Introduction & Objectives
Low-dose methotrexate (MTX; typically prescribed at doses of 10–25 mg/week) for systemic rheumatic diseases may induce relatively mild pulmonary adverse events (AEs), such as cough and dyspnea. However, a very small proportion of patients may experience severe pulmonary manifestations, such as pneumonitis, a relatively rare syndrome characterized by fever, shortness of breath, eosinophilia, and interstitial lung abnormalities on chest imaging. In some patients, the condition may progress to permanent lung damage. Prior studies suggest that pneumonitis occurs in 0.1–1% of patients receiving low-dose MTX.
In this study, Sparks et al. report details on the predictors and severity of pulmonary AEs in patients taking low-dose MTX.
The researchers conducted a prespecified analysis of pulmonary AEs in the Cardiovascular Inflammation Reduction Trial. Adults with known cardiovascular disease and diabetes/metabolic syndrome were randomly allocated to receive low-dose MTX (target dose 15–20 mg/week) or placebo after a six- to eight-week open-label run-in phase in which all patients received low-dose MTX. Individuals with systemic inflammatory diseases were excluded. Pulmonary AEs were adjudicated in a blinded manner. They described severe pulmonary AEs and examined associations of baseline characteristics with pulmonary AEs in patients receiving low-dose MTX.
A total of 2,391 subjects were randomized to receive low-dose MTX and 2,395 to receive placebo. There were 13 severe pulmonary AEs (0.5%) in the low-dose MTX group, compared with eight (0.3%) in the placebo group, and seven cases of possible pneumonitis (0.3%) in the low-dose MTX group, compared with one (<0.1%) in the placebo group. Among those randomized to receive low-dose MTX, risk factors for any pulmonary AE included female sex (hazard ratio [HR] 1.69 vs. male sex [95% confidence interval (95% CI) 1.16–2.45]), white race (HR 2.35 vs. other race [95% CI 1.03–5.36]), and insulin use (HR 1.60 versus non-use [95% CI 1.11–2.30]). The only risk factor for severe pulmonary AEs was older age at baseline (HR 1.09 per year increase [95% CI 1.02–1.16]).
In this large placebo-controlled trial, pulmonary AEs, including possible pneumonitis, were uncommon but more likely to occur in those randomized to receive low-dose MTX. White race, older age, male sex and insulin use were associated with an increased risk of pulmonary AEs in those receiving low-dose MTX.
The researchers conclude, “we found that low-dose MTX increased the risk of pulmonary AEs, including possible pneumonitis. … While we advocate continued use of low-dose MTX in RA and other systemic rheumatic diseases, clinicians should consider obtaining baseline chest imaging due to the susceptibility to pneumonitis and propensity for inflammatory lung disease from the underlying rheumatic disease. Pulmonary symptom surveillance should be universal in patients receiving low-dose MTX.”