Methotrexate and risk of interstitial lung disease and respiratory failure in rheumatoid arthritis: a nationwide population-based study

Abstract

Objectives MTX is the most commonly recommended DMARD for first-line treatment of RA, however, it has been hypothesized to cause lung disease as an adverse effect. We investigated the risk of interstitial lung disease (ILD) and acute and chronic respiratory failure in persons with RA treated with MTX and other medications. Methods From the Danish National Patient Register (NPR) and the DANBIO register for rheumatic diseases, we retrieved data on 30 512 persons with RA registered in 1997–2015. Information on ILD and respiratory failure was obtained from the NPR. Information on age and sex for all Danish citizens was obtained from the Danish Civil Registration System. MTX and other medication purchases were retrieved from the Danish Prescription Registry. Associations between MTX and lung disease outcomes were analysed in Cox regression models with adjustment for age, calendar time, sex and other medications. Standardized incidence ratios (SIRs) of lung disease were calculated to compare the RA population with the general population. Results There was no increased risk of lung disease with MTX treatment [one or more purchases compared with no purchases; HR 1.00 (95% CI 0.78, 1.27) for ILD and 0.54 (95% CI 0.43, 0.67) for respiratory failure] at the 5 year follow-up. The SIR was three to four times higher for ILD in MTX-treated persons with RA, but similar to the whole RA population compared with the background population. Conclusion Persons with RA had an increased risk of ILD compared with the general population, but there was no further increased risk associated with MTX treatment.

Interstitial Lung Disease in Connective Tissue Disease: A Common Lesion With Heterogeneous Mechanisms and Treatment Considerations

“…Although MTX-induced ILD is well-established by many studies, there is some emerging conflicting evidence suggesting no association between MTX and RA-ILD ( 108 ). For example, a study of MTX use and the risk of ILD in RA patients demonstrated that there was no further increase in risk associated with MTX treatment ( 109 ). Other studies have also reported similar findings suggesting that MTX may delay the onset of ILD ( 110 , 111 ).…”

“…The types of pulmonary manifestations may vary by underlying CTD diagnosis ( Table 2 ). The prevalence and mortality of ILD for each CTD are different, and the prevalence of ILD secondary to various CTDs varies as follows: 1 to 15% in SLE ( 106 ), 6.5 to 33% in RA ( 107 , 108 ), 19.9 to 86% in PM/DM ( 109 , 110 ), 86% in anti-Jo-1 positive patients ( 111 ), 40 to 91% in SSc ( 112 , 113 ), 47 to 90% in MCTD based on radiologic feature ( 108 , 114 ), and 9 to 20% in SS ( 115 ). Related reports indicate the mortality of ILD is 20% in RA-ILD ( 116 , 117 ), 12 to 44% in PM/DM ( 118 ), and a 10-year mortality of up to 40% in SSc ( 119 ).…”

Choosing pharmacotherapy for ILD in patients with connective tissue disease

“…In this cohort higher rates of RA-ILD were found in those who had never taken MTX (4.8%) compared with those who had (2.5%), and MTX use was associated with a longer time to the development of ILD. Several other studies have further supported these findings [38][39][40][41]; therefore, MTX should no longer be routinely discontinued in the rheumatoid patient with well-controlled joint disease who develops ILD.…”

Lunge – Interstitielle Lungenerkrankungen in der Rheumatologie

“…Im Gegenteil, bei Patienten mit RA zeigte sich ein selteneres und späteres Auftreten einer RA-ILD und eine geringere Mortalität, wenn diese mit MTX behandelt wurden. Es darf bei noch limitierter Datenlage also davon ausgegangen werden, dass MTX Häufigkeit und Verlauf einer ILD positiv beeinflusst, zumindest bei Patienten mit RA [25][26][27].…”