Phenotypic Heterogeneity in Crohn’s Disease-Associated Intestinal Strictures: An Exploratory Retrospective Cohort Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1. The manuscript addresses an important clinical issue, namely the heterogeneity of intestinal strictures in Crohn’s disease. This is a relevant topic, as stricturing disease remains a major source of morbidity and frequently requires endoscopic or surgical intervention. The Introduction is clear and well-structured, and the manuscript is generally readable. The idea of exploring different phenotypic aspects within one cohort is interesting. However, the study has several important limitations, including its retrospective, single-center design, the relatively small sample size, and the large number of multivariable analyses in relation to the number of events. As a result, many of the findings appear exploratory and should be interpreted with caution.
2.  The main aim seems to be to identify factors associated with different phenotypic aspects of Crohn’s disease, including extraintestinal manifestations, smoking, fistulas, hepatic steatosis, stenosis location, and abscess formation. However, this is not clearly formulated in the manuscript, and the authors should state more explicitly what the primary research question is and how the different analyses relate to it. The topic itself is clinically relevant, and the manuscript adds some value by combining multiple phenotypic features within a single cohort. That said, many of the associations explored have already been described in previous studies, so the level of novelty is moderate. In its current form, the study provides a broad overview of possible associations between clinical features and different disease phenotypes, but it is more useful as a descriptive and hypothesis-generating analysis rather than something that directly informs clinical decision-making.
3. The Methods section would benefit from additional detail. It is not entirely clear how patients were identified in the institutional database. The criteria used to define and classify strictures, especially when both endoscopy and imaging were available, should be explained more clearly. The definition and assessment of extraintestinal manifestations and autoimmune diseases should also be specified. In addition, the criteria for including variables in the multivariable models should be described more precisely. It would also be helpful to indicate whether any checks for model stability are performed.
4. There are also concerns regarding the statistical analysis. Several models include a relatively high number of predictors compared to the number of events, which raises the risk of overfitting. Many of the reported odds ratios have very wide confidence intervals, suggesting instability of the estimates. Some of the reported associations are therefore difficult to interpret robustly. These results should be presented more cautiously, and the text should avoid overly strong statements.
5. Another issue concerns the consistency of the results. There are discrepancies between the narrative text and the tables. For example, in the smoking model, the text reports a positive association with cholecystolithiasis, whereas the corresponding table shows the opposite. Some confidence intervals and values also appear inconsistent between tables and the main text. These issues need to be carefully checked and corrected, as they reduce confidence in the statistical reporting.
6. Although the total cohort includes 96 patients, several analyses are based on smaller numbers, and this is not clearly explained. The handling of missing data should be described more transparently, and each table should clearly indicate the number of observations included in the analysis. The tables themselves contain a large amount of data, but are not always easy to interpret due to inconsistent denominators, unclear handling of missing data, and insufficient labeling. Improving these aspects would significantly enhance readability.
7. The general conclusion that stricturing Crohn’s disease is a heterogeneous condition is supported by the data. However, some statements in the Discussion and Conclusions go beyond what can be justified based on the study design and results. Given the retrospective design and the limitations mentioned above, the findings should be presented more cautiously and framed as exploratory. The references are generally appropriate and relevant, although the inclusion of more recent literature on phenotyping and fibrosis could be considered.
8. Overall, this is a relevant and potentially useful study, but it requires substantial revision. In particular, the manuscript would benefit from a clearer definition of the study aim, improved methodological description, correction of inconsistencies, and a more cautious interpretation of the results. The main concerns relate to the methodological detail and the robustness of the statistical analyses, especially given the number of analyses performed relative to the sample size and the wide confidence intervals observed. Reconsideration after major revision is recommended.

Author Response

We sincerely thank the reviewer for the careful and constructive evaluation of our manuscript entitled
“Clinical Phenotypes and Associated Factors in Crohn’s Disease-Associated Intestinal Strictures: An Exploratory Retrospective Cohort Study.”

We highly appreciate the reviewer’s detailed comments and suggestions, which substantially helped improve the methodological transparency, conceptual structure, statistical interpretation, and overall clarity of the manuscript. In response to the reviewer’s recommendations, we extensively revised the manuscript, including major modifications to the Introduction, Methods, Results, Discussion, tables, statistical reporting, and Conclusions. All changes have been carefully incorporated into the revised version of the manuscript.

Below, we provide a detailed point-by-point response to each comment.

Comment 1

“The manuscript addresses an important clinical issue, namely the heterogeneity of intestinal strictures in Crohn’s disease. This is a relevant topic, as stricturing disease remains a major source of morbidity and frequently requires endoscopic or surgical intervention. The Introduction is clear and well-structured, and the manuscript is generally readable. The idea of exploring different phenotypic aspects within one cohort is interesting. However, the study has several important limitations, including its retrospective, single-center design, the relatively small sample size, and the large number of multivariable analyses in relation to the number of events. As a result, many of the findings appear exploratory and should be interpreted with caution.”

Response 1

We thank the reviewer for the positive assessment of the clinical relevance and conceptual interest of our study. We fully agree that the retrospective single-center design, limited sample size, and relatively large number of exploratory multivariable analyses require cautious interpretation.

In response to this important comment, we extensively revised the manuscript to more consistently frame the study as an exploratory and hypothesis-generating analysis rather than a predictive or confirmatory modeling study.

Specifically:

• The manuscript title was revised to explicitly emphasize the exploratory nature of the study.
• The Abstract, Methods, Results, Discussion, and Conclusions were systematically revised to consistently use cautious and non-causal language.
• Multiple statements emphasizing the exploratory and hypothesis-generating character of the analyses were added throughout the manuscript.
• The Statistical Analysis section was substantially revised to explicitly acknowledge the potential risk of statistical instability and overfitting due to the limited number of events relative to the number of variables included in some models.
• Additional statements discussing wide confidence intervals and the limited robustness of some exploratory associations were added to the Results and Discussion sections.
• The Limitations section was expanded to more comprehensively discuss the retrospective design, absence of a control cohort, limited sample size, model instability, and exploratory statistical framework.

The revised manuscript now consistently emphasizes that the findings should be interpreted cautiously and require validation in larger prospective multicenter cohorts.

Comment 2

“The main aim seems to be to identify factors associated with different phenotypic aspects of Crohn’s disease, including extraintestinal manifestations, smoking, fistulas, hepatic steatosis, stenosis location, and abscess formation. However, this is not clearly formulated in the manuscript, and the authors should state more explicitly what the primary research question is and how the different analyses relate to it. The topic itself is clinically relevant, and the manuscript adds some value by combining multiple phenotypic features within a single cohort. That said, many of the associations explored have already been described in previous studies, so the level of novelty is moderate. In its current form, the study provides a broad overview of possible associations between clinical features and different disease phenotypes, but it is more useful as a descriptive and hypothesis-generating analysis rather than something that directly informs clinical decision-making.”

Response 2

We thank the reviewer for this highly valuable conceptual comment. We fully agree that the primary objective and rationale underlying the different exploratory analyses required clearer definition and integration.

To address this concern, the Introduction, Outcomes section, Results, Discussion, and Conclusions were substantially revised to more clearly define the conceptual framework of the study.

Specifically:

• We clarified that the primary aim of the study was not to identify predictors of stricture development, but rather to explore multidimensional phenotypic heterogeneity within patients with established stricturing Crohn’s disease.
• A new conceptual framework was introduced emphasizing the interaction between systemic, structural, penetrating, behavioral, and metabolic disease domains within stricturing Crohn’s disease.
• The Outcomes section was revised to explicitly explain why exploratory analyses of EIM, smoking status, fistulizing disease, hepatic steatosis, stenosis location, and abscess formation were performed.
• Transitional statements were added throughout the Results section to better connect the different exploratory analyses to the overall phenotype-oriented study concept.
• The Discussion was substantially restructured to integrate the different exploratory findings into a broader phenotype-oriented interpretation framework rather than discussing isolated associations.
• The Conclusions were revised to avoid overinterpretation and to more clearly emphasize the exploratory and descriptive nature of the study.

We also fully agree that several investigated associations have previously been reported in the literature. Accordingly, the revised manuscript now more carefully frames the study as an exploratory phenotype-oriented analysis intended to generate hypotheses and support future prospective investigations rather than directly inform clinical decision-making.

Comment 3

“The Methods section would benefit from additional detail. It is not entirely clear how patients were identified in the institutional database. The criteria used to define and classify strictures, especially when both endoscopy and imaging were available, should be explained more clearly. The definition and assessment of extraintestinal manifestations and autoimmune diseases should also be specified. In addition, the criteria for including variables in the multivariable models should be described more precisely. It would also be helpful to indicate whether any checks for model stability are performed.”

Response 3

We sincerely thank the reviewer for these important methodological suggestions. In response, the Methods section was comprehensively revised and expanded to improve methodological transparency and reproducibility.

The following major changes were implemented:

Patient Identification and Cohort Selection

• We added a detailed description of the patient identification process, specifying that patients were retrospectively identified through screening of institutional electronic medical records, endoscopy reports, radiological databases, and discharge documentation at the University Hospital Tübingen.
• A detailed patient flowchart was added to transparently illustrate the screening process, duplicate exclusion, exclusion criteria, and final cohort selection.

Definition of Intestinal Strictures

• The definition of intestinal strictures was substantially expanded.
• We now specify that strictures were defined as persistent luminal narrowing with associated prestenotic dilatation, obstructive symptoms, and/or impaired endoscopic passage documented on endoscopy or cross-sectional imaging (MRE, CT, or intestinal ultrasound).
• We additionally clarified that when both endoscopic and radiological information were available, classification was based on the overall clinical assessment documented in the medical records.

Definition of Extraintestinal Manifestations and Autoimmune Diseases

• The assessment of extraintestinal manifestations was clarified in greater detail.
• We now explicitly state that EIM included musculoskeletal, dermatologic, ophthalmologic, and hepatobiliary manifestations documented according to established clinical criteria.
• Autoimmune diseases were additionally defined based on documented physician diagnoses and included autoimmune hepatobiliary disorders (e.g., autoimmune hepatitis, primary biliary cholangitis, autoimmune pancreatitis), autoimmune thyroiditis, and selected rheumatologic/systemic autoimmune disorders.

Multivariable Model Construction

• The Statistical Analysis section was substantially revised.
• We clarified that variable selection for multivariable analyses was based on a combination of clinical relevance, biological plausibility, and statistical significance in univariate analyses.
• We additionally clarified that the analyses were designed as exploratory phenotype-oriented models rather than predictive risk models.

Model Stability and Overfitting

• We explicitly acknowledged that formal model stability analyses were not performed due to the exploratory design and limited event numbers.
• Additional statements discussing potential statistical instability and overfitting risk were added to both the Methods and Limitations sections.

We believe that these revisions substantially improved the methodological transparency and clarity of the manuscript.

Comment 4

“There are also concerns regarding the statistical analysis. Several models include a relatively high number of predictors compared to the number of events, which raises the risk of overfitting. Many of the reported odds ratios have very wide confidence intervals, suggesting instability of the estimates. Some of the reported associations are therefore difficult to interpret robustly. These results should be presented more cautiously, and the text should avoid overly strong statements.”

Response 4

We fully agree with the reviewer’s concerns regarding the exploratory nature and limited robustness of some multivariable analyses.

In response, the statistical interpretation and wording throughout the manuscript were comprehensively revised to ensure substantially more cautious interpretation of the findings.

Specifically:

• The Statistical Analysis section now explicitly discusses the risk of overfitting and statistical instability due to limited event numbers relative to model complexity.
• The Results section was systematically revised to replace potentially overinterpretative formulations such as “independently associated” with more cautious wording including “associated within the exploratory model” or “exploratory association.”
• Additional cautionary statements regarding wide confidence intervals and limited robustness of estimates were added throughout the Results section.
• The Discussion and Conclusions were revised to avoid causal or mechanistic overinterpretation.
• The exploratory and hypothesis-generating character of the analyses is now consistently emphasized throughout the manuscript.
• The Limitations section was substantially expanded to discuss statistical uncertainty, model instability, and the need for validation in prospective cohorts.

We believe that these revisions substantially improved the statistical transparency and interpretative balance of the manuscript.

Comment 5

“Another issue concerns the consistency of the results. There are discrepancies between the narrative text and the tables. For example, in the smoking model, the text reports a positive association with cholecystolithiasis, whereas the corresponding table shows the opposite. Some confidence intervals and values also appear inconsistent between tables and the main text. These issues need to be carefully checked and corrected, as they reduce confidence in the statistical reporting.”

Response 5

We thank the reviewer for carefully identifying these important inconsistencies.

In response, all statistical analyses, tables, confidence intervals, odds ratios, and p-values were comprehensively rechecked against the original statistical outputs.

The following revisions were implemented:

• The inconsistency regarding smoking status and cholecystolithiasis was corrected.
• All multivariable regression outputs were carefully reverified and harmonized between the narrative text and corresponding tables.
• Odds ratios, confidence intervals, decimal formatting, and p-values were standardized throughout the manuscript.
• Variable definitions and table labels were revised to improve clarity and consistency.
• Additional table footnotes were added to clarify handling of missing data and variable-specific denominators.

These revisions substantially improved consistency and transparency of the statistical reporting.

Comment 6

“Although the total cohort includes 96 patients, several analyses are based on smaller numbers, and this is not clearly explained. The handling of missing data should be described more transparently, and each table should clearly indicate the number of observations included in the analysis. The tables themselves contain a large amount of data, but are not always easy to interpret due to inconsistent denominators, unclear handling of missing data, and insufficient labeling. Improving these aspects would significantly enhance readability.”

Response 6

We thank the reviewer for this important comment regarding transparency of missing data handling and table readability.

In response, both the Statistical Analysis section and the tables were substantially revised.

Specifically:

• We clarified that missing data were handled using case-wise exclusion.
• We explicitly stated that the number of observations available for individual variables and subgroup analyses varied slightly across models and tables.
• Table footnotes were added clarifying that percentages were calculated based on available cases for each variable.
• Table labels, formatting, and abbreviations were revised to improve readability and consistency.
• Variable terminology and subgroup definitions were harmonized across all tables.

These revisions substantially improved the interpretability and transparency of the presented data.

Comment 7

“The general conclusion that stricturing Crohn’s disease is a heterogeneous condition is supported by the data. However, some statements in the Discussion and Conclusions go beyond what can be justified based on the study design and results. Given the retrospective design and the limitations mentioned above, the findings should be presented more cautiously and framed as exploratory. The references are generally appropriate and relevant, although the inclusion of more recent literature on phenotyping and fibrosis could be considered.”

Response 7

We thank the reviewer for this highly valuable comment and fully agree that the Discussion and Conclusions required more cautious interpretation and stronger integration of recent fibrosis and phenotyping literature.

In response:

• The Discussion and Conclusions were comprehensively revised to consistently emphasize the exploratory and hypothesis-generating nature of the study.
• Potentially overinterpretative or causal language was systematically softened throughout the manuscript.
• Additional statements discussing the retrospective design, statistical uncertainty, and limited generalizability were added.
• A new discussion paragraph was incorporated addressing current concepts of fibrostenotic phenotype heterogeneity, fibrosis-oriented disease stratification, precision medicine approaches, and integrated phenotypic characterization in Crohn’s disease.
• Several recent references regarding fibrosis assessment, fibrostenotic phenotypes, and precision medicine in inflammatory bowel disease were added and discussed in the revised manuscript.

We believe these revisions substantially improved the scientific balance and contemporary contextualization of the Discussion.

Comment 8

“Overall, this is a relevant and potentially useful study, but it requires substantial revision. In particular, the manuscript would benefit from a clearer definition of the study aim, improved methodological description, correction of inconsistencies, and a more cautious interpretation of the results. The main concerns relate to the methodological detail and the robustness of the statistical analyses, especially given the number of analyses performed relative to the sample size and the wide confidence intervals observed. Reconsideration after major revision is recommended.”

Response 8

We sincerely thank the reviewer for the overall constructive evaluation and thoughtful recommendations.

In response to the reviewer’s comments, the manuscript underwent extensive revision involving major modifications to the Introduction, Methods, Results, Discussion, statistical analyses, tables, and Conclusions.

The revised manuscript now:

• more clearly defines the exploratory phenotype-oriented study aim,
• substantially improves methodological transparency,
• includes a detailed patient flowchart,
• clarifies variable definitions and statistical methodology,
• corrects inconsistencies between text and tables,
• consistently emphasizes the exploratory and hypothesis-generating nature of the analyses,
• acknowledges statistical instability and overfitting risk,
• incorporates additional contemporary fibrosis and phenotyping literature,
• and substantially softens interpretation of the findings.

We are very grateful for the reviewer’s insightful comments, which significantly improved the scientific quality, clarity, and transparency of the manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

I reviewed the paper entitled Clinical Phenotypes and Associated Factors in
Crohn’s Disease- Related Intestinal Strictures: A Retrospective Cohort Study
by Stefano Fusco et al.
Here are my comments
The majore shortcomings are:
One-center retrospective study , no controls cohort , small-size group.
Methodology is unclealry presented and is very confusing. The risk factors for
intestinal strictures are not clearly presented. They should assessed the
association between clinical factors and intestinal stricture in a unvariable and
multivariable analysis manner, repectively. Instead, they choose to analysis few
outcomes (Extraintestinal manifestations (EIM) Smoking status ,Perianal
fistulas , Hepatic steatosis , Stenosis location (rectal and ileal stenosis) Abscess
formation ......it is not clear why) in a very confusing manner and not in
relationship with the porpose of primary objective.
They used different clinical variables for different outcomes (why did they use
multivariable analysis for EIM , smoking, fistula....? is not clear).
A flow chart is missing so it is not clear how did the authors selecte the patients
and what were the reasons for exclusion.
Moreover, why is important the correlation between CD and hepatic steatosis or
cholecystolithiasis. If there are any data regarding the association between
intestinal stricture and liver steatosis or biliary lithiasis the authors should have
mentioned it at the introduction
Introduction dose not highlight the issue . The authors made a general
overview without emphazing the current status of CD phenotype and clinical
risk factors-related intestinal stricture.
The authors have mixed the results with the discussions. They should provide
results and then at the discussion section they should discuss the results.
It is not clear why the therapy with infliximab was administrated in patients
with rectal abcesses (infliximab is contraindicated in infections) probabily is a
bias of collecting data.
The tables are crowded, they dose not look smat and there are some errors
(e.g. ulcer in table 4, what do they mean? Gastric ulcer? Ileal? Colonic? )
Conclusions are only partially in concordance with the results. 

Author Response

We sincerely thank the reviewer for the careful evaluation of our manuscript and for the highly valuable comments and suggestions. We appreciate the reviewer’s critical assessment, which substantially improved the scientific clarity, methodological transparency, and overall structure of the manuscript. All comments were carefully considered, and the manuscript was extensively revised accordingly. Detailed responses are provided below.

Comment 1:
“One-center retrospective study, no controls cohort, small-size group.”

Response 1:
We thank the reviewer for this important comment and fully acknowledge these limitations. The retrospective single-center design, the absence of a non-stricturing control cohort, and the relatively limited sample size represent important methodological constraints of the present study.

To address this concern, we substantially revised the Discussion and Limitations sections and consistently emphasized the exploratory nature of the analyses throughout the manuscript. We additionally revised the manuscript title to explicitly reflect the exploratory study design:

“Phenotypic Heterogeneity in Crohn’s Disease-Associated Intestinal Strictures: An Exploratory Retrospective Cohort Study.”

Furthermore, we clarified that the aim of the study was not to identify definitive predictors of stricture development, but rather to explore multidimensional phenotypic heterogeneity within patients with established stricturing Crohn’s disease.

The following limitation statement was added and expanded in the Discussion section:

“This study has several limitations. The retrospective single-center design may introduce selection bias and limits causal inference. The absence of a non-stricturing control group prevents identification of factors specifically associated with stricture development. In addition, the relatively small sample size is reflected by wide confidence intervals in several analyses, and the results should therefore be interpreted cautiously within the exploratory framework of the study.”

Comment 2:
“Methodology is unclealry presented and is very confusing. The risk factors for intestinal strictures are not clearly presented. They should assessed the association between clinical factors and intestinal stricture in a unvariable and multivariable analysis manner, respectively. Instead, they choose to analysis few outcomes (Extraintestinal manifestations (EIM) Smoking status, Perianal fistulas, Hepatic steatosis, Stenosis location (rectal and ileal stenosis), Abscess formation ......it is not clear why) in a very confusing manner and not in relationship with the porpose of primary objective.”

Response 2:
We sincerely thank the reviewer for this important observation. We agree that the original version of the manuscript insufficiently distinguished between predictive analyses and exploratory phenotype-oriented analyses.

To address this concern, the Introduction, Outcomes section, Statistical Analysis section, Results, Discussion, and Conclusions were extensively revised.

Most importantly, the primary objective of the study was reformulated to clarify that the manuscript does not aim to identify predictors of stricture development, but rather to explore phenotypic heterogeneity within patients with established Crohn’s disease-associated intestinal strictures.

The following statement was added to the Introduction:

“Therefore, the primary aim of this exploratory retrospective cohort study was not to identify predictors of stricture development, but rather to explore phenotypic heterogeneity within patients with established Crohn’s disease-associated intestinal strictures by analyzing systemic, structural, penetrating, behavioral, and metabolic disease manifestations.”

Furthermore, the Outcomes section was revised to explicitly justify the selected exploratory disease domains analyzed in separate models, including:

• extraintestinal manifestations,

• smoking status,

• penetrating disease manifestations,

• hepatic steatosis,

• stenosis localization patterns,

• and abscess formation.

The Statistical Analysis section was also substantially revised to clarify that the multivariable analyses were intentionally designed as exploratory phenotype-oriented models rather than predictive risk models.

We believe these revisions substantially improve the conceptual clarity and methodological transparency of the manuscript.

Comment 3:
“They used different clinical variables for different outcomes (why did they use multivariable analysis for EIM, smoking, fistula....? is not clear).”

Response 3:
We appreciate this important methodological comment and agree that the conceptual framework underlying the exploratory multivariable analyses required clearer explanation.

To address this concern, we extensively revised the Statistical Analysis section and clarified that the analyses were designed to evaluate phenotype clustering patterns within stricturing Crohn’s disease rather than establish causal or predictive relationships.

The following clarification was added:

“The analyses were designed to evaluate phenotype clustering patterns within stricturing Crohn’s disease rather than establish causal or predictive relationships. As a result, certain variables were analyzed both as predictors and outcomes in different models.”

In addition, we clarified that separate exploratory models were constructed to evaluate clinically relevant disease domains within stricturing Crohn’s disease, including systemic manifestations, penetrating disease behavior, metabolic alterations, smoking-associated patterns, and stenosis localization.

Comment 4:
“A flow chart is missing so it is not clear how did the authors selecte the patients and what were the reasons for exclusion.”

Response 4:
We thank the reviewer for this valuable suggestion.

In response, a detailed flow chart illustrating patient identification, duplicate exclusion, exclusion criteria, and final cohort selection was added as Figure 1.

In addition, the Methods section was substantially expanded to describe:

• the institutional screening process,

• inclusion criteria,

• exclusion criteria,

• reasons for exclusion,

• and final cohort selection.

Specifically, we clarified that patients were excluded in cases of:

• insufficient clinical data,

• non-Crohn’s disease-related stenosis,

• lack of confirmed intestinal strictures,

• or missing follow-up information.

We believe this significantly improves methodological transparency and readability.

Comment 5:
“Moreover, why is important the correlation between CD and hepatic steatosis or cholecystolithiasis. If there are any data regarding the association between intestinal stricture and liver steatosis or biliary lithiasis the authors should have mentioned it at the introduction”

Response 5:
We sincerely thank the reviewer for this important observation.

To address this concern, we substantially expanded the Introduction by adding a dedicated paragraph discussing systemic metabolic and hepatobiliary manifestations in Crohn’s disease, including hepatic steatosis and biliary disease.

The revised Introduction now highlights that:

• chronic systemic inflammation,

• cumulative disease burden,

• intestinal surgery,

• nutritional alterations,

• and long-term therapy exposure

may contribute to metabolic and hepatobiliary manifestations in Crohn’s disease.

In addition, several references addressing NAFLD and hepatobiliary disease in inflammatory bowel disease were added to support the rationale for including these exploratory analyses.

Furthermore, the Discussion section was expanded to contextualize the observed exploratory associations between hepatic steatosis and penetrating or surgical disease manifestations.

Comment 6:
“Introduction dose not highlight the issue. The authors made a general overview without emphazing the current status of CD phenotype and clinical risk factors-related intestinal stricture.”

Response 6:
We thank the reviewer for this important suggestion.

The Introduction was substantially revised and restructured to better emphasize:

• the clinical relevance of fibrostenotic Crohn’s disease,

• current concepts of phenotypic heterogeneity,

• mechanisms of intestinal fibrosis,

• challenges in stricture phenotyping,

• and currently recognized risk factors associated with stricturing disease behavior.

Furthermore, the revised Introduction now more clearly frames stricturing Crohn’s disease as a heterogeneous and multidimensional disease phenotype rather than a uniform disease entity.

Comment 7:
“The authors have mixed the results with the discussions. They should provide results and then at the discussion section they should discuss the results.”

Response 7:
We appreciate this important comment and agree that the original manuscript occasionally mixed descriptive results with interpretative discussion.

To address this concern, the Results section was substantially revised to focus more strictly on descriptive and statistical findings, while interpretative statements were removed or transferred to the Discussion section.

In parallel, the Discussion section was restructured to provide clearer contextual interpretation of the findings while consistently emphasizing the exploratory nature of the analyses and the limitations of the study design.

We believe this restructuring substantially improved the readability and scientific clarity of the manuscript.

Comment 8:
“It is not clear why the therapy with infliximab was administrated in patients with rectal abcesses (infliximab is contraindicated in infections) probabily is a bias of collecting data.”

Response 8:
We thank the reviewer for this important observation and agree that this finding required clearer contextual interpretation.

To address this concern, the Results section was revised to describe infliximab exposure in a strictly descriptive manner without implying causality.

In addition, the Discussion section was expanded to clarify that the observed association likely reflects confounding by indication and treatment allocation bias within patients with severe penetrating disease phenotypes rather than a direct causal relationship between infliximab exposure and abscess formation.

We additionally clarified that biologic therapy may have been initiated after adequate infection control or in patients with previously treated fistulizing disease.

Comment 9:
“The tables are crowded, they dose not look smat and there are some errors (e.g. ulcer in table 4, what do they mean? Gastric ulcer? Ileal? Colonic?)”

Response 9:
We thank the reviewer for this valuable comment.

All tables were carefully revised to improve readability, consistency, and labeling.

Specifically:

• unclear terminology was corrected,

• formatting inconsistencies were revised,

• denominators were harmonized,

• and labels were clarified.

The term “ulcer” was replaced with the more precise term “intestinal ulceration” to avoid ambiguity.

In addition, several inconsistencies between tables and narrative text were carefully corrected after comprehensive re-review of the statistical output.

Comment 10:
“Conclusions are only partially in concordance with the results.”

Response 10:
We appreciate this important observation and agree that the conclusions in the original version occasionally exceeded what could be supported by the exploratory analyses.

Therefore, the Conclusions section was substantially revised and reformulated more cautiously.

The revised Conclusions now consistently emphasize:

• the exploratory nature of the analyses,

• the retrospective design,

• the limited sample size,

• the wide confidence intervals,

• and the need for external validation in larger prospective cohorts.

Interpretative statements were moderated accordingly, and causal implications were avoided throughout the revised manuscript.

Once again, we sincerely thank the reviewer for the thoughtful and highly constructive comments, which substantially improved the scientific quality, clarity, and methodological transparency of the manuscript.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Editor,

Thank you for the opportunity to evaluate the revised version of the manuscript.

The authors addressed most of my major comments, and the manuscript has improved substantially. In particular, they now clearly state that the study is exploratory and hypothesis-generating, both in the Abstract and throughout the Methods and Discussion sections. The primary aim of the study has also been clarified, with greater emphasis on phenotypic heterogeneity among patients with established Crohn’s disease-associated strictures rather than on predictors of stricture development.

The Methods section has been significantly expanded. The authors now provide a clearer description of patient identification, the definition and classification of strictures, the assessment of extraintestinal manifestations and autoimmune diseases, and the interpretation of endoscopic and imaging findings. The addition of a patient selection flow chart has also improved the transparency of the study design.

The revised manuscript addresses concerns regarding overfitting and wide confidence intervals. The authors repeatedly emphasize the exploratory nature of the analyses, use more cautious language when interpreting associations, and explicitly acknowledge the absence of formal model stability analyses. Information regarding missing data handling and case-wise exclusion has also been added.

Several inconsistencies in terminology and table presentation have been corrected, which has improved the overall readability of the manuscript.

Some limitations remain, particularly the relatively small cohort size in relation to the number of multivariable analyses performed and the wide confidence intervals observed in several models. In addition, a minor inconsistency still appears to persist regarding the cholecystolithiasis values reported in the smoking model.

Overall, however, the manuscript has been substantially improved, and most of my major concerns have been adequately addressed.

Kind regards,

Jakub Żurawski