Systemic lupus erythematosus (SLE) is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and arthritis, malar and other rashes, pleuritis or pericarditis, renal or CNS involvement, and hematologic cytopenias. Diagnosis requires clinical and serologic criteria. Treatment of severe, ongoing, active disease requires corticosteroids, often hydroxychloroquine, and sometimes immunosuppressants.
Of all cases, 70 to 90% occur in women (usually of child-bearing age). SLE is more common among blacks and Asians than whites. Some drugs (eg, hydralazine, procainamide, isoniazid) cause a reversible lupus-like syndrome.
Symptoms and Signs
"MD SOAP 'N HAIR"
Joint manifestations: Joint symptoms, ranging from intermittent arthralgias to acute polyarthritis, occur in about 90% of patients and may precede other manifestations by years. Most lupus polyarthritis is nondestructive and nondeforming.
Skin and mucous membrane manifestations: Skin lesions include malar butterfly erythema (flat or raised) that generally spares the nasolabial folds. The absence of papules and pustules helps distinguish SLE from rosacea. A variety of other erythematous, firm, maculopapular lesions can occur elsewhere, including exposed areas of the face and neck, upper chest, and elbows. Skin blistering and ulceration are rare, although recurrent ulcers on mucous membranes are common.
Neurologic manifestations: Neurologic symptoms can result from involvement of any part of the central or peripheral nervous system or meninges. Mild cognitive impairment is common. There may also be headaches, personality changes, ischemic stroke, subarachnoid hemorrhage, seizures, psychoses, organic brain syndrome, aseptic meningitis, peripheral and cranial neuropathies, transverse myelitis, or cerebellar dysfunction.
Renal manifestations: Renal involvement can develop at any time and may be the only manifestation of SLE. It may be benign and asymptomatic or progressive and fatal. Renal lesions can range in severity from a focal, usually benign, glomerulitis to a diffuse, potentially fatal, membranoproliferative glomerulonephritis. Common manifestations include proteinuria (most often), an abnormal urinary sediment manifested by RBC casts and leukocytes, hypertension, and edema.
Hematologic manifestations: Hematologic manifestations include anemia (autoimmune hemolytic), leukopenia (usually lymphopenia, with < 1500 cells/μL), and thrombocytopenia (sometimes life-threatening autoimmune thrombocytopenia). Recurrent arterial or venous thrombosis, thrombocytopenia, and a high probability of obstetric complications occur in patients with antiphospholipid antibodies. Thromboses probably account for many of the complications of SLE, including obstetric complications.
GI manifestations: GI manifestations can result from bowel vasculitis or impaired bowel motility. In addition, pancreatitis can result from SLE or perhaps from its treatment with high-dose corticosteroids or azathioprine. Manifestations may include abdominal pain resulting from serositis, nausea, vomiting, manifestations of bowel perforation, and pseudo-obstruction. SLE rarely causes parenchymal liver disease.
• Clinical criteria
SLE should be suspected in patients, particularly young women, with any of the symptoms and signs. Laboratory testing differentiates SLE from other connective tissue disorders. Routine testing should include the following:
• Antinuclear antibodies (ANA) and anti–double-stranded (ds) DNA
• Chemistry profile including renal and liver enzymes
Fluorescent ANA: The fluorescent test for ANA is the best screen for SLE; positive ANA tests (usually in high titer: > 1:80
) occur in > 98%. However, positive ANA tests can also occur in RA, other connective tissue disorders, cancers, and even in the general population. The false-positive rate varies from about 3% for ANA titers of 1:32
0 to about 30% for ANA titers of 1:40
among healthy controls. Drugs such as hydralazine, procainamide, and TNF-α antagonists can produce positive ANA results as well as a lupus-like syndrome; the ANA eventually becomes negative if the drug is stopped.
Other blood tests: Abnormal values in one or more of these assays suggest the presence of antiphospholipid antibodies (eg, anticardiolipin antibodies), which should then be measured directly by enzyme-linked immunosorbent assay (ELISA). Antiphospholipid antibodies are associated with arterial or venous thrombosis, thrombocytopenia, and, during pregnancy, spontaneous abortion or late fetal death but may be present in asymptomatic patients.
Renal involvement: Screening for renal involvement begins with urinalysis. RBC and/or WBC casts suggest active nephritis. Urinalysis should be done at regular intervals, even for patients in apparent remission, because kidney disease may be asymptomatic.
• NSAIDs and often antimalarials for mild disease
• Corticosteroids and often immunosuppressants for severe disease
Mild or remittent disease: Little or no therapy may be needed. Arthralgias are usually controlled with NSAIDs. Antimalarials help, particularly when joint and skin manifestations are prominent. Hydroxychloroquine 200 mg po once/day or bid reduces the frequency of SLE flares. Alternatives include chloroquine 250 mg po once/day and quinacrine 50 to 100 mg po once/day. Hydroxychloroquine can rarely cause retinal and skeletal or cardiac muscle toxicity. The eyes should be examined at 12-mo intervals.
Severe disease: Corticosteroids are first-line therapy. A combination of prednisone and immunosuppressants is recommended in active, serious CNS lupus, vasculitis especially affecting viscera or nerves, or active lupus nephritis. Methylprednisolone 1 g by slow (1-h) IV infusion on 3 successive days is often the initial treatment. Then, prednisone given in doses of 40 to 60 mg po once/day can be maintained, but the dose may vary according to the manifestation of SLE. In severe renal involvement, cyclophosphamide is usually given in intermittent IV pulses instead of daily oral doses; eg, about 500 mg to 1 g/m2 IV (together with mesna and fluid loading to protect the bladder) monthly for 6 mo and then once q 3 mo for 18 mo.
• Joint and skin manifestations are classic in SLE, but the disorder can affect various organ systems, such as the skin, heart and lungs, lymphoid tissue, kidneys, and GI, hematologic, reproductive, and nervous systems.
• Among tests, use the highly sensitive ANA for screening, but use more specific autoantibodies (eg, anti-dsDNA, anti-Sm) for confirmation.
• Evaluate all patients for kidney involvement.
• Treat mild disease with an NSAID or an antimalarial such as chloroquine or hydroxychloroquine.
• Use corticosteroids for moderate or severe SLE and often an immunosuppressant for nephritis, CNS disease, and vasculitis or if corticosteroids are ineffective.
• Use corticosteroids at the lowest possible dose to maintain remission.
A 35-year-old black woman has complained of weight loss and fatigue for several weeks. In advising her on the phone as to measures to take before her appointment with you the following week, you asked her to keep a record of her temperature 4 times per day. She arrives for the appointment with the record. She also notes diffusely thinning hair. The temperature graph shows that her temperature has sometimes been as high as 101F. However, the high points of the daily graphs appear at various times in the early hours of the morning or late mornings, not in the afternoons or evenings. She complains also of arthralgia involving her metacarpophalangeal joints of the first and second fingers bilaterally, with 30 to 60 minutes of stiffness in the morning. A urinalysis yields microscopic hematuria and red cell casts. Which of the following diagnoses is most likely, given the combination of clinical findings?
A. Chronic glomerulonephritis
B. Alopecia areata
D. Chronic pyelonephritis
E. Pulmonary tuberculosis
The answer is C. Systemic Lupus Erythematosus occurs in black women 4 times as frequently as in white women and 23 times as frequently as in white men. The febrile course that does not follow the normal diurnal variation occurs in inflammatory processes not involving response to infection. Eventually, some two-thirds of patients have arthralgia or arthritis. Nearly 3 of 4 have skin manifestations, of which alopecia is fairly common; of course, the facial butterfly rash, not shown in this patient, is a hall- mark of the disease. Renal involvement is found in 16% to 38% of cases. Pulmonary tuberculosis would manifest not only pulmonary symptoms but also a febrile course with normal diurnal variation. Although each of the other choices may be characterized by at least one of the clinical findings in the vignette, none except lupus would mani- fest all of them.
A 28-year-old woman has had deep vein thrombosis in the past 3 years and is in the emergency department with a diagnosis of pulmonary embolism. Laboratory studies over the following 2 days revealed normal levels of Proteins C and S and antithrombin III. Further testing showed a positive lupus erythematosus preparation. Serologic test for syphilis is falsely positive. There is no rash; renal function is normal. Which of the following might be the most helpful laboratory test at this point?
A. Complete blood cell (CBC)
B. Sedimentation rate
C. Anticardiolipin antibody level
D. Prothrombin time
E. Hemoglobin A1C
The answer is C. Anticardiolipin antibodies are as close to specific as it gets in the murky field of autoimmune diseases, which virtually are all defined arbitrarily. The diagnosis is anti-phospholipid antibody disease. The most significant reason to be aware of this syndrome is the high risk of both intravenous and intra-arterial thromboses. The disease is basically a subset of LE.
A patient has fatigue and joint pain and is concerned about the possibility of systemic lupus erythematosus (SLE) after reading about this condition on the Internet. After taking a brief history you decide that further evaluation is appropriate. In addition to the history and physical findings, which one of the following laboratory findings would most support the diagnosis of SLE?
A. An abnormal C-reactive protein level
B. An erythrocyte sedimentation rate of 48 mm/hr
C. A positive antimicrosomal antibody test
D. A positive test for antiphospholipid antibodies
E. A positive test for rheumatoid factor
ANSWER: D. The criteria for the diagnosis of systemic lupus erythematosus (SLE) includes the presence of an immunologic disorder. Evidence of an immunologic disorder includes a positive finding of antiphospholipid antibodies, based upon one of the following: an abnormal serum level of immunoglobulin G or M anticardiolipin antibodies, a positive lupus anticoagulant test, or a false-positive serologic test for syphilis. The other test results listed are not criteria for the diagnosis of SLE.
For several years, a hypertensive 65-year-old female has been treated with hydrochlorothiazide, 25 mg/day; atenolol, 100 mg/day; and hydralazine, 50 mg 4 times/day. Her blood pressure has been well controlled on this regimen. Over the past 2 months she has experienced malaise, along with diffuse joint pains that involve symmetric sites in the fingers, hands, elbows, and knees. A pleural friction rub is noted on examination. Laboratory testing shows that the patient has mild anemia and leukopenia, with a negative rheumatoid factor and a positive antinuclear antibody (ANA) titer of 1:64
0. Which one of the following would be the most appropriate INITIAL step?
A. Replace hydrochlorothiazide with furosemide
B. Discontinue hydralazine
C. Start prednisone, 40 mg/day orally
D. Start hydroxychloroquine, 400 mg/day
E. Order renal function studies and anticipate that a renal biopsy will be needed
ANSWER: B. There are many drugs that can induce a syndrome resembling systemic lupus erythematosus, but the most common offenders are antiarrhythmics such as procainamide. Hydralazine is also a common cause. There is a genetic predisposition for this drug-induced lupus, determined by drug acetylation rates. Polyarthritis and pleuropericarditis occur in half of patients, but CNS or renal involvement is rare. While all patients with this condition have positive antinuclear antibody titers and most have antibodies to histones, antibodies to double-stranded DNA and decreased complement levels are rare, which distinguishes drug-induced lupus from idiopathic lupus.
The best initial management for drug-induced lupus is to withdraw the drug, and most patients will improve in a few weeks. For those with severe symptoms, a short course of corticosteroids is indicated. Once the offending drug is discontinued, symptoms seldom last beyond 6 months.