1. 
   

   Does this patient have systemic lupus erythematosus (SLE)?

   
   
2. 
   

   Has SLE disease activity led to this patient’s hospitalization?

   
   
3. 
   

   How should flares of SLE be managed?

   
   
4. 
   

   How does treatment of other diseases affect the status of SLE?

   
   
5. 
   

   What are possible adverse consequences of the treatment of SLE?

   
   
6. 
   

   How should medications for SLE be managed upon hospital discharge?

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects about 1 in 2000 individuals. Women of childbearing age are most commonly affected. SLE can manifest in any organ system, and disease activity varies over time. Phenotypically, SLE is highly variable and may affect some organ systems but not others in certain individuals. Both the incidence and severity of SLE are increased in individuals of African or Caribbean descent, as well as in Hispanic populations within the United States.

In the past, SLE had relatively high mortality and morbidity rates. Recent estimates place 5-year survival rates around 95% and 20-year survival rates around 80%. As survival rates have improved in individuals with SLE, so have hospitalization rates. Most hospitalists care for individuals with active SLE during the course of a year. In one retrospective analysis, more than half the patients in a lupus cohort were hospitalized at some point over the previous two years. The most common reason for hospitalization in patients with SLE is disease flare. Patients are also commonly admitted for complications of SLE or its treatment, such as infections and cardiovascular and thromboembolic disease. Individuals with SLE are at high risk for premature atherosclerosis and may be admitted with chest pain, acute coronary syndromes, or cerebrovascular accidents. As well, patients may be first diagnosed with SLE when hospitalized for a severe disease manifestation, such as pericarditis, glomerulonephritis, or neurologic disease.

Autoimmune diseases are thought to occur when an environmental trigger, such as infection, sunlight, or smoking, activates an abnormal immune response in a genetically susceptible individual. Abnormalities in nearly every aspect of immune system function have been demonstrated either in humans or in animal models of SLE.

The serologic hallmark of SLE is the presence of serum autoantibodies, generally against nuclear proteins. The pathogenesis of autoantibodies may relate to defective clearance of apoptotic cells. When cells undergo apoptosis, internal proteins are displayed on surface blebs. If the apoptotic cells are not cleared, nuclear material is exposed to the immune system, which may become sensitized. Certain complement component deficiencies, namely of C4 and C1q, are associated with SLE; this may relate to the role of complement activation in clearing apoptotic cells and foreign antigens.

Autoantibodies can cause tissue damage through direct binding and subsequent immune system activation, or via formation and deposition of immune complexes in tissues. Autoantibodies are implicated in multiple manifestations of SLE, including glomerulonephritis, cutaneous lupus, cytopenias, and thrombosis. Anti–double stranded DNA (dsDNA) antibodies are associated with lupus nephritis, though glomerulonephritis can also occur in the absence of anti-dsDNA antibodies, likely mediated through other autoantibodies. Pathologic findings in the kidney in lupus nephritis include mesangial, subepithelial, and subendothelial deposits of immunoglobulin G (IgG), IgM, IgA, and complement components (the “full-house” immunofluorescence staining pattern). Cutaneous manifestations of SLE also are mediated by immune complexes, as shown by positivity of the lupus band test in involved and uninvolved skin (Figure 256-1). Ultraviolet light causes DNA damage and keratinocyte apoptosis, which can activate and perpetuate an immune response as described above. Autoantibodies against blood cell components may lead to Coombs-positive hemolytic anemia, thrombocytopenia, and neutropenia, and antiphospholipid antibodies may induce thrombotic events and recurrent pregnancy losses.

Patients with SLE also demonstrate abnormal B- and T-cell activation. B-cell hyperactivity may be present, partly due to increased levels of B-lymphocyte stimulator (BLyS); biologic therapy against BLyS, belimumab, was approved in 2011 for the treatment of adult patients with active, antibody-positive SLE despite standard therapy. Interferon-alpha probably also plays a role in abnormal immune activation; most lupus patients have a peripheral blood interferon signature of gene expression patterns consistent with interferon-alpha stimulation.

The pathogenesis of lupus serositis, arthritis, and neuropsychiatric disease are not well understood. Pleural effusions in active SLE are exudative, with decreased pleural fluid complement levels. Synovial fluid in lupus arthritis is generally mildly inflammatory, usually less than 2000 cells/mm3. Certain autoantibodies have been implicated in central nervous system (CNS) lupus (such as anti-N-methyl-D-aspartate [NMDA] antibodies), but neuropsychiatric lupus is also characterized by a bland vasculopathy of cerebral vessels. The vasculopathy of lupus is increasingly appreciated as a cause of morbidity and mortality in this disease, especially as a cause of accelerated cardiovascular disease.

There are two scenarios that require the hospitalist to consider SLE in the differential diagnosis: patients with symptoms that may represent new-onset SLE, or patients with known SLE and recent symptoms that might be due to SLE, its treatment, or other causes.

New Systemic Lupus Erythematosus

SLE should be considered in the differential diagnosis of a young person with serositis, cytopenias, or glomerulonephritis. A wide range of other diagnostic considerations are relevant in patients with these findings. New pleural and pericardial effusions are commonly caused by infection and malignancy. Pleural effusions are also caused by heart failure, liver disease, nephrotic syndrome, chylothorax, esophageal rupture, rheumatoid arthritis, and hypothyroidism; other causes of pericarditis include uremia, hypothyroidism, and radiation therapy.

Pancytopenia is common is SLE, but may also be caused by bone marrow infiltrative processes such as lymphoma, sarcoidosis, or infection. Isolated thrombocytopenia can result from SLE, as well as idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP; may appear concurrently with SLE), medications, infections, or liver disease. SLE is more likely to cause lymphopenia than neutropenia. Lymphopenia should prompt consideration of human immunodeficiency virus (HIV) infection and may also be caused by glucocorticoid therapy. SLE is one of many illnesses that can cause anemia of chronic disease. SLE is also associated with autoimmune hemolytic anemia, which may be associated with leukemia, lymphoma, Mycoplasma pneumoniae infection, and infectious mononucleosis.

In addition to SLE, other causes of new-onset glomerulonephritis include nonlupus nephritic syndromes such as acute and rapidly progressive glomerulonephritis, crescentic glomerulonephritis, or systemic necrotizing vasculitides such as Wegener granulomatosis or Goodpasture syndrome. New-onset nephrotic syndrome may be caused by SLE, as well as idiopathic membranous glomerulopathy, diabetic glomerulosclerosis, focal segmental glomerulosclerosis, or minimal change nephropathy.

Certain neurologic syndromes suggest the possibility of SLE. Transverse myelitis can be a forme fruste of SLE, and if seen in a young woman then SLE should be ruled out. New seizures may also be a presenting manifestation of SLE.

Inflammatory arthritis and rashes occur in up to 90% of individuals with SLE and support the diagnosis of SLE when present. Acute inflammatory arthritis may represent rheumatoid arthritis, parvovirus B19 infection, or reactive arthritis from infections such as Salmonella, Shigella, Campylobacter, and Chlamydia trachomatis. Mucocutaneous manifestations account for 4 of the 11 classification criteria for SLE. Certain variants of cutaneous lupus have a more robust link to systemic disease (Figure 256-2).

Established Systemic Lupus Erythematosus

When patients with SLE are admitted to the hospital, two questions should be asked: Does this patient actually have SLE? If so, is SLE responsible for the patient’s presentation? As noted above, disease flare is the most common reason for hospital admission in patients with SLE, followed by infection, cardiovascular disease, and thrombosis.

Hematologic manifestations, including anemia and thrombocytopenia, may require hospital admission. Anemia in SLE is often multifactorial. Patients may have anemia of chronic disease or autoimmune hemolytic anemia related to SLE, but lupus patients often take medications that can cause gastrointestinal bleeding, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and anticoagulants. The large number of lupus patients who are young women are also at risk for iron deficiency anemia from menstrual blood loss. Finally, patients with lupus nephritis may have anemia related to renal disease. Thrombocytopenia may be multifactorial as well, but immune-mediated thrombocytopenia or TTP must always be considered.

Neuropsychiatric lupus (NPSLE) can present in many ways. A new seizure may be a manifestation of NPSLE, but can also occur with accelerated hypertension from acute nephritis or noncompliance with antihypertensive therapy. In addition, posterior reversible encephalopathy syndrome (PRES) has been reported in patients with SLE, with or without significant hypertension. The causes for this syndrome and relationship to active SLE are incompletely understood. NPSLE can also present as acute delirium. Drugs and opportunistic infection of the CNS must also be considered. NPSLE can also manifest with severe depressive symptoms, even catatonia. This can be difficult to differentiate from primary depression.

Respiratory infection with typical or unusual pathogens must be considered in patients with SLE and serositis, dyspnea, or pulmonary infiltrates. Such individuals may be taking chronic glucocorticoids or other immunosuppressive medications that not only increase the risk of infection, but also blunt its symptoms when it occurs. Pulmonary infiltrates in patients with SLE may also represent life-threatening alveolar hemorrhage.

Premature cardiovascular disease is a major source of morbidity and early mortality in SLE. A 40-year-old woman with SLE is likely to have an equivalent atherosclerotic burden to a 70-year-old woman without SLE. SLE imparts a cardiovascular risk similar to that of diabetes mellitus. Chest pain and dyspnea may be manifestations of pericarditis or pleurisy, but they may also be the presenting symptoms of pulmonary embolism or pulmonary arterial hypertension. Patients with dyspnea and pericarditis should be assessed for possible tamponade. Nonbacterial thrombotic endocarditis (Libman-Sacks endocarditis) is rare, but it should be considered in any patient with SLE with dyspnea, chest pain, and signs of peripheral emboli. Accelerated hypertension suggests new glomerulonephritis.

SLE is a clinical syndrome, diagnosed by thorough history and physical examination with appropriate laboratory and other diagnostic testing. While the American College of Rheumatology (ACR) classification criteria for SLE were designed to improve homogeneity of individuals enrolled into clinical trials, they are also helpful for making a clinical diagnosis of SLE (Table 256-1). However, many signs, symptoms, and laboratory findings seen in individuals with SLE are not included in the classification criteria. These include Raynaud phenomenon, interstitial lung disease, and hypocomplementemia.

The history should elicit whether the patient has experienced typical lupus manifestations such as arthralgia, rash, mucosal ulcers, or serositis. More than 90% of individuals with SLE have musculoskeletal manifestations, including arthritis, defined as two or more swollen or tender joints. The most commonly involved joints include the small joints of the hands, wrists, elbows, and knees; these joints should be palpated for swelling and tenderness. Most individuals with SLE have mucocutaneous lesions at some point during the course of their disease. These manifestations range from generally painless oral and nasal ulcerations to photosensitive rashes, malar rash, and discoid lupus rash. Photosensitive rashes more typically occur on sun-exposed skin, but may also occur in non-sun-exposed regions. Discoid lesions are associated with complete loss of hair, central atrophy, and hypopigmentation. The face and scalp should be carefully examined for discoid lupus rashes, including the pinnae and external auditory canals. Patients may wear wigs or have hair glued over bald patches, so the patient should be asked about prior hair loss. The skin of the fingers and hands must be carefully examined, as both erythema between the interphalangeal joints and subcutaneous nodules on the fingers are common. Periungual infarcts can often be appreciated with the naked eye if observed carefully. Blanching livedo reticularis on the extremities is also common in individuals with SLE and can predict the presence of antiphospholipid antibodies.

Before autoantibody results return, other tests may suggest SLE (Table 256-2). A complete blood count is one of the most useful single tests in evaluating for SLE. Leukopenia, thrombocytopenia, and anemia are all consistent with a diagnosis of SLE. The erythrocyte sedimentation rate is generally increased in active SLE. Urine should be examined for cells or cellular casts; urine protein quantitation is recommended. Serum chemistries can be helpful as well. The serum total protein may be elevated in SLE and other autoimmune diseases because of high levels of autoantibodies. Serum albumin may be low, reflective either of chronic disease or of proteinuria associated with glomerulonephritis.

Serologic studies support the diagnosis of SLE (Table 256-3). Almost 100% of individuals with SLE have a positive antinuclear antibody (ANA) test. Although a negative ANA test essentially rules out a diagnosis of SLE, a positive ANA test is not diagnostic; up to 15% of the general population has a positive ANA. Antinuclear antibodies may be measured three different ways, each with different sensitivities and specificities. The fluorescent antinuclear antibody assay (FANA) is highly sensitive. The FANA is performed by applying progressively more dilute patient serum to standardized cells on microscope slides, then observing the pattern of immunofluorescence by microscopy. The FANA is reported as the dilution (titer) at which nuclear fluorescence is seen. A high-titer positive ANA means antinuclear antibody activity is present even when the patient’s serum is very dilute. Some laboratories use enzyme-linked immunosorbent (ELISA)-based autoantibody testing. Such testing can be automated and performed more quickly than the traditional FANA. However, ELISA testing tends to be less sensitive, as the only nuclear antibodies detected are those specifically sought by the assay. Thus, the results may be more specific for the autoantibodies associated with clinical disease. Finally, many laboratories now use multiplex immunoassays. In these assays, the patient’s serum is mixed with beads coated with a variety of autoantigens. Each autoantigen bead has a specific fluorescent dye. An immunoassay analyzer determines the identity and quantity of the reacting autoantigen beads. Like ELISA-based methods, this test only detects predefined autoantibodies. ANA-negative lupus is exceptionally rare; the ANA is occasionally negative in individuals with positive anti-Ro (SSA) antibody, because the antigen may result in a cytoplasmic staining pattern. ANA tests may become negative during the course of the disease.