Gastroenterology, Hepatology and Nutrition

While most children diagnosed with ulcerative colitis respond well to existing medications, some do not, which results in about 26% of patients needing colectomy surgery within five years.

Now the co-authors of the 29-center PROTECT study, led by co-principal investigator Lee Denson, MD, propose a fundamental shift in treatment approach. Using DNA genotyping, RNA sequencing and microbial analysis of more than 400 patient biopsy samples, the team reveals a collection of results that can help clinicians predict which children need earlier interventions and who is most likely to respond well to treatment.

“Our results show that you can predict who will achieve the primary outcome of corticosteroid-free remission at 52 weeks based on certain clinical factors,” says Denson, director of the Schubert-Martin Inflammatory Bowel Disease Center. “Early prediction could lead to more timely introduction of additional medical therapy when needed.”

Current protocols lack precision

When treating children with newly diagnosed ulcerative colitis, physicians typically choose between corticosteroids and mesalazine (a locally acting anti-inflammatory) for those presenting with mild symptoms. Many prescribe infliximab (a potent monoclonal antibody) for those with more severe symptoms.

However, outcomes have not been so clearly stratified. Some patients with mild symptoms do not respond to mesalazine, yet they linger on the drug. Meanwhile, others with moderate to severe symptoms sometimes do respond to mesalazine, suggesting that more intense treatments may not always be necessary.

Much of this inconsistency, Denson says, has reflected clinicians relying on adult-driven protocols because they have lacked evidence-based outcomes data—until now.

PROTECT study explores new data sources

The PROTECT (Predicting Response to Standardized Colitis Therapy) study tracked outcomes for about 400 patients ages 4-17 from 29 medical centers in the United States and Canada, while also obtaining stool samples and tissue biopsies for the most detailed analyses to date of this patient population.

Of the participants, complete biological data were available for 177 children; 206 had data from RNA sequencing; and 343 had microbiome data.

“We hypothesized that pretreatment clinical, transcriptomic, and microbial factors could predict disease course,” the co-authors wrote. “We found that rectal gene expression and gut microbial factors not only improved our ability to predict clinical outcomes…but also provided crucial insight into the biological reasons for widely disparate patient courses.”

The team identified 33 genes that were expressed differently in moderate-to-severe disease. They found that over-expression of genes that encode ion channels and transporters were associated with an increased likelihood of escalation to anti-TNFα therapy.

Similar predictive results appeared in more standard clinical testing, including baseline hemoglobin concentrations of less than 10 g/dL, low serum 25(OH)D concentration, and low eosinophil count.

Meanwhile, patients with a lower antimicrobial peptide gene signature and an abundance of Ruminococcaceae and Sutterella were more likely to achieve remission.

When patients achieve remission within four weeks using corticosteroids or mesalazine, the study suggests that such patients may not need further escalation to anti-TNFα drugs.

The study also found that the most effective safe dose of mesalazine is actually double the standard dose.

An achievable shift using existing clinical tests

While the study dove deep into genomic and microbial analysis, adjusting treatment for children with ulcerative colitis will not require every child to receive that level of testing.

“An important finding of our study was the importance of early response to mesalazine or corticosteroids and achieving clinical remission by week four as predictors of outcome at week 52,” Denson says. “Physicians can obtain this predictive information using the same blood tests and diagnostic measures they already use in the clinic setting.”

Looking forward, experts at Cincinnati Children’s have begun a clinical trial to test the potential benefits of the prebiotic 2'-fucosyllactose (2FL) in restoring a healthy microbiome in patients with inflammatory bowel disease.

Citation

Hyams JS, Davis Thomas S, Gotman N, Haberman Y, Karns R, Schirmer M, Mo A, Mack DR, Boyle B, Griffiths AM, LeLeiko NS, Sauer CG, Keljo DJ, Markowitz J, Baker SS, Rosh J, Baldassano RN, Patel A, Pfefferkorn M, Otley A, Heyman M, Noe J, Oliva-Hemker M, Rufo PA, Strople J, Ziring D, Guthery SL, Sudel B, Benkov K, Wali P, Moulton D, Evans J, Kappelman MD, Marquis MA, Sylvester FA, Collins MH, Venkateswaran S, Dubinsky M, Tangpricha V, Spada KL, Saul B, Wang J, Serrano J, Hommel K, Marigorta UM, Gibson G, Xavier RJ, Kugathasan S, Walters T, Denson LA. Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study. Lancet. 2019 Apr 27;393(10182):1708-1720.