Systemic Lupus Erythematosus

Essentials of Diagnosis

• Occurs mainly in young women

• Rash over areas exposed to sunlight

• Joint symptoms in 90% of patients

• Anemia, leukopenia, thrombocytopenia

• Glomerulonephritis, central nervous system disease, and complications of antiphospholipid antibodies are major sources of disease morbidity

• Serologic findings: antinuclear antibodies (100%), anti–double-stranded DNA antibodies (approximately two-thirds), and low serum complement levels (particularly during disease flares)

General Considerations

• An inflammatory autoimmune disorder

• Characterized by autoantibodies to nuclear antigens

• Can affect multiple organ systems

• Many of its clinical manifestations are secondary to the trapping of antigen-antibody complexes in capillaries of visceral structures or to autoantibody-mediated destruction of host cells (eg, thrombocytopenia)

• The clinical course is marked by spontaneous remission and relapses

• Severity may vary from a mild episodic disorder to a rapidly fulminant, life-threatening illness

Demographics

• About 85% of patients are women

• Sex hormones play a role; most cases develop after menarche and before menopause

• Among older individuals, the sex distribution is more equal

• Race is also a factor, as SLE occurs in 1:1000 white women but in 1:250 black women

• Familial occurrence of SLE has been repeatedly documented

Symptoms and Signs

• The systemic features include fever, anorexia, malaise, and weight loss

• Most patients have skin lesions at some time

  • The characteristic "butterfly" (malar) rash affects less than half of patients

  • Other cutaneous manifestations are

    • Panniculitis (lupus profundus)

    • Discoid lupus

    • Typical fingertip lesions

    • Periungual erythema

    • Nail fold infarcts

    • Splinter hemorrhages

• Alopecia is common

• Mucous membrane lesions tend to occur during periods of exacerbation

• Raynaud phenomenon, present in about 20% of patients, often antedates other features of the disease

• Joint symptoms, with or without active synovitis

  • Occur in over 90% of patients

  • Often the earliest manifestation

  • The arthritis can lead to reversible swan-neck deformities, but erosive changes are almost never noted on radiographs

  • Subcutaneous nodules are rare

• Ocular manifestations include

  • Keratoconjunctivitis sicca

  • Retinal vasculopathy, for example

    • Cotton-wool spots

    • Episcleritis

    • Scleritis

    • Optic neuropathy

• Pulmonary manifestations

  • Pleurisy and pleural effusion (common)

  • Pneumonitis, interstitial lung disease, and pulmonary hypertension (rare)

  • Alveolar hemorrhage (uncommon but life-threatening)

• Cardiac manifestations

  • The pericardium is affected in the majority of patients

  • Heart failure may result from myocarditis and hypertension

  • Cardiac arrhythmias are common

  • Atypical verrucous endocarditis of Libman-Sacks is usually clinically silent but occasionally can produce acute or chronic valvular regurgitation—most commonly mitral regurgitation

• Mesenteric vasculitis

  • May closely resemble polyarteritis nodosa, including the presence of aneurysms in medium-sized blood vessels

  • Abdominal pain (particularly postprandial), ileus, peritonitis, and perforation may result

• Several forms of glomerulonephritis may occur, including mesangial, focal proliferative, diffuse proliferative, and membranous; some patients may also have interstitial nephritis

• Hematologic manifestations include

  • Leukopenia

  • Autoimmune hemolytic anemia

  • Immune thrombocytopenia

  • Thrombotic thrombocytopenic purpura

Differential Diagnosis

• Drug-induced lupus

• Rheumatoid arthritis

• Systemic vasculitis

• Scleroderma

• Primary antiphospholipid syndrome

• Inflammatory myopathies

• Viral hepatitis

• Sarcoidosis

• Acute drug reactions

• The diagnosis of SLE can be made with reasonable probability if 4 of the following 11 criteria are met

  • Malar rash

  • Discoid rash

  • Photosensitivity

  • Oral ulcers

  • Arthritis

  • Serositis

  • Kidney disease

    • > 0.5 g/day proteinuria, or

    • ≥ 3+ dipstick proteinuria, or

    • Cellular casts

  • Neurologic disease

    • Seizures, or

    • Psychosis (without other cause)

  • Hematologic disorders

    • Hemolytic anemia, or

    • Leukopenia (< 4000/mcL), or

    • Lymphopenia (< 1500/mcL), or

    • Thrombocytopenia (< 100,000/mcL)

  • Immunologic abnormalities

    • Antibody to native DNA, or

    • Antibody to Sm, or

    • Antibodies to antiphospholipid antibodies based on (1) IgG or IgM anticardiolipin antibodies, (2) lupus anticoagulant, or (3) false-positive serologic test for syphilis

  • Positive antinuclear antibodies (ANA)

• These criteria, developed as guidelines for the inclusion of patients in research studies, do not supplant clinical judgment

Laboratory Findings

• ANA tests

  • When based on immunofluorescence assays using HEp-2 cells (a human cell line) as a source of nuclei, nearly 100% sensitive but not specific

  • False-negative results can occur with tests for ANAs based on multiplex assays that use specific nuclear antigens rather than cell lines

  • Therefore, SLE should not be excluded on the basis of a negative multiplex assay for ANAs

• Antibodies to double-stranded DNA and to Sm are specific for SLE but not sensitive

• Anti–double-stranded DNA antibody levels also correlate with disease activity in some patients; anti-Sm levels do not

• Other autoantibodies commonly seen in SLE include antibodies to SS-A/Ro, SS-B/La, ribonucleoprotein (RNP), and phospholipid

• During disease flares, elevations in the erythrocyte sedimentation rate are common, but the serum C-reactive protein is usually normal unless there is serositis or arthritis

• Patient education and emotional support are important

• Patients should be cautioned against sun exposure and should apply a protective lotion to the skin while outside

• Skin lesions often respond to the local administration of corticosteroids

• Minor joint symptoms can usually be alleviated by rest and NSAIDs

• Hydroxychloroquine (an antimalarial)

  • May be helpful in treating lupus rashes or joint symptoms

  • Appears to reduce the incidence of severe disease flares

  • Dosage: 200 or 400 mg/day orally and should not exceed 5 mg/kg/day

  • Annual monitoring for retinal changes is recommended

• Corticosteroids

  • Required for the control of certain complications

    • Glomerulonephritis

    • Hemolytic anemia

    • Pericarditis or myocarditis

    • Alveolar hemorrhage

    • CNS involvement

    • Thrombotic thrombocytopenic purpura

  • Forty to 60 mg of oral prednisone is often needed initially; however, the lowest dose of corticosteroid that controls the condition should be used

  • Higher doses of corticosteroids than are usually given may be required by CNS lupus; however, corticosteroid psychosis may mimic lupus cerebritis, in which case reduced doses are appropriate

• Immunosuppressive agents such as cyclophosphamide, mycophenolate mofetil, azathioprine, methotrexate or tacrolimus are used for long-term control of disease

• Cyclophosphamide

  • Improves renal survival but not patient survival

  • Dosage according to the National Institutes of Health regimen: 3–6 monthly intravenous pulses [0.5–1 g/m²] for induction followed by maintenance infusions every 3 months

  • Dosage according to the Euro-Lupus regimen: 500 mg intravenously every 2 weeks for 6 doses followed by maintenance with azathioprine

• Mycophenolate mofetil (1000 or 1500 mg orally twice daily) or cyclophosphamide are first-line induction treatments for lupus nephritis

  • Cyclophosphamide is usually administered using the Euro-Lupus regimen (500 mg intravenously every 2 weeks for six doses) but can also be administered according to the National Institutes of Health regimen (3–6 monthly intravenous pulses [0.5–1 g/m²] for induction followed by maintenance infusions every 3 months)

  • Mycophenolate mofetil or azathioprine are typically used for maintenance therapy for lupus nephritis

• Belimumab, a monoclonal antibody that inhibits the activity of a B-cell growth factor, is FDA approved for treating antibody-positive SLE patients with active disease who have not responded to standard therapies (eg, NSAIDs, antimalarials, or immunosuppressive therapies); it is not recommended for lupus nephritis or neuropsychiatric lupus and should not be used in conjunction with cyclophosphamide

• Rituximab is usually reserved for life-threatening or organ-threatening manifestations that have failed conventional therapies

Follow-Up

• Patients should receive influenza vaccination every year and pneumococcal vaccination every 5 years

• Preventive cancer screening recommendations should be followed assiduously, since patients with SLE have a higher risk of development malignancy (especially lymphoma, lung cancer, and cervical cancer) than the general population

Complications

• Neurologic complications include

  • Psychosis

  • Cognitive impairment

  • Seizures

  • Peripheral and cranial neuropathies

  • Transverse myelitis

  • Strokes

• Severe depression and psychosis are sometimes exacerbated by the administration of large doses of corticosteroids

• A substantial portion of patients with severe lupus nephritis still eventually require renal replacement therapy

Course & Prognosis

• With appropriate therapy, the survival rate even for patients with serious chronic kidney disease (proliferative glomerulonephritis) is favorable

• 10-year survival rates exceeding 85% are routine

• In most patients, the illness pursues a relapsing and remitting course

• There are some patients in whom the disease pursues a virulent course, leading to serious impairment of vital structures such as lungs, heart, brain, or kidneys, and the disease may lead to death

• Fertility is normal; women can pursue pregnancy under close supervision and when SLE is well-controlled and no teratogenic medications are being used

• Mortality in SLE shows a bimodal pattern

  • In the early years after diagnosis, infections—especially with opportunistic organisms—are the leading cause of death, followed by active SLE, chiefly due to kidney or central nervous system disease

  • In later years, accelerated atherosclerosis, linked to chronic inflammation, becomes a major cause of death

When to Refer

• Appropriate diagnosis and management of SLE requires the active participation of a rheumatologist

• The severity of organ involvement dictates referral to other subspecialists, such as nephrologists and pulmonologists

When to Admit

• Rapidly progressive glomerulonephritis, pulmonary hemorrhage, transverse myelitis, and other severe organ-threatening manifestations of lupus usually require in-patient assessment and management

• Severe infections, particularly in the setting of immunosuppressant therapy, should prompt admission