P281 A serum biomarker panel can accurately identify the presence of mucosal ulcers in patients with Crohn’s disease

Abstract Background Ulcer healing is the primary endoscopic treatment target in Crohn’s disease (CD) in routine practice. A novel serum-based biomarker panel named endoscopic healing index (EHI, Monitr, Prometheus Biosciences, San Diego, CA) was developed and validated for identifying mucosal inflammation as assessed by the simple endoscopic score for CD (SES-CD).1 We aimed to define the operating characteristics of EHI in routine practice for mucosal ulcers specifically. Methods EHI was analysed on serum samples paired with endoscopies from adult patients (≥18 years) participating in a prospective biobank (June 2014 to December 2018). Patients with an ileal pouch-anal anastomosis or an ileostomy were excluded. The performance of EHI for endoscopic disease activity was evaluated for subcomponents of SES-CD scores (0–60) including ulcer presence and size, extent of ulcerated surface, extent of affected surface, and presence of strictures. Diagnostic performance was assessed using previously identified cut-offs for optimal EHI performance in CD for ruling out endoscopic activity (20 points) and ruling in endoscopic activity (50 points). Logistic regression was performed to identify confounders of EHI (patient factors, disease characteristics) and for the strength of association between EHI and ulcers (presence, size). Results A total of 205 CD patients were included in the analysis (50% male, median age 37 years). EHI values were significantly higher with increasing ulcer size (p < 0.001). An EHI cut-off of 20 points exhibited modest sensitivity for ruling out any ulcers (85%, 95% CI 77–91), and large (0.5–20 mm) or very large (>20 mm) ulcers specifically (92%, 95% CI 84–97). An EHI cut-off of 50 points had modest specificity for ruling in the presence of any ulcers (85%, 95% CI 76–92), and large or very large ulcers specifically (87%, 95% CI 79–92). After accounting for the total extent of inflamed mucosa, extent of strictured mucosa, and disease location, each 20-point increase in EHI was independently associated with an incremental 1.7-fold increased probability for the presence of a large or very large ulcer (aOR 1.7, 95% CI 1.1–2.6). Conclusion EHI values were associated with ulcer size independent of inflammatory or stricture burden, and accurately identified the presence of ulcers and large or very large ulcers specifically. A cut-off of 50 points can reliably rule in the presence of ulcers and allow for treatment adjustment without endoscopy. A cut-off of 20 points can reliably rule out the presence of ulcers and signal completion of treatment adjustment algorithms. Reference

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P302 Diagnostic accuracy of a serum-based biomarker panel for endoscopic activity in ulcerative colitis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.431 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S304-S304

Author(s):

A HOLMER ◽

B Boland ◽

S Singh ◽

H Le ◽

J Neill ◽

...

Keyword(s):

Ulcerative Colitis ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Diagnostic Accuracy ◽

Operating Characteristic ◽

Mucosal Inflammation ◽

Serum Samples ◽

Receiver Operating Characteristic Curves ◽

Biomarker Panel ◽

Endoscopic Remission

Abstract Background The endoscopic healing index (EHI, Monitr, Prometheus Biosciences, San Diego, CA) is a serum-based biomarker panel available for identifying mucosal inflammation in Crohn’s disease.[1] We aimed to study its performance for identifying mucosal inflammation in ulcerative colitis. Methods EHI was analysed on serum samples paired with endoscopies from adult patients (≥18 years) participating in a prospective biobank (June 2014 to December 2017). Area under receiver operating characteristic curves (AUROC) were used to assess the accuracy of EHI for endoscopic improvement (EI; Mayo endoscopic sub-score [MES] 0–1) and endoscopic remission (ER; MES 0). Sensitivity for EHI was calculated using a cut-off previously identified for Crohn’s disease which optimised performance for ruling out endoscopic activity (20 points). Alternative cut-offs were explored. Results A total of 114 patients were included, with an overall prevalence of 56% and 44% for EI and ER. The AUROC was 0.79 (95% CI 0.70–0.87) for EI and 0.70 (95% CI 0.61–0.80) for ER. A cut-off of 20 points had a sensitivity of 94% (95% CI 83–99%) for ruling out moderate to severe (MES 2–3) endoscopic activity, and a sensitivity of 84% (95% CI 72–92%) for ruling out mild to severe (MES 1–3) endoscopic activity. A cut off of 40 points or higher had > 90% specificity for ruling in moderate to severe (MES 2–3) or mild to severe (MES 1–3) endoscopic activity. (Table 1) Conclusion EHI has favourable accuracy in identifying the presence of mucosal inflammation in patients with ulcerative colitis. Although it was not developed and validated for ulcerative colitis, further validation is warranted. Reference

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Achieving Target Infliximab Drug Concentrations Improves Blood and Fecal Neutrophil Biomarkers in Crohn’s Disease

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa241 ◽

2020 ◽

Cited By ~ 1

Author(s):

Ruben J Colman ◽

Yi-Ting Tsai ◽

Kimberly Jackson ◽

Brendan M Boyle ◽

Joshua D Noe ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Activity Index ◽

Disease Activity Index ◽

Mucosal Healing ◽

Mucosal Inflammation ◽

Operating Characteristics ◽

Cut Points ◽

Peripheral Blood Neutrophil ◽

Drug Concentrations

Abstract Background The neutrophil fecal biomarkers, calprotectin (FCP) and lactoferrin (LCT), and peripheral blood neutrophil CD64 surface receptor (nCD64) are biomarkers for mucosal inflammation in inflammatory bowel disease (IBD). Although FCP has been evaluated as a biomarker for mucosal healing, cut points for LCT and nCD64 are less known. We aimed to identify the cut points for LCT and nCD64 that were associated with FCP remission, with a secondary aim to evaluate the relationship between biochemical outcomes and infliximab (IFX) trough concentrations. Methods We analyzed FCP, LCT, and nCD64 before and after IFX induction in a pediatric Crohn’s disease (CD) cohort study. Week-14 FCP biomarker remission was defined as FCP <250 µg/g, with clinical response defined as a weighted Pediatric Crohn’s Disease Activity Index <12.5 or Δ>17.5 improvement. Predictive outcomes were calculated by receiver operating characteristics (ROCs). Results Among 56 CD patients, ROC analysis identified an infusion 4 LCT <8.06 (area under the receiver operator characteristics [AUROC], 0.934, P < 0.001) and nCD64 <6.12 (AUROC, 0.76, P = 0.02) as the ideal cut points for week-14 FCP biomarker remission. End of induction IFX-trough of >9.4 µg/mL (AUROC, 0.799, P = 0.002) and >11.5 µg/mL (AUROC, 0.835, P = 0.003) were associated with a FCP <250 and FCP <100, respectively. We found patients achieving end of induction trough >5 µg/mL had a median FCP improvement (dose 1 to dose 4) of 90% compared with a median of 35% with levels <5 µg/mL (P = 0.024) with a similar median reduction in nCD64 (48% vs 20%, P = 0.031). Conclusions This study establishes cut points in neutrophil stool and blood biomarkers for both biochemical remission and therapeutic trough levels following induction therapy. Further studies that evaluate pharmacodynamic biomarker targets for endoscopic and histologic healing are warranted.

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Serum Levels of Lipopolysaccharide and 1,3-β-D-Glucan Refer to the Severity in Patients with Crohn’s Disease

Mediators of Inflammation ◽

10.1155/2015/843089 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 20

Author(s):

Yanmin Guo ◽

Guangxi Zhou ◽

Chong He ◽

Wenjing Yang ◽

Zhenkun He ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Antibody Therapy ◽

Serum Levels ◽

Mucosal Barrier ◽

Mucosal Inflammation ◽

Healthy Controls ◽

Serum Samples ◽

Severity Of The Disease ◽

Gut Microbial Community

Objectives. Interactions between the host and gut microbial community contribute to the pathogenesis of Crohn’s disease (CD). In this study, we aimed to detect lipopolysaccharide (LPS) and 1,3-β-D-glucan (BG) in the sera of CD patients and clarify the potential role in the diagnosis and therapeutic approaches.Materials and Methods. Serum samples were collected from 46 patients with active CD (A-CD), 22 CD patients at remission stage (R-CD), and 20 healthy controls, and the levels of LPS, BG, and TNF in sera were determined by ELISA. Moreover, sixteen patients with A-CD received anti-TNF monoclonal antibody therapy (infliximab, IFX) at a dose of 5 mg/kg body weight at weeks 0, 2, and 6, and the levels of LPS and BG were also tested at week 12 after the first intravenous infusion.Results. Serum levels of LPS and BG were found to be markedly increased in A-CD patients compared with R-CD patients and healthy controls(P<0.05). They were also observed to be positively correlated with CDAI, ESR, and SES-CD, respectively(P<0.05). Furthermore, the levels of TNF in sera had a significant correlation with LPS and BG, respectively. The concentrations of LPS and BG were demonstrated to be significantly downregulated in the sera of A-CD patients 12 weeks after IFX treatment(P<0.05), suggesting that blockade of TNF could inhibit bacterial endotoxin absorption, partially through improving intestinal mucosal barrier.Conclusions. Serum levels of LPS and BG are significantly increased in A-CD patients and positively correlated with the severity of the disease. Blockade of intestinal mucosal inflammation with IFX could reduce the levels of LPS and BG in sera. Therefore, this study has shed some light on measurement of serum LPS and BG in the diagnosis and treatment of CD patients.

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Serum Metabolomics Identifies Altered Bioenergetics, Signaling Cascades in Parallel with Exposome Markers in Crohn’s Disease

Molecules ◽

10.3390/molecules24030449 ◽

2019 ◽

Vol 24 (3) ◽

pp. 449 ◽

Cited By ~ 12

Author(s):

Yunjia Lai ◽

Jingchuan Xue ◽

Chih-Wei Liu ◽

Bei Gao ◽

Liang Chi ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

High Resolution Mass Spectrometry ◽

Signaling Cascades ◽

Compound Identification ◽

Serum Samples ◽

Therapy Assessment ◽

Integral Role ◽

Important Pathway ◽

Biomarker Research

: Inflammatory bowel disease (IBD) has stimulated much interest due to its surging incidences and health impacts in the U.S. and worldwide. However, the exact cause of IBD remains incompletely understood, and biomarker is lacking towards early diagnostics and effective therapy assessment. To tackle these, the emerging high-resolution mass spectrometry (HRMS)-based metabolomics shows promise. Here, we conducted a pilot untargeted LC/MS metabolomic profiling in Crohn’s disease, for which serum samples of both active and inactive cases were collected, extracted, and profiled by a state-of-the-art compound identification workflow. Results show a distinct metabolic profile of Crohn’s from control, with most metabolites downregulated. The identified compounds are structurally diverse, pointing to important pathway perturbations ranging from energy metabolism (e.g., β-oxidation of fatty acids) to signaling cascades of lipids (e.g., DHA) and amino acid (e.g., L-tryptophan). Importantly, an integral role of gut microbiota in the pathogenesis of Crohn’s disease is highlighted. Xenobiotics and their biotransformants were widely detected, calling for massive exposomic profiling for future cohort studies as such. This study endorses the analytical capacity of untargeted metabolomics for biomarker development, cohort stratification, and mechanistic interpretation; the findings might be valuable for advancing biomarker research and etiologic inquiry in IBD.

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Targeted 1H NMR metabolomics and immunological phenotyping of human fresh blood and serum samples discriminate between healthy individuals and inflammatory bowel disease patients treated with anti-TNF

Journal of Molecular Medicine ◽

10.1007/s00109-021-02094-y ◽

2021 ◽

Author(s):

Sara Notararigo ◽

Manuel Martín-Pastor ◽

Juan E. Viñuela Roldán ◽

Adriano Quiroga ◽

J. Enrique Dominguez-Munoz ◽

...

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Crohn’S Disease ◽

Clinical Practice ◽

Crohn's Disease ◽

T Lymphocyte ◽

Fresh Blood ◽

Serum Samples ◽

Nmr Metabolomics ◽

Inflammatory Bowel

Abstract Inflammatory bowel disease is a multifactorial etiology, associated with environmental factors that can trigger both debut and relapses. A high level of tumor necrosis factor-α in the gut is the main consequence of immune system imbalance. The aim of treatment is to restore gut homeostasis. In this study, fresh blood and serum samples were used to identify biomarkers and to discriminate between Crohn’s disease and ulcerative colitis patients under remission treated with anti-TNF. Metabolomics based on Nuclear Magnetic Resonance spectroscopy (NMR) was used to detect unique biomarkers for each class of patients. Blood T lymphocyte repertories were characterized, as well as cytokine and transcription factor profiling, to complement the metabolomics data. Higher levels of homoserine-methionine and isobutyrate were identified as biomarkers of Crohn’s disease with ileocolic localization. For ulcerative colitis, lower levels of creatine-creatinine, proline, and tryptophan were found that reflect a deficit in the absorption of essential amino acids in the gut. T lymphocyte phenotyping and its functional profiling revealed that the overall inflammation was lower in Crohn’s disease patients than in those with ulcerative colitis. These results demonstrated that NMR metabolomics could be introduced as a high-throughput evaluation method in routine clinical practice to stratify both types of patients related to their pathology. Key messages NMR metabolomics is a non-invasive tool that could be implemented in the normal clinical practice for IBD to assess beneficial effect of the treatment. NMR metabolomics is a useful tool for precision medicine, in order to sew a specific treatment to a specific group of patients. Finding predictors of response to IFX would be desirable to select patients affected by IBD. Immunological status of inflammations correlates with NMR metabolomics biomarkers.

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P199 MR-enterography in Crohn's disease – evaluation of diagnostic and clinical impact in routine practice

Journal of Crohn s and Colitis ◽

10.1016/s1873-9946(13)60221-4 ◽

2013 ◽

Vol 7 ◽

pp. S88-S89

Author(s):

G. Lang ◽

V. Nicolas ◽

L. Kübler ◽

W. Schmiegel ◽

T. Brechmann

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Clinical Impact ◽

Mr Enterography ◽

Routine Practice

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Dysbiosis of Gut Fungal Microbiota is Associated With Mucosal Inflammation in Crohn’s Disease

Journal of Clinical Gastroenterology ◽

10.1097/mcg.0000000000000035 ◽

2014 ◽

Vol 48 (6) ◽

pp. 513-523 ◽

Cited By ~ 103

Author(s):

Qiurong Li ◽

Chenyang Wang ◽

Chun Tang ◽

Qin He ◽

Ning Li ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Mucosal Inflammation ◽

Fungal Microbiota

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Predicting endoscopic remission in Crohn’s disease by the modified multiplier SES-CD (MM-SES-CD)

Gut ◽

10.1136/gutjnl-2020-323799 ◽

2021 ◽

pp. gutjnl-2020-323799

Author(s):

Neeraj Narula ◽

Emily C L Wong ◽

Jean-Frederic Colombel ◽

William J Sandborn ◽

John Kenneth Marshall ◽

...

Keyword(s):

Logistic Regression ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Assessment Tool ◽

Training Dataset ◽

Mucosal Inflammation ◽

Youden Index ◽

Active Therapy ◽

Testing Dataset ◽

Endoscopic Remission

Background and aimsThe Simple Endoscopic Score for Crohn’s disease (SES-CD) is the primary tool for measurement of mucosal inflammation in clinical trials but lacks prognostic potential. We set to develop and validate a modified multiplier of the SES-CD (MM-SES-CD), which takes into consideration each individual parameter’s prognostic value for achieving endoscopic remission (ER) while on active therapy.MethodsIn this posthoc analysis of three CD clinical trial programmes (n=350 patients, baseline SES-CD ≥ 3 with confirmed ulceration), data were pooled and randomly split into a 70% training and 30% testing cohort. The MM-SES-CD was designed using weights for individual parameters as determined by logistic regression modelling, with 1-year ER (SES-CD < 3) being the dependent variable. A cut point score for low and high probability of ER was determined by using the maximum Youden Index and validated in the testing cohort.ResultsBaseline ulcer size, extent of ulceration and presence of non-passable strictures had the strongest association with 1-year ER as compared with affected surface area, with differential weighting of individual parameters across disease segments being observed during logistic regression. The MM-SES-CD was generated using this weighted regression model and demonstrated strong discrimination for ER in the training dataset (area under the receiver operator curve (AUC) 0.83, 95% CI 0.78 to 0.94) and in the testing dataset (AUC 0.82, 95% CI 0.77 to 0.92). In comparison to the MM-SES-CD scoring model, the original SES-CD score lacks accuracy (AUC 0.60, 95% CI 0.55 to 0.65) for predicting the achievement of ER.ConclusionsWe developed and internally validated the MM-SES-CD as an endoscopic severity assessment tool to predict one-year ER in patients with CD on active therapy.

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