Epidemiology

• Women: 15–44 years

Etiology

• Genetic predisposition
  • HLA-DR2 and HLA-DR3 are commonly present in individuals with SLE.
  • Genetic deficiency of classical pathway complement proteins (C1q, C2, C4) in approx. 10% of affected individuals
• Hormonal factors: Hyperestrogenic states (e.g., due to oral contraceptive use, postmenopausal hormonal therapy, endometriosis) are associated with an increased risk of SLE.
• Environmental factors
  • Cigarette smoking and silica exposure increase the risk of developing SLE.
  • UV light and EBV infection may trigger disease flares
    • Ultraviolet rays and sun exposure lead to increased cell apoptosis
  • Drugs such as procainamide or hydralazine (see “Drug-induced lupus erythematosus”)

Pathophysiology

Hypotheses:

1. Autoantibody development: deficiency of classical complement proteins (C1q, C4, C2) → failure of macrophages to phagocytose immune complexes and apoptotic cell material (i.e., plasma and nuclear antigens) → dysregulated, intolerant lymphocytes targeting normally hidden intracellular antigens → autoantibody production (e.g., ANA, anti-dsDNA)
   • Normally, apoptotic cells are engulfed by macrophages during apoptosis, avoiding the release of intracellular content that induces inflammation or an immune response in the extracellular environment.
2. Autoimmune reactions
   • Type III hypersensitivity (most common in SLE) → antibody-antigen complex formation in microvasculature → complement activation and inflammation → damage to skin, kidneys, joints, small vessels
   • Type II hypersensitivity → IgG and IgM antibodies directed against antigens on cells (e.g., red blood cells) → cytopenia

Clinical features

• SLE is a systemic disease characterized by phases of remission and relapse.
• SLE can affect any organ.

Common

• Constitutional: fatigue, fever, weight loss
• Joints (> 90% of cases)
  • Arthritis and arthralgia
  • Distal symmetrical polyarthritis: most commonly affects the joints of the fingers, carpal joints, and the knee
• Skin (85% of cases)
  • Malar rash (butterfly rash): flat or raised fixed erythema over both malar eminences (nasolabial folds tend to be spared)
  • Raynaud phenomenon
  • Photosensitivity → maculopapular rash
    • Ultraviolet rays and sun exposure lead to increased cell apoptosis
  • Discoid rash
  • Oral ulcers (usually painless)
  • Nonscarring alopecia (except with discoid rashes)
  • Periungual telangiectasia

Less common

• Hematological: petechiae, pallor, or recurrent infections due to cytopenias
  • Warm AIHA, IgG causes extravascular hemolysis.
• Kidneys: nephritis with proteinuria (see “Lupus nephritis”)
  • Mesangial and/or subendothelial deposition of immune complexes (e.g., anti-dsDNA antibodies, anti-Sm antibodies) → expansion and thickening of mesangium, capillary walls, and/or glomerular basement membrane
• Heart
  • Pericarditis, myocarditis, endocarditis (Libman-Sacks endocarditis)
  • Aortic valve lesions (e.g. Mitral valve prolapse)
  • Coronary artery disease

Diagnostics

Laboratory studies

• Antinuclear antibodies (ANAs)
  • Positive titers of ≥ 1:80 have ∼ 98% sensitivity for SLE
• Antigen-specific ANAs: Request only if ANAs are positive.
  • Anti-dsDNA antibodies
    • Autoantibodies against double-stranded DNA
    • Positive in 60–70% of patients
    • Highly specific for SLE
    • Levels correlate with disease activity (especially lupus nephritis activity).
  • Anti-Sm antibodies
    • Autoantibodies against Smith antigens (nonhistone nuclear proteins)
      • Smith can bond to snRNAs to form snRNPs, which can form a spliceosome.
    • Positive in < 30% of patients, but highly specific for SLE
• Antiphospholipid antibodies: Screen all patients for antiphospholipid syndrome.
• Laboratory markers of disease activity and/or organ damage in SLE
  • Complement levels: ↓ C3 and/or ↓ C4 in patients with active disease, factor B levels remain normal
    • Antigen-antibody complexes trigger classic pathway, which decreases C3 and C4. But factor B in alternative pathway is intact.
  • Inflammatory markers
    • ESR: may be elevated in patients with active disease
    • CRP: often normal (may be elevated in patients with serositis, arthritis, or infections)
  • CBC: may show leukopenia, thrombocytopenia, and/or autoimmune hemolytic anemia or anemia of chronic disease
  • CMP: may show ↑ BUN and/or creatinine, and/or electrolyte abnormalities
  • Urinalysis and urine microscopy: may show proteinuria, hematuria, and/or urinary casts

Skin biopsy

• Lupus band test (LBT): a direct immunofluorescence staining technique used to detect immunoglobulin and complement component deposits along the dermoepidermal junction in affected and unaffected skin in patients with SLE

Treatment

Complications

Cardiovascular disease

• ↑ Risk of thrombosis in all patients with SLE (especially if secondary antiphospholipid syndrome is present)
• ↑ Risk of myocardial infarction and stroke because of accelerated atherosclerosis