Sarcoidosis is a multi-organ inflammatory disease that often affects the lungs. Guidelines currently recommend prednisone as the first-line treatment for pulmonary sarcoidosis as it improves lung function short term but carries significant steroid-toxicity risks. Methotrexate is a guideline-endorsed second-line option, which is generally better tolerated but perceived to act more slowly.

The PREDMETH trial, led by Vivienne Kahlmann, MD, is an open-label, randomized, noninferiority trial across 17 Dutch hospitals. Previously, untreated adults with pulmonary sarcoidosis were assigned either prednisone (40 mg/day tapered to 10 mg by week 16) or methotrexate (protocol-directed escalation). The primary endpoint for the trial was the mean change in the percentage of the predicted forced vital capacity (FVC - a measure of the total volume of air a person can blow out).

The trial showed the mean change in predicted FVC at 24 weeks was +6.75 percentage points with prednisone and +6.11 percentage points with methotrexate. Prednisone had a faster impact, with most gains appearing within the first 4 weeks, but by week 24, the improvement in lung function was the same for both treatment protocols.

Prednisone has a well-documented and notorious side effect profile, and almost half the patients in the prednisone group saw their weight increase, with a mean increase of 5 kg. Patients in the prednisone group also encountered significant insomnia. While the study didn't explicitly measure steroid-toxicity, it did compare some of the shorter-term side effects encountered during the trial.

In a recent interview, Tricha Shivas, Chief of Staff and Strategy at the Foundation for Sarcoidosis Research, told Steritas:

“Our members are concerned about whether the drugs used to treat their disease are more harmful than the disease itself. Patients who have weaned off steroids fear going back on steroid treatments because of how they make them feel. And those who have not been able to wean off steroids fear long-term consequences of continued use, while simultaneously fearing disease relapse.” 

Methotrexate did cause more nausea/fatigue and more abnormal liver-function tests; however, most adverse events were short-term and manageable.

In an accompanying NEJM editorial, Robert Baughman, MD and Elyse Lower, MD, argue that this study shows methotrexate can be considered as a credible first-line alternative to steroids. They recommend clinicians consider starting treatment with methotrexate when rapid relief isn’t essential. If speed matters, they suggest short-term prednisone plus methotrexate, with methotrexate being used as the long-term backbone.

For first-line treatment of pulmonary sarcoidosis, this trial has shown that methotrexate delivers comparable disease control to prednisone but with a more favorable toxicity profile. Over time, one might expect guidelines and practice to shift further toward steroid-sparing treatments, with prednisone reserved for those who need rapid response.