Systemic Lupus Erythematosus
At the conclusion of this chapter, the reader should be able to:
• Compare the different forms of lupus, citing manifestations, incidence, and other features.
• Name the two most common drugs that can cause drug-induced lupus.
• Explain the epidemiology and signs and symptoms of SLE.
• Describe the immunologic manifestations of SLE, including diagnostic evaluation.
• Discuss the laboratory evaluation of antinuclear antibodies.
• Analyze selected SLE case studies. Correctly answer case study related multiple choice questions
• Be prepared to participate in a discussion of critical thinking questions.
• Describe the principle, sources of error, limitation, and clinical application of the antinuclear antibody visible method
• Describe the principle and clinical applications of the rapid slide test for antinucleoprotein and autoimmune enzyme immunoassay ANA screening test
Systemic lupus erythematosus (SLE) is the classic model of an autoimmune disease. SLE is a systemic rheumatic disorder and the term used most often for the group of disorders that includes SLE and other abnormalities involving multiple systems (e.g., joints, connective tissue, collagen vascular system) in the disease process. Table 29-1 lists the American College of Rheumatology criteria for the classification of SLE.
Table 29-1
| Criterion | Definition |
| 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 history or physician observation |
| 4. Oral ulcers | Oral or nasopharyngeal ulceration, usually painless, observed by physician |
| 5. Nonerosive arthritis | Involving two or more peripheral joints, characterized by tenderness, swelling, or effusion |
| 6. Pleuritis or pericarditis | |
| 7. Renal disorder | |
| 8. Neurologic disorder | |
| 9. Hematologic disorder | |
| 10. Immunologic disorder |
1. Anti-DNA—antibody to native DNA in abnormal titer 2. Anti-Sm—presence of antibody to Sm nuclear antigen 3. Positive finding of antiphospholipid antibodies on: 1. An abnormal serum level of IgG or IgM anticardiolipin antibodies 2. A positive test result for lupus anticoagulant using a standard method 3. A false-positive test result for at least 6 mo and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test Standard methods should be used in testing for the presence of antiphospholipids. |
| 11. Positive antinuclear antibody | An abnormal titer of antinuclear antibody 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 |
From Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus (letter), Arthritis Rheum 40:1725, 1997 and The American College of Rheumatology www.rheumatology.org 2012.
Different Forms of Lupus
There are several forms of lupus, including discoid, systemic, drug-induced, and neonatal lupus.
Discoid (cutaneous) lupus is always limited to the skin and is identified by biopsy of the rash that may appear on the face, neck, and scalp. Discoid lupus does not generally involve the body’s internal organs but can evolve into the systemic form of the disease, even if treated. Evolution to systemic lupus cannot be predicted or prevented. The antinuclear antibody (ANA) test may be negative or positive at a low titer. Discoid lupus accounts for approximately 10% of all cases of lupus.
Systemic lupus is usually more severe than discoid lupus and can affect the skin, joints, and almost any organ or body system, including the lungs, kidneys, heart, and brain. Systemic lupus may include periods in which few, if any, symptoms are evident (remission) and other times when the disease becomes more active (flare). Most often, when people mention “lupus,” they are referring to the systemic form of the disease. Approximately 70% of lupus cases are systemic. In about 50% of these cases, a major organ will be affected.
Drug-induced lupus occurs after the use of certain prescribed drugs (Box 29-1). The most frequently used drugs associated with drug-induced lupus are hydralazine hydrochloride and procainamide hydrochloride. Factors such as the rate of drug metabolism, the drug’s influence on immune regulation, and the host’s genetic composition are all believed to influence pathogenesis. Some drugs (e.g., oral contraceptives, isoniazid) induce serum antinuclear antibodies (ANAs) without symptoms. High antibody titers may exist for months without the development of clinical symptoms.
Procainamide-induced disease does not induce antibodies to double-stranded deoxyribonucleic acid (dsDNA). The ANAs in the drug-induced syndromes are histone-dependent and are never the only ANAs present in the blood. Even with discontinuation of the drug, antibody titers usually remain elevated for months or years.
Only about 4% of patients who take these drugs will develop the antibodies suggestive of lupus. Of those 4%, only an extremely small number will develop overt drug-induced lupus. The symptoms of drug-induced lupus are similar to those of systemic lupus, but milder. Patients with drug-related lupus have a predominance of pulmonary and polyserositic signs and symptoms. Patients with drug-induced lupus have no associated renal or central nervous system (CNS) disease. In addition, lupus-inducing drugs do not appear to exacerbate idiopathic SLE. The symptoms usually fade when the medications are discontinued.
Neonatal lupus is a rare condition acquired from the passage of maternal autoantibodies, specifically anti-Ro/SS-A or anti-La/SS-B, that can affect the skin, heart, and blood of the fetus and newborn. Neonatal lupus is associated with a rash that appears within the first several weeks of life and may persist for about 6 months before disappearing. Congenital heart block can occur but is much less common than a rash. Neonatal lupus is not systemic lupus.
Etiology
The cause of SLE is unknown (idiopathic). Although no single causative agent has been identified, a primary defect in the regulation of the immune system is considered important in the pathogenesis of the disorder. Genetic predisposition can be a factor. Hormones and environmental factors that may trigger the disease include infections, antibiotics (especially sulfonamides and penicillin derivatives), ultraviolet (UV) light, extreme stress, and certain drugs. A combination of these factors may be synergistic.
Antibodies directed against T lymphocytes, including the membrane molecules that mediate their responses, are regularly detected in patients with SLE. Their role in the pathogenesis of autoimmunity is still unclear.
Hormonal Influences
Hormonal factors may explain why lupus occurs more frequently in women than in men. Lupus is often called a woman’s disease because a disproportionate number of women between puberty and menopause suffer from SLE. The increase in disease symptoms may be caused by hormones, particularly estrogen. There is a risk that the disease will worsen during pregnancy and the immediate postpartum period. In addition, postmenopausal therapy is associated with an increased risk for developing SLE. The exact reason for the greater prevalence of lupus in women, and the cyclic increase in symptoms, is unknown.
A condition called the antiphospholipid syndrome can be secondary to lupus and may complicate pregnancy. Antibodies against specific autoantigens often present on coagulation factors can cause blood to clot faster than normal or, in some cases, not at all. Antiphospholipid antibodies can be found in many patients with lupus and pose a particular risk to pregnant lupus patients because their presence is often associated with miscarriages.
Both the developing fetus and the pregnant mother with lupus are at increased risk of various complications during and after pregnancy. Passive placental transfer of maternal antibodies can produce transient abnormalities such as hepatosplenomegaly, cytopenia, and a photosensitive rash in the newborn. These conditions do resolve themselves in the newborn after the antibody titer declines (see earlier discussion of neonatal lupus).
Genetic Predisposition
Lupus is known to occur within families, but there is no identified gene or genes associated with lupus. Previously, genes on chromosome 6 called immune response genes were associated with the disease. The discovery of a gene on chromosome 1 has been associated with lupus in certain families. Only 10% of lupus patients will have a parent or sibling who already has or may develop lupus. Statistics show that only about 5% of the children born to those with lupus will develop the illness.
Environmental Factors
Various factors, including UV light and bacterial and viral infections, are capable of inducing or exacerbating the signs and symptoms of SLE. These factors may act in different ways. For example, UV light may cause DNA to form thymine dimers, which significantly alters the antigenicity of DNA and could result in the formation of anti-DNA.
Epidemiology
Lupus can occur at any age and in either gender, although it occurs 10 to 15 times more frequently in women than in men after puberty. The Lupus Foundation of America estimates that approximately 1.4 million Americans have a form of lupus. The overall incidence of SLE is estimated to be 50 to 70 new cases/year/1 million population.
Racial groups such as blacks, Native Americans, Puerto Ricans, and Asians (particularly Chinese) demonstrate an increased frequency of SLE. Lupus is two to three times more prevalent among people of color. The incidence of SLE in black women between the 20 and 64 years old is 1 in 245. The reasons for ethnic differences are not clear.
The prevalence rate, based on a total population, is 1 in 2000, but it is 1 in 700 for women between 20 and 64 years old; 80% of those with systemic lupus develop it between ages 15 and 45 years.
Survival is estimated to be higher than 90% at 10 years after diagnosis. The highest mortality rate is in patients with progressive renal involvement or CNS disease. The two most frequent causes of death are renal failure and infectious complications.
Signs and Symptoms
SLE is a disease of acute and chronic inflammation. Symptoms of SLE often mimic other, less serious illnesses. Fever is one of the most common clinical manifestations of SLE. Disease activity accounts for more than 66% of febrile episodes in patients with SLE. Antibodies with elevated titers that are characteristic of lupus disease activity rather than infection include anti-dsDNA and anti–ribosomal P antibodies, as well as reduced levels of complement and leukopenia.
Many of the clinical manifestations of SLE are a consequence of tissue damage from vasculopathy mediated by immune complexes. Other conditions (e.g., thrombocytopenia, antiphospholipid syndrome) are the direct effects of antibodies to cell surface molecules or serum components.
Manifestations of the disease range from a typical mild illness limited to a photosensitive facial rash and transient diffuse arthritis to life-threatening involvement of the CNS or renal, cardiac, or respiratory system (Fig. 29-1). In the early phases, it is often difficult to distinguish SLE from other systemic rheumatic disorders, such as progressive systemic sclerosis (PSS), polymyositis, primary Sjögren’s syndrome, primary Raynaud’s phenomenon, and rheumatoid arthritis. Polyarthritis and dermatitis are the most common clinical manifestations.
The course of the disease is highly variable. It usually follows a chronic and irregular course, with periods of exacerbations and remissions. Clinical signs and symptoms can include fever, weight loss, malaise, arthralgia (joint pain) and arthritis (inflammation of the joints), and the characteristic erythematous, maculopapular (“butterfly”) rash over the bridge of the nose (Table 29-2). In addition, there is a tendency toward increased susceptibility to common and opportunistic infections. Multiple organ systems may be affected simultaneously.
Table 29-2
Systemic Lupus Erythematosus Symptoms
| Symptom | Percentage of Cases |
| Achy joints (arthralgia) | 95 |
| Frequent fevers >37.8° C (100° F) | 90 |
| Arthritis (swollen joints) | 90 |
| Prolonged or extreme fatigue | 81 |
| Skin rashes | 74 |
| Anemia | 71 |
| Kidney involvement | 50 |
| Pain in the chest on deep breathing (pleurisy) | 45 |
| Butterfly-shaped rash across the cheek and nose | 42 |
| Sun or light sensitivity (photosensitivity) | 30 |
| Hair loss | 27 |
| Abnormal blood clotting problems | 20 |
| Raynaud’s phenomenon (fingers turning white and/or blue in the cold) | 17 |
| Seizures | 15 |
| Mouth or nose ulcers | 12 |
Adapted from Lupus Foundation of America: General Lupus Fact Sheet, 2012 (http://www.lupus.org/webmodules/webarticlesnet/?z=8&a=351org).
Infection
About 20% of episodes of fever are caused by infections in patients with SLE. Infections are the leading cause of death in hospitalized patients. Infections can be caused by bacterial, viral, fungal, or parasitic pathogens. Immunosuppression produced by treatment (e.g., steroids) can interfere with host defense against opportunistic infections (e.g., Mycobacterium tuberculosis, Histoplasma capsulatum, Listeria monocytogenes).
Cutaneous Features
Approximately 20% to 25% of patients with SLE develop dermal disorders as the initial manifestation of the disease. As many as 65% of patients will develop a cutaneous abnormality during the course of the disease. The characteristic erythematous, maculopapular butterfly rash across the nose and upper cheeks is the cutaneous feature for which the disease is named—lupus erythematosus, the “red wolf” (Fig. 29-2). This rash may also be observed on the arms and trunk. Exposure to UV light will worsen erythematous, as well as other types of, cutaneous lesions.
The spectrum of cutaneous abnormalities includes urticaria, angioedema, nonthrombocytopenic purpura associated with the presence of cryoglobulins, scale formation, and ulcerations of oral and genital mucous membranes. Although neither the collection of immunoglobulins and complement at the dermal-epidermal junction nor the presence of specific antibody nuclear ribonucleoprotein (RNP), Sm, native DNA, and single-stranded DNA appears to play a direct role in the pathogenesis of cutaneous lupus lesion, Ro (SS-A) and perhaps La (SS-B) antibodies may be prominent factors.
Diffuse or patchy alopecia is also a common cutaneous manifestation. Hair loss is caused by pustular lesions of the scalp and is usually related to the stress of the disease process. Although the cause of pustular lesions is unknown, these inflammatory infiltrates are characterized by the presence of predominantly Ia-positive (activated) T lymphocytes with both CD4+ and CD8+ phenotypes.
Approximately 2% to 3% of SLE patients demonstrate lupus panniculitis. This condition is characterized by tender or nontender subcutaneous nodules that sometimes ulcerate and discharge a yellowish lipid material. In addition, various nonspecific skin changes are observable secondary to vascular insults. Raynaud’s phenomenon is demonstrated by approximately one third of patients with SLE and appears to be increased in those who have antibodies to nuclear RNP in their serum.
The presence of lesions does not distinguish between the limited cutaneous (discoid lupus erythematosus) and cutaneous manifestations of SLE. The term discoid lupus is used to differentiate the benign dermatitis of cutaneous lupus from the cutaneous involvement of SLE. In discoid lupus, the round lesion is an erythematous inflammatory dermatosis. These lesions are primarily located in light-exposed areas of the skin.
Renal Characteristics
Complement-mediated injury to the renal system is a usual consequence of the high levels of immune complexes in the blood that are deposited in tissues such as the kidneys. Renal disease progression is highly unpredictable. It may be acute, but more typically it progresses slowly. As the kidneys degenerate, the urinary sediment is typical of acute glomerulonephritis and later of chronic glomerulonephritis. Acute glomerulonephritis is characterized by the presence of erythrocytes, leukocytes, and granular and red blood cell (RBC) casts in urinary sediment. The presence of proteinuria may lead to nephrotic syndrome. If end-stage renal disease (renal failure) occurs, it can be managed by dialysis or allograft transplantation.
The systemic necrotizing vasculitis of SLE involves small blood vessels and leads to renal involvement. The most common method of classification of the renal involvement of SLE is the World Health Organization (WHO) system, which is based on histopathologic criteria. The stages of renal disease range from the earliest and least severe form, class II, characterized by mesangial deposits of immunoglobulin and C3, to class V, the most severe form of involvement.
Lymphadenopathy
Enlargement of peripheral and axial lymph nodes and splenomegaly both occur in patients with SLE, but these conditions are usually transient. Patients with SLE may be at greater risk of developing lymphoma than the general population, especially those with secondary Sjögren’s syndrome.
Serositis
Serositis is an inflammation of the membrane consisting of mesothelium, a thin layer of connective tissue that lines enclosed body cavities. Mesothelium, a type of epithelium, is originally derived from the mesoderm lining the primitive embryonic body cavity. It becomes the covering of the serous membranes of the body surfaces such as the peritoneum, pleura, and pericardium. Inflammation of these serosal surfaces leads to sterile peritonitis, pleuritis, or pericarditis and is frequently accompanied by severe pain. Serositis is associated with an increased frequency of thrombophlebitis, which may lead to pulmonary embolization.
Cardiopulmonary Characteristics
Inflammation of the myocardium in patients with SLE can produce persistent tachycardia and, occasionally, intractable congestive heart failure. Ischemic disease or, more often, atherosclerotic coronary disease may occur. Patients with severe nephrosis or those treated with corticosteroids for a prolonged period are at an increased risk for developing atherosclerosis.
Pulmonary function studies reveal occult diffusion and obstructive abnormalities in a high proportion of SLE patients, but clinical problems secondary to pulmonary involvement are unusual. Massive hemoptysis may result from acute alveolar hemorrhage. This particular complication occurs in the absence of any detectable bleeding diathesis and is associated with a high rate of mortality.
Gastrointestinal Manifestations
Nonspecific gastrointestinal symptoms are relatively common in patients with SLE, but acute abdominal crises caused by visceral and peritoneal vasculitis are less common. Infarction and perforation of the bowel and viscera are associated with a high rate of mortality. Acute and chronic pancreatitis may also develop as a secondary complication of acute lupus or as a complication during therapy.
Musculoskeletal Features
A characteristic arthritis of SLE is a transient and peripheral polyarthritis with symmetric involvement of small and large joints. Chronic arthritis can result in disability and deformity in SLE patients. Rheumatoid-like hand deformities develop in about 10% of patients. Osteonecrosis develops in 25% of all SLE patients. Arthropathy of osteonecrosis, or avascular necrosis, is often initially detected in weight-bearing joints such as the hips and knees.
Neuropsychiatric Features
In SLE, various neuropsychiatric manifestations develop secondary to involvement of the central and peripheral nervous systems. CNS involvement in SLE includes inflammation of the brain or intracranial blood vessels (vasculitis) and ischemic complications of vasculitis.
The most common abnormalities are disturbances of mental function, ranging from mild confusion, with memory deficiency and impairment of orientation and perception, to psychiatric disturbances such as hypomania, delirium, and schizophrenia. The most common manifestations are cognitive dysfunction, headache, seizures, and psychiatric conditions. Aseptic meningitis, stroke, encephalopathy, movement disorders, and myelopathy can be observed.
Seizures of the grand mal type may be the initial manifestation of SLE and may be present long before the multisystem disease develops. In addition, some patients may have epilepsy and severe headaches.
Antiribosomal P antibodies have been detected in patients with lupus suffer from psychosis or depression.
Late-Onset Lupus
Lupus can occur at any age, in either gender, and in any race. The average age of onset is 59 years; the average age at diagnosis is 62 years. Late-onset lupus affects women eight times more often than men. Late-onset lupus is found primarily in whites, but it occurs in all races.
Symptoms in most cases are relatively mild, but symptoms of lupus in older people can mimic those of other diseases (e.g., rheumatoid arthritis, Sjögren’s syndrome, polymyalgia rheumatica). Distinguishing among these disorders can be difficult and may result in a delayed or missed diagnosis. Drug-induced lupus occurs more often in older people because they are more likely to have conditions (e.g., high blood pressure, heart disease) that require treatment that may cause the symptoms of lupus. Symptoms generally fade when the medication is discontinued. Patients with late-onset lupus have a good survival rate and rarely die of the disease or complications of therapy when treated conservatively.
Immunologic Manifestations
B lymphocytes, T lymphocytes, and dendritic cells are involved in the pathogenesis of SLE. The pathogenesis of this systemic autoimmune disorder is characterized by the loss of tolerance to nuclear antigens, deposition of immune complexes in tissues, and multiorgan involvement.
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