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. 2023 Jun 23;18(6):e0286191. doi: 10.1371/journal.pone.0286191

Factors associated with interstitial lung disease in patients with rheumatoid arthritis: A systematic review and meta-analysis

Minjie Zhang 1, Jianwei Yin 2,*, Xiaoyan Zhang 3
Editor: Jan René Nkeck4
PMCID: PMC10289414  PMID: 37352174

Abstract

Objectives

Interstitial lung disease (ILD) is frequent in patients with rheumatoid arthritis (RA) and is a potentially life-threatening complication with significant morbidity and mortality. This meta-analysis aims to systematically determine the factors associated with the development of rheumatoid arthritis–related interstitial lung disease (RA-ILD).

Materials and methods

All primary studies which reported the factors associated with of RA-ILD were eligible for the review except case reports. The Cochrane Library, PubMed, Embase, Web of Science, Chinese Biological Medicine Database (CBM), China National Knowledge Infrastructure (CNKI), and WANFANG electronic databases were searched through to December 30, 2022, for studies investigating the factors associated with RA-ILD. The methodological quality assessment of the eligible studies was performed using the Newcastle-Ottawa Scale (NOS). 2 reviewers extracted relevant data independently. Then, weighed mean differences (WMDs) or pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were obtained for the relationships between the factors and RA-ILD. The statistical meta-analysis, subgroup and sensitivity analyses were performed using the Review Manager 5.3, and publication bias with Egger’s test were performed using the Stata12.0 software.

Results

A total of 22 articles were screened for a meta-analysis which involved 1887 RA-ILD patients and 8066 RA without ILD patients. Some identified factors that were associated with an increased risk of RA-ILD included male sex (OR = 1.92, 95% CI: 1.54–2.39; P < 0.00001), older age (WMD = 5.77 years, 95% CI: 3.50–8.04; P < 0.00001), longer duration of RA (WMD = 0.80 years, 95% CI 0.12–1.47; P = 0.02), older age at onset of RA (WMD = 6.41 years, 95% CI: 3.17–9.64; P = 0.0001), smoking (OR = 1.69, 95% CI: 1.30–2.18; P < 0.0001). Five factors of laboratory items associated with the development of RA-ILD were evaluated in the meta-analysis. Compared with RA without ILD patients, positive rheumatoid factor (RF) (OR = 1.72, 95% CI: 1.47–2.01; P < 0.00001) and positive anti-citrullinated protein antibodies (ACPA) (OR = 1.58, 95% CI: 1.31–1.90; P < 0.00001) increased the risk of RA-ILD. Meanwhile, RF titer (WMD = 183.62 (IU/mL), 95% CI: 66.94–300.30; P = 0.002) and ACPA titer (WMD = 194.18 (IU/mL), 95% CI: 115.89–272.47; P < 0.00001) were significantly associated with increased risk of RA-ILD. Elevated erythrocyte sedimentation rate (ESR) (WMD = 7.41 (mm/h), 95% CI: 2.21–12.61; P = 0.005) and C-reactive protein (CRP) (WMD = 4.98 (mg/L), 95% CI: 0.76–9.20; P = 0.02) were also significantly associated with the development of the RA-ILD, whereas antinuclear antibody (ANA) positive status was not significantly associated with increased risk of RA-ILD (OR = 1.27, 95% CI: 1.00–1.60; P = 0.05).

Conclusions

This meta-analysis showed that male gender, older age, longer duration of RA, older age at onset of RA, smoking, positive RF, positive ACPA, elevated RF titer, elevated ACPA titer, higher ESR and higher CRP were associated with RA-ILD.

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints that eventually lead to symmetric arthritis and bony destruction [1]. The lungs are a normally affected extraarticular location, and it can involve the pleura, airways, parenchyma, and vasculature [2]. Parenchymal disease in the form of interstitial lung disease (ILD) is a known complication with a potentially risk of devastating manifestation [3], however, reported prevalence and incidence of rheumatoid arthritis-related interstitial lung disease (RA-ILD) is variable, depending on the heterogeneous clinical presentation, disease course, the eligibility diagnostic criteria and the definition of disease types. Although the definition of ILD is based on histopathological criteria, currently, the diagnosis is established by high-resolution computed tomography (HRCT) and can often be established based on pulmonary function and clinical symptoms [4]. There are no formal guidelines for clinical screening of ILD in RA patients and specific strategic therapy has not been established yet. To identify factors/ predictors associated with ILD in people with RA is crucial to better understand the clinical characteristics and allow for earlier diagnosis and better treatment with the goal of preventing irreversible lung damage [5]. To date, there have not been any guidelines or RCTs for the treatment of RA-ILD. Although a great deal of research has found that the treatment of RA played beneficial roles in the prevention of RA-ILD. There are still many questions about RA-ILD. Some studies have tried to identify risk factors for RA-ILD, including demographic factors, such as male sex, age, duration of RA, age at onset of RA and smoking status. However, there is a dearth of specific predictive biomarkers to predict the development of RA-ILD at present. Few studies have investigated the association between serological factors on RA-ILD risk. It has been reported that an increased rheumatoid factor (RF), and anti-citrullinated protein antibodies (ACPA) antibody titer are predictors for the development of RA-ILD [6,7]. In addition, several other serological factors associated with RA-ILD have also been described, including antinuclear antibody (ANA), elevated erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Awareness and knowledge of factors associated with RA-ILD are crucial to the prevention of irreversible lung injury by early detection. Recently, while many studies have been published to assess the demographic and serological features of RA-ILD patients in comparison to RA patients without ILD and to identify the factors associated with ILD, the results are discordant, a few have not found an association. This systematic review and meta-analysis were performed to identify factors associated with RA-ILD.

Materials and methods

Search strategy

We searched the Chinese Biological Medicine Database (CBM), China National Knowledge Infrastructure (CNKI), Cochrane Library, Medline via PubMed, Embase, Web of Science, and WANFANG electronic databases. Searches were restricted to articles written in English and Chinese. We searched all relevant studies on RA-ILD published before December 30, 2022 and two authors extracted data from articles independently. The following keywords, subject headings and text words were used: “rheumatoid arthritis” OR “arthritis” OR “rheumatoid” OR “RA” combined with “interstitial lung disease” OR “lung diseases” OR “ILD”. In addition, relevant references of the articles identified through the search process were screened to identify potential primary articles.

Inclusion and exclusion criteria

All studies had to meet the following eligibility criteria: (1) studies reporting or providing data investigating risk factors for RA-ILD; (2) studies with detailed diagnostic criteria information about the ILD (including findings on HRCT, CT, clinical symptoms, chest x-ray, lung biopsy, pulmonary function tests, dyspnea scale, radiographic evidence) in RA-ILD patients; (3) included cases in accordance with definitive diagnosis criteria of RA; (4) included at least one potential risk factor. (5) included sufficient information to calculate weighed mean differences (WMDs) with 95% confidence intervals (CIs) and pooled odd ratios (ORs) with 95% CIs; (6) Only articles published in English and Chinese were considered.

The exclusion criteria of this study were set as follows: (1) lacked a control group (lacking RA without ILD patients) or provided data by comparing the difference in ILD between RA-ILD; (2) studies reporting only the prevalence, survival and characteristics of RA-ILD; (3) studies reporting the risk factors for progression and prognosis of RA-ILD; (4) the studies whose results were not presented as mean ± standard deviation or number (%); (5) RA patients in control group were complicated with other autoimmune diseases; (6) data could not be extracted.

Data extraction and quality assessment

Data from included studies were extracted by 2 researchers independently using the standard data collection forms. The following data was extracted from each eligible study: name of the first author, year of publication, study design, RA classification criteria, ILD diagnosis methods, the number of participants and their demographic features such as the gender, average age, duration of RA, age at onset of RA. In addition, the methodological quality of cross-sectional studies was evaluated using the assessment involving 11 items recommended by the Agency for Healthcare Research and Quality (AHRQ). The total score ranged from 0 to 11, with a score of 8 or higher considered high quality. The methodological quality of cohort and case-control studies were assessed using the Newcastle-Ottawa scale (NOS) with a total score of 9 points. A total score of 5 or less was considered low, 6 or 7was considered moderate, and 8 or 9 was deemed high quality. four of the studies were considered low quality, sixteen were considered moderate quality, and two were determined to be high quality based on their total scores. Evaluation of the quality of included studies was performed by 2 authors independently based on the study design. Two independent authors were blinded to the authors names, titles and years of publication of the included studies. Discrepancies in scores were resolved by consensus with a third author. The methodological quality assessment results were shown in S2 Table.

Statistical analysis

The Review Manager 5.3 software was used to calculate the summary values for estimating factors associated with RA-ILD. The results were presented as pooled ORs with 95% CIs for categorical variables and WMDs with 95% CIs for continuous variables. Heterogeneity test between studies was assessed using inconsistency index (Ι2) statistic and Cochran-Q statistic. A P value of <0.05 for the Cochrane Q test was considered to indicate significant heterogeneity, then the random effects model was used for the analysis among the included studies. The results from the fixed-effect model were presented only when there was mild and statistically non-significant heterogeneity. Subgroup analysis was performed to investigate the impact of different factors on the heterogeneity between the included studies and sensitivity analysis was conducted to determine the impact of each individual studies on the heterogeneity by sequential omission of individual studies. Forest plots were used to display the results from the individual studies and the pooled estimates. The potential for publication bias was evaluated by Egger test using STATA software (version 12). A P value of <0.05 was considered statistically significant.

Results

Study characteristics

The search of the CBM, CNKI, Cochrane Library, Medline via PubMed, Embase, Web of Science, and WANFANG electronic databases up to December 30, 2022. A total of 3942 literatures were obtained through preliminary screening, of which 1861 remained after duplicates were removed. 1814 articles were excluded after title screening and evaluating abstracts. The full text of the remaining 47 articles were reviewed for eligibility. Of these, 25 articles which were not related to the risk of developing RA-ILD or did not meet the eligibility criteria were discarded. Finally, 22 articles were included [8–29]. A flowchart of article screening was showed in Fig 1.

Fig 1. Flow diagram of selecting the literature and screening process.

Fig 1

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Data synthesis and meta-analysis

S1 Table list the characteristics of the included 22 studies with a total of 1887 RA-ILD patients and 8066 RA without ILD patients, including 15 retrospective cohort studies, and 7 observational studies (4 case-control studies and 3 cross-sectional studies). The pooled analysis results of the potential factors were as follows.

Demographic characteristics: analysis of 1858 RA-ILD patients and 7944 RA without ILD patients showed that male was associated with increased risk of RA-ILD (OR = 1.92, 95% CI: 1.54–2.39; P < 0.00001) in 21 studies (Fig 2). Number of males was not available for RA-ILD patients and RA without ILD patients in “Salaffi 2019” study. The identified factors associated with RA-ILD include average age, duration of RA, age at onset of RA and smoking. The meta-analysis results of the average age within the 16 studies reporting WMD age (WMD = 5.77 years, 95% CI: 3.50–8.04; P < 0.00001) (Fig 3) revealed that older age was associated with RA-ILD. Furthermore, RA-ILD patients had a longer RA duration than RA without ILD patients (WMD = 0.80 years, 95% CI 0.12–1.47; P = 0.02) (Fig 4). In addition, the risk of RA-ILD was increased in patients who were older at onset of RA (WMD = 6.41 years, 95% CI: 3.17–9.64; P = 0.0001) (Fig 5). A subgroup analysis by smoking status (divided into “ever-smoking group” and “current smoker group”) was performed to determine the association of smoking with RA-ILD, the pooled analysis results suggested that either smoking history (OR = 1.51, 95% CI: 1.08–2.13; P = 0.02) or current smokers (OR = 2.03, 95% CI: 1.37–3.01; P = 0.0004) had increased risk for RA-ILD (Fig 6).

Fig 2. Forest plot of the pooled ORs for correlation of male sex with RA-ILD.

Fig 2

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Fig 3. Forest plot of the pooled WMDs about average age.

Fig 3

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Fig 4. Forest plot of the pooled WMDs about duration of RA.

Fig 4

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Fig 5. Forest plot of the pooled WMDs about age at onset of RA.

Fig 5

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Fig 6. Forest plot of the pooled ORs for correlation of smoking with RA-ILD.

Fig 6

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There were ever and current smoking datas included in kodrui 2010 study and Yang 2019 study

Laboratory data: a total of 5 laboratory items were identified as factors associated with the RA-ILD. These were RF, ACPA, ANA, ESR, and CRP, we evaluated all of these factors for RA-ILD. The results of analysis showed positive RF (OR = 1.72, 95% CI: 1.47–2.01; P < 0.00001) (Fig 7), positive ACPA (OR = 1.58, 95% CI: 1.31–1.90; P < 0.00001) (Fig 8), RF titer (WMD = 183.62 (IU/mL), 95% CI: 66.94–300.30; P = 0.002) (Fig 9), ACPA titer (WMD = 194.18 (IU/mL), 95% CI: 115.89–272.47; P < 0.00001) (Fig 10), ESR level (WMD = 7.41 (mm/h), 95% CI: 2.21–12.61; P = 0.005) (Fig 11), and CRP level (WMD = 4.98 (mg/L), 95% CI: 0.76–9.20; P = 0.02) (Fig 12) were associated with increased risk of RA-ILD. However, positive ANA (OR = 1.27, 95% CI: 1.00–1.60; P = 0.05) (Fig 13) was not significantly associated with increased risk of RA-ILD.

Fig 7.

Fig 7

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Forest plot of the pooled ORs for correlation of positive RF with RA-ILD. Data about positive RF was available for 72 RA-ILD patients and 1117 RA without ILD patients in Denis 2022 study.

Fig 8. Forest plot of the pooled ORs for correlation of positive ACPA with RA-ILD.

Fig 8

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Data about positive ACPA was available for 67 RA-ILD patients and 1072 RA without ILD patients in Denis 2022 study.

Fig 9.

Fig 9

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Forest plot of the pooled WMDs for correlation of RF titer with RA-ILD.

Fig 10. Forest plot of the pooled WMDs for correlation of ACPA titer with RA-ILD.

Fig 10

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Fig 11. Forest plot of the pooled WMDs for correlation of ESR level with RA-ILD.

Fig 11

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Fig 12. Forest plot of the pooled WMDs for correlation of CRP level with RA-ILD.

Fig 12

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Fig 13. Forest plot of the pooled ORs for correlation of positive ANA with RA-ILD.

Fig 13

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Heterogeneity test and sensitivity analysis

Significant heterogeneity was observed for smoking, RF titer, ACPA titer, and ESR level (Table 1). In order to identify possible sources of heterogeneity, sensitivity analysis was conducted. The analyses were repeated by removing one study per iteration by using Review Manager. No single study significantly affected the pooled effects. Nevertheless, no significant heterogeneity was observed for RF titer (chi2 = 2.01, P = 0.57, I2 = 0%; fixed effects model) and ESR level (chi2 = 6.87, P = 0.23, I2 = 27%; fixed effects model) when study “Salaffi 2019” was removed as well as for ACPA titer (chi2 = 8.40, P = 0.08, I2 = 52%; fixed effects model) when study “Wang 2020” was removed.

Table 1. Factors associated with RA-ILD.

Factors Studies (n) Pooled effect Heterogeneity Egger’s test
OR/WMD [95%CI] P I2 (%) P t P
Demographic
Male 21 1.92 (1.54–2.39) < 0.01 60 < 0.01 -0.34 0.739
Average age 16 5.77 (3.50–8.04) < 0.01 92 < 0.01 -2.09 0.056
Duration of RA 10 0.80 (0.12–1.47) 0.02 0 0.65 0.30 0.772
Age at onset of RA 10 6.41 (3.17–9.64) < 0.01 93 < 0.01 -3.10 0.015a
Smoking 16 1.69 (1.30–2.18) < 0.01 58 < 0.01 -0.16 0.876
Ever-smoking (Subgroup) 11 1.51 (1.08–2.13) 0.02 66 < 0.01 -0.77 0.461
Current smokers (Subgroup) 7 2.03 (1.37–3.01) < 0.01 39 0.13 0.73 0.498
Laboratory data
Positive RF 18 1.72 (1.47–2.01) < 0.01 0 0.71 1.41 0.177
Positive ACPA 13 1.58 (1.31–1.90) < 0.01 20 0.24 2.61 0.024a
RF titer 5 183.62 (66.94–300.30) < 0.01 72 < 0.01 4.27 0.024a
RF titer (omitting Salaffi 2019) 4 217.52 (140.11–294.94) < 0.01 0 0.57 3.80 0.063
ACPA titer 6 194.18 (115.89–272.47) < 0.01 71 < 0.01 2.89 0.044a
ACPA titer (omitting Wang 2020) 5 147.94 (113.73–182.15) < 0.01 52 0.08 1.62 0.204
ACPA titer foreign group (Subgroup) 3 136.99 (101.64–172.34) < 0.01 0 0.55 2.36 0.255
ACPA titer China group (Subgroup) 3 380.30 (137.31–623.29) < 0.01 63 0.07 0.41 0.751
ESR level 7 7.41 (2.21–12.61) < 0.01 52 0.05 -0.29 0.781
ESR Level (omitting Salaffi 2019) 6 9.28 (5.47–13.09) < 0.01 27 0.23 -0.16 0.878
CRP level 6 4.98 (0.76–9.20) 0.02 46 0.10 0.89 0.424
Positive ANA 4 1.27 (1.00–1.60) 0.05 35 0.20 2.40 0.138
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a: P < 0.05, significant publication bias was observed.

Subgroup analysis

Due to significant heterogeneity for the analysis of smoking, ACPA titer and RA-ILD risk, subgroup analysis was conducted to evaluate the source of heterogeneity between the studies. Subgroup analysis by smoking status (divided into “ever-smoking group” and “current smoker group”) revealed that ever-smoking group (chi2 = 29.70, P = 0.001, I2 = 66%; random effects model) had a higher heterogeneity compared to current smoker group (chi2 = 9.85, P = 0.13, I2 = 39%; random effects model). There was no significant heterogeneity in the subgroup of current smoker (Fig 6). Based on the study area, subgroup analysis for the ACPA titer by region (divided into “foreign group” and “China group”) revealed that ACPA titer both in foreign and China populations was significantly related to the risk of RA-ILD, while there was no heterogeneity in the subgroup of foreign group (chi2 = 1.20, P = 0.55, I2 = 0%; random effects model). In addition, the ACPA titer of RA-ILD in China group (WMD = 380.30 (IU/mL), 95% CI: 137.31–623.29; P = 0.002) was higher than that of foreign group (WMD = 136.99 (IU/mL), 95% CI: 101.64–172.34; P < 0.00001) (Fig 14).

Fig 14. Forest plot of subgroup analysis for the ACPA titer.

Fig 14

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Risk of bias assessment

Publication bias of the included studies was examined. No significant publication bias was found by using Egger’s tests except for the analysis of age at onset of RA (t = -3.10, P = 0.015), positive ACPA (t = 2.61, P = 0.024), RF titer (t = 4.27, P = 0.024) and ACPA titer (t = 2.89, P = 0.044) (Table 1).

Discussion

In this systematic review and meta-analysis, we aimed to identify the factors associated with the development of RA-ILD. The results demonstrated that RA-ILD patients were older than the RA without ILD patients. Older patients might have a longer disease duration, and we found that longer duration of RA was associated with RA-ILD. Meanwhile, we found that ILD is more common in patients who were older at onset of RA. Thus, older age might be a useful predictor for predicting increased risk of developing RA-ILD and it is essential to screen ILD in older RA patients. Male sex was also associated with RA-ILD even though RA is more common among females [30]. Furthermore, smoking was associated with a substantially increased risk of RA-ILD. The mechanism for the association of smoking with RA-ILD remains unclear. However, it is well known that cigarette smoke components could trigger an immune reaction, and the production of serum autoantibodies against multiple citrullinated proteins in the lung may result in inflammation and epithelial cell injury which finally leads to ILD [31]. Given the heterogeneity in identifying smoking, subgroup analysis was conducted. Both current smoker and ever-smoking were statistically associated with an increased risk of RA-ILD, there was also no a significantly heterogeneity between current smoker and ever-smoking (chi2 = 1.22, P = 0.27, I2 = 18.1%). Additionally, heterogeneity in the subgroup of current smoker was low. Together, these results demonstrated the importance of smoking cessation to prevent RA-ILD, especially in patients who were a current smoker.

We found a considerable positive RF and ACPA as well as a higher titer of RF and ACPA in RA-ILD patients. Both of these antibodies were significantly related to the risk of RA-ILD at the high titer, which were customarily done in clinical laboratories highlighting the potential importance of these antibodies in the activity of RA and in the development of ILD. Although the underlying mechanism remained not fully understood. Multiple studies have demonstrated a high prevalence of both subclinical and clinical ILD throughout the RA disease course. Subclinical and clinical ILD occur frequently in preclinical, early, and established RA and may play a key role in RA-related autoantibody production and disease progression [32]. Multiple epidemiologic and genetic risk factors, as well as serum biomarkers, have been associated with RA-ILD. In this meta-analysis, the pooled result of 18 studies with dichotomous data showed that RF was significantly related to the risk of RA-ILD, heterogeneity across the studies was low. The combined effect of 5 studies with continuous data showed that the RF titer of RA-ILD group was significantly higher than that of RA without ILD group. Due to significantly heterogeneity for the analysis of RF titer (continuous data) and RA-ILD risk, a sensitivity analysis was performed to determine the reason for high heterogeneity. The pooled effect did not change significantly, and the risk estimates of RF titer and RA-ILD were stable. Sensitivity analysis revealed that “Salaffi 2019” primarily caused the heterogeneity. Meanwhile, the quantitative pooled results of ACPA and the qualitative pooled results of ACPA showed that there was significantly correlation between ACPA and RA-ILD risk. No significant heterogeneity was observed for dichotomous data of ACPA among the included 13 studies. Although the results of the pooled analysis showed that the high titers of ACPA were significantly related to the risk of RA-ILD, while considerable heterogeneity was detected. Sensitivity analysis revealed that the study by “Wang 2020” was likely to be the source of heterogeneity. When we omitted this study, the I2 value dropped significantly from 71% to 52%. Furthermore, subgroup analysis was performed to determine the source of heterogeneity between the 6 studies of ACPA titer, subgroup analysis found no causes of heterogeneity. However, there was no heterogeneity was observed in the subgroup of foreign group (chi2 = 1.20, P = 0.55, I2 = 0%; random effects model). Currently, the exact etiology of RA-ILD is not known. However, some factors and serum biomarkers have been reported to be involved in the pathogenesis of RA-ILD. It has been proposed that the lung is a production site for citrullinated proteins by peptidylarginine deiminases [33,34], some of these proteins may trigger immune responses in the lung and finally result in high titers of antibodies to citrullinated protein antigens. Recent studies found that citrullination is not only involved in the development of joint damage in RA but is also found in the bronchoalveolar lavage fluid of RA-associated interstitial pneumonia and idiopathic interstitial pneumonia subjects [35]. Based on these observations, two potential mechanisms that explain the pathogenesis of RA-ILD were proposed by Paulin et al [36]. First, citrullinated peptides of RA cause the activation and differentiation of lung fibroblasts into myofibroblasts to produce fibers. Second, aging alveolar epithelial cells promote the formation of fibers in susceptible patients. Environmental damage (such as smoking) leads to oxidative stress, which promotes fibroblast differentiation and proliferation. In addition, some studies demonstrated that lung abnormalities, increased protein citrullination, and ACPA enrichment in the lungs were present early after disease onset. This conjecture was strengthened by the finding that citrullinated proteins have been identified in lung tissue [35]. It is not clear whether these antibodies contribute to the initiation of pulmonary diseases in RA patients or whether they merely reflect ongoing pulmonary injury. Moreover, we identified that higher ESR and higher CRP were associated with RA-ILD. Heterogeneity between the seven studies of ESR was considerable, sensitivity analysis revealed that “Salaffi 2019” primarily caused the heterogeneity. When we omitted this study, the I2 value dropped significantly from 52% to 27%. We also analyzed the association between positive ANA and RA-ILD risk, while our meta-analysis has shown no association between ANA positive status and risk of RA-ILD. Additionally, we assumed that publication bias would not be a big issue in our analysis. “Salaffi 2019” might introduce bias for the analysis of RF titer, when we omitted this study, the P-value of Egger’s test increased significantly from 0.024 to 0.063. “Wang 2020” might introduce bias for the analysis of ACPA titer, when we omitted this study, the P-value of Egger’s test increased significantly from 0.044 to 0.204. Nevertheless, the P-value of Egger’s test was 0.024 for the analysis of positive ACPA, indicating that significant publication bias was observed.

In this study, we conducted a meta-analysis to identify the factors associated with the development of RA-ILD. Our study has some limitations that should be considered. The data should be interpreted cautiously due to the limited number of high-quality studies and the limitations inherent in observational studies. First, the studies included were heterogeneous and had variable methodological quality. Moreover, most of the studies were retrospective in design, with small sample sizes and conducted in single medical institutions. Second, the number of patients enrolled, RA disease duration, age at onset of RA and population distribution varied across studies and significant heterogeneity of male, average age and age at onset of RA among studies was noted, which might be attributed to study design, population characteristics, regions and sample size. Although the total number of studies included was not small, more studies, especially prospective studies with large sample sizes, are still needed to overcome all of these limitations.

Conclusions

In summary, our meta-analysis identified that male sex, older age, longer duration of RA, older age at onset of RA, smoking, positive RF, positive ACPA, elevated RF titer, elevated ACPA titer, higher ESR and higher CRP were factors associated with RA-ILD. Other factors contributing to heterogeneity may have been unidentified in our review.

Supporting information

S1 Table. Characteristics of the included studies.

(DOC)

Click here for additional data file. (100.5KB, doc)
S2 Table. Quality scores of the included studies.

(DOC)

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S1 Appendix. PRISMA 2020 checklist.

(PDF)

Click here for additional data file. (151.9KB, pdf)

Acknowledgments

We really appreciate the efforts of all the researchers whose articles were included in this study.

Abbreviations

ILD

Interstitial lung disease

RA

rheumatoid arthritis

RA-ILD

rheumatoid arthritis–related interstitial lung disease

CBM

Chinese Biological Medicine Database

CNKI

China National Knowledge Infrastructure

NOS

Newcastle-Ottawa Scale

WMD

weighed mean difference

OR

odds ratio

CI

confidence intervals

RF

rheumatoid factor

ACPA

anti-citrullinated protein antibodies

ESR

erythrocyte sedimentation rate

CRP

C-reactive protein

ANA

antinuclear antibody

HRCT

high-resolution computed tomography

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Jan René Nkeck

3 Apr 2023

PONE-D-23-05807Factors associated with interstitial lung disease in patients with rheumatoid arthritis: A systematic review and meta-analysisPLOS ONE

Dear Dr. Yin,

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Reviewer #2: Yes

Reviewer #3: Partly

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Reviewer #2: Yes

Reviewer #3: Yes

**********

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Reviewer #3: Yes

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Reviewer #1: this is an interesting work that defines the RA population at risk of ILD and therefore requires special monitoring, however:-

- It is useful to define the risk factors for IPF,

-Analyze the population that presents the association ACPA and FR

-Some authors have found obstructive ventilatory deficit in ACPA patients (Zaccardelli, Ketfi) is what you have identified in your meta-analysis of these anomalies.

Reviewer #2: Minor revisions

Introduction :

• Lines 63- 64, “… and data extracted by two authors…” : maybe a missing word here, please check

• Line 65, “arthritis”,”rheumatoid” : maybe a missing “OR” /”AND” here, please check

Material and Methods

• Line 75, “Studies reporting….”: did the authors mean “reporting only….” since even studies reporting risk factors could also report a prevalence and even outcome

• Line 84, “apply to cohort and… “: did authors mean “applied”? Please check

Results

• Lines 114-115, “the identified….smoking”, this sentence seems to be incomplete, please reformulate

• Lines 116-117, “revealed that ……risk of RA-ILD” : redundant information, please reformulate

• Table 1 : first column, please insert ACPA before Foreign group and China group, since this division concerned only ACPA.

Discussion

• Lines 196-197 : “of…. ACPA titer, and cannot be explain” : not clear, use of present time at the end of sentence, while past tense is use at the beginning of the sentence. Please re formulate

Major revisions

Introduction

• Is RA-ILD or its worsening preventable? Authors should clearly state this, to support the assertion on lines 47-48 “with the goal of preventing irreversible damage”

Methodology

• Authors should state whether the evaluation of the quality was blind or open : did the authors assessing the quality have access to article data such as authors names, journal, etc?

• Authors should provide the repartition of studies by language (Chinese and English) in the S1 table

• Figure 1 : on the first two steps of the flow chart, reasons for withdrawal are missing

Discussion

• An important question remains unresolved : are the factors you found predictors/risk factors of ILD only, or deal with RA severity. The clinical severity of RA (in terms of number and intensity of involved joints, as well as other extra articular involvement) has not been mentioned. Is it known as a factor associated with RA-ILD, if yes, this would be a major confounder. In fine, Is ILD just a marker of RA severity? Authors should provide data on severity, or at least (if data not available) discuss this issue.

Conclusion

• Authors should replace “risk factors of” by “factors associated with” as said in the title, since incident ILD have not been studied and the causality cannot be demonstrated from the data used

Reviewer #3: 1. The title and objective of the study do not tie as factors associated with a disease do not always imply they are risk factors.

2. In the methodology section, we have difficulty understanding certain points as they appear unclear us. These include

- The search strategy focused on studies published in English and Chinese, thus rendering studies carried out in other languages e.g. French to not be included. This could lead to loss of information as not all properly conducted studies are included.

- The exclusion criteria "data could not be extracted". Was it because of the lack of a full text article or language barrier or other factor that made the data not to be able to be extracted? We believe this point should be made clearer.

- The quality assessment of the studies is incomplete to us as we see scores of 5,6, 8 etc. Nothing is mentioned after this score to permit us know if the quality of the included studies were good enough to ensure we can trust the results.

3. In the results section:

- The figures presented are not on their own able to inform a review on what is presented because they have no titles and no clear legends

- The authors state presence of significant heterogeneity in the studies on several aspects yet still go on to have pooled estimates on these and even reach conclusions with some of these variables. This to us is of some concern.

- There also is risk of publication bias for several factors which later are considered as "risk factors" for RA-ILD. This to us is of some concern.

In general, there are many grammatical and typographical errors which make it difficult to read and understand the manuscript.

**********

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Reviewer #2: No

Reviewer #3: No

**********

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PLoS One. 2023 Jun 23;18(6):e0286191. doi: 10.1371/journal.pone.0286191.r002

Author response to Decision Letter 0

11 Apr 2023

Dear Editors and Reviewers:

Thank you for your letter and for the reviewers’comments concerning our manuscript entitled “Factors associated with interstitial lung disease in patients with rheumatoid arthritis: A systematic review and meta-analysis” (ID: PONE-D-23-05807).Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied comments carefully and have made correction which we hope meet with approval. The main corrections in the paper and the responds to the reviewer’s comments are as flowing:

Responds to the reviewer’s comments:

Reviewer #1: this is an interesting work that defines the RA population at risk of ILD and therefore requires special monitoring, however:-

- It is useful to define the risk factors for IPF

1. IPF (Idiopathic Pulmonary Fibrosis) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults. The definition of IPF requires the exclusion of other forms of interstitial pneumonia including other idiopathic interstitial pneumonias and ILD associated with environmental exposure, medication, or systemic disease. There are a number of clinical and mechanistic parallels between IPF and other fibrosing ILDs that may present a progressive phenotype.

2. The diagnosis of IPF requires: Exclusion of other known causes of interstitial lung disease (ILD) (e.g., domestic and occupational environmental exposures, connective tissue disease, and drug toxicity). Although IPF is, by definition, a disease of unknown etiology, a number of potential risk factors have been described such as: cigarette smoking, environmental exposures, microbial agents, gastroesophageal reflux and genetic factors. There are no reliable data on the role of screening serologies in patients with suspected IPF [1]. Park et al [2] conducted a systematic review and meta-analysis to evaluate the risk factor of IPF. They found that metal dust, wood dust, pesticide, occupational history of farming or agriculture and ever smoking increased the risk of IPF. It is really true as Reviewer mentioned that cigarette smoking, older age and environmental exposures were risk factors for IPF. The diagnosis of IPF requires exclusion of other known causes of ILD, such as connective tissue diseases (CTDs), encompass a spectrum of systemic immune diseases in which self-reactive T- and B-cells produce circulating autoantibodies leading to inflammation and organ damage. CTDs associated with ILD include RA, SSc, idiopathic inflammatory myopathy (polymyositis and dermatomyositis), Sjögren's syndrome, systemic lupus erythematosus and mixed CTDs. Of these conditions, SSc and RA are most commonly associated with ILD [3]. There are strong associations between RA-ILD and older age, male sex, cigarette smoking, high rheumatoid factor titres and increased anti-citrullinated protein antibody levels. However, there are a few patients who were defined as IPF can detect high titer of rheumatoid factor, anti-cyclic citrullinated peptide. Patients with IPF may have a mildly positive antinuclear antibody titer and/or rheumatoid factor level.

[1] Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. American journal of respiratory and critical care medicine. 2011;183(6):788-824. https://doi.org/10.1164/rccm.2009-040GL PMID: 21471066

[2] Park Y, Ahn C, Kim TH. Occupational and environmental risk factors of idiopathic pulmonary fibrosis: a systematic review and meta-analyses. Scientific reports. 2021;11(1):4318. https://doi.org/10.1038/s41598-021-81591-z PMID: 33654111

[3] Cottin V, Hirani NA, Hotchkin DL, Nambiar AM, Ogura T, Otaola M, et al. Presentation, diagnosis and clinical course of the spectrum of progressive-fibrosing interstitial lung diseases. European respiratory review : an official journal of the European Respiratory Society. 2018;27(150). https://doi.org/10.1183/16000617.0076-2018 PMID: 30578335

-Analyze the population that presents the association ACPA and FR

All the data in this systematic review and meta-analysis were derived from included 22 articles. We did not recruit patients. The detailed information of population is not available to us. We are very sorry for that.

-Some authors have found obstructive ventilatory deficit in ACPA patients (Zaccardelli, Ketfi) is what you have identified in your meta-analysis of these anomalies.

We found these studies as follows:

[4] Zaccardelli A, Liu X, Ford JA, Cui J, Lu B, Chu SH, et al. Elevated Anti-Citrullinated Protein Antibodies Prior to Rheumatoid Arthritis Diagnosis and Risks for Chronic Obstructive Pulmonary Disease or Asthma. Arthritis care & research. 2021;73(4):498-509. https://doi.org/10.1002/acr.24140 PMID: 31961487

As we can see from the Zaccardelli statements: ACPA positivity prior to RA onset was significantly associated with increased COPD risk, particularly in the pre-RA period. This may be due to loss of immune tolerance in the lungs from increased citrullination and ACPA production occurring before RA onset that pre-disposes to chronic airway disease and not explained by smoking. Women who went on to develop RA were also more likely to develop asthma compared to matched controls, however this was risk was not related to pre-RA ACPA status.

[5] Ketfi A, Tahiat A, Djouadi C, Djenouhat K, Ben Saad H. Lung function data of North-African patients with rheumatoid arthritis: a comparative study between anti-citrullinated peptides antibodies positive and negative patients. La Tunisie medicale. 2022;100(8-9):626-41. PMID: 36571731

Methods: This comparative pilot study was performed over a two-year period (2018-2019) in Algiers (Algeria). The study included two groups of RA non-smoker patients: 26 ACPA+ and 33 ACPA-. RA was diagnosed according to the ACR/EULAR 2010 RA classification criteria. Spirometry and plethysmography were performed. The following definitions were applied: Obstructive Ventilatory Impairment (OVI): FEV1/FVC z-score < -1.645; Restrictive Ventilatory Impairment (RVI): Total Lung Capacity (TLC) z-score < -1.645; Mixed Ventilatory Impairment (MVI): FEV1/FVC z-score < -1.645 and TLC z-score < -1.645; lung- hyperinflation: residual volume z-score > +1.645; Nonspecific Ventilatory Impairment (NSVI): FEV1 z-score < -1.645, FVC z-score < -1.645, FEV1/FVC z-score ≥ -1.645, and TLC z-score ≥ -1.645.

1. As we can see from the Ketfi statements, the study included two groups of RA patients: 26 ACPA+ and 33 ACPA-.RA is a systemic inflammatory disorder, with the most common extra-articular manifestation of RA being lung involvement. While essentially any of the lung compartments can be affected and manifest as interstitial lung disease (ILD), pleural effusion, cricoarytenoiditis, constrictive or follicular bronchiolitis, bronchiectasis, pulmonary vasculitis, and pulmonary hypertension, RA-ILD is a leading cause of death in patients with RA and is associated with significant morbidity and mortality. Though lung involvement in RA typically occurs following articular manifestations, pulmonary manifestations may occasionally precede joint symptoms [6]. Several studies have shown that pulmonary function testing (PFT) is helpful for the early detection of RA-ILD. PFT in RA-ILD patients often reveals restrictive ventilatory defects with decreases in gas exchange, and such abnormalities may be detected even in the absence of any clinical symptoms [7].

2. Prevalence of airway disease in RA is high and can occur in 39–60% of patients. Both the large (upper and lower) and distal small airways can be involved. The most common manifestations are bronchiectasis, bronchiolitis, airway hyperreactivity and cricoarytenoid arthritis[6]. As we can see from the Zaccardelli statements: ACPA positivity prior to RA onset was significantly associated with increased COPD risk, particularly in the pre-RA period. It has been found that patients with RA typically have circulating antibodies, most notably RF and ACPAs. These autoantibodies are present in an estimated 50–80% of RA patients and are often (though not always) present in the serum for several years prior to clinical disease onset. In individuals who are genetically predisposed, citrullination, a post-translational modification marked by the conversion of arginine to citrulline, can trigger an immune response leading to the production of ACPAs, which are strongly associated with development of RA.

3. Overall, Zaccardelli and Ketfi emphasize that ACPA positivity was significantly associated with increased obstructive ventilatory deficit risk, these results emphasize that clinicians should closely monitor seropositive RA patients for airway abnormalities, even prior to RA onset. Future work is needed to elucidate the bi-directional link between RA and chronic airway diseases.

[6] Kadura S, Raghu G. Rheumatoid arthritis-interstitial lung disease: manifestations and current concepts in pathogenesis and management. European respiratory review : an official journal of the European Respiratory Society. 2021;30(160). https://doi.org/10.1183/16000617.0011-2021 PMID: 34168062

[7] Solomon JJ, Chung JH, Cosgrove GP, Demoruelle MK, Fernandez-Perez ER, Fischer A, et al. Predictors of mortality in rheumatoid arthritis-associated interstitial lung disease. The European respiratory journal. 2016;47(2):588-96. https://doi.org/10.1183/13993003.00357-2015 PMID: 26585429

Reviewer #2: Minor revisions

Introduction :

• Lines 63- 64, “… and data extracted by two authors…” : maybe a missing word here, please check

Searches were restricted to articles written in English and Chinese. We searched all relevant studies on RA-ILD published before December 30, 2022 and two authors extracted data from articles independently.

• Line 65, “arthritis”,”rheumatoid” : maybe a missing “OR” /”AND” here, please check

“rheumatoid arthritis” OR “arthritis” OR “rheumatoid”

Material and Methods

• Line 75, “Studies reporting….”: did the authors mean “reporting only….” since even studies reporting risk factors could also report a prevalence and even outcome

studies reporting only

• Line 84, “apply to cohort and… “: did authors mean “applied”? Please check

The methodological quality of cohort and case-control studies were assessed using the Newcastle-Ottawa scale (NOS) with a total score of 9 points.

Results

• Lines 114-115, “the identified….smoking”, this sentence seems to be incomplete, please reformulate

The identified factors associated with RA-ILD include average age, duration of RA, age at onset of RA and smoking.

• Lines 116-117, “revealed that ……risk of RA-ILD” : redundant information, please reformulate

revealed that older age was associated with RA-ILD.

• Table 1 : first column, please insert ACPA before Foreign group and China group, since this division concerned only ACPA.

Discussion

• Lines 196-197 : “of…. ACPA titer, and cannot be explain” : not clear, use of present time at the end of sentence, while past tense is use at the beginning of the sentence. Please re formulate

Furthermore, subgroup analysis was performed to determine the source of heterogeneity between the 6 studies of ACPA titer, subgroup analysis found no causes of heterogeneity.

Major revisions

Introduction

• Is RA-ILD or its worsening preventable? Authors should clearly state this, to support the assertion on lines 47-48 “with the goal of preventing irreversible damage”

To date, there have not been any guidelines or RCTs for the treatment of RA-ILD. From recent data, conventional disease-modifying anti-rheumatic drugs (cDMARDS), including Methotrexate (MTX) and Leflunomide (LEF), play beneficial roles in the prevention and treatment of RA-ILD. Biologic disease-modifying anti-rheumatic drugs (bDMARDs) such as abatacept and rituximab are effective in stabilizing ILD involvement in RA patients [8]. Although a great deal of research has been conducted and breakthroughs have been achieved in the field of RA, there are still many questions about RA-ILD. How do clinicians help RA patients prevent the onset of ILD? When should clinicians initiate the treatment and choose the right option for different ILD patterns? However, most approaches are based on experts, without evidence from RCTs. To effectively care for these patients, further research is needed to define the pathogenesis and treatment of RA-ILD.

[8] Dai Y, Wang W, Yu Y, Hu S. Rheumatoid arthritis-associated interstitial lung disease: an overview of epidemiology, pathogenesis and management. Clinical rheumatology. 2021;40(4):1211-20. https://doi.org/10.1007/s10067-020-05320-z PMID: 32794076

Methodology

• Authors should state whether the evaluation of the quality was blind or open: did the authors assessing the quality have access to article data such as authors names, journal, etc?

the methodological quality of cross-sectional studies was evaluated using the assessment involving 11 items recommended by the Agency for Healthcare Research and Quality (AHRQ). The total score ranged from 0 to 11, with a score of 8 or higher considered high quality. The methodological quality of cohort and case-control studies were assessed using the Newcastle-Ottawa scale (NOS) with a total score of 9 points. A total score of 5 or less was considered low, 6 or 7was considered moderate, and 8 or 9 was deemed high quality. four of the studies were considered low quality, sixteen were considered moderate quality, and two were determined to be high quality based on their total scores. Evaluation of the quality of included studies was performed by 2 authors independently based on the study design. Two independent authors were blinded to the authors names, titles and years of publication of the included studies. Discrepancies in scores were resolved by consensus with a third author. The methodological quality assessment results were shown in S2 Table.

• Authors should provide the repartition of studies by language (Chinese and English) in the S1 table

We have made correction according to the Reviewer’s comments.

• Figure 1 : on the first two steps of the flow chart, reasons for withdrawal are missing

We have made correction according to the Reviewer’s comments.

Discussion

• An important question remains unresolved : are the factors you found predictors/risk factors of ILD only, or deal with RA severity. The clinical severity of RA (in terms of number and intensity of involved joints, as well as other extra articular involvement) has not been mentioned. Is it known as a factor associated with RA-ILD, if yes, this would be a major confounder. In fine, Is ILD just a marker of RA severity? Authors should provide data on severity, or at least (if data not available) discuss this issue.

We have re-written this part according to the Reviewer’s suggestion

1. This systematic review and meta-analysis were performed to identify risk factors for RA-ILD，

2. Whether the clinical severity of RA (in terms of number and intensity of involved joints, as well as other extra articular involvement) increases the risk of RA-ILD is disputed. We aimed to evaluate the association of demographic characteristics and laboratory items with development of RA-ILD.

3. The latest research shows that RA-ILD is a serious extra-articular complication of RA that involves several radiologic and pathologic subtypes. Previously considered a consequence of prolonged disease severity in longstanding RA, subclinical and clinical ILD are increasingly recognized throughout the entire RA disease course. Multiple studies have demonstrated a high prevalence of both subclinical and clinical ILD throughout the RA disease course. A significant proportion of RA-ILD patients develop ILD prior to articular manifestations, suggesting that the lung plays a central role RA development, perhaps through ACPA production. RA-ILD also occurs in early RA, when exuberant autoantibody production and systemic inflammation may propagate disease activity [9].

[9] McDermott GC, Doyle TJ, Sparks JA. Interstitial lung disease throughout the rheumatoid arthritis disease course. Current opinion in rheumatology. 2021;33(3):284-91. https://doi.org/10.1097/bor.0000000000000787 PMID: 33625044

Conclusion

• Authors should replace “risk factors of” by “factors associated with” as said in the title, since incident ILD have not been studied and the causality cannot be demonstrated from the data used

We have made correction according to the Reviewer’s comments.

Reviewer #3: 1. The title and objective of the study do not tie as factors associated with a disease do not always imply they are risk factors.

We have made correction according to the Reviewer’s comments.

2. In the methodology section, we have difficulty understanding certain points as they appear unclear us. These include

- The search strategy focused on studies published in English and Chinese, thus rendering studies carried out in other languages e.g. French to not be included. This could lead to loss of information as not all properly conducted studies are included.

We are very sorry for our negligence of studies carried out in other languages. Due to the limitation of language, we failed to include more research. We look forward to more studies carry out in English.

- The exclusion criteria "data could not be extracted". Was it because of the lack of a full text article or language barrier or other factor that made the data not to be able to be extracted? We believe this point should be made clearer.

The studies which data could not be extracted as follows:

[10] Natalini JG, Baker JF, Singh N, Mahajan TD, Roul P, Thiele GM, et al. Autoantibody Seropositivity and Risk for Interstitial Lung Disease in a Prospective Male-Predominant Rheumatoid Arthritis Cohort of U.S. Veterans. Annals of the American Thoracic Society. 2021;18(4):598-605. https://doi.org/10.1513/AnnalsATS.202006-590OC PMID: 33026891. In this study, the patients with combined RF/ACPA seropositivity had a higher probability of prevalent ILD compared with seronegative subjects. RF titers demonstrated a monotonic association with prevalent ILD (OR, 2.69; 95% CI, 1.11–6.51 for low-positive [15–45 IU/ml] titers; OR, 3.40; 95% CI, 1.61–7.18 for high-positive [>45 IU/ml] titers; P for trend 0.01). Patients with high-positive (>15 U/ml) ACPA titers were also at higher risk for prevalent ILD (OR, 1.91; 95% CI, 1.04–3.49) compared with ACPA-negative subjects. Combined RF/ACPA seropositivity was not associated with increased risk for incident ILD, nor were high- or low-positive RF or ACPA titers. It is impossible for us to extract data.

[11] Inui N, Enomoto N, Suda T, Kageyama Y, Watanabe H, Chida K. Anti-cyclic citrullinated peptide antibodies in lung diseases associated with rheumatoid arthritis. Clinical biochemistry. 2008;41(13):1074-7. https://doi.org/10.1016/j.clinbiochem.2008.06.014 PMID: 18638466. In this study, values are expressed as the number or median (interquartile range)

[12] Huang S, Doyle TJ, Hammer MM, Byrne SC, Huang W, Marshall AA, et al. Rheumatoid arthritis-related lung disease detected on clinical chest computed tomography imaging: Prevalence, risk factors, and impact on mortality. Seminars in arthritis and rheumatism. 2020;50(6):1216-25. https://doi.org/10.1016/j.semarthrit.2020.08.015 PMID: 33059295. In this study, RA-related lung disease was defined as ILD, bronchiectasis, or pleural disease on the impression of the radiologic report. It is difficult to make a distinction of data that is related to ILD among the three types of lung disease.

- The quality assessment of the studies is incomplete to us as we see scores of 5,6, 8 etc. Nothing is mentioned after this score to permit us know if the quality of the included studies were good enough to ensure we can trust the results.

We have made correction according to the Reviewer’s comments.

the methodological quality of cross-sectional studies was evaluated using the assessment involving 11 items recommended by the Agency for Healthcare Research and Quality (AHRQ). The total score ranged from 0 to 11, with a score of 8 or higher considered high quality. The methodological quality of cohort and case-control studies were assessed using the Newcastle-Ottawa scale (NOS) with a total score of 9 points. A total score of 5 or less was considered low, 6 or 7was considered moderate, and 8 or 9 was deemed high quality. four of the studies were considered low quality, sixteen were considered moderate quality, and two were determined to be high quality based on their total scores. Evaluation of the quality of included studies was performed by 2 authors independently based on the study design. Two independent authors were blinded to the authors names, titles and years of publication of the included studies. Discrepancies in scores were resolved by consensus with a third author. The methodological quality assessment results were shown in S2 Table.

3. In the results section:

- The figures presented are not on their own able to inform a review on what is presented because they have no titles and no clear legends

We are very sorry for this comment. We prepared the manuscript according to the MANUSCRIPT BODY FORMATTING GUIDELINES of PLOS.

- The authors state presence of significant heterogeneity in the studies on several aspects yet still go on to have pooled estimates on these and even reach conclusions with some of these variables. This to us is of some concern.

1. It is really true as reviewer suggested that significant heterogeneity exist in the studies. In order to identify possible sources of heterogeneity, we did an analysis to check the effect size and heterogeneity with each study removed one at a time. Sensitivity analysis was conducted to explore for potential outliers statistically and subgroup analysis was conducted to explain some of the potential sources of heterogeneity. Our study has some limitations that should be considered. It is possible that limitations exist in the searching and screening approach used, leading to eligible studies being inadvertently left out of the review. As the reviewer mentioned that the search strategy focused on studies published in English and Chinese, thus rendering studies carried out in other languages e.g. French to not be included.

2. The number of patients enrolled, RA disease duration, age at onset of RA and population distribution varied across studies and significant heterogeneity of male, average age and age at onset of RA among studies was noted, which might be attributed to study design, population characteristics, regions and sample size. The specific reasons for the heterogeneity cannot be explained in our systematic review and meta-analysis.

- There also is risk of publication bias for several factors which later are considered as "risk factors" for RA-ILD. This to us is of some concern.

Publication bias is the tendency of studies to be more likely to be published when they report positive and statistically significant results, or have larger effect sizes. 22 articles were included in our systematic review and meta-analysis, but not every study contains all the factors. The publication bias exists only partially.

In general, there are many grammatical and typographical errors which make it difficult to read and understand the manuscript.

We have made correction according to the Reviewer’s comments.

Attachment

Submitted filename: Response to Reviewers.doc

Click here for additional data file. (663.5KB, doc)

Decision Letter 1

Jan René Nkeck

11 May 2023

Factors associated with interstitial lung disease in patients with rheumatoid arthritis: A systematic review and meta-analysis

PONE-D-23-05807R1

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Acceptance letter

Jan René Nkeck

14 Jun 2023

PONE-D-23-05807R1

Factors associated with interstitial lung disease in patients with rheumatoid arthritis: A systematic review and meta-analysis

Dear Dr. Yin:

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Associated Data

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    Supplementary Materials

    S1 Table. Characteristics of the included studies.

    (DOC)

    Click here for additional data file. (100.5KB, doc)
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    Attachment

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