Key Facts

SLE is the prototypical autoimmune disease with an extraordinary range of clinical manifestations. No two patients are the same. The goal of management is to prevent damage accumulation using a treat-to-target strategy.

Epidemiology

• UK prevalence: ~1 in 1,000 (higher in Afro-Caribbean: 1 in 250)
• F:M 9:1; peak onset 15-45 years
• More severe disease in Afro-Caribbean, Asian, and Hispanic populations
• Childhood-onset SLE (<18 years): more aggressive with higher renal and neurological involvement

Aetiology

• Genetic: HLA-DR2/DR3, complement deficiency (C1q, C2, C4), TREX1, DNase1
• Environmental: UV light (major trigger), EBV infection, silica, smoking
• Hormonal: oestrogen promotes disease (explains female predominance, flares in pregnancy)
• Drugs (drug-induced lupus): hydralazine, isoniazid, procainamide, minocycline, anti-TNF agents

Pathophysiology

• Loss of self-tolerance → autoreactive B and T cells
• Defective clearance of apoptotic cells → nuclear antigen exposure
• Autoantibody production: ANA, anti-dsDNA, anti-Sm, anti-Ro/La, antiphospholipid
• Immune complex formation → complement activation → tissue damage
• Complement consumption → low C3/C4 during flares
• Type III hypersensitivity (immune complex deposition) in kidneys, skin, joints
• Type II hypersensitivity (autoantibodies) → cytopenias

Constitutional (>90%)

• Fatigue (most common symptom), fever, weight loss, malaise

Musculoskeletal (>90%)

• Arthralgia and non-erosive arthritis (unlike RA)
• Jaccoud arthropathy: reducible deformities (subluxation without erosion)
• Avascular necrosis (especially femoral head) – related to steroid use

Skin (80%)

• Malar (butterfly) rash: erythematous, spares nasolabial folds, photosensitive
• Discoid lupus: scarring, atrophic plaques; can occur without systemic disease
• Photosensitivity: rash in sun-exposed areas
• Oral/nasal ulcers (usually painless)
• Alopecia (diffuse, non-scarring in SLE; scarring in discoid)
• Raynaud phenomenon (30-50%)
• Livedo reticularis (associated with antiphospholipid)

Renal (50%)

• Lupus nephritis: proteinuria, haematuria, declining eGFR
• Class IV (diffuse proliferative) most common and severe
• Nephrotic syndrome (class V)

Neuropsychiatric (30-40%)

• Cognitive dysfunction ("lupus fog")
• Seizures, psychosis, headache
• Cerebrovascular disease (especially with antiphospholipid)
• Peripheral neuropathy, cranial neuropathy

Haematological (>50%)

• Lymphopenia (most common haematological abnormality)
• Autoimmune haemolytic anaemia (Coombs-positive)
• Thrombocytopenia (autoimmune)
• Leucopenia

Serositis

• Pleurisy (most common serositis), pericarditis
• Libman-Sacks endocarditis (sterile vegetations)

Red Flags

• Rapidly rising creatinine + active sediment → lupus nephritis flare → urgent biopsy
• New neurological symptoms → neuropsychiatric lupus or antiphospholipid-related stroke
• Pancytopenia → macrophage activation syndrome (MAS)
• Recurrent pregnancy loss → screen for antiphospholipid antibodies

Immunology

• ANA: positive in >95% (screening test; not specific)
• Anti-dsDNA: specific (>95%); titre correlates with nephritis activity
• Anti-Sm: highly specific for SLE (~30% sensitive)
• Anti-Ro (SSA): associated with photosensitivity, neonatal lupus, congenital heart block
• Anti-La (SSB): associated with Sjogren syndrome overlap
• Antiphospholipid antibodies: lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I
• C3/C4: low during flares (complement consumption)
• Anti-C1q: correlates with lupus nephritis

Bloods

• FBC: lymphopenia, anaemia, thrombocytopenia
• ESR: elevated (CRP often normal unless infection/serositis)
• U&Es, urine ACR: renal assessment
• Direct Coombs test: AIHA
• LDH, reticulocytes, haptoglobin: haemolysis screen

Urine

• Dipstick: protein, blood
• Urine ACR/PCR: quantify proteinuria
• Microscopy: red cell casts (active nephritis)

Imaging

• CXR: pleural effusion, pericardial effusion
• Echocardiogram: pericarditis, Libman-Sacks
• MRI brain: neuropsychiatric lupus
• Renal USS: kidney size

Biopsy

• Renal biopsy: essential for lupus nephritis classification (ISN/RPS classes I-VI)
• Skin biopsy: lupus band test (immunoglobulin/complement at dermo-epidermal junction)

All Patients

• Hydroxychloroquine 200-400mg daily: reduces flares by 50%, improves survival, reduces damage accumulation, lipid-lowering, antithrombotic
  • Annual ophthalmology screening after 5 years (retinal toxicity)
• Sun protection: high-factor SPF, protective clothing
• Cardiovascular risk management: statin, BP control
• Vaccination: influenza, pneumococcal (avoid live vaccines during immunosuppression)

Mild Disease (Skin, Joints)

• Topical steroids: for skin lesions
• NSAIDs: for arthralgia (short-term)
• Low-dose prednisolone: ≤7.5mg for flares
• Methotrexate: steroid-sparing for skin/joints

Moderate Disease

• Prednisolone 0.5mg/kg tapering
• Azathioprine 2mg/kg/day: maintenance immunosuppression
• Mycophenolate mofetil: alternative to azathioprine
• Belimumab (anti-BLyS): add-on therapy (NICE TA397); reduces flares

Severe Disease (Nephritis, Neuropsychiatric)

• See lupus nephritis topic for nephritis management
• IV methylprednisolone 500mg-1g × 3 days for severe flares
• Cyclophosphamide: for severe nephritis or neuropsychiatric lupus
• Rituximab: for refractory disease (off-label but widely used)
• Voclosporin + MMF: for nephritis (AURORA trial)

Pregnancy in SLE

• High-risk: flares, pre-eclampsia, fetal loss, neonatal lupus
• Continue hydroxychloroquine throughout pregnancy
• Anti-Ro positive: monitor fetal heart for congenital heart block (from 16 weeks)
• Antiphospholipid syndrome: aspirin 75mg + LMWH
• Avoid methotrexate, mycophenolate, cyclophosphamide (teratogenic)
• Safe in pregnancy: HCQ, azathioprine, tacrolimus, prednisolone (low dose)

Referral Criteria

• All suspected SLE → rheumatology
• Lupus nephritis → nephrology + rheumatology
• Neuropsychiatric lupus → neurology
• Pregnancy planning → obstetric medicine

• 10-year survival: >90% (significantly improved from 50% in the 1950s)
• Leading causes of death: infections (immunosuppression), cardiovascular disease (accelerated atherosclerosis), renal failure
• Damage accumulation: measured by SLICC/ACR Damage Index; increases over time
• Lupus nephritis: 10-year renal survival 80-90% with modern treatment
• Antiphospholipid syndrome: significantly increases morbidity
• Afro-Caribbean patients: more severe disease, higher renal involvement, worse outcomes
• Hydroxychloroquine: the single most important drug; reduces all-cause mortality

SLICC Classification Criteria (2012)

Requires ≥4 of 17 criteria (≥1 clinical + ≥1 immunological) OR biopsy-proven lupus nephritis + ANA or anti-dsDNA:

Clinical (11): acute cutaneous lupus, chronic cutaneous lupus, oral/nasal ulcers, non-scarring alopecia, arthritis, serositis, renal, neurological, haemolytic anaemia, leucopenia/lymphopenia, thrombocytopenia

Immunological (6): ANA, anti-dsDNA, anti-Sm, antiphospholipid, low complement, positive Coombs

Key Autoantibodies in SLE