Key messages
Prescribing a biologic to patients with Crohn’s disease is a complicated process that takes into account previous therapy, disease severity, cost, and other factors. Until now, however, there has been no ability to accurately predict endoscopic response to a particular biologic in order to facilitate the choice of therapy. New peripheral blood biomarkers based on DNA methylation may soon help predict endoscopic response to agents such as adalimumab, vedolizumab and ustekinumab in Crohn’s patients.
“Over the past decade, DNA methylation has been shown to differ significantly between people with inflammatory bowel disease (IBD) and healthy controls.Many of these studies suggest that DNA methylation plays a role in predicting response to treatment,” said Dr. Vincent Joustra at the presentation of the results of the EPIC-CD study at the 2023 Congress of the European Crohn’s and Colitis Organisation (ECCO) in Copenhagen.
After comparing endoscopic responders with non-responders, the scientists found that “DNA methylation profiles are indeed associated with response to adalimumab, vedolizumab and ustekinumab,” according to Joustra (Department of Gastroenterology and Hepatology, University of Amsterdam).
Methylation: Methodology
Joustra and colleagues prospectively investigated DNA methylation in the peripheral blood samples of 184 adults with Crohn’s disease. They compared biomarkers at baseline biologics therapy and again after a median of 28 weeks after treatment with adalimumab (58 patients), vedolizumab (64 patients) and ustekinumab (62 patients).
Participants were divided into a discovery cohort to identify relevant biomarkers and a validation cohort to confirm the results.The results were validated using a separate patient cohort at the University of Oxford. Response was strictly defined as a decrease of at least 50% in a simple endoscopic score for Crohn’s disease, steroid-free clinical response or remission using the Harvey Bradshaw Index and/or biochemical response or remission. Before treating the patients, the researchers created three epigenetic panels. The CpG loci of interest were identified using the “Infinium MethylationEPIC BeadChip Array”, which measures over 850,000 CpG sites throughout the genome.
Key findings
An epigenetic panel contained 100 adalimumab-relevant CpG loci correlated with a “high-accuracy endoscopic response” with an area under the curve (AUC) of 0.73 at validation. A second panel created for vedolizumab included 22 CpG loci and had an AUC accuracy of 0.89. The third panel, specific to ustekinumab, comprised 68 CpG loci and had an AUC accuracy of 0.94.
The markers are largely unique to each drug.Only two CpG loci overlapped between adalimumab and ustekinumab, Joustra reported. “Importantly, our model was able to predict pre-treatment response in a completely different group of patients than the Oxford validation cohort with an AUC of 0.75.”
A secondary analysis revealed no differences in the stability and robustness of methylation markers between baseline and 28 weeks. This result suggests that the biomarkers are stable during the induction and maintenance phase of treatment.
“Of course, we need to clinically validate our results in a clinical trial that is currently underway,” Joustra said. This work will continue in the EPIC-CD study as well as in the OMICROHN clinical trial.
Promising start
“These are really interesting results that address an important area in the treatment of Crohn’s disease patients,” said ECCO session co-moderator Dr. Tim Raine, who was not involved in the research.”The team found a signature that appears to provide a helpful prediction of response to certain treatments. Importantly, this signature appears to be stable over time, that it is specific to individual drugs, and that it could be validated in an external patient cohort,” added the gastroenterologist at Cambridge University Hospitals NHS Trust in the UK.
Although the methods used in EPIC-CD are not yet routinely available in clinical practice, “the methods are well established and, if developed appropriately in a validated laboratory and further validation work, could provide a useful test for gastroenterologists treating patients with Crohn’s disease,” said Raine.
This article was originally published on Medscape.com. It was translated by Dr. Petra Kittner.
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Source – https://www.univadis.de/viewarticle/neue-biomarker-k%25C3%25B6nnten-die-wahl-der-therapie-bei-morbus-2023a10005d7