Methotrexate is safer second-line sarcoidosis treatment than MMF
Real-world study analyzed immunosuppressants, TNF inhibitors
Among second-line treatments for sarcoidosis, methotrexate is safer and associated with a lower risk of hospitalization, intensive care, the need for breathing support, and death compared to mycophenolate mofetil (MMF), according to a large real-world study.
Methotrexate also showed a trend toward better efficacy and similar safety relative to azathioprine (sold as Imuran and others, with generics available) and leflunomide (sold as Arava, with generics available).
The TNF inhibitors infliximab (sold as Remicade, with biosimilars available) and adalimumab (sold as Humira, with biosimilars available), which are typically used as third-line treatments in sarcoidosis, were associated with comparable outcomes and side effects.
“This study highlighted the safety profile of immunosuppressants and TNF inhibitors in sarcoidosis,” researchers wrote. “Methotrexate, azathioprine, and leflunomide showed similar safety, whereas MMF carried higher risks of infection and bone marrow suppression, supporting methotrexate as the preferred second-line agent.” MMF is sold as CellCept and others, with generics available.
The study, “Comparative Outcomes and Side Effects of Immunosuppressants and Tumor Necrosis Factor Inhibitors in Sarcoidosis: A Real-World Data Analysis,” was published in CHEST.
Immunosuppressants used as second-line sarcoidosis treatments
Sarcoidosis is marked by an overactive immune system that leads to the formation of small clumps of inflammatory cells called granulomas. These clumps may accumulate in different tissues and organs, affecting their function.
In addition to first-line treatment with the approved therapy prednisone, immunosuppressive medications and TNF inhibitors have been used as second-line and third-line agents, respectively, in managing sarcoidosis.
However, few studies “have evaluated the efficacy and side effects of second-line and third-line treatments for sarcoidosis,” the researchers wrote.
To learn more, a pair of researchers retrospectively analyzed real-world data from the TriNetX Research Network, which includes de-identified medical records of more than 250 million patients across more than 200 healthcare organizations in the world.
The researchers specifically examined data from 13,814 sarcoidosis patients who received immunosuppressive medications or TNF inhibitors between 2012 and 2023 at 82 institutions, primarily located in the U.S. Clinical outcomes and side effects were analyzed within one year of starting treatment.
Methotrexate was the most commonly used immunosuppressive agent (57.4%), followed by MMF (24.9%), azathioprine (14.9%), and leuflunomide (2.7%).
The researchers employed a statistical method, known as propensity score matching (PSM), to match patients across different treatment groups based on similar characteristics. Because methotrexate was the most commonly used immunosuppressive treatment, patients receiving this therapy served as the reference group.
“After PSM match to patients who received methotrexate, the sample size of MMF, azathioprine, and leflunomide treatment groups were 2,772, 1,986, and 378, respectively,” the researchers wrote.
Patients on MMF had much higher mortality risk than those on methotrexate
Within one year of treatment, patients treated with MMF had a significantly higher risk, by two to four times, of hospitalization, critical care, need for mechanical breathing support, and mortality compared with those on methotrexate.
Participants treated with azathioprine had a 44% higher risk of death relative to those on methotrexate, but comparable risks of hospitalization, critical care, and breathing support.
Patients given MMF or azathioprine had similar risks of liver and kidney adverse events, but increased risks of low levels of blood cells and infections relative to the methotrexate group.
Our findings showed that methotrexate was the most commonly used immunosuppressive agent in the United States, with safety similar to azathioprine and leflunomide, whereas MMF increased infection and bone marrow suppression.
When comparing MMF with azathioprine, MMF was associated with a higher risk for poor outcomes and adverse events. Leflunomide showed similar outcomes and side effects compared with the methotrexate group.
“Our findings showed that methotrexate was the most commonly used immunosuppressive agent in the United States, with safety similar to azathioprine and leflunomide, whereas MMF increased infection and bone marrow suppression,” the researchers wrote.
As such, “leflunomide might be the alternative choice to methotrexate,” while “azathioprine may be the preferred second-line treatment after methotrexate for patients with sarcoidosis,” they added.
Regarding TNF inhibitors, researchers analyzed the one-year outcomes and side effects of infliximab and adalimumab in 1,615 matched patients in each group.
They found that both groups had similar hospital admission and mortality outcomes, but the infliximab group had a twofold higher risk of critical care use. Infliximab-treated patients also had a significantly higher risk of low blood cell counts and pneumonia (a lung infection), but a lower risk of infections affecting the skin and underlying tissues.
TNF inhibitors carried higher risks of hospitalization, liver dysfunction, and potentially life-threatening reactions to an infection than methotrexate, but lower risks of death, blood toxicity, and certain infections than MMF.
“Infliximab is favored as third-line therapy, with adalimumab as an alternative when [blood] toxicity or pneumonia is a concern,” the researchers wrote. “This study highlighted the safety profile of immunosuppressants and TNF inhibitors in sarcoidosis,” but “given the limitations of real-world data, these findings require confirmation in [appropriately-controlled clinical trials].”
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