Systemic Lupus Erythematosus — Symptoms, Causes & Treatment | MyMedicPlus

Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease characterised by widespread inflammation and damage to connective tissue throughout virtually every organ system, including the skin, joints, kidneys, heart, lungs, brain, and blood. The immune system produces autoantibodies — particularly anti-double-stranded DNA (anti-dsDNA) and anti-Smith (anti-Sm) antibodies — that form immune complexes which deposit in tissues and activate complement, causing organ injury. SLE follows a relapsing-remitting course with unpredictable flares and periods of relative remission. It predominantly affects women of childbearing age, with a 9:1 female-to-male ratio; this gender disparity implicates oestrogen and hormonal factors in pathogenesis. Prevalence is 20-150 per 100,000, with significantly higher rates in African Americans (3-4x higher), Asians, and Hispanics compared to Caucasians — likely reflecting both genetic and environmental influences. Without adequate treatment, SLE can cause progressive and irreversible organ damage, particularly lupus nephritis (affecting the kidneys in 40-60%) and accelerated cardiovascular disease. Ten-year survival now exceeds 90% in high-income countries with contemporary treatment.

SLE results from a failure of central and peripheral immune tolerance, leading to the production of pathogenic autoantibodies against nuclear antigens. The precise trigger is multifactorial: genetic susceptibility accounts for approximately 44% of SLE risk (higher in monozygotic twin concordance, ~25%). Key genetic associations: HLA-DR2 and HLA-DR3 haplotypes; complement deficiencies (C1q deficiency confers the highest genetic risk — ~90% of individuals with complete C1q deficiency develop SLE; C2 and C4 deficiencies also increase risk); and polymorphisms in IRF5, STAT4, and PTPN22 genes involved in type I interferon signalling. Hormonal factors: oestrogen promotes autoreactive B-cell survival and enhances type I interferon production — explains the female predominance and association with exogenous oestrogen (oral contraceptive pill, hormone replacement therapy). Environmental triggers: UV light exposure (induces apoptosis of keratinocytes, releasing nuclear antigens that trigger autoimmunity — the basis of photosensitivity); Epstein-Barr virus (EBV) infection (molecular mimicry between EBNA-1 and Sm antigens); cigarette smoking increases SLE risk and worsens disease activity. Drug-induced lupus (DILE) is caused by hydralazine, procainamide, isoniazid, minocycline, and anti-TNF biologics — resolves on drug discontinuation and is anti-histone antibody positive.

SLE is a great imitator — it can affect almost every organ system and its clinical presentation is highly variable between individuals. Constitutional symptoms: fatigue (the most common symptom, affecting 90%), fever, weight loss, and malaise during flares. Mucocutaneous manifestations: butterfly (malar) rash (40-50% — fixed erythema across the cheeks and nose bridge, characteristically sparing the nasolabial folds, lasting days to weeks); photosensitivity (abnormal skin reaction to UV light); discoid rash (chronic scarring plaques causing permanent skin damage and hair loss); painless oral or nasal ulcers. Musculoskeletal: non-erosive polyarthritis or arthralgia (90% of patients — symmetric, involving small and large joints; does not cause bone erosion, distinguishing it from rheumatoid arthritis); myositis (myalgia and proximal muscle weakness). Renal: lupus nephritis (40-60% of patients — proteinuria, haematuria, hypertension, and declining eGFR); the single most important organ involvement affecting long-term prognosis. Cardiac and pulmonary: serositis (pleuritis or pericarditis — pleuritic chest pain and exudate); Libman-Sacks endocarditis (sterile vegetations on heart valves). Neurological: neuropsychiatric lupus (NPSLE — seizures, psychosis, cognitive impairment, headache, peripheral neuropathy). Haematological: haemolytic anaemia, lymphopenia, thrombocytopenia. Raynaud's phenomenon (colour changes of fingers on cold exposure).

SLE diagnosis is clinical, supported by immunological testing. The 2019 ACR/EULAR classification criteria require: ANA (anti-nuclear antibody) as a mandatory entry criterion (sensitivity above 95% in SLE but non-specific); followed by weighted scoring across 10 clinical and immunological domains, with a score of 10 or more confirming SLE classification. Key autoantibodies: anti-double-stranded DNA (anti-dsDNA) — present in 60-70% of SLE patients; highly specific (97%); correlates with disease activity (titres rise during renal flares and fall with treatment response); anti-Smith (anti-Sm) — present in 25-30% but highly specific (~99%) for SLE; anti-Ro/SSA and anti-La/SSB — associated with neonatal lupus (heart block risk) and secondary Sjogren's syndrome; anti-phospholipid antibodies (anti-cardiolipin, anti-β2-glycoprotein I, lupus anticoagulant) — associated with antiphospholipid syndrome (thrombosis and recurrent pregnancy loss). Complement: serum C3 and C4 fall during active SLE (complement consumed in immune complex deposition) — useful for monitoring flares. Full blood count (CBC): pancytopenia (haemolytic anaemia, lymphopenia below 1.0, thrombocytopenia below 100). Urinalysis and urine protein-to-creatinine ratio (UPCR): proteinuria and haematuria indicate lupus nephritis. Renal biopsy: essential for nephritis classification (ISN/RPS Classes I-VI) — determines immunosuppressive treatment intensity. Additional tests: CRP (often normal in SLE flare — a raised CRP with active SLE suggests concurrent bacterial infection); liver function tests; lipid profile.

Hydroxychloroquine (HCQ) 200-400 mg per day is the cornerstone of SLE management for ALL patients without contraindication — it reduces flares by 50%, prevents organ damage, improves survival, reduces thrombosis risk (particularly important in antiphospholipid syndrome), and is safe in pregnancy. Ophthalmological screening (retinal OCT) is recommended annually after 5 years of HCQ use due to rare maculopathy risk at cumulative doses. Mild to moderate disease: topical sunscreens and UV avoidance (essential for photosensitive patients); NSAIDs for arthralgia and serositis; low-dose prednisolone (5-15 mg per day) for symptom control during flares. Moderate to severe disease: immunosuppressive agents — azathioprine (1-2 mg/kg/day) or mycophenolate mofetil (MMF, 2-3 g per day) for maintenance therapy; cyclophosphamide (IV Eurolupus protocol — 500 mg IV every 2 weeks for 6 doses) for severe proliferative lupus nephritis (Class III/IV). Biologic therapies: belimumab (anti-BLyS/BAFF monoclonal antibody, IV or SC) — reduces flares by 50% in seropositive patients, approved for active SLE; anifrolumab (anti-type I interferon receptor monoclonal antibody, IV monthly) — approved by FDA in 2021 and NICE in 2022 for moderate-to-severe SLE despite standard treatment; rituximab (anti-CD20, off-label) — used for refractory haematological and renal disease. Antiphospholipid syndrome: anticoagulation with warfarin (INR 2.5-3.5) or DOACs for thrombosis; aspirin and LMWH for pregnancy with aPL.

Lupus nephritis (40-60% of patients) is the leading cause of SLE morbidity — Class III-IV proliferative nephritis requires aggressive immunosuppression; approximately 10-20% of lupus nephritis patients progress to end-stage renal disease (ESRD) requiring dialysis or kidney transplantation. Accelerated atherosclerosis and cardiovascular disease: the leading cause of late mortality in SLE — young women with SLE have a 10-fold increased risk of myocardial infarction compared to age-matched controls, driven by chronic inflammation, steroids, and antiphospholipid antibodies. Antiphospholipid syndrome (APS) occurs in 30-40% of SLE patients — causes arterial and venous thrombosis (stroke, DVT, PE) and recurrent pregnancy loss. Neuropsychiatric lupus (NPSLE) affects 40% of patients — manifestations include cognitive impairment, seizures, psychosis, and depression. Infection: immunosuppressive therapy increases susceptibility to bacterial infections (Pneumocystis jirovecii prophylaxis with co-trimoxazole is indicated in patients on cyclophosphamide or high-dose steroids). Long-term steroid complications: osteoporosis, avascular necrosis (osteonecrosis of femoral head, affecting 5-10%), adrenal suppression, cataracts, and metabolic syndrome. Pregnancy complications: lupus flares during pregnancy, pre-eclampsia (4x increased risk), fetal growth restriction, and neonatal lupus (from anti-Ro antibodies — 2% risk of neonatal complete heart block).

Sun protection is essential for all SLE patients: broad-spectrum SPF 50+ sunscreen applied daily (not just on sunny days), UV-protective clothing (UPF 50+ rated), and minimising midday outdoor exposure — UV light triggers immune activation and flares. Continue hydroxychloroquine throughout pregnancy (stopping is associated with increased flare risk) — HCQ is safe in pregnancy and reduces neonatal lupus risk. Smoking cessation: smoking increases SLE disease activity, reduces response to HCQ and belimumab, and exacerbates cardiovascular risk. Avoid oestrogen-containing combined oral contraceptive pills in patients with antiphospholipid antibodies or active lupus nephritis (increased thrombosis risk) — use progestogen-only methods or barrier contraception. Vaccinations: influenza (annual), pneumococcal, meningococcal, and COVID-19 vaccines are recommended; live vaccines (MMR, yellow fever, varicella) are contraindicated in patients on immunosuppressants. Regular monitoring (every 3 months in active disease): CBC, CRP, complement (C3/C4), anti-dsDNA titre, urinalysis with UPCR, blood pressure, renal function, HbA1c, and lipid profile. Annual cardiovascular risk stratification and DEXA scan for steroid-treated patients. Vitamin D supplementation and calcium for patients on steroids.

Seek emergency care immediately for: acute chest pain with breathlessness in a person with known SLE (possible lupus pleuritis, pericarditis, or pulmonary embolism — SLE causes a hypercoagulable state); severe headache with confusion, new focal neurological deficit, or seizures (possible lupus cerebritis or stroke from antiphospholipid syndrome); acute kidney injury (falling urine output, rapid oedema) in an SLE patient — possible lupus nephritis flare requiring urgent renal biopsy and high-dose immunosuppression. See a rheumatologist urgently for: new or worsening arthritis, rash, fever, and fatigue in a woman of childbearing age — the classic SLE presentation; unexplained thrombocytopenia or haemolytic anaemia; or new proteinuria in a known SLE patient (possible lupus nephritis — requires prompt treatment to prevent renal scarring). SLE is a multisystem autoimmune condition requiring long-term specialist follow-up with rheumatology — do not self-discontinue hydroxychloroquine (reduced disease activity and organ damage across all SLE subtypes, including during pregnancy) without specialist advice.