In the longitudinal retrospective cohort study, we observed that 145 RA patients (12.0%) were diagnosed with RA-related lung diseases during a mean follow-up period of 3.5 years. We identified several potential risk indicators for RA-related lung diseases, including older age at RA onset, longer RA duration, higher RDCI scores, history of lung infections, and concomitant SLE. The recognition of these risk factors allows clinicians to prioritize their attention. Additionally, our data demonstrated a protective effect of MTX, tocilizumab and tsDMARDs against RA-related lung diseases.
Previous studies on overall RA-related lung diseases have been scarce [32–34]. These limited studies have reported an overall prevalence in RA patients ranged from 7.7–28.4%, which aligns with our findings (29.9% were combined with RA-related lung diseases, Supplementary Table S1). The majority of previous researches focused on ILD [10–16, 35], and have identified several risk factors for RA-ILD, including later onset RA, longer RA duration, which are also validated in this study. Previous studies have identified high levels of CRP as a potential risk factor for RA-ILD [11, 14]. Our analysis further complements their findings by identifying that CRP levels at multiple times the upper limit of normal (ULN) at baseline are predictive of RA-ILD. And high CRP levels are marginally significant in the context of RA-related lung diseases. Additionally, our study also highlighted RDCI, history of lung infections and concomitant SLE as potential risk factors. Existence of comorbid illnesses has been reported by a study conducted in Saudi Arabia as predictive of lung involvement in RA patients [33]. The RDCI is a tool used to quantify the total burden of comorbidity, which can reflect the functional status, health-related quality of life, and living burden. RDCI have also been validated as strong predictors of mortality in RA patients [31, 36]. Long-term use of steroids or other immunosuppressive drugs, often in conjunction with immune dysregulation, has been widely recognized as a predisposing factor for lung infections [37]. Lung infections can trigger diffuse alveolar damage. In patients with fibrotic lung diseases and acute respiratory decline, comprehensive diagnostic evaluations revealed a potential infectious cause in up to one-third of cases [38]. It is imperative to treat lung infections and traditional comorbidities as early as possible in RA patients, to reduce the occurrence of RA-related lung diseases.
In contrast to prior studies, our study intentionally included patients with overlap syndrome, to assess the impact of concomitant autoimmune diseases. Additionally, considering that these patients constitute approximately one-third (34.3%), it would be unreasonable to exclude them in real-world studies. Secondary SS is a frequently encountered extra-articular manifestation of RA. The available prevalence data regarding SS associated with RA are limited, with several studies reporting proportions ranging from 10–30% in RA patients [39–41]. Despite SLE accounted for only 4.6% of our patients, we found an association between concomitant SLE and RA-related lung diseases. Indeed, pulmonary involvement is more prevalent in SLE than RA patients and are seen in 50 to 70% of SLE patients, and may even be the initial symptoms in 4 to 5% of SLE patients [42].
Other reported potential risk factors include smoking status and autoantibodies level. Smoking can induce abnormal secretion of cytokines and enzymes in the lungs, leading to damage of airway epithelial and endothelial cells, promoting fibroblast proliferation, and reducing respiratory reserve capacity [13]. Unlike prior studies, despite observing a slightly higher proportion of smokers among patients developed RA-related lung diseases, we did not confirm the association. It is possible that we did not capture the real-time change of smoking habits after RA diagnosis and throughout the follow-up period, leading to a potential bias when only including baseline smoking status. Another plausible explanation was that smoking might demonstrate a threshold effect in its correlation with RA-ILD. Kronzer et al, [14] discovered that smoking with 30 pack-years or more was linked to a six-fold rise in the risk of RA-ILD, while smoking below this threshold did not exhibit an increased risk. For sero-positivity of RA autoantibodies, despite numerous studies demonstrating an association with elevated risk of ILD [10, 12, 13, 35], bronchiectasis [43], and overall RA-related lung diseases [33], our analysis did not confirm this. The observed discrepancy can be attributed to differences in study design. These findings have emerged from cross-sectional or case-control studies. When patients are combined with RA-related lung diseases, their autoantibodies levels are significantly influenced, whereas our study exclusively focused on patients without RA-related lung diseases at baseline and the autoantibody status were measured at that time. It’s worth noting that our cross-sectional analysis during baseline assessment found significant differences in autoantibody sero-positivity (Supplementary Table S1).
The relationship between conventional synthetic DMARDs and RA-related lung diseases continues to be a topic of controversy. Previous studies have observed a positive association between MTX and RA-ILD or potential pulmonary toxicity [17–19]. However, recent studies have increasingly provided evidence suggesting that MTX does not increase the risk of ILD development in RA and might even have beneficial effects on reducing this risk [22–25]. A longitudinal study using data retrieved from the Danish National Patient Register and the DANBIO register for rheumatic diseases showed that MTX treatment did not increase the risk of ILD and were protective for respiratory failure in RA patients [23]. Furthermore, a multicenter prospective early RA inception cohort study in the United Kingdom (UK) revealed an intriguing observation that MTX might delay the onset of ILD when compared to individuals who had never used MTX [24]. A multi-ethnic case-control study spanning five countries (Italy, UK, Mexico, Brazil, and the United States) [25] confirmed a significant delay of 3.6 years in the development of ILD among individuals with prior MTX use. Our analyses provide further evidence for Chinese patients, indicating a negative association between MTX and the development of RA-related lung diseases or ILD, and the protective effect were highlighted in those with higher inflammation status (sero-positivity, abnormal CRP, abnormal ESR, and high DAS28 disease activity). This may be due to the direct immune-suppressive effect of MTX on the lungs, or an indirect effect of MTX-driven reduction in RA-related systemic inflammation [25].
The impact of LEF remains inconclusive [20, 21, 26, 27]. Earlier on, in a cohort of 62,734 RA patients from a North American insurance claims database, an increased risk associated with LEF was found only among those with a previous history of ILD or prior MTX use [20]. A study from Japan also demonstrated that pre-existing ILD was the most important risk factor for LEF-induced ILD [21]. In a Korean RA-ILD cohort [44], LEF was found to increase the risk of ILD progression in patients with poor lung function, and this risk tended to be greater in patients using both MTX and LEF. These results seem revealing that preexisting ILD and MTX use is an important risk factor for LEF-induced or exacerbated ILD. Due to the exclusion of patients with prior lung involvement, we could not verify the effect of prior ILD. We found no association between LEF and incident ILD or RA-related lung diseases in patients treated with MTX (Supplementary Table S5). A recent finding indicates that LEF was related to a better prognosis in RA-ILD patients, but the researchers conservatively attribute part of this association to medication changes after baseline [27].
Besides, our study established a negative association between the utilization of b/tsDMARDs and the occurrence of RA-related lung diseases. This finding is consistent with several prior studies that reported a safety profile of b/tsDMARDs in patients with RA-ILD, suggesting a potential stabilizing effect on lung involvement [32, 45–47]. In general, additional research is still required to fully elucidate the mechanisms involved and to establish more definitive conclusions in this complex and evolving field.
To the best of our knowledge, there was a limited number of longitudinal studies to identify risk factors for RA-related lung diseases, including ILD. By utilizing a longitudinal study design in a large population, we were able to capture the development of RA-related lung diseases alongside RA progression, while also identifying long-term predictors. Importantly, our study specifically included patients without pre-existing RA-related lung diseases, allowing us to establish causal relationships between RA and the development of RA-related lung diseases. Nested case control design also guaranteed the temporal causality between drug use and RA-related lung diseases. Routine lung screenings for hospitalized patients in our hospital, irrespective of pulmonary symptoms, have facilitated accurate ascertainment of RA-related lung diseases at baseline and during the follow-up period. Moreover, we were able to describe a cumulative occurrence curve, which visually demonstrated the incidence trend of RA-related lung diseases since RA onset or along with age.
Our study also has some limitations. First, as it was a retrospective analysis, we encountered challenges in accurately phenotyping subtypes of ILD, since this information was rarely mentioned in the clinical radiologic reports. Although most patients with RA-related lung diseases undergo pulmonary function testing (PFT), only a small proportion of patients have specific PFT data available, which limited further detailed analysis. Second, given the retrospective design and many patients had disease courses exceeding 20 years, assessing the cumulative dose of drugs became less reliable. Thus, it’s difficult to further verify their effect on RA-related lung diseases. Another limitation of our study is the relatively short follow-up period. The shorter duration of follow-up might not fully capture the long-term development and progression of RA-related lung diseases, potentially leading to an incomplete understanding of the true risk factors and their impact over time. Fourth, this study was only derived from a single-center rheumatology and immunology department, and our patient population primarily consisted of hospitalized patients, who may exhibit more severe inflammatory states. As a result, there is a possibility that some milder cases might be underrepresented in our study population. In the future, well-designed prospective studies based on multiple centers and more representative populations are needed to validate our findings and functional studies are also warranted to explore the underlying mechanisms of protective effects from MTX and b/tsDMARDs.