What is the Risk for Methotrexate-Related Interstitial Lung Disease in RA?

Interstitial lung disease, CT scan
Drs Jeffrey A. Sparks and Vivian P. Bykerk join the ongoing debate about methotrexate as a potential risk factor for lung disease in rheumatoid arthritis and the current clinical implications.

Although rheumatoid arthritis (RA) has several extra-articular manifestations, RA-associated interstitial lung disease (RA-ILD) may be one of the most detrimental to physical function, quality of life, and survival.1,2 Research findings indicate an increasing prevalence of RA-ILD and point to articular disease activity, autoantibodies, the MUC5B promoter variant, and biomarkers of damaged pulmonary parenchyma as novel risk factors for the disease.1

A debate has been ongoing about methotrexate (MTX) as a potential risk factor for lung disease in RA. Several studies have shown that MTX use was associated with an increased risk for pneumonitis, with a reported frequency ranging from 0.3% to 11.6%, as well as interstitial lung disease (ILD).2,3

However, more recent evidence does not support the association between MTX and ILD and reveals a lower incidence of MTX-related pneumonitis than previously demonstrated, according to the authors of a narrative review published in November 2019 in Rheumatology.2 In a 2019 study of 2701 newly diagnosed RA patients, the investigators found no association between MTX exposure and increased risk for developing RA-ILD (OR, 0.85; 95% CI, 0.49-1.49; P =.578) in an analysis of cases (n=67) in which RA-ILD developed following initiation of any conventional synthetic disease-modifying antirheumatic drug treatment.4

Further analysis that included patients (n=92) with pre-existing RA-ILD at the time of RA diagnosis linked MTX exposure to a reduced risk for RA-ILD (OR, 0.48; 95% CI, 0.3-0.79; P =.004) as well as a longer time until ILD diagnosis (OR, 0.41; 95% CI, 0.23-0.75; P =.004).4 These results suggest that MTX may actually delay the onset of ILD in RA patients, according to the authors.4

For an in-depth discussion regarding this issue and current clinical implications, we interviewed Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine and director of immuno-oncology and autoimmunity in the division of rheumatology, inflammation, and immunity at Brigham and Women’s Hospital of Harvard Medical School in Boston; and Vivian P. Bykerk, BSc, MD, FRCPC, rheumatologist and director of the Inflammatory Arthritis Center of Excellence at the Hospital for Special Surgery in New York.

What does the evidence suggest thus far about the association between methotrexate and the risk for lung disease in people with RA?

Dr Sparks: Methotrexate can induce a hypersensitivity pneumonitis that can be severe in some but is fairly uncommon. This is characterized by dyspnea, fever, and cough and can sometimes present subacutely after methotrexate initiation. We recently analyzed the Cardiovascular Inflammation Reduction Trial that randomly assigned 4,786 patients with cardiovascular disease and no rheumatic disease to MTX or placebo.

There were 7 cases of pneumonitis in the MTX group (0.3%) and 1 case in the placebo group (<.01%). When considering any pulmonary adverse event, MTX had a 42% increased risk, and this was mostly characterized by symptoms that resembled bronchitis. Although this was a large study, people with RA were excluded, so there may be different risks in that population.5

Several recent observational studies have investigated MTX use and risk for incident ILD in patients with RA. Those studies have found no increased risk for RA-ILD from MTX.

Dr Bykerk: Inflammatory lung disease and ILD prevalence is variable and often rare in patients with systemic inflammatory autoimmune rheumatic diseases (SIARDs). They often go unrecognized when there are no clinical signs or symptoms, and in those in whom it is mild by nature. MTX rarely results in MTX pneumonitis and has been found to be effective in ILD. Given that the incidence of MTX pneumonitis is exceedingly rare, these days we frequently use MTX to treat ILD with success.

However, rheumatologists are cognizant that pneumonitis can be a potential adverse effect of MTX therapy. This risk may be greater in patients with other factors, and we do consider the risk for MTX-induced lung inflammation when prescribing MTX, especially in patients with advanced age and those who have a history of heavy smoking or existing lung diseases, such as chronic obstructive pulmonary disease (COPD) or emphysema.

What are recommendations for clinicians about how to moderate this risk in RA patients?

Dr Sparks: Some have recommended obtaining chest radiographs for patients with RA prior to starting MTX to exonerate any pre-existing lung disease and establish a baseline. Patients should be counseled to let their clinician know about new or worsening symptoms that could be suggestive of MTX-induced pneumonitis or RA-related lung disease. Research studies are ongoing to understand the role of screening for lung disease among patients with RA. At this time, considerations for advanced imaging and pulmonary function testing should be weighed individually according to the patient’s symptoms and medical history.

Dr Bykerk: There are no good risk calculators that can establish a precise risk because this adverse event is very uncommon. Clinical reports suggest that the mentioned risks are associated with MTX-related lung inflammation or pneumonitis. Thus, when these factors are present, we may ask patients to have a baseline chest X-ray prior to starting MTX. We also warn patients that in the case of any new lung symptoms, such as cough, fever, or shortness of breath, that they should stop their MTX and be assessed immediately. Clinical screening also occurs at follow-up visits. If MTX pneumonitis does occur, we may need to treat with a short course of glucocorticoids.

In general, the management of ILD really depends on its severity, how rapidly it is progressing, and in which SIARD it is present. There are many new therapies that are being used in ILD as well as effective therapies we are experienced in using. These include MTX, rituximab, mycophenolate mofetil, azathioprine, and cyclophosphamide. In addition, there are new therapies currently in clinical trials.

What are some of the top remaining research needs in this area? 

Dr Sparks: There is a large gap in understanding RA-related lung diseases and how medications for RA, including MTX, may contribute to them. We need to better understand the natural history of RA-related lung diseases and develop or enhance screening, prevention, and management strategies.

Dr Bykerk: There are many outstanding research needs in this area. In diseases such as RA, how to best screen for potential ILD is a challenge and represents an unmet research need. A standard chest X-ray or pulmonary function test is insufficient to capture all patients with subclinical ILD.

In more rare rheumatic diseases such as systemic sclerosis, where ILD is more frequent, patients are screened, often with a high-resolution CT scan and/or bronchoalveolar lavage (BAL). These are the best tests needed to identify and stratify the type of ILD or underlying lung disease and confirm the diagnosis. Given that these 2 tests have inherent risks, research is needed not only to use precision medicine tools to choose the most effective treatment in patients who have this, but also to identify disease-related lung conditions using cost-effective means for primary and secondary screening.

Early identification of progressive ILD potentially allows for resolution. ILD is a burdensome and debilitating condition in patients with rheumatic diseases, with links to greater mortality.

What are additional points for clinicians to consider regarding this topic?

Dr Bykerk: One of the challenges with using MTX is that we are unaware of underlying ILD. If MTX-induced pneumonitis does occur in a setting of subclinical ILD, given that there is literature linking MTX pneumonitis with ILD, it becomes difficult to understand whether this is due to treatment or disease. Of note, we also see exacerbations of pneumonitis with TNF inhibitors – this is not unique to methotrexate.

Having said all of this, we remain cautious and aware that this can be a complication of ILD but that the underlying rates are extremely low.


1. Huang S, Kronzer VL, Dellaripa PF, et al. Rheumatoid arthritis-associated interstitial lung disease: current update on prevalence, risk factors, and pharmacologic treatment. Curr Treatm Opt Rheumatol. 2020;6(4):337-353. doi:10.1007/s40674-020-00160-z

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(11):1900-1906. doi:10.1093/rheumatology/kez337

3. Huang S, Doyle TJ, Hammer MM, et al. Rheumatoid arthritis-related lung disease detected on clinical chest computed tomography imaging: prevalence, risk factors, and impact on mortality. Semin Arthritis Rheum. 2020;50(6):1216-1225. doi:10.1016/j.semarthrit.2020.08.015

4. Kiely P, Busby AD, Nikiphorou E, 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(5):e028466. doi:10.1136/bmjopen-2018-028466

5. Sparks JA, Dellaripa PF, Glynn RJ, et al. Pulmonary adverse events in patients receiving low-dose methotrexate in the randomized, double-blind, placebo-controlled Cardiovascular Inflammation Reduction Trial. Arthritis Rheumatol. 2020;72(12):2065-2071. doi:10.1002/art.41452