Systemic Lupus Erythematosus (SLE)

1. Clinical Overview

Summary

Systemic Lupus Erythematosus (SLE) is the distinct prototype of a systemic autoimmune disease. Unlike organ-specific destruction (e.g., Type 1 Diabetes), SLE is characterized by a loss of tolerance to nuclear antigens (DNA, Histones), resulting in the production of autoantibodies that form Immune Complexes. These complexes deposit in vascular beds across the body—Skin, Joints, Kidneys, Brain, and Pleura—triggering complement activation and inflammation (Type III Hypersensitivity).

It predominantly affects young women (9:1) of childbearing age, with a disproportionate burden on African-Caribbean and Asian populations. The clinical course is one of Relapsing-Remitting flares. The greatest threat to life is Lupus Nephritis (leading to ESRF) and accelerated Cardiovascular Disease. Management has evolved from high-dose steroids to steroid-sparing agents (Hydroxychloroquine for all, MMF/Cyclophosphamide for organs) and targeted Biologics (Belimumab, Anifrolumab).

Key Facts

• Demographic: Female:Male 9:1. Peak onset 15-45 years.
• Hallmark Antibody: ANA (> 95% sensitive).
• Specific Antibody: Anti-dsDNA (> 95% specific, tracks disease activity).
• Cornerstone Drug: Hydroxychloroquine (reduces mortality and flares).
• Major Complication: Lupus Nephritis (Class III/IV requires aggressive immunosuppression).

Clinical Pearls

"Hydroxychloroquine is Life Insurance": Every SLE patient should be on HCQ unless contraindicated. It prevents flares, reduces organ damage, reduces thrombosis, AND improves survival. Stopping it is the #1 cause of flare.

"The Renal Rule": Lupus Nephritis is often asymptomatic until it is too late. Every lupus patient needs a Urine Dipstick and BP check at EVERY clinic visit. "Frothy urine" means significant proteinuria.

"It's not just Lupus": 30-40% of SLE patients have Antiphospholipid Antibodies. They are at risk of clots (DVT/PE/Stroke) and recurrent miscarriage. Always screen for APS.

"Serositis vs Infection": A lupus patient with chest pain and fever. Is it Pleuritis (Lupus) or Pneumonia (Infection)?

• High CRP = Likely Infection (Lupus flares rarely raise CRP significantly unless there is synovitis/serositis).
• High ESR = Likely Lupus.

---

2. Epidemiology

Global Burden

The prevalence of SLE varies dramatically by geography and ethnicity, reflecting the complex interplay of genetic susceptibility and environmental factors. [1,2]

• Prevalence: 20–150 per 100,000 depending on ethnicity and geography
  • Highest in African-Caribbean populations (up to 200 per 100,000)
  • Intermediate in Asian and Hispanic populations (50-100 per 100,000)
  • Lowest in Northern European populations (20-40 per 100,000)
• Incidence: 1-10 per 100,000 person-years globally [2]
• Trends: Incidence has remained stable, but survival has dramatically improved with modern therapies (10-year survival now > 90% in developed countries) [1]

Demographics

Ethnicity-Based Disparities

The burden of SLE is not equal. Ethnicity profoundly affects both disease frequency and severity. [2,3]

• African-Caribbean:
  • Highest prevalence and severity
  • Earlier onset (mean age 28 vs 35 in Caucasians)
  • Higher risk of lupus nephritis (50-60% vs 30-40%)
  • Higher risk of end-stage renal failure
  • Worse cardiovascular outcomes
  • Higher frequency of Anti-Sm antibodies
• Caucasian:
  • Lower prevalence
  • Milder skin/joint predominant disease
  • Better overall prognosis
• Asian/Hispanic:
  • Intermediate to high risk
  • Higher nephritis rates than Caucasians
  • Increased photosensitivity

Risk Factors

Genetic Susceptibility

• Monozygotic Twin Concordance: 24-25% (compared to 2% in dizygotic twins—high heritability but environment clearly matters)
• HLA Associations:
  • HLA-DR2 and HLA-DR3: Increased SLE risk (Odds Ratio 2-3)
  • HLA-DRB1*03:01: Associated with anti-Ro/La antibodies
• Complement Deficiency:
  • Homozygous C1q deficiency: > 90% develop SLE
  • C2 and C4 deficiency: 10-30% risk
• Single Gene Variants: Over 100 risk loci identified via GWAS, each with small effect size

Hormonal Factors

• Oestrogen: Promotes survival of autoreactive B-cells and enhances interferon production
• Pregnancy: Risk of flare (especially if disease not quiescent for > 6 months pre-conception)
• Oral Contraceptive Pill: Modest increased risk in susceptible individuals
• Menopause: Disease activity often decreases

Environmental Triggers

• UV Light:
  • UVB (290-320nm) causes keratinocyte apoptosis
  • Releases nuclear antigens (DNA, histones) to immune system
  • Direct trigger for cutaneous and systemic flares
• Infections:
  • Epstein-Barr Virus (EBV): 99% of SLE patients are EBV seropositive vs 94% controls
  • Molecular mimicry: EBV nuclear antigen (EBNA-1) cross-reacts with human autoantigens
  • Other implicated viruses: CMV, Parvovirus B19
• Smoking: Increased risk of SLE and reduced efficacy of antimalarials
• Silica Dust: Occupational exposure associated with increased SLE risk
• Drugs: See Section 8 (Drug-Induced Lupus)

---

3. Pathophysiology: The "Waste Disposal" Failure

SLE is fundamentally a failure of the body to clear apoptotic debris, leading to chronic immune activation against self-antigens. The pathogenesis involves a complex interplay of defective clearance, loss of tolerance, immune complex formation, and sustained interferon signalling. [3,4]

Step 1: Defective Apoptotic Clearance

Normal Process:

• Billions of cells undergo apoptosis daily
• Macrophages recognize "eat-me" signals (phosphatidylserine) on apoptotic cells
• Rapid clearance prevents release of intracellular contents
• Process is immunologically silent (anti-inflammatory)

In SLE:

• Clearance is defective due to:
  • Complement deficiency (C1q, C4 needed for opsonization)
  • Macrophage dysfunction
  • Increased apoptotic burden (possibly UV-induced)
• Apoptotic cells undergo secondary necrosis
• Nuclear contents spill out: DNA, nucleosomes, Ro, La, Sm antigens
• Debris accumulates in germinal centres and tissues

Step 2: Loss of Tolerance (Innate Immune Activation)

Toll-Like Receptor (TLR) Activation:

• Plasmacytoid dendritic cells (pDCs) encounter extracellular DNA/RNA
• Misidentified as viral nucleic acids
• Activation via TLR-7 (recognizes ssRNA) and TLR-9 (recognizes unmethylated CpG DNA)
• Result: Massive secretion of Type I Interferons (IFN-α, IFN-β)

The Interferon Signature:

• Present in 50-80% of SLE patients [3,4]
• IFN-α:
  • Activates dendritic cells → present self-antigens to T-cells
  • Promotes B-cell differentiation into plasma cells
  • Drives production of high-affinity autoantibodies
  • Upregulates MHC expression
  • Inhibits regulatory T-cell function
• Interferon levels correlate with disease activity
• Therapeutic target: Anifrolumab blocks the Type I IFN receptor

Step 3: Adaptive Immune Activation

B-Cell Abnormalities:

• Loss of B-cell tolerance checkpoints
• Increased B-cell activating factor (BAFF/BLyS) levels
• Survival of autoreactive B-cells that should have been deleted
• Production of high-affinity IgG autoantibodies:
  • Anti-nuclear antibodies (ANA): Against DNA, histones, nucleosomes
  • Anti-dsDNA: Pathogenic, correlates with nephritis
  • Anti-Sm, Anti-Ro, Anti-La: Highly specific

T-Cell Abnormalities:

• Skewing toward Th1/Th17 (pro-inflammatory) responses
• Reduced Regulatory T-cell (Treg) function
• Aberrant T-cell signalling
• Increased T-cell help to autoreactive B-cells

Step 4: Immune Complex Formation and Deposition

Type III Hypersensitivity:

1. Autoantibody + Nuclear Antigen = Immune Complex
2. Complexes circulate in the bloodstream
3. Deposit in vascular beds with high filtration/blood flow:
   • Glomerular Basement Membrane → Lupus Nephritis
   • Dermal-Epidermal Junction → Cutaneous Lupus
   • Synovium → Arthritis
   • Choroid Plexus/Brain → Neuropsychiatric Lupus
   • Pleura/Pericardium → Serositis

Complement Activation (Classical Pathway):

• Immune complexes activate C1q
• Cascade: C1q → C4 → C2 → C3 → C5-C9 (MAC)
• Result:
  • Low serum C3 and C4 (consumed at tissue sites)
  • Generation of anaphylatoxins (C3a, C5a) → recruit neutrophils
  • Direct tissue damage via Membrane Attack Complex
• Complement levels inversely correlate with disease activity

Step 5: Tissue Inflammation and Damage

Cellular Infiltration:

• Neutrophils, macrophages, T-cells infiltrate affected organs
• Release of:
  • Proteases
  • Reactive oxygen species
  • Pro-inflammatory cytokines (IL-6, TNF-α, IL-1)

NETosis (Neutrophil Extracellular Traps):

• Neutrophils extrude DNA nets to trap pathogens
• In SLE, increased and abnormal NETosis
• Provides additional source of extracellular DNA
• Self-perpetuating cycle of immune activation

End Result:

• Chronic inflammation
• Fibrosis (kidneys, lungs)
• Vascular damage (accelerated atherosclerosis)
• Organ dysfunction

Step 6: Vicious Cycle

SLE is self-perpetuating:

• Inflammation → more cell death → more debris → more immune activation → more inflammation

Key Molecular Targets for Therapy

---

4. Clinical Features

"The Great Imitator"

• SLE can affect virtually any organ system, leading to protean manifestations. No two patients are identical. The clinical course is typically relapsing-remitting with unpredictable flares. [1,5]

1. Constitutional Symptoms (90%)

Present in nearly all patients during active disease:

• Fatigue: Often the most debilitating symptom
  • Disproportionate to organ damage
  • Multifactorial: cytokine-mediated, chronic inflammation, sleep disturbance, depression
  • May persist even when disease is controlled
• Fever: Low-grade during flares
  • Key Clinical Distinction: ALWAYS rule out infection before assuming lupus flare
  • High fever (> 38.5°C) more suggestive of infection
• Weight Loss: Unintentional, during active disease
• Malaise: General feeling of being unwell

2. Mucocutaneous Manifestations (80%)

The most visible manifestations—often the presenting feature.

Acute Cutaneous Lupus

Malar Rash ("Butterfly Rash"):

• Classic presentation: Erythematous rash over cheeks and nasal bridge
• Pathognomonic feature: Spares the nasolabial folds (distinguishes from rosacea)
• Triggered by sun exposure (photosensitive)
• Flat or raised
• Non-scarring (resolves without atrophy)
• May be malar flush (diffuse) or maculopapular

Photosensitivity:

• Skin rash as unusual reaction to sunlight (UVB 290-320nm)
• Present in 60-70% of patients
• Appears within hours to days of sun exposure
• Distribution: Face, V-neck area, dorsal hands/arms (sun-exposed sites)

Subacute Cutaneous Lupus Erythematosus (SCLE)

• Morphology:
  • Annular (ring-shaped) lesions with central clearing
  • Polycyclic (interconnecting rings)
  • Papulosquamous (psoriasiform) variant
• Distribution: Upper trunk, arms, shoulders (sun-exposed)
• Highly photosensitive
• Non-scarring (unlike discoid)
• Antibody Association: Anti-Ro (SS-A) positive in 70-90%
• Drug-Induced: Can be triggered by hydrochlorothiazide, calcium channel blockers, terbinafine

Chronic Cutaneous Lupus (Discoid Lupus Erythematosus - DLE)

• Morphology:
  • Well-demarcated, coin-shaped (discoid) plaques
  • Erythematous with adherent scale
  • Central atrophy and scarring
  • Hypopigmentation or hyperpigmentation
  • Follicular plugging (on dermoscopy)
• Distribution: Scalp, face, ears, neck (can be disseminated)
• Scarring Alopecia: When on scalp, leads to permanent hair loss
• Course: Chronic, progressive if untreated
• Isolated DLE: Only 5-10% progress to systemic SLE

Other Cutaneous Features

• Non-Scarring Alopecia: Diffuse thinning during active disease (reversible)
• Oral/Nasal Ulcers:
  • Usually painless (unlike Behçet's or aphthous ulcers)
  • Hard palate, buccal mucosa, nasal septum
  • May be asymptomatic (only seen on examination)
• Livedo Reticularis: Violaceous, net-like pattern (associated with antiphospholipid antibodies)
• Raynaud's Phenomenon: 30-40% of patients
• Vasculitic Lesions:
  • Nail fold infarcts
  • Digital ulcers
  • Palpable purpura (leukocytoclastic vasculitis)
• Lupus Panniculitis: Deep nodules, may ulcerate

3. Musculoskeletal (90%)

The most common manifestation—often the presenting complaint.

Arthralgia and Arthritis:

• Distribution: Symmetrical, polyarticular (5+ joints)
• Joints Affected: Small joints of hands (MCPs, PIPs), wrists, knees
• Character:
  • Morning stiffness (30+ minutes)
  • Swelling and tenderness
  • Migratory pattern possible
  • Non-erosive (unlike rheumatoid arthritis)
• Imaging: X-rays typically NORMAL (no bony erosions or joint space narrowing)

Jaccoud's Arthropathy:

• Chronic deforming arthropathy in 5-10% of patients
• Ulnar deviation of fingers, swan-neck deformities
• Looks like RA clinically
• Key Distinction: Deformities are reducible (passive correction possible)
• Caused by tendon/ligament laxity, NOT bone erosion
• X-rays show soft tissue abnormalities, not erosions

Myalgia/Myositis:

• Muscle pain common (30-40%)
• True myositis (inflammatory) is rare (5%)
• Check CK (usually normal or mildly elevated)

Avascular Necrosis (AVN):

• Especially femoral head, humeral head
• Risk factors: Corticosteroid use, antiphospholipid antibodies
• Presents with hip/shoulder pain
• MRI is diagnostic

4. Renal (Lupus Nephritis) (50%)

The most serious organ manifestation—leading cause of morbidity and mortality in SLE. [6,7]

Clinical Presentation:

• Often asymptomatic in early stages (silent killer)
• Only detected by routine urine dipstick and blood pressure monitoring
• Late signs:
  • Peripheral oedema (nephrotic syndrome)
  • Hypertension (glomerular damage)
  • "Frothy urine" (significant proteinuria)
  • Reduced urine output

Laboratory Findings:

• Urinalysis:
  • Proteinuria (often nephrotic range > 3.5g/day)
  • Haematuria (microscopic or macroscopic)
  • Active sediment: Red cell casts, white cell casts (pathognomonic for glomerulonephritis)
• Urine Protein:Creatinine Ratio (PCR): Quantify proteinuria
• Serum Creatinine: Elevated in significant disease
• eGFR: Reduced

Indications for Renal Biopsy (See Section 6 for classification):

• New proteinuria > 0.5g/day (or PCR > 50mg/mmol)
• Rising serum creatinine
• Active urinary sediment
• Biopsy is MANDATORY to determine class and guide therapy

Natural History:

• Without treatment: Progression to ESRF in 50% within 5 years
• With modern therapy: 80-90% achieve remission
• Renal flares are common (30-50%)
• End-stage kidney disease requiring dialysis/transplant: Now less than 10% at 10 years

5. Cardiovascular and Pulmonary

Serositis (50%)

Pleuritis:

• Pleuritic chest pain (sharp, worse on inspiration)
• Pleural effusion (usually small, bilateral)
• Pleural rub on auscultation

Pericarditis:

• Chest pain (relieved by sitting forward)
• Pericardial rub (scratching sound)
• Pericardial effusion (usually small, rarely tamponade)
• ECG: Widespread ST elevation, PR depression

Peritonitis (rare):

• Abdominal pain, ascites

Pulmonary Manifestations

Lupus Pneumonitis (Rare but serious):

• Acute dyspnoea, fever, cough
• CXR: Bilateral infiltrates
• Diagnosis of exclusion (must rule out infection)
• High mortality if untreated

Pulmonary Hypertension:

• Progressive dyspnoea
• May be primary (vasculopathy) or secondary (chronic thromboembolic disease from APS)
• Echocardiography: elevated RVSP
• Right heart catheterization for confirmation

Shrinking Lung Syndrome:

• Rare
• Diaphragmatic dysfunction (unknown cause)
• Progressive dyspnoea
• CXR: Small lung volumes, elevated hemidiaphragms
• PFTs: Restrictive pattern

Cardiac Manifestations

Libman-Sacks Endocarditis:

• Sterile vegetations (fibrinous, non-bacterial)
• Most commonly on mitral valve (ventricular surface)
• Usually asymptomatic
• Risk of embolic stroke
• Seen on transoesophageal echocardiography

Myocarditis:

• Rare but serious
• Heart failure, arrhythmias
• Elevated troponin, BNP
• Echocardiography: reduced ejection fraction

Accelerated Atherosclerosis:

• 50-fold increased risk of myocardial infarction in young women with SLE [1]
• Chronic inflammation damages endothelium
• Premature coronary artery disease
• Stroke risk increased 2-10 fold
• Prevention: Aggressive cardiovascular risk factor management

6. Neuropsychiatric Lupus (NPSLE) (40-50%)

One of the most challenging aspects of SLE—19 different syndromes recognized by ACR. [8]

Mechanisms:

• Cerebrovascular disease (vasculopathy, thrombosis from APS)
• Autoantibodies (anti-ribosomal P, anti-NR2 glutamate receptor)
• Cytokine-mediated neuronal dysfunction
• Direct immune complex deposition

Central Nervous System Manifestations:

Peripheral Nervous System:

• Peripheral Neuropathy: Sensory > motor
• Mononeuritis Multiplex: Vasculitis of nerves (painful, asymmetric)
• Guillain-Barré-like syndrome: Rare

Diagnosis:

• Clinical: Correlation with disease activity
• MRI Brain: White matter hyperintensities, infarcts
• Lumbar Puncture: Exclude infection; may show lymphocytic pleocytosis, elevated protein
• Autoantibodies: Anti-ribosomal P (associated with psychosis), anti-NR2
• Neuropsychometric Testing: Quantify cognitive impairment

Differential Diagnosis:

• Infection (meningitis, encephalitis)
• Drug side effects (corticosteroid psychosis)
• Metabolic (uraemia)
• Primary psychiatric disorder

7. Haematological (80%)

Cytopenias (Autoimmune destruction):

• Anaemia:
  • Anaemia of chronic disease (most common)
  • Autoimmune haemolytic anaemia (AIHA): Coombs positive, spherocytes, elevated LDH/bilirubin
  • Renal anaemia (erythropoietin deficiency)
• Leukopenia:
  • Lymphopenia (less than 1.5 x 10⁹/L) very common
  • Neutropenia (increases infection risk)
• Thrombocytopenia:
  • Immune-mediated (ITP-like)
  • Platelets less than 100 in 20-30%
  • Severe thrombocytopenia (less than 20) is a red flag

Lymphadenopathy:

• Reactive, generalized
• Biopsy if atypical (exclude lymphoma)

8. Gastrointestinal (Uncommon but Important)

• Mesenteric Vasculitis:
  • Acute abdominal pain, nausea, vomiting
  • CT: Bowel wall thickening, "target sign"
  • Serious: Risk of perforation
• Protein-Losing Enteropathy: Rare
• Hepatitis: Autoimmune hepatitis overlap (10%)
  • Elevated transaminases
  • Check anti-smooth muscle, anti-LKM antibodies
• Pancreatitis: Drug-induced (azathioprine) or primary SLE

---

5. Diagnostic Approach and Investigations

Classification Criteria

SLE is diagnosed clinically using classification criteria. The two main systems are:

2019 EULAR/ACR Criteria (Current Gold Standard)

• Entry Criterion: ANA titre ≥1:80 on HEp-2 cells (or equivalent positive test)
• Classification: Points assigned across 7 clinical and 3 immunological domains
• Threshold: ≥10 points = Classified as SLE
• Sensitivity: 96.1%
• Specificity: 93.4%

Note: Within each domain, only the highest score is counted.

Autoantibody Profile (The "Lupus Screen")

Autoantibodies are the serological hallmark of SLE. Understanding their sensitivity, specificity, and clinical utility is essential. [1,5]

Interpretation Tips:

• ANA-negative SLE: Rare (2-5%), but can occur with isolated Anti-Ro positivity
• Anti-dsDNA-negative: Does not exclude SLE (30-50% are negative)
• Combination matters: ANA + Anti-dsDNA + Low complement = High probability of active SLE

Complement Levels

• C3 (Normal: 90-180 mg/dL)
• C4 (Normal: 10-40 mg/dL)
• Mechanism: Consumed in tissues during immune complex activation
• Clinical Utility:
  • Low C3 and/or C4: Active disease (especially nephritis)
  • Serial monitoring: Rising C3/C4 = response to treatment
  • Falling C3/C4 = impending flare
• Note: Genetic complement deficiency (homozygous C1q, C2, C4) predisposes to SLE but gives persistently low levels

Acute Phase Reactants

• ESR (Erythrocyte Sedimentation Rate):
  • Elevated in active SLE (reflects hypergammaglobulinaemia, anaemia)
  • Can be very high (> 100mm/hr)
• CRP (C-Reactive Protein):
  • Usually NORMAL or mildly elevated in pure lupus flare
  • Marked elevation (> 50mg/L) suggests:
    • Infection (most important differential)
    • Serositis (pleuritis, pericarditis)
    • Synovitis

The ESR-CRP Discordance Rule:

• High ESR + Normal CRP = Lupus flare
• High ESR + High CRP = Infection or serositis

Full Blood Count

• Anaemia:
  • Normocytic normochromic (chronic disease)
  • Microcytic (blood loss, chronic disease)
  • Macrocytic (haemolysis)
  • Reticulocyte count elevated in haemolysis
• Leukopenia: WCC less than 4.0 (lymphopenia less than 1.5 very common)
• Thrombocytopenia: Platelets less than 100 (immune-mediated)

Renal Function

• Serum Creatinine and eGFR: Assess kidney function
• Urine Dipstick: Screen for proteinuria and haematuria (EVERY clinic visit)
• Urine Protein:Creatinine Ratio (PCR): Quantify proteinuria
  • Normal: less than 15 mg/mmol
  • Significant: > 50 mg/mmol (equivalent to > 0.5g/24h)
  • Nephrotic: > 300 mg/mmol
• Urine Microscopy: Look for casts (red cell casts = glomerulonephritis)

Additional Tests

• Direct Coombs Test (DAT): Positive in autoimmune haemolytic anaemia
• Liver Function Tests: Baseline before starting drugs; monitor for autoimmune hepatitis
• Serum Albumin: Low in nephrotic syndrome
• Lipid Profile: Cardiovascular risk assessment
• Vitamin D: Often deficient in SLE
• Thyroid Function: Autoimmune thyroid disease common (10-20%)
• Chest X-ray: Pleuritis, cardiomegaly, infection
• Echocardiogram: Pericardial effusion, pulmonary hypertension, valvular disease
• Urinalysis for Pregnancy: All women of childbearing age

Specialized Investigations

When Indicated:

• Renal Biopsy: For any significant proteinuria or renal impairment (see Section 6)
• Skin Biopsy: Atypical rashes (immunofluorescence shows IgG/C3 deposition at dermal-epidermal junction—"lupus band test")
• MRI Brain: Neuropsychiatric symptoms
• Lumbar Puncture: Exclude CNS infection in NPSLE
• CT Chest: Interstitial lung disease, pulmonary embolism
• Nerve Conduction Studies: Peripheral neuropathy, mononeuritis multiplex

---

6. Classification: Lupus Nephritis (ISN/RPS 2018 Revision)

Lupus nephritis is the most important prognostic factor in SLE. The International Society of Nephrology / Renal Pathology Society classification guides treatment decisions. [6,7]

Mixed Classes

• Combinations are common: Class III+V or Class IV+V
• Indicates both proliferative and membranous features
• Treated as proliferative disease (more aggressive pathology)

Transformation

• Important: Histology can change over time
• Repeat biopsy considered if:
  • Inadequate response to treatment (6 months)
  • Unexplained worsening of renal function
  • Flare after initial response
• Transformation examples:
  • Class II → Class IV (disease progression)
  • Class IV → Class II (successful treatment)
  • Class IV → Class VI (chronic damage despite treatment)

Activity vs Chronicity Indices

Renal biopsies are scored for:

• Activity Index (0-24): Reflects acute, reversible inflammation
  • Cellular proliferation, necrosis, crescents, leukocyte infiltration
  • High score: Aggressive immunosuppression likely to help
• Chronicity Index (0-12): Reflects irreversible scarring
  • Glomerular sclerosis, fibrous crescents, tubular atrophy, interstitial fibrosis
  • High score: Limited benefit from immunosuppression

---

7. Management Strategy

The management of SLE has evolved from a single-drug approach (high-dose corticosteroids) to a multi-targeted, steroid-sparing strategy. The 2023 EULAR recommendations provide the current evidence base. [9,10]

Core Principles

1. Treat to Target: Aim for remission or low disease activity
2. Hydroxychloroquine for ALL: Unless absolute contraindication
3. Minimize Steroids: Lowest dose for shortest time
4. Prevent Damage: Organ damage is irreversible; prevention is key
5. Screen for Comorbidities: Cardiovascular disease, osteoporosis, infection
6. Shared Decision-Making: Balance efficacy, toxicity, patient preferences

Disease Activity Monitoring

Clinical Scores:

• SLEDAI (SLE Disease Activity Index): 24-item score
  • Range 0-105
  • Score ≥6 = active disease
• BILAG (British Isles Lupus Assessment Group): Organ-specific scoring
• PGA (Physician Global Assessment): 0-3 scale

Biomarkers:

• Anti-dsDNA levels (especially for nephritis)
• Complement C3/C4
• Urine PCR (renal monitoring)

---

Part 1: Universal Measures (For ALL Patients)

These are non-negotiable foundations of SLE care. [9,10,11]

1. Hydroxychloroquine (HCQ)

The Cornerstone Drug

• Dose: 5 mg/kg actual body weight per day (usually 200-400mg daily)
  • Maximum 5mg/kg to reduce retinal toxicity risk
  • Take with food (GI side effects)
• Evidence:
  • Reduces flares by 50% [11]
  • Reduces organ damage accrual [11]
  • Reduces thrombotic events (especially in APS) [11]
  • Improves survival (30% reduction in mortality) [11]
  • Allows steroid dose reduction
• Mechanism:
  • Inhibits TLR signalling (blocks innate immune activation)
  • Reduces interferon production
  • Stabilizes lysosomal membranes
  • Mild anti-thrombotic effect
• Onset: Slow—takes 3-6 months to reach full effect
• Side Effects:
  • Retinal toxicity (rare less than 1% if dose correct)
    • Risk increases after 5 years of use
    • Screening: Baseline ophthalmology, then annual screening after 5 years
    • Automated visual field testing and Optical Coherence Tomography (OCT)
  • GI upset (nausea, diarrhoea)
  • Rarely: Skin hyperpigmentation, myopathy, cardiomyopathy (very rare)
• Contraindications:
  • Known retinopathy
  • Maculopathy
  • Severe renal impairment (reduce dose)
  • G6PD deficiency (risk of haemolysis)
• Key Message: "Hydroxychloroquine is life insurance"—stopping is the #1 cause of flare

2. Sun Protection

• UV Avoidance: Stay out of sun 10am-4pm (peak UVB)
• Sunscreen:
  • Broad spectrum (UVA + UVB)
  • SPF ≥50
  • Reapply every 2 hours
• Physical Barriers: Long sleeves, wide-brimmed hats, UV-protective clothing
• Avoid Photosensitizing Drugs: Thiazides, tetracyclines

3. Vaccination

• Inactivated Vaccines (safe, strongly recommended):
  • Influenza (annual)
  • Pneumococcal (PCV13 + PPSV23)
  • COVID-19
  • Hepatitis B (especially if on immunosuppression)
  • HPV (prevent cervical cancer)
• Live Vaccines (contraindicated if on immunosuppression):
  • MMR, Varicella, Yellow Fever (only give if immunocompetent)
  • Ideally give before starting immunosuppression

4. Cardiovascular Risk Reduction

SLE patients have 50-fold increased MI risk in young women. [1]

• Aggressive Risk Factor Management:
  • Blood Pressure: Target less than 130/80 mmHg (use ACEi/ARB in nephritis)
  • Lipids: Statins for primary prevention if additional risk factors (consider in all)
  • Smoking Cessation: Mandatory
  • Diabetes Control: Tight glycaemic control
  • Exercise: Regular moderate activity
• Monitor for Atherosclerosis:
  • Framingham risk score underestimates risk in SLE
  • Consider carotid ultrasound (intima-media thickness)

5. Bone Health

• Osteoporosis Prevention (corticosteroid-induced):
  • Calcium 1000-1200mg daily
  • Vitamin D 800-1000 IU daily (check levels—often deficient)
  • Bisphosphonate: If on prednisolone > 7.5mg for > 3 months
  • DEXA scan baseline and every 2 years if on steroids

6. Infection Prevention

• Education: Seek medical attention early for fever
• Avoid sick contacts
• Food hygiene (if on immunosuppression)
• Prophylaxis:
  • Co-trimoxazole: If on cyclophosphamide (Pneumocystis jirovecii prevention)
  • Antifungal: Consider if prolonged high-dose steroids

7. Contraception and Pregnancy Planning

• Contraception: Avoid oestrogen-containing OCP if high risk (APS, active disease)
  • Safe options: Progesterone-only pill, IUD, barrier methods
• Pregnancy Planning:
  • Disease must be quiescent for ≥6 months before conception
  • Switch teratogenic drugs (see Section 9)
  • Preconception counselling by rheumatology and obstetrics

8. Lifestyle

• Smoking Cessation: Reduces flares, improves HCQ efficacy
• Alcohol: Moderation (no evidence of harm in moderation)
• Diet: Balanced, anti-inflammatory (omega-3 fatty acids may help)
• Sleep Hygiene: Fatigue management

---

Part 2: Mild-Moderate Disease (Skin, Joints, Fatigue)

For patients WITHOUT major organ involvement (nephritis, CNS, severe haematology).

Cutaneous Lupus

• Topical Corticosteroids:
  • Moderate-potent steroids (betamethasone valerate, mometasone) for rash
  • Face: Use mild steroids (hydrocortisone) to avoid skin atrophy
• Topical Calcineurin Inhibitors: Tacrolimus, pimecrolimus (steroid-sparing for face)
• Intralesional Steroids: For discoid lesions (triamcinolone)

If Inadequate Response:

• Oral Corticosteroids: Prednisolone 10-20mg daily, taper rapidly
• Methotrexate: 10-25mg weekly (effective for skin and joint disease)
• Mycophenolate Mofetil: 1-2g daily (for refractory cutaneous lupus)
• Belimumab: Approved for skin/joint disease (see Biologics section)

Musculoskeletal

• NSAIDs:
  • Effective for arthralgia/arthritis
  • Use lowest effective dose (GI and renal toxicity)
  • Caution: May worsen renal function
  • Add PPI if on long-term NSAIDs
• Oral Corticosteroids: Prednisolone 5-15mg daily for flares, then taper
• Steroid-Sparing Agents (if requiring > 7.5mg pred for > 3 months):
  • Methotrexate: 15-25mg weekly (first-line for arthritis)
  • Azathioprine: 1-2mg/kg daily
  • Mycophenolate Mofetil: 1-2g daily (if MTX fails)

Constitutional Symptoms (Fatigue)

• Address reversible causes:
  • Anaemia (correct iron deficiency, treat haemolysis)
  • Hypothyroidism (screen for autoimmune thyroid disease)
  • Vitamin D deficiency (supplement)
  • Depression (screen and treat)
  • Sleep apnoea (consider if obese)
  • Poor disease control (optimize therapy)
• Non-pharmacological:
  • Graded exercise programs
  • Cognitive behavioural therapy
  • Pacing and energy conservation

---

Part 3: Severe/Organ-Threatening Disease

For lupus nephritis, neuropsychiatric lupus, severe haematology, or multi-organ disease. Requires aggressive immunosuppression with Induction (high intensity, 3-6 months) followed by Maintenance (lower intensity, indefinite). [6,7,9,10]

Lupus Nephritis (Class III/IV)

Induction Therapy (First 3-6 months):

Goal: Achieve remission (proteinuria less than 0.5g/day, normal renal function)

Option 1: Mycophenolate Mofetil (MMF) — Preferred

• Dose: 2-3g daily (1g BD or 1.5g BD)
• Evidence: Superior to cyclophosphamide in inducing remission, especially in African and Hispanic populations [6,7]
• Advantages: Oral, less toxicity than cyclophosphamide, preserves fertility
• Disadvantages: Teratogenic (Category D—contraception mandatory), GI side effects

Option 2: Cyclophosphamide (IV)

• Euro-Lupus Protocol (low-dose): 500mg IV every 2 weeks x 6 doses (total 3g)
• NIH Protocol (high-dose): 0.5-1g/m² IV monthly x 6 doses (rarely used now—more toxic)
• Evidence: Effective but inferior to MMF in some populations
• Indications: Rapidly progressive disease, MMF failure, poor adherence to oral therapy
• Toxicities:
  • Infertility (dose-dependent; offer fertility preservation before treatment)
  • Haemorrhagic cystitis (give MESNA, hydration)
  • Bladder cancer (long-term risk)
  • Bone marrow suppression
  • Infections

Plus: High-Dose Corticosteroids

• IV Methylprednisolone: 500-1000mg daily x 3 days (for severe disease)
• Followed by Oral Prednisolone: 0.5-1mg/kg daily (max 60mg)
• Rapid Taper Protocol (EULAR 2023):
  • Reduce by 50% every 2 weeks
  • Aim for ≤7.5mg by 3 months
  • Aim for ≤5mg by 6 months (if in remission)
  • Attempt complete withdrawal

Maintenance Therapy (After Induction):

Goal: Sustain remission, prevent flares, minimize damage

Option 1: Mycophenolate Mofetil (MMF) — Preferred

• Dose: 1-2g daily (lower than induction)
• Evidence: Superior to azathioprine in preventing relapse [6]
• Duration: Minimum 3-5 years, often indefinite

Option 2: Azathioprine (AZA)

• Dose: 1-2mg/kg daily
• Check TPMT genotype before starting (risk of myelosuppression if deficient)
• Advantages: Oral, safe in pregnancy
• Disadvantages: Slightly higher relapse rates than MMF

Plus:

• Hydroxychloroquine: Continue indefinitely
• Prednisolone: ≤5mg daily (or off completely)

Adjunctive Therapy for Nephritis:

• ACE Inhibitors or ARBs: All patients with proteinuria (reduces proteinuria, protects kidney)
• Blood Pressure Control: Target less than 130/80
• Diuretics: For oedema (loop diuretics)
• Statins: Cardiovascular protection

Refractory Lupus Nephritis

If no response to first-line therapy at 6 months:

• Switch MMF ↔ Cyclophosphamide
• Rituximab (anti-CD20): 1g IV x 2 doses (2 weeks apart)
  • Off-label but widely used
  • Effective in 50-70% of refractory cases
• Calcineurin Inhibitors: Tacrolimus, Voclosporin (new—FDA approved 2021)
• Belimumab as add-on therapy

Neuropsychiatric Lupus

Depends on Mechanism:

• Thrombotic/APS-related (stroke, TIA):
  • Anticoagulation (warfarin, target INR 2-3 or 3-4 depending on risk)
• Inflammatory/immune-mediated (psychosis, seizures, aseptic meningitis):
  • High-dose corticosteroids (IV methylprednisolone)
  • Cyclophosphamide (as for nephritis)
  • Rituximab (refractory cases)
• Seizures:
  • Antiepileptic drugs (levetiracetam, lamotrigine)
  • Treat underlying lupus

Supportive:

• Antidepressants (SSRIs for depression)
• Antipsychotics (for psychosis—use atypical agents)
• Cognitive rehabilitation

Severe Haematological Cytopenias

• Autoimmune Haemolytic Anaemia:
  • Prednisolone 1mg/kg
  • Folic acid supplementation
  • Consider rituximab if refractory
• Thrombocytopenia (platelets less than 20, or bleeding):
  • Prednisolone 1mg/kg
  • IV Immunoglobulin (IVIG) if life-threatening
  • Rituximab if refractory
• TTP-like syndrome (thrombotic thrombocytopenic purpura):
  • Urgent plasma exchange
  • High-dose steroids
  • Rituximab

---

Part 4: Biologic Therapies

Biologics have revolutionized SLE treatment, offering targeted therapy with fewer side effects than traditional immunosuppression. [9,10,12]

Belimumab (Benlysta)

• Mechanism: Monoclonal antibody that inhibits B-Lymphocyte Stimulator (BLyS/BAFF)
  • BLyS promotes B-cell survival
  • Blocking BLyS → B-cell apoptosis → reduced autoantibody production
• Route: IV infusion (10mg/kg at weeks 0, 2, 4, then every 4 weeks) or SC injection (200mg weekly)
• Indications (NICE/FDA approved):
  • Add-on therapy for active SLE (SLEDAI ≥8) despite standard therapy
  • Autoantibody-positive (ANA or anti-dsDNA)
  • Active skin/joint disease despite HCQ + steroids
  • Lupus nephritis (new indication 2020)
• Evidence:
  • Reduces disease activity by 30-40% [12]
  • Reduces flares and steroid use
  • Improves fatigue and quality of life
• Efficacy: Takes 6 months to see full benefit
• Not Effective: In severe active CNS lupus
• Side Effects: Infections (monitor), infusion reactions, depression (rare)

Anifrolumab (Saphnelo)

• Mechanism: Monoclonal antibody that blocks Type I Interferon Receptor (IFNAR)
  • Neutralizes effects of IFN-α/β
  • Dampens interferon signature
• Route: IV infusion (300mg every 4 weeks)
• Indications: Moderate-severe SLE despite standard therapy
  • Particularly effective in skin and joint disease
• Evidence:
  • TULIP trials: 47% response vs 32% placebo [10]
  • Steroid-sparing effect
  • Particularly effective in patients with high interferon signature
• Side Effects: Herpes zoster reactivation (consider prophylaxis), infections, infusion reactions
• Approval: FDA 2021, EMA 2022

Rituximab (MabThera)

• Mechanism: Anti-CD20 monoclonal antibody (depletes B-cells)
• Route: IV infusion (1g at weeks 0 and 2, or 375mg/m² weekly x 4)
• Indications (off-label in SLE):
  • Refractory lupus nephritis
  • Severe haematological cytopenias
  • Refractory skin/joint disease
  • Neuropsychiatric lupus
• Evidence: Paradoxically, RCTs were negative (EXPLORER, LUNAR trials) but extensive real-world evidence shows efficacy in 50-70% of refractory cases
• Side Effects: Infusion reactions, infections, hypogammaglobulinaemia (with repeated cycles), PML (very rare)

Voclosporin (Lupkynis)

• Mechanism: Calcineurin inhibitor (like tacrolimus, but more selective)
• Route: Oral capsules (23.7mg BD)
• Indication: Lupus nephritis (in combination with MMF)
• Evidence: AURORA trial—significantly improved complete renal response vs MMF alone [7]
• Approval: FDA 2021 (first oral drug for lupus nephritis in decades)
• Side Effects: Nephrotoxicity (paradoxical), hypertension, tremor

---

8. Drug-Induced Lupus Erythematosus (DILE)

"The Temporary Lupus"

Drug-induced lupus is a distinct clinical entity that mimics SLE but is triggered by medications. Recognition is critical because it resolves upon drug cessation. [13]

Epidemiology

• Accounts for ~10% of all lupus cases
• Male:Female ratio closer to 1:1 (unlike idiopathic SLE)
• Typically older age of onset (> 50 years)
• Caucasians more affected (opposite of SLE)

High-Risk Medications

Genetic Susceptibility:

• Slow acetylator phenotype (NAT2 polymorphism) increases risk with procainamide, hydralazine, isoniazid

Clinical Features

What is PRESENT:

• Constitutional symptoms (fatigue, fever, malaise) — 90%
• Arthralgia/arthritis (symmetrical polyarthritis) — 80-90%
• Myalgia — 50%
• Serositis (pleuritis, pericarditis) — 40-50%
• Rash (maculopapular, less commonly malar) — 25%

What is ABSENT (key distinguishing features):

• Renal involvement: Very rare (less than 5%) — major difference from idiopathic SLE
• CNS involvement: Very rare
• Severe haematological cytopenias: Rare (mild cytopenias may occur)
• Malar rash: Less common
• Photosensitivity: Less prominent

Autoantibody Profile

The "Histone Rule": Anti-histone antibodies are sensitive but NOT specific for DILE (since 50-70% of SLE patients also have them). However, the combination of:

• Anti-histone POSITIVE
• Anti-dsDNA NEGATIVE
• Normal complement
• Compatible drug exposure
• ...strongly suggests DILE.

Diagnosis

1. Compatible clinical features (arthritis, serositis, WITHOUT renal/CNS)
2. Exposure to high-risk medication
3. ANA positive + Anti-histone positive
4. Anti-dsDNA negative, normal complement
5. Exclusion of idiopathic SLE

Management

Primary Treatment:

• STOP THE OFFENDING DRUG — this is curative
• Symptoms typically resolve within weeks to months (antibodies may persist for years)

Symptomatic Treatment:

• NSAIDs: For arthralgia/mild serositis
• Short course of prednisolone: 10-30mg daily for severe symptoms (pleuritis, pericarditis), taper over 2-4 weeks
• Antimalarials: Rarely needed (reserve for prolonged symptoms)

Monitoring:

• Clinical improvement expected within 4-6 weeks
• If no improvement or worsening: Reconsider diagnosis (may be idiopathic SLE unmasked by drug)
• Autoantibodies may remain positive for months to years after resolution

Special Considerations

TNF-Inhibitor-Induced Lupus:

• Paradoxical phenomenon (using immunosuppressants to treat RA/IBD but causing lupus)
• More likely with infliximab and etanercept than adalimumab
• Switch to alternative biologic (rituximab, tocilizumab)

---

9. Pregnancy in Systemic Lupus Erythematosus

"High Risk, High Reward"

Pregnancy in SLE is a high-risk obstetric scenario requiring multidisciplinary care. Historically, women were advised against pregnancy. With modern management, successful pregnancy outcomes are achievable in > 90% of appropriately selected and managed patients. [14,15,16]

Pre-Pregnancy Counselling (ESSENTIAL)

Prerequisites for Safe Pregnancy:

1. Disease quiescence for ≥6 months (ideally 12 months)
   • No major organ involvement
   • No lupus nephritis (or stable nephritis with proteinuria less than 0.5g/day, normal creatinine)
   • Low disease activity (SLEDAI less than 4)
2. Medication review: Switch to pregnancy-safe drugs (see below)
3. Antibody screening: Anti-Ro, Anti-La, antiphospholipid antibodies
4. Multidisciplinary team: Rheumatology + Obstetrics + Nephrology (if nephritis)

Contraindications to Pregnancy (ABSOLUTE):

• Active lupus nephritis
• Severe pulmonary hypertension (mortality risk > 50%)
• Advanced renal impairment (creatinine > 250 µmol/L)
• Severe restrictive lung disease
• Previous severe pre-eclampsia with adverse outcome
• Stroke within 6 months

Maternal Risks During Pregnancy

Lupus Flares

• Risk: Flare occurs in 25-60% of pregnancies (depending on disease activity at conception)
• Timing: Most common in 2nd and 3rd trimesters and postpartum (first 3 months)
• Type: Usually mild-moderate (skin, joints)
• Severe flares (nephritis, severe haematology): 5-10%
• Predictors of flare:
  • Active disease at conception
  • Discontinuation of hydroxychloroquine
  • History of lupus nephritis
  • Previous flares

Management:

• Continue hydroxychloroquine throughout (MANDATORY)
• Low-dose prednisolone if needed
• Azathioprine if steroid-sparing needed
• Close monitoring (every 4-6 weeks)

Pre-Eclampsia

• Risk: 15-30% (vs 5-7% in general population)
• Higher risk if:
  • History of lupus nephritis
  • Antiphospholipid antibodies
  • Renal impairment
  • Hypertension
• Challenge: Distinguishing pre-eclampsia from lupus nephritis flare (both cause proteinuria, hypertension, renal impairment)

Prevention:

• Low-dose aspirin (75-150mg) from 12 weeks to delivery (reduces pre-eclampsia risk by 50%)

Thrombosis (if Antiphospholipid Antibodies Present)

• Risk of VTE, arterial thrombosis, placental insufficiency
• See Section 10 (APS)

Fetal and Neonatal Risks

Miscarriage

• 1st Trimester Loss: 10-20% (vs 10-15% in general population)
• Higher if:
  • Active disease
  • Antiphospholipid antibodies (30-40% risk without treatment)

Stillbirth and Fetal Death

• Risk: 3-5% (vs 0.5% general population)
• Risk factors: Active disease, lupus nephritis, APS

Preterm Birth

• Risk: 30-40% (vs 10% general population)
• Causes: Spontaneous preterm labour, iatrogenic (pre-eclampsia, IUGR)

Intrauterine Growth Restriction (IUGR)

• Risk: 15-30%
• Mechanism: Placental insufficiency (APS, hypertension, nephritis)
• Monitoring: Serial growth scans every 4 weeks from 24 weeks

Neonatal Lupus Syndrome (NLS)

Caused by Maternal Anti-Ro and/or Anti-La Antibodies

• Antibodies cross placenta (IgG) and attack fetal tissues
• Risk: Only if mother is Anti-Ro (SS-A) positive or Anti-La (SS-B) positive
  • Risk of NLS if Anti-Ro+: 2-5% (low, but serious)
  • Risk increases to 15-20% if previous child had NLS

Clinical Manifestations:

Congenital Heart Block:

• Irreversible damage to fetal cardiac conduction system
• Presentation:
  • In utero: Fetal bradycardia detected on ultrasound (16-26 weeks gestation)
  • After birth: Complete heart block (heart rate 50-80 bpm)
• Prognosis:
  • 1st degree block: May improve
  • 2nd degree block: May progress
  • 3rd degree (complete) block: Permanent, requires pacemaker (60-70% of cases)
  • Mortality: 15-30%

Monitoring (if Anti-Ro/La Positive):

• Serial fetal echocardiograms: Every 1-2 weeks from 16-26 weeks gestation
• Look for:
  • PR interval prolongation (early sign)
  • Heart block (2nd or 3rd degree)
  • Endocardial fibroelastosis

Treatment of CHB:

• If detected in utero:
  • Dexamethasone (crosses placenta) — controversial efficacy
  • IVIG — limited evidence
  • Delivery planning
• After birth: Pacemaker insertion

Medication Safety in Pregnancy

Understanding drug safety is CRITICAL. [14,15]

SAFE (Continue)

UNSAFE (Stop Before Conception)

Special Situations

Rituximab:

• Limited data
• B-cell depletion in neonate (transient)
• Avoid if possible; if given, avoid in 2nd/3rd trimester
• Long washout (6-12 months)

Belimumab:

• Limited data
• Likely safe but avoid unless essential
• Washout: 4 months before conception

IVIG:

• Safe

Antenatal Monitoring Protocol

Maternal Monitoring:

• Clinic visits: Every 4 weeks until 28 weeks, then every 2 weeks
• Each visit:
  • Clinical assessment (symptoms, BP, urine dipstick)
  • Urinalysis (protein, blood)
  • FBC (cytopenias)
  • U&E, creatinine
• Every trimester:
  • Anti-dsDNA, C3, C4 (detect flare)
  • Urine PCR (quantify proteinuria)

Fetal Monitoring:

• Growth scans: Every 4 weeks from 24 weeks
• Doppler studies: Umbilical artery (placental function)
• CTG: From 32 weeks if indicated (IUGR, reduced movements)
• Fetal echo: If Anti-Ro/La positive (16-26 weeks)

Labour and Delivery

• Mode of delivery: Vaginal delivery preferred (no contraindication)
• Indications for C-section: Usual obstetric indications
• Steroid cover: If on > 7.5mg prednisolone for > 2 weeks:
  • IV Hydrocortisone 100mg every 8 hours during labour

Postpartum Period

• Highest risk period for flares (first 3 months)
• Continue all SLE medications
• Resume pre-pregnancy medications (can restart MMF, methotrexate if not breastfeeding)
• Breastfeeding:
  • Compatible: Hydroxychloroquine, prednisolone, azathioprine, sulfasalazine
  • Avoid: Methotrexate, cyclophosphamide, MMF
• Contraception counselling (avoid oestrogen if APS)
• Close follow-up (every 2-4 weeks for 3 months)

---

10. Antiphospholipid Syndrome (APS)

"Sticky Blood"

Antiphospholipid Syndrome (APS) is a distinct autoimmune thrombophilia characterized by arterial/venous thrombosis and/or pregnancy morbidity in the presence of persistent antiphospholipid antibodies. [17,18]

Relationship to SLE

• Secondary APS: Occurs in association with SLE (30-40% of SLE patients have antiphospholipid antibodies)
• Primary APS: Occurs alone, without underlying SLE
• Clinical Importance: APS is the leading cause of acquired hypercoagulability and a major cause of morbidity in SLE

Diagnosis: Revised Sapporo Criteria (2006)

APS requires at least ONE clinical criterion AND at least ONE laboratory criterion.

Clinical Criteria

1. Vascular Thrombosis (≥1 episode):

• Arterial: Stroke, TIA, MI, limb ischaemia
• Venous: DVT, PE, hepatic vein thrombosis (Budd-Chiari), cerebral sinus thrombosis
• Small vessel: Livedo reticularis, digital ischaemia
• Confirmed by imaging or histopathology
• Exclude other causes (atherosclerosis, vasculitis)

2. Pregnancy Morbidity:

• ≥3 consecutive miscarriages before 10 weeks gestation (with maternal/fetal anatomical or chromosomal causes excluded)
• OR ≥1 unexplained fetal death at ≥10 weeks gestation (morphologically normal fetus)
• OR ≥1 premature birth before 34 weeks due to:
  • Severe pre-eclampsia or eclampsia
  • Placental insufficiency (IUGR, abnormal Dopplers)

Laboratory Criteria

Antiphospholipid Antibodies (must be positive on TWO occasions at least 12 weeks apart):

1. Lupus Anticoagulant (LA):
   • Functional assay (paradoxically prolongs clotting tests in vitro but causes thrombosis in vivo)
   • Tests: DRVVT (dilute Russell viper venom time), aPTT-based assays
   • Most specific for thrombosis risk
2. Anti-Cardiolipin Antibodies (aCL):
   • IgG and/or IgM
   • Medium-high titre (> 40 GPL or MPL units, or > 99th percentile)
3. Anti-β2-Glycoprotein I Antibodies (anti-β2GPI):
   • IgG and/or IgM

   • 99th percentile

Triple Positivity:

• Positive for all three tests (LA + aCL + anti-β2GPI)
• Highest risk for thrombosis and pregnancy morbidity
• Consider more aggressive management

Clinical Manifestations

Thrombotic APS

Venous Thromboembolism (Most common):

• Deep vein thrombosis (DVT) — lower limbs, upper limbs
• Pulmonary embolism (PE)
• Unusual site thrombosis:
  • Cerebral sinus thrombosis
  • Hepatic vein (Budd-Chiari syndrome)
  • Renal vein
  • Adrenal vein (adrenal insufficiency)

Arterial Thrombosis:

• Stroke / TIA (most common arterial event)
  • Young stroke (less than 50 years) → always screen for APS
• Myocardial infarction
• Peripheral arterial occlusion (limb ischaemia)
• Retinal artery occlusion (visual loss)

Recurrence:

• High rate of recurrent thrombosis without anticoagulation (30-70%)
• Arterial events tend to recur as arterial
• Venous events may recur as arterial

Obstetric APS

• Recurrent early miscarriages (less than 10 weeks)
• Late fetal loss (≥10 weeks)
• Severe pre-eclampsia
• Placental insufficiency (IUGR, placental abruption)
• HELLP syndrome

Non-Criteria Manifestations (Supportive but Not Diagnostic)

• Thrombocytopenia (50-100 x 10⁹/L, rarely severe)
• Livedo reticularis (violaceous net-like skin pattern)
• Cardiac valve disease:
  • Valvular thickening, regurgitation
  • Libman-Sacks endocarditis
• APS nephropathy (thrombotic microangiopathy in kidneys)
• Cognitive impairment (multiple small strokes)

Catastrophic Antiphospholipid Syndrome (CAPS)

"The APS Storm" — life-threatening variant

• Rare (1% of APS patients)
• Acute multi-organ thrombosis (≥3 organs) over days to weeks
• Microangiopathic process
• Organs Affected: Kidneys (most common), lungs, brain, heart, liver, adrenals, skin
• Triggers: Infection, surgery, anticoagulation withdrawal, malignancy
• Mortality: 30-50% despite treatment

Diagnosis (Preliminary Criteria):

• Evidence of ≥3 organ involvement
• Development within less than 1 week
• Histopathology: Small vessel occlusion
• Antiphospholipid antibodies present

Treatment (Triple Therapy):

1. Anticoagulation (IV heparin, then warfarin)
2. High-dose corticosteroids (IV methylprednisolone 1g x 3 days)
3. IVIG and/or Plasma Exchange
4. Treat precipitant (antibiotics for infection)
5. Consider rituximab or eculizumab (complement inhibitor) in refractory cases

Management of APS

Primary Thromboprophylaxis (No Previous Thrombosis)

Asymptomatic carriers (aPL positive but no thrombosis/pregnancy loss):

• Low-risk profile (isolated aCL low-titre):
  • Low-dose aspirin 75-100mg (controversial—some guidelines say observation only)
  • Risk factor modification (smoking cessation, BP control, avoid oestrogen)
• High-risk profile (triple positive, LA positive, high-titre):
  • Hydroxychloroquine (reduces thrombosis risk in SLE-APS)
  • Low-dose aspirin
  • Aggressive risk factor control
  • Avoid oestrogen-containing contraceptives
• Situational prophylaxis:
  • LMWH during surgery, prolonged immobility, pregnancy

Secondary Thromboprophylaxis (After Thrombotic Event)

Venous Thromboembolism:

• Warfarin: Target INR 2-3 (standard intensity)
• Duration: LIFELONG (very high recurrence risk off anticoagulation)
• DOACs (rivaroxaban, apixaban): Generally AVOID in high-risk APS (triple positive, arterial thrombosis)
  • Emerging evidence suggests higher failure rate vs warfarin
  • May consider in low-risk, venous-only APS with patient preference

Arterial Thromboembolism or Recurrent Thrombosis Despite Anticoagulation:

• Warfarin: Target INR 3-4 (high intensity)
• Consider adding low-dose aspirin (dual therapy)
• Consider hydroxychloroquine (in SLE-APS)
• If recurrent despite adequate anticoagulation:
  • Increase INR target
  • Add antiplatelet (aspirin, clopidogrel)
  • Consider LMWH instead of warfarin
  • Consider rituximab

Monitoring:

• INR monitoring every 2-4 weeks (or more frequently if unstable)
• Lupus anticoagulant can interfere with INR measurement—use chromogenic factor X assay if available

Obstetric APS Management

Recurrent Early Miscarriage or Previous Fetal Loss:

• Low-dose aspirin (75-150mg) from pre-conception/positive pregnancy test
• PLUS Prophylactic LMWH (enoxaparin 40mg SC daily or dalteparin 5000 units SC daily)
• Continue until 6 weeks postpartum
• Success rate: 70-80% live birth (vs 10-20% untreated)

Previous Thrombosis (on long-term warfarin):

• Switch warfarin to therapeutic LMWH before conception (or as soon as pregnancy confirmed)
• PLUS low-dose aspirin
• Continue until 6 weeks postpartum
• Restart warfarin postpartum

Adjuncts:

• Hydroxychloroquine (if SLE-APS)
• Prednisolone (low dose, if SLE active)
• IVIG (refractory cases, controversial)

Monitoring:

• Serial growth scans, Doppler studies
• Increased surveillance for pre-eclampsia, IUGR

SLE-Specific Considerations

• Hydroxychloroquine: Reduces thrombosis risk in APS—continue indefinitely
• Treat underlying lupus activity (reduces APS events)
• Avoid high-dose steroids if possible (increases thrombosis risk)

---

11. Prognosis and Long-Term Outcomes

Survival

The prognosis of SLE has dramatically improved over the past 50 years due to earlier diagnosis, better disease monitoring, and effective therapies. [1,19]

Historical vs Modern Survival:

• 1950s: 5-year survival less than 50%
• 1970s: 5-year survival ~80%
• 2020s:
  • 5-year survival: > 95%
  • 10-year survival: > 90%
  • 15-year survival: > 85%

Causes of Death

Bimodal Pattern:

Early Mortality (first 5 years):

• Lupus disease activity (40-50%):
  • Lupus nephritis → renal failure
  • Neuropsychiatric lupus
  • Thrombotic complications (APS)
  • Lupus pneumonitis
• Infection (30-40%):
  • Opportunistic infections (Pneumocystis, TB, fungal)
  • Related to immunosuppression
  • Common organisms: Pneumonia, sepsis, herpes zoster

Late Mortality (after 5-10 years):

• Cardiovascular disease (30-40%):
  • Myocardial infarction
  • Stroke
  • Accelerated atherosclerosis
• Malignancy (10%):
  • Lymphoma (2-fold increased risk)
  • Lung cancer
  • Cervical cancer (HPV—vaccination important)
• End-stage renal disease (10%)

Prognostic Factors

Poor Prognosis Indicators:

• Male sex
• African-Caribbean or Hispanic ethnicity
• Young age at onset (less than 20 years)
• Lupus nephritis (especially Class IV)
• Neuropsychiatric involvement
• Severe haematological disease
• Antiphospholipid antibodies (thrombotic risk)
• High disease activity at presentation
• Non-adherence to medications
• Low socioeconomic status

Good Prognosis Indicators:

• Caucasian ethnicity
• Late onset (> 50 years)
• Isolated skin/joint disease
• Early diagnosis and treatment
• Adherence to hydroxychloroquine
• Access to specialist care

Disease Damage Accrual

SLICC Damage Index (SDI):

• Measures irreversible organ damage (regardless of cause)
• Scored 0-47 across 12 organ systems
• Damage only counted if present for ≥6 months
• Predictive of mortality

Causes of Damage:

• Disease activity (50%): Scarring from inflammation
• Treatment toxicity (30%): Corticosteroids (osteoporosis, AVN, cataracts), cyclophosphamide (infertility)
• Comorbidities (20%): Atherosclerosis, infection

Common Damage Manifestations:

• Chronic kidney disease
• Osteoporotic fractures
• Avascular necrosis (hip, knee)
• Cataracts
• Cognitive impairment
• Premature coronary artery disease
• Peripheral neuropathy

Prevention:

• Achieve disease remission
• Minimize corticosteroid exposure
• Cardiovascular risk factor management
• Bone protection
• Early detection and treatment of complications

---

12. Complications

Infection

The Leading Cause of Morbidity and Mortality

• Risk: 5-10 fold increased compared to general population
• Mechanisms:
  • Immunosuppression (corticosteroids, cyclophosphamide, biologics)
  • Impaired neutrophil and lymphocyte function (intrinsic to SLE)
  • Complement deficiency (impaired bacterial clearance)
  • Splenectomy (if done for refractory ITP)
  • Nephrotic syndrome (loss of immunoglobulins)

Common Infections:

• Bacterial:
  • Pneumonia (Streptococcus pneumoniae, Haemophilus influenzae)
  • Urinary tract infections (E. coli)
  • Skin/soft tissue infections (Staphylococcus aureus)
  • Sepsis
• Viral:
  • Herpes zoster (shingles) — 10-fold increased risk
  • CMV (especially with high-dose immunosuppression)
  • COVID-19 (increased severity)
• Fungal:
  • Pneumocystis jirovecii pneumonia (PJP) — if on cyclophosphamide or high-dose steroids
  • Candida
  • Aspergillus (rare, severe immunosuppression)
• Mycobacterial:
  • Tuberculosis reactivation (screen before biologics)
  • Non-tuberculous mycobacteria

Prevention:

• Vaccination (pneumococcal, influenza, COVID-19)
• Prophylaxis:
  • Co-trimoxazole (if CD4 less than 200 or on cyclophosphamide)
  • Consider antiviral prophylaxis (aciclovir/valaciclovir) if recurrent herpes zoster
• Minimize steroid dose
• Early recognition and treatment

Clinical Pearl:

• Fever in an SLE patient on immunosuppression = INFECTION UNTIL PROVEN OTHERWISE
• Do NOT assume it's a lupus flare—investigate thoroughly

Cardiovascular Disease

Premature Atherosclerosis:

• Myocardial infarction risk: 50-fold increased in women 35-44 years [1]
• Stroke risk: 2-10 fold increased
• Mechanisms:
  • Chronic inflammation (endothelial damage)
  • Dyslipidaemia (disease + corticosteroids)
  • Hypertension (nephritis, steroids)
  • Oxidized lipids and autoantibodies
  • Antiphospholipid antibodies (thrombosis)

Prevention:

• Aggressive risk factor management
• Statins (primary prevention)
• Control disease activity (reduce inflammation)
• Hydroxychloroquine (cardioprotective)

Renal

• Chronic Kidney Disease: Progressive despite treatment in 10-20%
• End-Stage Renal Disease: Requiring dialysis/transplant (10% at 10 years)
• Renal transplant outcomes: Good (similar to non-lupus ESRD)
• Recurrent nephritis in transplant: Rare (less than 5%)

Malignancy

• Overall cancer risk: Modestly increased (1.5-fold)
• Lymphoma: 2-3 fold increased risk (Non-Hodgkin's lymphoma)
• Lung cancer: Increased (smoking, chronic inflammation)
• Cervical cancer: Increased (HPV, immunosuppression)
• Screening: Age-appropriate cancer screening + HPV vaccination

Osteoporosis and Fractures

• Cause: Corticosteroid-induced osteoporosis
• Risk: 5-fold increased fracture risk if on long-term steroids
• Prevention:
  • Minimize steroid dose and duration
  • Calcium + Vitamin D supplementation
  • Bisphosphonates if on prednisolone > 7.5mg for > 3 months
  • DEXA scan baseline and every 2 years

Avascular Necrosis (Osteonecrosis)

• Sites: Femoral head (most common), humeral head, knee
• Risk factors:
  • High-dose corticosteroids (> 20mg prednisolone)
  • Antiphospholipid antibodies
• Presentation: Hip pain, limited range of motion
• Diagnosis: MRI (more sensitive than X-ray)
• Treatment:
  • Early: Core decompression, bisphosphonates
  • Late: Total hip replacement

---

13. Monitoring and Follow-Up

Frequency of Follow-Up

• Active disease: Every 1-3 months
• Stable disease: Every 3-6 months
• Remission: Every 6-12 months

Clinical Assessment (Each Visit)

• Symptoms: Fatigue, fever, rash, joint pain, headache, chest pain, shortness of breath
• Disease Activity Score: SLEDAI or BILAG
• Examination:
  • Blood pressure (hypertension = nephritis or steroids)
  • Weight (oedema = nephrotic syndrome)
  • Skin (rash, alopecia, ulcers)
  • Joints (synovitis)
  • Urine dipstick (EVERY visit—proteinuria, haematuria)

Laboratory Monitoring

Every Visit:

• FBC: Cytopenias
• U&E, Creatinine, eGFR: Renal function
• Urinalysis (dipstick + microscopy)
• Urine PCR: If proteinuria present (quantify)

Every 3-6 Months (depending on stability):

• Anti-dsDNA titres: Predict flares (especially nephritis)
• Complement C3, C4: Falling levels = impending flare
• ESR, CRP: Disease activity vs infection

Baseline and Annually:

• Lipid profile: Cardiovascular risk
• HbA1c or fasting glucose: Diabetes (steroid-induced)
• Liver function tests: Drug toxicity
• Vitamin D: Often deficient

Drug-Specific Monitoring:

• Hydroxychloroquine: Ophthalmology review (baseline, then annually after 5 years)
• Azathioprine: FBC, LFTs monthly for 3 months, then every 3 months
• Mycophenolate: FBC weekly for 4 weeks, then monthly for 3 months, then every 3 months
• Methotrexate: FBC, LFTs every 2-4 weeks

Red Flags Requiring Urgent Assessment

• New or worsening proteinuria
• Rising creatinine
• Severe cytopenias (platelets less than 20, Hb less than 70)
• Neuropsychiatric symptoms (seizures, psychosis, severe headache)
• Severe chest pain (MI, pericarditis, PE)
• Fever (> 38°C) on immunosuppression
• Acute visual disturbance
• Acute abdominal pain (mesenteric vasculitis)

---

14. Examination Focus and Viva Preparation

Clinical Examination: Signs to Elicit

General Inspection:

• Cushingoid appearance (moon face, central obesity, buffalo hump—steroid side effects)
• Malar rash (butterfly distribution, sparing nasolabial folds)
• Alopecia (non-scarring or scarring)
• Photodistributed rash (V-neck, arms)

Hands:

• Rash: Look for rash between knuckles (lupus) vs on knuckles (dermatomyositis)
• Nail fold infarcts: Vasculitis
• Raynaud's phenomenon: Ask about colour changes
• Arthropathy: Swelling, tenderness, deformity
• Jaccoud's arthropathy: Ulnar deviation, swan-neck—but REDUCIBLE (passive correction possible)

Face:

• Mouth: Use torch to examine hard palate (painless ulcers)
• Eyes: Scleritis, episcleritis (rare)
• Nose: Septal ulceration

Scalp:

• Discoid lesions: Scarring, atrophy, follicular plugging
• Scarring alopecia: Permanent hair loss

Chest:

• Pleural rub: Pleuritis
• Pericardial rub: Pericarditis
• Reduced breath sounds: Pleural effusion

Abdomen:

• Splenomegaly: Felty's syndrome overlap (rare)

Legs:

• Oedema: Nephrotic syndrome, heart failure
• Livedo reticularis: Net-like pattern (APS)

Urinalysis:

• ALWAYS ask: "Has a urine dipstick been done?"
• Proteinuria and haematuria = lupus nephritis until proven otherwise

---

Common Viva Questions and Model Answers

Q1: "What is Systemic Lupus Erythematosus?"

Model Answer: "Systemic Lupus Erythematosus is a chronic, multisystem autoimmune disease characterized by loss of tolerance to nuclear antigens, leading to formation of autoantibodies and immune complexes. These complexes deposit in multiple organs—particularly the kidneys, skin, joints, and brain—causing inflammation via Type III hypersensitivity. It predominantly affects young women of childbearing age with a 9:1 female-to-male ratio and shows significant ethnic variation, with higher prevalence and severity in African-Caribbean and Asian populations."

Q2: "How would you investigate a patient with suspected SLE?"

Model Answer: "I would approach this systematically:

First-line investigations:

• ANA (antinuclear antibody)—98% sensitive, the gateway test. Negative ANA makes SLE very unlikely.
• If ANA positive, I would request ENA panel including anti-dsDNA (95% specific, correlates with disease activity), anti-Sm (99% specific), anti-Ro/La (associated with SCLE and neonatal lupus), and anti-RNP.
• Complement levels (C3, C4)—low in active disease due to consumption.
• FBC—look for cytopenias (anaemia, leukopenia, thrombocytopenia).
• U&E, creatinine—assess renal function.
• Urinalysis and urine PCR—screen for nephritis.
• ESR and CRP—high ESR with normal CRP suggests lupus; high CRP suggests infection.

If nephritis suspected:

• Renal biopsy to classify nephritis (ISN/RPS classification guides treatment).

Screen for APS:

• Lupus anticoagulant, anti-cardiolipin, anti-β2GP1 (especially if thrombosis or pregnancy morbidity)."

Q3: "What are the major causes of death in SLE?"

Model Answer: "Death in SLE follows a bimodal pattern:

Early mortality (first 5 years) is due to:

• Active lupus disease—particularly lupus nephritis progressing to renal failure, and neuropsychiatric lupus.
• Infection—related to both immunosuppression from treatment and intrinsic immune dysfunction. Common infections include pneumonia, sepsis, and opportunistic infections.

Late mortality (after 5-10 years) is due to:

• Accelerated cardiovascular disease—SLE patients have a 50-fold increased risk of MI in young women due to chronic inflammation, traditional risk factors, and steroid use.
• Malignancy—particularly lymphoma and cervical cancer.
• End-stage renal disease.

This bimodal pattern emphasizes the need for aggressive early disease control AND long-term cardiovascular risk management."

Q4: "How do you distinguish a lupus flare from infection in a febrile patient?"

Model Answer: "This is a critical clinical challenge. I would use a combination of clinical and laboratory features:

Lupus flare is more likely if:

• High ESR with normal or mildly elevated CRP (lupus typically doesn't raise CRP significantly unless there's serositis).
• Low complement (C3/C4 consumed).
• Rising anti-dsDNA titres.
• Active urinary sediment (nephritis).
• Other lupus features (new rash, arthritis, serositis).

Infection is more likely if:

• High CRP (> 50 mg/L).
• Normal complement levels.
• Localizing symptoms (cough, dysuria, wound infection).
• High neutrophil count.

However, when in doubt, assume infection and investigate thoroughly with cultures, imaging, and empirical antibiotics if unstable. You can always add immunosuppression later, but delaying antibiotics can be fatal."

Q5: "What is the difference between drug-induced lupus and idiopathic SLE?"

Model Answer: "The key differences are:

Clinical:

• Drug-induced lupus typically presents with arthritis and serositis (pleuritis, pericarditis).
• Renal and CNS involvement is very rare in drug-induced lupus but common in idiopathic SLE.
• Skin involvement is less prominent in drug-induced lupus.

Serological:

• Both are ANA positive.
• Drug-induced lupus: Anti-histone antibodies are positive in > 95%, but anti-dsDNA is usually negative.
• Idiopathic SLE: Anti-dsDNA and anti-Sm are positive.
• Complement levels are normal in drug-induced lupus but low in active idiopathic SLE.

Epidemiology:

• Drug-induced lupus has equal sex distribution; idiopathic SLE has 9:1 female predominance.

Treatment and outcome:

• Drug-induced lupus resolves within weeks to months after stopping the offending drug (procainamide, hydralazine, minocycline being the most common).
• Idiopathic SLE is lifelong and requires ongoing immunosuppression."

Q6: "How do you manage a woman with SLE who wants to become pregnant?"

Model Answer: "Pregnancy in SLE requires careful pre-conception counselling and multidisciplinary management:

Pre-conception:

• Ensure disease is quiescent for at least 6 months, ideally 12 months.
• No active nephritis (proteinuria less than 0.5g/day, normal creatinine).
• Switch teratogenic drugs: Stop mycophenolate (6 weeks before conception), methotrexate (3 months before), and ACE inhibitors. Switch to azathioprine if needed for disease control.
• Screen for Anti-Ro/La antibodies (risk of neonatal lupus and congenital heart block).
• Screen for antiphospholipid antibodies (risk of thrombosis and pregnancy loss).
• Continue hydroxychloroquine—this is mandatory throughout pregnancy as it reduces flares by 50%.

During pregnancy:

• Start low-dose aspirin from 12 weeks (reduce pre-eclampsia risk).
• If antiphospholipid antibodies positive, add prophylactic LMWH.
• Close monitoring every 4 weeks with urine dipstick, BP, anti-dsDNA, complement levels.
• Serial fetal growth scans (risk of IUGR).
• If Anti-Ro positive, serial fetal echocardiograms from 16-26 weeks to detect congenital heart block early.

Safe medications: Hydroxychloroquine, prednisolone, azathioprine, aspirin, heparin. Unsafe medications: Mycophenolate, methotrexate, cyclophosphamide, ACE inhibitors, warfarin.

Postpartum: Continue close monitoring for 3 months as this is the highest risk period for flares."

Q7: "Why do we measure complement levels in SLE?"

Model Answer: "Complement levels (C3 and C4) are consumed during active SLE due to immune complex deposition and activation of the classical complement pathway. Low complement levels indicate active disease, particularly lupus nephritis.

Falling C3/C4 levels can predict an impending flare, while rising levels indicate response to treatment. Complement monitoring is therefore a valuable biomarker for disease activity.

However, it's important to note that some patients have genetic complement deficiency (homozygous C1q, C2, or C4 deficiency), which actually predisposes to SLE and gives persistently low levels regardless of disease activity."

Q8: "What is the role of hydroxychloroquine in SLE?"

Model Answer: "Hydroxychloroquine is the cornerstone of SLE treatment and should be prescribed to every patient unless contraindicated.

Mechanism: It inhibits Toll-like receptor signalling, reducing interferon production and stabilizing the innate immune response.

Evidence-based benefits:

• Reduces disease flares by 50%.
• Reduces organ damage accrual.
• Reduces thrombotic risk (particularly important in antiphospholipid syndrome).
• Improves survival by 30%.
• Allows corticosteroid dose reduction.
• Safe in pregnancy—must be continued.

Dosing: 5 mg/kg actual body weight (usually 200-400mg daily).

Onset: Slow—takes 3-6 months to reach full effect, so patients need education about adherence.

Main side effect: Retinal toxicity (rare if dose correct less than 5mg/kg). Screening with OCT annually after 5 years of use.

Stopping hydroxychloroquine is the number one cause of flares—it's life insurance for SLE patients."

---

Common Examination Scenarios

Scenario 1: Lupus Nephritis Flare

Presentation: 28-year-old woman with known SLE on hydroxychloroquine, notices swollen ankles and frothy urine. BP 165/100.

Key Steps:

1. Urgent urine dipstick: Proteinuria 3+, Blood 2+
2. Urine PCR: 450 mg/mmol (nephrotic range)
3. Bloods: Rising creatinine (98 → 145), low C3/C4, rising anti-dsDNA
4. Urgent renal biopsy (mandatory to guide treatment)
5. If Class III/IV: Induction with MMF + high-dose steroids

Learning Point: Lupus nephritis is often asymptomatic—routine urine dipstick at EVERY visit is essential.

Scenario 2: Distinguishing Lupus Arthritis from RA

Presentation: 35-year-old woman with symmetrical polyarthritis affecting MCPs, wrists, knees. Morning stiffness 2 hours.

Key Differentiators:

---

High-Yield Facts for Exams

Classification Criteria:

• 2019 EULAR/ACR requires ANA positive PLUS ≥10 points from clinical and immunological domains

Antibody Pearls:

• ANA: Sensitive (98%), not specific—gateway test
• Anti-dsDNA: Specific (95%), tracks activity
• Anti-Sm: Most specific (99%), does not fluctuate
• Anti-Ro: Neonatal lupus, SCLE rash, congenital heart block

Management Pearls:

• Hydroxychloroquine for ALL patients (unless contraindicated)
• Class III/IV nephritis: MMF or cyclophosphamide + steroids
• Pregnancy: Continue HCQ, aspirin from 12 weeks, LMWH if APS
• APS: Lifelong warfarin (INR 2-3 for venous, 3-4 for arterial)

Distinguishing Features:

• ESR high + CRP normal = Lupus flare
• ESR high + CRP high = Infection (or serositis)
• Anti-histone + Anti-dsDNA negative = Drug-induced lupus

---

18. Advanced Clinical Pearls for Practice

The "Lupus Paradoxes"

1. The CRP Paradox:

• Lupus flares typically do NOT raise CRP significantly (unlike most inflammatory conditions)
• Exception: Serositis (pleuritis, pericarditis) and severe synovitis can raise CRP
• Clinical Use: High CRP in a lupus patient = Think INFECTION first, not flare

2. The Lupus Anticoagulant Paradox:

• Called "anticoagulant" because it prolongs clotting tests in vitro (aPTT, DRVVT)
• BUT causes thrombosis in vivo (pro-coagulant)
• Do NOT anticoagulate based on prolonged aPTT alone—need clinical thrombosis

3. The Steroid Paradox:

• Steroids are life-saving acutely but life-shortening chronically
• Goal: Lowest dose for shortest time
• Organ damage from steroids (AVN, fractures, CVD) rivals damage from SLE itself

4. The Rituximab Paradox:

• RCTs (EXPLORER, LUNAR) were negative for SLE
• Real-world experience shows 50-70% response in refractory cases
• Explanation: Trial design issues, patient selection, endpoints
• Now widely used off-label for refractory nephritis, haematology, NPSLE

High-Yield Differentials

Young Woman with Rash, Arthritis, and Positive ANA:

• Systemic Lupus Erythematosus
• Mixed Connective Tissue Disease (MCTD)—high Anti-RNP, features of SLE + scleroderma + myositis
• Sjögren's Syndrome—Anti-Ro/La, dry eyes/mouth
• Undifferentiated Connective Tissue Disease (UCTD)—doesn't meet full criteria yet

Distinguishing SLE from RA:

Thrombocytopenia in SLE:

• Immune thrombocytopenia (ITP-like)—most common
• TTP (thrombotic thrombocytopenic purpura)—microangiopathic haemolysis, fever, renal impairment, neuro symptoms
• Antiphospholipid syndrome—usually mild (50-100), not severe
• Bone marrow suppression (drugs: azathioprine, MMF, cyclophosphamide)

The "Lupus Nephritis Rule"

Every lupus patient needs:

• Urine dipstick at EVERY clinic visit
• Urine PCR if any proteinuria detected
• Renal biopsy if:
  • New proteinuria > 0.5g/day (PCR > 50)
  • Rising creatinine
  • Active urinary sediment

"Frothy urine" = Red flag:

• Indicates significant proteinuria (nephrotic range)
• Urgent nephrology review

The "Serositis vs Infection" Dilemma

Lupus patient with chest pain and fever:

Pleuritis (Lupus):

• Pleuritic pain (worse on breathing)
• ESR high, CRP normal/mildly elevated
• Low complement, rising anti-dsDNA
• Small bilateral effusions
• Responds to steroids

Pneumonia (Infection):

• Productive cough
• CRP > 50
• Normal complement
• Consolidation on CXR
• Responds to antibiotics

When in Doubt: Treat as infection (cultures, antibiotics) while awaiting results. Missing infection is more dangerous than delaying lupus treatment.

Drug Monitoring Essentials

Hydroxychloroquine:

• Retinal screening: Baseline, then annually after 5 years
• Max dose: 5mg/kg actual body weight
• No routine blood monitoring needed

Mycophenolate Mofetil:

• FBC weekly x 4 weeks, then monthly x 3 months, then every 3 months
• Teratogenic—contraception mandatory (two methods)
• GI side effects common (take with food, split dose)

Azathioprine:

• Check TPMT genotype BEFORE starting (deficiency = severe myelosuppression)
• FBC monthly for 3 months, then every 3 months
• LFTs (risk of hepatotoxicity)

Cyclophosphamide:

• FBC before each dose
• MESNA + hydration (prevent haemorrhagic cystitis)
• Fertility preservation counselling (egg/sperm banking)
• Co-trimoxazole prophylaxis (PJP prevention)

When to Refer Urgently to Rheumatology

• New diagnosis of SLE (any organ involvement)
• Lupus nephritis (new proteinuria > 0.5g/day or rising creatinine)
• Neuropsychiatric symptoms (seizures, psychosis, stroke)
• Severe haematological cytopenias (platelets less than 20, Hb less than 70)
• Pregnancy in SLE patient (pre-conception counselling)
• Suspected catastrophic APS
• Disease flare despite treatment

Predicting Flares

Warning Signs:

• Falling C3/C4 (complement consumption starting)
• Rising anti-dsDNA titres (especially if doubling)
• New proteinuria or haematuria (nephritis)
• Stopping hydroxychloroquine (flare within 6 months)
• Pregnancy (especially postpartum)
• Infection or surgery (stress)
• Sun exposure (photosensitivity)

Preventive Strategies:

• Never stop hydroxychloroquine
• Maintain low-dose steroids if needed (better than yo-yo dosing)
• Aggressive sun protection
• Prompt treatment of infections
• Pre-emptive steroid increase during surgery/stress

The "Treat to Target" Approach

Remission Goals (DORIS definition):

• Clinical remission: SLEDAI = 0 (no active disease)
• Serological remission: Normal complement, stable/negative anti-dsDNA
• Low-dose treatment: Prednisolone ≤5mg/day, HCQ, stable immunosuppressant

Benefits:

• Reduced organ damage
• Reduced flares
• Improved quality of life
• Improved survival

How to Achieve:

• Optimize hydroxychloroquine (ensure compliance, adequate dose)
• Add immunosuppressants early (steroid-sparing)
• Minimize steroid exposure (less than 7.5mg long-term)
• Consider biologics (belimumab, anifrolumab) if not achieving target

---

15. Patient Explanation and Education

What is Lupus?

Think of your immune system as a security guard protecting a building. Normally, the security guard only arrests intruders (viruses and bacteria). In lupus, the security guard gets confused and starts arresting the innocent staff (your own cells and tissues). This causes inflammation in different parts of the building (your body)—the skin, joints, kidneys, brain, and other organs.

Why do I have it?

Lupus develops from a combination of:

• Genes: You inherited genes that make you susceptible (it runs in families but isn't directly inherited).
• Environment: A trigger like sunlight, a virus, stress, or hormones (pregnancy, puberty) can set it off.
• Bad luck: The right (or wrong) combination of these factors.

It is NOT:

• An infection (you can't catch it or give it to others)
• Contagious
• Caused by anything you did wrong

Why does the sun make it worse?

Ultraviolet (UV) light from the sun damages skin cells. When these cells die, they release their contents. In lupus, your immune system sees these contents as "foreign invaders" and attacks, causing inflammation. This is why:

• You need high SPF sunscreen (50+)
• Avoid sun 10am-4pm
• Wear protective clothing, hats

Is it curable?

There is no cure yet, but lupus is highly treatable. Most people with lupus:

• Live normal lifespans
• Have successful careers
• Have healthy babies (with planning)
• Achieve remission (no active disease)

The key is taking your medications consistently and working with your rheumatology team.

Why do I need to take so many medications?

Different drugs target different parts of the disease:

Hydroxychloroquine (HCQ):

• Your "background protector"—the most important drug
• Calms down the overactive immune system
• Reduces flares by 50% and improves survival
• Takes 3-6 months to work fully (be patient!)
• You may need to take this for life

Steroids (Prednisolone):

• Work quickly to control inflammation during flares
• Goal: Use the lowest dose for the shortest time
• Side effects at high doses: Weight gain, diabetes, osteoporosis
• Never stop suddenly—must taper gradually

Immunosuppressants (Mycophenolate, Azathioprine):

• For severe disease affecting kidneys, brain, or blood
• Allow us to reduce steroid doses
• Require regular blood monitoring

Will I be able to have children?

Yes, most women with lupus can have successful pregnancies, BUT:

• Disease must be quiet for 6+ months before trying
• Need to switch some medications (your doctor will guide you)
• Never stop hydroxychloroquine during pregnancy—it protects you and the baby
• Require extra monitoring during pregnancy
• High-risk obstetrics team involved

Plan pregnancies with your rheumatology and obstetrics teams.

What is a "flare"?

A flare is when lupus becomes more active. Signs include:

• Increased fatigue
• New or worsening rash
• Joint pain and swelling
• Fever
• New symptoms (chest pain, headache, swollen legs)

When to seek help:

• Fever > 38°C (may be infection, not flare)
• Severe headache or confusion
• Chest pain or shortness of breath
• Frothy urine or swollen legs (kidney involvement)
• Any new concerning symptom

What can I do to stay healthy?

Lifestyle:

• Don't smoke: Smoking makes lupus worse and reduces medication effectiveness
• Sun protection: Daily sunscreen, avoid peak sun
• Exercise: Gentle, regular activity (walking, swimming, yoga)
• Balanced diet: No special lupus diet, but eat healthily
• Sleep: 7-9 hours per night
• Stress management: Meditation, support groups

Medical:

• Take medications exactly as prescribed
• Don't stop hydroxychloroquine (even if feeling well)
• Attend all appointments
• Regular blood tests and urine checks
• Get vaccinations (flu, pneumonia, COVID-19)
• Tell all doctors you have lupus

Can I work/study normally?

Most people with well-controlled lupus can:

• Work full-time (may need accommodations during flares)
• Study and attend university
• Exercise and play sports (with sun protection)
• Travel (bring medications, avoid excessive sun)

Communicate with employers/schools about lupus—they can make reasonable accommodations.

What about the future?

With modern treatments:

• 90% of people with lupus survive 10+ years

• Many achieve long-term remission
• New treatments (biologics) are being developed
• Research is ongoing for better therapies and potential cures

The future for lupus patients is much brighter than it was even 20 years ago.

---

16. References

1. Hoi A, Igel T, Mok CC, et al. Systemic lupus erythematosus. Lancet. 2024;403(10441):2326-2338. doi:10.1016/S0140-6736(24)00398-2. PMID: 38642569

2. Stojan G, Petri M. Epidemiology of systemic lupus erythematosus: an update. Curr Opin Rheumatol. 2018;30(2):144-150. doi:10.1097/BOR.0000000000000480. PMID: 29251660

3. Crow MK. Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets. Ann Rheum Dis. 2023;82(8):999-1014. doi:10.1136/ard-2022-223741. PMID: 36792346

4. Caielli S, Wan Z, Pascual V. Systemic Lupus Erythematosus Pathogenesis: Interferon and Beyond. Annu Rev Immunol. 2023;41:533-560. doi:10.1146/annurev-immunol-101921-042422. PMID: 36854182

5. Siegel CH, Sammaritano LR. Systemic Lupus Erythematosus: A Review. JAMA. 2024;331(17):1480-1491. doi:10.1001/jama.2024.2315. PMID: 38587826

6. Parikh SV, Almaani S, Brodsky S, et al. Update on Lupus Nephritis: Core Curriculum 2020. Am J Kidney Dis. 2020;76(2):265-281. doi:10.1053/j.ajkd.2019.10.017. PMID: 32220510

7. Fanouriakis A, Tziolos N, Bertsias G, et al. Update on the diagnosis and management of systemic lupus erythematosus. Ann Rheum Dis. 2021;80(1):14-25. doi:10.1136/annrheumdis-2020-218272. PMID: 33051219

8. Carrión-Barberà I, Salman-Monte TC, Vílchez-Oya F, et al. Neuropsychiatric involvement in systemic lupus erythematosus: A review. Autoimmun Rev. 2021;20(4):102780. doi:10.1016/j.autrev.2021.102780. PMID: 33609799

9. Fanouriakis A, Kostopoulou M, Andersen J, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis. 2024;83(1):15-29. doi:10.1136/ard-2023-224762. PMID: 37827694

10. Lazar S, Kahlenberg JM. Systemic Lupus Erythematosus: New Diagnostic and Therapeutic Approaches. Annu Rev Med. 2023;74:339-352. doi:10.1146/annurev-med-043021-032611. PMID: 35804480

11. Dima A, Jurcut C, Chasset F, et al. Hydroxychloroquine in systemic lupus erythematosus: overview of current knowledge. Ther Adv Musculoskelet Dis. 2022;14:1759720X211073001. doi:10.1177/1759720X211073001. PMID: 35186126

12. Kirou KA, Dall Era M, Aranow C, et al. Belimumab or anifrolumab for systemic lupus erythematosus? A risk-benefit assessment. Front Immunol. 2022;13:997111. doi:10.3389/fimmu.2022.997111. PMID: 36119023

13. He Y, Sawalha AH. Drug-induced lupus erythematosus: an update on drugs and mechanisms. Curr Opin Rheumatol. 2018;30(5):490-497. doi:10.1097/BOR.0000000000000522. PMID: 29870500

14. Zucchi D, Fischer-Betz R, Tani C. Pregnancy in systemic lupus erythematosus. Best Pract Res Clin Rheumatol. 2023;37(4):101912. doi:10.1016/j.berh.2023.101912. PMID: 37596173

15. Petri M. Pregnancy and Systemic Lupus Erythematosus. Best Pract Res Clin Obstet Gynaecol. 2020;64:24-34. doi:10.1016/j.bpobgyn.2019.09.002. PMID: 31677989

16. Wind M, Fierro JJ, Bloemenkamp KWM, et al. Pregnancy outcome predictors in systemic lupus erythematosus: a systematic review and meta-analysis. Lancet Rheumatol. 2024;6(10):e683-e696. doi:10.1016/S2665-9913(24)00155-0. PMID: 39153486

17. Garcia D, Erkan D. Diagnosis and Management of the Antiphospholipid Syndrome. N Engl J Med. 2018;378(21):2010-2021. doi:10.1056/NEJMra1705454. PMID: 29791829

18. Meroni PL, Tsokos GC. Editorial: Systemic Lupus Erythematosus and Antiphospholipid Syndrome. Front Immunol. 2019;10:199. doi:10.3389/fimmu.2019.00199. PMID: 30858846

19. Rees F, Doherty M, Grainge MJ, et al. The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studies. Rheumatology (Oxford). 2017;56(11):1945-1961. doi:10.1093/rheumatology/kex260. PMID: 28968809

20. Nehar-Belaid D, Hong S, Marches R, et al. Mapping systemic lupus erythematosus heterogeneity at the single-cell level. Nat Immunol. 2020;21(9):1094-1106. doi:10.1038/s41590-020-0743-0. PMID: 32747814

21. Postal M, Vivaldo JF, Fernandez-Ruiz R, et al. Type I interferon in the pathogenesis of systemic lupus erythematosus. Curr Opin Immunol. 2020;67:87-94. doi:10.1016/j.coi.2020.10.014. PMID: 33246136

22. Fava A, Petri M. Systemic lupus erythematosus: Diagnosis and clinical management. J Autoimmun. 2019;96:1-13. doi:10.1016/j.jaut.2018.11.001. PMID: 30448290

---

17. Clinical Case Studies

Case 1: The New Diagnosis—Mild Disease

Presentation: 24-year-old Afro-Caribbean woman presents to GP with:

• 3-month history of fatigue and joint pain (hands, wrists, knees)
• 2-week history of facial rash after holiday in Spain
• Morning stiffness lasting 90 minutes
• No other symptoms

Examination:

• Malar rash (spares nasolabial folds)
• Symmetrical swelling of MCPs and PIPs bilaterally
• No mouth ulcers, alopecia, or other findings
• BP 125/78 mmHg

Initial Investigations:

• FBC: Hb 118 g/L, WCC 3.2 (lymphocytes 0.9), Platelets 165
• U&E: Normal, Creatinine 68 µmol/L, eGFR > 90
• Urinalysis: Negative for protein and blood
• ESR 48 mm/hr, CRP 6 mg/L
• ANA: Positive 1:320 (homogeneous pattern)

Further Serology:

• Anti-dsDNA: Positive (high titre)
• Anti-Sm: Negative
• Anti-Ro, Anti-La: Negative
• C3: 0.65 g/L (low; normal 0.9-1.8)
• C4: 0.08 g/L (low; normal 0.1-0.4)
• Antiphospholipid antibodies: Negative

Diagnosis: Systemic Lupus Erythematosus (meets 2019 EULAR/ACR criteria: ANA positive + 21 points [mucocutaneous 6 + arthritis 6 + leukopenia 3 + low C3/C4 4 + anti-dsDNA 6])

Classification: Mild-moderate disease (skin and joints only, no organ-threatening features)

Management Plan:

1. Hydroxychloroquine 400mg daily (patient weighs 82kg, 5mg/kg = 410mg, so 200mg BD)
2. Prednisolone 15mg daily for 2 weeks, then taper by 5mg every 2 weeks
3. Sun protection education: SPF 50+, avoid peak sun, protective clothing
4. Lifestyle advice: Smoking cessation (currently smokes 5/day), exercise
5. Baseline ophthalmology review (for HCQ retinal screening)
6. Monitoring: Review in 4 weeks with FBC, U&E, urinalysis, anti-dsDNA, C3/C4

Follow-Up at 3 Months:

• Symptoms 70% improved, rash resolved
• Prednisolone reduced to 5mg daily
• Bloods: Normalized lymphocytes, C3/C4 rising
• Continued on HCQ long-term, prednisolone tapered off

Learning Points:

• Early diagnosis and treatment prevents organ damage
• HCQ is the cornerstone—must continue indefinitely
• Sun protection is non-negotiable
• Monitor for nephritis development (urine dipstick at every visit)

---

Case 2: Lupus Nephritis—Aggressive Disease

Presentation: 32-year-old Asian woman with known SLE (diagnosed 2 years ago, on HCQ 400mg) presents with:

• 2-week history of ankle swelling
• "Foamy urine" noticed in morning
• No other new symptoms
• Compliance with HCQ confirmed

Examination:

• BP 168/102 mmHg (previous BP 125/80)
• Bilateral pitting oedema to knees
• No rash, mouth ulcers, or active arthritis
• Fundoscopy: No papilloedema

Urgent Investigations:

• U&E: Creatinine 145 µmol/L (baseline 75), eGFR 38 (was > 90)
• Urinalysis: Protein 3+, Blood 2+
• Urine PCR: 485 mg/mmol (nephrotic range; normal less than 15)
• Urine microscopy: Red cell casts, dysmorphic RBCs
• FBC: Hb 102 g/L, WCC 4.2, Platelets 135
• Albumin: 25 g/L (low; normal 35-50)
• Anti-dsDNA: 580 IU/mL (was 120 at diagnosis)
• C3: 0.45 g/L (low), C4: 0.06 g/L (low)

Diagnosis: Lupus Nephritis flare (active urinary sediment, nephrotic-range proteinuria, impaired renal function, rising anti-dsDNA, low complement)

Renal Biopsy:

• Performed within 1 week
• Result: Class IV-G (Diffuse Global Proliferative Lupus Nephritis)
• Activity index: 14/24 (high)
• Chronicity index: 3/12 (low—good prognosis for treatment)
• Immunofluorescence: "Full house" (IgG, IgM, IgA, C3, C1q)

Management:

Induction Phase (6 months):

1. IV Methylprednisolone 500mg daily x 3 days
2. Oral Prednisolone 60mg daily (1mg/kg), rapid taper:
   • 50mg at 2 weeks
   • 40mg at 4 weeks
   • 30mg at 6 weeks
   • 20mg at 8 weeks
   • Target ≤7.5mg by 12 weeks
3. Mycophenolate Mofetil 1.5g BD (3g total daily)
   • Counsel about contraception (teratogenic)
   • Fitted for Mirena IUD
4. Continue Hydroxychloroquine 400mg
5. Ramipril 2.5mg daily → titrate to 10mg (ACEi for BP and antiproteinuric effect)
6. Amlodipine 5mg added for BP control (target less than 130/80)
7. Furosemide 40mg for oedema
8. Calcium/Vitamin D supplementation
9. Omeprazole 20mg (PPI—high-dose steroids)
10. Co-trimoxazole 480mg daily (PJP prophylaxis while on high-dose immunosuppression)

Monitoring:

• Weekly for first month: FBC, U&E, urinalysis
• Monthly: Urine PCR, anti-dsDNA, C3/C4
• MMF drug levels

Response at 3 Months:

• Urine PCR: 485 → 120 mg/mmol (75% reduction)
• Creatinine: 145 → 98 µmol/L
• C3/C4: Normalizing
• BP 128/78 on medications
• Partial remission achieved

Response at 6 Months:

• Urine PCR: 32 mg/mmol (Complete remission: less than 50)
• Creatinine: 82 µmol/L (back to near baseline)
• Anti-dsDNA: Falling
• Prednisolone: Tapered to 5mg
• Success—transition to maintenance therapy

Maintenance Phase:

1. Mycophenolate Mofetil reduced to 1g BD (2g total)
2. Prednisolone 5mg daily (attempt to wean off over next year)
3. Continue HCQ, ACEi
4. Stop co-trimoxazole (no longer on high-dose immunosuppression)
5. Long-term monitoring: Every 3 months

Learning Points:

• Lupus nephritis is often asymptomatic until advanced—routine urinalysis essential
• Red cell casts are pathognomonic for glomerulonephritis
• Renal biopsy is MANDATORY to guide therapy
• Aggressive immunosuppression for Class III/IV achieves remission in 80-90%
• Rising anti-dsDNA and falling complement predict nephritis flares
• Long-term maintenance therapy is essential to prevent relapse

---

Case 3: Neuropsychiatric Lupus—Diagnostic Challenge

Presentation: 19-year-old woman with SLE (diagnosed 1 year ago, on HCQ + prednisolone 10mg) presents to A&E with:

• Witnessed generalized tonic-clonic seizure (first ever)
• Duration: 3 minutes, post-ictal confusion
• No preceding illness, headache, or trauma
• No recreational drug use

Differential Diagnosis:

1. Neuropsychiatric lupus (primary CNS involvement)
2. CNS infection (meningitis, encephalitis)
3. Metabolic (hyponatraemia, hypoglycaemia, uraemia)
4. Cerebral venous sinus thrombosis (if APS)
5. Posterior reversible encephalopathy syndrome (PRES—if hypertensive)
6. Drug-induced seizure (prednisolone can lower seizure threshold)
7. Idiopathic epilepsy

Initial Management (A&E):

• Airway, Breathing, Circulation
• IV lorazepam 4mg (if seizing)
• Glucose, oxygen
• Bloods: FBC, U&E, LFTs, glucose, calcium, magnesium, anti-dsDNA, C3/C4
• Pregnancy test (all women of childbearing age)
• CT brain (exclude haemorrhage, mass lesion)

Investigations:

Bloods:

• U&E: Normal (creatinine 68, no uraemia)
• Glucose: 5.2 mmol/L (normal)
• Calcium, magnesium: Normal
• FBC: Hb 112, WCC 4.8, Platelets 178
• Anti-dsDNA: Elevated (310 IU/mL, was 80)
• C3: 0.58 g/L (low), C4: 0.09 g/L (low)
• ESR 52, CRP 8

CT Brain (emergency):

• No haemorrhage, mass, or acute infarct
• No hydrocephalus

MRI Brain (next day):

• Multiple punctate T2 hyperintensities in white matter (periventricular and subcortical)
• No mass effect
• No enhancement post-contrast
• Findings consistent with small vessel vasculopathy (NPSLE) or demyelination

Lumbar Puncture (to exclude infection):

• Opening pressure: 18 cmH₂O (normal)
• CSF: Clear, colourless
• WCC: 8 cells/µL (normal less than 5, mild lymphocytic pleocytosis—can occur in NPSLE)
• Protein: 0.58 g/L (mildly elevated; normal less than 0.45)
• Glucose: 3.2 mmol/L (paired blood glucose 5.2—CSF:blood ratio 0.6, normal)
• Gram stain, culture: Negative
• PCR: HSV, VZV, enterovirus negative
• Oligoclonal bands: Negative

Autoantibodies:

• Anti-ribosomal P: Positive (associated with NPSLE, particularly psychosis and depression)
• Antiphospholipid antibodies: Negative

EEG:

• Generalized slowing (post-ictal)
• No epileptiform discharges

Diagnosis: Neuropsychiatric Systemic Lupus Erythematosus (NPSLE)—seizure disorder secondary to lupus

Evidence Supporting NPSLE:

• Known SLE with elevated disease activity (rising anti-dsDNA, low complement)
• MRI findings consistent with lupus vasculopathy
• Positive anti-ribosomal P antibody
• Exclusion of infection and metabolic causes

Management:

Acute (Inpatient):

1. IV Methylprednisolone 1g daily x 3 days (pulse therapy for NPSLE)
2. Levetiracetam 500mg BD (antiepileptic—low interaction profile)
3. Switch from prednisolone 10mg to 60mg daily (post-pulse therapy), then taper
4. Continue HCQ 400mg
5. Safety: Seizure precautions, supervise bathing/showering

Induction Immunosuppression (for NPSLE):

• Cyclophosphamide IV (Euro-Lupus protocol: 500mg every 2 weeks x 6 doses)
• Rationale: Severe neuropsychiatric manifestation requires aggressive treatment

Maintenance (after 6 months):

• Mycophenolate Mofetil 1g BD
• Prednisolone less than 7.5mg
• Levetiracetam continued (typically for 2 years seizure-free, then consider withdrawal)
• HCQ indefinitely

Follow-Up:

• Neurology co-management
• Neuropsychological testing (baseline cognitive function)
• Repeat MRI at 6 months (assess for progression or improvement)
• DVLA notification (cannot drive for 6-12 months after first seizure)

Outcome:

• No further seizures
• MRI stable at 6 months
• Cognitive function preserved
• Remains on anticonvulsant and immunosuppression

Learning Points:

• NPSLE is a diagnosis of exclusion—must rule out infection
• MRI can be normal in NPSLE or show non-specific white matter changes
• Anti-ribosomal P is associated with NPSLE (especially psychosis)
• Treatment depends on mechanism (thrombotic vs inflammatory)
• Seizures in SLE may be primary NPSLE or secondary to metabolic/APS causes
• Multidisciplinary approach essential (rheumatology, neurology, psychiatry)

---

Case 4: Pregnancy in SLE—Successful Outcome

Background: 28-year-old woman with SLE (diagnosed 4 years ago) wishes to become pregnant.

Current Status:

• Disease in remission for 18 months
• Current medications: HCQ 400mg, prednisolone 5mg
• No nephritis (urine consistently negative, creatinine 72)
• No APS antibodies (tested twice, 12 weeks apart—negative)

Pre-Conception Counselling:

Risk Assessment:

• Good candidate: Disease quiescent > 6 months, no major organ involvement, no APS
• Risks discussed: Flare (25-30% risk), pre-eclampsia (15-20%), IUGR, preterm birth

Antibody Screening:

• Anti-Ro: Positive (high titre)
• Anti-La: Negative
• Implication: 2-5% risk of neonatal lupus (rash, heart block)

Medication Adjustment:

• Continue HCQ (ESSENTIAL—reduces flare risk)
• Continue prednisolone 5mg (safe in pregnancy)
• Folic acid 5mg daily (start pre-conception)

Plan:

• Try to conceive
• Once pregnant: Start aspirin 150mg from 12 weeks (pre-eclampsia prophylaxis)
• Serial fetal echocardiograms 16-26 weeks (Anti-Ro positive—monitor for heart block)

Pregnancy Course:

First Trimester:

• Pregnancy confirmed at 5 weeks
• Started on aspirin 150mg at 12 weeks
• No flare, feeling well
• Booking bloods: Normal renal function, no proteinuria

Second Trimester:

• Fetal Echo at 18 weeks: Normal cardiac structure, normal PR interval
• Fetal Echo at 22 weeks: Normal
• Fetal Echo at 26 weeks: Normal (low risk of late heart block development)
• Maternal monitoring every 4 weeks:
  • BP: 128/78 (normal)
  • Urinalysis: Negative
  • Anti-dsDNA, C3/C4: Stable
• Growth scan at 24 weeks: Normal fetal growth

Third Trimester:

• Growth scans every 4 weeks: Appropriate growth
• Doppler studies: Normal umbilical artery flow
• Maternal health: No flare, no pre-eclampsia
• Plan: Vaginal delivery (no obstetric indication for C-section)

Labour and Delivery (39 weeks):

• Spontaneous labour
• Steroid cover: IV Hydrocortisone 100mg every 8 hours during labour (on prednisolone > 7.5mg for > 2 weeks in recent past)
• Normal vaginal delivery: Baby girl, 3.2kg, Apgar 9/10
• No complications

Neonatal Assessment:

• Paediatrician review: No rash, no heart block
• ECG: Normal sinus rhythm, normal PR interval
• Plan: Follow-up at 6 weeks (neonatal lupus can manifest up to 6 months)

Postpartum:

• Flare risk highest in first 3 months—close monitoring
• Continue HCQ, prednisolone
• Breastfeeding: Compatible with HCQ and prednisolone
• Contraception: Progesterone-only pill started at 6 weeks
• Follow-up every 2-4 weeks for 3 months

Outcome:

• No postpartum flare
• Baby well, no neonatal lupus manifestations at 6 months
• Successful pregnancy

Learning Points:

• Pregnancy in SLE is achievable with careful planning
• Disease MUST be quiescent for ≥6 months before conception
• HCQ must be continued throughout pregnancy
• Anti-Ro positive mothers require serial fetal echocardiograms (16-26 weeks)
• Aspirin from 12 weeks reduces pre-eclampsia risk
• Postpartum period is highest risk for flares—continue close monitoring
• Multidisciplinary care (rheumatology + obstetrics) is essential

---

Case 5: Antiphospholipid Syndrome—Catastrophic Complication

Presentation: 35-year-old woman with SLE and known APS (on warfarin for previous DVT) presents to A&E with:

• 2-day history of confusion, dyspnoea, abdominal pain
• Stopped warfarin 1 week ago (dental extraction planned—not restarted)

Examination:

• Acutely unwell, confused (GCS 13/15)
• Tachypnoeic (RR 28), tachycardic (HR 118), BP 168/105
• Bilateral crackles on chest auscultation
• Livedo reticularis on trunk and limbs
• Abdominal tenderness (diffuse)

Urgent Investigations:

Bloods:

• FBC: Hb 98 g/L (was 125), WCC 16, Platelets 45 (was 180)
• U&E: Creatinine 285 µmol/L (was 85), eGFR 18
• LFTs: ALT 245, AST 312 (hepatic involvement)
• Coagulation: INR 1.1 (off warfarin), aPTT prolonged (lupus anticoagulant)
• LDH: 850 (elevated—haemolysis/tissue necrosis)
• Blood film: Schistocytes (microangiopathic haemolysis)
• Troponin: 450 ng/L (elevated—cardiac involvement)

Imaging:

• CXR: Bilateral infiltrates (ARDS pattern)
• CT Abdomen: Bowel wall thickening, splenic infarcts
• CT Brain: Multiple small acute infarcts

Diagnosis: Catastrophic Antiphospholipid Syndrome (CAPS)

Evidence:

• Multi-organ thrombosis (brain, lungs, kidneys, liver, bowel, heart)
• Acute onset over 2 days
• Known APS with precipitant (warfarin cessation)
• Microangiopathic haemolytic anaemia
• Confirmed antiphospholipid antibodies (triple positive)

Management (ICU):

Triple Therapy for CAPS:

1. Anticoagulation: IV heparin infusion (aPTT target 2-3x normal), then restart warfarin (target INR 3-4)
2. High-Dose Corticosteroids: IV methylprednisolone 1g daily x 3 days, then prednisolone 1mg/kg
3. IVIG: 2g/kg over 5 days (0.4g/kg/day)
4. Plasma Exchange: Daily for 5 days (remove antibodies and replace coagulation factors)

Additional:

• Rituximab: 375mg/m² weekly x 4 doses (B-cell depletion—reduce antibody production)
• Renal support: Haemofiltration (AKI stage 3)
• Respiratory support: Intubation and ventilation (ARDS)
• Treat precipitant: Resume anticoagulation

ICU Course:

• Remained intubated for 10 days
• Renal function slowly improved (creatinine 285 → 145 by day 14)
• Platelet count recovered (45 → 120)
• Neurological recovery (confusion resolved)

Outcome:

• Survived (CAPS mortality 30-50%)
• Discharged after 3 weeks
• Chronic kidney disease stage 3 (eGFR 42—permanent damage)
• Long-term warfarin (INR target 3-4)
• Hydroxychloroquine added (reduces APS thrombosis risk)
• Rituximab maintenance (every 6 months)

Learning Points:

• CAPS is a medical emergency—mortality 30-50%
• Triggered by infection, surgery, anticoagulation withdrawal, pregnancy
• Requires multi-organ thrombosis (≥3 organs) developing acutely (less than 1 week)
• Treatment: Triple therapy (anticoagulation + steroids + IVIG/plasma exchange)
• Rituximab and eculizumab (complement inhibitor) are rescue therapies
• Never stop anticoagulation in APS without bridging therapy

---

Signs to Elicit

1. Hands: Look for rash between knuckles (Lupus) vs on knuckles (Dermatomyositis). Look for nail fold infarcts.
2. Mouth: Use a torch to look at the hard palate (ulcers).
3. Scalp: Look for discoid scarring / alopecia.
4. Urine: Ask "Has a dipstick been done?"

Viva Questions

• Q: Distinguish Drug-Induced Lupus from SLE?
  • A: Anti-Histone positive. Anti-dsDNA negative. Normal Complement. Resolves on stopping drug.
• Q: Why do we measure Complement levels?
  • A: They drop during a flare because they are being consumed in immune complexes.
• Q: What is the risk of falling pregnant with active nephritis?
  • A: Very high risk of progression to renal failure and pre-eclampsia/fetal loss.

---

---

Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.