(Disseminated Lupus Erythematosus)
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 skin 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. It can affect patients of any age, including neonates. Increased awareness of mild forms has resulted in a worldwide rise in reported cases. In some countries, the prevalence of SLE rivals that of RA. SLE may be precipitated by currently unknown environmental triggers that cause autoimmune reactions in genetically predisposed people. Some drugs (eg, hydralazine, procainamide, isoniazid) cause a reversible lupus-like syndrome.
Symptoms and Signs
Clinical findings vary greatly. SLE may develop abruptly with fever or insidiously over months or years with episodes of arthralgias and malaise. Vascular headaches, epilepsy, or psychoses may be initial findings. Manifestations referable to any organ system may appear. Periodic exacerbations (flares) may occur.
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. However, in long-standing disease, deformities without bone erosions may develop (eg, the metacarpophalangeal and interphalangeal joints may rarely develop ulnar drift or swan-neck deformities without bony or cartilaginous erosions [Jaccoud's arthritis]).
Skin and mucous membrane manifestations (see also Autoimmune Rheumatic Disorders: Variant Forms of Lupus):
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 (particularly the central portion of the hard palate near the junction of the hard and soft palate, the buccal and gum mucosa, and the anterior nasal septum) are common. Generalized or focal alopecia is common during active phases of SLE. Panniculitis can cause subcutaneous nodular lesions. Vasculitic skin lesions may include mottled erythema on the palms and fingers, periungual erythema, nail-fold infarcts, urticaria, and palpable purpura. Petechiae may develop secondary to thrombocytopenia. Photosensitivity occurs in most patients.
Cardiopulmonary symptoms commonly include recurrent pleurisy, with or without pleural effusion. Pneumonitis is rare, although minor impairments in pulmonary function are common. Severe pulmonary hemorrhage occasionally occurs. Prognosis has traditionally been poor but seems to be improving, possibly because of better early, aggressive, critical care. Other complications include pulmonary emboli, pulmonary hypertension, and shrinking lung syndrome. Cardiac complications include pericarditis (most commonly), pericardial effusion, and myocarditis. Serious, rare complications are coronary artery vasculitis, valvular involvement, and Libman-Sacks endocarditis. Accelerated atherosclerosis is an increasing cause of morbidity and mortality. Congenital heart block can develop in neonates.
Adenopathy and splenic manifestations:
Generalized adenopathy is common, particularly among children, young adults, and blacks. Splenomegaly occurs in 10% of patients. The spleen may develop periarterial fibrosis.
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 neuropathies, transverse myelitis, or cerebellar dysfunction.
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.
Obstetric manifestations include early and late fetal loss. In patients with antiphospholipid antibodies, the risk of recurrent miscarriages is increased. Pregnancy can be successful (see Pregnancy Complicated by Disease: Systemic lupus erythematosus), particularly after 6 to 12 mo of remission, but SLE flares are common during pregnancy. Pregnancy should be timed for when disease is in remission. During pregnancy, the patient should be monitored closely for any disease flare or thrombotic events by a multidisciplinary team that includes a rheumatologist, an obstetrician who specializes in high-risk pregnancies, and a hematologist.
Hematologic manifestations include anemia (often 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 can result from bowel vasculitis or impaired bowel motility. In addition, pancreatitis can result from SLE or from its treatment with corticosteroids or azathioprine. Manifestations may include abdominal pain from serositis, nausea, vomiting, manifestations of bowel perforation, and pseudo-obstruction. SLE rarely causes parenchymal liver disease.
SLE should be suspected in patients, particularly young women, with any of the symptoms and signs. However, early-stage SLE can mimic other connective (or nonconnective) tissue disorders, including RA if arthritic symptoms predominate. Mixed connective tissue disease can mimic SLE but also may involve features of systemic sclerosis, rheumatoid-like polyarthritis, and polymyositis or dermatomyositis. Infections (eg, bacterial endocarditis, histoplasmosis) can mimic SLE and may develop as a result of treatment-caused immunosuppression. Disorders such as sarcoidosis and paraneoplastic syndromes can also mimic SLE.
Laboratory testing differentiates SLE from other connective tissue disorders. Routine testing should include the following:
The diagnosis is especially likely if ≥ 4 of the criteria inTable 1: Autoimmune Rheumatic Disorders: Criteria for the Classification of SLE* are present at any time but is still possible if < 4 criteria are present. If the diagnosis is suspected but not established, additional testing for autoantibodies can be useful. Establishing the diagnosis may require repeated evaluations over months or years.
|Criteria for the Classification of SLE*
At least 4 of the following are required to classify patients as having SLE in reports of clinical research:
Leukopenia (< 4000/μL), lymphopenia (< 1500/μL), hemolytic anemia, or thrombocytopenia (< 100,000/μL)
Positive test for anti-DNA, anti-Smith, or antiphospholipid antibodies
Antinuclear antibodies in high titers
*These 11 criteria are from the American College of Rheumatology and are also often used as aids in diagnosis. Although at least 4 criteria are not needed to make a diagnosis of SLE, the criteria help in recognizing manifestations of SLE.
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 1:320 to about 30% for ANA titers of 1:40 among healthy controls. Drugs such as hydralazine, procainamide, and tumor necrosis factor (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. Positive ANA should prompt more specific testing such as anti–double-stranded DNA antibodies; high titers are highly specific for SLE but occur in only 25 to 30% of people with SLE.
Other ANA and anticytoplasmic antibodies:
The ANA test is very sensitive, but it is not specific for SLE; thus, evidence of other autoantibodies is needed to establish the diagnosis. They include Ro [SSA], La [SSB], Smith [Sm], ribonucleoprotein [RNP], and double-stranded DNA. Ro is predominantly cytoplasmic; anti-Ro antibodies are occasionally present in ANA-negative SLE patients presenting with chronic cutaneous lupus. Anti-Ro is the causal antibody for neonatal lupus and congenital heart block. Anti-Sm is highly specific for SLE but, like anti–double-stranded DNA, is not sensitive. Anti-RNP occurs in patients with SLE, mixed connective tissue disease, and occasionally other systemic autoimmune disorders and systemic sclerosis
Other blood tests:
Leukopenia (usually lymphopenia) is common. Hemolytic anemia may occur. Thrombocytopenia in SLE may be difficult or impossible to differentiate from idiopathic thrombocytopenic purpura except that patients have other features of SLE. False-positive serologic tests for syphilis occur in 5 to 10% of SLE patients. These test results may be associated with the lupus anticoagulant and a prolonged PTT. 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.
Other tests help monitor disease severity and determine the need for treatment. Serum complement levels (C3, C4) are often depressed in active disease and are usually lowest in patients with active nephritis. ESR is elevated frequently during active disease. C-reactive protein levels are not necessarily elevated.
Screening for renal involvement begins with urinalysis. RBC and WBC casts suggest active nephritis. Urinalysis should be done at regular intervals, even for patients in apparent remission, because kidney disease may be asymptomatic. Renal biopsy is usually not necessary for diagnosis of SLE or to confirm renal involvement but is helpful in evaluating the status of renal disease (ie, active inflammation vs postinflammatory scarring) and guide therapy. Patients with chronic renal insufficiency and mostly sclerotic glomeruli are not likely to benefit from aggressive immunosuppressive therapy.
The course is usually chronic, relapsing, and unpredictable. Remissions may last for years. If the initial acute phase is controlled, even if very severe (eg, with cerebral thrombosis or severe nephritis), the long-term prognosis is usually good. The 10-yr survival in most developed countries is > 95%. Improved prognosis is in part due to earlier diagnosis and more effective therapies. More severe disease requires more toxic therapies, which increase risk of mortality. Examples of such complications include infection from immunosuppression or osteoporosis from long-term corticosteroid use. Increased risk of coronary artery disease can contribute to premature death.
To simplify therapy, SLE should be classified as mild (eg, fever, arthritis, pleurisy, pericarditis, headache, rash) or severe (eg, hemolytic anemia, thrombocytopenic purpura, massive pleural and pericardial involvement, significant renal damage, acute vasculitis of the extremities or GI tract, florid CNS involvement).
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 toxicity. The eyes should be examined at 12-mo intervals.
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. Prednisone is usually given in doses of 40 to 60 mg po once/day, but the dose may vary according to the manifestation of SLE. Oral azathioprine 1 to 2.5 mg/kg once/day or oral cyclophosphamide 1 to 4 mg/kg once/day can be used as an immunosuppressant. For 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 (less frequently if there is renal or hematologic toxicity—see Table 2: Autoimmune Rheumatic Disorders: Protocol for Chemotherapy With Cyclophosphamide and IV Mesna).
|Protocol for Chemotherapy With Cyclophosphamide and IV Mesna
Use constant supervision regarding tolerance throughout entire procedure.
1. Using 50 mL of normal saline, mix ondansetron 10 mg and dexamethasone 10 mg and infuse over 10 to 30 min.
2. Using 250 mL of normal saline, mix in mesna 250-500 mg (used to bind acrolein, a metabolite of cyclophosphamide that is a bladder irritant) and infuse along with 500-1000 mL of normal saline before the infusion of cyclophosphamide.
3. Using 250 mL of normal saline, mix in cyclophosphamide 500-1000 mg/m2 and infuse over 1 h.
4. Using 250 mL of normal saline, mix in mesna 250-500 mg and infuse second dose of mesna. Total dose of mesna should be equal to the total dose of cyclophosphamide used. Patient should be encouraged to drink plenty of fluids and to empty bladder every 2 h. Patient must take ondansetron 8 mg po the next morning.
In CNS lupus or other critical crises, methylprednisolone 1 g by slow (1-h) IV infusion on 3 successive days is often the initial treatment, followed by IV cyclophosphamide, as mentioned previously. Mycophenolate mofetil is an alternative to cyclophosphamide therapy for patients with active kidney disease who have preserved kidney function. IgG 400 mg/kg IV once/day for 5 consecutive days may be useful for refractory thrombocytopenia. Patients with end-stage renal disease can undergo kidney transplantation, as an alternative to dialysis, with a successful outcome, especially if their disease has been in remission.
Improvement of severe SLE often takes 4 to 12 wk. Thrombosis or embolism of cerebral, pulmonary, or placental vessels requires short-term treatment with heparin and longer treatment with warfarin, if the diagnosis of antiphospholipid syndrome is confirmed. The target INR is usually 3.
For most patients, the risk of flares can be decreased without prolonged high-dose corticosteroids. Chronic disease should be treated with the lowest dose of corticosteroids and other drugs that control inflammation (eg, antimalarials, low-dose immunosuppressants). Treatment should be guided by clinical features primarily, although anti–double-stranded DNA antibody titers or serum complement levels may be followed. Other pertinent blood and urine tests may be used to assess specific organ involvement. Anti–double-stranded DNA antibody titers or serum complement levels may not parallel nonrenal disease flares. If a patient needs long-term high-dose corticosteroids, alternative oral immunosuppressants should be considered. Ca, vitamin D, and bisphosphonate therapy should be considered in patients taking corticosteroids long term.
Focal complications and coexisting medical conditions:
All patients should be closely monitored for atherosclerosis. Long-term anticoagulation is vital in patients with antiphospholipid antibodies and recurrent thrombosis (see Peripheral Venous Disorders: Anticoagulants).
If a pregnant patient has antiphospholipid antibodies, thrombotic complications can be limited with corticosteroids (prednisone ≤ 30 mg po once/day), low-dose aspirin, or anticoagulation with heparin. Daily heparin given subcutaneously with or without one baby aspirin throughout the 2nd and 3rd trimesters may be the most successful prophylactic measure.
Variant Forms of Lupus
Discoid lupus erythematosus (DLE):
DLE, also sometimes called chronic cutaneous lupus erythematosus, is a set of skin changes that can occur as part of lupus, with or without systemic involvement. Skin lesions begin as erythematous plaques and progress to atrophic scars. They cluster in light-exposed areas of the skin, such as the face, scalp, and ears. Untreated, lesions extend and develop central atrophy and scarring. There may be widespread scarring alopecia. Mucous membrane involvement may be prominent, especially in the mouth.
Patients presenting with typical discoid lesions should be evaluated for SLE. Antibodies against double-stranded DNA are almost invariably absent in DLE. Although it does not differentiate DLE from SLE, biopsy can rule out other disorders (eg, lymphoma or sarcoidosis). Biopsy should be done from the active margin of a skin lesion.
Early treatment can prevent permanent atrophy. Exposure to sunlight or ultraviolet light should be minimized (eg, using potent sunscreens when outdoors). Topical corticosteroid ointments (particularly for dry skin) or creams (less greasy than ointments) tid to qid (eg, triamcinolone acetonide 0.1 or 0.5%, fluocinolone 0.025 or 0.2%, flurandrenolide 0.05%, betamethasone valerate 0.1%, and, particularly betamethasone dipropionate 0.05%) usually cause involution of small lesions; they should not be used excessively or on the face (where they cause skin atrophy). Resistant lesions can be covered with plastic tape coated with flurandrenolide. Alternatively, intradermal injection with triamcinolone acetonide 0.1% suspension (< 0.1 mL per site) may resolve lesions, but secondary atrophy frequently follows. Antimalarials (eg, hydroxychloroquine 200 mg po once/day or bid) can help, including for facial lesions. In resistant cases, combinations (eg, hydroxychloroquine 200 mg/day plus quinacrine 50 to 100 mg po once/day) may be required for months to years.
Subacute cutaneous lupus erythematosus (SCLE):
SCLE is a variant form of SLE in which skin involvement is prominent. Patients with SCLE develop extensive recurring rashes. Annular or papulosquamous lesions may develop on the face, arms, and trunk. Lesions are usually photosensitive and can develop hypopigmentation but rarely scar. Arthritis and fatigue are common in SCLE, but neurologic and renal manifestations are not. Patients may be ANA-positive or ANA-negative. Most have antibodies to Ro (SSA). Infants whose mothers have Ro antibodies may have congenital SCLE or congenital heart block. SCLE should be treated similarly to SLE.
Last full review/revision February 2008 by Rula A. Hajj-ali, MD
Content last modified February 2012