Methotrexate found to be effective alternative to prednisone for pulmonary sarcoidosis

Prednisone is recommended as the first-line treatment for pulmonary sarcoidosis, but this steroid causes a number of unwanted side effects. Now new research published at the ATS 2025 International Conference finds that methotrexate provides a comparable alternative.

Researchers found that methotrexate was as effective in controlling the disease, with potentially fewer side effects than prednisone. The randomized, controlled trial, conducted as part of a collaboration among 17 hospitals in the Netherlands, provides the first high-quality data comparing the two therapies in patients with pulmonary sarcoidosis.

The results of this trial show that methotrexate can be offered as an alternative for prednisone for patients with pulmonary sarcoidosis."

Vivienne Kahlmann, MD, first author, pulmonologist in training at Erasmus Medical Center in Rotterdam, Netherlands

Sarcoidosis is a complex immunological disease with a highly variable clinical course and prognosis. While some patients experience spontaneous remission, others require immunosuppressive treatment to maintain organ function and improve quality of life.

Even though international guidelines recommend prednisone to be used as standard-of-care for pulmonary sarcoidosis, these recommendations have not been based on randomized clinical trials. Prednisone is often accompanied by side effects like weight gain, sleep disturbance, and psychological symptoms, which can negatively affect patients' quality of life. In addition, long-term use is associated with a high risk of chronic complications.

For the PREDMETH trial, researchers compared 69 patients who received prednisone for pulmonary sarcoidosis with 68 who received methotrexate. They found that methotrexate was non-inferior to prednisone after 24 weeks of treatment but had a slower onset of efficacy.

Although the total number of side effects were similar, the methotrexate group had fewer ongoing side effects at 24 weeks. The side effects themselves were also different, with weight gain, insomnia, and increased appetite most common in the prednisone group, and nausea, fatigue, and liver function abnormalities common in the methotrexate group.

"Results were in line with what we hypothesized," last-author Marlies Wijsenbeek, MD, a pulmonologist at the Erasmus Medical Center said. "It was, however, surprising to see that some symptom scores already improved after four weeks of treatment in the methotrexate group. She said the findings will help doctors and patients make more personalized treatment plans, noting that treatment decisions should be based on individual patients' preferences and needs.

"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 steroid toxicity," Dr. Kahlmann noted.

Looking ahead, researchers plan to develop a decision-aid tool to help doctors and patients navigate treatment choices. They also plan follow-up studies, including analyzing blood samples from study participants to identify cellular biomarkers to predict treatment response.