Systemic lupus erythematosus
Description
- Multisystem autoimmune disease: autoantibodies to nuclear antigens -> immune complex deposition + complement consumption
- Relapsing-remitting, any organ, protean
Lupus-spectrum entities
- SLE - systemic
- Cutaneous lupus - may be isolated or part of SLE
- Acute (ACLE) - malar/butterfly rash (spares nasolabial folds), or generalised photosensitive erythema. Tracks disease activity
- Subacute (SCLE) - annular/psoriasiform, photodistributed, anti-Ro. Non-scarring. Drug-induced in ~1/3 (terbinafine, thiazides, PPIs, TNFi)
- Chronic/discoid (CCLE) - scarring, follicular plugging, dyspigmentation, scarring alopecia. Commonest chronic form. Only ~5% progress to SLE
- Drug-induced lupus - arthralgia + serositis dominant, renal and CNS disease rare, resolves on withdrawal
- Neonatal lupus - maternal anti-Ro/La transplacental -> rash, cytopenias, congenital heart block (irreversible, ~2% of anti-Ro mothers)
- Antiphospholipid syndrome - ~30% of SLE have aPL, ~15% develop APS
Organ involvement (approx frequency)
- Constitutional 90%, musculoskeletal 90%, mucocutaneous 80%, haematological 70%
- Renal 40-50%, neuropsychiatric 20-40%, serositis 30%, cardiac 15%
Epidemiology
- Prevalence ~50-100/100,000; incidence ~2-8/100,000/yr
- F:M 9-10:1 during reproductive years
- Falls to ~2-3:1 pre-pubertal and post-menopausal - the ratio itself is a clue to age
- Peak onset 15-45 yr
- Aboriginal and Torres Strait Islander Australians: ~3-4x prevalence, younger onset, more nephritis, worse outcomes
- Also inc in Asian, African and Hispanic ancestry
- Drug-induced lupus: M=F, older, the sex ratio breaks
Aetiopathogenesis
Genetic
- Sibling risk ratio ~30; monozygotic concordance ~25-50%
- Early complement component deficiency = strongest single genetic risk
- C1q homozygous ~90% develop SLE
- C4 homozygous ~70%; C2 ~10-20%
- -> failure to clear apoptotic debris and immune complexes
- TREX1 (DNA exonuclease) - loss -> cytosolic DNA -> type I IFN
- HLA-DR2, DR3; IRF5, STAT4, PTPN22, ITGAM
- Complement is both a cause (deficiency) and a marker (consumption) - do not confuse the two
Environmental
- UV light - keratinocyte apoptosis, antigen exposure
- EBV, smoking, silica, pollutants
- Oestrogen-containing preparations, sulfonamides, stress -> flare
Mechanism
- Defective clearance of apoptotic cells -> nuclear antigen exposure
- -> autoreactive B/T cells, loss of tolerance
- Nucleic acid-immune complexes -> TLR7/9 on plasmacytoid dendritic cells -> type I interferon
- -> IFN signature in most patients; the target of anifrolumab
- Immune complex deposition -> complement activation -> dec C3, dec C4 + tissue injury
- BAFF/BLyS drives autoreactive B cell survival (belimumab target)
Drug-induced lupus
- Procainamide (highest risk), hydralazine, minocycline, isoniazid, quinidine, methyldopa, chlorpromazine, diltiazem, penicillamine
- Interferon-alpha and TNF inhibitors - a distinct group
- Mechanism: DNA hypomethylation -> altered T-cell gene expression (procainamide, hydralazine)
- Slow acetylators at higher risk
Diagnosis
2019 EULAR/ACR classification criteria
- Entry criterion: ANA >=1:80 (HEp-2) - if negative, stop; classification cannot proceed
- Then weighted criteria across 7 clinical + 3 immunological domains
- Classify if >=10 points, with at least one clinical criterion
- Count only the highest-weighted item within each domain; do not count a criterion with a more likely alternative explanation
| Domain | Highest-weighted items (points) |
|---|---|
| Constitutional | Fever (2) |
| Haematological | Thrombocytopenia (4), autoimmune haemolysis (4), leukopenia (3) |
| Neuropsychiatric | Psychosis (3), seizure (5), delirium (2) |
| Mucocutaneous | Discoid/CCLE (4), SCLE/ACLE (6 acute), alopecia (2), oral ulcers (2) |
| Serosal | Pericardial or pleural effusion (5), acute pericarditis (6) |
| Musculoskeletal | Joint involvement, >=2 joints (6) |
| Renal | Class III/IV nephritis (10 - classifies alone), class II/V (8), proteinuria >0.5 g/24h (4) |
| Antiphospholipid | aCL / anti-beta2GPI / LA (2) |
| Complement | Low C3 AND C4 (4), low C3 or C4 (3) |
| SLE-specific antibody | Anti-dsDNA or anti-Sm (6) |
- Older systems still quoted: 1997 ACR (4 of 11) - more specific; SLICC 2012 - more sensitive
- SLICC also classifies on biopsy-proven lupus nephritis + ANA or anti-dsDNA alone
- *Classification criteria are not diagnostic criteria* - a patient can have SLE without meeting them
Serology
| Antibody | Prevalence | Value |
|---|---|---|
| ANA | >95% | Sensitive, not specific. A negative ANA effectively excludes SLE |
| Anti-dsDNA | ~30-70% | Specific. Titre tracks activity + nephritis; can be positive without clinical activity |
| Anti-Sm | ~20% | Most specific (>95%). Does NOT correlate with activity or nephritis |
| Anti-U1RNP | ~25% | Not specific - also RA, SSc, Sjogren, PM. High titre + no other antibody = MCTD |
| Anti-Ro/La | ~30/15% | SCLE, neonatal lupus, congenital heart block, sicca, ANA-negative lupus |
| Anti-histone | >95% of DILE | Also ~50% of idiopathic SLE - presence does not prove drug cause |
| Low C3/C4 | Consumption = active disease, esp. nephritis |
- Drug-induced lupus serology splits by drug
- Procainamide / hydralazine / isoniazid -> anti-histone
- Interferon or TNF inhibitor -> anti-dsDNA
Musculoskeletal
- Arthralgia > true arthritis; symmetrical, polyarticular, migratory - knees, wrists, small joints of hand
- Smaller and fewer effusions than RA; less morning stiffness
- Jaccoud's arthropathy - symmetrical non-erosive deformity of MCP/PIP from capsular and tendon laxity
- Deformity reduces when the hand is made into a fist - the discriminator from RA
- Hand X-ray: no erosions
- ~10-30% have anti-CCP -> "rhupus" overlap, may erode
Renal - biopsy is mandatory to classify
- Biopsy if: unexplained rise in creatinine, OR proteinuria >1 g/24h, OR proteinuria >0.5 g/24h with haematuria (>5 RBC/hpf) or red cell casts
- ISN/RPS classes
| Class | Lesion | Treat? |
|---|---|---|
| I | Minimal mesangial | No immunosuppression |
| II | Mesangial proliferative | No immunosuppression |
| III | Focal (<50% glomeruli) | Yes |
| IV | Diffuse (>=50%) - commonest and most severe | Yes |
| V | Membranous - nephrotic, may be pure or mixed III/V or IV/V | Yes if nephrotic or mixed |
| VI | Advanced sclerosis (>90%) | No - supportive/RRT |
- "Full house" immunofluorescence (IgG, IgA, IgM, C1q, C3) is characteristic
- Report activity and chronicity indices - chronicity predicts irreversibility
Other workup
- FBE (anaemia, leukopenia, lymphopenia, thrombocytopenia), ESR (CRP usually normal - a high CRP suggests infection or serositis), UEC, urinalysis + UPCR, C3/C4, dsDNA
- Skin biopsy with direct immunofluorescence: granular Ig + C3 along the basement membrane ("lupus band")
- aPL screen (LA, aCL, anti-beta2GPI) at baseline in everyone
Management
Axis: universal background therapy, then escalation by organ severity. Comorbidity prevention runs in parallel.
A. Background - every patient
- Hydroxychloroquine in all patients, all severities
- Target dose <=5 mg/kg actual body weight/day
- dec flares, dec damage accrual, dec thrombosis, dec lipids, improves survival, improves MMF response in nephritis, protects against congenital heart block
- Retinopathy is the dose- and duration-limiting toxicity
- Risk inc with >5 mg/kg, >5 yr, renal impairment, pre-existing maculopathy, concurrent tamoxifen
- Baseline then annual OCT + visual fields after 5 years
- Photoprotection - broad spectrum SPF50+, clothing
- Smoking cessation (also reduces HCQ efficacy), vitamin D
- Vaccination before immunosuppression (live vaccines contraindicated once immunosuppressed)
B. Glucocorticoids - bridge only
- Maintenance target <=5 mg/day prednisolone, and withdraw where possible
- Pulse methylprednisolone 250-1000 mg IV x3 for severe disease -> allows a lower oral starting dose
- Cumulative steroid dose is the dominant driver of irreversible damage - cataract, AVN, osteoporosis, diabetes, infection
C. By severity
- Mild (skin, joints, mucosal)
- HCQ +/- short-course low-dose prednisolone
- Add methotrexate or azathioprine if steroid-dependent
- Topical steroid/calcineurin inhibitor for skin
- Moderate (significant arthritis, cutaneous, serositis, cytopenias)
- MTX, AZA, or mycophenolate
- Biologic if refractory or steroid-dependent: belimumab OR anifrolumab
- No hierarchy between them; prior immunosuppressant not required
- Anifrolumab (anti-IFNAR1) - best evidence in skin and joint disease; inc herpes zoster
- Belimumab (anti-BAFF) - also evidence in nephritis; avoid in severe active CNS disease
- Severe / organ-threatening (nephritis, CNS, vasculitis, severe cytopenias, pneumonitis)
- Pulse methylprednisolone + mycophenolate or cyclophosphamide
- Rituximab for refractory disease (failed its RCTs but retains a role)
- IVIG or plasma exchange for TTP-like disease, catastrophic APS, refractory cytopenias
- CAR-T (anti-CD19) - emerging for refractory disease, drug-free remission reported
D. Lupus nephritis
- Anchor: glucocorticoid + mycophenolate OR low-dose IV cyclophosphamide (Euro-Lupus: 500 mg 2-weekly x6)
- Low-dose Euro-Lupus regimen: equal efficacy, far less gonadal toxicity than NIH high-dose
- Add-on from the start is now standard in class III/IV (+/- V)
- Belimumab (BLISS-LN), OR
- Calcineurin inhibitor - voclosporin (AURORA) or tacrolimus
- Maintenance: mycophenolate > azathioprine, continue >=3 years after complete response, then slow taper
- All patients: ACEi/ARB, BP <130/80, statin, and SGLT2 inhibitor for residual proteinuria
- Fertility preservation before cyclophosphamide
E. Antiphospholipid / thrombosis
- Aspirin if aPL-positive without thrombosis and high-risk profile
- Warfarin (not DOAC) for arterial or triple-positive APS
F. Pregnancy
- Plan for >=6 months of quiescent disease
- Continue HCQ throughout (stopping precipitates flare)
- Compatible: HCQ, azathioprine, tacrolimus/ciclosporin, prednisolone, low-dose aspirin
- Contraindicated: mycophenolate, methotrexate, cyclophosphamide, ACEi/ARB
- MMF must be swapped to AZA at least 3 months pre-conception
- Aspirin from <16 weeks in all - pre-eclampsia prophylaxis
- Anti-Ro/La -> fetal echo surveillance 16-28 weeks for heart block
G. Comorbidity - drives late mortality
- Accelerated atherosclerosis - aggressive BP, lipid and diabetes control
- Osteoporosis prophylaxis with steroid
- PJP prophylaxis if prednisolone >=20 mg/day for >4 weeks or on cyclophosphamide
- Cervical screening (inc HPV persistence), skin surveillance
Monitoring
- Clinical + ESR (not CRP), rising anti-dsDNA, falling C3/C4, FBE, creatinine, urinalysis + UPCR
- Validated index (SLEDAI-2K, BILAG) + SLICC/ACR damage index
- A rising dsDNA with falling complement predicts flare but does not by itself mandate treatment
Associations
- Antiphospholipid syndrome - thrombosis, pregnancy morbidity
- Secondary Sjogren syndrome (~20%)
- Accelerated coronary disease - ~20% of events before age 40
- Pericardial effusion - the commonest cardiac manifestation; also Libman-Sacks endocarditis, myocarditis
- Haematological: anaemia ~70% (ACD; Coombs-positive haemolysis ~10%), leukopenia ~50%, lymphadenopathy ~40%, splenomegaly 10-45%, thrombocytopenia
- ITP can precede SLE by years; ITP + AIHA = Evans syndrome; TTP-like microangiopathy
- Neuropsychiatric: headache 24-72%, cognitive dysfunction 50-80%, mood disorder 14-57%, cerebrovascular disease 5-18%
- Shrinking lung syndrome, pleuritis, pneumonitis, pulmonary hypertension, alveolar haemorrhage
- Autoimmune thyroid disease, coeliac, myasthenia gravis
- Non-Hodgkin lymphoma (~3-4x), lung and hepatobiliary cancer; dec breast and prostate cancer
- Avascular necrosis (steroid + APS)
Natural history & complications
- 5-yr survival >95%, 10-yr ~90% in developed settings
- Relapsing-remitting; ~10-20% achieve prolonged drug-free remission
- Bimodal mortality
- Early: active disease and infection (immunosuppression)
- Late: accelerated coronary atherosclerosis, ongoing activity, treatment complications
- Damage accrues irreversibly - SLICC damage index at 5 yr predicts mortality; much of it is glucocorticoid-attributable
Predictors of poor outcome
- Lupus nephritis, esp. class IV, high chronicity index
- Male sex, younger age at onset
- Aboriginal and Torres Strait Islander, African or Asian ancestry
- Persistent hypocomplementaemia, high anti-dsDNA
- Antiphospholipid antibodies
- Delayed diagnosis, poor adherence
Complications to monitor for
- ESKD - ~10-20% of nephritis within 10 yr
- Infection - the leading cause of hospitalisation and early death
- Premature cardiovascular disease
- Osteoporosis, avascular necrosis, cataract
- Malignancy, particularly NHL
- Distinguishing flare from infection is the recurring clinical problem: CRP is usually normal in flare and high in infection**
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