SLE & Antiphospholipid Syndrome
Board-focused SLE and antiphospholipid syndrome: the type III/type II immune-complex pathophysiology, buzzword presentations (malar rash, nonerosive arthritis, Libman–Sacks), the autoantibody panel and synovial-fluid/imaging clues that clinch the diagnosis, and next-best-step management — plus APS's clotting paradox (prolonged aPTT that won't correct, false-positive VDRL) and its warfarin-not-DOAC treatment.
Two diseases, one autoimmune thread
SLE is a systemic autoimmune disease driven by loss of self-tolerance and autoantibodies against nuclear antigens. Impaired clearance of apoptotic debris exposes nuclear material → antinuclear antibodies (ANA). Two hypersensitivity mechanisms explain the damage:
- Type III (immune-complex): DNA–anti-DNA complexes deposit in glomeruli, skin, joints, and vessels → nephritis, rash, arthritis, serositis. Complement is consumed (low C3/C4 in flares).
- Type II (antibody-mediated): antibodies against blood cells → hemolytic anemia, thrombocytopenia, leukopenia.
Classic patient: a reproductive-age woman (≈9:1 female), disproportionately African American / Hispanic. Genetics: HLA-DR2/DR3; early complement deficiencies (C1q, C4, C2) paradoxically predispose by impairing clearance of immune complexes and apoptotic cells (C1q deficiency = strongest single genetic risk).
Antiphospholipid syndrome (APS) frequently coexists: antibodies to phospholipid-binding proteins create a hypercoagulable state → arterial/venous thrombosis and pregnancy loss. It may be primary or secondary to SLE.
- Constitutional: fever, fatigue, weight loss; ESR high but CRP often normal — a rising CRP suggests infection (or serositis), not a bland flare
- Malar (butterfly) rash that spares the nasolabial folds; photosensitivity; discoid rash (scarring)
- Painless oral/nasopharyngeal ulcers; nonscarring alopecia
- Nonerosive, symmetric, small-joint arthritis; Jaccoud arthropathy = reducible deformities without erosions
- Serositis: pleuritis / pericarditis
- Libman–Sacks endocarditis — sterile verrucous vegetations on both surfaces of the mitral valve
- Raynaud phenomenon
- Renal: proteinuria + active sediment → lupus nephritis (diffuse proliferative, class IV = most common & most severe)
- Neuropsychiatric: seizures, psychosis
- Cytopenias (autoimmune hemolytic anemia, thrombocytopenia, leuko/lymphopenia)
Autoantibodies — the money tests
| Antibody | Board pearl |
|---|---|
| ANA | Best screen — very sensitive (~95%+), poorly specific; a negative ANA makes SLE unlikely |
| Anti-dsDNA | Specific; titer tracks disease activity and lupus nephritis |
| Anti-Smith (Sm) | Most specific for SLE; does not track activity |
| Anti-histone | Drug-induced lupus (>95% of classic cases) |
| Anti-Ro/SSA, Anti-La/SSB | Neonatal lupus / congenital heart block; ANA-negative SLE; Sjögren |
| Antiphospholipid (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I) | APS — thrombosis, pregnancy loss; false-positive VDRL/RPR |
| Anti-U1 RNP | Mixed connective tissue disease |
| Anti-ribosomal P | Lupus psychosis / cerebritis |
Vignette: A 26-year-old woman has 3 months of fatigue, symmetric wrist/hand arthralgias, a facial rash worsened by sun, and pleuritic chest pain. Labs: anemia, thrombocytopenia, proteinuria.
- Most likely dx: SLE.
- Best initial test → ANA (sensitive screen). If positive, order specific antibodies: anti-dsDNA and anti-Sm.
- Gauge activity: a rising anti-dsDNA with falling C3/C4 signals an active flare.
- Proteinuria / active urinary sediment → next best step = renal biopsy to classify lupus nephritis (the class guides immunosuppression).
- Trap: normal CRP with a high ESR fits a lupus flare; a high CRP should trigger a hunt for infection (or serositis).
Lupus joint vs its mimics (fluid & imaging)
| Feature | SLE arthritis | Rheumatoid arthritis | Septic arthritis |
|---|---|---|---|
| Pattern | Symmetric small joints, often migratory/transient | Symmetric small joints, persistent | Usually monoarticular |
| X-ray erosions | None (nonerosive) | Erosions, joint-space loss | Rapid destruction if untreated |
| Deformity | Jaccoud — reducible | Fixed (ulnar deviation, swan-neck) | — |
| Synovial fluid WBC | Noninflammatory→mildly inflammatory (often <2,000/µL) | Inflammatory (~2,000–50,000) | >50,000, purulent, +Gram stain/culture |
| Antibodies | ANA, anti-dsDNA/Sm | RF, anti-CCP | — |
Antiphospholipid syndrome (APS)
APS is a hypercoagulable state from persistent antibodies to phospholipid-binding proteins — lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I. Hallmarks: venous and arterial thrombosis (DVT/PE, stroke in a young patient), recurrent pregnancy loss (classically fetal death after 10 weeks / late loss), thrombocytopenia, and livedo reticularis.
The lab paradox boards love: lupus anticoagulant prolongs the aPTT in vitro and does NOT correct on a mixing study (it's an inhibitor, not a factor deficiency) — yet the patient clots in vivo. Anticardiolipin cross-reacts to give a false-positive VDRL/RPR for syphilis.
Diagnosis = ≥1 clinical event (thrombosis or pregnancy morbidity) plus a positive antibody confirmed on repeat testing ≥12 weeks apart. Catastrophic APS = rapid multi-organ small-vessel thrombosis (high mortality).
Vignette: A 30-year-old woman has had two second-trimester fetal losses and now presents with a left-leg DVT. aPTT is prolonged and fails to correct on a mixing study; RPR is falsely positive.
- Dx: antiphospholipid syndrome (screen for underlying SLE — secondary APS).
- Confirm: lupus anticoagulant + anticardiolipin/anti-β2-GPI, repeated in ≥12 weeks.
- Acute clot → next step: anticoagulate — heparin bridged to warfarin, target INR 2–3 (typically lifelong after unprovoked thrombosis).
- Avoid DOACs, especially in triple-positive or arterial APS (inferior in trials, e.g. TRAPS).
- Pregnancy: LMWH + low-dose aspirin (warfarin is teratogenic).
- Hydroxychloroquine is foundational for every SLE patient — cuts flares and organ damage; monitor for retinopathy (baseline + annual eye exam)
- NSAIDs for arthritis/serositis; glucocorticoids for flares (lowest effective dose)
- Lupus nephritis / severe organ disease: induction with mycophenolate or cyclophosphamide + steroids; add-ons belimumab, voclosporin, rituximab
- Sun protection, always
- Drug-induced lupus: classic agents procainamide (highest incidence), hydralazine (most commonly encountered), isoniazid → anti-histone + (>95%), spares kidney/CNS, reversible after withdrawal; newer causes minocycline, TNF inhibitors may instead be anti-histone–negative / anti-dsDNA–positive
- Neonatal lupus: maternal anti-Ro/La cross the placenta → congenital complete heart block (may need pacemaker) + rash
- Death is bimodal: early from infection/active disease; later from accelerated cardiovascular disease
Classic recall list mapping the older 1997 ACR SLE criteria (features accumulate over time):
- S — Serositis (pleuritis/pericarditis)
- O — Oral/nasopharyngeal ulcers (painless)
- A — Arthritis (nonerosive)
- P — Photosensitivity
- B — Blood (hemolytic anemia, cytopenias)
- R — Renal (proteinuria, cellular casts)
- A — ANA
- I — Immunologic (anti-dsDNA, anti-Sm, antiphospholipid)
- N — Neurologic (seizures, psychosis)
- M — Malar rash
- D — Discoid rash
Current standard (2019 EULAR/ACR): a positive ANA ≥1:80 is an obligatory entry criterion; you then tally weighted clinical + immunologic domains and classify SLE at ≥10 points (with ≥1 clinical criterion). Low C3/C4 and anti-dsDNA/anti-Sm are among the weighted immunologic items.
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