Of all cases, 70 to 90% occur in women (usually of child-bearing age). Systemic lupus erythematosus (SLE) is more common among blacks and Asians than whites. It can affect patients of any age, including neonates. In some countries, the prevalence of SLE rivals that of rheumatoid arthritis (RA). SLE may be precipitated by currently unknown environmental triggers that cause autoimmune reactions in genetically predisposed people. Some drugs (eg, hydralazine, procainamide, isoniazid, anti-tumor necrosis factor [TNF] drugs) cause a reversible lupus-like syndrome.
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 reducible ulnar drift or swan-neck deformities without bony or cartilaginous erosions [Jaccoud arthritis]). As in many other chronic diseases, the prevalence of fibromyalgia is increased, which may cause diagnostic confusion in patients with periarticular and generalized pain and fatigue.
Skin and mucous membrane manifestations (see also Variant Forms of Lupus Variant Forms of Lupus Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more )
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 (sometimes called mucosal lupus); findings can sometimes mimic toxic epidermal necrolysis.
Generalized or focal alopecia is common during active phases of SLE. Panniculitis can cause subcutaneous nodular lesions (sometimes called lupus panniculitis or profundus). 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 some patients.
Lupus erythematosus tumidus is characterized by pink to violaceous urticarial nonscarring plaques and/or nodules, some annular, in light-exposed areas.
Chilblain lupus is characterized by tender, bright red to reddish blue nodules on the toes, fingers, nose, or ears that occur in cold weather. Some patients with SLE have features of lichen planus Lichen Planus Lichen planus is a recurrent, pruritic, inflammatory eruption characterized by small, discrete, polygonal, flat-topped, violaceous papules that may coalesce into rough scaly plaques, often accompanied... read more .
Raynaud syndrome Raynaud Syndrome Raynaud syndrome is vasospasm of parts of the hand in response to cold or emotional stress, causing reversible discomfort and color changes (pallor, cyanosis, erythema, or a combination) in... read more due to vasospasm in the fingers and toes causes characteristic blanching and cyanosis.
Cardiopulmonary symptoms commonly include recurrent pleurisy, with or without pleural effusion. Pneumonitis is rare, although minor impairments in pulmonary function are common. Diffuse alveolar hemorrhage occasionally occurs. Prognosis has traditionally been poor. Other complications include pulmonary emboli, pulmonary hypertension, and shrinking lung syndrome. Cardiac complications include pericarditis (most commonly) 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 whose mother has the antibodies against Ro (SSA) or La (SSB).
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, aseptic meningitis, peripheral and cranial neuropathies, transverse myelitis, choreoathetosis, 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 Membranoproliferative Glomerulonephritis Membranoproliferative glomerulonephritis is a heterogeneous group of disorders that share mixed nephritic and nephrotic features and microscopic findings. They mostly affect children. Cause... read more . Common manifestations include proteinuria (most often), an abnormal urinary sediment manifested by red blood cell casts and leukocytes, hypertension, and edema. Early lupus glomerulonephritis may be misdiagnosed as asymptomatic urinary tract infection.
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 Systemic Lupus Erythematosus in Pregnancy Systemic Lupus Erythematosus in Pregnancy Autoimmune disorders are 5 times more common among women, and incidence tends to peak during reproductive years. Thus, these disorders commonly occur in pregnant women. Antiphospholipid antibody... read more ), particularly after 6 to 12 months of remission, but SLE flares are common during pregnancy and during the postpartum period. 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 an obstetrician who specializes in high-risk pregnancies. Women who are SSA antibody-positive should have weekly fetal ultrasonography between week 18 and week 26 to assess for congenital heart block.
Hematologic manifestations include anemia (autoimmune hemolytic), leukopenia (usually lymphopenia, with < 1500 cells/mcL), 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. Macrophage activation syndrome can occur.
Gastrointestinal manifestations can result from bowel vasculitis or impaired bowel motility. In addition, pancreatitis can result from SLE. Manifestations may include abdominal pain resulting 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 rheumatoid arthritis if arthritic symptoms predominate. Mixed connective tissue disease can mimic SLE but also may involve features of systemic sclerosis, rheumatoid-like polyarthritis, and polymyositis. 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:
In clinical practice, some clinicians rely on the classification criteria for SLE developed by the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR; see table EULAR/ACR Criteria for the Classification of Systemic Lupus Erythematosus EULAR/ACR Criteria for the Classification of Systemic Lupus Erythematosus[a] Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more ). Patients are eligible for these criteria only if they have a positive ANA ≥ 1:80. The 2019 EULAR/ACR classification criteria include clinical and immunologic domains, and each criterion is assigned a weight of 2 to 10. If the patient's score is 10 or more, and at least one clinical criterion is fulfilled, disease is classified as SLE.
The fluorescent test for ANA is the best initial test for SLE in patients who have compatible symptoms and signs; positive ANA tests (usually in high titer: > 1:80) occur in > 98% of people with SLE. However, positive ANA tests can also occur in rheumatoid arthritis, other connective tissue disorders, autoimmune thyroid disease, cancers, and even in the general population. The false-positive rate varies from about 3% with 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-alpha 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-dsDNA antibodies; high titers of anti-dsDNA are highly specific for SLE but occur in < 70% of people with SLE.
The ANA test is very sensitive, but it is not specific for SLE; thus, evidence of other autoantibodies is used to aid in diagnosis. They include Ro (SSA), La (SSB), Smith (Sm), ribonucleoprotein (RNP), and dsDNA. 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-dsDNA, is not sensitive. Anti-RNP occurs in patients with SLE, mixed connective tissue disease, and occasionally other systemic autoimmune disorders and systemic sclerosis.
Leukopenia Overview of Leukopenias Leukopenia is a reduction in the circulating white blood cell (WBC) count to read more (usually lymphopenia) is common. Hemolytic anemia Overview of Hemolytic Anemia At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span ( read more may occur. Thrombocytopenia in SLE may be difficult or impossible to differentiate from idiopathic thrombocytopenic purpura except that patients have other features of SLE and/or SLE-specific antibodies (anti-dsDNA or anti-Sm). 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 partial thromboplastin time (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. Erythrocyte sedimentation rate (ESR) is elevated frequently during active disease. C-reactive protein levels are not necessarily elevated.
Screening for renal involvement begins with urinalysis. Red blood cell (RBC) and/or white blood cell casts suggest active nephritis. Urinalysis should be done at regular intervals (eg, every 3 to 6 months), even for patients in apparent remission, because kidney disease is usually asymptomatic. Renal biopsy is indicated in patients whose protein excretion is > 500 mg/day and who have hematuria (thought to be glomerular) or RBC casts, which can be estimated by the urine protein/creatinine ratio or measured in a 24-hour urine collection. Renal biopsy is helpful in evaluating the status of renal disease (ie, active inflammation vs postinflammatory scarring) and in guiding 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-year survival in most developed countries is > 95%. Improved prognosis is in part due to earlier diagnosis and more effective therapies. 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, rash) or severe (eg, hemolytic anemia, severe thrombocytopenic purpura, massive pleural and pericardial involvement, diffuse alveolar hemorrhage or pneumonitis, nephritis, acute vasculitis of the extremities or gastrointestinal tract, florid central nervous system [CNS] involvement).
The antimalarial drug hydroxychloroquine is indicated for all patients with SLE regardless of disease severity because it decreases disease flares and decreases mortality (1 Treatment reference Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more ); however, hydroxychloroquine is not used in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzymatic defect common in blacks, which can result in hemolysis after acute illnesses or intake of oxidant drugs (including... read more because it can cause hemolysis.
(See also recommendations for the management of SLE from the European League Against Rheumatism [EULAR].)
Arthralgias are usually controlled with NSAIDs. However, chronic NSAID use is discouraged because of gastrointestinal adverse effects (eg, peptic ulcer disease) and potential renal toxicity (eg, interstitial nephritis, papillary necrosis).
Antimalarials, such as hydroxychloroquine, are useful for joint and skin manifestations. Hydroxychloroquine reduces the frequency of SLE flares and decreases mortality. Dose is 5 mg/kg orally of actual body weight once a day. Baseline ophthalmologic examination should be done before starting therapy to exclude maculopathy because chronic hydroxychloroquine use increases the risk of toxic maculopathy. Ophthalmologic screening should be done yearly after the drug has been used for 5 years to assess for retinal toxicity. Alternatives include oral chloroquine 250 mg once a day and oral quinacrine 50 to 100 mg once a day. (See also recommendations on screening for chloroquine and hydroxychloroquine retinopathy.) Hydroxychloroquine can rarely cause skeletal or cardiac muscle toxicity.
Treatment includes induction therapy to control acute severe manifestations followed by maintenance therapy. Corticosteroids are first-line therapy. A combination of a corticosteroid (usually methylprednisolone 1 g IV every day for 3 days) and other immunosuppressants is typically used in active severe disease (ie, lupus nephritis with impaired renal function or CNS involvement).
The complication for which there is the strongest evidence for treatment efficacy is lupus nephritis Lupus Nephritis Lupus nephritis is glomerulonephritis caused by systemic lupus erythematosus (SLE). Clinical findings include hematuria, nephrotic-range proteinuria, and, in advanced stages, azotemia. Diagnosis... read more . Methylprednisolone 1 g by slow (1-hour) IV infusion on 3 successive days is often the initial treatment. Then, oral prednisone given in doses of 40 to 60 mg once a day can be maintained, but the dose may vary according to the manifestation of SLE. Cyclophosphamide (see table IV Cyclophosphamide Protocols for Systemic Lupus Erythematosus IV Cyclophosphamide Protocols for Systemic Lupus Erythematosus Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more ) or mycophenolate mofetil (3 g/day orally in 2 doses) is also used for induction therapy along with corticosteroids.
Cyclophosphamide use for more than 6 months is discouraged because of potential toxicities, including increased risk of cancer. Once disease control is achieved, patients are transitioned to either mycophenolate mofetil (1 to 1.5 g orally 2 times a day) or azathioprine (1 to 3 mg/kg orally once a day) for maintenance. Women of childbearing age for whom cyclophosphamide is being considered should be informed about the risk of gonadal toxicity and offered a fertility consult for egg harvesting when possible.
In CNS lupus, including transverse myelitis, treatment recommendations are based on anecdotal evidence, and options include IV cyclophosphamide or IV rituximab (eg, 1 g on day 1 and day 15 given at 6-month intervals).
First-line therapy for thrombocytopenia and hemolytic anemia includes moderate- or high-dose corticosteroids (typically prednisone, 1 mg/kg orally once a day, maximum 80 mg a day) along with an immunosuppressant (azathioprine or mycophenolate mofetil). IV immune globulin 400 mg/kg once a day for 5 consecutive days or 1 g/kg once a day for 2 days may be useful, particularly if high-dose corticosteroids are contraindicated (eg, in patients with active infection). Rituximab is an alternative option for refractory cases. (See also recommendations for the management of SLE from the European League Against Rheumatism [EULAR].)
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 weeks. 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, lifelong therapy (usually warfarin) is usually indicated. The target international normalized ratio is usually 2 to 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 (eg, oral prednisone ≤ 7.5 mg once a day or its equivalent) and other drugs that control inflammation (eg, antimalarials, immunosuppressants [mycophenolate mofetil or azathioprine]) to maintain remission. (See also recommendations for the management of SLE from the European League Against Rheumatism [EULAR].) Treatment should be guided by clinical features primarily, although anti-dsDNA antibody titers or serum complement levels may be followed, particularly if they have correlated with disease activity in the past. However, anti-dsDNA antibody titers or serum complement levels may not parallel nonrenal disease flares. Other pertinent blood and urine tests may be used to assess specific organ involvement.
If a patient needs long-term high-dose corticosteroids, alternative oral immunosuppressants such as azathioprine, methotrexate (in the absence of significant renal disease), or mycophenolate mofetil should be considered. Calcium, vitamin D, and bisphosphonate therapy (see prevention of osteoporosis Prevention Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more ) should be considered in patients taking corticosteroids long term.
All patients should be closely monitored for atherosclerosis, and cardiovascular risk reduction is a key part of management (see treatment of atherosclerosis Treatment Atherosclerosis is characterized by patchy intimal plaques (atheromas) that encroach on the lumen of medium-sized and large arteries; the plaques contain lipids, inflammatory cells, smooth muscle... read more ). Long-term anticoagulation is vital in patients with antiphospholipid antibodies and history of thrombosis (see Anticoagulants Anticoagulants Deep venous thrombosis (DVT) is clotting of blood in a deep vein of an extremity (usually calf or thigh) or the pelvis. DVT is the primary cause of pulmonary embolism. DVT results from conditions... read more ).
Pregnant women should remain on hydroxychloroquine throughout their pregnancy, and low-dose aspirin is recommended as well. When clinical antiphospholipid syndrome is present, as manifested by prior thrombotic events, full anticoagulation therapy with low molecular weight or unfractionated heparin is advised. If the pregnant woman has positive antiphospholipid syndrome antibodies and prior late-stage fetal loss or recurrent 1st trimester miscarriages, prophylactic low molecular weight or unfractionated heparin can be considered during pregnancy and 6 weeks postpartum. When the patient has positive serologies but no prior obstetric or thrombotic events, recommendations are less clear. Comanagement by a hematologist, an obstetrician, and a rheumatologist is key in managing these patients.
Mycophenolate mofetil and other drugs are teratogenic. Because of this teratogenicity and the known poor outcomes related to active SLE during pregnancy, women should ideally conceive after their disease has been in remission for 6 months or longer. If the patient needs to remain on immunosuppression (eg, ongoing maintenance therapy for lupus nephritis), mycophenolate mofetil is usually switched to azathioprine at least 6 months prior to conceiving.
1. Alarcón GS, McGwin G, Bertoli AM, et al: Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: Data from LUMINA, a multiethnic US cohort (LUMINA L). Ann Rheum Dis 66(9):1168–1172, 2007. doi: 10.1136/ard.2006.068676.
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.
The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) criteria can be used to confirm the diagnosis of SLE.
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 all patients with hydroxychloroquine or another antimalarial and, for mild disease, NSAIDs as needed.
Use corticosteroids for moderate or severe SLE and an immunosuppressant for active lupus nephritis, CNS lupus, skin manifestations that do not respond to hydroxychloroquine, diffuse alveolar hemorrhage, vasculitis, recurrent serositis, or cardiac manifestations.
Use corticosteroids at the lowest possible dose and other drugs that control inflammation to maintain remission.
Recommendations for the management of SLE from the European League Against Rheumatism (EULAR)
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. Sometimes lesions are hypertrophic and may mimic lichen planus (called hypertrophic or verrucous lupus).
Patients presenting with typical discoid lesions should be evaluated for systemic lupus erythematosus (SLE) Diagnosis Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more . Antibodies against dsDNA 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 of DLE 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) 3 to 4 times a day (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, oral hydroxychloroquine 5 mg/kg once a day or 2.5 mg/kg 2 times a day) are also considered first-line therapy, including for facial lesions. If first-line therapy fails, combination therapy with hydroxychloroquine 200 mg/day plus oral quinacrine 50 to 100 mg once a day or hydroxychloroquine plus methotrexate, mycophenolate mofetil, or azathioprine is used.
Patients with SCLE develop extensive recurring rashes. Annular or papulosquamous lesions (psoriasiform lesions) may develop on the face, arms, and trunk. Lesions are usually photosensitive and can develop hypopigmentation but rarely scar. SCLE can be drug-induced, for example, triggered by antihypertensives (eg, diuretics, calcium channel blockers, beta blockers), proton pump inhibitors (eg, omeprazole, pantoprazole), anti-tumor necrosis factor (TNF) biologics (eg, adalimumab), and antifungal drugs (eg, terbinafine).
About 30 to 62% of patients with SCLE fulfill the American College of Rheumatology's classification criteria for SLE. Arthritis and fatigue are common in SCLE, but neurologic and renal manifestations are not. Patients may be antinuclear antibody (ANA)-positive or ANA-negative. Patients usually have antibodies to Ro (SSA). Infants whose mother has Ro antibodies may have congenital SCLE or congenital heart block. SCLE is treated similarly to SLE Treatment Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more .