Lung Disease in Methotrexate-Treated Patients with Rheumatoid Arthritis

Summary and Comment |
April 29, 2014

Lung Disease in Methotrexate-Treated Patients with Rheumatoid Arthritis

  1. Jonathan S. Coblyn, MD

In a meta-analysis, methotrexate was associated with slightly higher risk for adverse respiratory events.

  1. Jonathan S. Coblyn, MD

Pulmonary manifestations (e.g., interstitial lung disease, pleural effusions, nodules) are common in patients with rheumatoid arthritis (RA); the differential diagnosis includes infection, RA itself, and adverse effects of RA drugs. Drugs that have been implicated in causing pulmonary complications include the nonbiologic agents sulfasalazine, methotrexate, and leflunomide, as well as several biologic agents. Methotrexate has been implicated most often, but incidence of methotrexate-related lung disease among patients with RA is unknown. To assess risk for pulmonary disease among methotrexate-treated RA patients, investigators conducted a meta-analysis of 22 randomized, controlled trials (duration range, 24–104 weeks) of methotrexate versus other agents or placebo.

Mortality from lung disease was no higher among patients treated with methotrexate than among those in the comparator groups; however, methotrexate-treated patients were at slightly but significantly higher risk for all adverse respiratory events (relative risk, 1.10) and total infectious adverse respiratory events (RR, 1.11).


This study confirms our clinical suspicion that methotrexate is associated with higher risk for pulmonary complications than are other agents used in treating RA patients. In fact, methotrexate-induced pulmonary complications might be underrepresented in this study: Maximum follow-up was 2 years, and events have been reported to occur after that. However, the rheumatologist and the primary care physician can take comfort in the fact that excess risk for pulmonary complications in methotrexate-treated RA patients was very small, and no deaths from lung disease were attributed to methotrexate. A limitation of this analysis is that we are not told how respiratory or pulmonary events were defined in these studies.

Editor Disclosures at Time of Publication

  • Disclosures for Jonathan S. Coblyn, MD at time of publication Equity Johnson & Johnson


Reader Comments (6)

ali asghar ebrahimi Physician, Rheumatology, Tabriz - IRAN

Some of the RA patients , had lung problems so ILD ,IPF ,ASTHMA,etc apparently before the diagnosis of RA .
In this group of patients,there is a seriously chalenge for MTX use as a safe DMARD.9 exacerbation of lung problem)

Terry Satterwhite Infectious Disease, retired

What are the indications for methotrexate in arthritis?

phani kumar Resident, Rheumatology, nims institute,hyderabad

methotrexate is commonly used dmard in rheumatoid arthritis.conflicting studies regarding methotrexate causing ild and definitions of mtx induced ild ,is it necessary to follow up with regular PFT in patients with RA ,Dilemma ?

Paul DeMarco Physician, Rheumatology, Arthritis and Rheumatism Associates PC Wheaton MD

No one has confirmed that PFTs are cost effective for following methotrexate use in RA. It would be an interesting research topic, though, to answer the question of utility. The problem arises as to the cost efficiency of PFTS for the number of events you would detect.

E S MATE Physician, Pulmonary Medicine, solo practice

I wonder if MTX can contribute to re activation of Latent TB and if chemo prophylaxis is indicated?
Would welcome comments.

Paul DeMarco Physician, Rheumatology, Arthritis and Rheumatism Assoc Wheaton MD

Latent tb has not been shown to be activated with methotrexate use alone. The use of anti-TNF agents, such as etanercept, adalimumab and infliximab clearly do reactivate latent tb. In early studies of these compounds, the comparator groups were methotrexate alone, and the incidence did not exceed background activity which strongly suggests that methotrexate use is not the issue. Rheumatologist will routinely treat latent tb in anticipation of starting a biologic, and currently treatment for several weeks seems adequate to allow the practitioner to move forward with therapy. The journal J Rheumatology has a whole subsection dedicated to this topic in the last several months if you are interested

Your Comment

(will not be published)

Filtered HTML

  • Allowed HTML tags: <a> <em> <strong> <cite> <blockquote> <code> <ul> <ol> <li> <dl> <dt> <dd>
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Do you have any conflict of interest to disclose?
This question is for testing whether you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

* Required

Reader comments are intended to encourage lively discussion of clinical topics with your peers in the medical community. We ask that you keep your remarks to a reasonable length, and we reserve the right to withhold publication of remarks that do not meet this standard.

PRIVACY: We will not use your email address, submitted for a comment, for any other purpose nor sell, rent, or share your e-mail address with any third parties. Please see our Privacy Policy.