Defining the Failure of Medical Therapy for Inflammatory Bowel Disease in the Era of Advanced Therapies: A Systematic Review

Round 1

Reviewer 1 Report

-       - Use oxford comma

-        - PROSPERO ID 395550 in not present among protocols in evaluation

-        - “A retrospective analysis of 15 patients using either VEDO+IFX, USTE+IFX or VEDO+USTE identified frequent infections requiring antibiotics, the need for surgical intervention and hospitalization in a 24-month follow-up period.”

Other data a more encouraging (cite: “Dual biological therapy with anti-TNF, vedolizumab or ustekinumab in inflammatory bowel disease: a systematic review with pool analysis. Scand J Gastroenterol. 2019 Apr;54(4):407-413. doi: 10.1080/00365521.2019.1597159. Epub 2019 Apr 4. PMID: 30945576.”)

-    -    Add the limitations of your paper

-      -  Try to propose a definition of assessment of a lack/loss of response that could be used in all RCT and clinical practice

Author Response

Dear reviewer,

On behalf of all the authors, I would like to thank you for you comments and suggestions. We addressed all the issues raised as follows:

• We added the registration record for PROSPERO. Our protocol is not yet registered, but is being assessed by the editorial team (attached below)
• The citation you recommended was included in the combination therapy section
• We added a paragraph for limitations
• We proposed a definition of assessment of loss of response

The authors,

Reviewer 2 Report

In the present systematic review State et al summarized the main definitions of therapy failure for monoclonal antibodies in IBD, as well as definition of clinical/endoscopic remission and strategies for therapy optimization, showing a relevant heterogeneity.

This is an excellent review which clearly shows definitions used in clinical practice and trials. However, before starting therapy optimization, it would be better to discriminate between primary/secondary non response or loss of response. Therefore definitions of such situations should be added in the text (the definitions in page 9 lines 156-159 are quite vague, and a timing should be reported).

As shown in tables 1-2, heterogeneity exists only for CD. Please underline this.

Author Response

Dear reviewer,

On behalf of all the authors, I would like to thank you for you comments and suggestions. We addressed all the issues raised as follows:

• We expanded the definitions of LOR and added timing considerations recommened in current guidelines
• We underlined the limited heterogencity to CD of LOR definition

The authors,