P061 Epigenetic alterations at diagnosis predict susceptibility, prognosis and treatment escalation in inflammatory bowel disease – IBD Character

Abstract Gene-environment interactions play a pivotal role in the pathogenesis of Inflammatory Bowel Disease (IBD). Using the IBD Character inception cohort (295 controls, 154 CD, 161 UC, 28 IBD-U) we confirm the presence of a highly characteristic DNA methylation profile in peripheral blood implicating 137 differentially methylated positions (DMP) in IBD, including VMP1/MIR21 (p = 9.11×10− 15) and RPS6KA2 (6.43×10− 13); with consistency seen across Scandinavia and UK. Cell of origin analysis preferentially implicated the monocyte lineage. Dysregulated loci demonstrate strong genetic influence, notably VMP1 (p = 1.53×10− 15). Age acceleration is seen in IBD (coefficient 0.94, p < 2.2x10− 16). Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r -0.32, p 3.64×10− 7 vs. non-IBD r -0.14, p = 0.77). Multi-omic integration of methylome, genome and transcriptome also implicate specific pathways that associate with immune activation, response and regulation at disease inception. At follow up, a signature of 3 DMPs (TAP1, TESPA1, RPTOR) associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 (CI:2.14–12.56, logrank p = 9.70×10− 4).

Download Full-text

Serum N-Glycomic Biomarkers Predict Treatment Escalation in Inflammatory Bowel Disease

10.21203/rs.3.rs-820632/v1 ◽

2021 ◽

Author(s):

Archana Shubhakar ◽

Bas C Jansen ◽

Alex T. Adams ◽

Karli R. Reiding ◽

Nicholas T. Ventham ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

High Performance ◽

Clinical Decision Making ◽

Clinical Decision ◽

Predictive Capacity ◽

Cox Proportional Hazard Models ◽

Independent Replication ◽

Inflammatory Bowel ◽

Treatment Escalation

Abstract A blood-based prognostic biomarker to guide clinical decision-making at diagnosis of inflammatory bowel disease (IBD) would be immensely helpful. We investigated a composite serum N-glycomic biomarker to predict future disease course in 244 newly diagnosed IBD patients. Forty-seven individual glycan peaks were analysed using ultra-high performance liquid chromatography identifying 105 glycoforms from which 24 derived glycan traits were calculated. Multivariable logistic regression was performed to determine associations of derived glycan traits with disease. Cox proportional hazard models were used to predict treatment escalation from first-line treatment to biologics or surgery (hazard ratio (HR) 25.9, p = 1.1×10− 12; 95% confidence interval (CI), 8.52–78.78). Application to an independent replication cohort of 54 IBD patients yielded a HR of 5.1 (p = 1.1×10− 5; 95% CI, 2.54–10.1). These data demonstrate the predictive capacity of serum N-glycan biomarkers and represent a step towards personalized medicine in IBD.

Download Full-text

Intestinal Microbiota Transplantation for Patients With Inflammatory Bowel Disease Prevents Recurrence of C. difficile Infections but Not Recurrence of Gastrointestinal Symptoms

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz301 ◽

2019 ◽

Vol 26 (9) ◽

pp. 1421-1422

Author(s):

Lea Ann Chen

Keyword(s):

Inflammatory Bowel Disease ◽

Intestinal Microbiota ◽

Bowel Disease ◽

Gastrointestinal Symptoms ◽

Effective Therapy ◽

Clostridioides Difficile ◽

Inflammatory Bowel ◽

Treatment Escalation

Intestinal microbiota transplantation (IMT) is an effective therapy for recurrent Clostridioides difficile infections in patients with inflammatory bowel disease (IBD). However, further research is needed to understand the safety of this procedure, particularly given the frequency of gastrointestinal symptoms and of IBD treatment escalation after IMT.

Download Full-text

P317 Key features of bowel ultrasonography in managing inflammatory bowel disease patients

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.446 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S312-S313

Author(s):

A Les ◽

R Iacob ◽

R Costache ◽

L Gheorghe ◽

C Gheorghe

Keyword(s):

Inflammatory Bowel Disease ◽

Wall Thickness ◽

Biological Markers ◽

Bowel Disease ◽

Bowel Wall ◽

Independent Predictor ◽

Doppler Signal ◽

Bowel Wall Thickness ◽

Inflammatory Bowel ◽

Treatment Escalation

Abstract Background Bowel ultrasonography (BUS) is an accurate imaging method for detecting and monitoring inflammatory bowel disease (IBD) patients. This technique is recommended by current guidelines besides gold standard endoscopic assessment in managing IBD patients. Several BUS characteristics strongly correlate with biological markers of inflammation suggesting that these tests could be used in monitoring IBD patients but is yet unknown how these features predict the patient’s evolution. Methods Our study included 95 consecutive IBD patients (24 diagnosed with ulcerative colitis, 71 with Crohn’s disease) with both active and inactive disease at presentation. IBD diagnosis was established endoscopically and histologically. Patients with superimposed infection (viral or bacterial) and patients that had solely rectal involvement of the disease were excluded. BUS was conducted at baseline by one skilled examiner blinded to biological data. Biological markers were evaluated at baseline and all cases were prospectively followed-up for the need of therapy escalation during the next 6 months. The following BUS characteristics were registered in every patient: bowel wall thickness, alteration of wall structure, thickened mucosa or submucosa, presence of hyperechoic spots in the mucosal wall, irregularity of the external wall, Doppler signal, presence of mesenteric hypertrophy, presence of lymph nodes, and an overall assessment of the examination. No special preparation was needed before BUS. Results Of all the monitored sonographic features, the following characteristics correlated with the need of increasing treatment in the following 6 months: bowel wall thickness, altered structure of the wall, hypertrophic mucosa, Doppler signal, and the overall assessment of the examination (p < 0.001). The presence of the lymph nodes, hyperechoic spots in the mucosa, thickened submucosa and the irregularity of the external wall were not statistically significant correlated with the need for treatment escalation. The strongest correlation with the need for increasing treatment was documented for a mean bowel wall thickness > 5 mm and for Doppler signal presence in the bowel wall (p < 0.00001). In the multivariate analysis, Doppler signal presence was the only independent predictor for the need treatment escalation during a 6-month follow-up. Conclusion The most important sonographic features with an impact on therapeutic decision making in IBD patients are: bowel wall thickness, Doppler signal, altered stratification of the wall and mesenteric hypertrophy. In our analysis, the Doppler signal was the only independent predictor for the need for step-up therapy.

Download Full-text

Whole Blood Profiling of T-cell-Derived microRNA Allows the Development of Prognostic models in Inflammatory Bowel Disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjaa134 ◽

2020 ◽

Vol 14 (12) ◽

pp. 1724-1733

Author(s):

R Kalla ◽

A T Adams ◽

N T Ventham ◽

N A Kennedy ◽

R White ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

T Cells ◽

T Cell ◽

Bowel Disease ◽

Whole Blood ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Prognostic Models ◽

Inflammatory Bowel ◽

Treatment Escalation

Abstract Background MicroRNAs [miRNAs] are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease [IBD] pathogenesis. Here we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD. Methods In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohn’s disease [CD], 14 ulcerative colitis [UC], eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients [97 UC, 98 CD, 98 non-IBD, 1 IBDU] using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards. Results In stage 1, each leukocyte subset [CD4+ and CD8+ T-cells and CD14+ monocytes] was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4+ T-cells, including miR-1307-3p [p = 0.01], miR-3615 [p = 0.02] and miR-4792 [p = 0.01]. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20–3.27; logrank p = 1.80 × 10–3), in particular CD [HR 2.81; IQR: 1.11–3.53, p = 6.50 × 10–4]. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met. Interpretation We have identified and validated unique CD4+ T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated.

Download Full-text

Discovery of a simple two-gene expression biomarker in whole blood predictive of the need for treatment escalation in inflammatory bowel disease

10.1101/2021.07.09.21259804 ◽

2021 ◽

Author(s):

Jan K Nowak ◽

Rahul Kalla ◽

Alex T Adams ◽

Jonas Halfvarson ◽

Jack Satsangi ◽

...

Keyword(s):

Gene Expression ◽

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Validation Cohort ◽

Inception Cohort ◽

Treatment Intensification ◽

Discovery Cohort ◽

Inflammatory Bowel ◽

Treatment Escalation ◽

Risk Of Treatment

Background and aims: The IBD-Character consortium has recruited large internationally based inception cohorts of treatment-naive inflammatory bowel disease (IBD) patients, providing a unique resource to derive a simple transcriptome signature in the field of prognostication. Methods: The discovery cohort (n=160) was recruited in Norway, Sweden and Spain. The replication inception cohort from the United Kingdom (n=97) was followed-up for a mean (SD) of 350 (228) days. Treatment escalation was formally defined as the need for a biologic agent, ciclosporin and/or surgery, instituted for disease flare after initial remission, or colectomy during the index admission for ulcerative colitis. Whole blood RNA was subject to paired-end sequencing. In the discovery cohort a simple procedure was applied, which exploited differences of transcript ratios. The ten top performing ratios were tested using Cox regression models in the validation cohort. Results: Newly diagnosed IBD patients with high CACNA1E/LRRC42 expression ratio had an increased risk of treatment intensification (validation cohort: HR=19.3, 95%CI 2.6-143.9, p=0.000005; AUC 0.76, 95%CI 0.66-0.86). In 51 patients with CRP < 3.5 mg/L, CACNA1E/LRRC42 still predicted escalation (HR=10.4; 95%CI 1.2-86.5, p=0.007). The second best performing transcript ratio was CACNA1E/CEACAM21 yielding a HR of 10.9 (95%CI 2.5-46.7, p=0.00002) and an AUC of 0.76 (95%CI 0.65-0.86) in the validation cohort. Conclusion: Transcriptomic profiling of an IBD inception cohort identified gene expression ratios CACNA1E/LRRC42 and CACNA1E/CEACAM21 as prognostic biomarkers. These were validated in a replication cohort as strongly associated with short- and long-term risk of treatment intensification and may provide valuable information in clinical decision-making.

Download Full-text

DOP10 Serum N-glycomic biomarkers predict treatment escalation in inflammatory bowel disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjy222.045 ◽

2019 ◽

Vol 13 (Supplement_1) ◽

pp. S032-S033 ◽

Cited By ~ 1

Author(s):

A Shubhakar ◽

B Jansen ◽

A Adams ◽

K Reiding ◽

N Ventham ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Inflammatory Bowel ◽

Treatment Escalation

Download Full-text

Gastrointestinalis manifesztációk monogénes primer immundefektusokban

Orvosi Hetilap ◽

10.1556/650.2018.31275 ◽

2018 ◽

Vol 159 (49) ◽

pp. 2050-2056

Author(s):

Gábor Veres ◽

Zsuzsanna Gaál

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Early Onset ◽

Genetic Alterations ◽

Epigenetic Alterations ◽

Adequate Treatment ◽

Next Generation Sequencing Technology ◽

Bowel Diseases ◽

Continuous Interaction ◽

Inflammatory Bowel

Abstract: Although very early onset inflammatory bowel disease that develops in early childhood (before the age of 6 years) has a different etiology from Crohn’s disease and ulcerative colitis, it is also characterized by chronic inflammation of the gastrointestinal tract. Basically, very early onset inflammatory bowel disease should be considered as an immunodeficiency with monogenic origin where both gastrointestinal manifestations and symptoms of immunodeficiencies may develop in variable combinations. However, in the future, the evaluation of genetic alterations in the background of the disease will probably be performed by next-generation sequencing technology; one should also consider that the sequence of the DNA stands in continuous interaction with a wide variety of environmental effects, among which nutrition should be emphasized by all means. Epigenetic alterations that are induced by environmental factors, could contribute to the pathogenesis of inflammatory bowel diseases that develop during childhood, therefore, they should also be identified during further research. It has a key significance to establish the diagnosis of very early onset inflammatory bowel disease as early as possible, because this could give the opportunity to start the adequate treatment which is bone marrow transplantation in the case of monogenic immunodeficiencies. Orv Hetil. 2018; 159(49): 2050–2056.

Download Full-text