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  string(97) "Association of fecal calprotectin with the site and the extent of inflammation in Crohn's disease"
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  string(692) "Stool calprotectin is a marker for inflammation in IBD. However, it is not elevated in all patients with IBD, especially Crohn's disease. Research is needed to understand characteristics associated with its elevation in Crohn's disease. In this study, we aim to evaluate whether location (small bowel only, colon only or both small bowel and colon) and extent (affecting one or more segments of small bowel and colon) of inflammation in Crohn's disease affects calprotectin elevation. The findings will guide clinicians on when to choose fecal calprotectin for assessment of inflammation and when to forego its use in favor of a different method of inflammation assessment in Crohn's disease."
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      string(251) "NCT03464136 - A Phase 3b, Multicenter, Randomized, Blinded, Active-Controlled Study to Compare the Efficacy and Safety of Ustekinumab to That of Adalimumab in the Treatment of Biologic Naïve Subjects With Moderately-to-Severely Active Crohn's Disease"
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  string(3592) "Background
Fecal calprotectin (FCP) is a biomarker of IBD activity that correlates well with endoscopic inflammation. While it is highly sensitive in detecting active inflammation in IBD, its specificity is lower in Crohn?s disease (CD) relative to ulcerative colitis. This is thought to be due to its reduced accuracy in small bowel compared to colonic inflammation. However, the evidence for this hypothesis is mixed. Hence, it is unclear if CD location and extent effect the diagnostic performance of FCP.
Objectives
To compare FCP levels among patients with:
1. Limited CD (involving 1 segment of ileum/colon) and extensive CD (involving >1 segments of ileum/colon).
2. Ileal only, colon only and both ileum and colon involvement.
3. Ileal only involvement and single segment colon involvement.
4. To evaluate disease extent and disease location are independent predictors of FCP elevation in CD.
Study Design
Individual trial analysis
Participants
All subjects that participated in the SEAVUE trial (from the Yoda project) and the CALM trial (from Vivli) will be included.
Outcomes measures
Primary
1. Difference in median FCP between patients who have active CD limited to 1 colonic/ileal segment and those who have involvement of more than 1 segment.
2. Difference in median FCP between patients who have active CD limited to the ileum, to the colon and both ileum and colon.
3. Difference in median FCP between patients who have active CD limited to the ileum, to the colon and both ileum and colon.
Secondary
1. Sensitivity and specificity of FCP in patients who have active CD limited to 1 colonic/ileal segment and those who have involvement of more than 1 segment.
2. Sensitivity and specificity of FCP in patients who have active CD limited to the ileum, to the colon and both ileum and colon.
3. Sensitivity and specificity of FCP in patients have active CD limited to the ileum, to the colon and both ileum and colon.
Statistical analysis
We plan to combine data from two trials conducted in CD - SEAVUE and CALM.
The SEAVUE trial was a randomized controlled trial (RCT) comparing the effectiveness of ustekinumab and adalimumab in 386 biologic nave patients with active CD. The CALM trial was an RCT of 244 biologic nave patients with active CD comparing the outcomes of tight control and clinical management strategies. In both trials, all patients had a colonoscopy and FCP at baseline and at the end of the study. Hence, paired FCP and colonoscopy data are available for all patients from both trials on 2 separate occasions yielding a total of 1260 data pairs. In addition, inflammation was scored separately in each of the five segments on colonoscopy (terminal ileum, right colon, transverse colon, left colon and rectum) in both trials providing access to the extent and the location of inflammation in all participants.
Bivariate analysis will be performed using chi square test, student t-test or Wilcoxon rank sum tests as appropriate. Median FCP between the study groups will be compared using Wilcoxon-rank sum test. Sensitivity and specificity of FCP in each group (single segment disease, multiple segment disease, ileal only disease and single segment colon disease) will be calculated separately and ROC curves will be generated. Multivariable analysis will be conducted to identify independent predictors of FCP elevation. All statistical analyses will be conducted using the R software." ["project_brief_bg"]=> string(2210) "Background
Fecal calprotectin is a biomarker of IBD activity that is commonly utilized in clinical practice. Studies have shown that it correlates well with endoscopic inflammation and is useful for the diagnosis and follow-up of patients with IBD. While stool calprotectin is highly sensitive in detecting active inflammation in IBD in general, its specificity is lower in Crohn's disease (CD) relative to ulcerative colitis. One potential explanation is that its accuracy is variable depending on location of inflammation in CD, a finding that has been corroborated by some studies showing it to be less reliable in small bowel CD compared to large bowel CD. On the contrary, some other studies have shown that its accuracy is the same regardless of the location of inflammation. Hence, it is unclear if CD location and extent effect the diagnostic performance of stool calprotectin. Most studies performed to answer this question thus far have been limited by their retrospective design and/or small sample sizes. Hence, larger prospective studies have the potential to answer this question more reliably.
Project significance
While stool calprotectin is important in distinguishing active from inactive inflammation, predicting relapse of symptoms and monitoring response to treatment in IBD, its accuracy is not 100%, especially in CD. In clinical practice, it is not uncommon to see CD patients with active inflammation on colonoscopy but completely normal calprotectin. In such situations, a normal calprotectin might falsely reassure the care team into believing that there is no active inflammation and delay appropriate treatment change until disease is more advanced or the patient is worse symptomatically. This study will help us understand situations where calprotectin might not be a reliable marker of inflammation and help avoid inappropriate clinical decisions. It will promote appropriate care by guiding clinicians to forego stool calprotectin assessment in situations where it is inaccurate and choose alternative methods of disease activity assessment. It will also reduce the physical and financial burden of unreliable testing on patients and the healthcare system." ["project_specific_aims"]=> string(1138) "1. To compare fecal calprotectin levels among patients with limited CD (involving 1 segment of ileum/colon) and extensive CD (involving >1 segments of ileum/colon).
Hypothesis - Stool calprotectin level is lower in CD patients who have inflammation limited to one segment compared to those who have involvement of two or more segments.
2. To compare fecal calprotectin levels among CD patients with ileal only, colon only and both ileum and colon involvement.
Hypothesis - Stool calprotectin level in patients with CD is higher in colonic and ileocolonic disease location compared to ileum only disease.
3. To compare fecal calprotectin levels among CD patients with only ileal involvement and those only single segment colon involvement.
Hypothesis - Stool calprotectin level in patients with CD with similar extent is the same regardless of disease location.
4. To evaluate disease extent and disease location are independent predictors of fecal calprotectin elevation in CD.
Hypothesis- extent but not the location of disease is an independent predictor of fecal calprotectin elevation." ["project_study_design"]=> string(0) "" ["project_study_design_exp"]=> string(0) "" ["project_purposes"]=> array(1) { [0]=> array(2) { ["value"]=> string(50) "research_on_clinical_prediction_or_risk_prediction" ["label"]=> string(50) "Research on clinical prediction or risk prediction" } } ["project_purposes_exp"]=> string(0) "" ["project_software_used"]=> array(2) { ["value"]=> string(1) "r" ["label"]=> string(1) "R" } ["project_software_used_exp"]=> string(0) "" ["project_research_methods"]=> string(259) "Data source - The Yoda project for the SEAVUE trial; Vivli for the CALM trial.
We will include all participants from both trials in our analysis and no subjects will be excluded.
We will pool data from both trials and use R software for analysis" ["project_main_outcome_measure"]=> string(993) "Primary outcomes
1. Difference in median fecal calprotectin between patients who have active CD limited to 1 colonic/ileal segment and those who have involvement of more than 1 segment.
2. Difference in median fecal calprotectin between patients who have active CD limited to the ileum, to the colon and both ileum and colon.
3. Difference in median fecal calprotectin between patients who have active CD limited to the ileum, to the colon and both ileum and colon.
Secondary Outcomes
1. Sensitivity and specificity of fecal calprotectin in patients who have active CD limited to 1 colonic/ileal segment and those who have involvement of more than 1 segment.
2. Sensitivity and specificity of fecal calprotectin in patients who have active CD limited to the ileum, to the colon and both ileum and colon.
3. Sensitivity and specificity of fecal calprotectin in patients have active CD limited to the ileum, to the colon and both ileum and colon." ["project_main_predictor_indep"]=> string(145) "Disease extent - limited to 1 segment OR extending to >1 segment on colonoscopy
Disease location - ileum OR colon OR both ileum and colon." ["project_other_variables_interest"]=> string(202) "CDAI score at baseline
SES-CD score at baseline
Concomitant corticosteroid use
Baseline CRP
Age
Sex
Race
Prior CD related surgery
Disease duration" ["project_stat_analysis_plan"]=> string(2371) "Bivariate analysis of baseline variables will be performed using chi square test, student t-test or Wilcoxon rank sum tests as statistically appropriate. Median fecal calprotectin (FCP) between the study groups will be compared using Wilcoxon-rank sum test. Sensitivity and specificity of FCP in each group (single segment disease, multiple segment disease, ileal only disease and single segment colon disease) will be calculated separately and receiver operating characteristic (ROC) curves will be generated. Multivariable analysis will be conducted to identify independent predictors of FCP elevation including variables of interest (single segment vs multiple segment disease and ileal vs colonic disease) and other variables of interest (specified above). Missing values will be excluded. All statistical analyses will be conducted using the R software.

We chose these two trials since in both trials, all subjects had FCP and colonoscopy performed at week 0 and the end of the trial. So, we will have access to paired FCP and endoscopic severity of inflammation data to analyze and evaluate the chosen outcomes.

Samples size calculation
The AGA Biomarkers in Management of Crohn’s disease guidelines (unpublished but available for public comment on AGA website) reports sensitivity and specificity of fecal calprotectin cut-off of 150 as 81% and 72%, respectively, in Crohn’s disease. Assuming, FCP is elevated in 85% of patients with ileal and colonic disease and in 70% of patients with ileum or colon only disease, we will require 121 patients in each group to have 80% power to detect the difference between ileocolonic and ileal or colon only disease with 95% confidence. Across both SEAVUE and CALM studies, we have ~275 FCP and colonoscopy data pairs from patients with ileal only, ~240 data pairs from patients with colon only and ~610 data pairs from patients with ileum and colon disease, which is well over the sample size required based on our power calculation.

Both trials have data regarding patient age, gender, disease duration, site and severity of inflammation at study initiation and study completion and fecal calprotectin at study initiation and study completion. We will obtain these patient level data from each trial, pool these data and then analyze the data per the analysis plan." ["project_timeline"]=> string(300) "Anticipated project start date - 10/31/2023
Projected analysis completion date - 1/31/2024
Projected data of drafting of manuscript - 2/28/2024
Projected date of first submission for publication - 3/15/2024
Projected date of reporting of results to YODA project - 3/1/2024" ["project_dissemination_plan"]=> string(370) "We plan to disseminate the findings of this research project among the gastroenterology and IBD community. We plan to present the findings at one of the major GI conferences - DDW, ACG or ECCO. We also plan to publish the findings in one of the major GI/IBD journal - Clinical Gastroenterology and Hepatology, Journal of Crohn's and Colitis or Inflammatory Bowel Disease" ["project_bibliography"]=> string(1236) "

1. Kopylov U, Yung DE, Engel T, et al. Fecal calprotectin for the prediction of small-bowel Crohn’s disease by capsule endoscopy: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2016;28(10):1137-44, doi:10.1097/MEG.0000000000000692
2. D’Amico F, Nancey S, Danese S, et al. A Practical Guide for Faecal Calprotectin Measurement: Myths and Realities. J Crohns Colitis 2021;15(1):152-161, doi:10.1093/ecco-jcc/jjaa093
3. Colombel JF, Panaccione R, Bossuyt P, et al. Effect of tight control management on Crohn’s disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet 2017;390(10114):2779-2789, doi:10.1016/S0140-6736(17)32641-7
4. Sands BE, Irving PM, Hoops T, et al. Ustekinumab versus adalimumab for induction and maintenance therapy in biologic-naive patients with moderately to severely active Crohn’s disease: a multicentre, randomised, double-blind, parallel-group, phase 3b trial. Lancet 2022;399(10342):2200-2211, doi:10.1016/S0140-6736(22)00688-2
5. State M, Negreanu L, Voiosu T, et al. Surrogate markers of mucosal healing in inflammatory bowel disease: A systematic review. World J Gastroenterol 2021;27(16):1828-1840, doi:10.3748/wjg.v27.i16.1828

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2023-5192

General Information

How did you learn about the YODA Project?: Colleague

Conflict of Interest

Request Clinical Trials

Associated Trial(s):
  1. NCT03464136 - A Phase 3b, Multicenter, Randomized, Blinded, Active-Controlled Study to Compare the Efficacy and Safety of Ustekinumab to That of Adalimumab in the Treatment of Biologic Naïve Subjects With Moderately-to-Severely Active Crohn's Disease
What type of data are you looking for?: Individual Participant-Level Data, which includes Full CSR and all supporting documentation

Request Clinical Trials

Data Request Status

Status: Approved Pending DUA Signature

Research Proposal

Project Title: Association of fecal calprotectin with the site and the extent of inflammation in Crohn's disease

Scientific Abstract: Background
Fecal calprotectin (FCP) is a biomarker of IBD activity that correlates well with endoscopic inflammation. While it is highly sensitive in detecting active inflammation in IBD, its specificity is lower in Crohn?s disease (CD) relative to ulcerative colitis. This is thought to be due to its reduced accuracy in small bowel compared to colonic inflammation. However, the evidence for this hypothesis is mixed. Hence, it is unclear if CD location and extent effect the diagnostic performance of FCP.
Objectives
To compare FCP levels among patients with:
1. Limited CD (involving 1 segment of ileum/colon) and extensive CD (involving >1 segments of ileum/colon).
2. Ileal only, colon only and both ileum and colon involvement.
3. Ileal only involvement and single segment colon involvement.
4. To evaluate disease extent and disease location are independent predictors of FCP elevation in CD.
Study Design
Individual trial analysis
Participants
All subjects that participated in the SEAVUE trial (from the Yoda project) and the CALM trial (from Vivli) will be included.
Outcomes measures
Primary
1. Difference in median FCP between patients who have active CD limited to 1 colonic/ileal segment and those who have involvement of more than 1 segment.
2. Difference in median FCP between patients who have active CD limited to the ileum, to the colon and both ileum and colon.
3. Difference in median FCP between patients who have active CD limited to the ileum, to the colon and both ileum and colon.
Secondary
1. Sensitivity and specificity of FCP in patients who have active CD limited to 1 colonic/ileal segment and those who have involvement of more than 1 segment.
2. Sensitivity and specificity of FCP in patients who have active CD limited to the ileum, to the colon and both ileum and colon.
3. Sensitivity and specificity of FCP in patients have active CD limited to the ileum, to the colon and both ileum and colon.
Statistical analysis
We plan to combine data from two trials conducted in CD - SEAVUE and CALM.
The SEAVUE trial was a randomized controlled trial (RCT) comparing the effectiveness of ustekinumab and adalimumab in 386 biologic nave patients with active CD. The CALM trial was an RCT of 244 biologic nave patients with active CD comparing the outcomes of tight control and clinical management strategies. In both trials, all patients had a colonoscopy and FCP at baseline and at the end of the study. Hence, paired FCP and colonoscopy data are available for all patients from both trials on 2 separate occasions yielding a total of 1260 data pairs. In addition, inflammation was scored separately in each of the five segments on colonoscopy (terminal ileum, right colon, transverse colon, left colon and rectum) in both trials providing access to the extent and the location of inflammation in all participants.
Bivariate analysis will be performed using chi square test, student t-test or Wilcoxon rank sum tests as appropriate. Median FCP between the study groups will be compared using Wilcoxon-rank sum test. Sensitivity and specificity of FCP in each group (single segment disease, multiple segment disease, ileal only disease and single segment colon disease) will be calculated separately and ROC curves will be generated. Multivariable analysis will be conducted to identify independent predictors of FCP elevation. All statistical analyses will be conducted using the R software.

Brief Project Background and Statement of Project Significance: Background
Fecal calprotectin is a biomarker of IBD activity that is commonly utilized in clinical practice. Studies have shown that it correlates well with endoscopic inflammation and is useful for the diagnosis and follow-up of patients with IBD. While stool calprotectin is highly sensitive in detecting active inflammation in IBD in general, its specificity is lower in Crohn's disease (CD) relative to ulcerative colitis. One potential explanation is that its accuracy is variable depending on location of inflammation in CD, a finding that has been corroborated by some studies showing it to be less reliable in small bowel CD compared to large bowel CD. On the contrary, some other studies have shown that its accuracy is the same regardless of the location of inflammation. Hence, it is unclear if CD location and extent effect the diagnostic performance of stool calprotectin. Most studies performed to answer this question thus far have been limited by their retrospective design and/or small sample sizes. Hence, larger prospective studies have the potential to answer this question more reliably.
Project significance
While stool calprotectin is important in distinguishing active from inactive inflammation, predicting relapse of symptoms and monitoring response to treatment in IBD, its accuracy is not 100%, especially in CD. In clinical practice, it is not uncommon to see CD patients with active inflammation on colonoscopy but completely normal calprotectin. In such situations, a normal calprotectin might falsely reassure the care team into believing that there is no active inflammation and delay appropriate treatment change until disease is more advanced or the patient is worse symptomatically. This study will help us understand situations where calprotectin might not be a reliable marker of inflammation and help avoid inappropriate clinical decisions. It will promote appropriate care by guiding clinicians to forego stool calprotectin assessment in situations where it is inaccurate and choose alternative methods of disease activity assessment. It will also reduce the physical and financial burden of unreliable testing on patients and the healthcare system.

Specific Aims of the Project: 1. To compare fecal calprotectin levels among patients with limited CD (involving 1 segment of ileum/colon) and extensive CD (involving >1 segments of ileum/colon).
Hypothesis - Stool calprotectin level is lower in CD patients who have inflammation limited to one segment compared to those who have involvement of two or more segments.
2. To compare fecal calprotectin levels among CD patients with ileal only, colon only and both ileum and colon involvement.
Hypothesis - Stool calprotectin level in patients with CD is higher in colonic and ileocolonic disease location compared to ileum only disease.
3. To compare fecal calprotectin levels among CD patients with only ileal involvement and those only single segment colon involvement.
Hypothesis - Stool calprotectin level in patients with CD with similar extent is the same regardless of disease location.
4. To evaluate disease extent and disease location are independent predictors of fecal calprotectin elevation in CD.
Hypothesis- extent but not the location of disease is an independent predictor of fecal calprotectin elevation.

Study Design:

What is the purpose of the analysis being proposed? Please select all that apply.: Research on clinical prediction or risk prediction

Software Used: R

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: Data source - The Yoda project for the SEAVUE trial; Vivli for the CALM trial.
We will include all participants from both trials in our analysis and no subjects will be excluded.
We will pool data from both trials and use R software for analysis

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: Primary outcomes
1. Difference in median fecal calprotectin between patients who have active CD limited to 1 colonic/ileal segment and those who have involvement of more than 1 segment.
2. Difference in median fecal calprotectin between patients who have active CD limited to the ileum, to the colon and both ileum and colon.
3. Difference in median fecal calprotectin between patients who have active CD limited to the ileum, to the colon and both ileum and colon.
Secondary Outcomes
1. Sensitivity and specificity of fecal calprotectin in patients who have active CD limited to 1 colonic/ileal segment and those who have involvement of more than 1 segment.
2. Sensitivity and specificity of fecal calprotectin in patients who have active CD limited to the ileum, to the colon and both ileum and colon.
3. Sensitivity and specificity of fecal calprotectin in patients have active CD limited to the ileum, to the colon and both ileum and colon.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: Disease extent - limited to 1 segment OR extending to >1 segment on colonoscopy
Disease location - ileum OR colon OR both ileum and colon.

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: CDAI score at baseline
SES-CD score at baseline
Concomitant corticosteroid use
Baseline CRP
Age
Sex
Race
Prior CD related surgery
Disease duration

Statistical Analysis Plan: Bivariate analysis of baseline variables will be performed using chi square test, student t-test or Wilcoxon rank sum tests as statistically appropriate. Median fecal calprotectin (FCP) between the study groups will be compared using Wilcoxon-rank sum test. Sensitivity and specificity of FCP in each group (single segment disease, multiple segment disease, ileal only disease and single segment colon disease) will be calculated separately and receiver operating characteristic (ROC) curves will be generated. Multivariable analysis will be conducted to identify independent predictors of FCP elevation including variables of interest (single segment vs multiple segment disease and ileal vs colonic disease) and other variables of interest (specified above). Missing values will be excluded. All statistical analyses will be conducted using the R software.

We chose these two trials since in both trials, all subjects had FCP and colonoscopy performed at week 0 and the end of the trial. So, we will have access to paired FCP and endoscopic severity of inflammation data to analyze and evaluate the chosen outcomes.

Samples size calculation
The AGA Biomarkers in Management of Crohn’s disease guidelines (unpublished but available for public comment on AGA website) reports sensitivity and specificity of fecal calprotectin cut-off of 150 as 81% and 72%, respectively, in Crohn’s disease. Assuming, FCP is elevated in 85% of patients with ileal and colonic disease and in 70% of patients with ileum or colon only disease, we will require 121 patients in each group to have 80% power to detect the difference between ileocolonic and ileal or colon only disease with 95% confidence. Across both SEAVUE and CALM studies, we have ~275 FCP and colonoscopy data pairs from patients with ileal only, ~240 data pairs from patients with colon only and ~610 data pairs from patients with ileum and colon disease, which is well over the sample size required based on our power calculation.

Both trials have data regarding patient age, gender, disease duration, site and severity of inflammation at study initiation and study completion and fecal calprotectin at study initiation and study completion. We will obtain these patient level data from each trial, pool these data and then analyze the data per the analysis plan.

Narrative Summary: Stool calprotectin is a marker for inflammation in IBD. However, it is not elevated in all patients with IBD, especially Crohn's disease. Research is needed to understand characteristics associated with its elevation in Crohn's disease. In this study, we aim to evaluate whether location (small bowel only, colon only or both small bowel and colon) and extent (affecting one or more segments of small bowel and colon) of inflammation in Crohn's disease affects calprotectin elevation. The findings will guide clinicians on when to choose fecal calprotectin for assessment of inflammation and when to forego its use in favor of a different method of inflammation assessment in Crohn's disease.

Project Timeline: Anticipated project start date - 10/31/2023
Projected analysis completion date - 1/31/2024
Projected data of drafting of manuscript - 2/28/2024
Projected date of first submission for publication - 3/15/2024
Projected date of reporting of results to YODA project - 3/1/2024

Dissemination Plan: We plan to disseminate the findings of this research project among the gastroenterology and IBD community. We plan to present the findings at one of the major GI conferences - DDW, ACG or ECCO. We also plan to publish the findings in one of the major GI/IBD journal - Clinical Gastroenterology and Hepatology, Journal of Crohn's and Colitis or Inflammatory Bowel Disease

Bibliography:

1. Kopylov U, Yung DE, Engel T, et al. Fecal calprotectin for the prediction of small-bowel Crohn’s disease by capsule endoscopy: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2016;28(10):1137-44, doi:10.1097/MEG.0000000000000692
2. D’Amico F, Nancey S, Danese S, et al. A Practical Guide for Faecal Calprotectin Measurement: Myths and Realities. J Crohns Colitis 2021;15(1):152-161, doi:10.1093/ecco-jcc/jjaa093
3. Colombel JF, Panaccione R, Bossuyt P, et al. Effect of tight control management on Crohn’s disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet 2017;390(10114):2779-2789, doi:10.1016/S0140-6736(17)32641-7
4. Sands BE, Irving PM, Hoops T, et al. Ustekinumab versus adalimumab for induction and maintenance therapy in biologic-naive patients with moderately to severely active Crohn’s disease: a multicentre, randomised, double-blind, parallel-group, phase 3b trial. Lancet 2022;399(10342):2200-2211, doi:10.1016/S0140-6736(22)00688-2
5. State M, Negreanu L, Voiosu T, et al. Surrogate markers of mucosal healing in inflammatory bowel disease: A systematic review. World J Gastroenterol 2021;27(16):1828-1840, doi:10.3748/wjg.v27.i16.1828