Pulmonary Adverse Events in Patients Receiving Low‐Dose Methotrexate in the Randomized, Double‐Blind, Placebo‐Controlled Cardiovascular Inflammation Reduction Trial

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 72; no. 12; pp. 2065 - 2071
• Main Authors: Sparks, Jeffrey A., Dellaripa, Paul F., Glynn, Robert J., Paynter, Nina P., Xu, Chang, Ridker, Paul M., Solomon, Daniel H.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.12.2020
• Subjects: Adult; Age Factors; Cardiovascular diseases; Cardiovascular Diseases - prevention & control; Confidence intervals; Diabetes mellitus; Double-Blind Method; Double-blind studies; Female; Humans; Immunomodulators; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - therapeutic use; Inflammation - prevention & control; Inflammatory diseases; Insulin; Lung diseases; Male; Metabolic disorders; Metabolic syndrome; Methotrexate; Methotrexate - adverse effects; Methotrexate - therapeutic use; Middle Aged; Pneumonia - chemically induced; Pneumonitis; Race; Reduction; Risk analysis; Risk Factors; Sex; Sex Factors; Sex ratio
• ISSN: 2326-5191; 2326-5205; 2326-5205
• DOI: 10.1002/art.41452

Objective We previously reported that low‐dose methotrexate (MTX) was associated with an increased risk of pulmonary adverse events (AEs) in a large randomized, placebo‐controlled trial. Herein, we report details on the predictors and severity of pulmonary AEs. Methods We 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 6–8‐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. We described severe pulmonary AEs and examined associations of baseline characteristics with pulmonary AEs in patients receiving low‐dose MTX. Results 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%) and 7 cases of possible pneumonitis (0.3%) in the low‐dose MTX group, compared to 8 (0.3%) and 1 (<0.1%), respectively, 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 versus male sex [95% confidence interval (95% CI) 1.16–2.45]), white race (HR 2.35 versus 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]). Conclusion In this large placebo‐controlled trial, pulmonary AEs, including possible pneumonitis, were uncommon but were 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.