Systemic Lupus Erythematosus
Summary
Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease characterised by the production of pathogenic autoantibodies directed against nuclear antigens and immune complex deposition in multiple organs. It predominantly affects women of childbearing age, with a female-to-male ratio of 9:1. The disease follows a relapsing-remitting course and can affect virtually any organ system, including the skin, joints, kidneys, brain, heart, lungs, and blood. Diagnosis is based on the 2019 ACR/EULAR classification criteria, which require ANA positivity as an entry criterion followed by weighted clinical and immunological domains. Hydroxychloroquine is the cornerstone of therapy for all patients with SLE. Additional immunosuppression is tailored to organ involvement and disease severity.
Key Facts
- Definition: Chronic multisystem autoimmune disease with autoantibody production
- Incidence: 1-10 per 100,000 per year; prevalence 20-150 per 100,000
- Demographics: F:M ratio 9:1; peak onset 15-45 years; higher incidence in African, Asian, Hispanic populations
- Pathognomonic: ANA positivity + anti-dsDNA + multi-organ involvement
- Gold Standard Investigation: ANA, anti-dsDNA, anti-Sm, complement levels (C3/C4)
- First-line Treatment: Hydroxychloroquine for ALL patients
- Prognosis: 10-year survival greater than 90% with modern treatment; nephritis major determinant
Clinical Pearls
HCQ Pearl: Hydroxychloroquine reduces flares by 50%, prevents organ damage, reduces mortality, and is safe in pregnancy. ALL SLE patients should be on HCQ unless contraindicated.
Anti-dsDNA Pearl: Anti-dsDNA antibodies correlate with disease activity and are particularly associated with lupus nephritis. Rising titres often precede flares.
Complement Pearl: Low C3 and C4 levels suggest active disease and immune complex consumption. Persistently low complement with normal anti-dsDNA may indicate genetic complement deficiency.
Nephritis Pearl: All SLE patients should have regular urinalysis. Any proteinuria or active sediment warrants urgent renal assessment and consideration of biopsy.
Pregnancy Pearl: Plan pregnancies during disease quiescence. Anti-Ro/SSA antibodies carry risk of neonatal lupus and congenital heart block.
Why This Matters Clinically
SLE is the prototypical systemic autoimmune disease that rheumatologists, nephrologists, and general physicians must recognise and manage. Delayed diagnosis leads to organ damage. Understanding immunology, treat-to-target strategies, and new biologics transforms outcomes.
Incidence and Prevalence
| Population | Incidence (per 100,000/year) | Prevalence (per 100,000) |
|---|---|---|
| Overall | 1-10 | 20-150 |
| African descent | 8-11 | 200+ |
| Asian descent | 4-8 | 50-100 |
| European descent | 1-5 | 20-50 |
| Hispanic | 4-7 | 100+ |
Demographics
- Sex: Female predominance 9:1 (reproductive years); 2:1 in children and elderly
- Age: Peak incidence 15-45 years; can occur at any age
- Race/Ethnicity: Higher incidence and severity in African, Asian, Hispanic populations
- Geography: Higher prevalence in urban areas
Risk Factors
| Category | Factors | Relative Risk |
|---|---|---|
| Genetic | HLA-DR2, HLA-DR3, complement deficiencies (C1q, C2, C4), TREX1, IRF5 | 2-25x |
| Hormonal | Female sex, oestrogen exposure, early menarche | 9x |
| Environmental | UV light exposure, EBV infection, silica, smoking | 1.5-3x |
| Medications | Drug-induced lupus: hydralazine, procainamide, isoniazid, minocycline | Variable |
Mechanism Overview
Step 1: Genetic Predisposition
- Multiple susceptibility genes affecting immune regulation
- HLA associations (DR2, DR3) affect antigen presentation
- Complement deficiencies impair clearance of apoptotic debris
- Defects in DNA degradation (TREX1) and type I interferon signalling
Step 2: Environmental Triggers
- UV light induces apoptosis and exposes nuclear antigens
- Epstein-Barr virus molecular mimicry with nuclear antigens
- Hormonal factors modulate immune response
- Smoking and silica enhance autoimmunity
Step 3: Loss of Tolerance
- Defective clearance of apoptotic cells exposes nuclear antigens
- B cell hyperactivity and autoreactive B cell survival
- T cell dysregulation with reduced Treg function
- Dendritic cell activation and type I interferon overproduction
Step 4: Autoantibody Production
- Anti-nuclear antibodies (ANA) - screening marker
- Anti-dsDNA - specific for SLE, correlates with nephritis
- Anti-Sm - highly specific (pathognomonic) but less sensitive
- Anti-Ro/SSA, anti-La/SSB - associated with Sjögren's overlap, photosensitivity, neonatal lupus
- Antiphospholipid antibodies - thrombosis and pregnancy morbidity
Step 5: Immune Complex Deposition
- Circulating immune complexes deposit in tissues
- Complement activation via classical pathway
- Neutrophil and macrophage recruitment
- Tissue inflammation and damage
- Target organs: kidney, skin, joints, brain, heart, lungs
Step 6: Chronic Inflammation and Damage
- Ongoing cycles of flare and remission
- Cumulative organ damage (SLICC/ACR Damage Index)
- Accelerated atherosclerosis
- Medication-related toxicity
Autoantibody Associations
| Antibody | Prevalence | Clinical Association |
|---|---|---|
| ANA | 95-99% | Screening; not specific |
| Anti-dsDNA | 60-70% | Disease activity, lupus nephritis |
| Anti-Sm | 20-30% | Highly specific for SLE |
| Anti-Ro/SSA | 30-40% | Photosensitivity, neonatal lupus, Sjögren's |
| Anti-La/SSB | 10-15% | Sjögren's overlap |
| Anti-RNP | 25-30% | Mixed connective tissue disease overlap |
| Anti-ribosomal P | 10-20% | Neuropsychiatric lupus |
| Antiphospholipid | 30-40% | Thrombosis, pregnancy loss |
Constitutional Symptoms
Organ-Specific Manifestations
| System | Manifestations | Frequency |
|---|---|---|
| Mucocutaneous | Malar rash, discoid rash, photosensitivity, oral ulcers, alopecia | 80-90% |
| Musculoskeletal | Arthralgia, non-erosive arthritis, myalgia | 90% |
| Renal | Lupus nephritis (proteinuria, haematuria, casts) | 40-60% |
| Neuropsychiatric | Seizures, psychosis, cognitive dysfunction, headache | 30-40% |
| Haematological | Anaemia, leucopenia, lymphopenia, thrombocytopenia | 50-80% |
| Cardiopulmonary | Pericarditis, pleuritis, myocarditis, Libman-Sacks endocarditis | 30-50% |
| Vascular | Raynaud's, vasculitis, thrombosis (if APL positive) | 30-40% |
Classic Skin Manifestations
- Malar (butterfly) rash: Erythema over cheeks and nasal bridge, sparing nasolabial folds
- Discoid rash: Scarring, atrophic lesions with follicular plugging
- Photosensitivity: Rash after sun exposure
- Oral/nasal ulcers: Usually painless
- Non-scarring alopecia: Diffuse or frontal
Red Flags
[!CAUTION]
- Rapidly rising creatinine or nephrotic-range proteinuria (nephritis)
- New-onset seizures or psychosis (neuropsychiatric lupus)
- Severe thrombocytopenia (less than 20) or haemolytic anaemia
- Pulmonary haemorrhage or respiratory failure
- Multi-organ involvement with fever (catastrophic APS differential)
General Inspection
- Cushingoid features (steroid use)
- Malar rash, discoid lesions
- Alopecia (frontal, diffuse)
- Oral ulcers (palate, buccal mucosa)
- Pallor (anaemia)
- Peripheral oedema (nephrotic syndrome)
Cardiovascular
- Pericardial rub (pericarditis)
- Murmurs (Libman-Sacks endocarditis, valvular lesions)
- Signs of heart failure
- Blood pressure (hypertension from renal disease or steroids)
Respiratory
- Pleural rub or effusion
- Interstitial lung disease (shrinking lung syndrome)
- Pulmonary hypertension signs
Musculoskeletal
- Joint swelling (non-erosive arthritis - Jaccoud's arthropathy)
- Muscle tenderness
- Avascular necrosis (hips, shoulders - steroid related)
Neurological
- Cognitive assessment
- Focal neurological signs
- Cranial nerve palsies
Renal
- Blood pressure
- Oedema
- Fundoscopy for hypertensive changes
Diagnostic Workup
| Test | Finding | Interpretation |
|---|---|---|
| ANA | Positive (titre 1:80+) | Entry criterion; 95%+ sensitivity |
| Anti-dsDNA | Positive | Specific for SLE (70%), correlates with activity |
| Anti-Sm | Positive | Highly specific (pathognomonic) |
| C3/C4 | Low | Active disease, immune complex consumption |
| FBC | Cytopenias | Leucopenia, lymphopenia, thrombocytopenia, haemolytic anaemia |
| Urinalysis | Proteinuria, RBC casts | Lupus nephritis |
| Creatinine/eGFR | Elevated | Renal impairment |
| ESR | Elevated | Non-specific inflammation |
| CRP | Normal or mildly elevated | Usually lower than expected for degree of inflammation |
2019 ACR/EULAR Classification Criteria
Entry Criterion: ANA titre 1:80 or higher (HEp-2 cells)
Additive Criteria (need 10+ points for classification):
| Domain | Criterion | Points |
|---|---|---|
| Constitutional | Fever | 2 |
| Haematological | Leucopenia (less than 4.0) | 3 |
| Thrombocytopenia (less than 100) | 4 | |
| Autoimmune haemolysis | 4 | |
| Neuropsychiatric | Delirium | 2 |
| Psychosis | 3 | |
| Seizure | 5 | |
| Mucocutaneous | Non-scarring alopecia | 2 |
| Oral ulcers | 2 | |
| Subacute cutaneous or discoid | 4 | |
| Acute cutaneous (malar rash) | 6 | |
| Serosal | Pleural or pericardial effusion | 5 |
| Acute pericarditis | 6 | |
| Musculoskeletal | Joint involvement | 6 |
| Renal | Proteinuria greater than 0.5g/24h | 4 |
| Class II or V nephritis | 8 | |
| Class III or IV nephritis | 10 | |
| Immunological | Anti-dsDNA or anti-Sm | 6 |
| Antiphospholipid antibodies | 2 | |
| Low C3 OR C4 | 3 | |
| Low C3 AND C4 | 4 |
Lupus Nephritis Evaluation
- Urinalysis: Proteinuria, haematuria, RBC casts
- Spot urine protein:creatinine ratio: Quantify proteinuria
- 24-hour urine: If needed for accurate protein quantification
- Renal biopsy: Essential for classification and treatment planning
ISN/RPS Classification of Lupus Nephritis
| Class | Description | Prognosis |
|---|---|---|
| I | Minimal mesangial | Excellent |
| II | Mesangial proliferative | Good |
| III | Focal proliferative (less than 50% glomeruli) | Moderate |
| IV | Diffuse proliferative (50%+ glomeruli) | Guarded without treatment |
| V | Membranous | Variable |
| VI | Advanced sclerosing (90%+ sclerosis) | Poor |
Management Algorithm
SUSPECTED SLE
↓
┌─────────────────────────────────────────┐
│ CONFIRM DIAGNOSIS │
│ - ANA + specific antibodies │
│ - Apply ACR/EULAR 2019 criteria │
│ - Assess organ involvement │
└─────────────────────────────────────────┘
↓
┌─────────────────────────────────────────┐
│ ALL PATIENTS: HYDROXYCHLOROQUINE │
│ - 5mg/kg/day (max 400mg) │
│ - Annual ophthalmology after 5 years │
│ - Continue even in remission │
└─────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────────┐
│ ASSESS DISEASE ACTIVITY │
├─────────────────────────────────────────────────────────┤
│ MILD (skin, joints) │ MODERATE │ SEVERE │
│ NSAIDs │ Steroids │ High-dose │
│ Low-dose steroids │ + DMARD │ steroids + │
│ Topical steroids │ (AZA, MTX, MMF) │ IS agent │
└─────────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────┐
│ LUPUS NEPHRITIS (CLASS III-V) │
│ INDUCTION: │
│ - Mycophenolate OR Cyclophosphamide │
│ - ± Belimumab or Voclosporin (new) │
│ MAINTENANCE: │
│ - Mycophenolate OR Azathioprine │
└─────────────────────────────────────────┘
↓
┌─────────────────────────────────────────┐
│ REFRACTORY DISEASE │
│ - Rituximab │
│ - Belimumab │
│ - Anifrolumab (type I IFN inhibitor) │
│ - Clinical trials │
└─────────────────────────────────────────┘
General Measures
| Intervention | Details |
|---|---|
| Sun protection | High SPF sunscreen, protective clothing, avoid midday sun |
| Smoking cessation | Worsens disease activity and CV risk |
| Cardiovascular risk | Aggressive management of BP, lipids, diabetes |
| Bone health | Calcium, vitamin D, consider bisphosphonates if on steroids |
| Vaccination | Pneumococcal, influenza (avoid live vaccines if immunosuppressed) |
Hydroxychloroquine
- Dose: 5mg/kg actual body weight/day (maximum 400mg)
- Benefits: Reduces flares, prevents damage, reduces mortality, safe in pregnancy
- Monitoring: Baseline ophthalmology; annual screening after 5 years or earlier if risk factors
- Toxicity: Retinopathy (rare with correct dosing), QTc prolongation
Glucocorticoids
| Situation | Dose | Notes |
|---|---|---|
| Mild flare | Prednisolone 5-15mg/day | Taper rapidly |
| Moderate flare | Prednisolone 0.5mg/kg | Aim to taper to less than 7.5mg |
| Severe flare | IV methylprednisolone 500-1000mg x3 days | Then oral taper |
| Maintenance | Aim less than 7.5mg/day | Steroid-sparing agents essential |
Immunosuppressive Agents
| Drug | Indication | Dose | Monitoring |
|---|---|---|---|
| Azathioprine | Maintenance, steroid-sparing | 2-3mg/kg/day | FBC, LFTs, TPMT |
| Mycophenolate | Nephritis, severe disease | 2-3g/day | FBC, LFTs |
| Methotrexate | Arthritis, skin | 10-25mg/week | FBC, LFTs, renal |
| Cyclophosphamide | Severe nephritis, CNS | Euro-Lupus: 500mg fortnightly x6 | FBC, fertility |
Biologics
| Drug | Mechanism | Indication |
|---|---|---|
| Belimumab | Anti-BAFF/BLyS | Active SLE despite standard therapy; adjunct in nephritis |
| Rituximab | Anti-CD20 | Refractory disease (off-label) |
| Anifrolumab | Anti-type I IFN receptor | Moderate-severe SLE (skin, joints) |
| Voclosporin | Calcineurin inhibitor | Lupus nephritis (with MMF) |
| Complication | Incidence | Management |
|---|---|---|
| End-stage renal disease | 10-20% of nephritis | Dialysis, transplant |
| Cerebrovascular disease | 10% | Anticoagulation if APL+, risk factor control |
| Coronary artery disease | 2-10x general population | Aggressive CV risk management |
| Avascular necrosis | 5-15% | MRI, surgical intervention |
| Infections | Major cause of mortality | Prophylaxis, vaccination, vigilance |
| Malignancy | Lymphoma risk increased | Surveillance |
| Osteoporosis | Steroid-induced | Bone protection |
Survival
- 5-year survival: greater than 95%
- 10-year survival: greater than 90%
- 20-year survival: 75-85%
Prognostic Factors
Poor prognosis:
- Lupus nephritis (especially Class IV)
- Neuropsychiatric involvement
- Antiphospholipid syndrome
- African or Hispanic ethnicity
- Low socioeconomic status
- Male sex
- Childhood onset
Good prognosis:
- Mild disease (skin, joints only)
- Good response to initial therapy
- Adherence to hydroxychloroquine
Disease Activity Monitoring
- SLEDAI-2K (SLE Disease Activity Index)
- BILAG (British Isles Lupus Assessment Group)
- Anti-dsDNA titres and complement levels
- Urinalysis for nephritis monitoring
Key Guidelines
-
2019 EULAR Recommendations for SLE Management — Fanouriakis A et al. Ann Rheum Dis. 2019;78(6):736-745. PMID: 30926722
-
2019 ACR/EULAR Classification Criteria for SLE — Aringer M et al. Ann Rheum Dis. 2019;78(9):1151-1159. PMID: 31383717
-
2020 ACR Guideline for Lupus Nephritis — Hahn BH et al. Arthritis Rheumatol. 2012;64(4):797-808. PMID: 22556106
Landmark Trials
BLISS-52 and BLISS-76 (Belimumab)
- Population: Active SLE despite standard therapy
- Intervention: Belimumab vs placebo
- Result: Significant improvement in SRI-4 response
- Impact: First biologic approved for SLE
- PMID: 21296403
TULIP-2 (Anifrolumab)
- Population: Moderate-severe SLE
- Intervention: Anifrolumab vs placebo
- Result: Superior BICLA response (47.8% vs 31.5%)
- Impact: Type I IFN inhibition validated
- PMID: 31851795
AURORA (Voclosporin)
- Population: Active lupus nephritis
- Intervention: Voclosporin + MMF vs MMF alone
- Result: Higher complete renal response (40.8% vs 22.5%)
- Impact: New option for nephritis
- PMID: 33497604
ALMS (Mycophenolate vs Cyclophosphamide)
- Population: Lupus nephritis
- Result: MMF non-inferior to CYC for induction
- Impact: MMF preferred due to better side effect profile
- PMID: 19369404
What is SLE?
Lupus is a condition where your immune system, which normally fights infections, becomes overactive and attacks your own body's tissues. This can affect many parts of your body including your skin, joints, kidneys, heart, and brain. It tends to come and go in "flares."
What causes it?
We don't know exactly what causes lupus, but it involves a combination of your genes, hormones, and environmental triggers like sunlight or infections. It's not contagious.
How is it treated?
Nearly everyone with lupus takes hydroxychloroquine - a medication that reduces flares and protects your organs. During flares, you may need steroids or other medications to calm your immune system. The key is to control the disease to prevent organ damage.
Living with SLE
- Protect yourself from the sun (high SPF sunscreen, hats, avoid midday sun)
- Don't smoke
- Report any new symptoms promptly
- Take your medications regularly
- Plan pregnancies with your doctor
Warning signs to report
- New rash or worsening skin problems
- Swelling in legs or face
- Blood in urine or foamy urine
- Chest pain or shortness of breath
- Confusion, seizures, or severe headaches
-
Fanouriakis A et al. 2019 Update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2019;78(6):736-745. PMID: 30926722
-
Aringer M et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis. 2019;78(9):1151-1159. PMID: 31383717
-
Morand EF et al. Trial of Anifrolumab in Active Systemic Lupus Erythematosus (TULIP-2). N Engl J Med. 2020;382(3):211-221. PMID: 31851795
-
Rovin BH et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1). Lancet. 2021;397(10289):2070-2080. PMID: 33497604
-
Appel GB et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis (ALMS). J Am Soc Nephrol. 2009;20(5):1103-1112. PMID: 19369404
-
Navarra SV et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus (BLISS-52). Lancet. 2011;377(9767):721-731. PMID: 21296403
-
Ruiz-Irastorza G et al. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus. Ann Rheum Dis. 2010;69(1):20-28. PMID: 19103632
-
Bertsias GK et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations. Ann Rheum Dis. 2010;69(12):2074-2082. PMID: 20724309
-
Cervera R et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period. Medicine (Baltimore). 2003;82(5):299-308. PMID: 14530779
-
Tektonidou MG et al. Risk of end-stage renal disease in patients with lupus nephritis, 1971-2015. Arthritis Rheumatol. 2016;68(6):1432-1441. PMID: 26815602
Viva Points
"SLE is a chronic multisystem autoimmune disease characterised by ANA and anti-dsDNA antibodies, immune complex deposition, and multi-organ inflammation. Classification uses ACR/EULAR 2019 criteria (10+ points with ANA entry). Hydroxychloroquine for ALL patients. Lupus nephritis is treated with mycophenolate or cyclophosphamide induction. Belimumab, anifrolumab, and voclosporin are new biologics. Monitor anti-dsDNA and complement for activity."
Key Examination Points
- Malar rash (butterfly distribution, spares nasolabial folds)
- Discoid lesions (scarring, atrophic)
- Oral ulcers (usually painless)
- Non-erosive arthritis (Jaccoud's)
- Pericardial/pleural rubs
- Oedema (nephrotic syndrome)
- Hypertension (renal involvement)
Common Mistakes
- ❌ Not starting hydroxychloroquine in all patients
- ❌ Missing lupus nephritis (not checking urine)
- ❌ Prolonged high-dose steroids without steroid-sparing agent
- ❌ Confusing drug-induced lupus (anti-histone positive, anti-dsDNA usually negative)
- ❌ Not screening for antiphospholipid antibodies
Differentials
- Drug-induced lupus (anti-histone positive)
- Mixed connective tissue disease
- Rheumatoid arthritis
- Other connective tissue diseases (SSc, PM/DM)
- Viral infections
Last Reviewed: 2026-01-01 | MedVellum Editorial Team