Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have carried out a very comprehensive narrative review of the mechanisms related to treatment response in rheumatoid arthritis. However, among all the factors considered, only a few have evidence supporting their role in difficult-to-treat rheumatoid arthritis (D2TRA). The remaining factors, although plausible and worth considering, are not supported by scientific evidence demonstrating a direct association with the development of D2TRA.

One option to better align this review with its main objective would be to develop in greater depth those sections for which evidence in D2TRA does exist, or alternatively, to redefine the objectives and the title of the review based on the evidence summarized. As currently structured, the manuscript may be confusing for the reader, as it does not specifically focus on the mechanisms underlying D2TRA.

Author Response

Comments:

The authors have carried out a very comprehensive narrative review of the mechanisms related to treatment response in rheumatoid arthritis. However, among all the factors considered, only a few have evidence supporting their role in difficult-to-treat rheumatoid arthritis (D2TRA). The remaining factors, although plausible and worth considering, are not supported by scientific evidence demonstrating a direct association with the development of D2TRA.

One option to better align this review with its main objective would be to develop in greater depth those sections for which evidence in D2TRA does exist, or alternatively, to redefine the objectives and the title of the review based on the evidence summarized. As currently structured, the manuscript may be confusing for the reader, as it does not specifically focus on the mechanisms underlying D2TRA.

Response:

We thank the Reviewer for taking the time to evaluate this manuscript and providing valuable feedback. Considering the recent introduction of the D2T framework in RA care and research, direct evidence in this specific patient group is relatively scarce to date. However, our main aim was to consider and discuss a wide range of determinants that have been proposed to play a role in D2T disease. Therefore, we have included findings derived from broader RA populations or earlier disease stages, even if explicit evidence linking particular mechanisms to D2T RA is lacking.

In line with your suggestions, we have made a number of adjustments to our revised manuscript. First, we have placed greater emphasis on D2T disease by adding more detailed discussions of results that more clearly relate to this subgroup. Moreover, we have included a new table (Table 2) listing relevant findings from recent studies that specifically included D2T RA groups in their analysis, with the goal of highlighting more direct evidence linking biological characteristics to D2T disease. We have also added a ’Methods’ section detailing the process of literature search and article selection, which could provide greater transparency regarding the focus of the article. In the new ’Limitations’ section, we have detailed potential sources of bias, including the limited applicability of some findings within the context of D2T RA.

Reviewer 2 Report

Comments and Suggestions for Authors

This narrative review addresses the biological and contextual drivers of difficult-to-treat (D2T) rheumatoid arthritis (RA). It synthesizes evidence across genetics and epigenetics, autoantibodies, synovial profiling (including fibroblast and stromal biology), immune cell subsets, comorbidities, environmental exposures, and treatment-related mechanisms. The manuscript aims to integrate these domains to explain why a subset of patients remain refractory despite multiple targeted therapies and to highlight potential avenues for stratification and novel therapeutics. The major concerns are mentioned below:

Specific Comments

1. Add more information about the “true refractory RA” condition in the introduction. Provide a clear distinction between refractory RA and D2T RA. Additionally, the factors must be considered before concluding the condition to be difficult-to-treat rheumatoid arthritis.
2. As a narrative review that cites many primary studies and trials, the manuscript lacks a transparent description of how literature was identified, selected, and appraised. This omission reduces reproducibility and raises the risk of selection bias.  Add a concise Methods subsection specifying databases searched, date ranges, search terms or themes, and inclusion/exclusion criteria (even for a narrative review).
3. Figure 1 provides an overview of the review. It is suggested to elaborate on the legend of the figure, explaining the figure, especially about the molecular mediators mentioned in the inner circle.
4. Few of the sections start abruptly without providing the context (e.g., twin studies mentioned in the genetics and epigenetics section). Try to make the text connected for better readability.
5. Define acronyms at first use and maintain consistent terminology for pathotypes and cell subsets. Add a list of abbreviations.
6. The review has included studies that have used specific cohorts. Provide a brief list that provides information on the same.
7. Currently, in the review, the clinical translation gap exists.  The review suggests potential therapeutic targets but does not consistently evaluate feasibility, safety, or the current standing of clinical development for these approaches.
8. It is suggested to the authors to conclude on the basis of current evidence instead of speculations (e.g., that specific fibroblast subsets are primary drivers of clinical refractoriness across populations). The text should more clearly separate hypothesis-generating ideas from well-supported conclusions.
9. This narrative review must include and highlight the limitations, such as publication bias, and must suggest experimental/clinical associations.

Author Response

We thank the Reviewer for taking the time to evaluate this manuscript and providing detailed comments. Please see our specific answers below.

Comment 1: Add more information about the “true refractory RA” condition in the introduction. Provide a clear distinction between refractory RA and D2T RA. Additionally, the factors must be considered before concluding the condition to be difficult-to-treat rheumatoid arthritis.

Response 1: Thank you for this remark about the terminology used in the literature. ’True refractory’ RA refers to a tentative phenotype for which no standard classification exists and the underlying mechanisms remain unclear. Based on your suggestion, we have revised our explanation on this subgroup in the introduction. Furthermore, we have added a new table (Table 1) that briefly summarizes the general concept of more well-known categorizations used in relevant literature, including ’difficult-to-treat’, ’refractory’, and ’true refractory’ RA. We hope these additions offer greater clarity regarding these related yet non-interchangeable terms.

Comment 2: As a narrative review that cites many primary studies and trials, the manuscript lacks a transparent description of how literature was identified, selected, and appraised. This omission reduces reproducibility and raises the risk of selection bias.  Add a concise Methods subsection specifying databases searched, date ranges, search terms or themes, and inclusion/exclusion criteria (even for a narrative review).

Response 2: We agree that a description of methodology would enhance transparency. In line with the suggestion, we have included a brief ’Methods’ section (after the introduction) that provides more details on the databases searched and the identification and selection of studies during the manuscript’s preparation.

Comment 3: Figure 1 provides an overview of the review. It is suggested to elaborate on the legend of the figure, explaining the figure, especially about the molecular mediators mentioned in the inner circle.

Response 3: Thank you for this insightful remark. Based on this point, we have further expanded the legend of Figure 1 to provide context for featuring the mentioned molecular mediators/signalling pathways in the figure’s inner circle.

Comment 4: Few of the sections start abruptly without providing the context (e.g., twin studies mentioned in the genetics and epigenetics section). Try to make the text connected for better readability.

Response 4: Thank you for this suggestion. We have thoroughly reviewed them manuscript’s main text to enhance its structural flow and continuity across sections (including ’Genetics and epigenetics’) and made modifications where we felt that an updated wording would provide more clarity.

Comment 5: Define acronyms at first use and maintain consistent terminology for pathotypes and cell subsets. Add a list of abbreviations.

Response 5: We appreciate this observation and sincerely apologize for the omission. We have carefully checkced the text and added missing definitions of abbreviations the first time they appear. Furthermore, we have included an alphabetic list of abbreviations used throughout the article, and have made an effort to harmonize inconsistent terminology.

Comment 6: The review has included studies that have used specific cohorts. Provide a brief list that provides information on the same.

Response 6: Thank you for this thoughtful suggestion. We agree with the added value of highlighting studies using specific D2T cohorts. To this end, we have included Table 2 after the introduction, which includes relevant findings of recent studies providing pathogenic insights that reported on subgroups meeting the definition for D2T RA.

Comment 7: Currently, in the review, the clinical translation gap exists.  The review suggests potential therapeutic targets but does not consistently evaluate feasibility, safety, or the current standing of clinical development for these approaches.

Response 7: Thank you for this suggestion to provide more information on the clinical application of potential therapies in D2T RA. Based on this remark, we have further elaborated on the current status of clinical translation for the emerging therapeutic targets mentioned in the article.

Comment 8: It is suggested to the authors to conclude on the basis of current evidence instead of speculations (e.g., that specific fibroblast subsets are primary drivers of clinical refractoriness across populations). The text should more clearly separate hypothesis-generating ideas from well-supported conclusions.

Response 8: We appreciate this valuable suggestion. We have carefully reviewed the manuscript and refined the wording of certain statements with the goal of providing a more clear distinction between well-established associations and mechanisms whose connection to D2T disease relies on indirect evidence.

Comment 9: This narrative review must include and highlight the limitations, such as publication bias, and must suggest experimental/clinical associations.

Response 9: We agree that the discussion of limitations would be an important addition to the article. In accordance with this remark, we have included a ’Limitations’ section before the conclusions of the revised manuscript. This section more explicitly states reasons for potential sources of bias during the selection of articles and preparation of the manuscript.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The revised version of the manuscript seems good to me, so I suggesting accept the manuscript.

Comments on the Quality of English Language

The revised version of the manuscript seems good to me, so I suggesting accept the manuscript.