Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This case report presents a clinically valuable experience of refractory oral ulcers successfully managed with combination therapy of low-dose thalidomide and colchicine. However, as this case may serve as a reference for clinicians considering similar treatment approaches, several methodological concerns need to be addressed to ensure the therapeutic rationale and clinical decision-making process are clearly articulated and scientifically rigorous.

1. Each immunomodulatory agent individually (with concurrent prednisolone) was trialed for only one week before concluding inefficacy - thalidomide (50mg/day) + prednisolone (10mg/day) for one week (lines 99-101), then colchicine (1.0mg/day) + prednisolone (15mg/day) for one week (lines 109-111). Given the size and chronicity of these refractory ulcers, this duration appears insufficient to adequately assess individual drug efficacy. Please provide detailed discussion on the rationale for this short trial period and address whether combination therapy was truly necessary or premature.
2. The manuscript does not clearly define steroid resistance/dependency. Given the patient's multiple autoimmune conditions (Sjögren's, SLE, RA), prior steroid exposure is highly likely. Please discuss: (a) how steroid resistance was defined, (b) patient's previous steroid exposure history, and (c) whether chronic steroid use contributed to treatment resistance.
3. Lines 113-114 state that "brief discontinuation of thalidomide or colchicine independently led to ulceration recurrence." However, distinguishing true drug effect from natural disease fluctuation requires more rigorous evidence. Please provide: (a) exact discontinuation periods, (b) recurrence timeline, and (c) how confounding factors were controlled.
4. Prednisolone dose was abruptly reduced from 15mg to 2.5mg when initiating combination therapy (>80% reduction). Please explain the clinical rationale for this dramatic dose reduction and whether it might confound the interpretation of combination therapy efficacy.
5. Lines 112-113 describe combination therapy results as "clinical improvement with notable pain reduction within two weeks," which relies entirely on subjective assessment. The manuscript does not report quantitative ulcer size measurements during the initial 2-week combination therapy period, despite measuring ulcer dimensions at other timepoints (e.g., 2.3 × 2.3 cm at lines 98-101). Please provide: (a) serial ulcer measurements (cm²) at baseline, 1 week, and 2 weeks of combination therapy, (b) objective pain scales (e.g., VAS), and (c) standardized healing assessment criteria. Without these data, it is difficult to objectively evaluate treatment efficacy and compare combination therapy to single-agent trials.
6. Please add a dedicated limitations section addressing: single case design, lack of controlled comparison, limited long-term safety data, and generalizability concerns.

Line 176: "dianosis" should be "diagnosis"

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Title

• The title overstates the novelty by using expressions such as “Unique Case Study” without sufficient justification.
• The title implies generalizable therapeutic success despite being based on a single case.

Abstract

• The abstract does not clearly state why this case is clinically or scientifically distinct from previously reported cases.
• The term “comprehensive literature review” is misleading, as no structured review methodology is described.
• Safety claims are made without systematic adverse-event reporting or standardized assessment.

Introduction and Clinical Significance

• The introduction provides background information but fails to clearly define the specific knowledge gap addressed by this case.
• The rationale for combining thalidomide and colchicine is not sufficiently justified at the outset.
• Prior reports of similar pharmacological approaches are acknowledged but not critically contrasted with the current case.

Case Presentation

• The case description is excessively long and descriptive, lacking prioritization of clinically relevant details.
• Multiple therapeutic interventions are applied sequentially, making it difficult to isolate the effect of the final combination therapy.
• No standardized pain scale, ulcer severity index, or quality-of-life assessment is used to objectively document improvement.
• The timeline of interventions and responses is not presented in a concise or structured format.
• The role of systemic autoimmune conditions as confounding factors is insufficiently addressed.

Histopathological Evaluation

• Repeated biopsies are reported, but their added diagnostic or prognostic value is not clearly explained.
• The clinical relevance of low-grade dysplasia findings in relation to treatment decisions is not adequately discussed.
• Immunohistochemical findings (e.g., Ki-67) are described but not interpreted in a clinically meaningful way.

Treatment Strategy

• The rationale for dose adjustments and drug substitutions is largely retrospective and descriptive.
• The justification for combining thalidomide and colchicine, rather than escalating monotherapy, is not evidence-based.
• Potential drug–drug interactions and cumulative toxicity risks are not systematically discussed.
• Safety monitoring parameters (neuropathy, hematologic or hepatic effects) are not clearly reported.

Literature Review

• The review lacks a defined search strategy, databases, keywords, or inclusion/exclusion criteria.
• References are presented narratively without critical appraisal or synthesis.
• The review does not clearly demonstrate that combination therapy has not been previously reported.
• Comparative outcomes from existing studies are not summarized in a structured manner.

Discussion

• The discussion largely reiterates known mechanisms of thalidomide and colchicine without linking them directly to the presented case.
• The manuscript overinterprets a single-case outcome to suggest broader clinical applicability.
• Alternative explanations for remission (natural disease fluctuation, cumulative steroid effect) are not sufficiently considered.
• The discussion does not adequately acknowledge the inherent limitations of single-case evidence.

Conclusions

• The conclusions are overly assertive given the descriptive nature of the study.
• Claims of providing a “new treatment choice” are not supported by the level of evidence.
• The conclusion does not clearly distinguish between hypothesis-generating observations and clinical recommendations.

Ethics and Reporting Standards

• Ethical approval is mentioned, but the justification for waiver is not clearly contextualized.
• Long-term safety considerations, particularly for thalidomide use, are insufficiently emphasized in the reporting framework.

Overall Assessment

• The manuscript lacks clear originality and methodological rigor expected for a high-quality case report.
• The scientific contribution remains incremental and hypothesis-generating rather than practice-changing.
• Substantial revision is required to improve clarity, objectivity, and alignment with case-report reporting standards.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for incorporating the reviewer's feedback into the revisions.

 

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have adequately addressed all reviewer comments and have substantially improved the clarity, structure, and scientific framing of the manuscript. The revised version provides an appropriately balanced interpretation of findings, removes overly assertive claims, and aligns well with current standards for case report reporting. The methodological context, clinical rationale, and discussion of limitations are now clearly articulated, and the tone is consistent with hypothesis-generating evidence rather than practice-changing conclusions. Taken together, the revisions have resulted in a coherent and well-constructed manuscript that is suitable for publication in its current form.