A 2021 review discussing use of non-steroidal treatment in cardiac sarcoidosis describes available studies evaluating the use of various agents. Of 480 cases of cardiac sarcoidosis treated, methotrexate was the synthetic agent used most often (n= 83). It should be noted that studies differed in the criteria used for the diagnosis of cardiac sarcoidosis and typically used methotrexate as an adjunct to low-dose maintenance steroid therapy. Overall, methotrexate generally led to favorable results through improved cardiac imaging and left ventricular ejection fraction, but available data are primarily limited to smaller observational studies and case series/reports (see Table 1). [1]
A 2020 review discusses the management of cardiac sarcoidosis. Once identified, management is primarily based on the use of immunosuppressants, namely corticosteroids. However, there is an overall lack of recommendations or guidelines for optimal treatment. Methotrexate has been utilized both in steroid-saving scenarios and in combination with other steroids, such as prednisone. The benefits are typically observed in small-population studies, or individual case reports, as randomized controlled trials are seldom performed. A prominent study known as the Cardiac Sarcoidosis Multi-Center Randomized Controlled Trial (CHASM CS– RCT) will investigate the efficacy of low- versus standard-dose prednisone in combination with methotrexate and is expected to be completed by December 2024. [2], [3]
The 2021 European Respiratory Society (ERS) guidelines on the treatment of sarcoidosis include recommendations for the management of neurological and cardiac disease. Glucocorticoids are recommended for patients with clinically significant neurosarcoidosis (strong recommendation, very low quality of evidence). In patients with continued disease who have been treated with glucocorticoids, the guidelines recommend adding methotrexate (conditional recommendation, very low quality of evidence). An analysis from a single institution found a significant reduction in the relapse rate of neurosarcoidosis with methotrexate (hazard ratio [HR] 0.47; 95% confidence interval [CI] 0.25 to 0.87; p= 0.02) and hydroxychloroquine (HR 0.37; 95% CI 0.15 to 0.92; p= 0.03), but not with azathioprine (HR 1.88; 95% CI 0.69 to 5.14; p= 0.22) or mycophenolate mofetil (HR 0.58; 95% CI 0.25 to 1.34; p= 0.2). This study also found infliximab significantly lowered relapse rates with sarcoidosis; however, the relapse rate was not significantly lowered with infliximab for neurosarcoidosis. A meta-analysis described the treatment of neurosarcoidosis with methotrexate, azathioprine, and hydroxychloroquine in 27% (144/539) of patients; of the patients who were not switched to third-line therapy, a favorable outcome was observed in 55% (47/85) of patients (95% CI 45 to 66%). A retrospective analysis of patients (Table 3) with neurosarcoidosis treated with either methotrexate (n= 32) or mycophenolate mofetil (n= 14) as part of the regimen showed that methotrexate treatment was associated with a significantly lower yearly relapse rate (0.2 vs. 0.6; p= 0.058) and longer median time to relapse (28 vs. 11 months; p= 0.049). Overall, clinical evidence for the treatment of sarcoidosis is limited since there are no randomized controlled trials, as well as a wide range of outcomes evaluated in retrospective studies of various different medications. [4]
With regards to cardiac sarcoidosis, the ERS guidelines recommend glucocorticoids (with or without other immunosuppressives) for patients with evidence of functional cardiac abnormalities, including heart block, dysrhythmias, or cardiomyopathy (strong recommendation, very low quality of evidence). The most commonly prescribed steroid-sparing immunosuppressive agents reported include methotrexate, azathioprine, mycophenolate mofetil, leflunomide, and cyclophosphamide; evidence to support these therapies is poor and in most studies, patients treated with steroid-spring agents did not have better outcomes than those treated with glucocorticoid monotherapy. However, one single-center study comparing methotrexate plus prednisone compared with prednisone monotherapy suggested improved ejection fraction and brain natriuretic peptide after five years of treatment. [4]
A 2020 review discussed the treatment options for neurosarcoidosis. While corticosteroids are the mainstay of treatment, immunosuppressive agents, including methotrexate, are considered an important treatment option both as a steroid-sparing option and as disease modifiers. Corticosteroids are effective as they reduce inflammation, while immunosuppressants work to prevent recurrence. The author notes that methotrexate has been shown to be better than mycophenolate mofetil in both systemic and neurological disease. The standard dose of methotrexate is 15-20 mg weekly along with folate rescue; the dose can be adjusted according to disease response, corticosteroid dose, and adverse events. [5]
A 2017 review also briefly discusses the role of methotrexate in the treatment of neurosarcoidosis. In patients with partial, or without sustained response to steroids or if long-term treatment is required, methotrexate is a second-line option, along with hydroxychloroquine, azathioprine, and cyclophosphamide. [6]