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Methotrexate-induced pulmonary fibrosis risk examined in 10-year study

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Study generates hypothesis but leaves incidence unknown

The subject of this retrospective study is of great interest. The authors point out that pulmonary fibrosis (as opposed to acute allergic reaction, which is extremely rare) is also extremely uncommon in patients using methotrexate over the long haul. Over 10 years, their data points to a 3.1% incidence of symptomatic pulmonary fibrosis.

The issue here is its generalizability. There were 63 patients who used methotrexate for 10 years or more and 88 who used it for 5 years or more, according to the poster. This must represent a highly selected population. For example, what percent of the total RA/psoriatic arthritis/”inflammatory arthritis” population do these patients represent, i.e., what is the denominator here? The authors stated that the 63 patients who stayed on methotrexate for 10 or more years represent 49% of the 129 patients on methotrexate overall in the study. This is a highly unusual datum, as most of the literature indicates that only 40% or less of patients stay on methotrexate for even 5 years. And this completely ignores the issue of adherence over this long a period; these patients must represent a truly minuscule percentage of the total if they actually stayed on methotrexate with even moderate adherence for 10 years.

Importantly, the authors point out that they had only four cases of symptomatic pulmonary fibrosis. Once more, this points to the highly selective group of patients seen, as this study does not examine patients with asymptomatic pulmonary fibrosis, including those with fibrosis on high-resolution CT of the lungs or chest film or evidence of abnormalities on pulmonary function tests, but who do not have sufficient symptoms ascribed to methotrexate to bring them to medical attention.

Dr. Daniel E. Furst, professor of rheumatology at the University of Washington, Seattle, who also is affiliated with the University of California, Los Angeles, and the University of Florence, Italy.

Dr. Daniel E. Furst

This is a nice hypothesis-generating study, but the actual incidence of methotrexate-induced lung fibrosis remains completely unknown. I heartily applaud their intention to start a prospective study to answer this interesting question.

Daniel E. Furst, MD, is professor of rheumatology at the University of Washington, Seattle, who also is affiliated with the University of California, Los Angeles, and the University of Florence, Italy. He was not involved with the study.



– A 10-year follow up of patients with inflammatory arthritis has shown that methotrexate does not appear to increase the risk of pulmonary fibrosis.

“As rheumatologists, it’s a really important message that methotrexate does not cause chronic pulmonary fibrosis and it should not be stopped because of pulmonary fibrosis,” Julie Dawson, MD, said in an interview at the British Society for Rheumatology annual conference. “It’s the rheumatoid arthritis. It’s not the methotrexate.”

Dr. Dawson, of St. Helens and Knowsley Teaching Hospitals NHS Trust, St. Helens, England, added that the current findings were consistent with her team’s prior research looking at earlier time periods. There was also no correlation between the duration or dose of methotrexate used and the development of the lung disease, she said.

“If anything, the suggestion is you’d be more symptomatic if you delay using methotrexate,” Dr. Dawson observed. If patients are not doing well on methotrexate, then perhaps adjusting therapy or changing to another drug would of course be the next step, but if patients are well controlled then “stopping it is the worst thing to do” for their arthritis, she said.

“This is of great clinical interest, and we can be reassured now about this, I think. This is really good, long-term data,” said Devesh Mewar, MD, of Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, England, who was not involved in the research.

“We know that methotrexate is associated with a pneumonitis reaction, but there is no high-quality evidence that methotrexate is associated with a chronic pulmonary fibrosis” Dr. Dawson said, explaining the rationale for the current study she presented during a poster session. Previous studies considered data for up to 5 years, she added, so the aim of the current study, therefore, was to look at the longer-term effect of methotrexate use on the incidence of pulmonary fibrosis.

Data on 129 patients who had started treatment with methotrexate from 2004 to 2007 were analyzed, of whom 63 (49%) had stayed on methotrexate for 10 or more years. Most (82%) had been given methotrexate to treat rheumatoid arthritis (RA), with other indications including inflammatory arthritis (5.4%) and psoriatic arthritis (4.7%).

“Practice was different 10 years ago, so just 56% of patients commenced methotrexate within the first year of the diagnosis of rheumatoid arthritis,” Dr. Dawson reported.

Dr. Julie Dawson of St. Helens and Knowsley Teaching Hospitals NHS Trust, St. Helens, England Sara Freeman/MDedge News

Dr. Julie Dawson

Only four cases of symptomatic pulmonary fibrosis were seen, all in the RA patients, and three of these were in patients who had started methotrexate over 1 year after their diagnosis. The incidence of 3.8% seen in the study matches the expected incidence of pulmonary fibrosis in RA and was actually “at the lower end of the expected incidence,” Dr. Dawson said. Previous studies have suggested an incidence rate of RA-associated interstitial lung disease of about 3%-7%.

All of the pulmonary fibrosis cases had occurred in men and 75% were seropositive for rheumatoid factor. The mean duration of RA at the time of onset of pulmonary fibrosis was 7.8 years and the usual interstitial pattern of fibrosis was seen. The 125 patients without pulmonary fibrosis had taken methotrexate for a mean of 8 years at a mean final weekly dose of 16.3 mg, compared with a mean of 6 years at a mean dose of 18.1 mg per week in the 4 patients with pulmonary fibrosis.

One of the next steps is to look at cases where methotrexate has been stopped and the effects of that on pulmonary fibrosis and disease activity. In Dr. Dawson’s experience, stopping methotrexate just affects the management of the arthritis and had no difference to the progression of pulmonary fibrosis.

If patients start to experience any lung symptoms while continuing methotrexate, such as shortness of breath, then they would need to be assessed and undergo lung function tests to monitor their condition. Treating the fibrosis using an antifibrotic drug, such as pirfenidone, is something that might be possible in the future, but this needs investigation in inflammatory arthritis as the drug is currently only licensed for use in idiopathic cases.

This is something the British Rheumatoid Interstitial Lung network plans to investigate in a placebo-controlled study of RA patients with fibrotic lung disease. “We’re looking to see if antifibrotic agents are going to slow the disease as it does in idiopathic pulmonary fibrosis, which is obviously quite exciting when it’s such a hard condition to treat,” said Dr. Dawson, who will be one of the study’s investigators.

Dr. Dawson had no conflicts of interest to disclose. Dr. Mewar was not involved in the study and had nothing to disclose.

SOURCE: Dawson J et al. Rheumatology. 2018;57[Suppl. 3]:key075.470.

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