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"systemic lupus erythematosus"[MeSH Terms] AND diagnosis
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Systemic Lupus Erythematosus (SLE) - 10 Mark Answer
Definition
Systemic Lupus Erythematosus (SLE) is a chronic, relapsing and remitting, multisystem autoimmune disease characterized by the production of a vast array of autoantibodies - particularly antinuclear antibodies (ANAs) - causing injury primarily through immune complex deposition and antibody binding to various cells and tissues.
(Robbins, Cotran & Kumar Pathologic Basis of Disease)
Epidemiology
- Prevalence: up to 1 in 2500 in certain populations
- Female predominance: F:M ratio = 9:1 in reproductive age group (17-55 years); only 2:1 in childhood and after age 65
- Peak age of onset: 20s to 30s
- More prevalent and severe in African, Hispanic, and Asian individuals than in those of European ancestry
- Females of childbearing age: frequency of 1 in 700
(Robbins, Cotran & Kumar, p. 213-214)
Etiopathogenesis
SLE arises from a breakdown of self-tolerance due to a combination of genetic, environmental, and hormonal factors:
1. Genetic factors:
- HLA associations: HLA-B8, HLA-DR2, HLA-DR3 increase risk
- Complement deficiencies (C1q, C2, C4) predispose to SLE
- Fc receptor polymorphisms
- Over 40 genetic loci identified by GWAS studies
- 25% concordance in monozygotic twins (vs <5% in fraternal twins)
2. Environmental factors:
- Ultraviolet (UV) light - promotes apoptosis and release of nuclear antigens; causes DNA alterations that stimulate immune responses
- Viral infections (especially Epstein-Barr virus)
- Drugs (hydralazine, procainamide, isoniazid) can induce lupus-like syndrome
3. Immunological abnormalities:
- Failure to clear apoptotic cells leads to persistence of nuclear antigens
- Defective central and peripheral tolerance of autoreactive B and T cells
- Activated B cells produce autoantibodies (anti-dsDNA, anti-Sm, anti-Ro, anti-La, antiphospholipid)
- Type I interferons (especially IFN-α) play a key pathogenic role - the "interferon signature" is a hallmark
- Formation of immune complexes (especially anti-dsDNA) that deposit in vessels, kidneys, skin, joints, causing complement activation and inflammation
(Robbins, Cotran & Kumar, p. 213-217; Brenner and Rector's The Kidney)
Autoantibodies in SLE
| Autoantibody | Significance |
|---|---|
| ANA | Sensitive screening test (95%+); not specific |
| Anti-dsDNA | Highly specific; levels correlate with disease activity |
| Anti-Sm (Smith antigen) | Highly specific for SLE |
| Anti-histone | Drug-induced lupus |
| Anti-Ro (SSA) / Anti-La (SSB) | Associated with neonatal lupus, SCLE |
| Antiphospholipid antibodies | Thrombosis, recurrent miscarriages, thrombocytopenia |
The combination of anti-dsDNA + anti-Sm is essentially diagnostic.
Clinical Features (ACR Criteria)
The 1997 Revised ACR Classification Criteria (4 of 11 required):
| Feature | Details |
|---|---|
| Malar (butterfly) rash | Fixed erythema over malar eminences, sparing nasolabial folds |
| Discoid rash | Erythematous raised patches with scaling and follicular plugging |
| Photosensitivity | Skin rash from unusual reaction to sunlight |
| Oral/nasal ulcers | Usually painless |
| Arthritis | Nonerosive, involving ≥2 peripheral joints |
| Serositis | Pleuritis or pericarditis |
| Renal disorder | Proteinuria >500 mg/day or cellular casts |
| Neurological disorder | Seizures or psychosis |
| Hematological disorder | Hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia |
| Immunologic | Anti-dsDNA, anti-Sm, or antiphospholipid antibodies |
| ANA | Positive ANA at any time |
Prevalence of clinical manifestations:
- Hematologic: 100%
- Arthritis/arthralgia/myalgia: 80-90%
- Skin involvement: 85%
- Fever: 55-85%
- Fatigue: 90%+
(Robbins, Cotran & Kumar, Table 6.9 and 6.11)
Morphological/Pathological Features
Kidney (Lupus Nephritis):
- Most serious complication; 25-60% of patients develop renal disease
- Wire-loop lesion: thickened glomerular capillary walls due to subendothelial immune complex deposits
- WHO/ISN-RPS Classes I-VI (from minimal mesangial to advanced sclerosing)
- Immunofluorescence: "full house" pattern (IgG, IgM, IgA, C3, C1q)
Skin:
- Liquefaction degeneration of basal layer of epidermis
- Dermal edema, perivascular lymphocytic infiltrate
- Immunofluorescence: granular deposits of IgG and complement at dermo-epidermal junction ("lupus band test")
Heart:
- Libman-Sacks endocarditis: 1-3 mm warty, sterile vegetations on both surfaces of valve leaflets (usually mitral and aortic); characteristic of SLE
- Pericarditis in up to 50% of patients
- Accelerated coronary atherosclerosis in long-standing disease
Spleen:
- Onion-skin lesions: concentric periarteriolar fibrosis of penicilliary arteries (pathognomonic)
- Splenomegaly, capsular thickening, follicular hyperplasia
Joints: Nonerosive synovitis
Lungs: Pleuritis, pleural effusions, interstitial fibrosis, pulmonary hypertension
(Robbins, Cotran & Kumar, p. 217-219)
Investigations
- ANA: screening test (sensitive, not specific)
- Anti-dsDNA, Anti-Sm: specific for SLE; anti-dsDNA levels track disease activity
- CBC: anemia (hemolytic), leukopenia, thrombocytopenia
- Urinalysis + 24-hr urine protein: to assess renal involvement
- Complement (C3, C4, CH50): decreased in active disease (consumed by immune complexes)
- BMP/LFTs, ESR, CRP
- Renal biopsy: gold standard for lupus nephritis classification
- Direct immunofluorescence ("lupus band test") on skin
Treatment
General:
- Sun protection (sunscreens, protective clothing)
- Avoid triggers (infections, certain drugs, UV)
Pharmacological:
- Hydroxychloroquine (HCQ): backbone therapy for all SLE patients; reduces flares and organ damage
- NSAIDs: for arthritis, mild serositis, fever
- Corticosteroids: for moderate-to-severe disease and flares
- Immunosuppressants:
- Azathioprine: mild-moderate disease, maintenance
- Mycophenolate mofetil (MMF): preferred for lupus nephritis (induction and maintenance)
- Cyclophosphamide: severe lupus nephritis (NIH protocol), CNS lupus
- Methotrexate: skin and joint disease
- Biologics:
- Belimumab (anti-BLyS/BAFF): approved for active SLE
- Anifrolumab (anti-IFN receptor): approved for moderate-to-severe SLE (2021)
- Anticoagulation: for antiphospholipid syndrome
(Brenner and Rector's The Kidney; Firestein & Kelley's Textbook of Rheumatology)
Prognosis
- 10-year survival now exceeds 90% with modern treatment
- Major causes of death: renal failure, infections (due to immunosuppression), and accelerated cardiovascular disease
- Antiphospholipid antibodies increase risk of thrombotic events and pregnancy loss
- Neonatal lupus: maternal anti-Ro/SSA IgG crosses placenta causing neonatal complete heart block
Key Mnemonics:
- ACR criteria: "SOAP BRAIN MD" - Serositis, Oral ulcers, Arthritis, Photosensitivity, Blood disorders, Renal, ANA, Immunologic, Neurological, Malar rash, Discoid rash
- Highly specific antibodies: "Smith and DNA are SLE's DNA" (anti-Sm and anti-dsDNA are specific)
Sources: Robbins, Cotran & Kumar Pathologic Basis of Disease (10e) | Brenner and Rector's The Kidney | Firestein & Kelley's Textbook of Rheumatology
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