Chapter 219

Systemic Lupus Erythematosus

Francisco P. Quismorio Jr, Dorothy K. Johnson

Definition and Epidemiology

Systemic lupus erythematosus (SLE) is a chronic multisystem inflammatory rheumatic disease that may cause diverse symptoms, such as fatigue, joint pain, rashes, seizures, edema, and chest pain.¹^,² SLE has a predilection for women, particularly during the prime childbearing age of 15 to 35 years. A wide variety of autoantibodies, including antinuclear antibodies (ANAs), are the most characteristic laboratory finding in SLE. SLE can damage many organ systems, notably the kidneys, lungs, heart, and brain, and may result in severe disability and even death.

SLE is not an uncommon rheumatic disease. The incidence and prevalence rates are difficult to measure with great precision; these rates vary by geographic distribution and by demographic characteristics. Data from recent American surveys suggest that the prevalence of SLE among whites ranges from 5.5 to 10 per 100,000 persons.³ The reported incidence rates of SLE in the United States also vary from 1.8 to 7.6 cases per 100,000 persons per year. SLE is up to 10 times more common in women than in men.³ The disease is more common in African-American women, among whom the prevalence may be as high as 1 in 500. The morbidity and mortality of SLE are increased among African-American and Hispanic patients compared with whites.⁴ Epidemiologic data have suggested that the incidence of the disease may be increasing.⁵

The cause of SLE is unknown. Its association with certain genotypes, such as the C4 null allele and various HLA haplotypes, as well as the 25% rate of concordance in identical twins suggests that the disease is likely to be a result of an interaction between genetic makeup and one or more environmental triggers. Studies including genome-wide association analysis have identified several key susceptibility genes in SLE.⁶ Because certain drugs can induce lupus-like syndromes, it is speculated that certain environmental agents may promote the development of SLE.⁷ Other potential environmental triggers are a wide range of viruses (including the Epstein-Barr virus),⁸^,⁹ physical trauma, and emotional stress. Differences in the level and metabolism of estrogen, androgen, and other sex hormones may partly account for the female predilection for the disease.⁹

Pathophysiology

The pathophysiologic hallmark of SLE is the development of antibodies directed against components of “self” tissues, particularly structures found within cell nuclei. The lupus erythematosus (LE) cell test, the first laboratory diagnostic test for the disease, described in 1948 by Hargraves, is predicated on the presence of ANAs specific for deoxyribonucleoprotein.¹ A wide variety of autoantibodies have since been reported in SLE, including antibodies directed against DNA and other nuclear constituents, red blood cells, platelets, white blood cells, and phospholipids. Autoantibodies form immune complexes in the circulation or in situ and become deposited in kidneys, skin, lungs, and other target organs. Circulating immune complexes are normally solubilized and cleared from the circulation by the reticuloendothelial system. In SLE, there is an aberrant clearance of immune complexes that may be related to defective solubilization of antigen-antibody complexes and abnormalities of complement and cell receptor functions. Individuals with genetic deficiencies of the early complement components C1q, C2, and C4 are at an increased risk for lupus-like autoimmune disease. Defective apoptosis (programmed cell death) with phagocytosis of cell debris allowing nuclear antigens to become antigenic, abnormalities in T- and B-cell functions, cytokines, innate immunity, and other immune mechanisms that promote self-tolerance all contribute to the development of autoimmunity in SLE.⁹

The deposition of immune complexes in tissues generates a local inflammatory response that may have organ-specific effects. Inflammation in blood vessels can cause vasculitis, which may result in vessel occlusion, ischemia, or infarction of the affected organ. Inflammation of serosal surfaces (lining of visceral organs) may result in pleurisy or pericarditis. The deposition of pathogenic immune complexes in the renal glomeruli can result in the development of lupus nephritis.

Clinical Presentation and Physical Examination

SLE is a systemic inflammatory disorder characterized by varied presentation, disease relapses, and remissions. The disease can develop acutely, with obvious severe manifestations that include arthritis, nephritis, serositis, and vasculitis, or it may become apparent in an individual who has had mild symptoms and subtle physical findings (e.g., fatigue, arthralgia, rashes) sporadically for many years. The disorder is often misdiagnosed because many of the early symptoms of SLE are nonspecific (e.g., fatigue, oral ulcers, joint pain) and the ANA test result is positive in approximately 5% of healthy persons. The American College of Rheumatology has developed and validated a set of criteria for the classification of SLE¹⁰ (Box 219-1).

Box 219-1

Revised Criteria for Classification of Systemic Lupus Erythematosus

1. Malar rash: Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds.

2. Discoid rash: Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions.

3. Photosensitivity: Skin rash as a result of unusual reaction to sunlight, by patient or physician observation.

4. Oral ulcers: Oral or nasopharyngeal ulceration, usually painless, observed by a physician.

5. Arthritis: Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion.

6. Serositis.

a. Pleuritis—convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion or

b. Pericarditis—documented by electrocardiogram or rub or evidence of pericardial effusion

7. Renal disorder.

a. Persistent proteinuria—more than 0.5 g/day or greater than 3+ if quantitation not performed or

b. Cellular casts—may be red cell, hemoglobin, granular, tubular, or mixed

8. Neurologic disorder.

a. Seizures—in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance) or

b. Psychosis—in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance)

9. Hematologic disorder.

a. Hemolytic anemia—with reticulocytosis or

b. Leukopenia—less than 4000/mm³ total on two or more occasions or

c. Lymphopenia—less than 1500/mm³ on two or more occasions or

d. Thrombocytopenia—less than 100,000/mm³ in the absence of offending drugs

10. Immunologic disorder.

a. Anti-DNA antibody to native DNA in abnormal titer or

b. Anti-Sm—presence of antibody to Sm nuclear antigen or

c. Positive finding of antiphospholipid antibodies based on abnormal serum level of IgG or IgM anticardiolipin, positive test result for lupus anticoagulant, or false-positive serologic test result for syphilis known to be positive for at least 6 months and confirmed by fluorescent treponemal antibody absorption test or other specific treponemal antibody test.

11. ANA: An abnormal titer of ANA by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with “drug-induced lupus” syndrome.

IgG, immunoglobulin G; IgM, immunoglobulin M.

Modified from Tan EM, Cohen AS, Fries JF et al: The 1982 revised criteria for the classification of systemic lupus erythematosus, Arthritis Rheum 25(11):1271-1277, 1982; and Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus, Arthritis Rheum 40:1725, 1997.

Malaise and fatigue, often profound, are common but nonspecific complaints. Anorexia and weight loss may be seen in patients with active disease, as can fevers, lymphadenopathy, tachycardia, and anemia. The malar (or butterfly) rash, one of the most recognizable features of SLE, is observed in only 35% of patients. This is a photosensitive erythematous rash on the cheeks and over the bridge of the nose that tends to spare the nasolabial folds. Discoid lupus rash is seen in 20% of patients with SLE. In a more benign clinical form of lupus, termed discoid lupus erythematosus, the disease is predominantly cutaneous with no or mild visceral involvement. Discoid lupus skin lesions are thick, round, erythematous plaques on the face, scalp, and extremities that heal with scarring, atrophy, depigmentation, and loss of hair. Mucous membrane ulcers are also common, occurring in the oral and nasal cavities. Discoid LE lesions can be disfiguring.

Approximately one third of SLE patients experience Raynaud phenomenon, an episodic vasospastic phenomenon characterized by changes in blood flow to the extremities, accompanied by sequential color change of the digits, from white to purple to red, and often unpleasant tingling or painful sensations. Livedo reticularis is a purplish mottling or lacelike appearance of the skin, especially in the extremities, and is associated with antiphospholipid syndrome (see later). Cutaneous vasculitis may manifest as tender skin nodules, palpable purpura or skin infarcts, and ulcerations. Bruising or petechiae caused by immune thrombocytopenia may also occur.

Joint pain (arthralgia) occurs in 80% to 90% of patients with SLE, and inflammatory arthritis can be objectively documented in about 50% of patients.¹ The arthritis of SLE is typically milder than rheumatoid arthritis. It is nonerosive, and less than 10% of the patients will develop joint deformities, called Jaccoud arthropathy. Osteoporosis is common and is multifactorial in cause, including corticosteroid therapy, chronic inflammation, and physical inactivity. Metabolic bone disease related to vitamin D deficiency and secondary hyperparathyroidism may develop in those with chronic renal failure. Inflammatory myositis manifesting as proximal muscle weakness with elevated serum creatine kinase can be seen.

Chest pain is a common complaint and is often musculoskeletal in origin. More significantly, SLE can cause serious cardiopulmonary disease, including pleurisy, pericarditis, pneumonitis, interstitial lung disease, pulmonary hemorrhage, myocarditis, and valvular heart disease.

A subset of SLE patients develop antiphospholipid syndrome, characterized by hypercoagulability, recurrent venous or arterial thrombosis, repeated spontaneous abortions and fetal loss, and the presence of antiphospholipid antibodies as measured by anticardiolipin antibodies, anti–beta 2 glycoprotein 1, or lupus anticoagulant. These patients have an increased risk for pulmonary embolism, pulmonary hypertension, strokes, abortion and fetal loss, Libman-Sacks endocarditis, and valvular heart disease.

Lupus patients are at a greatly increased risk for development of ischemic heart disease, with a 1.5% annual incidence of a new coronary event and an overall prevalence of 6% to 10%. Compared with the general population, SLE patients are 5 to 10 times more likely to experience a coronary event.¹¹

Accelerated atherosclerosis in SLE may relate to both traditional and nontraditional risk factors, including hypertension, alterations in lipid metabolism associated with nephrotic syndrome, long-term use of corticosteroids, and endothelial damage caused by chronic inflammatory process.¹² Hypertension is common and may be associated with underlying lupus nephritis, the use of corticosteroids, and possibly nonsteroidal anti-inflammatory drugs (NSAIDs) as contributing factors.

Mood changes, depression, and migraine headaches are common. SLE can cause wide-ranging neuropsychiatric abnormalities, the most common being cognitive dysfunction with impaired memory and concentration. Psychosis, seizures, altered consciousness, confusion, stroke, myelopathy, and neuropathies may develop. The pathogenesis of neuropsychiatric manifestations probably involves different mechanisms, including small-vessel vasculopathy, thrombosis associated with antiphospholipid syndrome, effects of complement split products, cytokines, and antineuronal antibodies.

Lupus nephritis develops during the course of the disease in 25% to 50% of patients.¹ Persistent proteinuria of more than 500 mg/day, cellular casts, and red blood cells in the urine sediment are observed. There is a spectrum of renal involvement ranging from mesangial lupus nephritis with increased cellularity and deposition of immune complexes limited to the mesangium to severe diffuse proliferative glomerulonephritis with involvement of all glomeruli. Evaluation and staging of renal disease in SLE require a kidney biopsy, and the histopathologic findings are useful in assessing renal prognosis and determining a therapeutic regimen. Hemodialysis or kidney transplantation becomes necessary in those who develop end-stage renal disease. Most patients who undergo kidney transplantation do relatively well because of the immunosuppression required to prevent graft rejection. SLE kidney transplant recipients have outcomes generally equivalent to those of nonlupus transplant recipients.

Diagnostics

During a disease exacerbation of SLE, laboratory tests reveal nonspecific evidence of systemic inflammation with an elevated erythrocyte sedimentation rate (ESR), C-reactive protein, and serum gamma globulins.¹^,² Anemia is common and may result from one or a combination of several mechanisms, including iron deficiency, chronic systemic inflammation causing an anemia of chronic disease, autoimmune hemolysis with a positive Coombs test result, bone marrow damage, and, in patients with renal insufficiency, inadequate erythropoietin response. Leukopenia, lymphopenia, and thrombocytopenia are characteristic hematologic features of the disease and appear to be mediated by organ-specific autoantibodies. Immune thrombocytopenic purpura may be the presenting manifestation of SLE and is associated with antiplatelet and antiphospholipid antibodies.

A urinalysis should always be obtained during follow-up visits because lupus nephritis can develop de novo in patients without previous kidney involvement. Blood urea nitrogen (BUN), creatinine, 24-hour urine protein excretion, or spot urine protein/creatinine ratio, and creatinine clearance should be monitored for changes indicating new nephritis or worsening renal function.

Although the “total” ANA test is the most sensitive diagnostic test, a positive ANA test result is not specific for SLE. In contrast, anti-Smith (anti-Sm) and anti–double-stranded DNA (anti-dsDNA) autoantibodies are more specific for the diagnosis of lupus (Table 219-1). Both types of autoantibodies are present in 30% to 40% of patients; thus, a negative test result for either anti-Sm or anti-dsDNA does not necessarily exclude a diagnosis of SLE.⁹ The presence of anti-Ro/SSA and anti-La/SSB in 30% and 15% of patients, respectively, is associated with subacute cutaneous lupus, secondary Sjögren syndrome, and neonatal lupus syndrome (see Table 219-2).¹^,²

TABLE 219-1

Clinical Significance of Specific Types of Antinuclear Antibodies in Systemic Lupus Erythematosus (SLE)

Antinuclear Antibody	Clinical Associations and Significance
Anti-dsDNA	Characteristic of SLE, useful in diagnosis; rising serum titer associated with disease activity, especially nephritis
Anti-Sm	Highly characteristic of SLE, useful in diagnosis; serum titer does not correlate well with disease activity
Anti-U1 RNP	Associated with mixed connective tissue disease
Anti-Ro/SSA and anti-La/SSB	Associated with risk for neonatal lupus syndrome, photosensitivity, subacute cutaneous lupus, and Sjögren syndrome
Anti-histone	Associated with drug-induced lupus; however, may also be seen in idiopathic SLE