Systemic Lupus Erythematosus (SLE) - Complete Overview

Definition & Epidemiology

• Affects ~3.4 million people worldwide; ~400,000 new diagnoses per year
• Most common in women of reproductive age (15-40 years)
• Female:male ratio: 2:1 before puberty, rises to 4:1 after puberty
• Significantly higher incidence in African American and Latino women (up to 1 in 250 African American women ages 18-65)
• Poland, USA, Barbados, and China show the highest global incidence (2023 epidemiology study)
• 5-year survival: ~90% with modern treatment; >90% survive 15+ years
• Textbook of Family Medicine 9e

Pathogenesis

• Genetic factors: Strong HLA association with DR2, DR3, DR4, DR5; familial clustering evident
• Autoantibody production: ANA is the hallmark. Anti-double-stranded DNA (dsDNA) and anti-Sm antibodies are found almost exclusively in SLE and are diagnostically specific
• Three core mechanisms driving disease:
  1. Attenuated/dysregulated immune system (B cell, T cell, monocyte abnormalities)
  2. Cytokine microenvironment dysregulation
  3. Impaired apoptotic debris clearance - accumulation of nuclear material triggers autoimmunity
• Environmental triggers: Sunlight (UV), infections, stress (neuroendocrine changes), certain drugs, diet, toxins
• Hormonal influence: Estrogen drives female predominance; shifts in puberty affect sex ratio

• Textbook of Family Medicine 9e, Andrews' Diseases of the Skin

Clinical Features

Constitutional

Mucocutaneous (>90% of patients eventually affected)

Papulonodular mucinosis in SLE (back):

Bullous lupus erythematosus (vesicles and bullae on the arm):

Musculoskeletal (~90%)

• Non-erosive arthritis involving 2+ peripheral joints (tenderness, swelling, effusion) - this is the most common complaint
• Arthralgia is even more prevalent
• Avascular necrosis (especially femoral head) can occur with steroid use

Renal (~50%)

• Proteinuria >0.5 g/day
• Cellular casts (red cell, hemoglobin, granular, tubular, or mixed)
• Can progress to nephrotic syndrome or RPGN
• WHO/ISN classes I-VI on biopsy guide treatment
• Higher incidence and severity in Asian and African American populations

Neuropsychiatric

• Seizures (in absence of metabolic causes)
• Psychosis
• Cognitive dysfunction, headaches, peripheral neuropathy, stroke
• Transverse myelitis (rare but severe)

Serositis

• Pleuritis: pleuritic chest pain, pleural effusion
• Pericarditis: ECG changes, pericardial effusion, rub - most common cardiac manifestation
• Libman-Sacks endocarditis (non-bacterial verrucous endocarditis) - pathognomonic but rare

Hematologic

• Hemolytic anemia with reticulocytosis
• Leukopenia (<4,000/mm³) or lymphopenia (<1,500/mm³)
• Thrombocytopenia (<100,000/mm³)

Pulmonary

• Pleuritis, pleural effusion
• Interstitial lung disease
• Pulmonary hypertension
• Rarely: "shrinking lung" syndrome

Antiphospholipid Antibody Syndrome (secondary)

• Found in ~30-40% of SLE patients
• Venous/arterial thrombosis, recurrent pregnancy loss
• False-positive VDRL/RPR (syphilis test) is a classic finding

Diagnosis & Classification Criteria

ACR 1982/1997 Criteria (need ≥4 of 11)

SLICC 2012 Criteria

• At least 4 criteria (≥1 clinical + ≥1 immunologic), OR
• Biopsy-proven lupus nephritis + positive ANA or anti-dsDNA

2019 EULAR/ACR Criteria

• Andrews' Diseases of the Skin, Textbook of Family Medicine 9e, Rheumatology 2-Vol Set

Laboratory Investigations

Treatment

General Measures

• Sun protection (sunscreen, UV-protective clothing) - mandatory
• Lifestyle: avoid triggers (infections, stress, certain medications like hydralazine, procainamide, isoniazid)
• Monitoring: regular labs (CBC, urine, complement, anti-dsDNA), BP control, bone protection

Drug Therapy by Indication

• Textbook of Family Medicine 9e

Emerging & Recent Therapies (2024-2025)

• Obinutuzumab (anti-CD20): Phase III RCT in active lupus nephritis (NEJM, 2025) showed improved renal response vs placebo
• Telitacicept (TACI-Fc fusion protein, dual BLyS/APRIL inhibitor): Phase III trial in SLE (NEJM, 2025 Oct) demonstrated significant reduction in flares
• Teclistamab (BCMA-targeted biCAR-T approach): Case series showed induced remission in refractory SLE (NEJM, 2024) - early but promising
• CAR-T cell therapy for ultra-refractory SLE - small studies show complete remission

Prognosis & Monitoring

• 5-year survival: ~90%; 15-year survival: >90% with treatment
• Leading causes of death: renal failure, cardiovascular disease (accelerated atherosclerosis), infections (from immunosuppression), CNS lupus
• Disease follows a relapsing-remitting course - unpredictable, requiring lifelong monitoring
• Disease activity monitored with: SLEDAI score, complement levels (C3/C4), anti-dsDNA titers, urinalysis
• Co-morbidity management is critical: cardiovascular risk reduction, osteoporosis prevention (with chronic steroid use), infection prevention

Drug-Induced Lupus

• Anti-histone antibodies are the hallmark (positive in >95%)
• Anti-dsDNA and complement usually normal
• Resolves on drug withdrawal
• Renal and CNS involvement rare (unlike idiopathic SLE)

Special Populations

Summary Table