Methotrexate and rheumatoid arthritis associated interstitial lung disease

Abstract

<jats:sec><jats:title>Question addressed by the study</jats:title><jats:p>Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Through a case-control study design with discovery and international replication samples, we examined the association of MTX exposure with ILD in 410 patients with chronic fibrotic ILD associated with RA (RA-ILD) and 673 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Analysis of the discovery sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted odds ratio [OR], 0.46; 95% confidence interval [CI], 0.24–0.90; p=0.022), which was confirmed in the replication samples (pooled adjusted OR, 0.39; 95% CI, 0.19–0.79; p=0.009). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI, 0.26–0.69; p=0.0006). MTX ever users were less frequent among patients with RA-ILD compared to those without ILD, irrespective of chest high resolution computed tomography pattern. In patients with RA-ILD, ILD detection was significantly delayed in MTX ever users compared to never users (11.4±10.4 years and 4.0±7.4 years, respectively; p&lt;0.001).</jats:p></jats:sec><jats:sec><jats:title>Answer to the Question</jats:title><jats:p>Our results suggest that MTX use is not associated with an increased risk of RA-ILD in patients with RA, and that ILD was detected later in MTX treated patients.</jats:p></jats:sec>

Does methotrexate cause progressive fibrotic interstitial lung disease? A systematic review

“…Extended analysis, showed MTX exposure was associated with a reduced risk of developing incident ILD [Odds Ratio (OR) 0.48 P = 0.004] and longer time to ILD diagnosis (OR 0.41 P = 0.004). Juge et al [ 30 ] undertook a case–control study in 410 patients with HRCT diagnosed with fibrotic RA-ILD and 673 patients with RA without ILD on HRCT. The combined estimate revealed an adjusted OR of 0.43 (95% CI 0.26–0.69; P = 0.0006) in MTX ever users for ILD.…”

“…This may have led to the clinical picture becoming muddled in some cases. Two recent studies have shown MTX reduces the risk of developing fILD, delaying its onset [ 29 , 30 ] and one found MTX treatment was clinically and statistically associated with improved survival [ 28 ]. These findings are very much against MTX causing or exacerbating ILD in patients with RA and in fact may indicate some sort of protective mechanism afforded by use of MTX at least in RA f ILD cohorts.…”

Progression in the Management of Non-Idiopathic Pulmonary Fibrosis Interstitial Lung Diseases, Where Are We Now and Where We Would Like to Be

“…The effect of immunosuppressive agents in RA-UIP remains unclear, and patients with inflammatory types of ILD, such as NSIP and organizing pneumonia, generally have a better response to immunosuppressive agents. There are historical concerns about methotrexate (MTX)-related hypersensitivity pneumonitis and the association between MTX and RA-ILD, but in a recent study by Juge et al, MTX was not associated with an increased risk of RA-ILD, and ILD detection was delayed by 3.6 years [ 55 ].…”

Biomarkers for interstitial lung disease and acute-onset diffuse interstitial lung disease in rheumatoid arthritis

“…16,17 Recent studies indicate that treatment with methotrexate does not increase the risk of chronic ILD in RA. [18][19][20]…”

“… 16 , 17 Recent studies indicate that treatment with methotrexate does not increase the risk of chronic ILD in RA. 18 – 20 The pathogenesis of AoDILD is believed to involve “immune reconstitution inflammatory syndrome” caused by infection by pathogens including Pneumocystis jirovecii . 21 Patients with collagen disease treated with immunosuppressive drugs may be affected by immune reconstitution inflammatory syndrome.…”