Methotrexate on par with prednisone as first-line treatment for pulmonary sarcoidosis

The use of methotrexate as a first line of treatment for patients with pulmonary sarcoidosis delivers similar efficacy to prednisone as measured by forced vital capacity after 24 weeks, results of the PREDMETH trial have shown.

“Methotrexate was noninferior to prednisone as assessed with the change in FVC at 24 weeks,” said lead author Dr Vivienne Kahlmann, Respiratory Medicine, Erasmus Medical Center, Rotterdam, Netherlands, at ATS 2025. “The number of adverse events was similar, but side effect profiles were clearly different.”

A total of 138 treatment-naïve patients with pulmonary sarcoidosis (mean age 46.6 years, 73.7 percent male) were randomly allocated to receive either prednisone (n=70) or methotrexate (n=68). [Am J Respir Crit Care Med 2025;211:A1007]

In the prednisone group, one patient was excluded due to an alternative diagnosis (silicosis), and another withdrew consent due to adverse events (AEs). In the methotrexate group, one patient also withdrew consent because of AEs.

The baseline FVC% predicted was 79.8 percent and 74.8 percent for the prednisone and methotrexate arms, respectively. In intention-to-treat analysis, the primary endpoint of change in %FVC was 6.7 percent (95 percent confidence interval [CI], 4.50‒8.99) with prednisone and 6.1 percent (95 percent CI, 3.72‒8.50) with methotrexate.

Notably, at 24 weeks, no significant difference was observed in the change in %predicted FVC between the two groups (estimated mean difference, ‒1.17 percent, 95 percent CI, ‒4.27 to 1.93). This indicated the noninferiority of methotrexate to the standard first-line treatment.

Safety profile

In terms of safety, the number of AEs did not significantly differ between groups (308 with prednisone vs 283 with methotrexate). At 24 weeks, fewer AEs persisted in the methotrexate group relative to the prednisone group (104 vs 171).

Three serious AEs (ie, diabetes mellitus, pulmonary embolism, and ureteral stent insertion) were documented in the prednisone group (4 percent of patients) and seven (ie, COVID-19, respiratory tract infection, gastroenteritis, arrhythmia supraventricular, dyspnea, fractures, and afferent loop syndrome) in the methotrexate group.

For patients treated with prednisone, the most common AEs were increased weight and insomnia, followed by increased appetite, mood swings, nervousness, and reflux. For those who received methotrexate, the most frequently reported AE was nausea, followed by fatigue, abnormal liver function test, abdominal pain, respiratory tract infection, and malaise.

“We believe that for the first time this trial shows that methotrexate may be an alternative treatment to prednisone, and this trial provides evidence for shared decision-making between patients and doctors for choosing the optimal treatment,” Kahlmann said.

The randomized, noninferiority PREDMETH trial was designed by clinicians, researchers, and patients and conducted at 17 hospitals across the Netherlands. Eligible participants received prednisone or methotrexate according to a predefined schedule. Kahlmann and her team performed safety assessment using all physician-reported AEs.

“Sarcoidosis is an inflammatory disease with an unpredictable disease course,” Kahlmann said. “If treatment is indicated, prednisone is recommended as the first-line treatment, but it may also cause many side effects.”

“Methotrexate is currently used as a second-line treatment and appears to have fewer side effects but has not been studied as a first-line treatment,” she noted.