What is the overview of Systemic Lupus Erythematosus (SLE)?

Systemic Lupus Erythematosus: Clinical Overview

Disease Definition and Pathophysiology

Systemic lupus erythematosus (SLE) is a complex multisystemic autoimmune disease characterized by loss of immune tolerance, production of autoantibodies against nuclear antigens, immune complex deposition, and chronic inflammation affecting multiple organ systems. 1, 2

• The disease results from fundamental failure of immunological tolerance, leading to pathogenic autoantibody production present in virtually all patients 3
• Genetic factors (including MHC polymorphisms) and environmental triggers (particularly viral infections) interact to precipitate disease onset 1, 3
• Immune complex deposition activates complement, recruits inflammatory cells, and causes subsequent tissue damage 3

Epidemiology and Demographics

• Approximately 3.4 million people worldwide have SLE, with approximately 90% being female 4
• The disease predominantly affects women during childbearing years 1
• Latin American, North American Mestizo, African descendants, and Native Americans develop lupus earlier, experience more severe disease, higher disease activity, greater organ damage accumulation, and higher mortality rates 1
• These populations succumb primarily to disease activity and/or infections 1

Clinical Manifestations

The earliest complaints typically include constitutional, mucocutaneous, and musculoskeletal symptoms: fatigue, lupus-specific rash, mouth ulcers, alopecia, joint pain, and myalgia. 2

Organ System Involvement

The disease can affect multiple systems 1, 3:

• Mucocutaneous: lupus-specific rashes, discoid lesions, photosensitivity
• Musculoskeletal: arthritis, myalgia
• Renal: lupus nephritis (develops in approximately 40% of patients) 4
• Cardiovascular: pericarditis, myocarditis, accelerated atherosclerosis
• Pulmonary: pleuritis, interstitial lung disease (1-15% prevalence, typically NSIP pattern) 1
• Neuropsychiatric: seizures, psychosis, cognitive dysfunction
• Hematologic: cytopenias (anemia, thrombocytopenia, leukopenia)
• Gastrointestinal: various manifestations

Diagnostic Approach

The 2019 EULAR/ACR classification criteria are 96.1% sensitive and 93.4% specific for SLE, requiring both clinical manifestations and immunologic abnormalities. 1, 4

Key Diagnostic Elements

Clinical features (weighted within each domain) 1, 4:

• Fever
• Cytopenia
• Characteristic rash
• Arthritis
• Serositis
• Proteinuria (indicating possible lupus nephritis)

Immunologic markers 1, 4:

• Anti-double-stranded DNA (anti-dsDNA) antibodies
• Anti-Smith (anti-Sm) antibodies
• Hypocomplementemia (low C3/C4)
• Antiphospholipid antibodies
• Anti-Ro/SSA and anti-La/SSB antibodies
• Anti-RNP antibodies
• Anti-C1q antibodies (particularly associated with lupus nephritis) 1, 3

Prognostic Indicators

Clinical and laboratory parameters that correlate with worse outcomes include: 1

• Discoid lesions, arthritis, serositis, renal involvement, seizures/psychosis
• Anemia, thrombocytopenia
• Positive anti-dsDNA, anti-C1q, antiphospholipid antibodies
• Low serum complement concentrations
• Brain MRI abnormalities and renal biopsy findings

Treatment Goals and Principles

The primary treatment goal is achieving and maintaining remission or low disease activity as soon as diagnosis is made, using the lowest possible glucocorticoid dose for the shortest duration. 1, 5

Overarching Treatment Principles

The GLADEL/PANLAR and EULAR guidelines establish five core principles 1:

1. Multidisciplinary care with shared patient-physician decision-making and active family involvement
2. Target remission or low disease activity from diagnosis onward
3. Comprehensive preventive care: photo-protection, osteoporosis prevention, cardiovascular risk reduction, metabolic syndrome management, infection prevention, psychological support, and pregnancy counseling
4. Universal antimalarial therapy for all patients unless contraindicated
5. Glucocorticoid minimization to lowest dose and shortest duration regardless of manifestations

First-Line Pharmacotherapy

Hydroxychloroquine is standard of care for all SLE patients and has been associated with significant mortality reduction. 5, 4

• Dose should not exceed 5 mg/kg real body weight 5
• Should be used unless absolute contraindications exist 1

Glucocorticoids 1, 5:

• Dose and route depend on organ involvement type and severity
• Should be prescribed at lowest possible dose for shortest duration
• Can be used with hydroxychloroquine for non-major organ manifestations

Immunosuppressive Therapy

For patients not responding to hydroxychloroquine/glucocorticoids or unable to reduce steroids to acceptable chronic doses, add immunosuppressive agents: 1, 5, 4

• Azathioprine
• Mycophenolate mofetil
• Methotrexate
• Cyclophosphamide (for severe disease)
• Cyclosporin

Biologic Therapies

Three FDA-approved biologics are now available: 4

• Belimumab: approved for active SLE (2011) and lupus nephritis (2020)
• Anifrolumab: approved for active SLE
• Voclosporin: approved for lupus nephritis

Rituximab may be considered in organ-threatening, refractory disease 1

Organ-Specific Treatment Strategies

Cutaneous manifestations 5:

• First-line: topical glucocorticoids and hydroxychloroquine

Hematologic manifestations (thrombocytopenia, autoimmune hemolytic anemia) 5:

• Initial therapy: pulse methylprednisolone intravenously

Lupus nephritis 5:

• Treatment goal: achieve at least partial remission (≥50% reduction in proteinuria to subnephrotic levels, serum creatinine within 10% of baseline) within 6-12 months
• Approximately 10% develop end-stage kidney disease after 10 years 4
• Associated with anti-dsDNA and anti-C1q antibodies 3

Antiphospholipid syndrome 5:

• Low-dose aspirin for primary prevention of thrombosis and pregnancy loss

Monitoring Strategy

Regular monitoring should include: 1, 5

• Validated disease activity indices
• Clinical examination for new manifestations (rashes, arthritis, serositis, neurological signs)
• Complete blood count
• Serum creatinine, proteinuria, urinary sediment
• Immunologic tests: C3/C4, anti-dsDNA
• Brain MRI and renal biopsy in selected patients for prognostic information

Comorbidity Management

SLE patients face increased risk for multiple comorbidities requiring vigilant prevention: 1, 2, 4

Infections

• Represent 25-50% of global mortality 3
• Account for >20% of hospitalizations 3
• Require high index of suspicion and prompt evaluation

Cardiovascular Disease

• Accelerated atherosclerosis risk
• Requires aggressive risk factor modification
• Consider statins and antihypertensives (including ACE inhibitors) 1

Metabolic Complications

• Hypertension, dyslipidemia, diabetes
• Osteoporosis (consider calcium/vitamin D, bisphosphonates) 1
• Avascular necrosis

Malignancy

• Increased risk, especially non-Hodgkin's lymphoma 1

Pregnancy Considerations

Pregnancy can increase SLE disease activity, though flares are usually mild. 5

• Patients with lupus nephritis and antiphospholipid antibodies have higher preeclampsia risk and require close monitoring 5
• Safe medications during pregnancy: prednisolone, azathioprine, hydroxychloroquine, low-dose aspirin 5
• Pregnancy counseling should be part of routine care 1

Adjunctive Interventions

Non-pharmacologic management is essential: 1, 2

• Photo-protection for skin manifestations
• Lifestyle modifications: smoking cessation, weight control, exercise
• Patient education to improve quality of life and medication adherence
• Low-dose aspirin for cardiovascular prevention (when appropriate)

Prognosis and Outcomes

• Disease course remains variable with mortality unacceptably high 2
• Approximately 40% develop lupus nephritis, with 10% progressing to end-stage renal disease after 10 years 4
• The disease results in irreversible damage, diminished quality of life, and reduced life expectancy 1
• Treatment advances have improved outcomes, but access to expensive biologics remains restricted across regions 2

Critical Clinical Pitfalls

Before diagnosing idiopathic immune complex glomerulonephritis in SLE, exhaust all other diagnostic possibilities, as this is rare in adults. 3

• Exclude complement-mediated processes (C3G) that may mimic immune complex disease 3
• Rule out concomitant or preceding infections before attributing findings to primary disease 3
• Consider proteolytic digestion of paraffin-embedded biopsy tissue to detect masked monoclonal immunoglobulins 3
• NSAIDs should be used judiciously for limited periods only in patients at low risk for complications 1
• Estrogens (oral contraceptives, hormone replacement) may be used but require careful risk assessment 1