Systemic Lupus Erythematosus (SLE) - Robbins Pathology Notes

Definition

• Production of a vast array of autoantibodies, particularly antinuclear antibodies (ANAs)
• Tissue injury caused mainly by deposition of immune complexes (Type III hypersensitivity) and binding of antibodies to cells/tissues (Type II hypersensitivity)
• Chronic, remitting and relapsing febrile illness affecting virtually any organ

Epidemiology

Autoantibodies in SLE - The Hallmark

Antinuclear antibody (ANA) staining patterns on immunofluorescence (Robbins & Kumar Basic Pathology, p. 179)

Categories of ANAs

1. Antibodies to DNA (especially double-stranded DNA - most specific for SLE)
2. Antibodies to histones
3. Antibodies to nonhistone proteins bound to RNA (e.g., Smith/Sm antigen)
4. Antibodies to nucleolar antigens

Key Autoantibodies Table

Antiphospholipid Antibodies - Important Associations

• Present in 30-40% of SLE patients
• Bind to phospholipid-protein complexes (especially beta-2 glycoprotein)
• Cause false-positive VDRL/RPR for syphilis (cross-react with cardiolipin)
• Prolong PTT in vitro - called "lupus anticoagulant"
• Paradoxically cause hypercoagulable state in vivo - thrombosis, recurrent miscarriages, stroke

Pathogenesis

Pathogenesis of SLE (Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 217)

1. Genetic Factors

• Family risk: 20% of unaffected first-degree relatives have autoantibodies
• Twin concordance: >20% in monozygotic twins vs. 1-3% in dizygotic twins
• HLA associations: HLA-DQ locus alleles linked to anti-dsDNA, anti-Sm, and antiphospholipid antibodies
• Complement deficiencies: Inherited deficiencies of C1q, C2, C4 predispose to SLE (defective immune complex clearance and defective clearance of apoptotic cells)
• GWAS: Identified loci in genes involved in lymphocyte signaling and interferon responses

2. Immunologic Factors

• Defective B-cell tolerance: Failure to eliminate self-reactive B cells in bone marrow
• CD4+ T-cell activation: Helper T cells specific for nucleosomal antigens escape tolerance and help B cells produce high-affinity pathogenic autoantibodies
• TLR engagement: Nuclear DNA/RNA in immune complexes engage TLRs on B cells and dendritic cells → activates more ANA production
• Type I Interferons: High circulating Type I IFNs (correlate with disease severity); self nucleic acids engage TLRs on dendritic cells mimicking viral nucleic acids → IFN production → amplifies immune activation and apoptosis

3. Environmental Factors

• UV radiation - leads to increased apoptosis of skin cells
• Drugs - hydralazine, procainamide, isoniazid, D-penicillamine, anti-TNF agents
• Inadequate clearance of apoptotic cell nuclei creates a large burden of nuclear antigens

Pathogenesis Summary (Cycle)

UV/triggers → Apoptosis → Defective clearance of apoptotic nuclei → Nuclear antigens released → Self-reactive B and T cells (due to genetic susceptibility) activated → ANA production → Immune complexes bind Fc receptors on B cells/DCs → TLR engagement by nucleic acids → More autoantibodies + Type I IFN production → More apoptosis → Self-perpetuating cycle

Mechanisms of Tissue Injury

LE Bodies (Hematoxylin Bodies)

• Nuclei of damaged cells react with ANAs, lose their chromatin pattern, become homogeneous
• Produce LE bodies (also called hematoxylin bodies) in tissues
• LE cell = phagocytic leukocyte (neutrophil or monocyte) that has engulfed the denatured nucleus of an injured cell
• LE cell test is now largely historical; replaced by ANA testing

Morphology (Pathologic Changes)

1. Blood Vessels

• Acute: Necrotizing vasculitis of capillaries, small arteries, arterioles with fibrinoid necrosis of vessel walls
• Chronic: Fibrous thickening with luminal narrowing

2. Kidney (up to 50% have clinically significant involvement)

• Always abnormal on EM and immunofluorescence
• All forms associated with immune complex deposition in glomeruli
• Lupus nephritis classified into 6 classes (WHO/ISN-RPS):

• Class IV features: "Wire-loop" lesions on light microscopy = thickened capillary walls due to subendothelial immune complex deposits
• Immunofluorescence: Granular deposits of IgG and complement along glomerular capillary walls

3. Skin

• Butterfly (malar) rash: Erythema over bridge of nose and cheeks - in ~50% of patients
• Urticaria, bullae, maculopapular lesions, ulcerations also occur
• Photosensitivity: UV light exacerbates lesions
• Histology:
  • Vacuolar degeneration of basal layer of epidermis
  • Dermal edema and perivascular inflammation
  • Vasculitis with fibrinoid necrosis
• Immunofluorescence: Deposits of immunoglobulin and complement at the dermoepidermal junction (also present in uninvolved skin - "lupus band test")

4. Joints

• Nonerosive synovitis with little joint deformity (unlike RA)
• Synovial hypertrophy; mononuclear cell infiltration

5. Heart (up to 50% pericardial involvement)

• Pericarditis: Most common cardiac manifestation
• Libman-Sacks endocarditis: Nonbacterial verrucous endocarditis
  • Small (1-3 mm) warty deposits on either surface of valve leaflets (distinctive - both surfaces!)
  • Usually mitral and aortic valves
  • Compare: Infective endocarditis (larger), Rheumatic (smaller, confined to line of closure)
• Myocarditis: Mononuclear cell infiltration - resting tachycardia, ECG changes
• Coronary atherosclerosis: Accelerated - young patients with long-standing disease (especially on corticosteroids)

6. CNS

• No clear morphologic abnormality
• Noninflammatory occlusion of small vessels by intimal proliferation (due to endothelial damage by autoantibodies or immune complexes)

7. Serosal Cavities (Pericardium, Pleura)

• Acute: Fibrinous exudate covering mesothelial surfaces
• Chronic: Thickened, opaque surfaces; fibrous adhesions; obliteration of cavity
• Pleural/pericardial effusions common (present in ~50%)

8. Spleen

• Splenomegaly, capsular thickening, follicular hyperplasia
• "Onion-skin" lesions: Concentric intimal and smooth muscle cell hyperplasia of central penicilliary arteries

9. Lungs

• Pleuritis and pleural effusions (~50%)
• Chronic interstitial fibrosis and secondary pulmonary hypertension (some cases)

10. Other

• Bone marrow: LE/hematoxylin bodies - strongly indicative of SLE
• Lymph nodes: Enlarged with hyperplastic germinal centers; may show necrotizing lymphadenitis (can mimic T-cell lymphoma but is polyclonal/reactive)

Classification Criteria (1997 ACR Revised Criteria)

Clinical Manifestations and Prevalence

Related Conditions

Chronic Discoid Lupus Erythematosus (CDLE)

• Skin plaques with elevated erythematous borders (face and scalp)
• Edema, erythema, hyperpigmentation, scaliness, follicular plugging, atrophy
• Systemic manifestations rare
• Progresses to SLE in 5-10% of patients
• ~35% ANA positive; anti-dsDNA rarely present
• DIF: IgG and C3 at dermoepidermal junction (same as SLE)

Subacute Cutaneous Lupus Erythematosus

• Intermediate between SLE and localized CDLE
• Widespread, superficial skin rash
• Mild systemic symptoms similar to SLE

Drug-Induced Lupus

• Drugs: Hydralazine, Procainamide, Isoniazid, D-penicillamine, anti-TNF agents
• Most commonly associated with anti-histone antibodies
• Remits on drug withdrawal

Course and Prognosis

• Course: Unpredictable; chronic, remitting, and relapsing
• Rare acute cases: death within weeks to months
• With therapy: Relapsing/remitting over years to decades
• 5-year survival: ~90%
• 10-year survival: ~80%
• Most common causes of death: Renal failure and intercurrent infections
• During flares: Increased immune complex formation → complement consumption → hypocomplementemia (low C3/C4)
• Treatment: Corticosteroids and immunosuppressive drugs