Drug-Induced Lung Disease in Rheumatoid Arthritis

29/11/2020 Drug-induced lung disease in rheumatoid arthritis - UpToDate
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Drug-induced lung disease in rheumatoid arthritis

Author: Fiona R Lake, MD, FRACP
Section Editors: Talmadge E King, Jr, MD, Eric L Matteson, MD, MPH
Deputy Editor: Helen Hollingsworth, MD
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: Aug 14, 2020.
INTRODUCTION
Drug-induced pulmonary disease is an important consideration in the differential diagnosis of

patients with rheumatoid arthritis (RA) who present with respiratory symptoms [1]. Knowledge
of the types of lung toxicity that are associated with the individual agents used to treat RA, the
patterns of lung disease that are associated with RA (unrelated to medication), and the
spectrum of potential comorbid disease processes will help in the diagnosis and management
of drug-induced lung disease.
A review of drug-induced lung disease in patients with RA will be presented here. Other aspects
of pulmonary disease associated with rheumatoid arthritis are discussed separately. (See
"Overview of lung disease associated with rheumatoid arthritis" and "Interstitial lung disease in
rheumatoid arthritis" and "Overview of the systemic and nonarticular manifestations of
rheumatoid arthritis".)
ETIOLOGY
A number of drugs used to treat RA can induce alveolar inflammation, interstitial inflammation,
and/or interstitial fibrosis (Pneumotox.com), although the exact pathogenesis of the toxicity is
unknown [2,3]. The risk and type of lung toxicity varies among the different agents. (See
'Features of individual agents' below.)
In addition to direct lung toxicity, virtually all of the disease modifying antirheumatic drugs
(DMARDs) have immunosuppressive effects that increase the risk of bacterial and opportunistic
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lung infection [4-6]. As an example, in an observational study of 16,788 patients with RA,
patients taking prednisone had a higher risk of hospitalization due to pneumonia than patients
not taking glucocorticoids (hazard ratio 1.7, 95% CI 1.5-2.0) [7]. The effect was dose dependent.
Although methotrexate and tumor necrosis factor (TNF) antagonists were not associated with
an increased risk of pneumonia in this study, they have been associated with pneumonia in
other studies [8-16]. (See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal
infections".)
PREVALENCE
The net effect of the disease modifying antirheumatic drugs (DMARDs) on the incidence of
drug-induced lung disease in patients with RA is uncertain. Medication side effects may become
more common as the clinical use of DMARDs and biological agents such as tumor necrosis
factor (TNF) blockers increases [17-20].
Conversely, DMARDs may have a beneficial impact on the natural history of a variety of forms of
rheumatoid-associated lung disease, and use of these drugs may influence the frequency or
presentation of these problems [21]. In one study of 59 patients with RA who were taking
DMARDs but had no pulmonary symptoms, abnormal histology on transbronchial lung biopsy
was found in 18 percent of patients on DMARDs, compared to 42 percent of those not taking
one of these drugs [22].
CLINICAL MANIFESTATIONS
The clinical manifestations of drug-induced lung disease are variable and nonspecific.
Symptoms, when present, can develop days to years into therapy and can progress rapidly or
indolently. Drug-induced lung disease is one of the causes of rapid progression of interstitial
lung disease (ILD) to respiratory failure. Symptoms include cough, dyspnea, low-grade fever,
and occasionally a rash. Lung auscultation may reveal focal or bibasilar crackles, but is often
normal.
EVALUATION AND DIAGNOSIS
Drug-induced lung disease is often a diagnosis of exclusion, so the diagnostic approach involves
a combination of tests designed to exclude other processes (eg, heart failure, infection, RA-
associated interstitial lung disease) and to identify features that are suggestive of a drug-
induced process (eg, timing of symptoms relative to drug initiation, eosinophilia in blood or
bronchoalveolar lavage fluid). Empiric drug discontinuation is an important diagnostic step.

Underlying lung disease due to RA or cigarette smoking may complicate determination of
whether current symptoms are caused by a new process or progression/exacerbation of a
preexisting process. General approaches to interstitial lung disease and to lung disease in
patients with RA are described separately. (See "Interstitial lung disease in rheumatoid arthritis"
and "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to
the adult with interstitial lung disease: Diagnostic testing" and "Interpretation of lung biopsy
results in interstitial lung disease".)
● Laboratory testing – Laboratory testing is used to determine whether other disease

processes are contributing to the patient's respiratory compromise. Complete cell counts
and differential are obtained to look for anemia (suggestive of alveolar hemorrhage),
neutrophilia (suggestive of infection), or eosinophilia (suggestive of drug hypersensitivity or
fungal infection). B-type natriuretic peptide (BNP) can help exclude heart failure as an
etiology. Blood cultures, sputum cultures, C-reactive protein (CRP), and serologic studies
can also help to identify infectious causes. (See "Approach to the adult with interstitial lung
disease: Diagnostic testing", section on 'Laboratory tests'.)
● Imaging – A chest radiograph is obtained to assess the pattern and extent of disease but
high resolution computed tomography of the chest is usually needed for full
characterization. Various radiographic patterns of drug-induced injury are described,
including patchy or diffuse, unilateral or bilateral reticular markings, ground glass opacities,
or consolidation, and pulmonary nodules with or without cavitation. Newly appearing or
enlarging pulmonary nodules have been associated with methotrexate and leflunomide.
Pleural effusions have been associated with methotrexate [3]. (See 'Methotrexate' below
and 'Leflunomide' below.)
Hilar lymphadenopathy is an uncommon manifestation of drug induced disease, except in

the case of methotrexate-associated lymphoproliferative disease or anti-tumor necrosis
factor-alpha-induced lymphadenopathy. (See "Methotrexate-induced lung injury", section
on 'Pulmonary lymphoproliferative disease' and 'Granulomatous lung disease' below.)
● Pulmonary Physiology – Frequently, patients are too unwell for complete lung function
testing, but if they can be obtained, they can aid in documenting changes in lung function.
At a minimum, pulse oxygen saturation (SpO2) at rest and importantly on exertion, such as
during a six-minute walk test (6MWT), is helpful in determining the severity of impairment.
Hypoxemia at rest or with exertion is common. (See "Overview of pulmonary function
testing in adults".)

While uncommon, a diffusing capacity for carbon monoxide (DLCO) above the predicted
range suggests pulmonary hemorrhage. (See "Diffusing capacity for carbon monoxide",
section on 'Increased DLCO'.)
● Bronchoscopy – After review of clinical findings, laboratory data, and chest imaging,
bronchoscopy with bronchoalveolar lavage (BAL) may be needed to exclude processes such
as infection, diffuse alveolar hemorrhage, or lymphangitic spread of tumor (eg, in the
presence of fever, widespread or nodular opacities on chest imaging, or rapidly progressive
respiratory impairment).
There are no specific findings for drug-induced lung toxicity on bronchoscopy or BAL. BAL
fluid cell counts are usually elevated, but the pattern of cellularity is nonspecific.
Lymphocytosis, neutrophilia, or eosinophilia may be seen; among these, eosinophilia is
more suggestive of a drug-induced process. Thus, the main role of bronchoscopy is to
exclude alternative diagnoses. (See "Basic principles and technique of bronchoalveolar
lavage" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)
● Response to therapy – Empiric withdrawal of the implicated drug is a key diagnostic and
therapeutic step. In general, noninfectious drug-related lung disease often regresses upon
withdrawal of the offending medication. After exclusion of infection, a prompt response to
systemic glucocorticoid therapy may be a distinguishing feature of drug-induced lung
disease, which often responds better to glucocorticoid therapy than RA-related interstitial
lung disease. (See "Overview of lung disease associated with rheumatoid arthritis" and
"Interstitial lung disease in rheumatoid arthritis".)
● Lung biopsy – Lung biopsy is usually not required, and many patients may be too unwell to
undergo this procedure. Often, the clinical picture, radiologic findings, and BAL results
excluding infection are sufficiently convincing of the diagnosis to make a biopsy
unnecessary, particularly in patients who respond quickly to drug discontinuation. 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, and when the biopsy findings will change
therapy.
Lung biopsy rarely establishes an antirheumatic agent as the definitive source of the lung
injury, as there are no pathognomonic findings, and histologic criteria for drug-induced
lung disease have not been established [23]. However, when available, lung histopathology
can characterize the histopathologic pattern (eg, lymphocytic, granulomatous, eosinophilic,
or organizing pneumonia or diffuse alveolar damage), which may help to guide therapy.

(See "Role of lung biopsy in the diagnosis of interstitial lung disease" and "Interpretation of
lung biopsy results in interstitial lung disease".)
DIFFERENTIAL DIAGNOSIS
The differentiation between a drug reaction, underlying rheumatoid-associated lung disease,

infection, and heart failure may be difficult, since there is significant overlap in the clinical
syndromes. In addition, many of the pulmonary reactions to drugs used for the treatment of
rheumatoid arthritis are rare and are published as case reports ( table 1). An online repository
of drug-induced lung disease is available to help identify potential culprit medications
(Pneumotox.com) [2]. When patients present with fever, rapidly progressive respiratory
insufficiency, or widespread or nodular opacities on chest imaging, bacterial and opportunistic
lung infections are high on the differential and should be pursued vigorously. (See 'Evaluation
and diagnosis' above and "Approach to the immunocompromised patient with fever and
pulmonary infiltrates".)
FEATURES OF INDIVIDUAL AGENTS
Methotrexate — Methotrexate (MTX) is the most commonly used disease modifying

antirheumatic drug (DMARD) in RA. Pulmonary complications of methotrexate are not
associated with folate deficiency and may occur with the relatively low doses (<20 mg per week)
that are used in patients with RA [24,25]. In one study, MTX was associated with progression of
preclinical interstitial lung disease (ILD) in patients with RA [26]. The risk factors, clinical
manifestations, diagnosis, and treatment of MTX-induced pneumonitis are discussed in greater
detail separately. (See "Major side effects of low-dose methotrexate" and "Methotrexate-induced
lung injury".)
Acute or subacute interstitial pneumonitis is the most common noninfectious pulmonary

complication of MTX therapy. Patients typically present with nonproductive cough, dyspnea, and
sometimes fever or chest pain. Among those with a subacute onset of MTX-induced lung
disease, up to 50 percent demonstrate peripheral blood eosinophilia, which strongly supports
the diagnosis, when present. Early drug discontinuation at the onset of respiratory symptoms
may obviate the need for invasive testing.
Less commonly, interstitial fibrosis (honeycombing), accelerated rheumatoid lung nodulosis,

asthma, and air trapping may occur during MTX treatment. In many cases, it is not clear

whether these less common abnormalities are drug-related or are due to underlying
rheumatoid disease [27,28].
As noted above, the differential diagnosis of MTX-induced lung disease includes infectious
complications, which must be excluded prior to the initiation of immunosuppressive therapy to
treat a possible drug reaction. Infections reported in the setting of methotrexate therapy
include Pneumocystis jirovecii pneumonia, cryptococcal pneumonia, invasive pulmonary
aspergillosis, disseminated histoplasmosis, pulmonary Nocardia infection, and viral pneumonia
(eg, parainfluenza and cytomegalovirus) [6,8-13]. (See 'Evaluation and diagnosis' above.)
Leflunomide — Leflunomide is a DMARD used in RA that blocks a key enzyme of pyrimidine

synthesis in activated lymphocytes. ILD and cases of new or accelerated pulmonary nodule
formation have been reported, although the exact pathogenesis is not known [3,29-33]. As with
other immunosuppressive agents, leflunomide is associated with an increased risk of infection
in some [34], but not all studies [35]. (See "Pharmacology, dosing, and adverse effects of
leflunomide in the treatment of rheumatoid arthritis".)
Interstitial pneumonitis — Data on the risk of interstitial pneumonitis due to leflunomide

are conflicting [3,31-36]. Overall, the risk appears low, except possibly in patients with
underlying ILD or a history of MTX-induced lung toxicity. We generally avoid leflunomide in such
patients, realizing the limitations of the data. Decisions need to be individualized, however, as
the benefits of leflunomide may be substantial.
Studies showing the range of findings with leflunomide include the following:
● A systematic review and meta-analysis that included eight clinical trials with 4579
participants suggested a decreased risk of noninfectious respiratory adverse events (RR
0.64, 95% CI 0.41-0.97) with leflunomide compared with MTX or placebo [35]. This analysis
supports the contention that "channelling bias" may explain the results of the above
observational studies. However, clinical trials would have excluded patients with underlying
ILD. Thus, the safety of leflunomide in these patients requires further study.
● In a review that used linked prescribing and administrative databases for more than
235,000 patients with RA, the relative risk of ILD among those treated with leflunomide was
1.9 compared to those treated with other DMARDs [36]. However, there was no significant
increase in risk among patients who had no prior diagnosis of ILD and no prior MTX use.
● Similar findings were reported in an observational study of 5054 patients who were treated
with leflunomide; 1.2 percent developed new or worsening ILD [37]. Risk factors included

preexisting lung disease (most important factor) with an odds ratio of 8.17 (95% CI 4.63-
14.4), smoking, low body weight, and use of a loading dose.
Pneumonitis due to leflunomide usually presents within the first 20 weeks of therapy and may
occur after cessation of the medication [32,38-40]. Typical symptoms are fever, cough, and
dyspnea. The main findings on high resolution computed tomography (HRCT) are ground glass
opacities, bilateral reticular opacities, and honeycombing, although areas of consolidation can
also be seen [32,41]. Eosinophilia in the bronchoalveolar lavage (BAL) fluid has been described
[40]. Lung biopsies show interstitial pneumonitis (sometimes with eosinophilia), organizing
pneumonia, or diffuse alveolar damage.
In one report, leflunomide-induced pneumonitis was fatal for 11 of 29 patients [30]. In another
report, there were no fatalities; the authors attributed this to prompt recognition and treatment
with glucocorticoids and cholestyramine [31].
Leflunomide has a long half-life. Because of the hepatobiliary circulation of leflunomide,

cholestyramine resin (eg, 8 g/day for three days) can be used to hasten elimination [30,42]. (See
"Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid
arthritis", section on 'Pregnancy and lactation'.)
Rheumatoid pulmonary nodules — Leflunomide is also associated with appearance or

accelerated progression of rheumatoid (necrobiotic) pulmonary nodules, which can occasionally
lead to pneumothorax [29,43,44]. Development of pulmonary rheumatoid nodules may be
associated with cough and low grade fever [29,44]. On imaging studies, the nodules may be
cavitary [29]. Cessation of leflunomide usually leads to improvement or resolution of the
nodules. (See "Rheumatoid nodules" and "Overview of lung disease associated with rheumatoid
arthritis", section on 'Rheumatoid lung nodules'.)
Biological agents — Despite broad use of biologic agents to treat RA, cases of substantial
pulmonary toxicity are infrequently reported [3,21,45]. In general, the biologic agents, tumor
necrosis factor (TNF)-alpha blockers (soluble p75 TNF receptor fusion protein [etanercept],
dimeric anti-TNF-alpha antibody [infliximab], anti-TNF-alpha monoclonal antibody
[adalimumab]), interleukin (IL)-1 blockers (anakinra), anti-B-cell monoclonal antibody
(rituximab), and a selective costimulation modulator which prevents T cell CD28 binding
(abatacept), have been shown to improve symptoms and joint disease, and possibly also lung
disease in patients with RA [46-48]. Case series have also reported patients with other
pulmonary disorders, such as nodules and infection, in association with biologic therapies for
RA. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases".)

Due to the infrequent occurrence of ILD, the likelihood that these agents are used in patients
with more severe RA, and the risk of reporting bias, it is difficult to ascertain the exact risk of
drug-induced ILD or worsening of preexisting ILD [3]. The British Society for Rheumatology
Biologics Register (BSRBR) prospectively collects data on all patients in the UK receiving biologic
agents (>8000 patients) [49]. An early report in the organization's newsletter suggested that the
odds ratio for mortality was 4.4 times higher (95% CI 1.8-10.7) for those RA patients with
preexisting pulmonary disease who were treated with biologics compared to those without
pulmonary disease. However, further analysis of the BSRBR included a prospective study of 367
patients with preexisting ILD (299 on anti-TNF; 68 on DMARDS) [50]. The adjusted (overall)
mortality rate ratio comparing anti-TNF-alpha agents with DMARDS was 0.81 (95% CI 0.38-1.73),
suggesting that biologics do not increase overall mortality. On the other hand, ILD appeared to
be a more common cause of death with biologic agents compared with DMARDs (age and sex
adjusted mortality rate ratio 2.63, 95% CI 0.60-11.45), although the numbers were small. A
systematic review of published reports of drug-induced ILD in RA estimated the overall the risk
with biologic agents at around 1 percent, but the mortality associated with ILD due to anti-
TNFa-agents was high at 35 percent, compared with estimates of 18 and 13 percent for
leflunomide and MTX, respectively [3].
The importance of these findings is in balancing the great overall benefit of biologic agents in
controlling RA with the relative rarity, but potential severity, of drug-induced ILD. Additionally, as
new agents are introduced, clinicians should maintain a heightened awareness of the potential
for any drug to cause lung complications.
Inflammatory pneumonitis — Drug-induced ILD has been reported with the TNF-alpha

inhibitors, rituximab, tocilizumab, and anakinra, but not abatacept [2,51,52]. Development of
new or worsening cough, dyspnea, and radiographic abnormalities should alert the clinician to
the possibility of drug-induced ILD.
The frequency of drug-induced ILD and the possibility that underlying ILD can potentiate this
process are illustrated by the following studies, and are summarized in a review [21]:
● Etanercept and infliximab (TNF-alpha inhibitors) – Drug-induced ILD is uncommon, but

potentially severe in patients treated with etanercept or infliximab, particularly patients
aged 65 or older and those with preexisting ILD [20]. Among 108 patients with RA who
developed new-onset or worsening of preexisting ILD while taking these agents, the
majority of cases developed after the first six months of therapy. Drug-discontinuation and
glucocorticoids resulted in improvement or resolution in approximately 65 percent, but
progressive and death in 12 percent. In an observational study of 7091 patients with RA
who were treated with etanercept, ILD developed in 42 (0.6 percent) [53]. A number of case

reports have described lung toxicity as well. A patient with a prior history of MTX therapy
developed lung injury eight weeks after initiation of etanercept, but responded to cessation
of etanercept and treatment with oral prednisone 40 mg/day [54]. In two small case series,
10 patients with RA developed progressive usual interstitial pneumonitis (UIP) temporally
related to initiation of infliximab or etanercept, and one developed organizing pneumonia;
eight patients died from progressive UIP [55,56]. Among the fatal cases, all had preexisting
ILD with a UIP pattern and three were concomitantly taking azathioprine and
glucocorticoids. In these patients, MTX had been avoided because of the preexisting lung
disease. Three cases of acute interstitial pneumonitis have been reported shortly after
addition of infliximab in patients taking a stable dose of MTX [57]. All patients improved
with discontinuation of MTX and infliximab and treatment with methylprednisolone.
● Adalimumab (TNF-alpha inhibitor) – One patient with RA on a stable dose of MTX

developed rapidly worsening ILD after initiation of adalimumab [58]. Respiratory
improvement followed discontinuation of MTX and adalimumab, and treatment with oral
prednisolone.
● Certolizumab (TNF-alpha inhibitor) – In a patient with refractory RA despite MTX and

leflunomide, certolizumab was added with subsequent development of dry cough,
breathlessness, and basilar crackles [59]. Ground glass and reticular opacities were noted
on computed tomography (CT). Despite cessation of certolizumab and administration of
systemic glucocorticoids, the patient experienced progressive respiratory failure. Among
4049 patients with RA treated with certolizumab, no instances of drug-induced ILD were
reported [60].
● Rituximab (CD-20 antibody) – Several case reports have described ILD associated with
rituximab therapy for hematologic malignancies, but only a few have described ILD in
patients with RA [61-64]. In a report of patients with underlying RA-associated ILD who were
treated with rituximab, one experienced further progression and another developed acute
respiratory distress syndrome due to possible pneumonia [63]. A separate report described
development of organizing pneumonia in a patient with RA treated with rituximab and MTX
[61]. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted
agents", section on 'Rituximab'.)
● Tocilizumab (interleukin [IL]-6 receptor antibody) – Isolated cases of combined

pulmonary fibrosis with emphysema, ILD, acute pneumonitis, and idiopathic pulmonary
fibrosis have been reported with tocilizumab (monoclonal antibody to interleukin-6) [65-69].

● Anakinra (IL-1 inhibitor) – Although infrequently used in the treatment of RA, anakinra has
been associated with ILD in a small number of patients [70-72].
Treatment of drug-induced ILD due to the various biologic agents requires cessation of the
drug; concomitantly administered DMARDs (eg, MTX, leflunomide) will also need to be stopped.
If it is unclear which agent caused the lung toxicity, cautious reintroduction of one of the agents
may be possible after resolution of symptoms and radiographic changes. Alternatively, a
different biologic agent or DMARD may need to be substituted.
The efficacy of systemic glucocorticoids in this setting is not known. For patients who have
stable or improving pneumonitis after cessation of the drug, glucocorticoids are generally
withheld and the patient observed, as resolution of pulmonary toxicity often accompanies drug
discontinuation. In contrast, empiric glucocorticoid therapy is usually initiated in a patient who
has rapidly progressive or more severe pulmonary toxicity, although scientific evidence to
support this practice is lacking.
As noted, these reports describe the potential for serious, adverse effects with biologic agents,
particularly among patients with preexisting RA-induced ILD [20]. Predictors of which patients
with RA-ILD are at greatest risk of a severe lung reaction have not been determined, but caution
is advised for older adults, a UIP pattern, or severe disease [73]. However, biologic agents carry
the potential for significant improvement in overall RA disease activity, so the balance of all
factors should be considered when deciding to administer or withhold TNF-alpha blockers in
patients with preexisting RA-induced ILD.
Granulomatous lung disease — Lung disease characterized by granuloma formation (both

noncaseating and necrotizing) without evidence of mycobacterial or fungal infection has been
reported in a number of case reports [74-79]. In the largest series, six patients were on
etanercept, two infliximab, and three adalimumab; some were also taking leflunomide or MTX
[79]. Symptoms of cough, dyspnea, chest pain, or asthenia were reported by five of the patients.
Imaging revealed single, multiple, or cavitary nodules; one patient had hilar adenopathy. Anti-
TNF-alpha therapy was discontinued in six patients, but maintained in the others. Two patients
were treated with rituximab after discontinuation of anti-TNF-alpha therapy, with resolution of
the nodules.
Infections — A variety of serious infections have been described with use of biologic agents
to treat RA, especially TNF-alpha inhibitors. The presence of underlying chronic obstructive
pulmonary disease (COPD) and the combination of biologic agents with glucocorticoids or other
immunomodulatory agents may further increase the risk of infection [15]. Presenting symptoms

may be subtle, and a high degree of clinical suspicion for infection should be applied in the
assessment of patients treated with these agents.
In one study of 5326 patients, a four-fold increase in hospitalization due to infection was
attributed to use of TNF-alpha inhibitors, compared with a two-fold increase that was associated
with MTX [16]. The most common infection was bacterial pneumonia. In a separate
observational study of 7091 patients taking etanercept, pneumonia occurred in 0.8 percent [53].
In a retrospective study in 146 older adults receiving biological agents for rheumatoid arthritis,
the most common severe adverse reaction was infection, which occurred in 32 patients (22
percent) [80]. A variety of opportunistic infections (eg, Listeria, Mycobacteria tuberculosis,
Coccidioides, Histoplasma and other fungal species, and cytomegalovirus) are noted in case
reports and series. (See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal
infections" and "Tumor necrosis factor-alpha inhibitors and mycobacterial infections".)
Rituximab has also been associated with serious infections, including bacterial pneumonia and
Pneumocystis pneumonia [15,81-83]. It is not clear if the incidence of most of these infections is
greater than that associated with other DMARDs [84].
The incidence of serious infections is approximately doubled when abatacept is added to a TNF-
alpha inhibitor [47].
The use of anakinra at high dose may increase the risk of serious infection, although further
data are needed [83].
Tuberculosis screening — TNF-alpha inhibitors are associated with an increased risk of

reactivation tuberculosis (TB). Appropriate screening before the start of treatment and vigilance
for the occurrence of active TB during therapy are essential, although screening does not
eliminate the risk of development of active TB. These issues are reviewed separately. (See
"Tumor necrosis factor-alpha inhibitors and mycobacterial infections", section on 'Screening and
prevention'.)
Sulfasalazine — Sulfasalazine, which is sometimes used in combination therapy regimens for

RA, has been associated with pneumonitis, commonly in conjunction with fever and rash [3,85].
Nearly half of affected patients present with the clinical syndrome of pulmonary infiltrates with
eosinophilia [85]. Drug reaction with eosinophilia and systemic symptoms (DRESS) is also
reported [86,87]. Cough and crackles on lung examination are commonly present. Eosinophil
counts in the peripheral blood range from 432 to 7500/mm3. (See "Drug reaction with
eosinophilia and systemic symptoms (DRESS)".)

Clinical improvement typically follows cessation of sulfasalazine, while progressive respiratory

failure and death occurred in two of three patients who continued the medication. The role of
systemic glucocorticoid therapy is not well-studied, as most patients improve with sulfasalazine
withdrawal. Among 20 patients treated with systemic glucocorticoids, 13 had complete
symptom resolution, 3 improved, 1 had persistent disease, and 3 died of progressive respiratory
failure. Rechallenge is not recommended.
Other pulmonary disorders associated with sulfasalazine include nonspecific interstitial

pneumonia, organizing pneumonia (formerly known as bronchiolitis obliterans organizing
pneumonia), granulomatous lung disease, bronchiolitis obliterans, and rarely pleural effusion
[85,88-90].
Nonsteroidal anti-inflammatory drugs — Nonsteroidal anti-inflammatory drugs (NSAIDs)

have both analgesic and antiinflammatory properties, but do not alter articular outcomes in RA.
Several NSAIDs (eg, ibuprofen, naproxen, diflunisal) have been associated with pulmonary
infiltrates with eosinophilia, but not all of these reports were in patients with RA [91-95]. It is not
known whether this is a class effect or a unique feature of certain NSAIDs.
Cessation of the implicated agent is indicated, as resolution of pulmonary toxicity often

accompanies drug discontinuation. Systemic glucocorticoids are generally withheld as long as
pneumonitis is stable or improving. In contrast, empiric glucocorticoid therapy is usually
initiated in a patient who has rapidly progressive or more severe pulmonary toxicity, although
data to support this practice are limited to case reports. (See "Nonselective NSAIDs: Overview of
adverse effects", section on 'Pulmonary infiltrates with eosinophilia'.)
Rarely used medications
Gold — Pneumonitis due to gold therapy is well recognized but uncommon, particularly now
that more effective treatments for RA have supplanted the use of gold. Several forms of
pulmonary disease occur among patients treated with gold, including nonspecific interstitial
pneumonitis, organizing pneumonia, and bronchiolitis obliterans [96]. Of these, nonspecific
interstitial pneumonitis is the most common. The pneumonitis typically begins within the first
six months of therapy, after the cumulative ingestion of about 500 mg of gold. (See "Use of gold
compounds in rheumatic diseases" and "Major side effects of gold therapy".)
Dyspnea (on exertion or at rest) and cough are frequently observed (92 and 67 percent,
respectively) [96]. A rapid onset of symptoms is common. Fever (47 percent) and skin rash (38
percent) also may occur during the clinical course. Rare reports have described a fulminant
onset of acute respiratory failure requiring mechanical ventilation [97]. Crackles are usually

evident on physical examination. Gold-induced lung disease is generally not accompanied by a

flare of rheumatoid joint disease or the presence of cutaneous rheumatoid nodules.
Peripheral blood differential cell counts reveal leukocytosis (27 percent) and eosinophilia (38
percent) [96]. BAL typically demonstrates lymphocytosis (>25 percent) with a low CD4+/CD8+
ratio (<1) [96]. The chest radiograph is usually, but not always, abnormal, showing diffuse
opacities with a mid to upper zone predominance, which contrasts the lower zone
predominance observed in RA-ILD [98]. Moreover, pleural abnormalities are rare in gold-
induced ILD, but common in RA-ILD [99]. CT scans of the chest reveal ground glass or
consolidative opacities along the bronchovascular bundles in gold-induced pneumonitis [96].
Features of gold-induced pneumonitis that may allow differentiation from underlying RA-
induced ILD include the presence of fever (50 percent), absence of clubbing (1 percent), BAL
lymphocytosis (70 percent) rather than neutrophilia, and extrapulmonary signs of gold toxicity,
such as a skin rash (36 percent), eosinophilia (36 percent), liver dysfunction (19 percent), and
proteinuria (19 percent) [96]. For patients with fever and radiographic lung opacities in the
absence of eosinophilia, the possibility of infection should be vigorously evaluated and
excluded. (See "Major side effects of gold therapy" and "Overview of lung disease associated
with rheumatoid arthritis", section on 'Infection'.)
Gold therapy should be permanently discontinued in all cases. Systemic glucocorticoid therapy
(prednisone 40 to 60 mg per day) is usually initiated (after exclusion of infectious etiologies)
when respiratory impairment is severe or when drug discontinuation does not lead to
improvement [97]. This practice is based on clinical experience, rather than controlled trial data.
After clinical response, prednisone is gradually tapered over two to six months.
Complete remission (ie, improved symptoms and normalization of the chest radiograph or
pulmonary function tests) follows treatment in the majority of patients. Abrupt glucocorticoid
withdrawal may result in recurrence of pneumonitis [100].
Penicillamine — Pulmonary complications related to penicillamine are rare, particularly

given that more effective treatments for RA are preferred [1,101]. Original reports of
bronchiolitis obliterans in patients with RA suggested that penicillamine was the causative
agent, but bronchiolitis obliterans has occurred in the absence of medication in patients with
rheumatoid disease and has been associated with gold and sulfasalazine [17]. (See
'Sulfasalazine' above and 'Gold' above.)
Penicillamine has been extensively used in Wilson's disease with very few pulmonary reactions,
suggesting that some interaction between penicillamine and the underlying rheumatoid

disease may predispose to the development of bronchiolitis obliterans. This predisposition in

patients with RA also extends to the other side effects associated with penicillamine.
Bronchiolitis obliterans has been described between 3 and 14 months after the initiation of
penicillamine therapy, and at daily doses of 375 to 1250 mg [1,102]. Patients generally present
with the subacute onset of cough and dyspnea on exertion, frequently in the presence of a
chest radiograph that is normal or reveals only hyperinflation. CT scans may reveal gas trapping
(particularly on expiratory images) and/or a mosaic pattern of ground glass opacification. A
progressive obstructive ventilatory defect without bronchodilator response is generally present
on pulmonary function testing. Definitive diagnosis requires a lung biopsy, which reveals typical
findings of bronchiolitis obliterans. (See "Role of lung biopsy in the diagnosis of interstitial lung
disease".)
The management of bronchiolitis obliterans is discussed separately. (See "Overview of

bronchiolar disorders in adults", section on 'Treatment'.)
Other rare complications of penicillamine include membranous nephropathy, drug-induced

lupus erythematosus, pulmonary hemorrhage, and interstitial fibrosis [17]. (See "Drug-induced
lupus" and "Membranous nephropathy: Epidemiology, pathogenesis, and etiology", section on
'Drugs'.)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis"
and "Society guideline links: Interstitial lung disease".)
SUMMARY AND RECOMMENDATIONS
● Most of the drugs used to treat rheumatoid arthritis (RA) have been reported to cause
pneumonitis, including methotrexate, leflunomide, biologic agents, sulfasalazine, gold,
penicillamine, and nonsteroidal antiinflammatory drugs (NSAIDs). Many of the pulmonary
reactions to drugs used for the treatment of rheumatoid arthritis are rare and are
published as case reports, but have a high mortality. (See 'Prevalence' above.)
● Pulmonary disease may occur with the relatively low doses of methotrexate (<20 mg per
week) that are used in patients with RA. Acute to subacute interstitial pneumonitis is the

most common noninfectious complication of methotrexate in this setting. (See

'Methotrexate' above.)
● In patients with methotrexate-induced pneumonitis, the chest radiograph typically

demonstrates diffuse bilateral reticular opacities or mixed reticular and ground glass
patterns (40 percent). Unilateral or nodular changes, effusions, and bilateral hilar
lymphadenopathy are uncommon. Early drug discontinuation at the onset of respiratory
symptoms may obviate the need for invasive testing. (See 'Methotrexate' above and
"Methotrexate-induced lung injury".)
● Interstitial pneumonitis and new and accelerated pulmonary rheumatoid nodule formation
have been described with leflunomide, although the risk appears low. We generally avoid
leflunomide in patients with underlying lung disease or a history of methotrexate-induced
lung toxicity, but gathering evidence suggests this may not be necessary. (See 'Leflunomide'
above.)
● New onset or progressive pneumonitis may uncommonly occur in patients treated with the
tumor necrosis factor-alpha (TNF-alpha) blockers. A growing number of other biologic
agents are being used to treat RA; further study is needed to determine whether they also
cause or contribute to RA-associated interstitial pneumonitis. (See 'Inflammatory
pneumonitis' above.)
● TNF-alpha inhibitors are associated with an increased risk of reactivation tuberculosis (TB)
and other opportunistic infections. Appropriate screening before the start of treatment and
vigilance for the occurrence of active TB during therapy are essential. (See 'Tuberculosis
screening' above.)
● Granulomatous lung disease and hilar adenopathy are also associated with TNF-alpha
inhibitors in the absence of demonstrable mycobacterial or fungal infection. Beyond careful
exclusion of infection, the optimal management is not known. (See 'Granulomatous lung
disease' above.)
● The rarely used medications, gold and penicillamine, have been associated with interstitial
lung disease and bronchiolitis, respectively. (See 'Rarely used medications' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 4378 Version 16.0

GRAPHICS
Pulmonary complications from drugs for rheumatoid arthritis
Pneumonitis
Anakinra
Azathioprine
Cyclophosphamide
Methotrexate*
Leflunomide
NSAID ¶
Rituximab
TNF inhibitors Δ
Tocilizumab
Sulfasalazine
Chlorambucil
Gold*
d-Penicillamine
Fibrosis
Methotrexate
Gold
Cyclophosphamide
Chlorambucil
Azathioprine
Sulfasalazine
Obliterative bronchiolitis
d-Penicillamine
Gold
Sulfasalazine
Infection
TNF inhibitors Δ*
IL-1 inhibitors ◊
Methotrexate*
Glucocorticoids*
Cyclophosphamide
Abatacept
Rituximab
Noncardiogenic pulmonary edema

Aspirin (high doses)
NSAID ¶
Methotrexate
Cyclophosphamide

Colchicine (overdose)
Rituximab
Tocilizumab
Pulmonary renal syndrome
Pulmonary hemorrhage
d-Penicillamine
Drug-induced lupus
d-Penicillamine
TNF inhibitors Δ
Sulfasalazine
Bronchospasm
Aspirin
NSAID ¶
Methotrexate
Air trapping
? Methotrexate
* Most common reactions reported.

¶ Nonsteroidal anti-inflammatory medications.
Δ Tumor necrosis factor modifying agents (infliximab, etanercept, adalimumab).
◊ Interleukin-1 blocking agents (anakinra).
Graphic 65141 Version 5.0

Contributor Disclosures
Fiona R Lake, MD, FRACP Nothing to disclose Talmadge E King, Jr, MD Nothing to disclose Eric L
Matteson, MD, MPH Grant/Research/Clinical Trial Support: Sun Pharmaceutical Industries, Ltd [Basic
science investigation concentrating on rheumatoid lung disease]. Consultant/Advisory Boards: Boehringer-
Ingelheim [Interstitial lung disease]; Gilead Sciences [Rheumatoid arthritis]; TympoBio [Autoimmune
hearing loss]; Arena Pharmaceuticals [Autoimmune Diseases]. Speaker's Bureau: Practice Point
Communications [Treatment of rheumatoid arthritis]. Other Financial Interest: SAB Biotherapeutics, Inc –
Data and Safety Monitoring Board [Infectious diseases/viral neutralizing antibodies]. Helen
Hollingsworth, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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29/11/2020 Drug-induced lung disease in rheumatoid arthritis - UpToDate

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Drug-induced pulmonary disease is an important consideration in the differential diagnosis of

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EVALUATION AND DIAGNOSIS

bronchoalveolar lavage fluid). Empiric drug discontinuation is an important diagnostic step.

● Laboratory testing – Laboratory testing is used to determine whether other disease

Hilar lymphadenopathy is an uncommon manifestation of drug induced disease, except in

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The differentiation between a drug reaction, underlying rheumatoid-associated lung disease,

FEATURES OF INDIVIDUAL AGENTS

Methotrexate — Methotrexate (MTX) is the most commonly used disease modifying

Acute or subacute interstitial pneumonitis is the most common noninfectious pulmonary

Less commonly, interstitial fibrosis (honeycombing), accelerated rheumatoid lung nodulosis,

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/drug-induced-lung-disease-in-rheumatoid-arthritis/print?search=HYPERSENSITIVE NEUMONITIS… 5/27

Leflunomide — Leflunomide is a DMARD used in RA that blocks a key enzyme of pyrimidine

Interstitial pneumonitis — Data on the risk of interstitial pneumonitis due to leflunomide

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Leflunomide has a long half-life. Because of the hepatobiliary circulation of leflunomide,

Rheumatoid pulmonary nodules — Leflunomide is also associated with appearance or

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Inflammatory pneumonitis — Drug-induced ILD has been reported with the TNF-alpha

● Etanercept and infliximab (TNF-alpha inhibitors) – Drug-induced ILD is uncommon, but

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● Adalimumab (TNF-alpha inhibitor) – One patient with RA on a stable dose of MTX

● Certolizumab (TNF-alpha inhibitor) – In a patient with refractory RA despite MTX and

● Tocilizumab (interleukin [IL]-6 receptor antibody) – Isolated cases of combined

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Granulomatous lung disease — Lung disease characterized by granuloma formation (both

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Tuberculosis screening — TNF-alpha inhibitors are associated with an increased risk of

Sulfasalazine — Sulfasalazine, which is sometimes used in combination therapy regimens for

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Clinical improvement typically follows cessation of sulfasalazine, while progressive respiratory

Other pulmonary disorders associated with sulfasalazine include nonspecific interstitial

Nonsteroidal anti-inflammatory drugs — Nonsteroidal anti-inflammatory drugs (NSAIDs)

Cessation of the implicated agent is indicated, as resolution of pulmonary toxicity often

Rarely used medications

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evident on physical examination. Gold-induced lung disease is generally not accompanied by a

Penicillamine — Pulmonary complications related to penicillamine are rare, particularly

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disease may predispose to the development of bronchiolitis obliterans. This predisposition in

The management of bronchiolitis obliterans is discussed separately. (See "Overview of

Other rare complications of penicillamine include membranous nephropathy, drug-induced

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

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most common noninfectious complication of methotrexate in this setting. (See

● In patients with methotrexate-induced pneumonitis, the chest radiograph typically

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2. Camus P. The Drug-Induced Respiratory Disease Website. www.pneumotox.com (Accessed

3. Roubille C, Haraoui B. Interstitial lung diseases induced or exacerbated by DMARDS and

5. Strand V, Ahadieh S, French J, et al. Systematic review and meta-analysis of serious

6. Katsuyama T, Saito K, Kubo S, et al. Prophylaxis for Pneumocystis pneumonia in patients

8. Belin V, Tebib J, Vignon E. Cytomegalovirus infection in a patient with rheumatoid arthritis.

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20. Perez-Alvarez R, Perez-de-Lis M, Diaz-Lagares C, et al. Interstitial lung disease induced or

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32. Chikura B, Lane S, Dawson JK. Clinical expression of leflunomide-induced pneumonitis.

33. Raj R, Nugent K. Leflunomide-induced interstitial lung disease (a systematic review).