Concerns, Controversies in Pediatric IBD Persist in Era of Biologics

The treatment of pediatric inflammatory bowel disease has been revolutionized by the advent of biologic therapies, which have been shown to effectively treat symptoms, induce mucosal healing, and reverse growth impairment in many patients. However, experts continue to debate the positioning of biologics in IBD, and are seeking ways to better understand how to deliver optimal treatment to children affected by the disease.

Pediatric IBD rates are on the rise globally, and the 20% to 30% of patients with IBD onset before age 20 years often have more extensive, severe and complicated disease compared with those whose disease presents in adulthood. According to experts interviewed by Healio Gastroenterology, early treatment with biologics provides newfound hope for preventing these complications, though many factors must be considered when choosing an initial therapy for children. Unfortunately, despite their availability and impact, several barriers prevent the use of biologics as first-line therapies.

Payers, Guidelines Discrepancies

One major obstacle, experts agreed, is that most insurance policies require step-wise failure of conventional treatments before approving a biologic therapy.

A recent study published in Inflammatory Bowel Diseases evaluated the criteria for approval of biologics and showed that the majority “do not comply with the current standard of care for treating IBD based on the severity of disease and best available pharmacologic therapy.” Why these policies require certain drugs to fail before considering biologics is unclear, according to study investigator Joseph D. Feuerstein, MD, of the division of gastroenterology at Beth Israel Deaconess Medical Center, Harvard Medical School, and colleagues.

“There are no clinical studies to indicate that mesalamine must be tried and proved unsuccessful before infliximab [Remicade, Janssen] or vedolizumab [Entyvio, Takeda] can be considered,” they wrote. “In contrast, delaying appropriate therapy results in ongoing disease activity and resultant complications.”

This study showed that AGA guideline recommendations on the early use of biologics for patients with moderate-to-severe disease “are totally unaligned with insurance company policies requiring the failure of multiple agents before biologics are approved,” Jeffrey S. Hyams, MD, of the division of digestive diseases, hepatology, and nutrition at Connecticut Children’s Medical Center, said in an interview.

This is especially problematic for pediatric gastroenterologists, as insurance companies do not have separate treatment policies for children and adults even though children “require a much different approach,” he added. “One does not have an opportunity to wait for weeks to months in a sick child with growth failure to be treated with long-term corticosteroids and to wait for immunomodulators to fail. ... One doesn’t have that window in pediatrics, so there is a big disconnect between the insurers and what has become standard of practice.”

Iona M. Monteiro, MD, associate professor of pediatrics, and chief of the division of pediatric gastroenterology, hepatology and nutrition at Rutgers New Jersey Medical School, agreed with Hyams, and said she often appeals and re-appeals requests for insurance companies to approve first-line biologics for her patients. In fact, this problem extends even beyond biologics, she added.

“Exclusive enteral nutrition is being used extensively in Europe as induction therapy for Crohn’s disease, and here I’ve been struggling to get authorization from insurance to cover it,” she said in an interview.

The reasons behind these disconnects between insurance companies and practice guidelines need to be clarified to help overcome them, according to Neera Gupta, MD, MAS, director of research in the Pediatric Inflammatory Bowel Disease Center at Weill Cornell Medicine and NewYork-Presbyterian.

“I agree with [Feuerstein and colleagues’] statement that ‘further interventions are needed to better align policies with optimal evidence-based drug therapy,’” she told Healio Gastroenterology via email. “When there is a discrepancy between an insurance policy and recommended practice supported by evidence, we need to understand the reason for this discrepancy so that we can advocate more effectively for a change in the policy.”

However, payer policies are not the only barriers to early treatment with biologics, according to Corey Siegel, MD, MS, director of the IBD Center at the Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire.

“We can ultimately get access to biologics for almost all patients nationally,” he said in an interview. “You may need to go through a step-wise process to get there, but the fact that so few patients are ever getting exposed to biologics can’t just be about the payer barrier.”

Real-World Treatment Patterns

At DDW 2017, Siegel and colleagues presented their findings from a study of real-world treatment patterns, in which they used a large U.S. payer database to evaluate treatment pathways and visualized them using Sankey diagrams. They showed not only that few IBD patients are receiving first-line biologics, but that most are never exposed, and among those who are, few receive combination therapy despite evidence supporting the approach.

The most common pathway for both Crohn’s disease and ulcerative colitis was first-line corticosteroids and 5-aminosalicylic acid (5-ASA) drugs, according to Siegel.

“Although that might be ok for UC, all treatment guidelines for Crohn’s disease now suggest 5-ASAs are not part of the treatment algorithm, and the fact that there’s such predominant first-line use of 5-ASAs and corticosteroids makes me concerned that we’re not getting the message across that we have better treatments,” he said.

Further, Siegel said the “incredibly low use of early combination therapy,” — in less than 1% of patients — is troubling, considering almost 10 years have passed since the “practice changing article” published in the Lancet by Geert D’Haens, MD, PhD, of University of Amsterdam, and colleagues, established the “top-down” treatment paradigm as superior to the “step-up” approach.

Siegel noted that while the patients included in his study were adults, he expects the treatment patterns in children would be relatively comparable. The fact that only 19% of Crohn’s patients and only 6% of UC patients were ever treated with biologics “really makes me concerned that we are underutilizing some very good drugs that we have available to treat patients,” he said. “And we can’t blame it all on payers. There has to also be something about the way providers are offering these drugs, or something about the way patients are accepting these drugs.”

Studies have indeed shown that patient–provider communication can impact the treatment decision-making process for patients and parents of children with IBD, especially when it comes to the risks of medications. For example, a recent analysis of more than 15,000 social media posts showed IBD patients are more concerned about the negative side effects of biologics rather than their benefits or costs. Study investigators concluded that providers need to do more to help patients understand their treatment options.

“Physicians need to do a better job explaining the risks and benefits of medications,” study investigator Christopher V. Almario, MD, of the Cedars-Sinai Center for Outcomes Research and Education in Los Angeles, said in a press release. “When people hear ‘risk of lymphoma,’ that’s all they focus on even though the risk is very, very low, while the chance of getting better from the medication is quite high.”

Monteiro agreed: “We need to explain to the parents that having untreated disease carries a much greater risk than that of the malignancy.”

Unsurprisingly, parents of children with IBD and their pediatricians can be especially risk averse, according to Hyams, which he said particularly informs his position on the avoidance of combination therapy with thiopurines in children. However, because strong data support the effectiveness of thiopurines, this subject remains controversial among experts, such that Hyams and Siegel presented both sides of the debate during a symposium at DDW 2017.

Role of Thiopurines

Hyams emphasized two key ideas in support of avoiding combination therapy with thiopurines in children, the first of which is that therapeutic drug monitoring (TDM) probably obviates the benefits of adding an immunomodulator to treatment with a biologic.

“The utility of combination therapy probably largely rests on its ability to achieve adequate serum levels of the biologic and prevent antibody formation,” he said. “If one can employ TDM on a frequent enough basis to ensure adequate drug levels, you probably don’t get that much additional benefit from the addition of a concomitant immunomodulator.” However, he emphasized that TDM is the caveat, and if costs prevent it from being done frequently, “then utilizing a concomitant immunomodulator for the first 6 to 12 months of therapy is important.”

The second and more important issue is what concomitant immunomodulator one uses, Hyams said, as he finds the risk for lymphoma associated with the concomitant use of thiopurines particularly concerning.

“While the absolute risk may be low, the evidence is now incontrovertible that in both adults and pediatrics, thiopurines are associated with an increased risk, and we have increasing data that show thiopurines as primary therapy for pediatric IBD — or adult IBD for that matter — may have minimal efficacy on changing the natural history,” he said.

Thus, Hyams argued that thiopurines “are probably no longer an important element of therapy for pediatric IBD and shouldn’t be used at all as combination therapy with anti-TNF agents.” He recommended that combination therapy with methotrexate (often in a reduced dose) is a safe alternative. “The data we do have show it is equally efficacious if not more efficacious when used in combination therapy than the thiopurine,” he added.

Gupta added, “This is an area of ongoing debate in the pediatric IBD community, and an area where we have more to learn. Therefore substantial differences in opinion and interpretation of the literature with respect to the use of thiopurines remain.”

Also at DDW, Gupta and colleagues shared the results of a prospective cross-sectional study showing that azathioprine/6-mercaptopurine are negatively associated with certain anthropometric parameters, while methotrexate, adalimumab and infliximab are positively associated with certain anthropometric parameters in children with Crohn’s disease.

“These negative associations may reflect either a lack of efficacy of thiopurines on nutritional status/disease status vs. an actual negative impact of thiopurines in pediatric Crohn’s disease,” she said. “This is an interesting finding that requires further investigation in a prospective longitudinal study. At this point in time, I continue to favor other treatments and not prescribe thiopurines.”

Siegel argued there is a role for combination therapy with thiopurines in high-risk patients.

“We do know that immunomodulators have some association with malignancy in children, yet the malignancy risk is still very, very low,” he said. Further, he said it is important to note the risk is associated with duration of exposure: “It is incredibly unusual to experience a malignancy related to these drugs within 1 year or even 2 years within starting them.”

He argued that because thiopurines and biologics “are probably the most effective treatment combination we have,” it should still be considered in very sick patients for a limited duration, and discontinued after remission is achieved to prevent long-term exposure in high-risk patients, specifically young males.

Importantly, the ability to stratify patients at high risk for complications is essential for giving physicians, patients and the parents of children with IBD higher confidence in the early positioning of such intensive therapies, Siegel added.

“Early in the disease is our window of opportunity to make a difference for all of our patients, and kids are particularly vulnerable because their growing and nutrition is so important, so making sure we get it right early and not delay therapy is critical,” he said.

He and others have been working toward developing risk prediction tools to better identify patients who would benefit from early intensive therapies.

Risk Prediction Models

According to Hyams, the development of risk prediction models is informed by the recognition that “one size does not fit all” in terms of therapeutic approaches for children newly diagnosed with IBD.

“Those who present with very severe disease who are steroid-refractory declare quite early on that they are going to require biologic therapy and may even require surgery,” he said. “But there clearly is a large group of patients as well who may have a more severe phenotype at diagnosis, but who do extraordinarily well, and there’s no way of distinguishing one group from the other at the time of diagnosis.”

Hyams’ most recent efforts on this front include the PROTECT study, the findings of which he also presented at DDW. As prospective outcomes data are lacking on children newly diagnosed with UC treated with standard therapy (mesalamine or corticosteroids), this research aimed to identify risk predictors of complicated disease course in this population.

At the time of UC diagnosis, Hyams and colleagues assessed a variety of clinical, demographic, genetic, serologic, genomic, gene expression and microbiome elements.

“Not surprisingly we found that children who had more severe disease at the time of diagnosis, particularly those who presented requiring hospitalization and IV corticosteroids, were most likely to require additional therapy and most likely to require colectomy,” he said. About a quarter of those who presented with severe disease required rapid escalation of therapy in the first 12 weeks, mostly including anti-TNFs, and about 6% of them required colectomy. “This was much less likely in those presenting with more mild disease treated with mesalamine, and intermediate in the group treated with oral steroids, although the only colectomies seen in the first 3 months were in children who required IV steroids to start off with,” he noted.

They found that the distribution of disease was important: “Patients who had left-sided or limited disease did better, and we found that patients who had rectal sparing did better.”

Finally, two “novel and intriguing histologic findings” included that the absence or low numbers of eosinophils in rectal biopsies was “very significantly” associated with a worse prognosis, and an architectural change called surface villiform changes, present in about half of patients, was associated with the need for anti-TNF therapy or colectomy.

“We think that this probably represents a greater insult to the surface epithelium, the cause of which is not clear yet, but it was independent of disease severity,” Hyams said. “For the first time we have normative data on response and outcome to standard of care therapy and we’re starting to develop a risk model. This will be completed over the next 6 to 12 months with our translational studies.”

Siegel presented data at DDW on another risk prediction model, called the PROSPECT tool, which was developed in adults with Crohn’s disease and validated in a pediatric group.

“The PROSPECT tool is a mathematical model that allows us with fairly high accuracy to identify which patients are at low, moderate or at high risk to have complications of their disease based on clinical, serologic and genetic markers,” he said. “Medical therapy prevents those complications from occurring, but really doesn’t do a good job of fixing those problems after they occur, so if we can identify patients who are at high risk to have these complications, then providers should have much higher confidence in prescribing more intensive therapies.”

Further, Siegel said a secondary aim of the PROSPECT model is to develop it as a patient communication tool, to help patients and parents better understand their level of risk.

“Patient communication is so important because a lot of the barriers to getting people on the right drugs early enough is that patients are worried about side effects of the drug,” he said. “The ultimate goal of PROSPECT is to stratify patients early on in the course of their disease into how high their risk is for having complications so that patients and providers can have a more meaningful and personalized conversation about why they may or may not need biologics or other medical therapy early on in their disease course. We want to equip providers with the tools to help educate their patients that the complications that can occur from their disease far outweigh the potential risks of medications.”

In addition to preventing complications like strictures or fistulas, experts emphasized that early treatment with biologics can also prevent growth failure, a complication that is unique to children with IBD, particularly those with Crohn’s disease.

“Biologics have revolutionized what we do without any question,” Hyams said. “They keep people out of the hospital, they have dramatically decreased the use of corticosteroids, and I think the days of growth-stunted pediatric IBD patients should be over.”

Growth Failure

Growth failure (characterized by persistent severely decreased standardized height velocity), delayed puberty and delayed skeletal maturation are common in Crohn’s disease. This “should never be a problem again if providers intelligently use biologics and, when necessary, surgery,” Hyams said.

While inflammation from the disease itself and malabsorption are additional risk factors for growth failure in pediatric Crohn’s disease, chronic corticosteroid use has an especially significant impact, according to Monteiro.

“Before biologics, the mainstay treatment for active disease was corticosteroids, and that really impacted growth in children,” she said. “Biologics spare the use of corticosteroids and they also lead to mucosal healing which is thought to help children grow better because they are no longer in an inflammatory state.”

In a review article recently published in the British Medical Journal, Monteiro and colleagues emphasized that minimizing steroid exposure is essential for preventing growth failure, and cited evidence that biologic therapy and can promote “catch-up” growth in children with Crohn’s disease. The REACH study, for example, showed treatment with infliximab improved growth z scores in children with moderate-to-severe Crohn’s.

But despite the availability of biologics, growth impairment continues to be an important complication in children with Crohn’s disease, according to Gupta.

“Because of varying definitions of growth impairment used across studies, different study designs, differing primary outcomes, differing study sizes and differing study eligibility criteria, it’s difficult to compare the reported frequencies of growth impairment across various time periods,” she said. “Acknowledging these limitations, the existing literature does not suggest that the frequency of growth impairment is decreasing.”

Further, Gupta said that the data on the link between biologic agents and growth are conflicting.

“Some studies suggest biologic agents improve growth and some studies do not detect any relationship between biologic agents and growth,” she said. “In our study, we detected a positive relationship between infliximab and standardized height in girls, but no relationship in boys. We did not detect any relationship between adalimumab and standardized height in boys or girls. It’s important to further examine these findings longitudinally, assessing the impact of medications on standardized height velocity. We can do so with the Growth Study, an ongoing NIH-funded prospective multicenter longitudinal cohort study investigating sex differences in growth impairment in pediatric Crohn’s disease.”

Gupta hopes the Growth Study (follow on Twitter with #GrowthStudy) will improve the understanding of the underlying mechanisms of growth impairment, guide development of new targeted medical treatments and enhance risk-prediction.

“In our earlier studies, we found that girls with Crohn’s disease tend to have a more severe course of disease. For example, girls are more likely to need surgery,” she said. “In sharp contrast to these findings, boys are more likely to have growth problems. This does not make sense. The inflammation characteristic of Crohn’s disease is the major driver of growth impairment in Crohn’s disease. Therefore, I would expect more severe disease in girls would lead to more growth problems in girls, but it doesn’t. If we can figure out the underlying mechanisms causing this sex difference in growth impairment in pediatric Crohn’s disease, this would be a major leap in our overall understanding of mechanisms of growth impairment in Crohn’s disease and perhaps other pediatric chronic inflammatory conditions.”

Additionally, Gupta hopes that this research will lead to better identification of children at high risk for growth impairment refractory to standard therapeutic approaches. “Perhaps these high-risk children would benefit from the early introduction of aggressive medical therapy. We need an interventional clinical trial examining the effects of treatments on statural growth in high risk children. Determining which children are high risk will facilitate a more individualized approach to treatment.”

The Growth Study has almost reached 70% of its target enrollment, with a goal of enrolling 125 pediatric patients with Crohn’s disease. The researchers plan to follow each participant for 2 years.

“Science has come so far, yet there is still so much that we don’t know — so much that we have to figure out and discover to optimize the care we provide to children,” Gupta said. – by Adam Leitenberger

• References:
• D’Haens G, et al. Lancet. 2008;doi:10.1016/S0140-6736(08)60304-9.
• Gupta N, et al. Abstract #Tu1744. Presented at: Digestive Disease Week; May 6-9, 2017; Chicago.
• Hyams JS, et al. Abstract #1088. Presented at: Digestive Disease Week; May 6-9, 2017; Chicago.
• Martinez B et al. Inflamm Bowel Dis. 2017;doi:10.1097/MIB.0000000000001110.
• Oliveira SB, Monteiro IM. BMJ. 2017;doi:10.1136/bmj.j2083.
• Siegel CS, et al. Abstract #Sa1855. Presented at: Digestive Disease Week; May 6-9, 2017; Chicago.
• Thompson KD, et al. Abstract #20. Presented at: Digestive Disease Week; May 6-9, 2017; Chicago.
• Yadav A, et al. Inflamm Bowel Dis. 2017;doi:10.1097/MIB.0000000000001153.
• http://www.nyp.org/documents/komansky/pediatric-growthstudy-flyer.pdf

• For more information:
• Neera Gupta, MD, MAS, can be reached at @NeeraGuptaMD on Twitter.
• Jeffrey S. Hyams, MD, can be reached at Jhyams@connecticutchildrens.org.
• Iona M. Monteiro, MD, can be reached at monteiim@njms.rutgers.edu.
• Corey Siegel, MD, MS, can be reached at Corey.A.Siegel@hitchcock.org.

Disclosures: Hyams reports consulting and/or advisory relationships with Janssen, AbbVie, Celgene, Boehringer-Ingelheim, Lilly, Astra Zeneca, Takeda, Allergan, and UCB. Siegel reports consulting and/or speaking and teaching relationships with AbbVie, Amgen, Celgene, Lilly, Janssen, Sandoz, Pfizer, Prometheus and Takeda, and has received grant support from AbbVie, Janssen and Takeda. Dartmouth-Hitchcock Medical Center and Cedars-Sinai Medical Center have a patent pending for a “System and Method of Communicating Predicted Medical Outcomes.” Gupta and Monteiro report no relevant financial disclosures.