What is Systemic Lupus Erythematosus (SLE)?

Systemic Lupus Erythematosus (SLE)

Systemic lupus erythematosus (SLE) is a chronic multisystemic autoimmune disease characterized by immune complex deposition, vasculopathy, and the presence of autoantibodies against nuclear antigens that can affect any organ system in the body, leading to significant morbidity and mortality if not properly managed. 1, 2

Definition and Epidemiology

• A prototypic autoimmune disease resulting from complex interplay between genetic susceptibility and environmental factors
• Affects approximately 3.4 million people worldwide
• Predominantly affects women (90% of cases)
• Prevalence ranges from 20 to 150 cases per 100,000 population 3
• Higher disease severity and earlier onset observed in Latin American, African descendants, and Native American populations 3

Pathophysiology

• Characterized by dysregulation in both innate and adaptive immune systems
• Type-1 interferon dysregulation is a common denominator
• Production of autoantibodies against nuclear antigens
• Immune complex formation and deposition in tissues
• Complement activation and dysregulation
• Chronic inflammation in target organs 3, 4

Clinical Manifestations

SLE can affect multiple organ systems with varying severity:

1. Constitutional symptoms:

   • Fatigue
   • Fever
   • Weight loss

2. Mucocutaneous manifestations:

   • Malar (butterfly) rash
   • Discoid rash
   • Photosensitivity
   • Oral/nasal ulcers
   • Alopecia

3. Musculoskeletal involvement:

   • Arthritis/arthralgia
   • Myalgia/myositis

4. Renal involvement:

   • Lupus nephritis (affects ~40% of patients)
   • Can progress to end-stage kidney disease in 10% of cases after 10 years 5

5. Hematological abnormalities:

   • Leukopenia
   • Lymphopenia
   • Thrombocytopenia
   • Hemolytic anemia

6. Neuropsychiatric manifestations:

   • Seizures
   • Psychosis
   • Cognitive dysfunction
   • Headache

7. Cardiovascular involvement:

   • Pericarditis
   • Myocarditis
   • Accelerated atherosclerosis

8. Pulmonary involvement:

   • Pleuritis
   • Pneumonitis
   • Pulmonary hypertension

Diagnosis

Diagnosis is based on clinical features and laboratory findings. The 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology classification criteria are 96.1% sensitive and 93.4% specific for SLE 5:

1. Required entry criterion: Positive ANA (antinuclear antibody)

2. Clinical domains:

   • Constitutional (fever)
   • Hematologic (leukopenia, thrombocytopenia, autoimmune hemolysis)
   • Neuropsychiatric (seizure, psychosis, delirium)
   • Mucocutaneous (non-scarring alopecia, oral ulcers, subacute cutaneous or discoid lupus)
   • Serosal (pleural or pericardial effusion)
   • Musculoskeletal (arthritis)
   • Renal (proteinuria, lupus nephritis on biopsy)

3. Immunological criteria:

   • Anti-dsDNA antibodies
   • Anti-Sm antibodies
   • Antiphospholipid antibodies
   • Low complement (C3, C4)

Disease Activity Assessment

• SLEDAI-2K is a validated tool measuring disease activity over a 30-day period
• Scores range from 0 (remission) to >10 (high activity)
• Score ≥6 indicates significant active disease
• Guides treatment decisions and monitoring frequency 1

Management

Overarching Principles

1. Treatment goal: Achieve remission or low disease activity as quickly as possible and maintain it long-term 3, 1

2. Antimalarials: All patients should receive hydroxychloroquine (200-400 mg daily) unless contraindicated 3, 1, 5

   • Reduces disease activity, flares, organ damage
   • Associated with reduced mortality
   • Requires baseline and periodic ophthalmologic examinations

3. Glucocorticoids: Use at lowest possible dose for shortest duration 3, 1

   • For acute flares: Prednisone 0.5-1 mg/kg/day for moderate manifestations
   • Methylprednisolone pulses for severe manifestations
   • Aim to taper to maintenance dose or discontinue if possible

4. Immunosuppressants based on organ involvement and disease severity:

   • Mycophenolate mofetil (1-3 g/day)
   • Azathioprine
   • Cyclophosphamide (for severe disease)
   • Methotrexate (for skin and joint manifestations)

5. Biologics:

   • Belimumab: FDA-approved for active SLE and lupus nephritis 6, 5
   • Rituximab: For refractory cases, especially hematological manifestations
   • Anifrolumab: Recently approved for active SLE 5
   • Voclosporin: Approved for lupus nephritis 5

Organ-Specific Management

1. Lupus nephritis:

   • Class III/IV: Methylprednisolone pulses followed by oral prednisone with mycophenolate mofetil or cyclophosphamide
   • Class V: Prednisone with mycophenolate mofetil
   • High-risk: High-dose intravenous cyclophosphamide 1

2. Hematological manifestations:

   • Mild: Hydroxychloroquine
   • Moderate to severe: Corticosteroids, immunosuppressants
   • Refractory: Rituximab 1

Preventive Care

1. Infection prevention:

   • Screening for HIV, HCV, HBV, and tuberculosis before immunosuppressive therapy
   • Vaccinations with inactivated vaccines when disease is inactive
   • No live vaccines while on immunosuppressants 1, 6

2. Cardiovascular risk management:

   • Blood pressure control (target <130/80 mmHg)
   • Lipid management (target LDL <100 mg/dl)
   • Smoking cessation 1, 7

3. Bone health:

   • Calcium and vitamin D supplementation
   • Bone density monitoring
   • Bisphosphonates when indicated 1

4. Photoprotection:

   • UV light avoidance
   • Sunscreen use
   • Protective clothing 3, 1

Monitoring

1. Disease activity: Every 1-3 months during active disease, every 6-12 months when stable 1

2. Laboratory monitoring:

   • Complete blood count
   • Renal function tests and urinalysis
   • Anti-dsDNA antibodies and complement levels (C3, C4)
   • Drug-specific monitoring 1

3. Medication toxicity:

   • Hydroxychloroquine: Annual ophthalmologic examination (more frequent if risk factors present)
   • Immunosuppressants: Monitor for cytopenias, liver toxicity, infection 1

Prognosis

With proper treatment, the 10-year survival rate for SLE exceeds 90%. However, mortality remains higher than the general population due to:

• Disease activity
• Infections
• Cardiovascular disease
• End-organ damage

Early diagnosis, tight disease control, and preventive strategies are essential to improve outcomes and quality of life 2, 8.