OP03 Highly stable epigenome-wide peripheral blood DNA methylation signatures accurately predict endoscopic response to adalimumab, vedolizumab and ustekinumab in Crohn’s disease patients: The EPIC-CD study

Abstract

Background Despite the proven efficacy of biological treatments in Crohn’s disease (CD), many patients fail to respond or lose response over time. Therefore, predictive biomarkers for treatment efficacy would be of extreme value. Previous epigenome-wide association studies associated differential DNA methylation with CD-specific phenotypes, suggesting a potential use in classification and prediction of response to treatment. Methods We prospectively collected and measured longitudinal peripheral blood DNA methylation profiles of 184 adult CD patients prior to (T1) and after a median of 28 weeks (T2) following biological treatment with Adalimumab (ADA), Vedolizumab (VEDO) or Ustekinumab (USTE) in a discovery (n=88) and independently collected internal validation cohort (n=96) using the Illumina EPIC BeadChip array. Response (R) was defined as the combination of endoscopic response (≥50% reduction in SES-CD score) and steroid-free clinical response (≥3 point drop in HBI or HBI ≤4 AND no systemic steroids) and/or biochemical response (≥50% reduction in C-reactive protein (CRP) and fecal calprotectin or a CRP ≤5 g/mL and fecal calprotectin ≤250 µg/g). Biomarker identification and classification analyses were performed using stability selection gradient boosting on samples taken at T1 whereas samples taken at T2 and intraclass correlation (ICC) data were used to assess long-term stability of our identified CpG loci1. Results A total of 58 ADA-patients (NR=29, NNR=29), 64 VEDO-patients (NR=36, NNR=28) and 62 USTE-patients (NR=30, NNR=32) were included. Prior to treatment, at T1, we identified distinct panels of 100 ADA-, 22 VEDO- and 68 USTE-associated CpG loci that, in combination, predict clinical- and endoscopic response with high accuracy (AUC ADA=0.73, VEDO=0.89 and USTE=0.94) upon validation. Notably, for these CpG loci, methylation levels did not significantly differ between T1 and T2, implicating stability during both induction and maintenance treatment, irrespective of inflammatory status and therapeutic intervention. In addition, the majority of these CpG loci (>60%) demonstrated long-term hyper stability (ICC-values ≥0.90). Furthermore, genes annotated to the CpGs of interest suggest drug specific involvement in TNF-signaling, endothelial cell-cell adhesion, integrin dependent T-cell homing, the innate immune system and Th17/Treg differentiation, corroborating to the mode of action of each drug. Conclusion Here, we report on 3 validated panels of highly stable, epigenetic biomarkers that predict clinical and endoscopic response in CD patients treated with ADA, VEDO or USTE. Additional external- and clinical validation as part of EPIC-CD and the OMICROHN clinical trial are currently ongoing.

Use of Biomarkers in the Management of Inflammatory Bowel Disease

“…87 Distinct methylation patterns were identified in genome analysis of treatment-naïve UC patients, which identified hypermethylation of genes involved in homeostasis and defense, and hypomethylation of genes for cytokines and chemokines involved in the immune response. 89 Joustra et al 15 recently reported on three validated panels of highly stable epigenetic biomarkers that could be used to predict clinical and endoscopic response in CD patients treated with adalimumab, vedolizumab, or ustekinumab. They identified distinct CpG loci that, in combination, accurately predicted clinical and endoscopic responses.…”

“…Notably, for these CpG loci, methylation levels remained stable during both induction and maintenance of treatment, regardless of inflammatory status and therapeutic intervention. 15 Different mucosal methylation changes of several genes in IBD patients have been used to distinguish between CD and UC as well as differentiate from healthy controls. However, there are limitations due to differences in methylation profiles in different cell types and sites, as well as technical limitations and high cost.…”

Are We Ready to Reclassify Crohn’s Disease Using Molecular Classification?

“…Epigenetic panels are currently being evaluated for predicting treatment response to specific biologics for CD. CpG panels consisting of 100, 25 and 68 loci in peripheral blood can predict the clinical and endoscopic response to adalimumab, vedolizumab and ustekinumab, respectively, with accuracies of 73%, 88% and 94%, respectively [ 97 , 98 ]. For vedolizumab, a 23-CpG panel can predict deep remission with an accuracy of 75% [ 98 ].…”

Single-cell characterization of peripheral blood mononuclear cells from vedolizumab-treated patients with Crohn's disease identifies response-associated differences among the plasmacytoid dendritic cell and classical monocyte populations.

“…Patients included were obtained from the EPIC-CD study, which is a multi-center consortium with the goal of identifying prognostic biomarkers at the level of peripheral blood (PBL) DNA methylation capable of predicting response to adalimumab, infliximab, vedolizumab, and ustekinumab prior to treatment in CD patients (54). For the current study,…”

“…Blood samples were obtained from patients included in the EPIC-CD study, which is a multicenter consortium with the goal of identifying prognostic biomarkers at the level of peripheral blood (PBL) DNA methylation capable of predicting response to adalimumab, infliximab, vedolizumab, and ustekinumab prior to treatment in CD patients 19 . For the current study, 8 VDZ-treated CD patients (4 responders and 4 non-responders) were sampled for peripheral blood at a median of 26 weeks into treatment during routine care at the AmsterdamUMC hospital, location AMC, Amsterdam, Netherlands (Table 1).…”