Lymphocyte-to-Monocyte Ratio as a Marker for Endoscopic Activity in Ulcerative Colitis

Round 1

Reviewer 1 Report

it seems very interesting and in future applicable procedure. 
I'd like to know how does ratio did it, it would be that the significant correlation depends of an increase of lymphocyte or reduction of monocyte or the other way around.

Author Response

Comment: it seems very interesting and in future applicable procedure.

I'd like to know how does ratio did it, it would be that the significant correlation depends of an increase of lymphocyte or reduction of monocyte or the other way around.

 

Response: We are very grateful to the reviewer for peer reviewing this study.

As the reviewer pointed out, changes in lymphocyte and monocyte levels show a significant correlation with endoscopic score and LMR. The mechanism is discussed in the “Discussion” section of our manuscript (Page 8, Line 227).

Reviewer 2 Report

In this paper, Ishida et al. examine the correlation between a serum biomarker (LMR) and endoscopic activity in UC. The study is scientifically solid and the manuscript clearly written. LMR might prove useful for the management of UC, but I think the authors should investigate more deeply potential differences or superiority compared to CRP, in order to provide evidence supporting that its use might be useful and impactful in clinical practice. 

Based on the results presented in this paper, LMR can be considered an alternative to CRP as a serum biomarker to assess UC endoscopic activity. However, CRP use is already well-established in the clinical management of IBD and supported by solid evidence, so I do not see LMR replacing it. I would therefore suggest performing additional analysis, to investigate whether the combination of CRP and LMR is superior to CRP alone in predicting endoscopic activity, which would make the case for LMR assessment to be incorporated in the routine clinical management of IBD.

In the abstract, the authors write “In the ROC analysis for predicting mucosal healing, the AUC for the LMR was 29 larger than that for CRP (0.751 and 0.714, respectively).” However, later in the text, it is reported that such a difference does not reach statistical significance. I think that this sentence should therefore be removed from the abstract, as it may be misleading. Similarly, in the discussion paragraph, it is hypothesized that LMR might be superior to CRP in patients not taking immunomodulators; however, such a statement cannot be supported by the evidence presented in this manuscript (p is not significant, despite being close to 0.05), therefore I suggest to re-write it and nuance it. 

The authors correctly address that immunomodulators might affect leukocyte count. However, not every immunosuppressor used for IBD is equivalent in its impact on white cells. Specifically, corticosteroids alter leukocyte count by causing leukocytosis. Therefore, I think that patients taking systemic steroids should also be analyzed separately and compared with those not assuming steroids, to assess whether steroid treatment affects the performance of MLR in predicting endoscopic outcomes.

The retrospective design of the study should be acknowledged among the limitations.

Author Response

Comment: Based on the results presented in this paper, LMR can be considered an alternative to CRP as a serum biomarker to assess UC endoscopic activity. However, CRP use is already well-established in the clinical management of IBD and supported by solid evidence, so I do not see LMR replacing it. I would therefore suggest performing additional analysis, to investigate whether the combination of CRP and LMR is superior to CRP alone in predicting endoscopic activity, which would make the case for LMR assessment to be incorporated in the routine clinical management of IBD.

 

Response: As pointed out by the reviewer, analyzing the combination of CRP and LMR is important in this study. The results of this analysis have been added as Supplementary Table 1. The results show that the combination of CRP and LMR contributed to a higher positive predictive value than CRP and LMR measurements alone (Page 9, Line 252).

We are very grateful to the reviewers for adding meaningful analyses.

 

 

Comment: In the abstract, the authors write “In the ROC analysis for predicting mucosal healing, the AUC for the LMR was 29 larger than that for CRP (0.751 and 0.714, respectively).” However, later in the text, it is reported that such a difference does not reach statistical significance. I think that this sentence should therefore be removed from the abstract, as it may be misleading. Similarly, in the discussion paragraph, it is hypothesized that LMR might be superior to CRP in patients not taking immunomodulators; however, such a statement cannot be supported by the evidence presented in this manuscript (p is not significant, despite being close to 0.05), therefore I suggest to re-write it and nuance it.

 

Response: We thank the reviewers for their suggestions.

We have removed the sentence in the abstract about the AUCs of LMR and CRP. We have also removed the statement in the “Discussion” section that LMR may be more useful than CRP in the analysis of patients without immunomodulators.

 

 

Comment: The authors correctly address that immunomodulators might affect leukocyte count. However, not every immunosuppressor used for IBD is equivalent in its impact on white cells. Specifically, corticosteroids alter leukocyte count by causing leukocytosis. Therefore, I think that patients taking systemic steroids should also be analyzed separately and compared with those not assuming steroids, to assess whether steroid treatment affects the performance of MLR in predicting endoscopic outcomes.

 

Response: As reviewer pointed out in the analysis of this study, in order to rigorously examine the effect of each drug on leukocytes, it is necessary to conduct analysis with other drugs. In particular, since steroids affected leukocytes in this study, we analyzed LMR and CRP in the group of patients who were not consuming steroids. However, the AUCs of CRP and LMR were 0.789 (95% CI: 0.679 - 0.899) and 0.709 (95% CI: 0.59 - 0.828), respectively, which were not significantly different from those in the analysis of all subjects. This may be due to the fact that 27 of 89 patients used immunosuppressive drugs, while only 13 used steroids, and there were many patients who did not use steroids; thus, it was difficult to examine difference between patients with and without steroids. As more cases are accumulated in the future, it will be possible to analyze the results in patients who used steroids, and new findings may be obtained (Page 9, Line 268).

 

 

Comment: The retrospective design of the study should be acknowledged among the limitations.

 

Response: We have mentioned about the retrospective nature of the study to the limitations in the “Discussion” section (Page, 9 Line 272).

Reviewer 3 Report

Diseases activity in UC is an issue of great interest, especially for its therapeutic and prognostic meaning. Unfortunately, clinical macroscopic expression not always corresponds to microscopic features of the disese. In this study, the association between the LMR and UC was evaluated, with a focus on endoscopic activity. The LMR was negatively correlated with the endoscopic score, indicating that a low LMR is indicative of endoscopic activity. The Authours made a good job and the article  could be accepted in the present form.

Author Response

Comment: Disease activity in UC is an issue of great interest, especially for its therapeutic and prognostic meaning. Unfortunately, clinical macroscopic expression not always corresponds to microscopic features of the disease. In this study, the association between the LMR and UC was evaluated, with a focus on endoscopic activity. The LMR was negatively correlated with the endoscopic score, indicating that a low LMR is indicative of endoscopic activity. The Authors made a good job and the article could be accepted in the present form.

 

Response: We are very grateful to the reviewer for their review of this paper.

We are also very pleased with the above evaluation of this study.

Round 2

Reviewer 2 Report

I thank the authors for their effort in addressing my previous comments. 

No further comments.