ARTHRITIS & RHEUMATOLOGY Vol. 66, No. 4, April 2014, pp 803–812 DOI 10.1002/art.38322 © 2014, American College of Rheumatology Methotrexate and Lung Disease in Rheumatoid Arthritis A Meta-Analysis of Randomized Controlled Trials Richard Conway, 1 Candice Low, 2 Robert J. Coughlan, 1 Martin J. O’Donnell, 3 and John J. Carey 1 Objective. Methotrexate has shown efficacy for the treatment of several diseases, especially rheumatoid arthritis (RA). Methotrexate has also been implicated as a causative agent in interstitial lung disease. Patients with RA may develop pulmonary manifestations of their disease and are at increased risk of respiratory infec- tion. The aim of this study was to evaluate the relative risk (RR) of pulmonary disease among patients with RA treated with methotrexate. Methods. We searched the PubMed and Cochrane databases (publication dates January 1, 1990 to Febru- ary 1, 2013) for double-blind, randomized, controlled trials of methotrexate versus placebo or active compar- ator agents in adults with RA. Studies with <100 subjects or with a duration of <24 weeks were excluded. Two investigators independently searched both data- bases, and all of the investigators reviewed the selected studies. We compared differences in the RR using the Mantel-Haenszel random-effects method. Results. A total of 22 studies with 8,584 partici- pants met the inclusion criteria. Heterogeneity across studies was not significant (I 2  3%), allowing combi- nation of the trial results. Methotrexate was associated with an increased risk of all adverse respiratory events (RR 1.10, 95% confidence interval [95% CI] 1.021.19) and respiratory infection (RR 1.11, 95% CI 1.021.21). Patients treated with methotrexate were not at in- creased risk of death due to lung disease (RR 1.53, 95% CI 0.465.01) or noninfectious respiratory events (RR 1.02, 95% CI 0.651.60). A subgroup analysis of studies in which pneumonitis was described revealed an in- creased risk associated with methotrexate (RR 7.81, 95% CI 1.7634.72). Conclusion. Our study demonstrated a small but significant increase in the risk of lung disease in pa- tients with RA treated with methotrexate compared with other disease-modifying antirheumatic drugs and bio- logic agents. Rheumatoid arthritis (RA) is a chronic inflam- matory disease affecting 1% of the population in the industrialized world (1). Patients with RA are at signif- icant risk of disability and have increased mortality (1–6). Manifestations of RA include interstitial lung disease, and a higher rate of pulmonary infection in patients with RA contributes to overall and pulmonary- related fatalities (3,4,7). Methotrexate (MTX) has shown efficacy in treat- ing several diseases, including RA, psoriasis, psoriatic arthritis, inflammatory bowel disease, and small-vessel vasculitis (8). MTX is the most commonly recommended first-line disease-modifying treatment of RA (5,6). How- ever, MTX is also implicated as a causative agent in lung disease (9–13). The incidence of MTX-related lung disease has been reported to be as high as 7.6% (9–11). Two forms of lung disease have been attributed to MTX. MTX-related interstitial lung disease presents most commonly during the first year of treatment, and re- ported pathologic findings in different studies include neutrophil infiltration, lymphocytic infiltration, alveoli- tis, and an increased CD4+:CD8+ ratio (14–16). Chronic pulmonary fibrosis due to MTX has been reported in case series (17,18); however, longitudinal 1 Richard Conway, MB, Robert J. Coughlan, MB, John J. Carey, MB: Galway University Hospitals, Merlin Park, Galway, Ireland; 2 Candice Low, MB: St. James’s Hospital, Dublin, Ireland; 3 Martin J. O’Donnell, PhD: National University of Ireland, Galway, Ireland. Address correspondence to Richard Conway, MB, Depart- ment of Rheumatology, Galway University Hospitals, Merlin Park, Galway, Ireland. E-mail: drrichardconway@gmail.com. Submitted for publication August 16, 2013; accepted in revised form December 12, 2013. 803