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Benefits of Proactive Therapeutic Drug Monitoring in IBD

Lady Organic

Staff member
''Debating the Case for Proactive Therapeutic Drug Monitoring in IBD.
May improve outcomes, but without evidence-based recommendations, not ready for prime time.''


Inflammatory bowel disease (IBD) is characterized as chronic inflammation, typically within the gastrointestinal tract, and encompasses Crohn’s disease (CD) and ulcerative colitis (UC). The etiology of the disease is multifactorial and involves the interplay of genetics, immune dysregulation, microbial disarray, and environmental factors. Predicting the efficacy of a particular treatment regimen has not necessarily been elucidated, but the use of therapeutic drug monitoring (TDM) provides clinicians an opportunity to optimize therapy specifically to a patient in order to maximize efficacy.

As mentioned in the article below, many of the pivotal drug trials for biologics have demonstrated a positive correlation with high drug titers with favorable clinical outcomes from clinical to endoscopic remission. The next step from the trials is newer data supporting the role for proactive TDM to help individualize therapy but also increase the efficacy and durability of biologic therapy. Dr. Corey Siegel is one of the thought leaders in TDM, and through the BRIDGE group, has provided access to clinicians with respect to TDM. The algorithm provides expert recommendations based on TDM lab findings in order to individualize therapy to a particular patient.

Resistance is natural for new thoughts/ideas, especially with respect to TDM. One of the largest barriers to TDM was the high cost of assays in conjunction with limited data on the cost-effectiveness of TDM. However, multiple lab options have slowly driven down the price of testing, and more insurance companies are embracing the role of TDM due to the potential for cost savings associated with biologic therapy. Lack of data to mostly retrospective studies limited a formal recommendation from the AGA for proactive monitoring, but as noted, "reactive monitoring is usually too late."

One of the biggest pitfalls to TDM is the lack of clinically relevant thresholds levels for biologics. Due to the varying number of assays available, therapeutic cutoffs have not adequately been prospectively delineated, and is predominantly left up to expert opinion. Routine use of proactive TDM is difficult to achieve with no set standards/goals.

Proactive versus reactive TDM continues to remain a hot topic in IBD. Individualizing therapy to a particular patient is the hallmark of TDM and could potentially play a major role in the efficacy and durability of biologic therapy. Prospective studies are sorely needed to justify the use of proactive TDM in routine clinical practice, for now.

For patients with inflammatory bowel disease (IBD), proactive rather than reactive monitoring of serum biologic titers may increase the chance of a long-term response to anti-tumor necrosis factor (anti-TNF) and other agents. Solid data are lacking, however, on the true efficacy.

Currently approximately 10-30% of patients show no initial clinical benefit from anti-TNF drugs, and more than 50% with a primary favorable response will cease to show benefit by 1 year.

Recent research has reported an exposure-response relationship, with a positive correlation between high serum anti-TNF concentrations and good therapeutic outcomes -- including clinical, biomarker, and endoscopic remission. In contrast, immunogenicity-triggered antidrug antibodies have been associated with secondary lost response.

Now, however, mounting observational data are turning the tide in favor of early proactive therapeutic drug concentration monitoring (TDM) rather than taking a reactive approach after response has failed. Proponents believe a proactive treat-to-target therapeutic approach will help optimize biologic efficacy, durability, safety, and cost.

"There used to be a lot of resistance to proactive monitoring because of the high costs of the lab tests and because the data were not robust enough to allow an understanding of how to respond to test results," Corey A. Siegel, MD, of the Dartmouth Geisel School of Medicine in Hanover, NH, told MedPage Today. "But in the past few years, we've acquired multiple lab options and more data to support moving toward and understanding how to use monitoring to optimize therapy." In some patients, proactive monitoring can lead to cost savings through early de-escalation of biologic dosage, and more insurance carriers are covering proactive testing tests, he added.

Siegel is part of an expert panel called the Bridge Group, which has set up an online algorithm to guide response to results. "You put in the results from TDM lab findings and the clinical scenario and you get expert recommendations on how to alter the dose or change treatment," he explained. So far, the site has users in 130 countries, and it will soon be updated to include recommendations on all biologics, not just anti-TNF agents.

Gastroenterologists have already tentatively embraced the idea of reactive drug monitoring. Last year, a new American Gastroenterological Association clinical guideline gave a conditional recommendation, based on poor-quality evidence, to reactive therapeutic drug monitoring of anti-TNF agents or thiopurines to guide treatment adjustment in active IBD. Lack of data precluded any AGA recommendation on proactive monitoring.

"But," said Siegel, "reactive monitoring is oftentimes too late. We know that if we can get patients at the right dose and keep them there, then we can optimize care before the patient gets into trouble and before we measure the reason for why they failed treatment. Proactive TDM provides an opportunity to prevent rather than just explain failure."

To date, the studies on proactive monitoring have been retrospective, and well-controlled prospective trials are sorely needed.

In a 2018 retrospective study of 22 Crohn's disease patients with antibodies, for example, Konstantinos Papamichael and associates reported that overcoming immunogenicity by optimizing infliximab (Remicade) therapy fostered longer drug retention, preventing discontinuation in three out of four patients. There also were fewer disease recurrences and fewer infusion reactions, suggesting that maintaining a target infliximab concentration blocks the formation of drug antibodies and subsequent response loss and adverse reactions.

And in a larger 2017 analysis, Papamichael and colleagues compared long-term outcomes with proactive versus reactive monitoring of serum concentrations of infliximab. The multicenter retrospective study followed 264 consecutive IBD patients (167 with Crohn's disease) on maintenance therapy.

The participants had either proactive (n=130) or reactive (n=134) monitoring, based on measurements of initial infliximab concentration and infliximab antibodies, and were followed during 2006-2015 for a median of 2.4 years.

Compared with reactive monitoring, the proactive approach was independently associated with a reduced risk of treatment failure (hazard ratio [HR] 0.16, 95% confidence interval [CI] 0.09-0.27, P <0.001). The proactive approach also correlated with the following reduced risks:

IBD-related surgery (HR 0.30, 95% CI 0.11-0.80, P=0.017)
IBD-related hospitalization (HR 0.16, 95% CI 0.07-0.33, P<0.001)
Antibodies to infliximab (HR 0.25, 95% CI 0.07-0.84, P=0.025)
Serious infusion reaction (HR 0.17 95% CI 0.04-0.78, P=0.023).

Drug titer monitoring has been used for years to keep serum concentrations of antibiotics such as vancomycin and gentamicin in the therapeutic window, and it is common in measuring cyclosporine concentrations in transplant patients. In current IBD practice, however, most TDM occurs reactively after treatment failure for response loss, drug intolerance, or infusion reaction.

But routinely implementing proactive TDM in real-life IBD practice is hampered by the absence of established clinically relevant concentration thresholds. "We don't have the full robust data that we need to prove that proactive monitoring is right for all patients, but we have a lot of good observational data and good common sense that the right drug at the right dose does make people better," Siegel conceded.

"But my philosophy is that any time we've made the commitment to use a biologic, a drug that comes with potential side effects and significant costs to the healthcare system, we should make sure we're using the drug at the right dose. We have an obligation to the patients and to the healthcare system."

Many gastroenterologists, however, believe it is too soon to go the proactive monitoring route, saying it should be reserved for certain patients: "Although not recommended for routine care of all patients, proactive testing may also be appropriate in some cases (such as patients with aggressive disease phenotypes), and should be considered on an individual basis," wrote Heidi Su and colleagues in a commentary on the 2017 AGA guideline.

One skeptic is Hans Herfarth, MD, PhD, of the Center for Gastrointestinal Biology and Disease at the University of North Carolina at Chapel Hill, where reactive monitoring is commonly used to guide further treatment: "Proactive monitoring is a tempting approach that sounds logical, but it is not evidence-based medicine," he told MedPage Today, adding that well-controlled European studies such as TAXIT and the recent TAILORIX trial have not shown any advantage to drug concentration-based versus clinically based dosing of infliximab in achieving remission.

Obviously, more well-controlled study evidence is needed for both reactive and proactive monitoring, Herfarth said. "Physicians like to be in control, and we are not at the moment, since we don't understand why patients lose response. We hope drug monitoring may provide an answer." He said he hopes the next few years will supply solid evidence of whether monitoring-adjusted treatment works or not. "But now it's emotion-directed medicine. It's an emotional topic."