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BARCELONA -- Rheumatoid arthritis patients with existing interstitial lung disease (ILD) had less decline in lung function when receiving the antifibrotic agent pirfenidone (Esbriet) relative to placebo in a randomized trial, researchers reported here and in a simultaneous journal publication.

After a year of treatment, patients assigned to pirfenidone lost an average 66 mL of forced vital capacity (FVC) compared with a mean 146-mL decline in the placebo group, according to Ivan Rosas, MD, of Baylor College of Medicine in Houston, speaking at the European Respiratory Society (ERS) annual meeting. Results were also in Lancet Respiratory Medicine.

But change in FVC was not the trial's primary endpoint; instead, it was a composite of death or a 10% decline from baseline in FVC. This was met by 11% assigned to pirfenidone versus 15% with placebo (OR 0.67, 95% CI 0.22-2.03) -- i.e., no significant difference.

The investigators attributed the missed primary endpoint to having to shut down enrollment prematurely in March 2020, mainly because of the COVID-19 pandemic (although it had already been slow). The planned enrollment was 270, but ultimately only 123 were randomized.

Nevertheless, pirfenidone's clearly beneficial effect on FVC decline -- and its documented efficacy in idiopathic pulmonary fibrosis, for which the -- mean "the totality of the evidence suggests that pirfenidone is effective" for ILD in rheumatoid arthritis patients.

ILD is among the more severe complications of rheumatoid arthritis; along with increased risk of cardiovascular disease, it is a primary contributor to early mortality in rheumatoid arthritis patients seen in natural history studies. Yet until the current trial, a , there had been no randomized trial to examine use of antifibrotic agents specifically in this patient population.

At the ERS meeting, the session's discussant, Katerina Antoniou, MD, PhD, of the University of Crete in Rethymno, Greece, said the prevalence of ILD in rheumatoid arthritis patients appears to be increasing and has reached something like 10%. She also agreed with the investigators that the overall results were favorable, calling TRAIL1 a "very positive study, even if it was underpowered to evaluate the primary endpoint."

Study Details

Mean patient age was 68 (slightly older in the placebo group), and just over 60% were men. Some 90% were white. FVC at baseline averaged 70% of predicted, at 2.6 L.

Absolute FVC decline was the only outcome for which a statistically significant difference emerged with treatment. Trends, however, pointed toward a potential benefit for others. For example, 8% of the pirfenidone group had FVC declines of 10% or more, compared with 12% in the placebo group. Similarly, 25% treated with pirfenidone showed progression by criteria, versus 32% receiving placebo.

Safety findings were similar to those seen in other pirfenidone trials, the researchers said.

High-resolution CT lung scans were performed on all patients at enrollment, which showed that the specific types of ILD varied considerably. In the pirfenidone group, 54% had usual interstitial pneumonia (IP), 14% had non-specific IP, none had lymphocytic IP, and results were indeterminate for 32%. In the placebo group, however, IP was usual in fully 78%, non-specific in 7%, and lymphocytic in 5%; only 10% had indeterminate results.

Subgroup analysis suggested that these CT-defined subgroups responded differently to treatment, such that pirfenidone seemed most effective in those with usual IP (estimated mean decline from baseline 0.05 L vs 0.09 L for patients with non-usual IP). And the fact that the placebo group had a higher proportion of usual IP patients may have biased the results.

An focused on that point. "[T]he study might have enrolled patients with poorly progressive lung disease, and ... patients with more severe and probably more progressive disease might have been randomly assigned to the placebo group in greater numbers," wrote Marco Sebastiani, MD, and Andreina Manfredi, MD, PhD, both of the University of Modena and Reggio Emilia in Modena, Italy.

To inform clinical strategies going forward, these results "confirm the importance of a careful selection of patients to treat," the pair added. "[A]lthough a wait and see approach could be used for patients with fibrosing non-progressive lung disease, the TRAIL1 study suggests that patients with usual interstitial pneumonia should always be treated."

For their part, Rosas and colleagues argued that future trials should also consider the ILD phenotype as determined through imaging, stratifying participants according to high-resolution CT patterns.