Pulmonary Manifestations of Systemic LupusErythematosusShikha Mittoo, MD, MHS, FRCPC1 Charlene D. Fell, MD, MSc, FRCPC, FCCP2

1 Interstitial Lung Disease Program, Mount Sinai Hospital/UniversityHealth Network, University of Toronto, Toronto, Ontario, Canada

2Department of Medicine, University of Calgary, Calgary,Alberta, Canada

Semin Respir Crit Care Med 2014;35:249–254.

Address for correspondence Shikha Mittoo, MD, MHS, FRCPC,University of Toronto, L2-003, 60 Murray Street, Toronto, Ontario, M5T3L9 Canada (e-mail: smittoo@mtsinai.on.ca).

Systemic lupus erythematosus (SLE) is a systemic autoimmunediseasewith a predilection for youngwomen. Lung involvementis a known complication of the disease and/or its treatments; upto 50% of SLE patients experience such involvement during theirdisease course.1 Broadly speaking, pulmonary complications ofSLE can be divided into three categories: infectious, malignant,and disease related. Although pulmonary infections typicallyaffect the airways and/or parenchyma, complications attribut-able to SLE can affect all compartments of the lungs and includepleuritis (with or without effusion), interstitial lung disease(ILD), alveolar hemorrhage, shrinking lung syndrome (SLS),pulmonary hypertension (PH), airways disease, and thrombo-embolic disease. A heightened awareness of SLE-related pulmo-narymanifestations among clinicians and the evolution of moresensitive toolswhich capture lung involvement have also lead tothe recognition that subclinical lung involvement occurs at agreater frequency than clinically identifiable involvement. Thisreview will focus primarily on the clinical presentation, patho-genesis, pathology, management, and outcome of clinicallyidentifiable pulmonary manifestations attributable to SLE.

Vascular Involvement

Pulmonary Hypertension

Epidemiology and Clinical PresentationAlthough the frequency of SLE-related PH varies depending onthe ascertainment method from 0.5 to 17.5%, there is noscreening protocol established for this complication and PHmay not be as readily apparent until it is advanced.2 Typically,PH occurs after prolonged SLE disease duration, often after5 years, in women under the age of 40 years.3 The vast majorityof patients present with symptoms of chest pain, shortness ofbreath, or cough; nearly one-third will have signs of right heartfailure (loud pulmonic heart sound, murmurs of tricuspid orpulmonic regurgitation, right ventricular heave, elevated jugularvenous pressure, and lower extremity edema) at presentationincluding active pleural effusions and aminority will be asymp-tomatic at diagnosis of PH.2,4,5 In a case–control studyof 147 SLEpatients, Raynaud phenomenon and the presence of anticardio-lipin and anti-U1 ribonucleoprotein (RNP) antibodies werepredictive of PH, with a three-, four-, and fivefold increase risk

Keywords

► systemic lupuserythematosus

► lung► pleura► vascular► airways

Abstract Systemic lupus erythematosus (SLE) is a systemic inflammatory disease, characterizedserologically by an autoantibody response to nucleic antigens, and clinically by injuryand/or malfunction in any organ system. During their disease course, up to 50% of SLEpatients 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, airwaysdisease, and thromboembolic disease. Two major themes inform our understandingof SLE-associated pulmonary manifestations: first, the presence of specific autoanti-bodies correlates with the presence of certain pulmonary manifestations and second,vascular injurymarks a common pathophysiologic thread among the various SLE-relatedlung diseases. This review will focus on the clinical presentation, pathogenesis,pathology, management, and prognosis of these SLE-associated lung conditions.

Issue Theme Pulmonary Complicationsof Connective Tissue Disease; GuestEditors, Danielle Antin-Ozerkis, MD, andJeffrey Swigris, DO, MS

Copyright © 2014 by Thieme MedicalPublishers, Inc., 333 Seventh Avenue,New York, NY 10001, USA.Tel: +1(212) 584-4662.

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

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of PH comparedwith thosewithout suchmanifestations, respec-tively.6 In another study, serum rheumatoid factor positivitywassignificantly associated with PH, which is interesting to note asseropositivity for rheumatoid factor has been linked to hyper-viscosity in rheumatoid arthritis patients.4,7 Taken together, thissuggests that select autoantibodieswith a propensity to lead to aviscous and/or prothrombotic milieu may be important in thepathogenesis of SLE-PH.

PathophysiologyAcute/chronic thromboembolic disease, increased pulmo-nary vascular resistance, and rarely, vasculitis or pulmonaryveno-occlusive disease contribute to the development ofpathologic changes of PH (medial hypertrophy, intimal fibro-sis, and plexiform lesions); inflammation, immune dysregu-lation, and vascular remodeling at varying levels are centralcomponents of these major mechanism.8

Evaluation, Prognosis, and ManagementA transthoracic echocardiogram is used to screen for PH inSLE, however, because this method can be inaccurate when atricuspid regurgitation jet is not present or if other signs ofright heart stress (e.g., dilation, impaired systolic function)are absent, a right heart catheterization (RHC) is the goldstandard for PH diagnosis. Amean pulmonary artery pressureof � 25 mm Hg in the face of a pulmonary capillary wedgepressure < 15 mmHg defines PH by RHC.9 Given that PH canarise from causes other than SLE, patients should be ques-tioned about current or past use of anorexigens or illicitdrugs, evaluated for obstructive sleep apnea with a screeningpolysomnogram, evaluated for ILD and thromboembolic dis-ease with a chest computed tomography (CT) and a ventila-tion perfusion scan, and screened for the presence of humanimmunodeficiency virus and chronic liver disease.

There are no consensus guidelines on the management ofSLE-PH. In double-blind trials, in which only small numbers ofpatients (n ¼ 16–35) were enrolled, PH-specific therapy (selec-tive and nonselective endothelin receptor antagonists or phos-phodiesterase-5 inhibitors) have demonstrated improvementsin clinical and physiologic end points.2 Data supporting the useof immunosuppressive medications, such as intravenous cyclo-phosphamide and glucocorticoids, for SLE-PH are limited. Incertain retrospective series of small numbers of subjects, inves-tigators have reported amodest physiologic benefit from the useof immunosuppression in combination with vasodilator thera-py.10 In a recent systematic review, elevated mean pulmonaryartery pressure, Raynaud phenomenon, thrombocytopenia,plexiform lesion, infection, thrombosis, pregnancy, pulmonaryvasculitis, and anticardiolipin antibodies were associated withdecreased 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 PresentationDiffuse alveolar hemorrhage (DAH) is a rare, and oftenfatal, consequence of neutrophilic infiltration, immune

complex deposition, and destruction of pulmonary vascu-lar endothelium.13 Patients appear acutely unwell withdyspnea, fever, chest pain, and, in nearly half of patients,hemoptysis. Notably, DAH may be the presenting feature ofSLE in up to one-third of patients. Patients often needhospitalization and intensive care monitoring and support.Unfortunately, the diagnosis in some cases has been madeat autopsy; therefore, clinicians must have an increasedindex of suspicion for DAH in patients presenting with anacute, dramatic respiratory syndrome, particularly inyoung women regardless of a known medical history forSLE. Work-up for DAH includes chest imaging, bronchoal-veolar lavage (BAL), complete blood count, double-stranded(DS) DNA, serum complement levels, antiphospholipidantibodies, and renal function. Chest imaging revealsnew diffuse and infiltrates in a consolidative and/or groundglass pattern. Depending on the amount of blood loss,patients may present with a falling hematocrit, overtanemia, and/or hemosiderophages or increasing bloodyreturns on BAL. Hypocomplementemia and a positiveanti-DS DNA are common at presentation; less frequentare positive antiphospholipid antibodies.14 Active arthritisand glomerulonephritis, presenting as renal failure, havealso been reported at presentation.15

Management and PrognosisCatastrophic antiphospholipid antibody syndrome and over-lap with the primary vasculidites must be excluded becausetheir management differs from SLE-related DAH. In additionto screening for the presence of antiphospholipid antibodies,antibodies related to vasculitis (antiglomerular basementmembrane and antineutrophil cytoplasmic antibodies)should be screened. Patients should also be evaluated forpulmonary infection as a cause of DAH. Pulse methylprednis-olone, 1g daily for 3 days followed by 1 to 2mg/kg/d oralprednisone is the standard initial treatment of DAH. Plasmaexchange and cytotoxic agents are often used; however, thedata to support their use are largely empiric. Certain inves-tigators have successfully treated SLE-related DAH with cy-clophosphamide or rituximab.15,16 In DAH, poor prognosticmarkers include renal insufficiency, thrombocytopenia, andseverity of clinical presentation (i.e., need for mechanicalventilation).15 Patients are at increased risk for recurrenceof DAH, thus, vigilant follow-up is required.

Parenchymal Involvement

Interstitial Lung Disease and Pneumonitis

EpidemiologyClinically apparent ILD is far less common in SLE than in otherconnective tissue diseases, occurring in 1 to 15% of SLEpatients.17 Although ILD occurs in the setting of SLE, it isoften not the direct consequence of the disease. In a review of90 SLE autopsies from 1958 to 2006, Quadrelli et al noted thatalthough 97.8% of patients had some form of pleuropulmo-nary involvement, the majority of parenchymal lesions werenot attributable to SLE.18

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Clinical Presentation and Risk FactorsPatients with SLE-related ILD (SLE-ILD) typically present withexertional dyspnea and a nonproductive cough. Becausedyspnea is reported in nearly two-thirds of all-comers withSLE, it may be attributed to causes other than ILD, thusdelaying the diagnosis of ILD until its later stages.19 Thismay, in part, explain why two-thirds of patients with SLE-ILDhave auscultatory crackles on chest examination upon pre-sentation of ILD.20 Clubbing and peripheral cyanosis, signsobserved in idiopathic pulmonary fibrosis, are rarely found inSLE-ILD.20 Fewpredictors of SLE-ILD exist. Patients with long-standing disease (> 10 years of disease duration), those withRaynaud phenomenon, seropositivity for anti-(U1) RNP anti-bodies, sclerodactyly, and abnormal nailfold capillary loopsare associatedwith radiographic evidence of ILD.20,21 Patientswith an older age of SLE onset (> 50 years of age) aresignificantly more likely than those with a younger age ofonset to develop ILD.22 Serologic abnormalities associatedwith SLE-ILD include a high levels of high-sensitivityC-reactive protein, cryoglobulins, hypocomplementemia,and serum lupus erythematosus cells.17

Lupus Pneumonitis and Its Association with ILDLupus pneumonitis (LP) is a highly fatal syndrome character-ized by acute onset of fever, pleuritic chest pain, and tachyp-nea; up to 50% mortality rate is seen with this rare condition.It is often accompanied with auscultatory crackles and he-moptysis may rarely occur. Chest imaging usually revealsbilateral opacities.23 Pneumonitis may be a precursor tochronic ILD in a subset of patients.23 In one case series, 3 of12 patients with pneumonitis progressed to ILD, despitetreatment with high-dose corticosteroids. In both LP andSLE-ILD, immune complexes, lymphocytic aggregates, andvascular pathology are common.23

Evaluation and DiagnosisThe diagnosis of SLE-ILD relies on a combination of clinicalfeatures, chest imaging, histopathology, and abnormalities inlung physiology (►Fig. 1). A surgical lung biopsy is the goldstandard method to diagnose ILD. The most common histo-logic pattern of SLE-ILD is that of nonspecific interstitialpneumonia; less common patterns include organizing pneu-monia (OP), lymphoid interstitial pneumonia (LIP), and usualinterstitial pneumonia, desquamative interstitial pneumonia,and diffuse alveolar damage. However, in lieu of an invasiveinvestigational approach, a high-resolution chest CT scan incombination with compatible clinical features can clinch thediagnosis of ILD. However, clinicians must be vigilant toexclude ILD mimics such as DAH, drug toxicity congestiveheart failure, uremia, or infection.

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

moderate forms of ILDmay be treated initially withmoderatedoses of corticosteroids with either azathioprine or myco-phenolate mofetil. Tapering of corticosteroid therapy is oftenguided by favorable clinical, physiologic, and/or radiographicresponse.

Respiratory Physiology and Shrinking LungSyndrome

Restrictive Lung Disease

EpidemiologyRegardless of clinically identifiable pulmonary disease, ab-normal respiratory physiology is a common finding inSLE.24,25 In the first of three major studies demonstratingthe high frequency of abnormal lung function, 88% of 43consecutive SLE patients were found to have pulmonarydysfunction; the most common abnormality was a reductionin diffusing capacity of carbon monoxide (DLCO) (72%),followed by a restrictive (49%), and an obstructive (9%)pattern on pulmonary function test (PFT).25 Another studyof 70 nonsmoking asymptomatic SLE patients with normalchest radiograph found 67% with an isolated reduction inDLCO and 6% had a restrictive pattern.26 Finally, in a retro-spective study of 110 Japanese SLE patients, an abnormalDLCO and restrictive changes were found in 47 and 8% ofpatients, respectively; only 13% of patients with PFT abnor-malities exhibited clinical features, in particular radiographicevidence, of pulmonary involvement.27 In a small case–control study, Rolla et al discovered that greater SLE diseaseactivity may be associated with abnormal lung function andthat lung function abnormalities respond to escalation ofimmunosuppressive treatment targeted at overall SLE diseaseactivity.28 However, the specific mechanisms and/or patho-genesis of lung function abnormalities among SLE patients

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

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without overt clinical symptoms and signs of pulmonaryinvolvement are not well understood. PFTs may be a sensitivemethod to capture subclinical lung involvement and wepropose that abnormal lung function among select patients(those with the absence of parenchymal involvement) mayactually represent the milder spectrum of SLS, a specificpulmonary feature of SLE.

Shrinking Lung Syndrome

Clinical PresentationIn Hoffbrand’s original description in 1965, SLS was charac-terized by unexplained dyspnea, small lung volumes, andrestrictive lung physiology, with or without diaphragmaticelevation, in the absence of interstitial, alveolar, or vascularpulmonary disease.29

Epidemiology and Risk FactorsSLShas been considered a raremanifestation of SLE, occurringin 0.5% of patients.30 However, in a recent study of 110consecutive SLE patients who were systematically evaluatedfor pulmonary involvement, a surprising 10% of patients metHoffbrand’s original definition of SLS.28 Greater disease du-ration, seropositivity for anti-RNP antibodies, and a history ofpleuritis were independently associated with SLS after con-trolling for anti-DS DNA and SLE-disease manifestations.28

Some data suggest that progressive impairment in diaphrag-matic excursion from muscle weakness is a contributingfactor in the development of SLS.31

ManagementGuidance onmanagement is largely derived from case reportsand series. Corticosteroids (moderate to high doses), cytotoxicagents, biologic therapies (rituximab), and high-dose β-ago-nists have all been used to successfully treat this condition.31

Pleural Involvement

Epidemiology and Clinical PresentationPleuritis (with or without pleural effusion) is a definingfeature of and part of the classification criteria for SLE.32

Nearly one-third of prospectively followed up SLE patientsin large observational cohorts from Europe and Canada willhave clinically identifiable pleuritis during their diseasecourse; up to two-thirds will have involvement at autop-sy.10,33,34 Pleuritis may be unilateral or bilateral, though it ismore likely to be bilateral. Disease duration, late age ofdiagnosis of SLE (after age 50 years), greater cumulativedamage, and concomitant seropositivity for RNP and Smantibodies are factors that significantly increase the risk ofpleuritis by nearly twofold.34,35 Pleuritic chest pain is themost common symptom, but patients may also report cough,dyspnea, and fever.

Evaluation, Prognosis, and ManagementApleural rubmay beheard onphysical examination and chestimaging may reveal effusions. Pleural effusions are oftenbilateral and small; rarely, effusions from SLE-disease activity

involve more than two-thirds of the lung fields.10 It isimportant not only to make a diagnosis of an effusion butalso to determine the underlying cause. Common causes of apleural effusion in SLE are cardiac or renal failure.36 Consid-eration of underlying PH, especially in the setting of heartfailure, needs to be considered especially among patientsseropositive for antiphospholipid antibodies. A thoracentesismay be performed when there is a concern for infection, inparticular for atypical infections such as tuberculosis, ormalignancy. Screening pleural fluid for antinuclear antibod-ies (ANAs) in patients with SLE may aid in differentiatingeffusions related to disease activity from other etiologies. Apleural fluid ANA titer of � 1/160 has a sensitivity of 92% forSLE pleuritis when compared with all other etiologies forpleural effusions and is particularly helpful when screeningexudative effusions in SLE.37

The majority of SLE-related pleural effusions are not lifethreatening and respond favorably to treatment with nonste-roidal anti-inflammatory drugs, for mild or asymptomaticeffusions, and/or oral corticosteroids at a dose of 20 to 40 mgdaily, for moderate to severe effusions.38 Treatment can bediscontinued in 3 to 4 weeks depending on clinical response.Pleurodesis may be considered in refractory, treatment-re-sistant cases.39

Airways

Laryngeal involvement is an uncommonmanifestation of SLE,often presentingwith hoarseness and dyspnea. It results fromvarying levels of upper airway mucosal inflammation and isresponds to treatment with oral corticosteroids. In rarecircumstances, mucosal inflammation is accompanied byedema and can lead to airway obstruction.40 Bronchiectasiscan be seen in SLE but is often an incidental finding on chestimaging; its clinical significance in this population is notknown.41OPand acutefibrinouswithOPhave been describedas rare pulmonary manifestations of SLE.42 A combination ofhigh doses of corticosteroids, cyclophosphamide, and anti-cholinergics may be used in this setting.43,44

Pulmonary Infections and Lung Cancer

Pulmonary InfectionSLE patients have an increased mortality compared with thegeneral population. This is driven by increased rates of cardiacand renal disease; increased rates of infection, in particularpneumonia; and malignancies, particularly lung cancer andhematologic malignancies.45

It is not surprising that there may be increased risk ofinfection in SLE for many reasons, including end-organinvolvement (in particular, renal disease), high disease activ-ity, or treatment with immunosuppressants; however, stud-ies are conflicted about which mechanisms drive theinfection risk. Notably, the rate of infection in SLE occurs ata greater frequency than reported in other autoimmunediseases, suggesting factors unrelated to the disease contrib-ute to this risk.46 In a large, prospective cohort of SLE, 25% ofSLE patients developed an infection in a 5-year follow-up

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period; themost common site of infectionwas the respiratorytract and the most common organism was bacteria.47 Immu-nosuppressive therapy, particularly corticosteroids was sig-nificantly associatedwith an increased risk of infection in thisstudy, but as disease activity and corticosteroid use arecorrelated, it remains to be seen to what extent diseaseactivity is related to pulmonary infection.47 Notably, clini-cians must remain vigilant to rule out infection in an SLEpatients presenting with respiratory symptoms and considerboth usual and opportunistic organisms.48

Lung CancerAlthough the rate of lung cancer is greater than the generalpopulation, the distribution of pathologic subsets is similar tothat of the general population; adenocarcinomawas themostcommon histologic subset followed by squamous cell andsmall cell carcinoma.49

Smoking remains a relevant risk factor for lung cancer inSLE, even more than immunosuppressive medications.49,50

A link between lung cancer and pulmonary fibrosis is wellknown, however, it is not clear whether parenchymaldamage is a relevant factor in the risk of lung cancerin SLE.51

Concluding Remarks

Pulmonary involvement is a frequent manifestation of SLE. Itis important to identify the underlying etiology when pul-monary involvement occurs; clinicians need to particularlybe vigilant in excluding other etiologies, such as infections,before attributing the manifestation to SLE. Being mindful ofthe clinical context, in particular, the serologic profile of thepatientmay help support the diagnosis of specific SLE-relatedpulmonary manifestations. Management of pulmonary man-ifestations is based largely on clinical experience and caseseries; studies in large cohorts and/or clinical trials areneeded to establish effective therapies for pulmonary diseasein SLE.

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