Interstitial Lung Disease In Rheumatoid Arthritis Patients Research Articles

Factors associated with interstitial lung disease in patients with rheumatoid arthritis

Aim: Interstitial lung disease (ILD) is a significant extra-articular manifestation of rheumatoid arthritis (RA). The prevalence and risk factors for ILD in RA exhibit considerable variation. This study aimed to determine the prevalence and factors associated with ILD in Thai patients with RA. Methods: This cross-sectional study enrolled 290 RA patients from the Siriraj Rheumatoid Arthritis Registry between March and December 2022. Patient characteristics, disease activity and functional status were documented. Chest radiography (CXR) was employed for ILD screening, and suspected cases were further evaluated using high-resolution computed tomography (HRCT) and pulmonary function tests. Two radiologists independently analyzed CXR and HRCT images, with any discrepancies resolved by a pulmonologist. Results: Among the 290 patients, the majority were female (89.7%) with mean age (SD) of 58.8 (11.5) years, and the median disease duration was 10 years (range 6–17 years). Patients exhibited low disease activity [mean Disease Activity Score 28-erythrocyte sedimentation rate score (SD) 2.69 (0.90)] and mild functional impairment [median Health Assessment Questionnaire score (range) 0.25 (0–0.63)]. Thirteen patients (4.5%) were diagnosed with ILD via HRCT (RA-ILD), with nonspecific interstitial pneumonia being the predominant ILD pattern (69.2%). Pulmonary function tests showed normal results in most patients, with only 15.5% presenting restrictive ventilatory defects. Age (P = 0.04), breathlessness (P < 0.001), crackles (P < 0.001), and functional impairment (P = 0.02) exhibited significant associations with RA-ILD. Conclusions: ILD is relatively infrequent in Thai patients with RA. However, older age, breathlessness, crackles, and functional impairment should prompt investigations for ILD in RA patients.

Genetic evidence reveals a causal relationship between rheumatoid arthritis and interstitial lung disease.

Background/purpose: Previous epidemiological studies have associated interstitial lung disease (ILD) with rheumatoid arthritis (RA), yet the causality of this relationship remains uncertain. This study aimed to investigate the genetic causal link between ILD and RA. Methods: Genome-wide association study (GWAS) statistics for ILD and RA were collected from public datasets. Relevant single-nucleotide polymorphisms (SNPs) were selected by executing quality control steps from the GWAS summary results. A two-sample bidirectional Mendelian randomization (MR) analysis was performed to assess the causal relationship between the two conditions. The MR analysis primarily used the inverse variance weighting (IVW), weighted median (WM), and MR-Egger regression methods. Sensitivity analyses, including MR-Egger, leave-one-out, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), were conducted to evaluate the heterogeneity and pleiotropy. Replication analyses using Asian datasets were also conducted to enhance the robustness of our findings. Results: In the European population, RA was found to increase the risk of ILD by 9.6% (OR: 1.096, 95% CI: 1.023-1.174, p = 0.009). Conversely, ILD was associated with a 12.8% increased risk of RA (OR: 1.128, 95% CI: 1.013-1.256, p = 0.029). Replication analyses from Asian GWAS further supported these findings, particularly the increased risk of ILD attributable to RA (OR: 1.33, 95% CI: 1.18-1.49, p-value <0.001). Conclusion: Our findings underscore the clinical importance of screening for ILD in RA patients and suggest that effective management of RA could significantly benefit ILD patients. The potential applicability of novel RA treatments to ILD warrants further exploration. Additionally, racial disparities in the manifestation of these diseases should not be overlooked, as they may offer new perspectives for targeted therapies in diverse populations.

Risk factors for interstitial lung disease in rheumatoid arthritis: a cohort study from the KOBIO registry.

Interstitial lung disease (ILD) is a critical extra-articular manifestation of rheumatoid arthritis (RA). However, little is known about the risk factors of RA-ILD. Here, we examined the effect of demographic, clinical, therapeutic, and environmental factors on the incidence of ILD in RA patients using the Korean College of Rheumatology Biologics and Targeted Therapy (KOBIO) registry. We used data from the KOBIO registry, a multi-center, prospective, observational cohort that included RA patients in South Korea. RA patients who used biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) or conventional synthetic (cs)DMARDs, and were enrolled in the KOBIO registry, were examined. Demographic, clinical, and radiographic characteristics, as well as medications, were recorded at baseline and annually thereafter. Kaplan-Meier curves and the log-rank test were used to compare the incidence of ILD between RA patients taking different b/tsDMARDs. Hazard ratios (HRs) were calculated by Cox regression analyses. In total, 2492 patients (1967 in the b/tsDMARDs group and 525 in the csDMARDs group) were analyzed. The b/tsDMARDs group showed longer disease duration, higher erythrocyte sedimentation rate/C-reactive protein, and higher disease activity score-28 (DAS28) than the csDMARDs group. The incidence of ILD was significantly higher in those taking tumor necrosis factor inhibitors and abatacept than in those taking csDMARDs (log ranked p < 0.001). Multivariate Cox regression analysis identified older age (HR = 1.057, p = 0.001), male sex (HR = 2.824, p = 0.007), time-averaged DAS28 (HR = 2.241, p < 0.001), and rheumatoid factor titer (HR = 1.009, p = 0.007) as having a significantly increased HR for ILD occurrence. ILD is a rare but critical extra-articular symptom of RA patients. Therefore, RA patients with the above risk factors should be monitored carefully for ILD development.

Symposium 4

Extra-articular manifestations are common in Rheumatoid-arthritis (RA), involving the skin, eyes, heart, and lung, causing significant comorbidities. In particular, clinically significant rheumatoid arthritis-associated interstitial lung disease (RA-ILD) has a prevalence of about 10%-19% among RA patients. However, the exact prevalence of ILD in RA patients is not well known and there is also a lack of local data in Hong Kong. Early screening and identification of ILD in RA patients is important for improving patient outcomes. Currently, there is no established algorithm for screening in asymptomatic patients with RA. High resolution computed tomography (HRCT) is a standard assessment in ILD diagnosis but is associated with high cost. Pulmonary function test and lung ultrasound might also be useful in identifying ILD. Besides, multiple clinical risk factors and novel biomarkers have been explored for early identification of RA-ILD. To evaluate the usefulness of these predictors and to evaluate the burden of interstitial lung disease (ILD) among patients with RA, a local study (RAISE, Rheumatoid Arthritis-associated ILD: Screening and Evaluation in high-risk patients) was designed in Hong Kong to assess the prevalence of RA-ILD among RA patients with high risk, and to identify potential clinical and biochemical markers associated with the condition. In this session, Dr. Shirley Chan will share the protocol of the RAISE study and the screening approach. The interim results will also be analyzed and presented.

Symposium 4

Interstitial lung disease (ILD) is a fibrotic disease of the lung parenchyma. It can occur in different connective tissue diseases, including rheumatoid arthritis (RA). Smoking, male gender and longstanding RA are possible risk factors for developing ILD 1 . Being a common extra-articular manifestation of RA, it can contribute to decreased quality of life, chronic disability, high utilization of healthcare resources, and may also lead to substantial morbidity and mortality for affected patients1. Hence, early identification and management is of paramount importance to improve patient outcomes. Clinical presentation, chest X-ray, pulmonary function testing and high-resolution computed tomography are common tools for investigation and they also allows assessment of subtype and disease extent 2 . The histopathologic and radiographic features of RA-ILD are heterogeneous. The most frequent patterns of RA-ILD are usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP). Distinguishing the patterns is useful in predicting prognosis and would also affect subsequent management approach 2 . Traditionally treatment initiated for RA-ILD was generally empirical. Corticosteroids were often used as first-line agents and immunosuppressants maybe added2. However, these treatments are not specific and mainly target inflammation instead of fibrosis. With the advance in medicine, antifibrotic is now indicated for treating fibrosing ILD with progressive phenotype. FVC decline can be slowed in patients with connective tissue disease associated progressive ILD 3 . In this lecture, Prof. Vanessa Smith will share the current knowledge and evidence in RA-ILD. The approach on identifying and screening ILD in RA patients would be presented. The management strategy and options would also be reviewed.

Plasma Wnt7b protein in rheumatoid arthritis: Detection of interstitial lung disease

ObjectiveTo determine the plasma level of Wingless-related integration site 7b (Wnt7b) protein in rheumatoid arthritis (RA) patients (with and without interstitial lung disease (ILD)) and in idiopathic pulmonary fibrosis (IPF) patients and its relationship with RA disease activity and/or severity of pulmonary fibrosis. To assess the validity of plasma Wnt7b for the detection of ILD among RA patients. MethodThis case-control study included 128 subjects (32 RA-ILD, 32 RA, 32 IPF, and 32 healthy controls). RA and RA-ILD Patients were evaluated for disease activity by DAS28 and disease activity grades were recorded according to DAS28 grades. Laboratory parameters as Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Rheumatoid Factor (RF), Anti-citrullinated peptide (Anti-CCP) were recorded. Plasma Wnt7b levels were measured by ELISA. Diagnosis of pulmonary fibrosis (for RA-ILD and IPF patients) was done by high resolution computed tomography (HRCT) and its severity was assessed mainly by pulmonary function test using forced vital capacity (FVC) grading. ResultsComparison of Wnt7b plasma levels showed a significant difference between the studied groups with the P-value < 0.018 (RA-ILD had the highest levels). Post hoc analysis revealed a significant difference in Wnt7b plasma levels between RA-ILD and IPF groups (P = 0.008). Also, RA-ILD and control groups had a significant difference (P = 0.039). However, there was a non-significant relationship between Wnt7b plasma levels and RA disease activity as well as the severity of pulmonary fibrosis. ROC curve analysis for the plasma Wnt7b levels revealed that a level ≥285.1 pg/ml had a sensitivity of 87.5% and a specificity of 43.8% for the detection of ILD in RA patients with positive likelihood ratio of 1.56 and negative likelihood ratio of 0.29. ConclusionRA-ILD patients had significantly higher plasma Wnt7b levels than the controls and IPF patients. These data suggest that the Wnt7b secretion is augmented by the concomitant presence of RA with pulmonary fibrosis. In addition, plasma Wnt7b may be used as a highly sensitive test for the detection of immunologically induced fibrotic changes in lung tissue among RA patients.

Clinical characteristics of rheumatoid arthritis patients with interstitial lung disease: baseline data of a single-center prospective cohort

BackgroundTo introduce a prospective cohort for rheumatoid arthritis (RA) patients with interstitial lung disease (ILD) and to identify their clinical features in comparison with RA patients without ILD.MethodsUsing a multidisciplinary collaborative approach, a single-center cohort for RA patients with ILD (RA-ILD) was established in May 2017, and enrolment data from May 2017 to March 2021 were used to compare the clinical features of RA patients without ILD (RA-non ILD). Multivariable logistic regression analysis was used to identify factors associated with ILD in RA patients.ResultsAmong 148 RA-ILD and 410 RA-non ILD patients, participants in the RA-ILD group were older (65.8 ± 9.9 vs. 58.0 ± 10.4 years, P < 0.001) and included more males (35.8% vs. 14.6%, P < 0.001) than in the RA-non ILD group. The RA-ILD group had a higher proportion of late-onset RA patients (age ≥ 60 years) than in the comparator group (43.9% vs. 14.2%, P < 0.001). Multivariable logistic regression analysis showed that higher age at RA onset (OR 1.056, 95% CI 1.021–1.091), higher body mass index (BMI; OR 1.65, 95% CI 1.036–2.629), smoking history (OR 2.484, 95% CI 1.071–5.764), and oral glucocorticoid use (OR 3.562, 95% CI 2.160–5.874) were associated with ILD in RA patients, whereas methotrexate use was less likely to be associated with ILD (OR 0.253, 95% CI 0.155–0.412).ConclusionsHigher age at RA onset, smoking history, and higher BMI were associated with the presence of ILD among RA patients. Oral glucocorticoids were more frequently used whereas methotrexate was less likely to be used in RA-ILD patients.

Elevated VCAM-1, MCP-1 and ADMA serum levels related to pulmonary fibrosis of interstitial lung disease associated with rheumatoid arthritis.

Introduction: Early diagnosis of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA) constitutes a challenge for the clinicians. Pulmonary vasculopathy is relevant in the development of interstitial lung disease. Accordingly, we aimed to explore the role of vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and asymmetric dimethylarginine (ADMA), key molecules in the vasculopathy, as potential biomarkers of pulmonary fibrosis in RA-ILD+. Methods: We included 21 RA-ILD+ patients and two comparative groups: 25 RA-ILD- patients and 21 idiopathic pulmonary fibrosis (IPF) patients. Serum levels of the molecules were determined by ELISA, and mRNA expression was quantified by qPCR. Results: VCAM-1, MCP-1 and ADMA serum levels were increased in RA-ILD+ patients in relation to RA-ILD- and IPF patients. Additionally, RA-ILD+ patients exhibited increased CCL2 (gene encoding MCP-1) and decreased PRMT1 (gene related to ADMA synthesis) mRNA expression in relation to RA-ILD- patients. A lower expression of VCAM1, CCL2, and PRMT1 was observed in RA-ILD+ patients when compared with those with IPF. Furthermore, MCP-1 serum levels and PRMT1 mRNA expression were positively correlated with RA duration, and ADMA serum levels were positively associated with C-reactive protein in RA-ILD+ patients. Conclusion: Our study suggests that VCAM-1, MCP-1 and ADMA could be considered as useful biomarkers to identify ILD in RA patients, as well as to discriminate RA-ILD+ from IPF, contributing to the early diagnosis of RA-ILD+.

Frequency of Interstitial Lung Disease in Rheumatoid Arthritis Patients: A Hospital-Based Study.

Among various extra-articular manifestations of rheumatoid arthritis (RA), interstitial lung disease (ILD) is the most frequent and concerning manifestation. The reported frequency of RA-associated ILD (RA-ILD) varies in the literature. The objective of the present study was to determine the frequency of ILD in RA patients at a teaching hospital in Rawalpindi. 175 male and female patients between 18-70 years were enrolled in the study from January 21, 2022, till July 24, 2022. Patients diagnosed with RA were screened for the concomitant presence of ILD (increased pulmonary markings on chest X-rays and total lung capacity ≤ 80%, predicted on pulmonary function tests). In addition, the frequency of RA-ILD was noted and compared across various subgroups of patients based on age, gender, and disease duration. The mean age of the patients was 45.3 ± 11.5 years. The male-to-female ratio was 1:3.1. The mean disease duration was 6.2 ± 3.5 years at the time of presentation. A total of 118 (67.4%) patients were diagnosed with RA-ILD. The frequency of RA-ILD was significantly higher among patients with a prolonged duration of disease, < 5 years vs. ≥ 5 years (59.1% vs. 75.9%; p-value=0.018). Among 118 patients with RA-ILD, usual interstitial pneumonia (UIP) was the most frequent pattern and was noted in 74 (62.7%) patients, followed by nonspecific interstitial pneumonitis (NSIP), which was noted in 44 (37.3%) patients. When compared, there was no statistically significant difference in the frequency of high-resolution CT (HRCT) pattern of RA-ILD across various subgroups of patients based on age (p-value=0.969), gender (p-value=0.934), and duration of disease (p-value=0.881). In the present study, a substantial proportion of RA patients suffered RA-ILD, which warrants routine screening of these patients for undiagnosed pulmonary involvement so that timely identification and anticipated management may improve the outcome of such cases in future clinical practice.

Screening criteria for interstitial lung disease associated to rheumatoid arthritis: Expert proposal based on Delphi methodology

ObjectiveTo develop a joint proposal for screening criteria of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) and vice versa, which serves as a guidelines in patient referral between the Rheumatology and Pneumology departments to early detection of these patients. MethodsA systematic literature review was carried out on the risk factors for the development of ILD in RA patients, and for the referral criteria to Rheumatology for suspected early RA. Based on the available evidence, screening criteria were agreed using the Delphi method by a panel of pneumologists and rheumatologists with expertise in these pathologies. ResultsScreening criteria for ILD in patients with RA and for the early detection of RA in cases with ILD of unknown etiology have been developed. In both cases, a detection strategy was based on clinical risk factors. Recommendations also included the complementary tests to be carried out in the different clinical scenarios and on the periodicity that screening should be repeated. ConclusionA selective screening strategy is recommended for the first time in the early diagnosis of patients with ILD-RA. This multidisciplinary proposal aims to solve some common clinical questions and help decision-making, although its usefulness to identify these patients with good sensitivity must be confirmed in a validation study.

Development of a Risk Nomogram Model for Identifying Interstitial Lung Disease in Patients With Rheumatoid Arthritis

The clinical features of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (RA-ILD) usually manifest to an advanced stage of lung disease, which leads the challenge of early diagnosis and the difficulty in guiding treatments for patients with RA-ILD in clinical settings. The aim of this study was to construct a nomogram for identifying ILD in RA patients. Through the incorporation of the level of matrix metalloproteinase-3 (MMP-3) in plasma, demographics, clinical feature, and laboratory parameters of 223 RA patients (85 RA-ILD) which were grouped as training cohorts and validation cohorts, an identifying nomogram of RA-ILD was built. Candidate variables for the nomogram were screened using univariable analysis and multivariable logistic regression analysis. The accuracy of the diagnostic nomogram was measured via concordance index (C-index), calibration plots, and decision curve analysis (DCA). Results showed that plasma MMP-3 protein was elevated in RA-ILD patients compared with non-ILD RA patients in both training cohorts (p = 0.0475) and validation cohorts (p = 0.0006). Following a final regression analysis, the gender of male, current smoking state, levels of circulating rheumatoid factor (RF), C-reactive protein (CRP), and MMP-3 were identified as risk factors for the construction of the nomogram. The calibration plots further showed a favorable consistency between the identifying nomogram and actual clinical findings. In consistence, the C-index (0.826 for both training cohorts and validation cohorts) indicated the satisfactory discriminative ability of the nomogram. Although the incorporation of MMP-3 failed to significantly improve identified outcomes of the nomogram as determined by DCA, including the level of circulating MMP-3 increased the diagnostic accuracy of the nomogram for ILD in RA patients. Thus, our proposed model can serve as a non-invasive tool to identify ILD in RA patients, which may assist physicians to make treatment decisions for RA patients.

Predictors of progression in rheumatoid arthritis-associated interstitial lung disease: A single-center retrospective study from China.

Interstitial lung disease (ILD) is a common extra-articular manifestation of rheumatoid arthritis (RA) and is associated with high mortality, especially in progressive ILD. We aimed to identify predictors of disease progression in the early stages of ILD in a large sample of patients with RA. The medical records of 201 RA-ILD patients were retrospectively analyzed. According to changes in their pulmonary function tests, patients were divided into progressive disease and stable disease groups. Data were collected on clinical characteristics, laboratory findings, chest high-resolution computed tomography, and therapeutic agents. Univariate and multivariate analyses were performed to identify predictors of ILD progression. During a median follow up of 38 months, 105 (52.5%) patients were diagnosed with progressive ILD. These patients were mostly male, past or present smokers (P=0.028, P=0.021, respectively). Higher Health Assessment Questionnaire-Disability Index score and higher Disease Activity Score in 28 joints with erythrocyte sedimentation rate (DAS28-ESR) were observed in the ILD progression group (P=0.003, P < 0.001, respectively). There were no significant differences in baseline respiratory symptoms, pulmonary function, or laboratory features. Multivariate analysis indicated that high DAS28-ESR, definite usual interstitial pneumonia pattern, fibrosis score, and less use of cyclophosphamide were independent risk factors for RA-ILD progression. Fifteen (7.46%) patients died during the follow up, and the most frequent cause of death was lung infection. Our results suggested that high disease activity, definite usual interstitial pneumonia pattern, fibrosis score, and less use of cyclophosphamide at the onset of ILD may indicate the progression of ILD in RA patients.

Circulating Dickkof-1 as a potential biomarker associated with the prognosis of patients with rheumatoid arthritis-associated interstitial lung disease.

Circulating Dickkof-1 as a potential biomarker associated with the prognosis of patients with rheumatoid arthritis-associated interstitial lung disease.

Increased interleukin-11 associated with disease activity and development of interstitial lung disease in patients with rheumatoid arthritis.

To investigate the association of serum interleukin-11 (IL-11) with disease activity and occurrence of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). One hundred and six RA patients were included, including 31 with ILD. All patients were divided into two groups according to the 28-joint Disease Activity Score (DAS28), active-disease group (DAS28>3.2) and target-achieved group (DAS28≤3.2). Serum IL-11 was detected by ELISA. Serum autoantibodies [anticitrullinated protein antibody (ACPA) and rheumatoid factor (RF)], inflammatory markers [C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)], and complete blood count were measured with routine methods. Serum IL-11 was upregulated in RA patients compared with healthy controls (HC), and increased more significantly in patients with ILD (RA-ILD) than patients without ILD (RA-nonILD). In both RA-ILD and RA-nonILD patients, serum level of IL-11 was higher in the active-disease group than that in the target-achieved group. Pearson correlation analysis confirmed that IL-11 was positively correlated with DAS28. No significant correlation was found between serum level of IL-11 and ACPA or RF. IL-11 was positively correlated with ESR and CRP levels and PLT count in RA patients. IL-11 was found to be involved in the development of arthritis and ILD in RA patients, and might constitute a potential target for the treatment of RA-ILD.

Endothelial Progenitor Cells as a Potential Biomarker in Interstitial Lung Disease Associated with Rheumatoid Arthritis.

Interstitial lung disease (ILD) increases morbidity and mortality in patients with rheumatoid arthritis (RA). Although the pathogenesis of ILD associated with RA (RA-ILD+) remains poorly defined, vascular tissue is crucial in lung physiology. In this context, endothelial progenitor cells (EPC) are involved in endothelial tissue repair. However, little is known about their implication in RA-ILD+. Accordingly, we aimed to investigate the potential role of EPC related to endothelial damage in RA-ILD+. EPC quantification in peripheral blood from 80 individuals (20 RA-ILD+ patients, 25 RA-ILD− patients, 21 idiopathic pulmonary fibrosis (IPF) patients, and 14 healthy controls) was performed by flow cytometry. EPC were considered as CD34+, CD45low, CD309+ and CD133+. A significant increase in EPC frequency in RA-ILD+ patients, as well as in RA-ILD− and IPF patients, was found when compared with controls (p < 0.001, p = 0.02 and p < 0.001, respectively). RA-ILD+ patients exhibited a higher EPC frequency than the RA-ILD− ones (p = 0.003), but lower than IPF patients (p < 0.001). Our results suggest that EPC increase may represent a reparative compensatory mechanism in patients with RA-ILD+. The degree of EPC frequency may help to identify the presence of ILD in RA patients and to discriminate RA-ILD+ from IPF.

Rheumatoid arthritis-associated interstitial lung disease: an overview of epidemiology, pathogenesis and management.

Interstitial lung disease (ILD) accounts for the major cause of morbidity and mortality in rheumatoid arthritis (RA). However, little is known of the pathogenesis, diagnosis and treatment of RA-associated ILD. In this review, we describe our present understanding and ongoing research in RA-ILD. Its aetiology does appear to associate with anti-cyclic citrullinated peptide antibodies, MUC5B mutation and smoking. Another focus of this article is on recent diagnostic methods in RA-ILD. Compared with other methods, high-resolution computed tomography (HRCT) imaging is a main method for the evaluation of ILD in RA patients. Pulmonary function is better suited for assessing progression. An important topic relates to therapeutic intervention. Disease-modifying anti-rheumatic drugs (DMARDs) in RA lack strong evidence in the onset or worsening of ILD. The available literature support that methotrexate, leflunomide, abatacept and rituximab play beneficial roles in the prevention and treatment of RA-ILD.

Increased serum soluble programmed death ligand 1(sPD-L1) is associated with the presence of interstitial lung disease in rheumatoid arthritis: A monocentric cross-sectional study.

This paper is to examine the relationship between serum soluble programmed death ligand 1(sPD-L1) levels and the development of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). Serum sPD-L1 were measured by enzyme-linked immunosorbent assay. sPD-L1 levels in RA with ILD, RA without ILD and healthy controls were compared. Associations between ILD and various markers including sPD-L1 and confounding factors were investigated by logistic regression analysis. Diagnostic values of sPD-L1 for the presence of ILD were investigated using receiver operating characteristics curve analysis. Serum sPD-L1 levels were higher in RA patients with ILD than RA patients without ILD and healthy controls (23.7±9.8 vs. 18.0±7.7pg/mL, P=0.01 and 23.7±9.8 vs. 2.9±1.5pg/mL, P<0.0001). sPD-L1 levels were positively correlated with RF titer (r=0.245, P=0.03), CRP (r=0.265,P=0.01), HRCT score (r=0.265, P=0.04) and Ferritin (r=0.442, P=0.01), but negatively associated with FVC% (r=-0.359, P=0.01) and DLCO% (r=-0.399, P=0.008). sPD-L1 and anti-CCP antibody status were independently associated with the presence of ILD during multivariate logistic regression analysis. Sensitivity and specificity of sPD-L1 levels for the detection of ILD in RA patients were 51.7% and 79.3%, respectively (area under the curve=0.661). Serum sPD-L1 levels were increased in RA patients with ILD. Increased sPD-L1 levels were associated with the presence of ILD.

Analysis of clinical–analytical characteristics in patients with rheumatoid arthritis and interstitial lung disease: Case–control study

ObjectivesTo study the differences between rheumatoid arthritis (RA)-interstitial lung disease (ILD) patients and RA patients without ILD in severity markers and disease activity and to identify factors associated with the presence of ILD in RA patients. Patients and methodsPatients: RA-ILD patients selected from a multicentre cohort in Andalusia, Spain. Controls: RA-patients without ILD paired by sex, age and disease duration. Protocol: RA patients are reviewed every 3–6 months in rheumatology consultation. All patients are reviewed according to a predetermined protocol with systematic data collection. Outcomes: description of ILD type, differences in severity markers and disease activity in both groups. Other variables: ILD type by imaging technique (HRCT): nonspecific interstitial pneumonia (NSIP)/usual interstitial pneumonia (UIP). Lung function by PTF. Activity and severity markers of arthritis by DAS28-ESR, HAQ, RF, ACPA and erosions. Treatment with DMARD. Statistical analysis: descriptive and paired T-test or Chi-square test followed by binary logistic regression (DV: ILD in patients with RA). ResultsEighty-two patients were included, 41 RA-ILD and 41 RA controls. RF and ACPA positivity, serositis and osteoporosis were more frequent in RA-ILD patients. No significant differences in DAS28 were observed (P=.145) between RA-ILD and RA control patients. RA-ILD patients presented worse HAQ scores (P=.006). All patients were treated with disease modifying antirheumatic drugs (DMARDs). The risk of developing ILD in RA patients is tripled by a history of smoking or the presence of erosive arthritis (R2=.36). ConclusionsThe results of our study support the higher frequency of UIP and NSIP in RA patients. DLCO is the most sensitive parameter to detect ILD in RA patients. Our study showed that ILD in RA patients was associated with RA severity (presence of erosions and ACPA) and with a history of smoking.

A retrospective study on the predictive implications of clinical characteristics and therapeutic management in patients with rheumatoid arthritis-associated interstitial lung disease.

Rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) is associated with significant morbidity and is a critical cause of mortality in patients with RA. Our aim was to evaluate predictive and prognostic factors for RA-ILD and to describe the therapeutic management of the condition from a large China cohort. This was a retrospective cohort study. We collected data of 1121 RA patients who underwent chest HRCT from 2008 to 2017. Patients without ILD at RA diagnosis were included in the analysis. The development and evolution of ILD in RA patients were followed up. Determinants of ILD development and progression were identified through multivariable logistic analysis. Cox hazards analysis was used to determine significant variables associated with survival. A total of 923 patients without ILD at RA diagnosis were identified and enrolled. Among them, 278 cases (30.12%) were diagnosed as ILD during follow-up. Logistic regression analysis showed that advanced age (> 60 years old) at RA onset (OR: 1.485), male (OR: 1.882), short duration of RA (0~5 years) (OR: 2.099), RF positive (OR: 1.728), elevated lactate dehydrogenase (LDH) (OR: 3.032), and no medication (OR: 1.833) were closely correlated to the development of RA-ILD. No correlation was found between ILD development and traditional DMARDs such as methotrexate and leflunomide. According to the follow-up data, 83 RA-ILD patients were identified as interstitial lung disease (ILD) progression, and 102 participants were stable. Logistic regression modeling demonstrated that DLCO% < 45% (OR: 3.025) and UIP possible pattern on HRCT (OR: 3.476) were independent risk factors for the ILD progression. No correlation was found between ILD progression and traditional DMARDs such as methotrexate and leflunomide. A total of 53 RA-ILD deaths occurred during follow-up. Cox hazards analysis revealed that advanced age (> 60 years old) at RA-ILD diagnosis (HR: 3.181) and extensive lung involvement on HRCT (HR: 2.401) were associated with worse survival. Treatment with cyclophosphamide (HR: 0.210) was associated with better survival. Advanced age, male, short duration of RA, RF positive, elevated LDH, and no medication are closely correlated with RA-ILD. No correlation was found between traditional DMARDs and ILD development. DLCO% < 45% and UIP possible pattern are predictive factors for ILD progression. No correlation was found between traditional DMARDs and ILD progression. Advanced age and extensive lung involvement on HRCT independently predict mortality; cyclophosphamide treatment helps to improve the prognosis of RA-ILD.Key Points• We designed this study to investigate the predictive and prognostic factors for RA-ILD and to explore the potential role of DMARDs in the evolution of RA-ILD from the development to progression and death.• Patients without ILD at RA diagnosis were enrolled and followed up retrospectively.• Our results showed that no correlation was found between traditional DMARDs and the development and progression of ILD, and regular treatment may improve the development of RA-ILD.• Our results revealed that clinical variables appeared predictive implications for the diagnosis of ILD and physiological and radiological variables appeared predictive implications for the prognosis of ILD, which can provide reference to rheumatologists and help to improve poor prognosis of RA-ILD.

Increased circulating Wnt5a protein in patients with rheumatoid arthritis-associated interstitial pneumonia (RA-ILD)

An early diagnosis of interstitial lung disease (ILD) is important for guiding treatments of rheumatoid arthritis (RA)-associated ILD (RA-ILD) in clinical settings. The non-canonical Wnt signaling representative ligand Wnt5a was recently found to involve in idiopathic pulmonary fibrosis (IPF) and pathogenesis of RA. The goal of this study was to examine the clinical relevance of Wnt5a in RA-ILD. In this report, the clinical relevance of plasma Wnt5a protein was evaluated in 40 RA-ILD patients and 41 non-ILD RA cohorts. The results showed an elevated Wnt5a protein in plasmas of RA-ILD patients compared with non-ILD RA patients (p < 0.01), which was positively correlated with the plasma level of rheumatoid factor (RF). Of note, more abundant Wnt5a was also found in patients with usual interstitial pneumonia (UIP) than those with nonspecific interstitial pneumonia (NSIP) and other ILD patterns. More importantly, the disease severity was correlated with the circulating Wnt5a as ascertained by high-resolution computed tomography (HRCT)-UIP scores. The multiple-factor non-conditional logistic regression analysis further revealed that the age, RA duration, smoking and plasma Wnt5a were risk factors with clinical significance for RA-ILD. Interestingly, more Wnt5a-positive patients were identified in RA-ILD smokers relative to RA-ILD never-smokers, and longer smoking duration was strongly correlated with Wnt5a in RA-ILD patients. In consistence, ROC curve also suggested that the Wnt5a was a potential candidate biomarker for identifying patients with RA-UIP. These results demonstrate that the circulating Wnt5a may be a risk factor and potential biomarker for identifying UIP and accessing the severity and progression of ILD in RA patients.