Effective Treatments for Rheumatoid Arthritis ILD Save

The American College of Rheumatology (ACR) guidelines for the diagnosis and management of interstitial lung disease, which includes rheumatoid arthritis interstitial lung disease (RA-ILD), has been one of the most controversial topics in the runup to ACR Convergence. The guidelines expanded screening recommendations, which will likely result in overdiagnosis and overtreatment. They also recommended therapies with marginal benefits for rheumatoid arthritis (azathioprine and mycophenolate mofetil) and  inexplicably exclude options that have evidence in both RA and RA-ILD (abatacept). I find this latter point particularly vexing. Absent new data, it seems prudent to favor therapies for RA-ILD that have strong biological activity against RA, 

First and foremost, I would like to highlight a multicenter study in Spain, which included 509 patients with RA-ILD. Their study observed encouraging stabilization of disease over the first 24 months with abatacept (Abstr 2172), which appeared more pronounced among patients who initiated abatacept early (76% stabilized disease as compared to 54% among those who started late) (Abstr 2173).  Even among patients with a usual interstitial pneumonia (UIP) pattern, patients who received abatacept fared well, with 3 in 4 improving or stabilizing FVC and DLCO, respectively, and 4 in 5 stabilizing or improving symptomatically (Abstr 2165). These data lacked a comparator group, but overall supported abatacept as a reasonable agent for RA-ILD.

One of my favorite abstracts of the meeting (Abstract 1582) used a “target trial” approach to debunk concerns that TNF inhibitors cause higher mortality in RA-ILD. This has always seemed spurious to me. Why would a highly effective drug in RA with no known pulmonary toxicity suddenly result in elevated mortality when applied to RA-ILD? Their study identified over 1,000 patients with RA-ILD in the VA database and used propensity score matching to compare those who received TNFs or non-TNFs/JAKs. Ultimately there was no association between receiving a TNF inhibitor and subsequent mortality or respiratory hospitalization, among other outcomes. I found this encouraging and do not believe prior studies that suggested this association. 

Finally, multiple abstracts described the efficacy of antifibrotics, which have no known benefit to joints or other systemic manifestations of RA. The antifibrotic nintedanib does have randomized trial level data from the basket study INBUILD, which randomized patients with progressive fibrosing ILD (89 had RA-ILD) to receive nintedanib or placebo. The results of INBUILD were encouraging but underwhelming; the subset of 89 patients with RA-ILD who received nintedanib had high rates of adverse events experienced progressive disease, but they progressed significantly slower than the placebo group. The open label extension of INBUILD (INBUILD-ON, Abstr 0140) reported 96 week data, which again demonstrated poor tolerability and a steady loss of FVC. A “real world” observational study of 74 patients with RA-ILD who received nintedanib or pirfenidone (Abstr 2479) observed improved FVC trajectories in the year after fibrotics were started, but patients also had high rates (46%) of discontinuation from adverse events. Finally, the aforementioned multicenter Spanish study also presented data on nintedanib as a combination therapy with other immunosuppressive agents, observing an encouraging stabilization or improvement of dyspnea in 86% of patients (Abstr 1319). 

The ideal approach to treatment of RA-ILD remains unknown. Information at ACR Convergence suggests an important role for abatacept and - in my opinion - exonerates TNF inhibitors. Antifibrotic agents certainly have a role in patients who have progressed despite adequate control of RA with efficacious immunosuppressive agents. In my opinion, neither antifibrotics nor agents with marginal efficacy in RA, such as azathioprine, should be used as first line agents for RA-ILD. I am hoping the publication of the rather peculiar ILD guidelines by the ACR will encourage more research in this area.