What is Systemic Lupus Erythematosus (SLE), its pathology investigations, and management (mx)?

Systemic Lupus Erythematosus (SLE): Pathology, Investigations, and Management

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by autoantibody production against nuclear antigens, immune complex deposition, and inflammation affecting multiple organ systems that requires hydroxychloroquine as cornerstone therapy for all patients, with additional treatments tailored to specific organ involvement and disease severity. 1, 2

Definition and Pathophysiology

SLE is a multisystemic autoimmune disease with the following key characteristics:

• Dysregulated immune responses leading to autoantibody production (particularly against nuclear antigens)
• Immune complex deposition in various tissues
• Chronic inflammation affecting multiple organs including skin, joints, kidneys, and blood cells
• Collapse of immunological tolerance involving both innate and adaptive immunity
• Complex interplay between genetic susceptibility and environmental triggers 2, 3

Clinical Manifestations

SLE presents with diverse clinical manifestations:

Common Early Presentations

• Constitutional symptoms: fatigue, fever
• Mucocutaneous: malar (butterfly) rash, discoid rash, photosensitivity, oral ulcers
• Musculoskeletal: arthritis, arthralgia, myalgia
• Hematologic: anemia, leukopenia, lymphopenia, thrombocytopenia 2, 1

Organ-Specific Manifestations

• Renal: lupus nephritis (occurs in ~40% of patients)
• Neuropsychiatric: seizures, psychosis, cognitive dysfunction
• Cardiovascular: pericarditis, myocarditis, accelerated atherosclerosis
• Pulmonary: pleuritis, pneumonitis, pulmonary hypertension 4, 1

Diagnostic Investigations

Laboratory Tests

• Autoantibody Profile:

  • ANA (antinuclear antibody): screening test with high sensitivity
  • Anti-dsDNA: correlates with disease activity and renal involvement
  • Anti-Sm: highly specific for SLE
  • Anti-phospholipid antibodies: associated with thrombotic events 1, 4

• Complement Levels:

  • C3 and C4: low levels associated with active disease
  • Low C3 particularly correlates with active renal disease 1

• Hematologic Tests:

  • Complete blood count: anemia, leukopenia, lymphopenia, thrombocytopenia
  • Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP): inflammatory markers 1

• Renal Function Tests:

  • Serum creatinine
  • Urinalysis
  • Urine protein/creatinine ratio 1

Disease Activity Assessment

• SLEDAI-2K (SLE Disease Activity Index): validated tool measuring disease activity across 9 organ systems with 24 descriptors, scoring from 0 to 105 1

Tissue Biopsy

• Kidney biopsy: gold standard for diagnosing and classifying lupus nephritis
• Skin biopsy: may help confirm cutaneous lupus 4

Management

Non-Pharmacological Approaches

• Patient education on disease management
• Photoprotection to prevent flares
• Regular exercise to reduce fatigue and depressive symptoms
• Psychosocial interventions to improve quality of life 1

Pharmacological Treatment

First-Line Therapy

• Hydroxychloroquine (200-400 mg daily): Cornerstone medication for all SLE patients
  • Reduces disease activity, flares, organ damage, and mortality
  • Requires baseline and periodic ophthalmologic examinations 1, 4

Additional Therapies Based on Disease Severity

1. Mild Disease (predominantly musculoskeletal/cutaneous):

   • NSAIDs for symptom relief
   • Low-dose glucocorticoids (≤5 mg/day prednisone equivalent)
   • Methotrexate or leflunomide for predominant musculoskeletal manifestations 1

2. Moderate Disease:

   • Glucocorticoids (0.25-0.5 mg/kg/day)
   • Azathioprine for maintenance therapy 1

3. Severe Disease/Major Organ Involvement:

   • Higher-dose glucocorticoids initially
   • Immunosuppressants based on organ involvement:
     • Mycophenolate mofetil: preferred for lupus nephritis
     • Cyclophosphamide: for severe nephritis or neuropsychiatric lupus 1, 4

4. Biologic Therapies:

   • Belimumab: FDA-approved for active SLE and lupus nephritis
   • Anifrolumab: FDA-approved for active SLE
   • Voclosporin: FDA-approved for lupus nephritis 4

Specific Treatment for Lupus Nephritis

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

Monitoring and Follow-up

• Regular monitoring of disease activity using validated tools
• Laboratory monitoring every 1-3 months during active disease:
  • Complete blood count
  • Anti-dsDNA antibodies
  • Complement levels (C3, C4)
  • Renal function tests
  • Urinalysis 1

Prevention of Complications

• Vaccination with inactivated vaccines when disease is inactive
• Screening for HIV, HCV, HBV, and tuberculosis before immunosuppressive therapy
• Cardiovascular risk management: blood pressure control (<130/80 mmHg), lipid management
• Osteoporosis prevention with calcium, vitamin D, and bone density monitoring 1

Prognosis

• Disease course is variable with periods of flares and remission
• Renal flares occur in up to 45% of patients
• Risk of doubling serum creatinine is 7.4-8.5% at 5 years and 14.3-18.2% at 10 years
• Prognostic factors include age, ethnicity, serum creatinine, hypertension, C3 levels, and kidney biopsy findings 1

Treatment Goals

• Achieve disease remission or low disease activity
• Minimize glucocorticoid use
• Prevent organ damage
• Improve quality of life
• Reduce mortality 4