Systemic Lupus Erythematosus

A chronic multisystem autoimmune disease characterised by loss of tolerance to nuclear antigens, immune complex formation and complement mediated tissue injury, capable of affecting virtually any organ system, with a relapsing remitting course and a strong predilection for women of childbearing age.

Pathophysiology

Defective clearance of apoptotic cellular debris exposes nuclear antigens to the immune system, driving production of autoantibodies including anti double stranded DNA and anti Smith.

Immune complexes deposit in tissues, particularly the glomerular basement membrane, activating complement and recruiting inflammatory cells, producing the characteristic pattern of organ injury.

Type I interferon pathway activation is a central driver increasingly targeted therapeutically.

• Genetic susceptibility (complement deficiencies, HLA associations), ultraviolet light exposure, infection, hormonal factors and certain drugs (procainamide, hydralazine, causing drug induced lupus) contribute to disease onset and flares.

• Constitutional symptoms (fatigue, fever, weight loss) are near universal, often preceding other manifestations.

• Mucocutaneous involvement includes the classical malar (butterfly) rash sparing the nasolabial folds, photosensitivity, discoid lupus lesions, oral ulcers (typically painless), and non scarring alopecia.

• Musculoskeletal disease with non erosive, symmetrical arthralgia and arthritis affecting small joints is common, distinguishing from the erosive pattern of rheumatoid arthritis, though a subset develop Jaccoud arthropathy with reducible deformity from ligamentous laxity without erosion.

• Renal involvement (lupus nephritis) is a major determinant of long term morbidity, presenting with proteinuria, haematuria, hypertension and, in severe forms, rapidly progressive glomerulonephritis, often clinically silent in early stages and requiring active screening.

• Serositis with pleuritis and pericarditis produces chest pain, and neuropsychiatric involvement ranges from headache and mood disturbance to seizures, psychosis and cerebrovascular events.

• Haematological manifestations include leucopenia, lymphopenia, thrombocytopenia and autoimmune haemolytic anaemia.

• Antiphospholipid antibodies coexist in a substantial proportion, conferring additional thrombotic and obstetric risk.

• Cardiovascular disease risk is substantially elevated independent of traditional risk factors, reflecting accelerated atherosclerosis driven by chronic inflammation.

• Antinuclear antibody testing is the appropriate initial screen, positive in the great majority of patients, though non specific alone.

• Anti double stranded DNA and anti Smith antibodies are highly specific, with anti double stranded DNA titre and complement levels (low C3 and C4) useful for monitoring disease activity, particularly renal flares.

• Extractable nuclear antigen panel (anti Ro, anti La, anti RNP) assesses for overlap features and specific risks (anti Ro in pregnancy).

• Full blood count, renal function, urinalysis with microscopy and urine protein to creatinine ratio are checked at diagnosis and monitored regularly given the frequently silent onset of nephritis.

• Renal biopsy is indicated for any evidence of significant proteinuria, active urinary sediment or unexplained renal impairment, both to confirm lupus nephritis and to classify its histological class, which directly guides treatment intensity.

• Antiphospholipid antibody testing (lupus anticoagulant, anticardiolipin, anti beta 2 glycoprotein I) is performed given the frequent association and its implications for thrombotic and obstetric risk.

Classification criteria (combining clinical and immunological domains) support diagnosis but clinical judgement remains central, particularly in early or evolving disease.

• Hydroxychloroquine is recommended for essentially all patients with lupus regardless of severity, reducing flares, protecting against organ damage accrual, and improving long term survival, with baseline and annual ophthalmological screening for retinal toxicity after five years of use.

• Sun protection and smoking cessation are essential given photosensitivity and the substantial impact of smoking on disease activity and cardiovascular risk.

• Nonsteroidal anti inflammatory drugs and low dose corticosteroids manage mild musculoskeletal and cutaneous disease, with corticosteroid dose minimised given cumulative toxicity.

• Moderate to severe disease requires steroid sparing immunosuppression tailored to the organ involved: methotrexate or azathioprine for arthritis and skin disease, mycophenolate mofetil or cyclophosphamide for lupus nephritis (mycophenolate is generally preferred as induction therapy given comparable efficacy with better tolerability, with cyclophosphamide reserved for severe or refractory disease), and high dose corticosteroids for severe flares including neuropsychiatric and renal disease.

• Belimumab (targeting B lymphocyte stimulator) and anifrolumab (targeting the type I interferon receptor) are approved biologic therapies for active disease despite standard treatment, and voclosporin is an approved calcineurin inhibitor specifically for lupus nephritis in combination with mycophenolate. Rituximab is used for refractory disease, particularly haematological and renal manifestations, despite formal trial results being mixed.

Antiphospholipid syndrome overlap is managed with anticoagulation, and pregnancy is planned proactively with disease quiescence sought before conception, hydroxychloroquine continued throughout, low dose aspirin from early pregnancy, and close monitoring given risks of flare, preeclampsia and, in anti Ro positive women, fetal heart block.

Cardiovascular risk factor management (blood pressure, lipids, glucose, weight) is pursued aggressively given the markedly elevated cardiovascular risk independent of conventional factors.

Vaccination (avoiding live vaccines during significant immunosuppression) and bone protection with long term corticosteroid use complete routine preventive care.

Regular monitoring of disease activity, renal function, urinalysis and serology, with prompt escalation of therapy for flares, underpins long term management of this relapsing remitting disease.