Lupus (Systemic Lupus Erythematosus) — Symptoms, Causes & Treatment | MyMedicPlus

Systemic lupus erythematosus (SLE) is a chronic, relapsing-remitting, multisystem autoimmune disease characterised by the production of pathogenic autoantibodies — particularly anti-double-stranded DNA (anti-dsDNA) and anti-Smith (anti-Sm) antibodies — against nuclear antigens, causing immune complex-mediated tissue damage across multiple organ systems. SLE affects approximately 5 million people worldwide with a striking female predominance: 9 women are affected for every 1 man, with peak onset in the reproductive years (15-45 years), reflecting the role of oestrogen in immune system modulation. Incidence and severity varies significantly by ethnicity: Black and South Asian women have a 3-4x higher incidence than White women and tend to experience more severe disease including a higher rate of lupus nephritis and end-stage renal disease. The hallmark of SLE is immune system dysregulation in which T-cells fail to properly suppress autoreactive B-cells, leading to production of IgG autoantibodies against nuclear components. These immune complexes are deposited in tissues — particularly the kidneys, skin, and joints — activating complement and triggering inflammation. Virtually any organ system can be affected: skin (photosensitive rash, discoid lupus), joints (non-erosive arthritis), kidneys (lupus nephritis — present in 50-60%), heart (pericarditis, Libman-Sacks endocarditis), lungs (pleuritis, pneumonitis), brain (neuropsychiatric SLE), and blood (haemolytic anaemia, thrombocytopenia, lymphopenia). SLE runs a relapsing-remitting course — flares triggered by ultraviolet light, infections, certain drugs, and hormonal changes — interspersed with periods of disease quiescence.

SLE results from a complex interplay of genetic predisposition, hormonal factors, environmental triggers, and epigenetic modifications that collectively disrupt immune tolerance to self-antigens. Genetic factors: SLE heritability is estimated at 44-66%; more than 100 susceptibility loci have been identified in genome-wide association studies; key genetic associations include HLA-DR2 and HLA-DR3 (strongest genetic risk factors, particularly for anti-dsDNA and anti-Sm antibodies); complement component deficiencies (C1q deficiency confers the greatest risk — near-complete association with SLE — C4 null alleles also strongly associated); Fcgamma receptor polymorphisms (FCGR2A, FCGR3A — impair clearance of immune complexes and apoptotic debris); IRF5, STAT4, BLK, PTPN22, TREX1, and IFIH1 variants. Concordance in monozygotic twins is 25-50% — underscoring the substantial but incomplete genetic contribution. Hormonal factors: oestrogen activates B-cells and reduces apoptosis, promoting autoantibody production and explaining the striking female predominance during reproductive years; flares are more frequent in pregnancy (particularly during and after); exogenous oestrogen (OCP, HRT) may trigger flares in susceptible individuals. Environmental triggers: ultraviolet (UV) light exposure induces apoptosis in keratinocytes, releasing nuclear antigens and triggering disease flares; Epstein-Barr virus (EBV) infection is strongly linked (molecular mimicry between EBNA-1 and Sm/RNP autoantigens); cigarette smoking increases disease risk and severity; silica dust exposure; drug-induced lupus (procainamide, hydralazine, isoniazid, minocycline, TNF-alpha inhibitors — usually ANA and anti-histone positive, rarely anti-dsDNA, and typically resolves on drug withdrawal).

SLE is remarkably protean — presenting across a vast spectrum from mild skin and joint disease to severe life-threatening organ involvement. Constitutional symptoms (present in 90%): fatigue (the most common and disabling symptom — affects quality of life more than any other manifestation), low-grade fever during flares, weight loss, and lymphadenopathy. Musculoskeletal (95%): non-erosive polyarthritis or polyarthralgia — typically migratory, symmetric, affecting small joints of the hands (PIPs, MCPs), wrists, and knees; morning stiffness; Jaccoud's arthropathy (deforming but non-erosive joint disease from capsular laxity); avascular necrosis of the femoral head (from steroid therapy or vasculitis). Cutaneous (85%): the classic malar (butterfly) rash — erythematous (red), flat or raised rash across the cheeks and nasal bridge, sparing the nasolabial folds, precipitated or worsened by sun exposure; discoid lupus erythematosus (DLE) — chronic scarring, pigmented, coin-shaped plaques causing permanent scarring and hair loss; photosensitivity (defined as skin rash from UV exposure); subacute cutaneous lupus erythematosus (SCLE — annular or psoriasiform rash, strongly associated with anti-Ro/SSA antibodies); oral ulcers (painless, soft palate); alopecia. Renal (50-60%): lupus nephritis — presenting as proteinuria (above 0.5g/24h), haematuria, hypertension, and impaired renal function; WHO/ISN/RPS classifications I-VI guide management; Class III and IV proliferative lupus nephritis are the most severe and require aggressive immunosuppression. Neuropsychiatric SLE (NPSLE, 25-40%): headache, cognitive dysfunction, mood disorders (depression, anxiety), psychosis, seizures, cerebrovascular disease (stroke — from antiphospholipid syndrome or vasculitis), transverse myelitis, and peripheral neuropathy. Haematological (85%): lymphopenia most common; haemolytic anaemia (Coombs-positive); thrombocytopenia; leukopenia. Cardiovascular: pericarditis (most common cardiac manifestation — pleuritic chest pain, friction rub); myocarditis; Libman-Sacks (verrucous) endocarditis (associated with antiphospholipid syndrome); premature atherosclerosis (SLE patients have 50x higher MI risk than age-matched controls). Antiphospholipid syndrome (APS): present in 20-30% of SLE patients — causing arterial and venous thrombosis, recurrent miscarriage (>2 consecutive miscarriages), and thrombocytopenia.

SLE diagnosis uses the 2019 European League Against Rheumatism (EULAR)/ACR classification criteria, which require a positive ANA test (titer 1:80 or above on HEp-2 cells) as an entry criterion, then assign weighted scores across 7 domains (constitutional, haematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal), plus specific antibody criteria; a score of 10 or above classifies SLE with 96.1% sensitivity and 93.4% specificity. Key autoantibodies: antinuclear antibody (ANA) — positive in 97-99% of SLE patients (low specificity — also positive in healthy individuals at low titers and in other autoimmune conditions); anti-double-stranded DNA (anti-dsDNA) — highly specific for SLE (95-99%), present in 60-70%, and titers correlate with disease activity — particularly useful for monitoring lupus nephritis flares; anti-Sm (anti-Smith) — highly specific (97%) but insensitive (25-30%); anti-Ro/SSA and anti-La/SSB — associated with SCLE, neonatal lupus, and secondary Sjogren's syndrome; anti-phospholipid antibodies (anticardiolipin IgG/IgM, anti-beta-2-glycoprotein-I, lupus anticoagulant) — assessed in all SLE patients; complement C3 and C4 — reduced during active disease from immune complex consumption (useful disease activity marker alongside anti-dsDNA). Urinalysis with microscopy and protein:creatinine ratio (PCR) or 24-hour urinary protein quantification at every visit — renal involvement requires kidney biopsy for ISN/RPS histological classification to guide treatment. Complete blood count (lymphopenia, haemolytic anaemia, thrombocytopenia); renal and liver function; ferritin and ESR (raised in active disease); CRP (usually normal or mildly raised in SLE — marked elevation suggests superimposed bacterial infection). SLEDAI-2K (SLE Disease Activity Index 2000) and physician global assessment scores quantify disease activity for treatment decisions.

SLE management is lifelong and aims to control disease activity, prevent organ damage, minimise treatment toxicity, and improve quality of life. Hydroxychloroquine (HCQ, 400mg/day — Plaquenil): prescribed to all SLE patients regardless of disease severity — reduces flare frequency by 50%, prevents organ damage accrual, reduces thrombosis risk in antiphospholipid syndrome, and significantly improves mortality; annual retinal screening required after 5 years (rare retinopathy risk). Sunscreen (SPF 50+) and UV avoidance are essential for all SLE patients. Corticosteroids: the most rapidly effective agents for lupus flares — used at varying doses depending on severity (low-dose prednisolone 5-15mg/day for skin and joint disease; high-dose 0.5-1mg/kg/day for severe organ involvement; IV methylprednisolone 500-1000mg for 3 days for life-threatening flares); long-term steroids carry substantial toxicity (osteoporosis, metabolic syndrome, cardiovascular disease, cataracts, avascular necrosis) — the EULAR guidelines recommend a target of prednisolone dose below 5mg/day for maintenance. Conventional immunosuppressants for steroid-sparing or moderate-severe organ disease: azathioprine (2mg/kg/day — first-line for maintenance, pregnancy-compatible); mycophenolate mofetil (MMF, 2-3g/day — first-line for lupus nephritis induction and maintenance, superior to azathioprine for nephritis; teratogenic — must not be used in pregnancy); methotrexate (7.5-25mg/week — for skin and joint disease); cyclophosphamide (Euro-Lupus regimen: IV 500mg every 2 weeks for 6 doses — for severe Class III/IV lupus nephritis, neuropsychiatric SLE, pulmonary haemorrhage). Biologics: belimumab (Benlysta — anti-BAFF/BLyS monoclonal antibody, SC 200mg weekly or IV 10mg/kg monthly) — reduces flares and organ damage progression, NICE approved for active seropositive SLE; voclosporin (Lupkynis, calcineurin inhibitor) plus MMF plus steroids for active lupus nephritis — achieved 40.8% complete renal response in AURORA trial; anifrolumab (anti-interferon-alpha receptor) — reduces cutaneous, musculoskeletal, and overall disease activity. Antiphospholipid syndrome management: primary prevention — hydroxychloroquine; secondary prevention of thrombosis — lifelong warfarin (INR 2.5-3.5 for arterial events); aspirin 75mg for obstetric APS (recurrent miscarriage).

Lupus nephritis is the most serious organ manifestation — present in 50-60% of SLE patients, with 10-20% progressing to end-stage renal disease (ESRD) requiring dialysis or transplantation; early aggressive immunosuppression (MMF or cyclophosphamide with steroids) significantly reduces progression. Premature cardiovascular disease is a leading cause of SLE mortality (along with infections and renal disease): SLE patients have a 7-10x higher risk of ischaemic heart disease than age-matched controls — driven by systemic inflammation, corticosteroid-induced dyslipidaemia and hyperglycaemia, and antiphospholipid antibody-mediated thrombosis; young women with SLE aged 35-44 years have a 50-fold higher MI risk than age-matched controls without SLE. Antiphospholipid syndrome occurs in 20-30% of SLE patients: causing DVT, PE, stroke, MI, and recurrent pregnancy loss (spontaneous abortions, stillbirth, severe pre-eclampsia); management requires lifelong anticoagulation. Infections are a major cause of morbidity and mortality in SLE — both from the disease itself (immunodeficiency) and from immunosuppressive therapy; opportunistic infections (Pneumocystis, invasive fungal infection, reactivation TB) require prophylaxis with co-trimoxazole when high-dose immunosuppression is used. Neuropsychiatric SLE (NPSLE): seizures, stroke, psychosis, and cognitive impairment can cause permanent neurological deficits. Pregnancy complications: SLE confers increased risk of pre-eclampsia (25%), preterm birth, foetal growth restriction, and neonatal lupus (from maternal anti-Ro/La antibody transfer — causing complete heart block in the foetus in 1-2% of anti-Ro positive pregnancies). Damage accrual from chronic disease and cumulative corticosteroid exposure causes cataracts, osteoporosis, avascular necrosis, and metabolic syndrome over time.

Flare prevention is the cornerstone of long-term SLE management. Sun protection is mandatory: high-factor SPF 50+ sunscreen applied daily to all sun-exposed skin (UV light is the most common trigger for cutaneous and systemic flares); UV-protective clothing; avoidance of intense midday sunlight; this single measure substantially reduces flare frequency. Medication adherence: hydroxychloroquine must be taken consistently as its protective effects require sustained blood levels — non-adherence leads to markedly higher flare rates and organ damage accrual. Infection prevention: annual influenza vaccination and pneumococcal vaccination (using non-live vaccines — live vaccines contraindicated during immunosuppression); COVID-19 vaccination; antiviral prophylaxis (valacyclovir) for VZV reactivation risk during cyclophosphamide; co-trimoxazole prophylaxis for PCP during high-dose steroid and immunosuppressant use. Cardiovascular risk reduction: aggressive management of modifiable cardiovascular risk factors (hypertension target below 130/80mmHg, statins for dyslipidaemia, smoking cessation, tight glycaemic control); aspirin 75mg for those with antiphospholipid antibodies. Bone protection during corticosteroid use: calcium 1000-1200mg/day, vitamin D 800-1000 IU/day, and bisphosphonates (alendronate, risedronate, or zoledronic acid) for all patients on prednisolone above 5mg/day for more than 3 months (or zoledronic acid IV annually for established osteoporosis). Pregnancy planning: pre-conception counselling with rheumatologist and maternal-foetal medicine specialist; ensure disease is quiescent for 6 months before conception; anti-Ro/La antibody testing to assess foetal heart block risk; LMW heparin plus low-dose aspirin for APS.

Go to A&E immediately for: chest pain with breathlessness (possible pericarditis, pulmonary embolism, or myocarditis — all occur in SLE); sudden onset of one-sided limb weakness, speech difficulty, or facial drooping (stroke — antiphospholipid syndrome causes premature stroke even in young women with SLE); sudden severe headache ('worst ever' headache), confusion, or seizure in a known SLE patient (neuropsychiatric SLE or CNS vasculitis — requires urgent brain MRI and neurology review); haemoptysis (pulmonary haemorrhage — rare, life-threatening lupus manifestation); and vomiting with inability to take oral medication in a patient on corticosteroids (adrenal insufficiency from steroid withdrawal during illness — requires IV hydrocortisone). See your rheumatologist urgently for: significant worsening of lupus symptoms (new rash, new joint swelling, fever without infection, increasing fatigue); new proteinuria or blood in urine (possible lupus nephritis flare requiring urgent nephrology review and possible renal biopsy); a lupus patient attempting to conceive (requires pre-pregnancy optimisation of SLE activity and medication review). See your GP for: unexplained fatigue, butterfly-shaped facial rash, persistent joint pain in young women — SLE should be considered in the differential diagnosis of unexplained multisystem disease in women of childbearing age; ANA testing should be requested where SLE is suspected.