Dear Mme Jaume,

Thank you very much for submitting your manuscript "Methotrexate as a corticosteroid-sparing agent in leprosy reactions: a French multicenter retrospective study" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

In addition to the comments submitted by the reviewers please address:

General comments: This manuscript is valuable, but needs rewriting to make it more readable. The use of tense is inconsistent. Please review and provide citations where necessary (mainly in discussion)

Specific comments

Introduction: please

Line 86-101: Please make more succinct. Details can be added in discussion where many of these drugs are discussed again.

Line 106: There should be a mention that this is a retrospective study of patients treated with LR

Methods:

Line 123: Are these outcomes standard used across the world?If so, please provide citation. Otherwise state that these are outcomes that you have created for this study.

There is no mention of MTX monitoring or toxicities that were evaluated.

Line 191: Sub-group analysis is usually done in RCTs, and these are always predefined. suggest removing this sub-heading and simply describing both these groups.

Line 204: please mention more details about monitoring/lack of monitoring and hepatoxocity seen or not seen.

Discussion: Need significant editing and rewriting to make more readable. Use of tense is inconsistent

Please highlight that for 3/5 women, the desire to become pregnant necessitated stopping mTX

Line 228-229: should be in the concluding paragraph

Suggest moving lines 233-236 “We identified..” to after line 252

Line 247-250. Speculation without evidence. Please simply mention how your cohort differed from the published literature without any speculation to the reasons such as publication bias. Sug

Lines 253-301: Does not read well currently – please review and reorganize to ensure flow. Start with a discussion of overall outcomes of LR and standard of care with steroids and poor outcomes. Then discuss other options. For each drug, discuss its current use and outcomes from its use. For example lines 253 , 259, 260 can be rewritten into a single sentence. Much of this can be consolidated from the introduction.

Line 253-254: incorrect tense: GSs do not demonstrate clear benefits (please cite).

Line 256: “real life experience” – please say “in our experience or our practice” as your experience does not negate others' experience.

Line 259: please cite reference.

Lines 261: rewrite "Azathioprine acts by inhibiting T-cell immunity. "

Line 265: suspensive is not a commonly used word, and its meaning here is unclear as related to 48 week treatment group. Please clarify and rewrite the entire sentence.

Line 271-Line 272: should this be in the section on glucocorticoids? Seems out of place between azathioprine and clofazimine.

Line 273-274: please provide citation.

Line 278-280: please provide citation. Also rewrite – thalidomide is used with everyone fully knowing its teratogenicity; I doubt it is being prescribed without proper counselling and contraception. This line seems to imply that people are using it in pregnancy and teratogenicity is seen in patients receiving it.

Line 281-283: could you provide more detail here? How many cases.

Line 292-295 should be included with summary paragraph about your study at the start of the discussion; currently seems out of place.

Line 296-301: Please rewrite as a summary paragraph and include “in this case series of one of the largest cohorts of patients receiving MTX for LR, we demonstrate the potential of methotrexate as..." and include line 228

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Husain Poonawala

Academic Editor

PLOS Neglected Tropical Diseases

Joseph Vinetz

Section Editor

PLOS Neglected Tropical Diseases

***********************

In addition to the comments submitted by the reviewers please address:

General comments: This manuscript is valuable, but needs rewriting to make it more readable. The use of tense is inconsistent. Please review and provide citations where necessary (mainly in discussion)

Specific comments

Introduction: please

Line 86-101: Please make more succinct. Details can be added in discussion where many of these drugs are discussed again.

Line 106: There should be a mention that this is a retrospective study of patients treated with LR

Methods:

Line 123: Are these outcomes standard used across the world?If so, please provide citation. Otherwise state that these are outcomes that you have created for this study.

There is no mention of MTX monitoring or toxicities that were evaluated.

Line 191: Sub-group analysis is usually done in RCTs, and these are always predefined. suggest removing this sub-heading and simply describing both these groups.

Line 204: please mention more details about monitoring/lack of monitoring and hepatoxocity seen or not seen.

Discussion: Need significant editing and rewriting to make more readable. Use of tense is inconsistent

Please highlight that for 3/5 women, the desire to become pregnant necessitated stopping mTX

Line 228-229: should be in the concluding paragraph

Suggest moving lines 233-236 “We identified..” to after line 252

Line 247-250. Speculation without evidence. Please simply mention how your cohort differed from the published literature without any speculation to the reasons such as publication bias. Sug

Lines 253-301: Does not read well currently – please review and reorganize to ensure flow. Start with a discussion of overall outcomes of LR and standard of care with steroids and poor outcomes. Then discuss other options. For each drug, discuss its current use and outcomes from its use. For example lines 253 , 259, 260 can be rewritten into a single sentence. Much of this can be consolidated from the introduction.

Line 253-254: incorrect tense: GSs do not demonstrate clear benefits (please cite).

Line 256: “real life experience” – please say “in our experience or our practice” as your experience does not negate others' experience.

Line 259: please cite reference.

Lines 261: rewrite "Azathioprine acts by inhibiting T-cell immunity. "

Line 265: suspensive is not a commonly used word, and its meaning here is unclear as related to 48 week treatment group. Please clarify and rewrite the entire sentence.

Line 271-Line 272: should this be in the section on glucocorticoids? Seems out of place between azathioprine and clofazimine.

Line 273-274: please provide citation.

Line 278-280: please provide citation. Also rewrite – thalidomide is used with everyone fully knowing its teratogenicity; I doubt it is being prescribed without proper counselling and contraception. This line seems to imply that people are using it in pregnancy and teratogenicity is seen in patients receiving it.

Line 281-283: could you provide more detail here? How many cases.

Line 292-295 should be included with summary paragraph about your study at the start of the discussion; currently seems out of place.

Line 296-301: Please rewrite as a summary paragraph and include “in this case series of one of the largest cohorts of patients receiving MTX for LR, we demonstrate the potential of methotrexate as..." and include line 228

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: Small sample size

Reviewer #2: Slit skin smear of cases not given

No Histopathology examination done to differentiate Type 1 from 2 reactions as it is unusual to both exist together as was in two of cases

Inclusion criteria not clear

Dose of Methotrexate - how calculated not given

Dose of Corticosteroids nor given

Reviewer #3: (No Response)

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: yes results are clear and tables are sufficient quality

Reviewer #2: Outcome parameters seems subjective

How response was attributed to corticosteroids when all the patients were also in corticosteroids and continued for mor e than 6 months in addition to Thalidomide and pentoxifylline in few

Methotrexate is also acting drug in leprosy reactions takes 8-12 weeks to show meaningful clinical response

Reviewer #3: Results need some clarification

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: yes the study mentioned the limitations and addressed the public health

Reviewer #2: Not supported by the study findings

Reviewer #3: Conclusions need to be revised in view of the study limitations

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: I have mentioned the minor modifications in manuscript pdf, so article can be recommended with minor revision

Reviewer #2: Terminologies and descriptions of some terms is not as used in leprosy in scientific publications. eg Multi-neuritis, Lucio vasculitis in ENL...etc

Reviewer #3: (No Response)

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: Nothing specific

Reviewer #2: Not suitable as original article

Reviewer #3: The article is of interest and contributes with valuable information.

--------------------

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Seema Rani

Reviewer #2: No

Reviewer #3: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

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Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Attachments

Attachment

Submitted filename: Reviewercomments.pdf

Attachment

Submitted filename: PLOSNTD review.docx

Dear Mme Jaume,

We are pleased to inform you that your manuscript 'Methotrexate as a corticosteroid-sparing agent in leprosy reactions: a French multicenter retrospective study' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Husain Poonawala

Academic Editor

PLOS Neglected Tropical Diseases

Joseph Vinetz

Section Editor

PLOS Neglected Tropical Diseases

***********************************************************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: Nothing specific except the small sample size which the author have mentioned in lacunae.

Reviewer #2: Methods - Since MDT was given for median 3.5 years - there is no mention of baseline / annual Slit skin smears (BI) to suggest why it was extended beyond usual recommended schedule.

Spectrum of leprosy is not mentioned.

Which type of MDT given - PB/MB, Details of drugs not given

"Twelve (92%) patients received disulone, one of them was switched to ofloxacin due to a

157 dapsone-induced anemia - is it dapsone?. If Dapsone can not be give, there is no need to replace with any other drug as per WHO recommendations?

"One patient had a G6PD deficiency and was treated with clarithromycin - as there is no such recommendation - please mention reason.

" Aside from clofazimine, no MDT treatment was given during MTX therapy." - please make it clear if all patients were given MTX after completion of MDT (after 2 years?)..what was time of onset of reactions in these patients? what dose of clofazimine was given? why? how long? in all cases? to prevent which type of reactions? 0- it is important for readers to understand

Reviewer #3: (No Response)

**********

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: Nothing specific, author have already added the clarifications in results.

Reviewer #2: At mean 40+ mg dose of Prednisolone , how response was ascribed to MTX alone?

Effect on neuritis is not mentioned

Evaluation of inflammatory signs seems subjective

Did adding MTX at 20 mg per week to MDT (dapsone) increased risk of anemia?

Was any attempt made to differentiate from relapses (histopath/slit skin smears?) and drug resistance ?

Reviewer #3: (No Response)

**********

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: Agreed with the improved and re- written conclusions.

Reviewer #2: Need appropriate modification in view of limitations

Reviewer #3: (No Response)

**********

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: Minor changes in spelling-corrections

Reviewer #2: not clear

Reviewer #3: (No Response)

**********

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: Nothing specific.

Reviewer #2: (No Response)

Reviewer #3: (No Response)

**********

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Seema Rani

Reviewer #2: No

Reviewer #3: No

Attachments

Attachment

Submitted filename: Revised Manuscript.pdf