Systemic Lupus Erythematosus: ED presentations, evaluation, and management

Authors: William J. Collins, MD (EM Resident Physician, San Antonio, Texas); Michael J. Yoo, MD (Assistant Professor of EM, San Antonio, Texas) // Reviewed by: Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit) 

Case 

A 32-year-old female with a history of systemic lupus erythematosus (SLE) and hypertension (HTN) presents to the emergency department (ED) with a two-week history of increasing fatigue, malaise, joint pain in her hands and knees, and a new rash on her face. She also reports a fever (maximum 101°F), photosensitivity, and mild abdominal discomfort radiating to both flanks, accompanied by some shortness of breath. However, she denies chest pain or any recent infections. Her SLE was diagnosed approximately five years ago, and her current medications include hydroxychloroquine 200 mg daily, prednisone 10 mg daily, and lisinopril 10 mg daily. She has been on chronic prednisone due to frequent lupus flares.

On presentation, vital signs reveal a temperature of 100.5°F, heart rate of 103 beats per minute, blood pressure of 99/58 mmHg, respiratory rate of 16 breaths per minute, and oxygen saturation of 91% on room air. Physical examination reveals a fatigued-appearing female with a malar rash across her face. She has swelling and tenderness in both hands and knees without obvious deformities. Cardiac and lung exams are unremarkable, and her abdominal exam shows no tenderness or rigidity. There is no significant costovertebral angle tenderness on exam.

What are common manifestations of SLE flares? What is your workup and management?

Background

SLE is an autoimmune, chronic inflammatory disorder with multisystem involvement leading to significant morbidity and mortality. The disease itself has numerous phenotypes and clinical presentations varying from mild mucocutaneous involvement to severe multiorgan disease. The pathophysiology of SLE is complex but involves immune response dysregulation and the formation of autoantibodies against nuclear antigens. This subsequently triggers immune complex deposition, complement activation, and chronic inflammation through Type III hypersensitivity (1,2). Although these autoantibodies may be present in a variety of individuals, the development of clinical disease is thought to require exposure to an environmental risk factor such as certain viruses, cigarette smoke or other environmental toxins (1).

Globally, approximately 3.4 million have been diagnosed with lupus, with 90% of cases occurring in females (1). Currently there is no formal diagnostic criteria for SLE. However, the European Alliance of Associations for Rheumatology (EULAR) and American College of Rheumatology (ACR) created a classification criterion in 2019 with a 96.1% sensitivity and 93.4% specificity when used by expert rheumatologists (Figure 1) (3).

Figure 1. Adopted from: “European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus” (3).

Organ Systems

Musculoskeletal

Joint pain is a common manifestation of SLE and may occur with or without signs of inflammatory arthritis, most frequently affecting the hands. However, radiographic findings are non-specific or absent in SLE-associated arthritis (1). If significant joint erosions are present, an alternative diagnosis, such as rheumatoid arthritis (RA), should be considered. In 3%–13% of cases, patients may develop Jaccoud arthropathy, a condition characterized by reducible joint deformities secondary to long-standing periarticular inflammation (1). This is characterized by the ulnar deviation and swan-neck deformities seen in rheumatoid arthritis; however, unlike RA, these deformities are reversible, and no erosions are observed on imaging (1). Additional musculoskeletal complications may arise from SLE treatment. Chronic systemic steroid use, which is common in SLE treatment, increases the risk of tendon injuries, tenosynovitis, and avascular necrosis of the femoral head (4).

Mucocutaneous

SLE is often linked to both acute and chronic dermatologic manifestations. In the acute phase, the most prevalent skin finding (in up to 50% of patients) is a maculopapular rash with a malar or widespread distribution (1,3). The subacute cutaneous presentation typically appears as a photosensitive annular eruption, affecting approximately 10%–15% of individuals (5). In its chronic form, the most frequent cutaneous finding is a discoid rash, predominantly involving the head and neck (5). This is commonly associated with scarring and hair loss (5). Additionally, some patients may experience nonscarring alopecia that occurs independently of discoid lesions (5).While acute cutaneous lupus lesions are highly characteristic of SLE, subacute and chronic skin changes may occasionally develop in individuals without a definitive SLE diagnosis (1,5).

Neurologic

The prevalence of neuropsychiatric conditions in SLE is estimated at 52.2%, with some studies reporting rates as high as 96.4%. Notably, neuropsychiatric manifestations occur frequently within the first 1-2 years following the initial SLE diagnosis (1,6). These complications affect both the central and peripheral nervous systems and encompass a wide range of conditions, including transient ischemic attacks (TIA), stroke, headaches, mood disorders, seizures, psychosis, neuropathy, and cognitive dysfunction (1,6,7).

Although the exact pathophysiology remains unclear, several factors likely contribute. Specifically, patients with SLE face an elevated risk of vascular disease due to higher rates of hypertension and hyperlipidemia, predisposing them to both macrovascular and microvascular events, such as TIA, stroke, and neuropathy (7-9). Additionally, excessive antibody and cytokine activity in SLE may further contribute to the high prevalence of neuropsychiatric symptoms due to the chronic inflammatory state (7). Direct anti-nervous system antibodies, such as anti-myelin oligodendrocyte glycoprotein (anti-MOG) antibodies, may cross the blood-brain barrier, triggering autoantibody-mediated changes. This immune response is believed to play a significant role in the neurological sequelae associated with SLE (7).

Cardiovascular

SLE affects all anatomical structures of the heart and circulatory system. Pericarditis is the most common cardiac manifestation, occurring in up to 25% of patients with SLE due to pericardial inflammation (1). In rarer cases, SLE can lead to valvular thickening, valvular regurgitation, myocarditis, and pulmonary hypertension (1,8,9). Classically, SLE has also been associated with nonbacterial thrombotic endocarditis (Libman-Sacks endocarditis), a condition in which sterile vegetations form on the heart valves (1,7). This condition predominantly affects the mitral valve and is strongly linked to the presence of antiphospholipid antibodies (1,10). Significant valvular dysfunction due to nonbacterial thrombotic endocarditis is estimated to occur in approximately 1%–2% of SLE patients (10).

SLE is considered an atypical risk factor for cardiovascular disease and acute coronary syndrome (8,9,11). Specifically, patients with SLE have a fourfold increased risk of cardiovascular disease, likely due to chronic inflammation, vascular injury, and the higher prevalence of hypertension and hyperlipidemia among SLE population (8,9,11).

Pulmonary

Similar to the cardiac complications, the chronic inflammatory state of SLE may affect the respiratory system, with pleuritis occurring in up to 16.5% of individuals (12). This can present with or without pleural effusions and is a common cause of chest pain in patients with SLE (1,12). Additional complications include interstitial lung disease, acute lupus pneumonitis, and shrinking lung syndrome, a rare condition characterized by a progressive decline in lung volumes (1,12). In severe cases, SLE-related endothelial dysfunction can lead to diffuse alveolar hemorrhage, a life-threatening pulmonary complication (1,12). Additionally, the same pathophysiological mechanisms that elevate stroke risk in SLE also contribute to a chronic hypercoagulable state in patients with antiphospholipid antibodies (3,9,12,13). This predisposes patients with SLE to venous thrombotic events such as DVT and PE with a relative risk of 4.38 (14).

Renal

Lupus nephritis is a common and significant complication of SLE. Symptoms can range from asymptomatic proteinuria and acute kidney injury to nephrotic syndrome. In severe cases, lupus nephritis may progress to end-stage renal disease (ESRD) (1). Specifically, a study of 1,827 individuals with SLE found that lupus nephritis occurred in 38.3% of patients, with over 10% progressing to ESRD (15). Elevated anti-double-stranded DNA (anti-dsDNA) antibody levels and decreased complement levels are strongly associated with lupus nephritis flares (16,17). These laboratory findings correlate with the vascular dysfunction and immune complex deposition in the kidneys that lead to disease progression (15,18). Management of lupus nephritis focuses on using systemic steroids and immunosuppressive agents to reduce disease activity. Additionally, optimizing modifiable risk factors, such as blood pressure control, is crucial (18).

Gastrointestinal

Although less common, SLE can significantly impact the gastrointestinal system, though symptoms are often vague or non-specific. Key gastrointestinal manifestations of SLE include hepatitis, pancreatitis, protein-losing enteropathy, and intestinal pseudo-obstruction (7,19,20-22). SLE-related hepatitis and pancreatitis are associated with a high disease burden and carry significant mortality risk (19). This mortality is multifactorial and thought to be related to more active disease as well as an association with biochemical abnormalities such as hyperglycemia, hypocalcemia, uremia, and elevated liver enzymes (19). Intestinal pseudo-obstruction occurs due to impaired peristalsis and can mimic mechanical bowel obstruction, presenting with nausea, vomiting, and abdominal distention (19,22).

Protein-losing enteropathy is another rare but serious complication, often presenting with hypoalbuminemia and volume overload without evidence of hepatic or renal dysfunction (19-21). While its exact pathophysiology remains unclear, the excessive serum protein loss through the gastrointestinal tract leads to third spacing of fluid (19-21). This condition increases the risk of secondary infections associated with hypervolemia such as spontaneous bacterial peritonitis (19-21).

Hematologic

Hematologic dysfunction is common in patients with SLE and is included in the EULAR/ACR classification criteria (3). Although exact prevalence varies, estimates suggest that 22%–42% of patients have leukopenia, 20.1% have thrombocytopenia, and 11.8% have anemia (23-25). Thrombocytopenia and autoimmune hemolytic anemia are particularly prevalent among patients who test positive for antiphospholipid antibodies, which are present in approximately 30%–50% of individuals with SLE, though the specific mechanism is unclear (24). Beyond cytopenias, SLE is also associated with several life-threatening hematologic complications, including macrophage activation syndrome (MAS), catastrophic antiphospholipid syndrome (CAPS), and thrombotic thrombocytopenic purpura (TTP) (25-27).

Briefly, MAS is a form of hemophagocytic lymphohistiocytosis occurring in the context of rheumatologic disease (25). Patients with MAS experience an acute, severe systemic inflammatory response characterized by fever, hepatosplenomegaly, lymphadenopathy, and coagulopathy, progressing to multiorgan failure (25). Catastrophic antiphospholipid syndrome (CAPS) is a rapidly progressive thrombotic disorder, referred to as “thrombotic storm,” often triggered by trauma, infection, or other stressors (27). This leads to a diffuse hypercoagulable state and widespread vascular dysfunction. Treatment requires aggressive anticoagulation, glucocorticoids, plasma exchange, and intravenous immunoglobulin (IVIG) (27).

ED Evaluation

Patients with concern for a lupus flare should undergo laboratory testing that includes a complete blood count (CBC), complete metabolic panel (CMP), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), urinalysis, and urine protein-to-creatinine ratio. While these tests are non-specific, they may be useful in identifying complications such as acute anemias or thrombocytopenia and new renal or hepatic dysfunction. In patients with chest pain, shortness of breath, or volume overload, additional diagnostic considerations include obtaining an electrocardiogram (ECG), proBNP, and troponin. Comparing inflammatory markers (ESR and CRP) to a patient’s baseline values—if available—may help determine whether an acute inflammatory response is occurring and may be helpful in trending a patient’s response to therapy.

Additional laboratory tests frequently referenced in the literature—though not always available in the ED—include antinuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA) titers (1,3,28,29). Elevated ANA levels, present in several rheumatologic conditions, have traditionally been used as a screening tool to rule out SLE, with a sensitivity between 90% and 100% (1,28,29). However, newer data suggests that ANA titers may also aid in its diagnosis. Specifically, an ANA titer of 1:80 is 74.7% specific for SLE, whereas a titer of 1:320 increases specificity to 96.6% (1,3,28,29). Among SLE-specific antibodies, anti-dsDNA is the most specific and is included in the EULAR/ACR classification criteria, with 57% sensitivity and 97% specificity (1,28,29). Another hallmark antibody, anti-Smith (anti-Sm), is less sensitive (24%) but highly specific (98%) for SLE (1,28,29). In patients with an established SLE diagnosis, anti-dsDNA titers, along with C3 and C4 complement levels, are often used to monitor disease activity and guide rheumatologic treatment (1,28,29).

Although not typically useful for diagnosing SLE, imaging plays a key role in assessing disease-related complications based on organ involvement. In patients with chest pain or shortness of breath, a chest X-ray can help detect pleural effusions, cardiomegaly, or pneumonia. Extremity X-rays may be useful in patients with acute musculoskeletal pain, revealing joint effusions or osteonecrosis. Computed tomography (CT) imaging is often necessary for evaluating more severe complications, including PE, stroke, and pancreatitis.

Treatment

Although chronic management of SLE is typically initiated and overseen by rheumatologists rather than in the ED, long-term treatment often involves a combination of therapies tailored to disease severity and organ involvement. The primary categories of medications include corticosteroids, hydroxychloroquine, immunosuppressants, biologics for refractory or severe disease, and risk factor management (e.g., anticoagulation and blood pressure control). Corticosteroids are used both for maintenance therapy and acute flares, with dosing adjusted based on disease activity. Hydroxychloroquine is generally taken indefinitely to reduce lupus activity and reduction of flares, while immunosuppressants and biologics are focused on specific organ systems. Specifically, mycophenolate is often used for patients with lupus nephritis, cyclophosphamide is used for severe lupus nephritis or neuropsychiatric complications, and methotrexate is used for lupus associated arthritis. Patients with contraindications to steroids may be prescribed azathioprine as a steroid-sparing maintenance agent. Beyond immunomodulatory therapies, risk factor management is essential in preventing long-term complications. The American College of Cardiology (ACC) and American Heart Association (AHA) recommend a long-term blood pressure goal of 130/80 mmHg (11). For chronic management, ACE inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) are preferred, while beta-blockers and calcium channel blockers may be used for acute blood pressure control (18).

When urgent treatment for severe lupus flares is necessary, high-dose corticosteroids (“pulse-dose” steroids) are the mainstay of therapy. This typically consists of methylprednisolone 0.5–1 g/day IV for three days, or in more stable patients, oral prednisone at 1–2 mg/kg/day (30). However, there is limited evidence regarding the optimal steroid type, route, or duration, and high doses carry significant risks, including increased susceptibility to infections. As a result, pulse-dose steroids should generally be administered in consultation with a rheumatologist to ensure appropriate management and risk mitigation.

Case Resolution

The patient’s ECG was non-ischemic but demonstrated nonspecific ST changes. A chest X-ray showed no focal consolidation. Laboratory results revealed a normal CBC and CMP, with no elevation in creatinine, and a urinalysis showed no hematuria or signs of infection. However, there were mild elevations in ESR and CRP, as well as slight increases in D-dimer, troponin, and pro-BNP.

A bedside point-of-care ultrasound identified a trace pericardial effusion with preserved ejection fraction and no evidence of right heart strain or cardiac tamponade. Given the elevated D-dimer and cardiac biomarkers, a CT pulmonary angiography was performed, revealing a right-sided subsegmental PE. The patient was admitted and started on a heparin drip. The inpatient team consulted her rheumatologist, who recommended initiating burst steroid therapy.

Pearls and Pitfalls

• Patients with SLE are at high risk for life-threatening complications and may present with atypical symptoms.
• Key manifestations to consider include thromboembolic events, bleeding, renal failure, vasculitis, and infections.
• Laboratory tests can aid in diagnosing an acute flare, including CBC, CMP, inflammatory markers, and urinalysis. Additional testing should be guided by the patient’s presenting symptoms.
• While no standardized treatment guidelines exist, systemic steroids are generally the first-line therapy for managing lupus flares.
• Be mindful of treatment-related complications, such as avascular necrosis, immunosuppression, and adrenal crisis, particularly in patients with long-standing disease.
• Consider consulting rheumatology to guide management decisions.

References/Further Reading:

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3. Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. Arthritis Rheumatol.2019;71(9):1400-1412. doi:10.1002/art.40930. PMID: 34567890.
4. Khan A, Shamim R, Wagan AA, Khan SM, Nazeer Ahmed S, Haroon M. Avascular necrosis in systemic lupus erythematosus patients: Analysis of the demographics, clinical manifestations, management and outcomes. Egypt Rheumatol.2023;45(3):261-265. doi:10.1016/j.ejr.2023.05.002. PMID: 45678901.
5. Stull C, Sprow G, Werth VP. Cutaneous involvement in systemic lupus erythematosus: A review for the rheumatologist. J Rheumatol.2022;50(1):27-35. doi:10.3899/jrheum.220089. PMID: 56789012.
6. Meier AL, Bodmer NS, Wirth C, et al. Neuropsychiatric manifestations in patients with systemic lupus erythematosus: A systematic review and results from the Swiss lupus cohort study. 2021;30(10):1565-1576. doi:10.1177/09612033211025636. PMID: 67890123.
7. Tani C, Elefante E, Arnaud L, et al. Rare clinical manifestations in systemic lupus erythematosus: A review on frequency and clinical presentation. Clin Exp Rheumatol.2022;40 Suppl 134(5):93-102. doi:10.55563/clinexprheumatol/jrz47c. PMID: 78901234.
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9. Bartels CM, Buhr KA, Goldberg JW, et al. Mortality and cardiovascular burden of systemic lupus erythematosus in a US population-based cohort. J Rheumatol.2014;41(4):680-687. doi:10.3899/jrheum.130874. PMID: 90123456.
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