Harvey's Garden

Systemic lupus erythematosus

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aliasesSLE

7 min read

Epidemiology

  • Women: 15–44 years

Etiology

  • Genetic predisposition
    • HLA-DR2 and HLA-DR3 are commonly present in individuals with SLE.
    • Genetic deficiency of classical pathway complement proteins (C1q, C2, C4) in approx. 10% of affected individuals
  • Hormonal factors: Hyperestrogenic states (e.g., due to oral contraceptive use, postmenopausal hormonal therapy, endometriosis) are associated with an increased risk of SLE.
  • Environmental factors
    • Cigarette smoking and silica exposure increase the risk of developing SLE.
    • UV light and EBV infection may trigger disease flares
      • Ultraviolet rays and sun exposure lead to increased cell apoptosis
    • Drugs such as procainamide or hydralazine (see “Drug-induced lupus erythematosus”)

Pathophysiology

Hypotheses:

  1. Autoantibody development: deficiency of classical complement proteins (C1q, C4, C2) → failure of macrophages to phagocytose immune complexes and apoptotic cell material (i.e., plasma and nuclear antigens) → dysregulated, intolerant lymphocytes targeting normally hidden intracellular antigens → autoantibody production (e.g., ANA, anti-dsDNA)
    • Normally, apoptotic cells are engulfed by macrophages during apoptosis, avoiding the release of intracellular content that induces inflammation or an immune response in the extracellular environment.
  2. Autoimmune reactions
    • Type III hypersensitivity (most common in SLE) → antibody-antigen complex formation in microvasculature → complement activation and inflammation → damage to skin, kidneys, joints, small vessels
    • Type II hypersensitivity → IgG and IgM antibodies directed against antigens on cells (e.g., red blood cells) → cytopenia

Clinical features

  • Classic triad: fever, joint pain, and rash in a woman of childbearing age.
  • Highly variable presentation, known as “the great imitator”.

Common

  • Constitutional: fatigue, fever, weight loss
  • Joints (> 90% of cases)
    • Arthritis and arthralgia c
    • Distal symmetrical polyarthritis: most commonly affects the joints of the fingers, carpal joints, and the knee
  • Skin (85% of cases)
    • Malar rash: Fixed, erythematous maculopapular rash over the bridge of the nose and cheeks, sparing the nasolabial folds.
    • Discoid rash: Scarring, erythematous plaques with central atrophy and follicular plugging. c
    • Photosensitivity: Erythematous eruption following sunlight exposure.
      • Ultraviolet rays and sun exposure lead to increased cell apoptosis
    • Painless oral or nasopharyngeal ulcers.
    • Non-scarring alopecia.
    • Raynaud phenomenon c
  • Serositis: Pleuritis (pleuritic chest pain), pericarditis. t

Tip

Both rheumatoid arthritis and SLE arthritis affect the MCP and PIP joints, but SLE does not usually lead to deformities.

Less common

  • Hematological: petechiae, pallor, or recurrent infections due to cytopenias
  • Kidneys: nephritis with proteinuria (see “Lupus nephritis”)
    • Mesangial and/or subendothelial deposition of immune complexes (e.g., anti-dsDNA antibodies, anti-Sm antibodies) → expansion and thickening of mesangium, capillary walls, and/or glomerular basement membrane
  • Heart
    • Serositis (pleuritis, pericarditis w/ friction rub or effusion).
    • Libman-Sacks endocarditis (sterile verrucous vegetations on mitral/aortic valves). c
    • Increased risk of premature CAD/MI.
  • Neuropsychiatric:
    • Seizures, lupus psychosis (rule out steroid-induced psychosis), transverse myelitis, peripheral neuropathy, and cognitive impairment. c

Special clinical manifestations

Discoid lupus erythematosus

  • Epidemiology & Triggers
    • Demographics: F > M, 20–40 years of age, highest prevalence in African Americans.
    • Triggers: UV light, cigarette smoking (reduces antimalarial efficacy).
    • Prognosis: Primarily cutaneous; 5–10% progress to systemic lupus erythematosus (SLE).
  • Clinical Features
    • Distribution: Sun-exposed head and neck (scalp, face, conchal bowl of ear).
    • Triad: Erythema, hyperkeratosis, and atrophy.
    • Morphology: Indurated erythematous plaques with adherent scale; scale removal reveals keratotic spikes (“carpet tack sign”).
    • Late stage: Central depigmented/atrophic scarring with hyperpigmented, active borders.
    • Scalp: Permanent, irreversible scarring (cicatricial) alopecia.

Diagnostics

Laboratory studies

  • Best initial test: ANA (Antinuclear Antibody) - highly sensitive (>95%) but not specific.
  • Most specific antibodies: Anti-dsDNA and Anti-Sm (Anti-Smith).
    • Anti-dsDNA antibodies
      • Autoantibodies against double-stranded DNA
      • Positive in 60–70% of patients
      • Highly specific for SLE
      • Levels correlate with disease activity (especially lupus nephritis activity).
    • Anti-Sm antibodies
      • Autoantibodies against Smith antigens (nonhistone nuclear proteins)
        • Smith can bond to snRNAs to form snRNPs, which can form a spliceosome.
      • Positive in < 30% of patients, but highly specific for SLE
  • Antiphospholipid antibodies: Screen all patients for antiphospholipid syndrome.
  • Laboratory markers of disease activity and/or organ damage in SLE
    • Complement levels: ↓ C3 and/or ↓ C4 in patients with active disease, factor B levels remain normal
      • Antigen-antibody complexes trigger classic pathway, which decreases C3 and C4. But factor B in alternative pathway is intact.
    • Inflammatory markers
      • ESR: may be elevated in patients with active disease
      • CRP: often normal (may be elevated in patients with serositis, arthritis, or infections)
    • CBC: may show leukopenia, thrombocytopenia, and/or autoimmune hemolytic anemia or anemia of chronic disease c2
    • CMP: may show ↑ BUN and/or creatinine, and/or electrolyte abnormalities
    • Urinalysis and urine microscopy: may show proteinuria, hematuria, and/or urinary casts

Tip

RPR and VDRL are usually used to test for syphilis but may also be positive in SLE. This happens in antiphospholipid syndrome as well.

Skin biopsy

  • Lupus band test (LBT): a direct immunofluorescence staining technique used to detect immunoglobulin and complement component deposits along the dermoepidermal junction in affected and unaffected skin in patients with SLE

EULAR/ACR 2019 Criteria (≥10 Points Required)

  • Must include ≥1 clinical criterion. Count only the highest score per domain.
  • Clinical Domains:
    • Renal: Biopsy Class III/IV LN (10 pts), Class II/V LN (8 pts), Proteinuria >0.5g/24h (4 pts).
    • Skin: Malar/acute rash (6 pts), Discoid/subacute (4 pts), Alopecia or oral ulcers (2 pts).
    • Musculoskeletal: Arthritis (6 pts).
    • Serosal: Pericarditis (6 pts), Pleural/pericardial effusion (5 pts).
    • Neuro: Seizures (5 pts), Psychosis (3 pts), Delirium (2 pts).
    • Heme: Hemolytic anemia (4 pts), Thrombocytopenia (4 pts), Leukopenia (3 pts).
    • Fever: >38°C (2 pts).
  • Immunologic Domains:
    • Antibodies: Anti-dsDNA or Anti-Sm (6 pts), Antiphospholipid Ab (2 pts).
    • Complement: Low C3 AND C4 (4 pts), Low C3 OR C4 (3 pts).

Treatment

  • General: Sun protection, smoking cessation.
  • Mild disease (skin, joints): Hydroxychloroquine (for all patients), NSAIDs, low-dose corticosteroids.
    • Hydroxychloroquine: decreases complement-dependent antigen-antibody reactions.
  • Moderate disease (serositis, significant cytopenias): Add moderate-dose corticosteroids, possibly immunosuppressants like azathioprine or methotrexate.
  • Severe disease/Lupus Nephritis: High-dose corticosteroids plus cyclophosphamide or mycophenolate mofetil.

Complications

  • End-Stage Renal Disease (ESRD): Resulting from untreated or refractory proliferative LN.
  • Accelerated Atherosclerosis: Cardiovascular disease is the leading cause of death in long-standing SLE.
  • Antiphospholipid Syndrome (APS): Hypercoagulability leading to arterial/venous thrombosis and recurrent pregnancy loss. c
  • Neonatal Lupus: Occurs in infants of mothers with anti-Ro/SSA or anti-La/SSB; can cause permanent congenital third-degree heart block and transient cutaneous lesions.
  • Avascular Necrosis (AVN): Often of the femoral head, secondary to prolonged high-dose corticosteroid use.
  • Infections: Due to immunosuppressive therapy and intrinsic immune dysfunction (leading cause of death in early disease).

Cardiovascular disease

Special patient groups

Neonatal lupus syndrome

  • Etiology & Pathophysiology:
    • Transplacental transfer of maternal anti-SSA/Ro and anti-SSB/La IgG autoantibodies.
    • Mother may have diagnosed SLE, Sjögren syndrome, or be completely asymptomatic.
  • Clinical Features:
    • Cardiac (permanent, irreversible):
      • Congenital 3rd-degree (complete) AV block: Presents as persistent fetal/neonatal bradycardia (HR < 100 bpm). c
      • Cardiomyopathy, CHF, or endocardial fibroelastosis.
    • Cutaneous (transient, self-resolves by ~6–8 months as maternal IgG wanes):
      • Annular, erythematous scaly plaques with central clearing.
      • Classically involves face/scalp with periorbital distribution (“raccoon-eyes” appearance); photosensitive.
    • Extracardiac (transient):
      • Hematologic: Thrombocytopenia, anemia, neutropenia.
      • Hepatic: Transient transaminitis, conjugated hyperbilirubinemia, hepatomegaly.
  • Diagnosis:
    • Initial Serology: Positive maternal and neonatal anti-Ro/SSA or anti-La/SSB.
    • Cardiac Evaluation:
      • ECG: AV dissociation, ventricular escape rhythm.
      • Echocardiogram: Normal cardiac anatomy, impaired ventricular function, or endocardial fibroelastosis.
    • Adjunctive Labs: CBC (cytopenias), LFTs (cholestasis/transaminitis).
  • Management:
    • Cardiac (AV Block):
      • Established 3rd-degree block: Permanent cardiac pacemaker placement (definitive; AV nodal fibrosis is irreversible).
      • In utero detection of 1st-/2nd-degree block: Maternal dexamethasone (fluorinated steroid crossing placenta) to halt progression.
    • Cutaneous & Systemic:
      • First-line: Reassurance and strict photoprotection (sun avoidance, UV protection).
      • Second-line: Low-potency topical corticosteroids for severe rash.
      • Extracardiac manifestations resolve spontaneously within 6–9 months without specific therapy.
  • High-Yield Complications:
    • Hydrops fetalis and intrauterine fetal demise (IUFD) from profound bradycardia.
    • Sudden cardiac death from ventricular escape failure.

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