IBD Treatment Landscape

[00:30]

Hello, I’m Dr. Andres Yarur, and welcome to IBDIQ, part of The IBD Project by Takeda, where we’re coming together to help enhance expertise in IBD care—right from the start. 

Today, I will be discussing assessment of prognosis, how to determine targets of therapy, and therapeutic drug monitoring (or TDM) in patients with inflammatory bowel disease (or IBD).

In this chapter, we will first analyze personalized medicine approaches in IBD treatment, including assessment of clinical variables, biomarkers, and genetics. Then we will review monitoring techniques, including treat-to-target approach. Finally, we will learn about potential salvage strategies including TDM.

[01:16]

When it comes to IBD management, an important first step to personalizing care is determining prognosis, or disease outcome.¹ This helps to predict disease course and disease complications and establish a therapeutic approach.^2,3 

Let’s begin with establishing prognosis in Crohn’s disease (or CD). Crohn’s can affect the entire gastrointestinal, or GI, tract.² With repeated flare-ups, patients experience bowel damage that complicates the disease course and can result in short- and long-term disability.

Some clinical factors that are prognostic predictors of complicated and/or disabling Crohn’s include young age at diagnosis, involvement of the upper GI tract, smoking, and stricturing or fistulizing disease.^2,4,5

[02:06]

In my experience, clinical factors are easy to assess and incorporate in practice.

There has also been great interest in the potential use of serology with assessing circulating antibodies as prognostic markers.¹ We will be discussing that in more detail later.

Genetics may also have a role in determining prognosis. Genome-wide association studies have suggested that there are distinct genes implicated both in disease susceptibility and worse disease courses in Crohn’s and ulcerative colitis (or UC).¹

For establishing prognosis in UC, we can assess clinical factors as well. In UC, patients can progress to extensive forms of disease, including extensive colitis and pancolitis.²

[02:53]

Extensive colitis, one of the clinical factors we can assess, is important to consider because it may be associated with higher hospitalization rates, greater risk of colectomy, and increased risk of progression to dysplasia and colorectal cancer. ² By identifying those patients who have risk factors for complications, we can initiate closer monitoring and if needed, more intensive treatment.

Besides extensive colitis, other clinical prognostic predictors in UC include young age at diagnosis, comorbid primary sclerosing cholangitis, family history, and male sex.²

As I mentioned earlier, besides clinical factors, we can use serologic and genetic testing to help determine prognosis.¹ Blood-based biomarkers are useful because they are non-invasive and can be readily obtained.⁶

[03:47]

Antibodies we can assess include anti-Saccharomyces cerevisiae antibodies (or ASCA), perinuclear antineutrophil cytoplasmic antibodies (or pANCA), antibody to CBir1 flagellin (or anti-CBir1), and antibody to Escherichia coli outer membrane porin C (or anti-OmpC).¹ We will review each one of these and how they can help with prognosis.

ASCA have a high diagnostic value in distinguishing Crohn’s from UC.⁷ Patients with Crohn’s who are positive for ASCA are more likely to have fibrostenosis or a penetrating phenotype.^7-9 As a result, patients who are ASCA positive are more likely to undergo Crohn’s-related surgery due to the increased risk of ileal involvement.⁷

[04:36]

Serum pANCA have been widely studied and are generally accepted to be specific to UC.⁶ We can use this to our advantage to differentiate UC from Crohn’s. Crohn’s patients with UC-like features can have increased pANCA as well.

The antibodies anti-CBir1 and anti-OmpC are known to be more specific for Crohn’s.^6,10 They are associated with early postoperative recurrence or a more aggressive phenotype such as stricturing or penetrating Crohn’s.^6,11

It is important to note that many of these antibodies are associated with preclinical disease and could represent patients with longstanding untreated disease, rather than being truly predictive of prognosis.¹ It is also worth noting that though these markers can be helpful, some of them such as ASCA or pANCA may not be routinely checked in practice.^12,13

[05:34]

As for genetic testing, patients who have variants of nucleotide binding oligomerization domain 2, or NOD2 have been reported to have an increased risk of fibrostenotic disease behavior and stricturing phenotype in Crohn’s disease.¹⁴ A study of 645 patients with Crohn’s in the United Kingdom identified a relationship between NOD2 variation and stricturing phenotype.¹⁵

Now that we have reviewed how to determine prognosis, we can move on to determining targets of therapy.

Focusing on the resolution of symptoms alone may not be an acceptable target because there tends to be a poor correlation between symptoms and active mucosal inflammation in IBD.¹⁶ Thus, treatment strategies have shifted from symptom resolution to more objective therapeutic targets, incorporating treat-to-target.

[06:29]

The International Organization for the Study of IBD (or IOIBD) released the Selecting Therapeutic Targets in Inflammatory Bowel Disease (or STRIDE)-II guidelines. They were published in 2021 and outline short-, intermediate- and long-term treatment targets in Crohn’s and UC.¹⁷ We will review some of these targets now.

The primary serum biomarker used to monitor inflammation is C-reactive protein (or CRP), while fecal calprotectin is a frequently used stool biomarker.¹⁶ Both of these biomarkers are correlated with endoscopic activity.¹⁷ The STRIDE-II guidelines consider the normalization of CRP and fecal calprotectin in patients with UC and Crohn’s to be an intermediate target.

Let’s also remember that endoscopy and cross-sectional imaging can help us assess other goals like endoscopic healing and transmural healing.¹⁷ Endoscopic healing is considered a long-term target per the STRIDE-II guidelines.

[07:36]

At this point in the presentation, we have reviewed various prognostic indicators and learned about the treat-to-target approach. Let’s continue with therapeutic drug monitoring.

Therapeutic drug monitoring, or TDM, is defined as the measurement of serum drug and/or anti-drug antibody concentrations, with the goal of maintaining a dose that ensures drug efficacy while minimizing drug toxicity.¹⁸

TDM has been used in clinical practice for many years, and for a variety of medications including antibiotics and immunosuppressants.¹⁸ Recently, TDM has been applied to biologic medications with the added nuance of measuring anti-drug antibodies, which could impact drug efficacy.

[08:24]

Due to the impact of anti-drug antibodies, it is important to consider immunogenicity when discussing biologics.¹⁸ The immune system recognizes protein aspects of biologic drugs as foreign and creates antibodies, which form complexes with the drug and make it ineffective. Therefore, anti-drug antibodies can play a role in treatment failure for patients with IBD on biologic therapy.

Despite advancements in IBD management including the introduction of new therapies and incorporating treat-to-target strategies, patients with IBD may still experience treatment failure.¹⁸

While TDM was initially used as a reactive measure if loss of response to a drug was suspected, the continued unmet need of nonresponse to therapy or disease recurrence has led to interest in using TDM proactively during treatment.¹⁸ Proactive TDM involves measuring drug levels regardless of the patient’s response in order to maintain an optimal drug level.¹⁹

[09:28]

Though proactive TDM seems advantageous, there is conflicting evidence whether proactive TDM is more effective than reactive TDM.¹⁹ A few studies have been conducted to analyze the effects of proactive TDM for several different therapies, but none currently provide conclusive evidence for superiority of proactive TDM compared to reactive TDM.

Now that you know a little more about the concept of TDM, let’s talk about how it is applied to IBD treatment. Before advancements in the IBD treatment landscape, TDM was used for thiopurine treatment.¹⁹ TDM then became more prominent with the development of anti-tumor necrosis factor, or anti-TNF agents. TDM has less of an established role in biologics other than anti-TNF, as the literature available mainly supports the use of TDM for anti-TNFs.^18-20

[10:26]

One important variable is the lower rates of immunogenicity seen with these newer classes of biologics, like anti-integrins and anti-interleukins, compared to anti-TNFs.¹⁹ There is a need for well-designed studies investigating a TDM-based approach to using these newer biologics.¹⁸

How can we personalize treatment for our patients today with the TDM tools we have available?

We’ll begin with thiopurines, antimetabolite agents with immunosuppressive activity.²¹ TDM can be used to monitor efficacy and certain safety risks with thiopurines, such as bone marrow suppression and hepatotoxicity.¹⁹

A potential life-threatening adverse event of this treatment class is leukopenia, or low white blood cell count.^21,22 Fortunately, there are risk factors that can predict the development of thiopurine-induced leukopenia.²¹

[11:22]

First, let’s understand how thiopurines are metabolized.

Thiopurines undergo a series of enzymatic pathways that produce several sub-metabolites.¹⁹ 6-thioguanine nucleotide (or 6-TGN) and 6-methylmercaptopurine (or 6-MMP) are the most clinically relevant.

Increased 6-TGN concentrations have been associated with therapeutic efficacy, but also a higher risk of myelotoxicity.¹⁹ The cytotoxic effects can result in leukopenia, which can complicate IBD management.²¹

6-MMP is formed when 6-mercaptopurine, 6-MP, is metabolized by the enzyme thiopurine-S-methyltransferase, known as TPMT.²³ Higher 6-MMP levels are linked to an increased risk of hepatotoxicity.¹⁹

[12:16]

Patients with low TPMT activity are at risk for increased levels of 6-TGN, and thus may have a higher risk of leukopenia.^19,23

Despite our knowledge of these metabolites, therapeutic 6-TGN cutoffs do not always discriminate which patients may or may not respond to treatment.²⁴ 

I check TPMT before starting a thiopurine and consider thiopurine metabolite testing after treatment has started to adjust the dose if necessary.²³

Next, let’s discuss how can we utilize TDM in anti-TNF treatment.

[12:52]

Though anti-TNFs are an effective treatment for IBD, it has been estimated that 10% to 40% of patients with IBD were primary non-responders in a review of select published case series and clinical trials of patients with Crohn’s and UC.²⁵ There is no unanimous definition of primary non-response to anti-TNFs, but primary non-response should not be assessed before weeks 8 to 12, as remission during induction may still be achieved by that time.²⁵

Further, in a retrospective analysis of claims data from 4,129 patients with IBD in the HealthCore Integrated Research Database from 2016 to 2019, over 60% of these patients who initiated anti-TNF therapy had an inadequate response after the first year.²⁶

[13:45]

There is variability in drug exposure and subsequent treatment response among patients given standard doses of anti-TNFs, suggesting that personalized dosing may be beneficial in reducing primary and secondary loss of response.²⁷

Using population pharmacokinetic, or PK, models can help to identify sources of variability of PK parameters and their impact in a population, which can then be used to simulate and allow individualized dosing regimens for patients.²⁷ Dashboard systems have been developed in which a PK model with data from a similar patient population is used to calculate the precise dose and frequency of therapy a patient should receive in order to maintain a specific serum drug concentration using Bayesian approach.

[14:36]

Let’s look at an example of dashboard-driven dosing in the following study. A 2021 randomized controlled, multicenter trial in the Netherlands of 80 adult patients with UC or Crohn’s in remission investigated the efficacy of dashboard-driven anti-TNF dosing compared to conventional dosing in patients with IBD who were already being treated with an anti-TNF.²⁸

The study demonstrated that dashboard-driven anti-TNF dosing resulted in a higher proportion of patients in sustained clinical remission compared to conventional dosing during one year of follow-up.²⁸

[15:19]

But what do we do when a patient does not respond, or loses response to therapy, such as an anti-TNF agent? Though the reason why some patients do not respond or lose response to therapy may be unclear, it is likely related to multiple factors including PK, pharmacodynamics, or the development of anti-drug antibodies.²⁰

There may also be immunogenicity, which results in increased drug clearance and may contribute to treatment non-response.²⁰ Concomitant use of anti-TNF with immunomodulator therapies has been shown to lower incidence of anti-TNF antibodies compared to monotherapy.^19,29

Evaluating pharmacokinetics is one way to address non-response. However, the relationship between the dose given and the drug level achieved can vary among patients.²⁰

[16:13]

Additionally, before having the ability to measure drug levels and anti-drug antibodies, management of the non-responsive patient was empiric dose adjustment, such as increasing the dose, shortening the dose interval or switching to another drug in the same or different class.²⁰

This is where TDM comes into play. Assessing anti-TNF drug levels in patients can have an important role in how patients with IBD are managed.²⁰ Routinely measuring levels of anti-TNF and anti-drug antibodies (or ADA) will deepen understanding of why some patients lose response to therapy.

Another group with non-response is patients with high anti-TNF levels and no anti-drug antibodies. In these cases, we suspect the drug is simply not working from a mechanistic standpoint and can consider switching to another drug class.^20,24

[17:12]

Another approach to managing non-response is adding immunomodulator therapy, which is one of the potential options for a patient who has low-titer anti-drug antibodies.^20,30

We have learned about the importance of measuring anti-TNF serum levels, but what levels should we be targeting?

The drug concentration targets differs depending on specific treatment goals, disease phenotypes, and even the type of assays used.³⁰ In my clinical experience, a low or undetectable drug concentration level in the presence of high anti-drug antibodies concentrations likely means that the ADA is neutralizing the drug. This scenario can lead to subtherapeutic drug concentrations and may explain treatment failure.^31,32

Targeting higher drug levels may be beneficial for certain disease phenotypes, such as fistuli Crohn’s disease.³³

[18:09]

Evidence suggests that higher anti-TNF levels and the absence of anti-TNF antibodies are associated with increased rates of remission and mucosal healing.³⁴

For example, in a retrospective cross-sectional study of 117 patients from hospitals in Florida and Wisconsin investigating the correlation between perianal fistula healing and serum trough levels of anti-TNF in patients with Crohn’s disease, the patients who achieved fistula healing had higher levels of the anti-TNF and a decreased rate of detectable anti-TNF antibodies compared to those without fistula healing.³³ Patients with higher anti-TNF levels had a higher chance of achieving fistula healing compared to patients with lower levels of the anti-TNF.³³ Similarly, a retrospective cohort study conducted in Philadelphia and Boston demonstrated a correlation of high anti-TNF troughs with higher rates of endoscopic healing.³⁵

[19:10]

Is there any role of TDM in biologics other than anti-TNF?

For anti-integrins, an exposure-response relationship has been suggested.³⁶ However, it is still unclear if TDM is beneficial for patients who experience non-response or loss of response to this class of medication. In one study of patients with moderate to severe UC and early non-response to treatment, the proportion of patients who achieved endoscopic improvement was similar between groups who received standard dosing versus dose-optimization based on TDM.³⁶ Similar results were seen for rates of clinical remission between groups as well.

Patients with higher interleukin (or IL) antagonist drug concentrations have experienced higher remission rates compared with patients with lower levels.³⁷ For interleukin antagonists, there is a lack of evidence about the role of TDM.³⁸

[20:08]

Let’s review what we discussed today.

An important first step to personalizing care is determining prognosis to help predict disease course and establish a therapeutic approach.^1-3 We reviewed clinical prognostic indicators and serologic and genetic testing. Then we need to tailor therapy accordingly. 

We then learned about the established role of therapeutic drug monitoring for anti-TNF therapy.^18-20 Target drug concentration levels are based on individual treatment goals, disease phenotype, and assays used.³⁰ Remember that a low or undetectable drug concentration level in the presence of high ADA concentrations likely means that the ADA is neutralizing the drug. This scenario can lead to subtherapeutic drug concentrations and may explain treatment failure.^31,32

[21:06]

Thank you for your interest and for spending some time with IBDIQ today to help adapt to the evolving care needs of all patients with IBD.