Overview of lung disease associated with rheumatoid arthritis

Overview of lung disease associated with rheumatoid arthritis

Author
Fiona R Lake, MD, FRACP

Section Editors
Kevin R Flaherty, MD, MS
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 04, 2015.

INTRODUCTION — Rheumatoid arthritis (RA) is a generally progressive, systemic autoimmune process characterized by chronic symmetrical erosive synovitis. Nonarticular manifestations of RA include subcutaneous nodules, vasculitis, pericarditis, mononeuritis multiplex, and episcleritis [1]. The lung and pleura are also frequent sites of extraarticular involvement by RA, but may not result in significant symptoms.
The pleuropulmonary manifestations of RA include [2-7]:
●Rheumatoid-associated parenchymal lung disease including interstitial disease and pulmonary nodules (table 1)
●Pleuropulmonary infection, related to RA and drug-induced immunosuppression
●Large and small airway obstruction
●Rheumatoid pleural disease
●Drug-related lung disease secondary to drugs used to treat rheumatoid disease (table 2)
●Vascular disease with vasculitis and pulmonary hypertension
●Comorbid medical conditions (eg, thoracic cage immobility, venous thromboembolism, lung cancer)
●Overlapping clinical syndromes (eg, interstitial lung disease and pleural thickening)
An overview of lung disease associated with RA will be presented here. Other aspects of RA, including specific types of interstitial lung disease seen in patients with RA, are discussed separately. (See "Clinical manifestations of rheumatoid arthritis" and "Interstitial lung disease in rheumatoid arthritis" and "Drug-induced lung disease in rheumatoid arthritis".)
EPIDEMIOLOGY — The prevalence of the different types of rheumatoid arthritis (RA)-associated respiratory disease is difficult to estimate for a number of reasons. Patient populations have been heterogeneous among the various studies; examples include studies of patients with early versus late stage disease, and community versus hospital versus autopsy based studies. In addition, there is substantial variability in the sensitivity of tests used to detect disease, ranging from analysis of pulmonary function to chest radiographs to high resolution computed tomography (HRCT). Finally, the subclinical nature of the disease in many patients may further complicate definitive epidemiologic assessment [8,9]. (See "Interstitial lung disease in rheumatoid arthritis", section on 'Epidemiology'.)
Despite these limitations, it appears that interstitial lung disease (ILD) and pleural disease are most common, although ILD, obliterative bronchiolitis (OB), drug reactions, and infections have the greatest impact on patient outcome.
HLA associations have been correlated with the aggressiveness of joint disease [10]. Additionally, the shared epitope HLA-DRB1*04 alleles may interact with smoking in the pathogenesis of RA and RA-ILD [11]. In a separate study of patients with RA, carriage of HLA-DRB1*1502 was related to an increased risk for ILD (relative risk ratio [RRR] 4.02, p = 0.013), but not airways disease [12]. (See "HLA and other susceptibility genes in rheumatoid arthritis".)
INTERSTITIAL LUNG DISEASE — Interstitial lung disease is the most common pulmonary manifestation of rheumatoid disease [5]. The clinical presentation, pathology, disease spectrum, and pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) are similar to that of the idiopathic interstitial pneumonias (IIPs) [2,13,14]. Histologically, the abnormalities are highly variable but usually resemble one of the IIPs or a mixture of them (table 3) [15,16]:
●Usual interstitial pneumonia (UIP)
●Nonspecific interstitial pneumonia (NSIP)
●Organizing pneumonia (OP)
●Lymphocytic interstitial pneumonia (LIP)
●Desquamative interstitial pneumonia (DIP)
●Acute interstitial pneumonia (AIP)
The evaluation and management of ILD in RA is discussed separately. (See "Interstitial lung disease in rheumatoid arthritis" and "Idiopathic interstitial pneumonias: Clinical manifestations and pathology".)
PLEURAL DISEASE — Pleural disease is common in patients with rheumatoid arthritis (RA), but it is usually subclinical [17]. As an example, autopsy studies identified pleural disease in 38 to 73 percent of patients with RA, but only 5 to 21 percent of those affected had complained of pleurisy and just over 5 percent had radiologic evidence of a pleural effusion [3,18,19]. Pleural disease is most common in patients with longstanding RA, but can precede joint disease. In addition, it is more common in men and coexists with rheumatoid nodules and interstitial lung disease (ILD) in up to 30 percent of patients (image 1).
Types of pleural disease — RA-associated pleural abnormalities include exudative “rheumatoid” effusion, drug-induced pleuritis (eg, methotrexate, infliximab), empyema, bronchopleural fistula, hemopneumothorax, and pyopneumothorax [3,19,20]. Pleural effusion and pneumothorax can be caused by necrosis and cavitation of a nodule into the pleural space with creation of a bronchopleural fistula [21]. In addition, chronic pleural inflammation can cause cholesterol (also called chyliform) effusions, lung entrapment, or trapped lung. In lung entrapment, the lung is unexpandable due to visceral pleural restriction from active pleural disease, such as rheumatoid pleuritis; while trapped lung develops as a consequence of long-term pleural inflammation that has left behind a collagenous or fibrous peel (image 2A-B). (See 'Imaging' below and "Clinical presentation, diagnosis and management of cholesterol effusions" and "Diagnosis and management of pleural causes of unexpandable lung", section on 'Lung entrapment'.)
When symptoms or signs occur in rheumatoid pleuritis, chest pain and/or fever are most common. Patients with significant pleural effusions may report dyspnea. Physical examination may be normal or may reveal distant breath sounds, a pleural rub, or unilateral or bilateral dullness on percussion. Dyspnea out of proportion to the size of the effusion may be a clue to underlying lung or heart pathology [17].
Imaging — For most patients with chest pain or shortness of breath, one of the first steps is chest radiography. The presence of pleural fluid, pneumothorax, pyopneumothorax, or hemopneumothorax is usually identified by conventional radiography. Decubitus views may be needed to assess whether pleural fluid is free-flowing. Further evaluation of possible underlying ILD, adjacent rheumatoid nodules, pleural thickening, or unexpandable lung often requires high resolution computed tomography (image 2B). (See "Imaging of pleural effusions in adults".)
For patients with a pneumothorax or hemopneumothorax, a chest computed tomography (CT) scan can identify subpleural cavitating rheumatoid nodules or blebs (eg, due to cigarette smoking) that are not visible on the conventional chest radiograph [22]. These are typically the cause of the pneumothorax and may require specific attention to prevent recurrence. (See 'Treatment of pneumothorax due to rheumatoid lung nodules' below.)
When loculated pleural fluid is suggested by the chest radiograph (image 2A), the possibility of lung entrapment or trapped lung should be considered. In lung entrapment, the pleural surface may appear nodular and the pleural fluid loculated. With trapped lung, pleural thickening and loculation are also noted. Additionally, a paradoxical reduction in size of the hemithorax with the effusion compared to the contralateral side suggests a negative pleural pressure on the affected side, providing further evidence for the diagnosis of trapped lung. (See "Diagnosis and management of pleural causes of unexpandable lung".)
Thoracentesis — A diagnostic, ultrasound-guided thoracentesis should be performed in patients who have RA and a pleural effusion that creates a separation >1 cm from the pleural fluid line to the chest wall on a decubitus chest radiograph. The purpose of pleural fluid analysis is to confirm that the pleural fluid is an exudate with cytologic characteristics of a rheumatoid effusion and to rule out alternative etiologies, such as infection, malignancy, cholesterol effusion, or unexpandable lung. Thus, the fluid is usually sent for cell counts, glucose, lactic dehydrogenase, protein, cholesterol, triglycerides, cytology, gram stain, and culture. (See "Diagnostic thoracentesis".)
In rheumatoid effusions, pleural fluid analysis typically reveals a white cell count <5000/mm³, a pleural fluid glucose <60 mg/dL(3.33 mmol/L) or a pleural fluid to serum glucose ratio less than 0.5, a pH less than 7.3, and high pleural fluid LDH level (ie, greater than 700 IU/L) (table 4) [3,17,19]. (See "Diagnostic evaluation of a pleural effusion in adults: Initial testing", section on 'Chemical analysis'.)
Less commonly, patients with RA and a long-standing pleural effusion may have a cholesterol effusion (also known as a pseudochylous or chyliform effusion), diagnosed by the appearance and analysis of the pleural fluid. Cholesterol effusions have the milky or opaque appearance of an empyema, but are sterile [17]. The milky appearance is due to an elevated cholesterol level (above 200 mg/dL and sometimes over 1000 mg/dL); cholesterol crystals, identifiable with polarized light, may also be present. (See "Clinical presentation, diagnosis and management of cholesterol effusions".)
Empyema due to infection has similar pleural fluid chemistries to a rheumatoid effusion (ie, exudative, low pH, low glucose); the possibility of infection needs to be fully evaluated with bacterial and mycobacterial stains and culture, particularly in patients taking glucocorticoids. (See "Parapneumonic effusion and empyema in adults".)  
Cytologic examination of rheumatoid pleural fluid often reveals characteristic findings of slender or elongated multinucleated macrophages, round giant multinucleated macrophages, and necrotic background debris [21]. However, the specificity of these findings has not been fully evaluated [17]. The presence of ragocytes, also known as "RA cells" is neither sensitive nor specific.
Measurement of pleural pressures — Pleural pressure measurement is used to identify pleural processes (eg, lung entrapment, trapped lung) that prevent the lung from re-expanding when pleural fluid is removed and rheumatoid arthritis is an established (albeit rare) cause of both lung entrapment and trapped lung. Formal assessment for lung entrapment and trapped lung usually follows identification of loculated pleural fluid on imaging or absence of lung re-expansion after thoracentesis (image 3). Direct measurement of pleural pressure during incremental withdrawal of pleural fluid can be performed at the time of thoracentesis. The technique for measuring and analyzing pleural pressures is described separately. (See "Measurement of pleural pressure", section on 'Interpretation of pleural pressures'.)
Lung entrapment and trapped lung have different characteristic patterns of pleural pressure and elastance (figure 1). The presence of a characteristic pleural pressure pattern can provide strong suggestive evidence in favor of lung entrapment or trapped lung. Definitive confirmation of lung entrapment would require direct visualization via thoracoscopy, but this is rarely necessary in patients with RA. Similarly, confirmation that visceral pleural thickening (a pleural rind) is the cause of trapped lung pleural physiology requires air contrast CT or direct visualization via video-assisted thoracoscopy. (See "Diagnosis and management of pleural causes of unexpandable lung", section on 'Diagnosis'.)
Advanced testing — In a patient with a persistent, sterile exudative effusion, but without the classic cytologic finding of rheumatoid pleuritis, chemistries of cholesterol effusion, or pleural pressure characteristics of unexpandable lung, a pleural biopsy may be helpful in excluding other disorders, such as tuberculosis or malignancy, or securing a diagnosis of rheumatoid pleuritis [17]. Pleural tissue can be obtained percutaneously or during video-assisted thoracoscopy. The thoracoscopic appearance of a rheumatoid effusion is typically described as “gritty,” with numerous small granules and nodules, ranging in size from 2 to 7 mm. Similar changes are noted on the visceral pleura, although the visceral nodules tend to be smaller [17]. (See "Diagnostic evaluation of pleural effusion in adults: Additional tests for undetermined etiology", section on 'Pleural biopsy'.)
Treatment of rheumatoid pleural effusion — Rheumatoid pleuritis and pleural effusions usually do not require specific treatment as they commonly resolve spontaneously or with treatment of RA joint disease, over 1 to 36 months (mean 14 months) [17]. One area of controversy is whether a larger rheumatoid effusion should be treated to decrease the likelihood of long-term sequelae such as a trapped lung (fibrothorax) [17]. When rheumatoid pleuritis dose not resolve spontaneously, several therapies have been reported to be useful including non-steroidal anti-inflammatory drugs (NSAIDs), therapeutic thoracentesis, glucocorticoids (oral or intrapleural), pleurodesis, and decortication. The evidence for these treatments is mixed, but we would recommend starting with the least toxic.
When treatment is needed because of pleuritic chest pain or the size of the effusion, the initial choice is an NSAID, such as indomethacin [23]. The use of NSAIDs in RA, including dosing for a therapeutic anti-inflammatory effect and potential adverse effects, is discussed separately. (See "Initial treatment of moderately to severely active rheumatoid arthritis in adults", section on 'NSAIDs'.)
Therapeutic thoracentesis is usually helpful if the patient needs acute relief of dyspnea, as long as the effusion is not associated with unexpandable lung due to lung entrapment or trapped lung. (See 'Measurement of pleural pressures' above.)
The optimal therapy for patients who do not respond to a course of oral NSAID therapy or a therapeutic thoracentesis is not clear. Local and systemic glucocorticoid therapy and treatment of rheumatoid joint disease with disease modifying agents (DMARDs) have all been tried with variable success. For symptomatic effusions refractory to NSAIDs, we use a moderate dose of oral glucocorticoids. According to case reports, oral glucocorticoid therapy (eg, 10 to 20 mg of prednisolone daily) may be beneficial [17]. Following improvement, in our opinion, the glucocorticoids should be tapered slowly to prevent relapse (1 to 2 mg per month once the dose has reached 10 mg). If the patient is intolerant of the side effects of systemic glucocorticoid, we occasionally administer intrapleural glucocorticoids (eg, 120 to 160 mg of depo-methylprednisolone acetate) [17,24]. Intrapleural glucocorticoid therapy carries an increased risk of pleural infection.
Use of chemical pleurodesis and decortication have also been reported, but are reserved for refractory effusions and trapped lung from a fibrous pleural peel, respectively [17]. (See "General principles of management of rheumatoid arthritis in adults" and "Management of refractory nonmalignant pleural effusions".)
The initial management of cholesterol effusions due to rheumatoid pleurisy focuses on treatment of the underlying rheumatoid inflammation, usually with prednisone and sometimes an additional immunosuppressive agent (eg, methotrexate). For patients with dyspnea at rest or with minimal exertion, a therapeutic thoracentesis will often provide relief of respiratory symptoms while waiting for the effects of enhanced anti-inflammatory treatments. Less commonly, a thick fibrous peel may also be present, causing a trapped lung and thus preventing re-expansion with thoracentesis. In this case, decortication may also be necessary. The management of cholesterol effusions is discussed separately. (See "Clinical presentation, diagnosis and management of cholesterol effusions", section on 'Management'.)
Treatment of pneumothorax due to rheumatoid lung nodules — Pneumothorax caused by rupture of a subpleural rheumatoid nodule or rupture of an emphysematous bleb with creation of a bronchopleural fistula is initially treated following guidelines for secondary spontaneous pneumothorax, including supplemental oxygen and pleural drainage. (See "Secondary spontaneous pneumothorax in adults", section on 'Initial management'.)
After initial stabilization of the SSP, most patients will need a procedure to prevent recurrence (eg, resection of subpleural cavitary nodules, stapling of blebs, mechanical or chemical pleurodesis) and some will need an additional intervention to treat a persistent air leak. A chest CT scan is essential to guide therapy, as cavitating nodules and subpleural blebs that caused the pneumothorax may not be visible on the conventional chest radiograph [22]. The optimal management of pneumothorax due to rheumatoid nodules is not known. Several case reports describe difficulties achieving re-expansion, closure of air leaks, and prevention of recurrences [22,25-29].
For patients who have a persistent air leak or failure of the lung to re-expand fully after three days of tube thoracostomy drainage, it becomes progressively less likely that spontaneous closure of the leak will occur and additional interventions (eg, surgical stapling or resection of blebs, resection of cavitary nodules with bronchopleural fistula formation, intraoperative pleurodesis, blood patch or chemical pleurodesis) may be appropriate if the patient is a surgical candidate. A discussion of these options is provided separately. (See "Secondary spontaneous pneumothorax in adults", section on 'After initial stabilization'.)
Based on the high rate of recurrence of secondary spontaneous pneumothorax, we advocate performing an intervention to prevent recurrence in almost all patients after initial stabilization and drainage of pleural air. (See "Secondary spontaneous pneumothorax in adults", section on 'Preventing recurrence'.)
Treatment of pleural effusions due to unexpandable lung — In general, the treatment of lung entrapment due to rheumatoid inflammation is focused on treatment of the underlying inflammation.
AIRWAY OBSTRUCTION — Both upper and lower airway disease have been reported in patients with rheumatoid arthritis (RA).
Upper airway obstruction — The main cause of upper airway obstruction in patients with RA is cricoarytenoid arthritis; less common causes include rheumatoid nodules on the vocal cord or vasculitis involving the recurrent laryngeal or vagus nerves, which may cause obstruction due to vocal cord paralysis [4,9]. Upper airway disease is more common in women and in patients with long-standing RA. Studies comparing direct laryngoscopy and computed tomography (CT) scanning demonstrate that high resolution computed tomography (HRCT) is more sensitive than direct laryngoscopy and can identify abnormalities in asymptomatic patients [30-32].
When RA affects the cricoarytenoid joint, increased synovial fluid can impair joint mobility. In chronic disease, erosion of the cartilage can lead to ankylosis or luxation of the joint with vocal cord immobility and laryngeal obstruction [30].  
Early symptoms of upper airway disease may include a hoarse voice, dysphagia, odynophagia, tenderness of the throat, pain on coughing or speaking, or exertional dyspnea [30]. However, symptoms usually are absent until significant obstruction occurs. Patients may present with acute onset of respiratory failure and stridor when previously unsuspected disease is unmasked by subluxation of the cartilage or superimposed airway edema secondary to an infection or intubation for surgery. (See "Clinical presentation, diagnostic evaluation, and management of central airway obstruction in adults".)
The diagnosis of cricoarytenoid joint (CAJ) involvement is based on a combination of studies, often including inspiratory and expiratory flow volume loops, contrast enhanced HRCT, and laryngoscopy (frequently with a flexible laryngoscope). For stable patients, inspiratory and expiratory flow volume loops (figure 2) can help identify upper airway obstruction when limitation of inspiratory flow is present, but changes may not be appreciable until the obstruction is severe. HRCT findings in cricoarytenoid joint arthritis include prominent hyperdense intra-articular sclerotic foci in the arytenoid and cricoid cartilages, increased spacing between the arytenoid and cricoid cartilages due to joint effusion, and subluxation of the joint [30,31]. Direct laryngoscopy is used to exclude laryngeal masses and vocal fold edema or nodules and to confirm failure of vocal fold abduction. Rarely, an electromyogram (EMG) may be required to differentiate nerve from joint disease, although bilateral vocal fold involvement would be more likely due to CAJ involvement than vasculitis involving the recurrent laryngeal or vagus nerves. (See "Neurologic manifestations of rheumatoid arthritis", section on 'Peripheral nervous system'.)  
For patients with stridor and respiratory distress, urgent intubation or tracheostomy may be necessary prior to diagnostic procedures. Because RA can be complicated by cervical spine instability, intubation and invasive diagnostic procedures should be performed by experienced operators and without excessive neck flexion. (See "Cervical subluxation in rheumatoid arthritis" and "Clinical presentation, diagnostic evaluation, and management of central airway obstruction in adults".)
The management of tenderness of the throat or pain on coughing or speaking involves use of non-steroidal anti-inflammatory drugs (NSAIDs) and other medications to control RA joint inflammation. Surgical intervention with mobilization of the cricoarytenoid joints and lateral fixation of one of the cords has been reported in cases of severe obstruction [4,9]. In an emergency, severe obstruction may respond to inhalation of helium-oxygen mixtures while awaiting more definitive therapy. (See "Clinical presentation, diagnostic evaluation, and management of central airway obstruction in adults", section on 'Follow-up' and "Physiology and clinical use of heliox".)
Small airway obstruction — The prevalence of small airway obstruction and bronchial hyperresponsiveness in patients with RA remains controversial, and studies have been confounded by the presence of smoking or RA-associated interstitial lung disease (RA-ILD) [33,34]. Initial reports suggested up to a 60 percent prevalence of airflow obstruction on expiratory spirometry in patients with RA; later studies in non-smoking subjects noted a prevalence of 0 to 24 percent [35-38]. The prevalence of small airways abnormalities on HRCT is greater than that of physiologic airway obstruction detected by pulmonary function testing, although the clinical significance of radiographic small airways disease is unclear. In a study of patients with RA and without evidence of ILD, changes of small airways disease were noted on HRCT in 35 of 50 patients (70 percent). In patients with a normal HRCT, there were no physiological abnormalities; however, the HRCT was abnormal in 20 of 33 patients (60 percent) with normal physiology [36].
One review found an association with underlying Sjögren's syndrome and histological changes of a peribronchiolar lymphocytic infiltrate in six patients with RA and documented airflow obstruction [39]. However, another study found no correlation between small airways obstruction and Sjögren's syndrome, smoking history, or RA disease activity [36]; it is likely that a variety of types of pathology contribute to airway obstruction.
Treatment is similar to that used for airflow obstruction in other settings. No treatment is required in patients with mild, asymptomatic disease, whereas inhaled bronchodilators, glucocorticoids, and occasionally a trial of oral glucocorticoids are used in those with symptomatic obstruction. (See "An overview of asthma management".)
Obliterative bronchiolitis — Obliterative bronchiolitis (OB) is a rare, usually fatal, condition characterized by progressive concentric narrowing of membranous bronchioles. (See "Bronchiolitis in adults".) OB was first reported in patients with RA in association with d-penicillamine treatment. OB has subsequently been noted with the use of gold, sulfasalazine, and in patients not receiving drug therapy (table 2) [40,41]. OB is more common in women, patients with positive rheumatoid factor tests, and in one series in association with Sjögren's syndrome.
OB usually follows the onset of joint symptoms. However, it has been reported in the setting of a high serum rheumatoid factor with no joint disease, suggesting it was the lone manifestation of rheumatoid arthritis [42].
Patients typically present with the rapid onset of dyspnea and cough [43]. In one series, bronchorrhea was noted in 44 percent [43]. The rapidity of onset and severity of symptoms are out of keeping with most other forms of lung disease and should lead to suspicion of the diagnosis. Manifestations suggestive of organizing pneumonia, including fever, weight loss, and malaise, are generally not present. Findings on physical examination include inspiratory crackles and a classical mid-inspiratory squeak.
Laboratory and radiographic investigations demonstrate [43,44]:
●Airflow obstruction, normal or reduced diffusing capacity (DLCO), and hypoxemia on testing of pulmonary function and arterial blood gases
●A normal chest radiograph or hyperinflation
●Bronchial wall thickening, centrilobular emphysema, areas of low attenuation with a mosaic pattern, and bronchiectasis may be seen on HRCT.
Pathologic findings on transbronchial or open lung biopsy include constrictive bronchiolitis and peribronchiolar lymphocytic infiltration [45]. The diagnosis and differential diagnosis of OB are discussed separately. (See "Bronchiolitis in adults", section on 'Diagnosis'.)
The first step in treatment of RA-associated OB is to stop any medications that are potential culprits (eg, penicillamine, gold, sulfasalazine) (table 5). The response to immunosuppressive therapy is generally poor [43]. Nevertheless, a trial of high dose glucocorticoids (eg, prednisolone 1 to 1.5 mg/kg per day, maximum 100 mg/d) is warranted. The role of immunosuppressive therapy with cyclophosphamide, methotrexate, or a tumor necrosis factor-alpha inhibitor is unclear, and the use of these agents is typically dictated by the known poor prognosis, lack of response to glucocorticoids, and severity of the lung disease [43,46]. A few case reports have described improvement with a tumor necrosis factor-alpha inhibitor [43,46].
Macrolide antibiotics have been successful in the treatment of some types of bronchiolitis (eg, post lung transplant bronchiolitis obliterans, panbronchiolitis). While macrolides have not been formally assessed in rheumatoid arthritis, a trial of erythromycin (200 to 600 mg/day) or another macrolide antibiotic is a reasonable choice. (See "Bronchiolitis in adults", section on 'Treatment'.)
For patients with respiratory failure due to progressive obliterative bronchiolitis, lung transplantation may be an option [43]. (See "Lung transplantation: An overview" and "Lung transplantation: General guidelines for recipient selection".)
Follicular bronchiolitis — Follicular bronchiolitis, defined as lymphoid hyperplasia of bronchus-associated lymphoid tissue, occurs in patients with a variety of rheumatic diseases, including RA. Among 17 patients with RA who underwent lung biopsy, six had follicular bronchiolitis either alone or in combination with nonspecific interstitial pneumonitis [47].
The clinical presentation typically includes dyspnea, and sometimes fever and cough. A high titer rheumatoid factor is usually present. Both obstructive and restrictive patterns have been noted on pulmonary function tests (PFTs), although restrictive is more common. The chest radiograph shows bilateral reticular or nodular opacities [2]. On HRCT, follicular bronchiolitis presents as centrilobular or peribronchial micronodules (<3 mm) and branching linear structures that may show bronchial dilation and bronchial wall thickening [2,48,49]. Mosaic perfusion and honeycombing are not present. On histopathology, coalescent germinal centers are noted adjacent to airways. (See "Bronchiolitis in adults", section on 'Follicular bronchiolitis'.)
The optimal treatment of follicular bronchiolitis complicating RA is not known. In practice, mild disease is typically observed without treatment. For symptomatic patients, treatment is usually directed at the underlying RA or any associated interstitial lung disease. Treatment with glucocorticoids or macrolide antibiotics has yielded variable results [2,50-52].
Bronchiectasis — An association between bronchiectasis and rheumatoid arthritis has been noted, although the prevalence in case series has varied from 0 to 10 percent. In a HRCT study of patients with rheumatoid arthritis, 30 percent were noted to have bronchiectasis without evidence of ILD [53]. (See "Clinical manifestations and diagnosis of bronchiectasis in adults".)
One small study noted that 16 percent of patients with RA and diffuse bronchiectasis were heterozygous for the delta F508 mutation of the cystic fibrosis transmembrane conductance regulator gene (CFTR), which was significantly higher than in a control group of patients with RA but no bronchiectasis (0 percent) and in the population at large (2.8 percent) [54]. No alterations in sweat chloride concentration or nasal potential difference measurements were noted in heterozygotes, but CFTR abnormalities may predispose to the development of bronchiectasis in RA.
Bronchiectasis does not appear to be clinically significant in most patients with RA, but if severe, may influence the decision against use of a tumor necrosis factor-alpha inhibitor for the underlying RA. In those that require therapy, treatment should be similar to that used for other forms of bronchiectasis, including some combination of bronchial hygiene, antibiotics, bronchodilators, and possibly antiinflammatory agents. (See "Treatment of bronchiectasis in adults".)
RHEUMATOID LUNG NODULES — Rheumatoid nodules are the only pulmonary manifestation specific for rheumatoid arthritis (RA). The prevalence of rheumatoid lung nodules is not clear. Only 2 of 516 patients were noted to have nodules on conventional chest radiography in one clinical series [18]. Among 75 patients with RA and a mean disease duration of eight months who underwent high resolution computed tomography (HRCT), three (4 percent) had small pulmonary nodules [55]. However, a study of open lung biopsies from 40 patients with suspected lung disease found that rheumatoid nodules were the most common abnormality, present in 13 subjects (32 percent); in 8 of 13 patients, there were multiple nodules [56]. In general, rheumatoid lung nodules occur more often in patients with a longer disease duration and concomitant subcutaneous rheumatoid nodules.
Rheumatoid nodules are generally located in subpleural areas or in association with interlobular septa [2]. They range in size from a few millimeters to several centimeters and may be single or multiple, solid or cavitary [57]. Histologically, the pulmonary nodules are similar to nodules at other sites, with central necrosis, palisading epithelioid cells, a mononuclear cell infiltrate, and associated vasculitis [56]. (See "Rheumatoid nodules".)
Rheumatoid lung nodules are generally asymptomatic, but cavitation and rupture of nodules can lead to complications including pleural effusion, pneumothorax, pyopneumothorax, bronchopleural fistula, hemoptysis, and infection (image 1 and image 4).
Differentiation of rheumatoid nodules from a lung neoplasm is essential, particularly in patients with a history of cigarette smoking. For nodules identified on a chest radiograph, the next step is a chest computed tomography (CT) scan. For nodules that are increasing in size or have a diameter greater than 8 to 10 mm, further evaluation is indicated. Of note, 18-fluorodeoxyglucose positron emission tomography (FDG-PET) scans of rheumatoid nodules usually show little (1.4) or no uptake based on case reports [57,58]. However, in one report, a rheumatoid nodule had early (max 3.4) and delayed (max 4.4) uptake on FDG-PET; on biopsy, vasculitis was noted in association with the rheumatoid nodule. The evaluation of solitary and multiple pulmonary nodules is discussed separately. (See "Diagnostic evaluation and management of the solitary pulmonary nodule" and "Differential diagnosis and evaluation of multiple pulmonary nodules" and "Computed tomographic and positron emission tomographic scanning of pulmonary nodules".)
The prognosis of rheumatoid nodules is generally good, with spontaneous resolution and infrequent complications. In a case series, ten patients who were treated with rituximab for their rheumatoid articular disease experienced a regression in the size and number of pulmonary rheumatoid nodules over a mean treatment duration of 12 months [59].
Caplan syndrome — Caplan syndrome occurs only in patients with both rheumatoid arthritis and pneumoconiosis related to occupational dust (coal, asbestos, silica) exposure. The syndrome is characterized by rapid development of multiple peripheral basilar nodules in association with mild airflow obstruction [2,3]. Caplan syndrome can be complicated by the development of progressive massive fibrosis (PMF); however, patients with rheumatoid arthritis are at no greater risk of developing PMF than are other subjects exposed to mining dust. (See "Asbestosis" and "Silicosis".)
Histologically, Caplan syndrome nodules are similar to simple rheumatoid nodules, except that the Caplan nodules typically have a layer of black dust surrounding a central necrotic area. Inflammatory cells, such as polymorphonuclear granulocytes, macrophages, and occasional giant cells, form a layer outside the dust ring [60]. The macrophages may contain dust particles. This abnormality has most commonly been reported in Europe and is rare in the United States [2,3].
The majority of patients with Caplan syndrome are rheumatoid factor positive [60]. There is no effective treatment for Caplan's syndrome, but the prognosis is good.
DRUG-INDUCED LUNG TOXICITY — A variety of forms of drug-induced lung and pleural toxicity have been reported with agents used to treat rheumatoid arthritis (RA) and should always be in the differential diagnosis of new respiratory signs, symptoms, and radiographic abnormalities (table 2). Potential adverse effects include interstitial pneumonitis and fibrosis, pleural disease, obliterative bronchiolitis, infection, noncardiogenic pulmonary edema, pulmonary renal syndrome with pulmonary hemorrhage, bronchoconstriction, and drug-induced lupus. The typical manifestations of drug-induced lung disease in rheumatoid arthritis and their management are discussed separately. (See "Drug-induced lung disease in rheumatoid arthritis".)
OTHER ASSOCIATIONS — Other respiratory diseases associated with rheumatoid arthritis (RA) include apical fibrobullous disease, thoracic cage immobility, venous thromboembolic disease, vasculitis, lung cancer, and pneumonia.
Apical fibrobullous disease — Apical fibrotic and cavitary lesions similar to those in ankylosing spondylitis have been reported in patients with RA. In cases where the pathology was available, unsuspected necrobiotic nodules with cavitation appeared to be the cause [61]. (See "Diseases of the chest wall", section on 'Ankylosing spondylitis'.)
Thoracic cage immobility — Abnormalities of thoracic cage mobility, again similar to those seen with ankylosing spondylitis, have been reported and suggested to be associated with pleurisy, myopathy, and thoracic rigidity. Pulmonary function testing demonstrates a low total lung capacity with a low or normal diffusing capacity (DLCO) [2]. (See "Diseases of the chest wall", section on 'Ankylosing spondylitis'.)
Venous thromboembolic disease — The risk of venous thromboembolic disease is slightly increased among patients with RA, even after controlling for other risk factors such as hospitalization [62-64].
Pulmonary hypertension — Pulmonary arterial hypertension (PAH) is rare in patients with RA. It is thought to be related to an underlying vasculitis, and signs of a systemic vasculitis are often present simultaneously [4,65,66]. The clinical manifestations and prognosis are very similar to those with idiopathic PAH in the absence of RA. Secondary pulmonary hypertension has also been reported in patients with RA; this is usually seen in association with severe interstitial lung disease (ILD). (See "Overview of pulmonary hypertension in adults".)
Mild, subclinical elevations in pulmonary artery pressure (PAP), as assessed by echocardiography, have been described in a few case reports [67-69]. This is best illustrated in a study of 146 RA patients of whom 21 percent had an estimated systolic PAP of ≥30 mmHg without evidence of significant cardiac or lung disease, although right heart catheterization was not performed [68]. In a separate case series of 47 patients, the systolic PAP was mildly elevated (30.3 +/- 8 mmHg) [69]. However, diastolic dysfunction is also seen in patients with RA and may explain some instances of elevated PAP [69,70]. As an example, in a study of 35 RA patients, abnormal diastolic filling was detected in 12 (34 percent) in the absence of other evidence of heart failure [70]. Among 40 RA patients, an elevated systolic PAP (30 to 40 mmHg) was noted in 11; the mean PAP was not reported [67]. Thus, a definitive diagnosis of PAH requires confirmation and characterization by right heart catheterization.
Vasculitis — Vasculitis, manifest as skin ulcers and mononeuritis multiplex, is a well-recognized extraarticular manifestation of RA. Primary vasculitic involvement of the lung is rare, although pathologic evidence of vasculitis is an inherent feature of rheumatoid nodules at all sites. (See "Epidemiology and pathogenesis of rheumatoid vasculitis" and "Clinical manifestations and diagnosis of rheumatoid vasculitis".)
Lung cancer — The risk of developing lung cancer may be slightly greater in patients with RA than in the general population [4,71-74]. In a cohort of 3771 patients with RA who received nonbiologic disease-modifying therapy compared with the general population in the United Kingdom, the relative risk of lung cancer was 1.28 (95% CI 1.10-1.48), expressed as a standardized incidence ratio [74]. Adenocarcinomas have been described surrounding rheumatoid nodules [75,76].
Infection — The prevalence of pulmonary infection in patients with RA varies substantially among studies [77]. There is some suggestion that the incidence of infection is similar to that in the general population, but when infection is present in patients with RA, it results in higher morbidity and mortality [2,77-79]. Predisposing factors for pulmonary infections (eg, pneumonia, bronchiectasis, empyema, infected nodules) include underlying lung disease, host defense abnormalities (eg, poorly defined lymphocyte abnormalities), and immunosuppressive drugs. Fever is not a common feature of RA in adults. Infection must be excluded before ascribing fever to RA. On the other hand, clinical signs of infection can be altered in patients on immunosuppressive therapy, since fever and leukocytosis may not be present. Overall, treatment does not differ from that used in the general population.
Prophylaxis against PCP may be warranted for some RA treatment regimens. While the low doses of prednisone and methotrexate typically used in RA do not warrant prophylaxis, the combination of a glucocorticoid dose equivalent to ≥20 mg of prednisone daily for one month or longer and a second immunosuppressive agent or the combination of an anti-tumor necrosis factor-alpha agent with other intensive immunosuppression may warrant prophylaxis. (See "Treatment and prevention of Pneumocystis pneumonia in non-HIV-infected patients", section on 'Indications' and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections", section on 'Pneumocystis pneumonia'.)
Mycobacterial disease is a well-described consequence of anti-tumor necrosis factor (TNF)-alpha therapy, so pretreatment screening for latent tuberculous infection is essential. Atypical mycobacterial infections should also be considered in the differential diagnosis of pulmonary infection. (See "Tumor necrosis factor-alpha inhibitors and mycobacterial infections", section on 'Screening and prevention' and "Tumor necrosis factor-alpha inhibitors and mycobacterial infections", section on 'Risk of nontuberculous mycobacterial infections'.)
Vaccination with the influenza vaccine should be provided annually to all patents with rheumatoid arthritis [79]. Administration of the polysaccharide pneumococcal vaccine is recommended in all adults age 65 or older and in patients with chronic lung disease or chronic immunosuppression who are under age 65 (table 6). Using disease modifying antirheumatic drugs (DMARDs) to reduce the use of systemic glucocorticoids may also reduce the frequency and severity of lower respiratory tract infections [80]. (See "Seasonal influenza vaccination in adults" and "Pneumococcal vaccination in adults" and "Leflunomide in the treatment of rheumatoid arthritis".)
MONITORING FOR PLEUROPULMONARY DISEASE — The role of surveillance for lung disease in patients with rheumatoid arthritis (RA) is not clear, as it is difficult to predict which patients will develop lung or pleural disease that will require targeted treatment. Minor abnormalities of unclear clinical significance are common; the natural history and prognosis of the disorder are variable; and the role of therapy in asymptomatic patients is uncertain [81]. Early disease detection may be important in the following situations:
●Patients in whom life-threatening deterioration may occur (eg, upper airways obstruction due to cricoarytenoid disease) [9] (see 'Upper airway obstruction' above)
●Patients with preexisting interstitial lung disease who may have increased morbidity if a pulmonary-related drug reaction occurs [82] (see "Drug-induced lung disease in rheumatoid arthritis")
●Possibly in cases for which histopathologic evidence suggests that early treatment could be beneficial (eg, RA-associated interstitial lung disease [RA-ILD] when inflammatory rather than fibrotic disease is present), although evidence that early detection and treatment of RA-ILD alters outcomes is lacking (see "Interstitial lung disease in rheumatoid arthritis", section on 'Treatment')
Patients with RA should be seen on a regular basis for clinical evaluation and monitoring of articular and extra-articular disease activity and also screening for drug-induced lung toxicity. Symptoms such as dyspnea, decreased exercise tolerance, cough, chest pain, fever, hoarseness, dysphagia, and odynophagia are clues to possible lung or airway involvement. A directed physical examination can identify crackles, wheezes, decreased breath sounds, dullness to percussion, or a pleural rub. Most respiratory symptoms and signs will need further evaluation with a chest radiograph. Based on the findings of the clinical evaluation and chest radiograph and also the degree of clinical suspicion for RA-associated pleuropulmonary disease, additional studies (eg, high resolution computed tomography) are utilized as described above for the various processes.
For patients anticipating general anesthesia, a particular focus is directed to subtle changes that might be due to cricoarytenoid joint involvement, which can result in acute respiratory failure after extubation following general anesthesia. (See 'Upper airway obstruction' above.)
SUMMARY AND RECOMMENDATIONS
●Pleuropulmonary involvement by rheumatoid arthritis (RA) includes RA-associated interstitial lung disease (RA-ILD) (table 1), pleural disease, upper and lower airway obstruction, rheumatoid nodules, drug-induced lung toxicity, vasculitis, infection related to immunosuppression, and other less common manifestations. (See 'Epidemiology' above.)
●RA-ILD is composed of a spectrum of histologic types with different associated patterns of clinical presentation, imaging, response to treatment, and clinical course. The evaluation and management of RA-ILD is discussed separately. (See 'Interstitial lung disease' above and "Interstitial lung disease in rheumatoid arthritis".)
●Pleural disease is common in patients with RA, but it is usually subclinical; asymptomatic pleural thickening or small pleural effusions may be incidental findings on chest radiographs. For moderate to large or symptomatic effusions, thoracentesis is performed to look for the characteristic features of rheumatoid pleural effusions (eg, exudate with a pleural fluid glucose to serum glucose ratio less than 0.5, round or elongated multinucleated macrophages and necrotic background debris) and to exclude infection or malignancy. (See 'Pleural disease' above.)
●Chronic pleural inflammation can cause cholesterol effusions (also known as chyliform or pseudochylous effusions) and lung entrapment. As a consequence of long-term inflammation, a fibrous pleural peel may develop causing trapped lung. (See 'Pleural disease' above and "Clinical presentation, diagnosis and management of cholesterol effusions" and "Diagnosis and management of pleural causes of unexpandable lung".)
●Both upper and lower airway disease have been reported in patients with RA. The main cause of upper airway obstruction is cricoarytenoid arthritis, while lower airway involvement can include airway obstruction, obliterative bronchiolitis, follicular bronchiolitis, and bronchiectasis. (See 'Airway obstruction' above and "Clinical presentation, diagnostic evaluation, and management of central airway obstruction in adults" and "Bronchiolitis in adults".)
●Rheumatoid nodules are the only pulmonary manifestation specific for RA. They are uncommonly seen on conventional chest radiographs, but more often noted on computed tomography or lung biopsy. They are usually located in subpleural areas or in association with interlobular septa and range in size from a few millimeters to several centimeters and may be single or multiple, solid or cavitary. (See 'Rheumatoid lung nodules' above and "Diagnostic evaluation and management of the solitary pulmonary nodule" and "Differential diagnosis and evaluation of multiple pulmonary nodules".)
●A variety of forms of drug-induced lung toxicity have been reported with agents used to treat RA and should always be in the differential diagnosis of new respiratory signs, symptoms, and radiographic abnormalities (table 2). (See 'Drug-induced lung toxicity' above and "Drug-induced lung disease in rheumatoid arthritis" and "Methotrexate-induced lung injury".)
●Other respiratory diseases associated with RA include apical fibrobullous disease, thoracic cage immobility, venous thromboembolic disease, vasculitis, lung cancer, and pneumonia. (See 'Other associations' above.)
●Pulmonary infection is a major contributor to morbidity and mortality; when appropriate, patients should be screened for bronchiectasis. Vaccination against streptococcal pneumonia and influenza is appropriate in all patients.