Overview

Systemic Lupus Erythematosus (SLE) is a chronic, multisystem autoimmune disease characterized by the production of autoantibodies and the deposition of immune complexes in various tissues. It predominantly affects women of childbearing age, with a female-to-male ratio of approximately 9:1. The disease is more prevalent among individuals of African, Asian, and Hispanic descent, and its overall prevalence ranges from 20 to 150 cases per 100,000 people, varying by geographic region. The clinical course of SLE is highly variable, marked by alternating periods of remission and disease flare-ups.

Aetiology and Risk Factors

Multifactorial aetiology

• Genetics – common association with HLA-B8/DR3; ~10% have positive family history
• Complement deficiency C1q and C2
• TREX2 mutation
• Environment – UV radiation, cigarette smoking, infection, vitamin D deficiency
• Oestrogen
• Infection
• Certain drugs (hydralazine, procainamide, isoniazid — may cause drug-induced lupus)

Pathophysiology

Precipitating factors (factors that exacerbate and cause acute SLE reactions)

• Sun exposure (UV-B)
• Infections
• Stress
• Surgery
• Pregnancy

Pathophysiology

• Loss of immune tolerance → autoreactive T and B cells
• Production of autoantibodies (especially anti-dsDNA, anti-Smith)
• Formation of immune complexes → deposit in tissues
• Activation of complement and recruitment of inflammatory cells
• Tissue damage via type III hypersensitivity reaction

SLE can affect any organ system; key areas include:

• Joints: Synovial tissue inflammation leads to arthralgia or arthritis
• Kidneys: Glomeruli are susceptible to immune complex deposition (e.g. Class III/IV lupus nephritis)
• Skin: UV-exposed areas show photosensitive rashes due to keratinocyte apoptosis
• CNS: Blood-brain barrier disruption may allow entry of neurotoxic antibodies

Clinical Manifestations

• Constitutional: Fatigue, fever, weight loss
• Skin:
  • Malar rash (butterfly rash sparing nasolabial folds)
  • Discoid rash
  • Photosensitivity
  • Oral or nasal ulcers
• Joints: Non-erosive polyarthritis (often symmetric)
• Renal: Proteinuria, hematuria, cellular casts → Lupus nephritis
• Neurological: Seizures, psychosis, cognitive dysfunction
• Hematologic: Anemia, leukopenia, thrombocytopenia, lymphadenopathy
• Serosal: Pleuritis, pericarditis
• Cardiovascular: Raynaud’s phenomenon, livedo reticularis, Libman Sacks endocarditis
• Keratoconjunctivitis sicca

Diagnosis

• Screening: ANA (sensitive but not specific)
• Specific antibodies:
  • Anti-dsDNA (specific and correlates with disease activity)
  • Anti-Smith (highly specific but less sensitive)
• Other tests:
  • CBC (cytopenias), urinalysis (proteinuria, casts), renal function
  • Complement levels (C3/C4)
  • ESR (often ↑), CRP usually normal unless serositis or infection
  • Anti-phospholipid antibodies (linked to thrombosis)
  • Biopsy: Renal biopsy for lupus nephritis classification or skin biopsy of cutaneous lupus

2023 ACR/EULAR SLE Classification Criteria

• Entry criterion: Positive ANA at a titer ≥1:80
• Additive weighted criteria include:
  • Constitutional (fever), hematologic (leukopenia, thrombocytopenia)
  • Mucocutaneous (malar rash, ulcers), renal, neurologic, serologic (autoantibodies, complement)
• Score ≥10 is classified as SLE

Differential diagnoses

Treatment

Non pharmacological

• Avoid overexposure to sunlight: sun protection and sunblock
• Smoking cessation
• Alcohol cessation
• Calcium and Vitamin D supplements
• Vaccinations

Pharmacological

• Mild disease (e.g. rash, arthritis):
  • Hydroxychloroquine (mainstay)
  • NSAIDs, short-term corticosteroids
• Moderate disease (serositis, cytopenias):
  • Corticosteroids + immunosuppressants (azathioprine, methotrexate)
• Severe disease (nephritis, CNS):
  • High-dose corticosteroids + cyclophosphamide or mycophenolate
  • Biologics: Belimumab (anti-BLyS), Rituximab (off-label)

Complications and Prognosis

Complications
• Lupus nephritis → chronic kidney disease
• Neuropsychiatric lupus
• Increased infection risk due to immunosuppression
• Cardiovascular disease (accelerated atherosclerosis)
• Antiphospholipid syndrome (thrombosis, pregnancy loss)
• Osteoporosis (from corticosteroids)

Poor prognostic factors:
• Male gender
• Early onset nephritis
• Low complement, high anti-dsDNA
• African-American or Hispanic ethnicity
• Persistent cytopenias

Antiphospholipid Syndrome 

Antiphospholipid Syndrome is an autoimmune prothrombotic disorder first described in the 1980s, characterized by arterial and venous thromboses and/or pregnancy morbidity in the presence of antiphospholipid antibodies—namely anticardiolipin (aCL), lupus anticoagulant (LAC), and anti-β2 glycoprotein I. APS can occur as a primary condition or secondary to another autoimmune disease, most commonly Systemic Lupus Erythematosus (SLE), with which it is associated in approximately 30% of cases.

A useful mnemonic for remembering the clinical features is CLOTS:
• Coagulation defect (arterial or venous thrombosis)
• Livedo reticularis (mottled skin appearance)
• Obstetric complications (especially recurrent miscarriage)
• Thrombocytopaenia (low platelet count)
• SLE association (present in ~30% of SLE cases)

Drug-Induced Lupus 

Drug-Induced Lupus (DIL) is an autoimmune condition that mimics systemic lupus erythematosus (SLE) but is triggered by chronic exposure to certain medications. It typically presents with systemic features such as fever, arthralgia, myalgia, and serositis, but usually lacks the renal or central nervous system involvement seen in idiopathic SLE. The most commonly implicated drugs include hydralazine, procainamide, isoniazid, minocycline, and anti-TNF agents. Unlike SLE, DIL is more often associated with anti-histone antibodies and usually demonstrates a negative anti-dsDNA. Symptoms typically resolve within weeks to months after discontinuation of the offending agent, and long-term immunosuppressive therapy is rarely required.

References

1. Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the SLICC classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64(8):2677–2686.
2. Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis. 2019;78(9):1151–1159.
3. Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011;365(22):2110–2121.
4. Fanouriakis A, Kostopoulou M, Cheema K, et al. 2023 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2023;82(1):48–61.