Systemic Lupus Erythematosus (SLE)

Definition & Epidemiology

• Prevalence (US): ~204,295 cases (CDC National Lupus Registry)
• Sex: ~90% female, predominantly childbearing age; female:male ratio is approximately 9:1 overall
• Race: Highest prevalence in Black women, followed by Hispanic, White, and Asian/Pacific Islander women
• 5-year survival: ~90% after diagnosis
• Genetics: Strong familial tendency; association with MHC genes DR2, DR3, DR4, DR5; deficiencies in complement (C1q, C2, C4) are risk factors

Pathogenesis

• Autoantibody production - especially to nuclear antigens (anti-dsDNA, anti-Sm, ANA)
• Impaired clearance of apoptotic material (dead cells release nuclear debris that triggers immune activation)
• Type I interferon pathway dysregulation - excess IFN-α amplifies B and T cell activation
• Complement activation - immune complex deposition activates complement, causing tissue inflammation and vasculitis
• B and T cell abnormalities - loss of tolerance, excessive B cell activation, defective T regulatory cells

Classification Criteria

ACR 11-Criterion System (≥4 required for diagnosis)

The 2019 EULAR/ACR criteria require a positive ANA (≥1:80) as an entry criterion, then assign weighted points across clinical domains (≥10 points needed). These are classification criteria for clinical trials, not strict diagnostic criteria.

Clinical Features

1. Mucocutaneous (>90% of patients eventually affected)

• Malar/butterfly rash - in ~1/3 of patients; often precipitated by sun exposure
• Subacute cutaneous LE (SCLE) - annular or papulosquamous lesions on sun-exposed areas; associated with anti-Ro (70%); does NOT scar
• Discoid LE (DLE) - raised erythematous plaques with scaling; can scar with hypopigmented atrophic centers
• Alopecia - reversible in acute flare; permanent if due to discoid scarring
• Oral/nasal ulcers, photosensitivity, Raynaud phenomenon

2. Musculoskeletal

• Arthritis/arthralgia in ~90% - non-erosive (distinguishes from RA)
• Myositis, avascular necrosis (especially with steroid use)

3. Renal (Lupus Nephritis) - major determinant of prognosis

• Clinical renal disease in 15-75%; histologic evidence in most biopsy specimens
• WHO/ISN-RPS Classification:
  • Class I: Minimal mesangial - no treatment needed
  • Class II: Mesangial proliferative - no targeted renal therapy needed
  • Class III: Focal proliferative - aggressive therapy for active/necrotizing lesions
  • Class IV: Diffuse proliferative - always requires vigorous therapy
  • Class V: Membranous - therapy varies by severity

4. Neuropsychiatric (NPSLE)

• Seizures, psychosis, stroke, cognitive dysfunction, peripheral neuropathy
• Depression and anxiety are common (may overlap with "type 2 lupus" symptoms)

5. Hematologic

• Anemia of chronic disease (most common), autoimmune hemolytic anemia, aplastic anemia
• Leukopenia (<4000/µL) in ~50%, mostly lymphopenia
• Thrombocytopenia - immune-mediated; may be severe (<50,000)
• Antiphospholipid syndrome (APS) - thrombosis, recurrent pregnancy loss

6. Cardiovascular

• Pericarditis (most common cardiac manifestation), myocarditis, Libman-Sacks endocarditis
• Accelerated atherosclerosis - major long-term cause of morbidity/mortality

7. Pulmonary

• Pleuritis/pleural effusion, lupus pneumonitis, pulmonary hypertension, shrinking lung syndrome

8. Gastrointestinal

• Nausea/vomiting, mesenteric vasculitis (can cause intestinal perforation), lupus peritonitis, elevated liver enzymes

9. Ocular

• Keratoconjunctivitis sicca, retinal vasculitis (rare but can cause blindness), uveitis, optic neuritis

Key Autoantibodies

Treatment

General Principles

• Avoidance of triggers: Sun protection (all patients), avoid sulfonamides, procainamide, hydralazine
• All patients should be assessed for organ involvement at diagnosis and during flares

Drug Therapy by Indication

Recent evidence (EULAR 2023 update - PMID 38777375): The 2023 EULAR recommendations update reinforces treat-to-target strategies, minimizing glucocorticoid use, and expanding indications for biologics including anifrolumab.

Emerging (PMID 39754644): CAR-T cell therapy has shown early efficacy in refractory autoimmune diseases including SLE, representing a potential future treatment option.

Monitoring

• CBC, urinalysis, anti-dsDNA, complement (C3/C4) levels to assess disease activity
• Annual ophthalmologic exam for HCQ retinal toxicity (risk increases with >5 years use, >5 mg/kg/day)

Special Situations

• Drug-induced lupus: Procainamide, hydralazine, isoniazid, quinidine, phenytoin (ACLE); hydrochlorothiazide, CCBs, TNF antagonists (SCLE). Anti-histone antibodies are hallmark. Usually resolves with drug discontinuation.
• Neonatal lupus: Caused by transplacental passage of maternal anti-Ro/anti-La antibodies. Can cause congenital heart block.
• Pregnancy: SLE increases risk of preeclampsia, fetal loss, preterm birth. Disease should be in remission for ≥6 months before conception. HCQ should be continued; cyclophosphamide is contraindicated.
• Type 1 vs Type 2 lupus: Type 1 = inflammatory/immune (responds to immunosuppression); Type 2 = fatigue, pain, cognitive dysfunction (less immunosuppression-responsive).

Prognosis

• Bimodal mortality pattern: Early deaths from infection and active disease; late deaths from cardiovascular disease and damage accrual
• 5-year survival ~90%; 20-year survival significantly lower due to long-term complications
• Worse prognosis: Black/Hispanic race, male sex, early onset, lupus nephritis, neuropsychiatric involvement, APS, low socioeconomic status