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🔬 Systemic Lupus Erythematosus (SLE) - Pathology Notes

Based on Robbins & Cotran Pathologic Basis of Disease + Robbins & Kumar Basic Pathology

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📌 DEFINITION

• Production of autoantibodies (especially antinuclear antibodies - ANAs)
• Injury caused by immune complex deposition and antibody binding to cells and tissues
• Involvement of skin, joints, kidneys, serosal membranes, and virtually any organ

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📊 EPIDEMIOLOGY - Quick Flow

Prevalence: ~1 in 2500 (up to 400/100,000 in some populations)
         ↓
Female : Male = 9:1 (reproductive age 17-55 years)
         ↓
Female : Male = 2:1 (childhood or >65 years)
         ↓
Peak age: 20s-30s (but can occur at any age)
         ↓
More severe in: African-Americans > Hispanic > European-Americans

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🔬 PATHOGENESIS DIAGRAM (Robbins Fig. 6.25)

Pathogenesis Flowchart

SUSCEPTIBILITY GENES + EXTERNAL TRIGGERS (UV, drugs, viruses)
              ↓
    Defective clearance of apoptotic cells
              ↓
    Increased burden of nuclear antigens (DNA, RNA, histones)
              ↓
    ┌─────────────────────────┐
    │ Self-reactive B cells   │ + CD4+ helper T cells specific for nuclear antigens
    │ escape tolerance        │
    └──────────┬──────────────┘
               ↓
    Antinuclear antibodies (ANAs) produced
               ↓
    Immune complexes formed
          ↙          ↘
TLR engagement      Dendritic cells activated
by nuclear          → Type I Interferons produced
antigens            → Amplifies B & T cell activation
          ↘          ↙
    PERSISTENT HIGH-LEVEL ANA IgG PRODUCTION
               ↓
    Tissue injury via:
    ├── Immune complex deposition → Type III hypersensitivity
    ├── Antibody to cells → Type II hypersensitivity (cytopenias)
    └── Antiphospholipid antibodies → Thrombosis

Three Main Factors in Pathogenesis

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🧬 AUTOANTIBODIES IN SLE

Key Table: Autoantibodies and Their Significance

ANA Patterns (Immunofluorescence)

ANA Staining Pattern:
├── Homogeneous/Diffuse → anti-dsDNA, anti-histones, anti-nucleosomes → SLE
├── Speckled (coarse) → anti-Sm, anti-RNP → SLE / MCTD
├── Rim/Peripheral → anti-dsDNA → SLE (highly specific)
├── Nucleolar → anti-RNA polymerase → Systemic Sclerosis
└── Centromeric → anti-CENP → Systemic Sclerosis (CREST)

Key Exam Fact: False positive VDRL/syphilis test in SLE is due to antiphospholipid antibodies cross-reacting with cardiolipin antigen used in the test.

Lupus anticoagulant paradox: Despite prolonging PTT in vitro, antiphospholipid antibodies cause a hypercoagulable state in vivo (thrombosis, not bleeding).

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🏥 DIAGNOSTIC CRITERIA (ACR 1997 Revised)

Diagnosis: ≥4 criteria (sensitivity 85%, specificity 95%)

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🔬 MORPHOLOGY / ORGAN PATHOLOGY

Overview Flowchart

IMMUNE COMPLEX DEPOSITION
         ↓
    ┌────┴──────────────────────────────────────┐
    ↓           ↓          ↓          ↓         ↓
  SKIN        KIDNEY    JOINTS    HEART      BLOOD
  (50%)      (40-70%)             VESSELS   VESSELS

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1. SKIN

EPIDERMIS:
└── Vacuolar degeneration of basal layer (liquefactive degeneration)
└── Edema at dermoepidermal junction

DERMIS:
└── Perivascular lymphocytic inflammation
└── Vasculitis with fibrinoid necrosis

IMMUNOFLUORESCENCE (Lupus Band Test):
└── IgG + Complement deposits at dermoepidermal junction
    → Present in BOTH involved AND uninvolved skin

• (A) H&E: vacuolar degeneration of basal epidermis + dermal edema
• (B) Immunofluorescence: bright IgG deposits along the dermoepidermal junction (the "lupus band")

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2. KIDNEY (Lupus Nephritis)

WHO/ISN Classification of Lupus Nephritis

Massive subendothelial immune complex deposits
         ↓
"Wire loop" lesion on LM (GBM thickening)
         ↓
Endothelial swelling + neutrophil infiltration
         ↓
Complement activation → fibrinoid necrosis
         ↓
Hematuria + Proteinuria + Hypertension
         ↓
If untreated → Renal failure

• "Full house" pattern: IgG, IgA, IgM + C3, C1q all positive
• C1q deposition is characteristic of lupus nephritis

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3. HEART

Libman-Sacks Endocarditis:
├── Small (1-4mm), sterile, warty vegetations
├── Located on BOTH surfaces of valve leaflets
│   (atrial AND ventricular surface - distinguishes from RF)
├── Most common: Mitral valve > Tricuspid
├── Mechanism: immune complex deposition + inflammation
└── Complications: embolism, valve dysfunction, secondary infection

• Fibrinous pericarditis (serositis) - most common cardiac manifestation
• Myocarditis
• Accelerated coronary artery disease (from chronic inflammation)

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4. BLOOD VESSELS

Acute phase:
└── Necrotizing vasculitis
    ├── Capillaries, small arteries, arterioles affected
    ├── Fibrinoid necrosis of vessel walls
    └── Can affect ANY tissue

Chronic phase:
└── Fibrous thickening of vessel wall
└── Luminal narrowing → ischemia

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5. JOINTS

• Nonerosive synovitis in 2+ peripheral joints
• Synovial inflammation without cartilage/bone destruction
• Jaccoud arthropathy (chronic deformity without erosion) in some

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6. SPLEEN

• Splenomegaly
• Follicular hyperplasia
• "Onion skin" lesion: perivascular fibrosis of central arterioles (characteristic/pathognomonic)

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7. BLOOD (Cytopenias)

Anti-RBC antibodies → Coombs-positive hemolytic anemia (~50%)
Anti-platelet antibodies → Thrombocytopenia (~10%)
Anti-lymphocyte antibodies → Lymphopenia

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8. LUNGS

• Pleuritis + pleural effusion (serositis)
• Interstitial pneumonitis
• Pulmonary hypertension

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9. CNS

• Neuropsychiatric SLE
• Mechanism: antibodies cross the blood-brain barrier, react with neurons/neurotransmitter receptors
• Cognitive dysfunction, psychosis, seizures

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⚡ MECHANISMS OF TISSUE INJURY - Summary

MECHANISM                    MANIFESTATION
──────────────────────────────────────────────────
Type II Hypersensitivity  →  Hemolytic anemia
(Ab against cell surface)     Thrombocytopenia
                              Lymphopenia

Type III Hypersensitivity →  Glomerulonephritis
(Immune complex           →  Vasculitis
deposition)               →  Skin rash
                          →  Synovitis
                          →  Serositis

Antiphospholipid Ab       →  Thrombosis (arterial & venous)
                          →  Recurrent miscarriages
                          →  Stroke, DVT, PE

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📈 CLINICAL FEATURES - Memory Aid: "SOAP BRAIN MD"

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💊 DRUG-INDUCED LUPUS

Causative drugs:
├── Hydralazine
├── Procainamide  ← Most common
├── D-penicillamine
├── Isoniazid
└── Methyldopa

Key features:
├── Anti-HISTONE antibodies (not anti-dsDNA)
├── No renal/CNS involvement (usually)
├── REVERSIBLE on stopping drug
└── ANA positive

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🔬 SPECIAL HISTOLOGICAL FINDINGS IN SLE

LE Cell - Classic Finding

Nuclear material (denatured DNA) + Antibody (anti-dsDNA)
                    ↓
           Opsonized nuclear material
                    ↓
        Phagocytosed by PMN (neutrophil)
                    ↓
        LE CELL = PMN containing a large homogeneous 
                  nuclear inclusion (hematoxylin body)

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📊 COURSE AND PROGNOSIS

CLINICAL COURSE:
Relapsing and Remitting over years/decades
         ↓
During flares: ↑ immune complexes → ↓ complement (hypocomplementemia)
         ↓
Treatment: Corticosteroids + Hydroxychloroquine + Immunosuppressives

PROGNOSIS:
├── 5-year survival: ~90%
├── 10-year survival: ~80%
└── Most common causes of death:
    ├── Renal failure (lupus nephritis)
    ├── Intercurrent infections (immunosuppression)
    └── Cardiovascular disease (accelerated atherosclerosis)

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🏁 QUICK REVISION BOX

SLE at a Glance:
┌─────────────────────────────────────────────────────────┐
│ TYPE: Autoimmune; Type III (+ Type II) hypersensitivity  │
│ GENDER: F:M = 9:1                                        │
│ HALLMARK Ab: Anti-dsDNA (most specific), Anti-Sm         │
│ BEST SCREENING TEST: ANA (95-100% sensitive)             │
│ KIDNEY: Diffuse proliferative GN (Class IV) = most severe│
│ HEART: Libman-Sacks endocarditis (both valve surfaces)   │
│ SKIN: Butterfly rash + Vacuolar degeneration (basal)     │
│ SPLEEN: Onion skin lesion                                │
│ KEY FINDING: LE cell, Hematoxylin bodies                 │
│ DRUG-INDUCED: Anti-histone Ab, procainamide              │
│ FALSE +ve VDRL due to: antiphospholipid Ab               │
└─────────────────────────────────────────────────────────┘

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