Systemic Lupus Erythematosus (SLE)
Multisystem autoimmune disease with autoantibodies against nuclear antigens and immune-complex tissue injury.
Also known as: SLE, lupus, systemic lupus
Overview
Chronic relapsing-remitting autoimmune disease characterized by loss of tolerance to nuclear self-antigens, production of autoantibodies (notably ANA, anti-dsDNA, anti-Smith), and immune-complex deposition that drives inflammation across skin, joints, kidneys, blood, serosa, and the central nervous system.
Epidemiology
Female-to-male ratio ~9:1; peak onset 15-44 years. More common and more severe in Black, Hispanic, and Asian populations. Lupus nephritis is the strongest predictor of morbidity.
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Risk factors
- Female sex, reproductive age
- Black, Hispanic, Asian ancestry
- Family history of SLE or other autoimmune disease
- Environmental triggers: UV light, smoking, EBV exposure, silica
- Hormonal: estrogens, oral contraceptives
- Drug-induced lupus triggers (hydralazine, procainamide, isoniazid, minocycline, anti-TNF agents)
Pathophysiology
Defective clearance of apoptotic debris exposes nuclear antigens that bind self-reactive B and T cells. Autoantibodies form immune complexes that deposit in glomeruli, skin, and serosa, activating complement (low C3, C4) and recruiting neutrophils. Tissue injury results from immune-complex deposition, type I interferon overactivation, and direct cytotoxic mechanisms.
Clinical presentation
Symptoms
- Constitutional: fatigue, low-grade fever, weight loss
- Mucocutaneous: malar (butterfly) rash sparing nasolabial folds, discoid lesions, photosensitivity, oral or nasal ulcers (often painless), nonscarring alopecia
- Musculoskeletal: symmetric small-joint polyarthralgia/arthritis, typically nonerosive (Jaccoud arthropathy if deforming)
- Serositis: pleuritic chest pain, pericardial pain
- Renal: foamy urine, edema (lupus nephritis)
- Neuropsychiatric: headache, seizures, psychosis, cognitive dysfunction, stroke
- Hematologic: easy bruising, recurrent infection (cytopenias)
- Raynaud phenomenon
Signs / physical exam
- Malar rash, discoid plaques, oral ulcers
- Synovitis of MCPs, PIPs, wrists, knees
- Pleural or pericardial friction rub
- Hypertension and peripheral edema (nephritis)
- Livedo reticularis (consider APS)
Differential diagnosis
- Drug-induced lupus — Hydralazine, procainamide, isoniazid, minocycline, anti-TNFs; anti-histone antibodies positive; renal and CNS involvement rare; resolves on withdrawal
- Rheumatoid arthritis — Erosive symmetric polyarthritis; RF/anti-CCP positive; rarely causes renal disease or photosensitive rash
- Mixed connective tissue disease — Overlap of SLE, scleroderma, polymyositis; high-titer anti-U1 RNP
- Antiphospholipid syndrome — Arterial/venous thrombosis, pregnancy loss; lupus anticoagulant, anti-cardiolipin, anti-beta2 GP1; can coexist with SLE
- Fibromyalgia — Diffuse pain without inflammation; normal labs; often coexists with SLE and confounds disease activity assessment
- Viral arthritis (parvovirus B19, hepatitis C) — Self-limited polyarthritis ± rash; serologies and time course distinguish
- Behcet disease — Oral and genital aphthae, uveitis, pathergy; ANA negative
Diagnostic workup
Diagnostic criteria
EULAR/ACR 2019 classification criteria: ANA ≥1:80 as entry, then weighted clinical and immunologic domains (total ≥10 points classifies).
Labs
- ANA — screening test; sensitivity >95% but low specificity
- Anti-dsDNA — specific; titer correlates with disease activity (especially nephritis)
- Anti-Smith — highly specific
- Anti-Ro/SSA, anti-La/SSB (sicca features, neonatal lupus, subacute cutaneous lupus)
- Anti-U1 RNP (mixed connective tissue disease overlap)
- Antiphospholipid antibodies — lupus anticoagulant, anti-cardiolipin, anti-beta2 GP1
- Complement C3, C4 — low during active disease
- CBC (cytopenias), Coombs test if hemolysis
- Urinalysis with sediment, urine protein-to-creatinine ratio, BMP
- ESR elevated; CRP often normal-to-mildly elevated (use to flag infection)
Imaging
- Renal biopsy — definitive for lupus nephritis classification (ISN/RPS classes I-VI); guides immunosuppression
- Echo if pericardial effusion or Libman-Sacks endocarditis suspected
- MRI brain for neuropsychiatric SLE workup
Diagnostic algorithm
| Autoantibody | Clinical Association |
|---|---|
| ANA | Sensitive screen (>95%); not specific |
| Anti-dsDNA | Specific; tracks nephritis activity |
| Anti-Smith | Highly specific for SLE |
| Anti-Ro/SSA, anti-La/SSB | Sicca, subacute cutaneous lupus, neonatal lupus (congenital heart block) |
| Anti-U1 RNP | Mixed connective tissue disease overlap |
| Antiphospholipid (LAC, aCL, anti-beta2 GP1) | Thrombosis, pregnancy loss |
| Anti-histone | Drug-induced lupus |
| Low C3 / C4 | Active disease, especially nephritis |
Treatment
First-line
- Sun protection and smoking cessation for all patients
- Hydroxychloroquine 200-400 mg/day — foundational for all SLE; reduces flares, organ damage, and mortality (baseline eye exam, annually after 5 years)
- NSAIDs — ibuprofen, naproxen — for mild musculoskeletal or serositis symptoms (caution with renal disease)
- Low-dose glucocorticoids — prednisone ≤7.5 mg/day for ongoing activity; higher doses or pulse methylprednisolone for major organ flares
Complications
- Lupus nephritis → ESRD
- Accelerated atherosclerosis (premature CAD, stroke)
- Antiphospholipid syndrome — thrombosis, recurrent miscarriage
- Libman-Sacks endocarditis (sterile valvular vegetations)
- Avascular necrosis (often femoral head — steroid-related)
- Infection (immunosuppression-related, leading cause of death)
- Pregnancy complications: preeclampsia, fetal loss, neonatal lupus (anti-Ro/SSA → congenital heart block)
PANCE pearls
- ANA-negative SLE is rare; if ANA is negative, the diagnosis becomes very unlikely.
- Anti-dsDNA titer and complement levels often track with disease activity — particularly useful in lupus nephritis follow-up.
- CRP normal in active SLE; elevated CRP should raise concern for infection or serositis.
- Hydroxychloroquine retinopathy risk rises after 5 years; screen at baseline and annually thereafter (especially with renal impairment or tamoxifen).
- Avoid sulfa antibiotics — may precipitate flares.
References
- EULAR/ACR 2019 — 2019 EULAR/ACR Classification Criteria for SLE (Aringer et al., Ann Rheum Dis 2019)
- EULAR 2023 — EULAR Recommendations for the Management of SLE (Fanouriakis et al., Ann Rheum Dis 2024)
- ACR 2012 — ACR Guidelines for Screening, Treatment, and Management of Lupus Nephritis (Hahn et al., Arthritis Care Res 2012)
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