Systemic Lupus Erythematosus (SLE)

Definition & Epidemiology

Pathogenesis

• Genetic susceptibility - Monozygotic twin concordance ~24%; ~44% of SLE risk is heritable. Key associations include:
  • Complement deficiencies (C1q, C2, C4A mutations)
  • HLA-DR3 and HLA-DR15 alleles (strongest MHC associations)
  • 80+ non-HLA SNPs identified in large GWAS studies
  • Polymorphisms in TLR pathways (IRF5, IRF7) and Fc receptor genes (FCGR2A, FCGR3A)
• Type I Interferon Pathway - Central to SLE. Impaired clearance of apoptotic debris exposes endogenous nucleic acids, which trigger TLR-mediated innate immune activation, leading to massive type I interferon production.
• Environmental triggers - UV light (photosensitivity), infections (EBV), certain drugs, microbiome changes, oxidative stress
• Immune dysregulation - Results in production of autoantibodies (especially anti-dsDNA, anti-Sm), immune complex formation and deposition in tissues, complement activation, and end-organ damage.
• Sex - Impaired X-chromosome inactivation partially explains the female predominance.

Clinical Manifestations

Cutaneous Manifestations

Acute cutaneous LE showing prominent scaly malar erythema - Harrison's Principles of Internal Medicine 22E

Musculoskeletal

• Arthralgias and non-erosive arthritis in >85% - PIP, MCP joints, knees, wrists most common
• Jaccoud arthropathy (periarticular tissue damage with deformity) in ~10%
• Osteonecrosis (most commonly hip) from disease vasculopathy or corticosteroid use
• Fibromyalgia commonly coexists

Renal (Lupus Nephritis)

• Affects >50% of patients at some point
• Ranges from asymptomatic proteinuria to nephrotic syndrome to rapidly progressive GN
• WHO/ISN classification: Class I-VI (Class III and IV = proliferative, most serious)
• Renal biopsy guides management

Cardiovascular

• Pericarditis - most common cardiac manifestation (substernal pain relieved by leaning forward)
• Libman-Sacks endocarditis - sterile nodules on atrial side of mitral valve; can cause regurgitation
• Accelerated premature atherosclerosis is a major cause of long-term morbidity and mortality

Neuropsychiatric SLE (NPSLE)

• Peripheral neuropathy in 2-27%
• Spectrum includes: cognitive dysfunction, psychosis, seizures, stroke (often from antiphospholipid antibodies), mononeuritis multiplex, GBS/CIDP-like syndrome
• Seizures carry 5 points in EULAR/ACR classification

Hematologic

• Autoimmune hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia
• Antiphospholipid antibody syndrome - arterial/venous thrombosis, recurrent pregnancy loss

Serositis

• Pleuritis and pericarditis common; characteristic pleuritic chest pain

Autoantibodies in SLE

Classification Criteria (2019 EULAR/ACR)

Treatment

General Principles

• Hydroxychloroquine (HCQ) - cornerstone of SLE management for nearly all patients; reduces flares, prevents organ damage, improves survival, safe in pregnancy
• Sun protection - mandatory; UV triggers flares
• Monitoring for and treating cardiovascular risk factors (premature atherosclerosis)

Mild-Moderate Disease

• NSAIDs for arthritis and serositis
• Topical glucocorticoids + antimalarials for skin disease
• Low-dose prednisone for symptom control

Moderate-Severe / Organ-Threatening Disease

• Systemic glucocorticoids - rapid disease control but long-term toxicity limits use
• Immunosuppressives: azathioprine, mycophenolate mofetil (MMF), cyclophosphamide (reserved for severe nephritis/CNS disease)

Biologic Therapies

• Belimumab (anti-BLyS/BAFF) - approved for active SLE and lupus nephritis; reduces flares and organ damage
• Anifrolumab (anti-IFN-α receptor) - approved for moderate-to-severe SLE; targets the type I interferon pathway
• Voclosporin - calcineurin inhibitor approved in combination with MMF for lupus nephritis
• Rituximab (anti-CD20) - used off-label for refractory disease

Lupus Nephritis

• Induction: MMF + glucocorticoids (or cyclophosphamide for severe Class III/IV)
• Maintenance: MMF or azathioprine

Antiphospholipid Syndrome

• Thrombosis prophylaxis/treatment with anticoagulation (warfarin)
• Aspirin for pregnancy-related complications

Emerging (2024-2026)

• CAR-T cell therapy and B-cell depletion strategies are showing early promise in refractory SLE, with recent reviews in Annals of Rheumatic Diseases (PMID 38777374) and Molecular Biomedicine (PMID 39472388) highlighting targeted therapy approaches.

Monitoring & Prognosis

• Disease activity tools: SLEDAI (Systemic Lupus Erythematosus Disease Activity Index), BILAG
• Labs to monitor: CBC, urinalysis, anti-dsDNA titres, complement (C3/C4), creatinine
• Major causes of death: infection (from immunosuppression), renal failure, cardiovascular disease
• Prognosis has improved markedly; 10-year survival now >90% in developed countries