A recent study challenges the long-held practice of starting symptomatic pulmonary sarcoidosis patients on corticosteroids and points to a greater role for rheumatologists in its treatment.
In general, sarcoidosis involves development of granulomas in various parts of the body. These lumps or nodules are composed of white blood cells and surrounded by fibrous tissue. Depending on their location and size, granulomas can turn into fibrosis, causing permanent scarring. The lungs are the most involved organs, but others—including the skin, eyes, heart and liver—may also be affected. Guidelines issued by the European Respiratory Society (ERS) in 2021 recommend prednisone as the first-line treatment for pulmonary sarcoidosis, but this suggestion is based on low-quality evidence in the absence of well-designed trials.1
In a recent multicenter, open-label trial involving patients with previously untreated pulmonary sarcoidosis, researchers in The Netherlands show that initial treatment with the antimetabolite methotrexate is as effective as the corticosteroid prednisone in changing lung function, as measured by the percentage of the forced vital capacity (FVC). Types of adverse events differed somewhat between patients on prednisone and methotrexate. However, the percentage of patients who experienced adverse events was similar in both groups, according to the Effectiveness of Methotrexate Versus Prednisone as First-line Therapy for Pulmonary Sarcoidosis (PREDMETH) trial.2
“The main message from PREDMETH is that methotrexate can, and should, be considered a real alternative to prednisone for patients with pulmonary sarcoidosis,” says senior author Marlies Wijsenbeek-Lourens, MD, PhD, a pulmonologist and head of the Center for Interstitial Lung Diseases and Sarcoidosis, Erasmus Medical Center, Rotterdam. “Patient education and shared decision making are key, so together with the patient we can choose the treatment that best fits their situation.”
Because sarcoidosis can affect multiple organs, Dr. Wijsenbeek-Lourens emphasizes that no single specialty can cover all aspects of care. “We need each other’s expertise,” she notes.
Arthritis or bone involvement can significantly affect patients’ quality of life and require targeted rheumatologic treatment.
“Rheumatologists also bring valuable experience with long-term immunosuppressive therapy and monitoring of side effects, which can help pulmonologists optimize treatment strategies,” Dr. Wijsenbeek-Lourens adds. “Close interdisciplinary collaboration is not just helpful, but increasingly essential to deliver the best care for our patients.”
PREDMETH
Prednisone has long been the cornerstone of treatment for pulmonary sarcoidosis. But it has troublesome side effects, including weight gain, sleep disorders, psychological problems and increased cardiovascular risk. Sarcoidosis treatment guidelines issued in 1999 by the American Thoracic Society and the European Respiratory Society established corticosteroids as a first-line treatment, but pointed to the need for less toxic alternatives, notes Dr. Wijsenbeek-Lourens.3
The 2021 ERS pulmonary sarcoidosis treatment guideline continued to suggest prednisone or prednisolone as first-line treatment, but suggested adding methotrexate and other drugs for certain clinical situations. It recommended 20 to 40 mg of prednisone or prednisolone per day.
Methotrexate is commonly the second-line treatment for sarcoidosis and is often started if prednisone is not effective enough, cannot be tapered or causes side effects, according to Dr. Wijsenbeek-Lourens. She decided to start PREDMETH based on her personal clinical experience that methotrexate tends to cause fewer side effects than prednisone.
The researchers compared methotrexate with prednisone as initial therapy for symptomatic pulmonary sarcoidosis in an unblinded, multicenter trial without a placebo control conducted entirely within The Netherlands. They randomly assigned patients to receive either prednisone or methotrexate according to a prespecified treatment schedule. Individuals taking oral prednisone started at 40 mg daily and tapered every four weeks to 10 mg daily; individuals taking oral methotrexate started at 15 mg weekly and increased by 5 mg weekly to a maximum dose of 25 mg. The primary end point was the mean change in the percentage of the predicted forced vital capacity from baseline to week 24, as estimated with mixed models for repeated measures.
The unadjusted mean change from baseline to week 24 in the percentage of the predicted FVC was 6.75 percentage points in the prednisone group and 6.11 percentage points in the methotrexate group, with an adjusted between-group difference of –1.17 percentage points.
The researchers saw a quicker onset of action for prednisone than for methotrexate, with most FVC improvement in the prednisone group occurring four weeks from treatment start. In the methotrexate group, similar FVC improvement did not occur until week 24.
Adverse events occurred in similar percentages, with 96% of participants who took prednisone and 94% of those who took methotrexate experiencing them. Ongoing adverse events at week 24 occurred in 63% of the methotrexate group vs. 46% of the prednisone group. Ongoing elevated liver enzyme levels occurred in 25% of participants who took methotrexate, with the alanine aminotransferase level more than three times the upper limit of normal range in 9% of patients, a finding the authors say aligns with studies of methotrexate in rheumatoid arthritis patients.
But different adverse events were more common in each group of patients. At 24 weeks, individuals who took methotrexate suffered greater rates of nausea (13%) and fatigue (15%) than those who took prednisone (0% and 5%, respectively). In contrast, prednisone patients had higher rates of weight gain than methotrexate patients, at rates of 39% and 7%, respectively. Prednisone patients also had higher rates of insomnia at 24 weeks than methotrexate patients, at rates of 16% and 3%, respectively.
The researchers note limitations to their trial, including that it was conducted in a single country. “The study population in PREDMETH reflects the Dutch population, where Black, Asian and Hispanic patients are underrepresented. While we believe these results are an important basis for further research, registries and real-world studies are still needed to better understand differences in treatment response depending on genetic background,” says Dr. Wijsenbeek-Lourens.
The paper notes the PREDMETH design occurred prior to release of the 2021 ERS guideline, so its initial 40 mg/day and 15 mg/week doses of prednisone and methotrexate, respectively, differ from lower dosages endorsed by the guideline. The trial was also designed before an Indian trial that showed a 40 mg dose of prednisolone did not improve pulmonary sarcoidosis outcomes better than a 20 mg dose.4
Evidence for Less Glucocorticoid
That trial, known as SARCORT, was a single-center, open-label, randomized controlled trial of 86 patients in India who received either 20 or 40 mg daily of prednisolone over 18 months. The primary outcome was frequency of relapse or treatment failure in the high-dose group at 18 months, and secondary outcomes were time to relapse or treatment failure, overall response, change in FVC at 6 and 18 months, treatment-related adverse effects and health-related quality of life.
Patients who completed 18 months of follow-up included 86% of individuals taking the high dose and 95.3% of those taking the low dose. In the high-dose group, 46.5% had relapse or treatment failure vs. 44.2% of the low-dose group. Both groups had similar mean time to relapse or treatment failure, overall response, changes in FVC at 6 and 18 months and changes in health-related quality of life.
The SARCORT authors note, however, that their results are not generalizable because the study was conducted at a single center. They add that a 2021 British Thoracic Society statement had suggested a dose range of 20–40 mg of prednisolone.5
Choice of Drug
The SARCORT and PREDMETH trials “have been game changers in the field of sarcoidosis treatment,” says SARCORT first author Sahajal Dhooria, MD, MBBS, additional professor in the Department of Pulmonary Medicine in the Postgraduate Institute of Medical Education and Research, Chandigarh, India.
“While our trial places low-dose steroids on the same pedestal as high-dose steroids, PREDMETH goes one step ahead and takes steroid therapy off the shelf [in some cases] for sarcoidosis,” Dr. Dhooria says. He sees the trials as complementary because they both support reduced steroid dosing. However, “in the PREDMETH trial, outcomes at four weeks were much better with prednisolone.” Thus, there may be a role for short-course, low-dose prednisone treatment together with methotrexate when initiating treatment.
Prednisolone is not for all patients. It is relatively contraindicated for very common conditions—obesity, diabetes, prediabetes and low bone density, Dr. Dhooria points out. Some prediabetics on prednisolone will develop permanent diabetes, and osteopenia patients could develop osteoporosis. “Both SARCORT and the PREDMETH trial offer a lot of good evidence, so the physicians who are treating sarcoidosis can really reduce the steroid dose or take it away completely to avoid all these adverse effects,” he says.
The choice between the two drugs “may come down to faster relief with higher risk of long-term side effects [with steroids], or slower relief with fewer long-term side effects [with methotrexate],” adds Dr. Wijsenbeek-
Lourens. She notes, however, that her trial’s patients reported meaningful improvement in lung symptoms after four weeks. “Taken together in the context of SARCORT, [findings from both trials suggest] if prednisone is chosen, it should always be at the lowest effective dose. For most patients, 20 mg/day is sufficient as a starting point.”
“An alternative option could be to use combination therapy and taper prednisone quickly to minimize the risk of side effects, though we have not studied this approach,” she adds.
Rheumatologists’ Role
Both pulmonologists note that rheumatologists play an important role in pulmonary sarcoidosis treatment as part of interdisciplinary teams. Because sarcoidosis can affect any organ, close collaboration between specialists is essential, Dr. Wijsenbeek-Lourens says. At her hospital, a multidisciplinary sarcoidosis team meets weekly and includes a rheumatologist, immunologist, cardiologist and neurologist.
“We believe it is important for each patient to have one coordinator, depending on the major organ involvement,” says Dr. Wijsenbeek-Lourens. Because “the lungs are often involved, this role is frequently performed by the pulmonologist.”
Dr. Dhooria also calls for multidisciplinary patient management. Two decades ago in India, sarcoidosis was mainly treated by rheumatologists; today, pulmonologists are more likely to lead treatment teams due to frequent lung involvement and the increasing role of bronchoscopic diagnosis.
In contrast, pulmonologists have long dominated sarcoidosis treatment in the U.S., notes rheumatologist Arthur Yee, MD, PhD, director of the Hospital for Special Surgery Sarcoidosis Collaborative, New York. That’s because, in part, U.S. medical training usually covers sarcoidosis in units on lung disease, so most U.S. physicians—including rheumatologists—tend to think of it as a lung disease. In contrast to pulmonologists, rheumatologists “deal with diseases that affect many different organ systems, sometimes simultaneously, sometimes asynchronously,” he says. “We are familiar with that kind of illness, but we have never had a foothold in the sarcoid world [in the U.S.], even though we probably know the medicines better than most other specialists.”
Dr. Yee notes two components of treatment. The first reduces active inflammatory processes that can lead to damage and is very much in the purview of rheumatologists. The second involves treating or mitigating the fibrosis that results from long-term inflammation, which can affect various organs. Antifibrotic medications are familiar to pulmonologists. Cardiologists who are heart failure specialists or electrophysiologists have pharmacologic and nonpharmacologic modalities to lessen the burden of damaged myocardium.
Rheumatologists are familiar with glucocorticoids, which reduce inflammation, and methotrexate, which modulates both immunity and inflammation. Rheumatologists have long used these drugs and others, notably tumor necrosis factor-alpha (TNF-α) inhibitors. The TNF-α inhibitors infliximab and adalimumab have been used to treat multiple diseases, including rheumatoid arthritis and uveitis, for 20 years, Dr. Yee adds.
“These trials show that more rheumatologists should participate in teams that manage sarcoidosis,” Dr. Yee emphasizes. “Rheumatologists should not be afraid of treatment to reduce the inflammation in sarcoidosis, even though they may not have learned much about it in medical school. We know more about prednisone and methotrexate than any other type of specialty. So I think these studies will help rheumatologists get even more comfortable with sarcoidosis.”
Deborah Levenson is a writer and editor based in College Park, Md.
References
- Baughman RP, Veleyre D, Korsten P, et al. ERS clinical practice guidelines on treatment of sarcoidosis. Eur Respir J. 2021 Dec 16; 58(6):2004079.
- Kahlmann V, Janssen Bonás M, Moore CC, et al. First-line treatment of pulmonary sarcoidosis with prednisone or methotrexate. N Engl J Med. 2025 July 17;393(3):231–242.
- Statement on sarcoidosis: Joint statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS board of directors and by the ERS executive committee, February 1999. Am J Respir Crit Care Med. 1999 Aug;160(2)736–755.
- Dhooria S, Sehgal IS, Agarwal R, et al. High-dose (40mg) versus low-dose (20mg) prednisolone for treating sarcoidosis: A randomised trial (SARCORT trial). Eur Respir J. 2023 Sep 9;62(3):2300198.
- Thillai M, Atkins CT, Crawshaw A, et al. BTS clinical statement on pulmonary sarcoidosis. Thorax. 2021 Jan;76(1):4–20.
