Best of 2019 - Methotrexate and the Risk of Lung Disease Save

Rheumatology has a comprehensive overview of methotrexate (MTX) and the risk of lung injury, MTX-related pneumonitis and interstitial lung disease (RA-ILD) with rheumatoid arthritis (RA).  Past reports suggest the frequence of MTX-pneumonitis to be between 0.3 and 11.6%; recent studies suggest it may be much lower.

Clinical criteria for the diagnosis of MTX pneumonitis (acute, reversible) and RA-ILD (chronic, progressive) are quite different and are reviewed in this article.

Despite the large numbers of clinical trials that include MTX, very few of these are suitable for use to analyse the risk of MTX pneumonitis.

There are, however, 2 metanalyses that examined this issue and included 22 RCTs with 8584 patients. Overall they found that MTX was associated with an increased risk of total respiratory adverse events (RR 1.10; 95% CI 1.02, 1.19), with most of this risk being of increased infectious risks rather than non-infectious events. 

The authors believe that prior reports suggest two distinct patterns of lung disease influenced by MTX in RA.

1. A slight but significant increase risk of respiratory infections with MTX. (there appears to be no risk associated with the use of biologics, but there is a risk associated with the use of glucocorticoids.  The risk of pneumonia with MTX should support the use pneumococcal vaccination in this patient group.
2. Another study suggests there is an increased risk of MTX-induced pneumonitis. Even though the RR is 7.8, the absolute risk is small and possibly decreasing, with 13 in 4544 patients (0.3%).

In review of other clinical trial and observational outcomes they note that the large CIRT trial (studied the effect of MTX in cardiac outcomes) enrolled 4786 (non-RA) patients, randomized them to either placebo or MTX and after a median follow-up was 2.3 years, there were no cases of MTX pneumonitis reported. 

The authors also reviewed the often confused issue of MTX induced pneumonitis and whether MTX may contribute to or cause rheumatoid interstitial lung disease (RA-ILD) and found no convincing cause–effect relationship between MTX use and development of RA-ILD.

Nevertheless, there are some studies suggesting caution when prescribing MTX in patients with pre-existing lung disease. Many of these studies note that ILD appears to be a risk factor for MTX pneumonitis or MTX associated worsening of ILD. Yet, there are several studies showing that in patients with RA-ILD, use of MTX was associated with better outcomes or survival.  It appears that if MTX is used in patients with RA-ILD, close monitoring is warranted.

Takeaway messages from this overview include:

• Frequency of MTX-related pneumonitis has fallen, and is rarer than previously thought
• It seems that MTX is not associated with interstitial lung disease development in RA
• Caution is needed when commencing MTX in RA patients with pre-existing lung disease