Today, Dave Furfaro, Luke Hedrick, and Robert Wharton discuss the PREDMETH trial published in The New England Journal of Medicine in 2025. This was a non-inferiority trial comparing prednisone to methotrexate for upfront therapy in treatment-naive sarcoidosis patients. Listen in for a break down of the trial, analysis, and clinically applicable pearls.

Article and Reference

Todays’ episode discusses the PREDMETH trial published in NEJM in 2025.

Kahlmann V, Janssen Bonás M, Moor CC, Grutters JC, Mostard RLM, van Rijswijk HNAJ, van der Maten J, Marges ER, Moonen LAA, Overbeek MJ, Koopman B, Loth DW, Nossent EJ, Wagenaar M, Kramer H, Wielders PLML, Bonta PI, Walen S, Bogaarts BAHA, Kerstens R, Overgaauw M, Veltkamp M, Wijsenbeek MS; PREDMETH Collaborators. First-Line Treatment of Pulmonary Sarcoidosis with Prednisone or Methotrexate. N Engl J Med. 2025 Jul 17;393(3):231-242. doi: 10.1056/NEJMoa2501443. Epub 2025 May 18. PMID: 40387020.

https://www.nejm.org/doi/full/10.1056/NEJMoa2501443

Meet Our Hosts

Luke Hedrick is an Associate Editor at Pulm PEEPs and runs the Rapid Fire Journal Club Series. He is a senior PCCM fellow at Emory, and will be starting as a pulmonary attending at Duke University next year.

Robert Wharton is a recurring guest on Pulm PEEPs as a part of our Rapid Fire Journal Club Series. He completed his internal medicine residency at Mt. Sinai in New York City, and is currently a first year pulmonary and critical care fellow at Johns Hopkins.

Key Learning Points

Clinical context

Prednisone remains the traditional first-line treatment for pulmonary sarcoidosis when treatment is indicated, with evidence for short-term improvements in symptoms, radiographic findings, and pulmonary function—but with substantial, familiar steroid toxicities (weight gain, insomnia, HTN/DM, infection risk, etc.).
Despite widespread use, glucocorticoids haven’t been robustly tested head-to-head against many alternatives as initial therapy, and evidence for preventing long-term decline (especially in severe disease) is limited.
Immunosuppressants (like methotrexate) are often used as steroid-sparing agents, but guideline recommendations are generally conditional/low-quality evidence, and practice varies.

Why PREDMETH matters

It addresses a real-world question: Can methotrexate be an initial alternative to prednisone in pulmonary sarcoidosis, rather than being reserved only for steroid-sparing later?
It also probes a common clinical belief: MTX has slower onset than prednisone (often assumed, not well-proven).

Trial design (what to know)

Open-label, randomized, noninferiority trial across 17 hospitals in the Netherlands.
Included patients with pulmonary sarcoidosis who had a clear pulmonary indication to start systemic therapy (moderate/severe symptoms plus objective risk features like reduced FVC/DLCO or documented decline, plus parenchymal abnormalities).
Excluded: non–treatment-naïve patients and those whose primary indication was extrapulmonary disease.
Treat-to-tolerability with escalation: both drugs started low and were slowly increased; switch/add-on allowed for inadequate efficacy or unacceptable side effects.
Primary endpoint: change in FVC (with the usual caveat that FVC is “objective-ish,” but effort-dependent and not always patient-centered).
Noninferiority margin: 5% FVC, justified as within biologic/measurement variation and “not clinically relevant.”
Outcomes assessed at weeks 4, 16, 24; powered for ~110 patients to detect the NI margin.

Patient population (who this applies to)

Mostly middle-aged (~40s) with mild-to-moderate physiologic impairment on average (FVC ~77% predicted; DLCO ~70% predicted).
Netherlands-based cohort with limited Black representation (~7%), which matters for generalizability.
Would have been helpful to know more about comorbidities (e.g., diabetes), which can strongly influence prednisone risk.

Main findings (what happened)

Methotrexate was noninferior to prednisone at week 24 for FVC:
- Between-group difference in least-squares mean change at week 24: −1.17 percentage points (favoring prednisone) with CI −4.27 to +1.93, staying within the 5% NI margin.
Timing mattered:
- Prednisone showed earlier benefit (notably by week 4) in FVC and across quality-of-life measures.
- By week 24, those early differences largely washed out—possibly because MTX “catches up,” and/or because crossover increased over time.
- In their reporting, MTX didn’t meet noninferiority for FVC until week 24, supporting the practical message that prednisone works faster.

Crossover and analysis nuance (important for interpretation)

Crossover was fairly high, which complicates noninferiority interpretation:
- MTX arm: some switched to prednisone for adverse events and others had prednisone added for disease progression/persistent symptoms.
- Prednisone arm: some had MTX added.
In noninferiority trials, heavy crossover can bias intention-to-treat analyses toward finding “no difference” (making noninferiority easier to claim). Per-protocol analyses avoid some of that but introduce other biases. They reported both.

Safety signals (what to remember clinically)

Adverse events were very common in both arms (almost everyone), mostly mild.
Side-effect patterns fit expectations:
- Prednisone: more insomnia (and classic steroid issues).
- MTX: more headache/cough/rash, and notably liver enzyme elevations (about 1 in 4), with a small number discontinuing.
Serious adverse events were rare; numbers were too small to confidently separate “signal vs noise,” but overall known risk profiles apply.

Limitations (why you shouldn’t over-read it)

Open-label design, and FVC—while objective-ish—is still effort-dependent and can be influenced by expectation/behavior.
Small trial, limiting subgroup conclusions (e.g., severity strata, different phenotypes).
Generalizability issues (Netherlands demographics; US populations have higher rates of obesity/metabolic syndrome, which may tilt the steroid risk-benefit equation).
Crossover reduces precision and interpretability of between-group differences over time.

Practice implications (the “so what”)

For many patients with pulmonary sarcoidosis needing systemic therapy, MTX is a reasonable initial alternative to prednisone when thinking long-term tolerability and steroid avoidance.
Prednisone likely provides faster symptom/QoL relief in the first weeks—so it may be preferable when rapid improvement is important.
The trial strengthens the case for a patient-centered discussion: short-term relief vs side-effect tradeoffs, and the possibility of early combination therapy in more severe cases (suggested, not proven).

Kurt Bardella