Methotrexate-Induced Lung Injury - UpToDate

29/11/2020 Methotrexate-induced lung injury - UpToDate
Author: Robert A Balk, MD

Section Editors: Kevin R Flaherty, MD, MS, James R Jett, MD
Deputy Editors: Helen Hollingsworth, MD, Diane MF Savarese, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2020. | This topic last updated: May 12, 2020.
INTRODUCTION
Methotrexate is an analogue of the vitamin folic acid; it inhibits cellular proliferation by

inducing an acute intracellular deficiency of certain folate coenzymes ( figure 1) [1-3]. This
impairs the intracellular trafficking of single carbon groups and results in impaired synthesis
of thymidine, deoxyribonucleic acid (DNA), and ribonucleic acid (RNA) [1,4]. In addition to its
antiproliferative effects, methotrexate has antiinflammatory and immunomodulating
properties [2,3,5-7]. It is used to treat a variety of malignancies, connective tissue diseases,
and also psoriasis. Serious toxicity from methotrexate may affect the lungs, liver, and bone
marrow [1,2,8-11].
This topic review will review the pulmonary injury that may result from methotrexate use.
Other side effects of methotrexate therapy and an approach to pulmonary toxicity associated
with antineoplastic agents are discussed separately. (See "Major side effects of low-dose
methotrexate" and "Hepatotoxicity associated with chronic low-dose methotrexate for
nonmalignant disease" and "Pulmonary toxicity associated with systemic antineoplastic
therapy: Clinical presentation, diagnosis, and treatment" and "Therapeutic use and toxicity of
high-dose methotrexate", section on 'Overview of adverse effects' and "Use of methotrexate in
the treatment of rheumatoid arthritis", section on 'Mechanism of action'.)
INCIDENCE
Lung toxicity most often occurs after weeks to months of low-dose oral methotrexate therapy
(as is typically used for non-malignant disease), but can occur following relatively short term
use of intravenous or intrathecal administration of higher doses [10,12-14]. In a literature
review of 123 cases of methotrexate pneumonitis, about one-half arose in patients receiving
therapy for rheumatoid arthritis (range 2.5 to 15 mg weekly), about 20 percent arose during
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intensification/consolidation treatment for leukemia (doses approximately 20 to 80 mg

weekly), and 8 percent were in patients treated for other malignancies (weekly doses ranging
from 15 to 1400 mg) ( table 1) [10].
The precise frequency with which methotrexate pulmonary toxicity occurs is difficult to assess
as some reports have included patients who were receiving other cytotoxic medications, had
ongoing infectious diseases, or had underlying disease processes capable of involving the
lungs and pleura [1]. In addition, impure preparations of methotrexate may have played a role
in some of the earlier reports of toxicity [1]. Many series estimate that acute pulmonary
toxicity develops in 1 to 8 percent of patients receiving methotrexate for rheumatologic
condition, including rheumatoid arthritis, but some reports suggest an incidence as high as 33
percent [14-22]. On the other hand, others suggest that rates are much lower because not all
cases of pneumonitis occurring in patients treated with methotrexate are directly attributable
to the drug. The following examples show the frequency of pneumonitis among patients who
received methotrexate for rheumatoid arthritis or other inflammatory diseases:
● In a systematic literature review of 3463 patients with rheumatoid arthritis who were
receiving methotrexate, 84 patients (2 percent) had some type of lung toxicity, but only 15
were felt to be definitive cases of pneumonitis attributable to methotrexate (0.43 percent)
[23]. The mean duration of methotrexate use was 36.5 months and the average dose was
8.8 mg/week.
● In a literature review of studies that compared methotrexate to placebo or another agent

in patients with psoriasis, psoriatic arthritis, or inflammatory bowel disease, seven trials
(1630 subjects) were identified in which treatment lasted 16 to 52 weeks [24]. Adverse
respiratory events were not statistically increased in those taking methotrexate; only one
patient developed pneumonitis and that person was in the methotrexate group. While the
data are reassuring for patients with these diseases who may take methotrexate, the
relatively low total number of patients means that a small but clinically important risk
cannot be completely excluded.
PATHOGENESIS AND PATHOLOGY
Pulmonary complications of methotrexate may be classified as inflammatory, infectious, and

lymphoproliferative [25].
Inflammatory and fibrotic lung disease — Hypersensitivity pneumonitis is the most

common type of pulmonary toxicity associated with methotrexate and is characterized by a
lymphocytic infiltration of the interstitium with epithelial cell hyperplasia, small, poorly formed
granulomas, and sometimes eosinophilic infiltration [1-3,9,17]. This pattern is similar to the
hypersensitivity pneumonitis associated with inhaled organic antigens. (See "Hypersensitivity
pneumonitis (extrinsic allergic alveolitis): Epidemiology, causes, and pathogenesis", section on
'Etiologic agents' and "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical
manifestations and diagnosis", section on 'Surgical lung biopsy'.)
A number of other types of lung injury have been associated with methotrexate use, including
[1-3,15]:
● Organizing pneumonia (formerly called bronchiolitis obliterans with organizing

pneumonia or BOOP)
● Acute interstitial pneumonia with noncardiogenic pulmonary edema
● Pulmonary fibrosis (which may be rapidly progressive) [9,26]
● Pleural effusion and symptomatic pleuritis occur infrequently [14]
In advanced methotrexate pneumonitis, the lungs show extensive fibrosis and honeycombing,
especially at the bases [9]. Approximately 10 percent of patients will demonstrate fibrosis on
lung biopsy.
The precise mechanisms by which methotrexate cause pulmonary injury are unknown. Most
researchers suggest that methotrexate pneumonitis is a form of hypersensitivity lung disease
because there is typically fever, eosinophilia, an increase in CD4+ T cells in bronchoalveolar
lavage fluid, and a mononuclear cell infiltration of the lungs with granulomatous inflammation
[1,3]. Others suggest that injury may result from a direct toxic effect of methotrexate on lung
tissue, while a third theory proposes that impaired host resistance to acquired or latent viral
infection (eg, cytomegalovirus or Epstein-Barr virus) underlies the observed pathology [27-30].
Support for direct toxicity comes from a mouse model that demonstrated alveolar epithelial
injury, apoptosis, and fibrosis [31]. Finally, activation of mitogen-activated protein (MAP) kinase
pathways and altered cytokine expression may contribute to the pulmonary inflammatory
response [27,30].
Pulmonary toxicity has occurred following both low and high doses and by a variety of routes
of administration, suggesting that some of the pulmonary adverse effects may result from
idiosyncratic mechanisms unrelated to folate antagonism. None of the proposed mechanisms
account for the observation that pulmonary toxicity may remit despite continued therapy, and
may not occur upon rechallenge [1-3]. In summary, the mechanisms of methotrexate
pulmonary toxicity are unresolved and may be multiple.
Pulmonary infections — Methotrexate can compromise the immune response and increase

the risk for opportunistic infections due to Pneumocystis jirovecii (formerly Pneumocystis carinii),

cytomegalovirus, varicella-zoster virus, Nocardia, mycobacteria, or other fungi [32,33].

Pneumocystis has been the most commonly reported agent and has accounted for up to 40
percent of the infectious complications in some series [17,33,34]. (See "Epidemiology of
pulmonary infections in immunocompromised patients".)
Pulmonary lymphoproliferative disease — Lymphoproliferative disease (including non-

Hodgkin [B cell] and other lymphomas) may appear during methotrexate therapy and regress
after methotrexate discontinuation [33,35-40]. Among 48 patients with rheumatoid arthritis
receiving methotrexate who developed a lymphoproliferative disease, the primary site was the
lung in four [37]. In a separate report, 6 of 28 cases of lymphoproliferative disease involved
the lung or pleura, but details were not provided [36].
The reversibility of this disease without specific anti-lymphoma treatment suggests that
diminished immune surveillance due to methotrexate may facilitate the development and
expansion of malignant lymphoid clones. However, whether methotrexate-
immunosuppression has a direct effect on the malignant cells or an indirect effect via
recrudescence of Epstein-Barr virus (EBV) infection is not known. A portion of these cases (28
percent) are associated with EBV infection, a finding that is also seen in patients who are
immunosuppressed in the setting of organ transplantation or AIDS [37]. (See "Treatment and
prevention of post-transplant lymphoproliferative disorders" and "Major side effects of low-
dose methotrexate", section on 'Risk of lymphoproliferative disorders'.)
The causal relationship between lymphoma and methotrexate use has been difficult to prove
due to the increased rate of lymphoma among patients with rheumatoid arthritis. Large
database studies suggest that it is unlikely that long-term oral methotrexate therapy increases
the risk of lymphoma [23,41-43]. As an example, in a prospective study of 19,562 patients
(89,710 person-years of follow-up), with rheumatoid arthritis, similar risks of lymphoma were
observed among the 68 percent of patients who received methotrexate versus those who did
not [43]. However, there was no adjustment for the severity of the arthritis, a known factor in
the risk of lymphoma in these patients [23]. Thus, the relationship between methotrexate use
and lymphoma in patients with conditions such as rheumatoid arthritis remains uncertain.
However, there are also well-documented cases of regression of lymphoma when
methotrexate is held. (See "Disease outcome and functional capacity in rheumatoid arthritis",
section on 'Lymphoproliferative disorders'.)
RISK FACTORS

A number of studies have identified risk factors for methotrexate pulmonary toxicity. One
multicenter case-control study involving 36 patients with methotrexate-induced lung injury
following treatment for rheumatoid arthritis and 82 matched controls identified the following
risk factors [44]:
● Age greater than 60 years

● Rheumatoid pleuropulmonary involvement
● Previous use of disease-modifying antirheumatic drugs
● Hypoalbuminemia (either before or during therapy)
● Diabetes mellitus
The mechanism by which some of these factors may confer excess risk is unclear, although
there is evidence that hyperinsulinemia, which may occur with treatment for diabetes mellitus,
is associated with increased polyglutamation of methotrexate [45]. The previous use of
disease-modifying antirheumatic drugs may be a marker for more severe rheumatoid
arthritis, and hypoalbuminemia could potentially result in a lower degree of protein binding
and higher free levels of methotrexate.
Additional risk factors for methotrexate pneumonitis have been suggested by others,
including:
● Higher weekly doses of methotrexate [46]

● Daily, rather than weekly drug administration [1]
● Preexisting lung disease [29,47] (see 'Prevention' below)
● Abnormal pulmonary function tests prior to therapy [47]
● Decreased elimination of methotrexate (eg, as seen in renal insufficiency or with the
presence of third-space fluid collections such as ascites) [9,48]
● Inherited polymorphisms in some gene alleles related to methotrexate transport and
metabolism may be associated with increased risk of toxicity, but further studies are
needed to validate these associations [49]
CLINICAL MANIFESTATIONS
Methotrexate pulmonary toxicity may present in an acute, subacute, or chronic form.

Subacute presentations are most common. The majority of patients who develop
methotrexate pulmonary toxicity during chronic oral low-dose therapy do so within the first
year of treatment (mean nine months) [14], although cases have been reported as early as 12
days and as late as 18 years after the drug was initiated [14,17-20,28,29,50].

● The clinical presentation of acute methotrexate pneumonitis is generally nonspecific, with

symptoms (fever, chills, malaise, nonproductive cough, dyspnea, chest pain) that are
progressive over several days [10,14,18-20,28,29]. Rapid progression to respiratory failure
may occur [1,3].
● Subacute pneumonitis manifests with the insidious onset of dyspnea (82 percent),
nonproductive cough (81 percent), fever (76 percent), crackles (50 percent), and cyanosis
over a few weeks [10,28,51]. Approximately 17 percent of patients also have cutaneous
manifestations of methotrexate toxicity [28]. Progression to pulmonary fibrosis is
observed in approximately 10 percent of patients.
● Rarely, methotrexate is associated with a more chronic presentation of dyspnea, cough,

and coarse crackles that progress to respiratory failure over weeks to months [10,26,52].
The clinical manifestations of pulmonary involvement in methotrexate-associated

lymphoproliferative disorder are poorly described [36,37]. In a series of 48 patients with
rheumatoid arthritis receiving methotrexate who developed a lymphoproliferative disease,
four had a primary site in the lung but the exact pattern of lung involvement was not
delineated [37].
The extrapulmonary toxicities of methotrexate are listed in the table and are discussed
separately ( table 2). (See "Major side effects of low-dose methotrexate".)
DIFFERENTIAL DIAGNOSIS
The typical symptoms and signs of methotrexate-induced lung injury (eg, dyspnea, cough,
diffuse radiographic opacities and fever) are nonspecific and may be caused by intercurrent
infection (eg, Pneumocystis, Cryptococcus, cytomegalovirus, herpes zoster, Nocardia,
mycobacteria), the underlying disease (eg, rheumatoid arthritis), malignancy (eg, lymphangitic
tumor, lymphoproliferative disease), or a concomitant medication. Bacterial, fungal, and viral
infections are more likely to have an acute presentation of fever, dyspnea, and cough with or
without sputum production, while mycobacterial disease is usually more insidious in onset.
(See "Approach to the immunocompromised patient with fever and pulmonary infiltrates",
section on 'Initial evaluation' and 'Pulmonary infections' above and 'Pulmonary
lymphoproliferative disease' above and "Overview of lung disease associated with rheumatoid
arthritis".)
As both usual and opportunistic lung infections have been described in patients taking
methotrexate, it is imperative to exclude the possibility of pulmonary infection early in the

course of diagnosis and prior to initiating treatment with glucocorticoids [34]. (See 'Pulmonary
infections' above and "Approach to the immunocompromised patient with fever and
pulmonary infiltrates", section on 'Etiology of pulmonary infiltrates'.)
DIAGNOSTIC EVALUATION
While no test is absolutely diagnostic of methotrexate-induced pneumonitis, some tests can

help in the inclusion or exclusion of other processes. Radiographic evaluation, a trial of drug
cessation, bronchoalveolar lavage, and lung biopsy are the primary ways to narrow the
differential diagnosis when methotrexate-induced lung disease is suspected. However,
bronchoscopy and lung biopsy are not necessary in most patients. A beneficial response to
methotrexate withdrawal in the appropriate clinical setting may be sufficient in the patient
who is not acutely or severely ill.
Laboratory testing — Laboratory testing (eg, complete cell counts, coagulation tests, B-type
natriuretic peptide [BNP], blood cultures, sputum cultures, viral serology) is performed in most
patients to determine whether other disease processes are contributing to the patient's
respiratory compromise.
Up to 50 percent of patients with subacute onset of methotrexate lung toxicity demonstrate

peripheral blood eosinophilia, which strongly supports the diagnosis, when present [28].
Imaging — Diffuse lung parenchymal opacities are usually the earliest radiographic finding in
methotrexate lung toxicity, and they may progress rapidly to patchy acinar consolidation
[28,53,54]. Nodular or ill-defined acinar opacities may be diffusely scattered throughout the
lung fields. Less typical chest radiographic abnormalities include hilar lymphadenopathy,
atelectasis, and pleural effusions [4,52,54]. The chest film is rarely normal when the disease is
fully established, but may be normal in the early stages of dry cough. Patients who develop a
nonproductive cough on methotrexate, but do not have changes on radiographic studies,
often improve with methotrexate discontinuation, supporting the view that methotrexate lung
toxicity can be radiographically silent.
In general, high resolution computed tomographic (HRCT) scanning is superior to

conventional chest radiographs for characterizing the pattern, extent, and location of lung
involvement and is performed in most patients [55,56]. (See "Pulmonary toxicity associated
with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section
on 'Imaging'.)

A variety of HRCT patterns have been described with methotrexate-induced toxicity, all of
which can be seen with infection.
● Patchy areas of ground glass attenuation with small area of consolidation [55,57]
● Diffuse ground glass opacities with or without reticulation or consolidation [58]
● Ill-defined centrilobular nodules [58]
● Bilateral, symmetric, lower lung zone, irregular, reticular opacities, traction bronchiectasis
and architectural distortion with or without consolidation or honeycombing [26,57]
The degree of HRCT abnormality correlates quantitatively with lung volume reductions on
pulmonary function testing [55,59].
The radiographic manifestations of pulmonary lymphoproliferative disease associated with

rheumatoid arthritis and methotrexate are poorly described; pleural effusion has been
reported in a few cases in addition to single or multiple nodular opacities [14,33,35-38,60].
Pulmonary function testing — Pulmonary function tests (PFTs) are helpful for characterizing
the pattern (eg obstructive, restrictive) and severity of respiratory impairment in patients with
respiratory symptoms. Among patients suspected of having methotrexate-related lung injury,
PFTs are primarily performed in those who present with an indolent onset of dyspnea or
cough during methotrexate therapy, rather than a more fulminant presentation or respiratory
compromise.
PFTs in patients with methotrexate pneumonitis typically reveal a restrictive pattern with a
decrease in the diffusing capacity for carbon monoxide (DLCO), hypoxemia, and an increased
alveolar-arterial (A-a) gradient (calculator 1) [1,3]. Some reports have noted worsening of
airflow obstruction or development of a restrictive pattern with long-term, low-dose
methotrexate [61-63], but other reports have not found a clinically significant decrease in
pulmonary function in the majority of patients [50,61,64].
The utility of screening pulmonary function tests for the prevention or early detection of
methotrexate pneumonitis is not well established.
● As interstitial lung disease is a risk factor for methotrexate pneumonitis, some experts
recommend baseline pulmonary function testing prior to initiating chronic methotrexate
to identify underlying interstitial lung disease and to use as a baseline in case of a later
onset of symptoms [65]. We typically perform baseline pulmonary function tests prior to
initiation of methotrexate, if the patient reports dyspnea on exertion or if the
pretreatment chest radiograph is abnormal. We avoid use of methotrexate in patients
with more than mild respiratory impairment at baseline (eg, DLCO <70 percent predicted)
[65].
● The value of routine screening for methotrexate lung toxicity was assessed in a
prospective study of 124 patients with rheumatologic diseases receiving long-term oral
methotrexate. Surveillance spirometry, lung volumes, and DLCO were not helpful in the
preclinical diagnosis of methotrexate pneumonitis [66].
Bronchoscopy — Bronchoscopy with bronchoalveolar lavage (BAL) is performed in patients

with new onset lung disease complicating methotrexate therapy, when it is necessary to
exclude processes such as infection or malignancy (eg, in the presence of fever, widespread or
nodular opacities on chest imaging, or rapidly progressive respiratory impairment). BAL is
more helpful in ruling out processes such as infection and lymphangitic tumor spread, than in
making a definitive diagnosis of methotrexate pneumonitis.
BAL samples are sent for bacterial, fungal, and mycobacterial smear, special stains, and
culture. Samples are also sent for cytologic examination for viral inclusion bodies and
malignant cells. Samples are sent for viral culture and immunohistochemistry, where available.
(See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation,
diagnosis, and treatment", section on 'Bronchoscopy' and "Basic principles and technique of
bronchoalveolar lavage".)
In the BAL fluid of patients with methotrexate pneumonitis, cell counts reveal lymphocytic
predominance (eg, 33 to 68 percent) with an increase in the number of CD4 lymphocytes and
the CD4/CD8 ratio [67,68]. These findings are not specific and can be seen in a variety of
inflammatory lung processes, including sarcoidosis, berylliosis, rheumatoid arthritis, and
miliary tuberculosis; other forms of hypersensitivity pneumonitis may yield similar results,
although the CD4/CD8 ratio is usually decreased [67,68]. (See "Role of bronchoalveolar lavage
in diagnosis of interstitial lung disease".)
Atypical epithelial cells are sometimes seen in BAL fluid from patients with pulmonary fibrosis
due to methotrexate [1,3,9]. This manifestation may be detected earlier in the course of the
disease than histologic evidence of fibrosis on lung biopsy.
In patients without specific contraindications, transbronchial lung biopsy may improve the
likelihood of identifying lymphangitic spread of tumor or an invasive infection over BAL alone.
In addition, biopsy allows distinction between colonization and invasion in fungal (or viral)
infection. (See "Approach to the immunocompromised patient with fever and pulmonary
infiltrates", section on 'Lung sampling' and "Flexible bronchoscopy in adults: Indications and
contraindications", section on 'Contraindications' and "Flexible bronchoscopy in adults:

Overview" and "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic

procedures", section on 'Transbronchial biopsy'.)
Lung biopsy — Pulmonary histopathology may be helpful in establishing the diagnosis of

methotrexate-induced pulmonary toxicity, but is not always required. Patients who respond
quickly to drug discontinuation generally do not need a lung biopsy. In contrast, a lung biopsy
is indicated when the patient has acute, progressive or severe disease and the cause of the
pneumonitis is uncertain or when lymphoproliferative disease is suspected on the basis of
nodular opacities. Surgical lung biopsy can be obtained by video-assisted thoracoscopic
surgery or open thoracotomy, depending on the expertise and preference of the surgeon. (See
"Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Surgical lung
biopsy'.)
Lung biopsy can help to distinguish methotrexate-induced lung disease from other processes,
such as infection, neoplasia, and lung involvement by the underlying disease (eg, rheumatoid
arthritis), although this is not always possible. In a patient with rheumatoid arthritis, for
example, poorly formed granulomas with scattered eosinophils, consistent with
hypersensitivity pneumonitis due to methotrexate, are distinct from the lung injury usually
associated with rheumatoid arthritis. The latter is typically characterized by a usual interstitial
pneumonia (idiopathic pulmonary fibrosis) or nonspecific interstitial pneumonia pattern
(NSIP). On the other hand, acute interstitial pneumonitis (AIP) and organizing pneumonia (OP)
have been described with methotrexate alone and with rheumatoid arthritis in the absence of
methotrexate; thus, the finding of AIP or OP does not differentiate these processes. (See
'Inflammatory and fibrotic lung disease' above and "Interstitial lung disease in rheumatoid
arthritis", section on 'Lung biopsy'.)
Making the diagnosis — The diagnosis of methotrexate-induced pulmonary toxicity is based

on the combination of the appropriate clinical setting, clinical manifestations, radiographic
abnormalities, bronchoalveolar lavage findings, lung histology (when available), and response
to drug discontinuation.
Given the absence of a definitive diagnostic test, a set of diagnostic criteria has been proposed
to establish a diagnosis of methotrexate-induced lung injury [4,14].
In patients receiving methotrexate, the major criteria are:
● Hypersensitivity pneumonitis by histopathology without evidence of pathogenic

organisms
● Radiographic evidence of patchy or diffuse pulmonary ground glass or consolidative
opacities
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● Blood cultures (if febrile) and initial sputum cultures (if sputum is produced) that are
negative for pathogenic organisms.
The minor criteria are:
● Shortness of breath for less than eight weeks

● Nonproductive cough
● Oxygen saturation ≤90 percent on room air at the time of initial evaluation
● DLCO ≤70 percent of predicted for age
● Leukocyte count ≤15,000 cells/mm3
Methotrexate pneumonitis is characterized as "definite" if major criteria 1 or 2 and major

criterion 3 are present in conjunction with three of the five minor criteria. "Probable"
methotrexate pneumonitis is present if major criteria 2 and 3 plus two of the five minor
criteria are present.
While this combination of factors can support a diagnosis of methotrexate-induced lung

injury, the scoring system is predominantly useful in assuring comparable patient populations
in different clinical trials. The clinical utility of the scoring system has not been adequately
validated, and it should not be strictly relied upon to establish the diagnosis in a given patient
[4,14].
TREATMENT
The optimal therapy for methotrexate-induced lung toxicity has not been established and no
prospective trials of therapy have been performed. The treatments for opportunistic infections
in the lung and lymphoproliferative disease are discussed separately. (See "Approach to the
immunocompromised patient with fever and pulmonary infiltrates", section on 'Selection of
initial therapy' and "Major side effects of low-dose methotrexate", section on 'Risk of
lymphoproliferative disorders'.)
Initial management
● It is mandatory to exclude an infectious etiology of the pulmonary findings [12]. Empiric

antimicrobial therapy directed at likely pathogens may be indicated while definitive
procedures and cultures are performed.
● Discontinuation of methotrexate is the initial step in management. In most cases, clinical

improvement occurs within days of stopping the drug, followed by radiographic
improvement over several weeks [4]. While there are reports of successful rechallenge

with methotrexate and even regression of pulmonary toxicity despite continued therapy,
neither of these approaches is recommended [1,3,5,9,14,20,53].
● Supportive care includes supplemental oxygen as indicated by pulse oximetry and

mechanical ventilation, if clinically indicated.
● Systemic glucocorticoids are used in selected patients.
Glucocorticoids — The clinical and histological similarities of methotrexate-induced

pneumonitis to hypersensitivity pneumonitis imply a role for glucocorticoids. No prospective
trials of glucocorticoid therapy have been performed, but clinical experience and case reports
suggest that use of glucocorticoids accelerates the recovery of pneumonitis [10,28,69-71],
although fatalities may still occur [71]. The efficacy of glucocorticoid therapy is illustrated by
the following reports:
● In one report of nine patients with otherwise unexplained symptoms who experienced a
clinical course consistent with a drug-induced lung reaction to methotrexate, three had a
moderate severity of findings and fully recovered with discontinuation of methotrexate
[70]. All six patients who had marked respiratory compromise recovered fully with
methotrexate discontinuation and high-dose glucocorticoids.
● In a second series of nine patients with presumed methotrexate pneumonitis,

methotrexate was discontinued in all, and glucocorticoids given to eight [10]. One
patient's illness resolved completely after 5 days, five improved steadily over the course of
3 to 20 weeks; one continued to have respiratory insufficiency requiring periodic oxygen
supplementation at 19 months; and two died of respiratory failure.
● Among six patients who developed "life-threatening" methotrexate-induced pneumonitis,

drug discontinuation and administration of high-dose glucocorticoids were associated
with improvement in five, but death in one [16].
● In a third report, one of three patients with methotrexate-induced pneumonitis died

despite institution of high-dose methylprednisolone; the others recovered completely
[28].
Thus, although systemic glucocorticoid therapy may accelerate recovery, it does not appear to
prevent fatalities. We typically reserve glucocorticoids for patients with more severe initial
pulmonary toxicity (eg, dyspnea at rest, a decrease in oxygen saturation below 90 percent or
more than a 4 percent decrease from baseline) or worsening clinical status despite
methotrexate discontinuation.

Systemic glucocorticoid therapy is typically initiated with prednisone 1 mg/kg per day orally or
the equivalent ( table 3). If the patient is severely ill, intravenous glucocorticoids (eg,
methylprednisolone) 1 mg/kg once or twice a day are administered and transitioned to oral
prednisone as the patient stabilizes. Tapering of glucocorticoid therapy is dependent upon the
clinical response, as assessed by improvement in the clinical, physiologic (pulmonary function
tests), and radiographic parameters, but generally occurs over a few weeks [5,53].
For patients with advanced pulmonary fibrosis (eg, extensive reticular opacities and
honeycombing on HRCT or fibrosis on biopsy) and a slowly progressive course, we are
cautious in administering systemic glucocorticoids due to their known side effects and unlikely
benefit.
The potential adverse effects of glucocorticoid therapy are reviewed separately. (See "Major
side effects of systemic glucocorticoids".)
Prognosis — Most patients recover from methotrexate pneumonitis, although some

physiologic abnormalities may persist [1,10]. Thus, aggressive supportive care for acute
respiratory failure is reasonable while glucocorticoids are administered. A systematic review
reported a mortality rate of 13 percent, although other series have reported lower rates
[1,10,52]. The cause of the discrepancy in reported fatality rates is unclear.
Rechallenge — A high rate of relapse of lung disease has been reported with methotrexate
rechallenge, although individual patients who tolerate rechallenge have been reported [14]. In
addition, several cases of fatal lung toxicity have been reported with rechallenge. Thus,
rechallenge is avoided, and an alternate form of therapy employed, if possible.
PREVENTION
There is no established method for preventing methotrexate lung toxicity. Lung toxicity is less
common with lower doses of methotrexate, but still occurs. To reduce the risk of pulmonary
toxicity, dose adjustments of methotrexate may be needed in patients who have renal or
hepatic dysfunction, a third space fluid collection (ie, ascites or pleural effusion), or are elderly
[48]. (See 'Risk factors' above and "Chemotherapy nephrotoxicity and dose modification in
patients with kidney impairment: Conventional cytotoxic agents", section on 'Methotrexate'.)
● Folic acid and leucovorin – Many adverse reactions to methotrexate (eg, stomatitis,
myelosuppression) can be alleviated or prevented by the addition of either folic acid or
leucovorin (also called folinic acid). However, the use of these agents does not reduce the
risk for methotrexate pulmonary toxicity. (See "Major side effects of low-dose

methotrexate", section on 'Prevention of side effects with folate' and "Therapeutic use and
toxicity of high-dose methotrexate", section on 'Rationale for leucovorin rescue'.)
● Screening – Given that underlying pulmonary fibrosis may be a risk factor for developing
methotrexate lung toxicity, most experts obtain a chest radiograph prior to initiating long-
term methotrexate therapy [14,63,65,72]. If the chest radiograph suggests underlying
interstitial lung disease, further evaluation with pulmonary function testing and high
resolution computed tomography may be indicated. (See 'Pulmonary function testing'
above and "Interstitial lung disease in rheumatoid arthritis", section on 'Evaluation'.)
An alternate agent instead of methotrexate is preferred for patients who have evidence of
underlying interstitial lung disease. The baseline radiograph can also be useful for future
comparison should a patient develop dyspnea while on methotrexate.
SUMMARY AND RECOMMENDATIONS
Clinical manifestations and diagnostic evaluation
● Lung toxicity most often develops after chronic low-dose therapy with methotrexate, but
can occur following short-term administration of high-dose methotrexate. Risk factors for
methotrexate-induced lung toxicity include age greater than 60, rheumatoid
pleuropulmonary involvement, previous use of disease-modifying antirheumatic drugs,
hypoalbuminemia, higher weekly doses of methotrexate, pre-existing lung disease, and
decreased elimination of methotrexate. (See 'Incidence' above.)
● Methotrexate-induced pulmonary toxicity may present in acute, subacute, or chronic

forms; subacute presentations are most common. The acute presentation typically
includes fever, chills, malaise, nonproductive cough, dyspnea, and chest pain; the
subacute presentation is characterized by a more insidious onset of dyspnea, cough, and
fever. The majority of patients who develop methotrexate pulmonary toxicity do so within
the first year of therapy. (See 'Clinical manifestations' above.)
● Laboratory testing (eg, complete cell counts and differential, coagulation tests, brain
natriuretic peptide [BNP], blood cultures, sputum cultures, viral serology) is used to
determine whether other disease processes are contributing to the patient's respiratory
compromise. Up to 50 percent of patients with subacute methotrexate lung toxicity have
peripheral blood eosinophilia. (See 'Laboratory testing' above.)
● Methotrexate lung toxicity is characterized by a variety of radiographic patterns on high

resolution computed tomography (HRCT), including patchy or diffuse ground glass
attenuation, ill-defined centrilobular nodules, and bilateral, reticular opacities associated

with traction bronchiectasis and architectural distortion. (See 'Imaging' above.)
● Bronchoscopy with bronchoalveolar lavage (BAL) may be indicated in the evaluation of

lung disease complicating methotrexate therapy in patients whose symptoms and pattern
of onset suggest infection or malignancy (eg, acute onset, fever, widespread or nodular
radiographic opacities, moderate to severe respiratory impairment). BAL is more helpful in
ruling out an infectious or neoplastic etiology than in making a definitive diagnosis of
methotrexate pneumonitis. (See 'Bronchoscopy' above.)
● In patients without specific contraindications, transbronchial lung biopsy performed at

the time of bronchoscopy may improve the likelihood of identifying lymphangitic spread
of tumor or an invasive infection over BAL alone. Surgical lung biopsy is indicated when
the patient has progressive or severe respiratory impairment and the cause of the
pneumonitis is uncertain, or if methotrexate-induced lymphoproliferative disease is
suspected. (See 'Bronchoscopy' above and 'Lung biopsy' above.)
● The typical histopathology of methotrexate pneumonitis is characterized by lymphocytic

infiltration of the interstitium, epithelial cell hyperplasia, and cytologic dysplasia. Small,
poorly formed granulomas and eosinophilic infiltration may be present, suggestive of
hypersensitivity pneumonitis. In chronic methotrexate pneumonitis, extensive fibrosis and
honeycombing are seen, especially at the lung bases. (See 'Lung biopsy' above.)
● The diagnosis of methotrexate-induced pulmonary toxicity is typically based on the

combination of the appropriate clinical setting, clinical manifestations, radiographic
abnormalities, and either the response to drug withdrawal or the results of
bronchoalveolar lavage and lung histology. A beneficial response to methotrexate
withdrawal in the appropriate clinical setting may be sufficient in the patient who is not
acutely or severely ill. (See 'Diagnostic evaluation' above.)
● The differential diagnosis of methotrexate-induced lung injury includes opportunistic

infection (eg, Pneumocystis, Cryptococcus, cytomegalovirus, herpes zoster, Nocardia), the
underlying disease (eg, rheumatoid arthritis), malignancy (eg, lymphangitic tumor,
lymphoproliferative disease), and lung toxicity from a concomitant medication. (See
'Differential diagnosis' above.)
Treatment
● The management of methotrexate lung injury starts with discontinuation of the drug. In
most cases, clinical improvement occurs within days to weeks of stopping the drug,

followed by improvement in the chest radiograph over several weeks. (See 'Treatment'
above.)
● For patients with acute or subacute presumed methotrexate-induced pulmonary toxicity

and moderate to severe respiratory impairment (eg, a decrease in room air oxygen
saturation below 90 percent or more than a 4 percent decrease from baseline), we
suggest initiating systemic glucocorticoid therapy, rather than observation and supportive
care alone (Grade 2C). Among the factors to consider in the decision to initiate
glucocorticoid therapy are the rapidity of clinical deterioration, the worsening of
respiratory status despite discontinuation of methotrexate, and the presence of serious
comorbid conditions that would increase the risk of serious adverse effects from
glucocorticoids (eg, infection, myelosuppression, uncontrolled diabetes mellitus).
The usual initial dose of glucocorticoid is prednisone 1 mg/kg per day orally (or the
equivalent), or for impending respiratory failure, methylprednisolone 1 mg/kg is
administered once or twice a day intravenously ( table 3). Tapering is guided by the
clinical response. (See 'Treatment' above and "Major side effects of systemic
glucocorticoids".)
● For patients with evidence of advanced pulmonary fibrosis (eg, extensive honeycombing
on HRCT or biopsy), we avoid using systemic glucocorticoids because of the known side
effects and uncertain benefit. (See 'Treatment' above.)
● Methotrexate rechallenge should be avoided, due to the high risk of recurrent disease.
(See 'Rechallenge' above.)
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Topic 4372 Version 13.0


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29/11/2020 Methotrexate-induced lung injury - UpToDate

Author: Robert A Balk, MD

Methotrexate is an analogue of the vitamin folic acid; it inhibits cellular proliferation by

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intensification/consolidation treatment for leukemia (doses approximately 20 to 80 mg

● In a literature review of studies that compared methotrexate to placebo or another agent

PATHOGENESIS AND PATHOLOGY

Pulmonary complications of methotrexate may be classified as inflammatory, infectious, and

Inflammatory and fibrotic lung disease — Hypersensitivity pneumonitis is the most

● Organizing pneumonia (formerly called bronchiolitis obliterans with organizing

Pulmonary infections — Methotrexate can compromise the immune response and increase

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cytomegalovirus, varicella-zoster virus, Nocardia, mycobacteria, or other fungi [32,33].

Pulmonary lymphoproliferative disease — Lymphoproliferative disease (including non-

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● Age greater than 60 years

● Higher weekly doses of methotrexate [46]

Methotrexate pulmonary toxicity may present in an acute, subacute, or chronic form.

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● The clinical presentation of acute methotrexate pneumonitis is generally nonspecific, with

● Rarely, methotrexate is associated with a more chronic presentation of dyspnea, cough,

The clinical manifestations of pulmonary involvement in methotrexate-associated

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While no test is absolutely diagnostic of methotrexate-induced pneumonitis, some tests can

Up to 50 percent of patients with subacute onset of methotrexate lung toxicity demonstrate

In general, high resolution computed tomographic (HRCT) scanning is superior to

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● Diffuse ground glass opacities with or without reticulation or consolidation [58]

● Ill-defined centrilobular nodules [58]

The radiographic manifestations of pulmonary lymphoproliferative disease associated with

Bronchoscopy — Bronchoscopy with bronchoalveolar lavage (BAL) is performed in patients

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Overview" and "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic

Lung biopsy — Pulmonary histopathology may be helpful in establishing the diagnosis of

Making the diagnosis — The diagnosis of methotrexate-induced pulmonary toxicity is based

In patients receiving methotrexate, the major criteria are:

● Hypersensitivity pneumonitis by histopathology without evidence of pathogenic

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The minor criteria are:

● Shortness of breath for less than eight weeks

Methotrexate pneumonitis is characterized as "definite" if major criteria 1 or 2 and major

While this combination of factors can support a diagnosis of methotrexate-induced lung

● It is mandatory to exclude an infectious etiology of the pulmonary findings [12]. Empiric

● Discontinuation of methotrexate is the initial step in management. In most cases, clinical

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● Supportive care includes supplemental oxygen as indicated by pulse oximetry and

● Systemic glucocorticoids are used in selected patients.

Glucocorticoids — The clinical and histological similarities of methotrexate-induced

● In a second series of nine patients with presumed methotrexate pneumonitis,

● Among six patients who developed "life-threatening" methotrexate-induced pneumonitis,

● In a third report, one of three patients with methotrexate-induced pneumonitis died

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Prognosis — Most patients recover from methotrexate pneumonitis, although some

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SUMMARY AND RECOMMENDATIONS

Clinical manifestations and diagnostic evaluation

● Methotrexate-induced pulmonary toxicity may present in acute, subacute, or chronic

● Methotrexate lung toxicity is characterized by a variety of radiographic patterns on high

attenuation, ill-defined centrilobular nodules, and bilateral, reticular opacities associated

● Bronchoscopy with bronchoalveolar lavage (BAL) may be indicated in the evaluation of

● In patients without specific contraindications, transbronchial lung biopsy performed at

● The typical histopathology of methotrexate pneumonitis is characterized by lymphocytic

● The diagnosis of methotrexate-induced pulmonary toxicity is typically based on the