Pathology · Year 2 · from Pathology

Case 2: Systemic Lupus Erythematosus - Type III Hypersensitivity

Patient Demographics

• Age: 24 years
• Sex: Female
• Occupation: Graduate student

Chief Complaint

"I have joint pain, a rash on my face, and I've been so tired."

History of Present Illness

A 24-year-old woman presents with a 3-month history of fatigue, joint pain, and facial rash. She first noticed symmetric pain and swelling in her hands (particularly the small joints of her fingers and wrists) that is worse in the morning and lasts several hours. She developed a rash across her cheeks and nose that worsens with sun exposure. She reports profound fatigue, low-grade fevers, and oral ulcers that come and go. She has lost 10 pounds without trying. She also notes her fingers turn white then blue in cold weather. Over the past week, she has noticed ankle swelling and "foamy urine."

Past Medical History

• Previously healthy
• History of recurrent pregnancy loss (two first-trimester miscarriages)

Family History

• Mother with rheumatoid arthritis
• Maternal aunt with "lupus"

Physical Examination

• Vital Signs: BP 148/92 mmHg, HR 88 bpm, T 37.9C
• General: Tired-appearing young woman
• Skin: Erythematous, slightly raised rash over malar eminences bilaterally, sparing nasolabial folds (malar/butterfly rash); photosensitivity reported
• HEENT: Painless oral ulcers on hard palate
• Musculoskeletal: Symmetric synovitis of MCPs and wrists; no deformities
• Cardiovascular: Regular rhythm, no murmurs, rubs, or gallops
• Respiratory: Clear to auscultation
• Extremities: 2+ pitting edema bilaterally
• Neurologic: Alert, oriented; no focal deficits

Workup

Laboratory Studies:

• CBC: WBC 3,200 (leukopenia), Hgb 10.2 g/dL (anemia), Platelets 118,000 (thrombocytopenia)
• BMP: Cr 1.4 mg/dL (elevated), BUN 28 mg/dL
• Urinalysis: 3+ protein, 2+ blood, RBC casts present
• 24-hour urine protein: 3.2 g (nephrotic range)
• Complement levels: C3 42 mg/dL (low; normal 90-180), C4 8 mg/dL (low; normal 10-40)

Autoantibodies:

• ANA: Positive, 1:640 titer, homogeneous pattern
• Anti-dsDNA: Positive, 185 IU/mL (elevated; correlates with disease activity)
• Anti-Smith (Anti-Sm): Positive (highly specific for SLE)
• Antiphospholipid antibodies: Positive (lupus anticoagulant, anticardiolipin IgG)
• Direct Coombs: Positive (evidence of autoimmune hemolysis)

Renal Biopsy:

• Class IV diffuse proliferative lupus nephritis
• "Full house" immunofluorescence: IgG, IgA, IgM, C3, C1q deposits
• Active inflammatory lesions

Diagnosis

Systemic Lupus Erythematosus (SLE) with:

• Class IV lupus nephritis
• Antiphospholipid syndrome (positive aPL antibodies, recurrent pregnancy loss)
• Autoimmune cytopenias (leukopenia, anemia, thrombocytopenia)

2019 EULAR/ACR Classification Criteria Met:

• Entry criterion: ANA positive
• Clinical domains: Constitutional, mucocutaneous (malar rash, oral ulcers, photosensitivity), musculoskeletal (synovitis), renal (proteinuria, RBC casts)
• Immunologic domains: Low complement, anti-dsDNA, anti-Sm, antiphospholipid antibodies

Pathophysiology - Type III Hypersensitivity

Immune Complex Disease:

1. Autoantibody production: Loss of self-tolerance leads to antibodies against nuclear antigens (DNA, histones, ribonucleoproteins)
2. Immune complex formation: Antibodies bind circulating self-antigens, forming antigen-antibody complexes
3. Immune complex deposition: Complexes deposit in vessel walls, glomeruli, skin, joints, and other tissues
4. Complement activation: Deposited complexes activate complement (classical pathway via C1q binding)
5. Inflammatory response: Complement activation generates C3a/C5a (anaphylatoxins), recruits neutrophils, causes tissue damage
6. Tissue injury: Neutrophil degranulation, oxidative damage, fibrinoid necrosis

Why Complement is LOW in Active SLE:

• Complement is consumed during immune complex clearance
• Low C3 and C4 indicate active complement consumption
• C3/C4 levels and anti-dsDNA titers correlate with disease activity

Key Autoantibodies in SLE:

Treatment Plan

ACUTE MANAGEMENT OF LUPUS NEPHRITIS (Class IV):

1. Induction Therapy:

• Mycophenolate mofetil (MMF) 1 g BID (preferred for many patients)
• OR Cyclophosphamide IV (Euro-Lupus protocol: 500 mg every 2 weeks x 6 doses)
• PLUS Glucocorticoids:
• Methylprednisolone 500-1000 mg IV daily x 3 days (pulse)
• Then prednisone 1 mg/kg/day (max 60 mg), taper over months

2. Maintenance Therapy (after induction):

• MMF 1-2 g daily or azathioprine 2 mg/kg/day
• Low-dose prednisone (goal <7.5 mg/day)

3. Adjunctive Therapies:

• Hydroxychloroquine 200-400 mg daily - ALL SLE patients
• Reduces flares, damage accrual, mortality
• Mechanism: Inhibits TLR signaling, reduces cytokine production
• ACE inhibitor for proteinuria and hypertension

4. Antiphospholipid Syndrome Management:

• Aspirin 81 mg daily (primary prevention)
• If thrombosis occurs: Lifelong warfarin anticoagulation
• Discuss pregnancy planning (high risk)

MONITORING:

• Renal function and urinalysis regularly
• Anti-dsDNA and complement levels (activity markers)
• CBC for cytopenias
• Hydroxychloroquine: Annual ophthalmologic exam (retinal toxicity)

Follow-up

• Rheumatology and nephrology co-management
• Repeat renal function in 2-4 weeks
• Assess response to induction therapy at 3-6 months
• Transition to maintenance when remission achieved

Clinical Pearl

SLE is the prototypical immune complex (Type III hypersensitivity) disease. The "full house" immunofluorescence on renal biopsy (IgG, IgA, IgM, C3, C1q) is characteristic of lupus nephritis and reflects the broad polyclonal autoantibody production. Anti-dsDNA levels and complement consumption (low C3/C4) correlate with disease activity, particularly nephritis - rising anti-dsDNA and falling complement often herald a flare. Hydroxychloroquine is disease-modifying and should be prescribed to ALL SLE patients regardless of disease activity. Class IV (diffuse proliferative) lupus nephritis requires aggressive immunosuppression to prevent progression to ESRD. The combination of SLE with antiphospholipid antibodies significantly increases thromboembolic risk and requires careful management during pregnancy.

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