PREDMETH Trial: Methotrexate Noninferior to Prednisone as First-Line Therapy for Pulmonary Sarcoidosis
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A landmark Dutch randomized trial published in the New England Journal of Medicine has found that methotrexate, long used as a second-line therapy, is as effective as prednisone for improving lung function in people with newly diagnosed pulmonary sarcoidosis. After 24 weeks, patients in both groups showed nearly identical gains in forced vital capacity. For patients and clinicians concerned about steroid side effects like weight gain, insomnia, and bone loss, this trial opens the door to a steroid-sparing first-line option for sarcoidosis.
Abstract
Sarcoidosis is a multi-organ inflammatory disease that most commonly affects the lungs. Current guidelines recommend oral corticosteroids such as prednisone as first-line treatment for symptomatic pulmonary sarcoidosis, but long-term steroid use carries risks including weight gain, hyperglycemia, osteoporosis, and insomnia. Methotrexate is endorsed as a second-line steroid-sparing option but was historically thought to act too slowly to replace prednisone at diagnosis.
The PREDMETH trial was an open-label, randomized, noninferiority trial conducted across 17 Dutch hospitals. Previously untreated adults with symptomatic pulmonary sarcoidosis were assigned to receive either prednisone (40 mg per day tapering to 10 mg by week 16) or methotrexate (protocol-directed dose escalation). The primary endpoint was the mean change in percentage of predicted forced vital capacity (FVC) at 24 weeks.
The mean change in predicted FVC at 24 weeks was +6.75 percentage points in the prednisone group and +6.11 percentage points in the methotrexate group, demonstrating noninferiority. Prednisone produced faster early improvements within the first 4 weeks, but by week 24 lung function gains had converged between the two arms. Nearly half of patients receiving prednisone experienced weight gain (mean +5 kg), and insomnia was more common in that group. Methotrexate was associated with more nausea, fatigue, and transient liver enzyme elevations, though most adverse events were mild and manageable. An accompanying NEJM editorial concluded that methotrexate can be considered a credible first-line alternative to prednisone, particularly when rapid symptom relief is not required.