Title: Serological assessment of PRO-C16 (type XVI collagen formation) reflects intestinal
fibrostenotic strictures in patients with Crohn’s disease
Version: 3 Date: 13 Apr 2025
Reviewer's report:
Comments to the Authors
Intestinal fibrosis-associated stricture could lead to complications in patients with Crohn's
disease (CD). However, no ideal biomarkers are widely accepted for sequential monitoring
of fibrosis and disease progression. The study focuses on serum PRO-C16, which measures
the formation of type XVI collagen. PRO-C16 was significantly elevated in CD patients with
strictures and in an animal model of intestinal fibrosis. The findings in this study indicated that
PRO-C16 may serve as a biomarker of intestinal fibrosis. However, some concerns need to be
addressed.
1. This study showed PRO-16 was able to separate CD patients with strictures (B2) from CD
patients without strictures (B1 and B3). According to the literature, penetrating CD (B3) often
accompanies with intestinal stenosis (Jurgens M, Brand S, Laubender RP, et al. The presence
of fistulas and NOD2 homozygosity strongly predict intestinal stenosis in Crohn's disease
independent of the IL23R genotype. J Gastroenterol 2010;45:721-31). It is recommended to
explain this carefully.
2. In the section of INTRODUCTION, it would be beneficial to refer to additional evidence
of PRO-16 on IBD and gap in this field (the difference between the study and the previous
literature).
3. In Page 6 Line 127, please add the unit after “1”.
4. In Page 9, was PRO-16 associated with inflammatory indicators, such as C-reactive protein,
and erythrocyte sedimentation rate (ESR)?
5. In Table 1, CD patients with peri-anal disease are not included in this study, which may not
be representative of the real situation and affect the results.
6. In Table 1, it is recommended to add the medical treatment and the association with PRO-16.
7. In Table 1, some percentage values in Cohort 2 are missing.
8. In Page 9, the study mentioned that PRO-C16 did not correlate with disease activity, disease
location, gender, or age, but PRO-C16 was numerically elevated in CD patients with active
disease compared to inactive disease. I think the data should be added in the Supplementary
Materials.
9. In Page 11, it seems that the study also investigated PRO-C16 serum levels in CD patients
with inactive and active disease activity. However, the data of the result is missing.
10. In Page 14 Line 231, the study mentioned that the PRO-C16 marker measures active
fibrogenesis, which is not convincing.
11. In Figure 4, it is recommended to show the statistical data. Ideally, fibrosis in the later stage
would be more dominant.
12. The current form of Figure 5 is confusing. It is recommended to add any annotations (such
as day 7 or day 14) in the figure. Besides, it would be better to put Figure 5C and 5D in the
Supplementary Materials.
13. In the figure legends and relevant texts, please add the sample size of each group.
14. It is recommended to use colors in all figures to make them clear.
Title: Serological assessment of PRO-C16 (type XVI collagen formation) reflects intestinal
fibrostenotic strictures in patients with Crohn’s disease
Version: 3 Date: 13 Apr 2025
Reviewer's report:
Comments to the Authors
Intestinal fibrosis-associated stricture could lead to complications in patients with Crohn's
disease (CD). However, no ideal biomarkers are widely accepted for sequential monitoring
of fibrosis and disease progression. The study focuses on serum PRO-C16, which measures
the formation of type XVI collagen. PRO-C16 was significantly elevated in CD patients with
strictures and in an animal model of intestinal fibrosis. The findings in this study indicated that
PRO-C16 may serve as a biomarker of intestinal fibrosis. However, some concerns need to be
addressed.
1. This study showed PRO-16 was able to separate CD patients with strictures (B2) from CD
patients without strictures (B1 and B3). According to the literature, penetrating CD (B3) often
accompanies with intestinal stenosis (Jurgens M, Brand S, Laubender RP, et al. The presence
of fistulas and NOD2 homozygosity strongly predict intestinal stenosis in Crohn's disease
independent of the IL23R genotype. J Gastroenterol 2010;45:721-31). It is recommended to
explain this carefully.
2. In the section of INTRODUCTION, it would be beneficial to refer to additional evidence
of PRO-16 on IBD and gap in this field (the difference between the study and the previous
literature).
3. In Page 6 Line 127, please add the unit after “1”.
4. In Page 9, was PRO-16 associated with inflammatory indicators, such as C-reactive protein,
and erythrocyte sedimentation rate (ESR)?
5. In Table 1, CD patients with peri-anal disease are not included in this study, which may not
be representative of the real situation and affect the results.
6. In Table 1, it is recommended to add the medical treatment and the association with PRO-16.
7. In Table 1, some percentage values in Cohort 2 are missing.
8. In Page 9, the study mentioned that PRO-C16 did not correlate with disease activity, disease
location, gender, or age, but PRO-C16 was numerically elevated in CD patients with active
disease compared to inactive disease. I think the data should be added in the Supplementary
Materials.
9. In Page 11, it seems that the study also investigated PRO-C16 serum levels in CD patients
with inactive and active disease activity. However, the data of the result is missing.
10. In Page 14 Line 231, the study mentioned that the PRO-C16 marker measures active
fibrogenesis, which is not convincing.
11. In Figure 4, it is recommended to show the statistical data. Ideally, fibrosis in the later stage
would be more dominant.
12. The current form of Figure 5 is confusing. It is recommended to add any annotations (such
as day 7 or day 14) in the figure. Besides, it would be better to put Figure 5C and 5D in the
Supplementary Materials.
13. In the figure legends and relevant texts, please add the sample size of each group.
14. It is recommended to use colors in all figures to make them clear.
Please review this paper.
user
Title: Serological assessment of PRO-C16 (type XVI collagen formation) reflects intestinal
fibrostenotic strictures in patients with Crohn’s disease
Version: 3 Date: 13 Apr 2025
Reviewer's report:
Comments to the Authors
Intestinal fibrosis-associated stricture could lead to complications in patients with Crohn's
disease (CD). However, no ideal biomarkers are widely accepted for sequential monitoring
of fibrosis and disease progression. The study focuses on serum PRO-C16, which measures
the formation of type XVI collagen. PRO-C16 was significantly elevated in CD patients with
strictures and in an animal model of intestinal fibrosis. The findings in this study indicated that
PRO-C16 may serve as a biomarker of intestinal fibrosis. However, some concerns need to be
addressed.
1. This study showed PRO-16 was able to separate CD patients with strictures (B2) from CD
patients without strictures (B1 and B3). According to the literature, penetrating CD (B3) often
accompanies with intestinal stenosis (Jurgens M, Brand S, Laubender RP, et al. The presence
of fistulas and NOD2 homozygosity strongly predict intestinal stenosis in Crohn's disease
independent of the IL23R genotype. J Gastroenterol 2010;45:721-31). It is recommended to
explain this carefully.
2. In the section of INTRODUCTION, it would be beneficial to refer to additional evidence
of PRO-16 on IBD and gap in this field (the difference between the study and the previous
literature).
3. In Page 6 Line 127, please add the unit after “1”.
4. In Page 9, was PRO-16 associated with inflammatory indicators, such as C-reactive protein,
and erythrocyte sedimentation rate (ESR)?
5. In Table 1, CD patients with peri-anal disease are not included in this study, which may not
be representative of the real situation and affect the results.
6. In Table 1, it is recommended to add the medical treatment and the association with PRO-16.
7. In Table 1, some percentage values in Cohort 2 are missing.
8. In Page 9, the study mentioned that PRO-C16 did not correlate with disease activity, disease
location, gender, or age, but PRO-C16 was numerically elevated in CD patients with active
disease compared to inactive disease. I think the data should be added in the Supplementary
Materials.
9. In Page 11, it seems that the study also investigated PRO-C16 serum levels in CD patients
with inactive and active disease activity. However, the data of the result is missing.
10. In Page 14 Line 231, the study mentioned that the PRO-C16 marker measures active
fibrogenesis, which is not convincing.
11. In Figure 4, it is recommended to show the statistical data. Ideally, fibrosis in the later stage
would be more dominant.
12. The current form of Figure 5 is confusing. It is recommended to add any annotations (such
as day 7 or day 14) in the figure. Besides, it would be better to put Figure 5C and 5D in the
Supplementary Materials.
13. In the figure legends and relevant texts, please add the sample size of each group.
14. It is recommended to use colors in all figures to make them clear.
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