Rheumatoid arthritis

New details emerge on pulmonary injury with low-dose MTX


A major trial has provided more details about the risk of lung injury with low-dose methotrexate (MTX), and in particular for MTX-related pneumonitis.

One of the largest studies ever of low-dose methotrexate use – involving 2,391 people randomised to receive the drug – showed a rate of severe pulmonary adverse events of 0.5%, with more than half of these (0.3%) being pneumonitis.

The findings published in Arthritis and Rheumatology, come from a US trial whose goal was to investigate the anti-inflammatory effects of MTX in adults with coronary artery disease. The mean age of the participants was 66 years, 19% were female, the median MTX dose was 16 mg/week and follow up was for an average of two years.

The study investigators said that while the rate of severe lung adverse events seen with MTX was low, it was higher than seen in a placebo group, and in some cases the clinical course of pneumonitis was severe.

Nearly all of the suspected pneumonitis cases had chest imaging showing interstitial changes or fibrosis Two of the seven cases in the low-dose MTX group died of severe pulmonary complications of progressive interstitial lung disease.

The severe lung adverse events included shortness of breath and bronchitis, and in many cases were due to exacerbation of pre-existing lung disease

Risk factors for lung injury with MTX were female sex (hazard ratio 1.69), white race (HR 2.35) and insulin use (HR 1.60), while old age was a risk factor for severe pulmonary adverse events (HR 1.09 per year increase).

The study investigators said the clinical course of severe lung adverse effects was similar to that seen in previous studies in patients with RA, with subacute presentation over several weeks preceding clinical onset, peaking at around nine months after the initiation of low-dose MTX.

They noted that previous studies in patients with RA had suggested rates of severe lung injury as high as 7% with low dose MTX, “but the predilection of patients with systemic rheumatic diseases for pneumonia or disease-related pulmonary inflammation/fibrosis makes attribution of lung inflammation to low-dose MTX difficult.”

“While we advocate continued use of low-dose MTX in RA and other systemic rheumatic diseases, clinicians should consider obtaining baseline chest imaging due to the susceptibility to pneumonitis and propensity for inflammatory lung disease from the underlying rheumatic disease,” they suggested.

“Pulmonary symptom surveillance should be universal in patients receiving low-dose MTX,” they added.

However the case for routine chest radiography before starting low-dose MTX was questioned in an accompanying commentary by rheumatologist Dr Joel Kremer, Director of the Research division at the Center for Rheumatology, Albany New York.

Instead, he said there is an opportunity to intervene if patients show pulmonary symptoms such as dry cough that characterise the three to four weeks of a subacute (3–4-week) syndrome prior to evolution of full-blown MTX-associated pneumonitis.

“Anecdotally, over several decades we have seen many patients with RA receiving MTX who have presented with a new dry cough or pleuritic-type chest pain. Depending on the severity of the symptoms, we have simply lowered the weekly dose with instructions to skip the next weekly dose prior to initiating the new lower dose. In all cases in which the weekly dose was lowered, the pleuritic symptoms resolved in this somewhat limited experience,” he wrote.

Dr Kremer said he would obtain chest imaging if cough did not resolve, if there was dyspnea or tachypnea, or  finding of new rales on pulmonary examination.

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