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Serum Biomarkers Identify Patients Who Will Develop Inflammatory Bowel Diseases Up to 5 Years Before Diagnosis

Serum Biomarkers Identify Patients Who Will Develop Inflammatory Bowel Diseases Up to 5 Years Before Diagnosis

Published: March 09, 2020 DOI: https://doi.org/10.1053/j.gastro.2020.03.007

Background & Aims
Biomarkers are needed to identify patients at risk for development of inflammatory bowel diseases. We aimed to identify serum biomarkers of Crohn’s disease and ulcerative colitis that can be detected and quantified before diagnosis.

Methods
We obtained serum samples from patients archived before a diagnosis of Crohn’s disease (n = 200) or ulcerative colitis (n = 199), as well as from 200 healthy individuals (controls), collected from 1998 through 2013 as part of the US Defense Medical Surveillance System. We measured levels of antibodies against microbes (anti–Saccharomyces cerevisiae IgA or IgG, anti– Escherichia coli outer membrane porin C, anti-CBir1, anti-flagellin 2, anti-flagellin X, and perinuclear anti-neutrophil cytoplasmic antibodies) and 1129 proteins in each sample. We then used functional principal component analysis to derive the time-varying trajectory for each marker, which then was used in a multivariate model to predict disease status. Predictive performances at different prediagnosis timepoints were evaluated using area under the receiver operating characteristic curves (AUROCs). Biological pathways that were up-regulated in serum from patients with Crohn’s disease were identified based on changes in protein abundance at different time periods preceding diagnosis.

Results
We identified a panel of 51 protein biomarkers that were predictive of Crohn’s disease within 5 years with an AUROC of 0.76 and a diagnosis within 1 year with an AUROC of 0.87. Based on the proteins included in the panel, imminent development of CD was associated with changes in the complement cascade, lysosomes, innate immune response, and glycosaminoglycan metabolism. Serum antibodies and proteins identified patients who received a diagnosis of ulcerative colitis within 5 years with an AUROC of only 0.56 and within 1 year with an AUROC of 0.72.

Conclusions
We identified a panel of serum antibodies and proteins that were predictive of patients who will receive a diagnosis of Crohn’s disease within 5 years with high accuracy. By contrast we did not identify biomarkers associated with future diagnosis of ulcerative colitis.

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Article Info
Publication History
Published online: March 09, 2020
Accepted: March 2, 2020
Received: December 9, 2019
Publication stage
In Press Journal Pre-Proof
Footnotes
Conflicts of interest
These authors disclose the following: Joana Torres has received speaker fees from Takeda and Janssen. Takahiro Sato, Shannon Telesco, and Richard Strauss are employees of Janssen Research and Development. Xiao-jun Li and Fred Princen are employees of Prometheus. Scott Plevy is employee of Synlogic Therapeutics, past employee of Janssen, and shareholder of Johnson & Johnson. Joseph A. Murray has received research grants from ImmunoGenix, Takeda, Cour, and the National Institutes of Health; received payment for lectures from AbbVie, Amgen, Ferring Pharmaceuticals, Shire, and Takeda; received consulting fees from Amgen, Actobiotics, Bioniz, Celimmune, Eli Lilly Janssen Pharmaceuticals Inova Labs, and Innovate; and royalties from Evelo and Torax Medical. Jean Frédéric Colombel reports receiving research grants from AbbVie, Janssen Pharmaceuticals, and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan Inc, Ferring Pharmaceuticals, Shire, and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene Corporation, Celltrion, Eli Lilly, Enterome, Ferring Pharmaceuticals, Genentech, Janssen Pharmaceuticals, Landos, Ipsen, Medimmune, Merck, Novartis, Pfizer, Shire, Takeda, and TiGenix; and holding stock options in Intestinal Biotech Development and Genfit. A patent application named “A panel of biomarkers for inflammatory bowel disease and uses thereof” has been filed between NRMC, Mount Sinai, Janssen Research and Development, and Prometheus (JBI5154USPSP). The remaining authors disclose no conflicts.
Funding
Support for this study was provided by Janssen Pharmaceuticals and Prometheus Laboratories under a Cooperative Research and Development Agreement entitled “Antimicrobial antibodies as predictors of inflammatory bowel diseases” (NCRADA number NMR-11-3920). Joana Torres received support from the Sandford J. Grossman Charitable Trust .



Predicting Crohn’s Disease Five Years Before First Symptoms

In a study of serum biomarkers of military personnel collected and stored by the U.S. Department of Defense, researchers derived a predictive model for Crohn’s disease. In the PREDICTS study (Proteomic Evaluation and Discovery in an IBD Cohort of Tri-service subjects), researchers identified 51 protein biomarkers that were predictive of developing Crohn’s disease within five years before diagnosis with a 76 percent accuracy. In total, the researchers evaluated 200 patients with Crohn’s disease, 199 with ulcerative colitis, and 200 controls. “The study suggests that biological processes are activated many years before Crohn’s, opening the possibility of developing targeted strategies that could work to prevent or delay disease onset. Although we recognize that a preventive strategy may still be many years down the road, studies analyzing samples taken years before diagnosis will likely contribute to a greater knowledge of disease pathogenesis and have the potential to help us improve treatments. When we combine this finding with the knowledge that early intervention can lead to better outcomes for our Crohn’s patients, we have a truly relevant headline for a disease that has no cure,” says lead author, Joana Torres, PhD, MD, Adjunct Assistant Professor of Medicine (Gastroenterology) at the Icahn School of Medicine at Mount Sinai. In contrast to Crohn’s disease, no single marker, alone or in combination, provided good predictive performance for ulcerative colitis.
 
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Thanks.

Antibodies against Saccharomyces and E. Coli are nost just diagnostic tools to diagnose and predict crohn's disease, but Saccharomyces and E. Coli are involved in perpetuating and maintaining the disease. AIEC are found near granuloma.

The chronic nature of this disease, its unpredictability, and the deep intestinal inflammation involving chronically activated macrophages, are the hallmarks of an unresolved infection.

By contrast we did not identify biomarkers associated with future diagnosis of ulcerative colitis.

UC is a very different disease that has no relationship with crohn's disease in any shape or form. ASCA test fails in UC, antibiotics fail in UC, UC does not involve peyer's patches, ATG16L1 is not involved, UC features no granuloma and virulent E Coli like AIEC can not be isolated in UC patients.

TITLE: Serum Biomarkers Identify Patients Who Will Develop Inflammatory Bowel Diseases
I will continue to argue that the term IBD is unhelpful and should no longer be used. The study was able to identify people who will develop crohn's disease, but unable to do this for UC. Yet the study title clumsily uses the term IBD and the study later has to contradict itself, one can only identify crohn's disease with those biomarkers, not UC.

The term IBD is extremely unhelpful, to make progress we need to recognize that these diseases are not related in any way. More individualized treatment is the only way patients will be helped.
 
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