perianal fistulizing Crohn's disease is challenging as first, the limited treated options, and second, this condition is refractory to medical therapy. In fact, only one-third of patients achieve long-term durable remission, while one-third experience direct recurrent fistulas despite medical therapy.

Therefore, most patients undergo multiple surgical operations, leaving them with a chronic seton or at risk of incontinence, while up to 40% still require a stoma.

Dr. Cheifetz:  Excellent, very nice presentation about perianal fistulizing Crohn's disease. Now, let's talk about therapeutic drug monitoring or TDM. I would like you to go into the differences between reactive and proactive TDM. As an international expert and advocate of proactive TDM, what do you see as the biggest benefits of this type of monitoring for patients with inflammatory bowel disease?

Dr. Papamichail:  I would like to start first with a definition of therapeutic drug monitoring or TDM, which is the measurement of drug concentration and not the drug antibodies. This therapeutic drug monitoring has emerged as an important tool for optimizing biological therapy.

There are 2 different strategies for the use of TDM in IBD. The first is reactive TDM, in which certain drug concentrations and antidrug antibodies are assessed in the clinical context of lack or loss of response of a specific therapy.

The second is proactive TDM in which the quantification of drug concentrations and antidrug antibodies is performed in patients with quiescent disease. Those are the patients with target drug concentration.

Regarding reactive TDM, this is currently the new standard of care for optimizing biological therapy in IBD as it helps to better explain and manage treatment failure, and has been proven also more cost-effective than empiric drug optimization.

However, for some patients, reactive TDM is too late to receive any kind of treatment optimization as they have already developed irreversible severe intestinal inflammation and/or high titers of antidrug antibodies that cannot be overcome.

Regarding the role of proactive TDM in clinical practice, there is still a debate mainly due to the lack of high-quality data from well-designed prospective studies and randomized control trials. However, preliminary results have shown that proactive TDM compared to empiric dose optimization and to reactive TDM is associated with better therapeutic outcomes in IBD patients.

These include greater drug persistence, less need for IBD-related surgery or hospitalization, lower risk of antidrug antibodies, and a higher rate of corticosteroid-free clinical remission. Proactive TDM may also be used to decrease the dose of infliximab in patients in remission with greater than adequate drug concentration or after a drug holiday to assess for the antibodies to infliximab.

Dr. Cheifetz:  Excellent. Thank you. As you know, I agree. I do believe in the benefits of proactive TDM because, as you said, reactive TDM in a certain percentage of patients is already too late when they've developed antibodies.

Why wait till someone flares before optimize them? We certainly don't do that with some of our other agents. Why investigate the utility of TDM specifically for fistulizing Crohn's disease?

Dr. Papamichail:  It is very important to investigate the utility of TDM, and especially of proactive TDM in patients with fistulizing Crohn's disease, for 2 main reasons. The first is that these patients have a high inflammatory burden that can lead to an increased drug clearance and therefore have a greater risk of inadequate drug exposure, immunogenicity, and treatment failure.

The second one is that we don't have many drugs to treat these patients, so the current course of treatment is anti-TNF therapy, and specifically infliximab, for which we have the only data coming from randomized controlled trials. The ACCENT-2 trial demonstrated superior healing rates for infliximab treatment when compared to placebo in patients with fistulizing Crohn's disease.

Regarding other medical treatment options, there are some data from a subgroup analysis of randomized controlled trials and cohort studies for adalimumab, while data for certolizumab pegol and for those non-anti-TNFs like vedolizumab and ustekinumab are scarce.

Just to go back to the utility of TDM specifically for fistulizing Crohn's disease, it is possible that by utilizing an early proactive TDM-based approach for optimizing anti-TNF therapy, we can achieve improved fistula healing rates.

To support this hypothesis, preliminary data show that higher drug concentration during both induction and maintenance therapy are associated with higher rates of fistula closure.

Dr. Cheifetz:  Excellent, excellent. Now, would you give us an overview of your post hoc analysis of ACCENT 2 in regards to infliximab concentration amongst patients with fistulizing Crohn's disease? What did you analyze, and what were the important findings?

Dr. Papamichail:  ACCENT 2 was a multicenter randomized placebo-controlled trial including adult patients with active fistulizing Crohn's disease, most of whom had perianal disease. We investigated the association between infliximab serum concentration and favorable therapeutic outcomes assessed both early at week 14 and at long-term at week 54.

The most important findings of our study was that higher post-induction infliximab concentrations are independently associated with fairly and long-term composite remission. This is a stringent outcome defined as a combined complete fistula response and CRP normalization.

Based on ROC analysis, infliximab concentration thresholds of equal or greater than 20.2 at week 2, 15 at week 6, and 7.2 microgram per ml at week 14 were associated with week 14 composite remission. Moreover, based on quartile analysis, our study also demonstrated that to achieve composite remission, some patients may require even higher early drug concentrations.

In fact, infliximab concentrations of equal or greater than 26.1 microgram per ml at week 6 were associated with the highest rates of early composite remission. Infliximab concentrations of equal or greater than 11.3 microgram per ml at week 14 were associated with the highest rate of long-term composite remission.

Dr. Cheifetz:  Similar to your work and others’ work, suggesting that higher drug concentrations correlate with better outcomes and more important objective outcomes. What about limitations of the study?

Dr. Papamichail:  The main limitations of the study were the lack of an objective evaluation of fistulas using, for example, magnetic resonance imaging and the fact that only an association rather than causality between higher serum infliximab concentrations and improved therapeutic outcomes could be established mainly due to the study design, which was a post hoc analysis.

Another limitation was the fact that only a small subset of patient receiving maintenance therapy were followed until week 54, making it difficult to draw firm conclusions regarding the identification of clinically relevant maintenance infliximab concentration associated with favorable long-term therapeutic outcomes.

Dr. Cheifetz:  How can you translate the findings you mentioned previously into clinical care of patients with perianal Crohn's disease?

Dr. Papamichail:  I would like to remind you that the most important findings of our study was that higher serum infliximab concentrations during and early after induction therapy are associated with combined biological and clinical remission in patients with fistulizing Crohn's disease.

This is very important as deep remission has been related to a lower rate of surgery and hospitalization in these patients. Prompt TDM during or early after the induction therapy is probably very important to better optimize infliximab therapy in these patients.

Based on the results of our study, and infliximab concentration less than 15 micrograms per ml at week 6 and less than 7 micrograms per ml at week 14 should be considered as subtherapeutic and trigger drug optimization by increasing the dose and/or shortening the treatment interval.

However, we have to notice that regarding these cutoffs, we need to have in mind that drug concentrations thresholds to target can differ depending on treatment goals and assay use.

Dr. Cheifetz:  Excellent. Based on the conclusion that higher post-induction infliximab concentrations are associated with not just early but also long-term, favorable outcomes amongst patients with fistulizing Crohn's, would you recommend gastroenterologists apply this understanding to their practice? What's the best way to ensure that higher drug concentrations are achieved in these patients? How often should patients be monitored or consider to monitor these patients?

Dr. Papamichail:  This is a good question. In conjunction with a previous question, I would recommend gastroenterologist to start doing TDM in patients with perianal fistulizing Crohn's disease during or early after induction therapy, let's say at week 6.

If this is not feasible for any reason at week 14, then optimize therapy according to the infliximab cutoff that we have previously discussed. Regarding maintenance therapies, there are no any data for how often patients should be monitored, but once or twice per year seems reasonable.

Regarding the drug concentration to target during maintenance therapy based on previous studies, I would suggest an infliximab concentration of at least 10 micrograms per ml.

However, targeting either higher concentration, for example 15 or 20, should also be considered before changing to other therapeutic options especially as higher infliximab concentrations cannot be associated with more serious adverse events in IBD.

This is very important as, besides infliximab, there are limited drugs to treat perianal fistulizing Crohn's disease, and physicians should not give up infliximab for a presumed mechanistic failure before optimum treatment or optimization.

Dr. Cheifetz:  As you know, I am a believer particularly optimizing infliximab for this difficult group of patients and really not giving up on the drug before you attain drug concentrations of at least 10 and often in 15 if necessary. Importantly, what research would you like to see done next to further investigate the impact of TDM on fistulizing disease?

Dr. Papamichail:  I would like to see prospective studies that will use proactive TDM starting from the induction phase and send a reading off of objective radiological evaluation of fistulas. The proactive randomized controlled trial will shed some light on this comparing proactive TDM with standard infliximab therapy in other patients with perianal fistulizing Crohn's disease.

Moreover, I think that we should investigate the role of TDM in other anti-TNF biologics in patients with multiple versus single fistulas and in patients with complex versus simple fistulas.

Other areas of TDM that still need to be defined not only for patients with perianal fistulizing Crohn's disease but also for all IBD patients are the role of drug concentration measured in tissue and, in our case, in fistulas as opposed in serum and the role of peak or intermediate serum concentrations as opposed to those measured at trial.

Finally, I would like to see studies investigating the potential use of pharmacogenetics, point-of-care assays, and pharmacokinetic dashboards towards a more personalized therapeutic drug monitoring.

Dr. Cheifetz:  Any final thoughts for the audience out there that you'd like to share?

Dr. Papamichail:  I would like to highlight the importance of early TDM of infliximab in patients with fistulizing Crohn's disease as this can indicate in individual patients whether therapeutic drug exposure is achieved or not and guide subsequent rational treatment decision to achieve rapid fistula closure.

In addition to our study, several other studies have shown that higher infliximab concentrations at week 6 and 14 are associated with high rates of positive clinical outcomes in patients with perianal fistulizing Crohn's disease, so checking drug concentration at this time point seems very reasonable

Dr. Cheifetz:  Kostas, for everybody out there, I'd like to thank you for all the knowledge that you have imparted. Thank you.

Dr. Papamichail:  Thank you very much.