Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is the prototypic multisystem autoimmune disease driven by loss of tolerance to nuclear antigens, immune-complex deposition and complement activation. It is overwhelmingly a disease of young women (F:M ~9:1, peak 15–45 years) and is a perennial NEET PG favourite for its criteria, autoantibody specificities and lupus nephritis classification.

Definition & overview

SLE is a chronic, relapsing–remitting autoimmune disorder characterised by autoantibodies against nuclear and cytoplasmic antigens, with protean clinical manifestations ranging from mild mucocutaneous disease to life-threatening nephritis, cerebritis and serositis. The hallmark is immune-complex–mediated tissue injury (type III hypersensitivity), with a contribution from type II (cytopenias) reactions.

High-yield: SLE is the classic example of a type III hypersensitivity disease. Drug-induced lupus, antiphospholipid syndrome and neonatal lupus are exam-favourite "spin-off" entities.

Etiology & pathophysiology

The disease arises from an interplay of genetic susceptibility, hormonal (oestrogen) influence and environmental triggers acting on a dysregulated immune system.

Genetic: Strongest associations are with HLA-DR2 and HLA-DR3. Homozygous deficiency of early complement components — C1q > C4 > C2 — is the strongest single genetic risk (C1q deficiency carries the highest penetrance, ~90%). These defects impair clearance of apoptotic debris and immune complexes.

Core mechanism (stepwise):

Defective clearance of apoptotic cells → persistence of nuclear antigens (dsDNA, histones, Sm, Ro/La) → antigen presentation + loss of B/T-cell tolerance → autoantibody production by autoreactive B cells → immune-complex formation → deposition in tissues (glomeruli, skin, joints, serosa) → complement activation + neutrophil/cytokine recruitment → tissue injury & consumption of C3/C4.

A key amplification loop involves type I interferon (IFN-α): immune complexes containing nucleic acids engage TLR-7/TLR-9 in plasmacytoid dendritic cells, driving the "interferon signature" central to modern pathogenesis and the target of newer biologics (anifrolumab).

High-yield: Falling C3/C4 with rising anti-dsDNA titres signals active disease / impending flare, particularly nephritis. Complement is consumed, so low levels = active disease.

Triggers to remember: UV light (photosensitivity, keratinocyte apoptosis), oestrogens/pregnancy, EBV infection, and drugs.

Drug-induced lupus (DIL)

A clean, frequently tested contrast to idiopathic SLE.

Feature	Idiopathic SLE	Drug-induced lupus
Sex ratio	Strongly female	Equal M:F
Renal/CNS involvement	Common	Rare
Hallmark antibody	Anti-dsDNA, anti-Sm	Anti-histone (>95%)
Complement	Often low	Usually normal
Course	Chronic	Resolves on stopping drug

High-yield: Classic DIL drugs — Procainamide (highest risk), Hydralazine, Isoniazid, Minocycline, Quinidine, Methyldopa, anti-TNF agents. Mnemonic: "PHIMQ" / "Having Pretty Quick Memory Is Nice". Anti-histone antibody is the screening test; anti-dsDNA is typically absent (except in anti-TNF–induced DIL).

Clinical features

SLE can affect virtually every organ. The most common overall manifestations are constitutional symptoms, arthralgia/arthritis and mucocutaneous disease.

Constitutional: Fatigue, fever, weight loss (present in the majority).

Musculoskeletal (most common): Symmetrical, non-erosive, non-deforming polyarthritis. Jaccoud arthropathy = reducible deformities from ligamentous laxity without bony erosion (distinguishes from rheumatoid arthritis). Avascular necrosis (often steroid-related) is a recognised complication.

Mucocutaneous:

• Malar (butterfly) rash — spares the nasolabial folds (contrast with dermatomyositis/rosacea).
• Discoid lupus — scarring, follicular plugging, can cause scarring alopecia.
• Photosensitivity, oral/nasopharyngeal ulcers (typically painless), non-scarring alopecia.

Renal — lupus nephritis: A major determinant of prognosis (see classification below).

Haematological: Autoimmune haemolytic anaemia (Coombs +), leukopenia/lymphopenia, thrombocytopenia — any cytopenia is a criterion.

Serositis: Pleuritis, pericarditis (most common cardiac manifestation), peritonitis.

Cardiac: Libman–Sacks endocarditis — sterile, verrucous vegetations on both surfaces of valves (classically mitral); associated with antiphospholipid antibodies. Premature accelerated atherosclerosis is a leading cause of late mortality.

Pulmonary: Pleuritis, interstitial lung disease, and the rare but tested "shrinking lung syndrome".

Neuropsychiatric (NPSLE): Seizures, psychosis, cognitive dysfunction, stroke (often APS-related), aseptic meningitis.

High-yield: Libman–Sacks endocarditis = vegetations on both surfaces of the valve, sterile, associated with antiphospholipid antibodies — a recurrent NEET PG one-liner.

Autoantibodies — the exam core

Antibody	Sensitivity / Specificity	Clinical association
ANA	Highly sensitive (~95–99%); poor specificity	Screening test; if negative, SLE very unlikely
Anti-dsDNA	Specific; correlates with activity	Lupus nephritis, disease flare
Anti-Sm (Smith)	Most specific (least sensitive)	Diagnostic marker
Anti-histone	Sensitive for DIL	Drug-induced lupus
Anti-Ro (SSA)/La (SSB)	—	Neonatal lupus, congenital heart block, subacute cutaneous LE, Sjögren overlap, ANA-negative SLE
Anti-U1 RNP	High titres	Mixed connective tissue disease (MCTD)
Antiphospholipid (LA, anti-cardiolipin, anti-β2-GPI)	—	Thrombosis, recurrent miscarriage, false-positive VDRL
Anti-ribosomal P	Specific	Lupus psychosis / cerebritis

High-yield: ANA = best screening (sensitive); anti-dsDNA + anti-Sm = most specific (confirmatory). Anti-dsDNA tracks with nephritis activity; anti-Sm does NOT track activity but is diagnostic.

Mnemonic for the "specific pair": "dsDNA and Sm Specify SLE."

Classification / diagnostic criteria

Two named criteria sets are tested. Criteria are for classification, not strict diagnosis — clinical judgement prevails.

ACR 1997 (revised): 11 criteria, need ≥4 (need not be simultaneous). Mnemonic "SOAP BRAIN MD":

• S – Serositis
• O – Oral ulcers
• A – Arthritis (non-erosive)
• P – Photosensitivity
• B – Blood disorders (cytopenias)
• R – Renal (proteinuria >0.5 g/day or cellular casts)
• A – ANA
• I – Immunologic (anti-dsDNA, anti-Sm, antiphospholipid)
• N – Neurologic (seizures, psychosis)
• M – Malar rash
• D – Discoid rash

SLICC 2012: Requires ≥4 criteria (with ≥1 clinical AND ≥1 immunologic), OR biopsy-proven lupus nephritis with positive ANA or anti-dsDNA alone. More sensitive than ACR; added low complement and direct Coombs as immunologic criteria.

EULAR/ACR 2019 (newest, weighted): Entry criterion = positive ANA (≥1:80) — mandatory gate. Then weighted criteria across domains; score ≥10 classifies SLE. Anti-dsDNA/anti-Sm score the highest immunologic weight.

High-yield: In the 2019 EULAR/ACR criteria, a positive ANA is the mandatory entry requirement — without it you cannot classify SLE. Threshold score = 10.

Lupus nephritis — ISN/RPS 2003 classification

Renal biopsy is the investigation of choice to classify and guide therapy. Indications: proteinuria >0.5 g/day, active sediment, rising creatinine.

Class	Pattern	Key features / management note
I	Minimal mesangial	Normal LM; deposits on IF only
II	Mesangial proliferative	Mesangial hypercellularity; good prognosis
III	Focal (<50% glomeruli)	Proliferative; immunosuppression needed
IV	Diffuse (≥50%)	Most common & most severe; "wire-loop" lesions; aggressive therapy
V	Membranous	Subepithelial deposits; nephrotic syndrome
VI	Advanced sclerosing (>90% sclerosed)	Irreversible; transplant/dialysis

High-yield: Class IV (diffuse proliferative) is the most common and most aggressive; "wire-loop" capillary lesions are characteristic. Class V presents as nephrotic syndrome. Renal biopsy on IF shows the "full-house" pattern (IgG, IgA, IgM, C3, C1q all positive) — a classic NEET PG buzzword.

Investigations — approach

Screening → confirmation → activity → organ assessment:

1. ANA (immunofluorescence on HEp-2 cells) — sensitive screen. A negative ANA makes SLE unlikely.
2. Anti-dsDNA + anti-Sm — confirm specificity.
3. Complement C3/C4 — low in active disease.
4. CBC (cytopenias), Coombs test, ESR (raised; CRP usually normal/low — a rise in CRP suggests infection or serositis).
5. Urinalysis + spot protein:creatinine, renal function ± renal biopsy.
6. Antiphospholipid panel (lupus anticoagulant, anti-cardiolipin, anti-β2-GPI).

High-yield: In SLE, ESR is high but CRP is characteristically normal/low. A high CRP should prompt a search for infection or serositis — exam favourite discriminator.

Management & drug of choice

Treatment is stratified by disease severity and organ involvement.

Foundation for ALL patients — Hydroxychloroquine (HCQ):

• Reduces flares, improves survival, protects against thrombosis and organ damage.
• Mandatory baseline and during pregnancy.
• Toxicity = retinopathy → baseline and annual ophthalmologic screening (the classic "bull's-eye maculopathy").

High-yield: Hydroxychloroquine is the baseline/anchor drug for every SLE patient. Its dose-limiting toxicity is retinopathy (bull's-eye maculopathy) requiring annual eye screening.

Mild disease (skin/joints): HCQ + NSAIDs ± short low-dose steroids. Sun protection.

Moderate disease: Add steroids + steroid-sparing agents — methotrexate, azathioprine.

Severe disease (lupus nephritis class III/IV, CNS, severe cytopenias):

• Induction: High-dose corticosteroids + either IV cyclophosphamide (NIH/Euro-Lupus regimen) OR mycophenolate mofetil (MMF). MMF is preferred in younger patients wishing to preserve fertility and in Black/Hispanic populations.
• Maintenance: MMF or azathioprine (azathioprine is safe in pregnancy).
• Belimumab (anti-BLyS/BAFF monoclonal) and anifrolumab (anti–IFN-α receptor) are add-ons for refractory disease; voclosporin + MMF is now approved for lupus nephritis.

Refractory: Rituximab (anti-CD20) in selected cases.

High-yield: For severe proliferative lupus nephritis, induction = steroids + (cyclophosphamide OR mycophenolate). Azathioprine and HCQ are the pregnancy-safe options; cyclophosphamide, methotrexate and MMF are teratogenic/contraindicated in pregnancy.

Lifestyle/adjunct: Sunscreen (UV avoidance), vaccination (avoid live vaccines on immunosuppression), cardiovascular risk control, bone protection on steroids.

Antiphospholipid syndrome (APS) — high-yield overlap

APS may be primary or secondary to SLE. Defined by vascular thrombosis or pregnancy morbidity PLUS persistently positive antiphospholipid antibodies (≥12 weeks apart) — the Sapporo/revised Sydney criteria.

• Antibodies: lupus anticoagulant, anti-cardiolipin, anti-β2-glycoprotein I.
• Lab paradox: prolonged aPTT in vitro (lupus anticoagulant) but thrombosis in vivo; false-positive VDRL/RPR.
• Catastrophic APS (CAPS) = multi-organ thrombosis, high mortality.
• Management: thrombosis → lifelong warfarin (target INR 2–3); obstetric APS → LMWH + low-dose aspirin through pregnancy. DOACs are NOT recommended, especially in triple-positive patients.

High-yield: APS gives a false-positive VDRL and a prolonged aPTT that does not correct with mixing (presence of an inhibitor), yet the clinical picture is thrombosis. Treat thrombosis with warfarin (INR 2–3), not DOACs.

Neonatal lupus

Transplacental passage of maternal anti-Ro (SSA)/anti-La (SSB) antibodies.

• Reversible: rash, cytopenias, hepatitis (resolve as maternal antibody clears).
• Irreversible: congenital complete heart block (may require pacing).

High-yield: Anti-Ro/La → neonatal lupus → congenital heart block. Mother may be ANA-negative SLE or Sjögren.

Complications

• Renal failure from nephritis (major cause of morbidity).
• Accelerated atherosclerosis / premature CAD — leading late cause of death.
• Infection — leading early cause of death (disease + immunosuppression).
• Thrombosis (APS), pregnancy loss.
• Avascular necrosis, osteoporosis (steroids).
• NPSLE, antiphospholipid-related stroke.

High-yield: Bimodal mortality — early deaths from active disease + infection; late deaths from accelerated atherosclerosis/cardiovascular disease.

Key differentials

Condition	Distinguishing pointer
Rheumatoid arthritis	Erosive, deforming arthritis; anti-CCP positive
Drug-induced lupus	Anti-histone +, no renal/CNS, resolves on drug stop
Mixed connective tissue disease	High-titre anti-U1 RNP, overlap features, Raynaud
Systemic sclerosis	Anti-Scl-70/anti-centromere; skin thickening
Dermatomyositis	Heliotrope rash, Gottron papules, malar rash involves nasolabial folds
Adult-onset Still disease	Quotidian fever, salmon rash, very high ferritin, ANA negative

Recently asked / exam angle

• Most specific antibody in SLE → anti-Sm; most sensitive screen → ANA.
• Antibody correlating with disease activity/nephritis → anti-dsDNA (with falling C3/C4).
• "Full-house" immunofluorescence and wire-loop lesions → lupus nephritis (class IV).
• Drug-induced lupus antibody → anti-histone; commonest drug → procainamide (hydralazine for "highest in slow acetylators").
• Libman–Sacks endocarditis → sterile vegetations, both valve surfaces, linked to antiphospholipid antibodies.
• Anti-Ro/La → neonatal lupus + congenital heart block; also ANA-negative SLE and subacute cutaneous LE.
• Baseline drug for all SLE → hydroxychloroquine; toxicity → retinopathy.
• 2019 EULAR/ACR criteria → positive ANA is the mandatory entry criterion, cut-off score 10.
• CRP normal but ESR high in active SLE; high CRP → suspect infection.
• APS treatment → warfarin (INR 2–3); DOACs avoided in triple-positive APS.
• Investigation of choice for lupus nephritis → renal biopsy.
• Pregnancy-safe immunosuppressants → hydroxychloroquine, azathioprine; avoid cyclophosphamide, MMF, methotrexate.

Rapid revision

1. SLE = type III hypersensitivity; F:M ≈ 9:1, young women.
2. Strongest genetic link: C1q deficiency; HLA-DR2/DR3.
3. ANA = most sensitive screen; anti-Sm = most specific; anti-dsDNA = activity & nephritis.
4. Low C3/C4 + high anti-dsDNA = active disease / flare.
5. Anti-histone = drug-induced lupus (procainamide highest); renal/CNS spared.
6. Anti-Ro/La = neonatal lupus + congenital heart block + ANA-negative SLE.
7. Anti-U1 RNP = MCTD; anti-ribosomal P = lupus psychosis.
8. Class IV diffuse proliferative nephritis = commonest & worst; wire-loop + full-house IF.
9. Hydroxychloroquine = anchor for all; toxicity = bull's-eye retinopathy.
10. Severe nephritis induction = steroids + cyclophosphamide or MMF; maintenance = MMF/azathioprine.
11. Libman–Sacks = sterile vegetations on both valve surfaces; ESR high, CRP normal.
12. APS: thrombosis + antiphospholipid antibodies → warfarin INR 2–3, false-positive VDRL, prolonged aPTT; bimodal mortality (early infection, late atherosclerosis).