Systemic Lupus Erythematosus (SLE)

---

Definition

---

Epidemiology

---

Pathogenesis

1. Genetic susceptibility — polygenic (cumulative hit model); HLA-DR2, HLA-DR3, C4 null allele, Fcγ receptor polymorphisms
2. Type I interferon pathway — central driver; impaired clearance of apoptotic debris → persistent nucleic acid sensing → IFN-α production
3. Environmental triggers — UV light, EBV infection, drugs, microbiome
4. Impaired X-chromosome inactivation — explains female predominance
5. Loss of B-cell and T-cell tolerance → autoantibody production → immune complex deposition

---

Clinical Manifestations ("DOPAMINE" mnemonic or by system)

Mucocutaneous (most common)

• Malar (butterfly) rash — erythema over cheeks/nose, spares nasolabial folds
• Discoid rash — scarring, follicular plugging
• Photosensitivity
• Oral/nasopharyngeal ulcers (usually painless)
• Non-scarring alopecia
• Livedo reticularis (antiphospholipid association)

Musculoskeletal

• Non-erosive arthritis — symmetric, involving ≥2 peripheral joints; Jaccoud's arthropathy (reducible deformities)
• Myalgia, myositis

Renal (Lupus Nephritis — major cause of morbidity)

• Proteinuria, hematuria, casts
• WHO/ISN-RPS Classes I–VI
• Class III/IV (focal/diffuse proliferative) = most severe → requires aggressive immunosuppression

Neuropsychiatric (NPSLE)

• Seizures, psychosis, cognitive dysfunction
• Cerebrovascular disease, transverse myelitis
• Peripheral neuropathy (2–27%)

Cardiovascular

• Libman-Sacks endocarditis (sterile verrucous vegetations)
• Pericarditis (most common cardiac manifestation), myocarditis
• Accelerated atherosclerosis — leading cause of late mortality

Pulmonary

• Pleuritis/pleural effusion (most common)
• Acute lupus pneumonitis
• Diffuse alveolar hemorrhage
• "Shrinking lung" syndrome — diaphragm weakness; resistant to immunosuppression
• Pulmonary hypertension

Hematologic

• Hemolytic anemia (Coombs-positive)
• Leukopenia/lymphopenia
• Thrombocytopenia
• Antiphospholipid syndrome (APS) — 30–40% have antiphospholipid antibodies → thrombosis, recurrent pregnancy loss

Serositis

• Pleuritis or pericarditis

---

Autoantibodies — Diagnostic & Clinical Correlations

---

Classification Criteria

2019 EULAR/ACR Criteria (most current)

• Positive ANA (≥1:80 on HEp-2 cells) = entry criterion
• Then additive weighted scoring across 7 domains:
  • Constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal
  • Immunology domain (anti-dsDNA, anti-Sm, antiphospholipid Ab, complement, direct Coombs)
• Score ≥10 = SLE classification
• Each criterion counted only if not better explained by another diagnosis

Older SLICC Criteria (still used)

• Requires ≥4/11 criteria OR biopsy-proven lupus nephritis + positive ANA or anti-dsDNA
• At least 1 clinical + 1 immunologic criterion

---

Investigations

Tip: Rising anti-dsDNA + falling complement = impending flare (especially nephritis)

---

Treatment

General Principles (ACR 2025 Guideline — first update since 1999)

• Goal: Remission or low disease activity (LLDAS)
• Minimize organ damage and treatment toxicity
• Regular mood screening and CV risk reduction

1. Hydroxychloroquine (HCQ) — The Cornerstone

• All SLE patients unless contraindicated
• Dose: 5 mg/kg/day (≤400 mg/day)
• Benefits: Reduces flares, prevents damage accrual, improves survival, protects against thrombosis
• Monitor: Ophthalmology screening for retinopathy (dose- and duration-dependent)
• Do NOT stop in pregnancy — protects against neonatal lupus

2. NSAIDs

• Short-term for arthritis, pleuritis, fever
• Caution: renal/GI toxicity

3. Glucocorticoids

• Short-term for acute flares; minimize long-term use (damage accrual)
• High-dose IV methylprednisolone ("pulse") for severe organ-threatening disease

4. Immunosuppressants (organ-threatening/refractory disease)

5. Biologics

Lupus Nephritis Protocol

• Class I/II + normal proteinuria: treat underlying SLE only
• Class III/IV: MMF (2–3 g/day) OR low-dose cyclophosphamide + high-dose steroids (induction), then MMF or azathioprine (maintenance)
• Class V (membranous): MMF + steroids if proteinuria >3g/day
• Adjunct: ACE inhibitor/ARB (proteinuria reduction), hydroxychloroquine

---

Special Situations

Pregnancy

• SLE can flare (especially nephritis)
• Safe drugs: HCQ, azathioprine, low-dose steroids, low-dose aspirin (APS)
• Contraindicated: MMF, cyclophosphamide, methotrexate (teratogenic)
• Anti-Ro/La → fetal congenital heart block monitoring
• APS → heparin + aspirin during pregnancy

Drug-Induced Lupus

• Caused by: hydralazine, procainamide, isoniazid, minocycline, TNF-inhibitors
• Features: arthritis, serositis; anti-histone Ab positive; ANA positive; malar rash and major organ involvement rare
• Resolves on stopping the drug

---

Monitoring & Prognosis

• SLEDAI (SLE Disease Activity Index) — standard scoring tool
• Damage tracked by SLICC/ACR Damage Index
• Mortality: bimodal — early (active disease, infection) and late (cardiovascular disease, atherosclerosis)
• 10-year survival: >90% with modern therapy
• Poor prognostic factors: lupus nephritis, NPSLE, hypertension, thrombocytopenia, low socioeconomic status, Black/Hispanic ethnicity

---

Key Exam Points

• Most specific antibody: Anti-Sm
• Most sensitive antibody: ANA
• Most common cause of death (early): Infection
• Most common cause of death (late): Cardiovascular disease
• Most common cardiac manifestation: Pericarditis
• CRP normal in active SLE flare (rise suggests infection)
• Complement low (C3, C4) in active disease
• Shrinking lung = resistant to steroids
• HCQ is safe and recommended throughout pregnancy

---