We prospectively evaluated lung and joint function in 70 patients with RA-ILD receiving treatment with various DMARDs. We observed worsening of lung disease in a minority of patients after 24 months of follow-up, although arthritis continued to be well-controlled. Mean PFT values fell gradually during follow-up; however, most decreases were detected in 30% of patients.
In our study, csDMARDs were not generally associated with more marked worsening of lung disease after 24 months of follow-up, although individually, more patients presented worsening of lung involvement when receiving leflunomide, MMF, and corticosteroids, probably because patients with poorer lung outcomes were more likely to require corticosteroids and MMF (both are frequently used for treatment of ILD) (9). The same bias arises with leflunomide, especially in patients with more poorly controlled arthritis, since a systematic review and meta-analysis covering 4579 patients suggested a lower risk of noninfectious respiratory adverse events (RR, 0.64) with leflunomide than with methotrexate or placebo (17).
bDMARDs have also been reported to be possible triggers of ILD. They can worsen pre-existing ILD or increase susceptibility to infection (28). Similar to findings reported by other authors at 12 months (18), we found that lung disease had not worsened at 24 months in patients who took anti-TNF agents. However, other studies (19) reported more marked worsening of RA-ILD in patients treated with anti-TNF agents (24.1%) than in those treated with other biologics, thus suggesting that non–anti-TNF inhibitors are a good therapeutic option in this population. Our multivariate analysis revealed that non–anti-TNF biologics reduce the risk of worsening of lung disease at 24 months by 90%, with more importance given to abatacept, followed by rituximab and tocilizumab. We do not know whether these biologic agents have an intrinsic effect on RA-ILD, although in recent years, abatacept has been associated with improvement and stabilization of lung function in patients with RA-ILD in small case series (29–31). More recently, Fernández-Díaz et al. (20) reported the results of a multicenter prospective study of 63 patients with RA treated with abatacept, in which pulmonary function was stable after 12 months of treatment. In our study, 8 patients were receiving abatacept at 24 months, and none presented worsening of lung involvement. In experimental studies, cytotoxic T-lymphocyte antigen 4 has been tested as a major target in lung inflammation in other lung diseases such as hypersensitivity pneumonitis. In this context, abatacept may be a potential therapy for RA-ILD (20, 32).
In our study, 10 patients were taking rituximab, and in most (9/10), their condition improved or stabilized, although 1 patient died owing to worsening of lung disease. In the study of Yusof et al. (33), the authors observed that in most patients with RA-ILD treated with rituximab, their condition stabilized (23/44; 52%) or improved (7/44; 16%), although it worsened in 14 patients (32%). Of these, 9 died from worsening of lung involvement. As these patients had more severe RA-ILD before treatment, the results may have been subject to an indication bias.
The number of patients treated with tocilizumab in our study was too low to draw conclusions, although pulmonary function improved/stabilized in 3 of 4 patients treated with this agent. Some authors have reported isolated cases of worsening of RA-ILD after 24 months of follow-up (34, 35), whereas others (22) reported stabilization of lung disease after 30 months of follow-up.
It is noteworthy that the percentage of patients whose condition stabilized, improved, and worsened (57%, 12%, and 31%) in our study is similar to those reported in other prospective studies (18, 20, 33) and retrospective studies (22) with bDMARDs. Therefore, these findings can only be explained by the natural history of RA-ILD. In fact, during the prospective follow-up of the study patients, we observed no significant impairment in lung function at 12 months of follow-up, although we did record significant worsening at 24 months. Several authors have reported DLCO to be the earliest indicator of worsening of lung function in these patients (6, 36).
Our results also show that smoking and inflammatory activity in joints act independently in the worsening of lung disease. On the one hand, smoking and other stimuli could contribute to citrullination of proteins (37) and to other respiratory conditions, such as emphysema, which further impair lung function (38). On the other, systemic inflammation associated with poor disease control could be associated with worsening of lung involvement in RA-ILD (39) and control of arthritis with stabilization of lung involvement (20). We made a similar observation in our study.
Our study is subject to a series of limitations. First, the fact that this was a multicenter study could lead to differences in the evaluation of lung function. In order to mitigate this risk, HRCT was centralized by taking advantage of the fact that the radiological findings could be reported online. In addition, the prospective follow-up meant that no data were missing. Second, patients had already been treated at the start of the follow-up period. Third, we had no control group. This makes it difficult to interpret the effect of each of the drugs on the natural course of ILD. Nevertheless, our objective was to evaluate the clinical course of patients with RA-ILD treated under conditions of daily clinical practice. This did not prevent us from comparing different treatment groups. In fact, one of the strengths of the study was the prospective evaluation of different treatment groups in patients with RA-ILD in both joint and lung assessments.