Investigating the Role of Gastrointestinal-Specific Anxiety and Perceived Disability in the Adjustment to Inflammatory Bowel Disease

Round 1

Reviewer 1 Report

INTRODUCTION

The model appears consistent with the hypothesis described in the introduction, although it should have more supporting evidence. I wonder if there might also be the presence of mediators capable of influencing this hypothesized relationship

METHOD_PARTECIPANT

Is 16 the age that allows independent participation in the study?

Among the criteria, how did we adjust ourselves with respect to understanding the language? And in the case of pathologies capable of altering the cognitive sphere?

DISCUSSION

In discussions, reference to similar studies should include characteristics of the population studied in order to emphasize what the authors describe in their findings.

LIMITATION

Here I would include that part of the population was also excluded from the sampling as, it is hypothesized, not all subjects have access (or compliance) to the online platform

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Author Response

We would like to thank the reviewers for their time and effort in critiquing the manuscript. We agree that most of the points raised and suggested changes will significantly improve the quality of the manuscript. We provide below a detailed point by point response to each of the matters raised and we hope this will be to the standards of the reviewers.

Reviewer 1

INTRODUCTION

1. The model appears consistent with the hypothesis described in the introduction, although it should have more supporting evidence.

We thank the reviewer for the comment. We have expanded some of the evidence around the basis for the model in the introduction

2. I wonder if there might also be the presence of mediators capable of influencing this hypothesized relationship.

This is a very good point. Although the model being tested has some complexity, the authors believe that the trade-off of including further variables would result in an oversaturated model that would not provide a clearer answer to these specific research questions. This reflection and the recognition of additional mediators/moderators is now added in the limitations section.

METHOD_PARTiCIPANT

3. Is 16 the age that allows independent participation in the study?

This is a very relevant question. In Scotland where the study was conducted the age of consent starts at 16, hence the lower age limit of 16. This has been now highlighted in the participants description.

4. Among the criteria, how did we adjust ourselves with respect to understanding the language? And in the case of pathologies capable of altering the cognitive sphere?

This is a very good point and we thank the reviewer for pointing this out. However, due to the logistics of the study where data collection was done exclusively through an online platform and with limited human resources, such a detailed screening was not possible. Therefore the sample relied on self-selection when it comes to these potential confounders. This has now been highlighted in the limitations section of the discussion.

DISCUSSION

5. In discussion, reference to similar studies should include characteristics of the population studied in order to emphasize what the authors describe in their findings.

The discussion has been extended and updated with more recent references.

LIMITATION

6. Here I would include that part of the population was also excluded from the sampling as, it is hypothesized, not all subjects have access (or compliance) to the online platform.

As before this is a very astute point. We have now reflected this critique in the limitations section.

Reviewer 2 Report

The aim of the manuscript was generous, as it appeared by the end of Introduction. We do need research on this topic, in order to better approach our IBD patients. Even though I find the study too simplistic (and the authors mentioned its limitations), I appreciate their idea.

Major issues:

1.       Lines 154-155 and Table 1: Only 95.9% were diagnosed with CD or UC. Collagenic colitis and lymphocytic colitis are definitely not part of IBD. The manuscript has to be rewritten as those two entities do not pose the same problems as IBD does. They must be excluded. Moreover, “Other” should be excluded, as well. The manuscript has to be correct.

2.       References are incredibly old, while excellent, recent ones have been published. Please read and update. I did not find any reference from 2021, 2002 or 2023. This is not acceptable. (e.g. Trieschmann K, Chang L, Park S, Naliboff B, Joshi S, Labus JS, Sauk JS, Limketkai BN, Mayer EA. The visceral sensitivity index: A novel tool for measuring GI-symptom-specific anxiety in inflammatory bowel disease. Neurogastroenterol Motil. 2022 Sep;34(9):e14384. And many more...)

Other comments/suggestions:

1. Abstract:

a.          Objective: Please revise the long sentence and make it clearer.

b.         Methods: Please state that you included only patients older then 16 years of age.

c.      Results: Please generously expand them and make them clearer.

d.         Conclusion: What do you mean by “IBD experience”?

 2. Keywords: I would suggest to improve and expand Keywords. No need to insert those words that are already mentioned in the title. The importance of Keywords is to improve indexing. Please add here “disease activity”, “gastrointestinal-specific anxiety” maybe others too. “Visceral anxiety”, “perceived disability” and “IBD“ are part of the title.

 3. Introduction:

a. Line 17: Please correct: IBD are not “autoimmune” diseases per se.

b. Instead of ref.1 or to be added: Wang R, Li Z, Liu S, Zhang D. Global, regional and national burden of inflammatory bowel disease in 204 countries and territories from 1990 to 2019: a systematic analysis based on the Global Burden of Disease Study 2019. BMJ Open. 2023 Mar 28;13(3):e065186.

c. Ref. 3 is old. Please update and write the sentence accordingly.

d. Other references in this paragraph are quite old or not as important as recent specific guidelines, elaborated by scientific societies/organizations. Please revise. Most cited references related to the topic (stress coping, quality of life, perceived stigma, anxiety, depression etc etc) are from 2008-2010, some from 2012, 2013, 2016, 2017 and only one from 2019. Please update. There are plenty of good manuscripts, published between 2021 and 2023.

e. The sentence in Lines 37-39 should be reformulated, with pertinent reference. Nowadays, IBD is considered the result of interactions between genetics, epigenetics, immune responses, environmental factors and GI microbiota.

f. The authors wrote about “gastrointestinal-specific anxiety” and did not introduce the notion of “visceral anxiety”. I have no problem with using “gastrointestinal-specific anxiety”, as I know the topic. However, this could be confusing for those not familiar with the terms. The title contains “visceral anxiety”, as does the Abstract. However, in the main text, there is nothing about “visceral anxiety”. Please revise.

g. The aim is explained well here. This could be adapted to the Abstract.

h. Figure 1: Please adjust the horizontal arrow.

 4. Methods:

a. Line 96 – reference for HBI is [21], not [20]. Please correct.

b. Line 107: please correct ref. [21] with [22]

c. Line 108: ref. [22] should be replaced with [23]

d. It appears that, from line 96 and onwards, references are wrongly numbered (one number behind). Please revise.

 5. Results – need complete revision, according to the major issue I mentioned.

 6. Discussion – it appears pretty scarce. Please add and use recent references.

Except for typos and long sentences, that require correction, I find the English language fine (minor revision required).

Author Response

We would like to thank the reviewers for their time and effort in critiquing the manuscript. We agree that most of the points raised and suggested changes will significantly improve the quality of the manuscript. We provide below a detailed point by point response to each of the matters raised and we hope this will be to the standards of the reviewers.

The aim of the manuscript was generous, as it appeared by the end of Introduction. We do need research on this topic, in order to better approach our IBD patients. Even though I find the study too simplistic (and the authors mentioned its limitations), I appreciate their idea.

We would like to thank the reviewer for the overall generous comment.

Major issues:

1. Lines 154-155 and Table 1: Only 95.9% were diagnosed with CD or UC. Collagenic colitis and lymphocytic colitis are definitely not part of IBD. The manuscript has to be rewritten as those two entities do not pose the same problems as IBD does. They must be excluded. Moreover, “Other” should be excluded, as well. The manuscript has to be correct.

We would respectfully disagree with the reviewer on this issue. We understand there is an academic discussion regarding clinical presentation and histological markers, and whether forms of microscopic colitis should be included under the IBD umbrella. However, Microscopic colitis are widely recognized as forms of Inflammatory bowel disease by most health care providers as a less common form of IBD. More relevant to this study, the charity from which most participants were recruited recognizes Microscopic colitis as a form of IBD (see  https://crohnsandcolitis.org.uk/info-support/information-about-crohns-and-colitis/all-information-about-crohns-and-colitis/understanding-crohns-and-colitis/microscopic-colitis ) therefore not including these participants would be disingenuous. 

2. References are incredibly old, while excellent, recent ones have been published. Please read and update. I did not find any reference from 2021, 2002 or 2023. This is not acceptable. (e.g. Trieschmann K, Chang L, Park S, Naliboff B, Joshi S, Labus JS, Sauk JS, Limketkai BN, Mayer EA. The visceral sensitivity index: A novel tool for measuring GI-symptom-specific anxiety in inflammatory bowel disease. Neurogastroenterol Motil. 2022 Sep;34(9):e14384. And many more...)

The references and argument for the study have now been significantly updated throughout the introduction section.

Other comments/suggestions:

1. Abstract:
2. Objective: Please revise the long sentence and make it clearer.

We respectfully do not understand this point. The sentence describes the essence of the study in it’s shortest from naming all variables included and the proposed relationship between them. We believe the sentence is as clear as it can get.

1. Methods: Please state that you included only patients older then 16 years of age.

This has now been added in line xxx

1. Results: Please generously expand them and make them clearer.

Doing so would significantly take the abstract over the 200 word limit. We prefer to let the reader see the expanded section in the body of the manuscript rather than expand it here.

1. Conclusion: What do you mean by “IBD experience”?

This has now been reworded into “ Findings suggest that the effect of multiple psychosocial variables in the experience of people living with IBD  and its respective outcomes should be taken into account when planning treatment.”

2. Keywords: I would suggest to improve and expand Keywords. No need to insert those words that are already mentioned in the title. The importance of Keywords is to improve indexing. Please add here “disease activity”, “gastrointestinal-specific anxiety” maybe others too. “Visceral anxiety”, “perceived disability” and “IBD“ are part of the title.

The suggested keywords have now been added.

3. Introduction:
4. Line 17: Please correct: IBD are not “autoimmune” diseases per se.

This has now been amended to “Inflammatory Bowel Disease (IBD) encompasses a variety of non-infectious diseases that cause chronic inflammation of the gastrointestinal (GI) tract”

2019. Instead of ref.1 or to be added: Wang R, Li Z, Liu S, Zhang D. Global, regional and national burden of inflammatory bowel disease in 204 countries and territories from 1990 to 2019: a systematic analysis based on the Global Burden of Disease Study 2019. BMJ Open. 2023 Mar 28;13(3):e065186.

This reference has now been updated.

1. Ref. 3 is old. Please update and write the sentence accordingly.

This reference has been updated to: Seyedian, S. S., Nokhostin, F., & Malamir, M. D. (2019). A review of the diagnosis, prevention, and treatment methods of inflammatory bowel disease. Journal of medicine and life, 12(2), 113–122. https://doi.org/10.25122/jml-2018-0075

2019. Other references in this paragraph are quite old or not as important as recent specific guidelines, elaborated by scientific societies/organizations. Please revise. Most cited references related to the topic (stress coping, quality of life, perceived stigma, anxiety, depression etc etc) are from 2008-2010, some from 2012, 2013, 2016, 2017 and only one from 2019. Please update. There are plenty of good manuscripts, published between 2021 and 2023.

The references have been substantially updated throughout the manuscript.

1. The sentence in Lines 37-39 should be reformulated, with pertinent reference. Nowadays, IBD is considered the result of interactions between genetics, epigenetics, immune responses, environmental factors and GI microbiota.

This sentence has now been revised to reflect this more complex model.

1. The authors wrote about “gastrointestinal-specific anxiety” and did not introduce the notion of “visceral anxiety”. I have no problem with using “gastrointestinal-specific anxiety”, as I know the topic. However, this could be confusing for those not familiar with the terms. The title contains “visceral anxiety”, as does the Abstract. However, in the main text, there is nothing about “visceral anxiety”. Please revise.

The main reason for this is that visceral anxiety and GSA tend to be used interchangeably due to the title of the most common measure used to assess this construct (Visceral Sensitivity Index)This has now been revised throughout the manuscript.

1. The aim is explained well here. This could be adapted to the Abstract.

As stated before this would significantly increase the word count for the abstract above the recommended 200 words. So we chose to leave the objectives section of the abstract as it is. 

1. Figure 1: Please adjust the horizontal arrow.

I believe this will have to be done by the assistant editor as it happened when the original word file was converted to the template format of the journal. We have submitted a separate figure file as a picture to the editor so that this line does not appear out of sync with the rest of the picture.

4. Methods:
5. Line 96 – reference for HBI is [21], not [20]. Please correct.
6. Line 107: please correct ref. [21] with [22]
7. Line 108: ref. [22] should be replaced with [23]
8. It appears that, from line 96 and onwards, references are wrongly numbered (one number behind). Please revise.

For points a-d, the reference numbering has been revised.

5. Results – need complete revision, according to the major issue I mentioned.

As stated before we disagree with the point of the reviewer and have left the results section unchanged in terms of analyses. We have although expanded somewhat description of the serial mediated models.

6. Discussion – it appears pretty scarce. Please add and use recent references.

The discussion has been extended and updated with more recent references.

Round 2

Reviewer 1 Report

thanks authors for precious improve work about maniscript.Now it's clear

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Author Response

We would like to thank reviewer #1 for the clear and succinct feedback.

Reviewer 2 Report

I read the revised manuscript.

I have listed some Major Issues:

1.       Although the authors modified the sentence in Introduction, inserting “microscopic colitis”, patients with microscopic colitis will never pose the psychological problems and have the quality of life affected as those with Crohn’s disease and ulcerative colitis. There are separate guidelines for IBD, encompassing CD and UC (and sometimes IBD-U) and for microscopic colitis (e.g. 1 - Pardi DS, Tremaine WJ, Carrasco-Labra A. AMERICAN GASTROENTEROLOGICAL ASSOCIATION Institute technical review on the medical management of MICROSCOPIC COLITIS. Gastroenterology. 2016; 150: 247–74;  2 - Miehlke S, Guagnozzi D, Zabana Y, Tontini GE, Kanstrup Fiehn AM, Wildt S, Bohr J, Bonderup O, Bouma G, D'Amato M, Heiberg Engel PJ, Fernandez-Banares F, Macaigne G, Hjortswang H, Hultgren-Hörnquist E, Koulaouzidis A, Kupcinskas J, Landolfi S, Latella G, Lucendo A, Lyutakov I, Madisch A, Magro F, Marlicz W, Mihaly E, Munck LK, Ostvik AE, Patai ÁV, Penchev P, Skonieczna-Żydecka K, Verhaegh B, Münch A. EUROPEAN GUIDELINES ON MICROSCOPIC COLITIS: United European Gastroenterology and European Microscopic Colitis Group statements and recommendations. United European Gastroenterol J. 2021 Feb 22;9(1):13–37. doi: 10.1177/2050640620951905.).

Even the guidelines the authors inserted in references do not include microscopic colitis, but just CD and UC (e.g. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults, Lamb C, et al, 2019).

Moreover, and more to the point - even the reference the authors used when mentioning “however rarer forms of microscopic colitis (collagenous colitis, lymphocytic colitis) are commonly included under the umbrella term of IBD [2] (Sairenji, T., Collins, K. L., & Evans, D. V. (2017). An Update on Inflammatory Bowel Disease. Primary care, 44(4), 673–692. https://doi.org/10.1016/j.pop.2017.07.010) states in Introduction: “Inflammatory bowel disease (IBD) refers to ulcerative colitis (UC) and Crohn disease (CD); 2 chronic idiopathic inflammatory diseases.” And, after that, the paper mentions about “indeterminate colitis” (nowadays, IBD-U). The only time “microscopic colitis” is used in reference [2] is when differentiating IBD in the elderly – among other entities – with “microscopic colitis”.

Classical IBD and microscopic colitis cannot be compared. I know there are only 5 patients with microscopic colitis in this manuscript, this is why I suggested to be removed. The manuscript has to be accurate.

 2.       The authors did not address what “Others” in Table 1 represent.  There are 9 patients with “Other”. Could be anything.

 3.       THE MOST IMPORTANT ISSUE: The way the disease activity was determined - Harvey Bradshaw Index (Harvey, R. F., & Bradshaw, J. M. (1980). A simple index of Crohn's-disease activity. Lancet (London, England), 1(8167), 514. https://doi.org/10.1016/s0140-6736(80)92767-1) is wrong. This index is specific for Crohn’s disease. Therefore, it cannot be expanded to other IBD patients, e.g. UC. And, definitely, not to those with microscopic colitis. Given this mistake, the manuscript included 143 patients with wrongly appreciated activity disease. This renders the manuscript not accurate at all. Disease activity appears in all comparisons.

Also, the index takes into consideration five items (1- General well-being, 2 - abdominal pain, 3 - number of liquid stools per day, 4 - abdominal mass and 5 - complications.). The number of liquid stools per day is missing from the main text (lines 126-129).

Minor correction of the English language is required.

Author Response

We would like to thank reviewer #2 for the insightful comments. Please see below how these were addressed point by point.

1. Although the authors modified the sentence in Introduction, inserting “microscopic colitis”, patients with microscopic colitis will never pose the psychological problems and have the quality of life affected as those with Crohn’s disease and ulcerative colitis. There are separate guidelines for IBD, encompassing CD and UC (and sometimes IBD-U) and for microscopic colitis (e.g. 1 - Pardi DS, Tremaine WJ, Carrasco-Labra A. AMERICAN GASTROENTEROLOGICAL ASSOCIATION Institute technical review on the medical management of MICROSCOPIC COLITIS. Gastroenterology. 2016; 150: 247–74; 2 - Miehlke S, Guagnozzi D, Zabana Y, Tontini GE, Kanstrup Fiehn AM, Wildt S, Bohr J, Bonderup O, Bouma G, D'Amato M, Heiberg Engel PJ, Fernandez-Banares F, Macaigne G, Hjortswang H, Hultgren-Hörnquist E, Koulaouzidis A, Kupcinskas J, Landolfi S, Latella G, Lucendo A, Lyutakov I, Madisch A, Magro F, Marlicz W, Mihaly E, Munck LK, Ostvik AE, Patai ÁV, Penchev P, Skonieczna-Żydecka K, Verhaegh B, Münch A. EUROPEAN GUIDELINES ON MICROSCOPIC COLITIS: United European Gastroenterology and European Microscopic Colitis Group statements and recommendations. United European Gastroenterol J. 2021 Feb 22;9(1):13–37. doi: 10.1177/2050640620951905.).

Even the guidelines the authors inserted in references do not include microscopic colitis, but just CD and UC (e.g. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults, Lamb C, et al, 2019).

Moreover, and more to the point - even the reference the authors used when mentioning “however rarer forms of microscopic colitis (collagenous colitis, lymphocytic colitis) are commonly included under the umbrella term of IBD [2] (Sairenji, T., Collins, K. L., & Evans, D. V. (2017). An Update on Inflammatory Bowel Disease. Primary care, 44(4), 673–692. https://doi.org/10.1016/j.pop.2017.07.010) states in Introduction: “Inflammatory bowel disease (IBD) refers to ulcerative colitis (UC) and Crohn disease (CD); 2 chronic idiopathic inflammatory diseases.” And, after that, the paper mentions about “indeterminate colitis” (nowadays, IBD-U). The only time “microscopic colitis” is used in reference [2] is when differentiating IBD in the elderly – among other entities – with “microscopic colitis”.

Classical IBD and microscopic colitis cannot be compared. I know there are only 5 patients with microscopic colitis in this manuscript, this is why I suggested to be removed. The manuscript has to be accurate.

All non-UC or Non-CD cases were removed from the analysis. The text has been changed throughout the introduction, methodology, results and discussion to reflect this change.

2. The authors did not address what “Others” in Table 1 represent.  There are 9 patients with “Other”. Could be anything.

Please see point above (these cases were removed).

3. THE MOST IMPORTANT ISSUE: The way the disease activity was determined - Harvey Bradshaw Index (Harvey, R. F., & Bradshaw, J. M. (1980). A simple index of Crohn's-disease activity. Lancet (London, England), 1(8167), 514. https://doi.org/10.1016/s0140-6736(80)92767-1) is wrong. This index is specific for Crohn’s disease. Therefore, it cannot be expanded to other IBD patients, e.g. UC. And, definitely, not to those with microscopic colitis. Given this mistake, the manuscript included 143 patients with wrongly appreciated activity disease. This renders the manuscript not accurate at all. Disease activity appears in all comparisons.

Also, the index takes into consideration five items (1- General well-being, 2 - abdominal pain, 3 - number of liquid stools per day, 4 - abdominal mass and 5 - complications.). The number of liquid stools per day is missing from the main text (lines 126-129).

We have revised the results using an alternative measurement that was completed by the patients. This was a self-report of perceived disease activity where participants self-assessed their disease activity as constant/often active (3), sometimes/occasionally active (2), or rarely active/in remission (1). Therefore, a higher score indicates a higher level of perceived activity. We acknowledge this is not a clinical measure, however it reflects the actual perceived activity of the disease, which in the context of the subsequent psychologically relevant variables makes more sense. This also allows us to retain both UC and CD data as this measure is not specific to a sub-group of IBD.

The results remain unchanged in terms of the directionality and significance of the model previously presented with the exception of the direct path between disease activity and depression that under the new analyses becomes insignificant in the presence of the mediators. I.e. this relationship is fully rather than partly mediated by GSA and PD.  Therefore, most of the discussion is retained, with some considerations in the limitations to highlight the use of a non-clinical measure to assess perceived activity.

Round 3

Reviewer 2 Report

I was truly impressed with the new version of the manuscript. I congratulate the Authors for their perseverance and ambition. I know it took a lot of work, but it was worth it! Their great efforts resulted in an excellent paper, which appears correct and credible, as well as very useful for our community of GIs (and, obviously, our patients). Just a very minor issue: Please correct the Abstract, as well. This v-3 version (pdf) contains the previous Abstract – from v-2 (with Harvey Bradshaw Index and previous Results). Thank you very much indeed!

English language is fine. Just a few typos.

Author Response

We thank the reviewer for the very useful and insightful comments and feedback. We agree that the manuscript has improved significantly and we also share the hope that this will be useful for all professionals working with this population. 

As requested we have amended the abstract to match the changes in the manuscript. This was an oversight.