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 Table of Contents  
Year : 2020  |  Volume : 15  |  Issue : 1  |  Page : 61-62

Methotrexate does not cause interstitial lung disease

Department of Rheumatology, ISIC Superspeciality Hospital, New Delhi, India

Date of Web Publication30-Mar-2020

Correspondence Address:
Prof. Anand Narayan Malaviya
Flat 2015, Sector B-2, Vasant Kunj, New Delhi - 110 070
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_184_19

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How to cite this article:
Malaviya AN. Methotrexate does not cause interstitial lung disease. Indian J Rheumatol 2020;15:61-2

How to cite this URL:
Malaviya AN. Methotrexate does not cause interstitial lung disease. Indian J Rheumatol [serial online] 2020 [cited 2022 Jan 28];15:61-2. Available from:

Dear Editor,

The article "Drug-induced interstitial lung disease" by Lee and Hissaria in the special issue of the journal (2019;14:S19–26)[1] mentions methotrexate (MTX) as a cause of interstitial lung disease (ILD). However, the quoted reference (cross-reference number 27 of their article by Skeoch et al.) as a proof of MTX–ILD association and other publications provide the evidence to the contrary. Skeoch et al. state "Interestingly, no events were reported after 2002 in the RA meta-analysis, suggesting potential reporting bias or historic over-estimation of risk." A cross-reference in this article, a meta-analysis of randomized controlled trials,[2] states "Methotrexate was associated with an increased risk of total infectious adverse respiratory events but was not associated with an increased risk of total noninfectious respiratory adverse events. There was no difference in the risk of death due to lung disease between the 2 groups (RR 1.53, 95% CI 0.46-5.01, 12 = 0%)." This article also mentions one death due to MTX-hypersensitivity pneumonitis; hypersensitivity pneumonitis should not be confused with ILD, they are unrelated.[3] Also, by itself, it is an extremely rare condition (0.43%) and mysteriously, its incidence seems to be decreasing during this millennium.[3]

Additional articles on the issue of MTX–ILD provide proof against any association of MTX with ILD.[4],[5],[6] Thus, one article observed that MTX-treated patients with psoriatic arthritis and Crohn's disease have never been reported having developed ILD.[4] In a recent multivariate analysis, MTX was shown to be actually preventive of ILD in rheumatoid arthritis (RA).[5] The study was based on two multicentric early RA inception cohorts in the UK, the Early RA Study (ERAS) (1986–2001) and the Early RA Network (2002–2012) study with 1465 and 1236 patients from 9 and 23 different hospitals with a median follow-up of 10 years and 6 years, respectively, where STROBE reporting cohort guidelines were followed. The results were as follows: of 1578 MTX-exposed cases, ILD was not diagnosed in 1539 (97.5%), whereas ILD was diagnosed in 39 (2.5%) cases. In contrast, in 1114 cases not exposed to MTX, ILD was not diagnosed in 1061 (95.2%), whereas ILD was diagnosed in 53 (4.8%). It was concluded that MTX exposure was associated with a significantly reduced odds ratio (OR) of developing ILD (OR = 0.51, 95% confidence interval [CI] = 0.32–0.79, P = 0.001). Another recent article concluded that "However, treatment should not be delayed or limited in progressive RA that could lead to RA-ILD, and MTX remains one of the central players in the treat-to-target approach. In this review, we aimed to summarize the current evidence from observational studies and clinical trials on lung disease in MTX-treated RA patients. We focus the discussion on the lack of association between M-pneu (MTX-related hypersensitivity pneumonitis) and RA-ILD."[3]

In conclusion, with such overwhelming evidence against linking MTX with ILD, we should not deny this "anchor drug" for our patients. Moreover, one of the rarest of the rare adverse effects of MTX on lung, i.e., hypersensitivity pneumonia, occurs in 0.43%[3] with more recent evidence that it may be even less common and it does not lead to ILD.[3]

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Conflicts of interest

There are no conflicts of interest.

  References Top

Lee WI, Hissaria P. Drug-Induced Interstitial Lung Disease. Indian J Rheumatol 2019;14, Suppl S1:19-26.  Back to cited text no. 1
Conway R, Low C, Coughlan RJ, O'Donnell MJ, Carey JJ. Methotrexate and lung disease in rheumatoid arthritis: A meta-analysis of randomized controlled trials. Arthritis Rheumatol 2014;66:803-12.  Back to cited text no. 2
Fragoulis GE, Conway R, Nikiphorou E. Methotrexate and interstitial lung disease: Controversies and questions. A narrative review of the literature. Rheumatology (Oxford) 2019;58:1900-6.  Back to cited text no. 3
Conway R, Low C, Coughlan RJ, O'Donnell MJ, Carey JJ. Methotrexate use and risk of lung disease in psoriasis, psoriatic arthritis, and inflammatory bowel disease: Systematic literature review and meta-analysis of randomised controlled trials. BMJ 2015;350:h1269.  Back to cited text no. 4
Kiely P, Busby AD, Nikiphorou E, Sullivan K, Walsh DA, Creamer P, et al. Is incident rheumatoid arthritis interstitial lung disease associated with methotrexate treatment? Results from a multivariate analysis in the ERAS and ERAN inception cohorts. BMJ Open 2019;9:e028466.  Back to cited text no. 5
Dawson JK, Earnshaw BA, Rahiman I, Kapoor D. No evidence that pulmonary fibrosis as a complication of long term methotrexate use: 10 year follow up data of patients treated with methotrexate for inflammatory arthritis. Rheumatology 2018;57:246.  Back to cited text no. 6


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