Pulmonary manifestations of systemic lupus erythematosus in adults

INTRODUCTION — At some time during the course of their disease, most patients with systemic lupus erythematosus (SLE) show signs of involvement of the lung, pulmonary vasculature, pleura, and/or diaphragm [1-4]. Pleurisy, coughing, and/or dyspnea are often the first clues either to lung involvement or to SLE itself [5]. In some cases, however, abnormal pulmonary function tests (PFTs) and/or chest radiographs may be detected in asymptomatic patients [6].

Patients with SLE and lung involvement must always be evaluated for infection, particularly due to bacteria or viruses. Given that many patients with SLE are immunocompromised due to the underlying disease or ongoing medications, opportunistic infections (eg, mycobacteria or fungi) should also be considered [7,8].

Overviews of the clinical manifestations of SLE in adults and children and a review of pulmonary disease in children with SLE are presented separately. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Pulmonary' and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)

PLEURAL DISEASE — Pleural involvement is common in SLE, occurring in up to 93 percent in autopsy series, and can be manifest as pleuritic chest pain with or without pleural effusion.  

Clinical manifestations — Inflammation of the pleura may cause chest pain in the absence of a pleural effusion on the chest radiograph. In this setting, it is often difficult to determine whether the chest pain represents pleuritis. The presence of a rub, which may be transient, facilitates the diagnosis of pleurisy.

Pleural effusions in SLE are often bilateral (50 percent), exudative, and characterized by an elevation in pleural fluid lactate dehydrogenase (LDH). Patients may also report cough, dyspnea, and fever. Effusions are commonly small, but may occasionally be large. The fluid appearance varies from clear serous to serosanguineous to bloody [9]. Hemopneumothorax has been described, although spontaneous pneumothorax is uncommon [3]. (See "Pleural fluid analysis in adults with a pleural effusion".)

The pleural fluid findings in SLE differ from those in rheumatoid arthritis (RA); the total white cell count (with a predominance of either lymphocyte or polymorphonuclear cells) tends to be lower in SLE-related effusions than in RA [10]. In addition, pleural fluid glucose concentrations in SLE effusions are slightly lower than serum blood levels, whereas pleural glucose levels in rheumatoid effusions are significantly reduced. The pleural fluid pH is also low in 20 percent of SLE patients. While pleural fluid complement levels are often low in SLE and RA effusions [11], we do not recommend obtaining these tests. (See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis", section on 'Pleural disease'.)

Fibrothorax is a rare complication of lupus pleuritis and can lead to dyspnea by preventing lung expansion. In one reported case, otherwise normal lung was trapped in thickened visceral pleura causing dyspnea that was improved following pleural stripping (decortication) [12]. The evaluation and management of trapped lung is discussed separately. (See "Diagnosis and management of pleural causes of nonexpandable lung" and "Measurement and interpretation of pleural pressure (manometry): Indications and technique".)

Diagnostic evaluation — The definitive diagnosis of lupus pleuritis is typically clinical, based upon the presence of pleurisy with or without an exudative effusion in a patient with SLE, as well as exclusion of musculoskeletal pain and alternative causes of pleural inflammation such as drug-induced pleuritis, infection, heart failure, nephrotic syndrome, uremia, pulmonary embolism, or malignancy [13]. In many patients, however, it may be difficult to obtain adequate amounts of fluid for examination. Thus, the initial evaluation centers on the history and physical exam to determine whether other symptoms and signs suggest a flare of SLE, heart failure, or respiratory infection and a review of the patient’s medications for those associated with drug-induced pleurisy. (See 'Chest wall pain' below and "Pleural fluid analysis in adults with a pleural effusion" and "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion" and "Drug-induced lupus".)

Initial laboratory testing often includes a complete blood count and differential, blood urea nitrogen, creatinine, brain natriuretic peptide (BNP), or N-terminal pro-BNP (NT-proBNP). For patients without recent testing or a diagnosis of SLE, antinuclear antibody (ANA), anti-double-stranded (ds) DNA, anti-Sm and anti-RNP (aka, anti-U1-RNP), anti-Ro/SSA and anti-La/SSB, and antihistone antibodies are measured. Although the presence of antinuclear antibodies (ANA) and LE cells in pleural fluid suggest SLE, these findings provide no additional diagnostic information beyond that obtained from the measurement of these autoantibodies in serum [14]. Therefore these tests need not be performed on pleural fluid samples. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Pleural fluid analysis in adults with a pleural effusion".)

If sufficient pleural fluid is present, we recommend a diagnostic thoracentesis to determine whether the fluid is exudative and to send samples for microbiologic and in order to exclude alternative diagnoses. If imaging demonstrates insufficient pleural fluid for thoracentesis, a presumptive diagnosis of lupus pleuritis may be made in a patient with known SLE, and no clinical or imaging evidence of infection or pneumonia. (See "Ultrasound-guided thoracentesis".)

The differential diagnosis of pleuritic chest pain in patients with SLE includes chest wall pain which is discussed below. (See 'Chest wall pain' below.)

Treatment — Pleuritis with or without a pleural effusion in SLE can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs), unless contraindicated by gastrointestinal or renal disease or heart failure. We prefer naproxen 250 to 500 mg every 12 hours, but other NSAIDs are acceptable (table 1). If there is no response within one to two weeks, systemic glucocorticoids (eg, prednisone 20 mg/day followed by a taper over two to three weeks) will generally improve the symptoms, although the optimal dosing has not been determined. Occasionally, oral glucocorticoids are used as initial therapy to achieve a more rapid response. Other immunosuppressive agents are rarely indicated. Hydroxychloroquine usage has been associated with a reduced likelihood of development of pleuritis [15].

For patients with suspected pleuritis in the setting of drug-induced SLE (eg, procainamide, hydralazine, tumor necrosis factor-alpha antagonists), drug discontinuation may be sufficient both diagnostically and therapeutically. (See "Drug-induced lupus".)

ACUTE PNEUMONITIS — Acute lupus pneumonitis is an uncommon (1 to 12 percent) manifestation of SLE [16,17]. The clinical presentation is similar to acute interstitial pneumonia (AIP), one of the idiopathic interstitial pneumonias. (See "Acute interstitial pneumonia (Hamman-Rich syndrome)".)

Histopathologic examination in acute lupus pneumonitis and AIP reveals diffuse alveolar damage, alveolar edema, hyaline membrane formation, and mononuclear cell infiltration; immunoglobulin and complement deposition may be present in capillary walls [18-20]. Alveolar hemorrhage may also be noted, but vasculitis is uncommon.

Clinical manifestations — Acute lupus pneumonitis is characterized by the rapid onset of fever, cough (sometimes with hemoptysis), and dyspnea. The physical examination reveals tachypnea, tachycardia, basilar crackles (late inspiratory), and hypoxemia. In approximately half the patients with acute lupus pneumonitis, pneumonitis is the first manifestation of SLE [16].

Serum antinuclear antibodies and anti-DNA antibodies are typically elevated, although testing does not need to be repeated in patients with known SLE [16]. The chest radiograph shows diffuse or patchy opacities, predominantly in the lower lung zones.

Diagnostic evaluation — The diagnosis of acute lupus pneumonitis should be suspected in a patient with SLE who presents with the acute onset of respiratory symptoms, fever, inspiratory crackles, and hypoxemia. As the diagnosis is one of exclusion, the evaluation focuses on excluding alternative diagnoses including infection, organizing pneumonia, pulmonary embolism, drug toxicity, diffuse alveolar hemorrhage, heart failure, and malignancy. For patients without known SLE, the diagnosis of acute lupus pneumonitis is suspected when the patient does not respond to empiric treatment for pneumonia and when extrapulmonary features of SLE are noted (eg, malar rash, oral ulcers, alopecia, polyserositis, abnormal urine sediment, renal insufficiency, cytopenia, thrombophilia, lymphadenopathy, splenomegaly, joint swelling) [21]. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)

●Laboratory – A complete blood count and differential may identify cytopenia or thrombophilia, consistent with SLE. Microbiologic investigation may include rapid testing for viral pathogens, serologic tests for atypical pneumonias (eg, Coccidioides, Chlamydia pneumoniae, Mycoplasma pneumoniae, respiratory viruses), and urinary antigen tests (eg, Streptococcus pneumoniae, Histoplasma capsulatum, and Legionella pneumophila). If the patient is immunosuppressed, assessment for opportunistic infections, such as Aspergillus, Candida, Cryptococcus, and Pneumocystis jirovecii, is appropriate. A plasma brain natriuretic peptide (BNP or pro-NT-BNP) level and an echocardiogram are often obtained to help exclude cardiogenic pulmonary edema. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates", section on 'Diagnosis' and "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults", section on 'Initial diagnostic evaluation'.)

●Imaging – Computed tomography (CT) typically reveals a ground glass appearance; patchy areas of consolidation, traction bronchiectasis, or pleural effusion may be present [22-24]. Computed tomography with pulmonary angiography may be needed to exclude pulmonary embolism, particularly in patients with hypoxemia or known antiphospholipid antibodies. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Computed tomography pulmonary angiography'.)

●Diffusing capacity for carbon monoxide (DLCO) – Distinguishing between diffuse alveolar hemorrhage and acute lupus pneumonitis is difficult. Theoretically, a DLCO test could help differentiate these entities, as an increased DLCO is suggestive of alveolar hemorrhage, but in practice the patients are usually too ill to undergo the testing. (See "The diffuse alveolar hemorrhage syndromes" and 'Pulmonary hemorrhage' below.)

●Bronchoscopy with bronchoalveolar lavage (BAL) – BAL is valuable for ruling out infection and alveolar hemorrhage in patients with SLE. Further, obtaining sequential BAL samples is a key component of excluding alveolar hemorrhage. Transbronchial biopsy is typically not helpful in establishing this diagnosis. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease" and "The diffuse alveolar hemorrhage syndromes", section on 'Bronchoalveolar lavage'.)

●Lung biopsy – A lung biopsy via video-assisted thoracoscopic surgery (VATS) or open thoracotomy is rarely necessary to confirm the diagnosis of acute lupus pneumonitis or exclude infection, but is occasionally performed prior to adding immunosuppressive therapy when a patient has not responded to systemic glucocorticoids in order to rule out alternative diagnoses such as malignancy. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

The differential diagnosis of acute lupus pneumonitis is similar to that of acute respiratory distress syndrome and includes heart failure, infection (eg, viruses, Pneumocystis jirovecii in patients on immunosuppressive drugs) [25,26], organizing pneumonia, pulmonary infarction (possibly associated with antiphospholipid antibodies), acute eosinophilic pneumonia, aspiration, drug-induced lung toxicity, malignancy, and diffuse alveolar hemorrhage.

Treatment — There have been no controlled trials addressing treatment of acute lupus pneumonitis. The following recommendations are based on the authors’ experience, case reports, and experience with acute interstitial pneumonia. In our experience, acute lupus pneumonitis needs prompt intervention if the outcome, which has traditionally been poor, is to be improved. (See "Acute interstitial pneumonia (Hamman-Rich syndrome)", section on 'Treatment'.)

Broad spectrum antibiotics, including coverage of encapsulated organisms, should be given while awaiting culture results. The specific antibiotic choices are dependent on the underlying degree of immunosuppression and the likelihood of specific infections based on the patient’s history and geographic location, as described separately. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates", section on 'Selection of initial therapy'.)

The mainstay of therapy is systemic prednisone (1 to 1.5 mg/kg per day orally in divided doses or equivalent intravenous dosing). If no response is seen within 72 hours or if the patient declines clinically intravenous pulse glucocorticoids (ie, 1 gram of methylprednisolone per day for three days) are administered. In addition, immunosuppressive therapy (eg, cyclophosphamide, rituximab, intravenous immune globulin [IVIG]) is usually initiated. In the absence of data from a randomized trial, the choice of an additional immunosuppressive agent is guided by individual patient characteristics including comorbidities (eg, heart failure), physician familiarity with the various alternatives, and drug availability. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Approach to drug therapy'.)

Data on prognosis come from older studies and, therefore, may not reflect the outcomes of current medical practice. In a study from 1975 of 12 patients, the reported short-term mortality rate was 50 percent [16]. Survivors tend to have persistent pulmonary function abnormalities, including severe restrictive ventilatory defects [16]. Acute pneumonitis may be a precursor to the development of chronic interstitial lung disease [16].

PULMONARY HEMORRHAGE — Pulmonary hemorrhage is a rare complication in SLE [27-31]. As an example, one study found diffuse alveolar hemorrhage (DAH) in only 19 of 510 patients who were hospitalized for complications of SLE over a 10-year period [32]. While DAH may be the presenting manifestation of SLE, it is most commonly observed in those who are already known to have SLE [29,32]. (See "The diffuse alveolar hemorrhage syndromes".)

The underlying etiology of the alveolar damage and pulmonary hemorrhage in this setting is unknown, although both capillaritis and bland hemorrhage have been described on histopathology [33,34]. Antiphospholipid antibodies (aPL) may be contributory in some patients [33,35].

Clinical manifestations — Affected patients appear acutely ill and report dyspnea, cough, and hemoptysis, usually developing over three days [32]. While hemoptysis eventually occurs in the majority of episodes, it is present at admission in 40 to 70 percent, depending on the report [32]. Fever is inconsistent and occurs in about 25 percent. (See 'Diagnostic evaluation' above.)

In some patients, alveolar bleeding is sufficient to induce anemia, and many patients have concurrent lupus nephritis [31,32,36,37].

Chest radiography frequently shows bilateral opacities, which may be diffuse or patchy and are similar to those seen in acute lupus pneumonitis. (See 'Diagnostic evaluation' above.)

Evaluation and diagnosis — DAH is generally suspected in patients with hemoptysis, diffuse radiographic opacities, and hypoxemia, although hemoptysis may be absent. The evaluation of patients with suspected DAH mirrors that of acute lupus pneumonitis and should be pursued expeditiously due to the life-threatening nature of the disorder [32]. (See 'Diagnostic evaluation' above.)

As with DAH in general, patients should be assessed for excess anticoagulation, bleeding disorders, renal disease, and heart failure (table 2). Given the potential role of APL in patients with SLE, it is reasonable to obtain enzyme-linked immunosorbent assay (ELISA) testing for anticardiolipin antibodies (aCL) and anti-beta2-glycoprotein (GP) I, in addition to a lupus anticoagulant test.

Flexible bronchoscopy with sequential bronchoalveolar lavage (BAL) aliquots is the preferred method for making the diagnosis of DAH. Alveolar hemorrhage is confirmed when lavage aliquots are progressively more hemorrhagic, a finding characteristic of DAH from all causes. Cytology of the BAL effluent demonstrates hemosiderin-laden macrophages. BAL studies also help to exclude infection, eosinophilia, and malignancy. (See "The diffuse alveolar hemorrhage syndromes", section on 'Bronchoalveolar lavage'.)

Lung biopsy is rarely necessary in DAH. However, among patients who have undergone lung biopsy or autopsy, two different histologic patterns have been described: capillaritis with immune complex deposition and bland hemorrhage [32,38,39]. Bland pulmonary hemorrhage appears to be more common, accounting for 72 percent of cases in one report, compared with capillaritis, which was present in 14 percent [32].

The differential diagnosis of DAH is broad and mimics that of acute lupus pneumonitis. (See 'Diagnostic evaluation' above and "The diffuse alveolar hemorrhage syndromes", section on 'Clues to a specific etiology'.)

Treatment and prognosis — The optimal treatment for DAH due to SLE has not been determined by randomized trials. An approach to the management of diffuse alveolar hemorrhage is provided separately. (See "The diffuse alveolar hemorrhage syndromes", section on 'Treatment'.)

DAH due to SLE is considered life-threatening, and the majority of patients are treated with intensive initial therapy using a high dose of systemic glucocorticoids (eg, intravenous pulses of methylprednisolone, 0.5 to 1 g/day for three days, in acutely ill patients or prednisone, 1 to 2 mg/kg/day, in more stable patients) with another immunosuppressive agent (eg, cyclophosphamide, rituximab, mycophenolate, azathioprine) [30,31,40]. The choice of the second agent is based on the disease severity (eg, rapid clinical decline, use of high flow oxygen or mechanical ventilation), other organ involvement, and the pre-DAH immunosuppressive regimen. Cyclophosphamide may be preferred when a rapid onset of effect is needed. If the clinical presentation is less severe, use of mycophenolate or azathioprine may be reasonable with close observation for signs of decline or lack of response. Therapeutic apheresis (plasma exchange) and intravenous immune globulin (IVIG) are considerations as additional therapy for refractory disease, although supportive data are limited. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Approach to drug therapy' and "The diffuse alveolar hemorrhage syndromes", section on 'Additional immunosuppressive therapy' and "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

Outcomes of combined systemic glucocorticoid and immunosuppressive therapy for alveolar hemorrhage complicating SLE range from 28 to 75 percent survival have been reported in small case series [29,31,32,36,37,41-43]:

●In one series, six of eight patients survived after therapy with high-dose glucocorticoids (methylprednisolone 500 mg to 2000 mg/day, usually given intravenously) and a combination of cyclophosphamide, mechanical ventilation, and antibiotics [39].

●In a series of 22 patients with 29 episodes of DAH due to SLE, the survival rate per episode was 48 percent [37]. All patients received high-dose glucocorticoids and approximately 60 percent also received cyclophosphamide. Two of the most ill patients were additionally treated with rituximab, but did not survive.

●A survival rate of 47 percent was noted in another uncontrolled series when patients (15 patients; 19 episodes) were treated with glucocorticoids [32]. A lower survival rate of 30 percent was associated with the addition of cyclophosphamide, but it is possible that these patients had more severe disease.

●Rituximab has been used successfully in a small number of patients in combination with cyclophosphamide (as part of initial therapy), as an alternative to cyclophosphamide, and following failure or intolerance to cyclophosphamide in patients with recurrent DAH [43]. All of the patients also received high dose systemic glucocorticoids.

●Therapeutic apheresis has been described in a limited number of patients [44,45]. As an example, a series of 20 patients with SLE-DAH treated with adjunctive therapeutic apheresis found that 11 (55 percent) improved and 9 (45 percent) were unimproved or worsened [45].

The initial therapy is subsequently followed by a longer period of less intensive, and ideally less toxic, maintenance therapy to consolidate remission and prevent flares.

Successful use of activated recombinant factor VIIa has been described in a case report of an SLE patient with pulmonary hemorrhage refractory to standard therapy [46]. The therapeutic use of recombinant factor VIIa for pulmonary hemorrhage is discussed in detail separately. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'CNS bleeding'.)

INTERSTITIAL LUNG DISEASE — The true prevalence of chronic systemic lupus erythematosus-associated interstitial lung disease (SLE-ILD) is not known, but a prevalence of 3 to 9 percent has been reported [3,17,47]. As with other rheumatic diseases, the types of SLE-ILD follow the histopathology of the various idiopathic interstitial pneumonias (algorithm 1). Nonspecific interstitial pneumonia (NSIP, both cellular and fibrotic), usual interstitial pneumonia (UIP), organizing pneumonia (formerly called bronchiolitis obliterans organizing pneumonia), lymphocytic interstitial pneumonia (LIP), follicular bronchiolitis, and nodular lymphoid hyperplasia have all been reported in association with SLE. Among these types of ILD, NSIP appears to be the most common pattern in SLE [48-50], while the usual interstitial pneumonia pattern is uncommon. (See "Idiopathic interstitial pneumonias: Classification and pathology".)

The clinical characteristics of SLE-ILD vary somewhat with the particular type of ILD, although patients with ILD typically present with an insidious onset of chronic nonproductive cough, dyspnea, and decreased exercise tolerance, but some may be asymptomatic [16,51-53]. Physical examination typically reveals basilar crackles.

Evaluation — A general approach to the evaluation of suspected interstitial lung disease is provided separately. For patients with SLE, we typically review the laboratory tests supporting the diagnosis of SLE, assess the severity of respiratory impairment with pulmonary function tests, and determine the radiographic pattern of ILD with imaging studies. The history is reviewed carefully to exclude environmental causes of ILD (eg, hypersensitivity pneumonitis, pneumoconiosis) and drug toxicity (table 3). As heart failure and infection are in the differential diagnosis of ILD, other tests such as a brain natriuretic peptide (BNP), an echocardiogram, and bronchoalveolar lavage are often part of the evaluation. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)

●Laboratory testing – While serologic markers for SLE (eg, antinuclear antibody, anti-double stranded DNA) are helpful in confirming the diagnosis of SLE, none has shown a good correlation with development of ILD [3,54]. It is reasonable to assess other serologic markers, such as anti-extractable nuclear antigen antibodies, rheumatoid factor, antisynthetase antibodies, and creatine kinase to evaluate for overlap syndromes, if these have not been previously obtained. Tests that indicate greater disease activity, such as the C-reactive protein (CRP) or hypocomplementemia, are associated with SLE-ILD, but are not helpful diagnostically [47]. The laboratory tests used in the diagnosis of SLE and the evaluation of ILD in general are discussed separately. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Laboratory testing' and "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Laboratory tests'.)

As noted above, a plasma brain natriuretic peptide (BNP) or pro NT-BNP may be obtained to assess for heart failure and pulmonary hypertension.

●Pulmonary function tests – Pulmonary function tests (PFTs) are obtained to assess the pattern and severity of respiratory impairment. The most common PFT finding in SLE-ILD is a diminished diffusing capacity for carbon monoxide (DLCO); other findings may include a restrictive pattern (ie, reductions in forced vital capacity and total lung capacity) and oxygen desaturation during six-minute walk test (6MWT). A decrease in DLCO with normal lung volumes is consistent with early ILD, but may alternatively suggest pulmonary vascular disease. (See 'Pulmonary hypertension' below and "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Pulmonary function testing' and "Overview of pulmonary function testing in adults".)

●Imaging – Chest radiographs may reveal evidence of ILD, but high resolution computed tomography (HRCT) is the standard for determining the presence of ILD and defining pattern of ILD, which may correlate with a specific histopathologic diagnosis. We typically obtain both supine and prone HRCT images to distinguish dependent atelectasis from true parenchymal disease.

•A diffuse ground-glass appearance is most consistent with histopathologic findings of nonspecific pneumonia (NSIP) (image 1A-B and picture 1).

•Less commonly, a reticular pattern is associated with primarily fibrotic disease which, on lung biopsy, is most consistent with usual interstitial pneumonia (UIP), particularly when associated with honeycombing, or fibrotic NSIP (image 2A-B and picture 2).

•Patchy areas of air-space consolidation with or without air bronchograms or ground-glass opacities are more suggestive of organizing pneumonia [55]. (See "Cryptogenic organizing pneumonia", section on 'Computed tomographic (CT) scanning'.)

•Ground-glass attenuation, centrilobular nodules, and septal thickening are frequently seen in lymphocytic interstitial pneumonia, in addition to lung cysts of varying size (image 3).

●Bronchoalveolar lavage – Flexible bronchoscopy with bronchoalveolar lavage (BAL) can be useful to exclude infection, hemorrhage, and malignancy (eg, lymphoma). Assessment of specific BAL cell patterns does not appear to be helpful in SLE-ILD. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

●Echocardiogram – An echocardiogram may be obtained to assess for systolic or diastolic heart failure, or comorbid pulmonary hypertension as an alternate or additional explanation for dyspnea and HRCT abnormalities, depending of the degree of clinical suspicion and results of BNP/pro NT-BNP testing.

Diagnosis — The diagnosis of SLE-ILD is generally clinical, based on the presence of extrapulmonary and serologic evidence of SLE in combination with high resolution computed tomography confirming ILD and the exclusion of other potential causes (eg, infection, drug toxicity, heart failure), as described above. Rarely, lung biopsy is required if the diagnosis is still in doubt despite the less invasive tests described above [18]. The most common pathologic patterns of ILD in SLE include NSIP, organizing pneumonia, and lymphoid interstitial pneumonia (LIP); UIP is less common [48,56-58]. (See "Treatment and prognosis of nonspecific interstitial pneumonia" and "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Usual interstitial pneumonia' and "Lymphoid interstitial pneumonia" and "Cryptogenic organizing pneumonia" and "Overview of amyloidosis", section on 'Pulmonary disease'.)

Treatment — The optimal therapy for chronic SLE-ILD is not known due to the paucity of reported cases and absence of controlled trials of treatment.

Our approach is to assess the severity and rate of progression of ILD, the medication requirements for extrapulmonary SLE, and the type of idiopathic interstitial pneumonia (IIP) that is most similar clinically, radiographically, and histopathologically (if available) to the patient’s ILD. Putting all of these factors together, we determine whether the ILD needs treatment beyond what is needed for the patient’s SLE or whether ongoing observation is a reasonable alternative (eg, patients with mild or stable disease). For nonfibrotic ILDs, treatment is usually initiated in patients with evidence of worsening disease, such as a decline in FVC or DLCO of 10 percent or greater.

In general, patients with established fibrotic ILD (eg, usual interstitial pneumonia) are less likely to benefit from anti-inflammatory/immunosuppressive therapy. Those with a progressive fibrosing phenotype may benefit from antifibrotic therapy, if immunosuppressives fail to slow the disease. (See "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Future directions'.)

●Supportive care – As with the management of all types of lung disease, cigarette smoking cessation is strongly recommended. Supplemental oxygen is indicated in patients with resting or exercise-induced oxygen saturation <89 percent. Vaccinations against influenza and Streptococcus pneumoniae and SARS-CoV-2 are administered based on usual guidelines. (See "Long-term supplemental oxygen therapy" and "Seasonal influenza vaccination in adults" and "Pneumococcal vaccination in adults" and "COVID-19: Vaccines".)

●SLE-ILD – For the most common types of SLE-ILD (eg, NSIP, LIP), the usual initial agent is a systemic glucocorticoid, such as prednisone 0.5 to 1 mg/kg per day. In a case series, 14 patients with SLE-ILD were treated with prednisone 60 mg a day followed by gradual tapering [47]. Respiratory symptoms and diffusing capacity for carbon monoxide (DLCO) improved in the majority of patients, while forced vital capacity was unchanged. Eventually, three patients died, two of progressive lung fibrosis and one of bacterial pneumonia. In a separate series of 38 patients, there was no improvement in DLCO with glucocorticoid treatment [6]. The management of NSIP, LIP, and OP is discussed separately. (See "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Overview of treatment' and "Lymphoid interstitial pneumonia", section on 'LIP in rheumatic disease' and "Cryptogenic organizing pneumonia", section on 'Treatment'.)

Long-term systemic glucocorticoid therapy is associated with a number of adverse effects, such as infection, osteoporosis, and adrenal insufficiency, which are discussed separately; as a result, patients are often placed on a steroid-sparing agent. (See "Major adverse effects of systemic glucocorticoids" and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

Steroid sparing agents commonly used in other forms of connective tissue disease associated-ILD (eg, azathioprine, mycophenolate, rituximab) are typically administered, although data in SLE are limited [59-62]. Selection among these agents is based on degree of respiratory impairment, prior therapy, comorbidities, and patient preference. For patients with mild to moderate ILD, mycophenolate or azathioprine is a reasonable first choice; cyclophosphamide or rituximab might be preferred for more severe or rapidly progressive disease.

Dosing of azathioprine, mycophenolate, and rituximab are described separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)

●Flare of ILD – In patients with a flare of ILD that is progressive and severe (eg, characterized by hypoxemia and severe impairment on pulmonary function tests), therapy is initiated with high doses of glucocorticoids (eg, intravenous methylprednisolone 1 g daily for three days, or prednisone 1 to 2 mg/kg/day in less acute patients) and cyclophosphamide (usually intravenously) or rituximab with transition to either azathioprine or mycophenolate mofetil after 6 to 12 months. For those who have less severe disease or in whom cyclophosphamide is not well-tolerated, azathioprine or mycophenolate may be used as initial treatment [59]. (See "General principles of the use of cyclophosphamide in rheumatic diseases" and "Treatment and prognosis of nonspecific interstitial pneumonia".)

●Organizing pneumonia – When organizing pneumonia develops in a patient with SLE, oral prednisone (1 mg/kg per day for a month followed by gradual tapering) is effective over the short term, although the addition of another immunosuppressive agent is typically necessary, as prednisone is tapered. (See "Cryptogenic organizing pneumonia", section on 'Treatment'.)

●Fibrotic ILD – Usual interstitial pneumonia and fibrotic NSIP are fibrotic ILDs that may complicate SLE. No specific treatment has been established for fibrotic lung disease in SLE. However a clinical trial of the antifibrotic agent, nintedanib, in patients with various progressive fibrosing ILDs, including autoimmune disease-associated ILD, showed a reduction in the rate of decline of lung function [63,64]. Nintedanib has been approved for use in progressive fibrosing interstitial lung disease by the FDA. (See "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Future directions'.)

In addition, lung transplantation may be an option for carefully selected individuals with advanced fibrotic ILD [65,66]. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Lung transplantation'.)

THROMBOEMBOLIC DISEASE — Patients with SLE have an increased risk of venous thromboembolic disease based on healthcare database analyses [67,68]. Among hospitalized patients with SLE the risk of venous thromboembolism (VTE) is 1.23 (95% CI 1.15-1.32) compared with hospitalized patients without autoimmune disease [68]. SLE is associated with a number of risk factors for VTE, such as membranous nephropathy and the presence of antiphospholipid antibodies in some patients. The proportion of patients in the database studies who were affected by these comorbidities is not known [67,68]. The diagnosis and management of VTE and antiphospholipid syndrome (APS) and the risk for thrombosis in the nephrotic syndrome are discussed separately. (See "Epidemiology and pathogenesis of acute pulmonary embolism in adults" and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism" and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults" and "Diagnosis of antiphospholipid syndrome" and "Clinical manifestations of antiphospholipid syndrome", section on 'Pulmonary involvement' and "Management of antiphospholipid syndrome".)

PULMONARY HYPERTENSION — Among patients with SLE, pulmonary hypertension (PH) can be caused by pulmonary arterial hypertension (PAH, similar to idiopathic PAH), advanced interstitial lung disease (ILD) with hypoxemia, thromboembolic disease, pulmonary veno-occlusive disease (PVOD), and left ventricular dysfunction. The World Health Organization (WHO) has categorized the various causes of pulmonary hypertension into five groups based on the underlying cause (table 4). The classification of pulmonary hypertension is described separately. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Diagnosis'.)

Severe symptomatic PH is thought to be a rare complication of SLE [51], being more frequently associated with systemic sclerosis (SSc) or mixed connective tissue disease (MCTD) [69]. In a cross-sectional study of 283 patients with SLE, pulmonary hypertension was present in 12 (4 percent) based on Doppler echocardiography [70], and severe pulmonary hypertension (pulmonary systolic pressure by echocardiography >40 mmHg) was noted in about 1 percent. Based on case-control studies, pulmonary hypertension is most strongly associated with presence of interstitial lung disease, serositis (particularly pericardial effusion), active smoking, Raynaud phenomenon, and anti-RNP antibodies [71]. (See "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)".)

While lung biopsy is not indicated to make the diagnosis, the histopathology of SLE-induced pulmonary hypertension includes features common to PAH (plexiform angiomatous lesions and thickening of the muscular arterial wall, predominantly of the media) and immunoglobulin and complement deposition in the arterial wall consistent with inflammation due to SLE [72]. Vasculitis is rarely thought to play a pathogenic role. Cases of pulmonary vasculitis have, however, been reported [73,74].

Clinical manifestations — Symptomatic patients frequently complain of dyspnea, palpitations, fatigue, and impaired exercise tolerance, although early PH can be asymptomatic. Other symptoms that may occur include weakness, syncope, edema, and increased abdominal girth. Raynaud phenomenon is present in 60 percent [75].

Symptomatic patients may have physical findings of pulmonary hypertension (loud second heart sound) or cor pulmonale (eg, peripheral edema, ascites, hepatomegaly). These findings are described in more detail separately. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

Diagnostic evaluation — PH is suspected in a patient with exertional dyspnea, particularly when the chest radiograph does not show interstitial lung disease. The evaluation typically includes initial testing of plasma brain natriuretic peptide (BNP), pulmonary function tests, and an echocardiogram to assess the likelihood of PH. The diagnosis is based on the results of right heart catheterization (RHC).

●Pulmonary function tests – Pulmonary function tests (PFTs) are obtained to evaluate dyspnea and include spirometry, lung volumes, carbon monoxide diffusing capacity (DLCO), a six-minute walk distance (6MWD), and assessment of pulse oxygen saturation (oximetry) during exertion.

The characteristic pattern of PFTs in PAH is normal spirometry and lung volumes, with a reduced DLCO. The 6MWD is reduced, and oxygen desaturation ≥5 mmHg is common, often with an exaggerated heart rate response. In contrast, when PH is due to advanced ILD, lung volumes will show restriction and chest imaging will show ILD.

●Echocardiogram – Two-dimensional transthoracic and Doppler echocardiography provides a noninvasive estimate of pulmonary artery pressures as well as right atrial and right ventricular size and function. In addition, the transthoracic echocardiogram can assess systolic or diastolic left ventricular dysfunction and pericardial effusion as potential causes of elevated pulmonary artery pressures other than pulmonary hypertension [76]. A Doppler estimate of a pulmonary artery systolic pressure greater (ePASP) than 35 or tricuspid regurgitant velocity (TRV) of >2.8 m/s is suggestive of PH. However, the sensitivity and specificity of Doppler echocardiography are imperfect and right heart catheterization is needed to confirm the diagnosis.

●Right heart catheterization – Confirmation of the diagnosis of pulmonary hypertension is based on RHC showing a mean pulmonary artery pressure (mPAP) of ≥20 mmHg at rest with a mean pulmonary capillary wedge pressure <15 mmHg (to exclude occult left ventricular dysfunction). Clinically significant pulmonary hypertension may occasionally be missed by echocardiography alone, so RHC may be necessary when clinical suspicion is high despite a negative echocardiogram. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)

Differential diagnosis — Pulmonary hypertension in a patient with a well-established diagnosis of SLE is likely to be due to SLE itself. However, it is appropriate to consider other causes of secondary pulmonary hypertension, including the following:

●Recurrent thromboemboli – Recurrent thromboemboli may cause pulmonary hypertension (chronic thromboembolic pulmonary hypertension [CTEPH]), and the risk of this complication in patients with SLE is increased among those with antiphospholipid antibodies (aPLs). The principal aPLs measured for clinical use are the anticardiolipin antibodies (aCL), anti-beta2-glycoprotein (GP) I, and the lupus anticoagulant (LA). If CTEPH is suspected as the cause of elevated pulmonary artery pressures, a ventilation-perfusion lung scan can be used to differentiate PAH from CTEPH: patients with CTEPH have at least one (usually several) segmental or larger mismatched ventilation-perfusion defects, while patients with group 1 pulmonary arterial hypertension usually have a normal or mottled perfusion scan characterized by subsegmental defects. (See "Clinical manifestations of antiphospholipid syndrome" and "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension", section on 'Clinical features'.)

●Mixed connective tissue disease (MCTD) – Patients with MCTD, an overlap syndrome with features of SLE, systemic sclerosis, and polymyositis that is associated with antibodies to ribonucleoprotein (ie, anti-RNP or anti-U1-RNP), are more likely to develop PAH than patients with classic SLE. (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes" and "Mixed connective tissue disease", section on 'Diagnosis'.)

●Pulmonary veno-occlusive disease (PVOD) is a rare cause for pulmonary hypertension in SLE and other rheumatic diseases. Pathologically, it is characterized by intimal fibrosis that leads to occlusion of the pulmonary veins and edema in the interlobular septa. High resolution computed tomography (HRCT) shows thickened interlobular septa, lymph node enlargement, and ground glass opacities. It may be difficult to distinguish PVOD from pulmonary arterial hypertension, but the distinction is important as vasodilator therapy may result in pulmonary edema in patients with PVOD [77]. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults".)

●Disordered breathing during sleep (eg, sleep apnea) – Symptoms of sleep apnea include snoring and daytime sleepiness. Polysomnography (sleep study) is necessary to formally assess for this potential cause of pulmonary hypertension. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)

●Infection with human immunodeficiency virus (HIV) – There is a high prevalence of autoantibodies, including antinuclear antibodies (ANA), in patients infected with HIV (see "Measurement and clinical significance of antinuclear antibodies"). There is also an uncommon, but well-recognized, association between HIV infection and pulmonary hypertension. If risk factors for HIV infection are present, testing for HIV antibody should help exclude concomitant infection or misdiagnosis of SLE due to an HIV-associated ANA. (See "Cardiac and vascular disease in patients with HIV", section on 'Pulmonary hypertension'.)

Treatment — For patients with SLE-associated PAH, referral to a center with expertise in the evaluation and management is appropriate. The management of patients with SLE-associated PAH that is not due to pulmonary embolic disease is similar to that of idiopathic PAH [69]. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

General measures — General supportive measures for patients with PH include oxygen, exercise, diuretics, and sometimes anticoagulation. Supplemental oxygen is given as needed based on oximetry results. Pulmonary rehabilitation and exercise programs may be of benefit although not specifically assessed in this population. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

Anticoagulation has fallen out of favor for PAH due to conflicting data, and we suggest that anticoagulant therapy be administered on a case-by-case basis according to the clinician's assessment of the risks and benefits. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

Approach to advanced therapy — For patients who have SLE-associated PAH (confirmed by RHC) and are in WHO functional class II, III, or IV, referral to a center that specializes in treatment of PH is advised. As an initial step in the management of those patients in functional classes II and III, a vasoreactivity test is used to decide whether to initiate a three to six month trial of a calcium channel blocker (dihydropyridine or diltiazem). If the vasoreactivity test is negative or the patient does not respond to the calcium channel blocker, the next step is usually to select one of the alternate agents described below, based on assessment of the individual’s functional severity of disease and rate of progression. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Nonvasoreactive patients'.)

For patients in class II and III with SLE-associated PAH who are drug-naïve, many experts initiate therapy with a combination of oral agents that target the endothelin and nitric oxide-cyclic guanosine monophosphate (cGMP) pathways. The combination of ambrisentan and tadalafil is preferred because it is associated with a significant reduction in the rate of clinical failure compared to monotherapy with either drug alone [78]. For those who have a contraindication to either agent, substitution with another oral agent in the same class is preferred, although such combinations are less well proven. Alternatively, single agent therapy can be tried. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Nonvasoreactive patients'.)

The management of patients with PH due to ILD (group 3) is described separately. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis", section on 'Our approach'.)

Patients with severe PAH (WHO functional class IV) should be treated with a parenteral prostanoid, as described separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'WHO functional class IV or high risk (parenteral prostanoid-containing combination regimen)'.)

●Combination therapy – The therapy with the best evidence for benefit in PAH (class II and III) in general is the combination of ambrisentan (an endothelin-1 antagonist) plus tadalafil (a phosphodiesterase-5 inhibitor), and the benefit appears to extend to those with CTD-associated PAH. In a post hoc analysis of 187 patients with CTD-PAH (functional class II/III) who participated in the AMBITION trial [79], initial combination therapy with ambrisentan plus tadalafil reduced the risk of clinical failure compared with the pooled results of monotherapy with the individual agents (HR 0.43, 95% CI 0.24- 0.77) [78]. While the majority of patients in the analysis had systemic sclerosis, 17 had SLE.

In the AMBITION trial, ambrisentan was given at an initial dose of 5 mg/day for the first eight weeks, then increased to 10 mg/day; tadalafil was started at 20 mg/day for the first four weeks, then increased to 40 mg/day.

●Endothelin antagonists – The endothelin receptor antagonists used for PAH include the nonselective agents, bosentan and macitentan, and the selective agent ambrisentan. Given the benefits of combination therapy of ambrisentan and the phosphodiesterase-5 (PDE5) inhibitor tadalafil (described above), monotherapy with the individual endothelin antagonists is used less often and is described separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

●Phosphodiesterase-5 inhibition – Sildenafil, tadalafil, and vardenafil are orally administered PDE5 inhibitors that prolong the vasodilatory effect of nitric oxide. A study examining the effect of oral sildenafil in 19 patients with SLE-associated PAH found that sildenafil-treated patients had a mean increase in 6MWD of 42 meters compared with a decrease of 13 meters for placebo after 12 weeks of treatment [80]. Tadalafil has been used in combination with ambrisentan, as described above.

●Prostacyclin pathway agonists – Prostacyclin pathway agonists used to treat PAH include intravenous prostacyclin (epoprostenol), treprostinil (inhaled, subcutaneous, or intravenous), inhaled iloprost, and oral selexipag. In general, the parenteral agents are reserved for patients who have more severe disease or have failed other therapies. These agents are described in greater detail separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Evidence for benefit in patients with SLE-associated PAH comes from a randomized trial of 25 patients with SLE-associated PAH in which subcutaneous treprostinil improved exercise capacity, dyspnea fatigue, and hemodynamics [81]. In a case series of six patients with SLE on intravenous epoprostenol, patients showed improvement in functional class as well as hemodynamics [82].

Selexipag is an oral nonprostanoid prostacyclin receptor (IP receptor) agonist that results in vasodilation of the pulmonary vascular bed and may benefit patients with PAH who are WHO functional class II and III. An analysis of the GRIPHON study [83], which included 334 patients with connective tissue disease (CTD)-associated PAH (82 with SLE-PAH), found that selexipag (200 to 1600 mcg, twice daily) reduced the risk of composite morbidity/mortality events in CTD-PAH by 41 percent (HR 0.59, 95% CI 0.41-0.85) [84].

●Immunosuppressive therapy for selected patients – Immunosuppressive therapy may be of benefit in rare patients with concomitant PH and interstitial lung disease (ILD) or pulmonary vasculitis, although data are limited.

•One study randomly assigned 34 patients with SLE and moderate pulmonary hypertension to receive either intravenous cyclophosphamide (0.5 g/m² per month) or oral enalapril (10 mg per day) for six months [85]. Pulmonary systolic pressures fell in both groups (from a median of 41 to 28 mmHg and from 35 to 27 mmHg, respectively).

•A small retrospective study of 23 patients with PAH (13 SLE and 10 MCTD) showed 50 percent response to immunosuppressives alone and 58 percent response to immunosuppressives and PAH specific therapy [86].

•A single case report of successful treatment of pulmonary hypertension with rituximab in a woman with SLE has been published [87]. However, more data are needed before any recommendation can be made regarding its use for SLE-associated PAH.

Prognosis — The presence of pulmonary hypertension appears to increase mortality in patients with SLE. In a small study, PAH was associated with an increased mortality hazard ratio of 31 compared with patients with SLE without pulmonary hypertension [88].

SHRINKING LUNG SYNDROME — The shrinking lung syndrome (SLS) has been noted in approximately 1 to 6 percent of patients with SLE [89,90]. This syndrome is characterized by dyspnea, episodes of pleuritic chest pain (65 percent), a progressive decrease in lung volumes on pulmonary function tests (PFTs), and no evidence of interstitial disease or significant pleural disease on chest computed tomography (CT) [91-94]. In most patients, the onset of SLS is approximately four years after the initial diagnosis of SLE [95].

Conflicting results have been found concerning the underlying pathogenesis of this disorder. One possible mechanism is a myositis or myopathy affecting both diaphragms, resulting in elevation of the diaphragms and decreased function [96,97]. However, other reports have documented normal diaphragmatic muscle strength in patients with SLS [92,98]. Another hypothesis about the basis of shrinking lung syndrome has proposed that chronic pleural inflammation may impair deep inspiration and subsequently lead to parenchymal reorganization that impairs lung compliance [99].

In addition to the above noted decrease in lung volumes on PFTs, the diffusing capacity for carbon monoxide (DLCO) is often reduced. The etiology of the reduction in DLCO is not known, although it may be due to inability to perform a maximal inhalation or due to atelectasis.

While formal diagnostic criteria have not been established, SLS should be suspected in individuals with the combination of dyspnea, restrictive lung physiology on PFTs (ie, forced vital capacity [FVC] <80 percent predicted but normal ratio of forced expiratory volume in one second [FEV₁]/FVC), and no evidence of interstitial lung disease on imaging studies [100]. Differentiation from other causes of diaphragmatic weakness or paralysis is discussed separately. (See "Diagnostic evaluation of adults with bilateral diaphragm paralysis".).

The optimal therapy for SLS is not known. Glucocorticoids and immunosuppressive therapy (eg, cyclophosphamide, mycophenolate, azathioprine, rituximab) may improve both symptoms and pulmonary function [91,94,95,101-105]. Improvement in SLS has also been reported following hematopoietic cell transplantation, suggesting that disease control is important in the management of SLS [90].

Theophylline and beta-adrenergic agonists have been used in hopes of improving diaphragmatic strength, but without clear evidence of benefit [91,94,106,107].

OTHER DISORDERS — Other pulmonary manifestations of SLE include community acquired and opportunistic lung infection, and antiphospholipid syndrome (APS).

Lung infection — Patients with SLE are at increased risk for a variety of bacterial (encapsulated organisms) and opportunistic lung infections due to defects in innate immunity (eg, low complement, lymphopenia) and treatment with immunosuppressive therapy [25,108-110]. Infections such as cytomegalovirus and disseminated herpes simplex can mimic a SLE flare [111]. Bacterial and viral pneumonia and opportunistic infections, such as Pneumocystis jirovecii, Candida, Cryptococcus, and Aspergillus, are in the differential diagnosis of acute lupus pneumonitis and diffuse alveolar hemorrhage [108,112-114]. The evaluation of potential lung infection in immunocompromised hosts is discussed separately. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)

Chest wall pain — In our experience, although pleuritis is an important cause of chest pain in patients with SLE, pain from muscles, connective tissues, or the costochondral joints (costochondritis or Tietze’s syndrome) is also common. This chest pain is characterized by painful deep breaths, aggravated by motion or by change of position (especially during sleep), and elicited by palpation of the painful areas. The patient can be reassured that this specific pain does not represent lung involvement.

Chest wall pain generally responds to local heat, nonsteroidal anti-inflammatory drugs (NSAIDs), topical analgesics, and acetaminophen. (See "Major causes of musculoskeletal chest pain in adults" and "Management of isolated musculoskeletal chest pain" and "Overview of soft tissue musculoskeletal disorders", section on 'Myofascial pain syndrome'.)

Large airway involvement — Subglottic or tracheal stenosis has rarely been reported in patients with SLE [115]. Histopathologically, this condition results from granulomatous inflammation of the airway walls, which more commonly occurs in sarcoidosis and granulomatous polyangiitis but can also be seen in SLE. Vasculitic features are variably present. Another rheumatic etiology of tracheal stenosis is relapsing polychondritis (RP), which often manifests with concomitant inflammation of the ear or nose. Management of SLE-associated subglottic or tracheal stenosis primarily involves treatment of the underlying lupus but may also include local bronchoscopic dilation and thermal treatments. (See "Management of non-life-threatening, nonmalignant subglottic and tracheal stenosis in adults", section on 'Inflammatory/systemic etiologies' and "Overview of the management and prognosis of systemic lupus erythematosus in adults".)

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: Systemic lupus erythematosus".)

SUMMARY AND RECOMMENDATIONS

●Most patients with SLE develop involvement of the lung, its vasculature, the pleura, and/or the diaphragm at some time during their course. Pleurisy, coughing, and/or dyspnea are often the first clues either to lung involvement or to SLE itself. Patients with SLE and lung involvement must always be evaluated for infection. (See 'Introduction' above.)

●Pleural inflammation can cause pleuritic chest pain with or without radiographic evidence of a pleural effusion. Pleural disease in SLE often responds to therapy with NSAIDs; those who do not respond to NSAIDs within a few days may require a short course of glucocorticoids. Chest wall pain is also a common cause of pleuritic-type pain in SLE and derives from inflammation of muscles, connective tissues, or the costochondral joints; such chest wall pain generally responds to local heat, nonsteroidal anti-inflammatory drugs (NSAIDs), topical analgesics, and acetaminophen. (See 'Pleural disease' above and 'Chest wall pain' above.)

●Acute lupus pneumonitis is uncommon and characterized by the rapid onset of fever, cough (sometimes with hemoptysis), dyspnea, pulmonary opacities on radiograph, hypoxemia, and basilar crackles. Serum antinuclear and anti-DNA antibodies are commonly present. (See 'Acute pneumonitis' above.)

•The diagnosis of acute lupus pneumonitis is based on the clinical and serologic evidence of SLE and the exclusion of heart failure, infection, organizing pneumonia, pulmonary embolism, drug toxicity, diffuse alveolar hemorrhage, and malignancy. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)

•For patients who are able to undergo flexible bronchoscopy, bronchoalveolar lavage can help to exclude alternative diagnoses.

•While data from clinical trials are not available to guide treatment, better survival appears to be associated with prompt initiation of systemic glucocorticoids. Additional immunosuppression may be required depending on comorbidities and response to therapy. Empiric antibiotics should be given pending culture results. (See 'Treatment' above.)

●Pulmonary hemorrhage is a rare, life-threatening complication in SLE.

•Affected patients appear acutely ill and commonly complain of dyspnea, cough and hemoptysis. The bleeding may be sufficient to induce anemia; lupus nephritis may also be present. Bilateral diffuse or patchy opacities are typical on chest radiographs and CT.

•The evaluation of patients with suspected DAH should be pursued expeditiously due to the life-threatening nature of the disorder (table 2). Flexible bronchoscopy with sequential bronchoalveolar lavage (BAL) samples is the preferred diagnostic modality to confirm the diagnosis and exclude alternate diagnoses (eg, infection). A progressively more hemorrhagic BAL effluent supports the diagnosis. Sometimes, a definitive diagnosis can be made only by lung biopsy.

•Treatment is initiated promptly with high-dose glucocorticoids in combination with additional immunosuppressive agent(s) (eg, cyclophosphamide, rituximab, or mycophenolate mofetil). Data are limited regarding the roles of therapeutic apheresis (plasma exchange) and intravenous immune globulin (IVIG). (See 'Pulmonary hemorrhage' above.)

●Interstitial lung disease (ILD) in patients with SLE typically has an insidious onset of chronic nonproductive cough, dyspnea, and decreased exercise tolerance. PFTs typically reveal a restrictive pattern (eg, reduced total lung capacity and forced vital capacity), diminished diffusing capacity for carbon monoxide (DLCO), and oxygen desaturation with activity.

•High-resolution computed tomography (HRCT) scanning is the standard for determining the presence of ILD and defining its radiographic pattern, which often correlates with a specific histopathologic diagnosis. BAL may be used to exclude infection and eosinophilia (may suggest drug toxicity). Lung biopsy may be required if the diagnosis is still in doubt despite imaging and BAL.

•Treatment of inflammatory disease (eg, nonspecific interstitial pneumonia, lymphocytic interstitial pneumonia, organizing pneumonia) requires the use of a glucocorticoid, with an additional immunomodulating agent. Fibrotic disease (eg, usual interstitial pneumonia) is less likely to benefit from such therapy, but may be slowed by antifibrotic agents. (See 'Interstitial lung disease' above.)

●Pulmonary hypertension (PH) is a rare complication of SLE and usually presents with dyspnea, palpitations, fatigue, and impaired exercise tolerance. The diagnosis and management of patients with PH due to SLE that is not due to pulmonary thromboembolic disease is similar to that of idiopathic pulmonary arterial hypertension (PAH). (See 'Pulmonary hypertension' above and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

●The shrinking lung syndrome (SLS) is noted in less than 10 percent of patients with SLE. SLS is characterized by dyspnea, episodes of pleuritic chest pain, a progressive decrease in lung volume, and no evidence of interstitial fibrosis or significant pleural disease on chest CT. It is unclear whether SLS is due to myopathy or pleuritis, but systemic glucocorticoids and immunosuppressive therapy have been beneficial in case reports. (See 'Shrinking lung syndrome' above.)

●Other pulmonary disorders associated with SLE include thromboembolic disease, the antiphospholipid syndrome (APS), and infection. (See 'Thromboembolic disease' above and 'Lung infection' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter Schur, MD, who contributed to earlier versions of this topic review.