Rheumatoid arthritis (RA) is a systemic autoimmune disease that affects approximately 0.5 to 1.0% of the general population. The exact pathogenesis of RA is not fully understood, but it is believed to involve autoimmune and inflammatory responses, as well as environmental factors that contribute to the prevalence and progression of the disease (1). The initial manifestation of RA is typically characterized by symmetric polyarticular pain and swelling. Additionally, patients often experience nonspecific systemic symptoms such as fatigue, low-grade fever, muscle aches and pains, or weight loss (2). However, RA is not limited to joint involvement alone; it is a systemic inflammatory disease that can affect various organs, including the heart, lungs, skin, and eyes. The presence of extra-articular involvement in approximately 17.8–40.9% of RA patients can significantly impact their prognosis (2, 3).

Rheumatoid arthritis has the potential to substantially impact the lung parenchyma, presenting as interstitial lung disease (ILD), as an extra-articular manifestation that exhibits a heterogeneous condition characterized by diverse pathological manifestations and ultimately culminating in irreversible fibrosis; this association is linked to notable morbidity and mortality (4, 5). The reported prevalence of RA-ILD varies widely, ranging from 1.0 to 58.0%, reflecting differences in study designs and inclusion criteria (6). Advanced age, male gender, tobacco exposure, and the presence of positive rheumatoid factors (RF) or anti-cyclic citrullinated peptide (CCP) antibodies have been identified as risk factors for the development of RA-ILD (7). Respiratory symptoms commonly observed in RA-ILD resemble those seen in idiopathic interstitial pneumonia (IIP) and include dyspnea, cough, chest tightness, shortness of breath, and velcro crackles at the base of both lungs (8). In advanced stages, pleural friction sounds and pulmonary hypertension may also be present (8). Although overall mortality rates in RA have decreased, ILD has emerged as a leading cause of death in RA patients, second only to cardiovascular complications (9).

Preclinical ILD (pILD) refers to the incidental discovery of interstitial lung abnormalities on chest high-resolution computed tomography (HRCT) scans in individuals without a prior diagnosis of ILD (10). pILD exhibits resemblances to ILD, potentially signifying its early stages, such as sharing radiological findings characteristic of early ILDs (11–13). Patients with interstitial lung abnormalities can be divided into two categories: incidental interstitial lung abnormalities (ILA), which are detected during chest HRCT scans conducted for purposes such as cancer screening or general health examinations, and pILD, which is identified during screening for ILD in high-risk groups (such as those with connective tissue diseases or familial ILD) (14). Based on distinct imaging features and distributions, pILD can be classified into three patterns: non-subpleural non-fibrotic, subpleural non-fibrotic, and subpleural fibrotic, with an increasing risk of progression and mortality in that order (15). Fibrosis is characterized by lung distortion with traction bronchiectasis and/or honeycombing, consistent with the fibrosis criteria outlined in the latest guidelines for idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) in 2022 (16).

However, the characteristics and clinical outcomes of RA-ILD, including pILD and ILD, remain poorly understood. The objective of this study was to investigate the prevalence, clinical features, prognosis, and risk factors associated with the imaging progression of RA-ILD, encompassing both pILD and ILD.

This study provides a retrospective cohort analysis of patients with RA. The prevalence of ILD in RA patients varies widely, ranging from 1.0 to 58.0% in RA-ILD and 19.0 to 57.0% in RA-pILD patients (6). Previous studies reported abnormal chest HRCT findings in 15.0% of RA patients in the United States and interstitial lung changes in 22.0% of RA patients in Brazil (10, 20). In this cohort, 32.3% of RA patients had ILD (including pILD and ILD), with 19.7% classified as pILD and 12.7% as ILD. The difference in prevalence may be attributable to factors such as inpatient selection, older age, or different classification criteria for imaging description. Older male RA-ILD patients (>60.0 years) were more prevalent, consistent with previous findings (21, 22). While some patients had ILD prior to the RA diagnosis, many developed ILD as a secondary manifestation of RA. Nearly half of the RA-ILD patients, including pILD and ILD, did not exhibit respiratory symptoms or signs, with RA-pILD accounting for 83.3% of these patients. Therefore, it is recommended to perform routine chest HRCT scans in high-risk individuals (with connective tissue disease or familial ILD) to assess the presence or absence of ILD, irrespective of respiratory symptoms. Multidisciplinary discussions involving pulmonologists, rheumatologists, radiologists, and pathologists should be conducted if necessary for a comprehensive assessment (14).

The most common imaging pattern observed in RA-ILD patients was UIP, followed by nonspecific interstitial pneumonia (NSIP) (23, 24). However, the classification methods for pILD and ILD varied among studies, making it difficult to determine the exact proportion of each imaging pattern. HRCT currently remains the primary tool for identifying ILD in the absence of alternative biomarkers.

In this cohort, 51.0% of RA-ILD patients (including pILD and ILD) showed disease progression during a median follow-up period of 23.0 months. Among the RA-pILD patients, 23.0% were subsequently diagnosed with ILD, suggesting the importance of screening individuals with RA-pILD for RA-ILD in the future. Notably, RA-pILD patients who exhibited imaging regression (7 patients) showed improvement, with some transitioning to RA alone. Presence of DM, DAS28-ESR > 5.1, and baseline HRCT scores>5.0 were associated with imaging progression in RA-related pILD and ILD. Previous studies have also indicated that male gender, higher DAS28-ESR levels, HRCT-documented UIP-like fibrotic patterns, and higher baseline HRCT scores were risk factors for poor prognosis in RA-ILD (25, 26). Disease activity, as measured by DAS28-ESR, was strongly correlated with prognosis, with higher levels associated with increased risk of death (27). Identifying risk factors for imaging progression in RA related pILD and ILD could help identify patients with poor prognosis.

RA-ILD patients, including pILD and ILD, exhibited lower FVC% predicted and DLCO% predicted values compared to RA patients without ILD (26, 28–30). These findings suggest the presence of restrictive ventilatory dysfunction and decreased gas exchange capacity. Decline in FVC% predicted and DLCO% predicted values at baseline were independent predictors of worse survival in RA-ILD patients (30). Lower DLCO% predicted was particularly associated with increased risk of death (30). In this study, RA-ILD patients with progressive fibrotic CT scans showed lower FVC% predicted and DLCO% predicted values during follow-up.

The role of methotrexate in RA-ILD patients remains controversial. Some studies have shown that methotrexate is protective against the development of RA-ILD and delays its onset, while others have suggested that it increases the risk of ILD prevalence and progression (31, 32). Glucocorticoids are the mainstay treatment for RA-ILD, usually initiated with oral prednisone and tapered based on clinical response (6). However, glucocorticoids have been associated with increased risk of ILD prevalence and progression in RA patients (7). The choice of therapeutic drugs in this study was determined independently by the treating physicians based on the patients’ conditions.

This study provides valuable insights into the prevalence and clinical characteristics of pILD and ILD in patients with RA. It sheds light on the changes observed in RA related pILD and ILD patients and identifies potential risk factors for fibrosis progression in RA-ILD. However, it is important for readers to be mindful of the study’s limitations. Being a single-center study, there is a possibility of selection bias as only hospitalized individuals were included, which could have led to an overestimate of the prevalence of RA-ILD. Additionally, the retrospective design introduced some missing data and limited follow-up for certain patients, potentially introducing selection bias. The median follow-up duration of 19.1 months was relatively short for comprehensive evaluation of survival rates, overall mortality, ILD related mortality, and associated risk factors in RA-ILD patients. To obtain more precise and reliable results, prospective registration studies with larger sample sizes are necessary.

In summary, this study provides valuable insights into a hospital population-based cohort of RA patients, highlighting a significant prevalence of 32.3% for RA-ILD, encompassing both pILD and ILD. The presence and progression of ILD in RA patients are closely associated with a higher proportion of respiratory symptoms and signs, as well as impaired pulmonary function. Notably, almost half of the RA-ILD patients demonstrated imaging progression during the follow-up period. Risk factors for fibrosis progression in RA-ILD include DM, elevated DAS28-ESR levels, and advanced HRCT scores. Further investigations are warranted to better elucidate the roles of methotrexate and glucocorticoids in the management of RA-ILD.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Ethics Committee of Beijing Chao-Yang Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

DC: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing – original draft. DS: Data curation, Formal analysis, Methodology, Writing – review & editing. YW: Data curation, Writing – review & editing. YS: Data curation, Writing – review & editing. NW: Writing – review & editing. QY: Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – review & editing.