Systemic Lupus Erythematosus and the Vasculitides

Systemic Lupus Erythematosus

Key Concepts

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that can affect any organ system. A general approach to determine whether SLE is the cause of a nonspecific or single-organ symptom is to search for evidence of other organ involvement or systemic inflammation, which is expected in SLE-mediated presentations.
Patients with SLE are at significantly higher risk of coronary artery or thromboembolic disease, which should prompt more thorough evaluation for these etiologies even in otherwise low-risk patients, such as young women.
SLE itself, as well as its treatment, may lead to immunosuppression; thus, it is important to remain vigilant for the possibility of infection in patients with SLE.
Glucocorticoids are the mainstay for the initial management of the majority of conditions that are associated with increased SLE disease activity, including musculoskeletal, cutaneous, renal, pleural, or pericardial disease.
Antiphospholipid antibody syndrome (APS) is common in patients with SLE and carries with it an increased risk of venous and arterial thromboembolic disease.
Rheumatology input may be helpful in diagnostic, management, or disposition decisions for select patients with SLE.

Foundations

Background and Importance

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder with complex pathophysiology that can affect nearly any organ system in the body. The prevalence of SLE varies by age, gender, geography, and race. Women are the most commonly affected group worldwide, representing approximately 90% of cases. The disease is more common in young people with more than two-thirds of cases diagnosed before the age of 50. In the United States, the prevalence of SLE is higher in African, Asian, and Hispanic Americans compared to Caucasians.

Patients with SLE have an increased risk of mortality (2.6-fold) as compared to the general population. Morbidity and mortality for patients with SLE derive from four processes: (1) organ damage secondary to disease-mediated inflammation (e.g., nephritis, cerebritis, coronary artery disease), (2) hypercoagulability (e.g., stroke, pulmonary embolism), (3) complications of treatment (e.g., infection related to immunosuppression), and (4) increased risk of cardiovascular events. Care for the patient with SLE in the emergency department (ED) hinges on the recognition and treatment of these processes.

Etiology and Pathophysiology

The etiology of SLE is complex and incompletely understood. It appears to be related to multiple factors; genetics, hormones, and environmental factors such as smoking have all been implicated to varying degrees. With women representing 90% of SLE cases, a strong role for estrogen in disease development has been well supported in large cohort studies. The disease also has a strong genetic link, with high rates of monozygotic twin concordance.

The pathophysiology of SLE is mediated by the creation of autoantibodies with a multitude of downstream impacts. These effects include the formation and deposition of immune complexes leading to inflammation and tissue destruction (largely via complement activation) as well as autoantibodies directly targeting cell surface antigens and phospholipids, which may lead to tissue cell death, hemolysis, and hypercoagulability. The pathophysiologic mechanism of SLE may differ for each organ system. The organ systems involved in any given patient’s disease may be different and relate to antigen expression in those tissues, among other factors.

Clinical Features

Overview

SLE activity follows a relapsing and remitting pattern: acute episodes of increased disease activity (“flares”) are separated by periods of stable disease or relative quiescence. The frequency and severity of flares can vary significantly between patients and over time, as can the baseline level of disease activity. While SLE is a chronic condition, it is not necessarily progressive. Whether additional organs become involved and the degree to which previously involved organs are affected is variable.

Recognition of SLE-mediated morbidity can be challenging, as SLE can affect nearly any organ system in the body, and many symptoms of the disease lack specificity. In general, ED presentations for SLE are related to one or more of the following: (1) flares of increased SLE disease activity (e.g., nephritis, arthritis), (2) SLE-mediated hypercoagulability (e.g., stroke, pulmonary embolism), and (3) complications of treatment for SLE (e.g., opportunistic infection due to immunosuppression).

Even with good medication adherence, patients with SLE are prone to flares. SLE flares are typified by worsening physical symptoms from increased organ inflammation and destruction. Flares commonly involve organ systems previously affected by SLE, though new organ systems may also become affected. As a systemic disease, worsening symptoms in one organ system are often associated with evidence of systemic inflammation and, commonly, evidence of disease activity in other organs.

As a general approach, when evaluating whether a symptom is due to SLE, providers should look for other SLE manifestations and biomarkers that can point to active disease, such as those in the Systemic Lupus International Collaborating Clinics (SLICC) Criteria for Systemic Lupus Erythematosus ( Table 105.1 ). Single-organ symptoms without systemic inflammation should prompt consideration of pathology other than SLE. It is important to identify when overall disease activity is increased as this signals the need to initiate or escalate systemic therapy. In many cases, patients themselves are able to provide direction about the predictable course of their exacerbations and can be helpful in decision-making for therapy and disposition.

TABLE 105.1

Systemic Lupus International Collaborating Clinics Criteria for Systemic Lupus Erythematosus ^a

Criteria	Description
Clinical Criteria
Acute cutaneous lupus	May include acute cutaneous lupus (lupus malar rash, bullous lupus, toxic epidermal necrolysis variant of SLE, maculopapular lupus rash, photosensitive lupus rash) or subacute cutaneous lupus
Chronic cutaneous lupus	Classic discoid rash, generalized hypertrophic (verrucous) lupus, lupus panniculitis, mucosal lupus, others
Oral ulcers	Palate (buccal, tongue) or nasal ulcers
Non-scarring alopecia	Diffuse thinning or hair fragility
Synovitis	Involving two or more joints (swelling, effusion, or tenderness and ≥30 minutes of morning stiffness)
Serositis	Pleural (pleuritis, effusion, rub) or pericardial (pericarditis, effusion, rub)
Renal disorder	500 mg protein/24 h or red blood cell casts
Neurologic disorder	Seizures, psychosis, mononeuritis multiplex, myelitis, peripheral and cranial neuropathies, acute confusional state
Hemolytic anemia
Leukopenia	<4000/mm ³ at least once
Thrombocytopenia	<100,000/mm ³ at least once
Immunological Criteria
Anti-nuclear antibody	Any level above the laboratory reference range
Anti-dsDNA	Level above the laboratory reference range (or twofold the reference range if tested by ELISA)
Anti-Sm	Presence of antibody to Sm nuclear antigen
aPL antibody	As determined by a positive test for lupus anticoagulant or anti-2-glycoprotein, false-positive result for rapid plasma regain, medium- or high-titer anticardiolipin antibody level
Low complement	May include C3, C4, or CH50
Direct Coombs test	In the absence of hemolytic anemia

aPL, Antiphospholipid; ds, double-stranded; ELISA, enzyme-linked immunosorbent assay; SLE, systemic lupus erythematosus; Sm, Smith.

a Fulfillment of at least four criteria, with at least one clinical and one laboratory criterion, is required to establish the diagnosis of systemic lupus erythematosus.

Specific Symptoms

Fever

Fever in a patient with SLE can be related to systemic disease activity, infection (including opportunistic infection related to immunosuppression), or pathology unrelated to SLE. Recurrent fevers without evidence of infection may be the presenting symptom that leads to an initial diagnosis of SLE. Similarly, patients with diagnosed SLE may present with fever as a symptom attributable to a disease flare. Before attributing fever to SLE disease activity, however, care should be taken to exclude acute infection. This is particularly important for patients taking immunosuppressive medications. Most infections in SLE are caused by typical organisms. However, largely because of the immunomodulating therapies that are the cornerstone of SLE management, opportunistic diseases are possible; Pneumocystis (carinii) jiroveci pneumonia, cryptococcal meningitis, Listeria infection, and herpes zoster have all been described.

Cardiopulmonary Presentations

There is a broad range of cardiac and pulmonary pathology associated with SLE that may present with chest pain or shortness of breath. Given the lengthy differential for this spectrum of presentations and the significant degree of overlapping symptoms for the varied underlying disease processes, an anatomic approach may be useful when working through the differential.

Coronary Artery Disease

As with other systemic inflammatory conditions, there is a significantly increased risk of coronary artery disease (CAD) in patients with SLE. While SLE is associated with higher incidences of traditional risk factors such as hypertension and hypercholesterolemia, the increased risk of CAD persists even after controlling for these factors. Thus, whereas there are many considerations for the cause of chest pain in patients with SLE, acute coronary syndromes (ACS) should be considered highly in these cases, including in patients who would otherwise be deemed low risk (e.g., young women). Coronary disease should also be considered in patients with SLE presenting with atypical symptoms of ACS, such as shortness of breath, epigastric pain, or fatigue.

Pericardial and Myocardial Disease

Pericarditis and effusions of the pericardium occur commonly in patients with SLE and are among the classification criteria for the disease (see Table 105.1 ). An estimated 25% of patients with SLE will experience symptomatic pericarditis during the course of their lives, and pericardial effusion (often asymptomatic) occurs even more frequently. In patients with pericarditis, dyspnea and chest pain that is sharp, pleuritic, and positional (improved with leaning forward) are classic features of the disease. Auscultation may reveal a friction rub. Electrocardiography may reveal classic findings of diffuse ST elevation and PR depression ( Fig. 105.1 ); however, patients with pericarditis may also have normal or nonspecific ECG findings. Given the increased risk of CAD in patients with SLE, obtaining cardiac biomarkers in patients with ST elevation that would otherwise be diagnosed as pericarditis is generally encouraged. If there is diagnostic uncertainty as to whether ST elevation is related to pericarditis or an ST elevation myocardial infarction (STEMI), urgent cardiology consultation for consideration of cardiac catheterization is warranted. There are no specific signs of pericarditis on echocardiography. Visualization of pericardial effusion is supportive of the diagnosis of pericarditis; however, this finding may also be present in patients with SLE that do not have symptomatic pericarditis. Echocardiography is also useful to assess for associated cardiac tamponade, which is a rare but life-threatening complication of SLE. The presentation and diagnosis of cardiac tamponade are the same for patients with SLE as the general population. SLE myocarditis may present with chest discomfort and symptoms of heart failure, though acute symptomatic presentations are rare.

Fig. 105.1, Electrocardiogram of a 38-year-old woman with systemic lupus erythematosus (SLE) who presented to the emergency department (ED) with seizures and had chest pain while in the ED. Note diffuse ST elevation (with the absence of any reciprocal changes) and PR depression (particularly evident in lead II). Q waves anteriorly are related to prior myocardial infarct.

Valvular Disease

SLE is associated with a type of noninfectious endocarditis known as Libman-Sacks endocarditis ( Fig. 105.2 ). Mitral valve disease is most common, though other valves may also be affected. While the lesions formed on heart valves in this condition are more often associated with embolization than valvular dysfunction, some patients may develop valvular insufficiency that may present with shortness of breath, fatigue, or, in rare severe cases, pulmonary edema.

Fig. 105.2, Noninfectious endocarditis, known as a Libman-Sacks lesion, in a 56-year-old woman with systemic lupus erythematosus (SLE), a heart murmur, and dyspnea on exertion. (A) A parasternal long-axis view of the heart; a vegetation (Veg) is identified (arrow) on the mitral valve. (B) When color flow is superimposed on the valve, moderate to severe mitral regurgitation can be seen as a color jet entering the left atrium during systole. LA, Left atrium; LV, left ventricle.

Pulmonary Vascular Disease

Due to disease-associated hypercoagulability, deep venous thrombosis (DVT) and pulmonary embolism (PE) are more frequent in patients with SLE when compared to the general population. The degree of hypercoagulability in patients with concomitant antiphospholipid syndrome (APS) is even higher. Outside of the context of increased thromboembolic risk lowering the threshold for further testing, the evaluation for thrombosis and embolism in a patient with SLE does not differ from that of patients in the general population.

Though uncommon, patients with SLE may also develop pulmonary hypertension, which can present with shortness of breath, chest discomfort, and fatigue. Evaluation, in this case, may reveal a history of pathology known to lead to pulmonary hypertension (e.g., chronic thromboembolism, interstitial lung disease), physical exam findings of right heart failure, or evidence of right ventricular hypertrophy on electrocardiography or echocardiography. A definitive diagnosis is made via right heart catheterization.

Pleural Disease

Pleuritis is the most common respiratory condition occurring in SLE. Characterized by pleuritic chest pain with or without a pleural effusion or pleural rub, it has symptoms that overlap with those of other more serious conditions. A diagnosis of pleuritis should be arrived at only after other causes of pleuritic chest pain (e.g., PE) have been excluded.

Parenchymal Disease

Diseases of the lung parenchyma associated with SLE include infectious pneumonia, acute and chronic pneumonitis, interstitial lung disease, and, rarely, diffuse alveolar hemorrhage (DAH). The symptoms associated with infectious pneumonia, pneumonitis, and DAH have significant overlap; each of these entities may present with fever, cough, shortness of breath, and hemoptysis, and chest radiography may reveal nonspecific opacifications. Differentiating between these entities is difficult in the ED setting and may require further evaluation with bronchoscopy for bronchoalveolar lavage.

Mechanical Respiratory Disease

Shrinking lung syndrome is a rare condition associated with SLE that is characterized by symptoms of shortness of breath and pleurisy with low lung volumes and a restrictive pattern on pulmonary function testing. Patients may also have the elevation of one or both hemidiaphragms and pleural effusions. The etiology of this syndrome is unclear but appears to involve some degree of restriction of chest wall expansion with or without diaphragmatic dysfunction.

Renal Disease

Renal disease is a common complication of SLE occurring in approximately one-half of patients. ^, Renal disease related to SLE may cause a nephrotic-type disease, primarily characterized by significant proteinuria or nephritic disease with hematuria and increased creatinine concentration. Diagnosis based on clinical criteria alone is not possible as many patients with renal impairment are asymptomatic. Patients that do have symptoms may report hematuria, foamy urine, generalized edema, or an elevated blood pressure from baseline. Given the high prevalence and morbidity of renal disease and its tendency to carry few if any symptoms, a screening urinalysis and basic metabolic panel are prudent in all but the most straightforward presentations concerning SLE-mediated disease. Renal biopsy is indicated for all patients with new-onset lupus nephritis and can be considered in those with relapsing or refractory disease.

Gastrointestinal Presentations

The most common gastrointestinal (GI) manifestation of SLE is oral ulceration. Esophageal dysmotility and reflux are also more common in patients with SLE and may present with dysphagia or pain in the epigastric region or chest. In patients with SLE, most causes of abdominal symptoms (e.g., pain, nausea, diarrhea, constipation) are the same as in the general population. Accordingly, the ED evaluation should be largely similar for each of the two groups. Special considerations for patients with SLE, however, include an increased risk of pancreatitis due to medications, mesenteric vasculitis (also known as lupus enteritis), peritonitis due to serositis, or the side effects of medications including chronic NSAIDs (e.g., peptic ulcer disease), glucocorticoids (e.g., peptic ulcer disease, perforation, infection), or immunosuppressive agents (infection).

Patients taking glucocorticoids or other immunosuppressive medications may also have masking of traditional symptoms, so a lower threshold for further testing (e.g., computed tomography [CT] imaging) should be used for this population.

Dermatologic Presentations

The most characteristic cutaneous manifestation of SLE is the malar rash. The rash has a “butterfly” distribution of raised erythema over the bridge of the nose and malar eminences while sparing the chin, forehead, and nasal-labial folds ( Fig. 105.3 ). This sparing of the nasal-labial folds can help distinguish the classic malar rash from mimics such as rosacea or seborrheic dermatitis. Other common skin findings in patients with SLE include discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE). Each of these skin findings can present years before systemic manifestations of SLE occur, and while the characteristic malar rash is highly specific for SLE, DLE and SCLE more commonly present in isolation, without progression to SLE. DLE lesions are circular and raised, scaly lesions that may be commonly found on the face, scalp, and ears, often in association with pigment change, alopecia, and scarring ( Fig. 105.4 ). SCLE lesions are annular with an erythematous border, scaling, and central clearing. At times, these areas may coalesce to form more complex linear patterns of erythema. These lesions can be triggered by sunlight and are most commonly found in sun-exposed areas of the upper extremities, torso, and neck. The face is not usually affected by SCLE.

Fig. 105.3, The Malar or Butterfly Rash Is the Hallmark of Systemic Lupus Erythematosus (SLE).

Fig. 105.4, Right Ear of a Patient Suffering From Chronic Discoid Lupus.

Musculoskeletal Presentations

Arthritis commonly afflicts those with SLE, and increasing severity of joint pain may be a marker of increasing disease activity or an SLE flare. Arthritis or arthralgias are typically symmetrical and nonerosive (unlike rheumatoid arthritis, which is erosive) and always involve multiple joints. Arthritis most commonly presents in the hands (metacarpophalangeal and proximal interphalangeal joints), wrists, feet, and knees but may be manifested in any joint. While swelling may be present, often, the joint pain of lupus presents with arthralgia alone. Uncommonly, septic arthritis may complicate SLE. An isolated swollen joint is not typical of SLE and should prompt consideration for infectious arthritis. If septic arthritis is suspected, diagnostic arthrocentesis is recommended.

Myalgias are common in SLE and may be an early marker of increasing disease activity for some patients. It should be kept in mind that fibromyalgia may also coexist with SLE and chronic myalgia not associated with other disease activity or elevated inflammatory markers may point to this diagnosis. While generalized muscle pain is sometimes seen, muscle weakness is uncharacteristic. If muscle weakness is present, an underlying myositis or myopathy, potentially related to steroid or hydroxychloroquine use, should be considered. Musculoskeletal chest pain, related to underlying pectoral, intercostal muscle, or costochondral joint inflammation may also occur and should be treated the same as in patients without SLE. Similar to pleuritis, the threat of a more malicious underlying cause of the pain should prompt the clinician first to seek other causes before arriving at this more benign diagnosis.

Hematologic Disease

Anemia, present in up to 50% of patients with SLE, may present with a chief complaint of dyspnea or weakness. Iron deficiency anemia, anemia of chronic disease, autoimmune hemolytic anemia, or medication-induced bone marrow suppression can all contribute to anemia in a patient with SLE. SLE also shares a strong association with APS, which is associated with a significantly increased risk of thromboembolic disease.

Complications Due To Medications

Chronic NSAID use for the musculoskeletal consequences of SLE may contribute to peptic ulcer disease, especially if they are coadministered with glucocorticoids. Chronic glucocorticoids are associated with an increased risk of multiple conditions including CAD, osteoporosis, avascular necrosis, psychosis, hyperglycemia, hypertension, and weight gain, among many others. Therapy with antimalarials, such as hydroxychloroquine, is common and generally well tolerated; however, retinopathy has been associated with prolonged use. Medications that interfere with DNA synthesis such as cyclophosphamide, methotrexate, mycophenolate mofetil, and azathioprine suppress the immune response, leaving patients vulnerable to both conventional and opportunistic infections. These medications are also frequent causes of cytopenias and liver function test elevations. Cyclophosphamide is one of the most potent immunosuppressants and particular care should be given to assessing for infection in patients receiving this agent. Biologic agents such as rituximab and belimumab are also associated with an increased risk of infection or cytopenias.

Differential Diagnosis

In keeping with its highly varied presentations and permutations of disease activity, a number of other diseases may be confused with SLE before diagnosis. These include infection, thrombotic thrombocytopenic purpura (TTP), APS, vasculitis, rheumatoid arthritis, mixed connective tissue disease, undifferentiated connective tissue disease, Sjögren syndrome, fibromyalgia, and drug-induced lupus, among others. In the ED setting, the priority should be identifying severe illness with an acute threat to organ function or risk of death. Mild, subacute, and nonspecific disease processes generally do not require definitive diagnosis in the ED setting if not associated with evidence of near-term risk to organ function. Chief complaint-driven considerations for acute presentations of SLE are listed in Table 105.2 .

TABLE 105.2

Common or Specific Differential Considerations for Patients With Systemic Lupus Erythematosus Based on Common Presentations, Comorbidities, or Complications

Chief Complaint	Condition
Altered Mental Status	Neuropsychiatric lupus Medication effect (e.g., steroid psychosis) Seizure Infection
Fever	Infection Increased disease activity (SLE flare)
Chest pain	Acute coronary syndrome Pulmonary embolism Pericarditis/pericardial effusion Pleuritis/pleural effusion Musculoskeletal chest wall pain (diagnosis of exclusion)
Shortness of breath	Acute coronary syndrome Pulmonary embolism Pulmonary hypertension/right heart failure Pneumonia Pericarditis/pericardial effusion Pleuritis/pleural effusion Interstitial lung disease Shrinking lung syndrome Anemia
Abdominal pain	Pancreatitis Peptic ulcer disease Pseudo-obstruction Lupus enteritis
Leg swelling	Deep venous thrombosis Nephrotic syndrome Renal failure Heart failure (left- or right-sided)
Pruritic or painful rash	Discoid SLE Drug reaction Sun exposure
Arthritis	Increased disease activity (SLE flare) Osteoarthritis Septic arthritis

SLE, Systemic lupus erythematosus.

Diagnostic Testing

Patients carrying a diagnosis of SLE presenting with symptoms concerning SLE-related pathology will typically require evaluation for evidence of systemic disease activity in addition to symptom-specific testing. In general, patients will not undergo testing for an initial diagnosis of SLE in the ED.

The general approach to assessing whether a symptom is caused by overall SLE disease activity is to look for signs and symptoms of the disease in other organs or systemically. For example, a patient presenting with pleurisy, arthralgias, and fever that has laboratory testing consistent with increased disease activity and chest radiography that is negative for evidence of infection may be diagnosed with a lupus flare. A patient with isolated pleurisy in the absence of other symptoms, laboratory tests, or imaging studies consistent with active SLE, however, is less likely to be suffering from an SLE flare and therefore warrants further evaluation for non-SLE pathology.

Symptom-specific testing will be the same for patients with and without SLE, with the caveat that certain testing thresholds may be lowered for patients with SLE given the increased risks associated with this disease and its treatment (e.g., cardiovascular disease, thromboembolic disease, infection).

Laboratory Tests

While patients will not typically undergo laboratory testing for an initial diagnosis of SLE in the ED, special circumstances such as low resource settings, poor outpatient follow-up, or severe illness requiring expedited diagnosis may prompt emergency physicians to begin this evaluation.

For patients carrying a diagnosis of SLE with all but the most trivial presentations of potential SLE-mediated disease, laboratory studies are indicated to assess for increased disease activity as the etiology of the patient’s symptoms.

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