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Systemic Lupus Erythematosus¶

Chapter 368 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology · Chapter 368

Key Clinical Points¶

SLE is an autoimmune disease where overactive innate and adaptive immune systems cause tissue damage through the effects of autoantibodies and immune complexes.
ANA titer of at least 1:80 is required for EULAR/ACR classification; repeated negative tests by immunofluorescence make a diagnosis unlikely.
Anti-dsDNA antibodies correlate with disease activity and nephritis; anti-Sm is the most specific autoantibody for SLE.
Hydroxychloroquine (HCQ) is first-line therapy for skin manifestations and arthritis; dose is 5 mg/kg per day (actual body weight) with retinal monitoring.
Lupus nephritis classification is based on renal biopsy (ISN/RPS criteria); aggressive therapy is required for class III (focal proliferative), class IV (diffuse proliferative), or class V (membranous).
Type 1 lupus has classic findings (nephritis, arthritis) and responds to immunosuppression; Type 2 lupus has predominant symptoms of fatigue, brain fog, and depression and is less responsive to therapy.
Drug-induced lupus is characterized by antihistone antibodies and is often abrogated by discontinuation of the offending drug.
Stroke has been reported in up to 19% of patients with SLE, a result of atherosclerosis and increased risk from antiphospholipid syndrome (APS).
Approximately 90% of affected individuals are women, most of childbearing age; prevalence is nine times higher in women compared to men.
HCQ use during pregnancy and breastfeeding has been demonstrated to be safe; risk factors for retinal toxicity include higher dose and longer duration of use.

DEFINITION & OVERVIEW¶

• Definition: Systemic lupus erythematosus (SLE) is an autoimmune disease in which overactive innate and adaptive immune systems cause tissue damage through the effects of autoantibodies and immune complexes. • Clinical Scope: Multiple organ systems can be affected; cutaneous, musculoskeletal, and renal systems are most commonly involved. Pulmonary, hematologic, cardiovascular, serosal, and central nervous system involvement also occur. • Prognostic Indicators: Autoantibodies can be detected years prior to a clinical diagnosis.

Iatrogenic & Drug-Induced Autoimmunity¶

• Immune Checkpoint Inhibitors (ICIs): ◦ Act by blocking inhibitory molecules to promote tumor destruction. ◦ Immune-related adverse events (irAEs) occur in up to 85% of patients. ◦ Common irAEs: diabetes mellitus, arthritis, thyroiditis, and colitis. • Drug-Induced Lupus: ◦ Associated with antibiotics, antihypertensives, antiarrhythmics, TNF inhibitors, and antiseizure medications. ◦ Characterized by the detection of antihistone antibodies. ◦ Often abrogated or decreased upon discontinuation of the offending drug.

EPIDEMIOLOGY¶

• Gender Prevalence: Approximately 90% of affected individuals are women; prevalence is nine times higher in women compared to men. • Demographics: Highest prevalence seen in Black women, followed by Hispanic, White, and Asian/Pacific Islander women. Among men, Black men have the highest prevalence and White men have the lowest. • Prognosis Factors: Survival varies significantly by geographic region, race, ethnicity, and access to care.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Core Mechanism: Interaction of environmental factors with stochastic dysregulation of genes (e.g., HLA-DR, IRF5, STAT4, TYK2). • Environmental Factors: ◦ UV light: Impacts DNA methylation and generates self-stimulatory nucleic acids. ◦ Viral infections: E.g., Epstein-Barr virus (EBV) inducing IFN response. ◦ Toxins & Environment: Mercury, pesticides, and low socioeconomic status. ◦ Gut Microbiome: Increased permeability may promote translocation of microbes into the blood.

Genetics¶

• Genetic Basis: Strong component; 24% monozygotic twin concordance vs. 2% dizygotic. ◦ Over 150 susceptibility loci identified via GWAS. • Key Pathways: ◦ Major histocompatibility complex (MHC) genes for antigen presentation and complement components. ◦ Type 1 Interferon (IFN) pathway: ~50% of loci associated with IFN production or signaling (TLR7, ADAR, IFIH1, SAMHD1, RNASEH2B, TREX1, IRF5, IRF7, IRF8, STAT4). ◦ Cell-specific genes: OX40L (T cells), BANK1, BACH2 (B cells).

Innate Immunity¶

• Neutrophil Dysfunction: ◦ Higher turnover leads to a large load of stimulatory nucleic acids and autoantigens. ◦ Impaired clearance of cellular debris and immune complexes by macrophages/dendritic cells. • Plasmacytoid Dendritic Cells (pDCs): ◦ Sense nucleic acids via TLRs → produce type 1 IFN. ◦ IFN primes neutrophils and sensitizes the adaptive immune system. • Monocytes: ◦ Classical monocytes: Infiltrate and repair tissue due to immune complex deposition. ◦ Non-classical monocytes: Patrol the vascular lumen for injury.

Adaptive Immunity¶

• B Cells: ◦ Loss of tolerance leads to autoantibody production (especially those complexed with nucleic acids). ◦ Age-associated B cells (ABCs) expand and mature into autoantibody-secreting plasma cells. • T Cells: ◦ T follicular and T peripheral helper cells promote B-cell differentiation into pathogenic, high-affinity, autoantibody-secreting plasma cells. • Regulatory Defect: T regulatory cells are defective in maintaining tolerance in both T and B cells.

CLINICAL FEATURES¶

• General Presentation: Variable; can be mild (15% of patients) or severe. ◦ Symptoms: Fever, anorexia, weight loss, fatigue, brain fog. • Table 368-2 (Autoantibodies): ◦ ANA: 95% prevalence ◦ [dsDNA]: 70% prevalence ◦ Anti-Sm: 30% prevalence; 25% specificity ◦ Anti-Ro (SS-A): 30% prevalence; 20% specificity ◦ Antiribosomal P: 15% prevalence; 70% specificity ◦ Anti-U1-RNP: 13% prevalence; 50% specificity • Systemic Manifestations: ◦ Constitutional: Fatigue, malaise, fever, weight loss, anorexia. ◦ Cutaneous: Photosensitivity, oral/nasal ulcers, alopecia; Malar rash (acute), Discoid rash (chronic). ◦ Musculoskeletal: Polyarthritis (wrists, MCP, PIP), Jaccoud hand deformity, rhupus. ◦ Hematologic: Anemia, leukopenia, thrombocytopenia, lymphadenopathy, splenomegaly, thrombosis. ◦ Cardiopulmonary: Pleurisy, pericarditis, myocarditis, pulmonary hypertension, shrinking lung syndrome. ◦ Vascular: Stroke (19%), Pulmonary embolism, Raynaud's phenomenon. ◦ Neurologic: Cognitive dysfunction, mood disorder, seizures, psychosis. ◦ Renal: Proteinuria ≥ 500 mg/24 h, cellular casts, nephrotic syndrome. ◦ Gastrointestinal: Nausea, abdominal pain, elevated liver enzymes, peritonitis. ◦ Ocular: Sicca syndrome, uveitis, retinal vasculitis.

Musculoskeletal¶

• Arthritis: Polyarthritis of hands and knees; Jaccoud-like changes (fibrotic retraction). ◦ Rhupus: Simultaneous occurrence of RA and SLE. • Myopathy: Symmetrical proximal weakness, elevated CK/aldolase. ◦ Note: Corticosteroids or antimalarials can rarely cause myopathy.

Cutaneous¶

• Acute (ACLE): Malar rash (butterfly distribution, nasolabial sparing); maculopapular rash. ◦ Differentiation: Rosacea involves nasolabial folds; ACLE spares them. • Subacute (SCLE): Associated with anti-Ro/SSA; flat, red-rimmed annular or psoriasiform lesions. • Chronic: Discoid rash (scaly, hyperpigmented); verrucous lupus; cutaneous vasculitis.

Renal¶

• Prevalence: ~35% of patients. ◦ High risk for ESRD in non-White patients. • Classification (ISN/RPS): ◦ Class III: Focal proliferative. ◦ Class IV: Diffuse proliferative. ◦ Class V: Membranous (20% with significant proteinuria; better prognosis than III/IV). ◦ Aggressive therapy required for Class III, IV, or III+V.

Neurologic¶

• Cognitive: 'Brain fog' (common); headache. ◦ Differentiation: Rule out glucocorticoid-induced psychosis and infectious encephalitis. ◦ Rare: Transverse myelitis (bilateral deficits).

Vascular, Cardiac, & Pulmonary¶

• Coronary Disease: Accelerated atherosclerosis; risk increased by APS. ◦ Antiphospholipid Syndrome (APS): Risk of stroke (19%), pulmonary embolism, and thrombosis. ◦ Pericarditis: Most frequent cardiac involvement; managed with anti-inflammatories/colchicine. ◦ Pulmonary: Pleurisy (most common); shrinking lung syndrome (rare).

Hematologic¶

• Anemia: Common; can be due to chronic disease, iron deficiency, or hemolysis. ◦ Leukopenia: ~50% of patients (usually lymphopenia <1500/μL). ◦ Thrombocytopenia: Often due to immune mechanisms or APS. ◦ Atypical Hemolytic-Uremic Syndrome (HUS): Schistocytes, low ADAMTS13, high LDH.

Gastrointestinal & Ocular¶

• GI: Nausea, abdominal pain; Mesenteric vasculitis (requires high-dose glucocorticoids). ◦ APS associations: Budd-Chiari syndrome, hepatic venoocclusive disease. ◦ Ocular: Sicca syndrome; Retinal vasculitis (rare but requires aggressive immunosuppression).

DIFFERENTIAL DIAGNOSIS¶

• Approach: Individualized based on clinical data and exclusion of other entities. ◦ Target: Early identification of serologic markers to initiate treatment with favorable efficacy-to-safety ratios.

DIAGNOSTIC APPROACH¶

Screening: ANA titer ≥ 1:80 (95% prevalence in SLE).
Specificity Check: Anti-Sm (30% prevalence; most specific for SLE).
Additional Markers: ◦ Anti-Ro (SS-A): 30% prevalence. ◦ Antiribosomal P: 15% prevalence. ◦ Anti-U1-RNP: 13% prevalence.
Monitoring & Risk Assessment: ◦ Anti-dsDNA: Correlates with disease activity and nephritis. ◦ Complement (C3/C4): Decreased levels serve as warning signs of impending active nephritis.
Renal Monitoring: Routine 3-month interval urine protein-to-creatinine ratio (UPCr) or 24-h urine protein.

MANAGEMENT & TREATMENT¶

General Measures & Antimalarials: ◦ Standard: Sun protection, exercise, no smoking, balanced diet, vaccination. ◦ Hydroxychloroquine (HCQ): First-line for skin and arthritis; dose 5 mg/kg per day (actual body weight); requires retinal monitoring.
Glucocorticoids (GC): ◦ Oral or IV; used to control active disease. ◦ Taper: Goal is ≤ 5 mg/day as quickly as possible.
Non-renal SLE Management (based on severity): • Mild:
First-line: HCQ + MTX or AZA.
Second-line: HCQ + MMF. • Moderate:
First-line: HCQ + (BEL or ANI) OR HCQ + CNI.
Second-line: HCQ + MMF or HCQ + CNI. • Severe:
First-line: HCQ + (BEL or ANI) OR HCQ + CNI.
Second-line: HCQ + CYC or HCQ + RTX.
Lupus Nephritis Management:
Initial Therapy: HCQ, GC, and ACEI/ARBs.
Renal Protection: SGLT2 inhibitors if eGFR is further decreased.
Maintenance (Standard): MMF or low-dose CYC.
Maintenance (with APS): MMF/low-dose CYC + BEL.
Refractory Cases: Rituximab (RTX) or other options.
Specialized Interventions: ◦ Retinal vasculitis → aggressive immunosuppression. ◦ Mesenteric vasculitis → high doses of glucocorticoids.

Flowchart 1: Treatment of nonrenal systemic lupus erythematosus (SLE)¶

• Step 1: Determine Severity ◦ Mild: No significant organ involvement; SLEDAI ≤ 6; BILAG C or ≤ 1 BILAG B. ◦ Moderate: Not mild, not severe; SLEDAI 7–12; ≥ 2 BILAG B. ◦ Severe: Major organ-threatening (cerebritis, myelitis, pneumonitis, mesenteric vasculitis); PLT < 20 imes 10^3/μL; rash > 18% BSA; SLEDAI > 12; ≥ 1 BILAG A. • Step 2: Treatment Pathway based on Severity ◦ Mild Path: 1. First-line: HCQ + MTX or AZA. 2. Second-line: HCQ + MMF. ◦ Moderate Path: 1. First-line: HCQ + (BEL or ANI) OR HCQ + CNI. 2. Second-line: HCQ + MMF or HCQ + CNI. ◦ Severe Path: 1. First-line: HCQ + (BEL or ANI) OR HCQ + CNI. 2. Second-line: HCQ + CYC or HCQ + RTX. • Step 3: Special Considerations ◦ BEL and ANI are recommended for extrarenal SLE with nonmajor organ involvement but extensive disease (skin, joints). ◦ ANI is NOT recommended for severe neuropsychiatric disease.

Flowchart 2: Treatment of lupus nephritis¶

• Step 1: Initial Management 1. HCQ + GC (taper to ≤ 5 mg/day). 2. ACEI/ARBs for proteinuria or reduced eGFR. 3. SGLT2 inhibitors if eGFR further decreases. • Step 2: Maintenance Pathway 1. Standard: MMF or low-dose CYC. 2. If APS present: M1 (MMF/low-dose CYC) + BEL. 3. Long-term transition: AZA/MMF or MMF/AZA + BEL. • Step 3: Refractory Pathway 1. Rituximab (RTX) if targets not met. • Step 4: Monitoring Targets 1. 3 months → ≥25% reduction in UP. 2. 6 months → ≥50% reduction in UP to <3 g/day. 3. 12–24 months → UP ≤ 0.5–0.7 g/day (all with ≥10% from baseline).

PROGNOSIS & COMPLICATIONS¶

• Mortality Factors: Coronary heart disease (accelerated atherosclerosis), stroke, and renal failure. ◦ Risk factors for stroke: Atherosclerosis and Antiphospholipid Syndrome (APS). • Renal Outcome: ~20% of patients with class IV nephritis die or develop ESRD within 10 years.

SPECIAL CONSIDERATIONS¶

• Pregnancy/Breastfeeding: HCQ is demonstrated to be safe. ◦ Risk factors for retinal toxicity: Higher dose and longer duration of use. • Pediatric: Can affect neonates, children, and elderly.

KEY PEARLS & CLINICAL TRAPS¶

• HCQ Dosage: Exactly 5 mg/kg per day (actual body weight). ◦ Target for GC: ≤ 5 mg/day. • Diagnostic Thresholds: ANA ≥ 1:80; Renal biopsy if UPCr >0.5. ◦ Anti-dsDNA and C3/C4 are key indicators of impending nephritis. • Clinical Phenotypes: ◦ Type 1 (Classic): Nephritis, arthritis, responsive to treatment. ◦ Type 2: Fatigue, brain fog, depression, less responsive. • Drug-Induced Lupus: Characterized by antihistone antibodies; often reversible upon drug cessation.

Reference Tables¶

TABLE 368-2 Autoantibodies in Systemic Lupus Erythematosus¶

Harrison's 22e, p.2832

Constitutional	Fatigue, malaise, fever, weight loss, anorexia

TABLE 368-2 Autoantibodies in Systemic Lupus Erythematosus

ANTIBODY	PREVALENCE, %	CLINICAL ASSOCIATIONS
ANA	95	Titers of 1:80 or higher are considered positive and are sensitive for SLE but not specific.
	70
Anti-Sm	30	Most specific autoantibody for SLE and more common in black and Asian patients. May correlate with CNS manifestations and incidence of nephritis.
	25
Anti-Ro (SS-A)	30	Not SLE-specific. Associated with sicca syndrome, neonatal lupus and congenital heart block, and subacute cutaneous lupus.
	20
Antiribosomal P	15	May be associated with CNS involvement. Specific for SLE but not sensitive.
	70
Anti–U1-RNP	13	Associated with musculoskeletal and lung impairment.
	50
Musculoskeletal	Arthralgia, myalgia, polyarthritis, Jaccoud hand deformity, inflammatory myopathy, avascular necrosis of bone
Cardiopulmonary	Pleurisy, pericarditis, pleural and pericardial effusions, myocarditis, endocarditis, pneumonitis, coronary artery disease, interstitial fibrosis, pulmonary hypertension, diffuse alveolar hemorrhage, shrinking lung syndrome
Neurologic	Cognitive dysfunction, mood disorder, depression, headache, seizures, mononeuropathy, polyneuropathy, stroke, transient ischemic attack, psychosis, aseptic meningitis, transverse myelitis
Gastrointestinal	Nausea, abdominal pain, diarrhea, elevated liver enzymes, lupus peritonitis or enteritis, vasculitis, pancreatitis