F1000Research F1000Research 2046-1402 F1000 Research Limited London, UK 10.12688/f1000research.146498.1 Research Article Articles Pulmonary function in Thai patients with systemic sclerosis; a single center 6-year retrospective study

[version 1; peer review: 3 approved with reservations]

 Pirompanich Pattarin Conceptualization Formal Analysis Methodology Project Administration Supervision Writing – Review & Editing https://orcid.org/0000-0003-0181-5394 a 1 Sathitakorn Ornnicha Validation Writing – Review & Editing 2 Sakulvorakitti Thitisak Data Curation Investigation Writing – Original Draft Preparation 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Faculty of Medicine, Thammasat University, Bangkok, Bangkok, 12120, Thailand Department of Medicine, Faculty of Medicine, Thammasat University, Bangkok, Bangkok, 12120, Thailand pattarin@tu.ac.th

No competing interests were disclosed.

 18 4 2024 2024 13 296 1 4 2024 Copyright: © 2024 Pirompanich P et al. 2024 This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background

Interstitial lung fibrosis is a major cause of internal organ involvement and the leading cause of death in patients with systemic sclerosis (SSc). This study aimed to demonstrate the characteristics of pulmonary function (PF) in Thai patients with SSc and the association between PF and body mass index (BMI) and anti-topoisomerase (anti-Scl70).

 Methods

All patients diagnosed with SSc in our tertiary care teaching hospital database between 2016 and 2021 were reviewed. Clinical characteristics and PF were recorded and analyzed.

 Results

Of 211 SSc patients, 128 patients who underwent the PF test were enrolled; 102 (79.7%) were female. The mean (SD) age was 54.0 (12.5) years. The mean (SD) forced expiratory volume in one second (FEV1) forced vital capacity (FVC) ratio was 0.8 (0.1). The mean (SD) % predicted values of FEV1, FVC, and diffusing capacity of the lungs for carbon monoxide (DLCO) were 76.3 (16.3), 69.1 (15.8), and 75.5 (22.8), respectively. A restrictive spirometry pattern (RSP), defined as FVC < 80% predicted, was found in 78.8% of the patients. DLCO had a moderate positive linear correlation with FVC (r=0.50, p <0.001) and a moderate negative linear correlation with BMI (r=-0.36, p <0.001). However, there was no correlation between FVC and BMI. There was no statistical difference in demographic data or the presence of anti-Scl70 among patients with or without RSP.

 Conclusions

RSP is common among Thai patients with SSc. Spirometry is a cost-effective screening tool for detecting SSc-related pulmonary involvement in resource-limited settings. However, the power of using demographic data and the presence of anti-Scl70 to determine the probability of pulmonary complications remains limited.

 Systemic sclerosis Pulmonary function Interstitial lung disease ILD Thailand Faculty of Medicine, Thammasat University 2-02/2565 This study was financially supported by the Faculty of Medicine, Thammasat University (funding number 2-02/2565). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Background

Systemic sclerosis (SSc) is an autoimmune disease that results from microvascular damage, dysregulation of innate and adaptive immunity, and widespread fibrosis that affects multiple organs. While skin fibrosis is a key feature in patients with SSc, the clinical prognosis is determined by the severity of internal organ involvement. 1 The prevalence of SSc ranged from 38 to 341 cases per million, and the 5- and 10-year survival rates following diagnosis are 75% and 63%, respectively. 2

Major internal organ involvements in SSc include the pulmonary, cardiovascular, renal, and gastrointestinal systems. Notably, interstitial lung disease (ILD) has emerged as a primary complication during the initial stages in Thai patients and is a significant contributor to mortality. 3 – 5 The clinical presentations of SSc patients with ILD include dyspnea, non-productive cough, and fine crackles at the lung based on auscultation. The decline in forced vital capacity (FVC) was significantly higher in patients who had anti-topoisomerase autoantibody (anti-Scl70). In contrast, sex and age did not correlate with pulmonary function. 3

This study aimed to demonstrate the characteristics of pulmonary function in Thai patients with SSc and to explore the potential association between pulmonary function, body mass index (BMI), and the presence of anti-Scl70. The findings of this study may hold significant value in shaping management guidelines and provide insights for future studies on pulmonary complications in Thai patients with SSc.

 Methods Study design and setting

This was a single-center, 6-year retrospective observational study conducted between January 2016 and December 2021. This study was approved by the Human Research Ethics Committee of the Faculty of Medicine, Thammasat University, Thailand (Project number MTU-EC-IM-1-177/65, Approval number 193/2022, Date of approval September 19, 2022), which was conducted in accordance with the Declaration of Helsinki. The informed consent was waived in view of the retrospective nature of the study. Patient data were sourced from our institutional database at a 650-bed tertiary care university hospital.

 Patient selection and sample size

The enrollment criteria included individuals aged ≥ 18 years diagnosed with systemic sclerosis. All patients fulfilled the 1980 classification criteria for SSc 6 and underwent a pulmonary function test (PFT) during the study period. Demographic data, presence of anti-Scl70, forced expiratory volume in one second (FEV1), FVC, and diffusing capacity of the lungs for carbon monoxide (DLCO) were recorded. In cases with multiple PFT results for a single patient, the earliest test conducted during the study period was employed to mitigate the impact of ongoing treatment and disease progression. This retrospective study included all eligible patients with available data, providing a complete representation of the entire population under investigation.

 Outcomes

The primary objective was to identify the characteristics of pulmonary function in patients with SSc. The secondary outcomes included comparing the pulmonary function based on the presence of anti-Scl70, demonstrating the association between body mass index (BMI), FVC, and DLCO, and distinguishing characteristics of the patients who had restrictive spirometry patterns, defined as FVC of less than 80% predicted.

 Statistical analysis

Normality was assessed using the Shapiro-Wilk normality test. Categorical variables were reported as counts and percentages, and continuous variables as means with standard deviations (SD) or medians with interquartile ranges (IQR). Differences in continuous variables were compared using Student’s t-test or Mann-Whitney U test. Differences between separate groups of variables were compared using Fisher’s test or the chi-square test. The relationship between parameters was evaluated using Pearson’s correlation or Spearman’s correlation. Cases with any missing data points were removed from the analysis. A two-sided P value of less than 0.05 was considered to indicate statistical significance for the outcomes. Analyses were performed using STATA software 17.0 (StataCorp LLC, College Station, TX, US).

 Results

From a total of 211 SSc patients, 128 who underwent PFT were enrolled. Spirometry results were available for 118 (92.2%) patients, and DLCO results were available for 108 (84.4%) patients. The mean (SD) age of the patients was 54.0 (12.5) years, with 102 (79.7%) being female. The median (IQR) BMI for all patients was 21.7 (19.6-25.5) kg/m 2, as detailed in Table 1. 9

Patient characteristics.
Characteristics Overall (n = 128)
Age – mean (SD) years 54.0 (12.5)
Female – n (%) 102 (79.7)
BMI – median (IQR) kg/m 2 21.7 (19.6-25.5)
Presence of anti-topoisomerase – n (%)
 Positive 14 (10.9)
 Negative 10 (7.8)
 Not reported 104 (81.3)

BMI: body mass index; IQR: interquartile ranges; SD: standard deviations.

The primary outcome of the study revealed mean (SD) % predicted of FEV1, FVC, and DLCO as 76.3 (16.3), 69.1 (15.8), and 75.5 (22.8), respectively. The mean (SD) FEV1/FVC ratio was 0.8 (0.1). Notably, a restrictive spirometry pattern was predominant among the majority of the patients, accounting for 78.8% (93/118) of the study population. Further details regarding pulmonary function are presented in Table 2.

Pulmonary function test of all participants.
Pulmonary function Presence of spirometry (n = 118)
FVC – mean (SD) L 2.1 (0.6)
FVC – mean (SD) % predicted 69.1 (15.8)
FVC<80% predicted – n (%) 93 (78.8)
FEV1 – mean (SD) L 1.7 (0.5)
FEV1 – mean (SD) % predicted 76.3 (16.3)
FEV1/FVC ratio – mean (SD) 0.8 (0.1)
FEV1/FVC>0.75 – n (%) 102 (86.4)
Presence of DLCO (n = 108)
DLCO – mean (SD) % predicted 75.5 (22.8)
DL adj – mean (SD) % predicted 78.5 (24.3)

FVC: forced vital capacity; FEV1: forced expiratory volume in one second; DLCO: diffusing capacity for carbon monoxide; DLadj: diffusing capacity for carbon monoxide adjusted for hemoglobin content.

In the secondary outcome analysis, following the categorization of patients based on the presence of anti-Scl70, no statistical differences were observed in FVC, FEV1, FEV1/FVC, or DLCO ( Table 3). DLCO demonstrated a moderate positive linear correlation with FVC (r=0.50, p<0.001) and a moderate negative linear correlation with BMI (r=-0.36, p<0.001) ( Figure 1). However, there was no correlation between FVC and BMI (r=-0.15, p-value=0.107).

Pulmonary function test stratified by anti-topoisomerase antibody.
Pulmonary function Anti-topoisomerase positive (n=14) Anti-topoisomerase negative (n=10) P-value
FVC – mean (SD) L 2.1 (0.5) 1.9 (0.7) 0.305
FVC – mean (SD) % predicted 68.4 (16.5) 71.4 (17.2) 0.673
FVC<80% predicted - n (%) 11 (78.6) 7 (70.0) 0.665
FEV1 – n (%)
 >70% predicted 6 (54.6) 2 (28.6)
 60-69% predicted 3 (27.3) 4 (57.1)
 50-59% predicted 1 (9.1) 0 (0.0)
 35-49% predicted 1 (9.1) 1 (14.3)
 <35% predicted 0 (0.0) 0 (0.0)
FEV1 – mean (SD) L 1.8 (0.4) 1.5 (0.5) 0.203
FEV1 – mean (SD) % predicted 75.2 (18.0) 72.0 (15.7) 0.650
FEV1/FVC mean (SD) 0.8 (0.1) 0.8 (0.1) 0.203
Anti-topoisomerase positive (n = 11) Anti-topoisomerase negative (n = 7)
DLCO – mean (SD) % predicted 64.5 (18.4) 70.3 (16.8) 0.509
DLCO – n (%)
 >75% predicted – n (%) 3 (27.3) 4 (57.1)
 61-75% predicted – n (%) 3 (27.3) 2 (28.6)
 40-60% predicted – n (%) 5 (45.5) 0 (0.0)
 <40% predicted – n (%) 0 (0.0) 1 (14.3)
DLCO adj – mean (SD) % predicted 65.1 (19.0) 73.7 (16.9) 0.344

DLCO: diffusing capacity for carbon monoxide; DLadj: diffusing capacity for carbon monoxide adjusted for hemoglobin content; FEV1: forced expiratory volume in one second; FVC: forced vital capacity.

 The correlation between diffusing capacity for carbon monoxide (DLCO) and forced vital capacity (FVC) (left) and DLCO and body mass index (BMI) (right).

Patient characteristics, including age, sex, BMI, and the presence of anti-topoisomerase, did not demonstrate significant differences between those with and without a restrictive spirometry pattern. Notably, the majority of the patients with decreased DLCO exhibited a restrictive spirometry pattern ( Table 4).

Patient characteristics stratified by restrictive spirometry pattern.
FVC≥80% predicted (n=25) FVC<80% predicted (n=93) p-value
Age – mean (SD) years 53.6 (15.0) 54.7 (12.1) 0.688
Sex – n (%) 0.589
 Female 21 (84.0) 72 (77.4)
 Male 4 (16.0) 21 (22.6)
BMI – median (IQR) kg/m 2 21.7 (19.9-24.4) 21.8 (19.6-25.8) 0.489
Anti-topoisomerase – n (%) 0.665
 Positive 3 (50.0) 11 (61.1)
 Negative 3 (50.0) 7 (38.9)
DLCO – n (%) 0.018
 >75% predicted 15 (83.3) 33 (41.3)
 61-75% predicted 2 (11.1) 21 (26.3)
 40-60% predicted 1 (5.6) 22 (27.5)
 <40% predicted 0 (0.0) 4 (5.0)

BMI: body mass index; DLCO: diffusing capacity for carbon monoxide; FVC: forced vital capacity.

 Discussion

In this study, the mean % predicted values of FVC and DLCO were 69.1 and 75.5, respectively. A substantial majority of the patients (78.8%) exhibited a restrictive spirometry pattern. These results are consistent with those of a prior study on ILD in Thai patients with SSc, where the % predicted FVC ranged from 71.8 to 77.6. 7 In that study, the mean % predicted FVC and incidence of ILD within 5 years from disease onset were 71.8 and 86% in patients with diffuse cutaneous SSc, and 77.6 and 54% in patients with limited cutaneous SSc, respectively. 7 These findings emphasize the impact of pulmonary involvement on SSc.

However, the % predicted FVC in our study and the previously mentioned study appears to be lower than that reported in a previous large-scale study, The European Scleroderma Trials and Research group (EUSTAR) cohort, 3 where the mean % predicted FVC and DLCO in SSc patients were 93.5 and 68.9, respectively. This discrepancy may be attributed to the fact that the EUSTAR cohort assessed patients who presented within one year after the onset of Raynaud’s phenomenon, the most common initial presentation, accounting for 59.5% of SSc cases. 5 Furthermore, the EUSTAR cohort’s shorter disease duration compared to the referenced Thai study 7 might have contributed to the higher FVC values observed. These findings suggest a potential negative impact of disease duration on FVC, emphasizing the need for further studies to comprehensively explore this relationship.

Our study revealed no association between demographic data and restrictive spirometry results in patients with SSc. This suggests that the manifestation of a restrictive spirometry pattern in patients with SSc may be influenced by disease-specific factors rather than by general demographic characteristics. Similarly, the presence of anti-topoisomerase antibody did not significantly affect pulmonary function, although this finding diverges from previous studies suggesting a negative association with pulmonary outcome. 3 , 7 However, it is important to note that a majority of our patients in this study demonstrated a restrictive spirometry pattern and only a small number of our patients had documented records of the presence of this antibody. These limitations may constrain our ability to thoroughly assess the impact of these factors on the pulmonary function. Notably, reduced chest wall compliance, potentially contributing to restrictive pulmonary defects, could also be found in SSc, which may have influenced our results.

DLCO and FVC are the two most frequently used PFT for assessing the outcomes of SSc ILD. 8 SSc usually undergo regular DLCO and FVC. Our findings revealed a moderate linear correlation between DLCO and FVC, and nearly all patients with decreased DLCO exhibited a restrictive spirometry pattern. This finding suggests that spirometry can serve as an effective screening test for pulmonary involvement in SSc and is a cost-effective option, particularly in resource-limited settings.

In this study, some essential medical history, particularly patient symptoms, previous treatments, disease duration, and co-existing organ involvement, were documented in diverse formats, posing challenges for analysis. Therefore, the earliest test conducted during the study period was employed to mitigate the impact of ongoing treatment and disease progression. However, this limits our ability to evaluate the relationship between pulmonary function and these factors. Further studies with pre-specified data collection of these factors may reveal new tools for the detection of pulmonary involvement.

The strengths of our study are its considerable number of participants in a data-scarce field and being the only study that aims to explore pulmonary function exclusively in Thai patients with SSc. The effect of selective bias in the study is modest because most of our patients with SSc were screened with spirometry annually, regardless of patient symptoms.

However, this study has some limitations. First, since SSc is a progressive disease, lack of disease duration data limited us from defining patient disease stage and severity. Second, the small number of documented anti-topoisomerase antibodies decreased our power to examine its relationship with patient pulmonary function. Third, our study did not capture data on the type of systemic sclerosis in all participants. This omission limits our ability to assess the potential influence of SSc type on FVC and DLCO. Lastly, our study did not include pulmonary hypertension (PH) assessments, thus limiting our ability to conclusively determine the extent to which PH contributed to the observed DLCO values.

 Conclusion

A restrictive spirometry pattern is common among Thai patients with SSc. Spirometry is a cost-effective screening tool for detecting SSc-related pulmonary involvement in resource-limited settings. However, the power of using demographic data and presence of anti-topoisomerase to determine the probability of pulmonary complications remains limited. Further studies are required to evaluate anti-topoisomerase antibody data, SSc type, and pulmonary hypertension assessment.

 Ethics and consent

Ethical approval was obtained from the Human Research Ethics Committee of Thammasat University (Faculty of Medicine), Thailand (Project number MTU-EC-IM-1-177/65, Approval number 193/2022, Date of approval September 19, 2022), and the study was conducted according to the Declaration of Helsinki. The informed consent was waived in view of the retrospective nature of the study.

 Data availability

Zenodo: Pulmonary function in Thai patients with systemic sclerosis data. https://zenodo.org/doi/10.5281/zenodo.10440509. 9

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

 Acknowledgment

The authors would like to express their gratitude to Thammasat University Hospital for providing the patient data and to Sam Ormond for reviewing the English language used in our manuscript.

 References Allanore Y Simms R Distler O : Systemic sclerosis. Nat. Rev. Dis. Prim. 2015;1:15002. 10.1038/nrdp.2015.2 Ingegnoli F Ughi N Mihai C : Update on the epidemiology, risk factors, and disease outcomes of systemic sclerosis. Best Pract. Res. Clin. Rheumatol. 2018;32(2):223–240. 30527428 10.1016/j.berh.2018.08.005 Jaeger VK Wirz EG Allanore Y : Incidences and Risk Factors of Organ Manifestations in the Early Course of Systemic Sclerosis: A Longitudinal EUSTAR Study. PLoS One. 2016;11(10):e0163894. 27706206 10.1371/journal.pone.0163894 PMC5051961 Tyndall AJ Bannert B Vonk M : Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann. Rheum. Dis. 2010;69(10):1809–1815. 20551155 10.1136/ard.2009.114264 Foocharoen C Peansukwech U Mahakkanukrauh A : Clinical characteristics and outcomes of 566 Thais with systemic sclerosis: A cohort study. Int. J. Rheum. Dis. 2020;23(7):945–957. 32420701 10.1111/1756-185X.13859 Preliminary criteria for the classification of systemic sclerosis (scleroderma): Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum. 1980;23(5):581–590. 10.1002/art.1780230510 Wangkaew S Euathrongchit J Wattanawittawas P : Incidence and predictors of interstitial lung disease (ILD) in Thai patients with early systemic sclerosis: Inception cohort study. Mod. Rheumatol. 2016;26(4):588–593. 26561397 10.3109/14397595.2015.1115455 Caron M Hoa S Hudson M : Pulmonary function tests as outcomes for systemic sclerosis interstitial lung disease. Eur. Respir. Rev. 2018;27(148):170102. 29769294 10.1183/16000617.0102-2017 PMC9488607 Pirompanich P Sathitakorn O Sakulvorakitti T : Pulmonary function in Thai patients with systemic sclerosis data.[Dataset]. Zenodo. 2023. 10.5281/zenodo.10440510 10.5256/f1000research.160591.r271795 Reviewer response for version 1 Tajarernmuang Pattraporn 1 Referee https://orcid.org/0000-0003-4409-1832 Division of Pulmonary, Critical Care, and Allergy, Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand

Competing interests: No competing interests were disclosed.

 23 5 2024 Copyright: © 2024 Tajarernmuang P 2024 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation approve-with-reservations

Thank you for the invitation to review the manuscript by Pirompanich et al. The authors presented a single-center retrospective study aiming to identify the clinical characteristics of pulmonary function in patients with systemic sclerosis. The minor concerns and suggestions for this study are as follows:

As we know, lung involvement in diffuse systemic sclerosis (SSc) is more common than in limited SSc. It would be beneficial to demonstrate the proportion of diffuse SSc and limited SSc in the patient characteristics.

There were 211 SSc patients, but only 128 (~60%) patients who had PFT results were enrolled. The possible reason for the unavailability of PFT results might be that the patients were too sick to perform the test. This selection bias could make the PFT results appear too favorable. The authors should mention this point in the limitations of the study.

The authors mentioned that limited chest wall compliance can cause restrictive pulmonary defects; however, lung imaging (e.g., HRCT) can help distinguish between chest wall and lung problems. Also, some patients with abnormal HRCT can have normal spirometry. I think the authors should clarify this point.

Is the work clearly and accurately presented and does it cite the current literature?

Yes

If applicable, is the statistical analysis and its interpretation appropriate?

Yes

Are all the source data underlying the results available to ensure full reproducibility?

No source data required

Is the study design appropriate and is the work technically sound?

Yes

Are the conclusions drawn adequately supported by the results?

Yes

Are sufficient details of methods and analysis provided to allow replication by others?

Partly

Reviewer Expertise:

pulmonary, interventional respirology, lung cancer, critical care

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Pirompanich Pattarin Medicine, Thammasat University, Klong Luang, Pathumthani, Thailand

Competing interests: None

 27 5 2024

Response to reviewer 3:

Thank you very much for you kindly review. We really appreciate your response and revised our manuscript as you suggested.

Point 1: As we know, lung involvement in diffuse systemic sclerosis (SSc) is more common than in limited SSc. It would be beneficial to demonstrate the proportion of diffuse SSc and limited SSc in the patient characteristics.

Response 1:  We have acknowledged these on Discussion (Page 7, paragraph 2, line 8-10) and limitation (Page 8, paragraph 5, line 6-7).

Point 2: There were 211 SSc patients, but only 128 (~60%) patients who had PFT results were enrolled. The possible reason for the unavailability of PFT results might be that the patients were too sick to perform the test. This selection bias could make the PFT results appear too favorable. The authors should mention this point in the limitations of the study.

Response 2:  We have acknowledged these on limitation (Page 8, paragraph 5, line 10-12).

Point 3: The authors mentioned that limited chest wall compliance can cause restrictive pulmonary defects; however, lung imaging (e.g., HRCT) can help distinguish between chest wall and lung problems. Also, some patients with abnormal HRCT can have normal spirometry. I think the authors should clarify this point.

Response 3:  Thank you for the insightful comment regarding the role of chest wall compliance in restrictive lung disease. We acknowledge that reduced chest wall compliance can be a contributing factor, and ideally, lung imaging techniques like HRCT would be incorporated to differentiate between restrictive etiologies. Unfortunately, due to limitations in our study design, we were unable to collect data on chest wall compliance. Therefore, we have decided to remove the sentence mentioning this factor from the manuscript.

 10.5256/f1000research.160591.r271791 Reviewer response for version 1 Somboonviboon Dujrath 1 Referee https://orcid.org/0000-0002-9309-1284 Phramongkutklao Hospital, Bangkok, Thailand

Competing interests: No competing interests were disclosed.

 20 5 2024 Copyright: © 2024 Somboonviboon D 2024 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation approve-with-reservations

I appreciate the opportunity to review this article, which presents on pulmonary function in Thai systemic sclerosis patients, and I would like to offer a few comments and suggestions to further enhances its clarity and impact.

Abstract

The authors did not compare spirometry to other interventions, particularly HRCT. Therefore, the conclusion regarding the cost-effectiveness of spirometry should be revised.

Full manuscript 

Background

The correlation between pulmonary function and SSc is understandable, but the authors should explain why they were interested in BMI.  

The authors mentioned the importance of ILD in SSc patients, however, this study did not include HRCT data, only pulmonary functions were recorded. Therefore, using ‘pulmonary involvement’ would be more appropriate than ILD.

 Discussion

There are several confusing points in the discussion section, particularly when the authors compare the findings from this cohort to those of previous studies.

Please check the numbers, particularly regarding the data from the referenced papers.

The authors found that FVC in this cohort was lower than in the EUSTAR cohort and explained this by noting that EUSTAR cohort had shorter disease duration. However, a previous Thai cohort [Ref -1] demonstrated that a shorter duration of pulmonary fibrosis after onset also correlated with poorer outcome based on the longitudinal data analysis. Furthermore, the mean disease duration in the referenced Thai study [Ref - 2] was only 12.9 months. Therefore, this part should be revised.

As mentioned earlier, the authors did not investigate the cost-effectiveness of spirometry.

Is the work clearly and accurately presented and does it cite the current literature?

Partly

If applicable, is the statistical analysis and its interpretation appropriate?

Yes

Are all the source data underlying the results available to ensure full reproducibility?

No source data required

Is the study design appropriate and is the work technically sound?

Yes

Are the conclusions drawn adequately supported by the results?

Partly

Are sufficient details of methods and analysis provided to allow replication by others?

Partly

Reviewer Expertise:

Internal Medicine and Pulmonology.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

References : Clinical characteristics and outcomes of 566 Thais with systemic sclerosis: A cohort study. Int J Rheum Dis .2020;23(7) : 10.1111/1756-185X.13859 945-957 32420701 10.1111/1756-185X.13859 : Incidence and predictors of interstitial lung disease (ILD) in Thai patients with early systemic sclerosis: Inception cohort study. Mod Rheumatol .2016;26(4) : 10.3109/14397595.2015.1115455 588-93 26561397 10.3109/14397595.2015.1115455 Pirompanich Pattarin Medicine, Thammasat University, Klong Luang, Pathumthani, Thailand

Competing interests: None

 27 5 2024

Thank you very much for you kindly review. We really appreciate your response and revised our manuscript as you suggested.

Abstract

Point 1: The authors did not compare spirometry to other interventions, particularly HRCT. Therefore, the conclusion regarding the cost-effectiveness of spirometry should be revised.

Response 1:  We have deleted this sentence from the abstract section and also in conclusion section.

Background

Point 1: The correlation between pulmonary function and SSc is understandable, but the authors should explain why they were interested in BMI.  

Response 1:  BMI was included because it's a readily available measure of body composition that might influence lung function through various mechanisms. Understanding this relationship can provide insights into disease severity and potential risk factors for SSc patients.

We have added this data on Background (Page 2, paragraph 2, line 8-9) (reference 6).

Ishikawa C, Barbieri MA, Bettiol H, Bazo G, Ferraro AA, Vianna EO. Comparison of body composition parameters in the study of the association between body composition and pulmonary function. BMC Pulm Med. 2021;21(1):178.

Point 2: The authors mentioned the importance of ILD in SSc patients, however, this study did not include HRCT data, only pulmonary functions were recorded. Therefore, using ‘pulmonary involvement’ would be more appropriate than ILD.

Response 2:  We have changed accordingly.

Discussion

Point 1: There are several confusing points in the discussion section, particularly when the authors compare the findings from this cohort to those of previous studies.

Response 1:  We have revised the data in the Discussion section to provide a clearer picture of the findings (Page 7, paragraph 1 and 2).

Point 2: Please check the numbers, particularly regarding the data from the referenced papers.

Response 2:  We have revised the data in the Discussion section to accurately reflect the information from the referenced papers (Page 7, paragraph 1 and 2).

Point 3: The authors found that FVC in this cohort was lower than in the EUSTAR cohort and explained this by noting that EUSTAR cohort had shorter disease duration. However, a previous Thai cohort [Ref -1] demonstrated that a shorter duration of pulmonary fibrosis after onset also correlated with poorer outcome based on the longitudinal data analysis. Furthermore, the mean disease duration in the referenced Thai study [Ref - 2] was only 12.9 months. Therefore, this part should be revised.

Response 3:  We have revised the data in the Discussion section to provide a clearer picture of the findings and to accurately reflect the information from the referenced papers (Page 7, paragraph 1 and 2).

Point 4: As mentioned earlier, the authors did not investigate the cost-effectiveness of spirometry.

Response 4:  We have deleted this sentence from the abstract section and also in conclusion section.

 10.5256/f1000research.160591.r271788 Reviewer response for version 1 Foocharoen Chingching 1 Referee Department of Medicine, Khon Kaen University, Nai Mueang, Khon Kaen, Thailand

Competing interests: No competing interests were disclosed.

 10 5 2024 Copyright: © 2024 Foocharoen C 2024 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation approve-with-reservations

The authors presented an association factors with pulmonary function in scleroderma. However, I believe there are some areas where additional details would strengthen the manuscript and provide a more convincing argument for the coexistence of both conditions. I have listed my points of concern below:

Abstract

Mean BMI and the proportion of patient with positive for anti-Scl70 should be mentioned in abstract because they were endpoints of the study.

This study did not investigate the cost-effectiveness of spirometry. Please revise the conclusion in abstract section and also in conclusion section.

 Background

The authors should mention why BMI was in your interested to be an endpoint of the study. What is/are the rationales for defining the association between BMI and spirometry parameters?

 Methods

The diagnosis of systemic sclerosis is now using the 2013 ACR/EULAR Classification criteria not from 1980 ACR criteria.

128 out of 211 SSc patients underwent spirometry, so nearly 40% were not performed the spirometry. This may cause selection bias. Of those 40% who were not performed the test, they might be too tired to do the test or have difficulty to do the test for example air leak from mouth related to skin tightness of face, etc. Please clarify this point.

Spirometry parameters and BMI can dynamically change or fluctuate over the course of follow-up, but anti-Scl70 is still be stable. Please clarify when of the spirometry test as well as BMI was picked up for analysis.

The association between spirometry and anti-Scl70 might not be reliable and valid due to fluctuations during follow-up, as mentioned above.

The authors presented only a 10% positivity rate for anti-Scl70. From previous study of SSc in Thailand, the proportion of patients with anti-Scl70 was reported around 70-80% [Int J Rheum Dis. 2020 Jul;23(7):945-957.]. Why was the prevalence of anti-Scl70 in this study much lower than previous large cohort among Thais?

 Minor points

The term anti-topoisomerase I and anti-Scl70 were alternately used in the text. The authors should choose only 1 term and make it consistency to the whole manuscript.

Is the work clearly and accurately presented and does it cite the current literature?

Partly

If applicable, is the statistical analysis and its interpretation appropriate?

Yes

Are all the source data underlying the results available to ensure full reproducibility?

No source data required

Is the study design appropriate and is the work technically sound?

Yes

Are the conclusions drawn adequately supported by the results?

Partly

Are sufficient details of methods and analysis provided to allow replication by others?

Partly

Reviewer Expertise:

Internal Medicine and Rheumatology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Pirompanich Pattarin Medicine, Thammasat University, Klong Luang, Pathumthani, Thailand

Competing interests: None

 27 5 2024

Thank you very much for you kindly review. We really appreciate your response and revised our manuscript as you suggested.

Abstract

Point 1: Mean BMI and the proportion of patient with positive for anti-Scl70 should be mentioned in abstract because they were endpoints of the study.

Response 1:  We have added this data on Abstract (Page 2, Line 9-11).

Point 2: This study did not investigate the cost-effectiveness of spirometry. Please revise the conclusion in abstract section and also in conclusion section.

Response 2:  We have deleted this sentence from the abstract section and also in conclusion section.

Background

Point 1: The authors should mention why BMI was in your interested to be an endpoint of the study. What is/are the rationales for defining the association between BMI and spirometry parameters?

Response 1:

BMI was included because it's a readily available measure of body composition that might influence lung function through various mechanisms. Understanding this relationship can provide insights into disease severity and potential risk factors for SSc patients.

We have added this data on Background (Page 2, paragraph 2, line 8-9) (reference 6).

Ishikawa C, Barbieri MA, Bettiol H, Bazo G, Ferraro AA, Vianna EO. Comparison of body composition parameters in the study of the association between body composition and pulmonary function. BMC Pulm Med. 2021;21(1):178.

Methods

Point 1: The diagnosis of systemic sclerosis is now using the 2013 ACR/EULAR Classification criteria not from 1980 ACR criteria.

Response 1:  Thank you for your value suggestion. We have already revised (Page 3, paragraph 2, line 2-3).

Point 2: 128 out of 211 SSc patients underwent spirometry, so nearly 40% were not performed the spirometry. This may cause selection bias. Of those 40% who were not performed the test, they might be too tired to do the test or have difficulty to do the test for example air leak from mouth related to skin tightness of face, etc. Please clarify this point.

Response 2:  We have acknowledged these on limitation (Page 8, paragraph 5, line 10-12).

Point 3: Spirometry parameters and BMI can dynamically change or fluctuate over the course of follow-up, but anti-Scl70 is still be stable. Please clarify when of the spirometry test as well as BMI was picked up for analysis.

Response 3:  In cases with multiple PFT results for a single patient, the earliest test conducted during the study period was employed to mitigate the impact of ongoing treatment and disease progression. BMI was obtained at the time of the PFT was done.

We have added this data in Methods (Page 3, paragraph 2, line 6-9).

Point 4: The association between spirometry and anti-Scl70 might not be reliable and valid due to fluctuations during follow-up, as mentioned above.

Response 4:  While spirometry parameters and BMI can fluctuate over time, anti-Scl-70 is known for its relative stability. To minimize the impact of ongoing treatment and disease progression on lung function analysis, this study used the earliest PFT result for each participant (Page 3, paragraph 2, line 6-7).

However, this approach might not fully capture the potential influence of anti-Scl-70 levels on spirometry, as anti-Scl-70 is considered stable. Future longitudinal studies with repeated measurements of both anti-Scl-70 and spirometry parameters could provide a more comprehensive understanding of the interplay between these factors and their impact on lung function in SSc patients.

We have acknowledged these on limitation (Page 8, paragraph 5, line 1-4).

Further studies are required to evaluate comprehensive data on disease duration to gain a more understanding of the disease course and its impact on SSc patients.

We have added this data in Conclusion (Page 8, line 4-5).

Point 5: The authors presented only a 10% positivity rate for anti-Scl70. From previous study of SSc in Thailand, the proportion of patients with anti-Scl70 was reported around 70-80% [Int J Rheum Dis. 2020 Jul;23(7):945-957.]. Why was the prevalence of anti-Scl70 in this study much lower than previous large cohort among Thais?

Response 5:  Among the analyzed samples, 14 patients (10.9%) were positive for anti-topoisomerase antibodies, while 10 patients (7.8%) were negative. However, anti-topoisomerase antibody status was unreported for a large portion of the study group (n=104, 81.3%) due to limitations in data availability. This high percentage of missing data  precludes definitive conclusions about the overall prevalence of anti-Scl-70 in our cohort and hinders comparisons with previous studies that likely had more complete data.

We have added this data in Results (Page 3, paragraph 1, line 2-4).

Minor point

Point 1: The term anti-topoisomerase I and anti-Scl70 were alternately used in the text. The authors should choose only 1 term and make it consistency to the whole manuscript.

Response 1:  We revised throughout the manuscript.

Additional revision: Because the interest of brevity, we delete some wordings in Abstract and the total wording is 262 words.