Methotrexate slower, but effective in treating pulmonary sarcoidosis
Study: Treatment takes longer to start acting than prednisone, but works
Methotrexate appears to take longer to start acting, but is no less effective than the corticosteroid prednisone as a first-line treatment for pulmonary sarcoidosis, according to the early findings of an ongoing Phase 4 clinical trial.
The researchers noted that, while methotrexate treatment is associated with a similar number of adverse events among patients, fewer persisted after nearly six months relative to prednisone — the currently recommended first-line treatment for pulmonary sarcoidosis.
These findings come from PREDMETH (NCT04314193), a Phase 4 trial testing whether methotrexate is or is not inferior to prednisone for treating the rare inflammatory disease when it occurs in the lungs. The trial has enrolled nearly 140 patients across 17 hospitals in the Netherlands.
“The results of this trial show that methotrexate can be offered as an alternative for prednisone for patients with pulmonary sarcoidosis,” Vivienne Kahlmann, MD, the study’s first author and a pulmonologist in training at Erasmus Medical Center in Rotterdam, said in an ATS press release.
These results were simultaneously presented at this year’s American Thoracic Society (ATS) international conference, held May 16-21 in San Francisco, and published in the New England Journal of Medicine under the title “First-Line Treatment of Pulmonary Sarcoidosis with Prednisone or Methotrexate.”
“Some patients prioritize fast improvement of symptoms and are less afraid of side effects, while other patients may want to wait longer for treatment effects if this means they can avoid [side effects from corticosteroids],” said Kahlmann, who presented the data at the conference.
Methotrexate now recommended as a second-line treatment
In sarcoidosis, an overly reactive immune system forms granulomas — small clumps of inflammatory immune cells — in organs of the body. While the disease goes away on its own in some patients, others need immunosuppressive treatment to protect their organs.
Prednisone is the first-line treatment for pulmonary sarcoidosis, which occurs when sarcoidosis develops in the lungs. The medication can be effective at easing symptoms and improving lung function, but — as with other corticosteroids — its prolonged use can cause a number of serious side effects.
Among them, the researchers noted, are “weight gain, sleep problems, [high blood pressure], and diabetes, which may reduce quality of life and could lead to long-term adverse effects on health,” the researchers wrote.
Methotrexate, an immunosuppressive agent recommended as a second-line treatment for pulmonary sarcoidosis, appears to cause fewer side effects than prednisone. While it’s thought to have a slower onset of action, this hasn’t been fully tested when used as a first-line treatment.
Now, the PREDMETH trial is evaluating the safety and efficacy of methotrexate against prednisone as a first-line treatment in adults with pulmonary sarcoidosis. Researchers put forward the hypothesis that methotrexate may work just as well while being safer than prednisone.
Improvements more gradual, but similar, with methotrexate
The trial enrolled 138 participants with a mean age of 46.6 years. All were randomly assigned to receive either oral prednisone — starting at 40 mg per day and gradually reduced to 10 mg by week 16 — or oral methotrexate, starting at 15 mg per week and increasing by 5 mg every four weeks up to 25 mg per week.
PREDMETH’s main goal was to assess whether changes in forced vital capacity (FVC), a lung function measure that reflects how much air a person can exhale after taking a deep breath, did not differ significantly between groups after 24 weeks, or nearly six months.
Up to week 24, the average daily dose was 21.1 mg for prednisone and 20.1 mg for methotrexate. After nearly six months, FVC improved by 6.75 points in the prednisone group and 6.11 points in the methotrexate group, indicating that “methotrexate was noninferior to prednisone,” the researchers wrote.
This study shows for the first time that methotrexate may be a good alternative for prednisone as first-line treatment.
While prednisone “led to a rapid increase” in FVC within four weeks, FVC improvements were “more gradual with methotrexate … but the change between [study’s start] and week 24 was similar in the two groups,” the scientists wrote.
Improvements in other measures of symptoms and health-related quality of life were also similar between groups after six months. The researchers noted that benefits were observed as early as after four weeks in both groups, even if they were more pronounced in the prednisone group.
“Results were in line with what we hypothesized,” said Marlies Wijsenbeek, MD, a pulmonologist at the Erasmus Medical Center and the trial’s principal investigator. “It was, however, surprising to see that some symptom scores already improved after four weeks of treatment in the methotrexate group.”
In addition, 96% of prednisone-treated patients experienced a total of 308 adverse events, and 94% of those treated with methotrexate experienced a total of 283 adverse events, the data showed. Still, a higher proportion of adverse events persisted at week 24 in the prednisone group than in the methotrexate group (54% vs. 37%).
Rates of adverse events leading to discontinuation were similar between the prednisone and methotrexate groups (14% vs. 13%), per the researchers.
The types of adverse events differed. Prednisone most commonly caused weight gain, insomnia, increased appetite, and mood changes, while methotrexate was more likely to cause nausea, fatigue, elevated liver enzymes (suggestive of liver damage), and abdominal pain.
“Side effect profiles were clearly different,” the researchers wrote in the abstract submitted to the ATS 2025.
The team noted, though, that “this study shows for the first time that methotrexate may be a good alternative for prednisone as first-line treatment.”
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