Pirfenidone was found to slow the rate of decline in lung function in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD), according to study findings published in Lancet Respiratory Medicine.

Often used in the treatment of idiopathic pulmonary fibrosis (IPF), pirfenidone has been shown to have anti-inflammatory and antifibrotic effects.

The objective of the current study was to determine the safety, tolerability, and efficacy of pirfenidone in the treatment of RA-ILD.


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Researchers conducted a multicenter, randomized, double-blind, placebo-controlled trial (TRAIL1; NCT02808871) between May 15, 2017 and March 31, 2020 at 34 academic centers in the United Kingdom, the United States of America, Canada, and Australia that specialized in ILD. The trial was halted earlier than anticipated due to the COVID-19 pandemic and slow enrollment.

The researchers randomly assigned patients aged between 18 and 85 years diagnosed with RA-ILD into the pirfenidone treatment group or the placebo group. The treatment group received 267 mg of oral pirfenidone thrice-daily for week 1, twice-daily for week 2, and thrice-daily from day 14 to week 52.

At baseline and weeks 13, 26, 39, and 52, patients underwent spirometry assessments to determine decline in forced vital capacity (FVC%). Patients also completed self-reported health-related questionnaires, including the Leicester Cough Questionnaire, the Patient Global Assessment, and the Health Assessment Questionnaire.

Researchers also examined changes in erythrocyte sedimentation rate, RA disease activity, biomarker levels, high-resolution computed tomography (HRCT) of the lungs, and Routine Assessment of Patient Index Data 3 score.

The primary endpoint of the study was the incidence in decline in FVC% of 10% or more or death.

A total of 123 patients with RA-ILD were included in the study; 63 were assigned to the treatment group and 60 to the placebo group.

Adverse events occurred among all the patients in the treatment group and 94% of patients in the placebo group. The most common adverse events in the pirfenidone group included nausea, fatigue, and diarrhea. Serious adverse events, including death, occurred at similar rates in both the treatment and placebo groups and were unrelated to pirfenidone use.

In the treatment group, 15 patients (24%) discontinued receiving pirfenidone and 6 patients (10%) discontinued receiving the placebo due to adverse events. Overall, patients tolerated pirfenidone well.

Decline of FVC by 10% or greater from baseline measurements and patient mortality due to RA-ILD complications did not differ significantly between the groups, occurring in 7 (11%) of 63 patients in the pirfenidone group compared with 9 (15%) of 60 patients in the placebo group (odds ratio [OR], 0.67; 95% CI, 0.22-2.03; P =.48).

Over a period of 52 weeks, the pirfenidone group demonstrated slower FVC decline compared with the placebo group, based on estimated annual change in FVC (P =.0082). None of the other outcomes differed significantly between the 2 groups.

Pirfenidone demonstrated an especially pronounced effect on FVC decline in patients with usual interstitial pneumonia patterns seen on HRCT vs patients with any ILD pattern on HRCT. A total of 34 patients (54%) with usual interstitial pneumonia patterns in the pirfenidone group showed a much smaller decline in annual FVC change compared with 47 patients (78%) with usual interstitial pneumonia patterns in the placebo group (-43 mL vs -169 mL; P =.0014).

Early termination due to the COVID-19 pandemic may have affected achievement of primary endpoint of the study and influenced safety and tolerability results due to decreased time on the medication. In addition, study limitations included selection bias, more people with usual interstitial pneumonia patterns being assigned to the placebo group, and rigorous physiologic FVC endpoints.

“The use of pirfenidone was associated with a clinically significant slower rate of FVC% decline in patients with RA-ILD compared with placebo… [suggesting] that pirfenidone is effective in the treatment of RA-ILD,” the study authors said. “Treatment was well tolerated, even in patients receiving background treatment for rheumatoid arthritis, and no new safety signals were identified,” they added.

Disclosures: This research was supported by Genentech. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Reference

Solomon JJ, Danoff SK, Woodhead FA, et al. Safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis-associated interstitial lung disease: a randomised, double-blind, placebo-controlled, phase 2 study. Lancet Respir Med. Published online September 2, 2022. doi:10.1016/S2213-2600(22)00260-0