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

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.

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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.

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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.

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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.

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OC-047 Epigenetic alterations at diagnosis predict susceptibility, prognosis and treatment escalation in inflammatory bowel disease – ibd character

10.1136/gutjnl-2017-314472.47 ◽

2017 ◽

Cited By ~ 1

Author(s):

R Kalla ◽

AT Adams ◽

S Vatn ◽

F Bonfiglio ◽

ER Nimmo ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Epigenetic Alterations ◽

Inflammatory Bowel ◽

Treatment Escalation

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

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjx002.187 ◽

2017 ◽

Vol 11 (suppl_1) ◽

pp. S108-S108

Author(s):

A. Adams ◽

R. Kalla ◽

S. Vatn ◽

F. Bonfiglio ◽

E. Nimmo ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Epigenetic Alterations ◽

Inflammatory Bowel ◽

Treatment Escalation

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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.

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Current perspectives on the diagnosis and management of functional anorectal disorders in patients with inflammatory bowel disease

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284818816956 ◽

2018 ◽

Vol 11 ◽

pp. 175628481881695 ◽

Cited By ~ 6

Author(s):

Gaurav B. Nigam ◽

Jimmy K. Limdi ◽

Dipesh H. Vasant

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Significant Proportion ◽

Future Research ◽

Anorectal Dysfunction ◽

Inflammatory Bowel ◽

Treatment Escalation ◽

Inflammatory Changes ◽

Neuromuscular Coordination ◽

Quiescent Disease

Despite advances in inflammatory bowel disease (IBD) therapies, a significant proportion of patients with quiescent disease experience persistent, debilitating symptoms of faecal incontinence (FI), urgency and defaecatory disorders due to anorectal dysfunction. Such symptoms are often underreported or misdiagnosed and can lead to potentially premature treatment ‘escalation’ and under-utilisation of pelvic floor investigations. In this review article, we consider putative pathophysiological post-inflammatory changes resulting in altered anorectal sensitivity, motility and neuromuscular coordination and how this may drive symptoms in quiescent IBD. Finally, we discuss a pragmatic approach to investigating and managing anorectal dysfunction and highlight areas for future research for this often-neglected group of patients.

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OP34 Whole blood profiling of T-cell-derived miRNA allows the development of prognostic models in inflammatory bowel disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.033 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S034-S036

Author(s):

R Kalla ◽

A Adams ◽

R White ◽

C Clarke ◽

A Ivens ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Bowel Disease ◽

Whole Blood ◽

Cd4 T Cells ◽

Differentially Expressed ◽

Inflammatory Bowel ◽

Treatment Escalation

Abstract Background There is an unmet need for blood-based biomarkers that help predict disease and its course at inception to allow tailoring of treatments, achieve early mucosal healing and improve clinical outcomes. In our study, we explore the clinical utility of miRNAs in Inflammatory bowel disease (IBD). Methods A 2-stage prospective multi-centre case–control study was performed. Small RNA sequencing was performed on a discovery cohort of immunomagnetically separated leucocytes (90 CD4+ and CD8+ T-lymphocytes and CD14+ monocytes) from 32 patients (9 CD, 14 UC, 8 healthy controls) to identify differentially expressed cell-specific miRNAs.Top miRNAs were then validated in whole blood in 294 treatment naïve newly diagnosed IBD and non-IBD patients (97 UC, 98 CD, 98 non-IBD) using RT-qPCR, recruited across 5 centres in UK and Europe. Phenotype and outcome data were collected and Cox proportional hazards were derived to assess the contribution of each miRNA to outcomes; defined as the need for 2 or more immunosuppressants and/or surgery after initial disease remission. RT-qPCR target miRNA relative quantification was calculated using 2−ΔΔCq method. Results Each leucocyte subset (30 CD4+ T cells, 28 CD8+ T cells and 32 CD14+ monocytes) was analysed between disease and controls, adjusting for age, gender and batch effects. A total of three miRNAs differentiated IBD from controls in CD4+ T cells including miR-1307-3p (FDR p = 0.01), miR-3615 (p = 0.02) and miR-4792 (p = 0.01); these signals being UC specific. In CD8 T cells, miR-200b-3p was the only differentially expressed miRNA and no CD14+ signals were seen.Three miRNAs were validated in whole blood in an independent multi-centre cohort of 294 patients using RT-qPCR. miR-1307-3p predicted IBD (1.55 fold change (fc),IQR: 1.00–1.87; p = 2.77 × 10–5),in particular UC (1.69 fc, IQR: 1.01–2.00; p = 1.56 × 10–6). Similarly, miR-3615 and miR-4792 were up-regulated in UC compared with controls (1.21fc, IQR:0.91–1.48; p = 8.26 × 10−4and 1.91 fc, IQR: 0.81–2.56; p = 9.21 × 10–3, respectively).There was no correlation with conventional inflammatory markers. Follow-up data were available on 195 IBD patients of which 80 patients required treatment escalation over a median time of 371 days (IQR: 140–711). miR-1307-3p was able to predict disease course in IBD (HR 1.98, IQR: 1.20–3.27; log-rank p = 1.80 × 10−3), in particular CD (HR 2.81; IQR: 1.11–3.53, p = 6.50 × 10–4). In UC, both miR-3615 (HR 3.34, CI: 1.43–7.78, p = 0.01) and miR-4792 (HR 3.96, CI: 1.65–9.52; p = 2.11 × 10–3) predicted treatment escalation. Conclusion We have identified unique CD4+ T-cell miRNAs that are differentially regulated in IBD. These blood-based miRNAs are able to predict treatment escalation at disease inception and have the potential for clinical translation.

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