Frontiers in Rheumatoid Arthritis: Emerging Research and Unmet Needs in Pharmacologic Management

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors This review provides a comprehensive overview of unmet needs and emerging research in rheumatoid arthritis (RA) pharmacologic management, with a strong focus on precision medicine and real-world evidence—topics of high relevance to the field. However, the abstract could be refined to more explicitly highlight key actionable insights (e.g., specific biomarker-clinical phenotype correlations or comparative effectiveness findings from real-world registries) to enhance its impact for readers. In the "Current treatment paradigms" section, while the 2021 ACR guidelines are thoroughly discussed, a brief comparative summary of key differences with major international guidelines (e.g., EULAR 2022 updates) would strengthen the global relevance of the treatment recommendations, particularly regarding DMARD sequencing and glucocorticoid use in resource-limited settings. The characterization of "difficult-to-treat (D2T) RA" is well-structured, but adding a concise table summarizing key clinical predictors (e.g., seropositivity, comorbidities) and associated therapeutic implications would improve readability and utility for clinicians seeking quick reference. In the "Biomarkers" subsection, the discussion of anti-SS-A antibodies and their impact on treatment response is insightful, but further elaboration on the practical barriers to integrating these biomarkers into routine clinical decision-making (e.g., test availability, cost, turnaround time) would address a critical implementation gap. The section on "Real-world safety of b/tsDMARDs" provides valuable data, but it would benefit from a more nuanced analysis of age-related differences in adverse event profiles—especially for LORA patients—given the growing emphasis on geriatric rheumatology and individualized risk-benefit assessment. While multiple real-world registries (e.g., JAK-pot, KURAMA) are cited, a brief comparison of their methodological strengths and limitations (e.g., sample size, follow-up duration, confounding adjustment) would help readers interpret the generalizability of their findings across diverse patient populations. The "Shared decision making" subsection is somewhat brief relative to its importance. Expanding on specific tools or frameworks (e.g., patient-reported outcome measures integrated with biomarker data) to facilitate shared decision-making in precision medicine would enhance the review’s clinical applicability. Several recent key studies (e.g., 2023–2024 trials on FLS-targeted therapies or novel cytokine inhibitors) appear underrepresented in the references. Updating the citation list to include these latest advancements would ensure the review reflects the most current state of research. It is recommended that the author quote some relevant literatures: Chinese Journal of natural medicines, 2025, 23 (4): 480-491 and Acta Pharmaceutica Sinica BVolume 13, Issue 11, November 2023, Pages 4417-4441. The conclusion could be strengthened by prioritizing future research directions (e.g., validation of synovial phenotypes in multi-center cohorts, long-term outcomes of dual biologic therapy) to guide the field’s focus, rather than providing a general overview of emerging technologies. Minor editorial note: Ensure consistent formatting of abbreviations (e.g., "TTT" vs. "T2T") throughout the manuscript, and verify that all newly introduced terms (e.g., "PIRRA," "NIRRA") are clearly defined at first mention to avoid confusion for readers less familiar with specialized RA nomenclature.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

 

pharmaceuticals-4017359

Pharmaceuticals (MDPI)

Title: Frontiers in Rheumatoid Arthritis: Emerging Research and Unmet Needs in

          Pharmacologic Management.

 

Comments:

• In the abstract, the Source of information and the duration of the literature report must be mentioned. Also, the abbreviations (DMARD) must be spelt.
• Objective must be more clarified and elaborated.
• Types of RA and recommended drugs must be incorporated in a table format along with references in the introduction section.
• Probable reasons and mechanisms for the lack of durable response to DMARD therapy in patients with RA must be mentioned along with references.
• Since when Glucocorticoid avoidance is recommended for most patients and why? What is its mechanism? Incorporate information along with references.
• A table showing all types of DMARDS, year of recommendation, benefits, drawbacks, how these drugs works, availability of various DMARDs, number of patients benefited/unbenefited (sex, age, duration etc), whether these patients suffer from only RA or have comorbid disease along with RA, analysis report of these patients etc, must be mentioned with references.
• Difference between Circulating rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs), its mechanism in severe/non-severe RA patients and year of  recomendation must be incorporated along with references.
• Lists the microorganism identified as a risk factor for progression to RA along with references and recommended drugs (DMARD) for RA management must be incorporated.
• What are the numerous therapies that have been evaluated for use in RA prevention? Name them along with references.
• Define biomarkers. List of gene/protein biomarkers identified, validated in how many RA patients’ (age sex) samples (blood, synovial fluid, microphages), which pathway targeted, clinically practised in which countries etc information must be incorporated
• Recent advanced technique used to identify novel biomarkers must be incorporated.

How can biomarkers, cytokines, synovial types, and immune-cell profiles help and guide treatment decisions for patients with RA? Elaborate it along with references.

• Elaborate “early clinical disease” with references.
• Why Sjogren’s disease, sicca discussed ? Is it a type of RA? How is it associated with RA? It is very much unclear, may be removed.
• The mechanism of DMARDs, TNF inhibitors for RA treatment must be incorporated along with Figure. Advantage/disadvantage to TNF inhibitor therapies over DMARDs must be incorporated along with references
• Elaborate on seronegative/seropositive patients and incorporate information along with references
• Elaborate DNMT3A , TET2 mutations and their differences.
• Reference for the line “Currently, rates of DMARD … across cohorts” must be incorporated.
• How MACE and VTE is associated with RA? Clarify.
• Explain more about how change in lifestyle and environmental changes helps to prevent rheumatoid arthritis (RA).
• Discuss lifestyle factors like smoking, obesity, vitamin D levels, and oral microbiome. The current prevention trials in this area to provide more context must be mentioned.
• Clarify the difference between established safety signals, such as the risk of blood clots with JAK inhibitors and the potential link between TNF inhibitors and multiple sclerosis.Elaborate more about safety concerns.
• The main challenges of using advanced methods like synovial biopsies and transcriptomics in RA research, practical difficulties involved must be incorporated along with references.
• What are the barriers to consistently using a treat-to-target approach in managing rheumatoid arthritis? 

 

Conclusion: The article is collection of some information.The analysis of review literature is very weak. It must have been carried out and appropriate conclusion should have drawn.

 

Additional comments

• Page number, Line number must be mentioned for each comments response.
  
  
  
  

 

Comments on the Quality of English Language

English language must be improved

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

In pharmaceuticals-4017359, Joshua J. Skydel  and Betty Hsiao discuss the frontiers in rheumatoid arthritis (RA) and review the emerging research and unmet needs in pharmacologic management of RA.  Although this review lack in-depth analysis, the reviewer feels it can be accepted after some major amendments.

(1) The major recent progresses in the pathogenesis of RA should be briefly summarized. A better know how will lead to better treatment.

(2) The manuscript contains zero figure or table. This is not acceptable. For a review article, visual summaries are essential.

(3) The safety should be carefully discussed.

(4) The cost-effectiveness of treatment carefully discussed.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

This is a very interesting and comprehensive work, which includes Emerging Research and Unmet Needs in Pharmacologic Management for Rheumatoid Arthritis. It is well designed, presented and discussed. I actually, enjoyed reading but still have the following comments.

The authors are requested to add graphical abstract for better representation.

The authors are requested to add some figures regarding comparison between healthy and Rheumatoid Arthritis joints or pathophysiological pathway for better representation.

The authors are requested to include some tables  comparison between NSAIDs, DEMARDs, and Biologics Drug treatment for Rheumatoid Arthritis for better representation.

The introduction provides a clear overview of the significance of rheumatoid arthritis (RA) and its global impact, but it could benefit from a more in-depth discussion of the historical evolution of pharmacologic treatments. 

The authors are requested to highlights the section on emerging pharmacologic therapies is comprehensive but could further explore the mechanisms of action of novel biologics and small molecules, especially in relation to their targeting of specific immune pathways.

The article effectively identifies several unmet needs in RA pharmacologic management, such as the need for personalized treatment strategies and improved drug safety by discussing the role of biomarkers in guiding therapy might help address this gap. 

The review touches on the growing importance of personalized medicine in RA, but this section could benefit from a more thorough exploration of the genetic and environmental factors that influence treatment response.

The article could conclude with a stronger focus on future research directions. For instance, the potential of combination therapies, and the development of more effective drug delivery systems could be explored.

The authors are requested to highlights or add the limited section of the current article.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript has been improved and it appears to be accepted. 

Reviewer 4 Report

Comments and Suggestions for Authors

Thank you for your thorough response to my comments.I appreciate the clear justification provided for all comments and satisfied with the explanations you have given for several points. Your revision have addressed my concern, and happy to recommend your manuscript for publication.