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Overview of pleuropulmonary diseases associated with rheumatoid arthritis

Overview of pleuropulmonary diseases associated with rheumatoid arthritis
Literature review current through: Jan 2024.
This topic last updated: Sep 17, 2021.

INTRODUCTION — Rheumatoid arthritis (RA) is a generally progressive, systemic autoimmune process characterized by chronic symmetrical erosive synovitis. The lung and pleura are also frequent sites of extraarticular involvement by RA but may not result in significant symptoms (table 1 and table 2) [1-5].

An overview of lung disease associated with RA will be presented here. Other aspects of RA, including specific types of interstitial lung disease (ILD) seen in patients with RA, are discussed separately. (See "Clinical manifestations of rheumatoid arthritis" and "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis" and "Clinical manifestations and diagnosis of rheumatoid vasculitis" and "Interstitial lung disease in rheumatoid arthritis" and "Drug-induced lung disease in rheumatoid arthritis".)

EPIDEMIOLOGY AND RISK FACTORS — The prevalence of the different types of RA-associated respiratory disease is difficult to estimate for a number of reasons. Patient populations are heterogeneous with varying numbers of patients with early- versus late-stage disease and varying types of settings, such as 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 tests 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 [6,7]. (See "Interstitial lung disease in rheumatoid arthritis", section on 'Epidemiology'.)

Relative frequency of types of respiratory involvement in RA – Despite the various limitations, it appears that interstitial lung disease (ILD) and pleural disease are the most common types of respiratory involvement. In a study of 1129 patients with RA who underwent CT, lung involvement was reported in 87 (8 percent) and developed after articular symptoms in 98 percent [8]. ILD was reported in 45 patients (52 percent), rheumatoid nodules in 5 percent, pleural effusion in 3 percent, and drug-induced lung disease in 3 percent.

Interactions between tobacco smoking and HLA epitopes – An increasing body of evidence suggests that the lungs and oral mucosa may act as initiation sites contributing to the development of RA-associated auto-immunity [9,10]. Interactions between external factors such as tobacco smoking and human leukocyte antigen (HLA) susceptibility are thought to result in citrullination of proteins and development of autoantibodies to the citrullinated proteins. As an example, the shared epitope HLA-DRB1*04 alleles may interact with smoking in the pathogenesis of RA and RA-ILD [11]. RA-associated antibodies are found in the sputum of patients at risk of RA well before joint disease develops [9], and shared epitopes between the lungs and joints have been described in patients with RA [12]. (See "Pathogenesis of rheumatoid arthritis".)

A separate study of patients with RA found that 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, and did not find an association with tobacco smoking [13]. (See "HLA and other susceptibility genes in rheumatoid arthritis".)

INTERSTITIAL LUNG DISEASE — Interstitial lung disease (ILD) is the most common pulmonary manifestation of rheumatoid disease [14]. The clinical presentation, pathology, disease spectrum, and pathogenesis of rheumatoid arthritis (RA)-associated ILD (RA-ILD) are similar to that of the idiopathic interstitial pneumonias (IIPs) [15-17]. Histologically, the abnormalities are highly variable but usually resemble one of the IIPs or a mixture of them (table 3) [18-21]:

Usual interstitial pneumonia

Nonspecific interstitial pneumonia

Organizing pneumonia

Lymphoid interstitial pneumonia

Desquamative interstitial pneumonia

Acute interstitial pneumonia

Pleuroparenchymal fibroelastosis (rare)

The evaluation and management of ILD in RA is discussed separately. (See "Interstitial lung disease in rheumatoid arthritis" and "Idiopathic interstitial pneumonias: Classification and pathology".)

PLEURAL DISEASE — Pleural disease is common in patients with rheumatoid arthritis (RA), but it is usually subclinical [22]. 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 [1,23]. 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.

Types of pleural disease — RA-associated pleural abnormalities include the following [1,24,25]:

Exudative “rheumatoid” effusion

Cholesterol (chyliform) effusion

Nonexpandable lung due to pleural inflammation or fibrous peel

Drug-induced pleuritis (eg, methotrexate, infliximab)

Empyema and pyopneumothorax

Bronchopleural fistula

Pneumothorax or hemopneumothorax

Pleural effusions due to rheumatoid pleurisy are exudates that are associated with rheumatoid nodules on the pleural surface [25]. Less commonly, rheumatoid pleural inflammation can cause cholesterol (also called chyliform) effusions. Necrosis and cavitation of a rheumatoid nodule into the pleural space can create a bronchopleural fistula with resultant pneumothorax or hemopneumothorax [3,24,26]. Patients with rheumatoid pleural effusions are at an increased risk for developing empyema.

Chronic pleural inflammation such as with rheumatoid pleurisy can lead to nonexpandable lung. In "lung entrapment," the lung is nonexpandable due to visceral pleural restriction from active pleural inflammation, 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 1A-B). (See 'Imaging' below and "Clinical presentation, diagnosis, and management of cholesterol pleural effusions" and "Diagnosis and management of pleural causes of nonexpandable 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 [22].

Evaluation — The evaluation of a pleural disease in patients with RA follows the same steps as a pleural effusion in general with the key goals of excluding infection and neoplasm, alleviating dyspnea, and reexpanding lung that is compressed by a pneumothorax. (See "Pleural fluid analysis in adults with a pleural effusion".)

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 (image 1A). Decubitus views may be needed to assess whether pleural fluid is free flowing. Further evaluation of pleural abnormalities (eg, loculated fluid, thickened visceral pleura, nonexpandable lung) often requires high-resolution computed tomography (HRCT) (image 1B). HRCT may also reveal features such as underlying ILD or rheumatoid nodules. (See "Imaging of pleural effusions in adults".)

For patients with a pneumothorax or hemopneumothorax, a chest CT scan can identify subpleural cavitating rheumatoid nodules or blebs (eg, due to cigarette smoking) that are not visible on the conventional chest radiograph [27]. These are typically the cause of the pneumothorax, and they 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 1A), 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 (image 2). Additionally, a paradoxical reduction in size of the hemithorax with the effusion compared with 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 nonexpandable 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 nonexpandable lung. Thus, the fluid is usually sent for cell counts, glucose, lactic dehydrogenase, protein, cholesterol, triglycerides, cytology, Gram stain, and culture. (See "Ultrasound-guided thoracentesis".)

Rheumatoid effusion – 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 lactate dehydrogenase (LDH) level (ie, greater than 700 international units/L) (table 4) [1,22]. (See "Pleural fluid analysis in adults with a pleural effusion".)

Cytologic examination of rheumatoid pleural fluid often reveals characteristic findings of slender or elongated multinucleated macrophages, round giant multinucleated macrophages, and necrotic background debris [26]. However, the specificity of these findings has not been fully evaluated [22]. The presence of ragocytes, also known as "RA cells," is neither sensitive nor specific.

Cholesterol effusion – Less commonly, patients with RA and a longstanding 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 [22]. 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 pleural effusions".)

Empyema – 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 "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults".)

Entrapped or trapped lung – RA is an established (albeit rare) cause of both lung entrapment and trapped lung, processes that prevent the lung from reexpanding after pleural fluid are removed. Formal assessment for lung entrapment and trapped lung usually follows identification of loculated pleural fluid on imaging or absence of lung reexpansion after thoracentesis (image 2). 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 and interpretation of pleural pressure (manometry): Indications and technique", section on 'Interpretation of pleural pressures'.)

Characteristic pleural pressure patterns can provide strong suggestive evidence in favor of lung entrapment or trapped lung. Definitive confirmation of lung entrapment requires 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 nonexpandable 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 nonexpandable lung, a pleural biopsy may be helpful in excluding other disorders, such as tuberculosis or malignancy, or securing a diagnosis of rheumatoid pleuritis [22]. 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 visceral pleura nodules tend to be smaller than parietal pleura ones [22]. (See "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion", 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) [22], although larger effusions are more likely to be symptomatic and require treatment. It is not known whether anti-inflammatory treatment of larger rheumatoid effusions will decrease the likelihood of long-term sequelae such as a trapped lung (fibrothorax) [22]. When rheumatoid pleuritis is symptomatic and does not resolve spontaneously, we utilize one or more of the following therapies, starting with the least toxic:

Nonsteroidal anti-inflammatory drugs – When treatment is needed because of pleuritic chest pain or the size of the effusion, the initial choice is an nonsteroidal anti-inflammatory drug (NSAID) [28]; improvement is generally seen within a week. 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 rheumatoid arthritis in adults", section on 'NSAIDs'.)

Glucocorticoids (oral or intrapleural) – For symptomatic rheumatoid effusions refractory to NSAIDs, after excluding infection, we use a moderate dose of oral glucocorticoids (eg, 10 to 20 mg of prednisolone daily) based upon case reports and our clinical experience [22]. 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) [22,29]. Intrapleural glucocorticoid therapy carries an increased risk of pleural infection.

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). The management of cholesterol effusions is discussed separately. (See "Clinical presentation, diagnosis, and management of cholesterol pleural effusions", section on 'Management'.)

Therapeutic thoracentesis for urgent control of dyspnea – The main role of therapeutic thoracentesis is acute relief of dyspnea in a patient with a moderate to large pleural effusion, as long as the effusion is not associated with lung entrapment or trapped lung. 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. (See 'Thoracentesis' above and "Diagnosis and management of pleural causes of nonexpandable lung".)

Pleurodesis and decortication – Use of chemical pleurodesis and decortication are reserved for refractory effusions and trapped lung from a fibrous pleural peel, respectively [22,30]. (See "General principles and overview of management of rheumatoid arthritis in adults" and "Management of nonmalignant pleural effusions in adults".)

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 (SSP), including supplemental oxygen and pleural drainage. (See "Treatment of secondary spontaneous pneumothorax in adults", section on 'Initial management of first event'.)

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 [27].

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. Several case reports describe difficulties achieving lung reexpansion, closure of air leaks, and prevention of recurrences [27,31-35].

The management of persistent air leak and incomplete reexpansion, and also the prevention of recurrent SSP are discussed separately. (See "Treatment of secondary spontaneous pneumothorax in adults".)

Treatment of pleural effusions due to nonexpandable lung — In general, the treatment of lung entrapment due to rheumatoid inflammation is focused on treatment of the underlying inflammation. (See 'Treatment of rheumatoid pleural effusion' above.)

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 fold paralysis [2,7,36]. The cricoarytenoid joints participate in vocal fold abduction and adduction.

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 [37].

Upper airway disease is more common in women and in patients with longstanding RA. Overall, cricoarytenoid arthritis is less common than a few decades ago [38].

Clinical features – 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 [37]. However, symptoms are usually 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 by superimposed airway edema secondary to an infection or intubation for surgery. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults".)

Evaluation – Direct laryngoscopy of cricoarytenoid joint (CAJ) arthritis usually reveals swelling of the arytenoids and piriform recess, while thin-section computed tomography (CT) may show prominent hyperdense intraarticular sclerotic foci in the arytenoid and cricoid cartilages, widening of the joint space between the arytenoid and cricoid cartilages due to joint effusion, and subluxation of the joint [37,39]. Inflammation, ankylosis, or subluxation of the CAJ can lead to impaired vocal fold abduction.

Studies comparing direct laryngoscopy and scanning demonstrate that contrast-enhanced thin-section CT (1 mm slice thickness) is more sensitive than direct laryngoscopy and can identify abnormalities in asymptomatic patients [37,39,40].

Diagnosis – The diagnosis of CAJ involvement is based on a combination of studies, often including inspiratory and expiratory flow volume loops, contrast-enhanced high-resolution CT (HRCT), and laryngoscopy (frequently with a flexible laryngoscope). For stable patients, inspiratory and expiratory flow volume loops (figure 1) can help identify upper airway obstruction when limitation of inspiratory flow is present, but changes may not be appreciable until the obstruction is severe.

The differential diagnosis includes mycobacterial or fungal infection of the CAJ, laryngeal masses, vocal fold nodules, vocal fold swelling, and neurologic impairment. 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 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'.)

Management – 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, preferably using video laryngoscopy for intubation and avoiding excessive neck flexion. (See "Cervical subluxation in rheumatoid arthritis" and "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults".)

For patients with less severe CAJ arthritis who have tenderness of the throat or pain on coughing or speaking, nonsteroidal anti-inflammatory drugs (NSAIDs) and other medications used to control RA can help control 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 [2,7].

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 malignant central airway obstruction in adults", section on 'Follow-up' and "Physiology and clinical use of heliox".)

Small airways obstruction — The prevalence of small airways 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) [41,42]. 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 [43-45]. 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 [44].

One review found an association with underlying Sjögren's disease and histologic changes of a peribronchiolar lymphocytic infiltrate in six patients with RA and documented airflow obstruction [46]. However, another study found no correlation between small airways obstruction and Sjögren's disease, smoking history, or RA disease activity [44]; 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, inhaled 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 "Overview of bronchiolar disorders 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 and sulfasalazine and in patients not receiving drug therapy (table 2) [47,48]. OB is more common in women (93 percent) [49], in patients with positive rheumatoid factor tests, and in association with Sjögren's disease.

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 RA [50].

Patients typically present with the rapid onset of dyspnea and cough [51]. In one series, bronchorrhea was noted in 44 percent [51]. The rapidity of onset and severity of symptoms are out of keeping with most other forms of RA-associated 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 may include inspiratory crackles and/or a classical mid-inspiratory squeak [51].

Laboratory and radiographic investigations demonstrate [51,52]:

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

HRCT images may demonstrate bronchial wall thickening, centrilobular emphysema, areas of low attenuation with a mosaic pattern, pulmonary nodules, and bronchiectasis [49].

A firm diagnosis of OB usually requires a lung biopsy, although the combination of airflow limitation on spirometry, reduced DLCO, and HRCT showing expiratory air trapping (mosaic or diffuse), bronchial wall thickening, and centrilobular nodules may be sufficient to make a clinical diagnosis. Pathologic findings on transbronchial or surgical lung biopsy include constrictive bronchiolitis and peribronchiolar lymphocytic infiltration [53]. The diagnosis and differential diagnosis of OB are discussed separately. (See "Overview of bronchiolar disorders 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 [51]. Nevertheless, a trial of high-dose glucocorticoids (eg, prednisone 1 mg/kg [ideal body weight] per day, usual starting dose 40 to 60 mg per day; maximum 100 mg/day) is warranted [49]. 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 [51,54]. A few case reports have described improvement with a tumor necrosis factor-alpha inhibitor [51,54].

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 RA, a trial of erythromycin (200 to 600 mg per day) or another macrolide antibiotic is a reasonable choice. (See "Overview of bronchiolar disorders in adults", section on 'Treatment'.)

For patients with respiratory failure due to progressive OB, lung transplantation may be an option [51,55]. (See "Lung transplantation: An overview" and "Lung transplantation: General guidelines for recipient selection".)

While the prognosis of OB complicating RA is generally felt to be poor, a retrospective series of 41 patients seen at one center between 2000 and 2015 demonstrated stable, but persistent, severe airflow limitation and an all-cause mortality of 27 percent over a median follow-up period of 62 months [49]. No features predicting prognosis were identified.

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 [56].

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 [15]. 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 [15,57,58]. Mosaic perfusion and honeycombing are not present.

While lung biopsy is usually not necessary, coalescent germinal centers are noted adjacent to airways on histopathology. (See "Overview of bronchiolar disorders 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 (ILD). Treatment with glucocorticoids or macrolide antibiotics has yielded variable results [15,59-61].

Bronchiectasis — An association between bronchiectasis and RA has been noted, although the prevalence in case series has varied from 0 to 10 percent. In a HRCT study of patients with RA, 30 percent were noted to have bronchiectasis without evidence of ILD [62]. (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) [63]. 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, it 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 anti-inflammatory agents. (See "Bronchiectasis in adults: Treatment of acute and recurrent exacerbations".)

RHEUMATOID LUNG NODULES — Rheumatoid nodules are the only pulmonary manifestation specific for rheumatoid arthritis (RA). The prevalence of rheumatoid lung nodules varies among studies.

Clinical presentation – 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 3 and image 4). 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 [64]. 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 [65]. In general, rheumatoid lung nodules occur more often in patients with a longer disease duration and concomitant subcutaneous rheumatoid nodules.

Reports of changes in nodule size and number with various therapies for RA (eg, methotrexate, azathioprine, leflunomide, etanercept) are mixed and without a clear pattern [27,66-73].

Chest radiographs are insensitive for identification of rheumatoid nodules: only 2 of 516 patients (0.04 percent) were noted to have nodules on conventional chest radiography in one clinical series [23].

HRCT features – On HRCT, rheumatoid nodules may be solitary or multiple; are generally located in subpleural areas or in association with interlobular septa; can be solid, part solid, or cavitary; and typically have a smooth border [15,74-76]. They range in size from a few millimeters to several centimeters [74]. Histologically, the pulmonary nodules are similar to nodules at other sites, with central necrosis, palisading epithelioid cells, a mononuclear cell infiltrate, and associated vasculitis [65]. (See "Rheumatoid nodules".)

Differentiation from lung neoplasm – Differentiation of rheumatoid nodules from a lung neoplasm is essential, particularly in patients with a history of cigarette smoking. Nodules that are increasing in size or have a diameter greater than 8 to 10 mm generally require further evaluation, assuming that the patient is a candidate for diagnostic procedures and potential surgery.

18-fluorodeoxyglucose positron emission tomography (FDG-PET) scans can help to determine whether nodules with a diameter of 8 mm or greater have metabolic activity consistent with malignancy, as rheumatoid nodules usually show little or no uptake [74,76,77]. However, in one report, a rheumatoid nodule had early (max 3.4 standardized uptake value [SUV]) and delayed (max 4.4 SUV) uptake on FDG-PET; on biopsy, vasculitis was noted in association with the rheumatoid nodule [78].

The decision to proceed with a tissue biopsy is based on the relative likelihood of rheumatoid nodule versus lung malignancy (eg, current or previous smoker, family history, enlarging and/or PET positive nodule) and how well the patient would tolerate a diagnostic procedure or resectional surgery. The evaluation of solitary and multiple pulmonary nodules is discussed separately. (See "Diagnostic evaluation of the incidental pulmonary nodule".)

Treatment and prognosis – In the absence of complications such as cavitation and rupture, no specific treatment is needed for rheumatoid lung nodules. The prognosis is generally good, with spontaneous resolution and infrequent complications. Sometimes rheumatoid lung nodules will regress during treatment of articular disease with a biologic agent. In a case series, 10 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 [79].

Caplan syndrome — Caplan syndrome occurs only in patients with both RA 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 [1,15]. Caplan syndrome can be complicated by the development of progressive massive fibrosis (PMF); however, patients with RA are at no greater risk of developing PMF than are other subjects exposed to mining dust. (See "Asbestos-related pleuropulmonary disease" 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 [80]. The macrophages may contain dust particles. This abnormality has most commonly been reported in Europe and is rare in the United States [1,15].

The majority of patients with Caplan syndrome are rheumatoid factor positive [80]. There is no effective treatment for Caplan 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). Many of these drugs, however, have been reported to both improve lung disease and cause adverse reactions, such that it can be difficult to determine whether the lung disease is due to RA or the agent used to treat RA [81,82]. Potential adverse effects include interstitial pneumonitis and fibrosis, pleural disease, obliterative bronchiolitis (OB), infection, noncardiogenic pulmonary edema, pulmonary renal syndrome with pulmonary hemorrhage, bronchoconstriction, and drug-induced lupus. The typical manifestations of drug-induced lung disease in RA 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 bullous or cavitary lesions have rarely been reported in patients with RA [83-85]. In cases where pathology was available, unsuspected necrobiotic nodules with cavitation appeared to be the cause [83].

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) [15]. (See "Chest wall diseases and restrictive physiology", 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 [86-88]. In a nationwide cohort study from Taiwan, the risks of deep venous thrombosis and pulmonary embolism in patients with RA were increased by 3.36- and 2.07-fold, respectively, compared with matched individuals from the general population [89].

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 [2,90,91]. The clinical manifestations and prognosis are very similar to those with idiopathic PAH in the absence of RA. Pulmonary hypertension (PH) due to chronic hypoxemia can develop in patients with severe interstitial lung disease (ILD). (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)" and "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis".)

Mild, subclinical elevations in pulmonary artery pressure (PAP), as assessed by echocardiography, have been described in a few case reports [92-94]. 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 [93]. In a separate case series of 47 patients, the systolic PAP was mildly elevated (30.3 +/- 8 mmHg) [94]. However, diastolic dysfunction is also seen in patients with RA and may explain some instances of elevated PAP [94,95]. 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 [95]. Among 40 RA patients, an elevated systolic PAP (30 to 40 mmHg) was noted in 11; the mean PAP was not reported [92]. Thus, a definitive diagnosis of PH 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 "Etiology and pathogenesis of rheumatoid vasculitis" and "Clinical manifestations and diagnosis of rheumatoid vasculitis" and "Treatment of rheumatoid vasculitis".)

Lung cancer — The risk of developing lung cancer may be slightly greater in patients with RA than in the general population [96,97]. 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 [97]. Adenocarcinomas have been described surrounding rheumatoid nodules [98,99].

Infection — The prevalence of pulmonary infection in patients with RA varies substantially among studies [100]. 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 [15,100-102]. Predisposing factors for pulmonary infections (eg, pneumonia, empyema, infected nodules) include underlying lung disease (eg, bronchiectasis), 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.

Pneumocystis prophylaxis – Prophylaxis against Pneumocystis pneumonia (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 per day 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 patients without HIV", section on 'Indications' and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections", section on 'Pneumocystis pneumonia'.)

Pretreatment screening for latent tuberculosis – Mycobacterial disease is a well-described consequence of anti-tumor necrosis factor-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 "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors", section on 'Screening'.)

Vaccinations to prevent pneumonia – Vaccination with the influenza vaccine should be provided annually to all patents with RA [102]. Vaccination with pneumococcal polysaccharide vaccine (PPSV) is indicated in all adults age 65 or older, and PPSV and pneumococcal conjugate vaccine are indicated in patients with chronic lung disease or chronic immunosuppression (table 6). Using disease-modifying antirheumatic drugs to reduce the use of systemic glucocorticoids may also reduce the frequency and severity of lower respiratory tract infections [103]. (See "Seasonal influenza vaccination in adults" and "Pneumococcal vaccination in adults".)

For most patients with RA, we suggest COVID-19 vaccination. Although the immunogenicity and efficacy of these vaccines are uncertain in patients on immunomodulatory therapy, the potential for benefit during the COVID-19 pandemic likely outweighs the uncertainties. COVID-19 vaccines, their general use, and vaccine-induced thrombotic thrombocytopenia are discussed in detail separately. (See "COVID-19: Vaccines" and "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

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 [104]. 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) [7] (see 'Upper airway obstruction' above)

Patients with preexisting interstitial lung disease (ILD) who may have increased morbidity if a pulmonary-related drug reaction occurs [105] (see "Drug-induced lung disease in rheumatoid arthritis")

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 [HRCT]) are utilized as described above for the various processes. As an example, a low threshold for obtaining HRCT imaging may be appropriate for patients with risk factors such as older age, male sex, seropositive, and history of cigarette smoking.

For patients anticipating general anesthesia, a particular focus is directed to subtle changes that might be due to cricoarytenoid joint (CAJ) involvement, which can result in acute-respiratory failure after extubation following general anesthesia. (See 'Upper airway obstruction' above.)

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

Types of pleuropulmonary involvement – Rheumatoid arthritis (RA) is associated with a broad spectrum of pleuropulmonary involvement (table 1) with interstitial lung disease (ILD) and pleural disease being the most common. (See 'Epidemiology and risk factors' above.)

Rheumatoid arthritis-associated interstitial lung disease – RA-ILD is composed several different histologic types that mimic those associated with the idiopathic interstitial pneumonias (IIPs) (table 3). The evaluation and management of RA-ILD is discussed separately. (See 'Interstitial lung disease' above and "Interstitial lung disease in rheumatoid arthritis".)

Pleural disease in RA – 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.)

Cholesterol pleural effusion and nonexpandable lung – Chronic pleural inflammation can cause cholesterol effusions (also known as chyliform or pseudochylous effusions) and nonexpandable lung due to 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 pleural effusions" and "Diagnosis and management of pleural causes of nonexpandable lung".)

Airway disease – 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 malignant central airway obstruction in adults" and "Overview of bronchiolar disorders in adults".)

Rheumatoid nodules – Rheumatoid nodules are the only pulmonary manifestation that is specific for RA. They are uncommonly seen on conventional chest radiographs, but they are more often noted on computed tomography (CT) 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 of the incidental pulmonary nodule".)

Drug-induced lung toxicity – 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 associated respiratory diseases – Other respiratory diseases associated with RA include apical fibrobullous disease, thoracic cage immobility, venous thromboembolic disease, vasculitis, lung cancer, and pneumonia. Vaccination against streptococcal pneumonia and influenza is appropriate in all patients. (See 'Other associations' above.)

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Topic 4380 Version 21.0

References

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