Comparison of Biological Agent Monotherapy and Associations Including Disease-Modifying Antirheumatic Drugs for Rheumatoid Arthritis: Literature Review and Meta-Analysis of Randomized Trials

Round 1

Reviewer 1 Report

Delpech et al. present an interesting and thorough review and meta-analysis of the literature regarding therapeutic effects of biologicals monotherapy vs combination therapy. The article is well written and the methodology seems to be correct. However, the main result (combination therapyà ‘‘better‘‘ than monotherapy) can not be described as novel. Moreover, this statement could be seen generalized (some biologicals are also effective as monotherapies, as the authors also shortly mention in the discussion part oft he work). Changes of this paper are thus needed, in order to form a clearer message. Moreover, it would be suggested to highlight the novel aspects of this work. 

Some other minor comments:

Abstract:

‘‘Update the available evidence comparing biologic disease-modifying antirheumatic drugs (bDMARD) and conventional synthetic disease-modifying antirheumatic drugs (CsDMARD) as a combination therapy to bDMARD in monotherapy in patients with rheumatoid arthritis….‘‘

This sentence is somehow difficult to understand. Please describe your objective more clearly. 

Conclusion:

1. the word ‘‘Combinaison‘‘ should be corrected. ‘‘Combination‘‘ is the right word.

2. The authors state: ‘‘prescribers should switch to CsDMARDs when methotrexate is contraindicated/intolerant‘‘. First of all, the term ‘‘intolerant‘‘ is used for patients and not for drugs. Please correct this sentence. 

Secondly, I did not find any results justifying this suggestion in the results part of the abstract and in the manuscript. Here you should include only conclusions that are directly associated with your work. Moreover, some biologicals (i.e. Tocilizumab) show good therapeutic effects also in monotherapy regimes, so all in all this suggestion seems generalized and probably oversimplified.  

Main document:

line 67: change ‘‘synthetics‘‘ to ‘‘synthetic‘‘.

line 92, 93: there is something missing in the sentence: ‘‘The GRADE ratings reflect the extent to which we are confident that the true effect (Figure 1)‘‘.  Other language and typing mistakes can be found in the discussion and throughout the manuscript (i.e. line 256, etc)

Please perform a thorough language control of your paper, preferably assisted by a native speaker.

Discussion: here would be a good place to point out the novel apsects of this work, as mentioned earlier.

Thank you  

Author Response

First of all, I would like to thank you for the attention you have paid to our article. 

We have made the changes you suggested to the astract but also to the main document. 

The aim of this work was to provide EBM for the therapeutic management of patients with rheumatoid arthritis. This is the second meta-analysis on the subject, confirming the results of the first study, but above all allowing the inclusion of a larger number of articles and patients. The literature data suggested that Tocilizumab and Etanercept were more effective as monotherapy, which is why we performed subgroup analyses. The results were compared with the literature in the discussion section. 
As you have suggested, we have modified the manuscript to provide a clearer message. 

Thanking you once again for your interest in this work. 

Reviewer 2 Report

This review article is relevant in Rheumatology in the clinical settings.

I understand that your conclusion that the combination therapy was superior to monotherapy of bDMARDs. 

However, about the ages for cases, are they no significant and did the differences of ages for patients inhibit the statistical analysis?

In additon, I would like to know the adverse events for methotrexate itself in your meta-analysis.

Author Response

First of all, I would like to thank you for the attention you have given to this work.

However, about the ages for cases, are they no significant and did the differences of ages for patients inhibit the statistical analysis?

--> The age of the patients was not significantly different between the studies, and corresponds to the classic age of diagnosis of patients with rheumatoid arthritis. This did not interfere with the statistical analysis. 

In additon, I would like to know the adverse events for methotrexate itself in your meta-analysis.

--> We did not have a methotrexate alone arm in this analysis, but only a biologic monotherapy arm and a biologic + methotrexate arm. The side effects analysed were therefore those of these two arms, with no significant difference between them. 

Sincerely