Pulmonary function in Thai patients with systemic sclerosis; a single center 6-year retrospective study

Background Pulmonary involvement is a major cause of internal organ complication 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 and analyzed. Results Of 211 SSc patients, 128 patients who underwent the PF test were enrolled; 102 (79.7%) were female. The mean age was 54 years. The median BMI for all patients was 21.7 kg/m 2. Regarding anti-Scl70, 10.9% of patients were positive, 7.8% were negative, and the status was unreported for 81.3%. 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) 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. However, the power of using demographic data and the presence of anti-Scl70 to determine the probability of pulmonary involvement remains limited.


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. 2jor internal organ involvements in SSc include the pulmonary, cardiovascular, renal, and gastrointestinal systems.4][5] The clinical presentations of SSc patients with pulmonary involvement 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. 3In particular, both high and low BMI might influence lung function due to changing in chest wall elastance, potentially impacting disease outcome. 6is 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.

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 2013 American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) classification criteria for SSc 7 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.BMI was obtained at the time of the PFT was done.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

REVISED Amendments from Version 1
This version has included more details on BMI and anti-Scl70 and discussed more about diffuse vs limited systemic sclerosis.
Any further responses from the reviewers can be found at the end of the article 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).
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).
Patient characteristics, including age, sex, BMI, and the presence of anti-Scl70, 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).

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 mean % predicted FVC were 71.8 in diffuse cutaneous SSc (dcSSC) and 77.6 in limited cutaneous SSc (lcSSc).They also found that patients with dcSSc had a higher prevalence of ILD (78.7% vs. 45.8%,p=0.002). 8These findings emphasize the impact of pulmonary involvement on SSc.
Our study found a lower mean % predicted FVC (69.1%) compared to the previous large-scale study, The European Scleroderma Trials and Research group (EUSTAR) cohort, where the mean % predicted FVC in SSc patients were 90.3%.This difference 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.In addition, a prior Thai study by Foocharoen et al. 5 found that the shorter duration of pulmonary fibrosis after onset correlated with poorer outcome.This highlights the intricate nature of the association between disease duration and lung function in SSc.Another important contributing factor is the prevalence of dcSSc, which is a risk factor of pulmonary involvement, is higher in Thai (72.6%) compared to EUSTAR (20.6%) cohort. 3,5r 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-Scl70 did not significantly affect pulmonary function, although this finding diverges from previous studies suggesting a negative association with pulmonary outcome. 3,8However, 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 anti-Scl70.These limitations may constrain our ability to thoroughly assess the impact of these factors on the pulmonary function.
DLCO and FVC are the two most frequently used PFT for assessing the pulmonary involvement of SSc. 9 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 our ability to comprehensively assess disease severity and explore potential relationships between disease severity, anti-Scl-70 levels, and their combined impact on lung function in SSc patients.Second, the small number of documented anti-Scl70 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.Fourth, 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.Lastly, the 40% non-participation rate in spirometry testing (83/211) introduces potential selection bias, as participants who underwent testing may differ in disease severity, functional capacity, or willingness.

Conclusion
A restrictive spirometry pattern is common among Thai patients with SSc.However, the power of using demographic data and presence of anti-Scl70 to determine the probability of pulmonary complications remains limited.Further studies are required to evaluate anti-Scl70 data, SSc type, pulmonary hypertension assessment, including comprehensive data on disease duration to gain a more understanding of the disease course and its impact on SSc patients.1.

Ethics and consent
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.

2.
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.

Are all the source data underlying the results available to ensure full reproducibility?
No source data required

Are the conclusions drawn adequately supported by the results? Yes
Competing Interests: No competing interests were disclosed.
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.
Author Response 27 May 2024

Pattarin Pirompanich
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.
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.

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.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.

Competing Interests: None
Reviewer Report 10 May 2024 https://doi.org/10.5256/f1000research.160591.r271788 This study did not investigate the cost-effectiveness of spirometry.Please revise the conclusion in abstract section and also in conclusion section. 2.

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? 1.

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

2.
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.

3.
The association between spirometry and anti-Scl70 might not be reliable and valid due to fluctuations during follow-up, as mentioned above.

4.
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? 5.

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. 1.

Is the work clearly and accurately presented and does it cite the current literature? Partly
Is the study design appropriate and is the work technically sound?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

Are the conclusions drawn adequately supported by the results? Partly
Competing Interests: No competing interests were disclosed.

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.
Author Response 27 May 2024

Pattarin Pirompanich
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.
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?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.
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.
The benefits of publishing with F1000Research: Your article published within days, with no editorial bias • You can publish traditional articles, null/negative results, case reports, data notes and more • The peer review process is transparent and collaborative • Your article is indexed in PubMed after passing peer review • Dedicated customer support at every stage • For pre-submission enquiries, contact research@f1000.com 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.

Figure 1 .
Figure 1.The correlation between diffusing capacity for carbon monoxide (DLCO) and forced vital capacity (FVC) (left) and DLCO and body mass index (BMI) (right).

©
2024 Tajarernmuang P.This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Pattraporn Tajarernmuang Division of Pulmonary, Critical Care, and Allergy, Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand 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.

Response 1 :Methods Point 1 : 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.○ The diagnosis of systemic sclerosis is now using the 2013 ACR/EULAR Classification criteria not from 1980 ACR criteria.Response Thank you for your value suggestion.We have already revised (Page 3, paragraph 2, line 2-3).

Table 2 .
Pulmonary function test of all participants.
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.

Table 3 .
Pulmonary function test stratified by anti-topoisomerase antibody.

Table 4 .
Patient characteristics stratified by restrictive spirometry pattern.
This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The correlation between pulmonary function and SSc is understandable, but the authors should explain why they were interested in BMI.