Epidemiology

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”)

Hypotheses:

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.
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

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
Serositis: Pleuritis (pleuritic chest pain), pericarditis.

Tip

Both rheumatoid arthritis and SLE arthritis affect the MCP and PIP joints, but SLE does not usually lead to deformities.

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

Best initial test: ANA (Antinuclear Antibody) - highly sensitive (>95%) but not specific.
Most specific antibodies: Anti-dsDNA and Anti-Sm (Anti-Smith).
- 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

Tip

RPR and VDRL are usually used to test for syphilis but may also be positive in SLE. This happens in antiphospholipid syndrome as well.

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

General: Sun protection, smoking cessation.
Mild disease (skin, joints): Hydroxychloroquine (for all patients), NSAIDs, low-dose corticosteroids.
- Hydroxychloroquine: decreases complement-dependent antigen-antibody reactions.
Moderate disease (serositis, significant cytopenias): Add moderate-dose corticosteroids, possibly immunosuppressants like azathioprine or methotrexate.
Severe disease/Lupus Nephritis: High-dose corticosteroids plus cyclophosphamide or mycophenolate mofetil.

↑ 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