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Pulmonary Manifestations of Systemic Lupus Erythematosus Shikha Mittoo, MD, MHS, FRCPC1

Charlene D. Fell, MD, MSc, FRCPC, FCCP2

1 Interstitial Lung Disease Program, Mount Sinai Hospital/University

Health Network, University of Toronto, Toronto, Ontario, Canada 2 Department of Medicine, University of Calgary, Calgary, Alberta, Canada

Address for correspondence Shikha Mittoo, MD, MHS, FRCPC, University of Toronto, L2-003, 60 Murray Street, Toronto, Ontario, M5T 3L9 Canada (e-mail: [email protected]).

Abstract

Keywords

► systemic lupus erythematosus ► lung ► pleura ► vascular ► airways

Systemic lupus erythematosus (SLE) is a systemic inflammatory disease, characterized serologically by an autoantibody response to nucleic antigens, and clinically by injury and/or malfunction in any organ system. During their disease course, up to 50% of SLE patients will develop lung disease. Pulmonary manifestations of SLE include pleuritis (with or without effusion), inflammatory and fibrotic forms of interstitial lung disease, alveolar hemorrhage, shrinking lung syndrome, pulmonary hypertension, airways disease, and thromboembolic disease. Two major themes inform our understanding of SLE-associated pulmonary manifestations: first, the presence of specific autoantibodies correlates with the presence of certain pulmonary manifestations and second, vascular injury marks a common pathophysiologic thread among the various SLE-related lung diseases. This review will focus on the clinical presentation, pathogenesis, pathology, management, and prognosis of these SLE-associated lung conditions.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a predilection for young women. Lung involvement is a known complication of the disease and/or its treatments; up to 50% of SLE patients experience such involvement during their disease course.1 Broadly speaking, pulmonary complications of SLE can be divided into three categories: infectious, malignant, and disease related. Although pulmonary infections typically affect the airways and/or parenchyma, complications attributable to SLE can affect all compartments of the lungs and include pleuritis (with or without effusion), interstitial lung disease (ILD), alveolar hemorrhage, shrinking lung syndrome (SLS), pulmonary hypertension (PH), airways disease, and thromboembolic disease. A heightened awareness of SLE-related pulmonary manifestations among clinicians and the evolution of more sensitive tools which capture lung involvement have also lead to the recognition that subclinical lung involvement occurs at a greater frequency than clinically identifiable involvement. This review will focus primarily on the clinical presentation, pathogenesis, pathology, management, and outcome of clinically identifiable pulmonary manifestations attributable to SLE.

Issue Theme Pulmonary Complications of Connective Tissue Disease; Guest Editors, Danielle Antin-Ozerkis, MD, and Jeffrey Swigris, DO, MS

Vascular Involvement Pulmonary Hypertension Epidemiology and Clinical Presentation Although the frequency of SLE-related PH varies depending on the ascertainment method from 0.5 to 17.5%, there is no screening protocol established for this complication and PH may not be as readily apparent until it is advanced.2 Typically, PH occurs after prolonged SLE disease duration, often after 5 years, in women under the age of 40 years.3 The vast majority of patients present with symptoms of chest pain, shortness of breath, or cough; nearly one-third will have signs of right heart failure (loud pulmonic heart sound, murmurs of tricuspid or pulmonic regurgitation, right ventricular heave, elevated jugular venous pressure, and lower extremity edema) at presentation including active pleural effusions and a minority will be asymptomatic at diagnosis of PH.2,4,5 In a case–control study of 147 SLE patients, Raynaud phenomenon and the presence of anticardiolipin and anti-U1 ribonucleoprotein (RNP) antibodies were predictive of PH, with a three-, four-, and fivefold increase risk

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DOI http://dx.doi.org/ 10.1055/s-0034-1371537. ISSN 1069-3424.

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of PH compared with those without such manifestations, respectively.6 In another study, serum rheumatoid factor positivity was significantly associated with PH, which is interesting to note as seropositivity for rheumatoid factor has been linked to hyperviscosity in rheumatoid arthritis patients.4,7 Taken together, this suggests that select autoantibodies with a propensity to lead to a viscous and/or prothrombotic milieu may be important in the pathogenesis of SLE-PH.

Pathophysiology Acute/chronic thromboembolic disease, increased pulmonary vascular resistance, and rarely, vasculitis or pulmonary veno-occlusive disease contribute to the development of pathologic changes of PH (medial hypertrophy, intimal fibrosis, and plexiform lesions); inflammation, immune dysregulation, and vascular remodeling at varying levels are central components of these major mechanism.8

Evaluation, Prognosis, and Management A transthoracic echocardiogram is used to screen for PH in SLE, however, because this method can be inaccurate when a tricuspid regurgitation jet is not present or if other signs of right heart stress (e.g., dilation, impaired systolic function) are absent, a right heart catheterization (RHC) is the gold standard for PH diagnosis. A mean pulmonary artery pressure of
25 mm Hg in the face of a pulmonary capillary wedge pressure < 15 mm Hg defines PH by RHC.9 Given that PH can arise from causes other than SLE, patients should be questioned about current or past use of anorexigens or illicit drugs, evaluated for obstructive sleep apnea with a screening polysomnogram, evaluated for ILD and thromboembolic disease with a chest computed tomography (CT) and a ventilation perfusion scan, and screened for the presence of human immunodeficiency virus and chronic liver disease. There are no consensus guidelines on the management of SLE-PH. In double-blind trials, in which only small numbers of patients (n ¼ 16–35) were enrolled, PH-specific therapy (selective and nonselective endothelin receptor antagonists or phosphodiesterase-5 inhibitors) have demonstrated improvements in clinical and physiologic end points.2 Data supporting the use of immunosuppressive medications, such as intravenous cyclophosphamide and glucocorticoids, for SLE-PH are limited. In certain retrospective series of small numbers of subjects, investigators have reported a modest physiologic benefit from the use of immunosuppression in combination with vasodilator therapy.10 In a recent systematic review, elevated mean pulmonary artery pressure, Raynaud phenomenon, thrombocytopenia, plexiform lesion, infection, thrombosis, pregnancy, pulmonary vasculitis, and anticardiolipin antibodies were associated with decreased survival among patients with SLE-PH.11 However, overall, the prognosis for SLE-associated PH is relatively good, with a 75% 3-year survival.12

Diffuse Alveolar Hemorrhage Epidemiology and Clinical Presentation Diffuse alveolar hemorrhage (DAH) is a rare, and often fatal, consequence of neutrophilic infiltration, immune Seminars in Respiratory and Critical Care Medicine

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complex deposition, and destruction of pulmonary vascular endothelium. 13 Patients appear acutely unwell with dyspnea, fever, chest pain, and, in nearly half of patients, hemoptysis. Notably, DAH may be the presenting feature of SLE in up to one-third of patients. Patients often need hospitalization and intensive care monitoring and support. Unfortunately, the diagnosis in some cases has been made at autopsy; therefore, clinicians must have an increased index of suspicion for DAH in patients presenting with an acute, dramatic respiratory syndrome, particularly in young women regardless of a known medical history for SLE. Work-up for DAH includes chest imaging, bronchoalveolar lavage (BAL), complete blood count, double-stranded (DS) DNA, serum complement levels, antiphospholipid antibodies, and renal function. Chest imaging reveals new diffuse and infiltrates in a consolidative and/or ground glass pattern. Depending on the amount of blood loss, patients may present with a falling hematocrit, overt anemia, and/or hemosiderophages or increasing bloody returns on BAL. Hypocomplementemia and a positive anti-DS DNA are common at presentation; less frequent are positive antiphospholipid antibodies. 14 Active arthritis and glomerulonephritis, presenting as renal failure, have also been reported at presentation.15

Management and Prognosis Catastrophic antiphospholipid antibody syndrome and overlap with the primary vasculidites must be excluded because their management differs from SLE-related DAH. In addition to screening for the presence of antiphospholipid antibodies, antibodies related to vasculitis (antiglomerular basement membrane and antineutrophil cytoplasmic antibodies) should be screened. Patients should also be evaluated for pulmonary infection as a cause of DAH. Pulse methylprednisolone, 1g daily for 3 days followed by 1 to 2mg/kg/d oral prednisone is the standard initial treatment of DAH. Plasma exchange and cytotoxic agents are often used; however, the data to support their use are largely empiric. Certain investigators have successfully treated SLE-related DAH with cyclophosphamide or rituximab.15,16 In DAH, poor prognostic markers include renal insufficiency, thrombocytopenia, and severity of clinical presentation (i.e., need for mechanical ventilation).15 Patients are at increased risk for recurrence of DAH, thus, vigilant follow-up is required.

Parenchymal Involvement Interstitial Lung Disease and Pneumonitis Epidemiology Clinically apparent ILD is far less common in SLE than in other connective tissue diseases, occurring in 1 to 15% of SLE patients.17 Although ILD occurs in the setting of SLE, it is often not the direct consequence of the disease. In a review of 90 SLE autopsies from 1958 to 2006, Quadrelli et al noted that although 97.8% of patients had some form of pleuropulmonary involvement, the majority of parenchymal lesions were not attributable to SLE.18

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Patients with SLE-related ILD (SLE-ILD) typically present with exertional dyspnea and a nonproductive cough. Because dyspnea is reported in nearly two-thirds of all-comers with SLE, it may be attributed to causes other than ILD, thus delaying the diagnosis of ILD until its later stages.19 This may, in part, explain why two-thirds of patients with SLE-ILD have auscultatory crackles on chest examination upon presentation of ILD.20 Clubbing and peripheral cyanosis, signs observed in idiopathic pulmonary fibrosis, are rarely found in SLE-ILD.20 Few predictors of SLE-ILD exist. Patients with longstanding disease (> 10 years of disease duration), those with Raynaud phenomenon, seropositivity for anti-(U1) RNP antibodies, sclerodactyly, and abnormal nailfold capillary loops are associated with radiographic evidence of ILD.20,21 Patients with an older age of SLE onset (> 50 years of age) are significantly more likely than those with a younger age of onset to develop ILD.22 Serologic abnormalities associated with SLE-ILD include a high levels of high-sensitivity C-reactive protein, cryoglobulins, hypocomplementemia, and serum lupus erythematosus cells.17

Fig. 1 High-resolution computed tomography scan from a patient with systemic lupus erythematosus-related interstitial lung disease. Note the reticulation, mainly intralobular, with traction bronchiectasis.

Lupus Pneumonitis and Its Association with ILD Lupus pneumonitis (LP) is a highly fatal syndrome characterized by acute onset of fever, pleuritic chest pain, and tachypnea; up to 50% mortality rate is seen with this rare condition. It is often accompanied with auscultatory crackles and hemoptysis may rarely occur. Chest imaging usually reveals bilateral opacities.23 Pneumonitis may be a precursor to chronic ILD in a subset of patients.23 In one case series, 3 of 12 patients with pneumonitis progressed to ILD, despite treatment with high-dose corticosteroids. In both LP and SLE-ILD, immune complexes, lymphocytic aggregates, and vascular pathology are common.23

moderate forms of ILD may be treated initially with moderate doses of corticosteroids with either azathioprine or mycophenolate mofetil. Tapering of corticosteroid therapy is often guided by favorable clinical, physiologic, and/or radiographic response.

Respiratory Physiology and Shrinking Lung Syndrome Restrictive Lung Disease Epidemiology

Evaluation and Diagnosis The diagnosis of SLE-ILD relies on a combination of clinical features, chest imaging, histopathology, and abnormalities in lung physiology (►Fig. 1). A surgical lung biopsy is the gold standard method to diagnose ILD. The most common histologic pattern of SLE-ILD is that of nonspecific interstitial pneumonia; less common patterns include organizing pneumonia (OP), lymphoid interstitial pneumonia (LIP), and usual interstitial pneumonia, desquamative interstitial pneumonia, and diffuse alveolar damage. However, in lieu of an invasive investigational approach, a high-resolution chest CT scan in combination with compatible clinical features can clinch the diagnosis of ILD. However, clinicians must be vigilant to exclude ILD mimics such as DAH, drug toxicity congestive heart failure, uremia, or infection.

Management and Prognosis Treatment for SLE-ILD is based largely on expert opinion. High-dose oral corticosteroids (1 mg/kg body weight of oral prednisone, up to 60 mg, or its equivalent) and a steroidsparing agent, often cyclophosphamide (daily oral of 1–2 mg/kg depending on renal function and age of patient or intravenous equivalent), are initiated for severe ILD. Mild to

Regardless of clinically identifiable pulmonary disease, abnormal respiratory physiology is a common finding in SLE.24,25 In the first of three major studies demonstrating the high frequency of abnormal lung function, 88% of 43 consecutive SLE patients were found to have pulmonary dysfunction; the most common abnormality was a reduction in diffusing capacity of carbon monoxide (DLCO) (72%), followed by a restrictive (49%), and an obstructive (9%) pattern on pulmonary function test (PFT).25 Another study of 70 nonsmoking asymptomatic SLE patients with normal chest radiograph found 67% with an isolated reduction in DLCO and 6% had a restrictive pattern.26 Finally, in a retrospective study of 110 Japanese SLE patients, an abnormal DLCO and restrictive changes were found in 47 and 8% of patients, respectively; only 13% of patients with PFT abnormalities exhibited clinical features, in particular radiographic evidence, of pulmonary involvement.27 In a small case– control study, Rolla et al discovered that greater SLE disease activity may be associated with abnormal lung function and that lung function abnormalities respond to escalation of immunosuppressive treatment targeted at overall SLE disease activity.28 However, the specific mechanisms and/or pathogenesis of lung function abnormalities among SLE patients Seminars in Respiratory and Critical Care Medicine

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Clinical Presentation and Risk Factors

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without overt clinical symptoms and signs of pulmonary involvement are not well understood. PFTs may be a sensitive method to capture subclinical lung involvement and we propose that abnormal lung function among select patients (those with the absence of parenchymal involvement) may actually represent the milder spectrum of SLS, a specific pulmonary feature of SLE.

Shrinking Lung Syndrome Clinical Presentation In Hoffbrand’s original description in 1965, SLS was characterized by unexplained dyspnea, small lung volumes, and restrictive lung physiology, with or without diaphragmatic elevation, in the absence of interstitial, alveolar, or vascular pulmonary disease.29

Epidemiology and Risk Factors SLS has been considered a rare manifestation of SLE, occurring in 0.5% of patients.30 However, in a recent study of 110 consecutive SLE patients who were systematically evaluated for pulmonary involvement, a surprising 10% of patients met Hoffbrand’s original definition of SLS.28 Greater disease duration, seropositivity for anti-RNP antibodies, and a history of pleuritis were independently associated with SLS after controlling for anti-DS DNA and SLE-disease manifestations.28 Some data suggest that progressive impairment in diaphragmatic excursion from muscle weakness is a contributing factor in the development of SLS.31

Management Guidance on management is largely derived from case reports and series. Corticosteroids (moderate to high doses), cytotoxic agents, biologic therapies (rituximab), and high-dose β-agonists have all been used to successfully treat this condition.31

Pleural Involvement Epidemiology and Clinical Presentation Pleuritis (with or without pleural effusion) is a defining feature of and part of the classification criteria for SLE.32 Nearly one-third of prospectively followed up SLE patients in large observational cohorts from Europe and Canada will have clinically identifiable pleuritis during their disease course; up to two-thirds will have involvement at autopsy.10,33,34 Pleuritis may be unilateral or bilateral, though it is more likely to be bilateral. Disease duration, late age of diagnosis of SLE (after age 50 years), greater cumulative damage, and concomitant seropositivity for RNP and Sm antibodies are factors that significantly increase the risk of pleuritis by nearly twofold.34,35 Pleuritic chest pain is the most common symptom, but patients may also report cough, dyspnea, and fever.

Evaluation, Prognosis, and Management A pleural rub may be heard on physical examination and chest imaging may reveal effusions. Pleural effusions are often bilateral and small; rarely, effusions from SLE-disease activity Seminars in Respiratory and Critical Care Medicine

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involve more than two-thirds of the lung fields.10 It is important not only to make a diagnosis of an effusion but also to determine the underlying cause. Common causes of a pleural effusion in SLE are cardiac or renal failure.36 Consideration of underlying PH, especially in the setting of heart failure, needs to be considered especially among patients seropositive for antiphospholipid antibodies. A thoracentesis may be performed when there is a concern for infection, in particular for atypical infections such as tuberculosis, or malignancy. Screening pleural fluid for antinuclear antibodies (ANAs) in patients with SLE may aid in differentiating effusions related to disease activity from other etiologies. A pleural fluid ANA titer of
1/160 has a sensitivity of 92% for SLE pleuritis when compared with all other etiologies for pleural effusions and is particularly helpful when screening exudative effusions in SLE.37 The majority of SLE-related pleural effusions are not life threatening and respond favorably to treatment with nonsteroidal anti-inflammatory drugs, for mild or asymptomatic effusions, and/or oral corticosteroids at a dose of 20 to 40 mg daily, for moderate to severe effusions.38 Treatment can be discontinued in 3 to 4 weeks depending on clinical response. Pleurodesis may be considered in refractory, treatment-resistant cases.39

Airways Laryngeal involvement is an uncommon manifestation of SLE, often presenting with hoarseness and dyspnea. It results from varying levels of upper airway mucosal inflammation and is responds to treatment with oral corticosteroids. In rare circumstances, mucosal inflammation is accompanied by edema and can lead to airway obstruction.40 Bronchiectasis can be seen in SLE but is often an incidental finding on chest imaging; its clinical significance in this population is not known.41 OP and acute fibrinous with OP have been described as rare pulmonary manifestations of SLE.42 A combination of high doses of corticosteroids, cyclophosphamide, and anticholinergics may be used in this setting.43,44

Pulmonary Infections and Lung Cancer Pulmonary Infection SLE patients have an increased mortality compared with the general population. This is driven by increased rates of cardiac and renal disease; increased rates of infection, in particular pneumonia; and malignancies, particularly lung cancer and hematologic malignancies.45 It is not surprising that there may be increased risk of infection in SLE for many reasons, including end-organ involvement (in particular, renal disease), high disease activity, or treatment with immunosuppressants; however, studies are conflicted about which mechanisms drive the infection risk. Notably, the rate of infection in SLE occurs at a greater frequency than reported in other autoimmune diseases, suggesting factors unrelated to the disease contribute to this risk.46 In a large, prospective cohort of SLE, 25% of SLE patients developed an infection in a 5-year follow-up

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Lung Cancer Although the rate of lung cancer is greater than the general population, the distribution of pathologic subsets is similar to that of the general population; adenocarcinoma was the most common histologic subset followed by squamous cell and small cell carcinoma.49 Smoking remains a relevant risk factor for lung cancer in SLE, even more than immunosuppressive medications.49,50 A link between lung cancer and pulmonary fibrosis is well known, however, it is not clear whether parenchymal damage is a relevant factor in the risk of lung cancer in SLE. 51

Concluding Remarks Pulmonary involvement is a frequent manifestation of SLE. It is important to identify the underlying etiology when pulmonary involvement occurs; clinicians need to particularly be vigilant in excluding other etiologies, such as infections, before attributing the manifestation to SLE. Being mindful of the clinical context, in particular, the serologic profile of the patient may help support the diagnosis of specific SLE-related pulmonary manifestations. Management of pulmonary manifestations is based largely on clinical experience and case series; studies in large cohorts and/or clinical trials are needed to establish effective therapies for pulmonary disease in SLE.

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