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More rigorous endpoints needed in pediatric IBD
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ORLANDO — Athos Bousvaros, MD, MPH, associate chief of the division of gastroenterology, hepatology and nutrition, and associate director of the Inflammatory Bowel Disease Center at Boston Children’s Hospital, discussed important literature from the past year on disease assessments and treatments, and what is needed for the future of pediatric IBD at AIBD 2016.
“Regulators, both at the FDA and European Medicines Association, are encouraging a transition from physician reported activity and disease … to patient reported outcomes, and also endoscopic measurable disease inflammation. They want harder endpoints,” Bousvaros said during his presentation.
There is a changing landscape of pediatric IBD, according to Bousvaros, where there is increasing data on therapeutic drug monitoring and dose escalation of biologics, new medications currently being used off label (vedolizumab and ustekinumab), increasing recognition of how psychological factors affect quality of life, and ongoing patient interest in non-immunosuppressive therapies such as dietary modifications.
Bousvaros touched upon various studies he believed are making a change in pediatric IBD. Some of them are as follows:
Measures, biomarkers
In one study entitled: “Pediatric Crohn’s Disease Clinical Outcome Assessments and Biomarkers: Current State and Path Forward for Global Collaboration,” the authors state the pediatric Crohn’s disease activity index (pCDAI) and Harvey-Bradshaw’s index lack validity, reliability and ability to detect change of treatment.
“This means that the measures and rulers we have been using for years to track patient outcomes and efficacy aren’t good enough anymore,” Bousvaros said. “We need better markers and more careful sensitive tests.”
Another study conducted by Turner and colleagues published in JPGN compared four current disease pCDAIs with endoscopic inflammation and CRP in two large pediatric cohorts. There was a fair correlation between pCDAI and SES-CD. Bousvaros said the measurements were all over the map.
“Crohn’s is a sneaky disease. You can look good on the outside but still have significant inflammation brewing on the inside, so correlation and symptoms in endoscopy at best are fair … We need better markers and more carefully sensitive testing.”
Bousvaros also emphasized that clinicians don’t want to be performing colonoscopy every 2 months or every year; but are there any other noninvasive biomarkers that could be used instead, he asked.
A study by Moy and colleagues compared the use of MRI to colonoscopy in 30 children with Crohn’s disease.
“They showed MRI strongly correlated with healing,” Bousvaros said.
They also identified several factors with MRI consistent with healing including reduction in wall thickness and hypervascularity.
“So colonoscopy and MRI are pretty good objective markers,” Bousvaros said, adding that he personally uses MRI in the mid-small bowel where it is hard to reach disease with colonoscopy.
Patient reported outcomes
The following clinical outcome assessments are needed in pediatric IBD, according to regulators at the FDA: patient reported outcomes, quality of life measures like school attendance, endoscopic disease activity indices, and validated biomarkers. Bousvaros said many people are working hard at developing patient reported outcomes acceptable to regulators.
A study published in JPGN by Marcovitch and colleagues developed UC patient reported outcomes but they are still being validated. They are conducting qualitative interviews of children and trying to figure out what constitutes a “good day” and “bad day.” They then used biostatistics to try to figure out the most statistically significant aspects of relapse vs. remission.
“Not too many dramatic changes [in this study], but we will have tools patients can fill out themselves either online or in a clinic that will be validated in the future,” he said, adding that one for Crohn’s is also underway but hasn’t been published yet.
Bousvaros said another study published in the Journal of Pediatrics used PRO measurement that has been validated in adults: the PROMIS score. It measures five domains (pain interference, anxiety, depression, fatigue and peer relationships), but is not disease specific. The study included 276 children with Crohn’s disease, and there was a strong correlation between PROMIS scores and disease activity.
“There are more measures moving from what a physician fills out to endoscopy and what the patient fills out,” Bousvaros said.
When measuring patient outcomes, psychological outcomes come into play and Bousvaros said one down side is the psychological may affect the outcome measure itself. A study published in the IBD Journal conducted by Reigada and colleagues questioned whether IBD results in anxiety or anxiety increases the risk for an IBD flare. They administered the SCARED survey to 86 children, and found that 25% of children randomly screened at baseline had anxiety, and this fraction were more likely to experience clinical relapse and hospital-based interventions, even after adjusting for disease activity.
“I think we’re going to start seeing more screening for anxiety and depression in clinics,” Bousvaros said.
In the future, Bousvaros said he expects the development of a Crohn’s PRO, figuring out how much of an impact anxiety and depression has on PROs, the development of simpler and easier psychological assessments, correlation with physician reported outcomes, correlation with endoscopic disease activity and biomarkers and routine PRO use in clinical trials.
Treatments
Bousvaros said the literature within the last year discussed ways to use the old drugs better and how to use new drugs, such vedolizumab and ustekinumab. He said there is limited data on the new drugs, but some.
In the TAXIT trial, by Casteele and colleagues, patients were randomly assigned to a clinical dose adjustment of infliximab (n = 123) or a level-based dose adjustment (n = 128).
“This is a slightly older study but important,” Bousvaros said.
The researchers looked for a stable clinical response by 14 weeks of therapy. Half of patients got adjustment if the physician thought it was appropriate and others were dosed by a very complicated algorithm, but all they did was measure levels and then almost every infusion tweaked the dose based on the level.
“This is interesting because after 1 year, there was no difference in 1 year remission rates,” Bousvaros said. “Actually two-thirds of both groups were in remission.”
Another study conducted at Boston Children’s Hospital focused on antibodies to infliximab levels in 133 children with IBD. Results showed 20% had antibodies to infliximab.
“They correlated with lower infliximab levels but they had not yet developed loss of response or infusion reaction,” Bousvaros said. “This raises the question that there may be a latency period between the time you get antibodies and the time your level drops, to the time you lose response. You may be able to stay healthy for a while even if your level is low and you have no antibodies.”
In a prospective study conducted by Stein and colleagues, looking at the same antibody issue, 77 children were treated with infliximab and 38% were on immunomodulators. After 12 months, 80% remained on infliximab and others were taken off for various reasons.
“They said a level of 9 is good and a level below 9 basically may be at higher likelihood to lose response. This is interesting because they did not know the effect of immunomodulators on the primary outcome,” Bousvaros said, adding that this view is in direct contrast with another study conducted by Grossi and colleagues. In the study, 502 children with Crohn’s disease treated with infliximab were followed for 5 years or more and showed that longer use of immunomodulators was associated with increased duration of infliximab therapy.
“These are two studies [with] two very different results. I’m not sure which one to believe yet; we need more data on this topic,” Bousvaros said.
In terms of new treatments, Bousvaros said vedolizumab is a very selective drug that has been shown to work in children almost as well as it does in adults. In a new study by Singh and colleaues, 52 children were treated with vedolizumab. At 6 weeks, 14 of 22 patients with UC were in remission, and at 14 weeks, 76% of UC patients were in remission and 42% of Crohn’s patients were as well.
Ustekinumab use has even less data available. In a study of four patients, dosing was 90 mg of ustekinumab between weeks 0 and 4 followed by 90 mg every 8 weeks after for maintenance. Of the four patients, two responded and two didn’t. Bousvaros said adverse events observed were only related to Crohn’s disease.
Future of pediatric IBD
Bousvaros said the following is needed for management and treatment of pediatric IBD:
- Development and validation of indices;
- Use of objective measures in assessing drug efficacy;
- Determination of the optimal regimen of therapeutic drug monitoring in patients receiving thiopurines, methotrexate and biologics;
- Larger randomized controlled studies to gain pediatric labeling of our newer treatments, plus shortening the duration of off-label therapy; and
- More studies of non-immunosuppressive treatments, with more rigorous endpoints.
“There’s a lot more work that needs to be done,” Bousvaros concluded. – by Melinda Stevens
Reference:
Bousvaros A. “Clinical pediatric inflammatory bowel disease - the year in review (highlights from literature).” Presented at: Advances in Inflammatory Bowel Diseases; Dec. 8-10, 2016; Orlando, Fla.
Disclosures: Healio Gastroenterology was unable to confirm relevant financial disclosures at the time of publication.