Drug-induced lung disease in rheumatoid arthritis

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: May 2016. &#124 This topic last updated: Jun 03, 2016.

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/orinterstitial 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 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, respectively. 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]. MTX has also been 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 "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.
●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.
●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.
Leflunomide-associated ILD 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-associated ILD 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 "Leflunomide in the treatment of rheumatoid arthritis", section on 'Pregnancy'.)
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 — 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), a selective co-stimulation modulator which prevents T cell CD28 binding (abatacept), and similar agents have been shown to improve symptoms, joint disease, and possibly lung disease in patients with RA [45-47]. However, rare cases of substantial pulmonary toxicity have also been described, including over 100 cases of induction or exacerbation of ILD in patients with RA [20,21,48]. (See "Overview of biologic agents in the rheumatic diseases".)
Due to the infrequent occurrence, likelihood that these agents are used in patients with more severe RA, and 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.  
Inflammatory pneumonitis — Drug-induced ILD has been reported with the TNF-alpha inhibitors 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 recent review [21]:
●Etanercept and infliximab – 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 – 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 – 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 – 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 – Single cases of combined pulmonary fibrosis with emphysema, ILD, acute pneumonitis, and idiopathic pulmonary fibrosis have been reported with tocilizumab [65-67].
●Anakinra – Although infrequently used in the treatment of RA, anakinra has been associated with ILD in a small number of patients [68-70].
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, an alternate agent 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]. 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 [71-76]. In the largest series, six patients were on etanercept, two infliximab, and three adalimumab; some were also taking leflunomide or MTX [76]. 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, 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]. 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 [15,77-79]. It is not clear if the incidence of most of these infections is greater than that associated with other DMARDs [80].
The incidence of serious infections is approximately doubled when abatacept is added to a TNF-alpha inhibitor [46].
The use of anakinra at high dose may increase the risk of serious infection, although further data are needed [79].
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 [3,81]. Nearly half of affected patients present with the clinical syndrome of pulmonary infiltrates with eosinophilia [81]. Drug reaction with eosinophilia and systemic symptoms (DRESS) is also reported [82,83]. 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, 16 percent improved 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 [81,84-86].
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 [87]. 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) [87]. 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 [88].
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) [87]. BAL typically demonstrates lymphocytosis (>25 percent) with a low CD4+/CD8+ ratio (<1) [87].
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 [89]. Moreover, pleural abnormalities are rare in gold-induced ILD, but common in RA-ILD [90]. CT scans of the chest reveal ground glass or consolidative opacities along the bronchovascular bundles in gold-induced pneumonitis [87].
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) [87]. 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 [88]. 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 [91].
Penicillamine — Pulmonary complications related to d-penicillamine are rare, occurring in 1 to 3 percent of cases [1,92]. Original reports of bronchiolitis obliterans in patients with RA suggested that d-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.)
D-penicillamine has been extensively used in Wilson's disease with very few pulmonary reactions, suggesting that some interaction between d-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 d-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 [1,93]. 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 prognosis of bronchiolitis obliterans associated with d-penicillamine is poor, with an estimated mortality of 50 percent [1]. There is little evidence that glucocorticoids are of benefit, although a trial of therapy (prednisolone 1 to 1.5 mg/kg per day) is warranted because of the dismal prognosis. Trials of other immunosuppressive agents (eg, cyclophosphamide 100 to 120mg/day or azathioprine 3 mg/kg per day up to a daily maximum of 200 mg) can also be attempted [93]. The management of bronchiolitis obliterans is discussed separately. (See "Bronchiolitis in adults", section on 'Treatment'.)
Other rare complications of d-penicillamine include a pulmonary-renal syndrome, drug-induced lupus erythematosus, pulmonary hemorrhage, and interstitial fibrosis [17]. (See "Pathogenesis and diagnosis of anti-GBM antibody (Goodpasture's) disease" and "Drug-induced lupus".)
Nonsteroidal antiinflammatory drugs — Nonsteroidal antiinflammatory 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 [94-98]. 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'.)
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.)
●Interstitial lung disease due to gold therapy is uncommon and usually occurs after ingestion of a cumulative gold dose of about 500 mg. Withdrawal of gold is usually sufficient treatment, but occasionally glucocorticoids are necessary. (See 'Gold' above.)
●Bronchiolitis obliterans has been described between 3 and 14 months after the initiation of penicillamine therapy. Patients present with cough and dyspnea; chest radiograph shows hyperinflation. There is little evidence that glucocorticoids are of benefit, although a trial of therapy is warranted because of the dismal prognosis. (See 'Penicillamine' above.)