Title: Extracellular matrix remodeling proteins as biomarkers for clinical assessment and
treatment outcomes in eosinophilic esophagitis
Version: 1 Date: 02 Feb 2023
Reviewer:  Cary C. Cotton
Reviewer's report:
Summary
Eosinophilic esophagitis (EoE) is a common chronic inflammatory condition with an up-
trending epidemiology in Western countries. EoE is caused by an aberrant immune response to
dietary antigens and empiric food elimination diets can induce remission of EoE. The authors
analyzed biomarkers of collagen and neutrophil activity biopsies at baseline and after six weeks
treatment in a small cohort of patients with EoE. In participants with a severe fibrostenotic
disease phenotype compared to mild fibrostenotic features, the authors describe increased CTX-
III and net type 3 collagen fibrolysis at baseline and after treatment. Participants with improved
endoscopic fibrosis scores had increased PRO-C3, increased PRO-C6, and increased type 4
collagen degradation. In participants with a highly inflammatory endoscopic phenotype, they
observed increased neutrophil activity at baseline and after treatment. Markers of type 3 collagen
breakdown were lower in patients with histologic remission than without, but higher in patients
with transient food impactions. Type 4 collagen degradation was also at baseline and post-
treatment in patients that had no food impactions after the diet treatment.
Strengths
• The study employs validated, clinically relevant measures of disease activity: the Straumann
dysphagia index, the EoE endoscopic reference score, post-treatment eosinophil count under 15
per high-power field.
• The study translationally links biomarkers of collagen physiology and neutrophil activity to
clinically measures of disease activity.
• The authors include experts in the clinical care of benign esophageal disease with a strong
track record of well-conducted research published in the literature.
Criticisms
• A significant limitation was the poor histologic response rate to the dietary treatment in the
study, with only 10 patients (35%) achieving an eosinophil count per high-power field under 15
after the diet (Molina-Infante, 2014). This is significantly lower than expected for the four-food
elimination diet. The discussion would be strengthened by comparing the histologic response
rate to the estimates in the literature. To what do the authors attribute this relatively low response
rate?
• It is not clear from the methods whether endoscopic dilation was allowed at either baseline,
or at the six-week follow-up, and if so, whether this was before or after symptoms assessment.
If dilation is a potential factor in symptom and endoscopic changes it should be considered as
a covariate in analysis for symptom-based outcomes.
• All the reported biomarker measurements compare results between subgroups of the cohort,
but I would like to see changes in these biomarkers for the overall cohort as well. Where the
markers relatively flat in the overall cohort with treatment?
• The discussion would benefit from a brief acknowledgement of the observational nature of the
study and its limitations. The heterogeneity that was found with respect to the biomarkers does
not experimentally measure treatment affects, and could plausibly reflect differences at baseline
rather than true differences in effectiveness of the treatment.
References
Molina-Infante J, Arias A, Barrio J, Rodríguez-Sánchez J, Sanchez-Cazalilla M, Lucendo AJ.
Four-food group elimination diet for adult eosinophilic esophagitis: A prospective multicenter
study. J Allergy Clin Immunol. 2014 Nov;134(5):1093-9.e1. doi: 10.1016/j.jaci.2014.07.023.
Epub 2014 Aug 28. PMID: 25174868.
Title: Extracellular matrix remodeling proteins as biomarkers for clinical assessment and
treatment outcomes in eosinophilic esophagitis
Version: 1 Date: 02 Feb 2023
Reviewer:  Cary C. Cotton
Reviewer's report:
Summary
Eosinophilic esophagitis (EoE) is a common chronic inflammatory condition with an up-
trending epidemiology in Western countries. EoE is caused by an aberrant immune response to
dietary antigens and empiric food elimination diets can induce remission of EoE. The authors
analyzed biomarkers of collagen and neutrophil activity biopsies at baseline and after six weeks
treatment in a small cohort of patients with EoE. In participants with a severe fibrostenotic
disease phenotype compared to mild fibrostenotic features, the authors describe increased CTX-
III and net type 3 collagen fibrolysis at baseline and after treatment. Participants with improved
endoscopic fibrosis scores had increased PRO-C3, increased PRO-C6, and increased type 4
collagen degradation. In participants with a highly inflammatory endoscopic phenotype, they
observed increased neutrophil activity at baseline and after treatment. Markers of type 3 collagen
breakdown were lower in patients with histologic remission than without, but higher in patients
with transient food impactions. Type 4 collagen degradation was also at baseline and post-
treatment in patients that had no food impactions after the diet treatment.
Strengths
• The study employs validated, clinically relevant measures of disease activity: the Straumann
dysphagia index, the EoE endoscopic reference score, post-treatment eosinophil count under 15
per high-power field.
• The study translationally links biomarkers of collagen physiology and neutrophil activity to
clinically measures of disease activity.
• The authors include experts in the clinical care of benign esophageal disease with a strong
track record of well-conducted research published in the literature.
Criticisms
• A significant limitation was the poor histologic response rate to the dietary treatment in the
study, with only 10 patients (35%) achieving an eosinophil count per high-power field under 15
after the diet (Molina-Infante, 2014). This is significantly lower than expected for the four-food
elimination diet. The discussion would be strengthened by comparing the histologic response
rate to the estimates in the literature. To what do the authors attribute this relatively low response
rate?
• It is not clear from the methods whether endoscopic dilation was allowed at either baseline,
or at the six-week follow-up, and if so, whether this was before or after symptoms assessment.
If dilation is a potential factor in symptom and endoscopic changes it should be considered as
a covariate in analysis for symptom-based outcomes.
• All the reported biomarker measurements compare results between subgroups of the cohort,
but I would like to see changes in these biomarkers for the overall cohort as well. Where the
markers relatively flat in the overall cohort with treatment?
• The discussion would benefit from a brief acknowledgement of the observational nature of the
study and its limitations. The heterogeneity that was found with respect to the biomarkers does
not experimentally measure treatment affects, and could plausibly reflect differences at baseline
rather than true differences in effectiveness of the treatment.
References
Molina-Infante J, Arias A, Barrio J, Rodríguez-Sánchez J, Sanchez-Cazalilla M, Lucendo AJ.
Four-food group elimination diet for adult eosinophilic esophagitis: A prospective multicenter
study. J Allergy Clin Immunol. 2014 Nov;134(5):1093-9.e1. doi: 10.1016/j.jaci.2014.07.023.
Epub 2014 Aug 28. PMID: 25174868.
Please review this paper.
user
Title: Extracellular matrix remodeling proteins as biomarkers for clinical assessment and
treatment outcomes in eosinophilic esophagitis
Version: 1 Date: 02 Feb 2023
Reviewer:  Cary C. Cotton
Reviewer's report:
Summary
Eosinophilic esophagitis (EoE) is a common chronic inflammatory condition with an up-
trending epidemiology in Western countries. EoE is caused by an aberrant immune response to
dietary antigens and empiric food elimination diets can induce remission of EoE. The authors
analyzed biomarkers of collagen and neutrophil activity biopsies at baseline and after six weeks
treatment in a small cohort of patients with EoE. In participants with a severe fibrostenotic
disease phenotype compared to mild fibrostenotic features, the authors describe increased CTX-
III and net type 3 collagen fibrolysis at baseline and after treatment. Participants with improved
endoscopic fibrosis scores had increased PRO-C3, increased PRO-C6, and increased type 4
collagen degradation. In participants with a highly inflammatory endoscopic phenotype, they
observed increased neutrophil activity at baseline and after treatment. Markers of type 3 collagen
breakdown were lower in patients with histologic remission than without, but higher in patients
with transient food impactions. Type 4 collagen degradation was also at baseline and post-
treatment in patients that had no food impactions after the diet treatment.
Strengths
• The study employs validated, clinically relevant measures of disease activity: the Straumann
dysphagia index, the EoE endoscopic reference score, post-treatment eosinophil count under 15
per high-power field.
• The study translationally links biomarkers of collagen physiology and neutrophil activity to
clinically measures of disease activity.
• The authors include experts in the clinical care of benign esophageal disease with a strong
track record of well-conducted research published in the literature.
Criticisms
• A significant limitation was the poor histologic response rate to the dietary treatment in the
study, with only 10 patients (35%) achieving an eosinophil count per high-power field under 15
after the diet (Molina-Infante, 2014). This is significantly lower than expected for the four-food
elimination diet. The discussion would be strengthened by comparing the histologic response
rate to the estimates in the literature. To what do the authors attribute this relatively low response
rate?
• It is not clear from the methods whether endoscopic dilation was allowed at either baseline,
or at the six-week follow-up, and if so, whether this was before or after symptoms assessment.
If dilation is a potential factor in symptom and endoscopic changes it should be considered as
a covariate in analysis for symptom-based outcomes.
• All the reported biomarker measurements compare results between subgroups of the cohort,
but I would like to see changes in these biomarkers for the overall cohort as well. Where the
markers relatively flat in the overall cohort with treatment?
• The discussion would benefit from a brief acknowledgement of the observational nature of the
study and its limitations. The heterogeneity that was found with respect to the biomarkers does
not experimentally measure treatment affects, and could plausibly reflect differences at baseline
rather than true differences in effectiveness of the treatment.
References
Molina-Infante J, Arias A, Barrio J, Rodríguez-Sánchez J, Sanchez-Cazalilla M, Lucendo AJ.
Four-food group elimination diet for adult eosinophilic esophagitis: A prospective multicenter
study. J Allergy Clin Immunol. 2014 Nov;134(5):1093-9.e1. doi: 10.1016/j.jaci.2014.07.023.
Epub 2014 Aug 28. PMID: 25174868.
assistant