PulmPEEPs

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).

Today we're kicking off another segment in our Guidelines Series, and doing a deep dive into the 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Over a series of episodes we'll talk about the most recent updates … Continue reading →

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For today's podcast we have a special episode. We were extremely grateful to be invited to present live at CHEST 2025 this year. Kristina Montemayor, and Pulm PEEPs Associate Editors Luke Hedrick, Tom Di Vitantonio, and Rupali Sood hosted a … Continue reading →

In this episode, we're concluding our review of the Global Initiative for Asthma (GINA) guidelines on asthma today with a cased based episode on special considerations in asthma care. We've covered asthma diagnosis and phenotyping, the approach to therapy inhaler … Continue reading →

We're back with our 4th episode in our collaborative series with BMJ Thorax. This week's episode covers four articles related to bronchiectasis and covers a range of topics in this domain including novel therapeutics, registry data to understand risk, and … Continue reading →

After a brief hiatus, we are excited to be back today with another Fellows' Case Files! Today we're virtually visiting the University of Kansas Medical Center (KUMC) to hear about a fascinating pulmonary presentation. There are some fantastic case images … Continue reading →

We are so excited to be launching a new series here at Pulm PEEPs! We'll be talking about high yield topics in 15 minutes or less. In this series, Furf and Monty will tackle core points and provide an overview, … Continue reading →

Today we're talking about a topic that is relevant for all critical care physicians but under-examined: ICU Acquired Weakness. We are joined by two excellent guests to walk through a case and discuss the diagnosis, pathophysiology, prevention, and treatment of … Continue reading →

Hi Pulm PEEPs! Today we have a special episode for you. Monty and Furf were invited on the Core IM Podcast to talk about the work up and management of pleural effusions. This is a great overview and we hope … Continue reading →

Today, we're virtually visiting the University of Virginia for another Fellows' Case Files. This is a fantastic case that covers ARDS, the infectious work up of an immunosuppressed patient, and the evaluation of undifferentiated shock. Please let us know what … Continue reading →

Today is our third episode in our collaborative series with BMJ Thorax. Our mission at Pulm PEEPs is to disseminate and promote pulmonary and critical care education, and we highly value the importance of peer reviewed journals in this endeavor. … Continue reading →

We're back with another Rapid Fire Journal Club. Luke Hedrick and Dave Furfaro discuss the NAVIGATOR trial published in NEJM in 2021 evaluating tezepelumab for adults with asthma. Article and Reference We are talking today about the NAVIGATOR trial evaluating … Continue reading →

We are podcasting today directly from ATS 2025 in San Francisco! Every year, in collaboration with the ATS Critical Care Assembly, we highlight some of the scientific symposium programming from the conference. Today, Furf and Monty sit down with the … Continue reading →

We're back with another edition of Fellows' Case Files! Today, we're virtually visiting Rutgers University, Robert Wood Johnson Medical School to work through a fascinating pulmonary case. Enjoy, and let us know your thoughts. Meet Our Guests Khalil El Gharib … Continue reading →

Today, we continue our review of the Global Initiative for Asthma (GINA) guidelines on asthma. We've covered asthma diagnosis and phenotyping, and the initial approach to therapy. On today's episode we're talking about biologic therapies for asthma and will cover … Continue reading →

In this episode, we add another article to our Rapid Fire Journal Club. Luke Hedrick and Dave Furfaro discuss the MIST 2 trial published in NEJM in 2011 evaluating enzymatic therapy for complex parapneumonic effusions and empyemas.   Article and … Continue reading →

We're back with our second episode in our guideline initiative, and continuing our review of the Global Initiative for Asthma (GINA) guidelines on asthma. In our first episode of this series, we talked about making the diagnosis of asthma, the … Continue reading →

Today we have a mini-episode / clinical pearl. We previously discussed the PROSEVA trial and the evidence for prone positioning in ARDS. In that trial, patients with elevated intracranial pressure (ICP) were excluded. We are joined now by Dr. Jon … Continue reading →

On February 7, 2025 it was announced that the National Institutes of Health (NIH) would be capping indirect cost payments for research grants at 15%. This is a massive reduction from the current standard, and will have widespread impacts on … Continue reading →

Today we are launching a new Pulm PEEPs initiative! We are going to be reviewing some of the major guidelines that are available in pulmonary and critical care. We are starting by diving into the Global Initiative for Asthma (GINA) … Continue reading →

Today is our second episode in our collaborative series with BMJ Thorax. Our mission at Pulm PEEPs is to disseminate and promote pulmonary and critical care education, and we highly value the importance of peer reviewed journals in this endeavor. … Continue reading →

This week we're talking about a case as a lens for discussing Tylenol toxicity and Acute Liver Failure. These relatively common critical care presentations are essential knowledge for anyone practicing in the ICU. Listen in for some key discussion both … Continue reading →

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Our episode today is diving into a broader initiative to discuss the management of interstitial lung disease. In this episode we will be talking about the treatment of Idiopathic Pulmonary Fibrosis through the lens of a journal club discussion of … Continue reading →

We are joined today by two amazing educators from NYU for our latest Fellows' Case Files Episode. Listen today as we go through a great case with some fantastic teaching points highlighted throughout the episode. Meet Our Guests Dr. Jeremy … Continue reading →

Here at Pulm PEEPs we have always loved the CHEST Annual Meetings. We have enjoyed learning at them, reuniting with and meeting colleagues, and having conference specific episodes the past two years. This year, we had the opportunity to podcast … Continue reading →

We are excited to be back with our colleagues from CHEST to be previewing the CHEST 2024 Annual Meeting. CHEST his year is in Boston, MA from October 5th to October 9th. Listen in to hear about some great new … Continue reading →

We are extremely excited today to announce a new collaboration with BMJ Thorax. Our mission at Pulm PEEPs is to disseminate and promote pulmonary and critical care education, and we highly value the importance of peer reviewed journals in this … Continue reading →

In this podcast episode, we continue our summer series reviewing landmark ARDS studies. Today, Dave and Luke discuss the Driving Pressure trial (published in NEJM in 2015) which evaluated the impact of driving pressure on survival in patients with ARDS. Article … Continue reading →

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We have another great case in our Fellows' Case Files coming today from UMass Chan. Listen in for a great discussion about a fascinating case with interesting physical exam and radiographic findings. Meet Our Guests Dr. Jen Kodela completed her … Continue reading →

In this podcast episode, we continue our summer series reviewing landmark ARDS studies. Today, Dave and Luke discuss the PROSEVA trial (published in NEJM in 2013) which evaluated the impact of early, prolonged proning in patients with severe ARDS. Article and … Continue reading →

In this podcast episode, we continue our summer series reviewing landmark ARDS studies. Today, Dave and Luke discuss the ROSE trial (published in NEJM in 2019) which investigated use of continuous neuromuscular blockade in moderate to severe ARDS. Article and Reference … Continue reading →

In this podcast episode, we continue our summer series reviewing landmark ARDS studies. Today, Dave and Luke discuss the FACTT trial, which investigated fluid management strategies in ARDS. This was published in the NEJM in 2006. Article and Reference We're … Continue reading →

Today, we're going to be talking about pre-oxygenation methods for endotracheal intubation and the PREOXI Trial which is hot off the presses in the New England Journal of Medicine in June of 2024. This trial has potentially widespread, practice changing … Continue reading →

This episode is launching our 2024 Rapid Fire Journal Club summer series on ARDS! This summer we will be talking about landmark ARDS trials that have defined the literature and shaped patient care. Journal clubs often focus on new trials, … Continue reading →

Today we're back with another stop on our Fellows' Case Files journey and making our way to the University of Rochester. Tune in to hear about this fascinating case and learn some key teaching points along the way. Meet Our … Continue reading →

We're back with our Rapid Fire Journal Club, and talking about the NEJM 2023 STELLAR Trial of Sotatercept in Pulmonary Arterial Hypertension. This is a landmark trial that is actively changing the face of PAH treatment today. Listen to hear … Continue reading →

We have had a number of episodes on Acute Respiratory Distress Syndrome or ARDS. These episodes have ranged from how to titrate PEEP, subphenotypes in ARDS, and the future of ARDS research. Today, we are talking about how we all … Continue reading →

Welcome to our second episode of ATS 2024 highlighting content featured through the ATS Critical Care Assembly. Today we are going to be talking about one of the Critical Care Assembly Symposiums entitled: “Care of Dying in the ICU: End … Continue reading →

Welcome to our first episode of ATS 2024 highlighting content featured through the ATS Critical Care Assembly. Today we are going to be talking about one of the Critical Care Assembly Symposiums entitled: “A New Reality for Critical Care after … Continue reading →

Today we're visiting the University of New Mexico for another interesting entry in our Fellows' Case Files.   Meet Our Guests Neel Vahil is a second-year internal medicine resident at the University of New Mexico. He completed medical school at … Continue reading →

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Today on Rapid Fire Journal Club we're reviewing a new article type and discussing a meta-analysis of Single Maintenance and Reliever Therapy (SMART) for asthma. Article and Reference Today we're taking a deeper diver into SMART treatment for asthma to … Continue reading →

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We are excited to bring an a dedicated episode all about inhalers. We know there are many type of inhalers, formulations and techniques that are needed for successful use and we cover them all. Take a listen today! Meet our … Continue reading →

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Hi everyone, we're here with another Fellows' Case Files. Today, we're going virtually to Emory University School of Medicine. We're joined by Associated Editor Luke Hedrick to dive into a critical care case. Listen in and let us know if … Continue reading →

Today on our Rapid Fire Journal Club series, we're discussing the Novel START study published in the NEJM in 2019. This study evaluated multiple strategies for the management of mild asthma with exacerbations, and it guides our current therapeutic approach. … Continue reading →