> Table of Contents > Lupus Erythematosus, Systemic (SLE)
Lupus Erythematosus, Systemic (SLE)
Katherine M. Tromp, PharmD
Hershey S. Bell, MD, MS, FAAFP
image BASICS
DESCRIPTION
  • Systemic lupus erythematosus (SLE) is a multisystem autoimmune inflammatory disease characterized by a chronic relapsing/remitting course; can be mild to severe and may be life-threatening (CNS and renal forms)
  • System(s) affected: mucocutaneous; musculoskeletal; renal; nervous; pulmonary; cardiac; hematologic; vascular; gastrointestinal (GI)
  • Synonym(s): SLE; lupus
EPIDEMIOLOGY
Predominant age: 15 to 45 years
Incidence
  • Per year, 1.6 to 7.6/100,000 and increasing due to better diagnosis
  • Most common: African American women (8.1 to 11.4/100,000/year)
  • Least common: Caucasian men (0.3 to 0.9/100,000/year)
Prevalence
Occurs in 30 to 50/100,000 and increasing due to increased survival
ETIOLOGY AND PATHOPHYSIOLOGY
  • Skin: photosensitivity; scaly erythematous, plaques with follicular plugging, dermal atrophy, and scarring; nonscarring erythematous psoriasiform/annular rash; alopecia; mucosal ulcers
  • Musculoskeletal: nonerosive arthritis; ligament and tendon laxity, ulnar deviation, and swan neck deformities; avascular necrosis
  • Renal: glomerulonephritis
  • Pulmonary: pleuritis, pleural effusion, alveolar hemorrhage, pneumonitis, interstitial fibrosis, pulmonary hypertension, pulmonary embolism (PE)
  • Cardiac: nonbacterial verrucous endocarditis, pericarditis, myocarditis, atherosclerosis
  • CNS: thrombosis of small intracranial vessels ± perivascular inflammation resulting in micro- or macroinfarcts ± hemorrhage
  • Peripheral nervous system: mononeuritis multiplex, peripheral neuropathy
  • GI: pancreatitis, peritonitis, colitis
  • Hematologic: hemolytic anemia, thrombocytopenia, leukopenia, lymphopenia
  • Vascular: vasculitis, thromboembolism
  • Most cases are idiopathic with possible environmental factors.
  • Drug-induced lupus: hydralazine, D penicillamine, quinidine, procainamide, minocycline, isoniazid, etc
Genetics
  • Identical twins: 24-58% concordance
  • Fraternal twins and siblings: 2-5% concordance
  • 8-fold risk if first-degree relative with SLE
  • Major histocompatability complex associations: HLA-DR2, HLA-DR3
  • Deficiency of early complement components, especially C1q, C1r/s, C2, and C4
  • Immunoglobulin receptor polymorphisms: FC&ggr;R2A, FC&ggr;R3A, and others
  • Polymorphism in genes associated with regulation of programmed cell death, protein tyrosine kinases, and interferon production
RISK FACTORS
  • Race: African Americans, Hispanics, Asians, and Native Americans
  • Predominant sex: females > males (8:1)
  • Environmental: UV light, infectious agents, stress, diet, drugs, hormones, vitamin D deficiency, and tobacco
COMMONLY ASSOCIATED CONDITIONS
  • Overlap syndromes: rheumatoid arthritis (RA), Sjögren syndrome, scleroderma
  • Antiphospholipid syndrome; coronary artery disease; nephritis; depression
image DIAGNOSIS
Consider SLE in multisystem disease including fever, fatigue, and signs of inflammation.
PHYSICAL EXAM
  • Vital signs: fever, hypertension
  • Malar, discoid, psoriasiform, or annular rash, alopecia
  • Oral/nasal ulcers (often minimally symptomatic)
  • Lymphadenopathy, splenomegaly
  • Acrocyanosis
  • Inflammatory arthritis, tenosynovitis
  • Pleural/pericardial rub, heart murmur
  • Bibasilar rales
  • Cranial/peripheral neuropathies
DIFFERENTIAL DIAGNOSIS
Undifferentiated connective tissue disease, Sjögren syndrome, fibromyalgia, RA, vasculitis, idiopathic thrombocytopenia purpura, antiphospholipid antibody syndrome, drug-induced lupus
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Antinuclear antibody (ANA)
    • High sensitivity (98%), low specificity
    • False-positive rate of 5-30%: elderly, autoimmune thyroid/liver disease, chronic infection, etc
    • Low titers <1:160 of limited clinical use
  • Anti-double-stranded DNA (dsDNA) and anti-Smith antibodies: high specificity for SLE; predictor of nephritis and hemolytic anemia
    • Correlates with disease activity
  • RNA protein antibodies (anti-RNP, anti-Ro, anti-La): less specific for SLE
  • False-positive Venereal Disease Research Laboratory (VDRL) test: high sensitivity, low specificity. Surrogate marker of cardiolipin antibody presence
  • Low serum complement levels: C3, C4
  • Erythrocyte sediment rate (ESR): nonspecific, often high in active disease
  • CBC: hemolytic anemia, thrombocytopenia, leukopenia, or lymphopenia
  • Serum creatinine: elevated in lupus nephritis
  • Urinalysis (UA): proteinuria, hematuria, cellular cast
  • Phospholipid antibodies: cardiolipin immunoglobulin (Ig) G/IgM, lupus anticoagulant, &bgr;2-glycoprotein IgG/IgM
  • Anti-P (ribosomal autoantibodies) is associated with SLE arthritis and disease activity.
  • Initial imaging is dependent on presenting symptoms.
  • Radiograph of involved joints
  • Chest x-ray: infiltrates, pleural effusion, low lung volumes
  • Chest CT scan, ventilation-perfusion (V-Q) scan, duplex ultrasound for PE or deep vein thrombosis
  • Head CT scan: ischemia, infarct, hemorrhage
  • Brain MRI: focal areas of increased signal intensity
  • Echocardiogram: pericardial effusion, valvular vegetations, pulmonary hypertension
  • Contrast angiography for medium-size artery vasculitis: mesenteric/limb ischemia, CNS symptom
Follow-Up Tests & Special Considerations
  • Hemolytic anemia: elevated reticulocyte count and indirect bilirubin, low haptoglobin, positive direct Coombs test
  • Confirm positive phospholipid antibodies results in 12 weeks.
  • If phospholipid antibodies are initially negative, but symptoms arise, repeat, as they may become positive over time.
  • 24-hour urine collection/spot protein/creatinine to quantify proteinuria
  • Histone antibodies present in >95% of druginduced lupus (vs. 80% of idiopathic SLE)
  • Fasting lipid panel and glucose
  • Follow vitamin D[25(O)H] levels and replenish PRN.
Diagnostic Procedures/Other
  • Renal biopsy to diagnose lupus nephritis (if UA abnormal)
  • Skin biopsy with immunofluorescence on involved and uninvolved non-sun-exposed skin (lupus band test) may help differentiate SLE rash from others.
  • Lumbar puncture in patients with fever and CNS/meningeal symptoms
  • EEG for seizures/global CNS dysfunction
  • Neuropsychiatric testing for cognitive impairment
  • EMG/nerve conduction study (NCS) for peripheral neuropathy and myositis
  • Nerve and/or muscle biopsy
  • ECG, cardiac enzymes, stress tests
  • American College of Rheumatology classification (not diagnostic) criteria: any 4 of the 11 listed (95% specificity and 85% sensitivity):
    • Malar (butterfly) rash
    • Discoid rash
    • Photosensitivity: by patient history/physician observation
    • Oral/nasopharyngeal ulcers
    • Nonerosive arthritis: involving ≥2 peripheral joints
    • Pleuritis OR pericarditis
    • Renal disorder: proteinuria (>0.5 g/day or >3+)
      P.619

      OR cellular casts (red cell, hemoglobin, granular, tubular, or mixed)
    • Neurologic disorder: psychosis/seizures
    • Hematologic disorder: hemolytic anemia, leukopenia (<4,000/mm3 on ≥2 tests), lymphopenia (<1,500/mm3 on ≥2 tests), thrombocytopenia (<100,000/mm3)
    • Immunologic disorder: anti-DNA, anti-Sm, anticardiolipin IgG/IgM, lupus anticoagulant, or false-positive VDRL findings
    • Positive ANA in absence of drugs known to cause positive ANA
Test Interpretation
  • Skin: vascular/perivascular inflammation, immunecomplex deposition at dermal-epidermal junction, mucinosis, basal layer vacuolar changes
    • Similar findings seen in other connective tissue disorders such as dermatomyositis
  • Renal: mesangial hypercellularity/matrix expansion, subendothelial/subepithelial immune deposits, glomerular sclerosis, fibrous crescents
    • Vary depending on degree of involvement
  • Vascular: immune-complex deposition in vessel walls with fibrinoid necrosis and perivascular mononuclear cell infiltrates, intraluminal fibrin thrombi
image TREATMENT
GENERAL MEASURES
  • Education, counseling, and support
  • Influenza/pneumococcal vaccines are safe; avoid live vaccines in immunocompromised patients.
  • Low-estrogen oral contraceptives safe in mild SLE
MEDICATION
First Line
  • Antimalarial agents and NSAIDs are first-line therapy for patients with mild SLE (1)[A].
    • Hydroxychloroquine for constitutional and musculoskeletal symptoms, rash, mild serositis; may reduce flares and increase long-term survival (2,3)[A]. NSAIDs for musculoskeletal manifestations, mild serositis, headache, and fever (2)[C]
  • Systemic glucocorticoids (prednisone or equivalent)
    • Low dose (<0.5 mg/kg) for minor disease activity not responsive to NSAIDs or when NSAIDs are contraindicated (2)[A]
    • High-dose (1 to 2 mg/kg/day) (2)[A] or IV pulse methylprednisolone for organ-threatening disease, particularly CNS and renal; often combined with immunosuppressive agent (2)[A]
  • Topical glucocorticosteroids for skin manifestations
Second Line
  • Belimumab as adjunct for preventing flares in patients with active lupus despite first-line therapy (4)[A]
    • 10 mg/kg IV every 2 weeks × 3 doses, then monthly
  • Methotrexate (2)[A], azathioprine (2)[B], mycophenolate mofetil (2)[C], or leflunomide as steroid-sparing agent for persistent active disease or to maintain remission
    • Requires laboratory monitoring for toxicity
  • Treatments under investigation: rituximab, epratuzumab, abatacept, interferon-&agr; inhibitors
  • Immunosuppressive agents for severe disease
    • Cyclophosphamide (2)[A]: adequate hydration to reduce risk of hemorrhagic cystitis
    • Mycophenolate mofetil (2)[A]: more efficacious for lupus nephritis (1)[A]
SURGERY/OTHER PROCEDURES
Renal transplant for end-stage renal disease
COMPLEMENTARY & ALTERNATIVE MEDICINE
Biofeedback, visual imagery, cognitive therapy
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • Difficult to differentiate SLE flare from infection; may need to treat both pending full evaluation
  • IV pulse Solu-Medrol 1 g/day for 3 to 5 days for lifeor organ-threatening disease (2)[A]
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Clinical evaluation for signs and symptoms
    • Weekly to monthly for active disease
    • Every 3 to 6 months for mild/inactive disease
  • Measures of disease activity and damage: Systemic Lupus Erythematosus Disease Activity Index, British Isles Lupus Assessment Group Index, European Consensus Lupus Activity Measure
  • Laboratory studies
    • CBC with differential
    • Serum creatinine, UA
    • Vitamin D
    • Declining C3/C4 and rising DS-DNA and ESR may correlate with disease activity.
  • Monitor for adverse effects of treatment
    • NSAIDs: GI bleeding and/or ulceration
    • Glucocorticoids: glucose, lipids, bone density
    • Hydroxychloroquine: ophthalmologic exam every 6 to 12 months
    • Methotrexate: CBC, creatinine, albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) every 2 months
    • Azathioprine and mycophenolate mofetil: CBC every 1 to 3 months
    • Cyclophosphamide
      • CBC, creatinine, UA every 2 weeks, and liver function tests monthly during treatment
      • UA every 6 to 12 months for life
DIET
  • No special diet unless for complications such as renal failure, diabetes, hyperlipidemia (2)[C]
  • Adequate calcium/vitamin D intake in patients on corticosteroids (2)[A]
  • Low glycemic index or calorie-restricted diet in patients on corticosteroids
PATIENT EDUCATION
  • Avoid UV light exposure: sunscreens (SPF ≥30), protective clothing (2)[B]
  • Weight control, smoking cessation, exercise (2)[C]
  • Stress avoidance/management
PROGNOSIS
  • Permanent treatment-free remission is uncommon.
  • 5-year survival after diagnosis is 95%.
  • Poor prognostic factor: major organ involvement
  • Drug-induced lupus resolves within weeks to months after discontinuation of the offending drug.
REFERENCES
1. Yildirim-Toruner C, Diamond B. Current and novel therapeutics in the treatment of systemic lupus erythematosus. J Allergy Clin Immunol. 2011;127(2):303-312.
2. Bertsias G, Ioannidis JP, Boletis J, et al. EULAR recommendations for the management of systemic lupus erythematosus. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. Ann Rheum Dis. 2008;67(2):195-205.
3. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, et al. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis. 2010;69(1):20-28.
4. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721-731.
Additional Reading
&NA;
Lisnevskaia L, Murphy G, Isenberg D. Systemic lupus erythematosus. Lancet. 2014;384(9957):1878-1888.
See Also
&NA;
Antiphospholipid Antibody Syndrome
Codes
&NA;
ICD10
  • M32.9 Systemic lupus erythematosus, unspecified
  • M32.10 Systemic lupus erythematosus, organ or system involv unsp
  • M32.14 Glomerular disease in systemic lupus erythematosus
Clinical Pearls
&NA;
  • Aggressiveness of therapy should reflect intensity of disease.
  • Most important diagnostic test is the UA: if abnormal, order kidney biopsy; serum and urine lab values often do not reveal extent of kidney disease.
  • Atherosclerotic and atheroembolic complications are the major cause of death; address modifiable cardiovascular risk factors.