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Discovery of biomarker candidates associated with the risk of short- and long-term relapse after infliximab withdrawal in Crohns patients: a proteomics-based study

ABSTRACT: Objective: A subset of Crohns disease (CD) patients experiences long-term remission after infliximab withdrawal. Biomarkers are needed to identify those patients.Design: New biomarkers of relapse were searched in the baseline serum of CD patients stopping infliximab when they were under combined therapy (antimetabolite and infliximab) and stable clinical remission (STORI cohort, n=102). From shotgun proteomics experiment (discovery step), biomarker candidates were identified and further targeted by selected reaction monitoring (verification step). The dataset was stratified to search for markers of short- (<6 months) or long-term relapse (>6 months). The risk of relapse and the predicting capacity associated with biomarker candidates were evaluated using univariate Cox model and log-rank statistic, respectively. To test their complementary predicting capacity, biomarker candidates were systematically combined in pairs. Results: Distinct biomarker candidates were associated with the risk (hazard ratio: HR) of short- (15 proteins, 2.9

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Serum

DISEASE(S): Crohn's Disease

SUBMITTER: nicolas Pierre

LAB HEAD: Edouard LOUIS

PROVIDER: PXD019008 | Pride | 2020-10-19

REPOSITORIES: Pride

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			Action	DRS
	121130-24743-09-AII-F01_IA_final_protein.csv	Csv
	121130-24750-09-AII-F01_IA_final_protein.csv	Csv
	121130-24752-09-AII-F01_IA_final_protein.csv	Csv
	121203-24741-09-AII-F01_IA_final_protein.csv	Csv
	121203-24745-09-AII-F01_IA_final_protein.csv	Csv

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Discovery of biomarker candidates associated with the risk of short- and long-term relapse after infliximab withdrawal in Crohn’s patients: a proteomics-based study

Project description:Objective: A subset of Crohn’s disease (CD) patients experiences long-term remission after infliximab withdrawal. Biomarkers are needed to identify those patients. Design: New biomarkers of relapse were searched in the baseline serum of CD patients stopping infliximab when they were under combined therapy (antimetabolite and infliximab) and stable clinical remission (STORI cohort, n=102). From shotgun proteomics experiment (discovery step), biomarker candidates were identified and further targeted by selected reaction monitoring (verification step). The dataset was stratified to search for markers of short- (<6 months) or long-term relapse (>6 months). The risk of relapse and the predicting capacity associated with biomarker candidates were evaluated using univariate Cox model and log-rank statistic, respectively. To test their complementary predicting capacity, biomarker candidates were systematically combined in pairs. Results: Distinct biomarker candidates were associated with the risk (hazard ratio: HR) of short- (15 proteins, 2.9<HR<16.1, p<0.05) and long-term (17 proteins, 2<HR<4.4, p<0.05) relapse, they reflect different pathophysiological processes. In stratified and non-stratified datasets, novel marker combinations exhibited a high predicting capacity as shown by their higher Z-scores (FDR<0.001) than CRP and faecal calprotectin (current references in predicting relapse). Conclusion: We identified for the first time circulating biomarker candidates associated with the risk of long-term relapse in CD patients stopping infliximab. We also highlight a sequence of pathophysiological processes leading to relapse, this could help to better understand the disease progression. Our findings may pave the way for a better non-invasive evaluation of the risk of relapse when contemplating anti-TNFα withdrawal in CD patients.

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External validation of serum biomarkers predicting short-term and mid/long-term relapse in Crohn’s disease patients stopping infliximab

Project description:Background and aims: In Crohn’s disease (CD) patients on combination therapy (infliximab and immunosuppressant) and stopping infliximab (STORI cohort), the risk of short-term (<6 months) and mid/long-term relapse (>6 months) was associated with specific blood protein profiles. Our aim was to test the external validity of this finding in the SPARE cohort. Methods: The SPARE trial included patients with CD in sustained steroid-free clinical remission, on combination therapy and randomly allocated to one of three arms: continuing combination therapy, stopping infliximab or stopping immunosuppressant. As it was performed in STORI, 202 immune-related proteins were measured in the baseline serum of SPARE (arm stopping infliximab, n=63-67). The proteins associated with time to relapse (univariable Cox model) were compared between STORI and SPARE. The external validation of biomarkers (individually and combined by pairs) was evaluated by a discrimination analysis (c-statistic) and compared to CRP, faecal calprotectin and a previously validated model (CEASE). Results: In STORI and SPARE, specific blood protein profiles were associated with the risk of short-term (eg, high level: CRP, HP, IL6, CLEC4C, 3.5<HR<17.5, p<0.05) and mid/long-term relapse (eg, low level: FLT3LG, SERPINA4, FGF2, 0.15<HR<0.36, p<0.05). At external validation, our top 10 biomarker pairs showed a higher discriminative ability (c-statistic) than the CEASE model, CRP and faecal calprotectin to predict short-term (0.76-0.80 vs 0.74 vs 0.71 vs 0.69, respectively ) and mid/long-term relapse (0.66-0.68 vs 0.61 vs 0.52 vs 0.59, respectively). Conclusion: In CD patients stopping infliximab, we confirm that the risk of short-term and mid/long-term relapse is associated with specific blood protein profiles showing the potential to guide infliximab withdrawal.

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Expression data in LoVo cells treated with MEK inhibitor

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