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 Table of Contents  
Year : 2020  |  Volume : 15  |  Issue : 1  |  Page : 63

Response to: “methotrexate does not cause interstitial lung disease”

1 Department of Clinical Immunology and Allergy, Royal Adelaide Hospital, Adelaide, SA, Australia
2 Department of Clinical Immunology and Allergy, Royal Adelaide Hospital; Department of Immunopathology, SA Pathology, Adelaide, SA, Australia

Date of Web Publication30-Mar-2020

Correspondence Address:
Dr. Pravin Hissaria
Department of Clinical Immunology and Allergy, Royal Adelaide Hospital, Adelaide, SA 5000
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_27_20

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How to cite this article:
Lee WI, Hissaria P. Response to: “methotrexate does not cause interstitial lung disease”. Indian J Rheumatol 2020;15:63

How to cite this URL:
Lee WI, Hissaria P. Response to: “methotrexate does not cause interstitial lung disease”. Indian J Rheumatol [serial online] 2020 [cited 2022 Aug 12];15:63. Available from:

Dear Editor,

Thanks to Prof. A N Malaviya for the insightful response to our review article entitled, “drug-induced interstitial lung disease.” Regarding the apparently reduction in incidence of methotrexate-related respiratory complications over time observed in Conway et al.'s meta-analysis of the randomized controlled trials on rheumatoid arthritis (RA) patients,[1] we proposed lack of baseline assessment and misattribution of RA-interstitial lung disease (ILD) or infectious respiratory complication to methotrexate side effect as a likely explanation. Certainly, a lack of association between methotrexate and ILD would present an alternative hypothesis to the observation.

Your thought (and that of Fragoulis et al.'s) on methotrexate-related pneumonitis and ILD as two separate entities is refreshing.[2] Pneumonitis and ILD are often used interchangeably for drug-related respiratory complications. Conway et al. also noted a significant variation in the terms used to describe respiratory complications in the studies included in the meta-analysis.[1] Documentation of complete respiratory assessment at baseline (so as to avoid misattribution) and chronological reversibility in addition to histopathology evidence of inflammation and fibrosis has been patchy historically. It is certainly worth further exploring this subject with additional long-term longitudinal study that has meticulous documentation of spirometry and computed tomographic imaging (at baseline before drug therapy and at symptom onset), histopathology after symptom onset as well as concomitant immune cell profiling and cytokine studies to definitely differentiate between the two disease entities.

While Conway et al.'s meta-analysis showed methotrexate does not significantly increase noninfectious respiratory complications, a subgroup analysis of studies in which pneumonitis was described revealed increased risk of methotrexate compared to other disease-modifying antirheumatic drugs (with a relative risk of 7.81).[1] Therefore, while we agree that clinicians should not underuse methotrexate out of concern regarding its rare pulmonary adverse reactions, the association (or lack of association) between methotrexate and ILD remains a controversial field that clinicians need to be aware of.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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. 1
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. 2


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