Rheumatoid arthritis

MTX does not increase risk of ILD in RA patients: study

Suspicions that methotrexate (MTX) may increase the risk of RA-associated interstitial lung disease (ILD) have been allayed by a study showing an inverse association between exposure to the DMARD and the lung disease.

Although MTX has been associated with hypersensitivity pneumonitis, its link to ILD in patients with RA has been disputed, according to Dr Pierre-Antoine Juge of the Bichat-Claude Hospital in Paris.

In a presentation at the EULAR 2020 Virtual Congress, Dr Juge said ILD was a frequent extra-articular manifestation in RA, detected by CT in up to 30% of patients and with a high frequency of the usual interstitial pneumonia (UIP) pattern.

MTX had been suspected as a possible contributory factor but studies to date have been limited by numerous biases and inconsistencies, he said.

Therefore in a retrospective case control study, Dr Juge and colleagues investigated the association between MTX exposure in 100 RA-ILD patients and 165 RA patients without ILD. They replicated the analysis in a further 382 RA-ILD patients to give a combined pooled data of 482 RA-ILD patients and 741 RA patients with no ILD.

After excluding patients with MTX-related hypersensitivity pneumonitis they found that the significant risk factors for ILD in RA patients were being male, smoking and older age at onset of RA.

The period of exposure to MTX was significantly longer for patients without ILD compared to those with ILD (13 vs six years, p <0.0001). Similarly, there were significantly higher rates of ever use of MTX (91.6% vs 74.3%, p <0.0001) in patients without ILD compared to those with ILD, and also of cumulative dose exposure (3.9g vs 1g p< 0.001).

The odds ratio of ILD risk with MTX exposure was 0.41 (0.27-0.63), which was similar to that seen (0.38) in a pooled analysis of results from other studies.

The inverse relationship was seen across all patterns of ILD on high-resolution CT, including both UIP  and non-UIP.

Dr Juge said it can now be concluded that with the exception of MTX-related hypersensitivity pneumonitis, MTX should not be considered as causal factor for RA-associated ILD.


However it was still not known whether MTX use influenced the prognosis of ILD, and therefore “the discontinuation of MTX should be discussed in a multidisciplinary discussion including at least a rheumatologist and pulmonologist,” he advised

And while the study showed that MTX use was  associated with a delayed onset of ILD, this would need to be confirmed in a dedicated prospective randomised controlled trial, he added.

In a separate study presented at EULAR 2020 virtual meeting, researchers from Spain showed that neither csDMARDs nor anti-TNF agents were associated with significant worsening of ILD in RA patients.

In a follow up at 24 months of DMARD treatment in RA they also showed that non-antiTNF biologics were associated with less progression of lung disease (Odds Ratio 0.102, p< 0.019). The factors associated with worsening progression of lung disease were smoking and poor DAS28 scores.

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