Pulmonary AE risk factors identified in low-dose methotrexate trial
medwireNews: White race, female sex, and insulin use may be associated with an increased risk for pulmonary adverse events (AEs) among individuals undergoing treatment with low‐dose methotrexate (LD‐MTX), US study data show.
The findings from the Cardiovascular Inflammation Reduction Trial extend those of a previous analysis of the same data that found LD-MTX use was associated with an increased risk for any pulmonary AE.
The study included 4786 adults (mean age 66 years, 19% women) with a history of myocardial infarction or multi-vessel coronary artery disease, diabetes, or metabolic syndrome who were randomly assigned to undergo treatment with LD‐MTX (target dose 15–20 mg/week; n=2391) or placebo (n=2395) after a 5- to 8-week run-in period with open‐label LD‐MTX.
Jeffrey Sparks (Brigham and Women’s Hospital, Boston, Massachusetts) and co-investigators note that individuals with systemic inflammatory diseases were excluded from the study. This is important because “pulmonary manifestations of systemic rheumatic diseases such as interstitial lung disease unrelated to LD-MTX make causal inference to LD-MTX difficult in observational studies,” they remark.
During a median 23 months of follow-up, 5.7% of participants in the LD-MTX group and 5.6% of those in the placebo group experienced a pulmonary AE.
The corresponding rates of severe pulmonary AEs were 0.5% and 0.3% (n=13 and n=8, respectively), which included seven (0.3%) cases of possible pneumonitis in the LD-MTX group, and one (<0.1%) case of possible pneumonitis in the placebo group.
The remaining severe pulmonary AEs comprised four reports of shortness of breath and two of bronchitis in the LD-MTX group and seven reports of shortness of breath in the placebo group.
The most common presenting symptoms among the individuals with possible pneumonitis were subacute worsening of dyspnea (n=6) and dry cough (n=2), while there was one case each of acute on chronic worsening dyspnea and acute dyspnea.
After adjustment for potential confounders among patients in the LD-MTX group, Sparks and team report that White race, female sex, and insulin use were each independently associated with a significantly increased risk for any pulmonary AE, at hazard ratios (HRs) of 2.35, 1.69, and 1.60, respectively.
The only variable significantly associated with an increased risk for severe pulmonary AEs was age at baseline, with each additional year increasing the risk by 9%.
Writing in Arthritis & Rheumatology, Sparks and co-authors conclude that their findings “add important new details regarding [the] pulmonary safety profile of LD-MTX.”
They say: “While we advocate continued use of LD-MTX in [rheumatoid arthritis] and other systemic rheumatic diseases, clinicians should consider obtaining baseline chest imaging due to the susceptibility of pneumonitis and propensity for inflammatory lung disease from the underlying rheumatic disease.”
The authors also believe that “[p]ulmonary symptom surveillance should be universal during the use of LD-MTX.”
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