Systemic lupus erythematosus

Overview

•Chronic relapsing-remitting autoimmune disease - immune complex deposition across multiple organ systems

•Female:male ratio 9:1; peak onset 15-45 years; higher severity in Afro-Caribbean patients

•Key mechanism: defective apoptotic debris clearance → autoantibody production (anti-dsDNA, anti-Sm) → immune complex deposition → complement consumption → tissue injury

Presentation

•Constitutional - fatigue, fever, weight loss, lymphadenopathy

•Dermatological (80%)

•Malar (butterfly) rash - erythema across cheeks and nasal bridge, sparing nasolabial folds (cf. rosacea which affects folds)

•Photosensitivity - rash/flare triggered by UV exposure

•Discoid rash - scarring alopecia; oral ulcers typically painless; Raynaud's phenomenon

•Musculoskeletal - non-erosive symmetrical polyarthritis (knees, wrists, hands); Jaccoud's arthropathy (deformity without erosions)

•Renal (lupus nephritis) - proteinuria, haematuria, red cell casts; may be clinically silent - routine dipstick monitoring essential

•Cardiovascular - pericarditis (most common cardiac feature); Libman-Sacks endocarditis (associated with antiphospholipid antibodies); premature atherosclerosis

•Respiratory - pleuritis (sharp pleuritic pain); exudative pleural effusion; pulmonary embolism (especially with antiphospholipid syndrome)

•Neuropsychiatric (NPSLE, up to 50%) - seizures, psychosis, cognitive dysfunction, peripheral neuropathy, cerebrovascular disease

•Haematological - normocytic anaemia of chronic disease; autoimmune haemolytic anaemia (Coombs-positive); leukopenia; lymphopenia; thrombocytopenia

🎯

The arthritis of SLE is NON-EROSIVE - the key distinguishing feature from rheumatoid arthritis. If erosions are present on imaging, reconsider the diagnosis.

Investigations

🥇 First-line

•urine dipstick + protein:creatinine ratio; urine microscopy (red cell casts = nephritis); FBC; U&Es; ESR/CRP

•ANA - sensitivity >95%, titre ≥1:160 positive; NOT specific (positive in other CTDs and healthy individuals); entry criterion for 2019 EULAR/ACR classification (≥1:80)

•Anti-dsDNA - highly specific for SLE; titres correlate with disease activity (especially nephritis); rising titres herald flare

•Anti-Sm - highly specific for SLE; titres do NOT correlate with disease activity

•Complement C3/C4 - consumed by immune complex deposition; low levels indicate active disease

•Antiphospholipid antibodies (anti-cardiolipin, anti-beta-2 glycoprotein I, lupus anticoagulant) - all patients should be tested; lupus anticoagulant prolongs APTT in vitro yet causes thrombosis in vivo

•Anti-Ro/anti-La - associated with neonatal lupus and congenital heart block; screen all women planning pregnancy

•Anti-histone antibodies - positive in SLE and drug-induced lupus

•Direct Coombs' test - screens for autoimmune haemolytic anaemia

🏆 Gold standard

•renal biopsy - classifies lupus nephritis (Classes I-VI); indicated when proteinuria >0.5 g/24 h or unexplained renal impairment

⚠️

CRP is often normal or only mildly raised in active SLE. A markedly elevated CRP should prompt consideration of concurrent infection rather than just a lupus flare.

Management

•Conservative (all patients): sun protection; cardiovascular risk optimisation; avoid combined OCP (flare risk + thromboembolism risk - especially with antiphospholipid antibodies, use progestogen-only); vaccinations (no live vaccines if immunosuppressed)

🥇 First-line

•hydroxychloroquine - given to ALL patients regardless of severity; reduces flare frequency, organ damage, and mortality; annual ophthalmology review required (retinal toxicity)

•prednisolone (oral) for active flares; high-dose IV methylprednisolone for severe manifestations (acute nephritis, NPSLE); taper to lowest effective dose

•NSAIDs (ibuprofen, naproxen) - musculoskeletal symptoms and pleuritis; caution in renal involvement

•Second-line steroid-sparing agents:

•Methotrexate - skin and joint disease

•Azathioprine - maintenance therapy; safe in pregnancy

•Mycophenolate mofetil (MMF) - first-line for induction and maintenance of lupus nephritis Classes III-V

•Cyclophosphamide - severe/refractory nephritis (Classes III-IV induction) and severe NPSLE; risks: haemorrhagic cystitis, gonadotoxicity, infection

🥉 Third-line

•belimumab (anti-BLyS, NICE-approved) - active autoantibody-positive SLE inadequately controlled by standard therapy; rituximab (anti-CD20, off-label) - refractory SLE/nephritis

•Antiphospholipid syndrome: anticoagulation with warfarin (target INR 2-3 venous; higher for arterial events)

•Bone protection: calcium and vitamin D for all patients on long-term corticosteroids; bisphosphonate if indicated

💡

Hydroxychloroquine is given to ALL patients with SLE - not just those with skin or joint involvement. The main long-term risk is cumulative, dose-dependent retinal toxicity - annual ophthalmological screening is mandatory.

Complications

•Lupus nephritis - progression to end-stage renal disease (~4%); Class IV highest risk

•Premature cardiovascular disease - 5-10 fold increased MI risk; driven by chronic inflammation, corticosteroids, dyslipidaemia, antiphospholipid antibodies

•Antiphospholipid syndrome - 30-40% of SLE patients; arterial/venous thrombosis, recurrent miscarriage

•Infections - leading cause of early mortality; opportunistic infections (PCP, fungal) with intensive immunosuppression; screen for latent TB before biologics

•Neonatal lupus - transplacental anti-Ro/La → congenital heart block, transient neonatal rash; screen all women with SLE planning pregnancy

•Osteoporosis/avascular necrosis - secondary to long-term corticosteroids; avascular necrosis of femoral head is well-recognised

•Drug toxicity - methotrexate (hepatotoxicity, pneumonitis); cyclophosphamide (haemorrhagic cystitis, gonadotoxicity, malignancy risk); azathioprine (myelosuppression)

Prognosis

•10-year survival now >90%; bimodal mortality - early deaths from active disease and infection; late deaths from cardiovascular disease, renal failure, and treatment toxicity

•Worst prognosis: lupus nephritis, neuropsychiatric involvement, antiphospholipid syndrome; Afro-Caribbean patients have more severe nephritis and greater damage accrual