In this single-centre prospective cohort study, we identified the differing characteristics between RA-ILD and RA-nonILD patients. Deaths occurred only in the RA-ILD group over 2.6 years of observation, whereas none occurred in the RA-nonILD group over the 4.2-year observation period. The most common cause of death was infection, and the risk factors for mortality among RA-ILD patients were high RA activity, baseline DLCO < 60% of the predicted value, and the UIP pattern on chest CT scan.
The characteristics of patients with RA-ILD were markedly different from those of patients with RA without ILD. The proportion of male patients was higher in the RA-ILD group than in the RA-nonILD group. Patients with RA-ILD also had more comorbidities; however, a history of pulmonary tuberculosis was more common in the RA-nonILD group. In our study, the proportion of patients with a history of pulmonary tuberculosis was high. According to a previous study on the comorbidities in Korean patients with RA, 8.6% of patients with RA had pulmonary tuberculosis [22]. In addition, our previous study revealed that the latent tuberculosis infection positivity rate was 26.5% in patients with RA initiating targeted therapy at a tertiary referral hospital in Korea [23]. The information about the history of pulmonary tuberculosis was obtained by interviewing patients in addition to reviewing medical records; therefore, the prevalence of pulmonary tuberculosis could be overestimated. Nevertheless, none of the patients had active pulmonary tuberculosis at enrolment.
One intriguing finding of this study was that deaths occurred exclusively in the RA-ILD group, which made a direct comparison of the mortality rates between the two groups not possible. However, this observation suggests a potential association between ILD and an increased risk of mortality in patients with RA. It is important to acknowledge the differences in the baseline characteristics between the two groups, such as age, smoking status, comorbidities, and RA activity, as these factors may have influenced the outcomes. Although a comprehensive analysis adjusting for these variables would provide a more accurate understanding of the impact of ILD on mortality, we were unable to conduct further analysis due to the absence of deaths in the RA-nonILD group.
The primary cause of death in this study was infection, with pneumonia being the most prevalent cases of urosepsis and biliary sepsis. Patients with RA have an increased susceptibility to infections compared to the general population. This susceptibility can be attributed to immunological dysfunction, comorbidities, and the use of immunomodulatory drugs [24]. Considering that no deaths occurred in the RA-nonILD group, RA-ILD may be a potential risk factor for developing fatal pneumonia. It is worth noting that, of the 15 deceased patients, six had received targeted therapy, and five of them had their deaths attributed to infection. This observation raises the possibility of an increased risk of infection associated with the targeted therapy. However, it is important to note the high RA disease activity levels that necessitated the use of targeted therapy in these patients.
The second most common cause of death in patients with RA-ILD was cancer, with all five cases being lung cancer. Patients with RA have an approximately 1.5-fold higher risk of developing lung cancer than the general population [25, 26]. The hypothesis is that lung cancer and RA share a common risk factor: smoking [27]. In addition, ILD is considered as a possible risk factor for lung cancer, with a recent retrospective cohort study conducted in China reporting that approximately 3% of patients with ILD were diagnosed with lung cancer [27, 28]. In our study, all five patients who died of lung cancer were smokers.
Higher RA activity and the UIP pattern were significant risk factors for mortality in patients with RA-ILD. The UIP pattern has been recognised as a poor prognostic factor compared with other patterns, such as the NSIP pattern [11, 12, 15], and our study showed similar trends. However, it is important to investigate whether the UIP pattern association with poor outcomes is truly due to an ILD flare-up or other factors, such as infection or malignancy. Further detailed analyses are required to confirm this hypothesis.
One of the risk factors for mortality in the RA-ILD group was a baseline DLCO < 60% of the predicted value. The importance of pulmonary physiology in the prognosis of patients with RA-ILD has been previously reported. According to previous studies, low baseline DLCO was related to the risk of ILD progression and mortality [12, 13, 29]. Low baseline FVC is also known to be a risk factor for mortality in patients with RA-ILD [11, 12, 15, 29]; however, this was not true in our study. PFT results correlate more significantly with the extent of lung involvement than with the ILD pattern [30]. This indicates that the importance of PFT results and CT findings may differ when evaluating the prognosis of patients with RA-ILD as individuals or in a group.
Considerations when prescribing DMARDs for patients with RA-ILD are more complex compared to those without ILD. Methotrexate is the first-line treatment recommended for patients with RA; however, its effects on ILD remain controversial [31, 32]. An inception cohort study of patients with early RA showed that methotrexate treatment reduced the risk and delayed the incidence of ILD [33]. In contrast, leflunomide is not recommended for patients with RA-ILD because of its association with an increased risk of the development and/or exacerbation of ILD [34]. However, a meta-analysis of RCTs found no evidence of increased respiratory adverse events in RA patients [35]. In our study, the proportion of patients with RA-ILD treated with methotrexate or leflunomide was significantly lower than that of RA-nonILD patients. Regarding targeted therapy, abatacept was most frequently used in the RA-ILD group and was associated with a slower deterioration of ILD and a lower risk of infection than TNF inhibitors [36, 37].
The 2023 ACR guidelines for the treatment of ILD in individuals with systemic autoimmune rheumatic disease were recently announced, and a summary was posted [38]. Mycophenolate, azathioprine, and rituximab are recommended as first-line therapies for patients with RA-ILD according to the guidelines. However, mycophenolate mofetil is not approved for patients with RA in Korea. In addition, the prescription rates for azathioprine and rituximab were low in our study. In Korea, rituximab is approved only for patients who have an inadequate response to other targeted therapies (TNF inhibitors, non-TNF inhibitors, or Janus kinase inhibitors). Our results are expected to serve as important evidence demonstrating the discrepancies between the new ACR guidelines and medication use in Korean patients with RA-ILD.
This study had several strengths. First, we used data from a well-established multidisciplinary prospective cohort. In particular, we improved the reliability of CT readings by reaching a consensus through discussions between rheumatologists and radiologists. Second, we identified the risk factors for mortality in patients with RA-ILD, which still have an unmet need for clinical studies in Korea.
This study had several limitations. First, this was a single-centre study, which could be questioned for generalisability. However, our hospital contains the largest rheumatology centre in the nation, drawing patients from across the country. In addition, more detailed information could be collected by interviewing patients directly or through medical records because the study was performed at a single institution. Second, all patients in the RA-nonILD group survived the observation period; therefore, it was not possible to compare the mortality risk between the two groups. Further studies with longer observation periods are necessary. Third, some ILD patients and the majority of nonILD patients did not undergo PFTs; therefore, we could not compare the PFT results between the two groups. However, there were only 12 patients without PFTs in the ILD group, and the number of RA-ILD patients with PFTs was considered sufficient for multivariable analysis.
In conclusion, patients with RA-ILD had an increased risk of mortality compared to RA-nonILD patients. The main causes of death were infections, especially pneumonia, and lung cancer. Risk factors for mortality in patients with RA-ILD are high RA disease activity, low baseline DLCO, and the UIP pattern. Further studies with longer observation periods are needed to clarify the increased incidence of mortality in RA-ILD patients compared to that in RA-nonILD patients.
Add Comment