Systemic Lupus Erythematosus

Notes

Connective Tissue Diseases | Rheumatology

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.

Definition

Autoimmunity: Immune system’s attack on self-antigens. Does not mean an autoimmune disease. Autoimmune disease is when autoimmunity causes signs and symptoms of a disease.
Antinuclear antibodies (ANA): Autoantibodies directed against nuclear antigens, hallmark of SLE.
Immune complex: Antigen-antibody aggregate that can deposit in tissues causing inflammation.
Lupus nephritis: Kidney inflammation due to immune complex deposition, a major complication of SLE.

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)

Estrogen may enhance autoantibody production — a possible reason for female predominance.

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

Low complement (C3, C4) levels suggest ongoing immune complex consumption and active disease.

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

Malar rash, arthritis, and nephritis are among the most common presentations.

In young females with multisystem symptoms, always consider SLE.

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

Condition	Key Differentiator
Rheumatoid Arthritis	Erosive arthritis, RF/anti-CCP +
Dermatomyositis	Muscle weakness, elevated CK, Gottron’s papules
Drug-induced lupus	Positive anti-histone, no nephritis or CNS. Typically arthritis and cutaneous manifestations
Mixed connective tissue disease	Overlap features + anti-U1 RNP

SLE can overlap with other autoimmune diseases. For example SLE can occur with seropositive rheumatoid arthritis overlap typically referred to as Rupus.

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)

Hydroxychloroquine improves survival and reduces flares — baseline and annual eye exams are required after 5 years use.

Always tailor immunosuppressants to organ system involvement and disease severity.

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

Most deaths are due to cardiovascular disease or infections in late disease.

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.

Anti-histone antibodies are present in over 90% of DIL cases.

Renal and CNS involvement is rare.

Resolution occurs with drug withdrawal.

In a patient with new-onset lupus-like symptoms and no prior autoimmune history, always review the medication list for potential triggers.

References

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.
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.
Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011;365(22):2110–2121.
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.