Inflammatory Bowel Disease Treatments and Predictive Biomarkers of Therapeutic Response

Round 1

Reviewer 1 Report

I have no idea when this manuscript was originally written, but references are old (and only 2 from 2021, none from 2022), while many other new wonderful papers on this topic have been published recently. There are so many recent guidelines regarding IBD and its subclasses, published recently, belonging to different medical societies, but not even one recently published has been included in this manuscript. Except for the Table 3, I do not see anything new in this review, worth publishing it. Maybe the authors should focus on what they call “Emerging therapy…” – paragraph 4 and add there all new studies that have been recently published.

Abstract: should be more generous regarding the topic of the manuscript. As it appears, it contains just general data, known by anyone in the field. Which are current? Which are emerging? Please revise.

1. Introduction: a. For what refers to reference [4], please read and insert the most important data from “Verstockt B, Bressler B, Martinez-Lozano H, McGovern D, Silverberg MS. Time to Revisit Disease Classification in Inflammatory Bowel Disease: Is the Current Classification of Inflammatory Bowel Disease Good Enough for Optimal Clinical Management? Gastroenterology. 2022 Apr;162(5):1370-1382.” b. The authors wrote: “The past three decades of research have resulted in a better understanding of the disease's etiology…” – please revise – clear etiology is still unknown. c. The authors wrote: “Despite the fact that emerging therapies have improved the quality of life for IBD patients…” – please define what is current and what is emerging. d. Since the aim of the review is also to discuss “predictive biomarkers of therapeutic response to various IBD treatments”, I suggest this aspect to be reflected in the title, as it would appear important for readers.
2. Disease activity and severity assessment tools. a. “disease phenotype” – includes disease extent and severity in UC, as well as disease extent and disease behaviour in CD. Please revise. b. “Disease activity in IBD patients is evaluated by combining multiple parameters such as patients-reported symptoms, inflammatory markers score, endoscoic assessment, imaging, and histology scores [6, 8]”. Besides typos (e.g. endoscoic)… Instead of old references – 6,8, please use some scientific associations guidelines – AGA, ECCO etc. Also, please make sure that you include all references pertinent to ultrasound scores, MRI-scores and histologic scores (including the recent PICaSSO in UC). c. Table 1: Full of mistakes. PUCA is, in fact, PUCAI. wPCDAI was not included. UCEIS is missing. The authors mentioned UCEIS in reference [103], but…did not include it. It is crucial. Many other scores were ignored.
3. Current treatment options for CD and UC: Therapies-to-symptom approach. a. The authors should read and include here the STRIDE-II directions, mentioning what the therapeutic targets in IBD are, currently. This paper was published in 2021, but probably the authors did not read it (Turner D, Ricciuto A, Lewis A, D'Amico F, Dhaliwal J, Griffiths AM, Bettenworth D, Sandborn WJ, Sands BE, Reinisch W, Schölmerich J, Bemelman W, Danese S, Mary JY, Rubin D, Colombel JF, Peyrin-Biroulet L, Dotan I, Abreu MT, Dignass A; International Organization for the Study of IBD. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology. 2021 Apr;160(5):1570-1583). Controlling symptoms is not anymore the goal, therefore this paragraph is useless. b. Figure 1 is old. c. Figure 2 is not correct, as (just an example) 5-ASA are not recommended in mild-to-moderate CD; in fact, they have been shown to have no benefit, except for mild colonic CD. d. Table 2 – nothing new. e. Moreover, this paragraph misses a lot of info about the current therapies in IBD (e.g. antibiotics in UC and CD) but many more are not included. Very superficial. f. Also, intriguingly, as diet is part of current therapies - EEN, CDED and other diets are not mentioned. Some of the diets have strong scientific evidence of inducing mucosal healing (even transmural healing) in CD, but the authors did not include them.

3.5.2. TNF-inhibitors – They are still included in the paragraph - "3. Current treatment options for CD and UC: Therapies-to-symptom approach" – while they have been proven to induce mucosal healing (in both UC and CD) and, in a lesser extent, also transmural healing (in CD)

4. Emerging therapy for CD and UC: old data, no new recent manuscripts. Please update.
5. Predictor biomarkers for evaluating therapeutic response to different IBD treatments: old data. Figure 3 appears interesting, but it is not fully understandable. Requires a lot of clarifications. Please explain what the arrows mean and include all known markers to date. Please explain all abbreviations.

6. Future Directions – first lines - have no sense, since STRIDE II mentioned clearly the therapeutic targets in IBD. Then, this paragraph is way too long, including references. This paragraph should be clear and crispy, with practical advice. But, since the whole manuscript is confusing, this paragraph follows the rule. Too many sentences and nothing clear.

*** English language: there are many typos; grammar requires revision.

Author Response

Response to Reviewer 1 Comments

I have no idea when this manuscript was originally written, but references are old (and only 2 from 2021, none from 2022), while many other new wonderful papers on this topic have been published recently. There are so many recent guidelines regarding IBD and its subclasses, published recently, belonging to different medical societies, but not even one recently published has been included in this manuscript. Except for the Table 3, I do not see anything new in this review, worth publishing it. Maybe the authors should focus on what they call “Emerging therapy…” – paragraph 4 and add there all new studies that have been recently published.

Response: We appreciate your feedback. We have substantially revised the manuscript to include the recent guidelines regarding IBD and its subclasses and updated our references list with the latest papers.

Abstract: should be more generous regarding the topic of the manuscript. As it appears, it contains just general data, known by anyone in the field. Which are current? Which are emerging? Please revise. 

Response: Thank you for your suggestions. We have revised the abstract as requested

1. Introduction: a. For what refers to reference [4], please read and insert the most important data from “Verstockt B, Bressler B, Martinez-Lozano H, McGovern D, Silverberg MS. Time to Revisit Disease Classification in Inflammatory Bowel Disease: Is the Current Classification of Inflammatory Bowel Disease Good Enough for Optimal Clinical Management? Gastroenterology. 2022 Apr;162(5):1370-1382.” b. The authors wrote: “The past three decades of research have resulted in a better understanding of the disease's etiology…” – please revise – clear etiology is still unknown. c. The authors wrote: “Despite the fact that emerging therapies have improved the quality of life for IBD patients…” – please define what is current and what is emerging. d. Since the aim of the review is also to discuss “predictive biomarkers of therapeutic response to various IBD treatments”, I suggest this aspect to be reflected in the title, as it would appear important for readers.

Response: We have revised the manuscript to include the latest references and suggested changes.

1. Disease activity and severity assessment tools. a. “disease phenotype” – includes disease extent and severity in UC, as well as disease extent and disease behaviour in CD. Please revise. b. “Disease activity in IBD patients is evaluated by combining multiple parameters such as patients-reported symptoms, inflammatory markers score, endoscoic assessment, imaging, and histology scores [6, 8]”. Besides typos (e.g. endoscoic)… Instead of old references – 6,8, please use some scientific associations guidelines – AGA, ECCO etc. Also, please make sure that you include all references pertinent to ultrasound scores, MRI-scores and histologic scores (including the recent PICaSSO in UC). c. Table 1: Full of mistakes. PUCA is, in fact, PUCAI. wPCDAI was not included. UCEIS is missing. The authors mentioned UCEIS in reference [103], but…did not include it. It is crucial. Many other scores were ignored..

Response: We have revised the manuscript to include the latest guidelines and suggested changes.

1. Current treatment options for CD and UC: Therapies-to-symptom approach. a. The authors should read and include here the STRIDE-II directions, mentioning what the therapeutic targets in IBD are, currently. This paper was published in 2021, but probably the authors did not read it (Turner D, Ricciuto A, Lewis A, D'Amico F, Dhaliwal J, Griffiths AM, Bettenworth D, Sandborn WJ, Sands BE, Reinisch W, Schölmerich J, Bemelman W, Danese S, Mary JY, Rubin D, Colombel JF, Peyrin-Biroulet L, Dotan I, Abreu MT, Dignass A; International Organization for the Study of IBD. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology. 2021 Apr;160(5):1570-1583).

Controlling symptoms is not anymore the goal, therefore this paragraph is useless. b. Figure 1 is old. c. Figure 2 is not correct, as (just an example) 5-ASA are not recommended in mild-to-moderate CD; in fact, they have been shown to have no benefit, except for mild colonic CD. d. Table 2 – nothing new. e. Moreover, this paragraph misses a lot of info about the current therapies in IBD (e.g. antibiotics in UC and CD) but many more are not included. Very superficial. f. Also, intriguingly, as diet is part of current therapies - EEN, CDED and other diets are not mentioned. Some of the diets have strong scientific evidence of inducing mucosal healing (even transmural healing) in CD, but the authors did not include them.

Response: We appreciate your suggestions. We agree with you suggestion. The recent STRIDE-II recommendation has shifted the IBD treatment goal to treat-to-target strategies (PMID: 33359090). We have substantially revised the manuscript to capture new STRIDE-II recommendations. We have also included the emerging antibiotics therapies for UC and CD from the clinical trial website (Ph-II or Ph-III).

We have included a new figure (fig1) and revised the figure 2 and also included the latest references regarding the use of 5-ASA (Nagahori, M., Kochi, S., Hanai, H. et al. Real life results in using 5-ASA for maintaining mild to moderate UC patients in Japan, a multi-center study, OPTIMUM Study. BMC Gastroenterol 17, 47 (2017). https://doi.org/10.1186/s12876-017-0604-y; Louis E, Paridaens K, Al Awadhi S, et al Modelling the benefits of an optimised treatment strategy for 5-ASA in mild-to-moderate ulcerative colitis BMJ Open Gastroenterology 2022;9:e000853. doi: 10.1136/bmjgast-2021-000853; https://doi.org/10.1159/000504092).

3.5.2. TNF-inhibitors – They are still included in the paragraph - "3. Current treatment options for CD and UC: Therapies-to-symptom approach" – while they have been proven to induce mucosal healing (in both UC and CD) and, in a lesser extent, also transmural healing (in CD)

Response: We have substantially revised paragraph 3 to discuss the recent IBD treatment goals and new guidelines.

1. Emerging therapy for CD and UC: old data, no new recent manuscripts. Please update.

Response: Updates as suggested.

1. Predictor biomarkers for evaluating therapeutic response to different IBD treatments: old data. Figure 3 appears interesting, but it is not fully understandable. Requires a lot of clarifications. Please explain what the arrows mean and include all known markers to date. Please explain all abbreviations.

Response: We have revised the manuscript to capture predictor biomarkers and as suggested also revised the figure 3 to capture details of abbreviations and arrows.

1. Future Directions – first lines - have no sense, since STRIDE II mentioned clearly the therapeutic targets in IBD. Then, this paragraph is way too long, including references. This paragraph should be clear and crispy, with practical advice. But, since the whole manuscript is confusing, this paragraph follows the rule. Too many sentences and nothing clear.

Response: This section is revised as suggested.

*** English language: there are many typos; grammar requires revision.

Response: This section is corrected the typo errors.

Author Response File: Author Response.docx

Reviewer 2 Report

This review effectively summarizes current state of IBD therapeutics and emerging therapies. The paper is well written and figures are clear and to the point. The paper merits publication. 

Author Response

Response to Reviewer 2 Comments

This review effectively summarizes current state of IBD therapeutics and emerging therapies. The paper is well written and figures are clear and to the point. The paper merits publication. 

Response: We appreciate your recommendation.

Reviewer 3 Report

Manuscript title:  Current and Emerging Therapies for Inflammatory Bowel Disease

This is an important review that opens a new perspective on IBD problematics. It describes the current challenges of IBD treatment and diagnostics.

The manuscript is very clear and easy to understand, the methods are adequately described. This is an interesting paper that addresses a topic of high importance in daily practice.

I have some minor comments on the text.

• There are several spelling and grammar errors in the text that will need to be corrected – all are highlighted in the proof.
• In Table 2, SC route for IFX and VDZ is missing, and no application route for UST is stated. Moreover, tofacitinib is approved only for UC treatment (at least in EU).
• In 3.2 section, CS adverse effects are described too briefly.

Author Response

Response to Reviewer 3 Comments

This is an important review that opens a new perspective on IBD problematics. It describes the current challenges of IBD treatment and diagnostics.

The manuscript is very clear and easy to understand, the methods are adequately described. This is an interesting paper that addresses a topic of high importance in daily practice.

Response: We appreciate your recommendation.

I have some minor comments on the text.

• There are several spelling and grammar errors in the text that will need to be corrected – all are highlighted in the proof.

Response: We apologize for this oversight. We have corrected the spelling and grammar errors in the revised manuscript.

• In Table 2, SC route for IFX and VDZ is missing, and no application route for UST is stated. Moreover, tofacitinib is approved only for UC treatment (at least in EU).

Response: Thank you for your comments. We have added the missing information in the table 2.

• In 3.2 section, CS adverse effects are described too briefly.

Response: We appreciate your recommendation. We added more details in the revised manuscript.

Round 2

Reviewer 1 Report

The authors inserted many new sentences, but I do not see much improvement in the quality of the manuscript. They wrote “We have revised the manuscript to include the latest guidelines and suggested changes.”, but, in fact, they did not.

Some examples:

1. I wrote “Please read and insert the most important data from “Verstockt B, Bressler B, Martinez-Lozano H, McGovern D, Silverberg MS. Time to Revisit Disease Classification in Inflammatory Bowel Disease: Is the Current Classification of Inflammatory Bowel Disease Good Enough for Optimal Clinical Management? Gastroenterology. 2022 Apr;162(5):1370-1382.” WAS NOT DONE!

2. I wrote “Also, intriguingly, as diet is part of current therapies - EEN, CDED and other diets are not mentioned. Some of the diets have strong scientific evidence of inducing mucosal healing (even transmural healing) in CD, but the authors did not include them”. WAS NOT DONE!

3. Current treatment options for CD and UC – 3.4. Nothing was added about current therapies in UC and CD (antibiotics). I previously wrote in my review:” Moreover, this paragraph misses a lot of info about the current therapies in IBD (e.g. antibiotics in UC and CD)…”

4. Future Directions – I wrote “this paragraph is way too long, including references. This paragraph should be clear and crispy, with practical advice and not include references”. WAS NOT DONE!

5. I wrote “Figure 2a is not correct!” WAS NOT CORRECTED TOTALLY!

6. “Predictor biomarkers for evaluating therapeutic response to different IBD treatments”: was not improved much.

 OTHER VERY IMPORTANT COMMENTS:

1. Table 3 presents “Emerging therapies”, but it is inserted in the paragraph “Current treatment options for CD and UC”. As I previously wrote, the authors do not seem to have any idea about the difference between “current” and “emerging”.

2. The aim of the review differs in the Abstract from that in the main text.

3. Paragraph “Disease activity and severity assessment tools”

a. What do the authors mean by “endoscopic ultrasound assessment”? ultrasound is part of imaging techniques! Endoscopy and ultrasonography are two different methods. Endoscopic ultrasound technique exists, but it is not usually performed in IBD. Endoscopy and imaging techniques are recommended.

b. The authors wrote “Endoscopic healing; which can be defined as transmural healing in CD patients  and histological healing in UC patients.” This sentence is a complete mistake. It shows that the authors have no idea what endoscopic healing means, transmural healing means and histological healing means. Transmural healing cannot be appreciated by endoscopy, only by imaging. Moreover, endoscopic healing does not mean histologic healing. Endoscopical aspects are what you see with the endoscope, histology is what you see with the microscope. These mistakes are unacceptable.

4. Fig. 1 – please insert II after STRIDE.

Author Response

The authors inserted many new sentences, but I do not see much improvement in the quality of the manuscript. They wrote “We have revised the manuscript to include the latest guidelines and suggested changes.”, but, in fact, they did not. 

Some examples:

1. I wrote “Please read and insert the most important data from “Verstockt B, Bressler B, Martinez-Lozano H, McGovern D, Silverberg MS. Time to Revisit Disease Classification in Inflammatory Bowel Disease: Is the Current Classification of Inflammatory Bowel Disease Good Enough for Optimal Clinical Management? Gastroenterology. 2022 Apr;162(5):1370-1382.” WAS NOT DONE!

Response: We appreciate your suggestion. We have substantially revised the section 2 and added details from suggested article “Verstockt B, Bressler B, Martinez-Lozano H, McGovern D, Silverberg MS. Time to Revisit Disease Classification in Inflammatory Bowel Disease: Is the Current Classification of Inflammatory Bowel Disease Good Enough for Optimal Clinical Management? Gastroenterology. 2022 Apr;162(5):1370-1382”.

2. I wrote “Also, intriguingly, as diet is part of current therapies - EEN, CDED and other diets are not mentioned. Some of the diets have strong scientific evidence of inducing mucosal healing (even transmural healing) in CD, but the authors did not include them”. WAS NOT DONE!

Response: Thank you for your feedback. As suggested, we have added the dietary therapies (section 3.7) in the revised manuscript.

3. Current treatment options for CD and UC – 3.4. Nothing was added about current therapies in UC and CD (antibiotics). I previously wrote in my review:” Moreover, this paragraph misses a lot of info about the current therapies in IBD (e.g. antibiotics in UC and CD)…”

Response: Thank you for your suggestions. We have substantially revised the paragraph -3.4 and table 2 to add the details antibiotics that are being often prescribed for managing the IBD.

4. Future Directions – I wrote “this paragraph is way too long, including references. This paragraph should be clear and crispy, with practical advice and not include references”. WAS NOT DONE!

Response: Thank you for your suggestions. We have substantially revised the future directions also in the revised manuscript.

5. I wrote “Figure 2a is not correct!” WAS NOT CORRECTED TOTALLY!

Response: We have revised the Figure 2a to address the concern. As shown in table 2 and Figure 2a some aminosalicylates (such as balsalazide and mesalamine) are approved for mild-to-moderate UC patients. We have cited the references in section 3.1 and also added these details in figure 2a legends.

6. “Predictor biomarkers for evaluating therapeutic response to different IBD treatments”: was not improved much.

Response: We appreciate your feedback. We have substantially revised the “Predictor biomarkers for evaluating therapeutic response to different IBD treatments” section to add more promising predictive biomarkers in the revised manuscript.

 OTHER VERY IMPORTANT COMMENTS:

1. Table 3 presents “Emerging therapies”, but it is inserted in the paragraph “Current treatment options for CD and UC”. As I previously wrote, the authors do not seem to have any idea about the difference between “current” and “emerging”.

Response: We apologized for oversighting this mistake. We have corrected the citation of Table 3 in revised manuscript.

2. The aim of the review differs in the Abstract from that in the main text.

Response: We appreciate your feedback. We have revised the abstract again and we feel precisely summarizing the main text of review.

3. Paragraph “Disease activity and severity assessment tools” What do the authors mean by “endoscopic ultrasound assessment”? ultrasound is part of imaging techniques! Endoscopy and ultrasonography are two different methods. Endoscopic ultrasound technique exists, but it is not usually performed in IBD. Endoscopy and imaging techniques are recommended. b. The authors wrote “Endoscopic healing; which can be defined as transmural healing in CD patients  and histological healing in UC patients.” This sentence is a complete mistake. It shows that the authors have no idea what endoscopic healing means, transmural healing means and histological healing means. Transmural healing cannot be appreciated by endoscopy, only by imaging. Moreover, endoscopic healing does not mean histologic healing. Endoscopical aspects are what you see with the endoscope, histology is what you see with the microscope. These mistakes are unacceptable. 

Response: We apologized for oversighting this mistake. We have revised the paragraph “Disease activity and severity assessment tools” to address these concerns.

4. Fig. 1 – please insert II after STRIDE.

Response: Thank you for your suggestions. We have added II after STRIDE in the figure 1 legend.

Round 3

Reviewer 1 Report

Finally, after many attempts, the Authors made it. It took a long while, but in the end the manuscript appears as substantially improved and showing the scientifically proven, as well as new data. The Authors finally considered my suggestions and now their review looks good, with important and appealing information for the readers. Although minor revision of the English language is still needed, the scientific content qualifies for the paper being published.