Lung Involvement in Systemic Sclerosis—From Pathogenesis to Prediction

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors, Thank you for the oppertunity to review your review concerning lung involvement. Your comprehensive review is wellwritten and of great interests for all clinicians diagnosing and treating patients with lung involvement in systemic sclerosis. However I have a few comments that may improve your paper even more:

1. Your title : Lung involvement in systemic sclerosis- from pathogenesis til prediction is fine but would it be possible to get your point of view on where the actual knowledge on prediction will help us futher - I lack reading thorugh your paper a final comment concerning this 'prediction' in your concluding remarks/conclusions (page 11)

2. Your review is written using 58 references - how was the references picted - why these references instead of others (the pick and choose process)? - What was the methodology of your review process? Did you use a speciel way of selection? What was your search strategy and where did you search for references? Could you please explain this in a subtitle: Methodology after your introduction section.

Comments on the Quality of English Language

I have no extra comments. The quality of English is fine

Author Response

Dear Authors, Thank you for the opportunity to review your review concerning lung involvement. Your comprehensive review is well written and of great interests for all clinicians diagnosing and treating patients with lung involvement in systemic sclerosis. However I have a few comments that may improve your paper even more:

• Authors` response: Thank you very much for your time to revise our manuscript. We acknowledge that our paper might have some issues and we corrected the manuscript in accordance to your comments.

1. Your title : Lung involvement in systemic sclerosis- from pathogenesis til prediction is fine but would it be possible to get your point of view on where the actual knowledge on prediction will help us further - I lack reading through your paper a final comment concerning this 'prediction' in your concluding remarks/conclusions (page 11)

• Authors` response: Thank you for your insightful feedback. We have revised the conclusion to address the role of prediction in advancing the management of lung involvement in systemic sclerosis, and therefore, to reflect the title completely. Our updated concluding remarks emphasize that predictive models and biomarkers can significantly enhance early diagnosis, enable more personalized treatment strategies, and improve patient outcomes. Many SSc patients are stable over time, we focused on the options to predict the progression of the disease, based on different markers, etc. By identifying high-risk individuals and monitoring disease progression more effectively, these predictive tools can guide clinical decision-making, potentially reducing lung damage and improving overall prognosis. We believe these advancements will contribute to more targeted and proactive approaches in managing systemic sclerosis-related lung complications.

 

2. Your review is written using 58 references - how was the references picted - why these references instead of others (the pick and choose process)? - What was the methodology of your review process? Did you use a speciel way of selection? What was your search strategy and where did you search for references? Could you please explain this in a subtitle: Methodology after your introduction section.

• Authors` response: Thank you very much for the valuable comment, we agree with the referee that we have to elucidate our search strategy. We added a section in the paper on this, including the paper selection, the methodology, etc. And also a figure on paper selection.

Reviewer 2 Report

Comments and Suggestions for Authors

Major points

1. I think there is too little description of the histopathology. For this reason, the authors use the terms "ILD" and "IPF" for "type of lung involvement" (Table 1), but they should use the terms "NSIP" and "UIP". Generally speaking, lung involvement in SSc is not "idiopathic", so it cannot be described as IPF. For the same reason, the sentence on line 243, "Lung involvement in the case of SSc can follow the pattern of IPF or ILD.", is also incorrect.

It should be changed to either a sentence comparing SSc-ILD with IPF, or to a description of the difference between NSIP and UIP seen in SSc patients.

The authors need to revise the description, keeping in mind that "IPF is not a complication of SSc."

2. Is it necessary to describe PAH?  PAH may fall under the category of "lung involvement." However, this would make the review point unclear. The description of PAH on pages 3-4 should be deleted and the description of the pathological tissue of ILD should be expanded. If pulmonary hypertension is to be described, a description of group III PH is necessary.

3. Tocilizumab is one of the few biologics that can be used for SSc-ILD, but the description of this drug is limited to only three lines, which is insufficient information.

I would also like the document to be consistent in whether or not it lists the trial abbreviation.

"SLS1," "SLS2," "RECITAL," and "SENCIS" appear in the text on page 10, but the description of tocilizumab does not include the trial abbreviation.

4. The authors need to check how to use abbreviations. It seems that the writing was divided among the several authors, and explanations of abbreviations appear in multiple places. Conversely, abbreviations also appear without explanation.

a. "Interstitial Lung Disease (ILD)" on line 80 has already been mentioned on line 51.

b. "Interstitial Lung Disease (ILD)" on line 170 has already been mentioned on line 51.

c. "diffusing capacity for carbon monoxide (DLco)" on line 195 has already been mentioned on line 145.

d. "nonspecific interstitial pneumonia" on line 227 has already been mentioned on line 222.

e. "pulmonary arterial hypertension (PAH)" on line 313 has already been mentioned on line 134.

f. "diffusing capacity for carbon monooxide (DLco)" on line 315 has already been mentioned on line 145.

g. "N-terminal Pro-Brain natriuretic peptide (NT-proBNP)" on line 325 has already been mentioned on line 149.

h. "FVC" on line 198 requires "Forced Vital Capacity (FVC)" on line 195.

i. "CXR" on line 207 requires "chest X-ray picture (CXR)".

j. "ANA" on line 211 requires "anti-nuclear antibodies (ANA)".

k. On line 226, (IPF) is missing.

l. "CRP" on line 352 requires "C-reactive protein (CRP)" on line 351.

Minor points

1. This manuscript contains some unclear words, likely spelling mistakes, and these need to be corrected.

a. Line 139, what is "sSSc-PA"?

b. Line 260, what is "SScl"?

c. Line 272, what is "the activating platform (NLRP1)"?

2. I don't understand the meaning of line 211, "ANA are present in more than 90% of SSc patients, while several studies have suggested that TGF-β plays an essential role in the fibrotic process." What impact does "antinuclear antibodies are positive in more than 90% of patients" have?

3. I don't understand what "pattern" means in line 243, "Lung involvement in the case of SSc can follow the pattern of IPF or ILD."  Is it a pathological pattern or a clinical course pattern?

 

Author Response

Major points

• Thank you for taking the time to review our manuscript and for providing detailed feedback. We appreciate your constructive comments and recognize the importance of addressing the major points raised. We are committed to improving our manuscript based on your suggestions and believe that incorporating your feedback will significantly enhance the clarity and impact of our work. We will carefully revise the sections you highlighted, ensuring that we provide a more thorough discussion of key aspects, such as the role of antibodies in disease activity, the integration of graphs to elucidate pathogenesis, and the influence of nutrition on clinical outcomes. Your insights are invaluable to us, and we are confident that addressing these concerns will strengthen our manuscript. Thank you again for your thoughtful review and guidance.

1. I think there is too little description of histopathology. For this reason, the authors use the terms "ILD" and "IPF" for "type of lung involvement" (Table 1), but they should use the terms "NSIP" and "UIP". Generally speaking, lung involvement in SSc is not "idiopathic", so it cannot be described as IPF. For the same reason, the sentence on line 243, "Lung involvement in the case of SSc can follow the pattern of IPF or ILD.", is also incorrect.

It should be changed to either a sentence comparing SSc-ILD with IPF, or to a description of the difference between NSIP and UIP seen in SSc patients.

The authors need to revise the description, keeping in mind that "IPF is not a complication of SSc."

• Authors` response: Thank you for your valuable feedback on our manuscript. We appreciate the opportunity to correct the terminology used. For this purpose, we have completely omitted the term IPF from this section because it refers to another disease. We have included the term non-specific interstitial pneumonia (NSIP), which corresponds to the ground-glass pattern observed on chest CT, as well as the usual interstitial pneumonia (UIP) pattern that corresponds to fibrosis. Furthermore, in Table 1, we have deleted the row pertaining to IPF.
• We also expanded the description of the pathological tissue of ILD in SSc.

 

2. Is it necessary to describe PAH? PAH may fall under the category of "lung involvement." However, this would make the review point unclear. The description of PAH on pages 3-4 should be deleted and the description of the pathological tissue of ILD should be expanded. If pulmonary hypertension is to be described, a description of group III PH is necessary.

• Authors` response: Thank you for your thoughtful feedback regarding the inclusion of PAH in our manuscript. We appreciate the opportunity to clarify the relevance of PAH to our review and our rationale for its inclusion.
• PAH specifically affects the pulmonary vasculature and can significantly influence the prognosis and treatment strategies for SSc patients. Given this distinction, we believe that discussing PAH provides a more comprehensive overview of lung involvement in SSc. Furthermore, the inclusion of PAH in the manuscript highlights the importance of early diagnosis and management, which are critical for improving patient outcomes. PAH is associated with a different set of clinical symptoms, diagnostic criteria, and therapeutic interventions compared to ILD. By detailing these differences, our review aims to provide a nuanced understanding of the spectrum of pulmonary complications in SSc.
• We acknowledge the potential overlap with Group III pulmonary hypertension, which involves lung diseases and/or hypoxia. However, given the primary focus on SSc, our review aims to emphasize PAH (which is more closely related to vascular changes rather than parenchymal lung disease). We will clarify this distinction in the manuscript to avoid any confusion.
• We agree on the importance of expanding the description of the pathological tissue of ILD in SSc, and added a paragraph on this topic.

 

3. Tocilizumab is one of the few biologics that can be used for SSc-ILD, but the description of this drug is limited to only three lines, which is insufficient information.

• Authors` response: We are grateful to the review for raising the issue of insufficient data presented on tocilizumab. Indeed, tocilizumab does play an important role in the treatment of systemic sclerosis, primarily interstitial lung disease. To increase the clarity and the content pertaining to the therapeutic role of tocilizumab, we have expanded the respective paragraph, explaining the nuances of the trial that led to the approval of this drug by the FDA (Khanna et al, 2020).

I would also like the document to be consistent in whether or not it lists the trial abbreviation.

"SLS1," "SLS2," "RECITAL," and "SENCIS" appear in the text on page 10, but the description of tocilizumab does not include the trial abbreviation.

• Authors` response: We thank the reviewers for their advice to include the trial abbreviation for the tocilizumab trial. Unfortunately, the trial that we have referred to does not have a specific abbreviation. Thank you very much for your understanding.

 

4. The authors need to check how to use abbreviations. It seems that the writing was divided among the several authors, and explanations of abbreviations appear in multiple places. Conversely, abbreviations also appear without explanation.
5. "Interstitial Lung Disease (ILD)" on line 80 has already been mentioned on line 51.
6. "Interstitial Lung Disease (ILD)" on line 170 has already been mentioned on line 51.
7. "diffusing capacity for carbon monoxide (DLco)" on line 195 has already been mentioned on line 145.
8. "nonspecific interstitial pneumonia" on line 227 has already been mentioned on line 222.
9. "pulmonary arterial hypertension (PAH)" on line 313 has already been mentioned on line 134.
10. "diffusing capacity for carbon monooxide (DLco)" on line 315 has already been mentioned on line 145.
11. "N-terminal Pro-Brain natriuretic peptide (NT-proBNP)" on line 325 has already been mentioned on line 149.
12. "FVC" on line 198 requires "Forced Vital Capacity (FVC)" on line 195.
13. "CXR" on line 207 requires "chest X-ray picture (CXR)".
14. "ANA" on line 211 requires "anti-nuclear antibodies (ANA)".
15. On line 226, (IPF) is missing.
16. "CRP" on line 352 requires "C-reactive protein (CRP)" on line 351.

• Authors` response: Thank you for your feedback regarding the use of abbreviations. We reviewed the manuscript and identified instances where abbreviations were either explained multiple times or not explained at all. We standardized the use of abbreviations, ensuring that each was introduced with a full explanation at its first occurrence and consistently used thereafter to enhance clarity and coherence throughout the text.

Minor points

1. This manuscript contains some unclear words, likely spelling mistakes, and these need to be corrected.
2. Line 139, what is "sSSc-PA"?
3. Line 260, what is "SScl"?

`c. Line 272, what is "the activating platform (NLRP1)"?

• Authors` response: Thank you for your detailed feedback. We have addressed the points raised. We corrected the unclear terms:
• "sSSc-PA" was a typographical error. The correct term is "SSc-PAH," referring to systemic sclerosis-associated pulmonary arterial hypertension.
• "SScl" was also a typographical error. It should be "SSc," indicating systemic sclerosis.
• We corrected the issue by rephrasing and adding more details from the cited study.

2. I don't understand the meaning of line 211, "ANA are present in more than 90% of SSc patients, while several studies have suggested that TGF-β plays an essential role in the fibrotic process." What impact does "antinuclear antibodies are positive in more than 90% of patients" have?

• Authors` response: Thank you for noticing this, we separated the sentence into two statements, since they are not related, and not opposite to each other.

3. I don't understand what "pattern" means in line 243, "Lung involvement in the case of SSc can follow the pattern of IPF or ILD." Is it a pathological pattern or a clinical course pattern?

• Authors` response: We thank the reviewer for raising this important question. As indicated above, we appreciate the opportunity to correct the terminology used. For this purpose we have completely omitted the term IPF from this section because it refers to another disease (idiopathic pulmonary fibrosis which is not a part of the CTD-ILD spectrum). We have included the term non-specific interstitial pneumonia (NSIP) which corresponds to the ground-glass pattern observed on chest CT, as well as the usual interstitial pneumonia (UIP) pattern that corresponds to fibrosis. Furthermore, in Table 1 we have deleted the row pertaining to IPF. We hope this adjustment is sufficient.

Reviewer 3 Report

Comments and Suggestions for Authors

The paper titled: “Lung Involvement in Systemic Sclerosis - from Pathogenesis to Prediction” describes the recent findings in immunological biomarkers, inflammatory indicators, and other parameters that can function as potential diagnostic and prognostic tools.

 

 

1.      Particularly interesting is paragraphs 77-82. Mentioned antibodies are commonly analyzed in clinical practice. Does the level of these antibodies correlate with the activity of diseases and lung involvement?

2.      It will be easier for a reader to follow paragraph 2.2. Pathogenesis of Lung Involvement in SSc if it is supplied by graph gathering various mechanisms present in pulmonary process in systemic sclerosis.

3.      The Authors mention pharmacological possibilities in paragraph 5.1. What about the methotrexate, given in the early stage with skin involvement? Can we safely use this medication in the early stages of SSc without lung involvement, or should we avoid it to prevent lung fibrosis?

4.      Paragraph 5.2: In non-pharmacological approaches, the author mentions oxygen therapy and rehabilitation. Does nutrition influence the clinical state of patients with SSc? Can it be beneficial in lung fibrosis?

5.      What kind of rehabilitation should be recommended for patients with lung fibrosis?

 

If the Authors answer the question, I believe the manuscript is worthy of publication.

Author Response

The paper titled: “Lung Involvement in Systemic Sclerosis - from Pathogenesis to Prediction” describes the recent findings in immunological biomarkers, inflammatory indicators, and other parameters that can function as potential diagnostic and prognostic tools.

• Authors` response: Thank you for your review. We appreciate your acknowledgment of our efforts to explore immunological biomarkers and inflammatory indicators in systemic sclerosis-related lung involvement as potential diagnostic and prognostic tools. We hope our detailed discussion on these emerging biomarkers and indicators will contribute to advancing the understanding and management of lung involvement in systemic sclerosis. Your feedback has been valuable, and we have made revisions to enhance the clarity and comprehensiveness of the manuscript.

 

1. Particularly interesting is paragraphs 77-82. Mentioned antibodies are commonly analyzed in clinical practice. Does the level of these antibodies correlate with the activity of diseases and lung involvement?

• Authors` response: To clarify, the antibodies mentioned in these paragraphs, such as antinuclear antibodies (ANA), anti-centromere antibodies (ACA), and anti-topoisomerase I antibodies (anti-Scl-70), are indeed significant in diagnosing and monitoring systemic sclerosis (SSc). However, the correlation between these antibody levels and disease activity, particularly lung involvement, varies. While these antibodies are valuable in identifying subsets of SSc patients and predicting disease patterns, their levels do not always directly correlate with disease activity or severity. For example, anti-Scl-70 antibodies are associated with diffuse cutaneous SSc and an increased risk of interstitial lung disease (ILD), yet their presence or titer may not reflect the current activity or progression of ILD. Similarly, anti-centromere antibodies are linked to limited cutaneous SSc and a lower risk of severe ILD, but their titers do not necessarily correlate with pulmonary involvement. We revised the manuscript to emphasize that while these antibodies are useful markers for diagnosis and prognosis, their levels are not consistently reliable indicators of disease activity or lung involvement. This distinction is crucial for clinicians to avoid over-reliance on antibody levels when assessing disease progression and deciding on management strategies. We incorporated relevant studies that have explored these correlations to provide a clearer understanding of the limitations and utility of these biomarkers in clinical practice.

2. It will be easier for a reader to follow paragraph 2.2. Pathogenesis of Lung Involvement in SSc if it is supplied by graph gathering various mechanisms present in pulmonary process in systemic sclerosis.

• Authors` response: We acknowledged the suggestion to enhance paragraph 2.2, "Pathogenesis of Lung Involvement in SSc," by incorporating a graph that illustrates the various mechanisms involved in the pulmonary process associated with systemic sclerosis (SSc). We agreed that a visual representation would aid readers in understanding the complex interactions between different pathways. In response, we created and included a comprehensive diagram in the revised manuscript. This graph visually summarized the key mechanisms of lung involvement in SSc

3. The Authors mention pharmacological possibilities in paragraph 5.1. What about the methotrexate, given in the early stage with skin involvement? Can we safely use this medication in the early stages of SSc without lung involvement, or should we avoid it to prevent lung fibrosis?

• Authors` response: We appreciated the reviewer's insightful question regarding the use of methotrexate in systemic sclerosis (SSc), particularly in the early stages with skin involvement. We recognized that this medication's role in SSc management, especially concerning potential lung fibrosis, needed further clarification. In response, we expanded our discussion in paragraph 5.1 to address the use of methotrexate in early-stage SSc. We reviewed the available literature and summarized the following points:
• Methotrexate Use in SSc: Due to its anti-inflammatory and immunosuppressive effects methotrexate has been used to manage mainly skin, joint and muscle involvement in SSc. So far methotrexate is recommended for treating skin changes in patients with early-diffuse SSc demonstrating efficacy in reducing skin fibrosis and improving skin scores. However, its use in patients without lung involvement requires careful consideration. Potential Risks: There is a concern that methotrexate could contribute to the development of lung fibrosis due to allergic, cytotoxic or immunologic reactions, particularly in patients with pre-existing pulmonary symptoms or those at risk for pulmonary complications. The risk of methotrexate-induced lung fibrosis, although relatively low, needs to be weighed against its potential benefits. Clinical Practice Recommendations: Based on current evidence, methotrexate may be used in early-stage SSc with skin involvement, provided that patients are closely monitored for any signs of lung involvement. Regular pulmonary assessments and imaging may be warranted to detect any early signs of lung fibrosis.
• We have incorporated these considerations into the revised manuscript to provide a balanced view of methotrexate use in SSc, addressing both its benefits and potential risks. Thank you for raising this important issue, which has helped refine the discussion on pharmacological management in SSc.

 

4. Paragraph 5.2: In non-pharmacological approaches, the author mentions oxygen therapy and rehabilitation. Does nutrition influence the clinical state of patients with SSc? Can it be beneficial in lung fibrosis?

• Authors` response: We appreciated the reviewer's important query regarding the role of nutrition in the management of systemic sclerosis (SSc) and its potential impact on lung fibrosis. We have revised paragraph 5.2 to address this aspect comprehensively. In response to the reviewer's comment, we expanded the discussion on non-pharmacological approaches to include the influence of nutrition on SSc and lung fibrosis.

5. What kind of rehabilitation should be recommended for patients with lung fibrosis?

• Author's response: We appreciate the reviewer’s interest in the rehabilitation strategies for patients with lung fibrosis associated with systemic sclerosis (SSc). In response to this comment, we have expanded our discussion on rehabilitation in the revised manuscript, citing a systematic review that explored types of rehabilitation interventions beneficial for SSc.

 

If the Authors answer the question, I believe the manuscript is worthy of publication.

• Authors` response: Thank you for your positive feedback and for considering the manuscript for publication. We have addressed the questions and concerns raised, including those related to the recommendations for rehabilitation in patients with lung fibrosis associated with systemic sclerosis.

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

I believe that version 2 of the manuscript has been improved.

Regarding the issue of a paragraph on PAH, I cannot understand the logic behind including PH due to pulmonary artery abnormalities in the review of SSc-ILD without including PH due to ILD.  However, I respect the authors’ opinions here.

Minor points

1. On line 104, "scSSc" should be dcSSc.

2. On line 456, "in patients without lung involvement" should probably be a mistake for "in patients with lung involvement."

Author Response

Regarding the issue of a paragraph on PAH, I cannot understand the logic behind including PH due to pulmonary artery abnormalities in the review of SSc-ILD without including PH due to ILD.  However, I respect the authors’ opinions here.

- Authors` response: Dear reviewer, we highly appreciate your contribution and the chance to improve our paper. We understand your recommendations, and although we are at a minor revision stage, we made a few necessary corrections to increase the punctuality of the terms PH due to the ILD and PAH used. Based on your recommendations, we provided the WHO PH classification and some paragraphs on each, including PH due to ILD.

Minor points

1. On line 104, "scSSc" should be dcSSc. - corrected

2. On line 456, "in patients without lung involvement" should probably be a mistake for "in patients with lung involvement." - it should remain "without" because we state that methotrexate could cause lung fibrosis in patients without such.