Systemic Lupus Erythematosus
Systemic lupus erythematosus is a chronic multisystem autoimmune disorder characterized by the production of autoantibodies (notably anti-dsDNA and anti-Smith) causing widespread inflammation and tissue damage affecting the skin, joints, kidneys, blood cells, and other organs.
Systemic Lupus Erythematosus (SLE)
"Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder. It is characterised by profound immunological disturbances resulting in an excessive production of autoantibodies, some of which may cause direct tissue damage while others take part in immune complex (IC) formation. Failure to remove these ICs is the most important pathological mechanism of tissue damage in SLE." [1]
Let's break down the name:
- "Systemic" = affects multiple organ systems (not just one tissue)
- "Lupus" = Latin for "wolf" — historically referring to the destructive facial rash that was thought to resemble a wolf's bite
- "Erythematosus" = Latin for "reddened" — referring to the characteristic erythematous skin lesions
So the name itself tells you: a systemic disease with red, destructive skin manifestations driven by autoimmunity.
The key concept to grasp from the outset is that SLE is fundamentally a disease of loss of self-tolerance. The immune system fails to distinguish self from non-self, producing autoantibodies against nuclear components (DNA, histones, ribonucleoproteins). These autoantibodies either directly attack cells (Type II hypersensitivity → cytopenias) or form immune complexes that deposit in tissues (Type III hypersensitivity → nephritis, vasculitis, serositis). The failure to clear these immune complexes — due to complement consumption and defective phagocytosis — perpetuates the cycle of inflammation [1][2][3].
Core Concept
SLE is NOT just one type of hypersensitivity. It involves both Type II HSR (autoantibodies directly attacking blood cells → haemolytic anaemia, thrombocytopenia, leukopenia) and Type III HSR (immune complex deposition → glomerulonephritis, vasculitis, serositis). Understanding this duality explains why SLE has such a wide range of manifestations.
2. Epidemiology
- Female predominance (M:F = 1:9) [2][3][4]
- Some sources quote M:F = 1:7 to 1:15, but the commonly examined ratio is 1:9 [3][4][5]
- Predominantly affects women in their 20s–40s (reproductive age) [5]
- Childhood-onset SLE (before age 16) tends to be more severe, with higher rates of nephritis and CNS involvement
- Male SLE, though rarer, also tends to have a more aggressive course
Why females? The increased frequency in women is attributed to an oestrogen hormone effect [5]. Oestrogen promotes B-cell survival, enhances antibody production, and inhibits T-suppressor cell function. This is why:
- SLE flares can occur during pregnancy (high oestrogen state)
- SLE can be triggered or worsened by oral contraceptive pills (exogenous oestrogen)
- Peripartum is a risk factor for lupus flare [6]
- Early menopause is common in autoimmune disease, especially for those treated with immunosuppressive therapy [6]
- Wide ethnic variations in prevalence, clinical course, and prognosis [4]:
- Prevalence: Caribbean Blacks (1 in 250) > Orientals (6 in 10,000) > Caucasians (1 in 10,000)
- Prognosis: Caucasians > Orientals > Caribbean Blacks
- In Hong Kong, SLE is relatively common — it is a bread-and-butter rheumatology condition and a favourite topic for HKUMed exams
- Chinese females in Hong Kong have a relatively high incidence of SLE
- Lupus nephritis is more common and often more severe in Asian and Black populations compared to Caucasians
- This has implications for screening and monitoring in our local clinical practice
3. Risk Factors
- Most common genetic predisposition is found at the MHC locus [5]:
- High concordance rate in monozygotic twins (~25–50%, compared to ~5% in dizygotic twins) [5]
- Increased risk of SLE in 1st-degree relatives [5]
- ~5% associated with complement deficiency (C1q, C2, C4 deficiency) → impaired clearance of immune complexes and apoptotic debris [4]
- C1q deficiency carries the highest risk (~90% develop SLE-like illness) — because C1q is critical for opsonisation and clearance of apoptotic cells
- C4 deficiency and C2 deficiency also predispose but with lower penetrance
- Other genetic associations: TREX1, IRF5, STAT4, PTPN22, ITGAM
Why complement deficiency causes SLE
Complement proteins (especially C1q, C2, C4) are responsible for opsonising and clearing apoptotic cell debris and immune complexes. When complement is deficient, apoptotic cells persist → nuclear self-antigens become exposed to the immune system → break in self-tolerance → autoantibody production. This is the link between complement deficiency and autoimmunity.
- Oestradiol, progesterone, testosterone, dehydroepiandrosterone (DHEA) and prolactin have immunoregulatory functions that modulate incidence and severity of SLE [5]
- Oestrogen: promotes B-cell activation and survival, reduces T-suppressor activity
- Oestrogens can exacerbate SLE [4]
- Hyperprolactinaemia can exacerbate SLE (note: bromocriptine used to lower prolactin is not good for Raynaud's) [6]
- UV light [4] — induces keratinocyte apoptosis → exposes nuclear antigens → drives autoimmune response. This is why SLE patients are photosensitive and flares occur after sun exposure. The case in the GC lecture: "Trip to Thailand" was identified as a possible triggering factor [1]
- Infections: EBV (molecular mimicry — EBV nuclear antigen-1 shares epitopes with self-antigens), parvovirus B19, HIV-1 [4][5]
- Drugs (Drug-induced lupus — see below) [2][4]
- Chemical agents: dyes, eosin, heavy metals (mercury, gold, cadmium) [4]
- Food: L-canavanine (found in alfalfa seeds and sprouts) [4]
This is a distinct entity from idiopathic SLE and is a very common exam question [2][4]:
| Feature | Drug-Induced Lupus | Idiopathic SLE |
|---|---|---|
| Sex ratio | M:F = 1:1 | M:F = 1:9 |
| Characteristic autoantibody | Anti-histone | Anti-dsDNA |
| Organ involvement | Lung (serositis), joints | Renal, CNS |
| Drug discontinuation | Resolves within days–weeks | No effect |
| Complement levels | Usually normal | Usually low |
Drugs that INDUCE SLE [4]:
- Procainamide (highest risk)
- Hydralazine (most common cause because it is more widely used)
- Isoniazid
- Others (rare): beta-blockers, quinidine, penicillamine, phenytoin, chlorpromazine
Drugs that EXACERBATE existing SLE [4]:
- Lovastatin
- Sulphonamides
- Oestrogens
High Yield: The classic mnemonic for Drug-induced lupus is "HIP" — Hydralazine, Isoniazid, Procainamide. Anti-histone antibody is the hallmark. Renal and CNS involvement are rare (unlike idiopathic SLE). It resolves on stopping the drug.
SLE can affect virtually any organ system. Understanding which organs are affected and why requires understanding where immune complexes tend to deposit:
- Kidneys: The glomerular basement membrane is a natural filter → circulating immune complexes get trapped here → glomerulonephritis (lupus nephritis is the most important cause of morbidity and mortality)
- Skin: UV light induces keratinocyte apoptosis → exposure of nuclear antigens → local immune complex formation → cutaneous lupus
- Joints: Synovial membrane inflammation from immune complex deposition
- Serosal surfaces (pleura, pericardium, peritoneum): Immune complex deposition → serositis
- Blood vessels: Immune complex deposition in vessel walls → vasculitis
- Blood cells: Direct autoantibody-mediated destruction (Type II HSR)
- CNS: Immune complex deposition in choroid plexus and cerebral vasculature; also anti-neuronal antibodies
5. Etiology and Pathophysiology (Detailed)
SLE is primarily a disease with abnormalities in immune regulation and is thought to be secondary to a loss of self-tolerance [5]. The pathogenesis is multifactorial:
5.2 Immunological Mechanisms in Detail
- B cells or plasma cells that make autoantibodies are more persistently activated and driven to maturation by B cell activating factor (BAFF/BLyS) and by persistently activated T helper cells making B-supporting cytokines such as IL-6 and IL-10 [5]
- Autoantibodies may be present for years before the first symptom of disease appears, leading to formation of immune complexes [5]
- This is why ANA can be positive years before clinical SLE manifests
- Phagocytosis and clearing of immune complexes are defective in SLE, allowing persistence of antigen and immune complexes [5]
- Self-antigens that are recognized by autoantibodies are presented primarily on cell surfaces, particularly by cells that are activated or undergoing apoptosis [5]
- Defective clearance of apoptotic bodies → persistent exposure of intracellular nuclear antigens (dsDNA, histones, Sm, RNP) to the immune system → autoantibody generation
- Immune complex deposition activates the classical complement pathway → consumption of C3 and C4 → low complement levels
- Low complement is both a marker of disease activity AND contributes to the pathology (less complement available to clear immune complexes → vicious cycle)
- Lowered complement levels were identified as a salient feature in the GC lecture case [1]
| Mechanism | Type II HSR | Type III HSR |
|---|---|---|
| What happens | Autoantibodies bind directly to cell surface antigens | Autoantibodies form immune complexes with soluble antigens |
| Consequence | Cell destruction via complement/phagocytosis | IC deposition → complement activation → tissue inflammation |
| Clinical manifestation | Haemolytic anaemia, thrombocytopenia, leukopenia | Nephritis, vasculitis, serositis, arthritis |
| Autoantibody | Target | Clinical Significance |
|---|---|---|
| ANA | Various nuclear antigens | Screening test — very sensitive (~95–99%) but NOT specific |
| Anti-dsDNA | Double-stranded DNA | Specific for SLE; correlates with disease activity; associated with lupus nephritis |
| Anti-Smith (Sm) | Small nuclear ribonucleoprotein (snRNP) | Most specific for SLE (but low sensitivity ~30%) |
| Anti-histone | Histones | Drug-induced lupus |
| Anti-Ro (SSA) | Ro ribonucleoprotein | Neonatal lupus, congenital heart block, subacute cutaneous LE, Sjögren's syndrome overlap |
| Anti-La (SSB) | La ribonucleoprotein | Usually co-exists with anti-Ro; Sjögren's overlap |
| Anti-RNP | U1 ribonucleoprotein | Mixed connective tissue disease (MCTD) |
| Anti-ribosomal P | Ribosomal P protein | CNS lupus (psychosis, depression) |
| Lupus anticoagulant / Anti-cardiolipin / Anti-β2-GP1 | Phospholipid-binding proteins | Antiphospholipid syndrome (thrombosis, recurrent miscarriage) [7] |
High Yield: ANA Sensitivity vs Specificity
ANA is the best screening test because it is very sensitive (~95–99%) — a negative ANA virtually rules out SLE. However, ANA is NOT specific: it can be positive in many other conditions (other autoimmune diseases, infections, even healthy elderly people). Anti-dsDNA and anti-Sm are the confirmatory (specific) antibodies. Entry criterion for the 2019 EULAR/ACR classification: ANA must be positive (≥1:80) as the entry criterion.
6. Classification
Cutaneous lupus and systemic lupus are different manifestations [8]. A patient can have pure cutaneous lupus without systemic lupus [8].
Cutaneous lupus is classified by temporal course:
| Type | Features | Scarring? |
|---|---|---|
| Acute | Malar rash (butterfly rash) | No |
| Subacute | Annular, papulosquamous type (appears as eczema/psoriasis) | No (but may have dyspigmentation) |
| Chronic | Discoid lupus | Yes — scarring, follicular plugging, scarring alopecia |
This is critical for management decisions:
| Class | Description | Key Features |
|---|---|---|
| I | Minimal mesangial | Normal LM, mesangial IC deposits on IF/EM |
| II | Mesangial proliferative | Mesangial hypercellularity |
| III | Focal proliferative | < 50% glomeruli affected; active ± chronic lesions |
| IV | Diffuse proliferative | ≥ 50% glomeruli affected; most common & most severe |
| V | Membranous | Subepithelial IC deposits; presents as nephrotic syndrome |
| VI | Advanced sclerotic | ≥ 90% glomeruli globally sclerosed; end-stage |
A separate clinical entity — see Section 3.4.
7. Clinical Features
From the GC lecture case [1]:
Salient features of SLE:
- Young female
- Multi-system disease:
- Constitutional symptoms
- Inflammatory polyarthritis
- Skin rashes
- Haemic involvement
- Renal involvement
- Possible triggering factor (e.g. trip to Thailand — UV exposure)
- Autoimmunity — positive autoantibody screen, Coombs' test
- Immune complex disease — lowered complement levels
- Fever, weight loss, poor appetite [2]
- Fatigue (extremely common, often the most debilitating symptom)
- Malaise, generalised weakness
Pathophysiological basis: Systemic inflammation drives cytokine production (TNF-α, IL-1, IL-6) → constitutional symptoms. Fever in SLE can be due to disease activity itself (lupus fever) OR infection (always exclude infection first because these patients are often immunosuppressed).
7.2 Cutaneous Manifestations
- Erythematous maculopapular rash in butterfly distribution over the cheeks and bridge of nose, sparing the nasolabial fold [2]
- Usually no scarring [2]
- This is an acute cutaneous lupus lesion
- Why does it spare the nasolabial fold? The nasolabial folds are relatively protected from UV exposure (they are in a natural shadow), and the malar rash is UV-triggered
- Photosensitivity [2] — an exaggerated skin response to UV light
- Mechanism: UV radiation → keratinocyte apoptosis → release of nuclear antigens (dsDNA, Ro, La) onto the cell surface → autoantibody binding → immune complex formation → local inflammation
- This is why sun avoidance and photoprotection are cornerstones of SLE management
- Raised erythema with scaling, follicular plugging and scarring [2]
- This is a chronic cutaneous lupus lesion
- Can occur with or without systemic lupus
- Scarring alopecia results from discoid lesions on the scalp (destruction of hair follicles)
- Non-scarring alopecia [2]
- Diffuse hair thinning, "lupus hair" (short broken hairs along the frontal hairline)
- Mechanism: Inflammation around hair follicles without destruction → reversible hair loss (unlike discoid lupus which is scarring)
- Oral/nasal ulcers (usually painless) [2] — an important differentiator: SLE oral ulcers are typically painless (in contrast to aphthous ulcers which are painful). They tend to occur on the hard palate
- Nail changes: periungual infarcts, splinter haemorrhages [2] — from small vessel vasculitis/thrombosis
- Palmar erythema [2]
- Vasculitis rash (purpura) [2] — palpable purpura from small vessel leukocytoclastic vasculitis
- Livedo reticularis [2] — a reticular (net-like) purplish discoloration of the skin, often associated with antiphospholipid syndrome [7]
- Subcutaneous nodules (5%) [2] — lupus profundus/panniculitis
- Raynaud's phenomenon (20%) [2] — episodic vasospasm of digital arteries: white (ischaemia) → blue (cyanosis) → red (reperfusion). Caused by immune-mediated endothelial damage and vasospasm
- Joint involvement occurs in ~90% of SLE patients [2] — the most common manifestation overall
- Symmetrical non-erosive small joint polyarthritis resembling RA [2]
- Key difference from RA: lupus arthritis is non-erosive (no joint destruction on X-ray). RA causes erosive arthritis
- If deformed: Jaccoud arthropathy (involves ligament and peri-articular soft tissue) [2] — this is a reducible deformity (unlike RA deformities which are fixed), caused by ligamentous laxity rather than bone erosion
- Myalgia: inflammatory myositis (less common) vs drug-induced (steroid, statin, HCQ) [2]
- AVN (avascular necrosis) of hip: active disease, steroid-induced [2]
- Mechanism: High-dose corticosteroids → fat embolism in subchondral vessels + osteocyte apoptosis → bone infarction
- Osteoporosis [2]:
- Disease-related: lack of sun exposure (patients avoid UV), renal osteodystrophy (from lupus nephritis)
- Treatment-related: steroid use, cyclophosphamide (causes premature menopause → oestrogen deficiency)
Jaccoud Arthropathy
Jaccoud arthropathy is a non-erosive, reducible deformity — the deformities look like RA (ulnar deviation, swan-neck, boutonnière) but they can be passively corrected and X-rays show NO erosions. Think of it as "the arthritis that mimics RA but doesn't destroy bone." This is because the damage is in the peri-articular soft tissues (tendons, ligaments), not in the joint itself.
- One of the most important organ involvements — determines prognosis
- Renal involvement was highlighted as a salient feature [1]
- Nephritic presentation: haematuria, proteinuria, hypertension, oedema [9]
- Nephrotic presentation (especially Class V membranous): heavy proteinuria, hypoalbuminaemia, oedema, hyperlipidaemia
- Mixed nephritic-nephrotic picture is common
- Class IV (diffuse proliferative) is the most common and most severe form
- Serositis in lupus can contribute to ascites and pleural effusion — but note these cannot be explained by nephrotic syndrome alone [6]
Pathophysiological basis: Anti-dsDNA antibodies form immune complexes → deposit in glomeruli (subendothelial in proliferative types, subepithelial in membranous type) → complement activation → inflammation → glomerular damage. The location of immune complex deposition determines the class and clinical presentation.
- Haemic involvement [1]
- These are primarily Type II HSR — autoantibodies directly targeting blood cells:
- Haemolytic anaemia (Coombs' positive / direct antiglobulin test positive) — anti-RBC antibodies
- Thrombocytopenia — anti-platelet antibodies (can present as bleeding, purpura)
- Leukopenia/lymphopenia — anti-lymphocyte antibodies; lymphopenia is very common and correlates with disease activity
- Positive Coombs' test was identified as a salient autoimmune feature in the GC lecture [1]
- Anaemia in SLE can also be from:
- Anaemia of chronic disease (most common cause of anaemia in SLE)
- Iron deficiency (from chronic disease, NSAID-related GI bleeding)
- Renal anaemia (from lupus nephritis → reduced EPO)
- Pleuritis → pleuritic chest pain, pleural effusion (usually exudative)
- Pericarditis → pericardial chest pain, pericardial effusion (most common cardiac manifestation)
- Peritonitis → abdominal pain, ascites (sterile)
- Mechanism: Immune complex deposition on serosal surfaces → complement activation → inflammation → fluid exudation
- Pericarditis — most common cardiac manifestation (see above)
- Myocarditis — can cause heart failure, arrhythmias
- Libman-Sacks endocarditis — sterile verrucous vegetations, typically on the mitral valve (ventricular surface). Associated with antiphospholipid syndrome. Usually asymptomatic but can cause valvular regurgitation or serve as a nidus for infective endocarditis
- Accelerated atherosclerosis — SLE patients have greatly increased cardiovascular risk. Mechanism: chronic inflammation → endothelial dysfunction + corticosteroid use → dyslipidaemia + premature atherosclerosis. Cardiovascular disease is a leading cause of death in SLE patients who survive the first 5 years
- Raynaud's phenomenon (see Skin section above)
- Pleuritis/pleural effusion (most common pulmonary manifestation)
- Acute lupus pneumonitis — rare but severe; presents like pneumonia with dyspnoea, cough, fever, infiltrates
- Chronic interstitial lung disease — uncommon in SLE (more common in SSc and MCTD)
- Shrinking lung syndrome — diaphragmatic dysfunction due to myopathy/phrenic nerve involvement → progressive dyspnoea with elevated hemidiaphragm but clear lung fields
- Pulmonary hypertension — from chronic thromboembolic disease (especially with antiphospholipid syndrome), vasculitis, or interstitial lung disease
- Diffuse alveolar haemorrhage — rare, life-threatening; presents with haemoptysis, dyspnoea, falling haemoglobin
- Can affect both central and peripheral nervous system
- CNS: seizures, psychosis (lupus cerebritis), cognitive dysfunction, headache, cerebrovascular disease (especially with antiphospholipid syndrome), transverse myelitis, aseptic meningitis, cranial neuropathies
- PNS: peripheral neuropathy, mononeuritis multiplex, myasthenia gravis (overlap)
- Anti-ribosomal P antibodies are associated with CNS lupus, particularly psychosis and depression
- Mechanism: Multifactorial — anti-neuronal antibodies, immune complex deposition in choroid plexus and cerebral vasculature, thrombosis (especially with antiphospholipid syndrome), vasculitis
- CNS involvement is one of the major organ involvements in idiopathic SLE (but rare in drug-induced lupus) [2]
- Oral ulcers (usually painless — see Skin section)
- Mesenteric vasculitis → abdominal pain, can progress to bowel ischaemia/infarction
- Lupus peritonitis → sterile ascites
- Protein-losing enteropathy
- Pancreatitis (rare, can be disease-related or drug-related)
- Hepatomegaly (lupoid hepatitis is a separate entity — autoimmune hepatitis — and is NOT the same as hepatic lupus)
- Keratoconjunctivitis sicca (dry eyes) — secondary Sjögren's syndrome overlap
- Retinal vasculitis — cotton-wool spots (retinal ischaemia), hard exudates
- Optic neuritis
- Hydroxychloroquine retinal toxicity — important iatrogenic cause; requires regular ophthalmological screening
Antiphospholipid syndrome is an important associated condition in SLE (secondary APS) [7]:
- An autoimmune condition that causes the production of antibodies against phospholipid-binding proteins [7]
- Antibodies: anti-cardiolipin (IgG/IgM), anti-β2-glycoprotein I, lupus anticoagulant [7]
- Clinical manifestations [7]:
- Recurrent arterial (stroke, MI) and venous (DVT, PE) thrombosis
- Livedo reticularis
- Recurrent fetal loss/miscarriage
- Thrombocytopenia
- Lupus anticoagulant / antiphospholipid syndrome → classical example of risk factor that can increase risk of both arterial and venous thrombosis [7]
- Diagnosis (Sapporo criteria): Demonstration of circulating antibody (positive for any of the 3), at least 12 weeks apart, PLUS characteristic clinical manifestation [7]
Lupus Anticoagulant Paradox
A common exam trap: Despite its name, lupus anticoagulant is PRO-thrombotic, not anticoagulant. The name comes from the fact that it prolongs the aPTT in vitro (because it interferes with the phospholipid-dependent coagulation assay in the test tube), but in vivo it promotes thrombosis by activating endothelium and platelets.
- Hashimoto's thyroiditis is often associated with other autoimmune diseases including SLE [10]
- SLE patients should be screened for other autoimmune conditions: Sjögren's syndrome, autoimmune thyroid disease, autoimmune hepatitis, pernicious anaemia
| System | Symptoms | Signs | Pathophysiology |
|---|---|---|---|
| Constitutional | Fever, fatigue, weight loss, poor appetite | Cachexia | Systemic cytokine release (TNF-α, IL-1, IL-6) |
| Skin (Acute) | Facial rash worsened by sun | Malar butterfly rash sparing nasolabial fold | UV-induced keratinocyte apoptosis → IC deposition |
| Skin (Subacute) | Annular/papulosquamous rash | Annular lesions with central clearing | Anti-Ro mediated; UV-triggered |
| Skin (Chronic) | Scarring skin lesions, hair loss | Discoid rash: scaling, follicular plugging, scarring | Chronic IC deposition → fibrosis |
| Skin (Other) | Painless mouth sores, cold fingers | Oral ulcers (hard palate), Raynaud's, livedo reticularis, palmar erythema, periungual infarcts | Vasculitis, vasospasm, IC deposition |
| MSK | Joint pain/swelling, muscle pain | Non-erosive polyarthritis, Jaccoud arthropathy | IC deposition in synovium; ligamentous laxity |
| Renal | Oedema, frothy urine, reduced urine output | Hypertension, peripheral oedema | IC deposition in glomeruli → nephritis |
| Haematological | Easy bruising, bleeding, fatigue, recurrent infections | Pallor, purpura, lymphadenopathy | Type II HSR: anti-cell antibodies → cytopenias |
| Serosal | Chest pain (pleuritic/pericardial), abdominal pain | Pleural/pericardial rub, effusions, ascites | IC deposition on serosal surfaces |
| Cardiovascular | Chest pain, dyspnoea | Murmur (Libman-Sacks), pericardial rub | IC deposition, accelerated atherosclerosis |
| Pulmonary | Dyspnoea, cough, haemoptysis | Pleural effusion, crackles, elevated hemidiaphragm | Pleuritis, pneumonitis, DAH, shrinking lung |
| Neuropsychiatric | Headache, seizures, psychosis, cognitive dysfunction | Focal neurological deficits, cranial nerve palsies | Anti-neuronal Ab, IC deposition, vasculitis, thrombosis |
| Ophthalmological | Dry eyes, visual changes | Cotton-wool spots, keratoconjunctivitis sicca | Vasculitis, Sjögren's overlap, HCQ toxicity |
| GI | Painless mouth sores, abdominal pain, nausea | Oral ulcers, hepatomegaly, ascites | Vasculitis, serositis, peritonitis |
A systematic approach to examining an SLE patient:
- General inspection: Cushingoid facies (steroid side effect), cachexia, pallor
- Hands: Raynaud's changes, periungual infarcts, splinter haemorrhages, Jaccoud arthropathy, palmar erythema, joint swelling (MCP, PIP)
- Face: Malar rash (butterfly distribution, sparing nasolabial fold), discoid lesions, alopecia ("lupus hair" at frontal hairline)
- Mouth: Painless oral ulcers (inspect hard palate)
- Eyes: Dry eyes (Sjögren's), retinal changes (fundoscopy)
- Neck: Lymphadenopathy, thyroid (associated autoimmune thyroid disease)
- Chest: Pleural rub, decreased breath sounds (effusion), pericardial rub
- Heart: Murmur (Libman-Sacks endocarditis — usually mitral regurgitation)
- Abdomen: Hepatosplenomegaly, ascites
- Lower limbs: Oedema (nephrotic syndrome, nephritic syndrome, heart failure), purpura, livedo reticularis, DVT signs (if APS)
- Neurological: Cranial nerve examination, motor/sensory examination, cognitive assessment
- Blood pressure: Hypertension (lupus nephritis)
High Yield Summary
Definition: SLE is a chronic multisystem autoimmune disorder characterised by autoantibody production and immune complex deposition → tissue damage. The failure to remove ICs is the most important pathological mechanism.
Epidemiology: F:M = 9:1, peak age 20s–40s, more common and more severe in Asians and Blacks than Caucasians.
Risk Factors: Genetic (HLA-DR2/DR3, complement deficiency), hormonal (oestrogen), environmental (UV light, EBV, drugs).
Drug-Induced Lupus: HIP (Hydralazine, Isoniazid, Procainamide) → anti-histone Ab, M=F, lung/joint involvement, resolves on stopping drug, NO renal/CNS involvement.
Pathophysiology: Loss of self-tolerance → autoantibodies → Type II HSR (cytopenias) + Type III HSR (IC deposition → nephritis, vasculitis, serositis). Defective IC clearance perpetuates the cycle.
Key Autoantibodies: ANA (screening, sensitive), anti-dsDNA (specific, correlates with activity, associated with nephritis), anti-Sm (most specific), anti-Ro (subacute CLE, neonatal lupus), anti-histone (drug-induced lupus).
Clinical Features: Constitutional (fever, fatigue, weight loss), Skin (malar rash sparing nasolabial fold, photosensitivity, discoid lupus, oral ulcers, alopecia, Raynaud's), MSK (non-erosive polyarthritis, Jaccoud arthropathy), Renal (lupus nephritis — Class IV is most common and severe), Haematological (Coombs' +ve haemolytic anaemia, thrombocytopenia, lymphopenia), Serosal (pleuritis, pericarditis), CVS (Libman-Sacks, accelerated atherosclerosis), Neuro (seizures, psychosis, stroke), APS (thrombosis, miscarriage, livedo reticularis).
Cutaneous Lupus Classification: Acute (malar rash), Subacute (annular/papulosquamous, anti-Ro), Chronic (discoid — scarring).
Lupus Nephritis: Class I–VI. Class IV (diffuse proliferative) is most common and most severe. Activity index high → aggressive immunosuppression. Chronicity index high → conservative.
Active Recall - Systemic Lupus Erythematosus (Definition to Clinical Features)
[1] Lecture slides: GC 046. Facial rash and painful fingers_SLE.pdf (Definition slide, Salient features slide, Title slide) [2] Senior notes: Maksim Medicine Notes.pdf (Rheumatology section — SLE) [3] Senior notes: Ryan Ho Rheumatology.pdf (Section 3.1 — Systemic Lupus Erythematosus) [4] Senior notes: Ryan Ho Rheumatology.pdf (Risk factors, drugs table, pathogenesis) [5] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (SLE — Overview, Epidemiology, Etiology) [6] Senior notes: Block A - Syncope and irregular heartbeat_ Cardiac arrhythmia; Heart blocks, Bradycardia.pdf (Lupus clinical pearls) [7] Senior notes: Block A - Leg swelling and chest pain_ deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (Antiphospholipid syndrome section) [8] Senior notes: Block A - Dermatology PBL 2.pdf (Case 18 — Cutaneous lupus classification) [9] Senior notes: Block A - Nephrology Interactive Tutorial.pdf (Case 1 — Acute nephritis syndrome) [10] Senior notes: Block A - I am losing weight and sweating all the time_ causes of severe, weight loss; thyrotoxicosis; hypothyroidism.pdf (Hashimoto's associations)
Differential Diagnosis of SLE
The differential diagnosis of SLE is challenging precisely because it is a multi-system disease — the presenting complaint dictates which differentials you must consider. A patient presenting primarily with polyarthritis will have a different DDx list from one presenting with nephritis or with a facial rash. The key is to think by presenting syndrome, then narrow down.
Before listing specific conditions, let's understand the logical framework. When you suspect SLE, you are usually looking at a combination from the GC lecture salient features [1]:
Young female with multi-system disease (constitutional symptoms, inflammatory polyarthritis, skin rashes, haemic involvement, renal involvement), positive autoantibody screen, Coombs' test positive, and lowered complement levels
The differential therefore depends on which features dominate. Think of it in layers:
2. Differential Diagnosis by Presenting Syndrome
When a patient presents with symmetrical small joint polyarthritis, the key DDx is SLE vs RA. This is a favourite exam comparison [2][3]:
| Feature | SLE | RA |
|---|---|---|
| Myalgia | Common | Myositis |
| Symmetry | Yes | Yes |
| Arthralgia | Common | Common |
| Deforming | Rare | Common |
| Joints involved | PIP > MCP > Wrist > Knee | MCP > Wrist > Knee |
| Morning stiffness | Minutes | Hours |
| Synovial membrane | Minimal abnormality | Proliferative |
| Synovial fluid | Transudate | Exudate |
| Synovial hypertrophy | Rare | Common |
| Subcutaneous nodules | Rare | Common |
| Erosions | Rare | Common |
| Swan neck deformities | Rare (reducible) | Common (not reducible) |
| Ulnar deviation | Rare (reducible) | Common (not reducible) |
| Osteoporosis | Variable | Common |
| Avascular necrosis | Common | Rare |
Why is SLE arthritis non-erosive while RA is erosive? In RA, there is florid synovial proliferation (pannus formation) that directly invades and destroys cartilage and bone. In SLE, the synovial inflammation is much milder — the immune complex deposition causes inflammation but does NOT form a destructive pannus. The deformities in SLE (Jaccoud arthropathy) arise from ligamentous laxity and periarticular soft tissue involvement, not from bony destruction — hence they are reducible [2][3][4].
Other polyarthritis DDx [4][5]:
- Viral polyarthritis: HBV, HCV, parvovirus B19, EBV, Dengue, rubella — symmetrical small joint arthritis ± rash and prodromal illness, usually self-limiting within ≤6 weeks [5]
- Psoriatic arthritis: Usually asymmetrical oligoarthritis or symmetrical polyarthritis; diagnosed in patients who have psoriasis and are seronegative for RF and anti-CCP [3]
- Crystal arthritis: Gout/pseudogout — usually monoarticular/oligoarticular; confirmed by crystals in synovial fluid [3]
- Reactive arthritis: Monoarthritis or oligoarthritis, asymmetrical, history of recent urethritis or enteric infection [3]
- Septic arthritis: Usually monoarticular (polyarthritis can occur); diagnosed by culturing pathogen from synovial fluid [3]
Exam Pearl: SLE vs RA Arthritis
The quick distinguishing features: SLE arthritis has minimal morning stiffness (minutes), is non-erosive, and deformities are reducible. RA has prolonged morning stiffness (hours), is erosive on X-ray, and deformities are fixed. SLE arthritis produces a transudate synovial fluid (mild inflammation); RA produces an exudate (florid synovial inflammation).
2.2 Other Connective Tissue Diseases (CTDs) — The "ANA-Positive Multi-System" DDx
When a patient has multi-system features with positive ANA, the DDx includes the other CTDs. These are the conditions most commonly confused with SLE [2][3]:
- Coexistence of Raynaud phenomenon and GERD are typically observed in systemic sclerosis [2][3]
- Expresses anti-Scl-70 (topoisomerase I — diffuse cutaneous SSc) or anti-centromere Ab (limited cutaneous SSc / CREST) [2][3]
- Key distinguishing features: Skin thickening/sclerosis (not rash), severe Raynaud's with digital ulcers/gangrene, ILD, pulmonary hypertension, GI dysmotility. SLE has rashes (malar, discoid) but NOT skin thickening [6]
- SSc presents insidiously without a trigger, cf. SLE which often has identifiable triggers (UV, infection, drugs) [6]
- Presents with objective signs of keratoconjunctivitis sicca and xerostomia (dry eyes, dry mouth) [2][3]
- Expresses anti-Ro/SSA and anti-La/SSB [2][3]
- Overlap: Anti-Ro/SSA and anti-La/SSB can also be positive in SLE (these are not specific for Sjögren's) [7]. The distinction is that Sjögren's has prominent sicca symptoms as the primary feature, whereas in SLE, sicca is secondary/minor
- Both Sjögren's and SLE can cause distal RTA (Type 1 — inability to excrete H+ → hypokalaemia, non-anion-gap metabolic acidosis, nephrocalcinosis) [8]
- Oral aphthae are present in almost all patients with Behçet's syndrome [2][3]
- Other overlapping features include inflammatory eye disease, neurological disease, vascular disease and arthritis [2][3]
- Usually ANA negative [2][3] — this is the critical distinction from SLE. Both cause oral ulcers, but Behçet's ulcers are painful (vs SLE ulcers which are typically painless)
- Behçet's also has pathergy (exaggerated skin injury response to needle prick) and genital ulcers
- More overt proximal muscle weakness [2][3] — this is the defining feature. SLE can have myalgia/mild myopathy, but frank proximal weakness with markedly elevated CK points to DM/PM
- Dermatomyositis has characteristic skin findings including Gottron's papules, heliotrope eruption and photodistributed poikiloderma [2][3]
- Overlap with SLE: Both can have photosensitivity and ANA positivity. Key distinction — Gottron's papules affect the dorsum of the MCP/PIP joints (vs SLE which affects the skin between the joints). The heliotrope rash affects the eyelids (vs malar rash in SLE which spares the eyelids)
- Features of SLE + SSc + PM/DM in the same patient
- Characterised by anti-U1 RNP antibodies (high titre)
- Prominent Raynaud's, swollen "sausage" fingers, myositis, ILD
- Distinguished from SLE by the overlap pattern and high-titre anti-RNP without anti-dsDNA or anti-Sm
When the malar rash is the dominant presenting feature:
| Condition | Key Distinguishing Feature |
|---|---|
| SLE malar rash | Spares nasolabial fold, photosensitive, associated multi-system features |
| Rosacea | Does NOT spare nasolabial fold, papules/pustules, telangiectasia, no systemic features, ANA negative |
| Seborrhoeic dermatitis | Involves nasolabial fold, greasy scales, no systemic features |
| Contact dermatitis | History of allergen/irritant exposure, distribution follows contact pattern |
| Dermatomyositis | Heliotrope rash (eyelids), Gottron's papules (dorsum MCP/PIP), proximal weakness |
| Psoriasis | Well-defined silvery plaques, extensor surfaces, nail pitting |
For subacute cutaneous lupus (annular/papulosquamous lesions), the DDx includes eczema, psoriasis, and tinea corporis (annular with central clearing). The annular patch with central clearing pattern can mimic fungal infection, but the ANA positivity and anti-Ro association distinguish it [9].
For discoid lupus, the DDx includes lichen planus, hypertrophic lupus, and cutaneous lymphoma.
Cutaneous lupus vs systemic lupus are different manifestations. A patient can have pure cutaneous lupus without systemic lupus [9].
When lupus nephritis is the presenting feature (haematuria, proteinuria, hypertension, oedema), the DDx of glomerulonephritis must be considered. Serum complement levels are critical for narrowing the DDx [11][12][13]:
| Low complement (↓C3/C4) | Normal complement |
|---|---|
| IC-mediated GN: | Non-IC-mediated GN: |
| MPGN | PAN |
| PSGN | Goodpasture's (anti-GBM disease) |
| Lupus nephritis | HSP / IgA nephropathy |
| Cryoglobulinaemia | ANCA-related renal vasculitis |
| IE and shunt nephritis |
Why does lupus nephritis cause low complement? Because immune complex formation activates the classical complement pathway, consuming C3 and C4. In contrast, ANCA-associated vasculitis is pauci-immune (no significant IC deposition → complement is normal) [11][12].
The diagnostic approach from the nephrology lectures [11][12][13]:
Suggestive clinical findings:
- Relationship with URTI: URTI 7–10 days before (PSGN) or concurrently (IgAN)
- Palpable purpura/petechial rash → suggests vasculitis
- Haemoptysis → suggests pulmonary haemorrhage (pulmonary vasculitis)
- Triad of sinusitis, pulmonary infiltrates and nephritis → suggests Wegener's (GPA)
- Characteristic rash and arthritis → suggests SLE [11][12]
Key serological workup for nephritic syndrome [11][12]:
- ANA, anti-dsDNA → for lupus nephritis
- ANCA and its subtypes → for ANCA-vasculitis
- Anti-GBM autoantibodies → for anti-GBM disease (Goodpasture's)
- ASLO → for PSGN (confirms recent streptococcal infection)
- Anti-HCV, HBV → for HBV/HCV-related MPGN
- Cryocrit → for cryoglobulinaemia
- Blood culture → for infective endocarditis
SLE can also cause a nephrotic picture (especially Class V membranous lupus nephritis). In the nephrotic DDx, SLE is listed among the secondary causes of membranous nephropathy (along with HBV, HCV, malignancy, drugs) [14][15].
When cytopenias dominate (e.g. thrombocytopenia, haemolytic anaemia):
- Idiopathic thrombocytopenic purpura (ITP): Can be the first presentation of SLE — always check ANA in a young woman with ITP
- Thrombotic thrombocytopenic purpura (TTP) / Haemolytic uraemic syndrome (HUS): Microangiopathic haemolytic anaemia (MAHA) with thrombocytopenia. SLE is listed as a cause of secondary TMA [16]
- Evans syndrome: Simultaneous autoimmune haemolytic anaemia + ITP — can occur in SLE
- Aplastic anaemia, leukaemia, lymphoma: Pancytopenia with different bone marrow findings
- Antiphospholipid syndrome (APS): Can cause thrombocytopenia + thrombosis. Remember, APS may occur as a primary condition or secondary to SLE [17]
When pleuritis or pericarditis is the presenting feature:
- Tuberculosis: Very important in Hong Kong — TB pleuritis and TB pericarditis are common
- Malignancy: Lung cancer, breast cancer, lymphoma
- Other CTDs: RA (pleuritis), SSc
- Viral pericarditis / pleuritis
- Uraemic pericarditis / pleuritis (if concurrent renal failure)
Other conditions that can mimic multi-system SLE:
- Sarcoidosis: Multi-system granulomatous disorder with arthralgia, skin lesions (erythema nodosum, lupus pernio), lymphadenopathy, lung involvement, hypercalcaemia, elevated ACE. Key difference: non-caseating granulomas on biopsy, and specific autoantibody profile of SLE is absent [18]
- Adult-onset Still's disease: Quotidian fever, salmon-coloured evanescent rash, arthritis, serositis, ferritin markedly elevated, ANA usually negative
- Lymphoma: Can mimic SLE with fever, lymphadenopathy, cytopenias, constitutional symptoms
- Infective endocarditis: Fever, murmur, cytopenias, immune complex–mediated GN (can cause low complement), positive blood cultures distinguish it
- Systemic vasculitis: GPA, MPA, EGPA — overlap with renal and pulmonary involvement but have ANCA positivity and specific histological patterns
Always consider drug-induced lupus in the DDx of SLE [2][19]:
- Ask about exposure to procainamide, hydralazine, isoniazid and other culprit drugs
- Key distinguishing features: M:F = 1:1, anti-histone antibodies (not anti-dsDNA), lung and joint involvement (NOT renal or CNS), resolves within days–weeks on stopping the drug [2]
| Condition | Key distinguishing feature from SLE |
|---|---|
| RA | Erosive arthritis, prolonged morning stiffness, RF/anti-CCP +ve, synovial hypertrophy |
| SSc | Skin thickening (not rash), severe Raynaud's, GERD, anti-Scl-70/ACA |
| Sjögren's | Prominent sicca symptoms (dry eyes, dry mouth), anti-Ro/La |
| Behçet's | Painful oral ulcers (not painless), genital ulcers, pathergy, ANA negative |
| DM/PM | Proximal muscle weakness, Gottron's papules, heliotrope rash, elevated CK |
| MCTD | Overlap features, high-titre anti-U1 RNP |
| Drug-induced lupus | Drug history, anti-histone, no renal/CNS, resolves on stopping drug |
| Sarcoidosis | Non-caseating granulomas, elevated ACE, hypercalcaemia |
| Adult-onset Still's | Quotidian fever, salmon rash, very high ferritin, ANA negative |
| PSGN | Recent streptococcal infection, low C3, ASLO +ve, resolves spontaneously |
| ANCA vasculitis | ANCA +ve, pauci-immune GN, normal complement |
| APS (primary) | Thrombosis/miscarriage without other SLE features, aPL antibodies |
When an established SLE patient deteriorates, consider whether it is a flare or a new/superimposed condition (especially infection — these patients are immunosuppressed) [2][3]:
Precipitating factors for relapse [2][3]:
- Drug non-compliance (most common)
- Infection
- Stress (physical including surgery, psychological)
- Pregnancy
- Drug-induced
- UV light exposure
Flare vs Infection in SLE
This is a critical clinical dilemma. Both SLE flare and infection cause fever, elevated ESR, and malaise. Key distinctions: Active SLE doesn't usually evoke ↑CRP — if CRP is markedly elevated, think infection. However, CRP may rise in active SLE arthritis, serositis, or vasculitis [17]. Low complement and rising anti-dsDNA titre favour flare. Procalcitonin may help distinguish infection from flare. Always obtain cultures before escalating immunosuppression.
High Yield Summary — Differential Diagnosis of SLE
-
DDx depends on the dominant presenting syndrome: polyarthritis, skin rash, nephritis, cytopenias, serositis, or multi-system inflammation.
-
SLE vs RA (most common exam comparison): SLE arthritis is non-erosive, minimal morning stiffness (minutes), reducible deformities, transudate synovial fluid. RA is erosive, prolonged morning stiffness (hours), fixed deformities, exudate.
-
Other CTDs: SSc (skin thickening, GERD, anti-Scl-70), Sjögren's (sicca, anti-Ro/La), Behçet's (painful oral ulcers, ANA −ve), DM/PM (proximal weakness, Gottron's, heliotrope).
-
Nephritis DDx: Use complement levels to narrow — ↓C3/C4 = IC-mediated GN (lupus, PSGN, MPGN, cryoglobulinaemia, IE). Normal C3/C4 = pauci-immune/non-IC (ANCA vasculitis, anti-GBM, IgAN/HSP).
-
Drug-induced lupus: HIP drugs, anti-histone Ab, M=F, no renal/CNS, resolves on stopping drug.
-
Flare vs infection: CRP markedly elevated → think infection. Low complement + rising anti-dsDNA → think flare.
Active Recall - Differential Diagnosis of SLE
References
[1] Lecture slides: GC 046. Facial rash and painful fingers_SLE.pdf (Salient features slide) [2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (SLE — Differential diagnosis, SLE vs RA table) [3] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (SLE — Differential diagnosis, SLE vs RA table) [4] Senior notes: Ryan Ho Rheumatology.pdf (Section 3.1 — Clinical features, arthritis) [5] Senior notes: Ryan Ho Fundamentals.pdf (Section 3.7.2 — Polyarthritis differential) [6] Senior notes: Ryan Ho Rheumatology.pdf (Section 3.2.3 — Systemic Sclerosis) [7] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Sjögren's — Autoantibodies) [8] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (Distal RTA — SLE and Sjögren's) [9] Senior notes: Block A - Dermatology PBL 2.pdf (Case 18 — Cutaneous lupus classification) [10] Senior notes: Maksim Medicine Notes.pdf (Cutaneous lupus erythematosus — ACLE vs CCLE) [11] Senior notes: Adrian Lui Pediatrics Notes.pdf (Evaluation of nephritic syndrome — complement levels, serology) [12] Senior notes: Ryan Ho Urogenital.pdf (Evaluation of nephritic syndrome — complement levels, serology) [13] Senior notes: Block A - Nephrology Interactive Tutorial.pdf (Case 1 — Acute nephritis syndrome) [14] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (Secondary nephrotic syndrome causes) [15] Lecture slides: Glomerular diseases.pdf (Secondary forms of MN) [16] Senior notes: Ryan Ho Haemtology.pdf (TMA — secondary causes including SLE) [17] Senior notes: Ryan Ho Rheumatology.pdf (APS, SLE diagnostic workup — CRP in active SLE) [18] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Sarcoidosis — ILD differential) [19] Senior notes: Maksim Medicine Notes.pdf (Drug-induced lupus table)
Diagnostic Criteria, Algorithm, and Investigations for SLE
Understanding why classification criteria exist and how they evolved is important. Classification criteria are designed primarily for research — to ensure study populations are homogeneous — but in practice they are widely used to support clinical diagnosis. The learning objectives from the GC lecture explicitly state: "Evolution of the classification criteria of SLE based on: systemic disease, common disease manifestations, demonstration of autoimmunity" [20].
There are three major classification systems to be aware of. The most current and the one examined at HKUMed is the 2019 EULAR/ACR criteria.
2. The 2019 EULAR/ACR Classification Criteria (Current Standard)
Classification criteria: EULAR/ACR criteria 2019 [2]:
- 7 Clinical domains + 3 immunological domains
- SLE if ANA positive + total score of ≥10
ANA ≥ 1:80 (on HEp-2 cells or equivalent) at least once — this is the mandatory entry gate. If ANA is negative, you do NOT proceed further with these criteria.
Why ANA as entry criterion? ANA is the most sensitive test for SLE (~95–99%). A negative ANA effectively rules out SLE in most cases. However, ANA is not specific (positive in many conditions including other CTDs, infections, medications, and even healthy elderly). That's why it is the entry gate — sensitive enough to catch almost all cases — but the additive weighted scoring system then ensures specificity.
GC Exam High Yield
ANA positive is the mandatory entry criterion. If ANA is negative, the patient does NOT meet criteria for SLE classification by 2019 EULAR/ACR. However, in clinical practice, there are rare ANA-negative SLE cases (up to ~5%), particularly those positive for anti-Ro/SSA only. The criteria acknowledge this limitation.
Once ANA is positive, the patient is scored across 10 domains (7 clinical + 3 immunological). Each criterion within a domain is assigned a weight. Only the highest-weighted criterion within each domain is counted (you don't double-count within a domain). A total score ≥ 10 classifies the patient as SLE.
| Domain | Criterion | Weight |
|---|---|---|
| Constitutional | Fever ( > 38.3°C) | 2 |
| Haematological | Leukopenia ( < 4.0 × 10⁹/L) | 3 |
| Thrombocytopenia ( < 100 × 10⁹/L) | 4 | |
| Autoimmune haemolysis | 4 | |
| Neuropsychiatric | Delirium | 2 |
| Psychosis | 3 | |
| Seizure | 5 | |
| Mucocutaneous | Non-scarring alopecia | 2 |
| Oral ulcers | 2 | |
| Subacute cutaneous OR discoid lupus | 4 | |
| Acute cutaneous lupus | 6 | |
| Serosal | Pleural or pericardial effusion | 5 |
| Acute pericarditis | 6 | |
| Musculoskeletal | Joint involvement (≥ 2 joints with synovitis, OR tenderness + morning stiffness ≥ 30 min) | 6 |
| Renal | Proteinuria > 0.5 g/24h | 4 |
| Renal biopsy Class II or V lupus nephritis | 8 | |
| Renal biopsy Class III or IV lupus nephritis | 10 | |
| Anti-phospholipid antibodies | Anti-cardiolipin OR anti-β2GP1 OR lupus anticoagulant | 2 |
| Complement | Low C3 OR low C4 | 3 |
| Low C3 AND low C4 | 4 | |
| SLE-specific antibodies | Anti-dsDNA OR anti-Sm | 6 |
Key points on interpretation:
- Class III or IV lupus nephritis on biopsy alone scores 10 — meeting the threshold by itself (with positive ANA)
- Anti-dsDNA or anti-Sm scores 6 — reflects their high specificity for SLE
- Joint involvement scores 6 — reflects how common and characteristic it is
- Within the haematological domain, if a patient has both thrombocytopenia (4) and leukopenia (3), only the highest score (4) is counted
- Each criterion should be attributed to SLE (not to another cause) — this is a critical principle
For every criterion, you must ensure it is not better explained by another cause. For example:
- Fever must not be from infection
- Oral ulcers must not be from Behçet's, herpes, IBD [3][4]
- Serositis must not be from infection, uraemia, or Dressler's syndrome [3][4]
- Alopecia must not be from alopecia areata, drugs, iron deficiency, or androgenic alopecia [3][4]
The SLICC criteria are still referenced in many senior notes and may appear in exams [3][4]:
4 out of 17 criteria including at least 1 clinical criterion and 1 immunological criterion (OR) Biopsy-proven lupus nephritis with +ve ANA or anti-dsDNA [3][4]
| # | Criterion | Key Details |
|---|---|---|
| 1 | Acute cutaneous lupus | Malar rash (butterfly rash) — do NOT count if malar discoid, photosensitive lupus rash (in absence of dermatomyositis), maculopapular lupus rash, bullous lupus, TEN-like variant. Also subacute cutaneous lupus (annular polycyclic lesion, psoriaform) |
| 2 | Chronic cutaneous lupus | Discoid rash (localised: above neck; generalised: above + below neck), hypertrophic lupus, lupus panniculitis, lupus tumidus, mucosal lupus, chilblain lupus |
| 3 | Non-scarring alopecia | Diffuse thinning or hair fragility with visible broken hairs |
| 4 | Oral or nasal ulcers | Palate, buccal, tongue or nasal ulcers — in absence of other causes |
| 5 | Joint disease | Synovitis involving ≥ 2 joints (swelling or effusion) OR tenderness in ≥ 2 joints + ≥ 30 min morning stiffness |
| 6 | Serositis | Typical pleurisy ≥ 1 day / pleural effusion / pleural rub OR typical pericardial pain ≥ 1 day (pain with recumbency improved by sitting forward) / pericardial effusion / pericardial rub / pericarditis by ECG |
| 7 | Renal | Urine protein-to-creatinine ratio or 24h urine protein representing 500 mg protein/24h OR Red blood cell casts |
| 8 | Neurological | Seizures, psychosis, mononeuritis multiplex, myelitis, peripheral/cranial neuropathy, acute confusional state |
| 9 | Haemolytic anaemia | Positive DAT (Coombs' test) |
| 10 | Leukopenia/lymphopenia | Leukopenia < 4.0 × 10⁹/L OR lymphopenia < 1.0 × 10⁹/L |
| 11 | Thrombocytopenia | < 100 × 10⁹/L |
6 Immunological criteria [3][4]:
| # | Criterion |
|---|---|
| 1 | ANA |
| 2 | Anti-dsDNA |
| 3 | Anti-Sm |
| 4 | Antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, anti-β2GP1, false-positive VDRL) |
| 5 | Low complement (C3, C4, or CH50) |
| 6 | Direct Coombs' test (in absence of haemolytic anaemia) |
SLICC vs EULAR/ACR 2019
The SLICC criteria have greater sensitivity (97% vs 83%) but lower specificity (84% vs 96%) compared to the older 1997 ACR criteria [17]. The 2019 EULAR/ACR criteria use a weighted additive scoring system which achieves sensitivity ~96% and specificity ~93% — a good balance. The key innovation of the 2019 criteria is the ANA entry criterion and the hierarchical weighting that prevents double-counting correlated features. For exams, know the 2019 EULAR/ACR criteria as the current standard, but be able to discuss SLICC as well.
5. Investigation Modalities: What to Order and Why
5.1 First-Line Screening
- What it tests: Antibodies against various nuclear antigens (detected by immunofluorescence on HEp-2 cells)
- Why it's ordered first: ANA is the screening test — it is the most sensitive marker for SLE (~95–99%) [17]
- Interpretation:
- Positive ANA ( ≥ 1:80): Proceed with further workup
- Negative ANA: SLE is very unlikely (NPV > 95%)
- ANA can be positive in many other conditions: other CTDs, infections, drugs, malignancy, healthy elderly (~15–20% of population over age 60)
- Patterns (of academic interest and occasionally tested):
- Homogeneous: SLE, drug-induced lupus
- Speckled: Anti-Sm, anti-RNP, anti-Ro, anti-La (SLE, MCTD, Sjögren's)
- Nucleolar: Systemic sclerosis
- Centromere: Limited SSc (CREST)
ANA is NOT diagnostic on its own
A positive ANA does NOT equal SLE. It is a screening test with high sensitivity but low specificity. ANA should not be used as the only screening test since 15–40% of patients have negative ANA despite having positive anti-Ro/SSA or anti-La/SSB [7]. Always proceed to confirmatory antibodies and clinical assessment.
- What to look for [17][5]:
- Leukopenia ( < 4.0 × 10⁹/L) — anti-leukocyte antibodies; lymphopenia is particularly characteristic
- Thrombocytopenia ( < 100 × 10⁹/L) — anti-platelet antibodies (Type II HSR)
- Anaemia: Usually normochromic normocytic (anaemia of chronic disease — most common type). If haemolytic → reticulocytosis, ↑LDH, ↑unconjugated bilirubin, ↓haptoglobin, positive Coombs' test [21]
- NcNc anaemia with ↓Hct [11][12]
- ESR: usually increased in active SLE [11][12][5]
- CRP: This is a critical nuance — active SLE doesn't usually evoke markedly ↑CRP [17]. A markedly elevated CRP in an SLE patient should raise suspicion for infection, though CRP may be elevated in active arthritis, serositis or vasculitis [17]. ESR is more reliably elevated with disease activity because it reflects hypergammaglobulinaemia
- Why the ESR-CRP dissociation? In SLE, interferon-α (which is elevated) actually suppresses hepatic CRP production. So active SLE often shows ↑ESR with normal/mildly elevated CRP — a characteristic pattern
- Serum creatinine, urea, eGFR: Document degree of renal impairment [11][12][22]
- Urinalysis: document glomerular haematuria, proteinuria, and sterile pyuria [11][12]
- Dipstick: Haematuria and proteinuria screening
- Urine microscopy: Dysmorphic RBCs and RBC casts confirm glomerular origin of haematuria [23]
- Urine protein quantification: Spot urine protein-to-creatinine ratio (uPCR) or 24h urine protein — gold standard is 24h urine protein but uPCR is more practical [22][24]
- UACR (urine albumin-to-creatinine ratio) — especially for diabetic patients or CKD monitoring [22]
5.2 Confirmatory Autoantibodies
- Target: Double-stranded DNA
- Clinical significance: Specific for SLE; correlates with disease activity (titres rise during flares and fall during remission); strongly associated with lupus nephritis [17]
- ↑Anti-dsDNA titres + ↓C3/C4 indicates active lupus and may imply lupus nephritis [25]
- Monitoring role: Serial anti-dsDNA levels are used to monitor disease activity — a rising titre may predict an impending flare
- Target: Small nuclear ribonucleoprotein (snRNP)
- Most specific antibody for SLE (specificity ~99%), but low sensitivity (~30%)
- Does NOT correlate with disease activity (unlike anti-dsDNA)
This panel typically includes anti-Ro/SSA, anti-La/SSB, anti-RNP, anti-Sm, anti-Scl-70, anti-Jo-1. In the context of SLE:
- Anti-Ro (SSA): Associated with subacute cutaneous lupus, neonatal lupus/congenital heart block, photosensitivity, Sjögren's overlap
- Anti-La (SSB): Usually co-exists with anti-Ro; Sjögren's overlap
- Anti-RNP: High-titre → MCTD; also present in some SLE patients
- Anti-cardiolipin antibodies (IgG or IgM) → measured by immunoassay [26]
- Anti-β2-glycoprotein I → measured by immunoassay [26]
- Lupus anticoagulant → measured by clotting-based assay [26]
- At QMH, lupus anticoagulant is tested using DRVVT (Dilute Russell's Viper Venom Time) [27]
- Lupus anticoagulant classically causes a prolonged aPTT and normal PT [27]
- Must be positive on at least 2 occasions, at least 12 weeks apart for diagnosis of APS [26]
- Detects antibodies or complement bound to the surface of RBCs
- Positive Coombs' test was identified as a salient feature [1]
- Interpretation: Positive DAT in the setting of anaemia + reticulocytosis + ↑LDH + ↓haptoglobin = autoimmune haemolytic anaemia (AIHA)
- Note: Some healthy individuals have a positive DAT without haemolysis — the pre-test probability must be considered [21]
- C3 and C4:
- Lowered complement levels are characteristic of active SLE [1]
- Low C3 AND low C4 reflects active immune complex–mediated complement consumption (classical pathway activation)
- Low C4 alone can also indicate hereditary complement deficiency (a risk factor for SLE)
- ↓C3/C4 generally indicates IC-mediated GN [11][12]
- Monitoring role: Serial complement levels are used alongside anti-dsDNA to monitor disease activity. ↓C3/C4 + ↑anti-dsDNA = active lupus
| Investigation | Rationale |
|---|---|
| LFT | Assess hepatic involvement (lupoid hepatitis, drug-related hepatotoxicity) |
| Fasting glucose, HbA1c | Steroid-induced diabetes screening; baseline before treatment |
| Fasting lipid profile | Accelerated atherosclerosis risk; steroid-induced dyslipidaemia; nephrotic syndrome |
| Serum albumin | Low in nephrotic syndrome, protein-losing enteropathy, liver disease |
| Coagulation screen (PT/aPTT) | Prolonged aPTT may indicate lupus anticoagulant [27] |
| Blood cultures | If febrile — always exclude infection before attributing to disease activity |
| Urinary sediment analysis | RBC casts = glomerular haematuria = active nephritis |
| Pregnancy test | In women of childbearing age — SLE management differs significantly in pregnancy |
5.5 Organ-Specific Investigations
This is the gold standard for diagnosing and classifying lupus nephritis [25]:
- Indications for renal biopsy [25]:
- Proteinuria > 500 mg/day
- Active urinary sediment with persistent haematuria
- Rising serum creatinine not otherwise accounted for
- Timing: generally recommended immediately — delayed biopsy associated with ↑ risk of ESRD [25]
- What the biopsy provides:
- Light microscopy (LM): Histological pattern (mesangial, focal/diffuse proliferative, membranous, sclerotic)
- Immunofluorescence (IF): "Full house" pattern is characteristic of lupus nephritis — deposition of IgG, IgA, IgM, C3, C4, C1q. This is virtually pathognomonic
- Electron microscopy (EM): Location of immune complex deposits (mesangial, subendothelial, subepithelial)
- Activity index (reversible inflammatory lesions) and chronicity index (irreversible fibrotic/sclerotic changes) [6]
- Immunofluorescence pattern is most helpful for diagnosis [11][12]
- Repeat biopsy indications [25]:
- Development of active sediments in a patient with previous membranous LN
- Slowly rising creatinine or persistent proteinuria with inactive sediment → to rule out progression to Class VI (immunosuppression not helpful)
Full House Immunofluorescence
Lupus nephritis characteristically shows a "full house" staining pattern on immunofluorescence: IgG + IgA + IgM + C3 + C4 + C1q. This reflects the polyclonal nature of the autoimmune response in SLE. No other glomerulonephritis typically shows this full pattern — it is virtually diagnostic of lupus nephritis.
- For neuropsychiatric SLE — MRI may show white matter lesions, cerebral infarcts, cortical atrophy
- LP (cerebrospinal fluid analysis) may be needed to exclude infection or confirm CNS lupus
| Organ/System | Investigation | Key Finding |
|---|---|---|
| Eyes | Fundoscopy | Cotton-wool spots (retinal vasculitis) |
| Annual retinal screening | HCQ retinopathy screening | |
| Bones | DEXA scan | Osteoporosis (steroid use, disease-related) |
| Joints | Plain X-ray | Non-erosive arthritis; periarticular osteopenia (if erosive → reconsider diagnosis) |
| Lungs | HRCT, DLCO | ILD, pulmonary hypertension |
| Heart | ECG | Pericarditis (diffuse ST elevation, PR depression), conduction abnormalities |
Once SLE is diagnosed, serial monitoring is essential to detect flares and guide treatment:
| Marker | Significance |
|---|---|
| Anti-dsDNA titre | Rising titre → impending flare; correlates with disease activity (especially nephritis) |
| C3 and C4 | Falling levels → active complement consumption → flare |
| ESR | Elevated in active disease |
| CRP | Usually NOT markedly elevated in SLE flare (if markedly elevated → think infection) |
| CBC | Worsening cytopenias → haematological flare |
| Urinalysis + uPCR | New haematuria/proteinuria or worsening → renal flare |
| Serum creatinine | Rising → renal flare or progression |
Interpretation of serological tests in SLE diagnosis and management is a specific learning objective of the GC lecture [20].
| Stage | Investigations | Rationale |
|---|---|---|
| Screening | ANA | Entry criterion — must be positive |
| Confirmation | Anti-dsDNA, anti-Sm | Specific for SLE; needed for criteria scoring |
| Characterisation | Anti-ENA panel, aPL antibodies, DAT, complement C3/C4 | Determine overlap features, APS, haemolysis, disease activity |
| Organ assessment | CBC, L/RFT, LFT, urinalysis + uPCR, ESR/CRP | Baseline organ function and activity markers |
| Renal | Kidney biopsy (if indicated) | ISN/RPS classification → guides immunosuppressive regimen |
| Organ-specific | CXR, Echo, MRI brain, DEXA, fundoscopy | Targeted investigation based on clinical features |
| Monitoring | Anti-dsDNA, C3/C4, CBC, RFT, uPCR | Serial monitoring for flares and treatment response |
High Yield Summary — Diagnosis of SLE
-
2019 EULAR/ACR Criteria: ANA ≥ 1:80 is the mandatory entry criterion → then weighted scoring across 7 clinical + 3 immunological domains → total score ≥ 10 = SLE.
-
SLICC Criteria (2012): 4/17 criteria (≥1 clinical + ≥1 immunological) OR biopsy-proven lupus nephritis + ANA/anti-dsDNA positive.
-
Key autoantibodies: ANA (screening, sensitive), anti-dsDNA (specific, correlates with activity, associated with nephritis), anti-Sm (most specific but low sensitivity), anti-Ro (subacute CLE, neonatal lupus).
-
Complement C3/C4: Low levels indicate active IC-mediated disease. Combined with rising anti-dsDNA → active lupus.
-
ESR-CRP dissociation: ESR elevated in active SLE but CRP usually NOT markedly elevated (due to IFN-α suppression of CRP). Markedly elevated CRP → think infection.
-
Kidney biopsy: Indicated for proteinuria > 500 mg/d, active urinary sediment, or unexplained rising creatinine. "Full house" IF pattern is characteristic. Activity index guides aggressiveness of treatment; chronicity index guides conservatism.
-
Lupus anticoagulant: Tested by DRVVT at QMH. Causes prolonged aPTT in vitro but is PRO-thrombotic in vivo.
Active Recall - Diagnostic Criteria, Algorithm, and Investigations for SLE
References
[1] Lecture slides: GC 046. Facial rash and painful fingers_SLE.pdf (Salient features slide, Definition slide) [2] Senior notes: Maksim Medicine Notes.pdf (SLE — Classification criteria EULAR/ACR 2019) [3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (SLE — SLICC diagnostic criteria, Clinical and Immunological criteria tables) [4] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (SLE — SLICC diagnostic criteria, Clinical and Immunological criteria tables) [5] Senior notes: Ryan Ho Fundamentals.pdf (Polyarthritis workup — Initial investigations, ESR/CRP in SLE) [6] Senior notes: Block A - Syncope and irregular heartbeat.pdf (Lupus activity/chronicity index) [7] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Sjögren's — ANA limitations) [11] Senior notes: Adrian Lui Pediatrics Notes.pdf (Evaluation of nephritic syndrome — complement, serology, renal biopsy) [12] Senior notes: Ryan Ho Urogenital.pdf (Evaluation of nephritic syndrome — complement, serology, renal biopsy) [17] Senior notes: Ryan Ho Rheumatology.pdf (SLE classification criteria, diagnostic workup, CRP in active SLE) [20] Senior notes: Block A - Facial rash and painful fingers_ SLE.pdf (Learning objectives) [21] Senior notes: Block A - Family history of anaemia.pdf (Haemolysis workup — DAT, algorithm) [22] Senior notes: Block A - Introduction to Renal Investigations.pdf (uPCR, UACR, urine protein quantification) [23] Senior notes: Adrian Lui Pediatrics Notes.pdf (Urinalysis — dysmorphic RBCs, RBC casts, urine microscopy) [24] Senior notes: Block A - Nephrology Data Interpretation.pdf (Diagnostic approach to renal diseases) [25] Senior notes: Ryan Ho Urogenital.pdf (Lupus nephritis — Diagnostic evaluation, kidney biopsy indications) [26] Senior notes: Block A - Leg swelling and chest pain.pdf (APS antibodies, Sapporo criteria) [27] Senior notes: Block A - Introduction to Haematological investigations.pdf (DRVVT for lupus anticoagulant, aPTT interpretation)
Management of SLE
The management of SLE rests on a few foundational principles that you must understand before diving into specific regimens:
- There is no cure for SLE — the goal is to control disease activity, prevent flares, minimise organ damage, and reduce drug toxicity
- Treatment is stratified by severity — mild, moderate, and severe disease each have different regimens
- Hydroxychloroquine (HCQ) is the backbone for ALL SLE patients unless contraindicated [17]
- Steroids are effective but NOT for long-term use — the aim is always to taper and achieve the lowest possible dose (ideally ≤ 5–7.5 mg/day prednisolone) [17]
- Steroid-sparing immunosuppressants are the long-term maintenance strategy
- Treatment of SLE includes organ-specific measures [20]
- General care and patient education are as important as pharmacological therapy — poor compliance is a major risk factor for poor prognosis [17]
GC Lecture — General Management Principles
The GC lecture learning objectives explicitly include: "General management principles" and "General use of immunosuppressive drugs" [20]. Expect exam questions on which drug to use for which severity level, when to escalate, and the side effect profiles — especially of HCQ and cyclophosphamide.
These measures apply to ALL SLE patients [17]:
| Measure | Rationale |
|---|---|
| Counselling with patients, spouse, relatives | Explain disease, drug compliance, pregnancy issues and fertility issues |
| Regular monitoring | Check BP and urine dipstick every visit with thorough PE; regular bloods: anti-dsDNA, C3/C4, ESR, CBC, L/RFT |
| Eye check before HCQ treatment and every 1 year after 5 years of HCQ use | Screen for HCQ retinal toxicity (bull's eye maculopathy) |
| Smoking cessation | Smoking associated with poor response to HCQ + accelerates atherosclerosis |
| Avoid excessive sun exposure | UV triggers keratinocyte apoptosis → releases nuclear antigens → flare. Use broad-spectrum sunscreen (SPF ≥ 50), protective clothing |
| Avoid potential antigenic stimuli | Drugs (oestrogen, sulphonamides), environmental triggers |
| Infection control | Patients are immunosuppressed — vaccinations (pneumococcal, influenza, COVID-19; avoid live vaccines if immunosuppressed), screening for latent TB, HBV screening before immunosuppression [28] |
| Supportive treatment | Dialysis if ESRD, physiotherapy for joint disease, psychological support |
| Cardiovascular risk management | Aggressive management of traditional CV risk factors (HTN, DM, dyslipidaemia) — SLE patients have accelerated atherosclerosis |
| Bone protection | Calcium + Vitamin D supplementation, bisphosphonates if on long-term steroids |
| Contraception counselling | Avoid combined OCP in active SLE/APS (oestrogen → flare + thrombosis). Use progesterone-only methods or IUDs |
HBV Screening Before Immunosuppression
This is a critical step often tested in exams. Check HBsAg, anti-HBs, anti-HBc before starting immunosuppression [28]. If HBsAg positive or HBcAb positive → check baseline HBV DNA + LFT and start prophylactic antiviral therapy (entecavir or TDF/TAF) irrespective of baseline HBV DNA levels — this is superior and safer than monitoring for reactivation and treating when it occurs [28]. Continue antiviral for at least 6 months (12 months if using anti-CD20) after completion of immunosuppression. This is especially important in Hong Kong where HBV prevalence is high.
4. Pharmacological Management — Drug-by-Drug
The name comes from "hydroxy" + "chloroquine" — it is a hydroxylated derivative of chloroquine, an antimalarial drug.
- Indication: ALL SLE patients unless contraindicated [17]
- Dosage: < 7 mg/kg to avoid toxicity [17] (current guidelines recommend ≤ 5 mg/kg/day actual body weight)
Mechanism of action:
- Increases pH in lysosomes → interferes with antigen processing and MHC class II presentation → reduces autoimmune T-cell activation
- Inhibits toll-like receptor (TLR) signalling → reduces innate immune activation by nucleic acid–containing immune complexes
- Reduces UV-mediated skin inflammation
- Anti-thrombotic properties (reduces APS-related thrombosis risk)
- Lipid-lowering and anti-hyperglycaemic effects (improves metabolic profile)
Benefits (why it's used in ALL patients):
- Reduces flare frequency
- Improves survival
- Protects against organ damage accrual
- Reduces thrombosis risk
- Improves lipid profile
- Safe in pregnancy
Side effects [17]:
- Bluish skin discolouration (especially with UV exposure)
- Corneal deposits (reversible on stopping)
- Bull's eye maculopathy — irreversible retinal toxicity; this is why eye check is required before treatment and every 1 year after 5 years of use [17]. The toxicity involves damage to the retinal pigment epithelium, particularly in the macula, creating a characteristic "bull's eye" pattern on fundoscopy/OCT
- GI upset (nausea, diarrhoea)
- Rarely: cardiomyopathy (with long-term use), neuromyotoxicity
Contraindications: Pre-existing retinal disease, known hypersensitivity, G6PD deficiency (relative — can be used with caution)
These are the most rapidly effective immunosuppressants but carry the heaviest side-effect burden with long-term use.
Mechanism: Bind to intracellular glucocorticoid receptors → translocate to nucleus → suppress transcription of pro-inflammatory genes (NF-κB pathway) → broad suppression of immune cell function, cytokine production, and complement activation.
Dosing by severity [17]:
| Severity | Steroid Regimen |
|---|---|
| Mild lupus | Short-term low-dose steroids (≤ 7.5 mg/d prednisolone) |
| Moderate lupus | Short-term 5–15 mg/d prednisolone, taper down once HCQ/CQ takes effect |
| Severe lupus | IV pulses of methylprednisolone 0.5–1 g/d for 3 days (life-threatening situations) OR 1–2 mg/kg/d if more stable patient |
Key principle: Always taper steroids as soon as possible. The 2023 EULAR recommendation targets prednisolone ≤ 5 mg/day (ideally withdrawal) for maintenance. Steroids are effective but contraindicated for long-term use [17].
Side effects of long-term steroids (important to explain why we avoid them):
- Cushing syndrome, weight gain, hyperglycaemia/steroid-induced DM
- Osteoporosis → fractures (especially vertebral)
- Avascular necrosis (especially femoral head)
- Cataracts, glaucoma
- Increased infection risk (immunosuppression)
- Hypertension, fluid retention
- Psychiatric effects (insomnia, mood disturbance, psychosis)
- Skin thinning, easy bruising, poor wound healing
- Adrenal suppression (must not abruptly stop)
The name: "aza" = nitrogen-containing, "thio" = sulphur-containing, "purine" = purine analogue — it is an anti-metabolite.
- Indications: SLE (maintenance therapy), RA, IBD, dermatomyositis, polymyositis, myasthenia gravis, transplant rejection prophylaxis [29]
Mechanism [29]:
- AZA is converted to 6-mercaptopurine (6-MP)
- 6-MP is converted to thioinosine monophosphate (TIMP)
- TIMP inhibits de novo purine ring synthesis which is required for lymphocyte proliferation
- TIMP is converted to 6-thioguanine (6-TG) which is incorporated into DNA as a false nucleotide → non-functional DNA/RNA
- Net effect: suppresses B and T lymphocyte proliferation
- Hepatotoxicity
- Bone marrow toxicity (myelosuppression): anaemia, leukopenia, thrombocytopenia
- Pancreatitis
- Allergy
- Increased infection risk
CRITICAL: What to measure before starting azathioprine [30][29]:
Azathioprine can be broken down via three mechanisms → defect of these mechanisms can lead to excessive and toxic accumulation of the azathioprine metabolite 6-TGTP, resulting in bone marrow suppression / neutropenic fever [30]:
- TPMT enzyme activity — helps convert active 6-MP into inactive 6-MMP. Low TPMT → higher 6-TG levels → bone marrow toxicity [29]
- NUDT15 enzyme activity — helps prevent excessive accumulation of toxic 6-TGTP (more common in HK/Asian population) [30]
- Is the patient taking any xanthine oxidase inhibitors (e.g. allopurinol, febuxostat)? — XO is crucial for converting active 6-MP into inactive 6-TU. If XO is inhibited, 6-MP accumulates → toxicity [30]
Reduction of dosage required when prescribed with allopurinol (associated with SJS) [29]
Azathioprine + Allopurinol = Danger
If a patient is on azathioprine and you add allopurinol (or vice versa), the xanthine oxidase pathway is blocked → 6-MP accumulates → severe myelosuppression. You must either avoid the combination, or reduce azathioprine dose to ~25% and monitor closely. This is a classic drug interaction tested in exams.
The name: "mycophenolate" = from the fungus Penicillium species, "mofetil" = the ester prodrug form.
- Indications: lupus nephritis (induction and maintenance), transplant rejection prophylaxis, ILD, myasthenia gravis [29]
- Increasingly preferred over azathioprine for SLE maintenance, especially for lupus nephritis
Mechanism [29]:
- Inhibits inosine monophosphate dehydrogenase (IMPDH)
- Blocks purine synthesis (guanosine phosphate) which is required for lymphocyte proliferation
- Deprives B and T cells of a key component of nucleic acids
- More selective for lymphocytes than AZA (lymphocytes are more dependent on the de novo pathway than other cells, which can use the salvage pathway)
Side effects [29]:
- Abdominal pain, diarrhoea, constipation, nausea and vomiting (GI side effects most common)
- Anaemia, leukopenia
- Teratogenic — absolutely contraindicated in pregnancy (must switch to AZA if planning pregnancy)
- Increased infection risk
In HK/QMH, mycophenolate mofetil is being touted to replace azathioprine as it may be safer, becoming the first line for autoimmune hepatitis maintenance (and increasingly for SLE maintenance as well) [31]
The name: "cyclo" = cyclic, "phosph" = phosphorus-containing, "amide" = amide group — it is a nitrogen mustard alkylating agent.
- Indications: Severe SLE (lupus nephritis Class III/IV induction, CNS lupus, diffuse alveolar haemorrhage, severe refractory cytopenias)
- The "big gun" — reserved for life-threatening or major organ-threatening disease
Mechanism:
- Alkylating agent → cross-links DNA strands → prevents DNA replication → kills rapidly dividing cells (especially lymphocytes)
- Potent suppression of both B and T cells
Regimens for lupus nephritis (two main protocols):
- Euro-Lupus regimen (low-dose IV CYC): 500 mg IV every 2 weeks × 6 doses (3 months). Preferred in many centres including HKU due to lower toxicity with comparable efficacy (in White and Asian populations)
- NIH regimen (high-dose IV CYC): 0.5–1 g/m² IV monthly × 6 months. More toxicity, historically used but now less preferred
Side effects:
- Myelosuppression (neutropenia → infection risk)
- Haemorrhagic cystitis (acrolein metabolite damages bladder mucosa) — prevented by MESNA (2-mercaptoethane sulfonate sodium) and aggressive hydration
- Gonadal toxicity: premature ovarian failure (very important in young women) → offer GnRH agonist (e.g. leuprorelin) for ovarian protection before starting CYC; sperm banking for men [2]
- Alopecia
- Nausea, vomiting
- Increased malignancy risk (bladder cancer, lymphoma) with prolonged use
- Teratogenic — contraindicated in pregnancy
Premature Menopause with Cyclophosphamide
Cyclophosphamide causes premature menopause [2]. This is critical to discuss with young female SLE patients. Risk increases with cumulative dose and age. GnRH agonist co-administration can help preserve ovarian function. This premature menopause then contributes to osteoporosis (treatment-related) [2].
- Used for refractory joint and skin manifestations of SLE
- Add MTX if refractory and persistent joint symptoms [17]
- Mechanism: Folate antagonist → inhibits dihydrofolate reductase → impairs purine/pyrimidine synthesis → reduces lymphocyte proliferation
- Side effects: Hepatotoxicity, myelosuppression, pulmonary toxicity (MTX pneumonitis), oral ulcers, teratogenic
- Always co-prescribe folic acid to reduce toxicity
4.7 Biologics
These are targeted therapies for refractory SLE:
- Anti-BAFF (belimumab) [17]
- "Beli" = B-cell lymphocyte, "mab" = monoclonal antibody
- Mechanism: Inhibits B lymphocyte stimulator (BLyS/BAFF) → reduces B cell survival, differentiation, and autoantibody production
- Indication: Add-on therapy for active SLE despite standard treatment (HCQ + steroid + immunosuppressant). Now also approved for active lupus nephritis (in combination with standard therapy)
- First biologic approved specifically for SLE (2011)
- Add belimumab if still suboptimal control of joint symptoms [17]
- Anti-CD20 (rituximab) [17]
- Mechanism: Monoclonal antibody targeting CD20 on B cells → B cell depletion via ADCC, CDC, and apoptosis → reduces autoantibody production
- Indication: Refractory SLE (especially refractory cytopenias, refractory nephritis, CNS lupus). Used off-label for SLE (RCTs were negative but widely used in practice for refractory cases)
- Important: Depletes B cells → increased infection risk, check HBV status (anti-CD20 carries highest risk of HBV reactivation — continue antiviral for 12 months if using anti-CD20) [28]
- Anifrolumab — referenced in the GC lecture [20]
- Mechanism: Monoclonal antibody blocking the type I interferon receptor (IFNAR1) → inhibits IFN-α/β signalling. SLE is characterised by an "interferon signature" — excessive type I IFN drives disease
- Indication: Moderate-to-severe active SLE despite standard therapy. Approved 2021
- Particularly effective for skin and joint manifestations
- Side effects: Herpes zoster reactivation, upper respiratory infections
- Mechanism: Calcineurin inhibitor (like ciclosporin/tacrolimus) → inhibits T cell activation → reduces immune response. Also has direct podocyte-stabilising effects
- Indication: Active lupus nephritis (approved 2021), used in combination with MMF and low-dose steroids
- Advantage over traditional calcineurin inhibitors: More predictable pharmacokinetics, does not require therapeutic drug monitoring
- Side effects: Nephrotoxicity, hypertension, hyperglycaemia, hypertrichosis
5. Severity-Stratified Management (Detailed)
Definition: Significant but non-organ-threatening — i.e. constitutional, cutaneous, MSK, or haematological symptoms [17]
Regimen [17]:
- HCQ / CQ + induction + maintenance
- Induction: short-term 5–15 mg/d prednisolone, taper down once HCQ/CQ takes effect
- Maintenance: non-steroid agents (prefer MMF) [17]
Definition: Life-threatening with major organ involvement — i.e. renal, CNS symptoms [17]
Regimen [17]:
- HCQ / CQ + induction + maintenance
- Induction: short-term high-dose steroids (IV pulses of methylprednisolone 0.5–1 g/d for 3 days or 1–2 mg/kg/d if more stable patient)
- Maintenance: lower-dose steroids ± non-steroid agents (prefer MMF) [17]
6. Organ-Specific Management
Treatment modality is guided by histologic subtype — clinical presentation may not accurately reflect severity or class of histological findings [25]. This is why renal biopsy is essential.
| LN Class | Management |
|---|---|
| Class I/II (Minimal/Mesangial) | Generally no renal-specific immunosuppression needed. Treat underlying SLE. ACEI/ARB for proteinuria |
| Class III/IV (Focal/Diffuse Proliferative) | Induction: IV CYC (Euro-Lupus preferred) OR MMF (2–3 g/d) × 6 months + IV pulse methylprednisolone then oral steroids with taper. Maintenance: MMF (1–2 g/d) OR AZA (2 mg/kg/d) ± low-dose steroids. Consider adding belimumab or voclosporin |
| Class V (Membranous) | If significant proteinuria ( > 1 g/d after ACEI/ARB): MMF or CYC + steroids. If sub-nephrotic: ACEI/ARB may suffice |
| Class VI (Sclerotic) | Immunosuppression not helpful [25] — irreversible. Supportive CKD management, consider renal replacement therapy |
Non-immunosuppressive therapy in ALL instances of CKD [25][32]:
- Anti-proteinuric therapy by ACEI/ARB — indication: in ALL glomerulonephropathy [32]. Mechanism: ↓ intraglomerular pressure → ↓ proteinuria, which is associated with ↓ rate of GFR decline [32]. Goal: keep proteinuria < 1 g/d
- Anti-oedema therapy by salt restriction and diuretics [32]
- Lipid-lowering drugs by statins if hyperlipidaemia persists [32]
- Blood pressure control (target < 130/80 mmHg)
- Pneumococcal vaccination: indicated for ALL [32]
Activity and chronicity index guide treatment intensity [6]:
- High activity index → need to be fast to immunosuppress (reversible inflammation)
- High chronicity index → try to be more conservative (irreversible damage — immunosuppression won't help and side effects aren't justified)
Fever [17]:
- NSAIDs, paracetamol ± low to moderate dose steroids
- MUST rule out underlying infective or drug-related causes if unresponsive
Raynaud's phenomenon [17]:
- General measures: avoid sudden cold exposure, keep hands warm, smoking cessation, avoid sympathomimetic drugs, avoid repeated trauma to fingertips
- Pharmacological (1st line): slow-release/long-acting CCB, e.g. nifedipine, amlodipine
- 2nd line: sildenafil, topical nitrates, losartan, fluoxetine, Botox A injection (sympathectomy)
Joint pain [17]:
- Symptomatic relief: NSAIDs, acetaminophen
- HCQ/CQ effective for joint symptoms
- MMF as maintenance associated with better joint outcomes
- Avoid anti-TNF — associated with ↑ANA, anti-dsDNA and other autoimmune diseases
- Suboptimal control: add steroids ( < 3 weeks), add immunosuppressants/DMARD while tapering, add MTX if refractory, change to AZA if unresponsive to MTX after 3–6 months, add belimumab/rituximab if still suboptimal
Pleuritis [17]:
- NSAIDs (e.g. naproxen)
- Systemic steroids: prednisolone 20 mg/d if no response in 1–2 weeks → taper over 2–3 weeks
Pericarditis [17]:
- Asymptomatic: conservative treatment
- Symptomatic: HCQ, short course NSAIDs, or low-to-medium dose steroids
- Colchicine may be used if unresponsive
- Percutaneous drainage with echocardiographic guidance if cardiac tamponade
Neuropsychiatric lupus [17]:
- Symptomatic relief: anticonvulsant, antipsychotics, antidepressants, sedatives
- Prophylaxis for CVD: aspirin / warfarin
- High-dose steroids + CYC or rituximab for inflammatory NPSLE
- Anticoagulation if thrombotic (APS-related) NPSLE
Haematological (severe cytopenias):
- Thrombotic APS: Long-term anticoagulation with warfarin (target INR 2–3 for venous, 2–3 or 3–4 for arterial events)
- Obstetric APS: Low-dose aspirin + prophylactic LMWH throughout pregnancy
- DOACs are NOT recommended for APS (inferior to warfarin, especially for triple-positive APS)
This is a high-yield topic:
- Plan pregnancy during disease remission (at least 6 months of quiescence)
- Safe drugs in pregnancy: HCQ (continue — reduces flare risk and neonatal lupus risk), low-dose prednisolone, azathioprine (safe as maintenance)
- Contraindicated in pregnancy: MMF (teratogenic — switch to AZA at least 3 months before conception), CYC (teratogenic), MTX (teratogenic), warfarin (1st trimester — switch to LMWH)
- Monitor: Anti-Ro/La (risk of neonatal lupus / congenital heart block — fetal echo from 16 weeks), antiphospholipid antibodies (risk of obstetric complications)
- Postpartum: Flare risk is high — monitor closely
Poor prognostic factors [17]:
- Demographics: Black male, old age at presentation, low socioeconomic status
- Clinical: APS or presence of antiphospholipid antibodies, renal involvement, hypertension, high overall disease activity
Common causes of death [17]:
- Infection (early stage) — due to immunosuppression and the disease itself
- Cardiovascular deaths (late stage) — due to accelerated atherosclerosis
Modern 10-year survival exceeds 90% with appropriate management. The "bimodal mortality" pattern reflects early deaths from active disease/infection and late deaths from cardiovascular disease.
| Drug | Mechanism | Indication | Key Side Effects | Special Considerations |
|---|---|---|---|---|
| HCQ | ↑Lysosomal pH, inhibits TLR signalling | ALL SLE patients | Bull's eye maculopathy, skin discolouration | Annual eye screening after 5 years; safe in pregnancy |
| Prednisolone | Suppresses NF-κB, broad immune suppression | Flares of any severity | Cushing's, osteoporosis, AVN, DM, infections | Taper ASAP; target ≤ 5 mg/d |
| AZA | Purine synthesis inhibition | Maintenance (LN, haem) | Myelosuppression, hepatotoxicity, pancreatitis | Check TPMT + NUDT15; avoid with allopurinol |
| MMF | IMPDH inhibition | Induction + maintenance (LN) | GI upset, myelosuppression | Teratogenic — switch to AZA before pregnancy |
| CYC | DNA alkylation | Severe LN induction, CNS lupus | Myelosuppression, haemorrhagic cystitis, gonadal toxicity | MESNA + hydration; GnRH agonist for ovarian protection |
| MTX | DHFR inhibition | Refractory joints/skin | Hepatotoxicity, pneumonitis | Co-prescribe folic acid |
| Belimumab | Anti-BAFF/BLyS | Active SLE despite standard Tx, LN | Infections, infusion reactions | First SLE-approved biologic |
| Rituximab | Anti-CD20 (B cell depletion) | Refractory cytopenias, nephritis | Infections, HBV reactivation, PML | Check HBV; continue antiviral 12 months |
| Anifrolumab | Anti-IFN receptor | Moderate-severe active SLE | Herpes zoster, URTIs | Effective for skin/joints |
| Voclosporin | Calcineurin inhibitor | Active LN (with MMF) | Nephrotoxicity, HTN | No TDM needed |
High Yield Summary — Management of SLE
-
ALL patients: HCQ (unless contraindicated) + sun protection + general measures + regular monitoring (anti-dsDNA, C3/C4, CBC, RFT, urine dipstick).
-
Mild (skin/joints/mucosal): HCQ ± NSAIDs ± low-dose prednisolone (≤ 7.5 mg/d).
-
Moderate (constitutional, cutaneous, MSK, haem): HCQ + short-term prednisolone 5–15 mg/d → taper → maintenance with MMF or AZA.
-
Severe (renal, CNS): HCQ + IV methylprednisolone pulse → induction with CYC or MMF → maintenance with MMF or AZA. Add belimumab or voclosporin for LN. Rituximab for refractory.
-
Lupus nephritis: Biopsy-guided. Class III/IV → induction CYC or MMF + steroids → maintenance MMF or AZA. Class V → MMF if significant proteinuria. Class VI → no immunosuppression. ALL get ACEI/ARB.
-
Before immunosuppression: Screen HBV (HBsAg/anti-HBs/anti-HBc), check TPMT/NUDT15 before AZA, offer GnRH agonist before CYC in young women.
-
Steroids: Effective but taper ASAP. Target ≤ 5 mg/d maintenance. Avoid long-term high-dose.
-
Pregnancy: Continue HCQ. Safe: AZA, low-dose prednisolone. Contraindicated: MMF, CYC, MTX, warfarin (1st trimester).
-
Prognosis: Poor = APS, renal involvement, non-compliance. Death: early = infection; late = CVD.
Active Recall - Management of SLE
References
[2] Senior notes: Maksim Medicine Notes.pdf (SLE — Overview, osteoporosis causes) [6] Senior notes: Block A - Syncope and irregular heartbeat.pdf (Activity and chronicity index for lupus) [17] Senior notes: Ryan Ho Rheumatology.pdf (SLE — Management, severity-stratified regimen, symptom-oriented management, prognosis) [20] Senior notes: Block A - Facial rash and painful fingers_ SLE.pdf (Learning objectives — management principles, immunosuppressive drugs; Anifrolumab reference slide) [25] Senior notes: Ryan Ho Urogenital.pdf (Lupus nephritis — diagnostic evaluation, approach to management, biopsy indications) [28] Senior notes: Block A - I am a hepatitis B carrier.pdf (HBV screening before immunosuppression, prophylactic antiviral strategy) [29] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (Azathioprine and MMF — mechanism, indications, side effects) [30] Senior notes: Block A - Chronic diarrhoea_ irritable bowel syndrome and inflammatory bowel disease.pdf (Azathioprine — TPMT, NUDT15, XO inhibitor interaction) [31] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf (MMF replacing azathioprine) [32] Senior notes: Ryan Ho Fundamentals.pdf (General approach to glomerulonephropathy management — ACEI/ARB, anti-oedema, statins, vaccination) [33] Senior notes: Block A - Abnormal bleeding after tooth extraction.pdf (ITP treatment — steroids, IVIg, TPO receptor agonists)
Complications of SLE
SLE complications arise from three distinct but interacting sources: (1) the disease itself (organ damage from autoimmunity and immune complex deposition), (2) treatment-related side effects (especially long-term corticosteroids and immunosuppressants), and (3) comorbidities accelerated by chronic inflammation. Understanding which complications come from which source is essential for prevention, monitoring, and management.
The GC lecture explicitly states the four overarching principles [1]:
1. SLE is a multisystem disease. Diagnosis is based on clinical grounds + serologic abnormalities. 2. SLE care is multidisciplinary, based on a shared patient-physician decision. 3. Organ-/life-threatening complications require initial high-intensity and subsequent maintenance immunosuppressive therapy. 4. Treatment goals include long-term patient survival, prevention of organ damage and optimisation of health-related quality of life.
The changing prognosis of SLE is a core learning objective [1] — modern 10-year survival exceeds 90%, but this means patients live long enough to accumulate organ damage, treatment toxicity, and cardiovascular disease. This creates a characteristic bimodal mortality pattern:
- Common causes of death: infection (early stage), cardiovascular deaths (late stage) [17]
1. Disease-Related Complications
This is the single most important complication of SLE, driving the majority of morbidity.
- Lupus nephritis occurs in ~50% of SLE patients. Class IV (diffuse proliferative) is the most common and most severe form
- SLE is a common cause of end-stage renal failure, especially in young adults in Hong Kong. A surgery case vignette specifically lists DM, SLE, and IgA nephropathy as the common causes of ESRD requiring transplantation [34]
- Pathophysiology: Anti-dsDNA immune complexes deposit in the glomerulus → complement activation → progressive glomerular inflammation → if untreated or inadequately treated → glomerulosclerosis → CKD → ESRD
- Lupus nephritis can also cause rapidly progressive glomerulonephritis (RPGN) with crescent formation — SLE is listed as a systemic cause of secondary RPGN alongside systemic vasculitides and cryoglobulinaemia [35]
- SLE can create a "secondary" nephrotic syndrome [14][36] — particularly Class V membranous lupus nephritis. Nephrotic syndrome carries its own complications:
- Prothrombotic state: Urinary loss of antithrombin III + increased hepatic synthesis of clotting factors → DVT, renal vein thrombosis, PE [37]
- Infection risk: Urinary loss of immunoglobulins and complement → impaired humoral immunity [37]
- Hyperlipidaemia: Increased hepatic LDL/VLDL synthesis with urinary HDL loss → accelerated atherosclerosis [37]
Why does lupus nephritis progress to ESRD? Each flare of nephritis causes a wave of inflammation → some glomeruli heal, some are permanently scarred → cumulative damage → reduced nephron mass → hyperfiltration of remaining nephrons → further damage (vicious cycle). This is why aggressive early treatment (high activity index → fast immunosuppression) and maintenance therapy are critical.
Distal RTA from SLE
An important but easily overlooked renal complication: SLE can cause distal (Type 1) renal tubular acidosis [13]. Typical presentation: a young lady with multiple episodes of renal nephrocalcinosis or stones → found to have low potassium, normal anion gap metabolic acidosis → diagnosis of SLE made [13]. The mechanism is autoimmune damage to the distal tubular H⁺-ATPase. Remember that Sjögren's syndrome can also cause RTA (usually distal, but sometimes proximal) [13].
1.2 Cardiovascular Complications
This is the leading cause of late death in SLE patients.
- Pathophysiology: Chronic systemic inflammation → endothelial dysfunction → accelerated atherogenesis. Compounded by corticosteroid use (dyslipidaemia, hyperglycaemia, hypertension), renal disease (uraemic acceleration), and antiphospholipid antibodies (endothelial activation)
- SLE patients have a 5–10× increased risk of coronary artery disease compared to age-matched controls
- Screening and treatment of atherosclerosis is part of the general management of SLE [3][4]
- Young women with SLE can have myocardial infarction in their 30s–40s — this is one of the most striking manifestations of accelerated cardiovascular disease
- Pericarditis is the most common cardiac manifestation (discussed in clinical features section)
- Can progress to cardiac tamponade (rare but life-threatening)
- Myocarditis can cause heart failure and arrhythmias
- Sterile verrucous vegetations, typically on the mitral valve
- Usually asymptomatic but can cause:
- Valvular regurgitation (usually mitral)
- Embolic phenomena (stroke, peripheral embolism)
- Serve as a nidus for infective endocarditis (secondary bacterial infection of the sterile vegetations)
- Seizures, psychosis, cognitive dysfunction, stroke, transverse myelitis, cranial and peripheral neuropathies
- Mechanisms are multiple and important to distinguish because treatment differs:
- Inflammatory (immune complex deposition, vasculitis, anti-neuronal antibodies) → treat with immunosuppression
- Thrombotic (APS-related ischaemia) → treat with anticoagulation
- Cognitive dysfunction ("lupus fog") is extremely common and debilitating, affecting memory, concentration, and executive function — often underappreciated
- Autoimmune haemolytic anaemia (AIHA): Coombs-positive, warm type
- Immune thrombocytopenic purpura (ITP): Can be the first presentation of SLE. Always check ANA in a young woman with ITP
- Thrombotic thrombocytopenic purpura (TTP): Rare but life-threatening — TTP is listed as a severe SLE manifestation requiring intensive treatment [38]
- Lymphopenia: Very common, correlates with disease activity
- Macrophage activation syndrome (MAS): A hyperinflammatory state characterised by pancytopenia, hyperferritinaemia, hypertriglyceridaemia, hepatosplenomegaly, and haemophagocytosis — a medical emergency
- Occurs as secondary APS in ~30–40% of SLE patients
- Causes:
- Recurrent arterial and venous thrombosis (stroke, MI, DVT, PE)
- Recurrent fetal loss/miscarriage
- Thrombocytopenia
- Livedo reticularis
- Valvular heart disease (Libman-Sacks)
- Lupus anticoagulant / antiphospholipid syndrome → classical example of a risk factor that can increase risk of both arterial and venous thrombosis [26]
- Catastrophic APS (CAPS): Rare, life-threatening complication with widespread small vessel thrombosis affecting ≥ 3 organs simultaneously → multi-organ failure. Treat with anticoagulation + steroids + plasmapheresis ± IVIg
- Pleuritis/pleural effusion (most common — discussed in clinical features)
- Acute lupus pneumonitis: Rare; presents with fever, dyspnoea, cough, pulmonary infiltrates
- Diffuse alveolar haemorrhage (DAH): Rare but life-threatening — listed as a severe SLE manifestation requiring intensive treatment [38]. Presents with haemoptysis, dyspnoea, falling haemoglobin, bilateral infiltrates on CXR
- Shrinking lung syndrome: Diaphragmatic dysfunction → progressive dyspnoea with elevated hemidiaphragm and clear lung fields
- Interstitial lung disease: Uncommon in SLE (more common in SSc)
- Pulmonary arterial hypertension: As above
Q: How does pregnancy affect SLE? [3][4]:
- Pregnancy and the postpartum period is associated with a higher rate of SLE disease flares and exacerbation (in contrast with RA which generally has reduced disease activity during pregnancy)
Q: How does SLE affect pregnancy? [3][4]:
- Maternal complications: Pre-eclampsia, preterm delivery, fetal loss (recurrent miscarriage, stillbirth)
- Fetal complications:
- Intrauterine growth restriction (IUGR)
- Neonatal lupus (anti-Ro/anti-La associated): congenital complete heart block (irreversible — the most feared complication), erythematous rash, hepatic abnormalities (elevated liver enzymes, hepatosplenomegaly, cholestasis, hepatitis), haematological abnormalities (anaemia, neutropenia, thrombocytopenia)
Why does anti-Ro cause congenital heart block? Maternal anti-Ro (SSA) IgG antibodies cross the placenta (IgG is the only immunoglobulin class that crosses the placenta) → bind to fetal cardiac conduction tissue → inflammatory destruction of the AV node → permanent congenital complete heart block (3rd degree). This occurs between 16–24 weeks gestation. Once fibrosis is established, it is irreversible, and the infant may require a permanent pacemaker.
Neonatal Lupus
Neonatal lupus is NOT the same as the mother having lupus. It is caused by transplacental passage of maternal anti-Ro/anti-La antibodies. The cutaneous and haematological manifestations are self-limiting (resolve by ~6 months as maternal antibodies are cleared), but congenital complete heart block is permanent and irreversible. This is why all pregnant SLE patients must have anti-Ro/anti-La checked, and if positive, fetal echocardiography is performed from 16 weeks.
SLE patients have an increased risk of developing other autoimmune conditions (autoimmune clustering):
- Hashimoto's thyroiditis — 1/10th of lupus patients have thyroid problems [6]
- Sjögren's syndrome (secondary)
- Autoimmune hepatitis
- Pernicious anaemia
- Antiphospholipid syndrome
- Type 1 diabetes mellitus
2. Treatment-Related Complications
These are critical to understand because they are often preventable and modifiable.
Long-term steroid use causes:
| Complication | Mechanism |
|---|---|
| Osteoporosis | Inhibits osteoblast activity, increases osteoclast activity, reduces intestinal calcium absorption, increases renal calcium excretion |
| Avascular necrosis (AVN) of hip | Fat embolism in subchondral vessels + osteocyte apoptosis → bone infarction. AVN hip: active disease, steroid-induced [2] |
| Cushingoid features | Redistribution of fat (moon face, buffalo hump, central obesity) |
| Steroid-induced diabetes mellitus | Increases hepatic gluconeogenesis, causes insulin resistance |
| Cataracts (posterior subcapsular) | Steroid-induced lens protein cross-linking |
| Glaucoma | Increased aqueous humour production, decreased outflow |
| Hypertension | Mineralocorticoid effect → sodium and water retention |
| Increased infection risk | Broad immunosuppression |
| Adrenal suppression | Exogenous steroid suppresses HPA axis → cannot mount stress cortisol response |
| Psychiatric effects | Insomnia, mood disturbance, psychosis |
| Skin thinning, easy bruising | Inhibition of collagen synthesis |
| Growth retardation in children | Inhibition of growth hormone and IGF-1 |
Osteoporosis has both disease-related and treatment-related causes [2]:
- Premature ovarian failure → premature menopause → infertility, osteoporosis
- Haemorrhagic cystitis → prevented by MESNA + hydration
- Myelosuppression → neutropenic sepsis
- Malignancy risk → bladder cancer, lymphoma (with prolonged use)
- GI side effects (diarrhoea, nausea)
- Myelosuppression
- Teratogenicity — absolute contraindication in pregnancy
- Infection risk (especially zoster reactivation — the main issue with MMF) [39]
- Bull's eye maculopathy — irreversible damage to the retinal pigment epithelium
- Risk increases with cumulative dose and duration (usually after > 5 years)
- Eye check required before treatment and every 1 year after 5 years of use [17]
- Early detection by OCT (optical coherence tomography) allows drug discontinuation before visual loss occurs
This is the leading cause of early death in SLE.
- SLE patients are immunosuppressed both by the disease itself (lymphopenia, complement consumption) and by treatment (steroids, CYC, MMF, rituximab)
- Common infections:
- Bacterial: pneumonia (especially pneumococcal — pneumococcal vaccination indicated for ALL [32]), urinary tract infections, bacteraemia
- Viral: herpes zoster reactivation (especially with MMF), CMV reactivation, BK virus (in renal transplant patients)
- Fungal: Pneumocystis jirovecii pneumonia (PJP) — prophylaxis with TMP-SMX indicated in patients on high-dose steroids + immunosuppressants
- Opportunistic: TB reactivation, especially in Hong Kong. Screen for latent TB before starting immunosuppression
- HBV reactivation is a particular concern in Hong Kong. Must screen and provide prophylactic antivirals [28]
- Do NOT give live attenuated vaccines to immunosuppressed SLE patients [3][4]
- Vaccination for infection prevention — immunisation prior to institution of immunosuppressive therapies [3][4]
Infection vs Flare — The SLE Dilemma
Distinguishing infection from disease flare is one of the most challenging clinical problems in SLE. Both cause fever, cytopenias, and elevated ESR. Key clues: markedly elevated CRP favours infection (active SLE rarely elevates CRP significantly). Low complement and rising anti-dsDNA favour flare. Procalcitonin may help. Always obtain cultures before escalating immunosuppression. Getting this wrong can be fatal — treating infection with more immunosuppression, or undertreating a flare while searching for an absent infection.
3. Comorbidity-Related Complications
As discussed above — the combination of chronic inflammation, steroid-induced metabolic syndrome, renal disease, and APS creates a "perfect storm" for premature atherosclerosis. Cardiovascular disease is the leading cause of death in SLE patients who survive the first 5 years.
Management: Screening and treatment of cardiovascular risk factors [3][4] — aggressive blood pressure control, statin therapy, glycaemic control, smoking cessation, weight management.
Common cause of death in early stage [17].
- SLE patients have a modestly increased risk of certain malignancies, particularly:
- Non-Hodgkin lymphoma (especially diffuse large B-cell lymphoma) — likely related to chronic B-cell stimulation
- Cervical cancer — immunosuppression + HPV vulnerability. Regular cervical screening is important
- Lung cancer — especially in smokers on immunosuppression
- Cyclophosphamide increases risk of bladder cancer and haematological malignancies with prolonged use
| Category | Complication | Mechanism / Source |
|---|---|---|
| Renal | Lupus nephritis → CKD → ESRD | IC deposition in glomeruli → progressive sclerosis |
| RPGN | Severe proliferative nephritis with crescents | |
| Distal RTA | Autoimmune damage to distal tubular H⁺-ATPase | |
| Cardiovascular | Accelerated atherosclerosis | Chronic inflammation + steroids + renal disease |
| Pericarditis → tamponade | IC deposition on pericardium | |
| Libman-Sacks endocarditis | Sterile vegetations → valve damage, embolism | |
| Pulmonary hypertension | Chronic thromboembolic disease, vasculitis, ILD | |
| Haematological | AIHA, ITP, TTP | Type II HSR: autoantibodies against blood cells |
| MAS | Hyperinflammatory state → haemophagocytosis | |
| Thrombotic | APS → DVT, PE, stroke, MI | Antiphospholipid antibodies → thrombosis |
| CAPS | Widespread small vessel thrombosis → MOF | |
| Pulmonary | DAH | Capillaritis → alveolar haemorrhage |
| Shrinking lung | Diaphragmatic dysfunction | |
| Neuropsychiatric | Seizures, psychosis, stroke | Vasculitis, anti-neuronal Ab, APS-related thrombosis |
| Obstetric | Miscarriage, pre-eclampsia, IUGR | APS, placental insufficiency |
| Neonatal lupus / CHB | Transplacental anti-Ro/La → AV node damage | |
| Musculoskeletal | AVN hip | Active disease + steroid-induced |
| Osteoporosis | Disease + steroid + CYC (premature menopause) | |
| Treatment | Infections (leading early cause of death) | Immunosuppression (disease + drugs) |
| HBV reactivation | Immunosuppression in HBV-endemic area | |
| HCQ retinopathy | Cumulative dose-dependent retinal toxicity | |
| Myelosuppression | AZA (TPMT/NUDT15), CYC, MMF | |
| Haemorrhagic cystitis | CYC acrolein metabolite | |
| Infertility (premature menopause) | CYC gonadotoxicity | |
| Steroid complications | Cushing's, DM, osteoporosis, AVN, cataracts | |
| Comorbidity | Autoimmune thyroid disease | Autoimmune clustering |
| Malignancy | Chronic B-cell stimulation + immunosuppression |
High Yield Summary — Complications of SLE
-
Bimodal mortality: Infection (early stage) and cardiovascular deaths (late stage) are the commonest causes of death.
-
Lupus nephritis → ESRD is the most important disease complication. SLE is a major cause of ESRD in young adults (Hong Kong). RPGN can occur. Also causes distal RTA.
-
Accelerated atherosclerosis is driven by chronic inflammation + steroids + renal disease + APS. Screen and treat CV risk factors aggressively.
-
APS (secondary): Thrombosis (arterial AND venous), recurrent miscarriage, CAPS. Lupus anticoagulant is prothrombotic despite prolonging aPTT.
-
Pregnancy complications: SLE flares during pregnancy/postpartum. Maternal: pre-eclampsia, preterm delivery, miscarriage. Fetal: IUGR, neonatal lupus (anti-Ro/La → congenital complete heart block — IRREVERSIBLE).
-
Treatment complications: Steroids → osteoporosis, AVN, DM, infections. CYC → premature menopause, haemorrhagic cystitis, malignancy. AZA → myelosuppression (check TPMT/NUDT15). MMF → teratogenic, zoster reactivation. HCQ → bull's eye maculopathy (annual eye screening after 5 years).
-
Infection is the leading early cause of death. Screen HBV before immunosuppression (especially in HK). No live vaccines. PJP prophylaxis if on high-dose steroids + immunosuppressants.
-
Autoimmune clustering: 1/10 lupus patients develop thyroid disease. Screen for Sjögren's, autoimmune hepatitis, pernicious anaemia.
Active Recall - Complications of SLE
References
[1] Lecture slides: GC 046. Facial rash and painful fingers_SLE.pdf (Four overarching principles slide, Core knowledge slide, Salient features slide, Definition slide) [2] Senior notes: Maksim Medicine Notes.pdf (SLE — Osteoporosis causes, AVN, clinical features) [3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (SLE — General measures, pregnancy management, comorbid screening) [4] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (SLE — General measures, pregnancy management, comorbid screening) [6] Senior notes: Block A - Syncope and irregular heartbeat.pdf (1/10 lupus patients have thyroid problems) [13] Senior notes: Block A - Nephrology Interactive Tutorial.pdf (Distal RTA in SLE — typical presentation) [14] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (SLE as cause of secondary nephrotic syndrome) [17] Senior notes: Ryan Ho Rheumatology.pdf (SLE — Prognosis, causes of death, management, monitoring) [26] Senior notes: Block A - Leg swelling and chest pain.pdf (APS and lupus anticoagulant — both arterial and venous thrombosis) [28] Senior notes: Block A - I am a hepatitis B carrier.pdf (HBV screening before immunosuppression) [30] Senior notes: Block A - Chronic diarrhoea.pdf (Azathioprine — TPMT, NUDT15, allopurinol interaction) [32] Senior notes: Ryan Ho Fundamentals.pdf (Pneumococcal vaccination for all glomerulonephropathy patients) [34] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (Common causes of ESRD — DM, SLE, IgAN) [35] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (SLE as cause of secondary RPGN) [36] Lecture slides: GC 057. Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (SLE as systemic cause of nephrotic syndrome and RPGN) [37] Senior notes: learning_points_output.txt (Nephrotic syndrome complications — prothrombotic state, infection risk, hyperlipidaemia) [38] Lecture slides: Handbook of Internal Medicine 2024.pdf (Severe SLE manifestations list — TTP, pulmonary haemorrhage, myocarditis) [39] Senior notes: Block A - Treatments for skin diseases.pdf (Azathioprine neutropenic fever death; MMF zoster reactivation as main issue)
High Yield Summary
Definition: SLE is a chronic multisystem autoimmune disorder characterised by autoantibody production and immune complex deposition → tissue damage. The failure to remove ICs is the most important pathological mechanism.
Epidemiology: F:M = 9:1, peak age 20s–40s, more common and more severe in Asians and Blacks than Caucasians.
Risk Factors: Genetic (HLA-DR2/DR3, complement deficiency), hormonal (oestrogen), environmental (UV light, EBV, drugs).
Drug-Induced Lupus: HIP (Hydralazine, Isoniazid, Procainamide) → anti-histone Ab, M=F, lung/joint involvement, resolves on stopping drug, NO renal/CNS involvement.
Pathophysiology: Loss of self-tolerance → autoantibodies → Type II HSR (cytopenias) + Type III HSR (IC deposition → nephritis, vasculitis, serositis). Defective IC clearance perpetuates the cycle.
Key Autoantibodies: ANA (screening, sensitive), anti-dsDNA (specific, correlates with activity, associated with nephritis), anti-Sm (most specific), anti-Ro (subacute CLE, neonatal lupus), anti-histone (drug-induced lupus).
Clinical Features: Constitutional (fever, fatigue, weight loss), Skin (malar rash sparing nasolabial fold, photosensitivity, discoid lupus, oral ulcers, alopecia, Raynaud's), MSK (non-erosive polyarthritis, Jaccoud arthropathy), Renal (lupus nephritis — Class IV is most common and severe), Haematological (Coombs' +ve haemolytic anaemia, thrombocytopenia, lymphopenia), Serosal (pleuritis, pericarditis), CVS (Libman-Sacks, accelerated atherosclerosis), Neuro (seizures, psychosis, stroke), APS (thrombosis, miscarriage, livedo reticularis).
Cutaneous Lupus Classification: Acute (malar rash), Subacute (annular/papulosquamous, anti-Ro), Chronic (discoid — scarring).
Lupus Nephritis: Class I–VI. Class IV (diffuse proliferative) is most common and most severe. Activity index high → aggressive immunosuppression. Chronicity index high → conservative.
High Yield Summary — Differential Diagnosis of SLE
-
DDx depends on the dominant presenting syndrome: polyarthritis, skin rash, nephritis, cytopenias, serositis, or multi-system inflammation.
-
SLE vs RA (most common exam comparison): SLE arthritis is non-erosive, minimal morning stiffness (minutes), reducible deformities, transudate synovial fluid. RA is erosive, prolonged morning stiffness (hours), fixed deformities, exudate.
-
Other CTDs: SSc (skin thickening, GERD, anti-Scl-70), Sjögren's (sicca, anti-Ro/La), Behçet's (painful oral ulcers, ANA −ve), DM/PM (proximal weakness, Gottron's, heliotrope).
-
Nephritis DDx: Use complement levels to narrow — ↓C3/C4 = IC-mediated GN (lupus, PSGN, MPGN, cryoglobulinaemia, IE). Normal C3/C4 = pauci-immune/non-IC (ANCA vasculitis, anti-GBM, IgAN/HSP).
-
Drug-induced lupus: HIP drugs, anti-histone Ab, M=F, no renal/CNS, resolves on stopping drug.
-
Flare vs infection: CRP markedly elevated → think infection. Low complement + rising anti-dsDNA → think flare.
High Yield Summary — Diagnosis of SLE
-
2019 EULAR/ACR Criteria: ANA ≥ 1:80 is the mandatory entry criterion → then weighted scoring across 7 clinical + 3 immunological domains → total score ≥ 10 = SLE.
-
SLICC Criteria (2012): 4/17 criteria (≥1 clinical + ≥1 immunological) OR biopsy-proven lupus nephritis + ANA/anti-dsDNA positive.
-
Key autoantibodies: ANA (screening, sensitive), anti-dsDNA (specific, correlates with activity, associated with nephritis), anti-Sm (most specific but low sensitivity), anti-Ro (subacute CLE, neonatal lupus).
-
Complement C3/C4: Low levels indicate active IC-mediated disease. Combined with rising anti-dsDNA → active lupus.
-
ESR-CRP dissociation: ESR elevated in active SLE but CRP usually NOT markedly elevated (due to IFN-α suppression of CRP). Markedly elevated CRP → think infection.
-
Kidney biopsy: Indicated for proteinuria > 500 mg/d, active urinary sediment, or unexplained rising creatinine. "Full house" IF pattern is characteristic. Activity index guides aggressiveness of treatment; chronicity index guides conservatism.
-
Lupus anticoagulant: Tested by DRVVT at QMH. Causes prolonged aPTT in vitro but is PRO-thrombotic in vivo.
High Yield Summary — Management of SLE
-
ALL patients: HCQ (unless contraindicated) + sun protection + general measures + regular monitoring (anti-dsDNA, C3/C4, CBC, RFT, urine dipstick).
-
Mild (skin/joints/mucosal): HCQ ± NSAIDs ± low-dose prednisolone (≤ 7.5 mg/d).
-
Moderate (constitutional, cutaneous, MSK, haem): HCQ + short-term prednisolone 5–15 mg/d → taper → maintenance with MMF or AZA.
-
Severe (renal, CNS): HCQ + IV methylprednisolone pulse → induction with CYC or MMF → maintenance with MMF or AZA. Add belimumab or voclosporin for LN. Rituximab for refractory.
-
Lupus nephritis: Biopsy-guided. Class III/IV → induction CYC or MMF + steroids → maintenance MMF or AZA. Class V → MMF if significant proteinuria. Class VI → no immunosuppression. ALL get ACEI/ARB.
-
Before immunosuppression: Screen HBV (HBsAg/anti-HBs/anti-HBc), check TPMT/NUDT15 before AZA, offer GnRH agonist before CYC in young women.
-
Steroids: Effective but taper ASAP. Target ≤ 5 mg/d maintenance. Avoid long-term high-dose.
-
Pregnancy: Continue HCQ. Safe: AZA, low-dose prednisolone. Contraindicated: MMF, CYC, MTX, warfarin (1st trimester).
-
Prognosis: Poor = APS, renal involvement, non-compliance. Death: early = infection; late = CVD.
High Yield Summary — Complications of SLE
-
Bimodal mortality: Infection (early stage) and cardiovascular deaths (late stage) are the commonest causes of death.
-
Lupus nephritis → ESRD is the most important disease complication. SLE is a major cause of ESRD in young adults (Hong Kong). RPGN can occur. Also causes distal RTA.
-
Accelerated atherosclerosis is driven by chronic inflammation + steroids + renal disease + APS. Screen and treat CV risk factors aggressively.
-
APS (secondary): Thrombosis (arterial AND venous), recurrent miscarriage, CAPS. Lupus anticoagulant is prothrombotic despite prolonging aPTT.
-
Pregnancy complications: SLE flares during pregnancy/postpartum. Maternal: pre-eclampsia, preterm delivery, miscarriage. Fetal: IUGR, neonatal lupus (anti-Ro/La → congenital complete heart block — IRREVERSIBLE).
-
Treatment complications: Steroids → osteoporosis, AVN, DM, infections. CYC → premature menopause, haemorrhagic cystitis, malignancy. AZA → myelosuppression (check TPMT/NUDT15). MMF → teratogenic, zoster reactivation. HCQ → bull's eye maculopathy (annual eye screening after 5 years).
-
Infection is the leading early cause of death. Screen HBV before immunosuppression (especially in HK). No live vaccines. PJP prophylaxis if on high-dose steroids + immunosuppressants.
-
Autoimmune clustering: 1/10 lupus patients develop thyroid disease. Screen for Sjögren's, autoimmune hepatitis, pernicious anaemia.
Diabetes Mellutus
Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia resulting from defects in insulin secretion, insulin action, or both.
Systemic Sclerosis
Systemic sclerosis is a chronic autoimmune connective tissue disease characterized by widespread vascular dysfunction, fibrosis of the skin and internal organs, and immune dysregulation.