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Systemic Lupus Erythematosus (SLE) - Complete Notes

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1. Overview

• Incidence: ~1 in 700 women aged 20-60 years in the US; ~1 in 250 among Black women
• Sex ratio: Female:Male = 10:1
• Principal manifestations: Rashes, arthritis, glomerulonephritis; also hemolytic anemia, thrombocytopenia, neuropsychiatric disorders

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2. Pathogenesis

Genetic Factors

• HLA alleles: HLA-DR2 or HLA-DR3 each confer an odds ratio of 2-3; both together = ~5
• Complement deficiencies (C1q, C2, or C4) in ~5% of patients - leads to defective clearance of immune complexes and apoptotic cells, and failure of B cell tolerance
• FcγRIIB polymorphism (inhibitory Fc receptor) - may contribute to inadequate B cell activation control
• PTPN22 polymorphism and multiple other genes identified by genome-wide association studies

Environmental Triggers

• UV light - induces apoptosis of skin cells, releases nuclear antigens

Key Pathogenic Mechanisms

1. IFN-α signature: Blood cells in SLE patients show striking gene expression indicating exposure to IFN-α (produced mainly by plasmacytoid DCs). Plasmacytoid DCs from SLE patients produce abnormally large amounts of IFN-α.
2. TLR activation: Toll-like receptors TLR9 (DNA-recognizing) and TLR7 (RNA-recognizing) activate B cells specific for self nuclear antigens.
3. Defective apoptotic clearance: Inadequate clearance of apoptotic nuclei (due to complement defects and nucleases like TREX1) leads to a large burden of nuclear antigens.
4. Immune complex deposition: Autoantibodies form complexes with their antigens, which deposit in small arteries and capillaries causing glomerulonephritis, arthritis, and vasculitis.
5. Direct autoantibody cytotoxicity: Anti-erythrocyte antibodies → hemolytic anemia; anti-platelet antibodies → thrombocytopenia

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3. Classification Criteria

ACR Criteria (11 criteria - need ≥4)

2019 EULAR/ACR Weighted Scoring Criteria

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4. Autoantibodies

• Anti-dsDNA and anti-Sm are highly specific for SLE
• Anti-dsDNA levels correlate with disease activity (especially nephritis)
• ANA is the most sensitive test (99% frequency)

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5. Clinical Manifestations

Cutaneous (80% of patients - 4 of 11 ACR criteria are mucocutaneous)

• Butterfly (malar) rash - erythema over malar area and bridge of nose; nasolabial folds characteristically spared (distinguishes from dermatomyositis); may have associated edema; resolves without scarring
• Histology: interface dermatitis, scant perivascular lymphoid infiltrate

• Single or grouped vesicles/bullae, often widespread, predilection for sun-exposed areas
• Neutrophils accumulate at DEJ and within dermal papillae
• DIF: IgG, IgM, IgA, or C3 in continuous granular pattern at BMZ
• Most patients are HLA-DR2 positive
• Dramatic response to dapsone (unlike epidermolysis bullosa acquisita)

• Vascular lesions in 50% - fingertip/toe edema, erythema, telangiectasia
• Nailfold capillary loops: wandering glomeruloid loops (vs. symmetric dilation in DM/scleroderma)
• Diffuse non-scarring alopecia; "lupus hairs" - short fragile hairs in frontal region
• Discoid lupus (scarring)
• Leg ulcers - deeply punched out
• Mucous membrane lesions in 20-30%: oral erosions, shallow ulcers, gingivitis; erythema and ulceration of hard palate

Musculoskeletal

• Arthritis (non-erosive, unlike RA) - one of the most common manifestations

Renal - Lupus Nephritis

Neuropsychiatric (NPSLE)

• MRI: white matter lesions, cerebral infarction, venous sinus thrombosis, atrophy (seen in 19-70%)
• Manifestations: seizures (5 pts in EULAR criteria), psychosis (3 pts), delirium (2 pts)
• MR angiography and spectroscopy for cerebral blood flow and neuronal metabolism assessment

Cardiopulmonary

• Pericarditis, pleuritis, pleural/pericardial effusions
• Diffuse alveolar hemorrhage (DAH) - rare but potentially catastrophic complication
  • Mortality up to 62%
  • Almost invariably accompanied by other active SLE manifestations
  • Glomerulonephritis present in >90% of DAH cases
  • Presents with bilateral alveolar infiltrates, dyspnea, hypoxemia; hemoptysis in minority at presentation
  • Histology: intra-alveolar hemorrhage and capillaritis, without macroscopic necrosis
  • BAL is adequate for diagnosis in critically ill patients (avoid biopsy in severe DAH)
  • Factors associated with mortality: MV, infection, prior cyclophosphamide use

Hematologic

• Leukopenia, thrombocytopenia, autoimmune hemolytic anemia

Antiphospholipid syndrome overlap

• Increased thrombosis risk; thrombotic microangiopathy

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6. Treatment

Counseling & General

• Avoid UV light exposure
• Adequate rest
• Sunscreen

Mild-Moderate Disease (no major organ involvement)

• NSAIDs - for arthralgia, serositis, constitutional symptoms
• Low-dose corticosteroids - prednisone 5-30 mg/day; effective for constitutional symptoms, arthralgias, pericarditis, pleuritis, skin disease; disease may flare if maintenance doses as low as 5 mg/day are stopped
• Hydroxychloroquine (HCQ) - 200-400 mg/day (max ≤5 mg/kg actual body weight/day)
  • Controls skin and arthralgias; used routinely in most lupus patients
  • Associated with decreased incidence of thrombosis
  • Well tolerated; most serious toxicity = retinal damage (cumulative dose-dependent)
  • Ophthalmologic exam before starting, then every 12 months

Serious Organ-System Disease

• Induction therapy for proliferative lupus nephritis:
  • Option A: Mycophenolate mofetil (MMF) 2-3 g/day + IV methylprednisolone 500-2500 mg over 1-3 days then oral prednisone 0.3-0.5 mg/kg/day
  • Option B: Low-dose cyclophosphamide (500 mg IV every 2 weeks × 6 doses) + IV methylprednisolone then oral prednisone
  • Multitarget therapy (tacrolimus 4 mg/day + MMF 1 g/day + pulse methylprednisolone then prednisone) is superior to IV CYC for induction
  • Voclosporin (23.7 mg BID) + background immunosuppression: improves clinical response in LN
  • Belimumab (10 mg/kg IV or 200 mg SC weekly) + background immunosuppression: approved for LN
  • Target: reduce prednisone to ≤7.5 mg/day by 3-6 months
• Maintenance: MMF preferred over azathioprine
• CNS disease, severe flares: High-dose CS ± cyclophosphamide or MMF
• Pericarditis: Prednisone 20-30 mg/day

Biologics & Emerging Therapies

Cyclophosphamide

• Given to ~33% of lupus patients during disease course
• Dose: 0.5-1 g/m² BSA IV monthly × 6 months, then quarterly × 2 years + oral prednisone
• Toxicities: hemorrhagic cystitis (give mesna + hydration), infertility, infection, malignancy

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7. Monitoring

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8. Prognosis & Complications

• Chronic remitting-relapsing course
• Major causes of morbidity: nephritis, NPSLE, cardiovascular disease, infections (from immunosuppression)
• Hydroxychloroquine reduces organ damage and thrombosis over time
• DAH carries mortality up to 62%

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• Cellular and Molecular Immunology, p. 1274-1275
• Goldman-Cecil Medicine, International Edition, Table 245, p. 2817-2818
• Andrews' Diseases of the Skin: Clinical Dermatology, p. 189
• Fishman's Pulmonary Diseases and Disorders, p. 4263-4282