Musculoskeletal · PANCE / PANRE

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

Lupus autoantibody profile — high-yield clinical associations.

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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