systemic lupus erythematosus. epidemiology of sle prevalence - 1/2,000 people sex - 10:1 female...
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Systemic Lupus Erythematosus
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Epidemiology of SLE
• Prevalence - 1/2,000 people
• Sex - 10:1 female predominance
• Age at onset16-55 years: 65% (F:M = 10:1) <16 years: 20% (F:M = 3:1) >55 years: 15% (F:M = 7:1)
• Race - more common in Blacks, Hispanics, and Asians than in Whites
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Common Manifestations of SLE
Constitutional Symptoms• Fatigue• Fever• Weight loss
Mucocutaneous Involvement• Photosensitive rash• Oral ulcers• Alopecia
Arthralgias/Arthritis
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Manifestations of SLE (con’d)
Kidneys - Glomerulonephritis
Central Nervous System - Headache, seizures, stroke
Peripheral Nervous System - sensory or motor
Lungs - pleuritis, pneumonitis, hemorrhage
Heart - pericarditis, myocardial infarction, valve disease
GI - serositis, mesenteric vasculitis, pancreatitis
Hematopoietic - lymphadenopathy, autoimmune cytopenias, antiphospholipid antibody syndrome
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Target Antigens in SLE
• Nuclear antigens (e.g., dsDNA)
• Cytoplasmic antigens (e.g., ribosomal proteins)
• Cell surface antigens (e.g., blood cells)
• Soluble antigens in sera (e.g., IgG, phospholipids)
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Anti-dsDNA AntibodiesEvidence for a Pathogenic Role
• Presence correlates with renal involvement
• Serum levels correlate with disease activity
• Concentration is enriched in glomerular eluates
• Some monoclonal anti-dsDNA can produce lupus nephritis
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Anti-DNA Mediated Renal InjuryProposed Mechanisms
• Deposition of circulating immune complexes
• Binding of DNA to GBM (e.g., based on charge)
• Binding of anti-dsDNA to glomerular antigens
(e.g., due to polyspecificity - heparin sulfate, laminin)
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Autoantibodies in CNS Lupus (DeGiorgio et al.: Nature Med 7:1189,2001)
1) Some anti-DNA antibodies bind receptors for glutamate.
2) Glutamate receptors contribute to learning and memory.
3) Overstimulation of glutamate receptors can cause excitotoxic neuron death.
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Autoantibodies in CNS Lupus (DeGiorgio et al.: Nature Med 7:1189,2001)
(continued)
4) Anti-DNA antibodies mediate neuronal cell death.
5) CSF from a patient with CNS lupus contain anti-DNA antibodies that mediate neuronal death.
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Antiphospholipid Antibodies
aPL antibodies bind complexes of phospholipids and plasma proteins:
• Prothrombin-activator complex (activated factor X, factor V, prothrombin, calcium, phospholipid)
• b2-glycoprotein I (a naturally occurring anticoagulant)
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Antiphospholipid Antibody Syndrome (APS)
• Venous thrombosis
• Arterial thrombosis
• Recurrent fetal loss
• Thrombocytopenia
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Prevention of Fetal Loss with Crry-Ig(Holers VM…Salmon JE: J Exp Med 195:211, 2002)
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Other Postulated Mechanisms
• Defective clearance of apoptotic bodies (persistence of self nuclear antigens)
• Failure of tolerance (T cells and/or B cells)
• Activation of B cells and/or dendritic cells by self DNA or RNA through toll-like receptors (i.e., TLR-7 and TLR-9)
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Special Serologic Studies in SLE
Antinuclear Antibodies (ANA)
Anti-dsDNA Antibodies
Anti-ENA Antibodies (RNP, Sm)
Rheumatoid Factor (RF)
Complement (C3, C4, CH50)
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ACR Criteria For SLE
1. Malar rash
2. Discoid Rash
3. Photosensitivity
4. Oral ulcers
5. Arthritis
6. Serositis
7. Renal disorder
8. Neurologic disorder
9. Hematologic disorder
10. Antinuclear antibody
11. Immunologic disorder
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Case History
Patient: 33-year-old woman
Symptoms: Fatigue, myalgias/arthralgias,pleuritic chest pain
Signs: T-38.5oCNodes - mild diffuse adenopathyLungs - dullness at right baseJoints - synovitis at the wrists and MCPs; small effusions in both knees
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Differential Diagnosis
Infection• Virus (HIV, hepatitis, EBV, Coxsackie)
• Gonococcus
• Subacute bacterial endocarditis
• Pneumonia
• Tuberculosis
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Differential Diagnosis
Infection• Virus (HIV, hepatitis, EBV, Coxsackie)• Gonococcus• Subacute bacterial endocarditis• Pneumonia• Tuberculosis
Rheumatic Disease • Rheumatoid arthritis• Systemic lupus erythematosus
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Differential Diagnosis
Infection• Virus (HIV, hepatitis, EBV, Coxsackie)• Gonococcus• Subacute bacterial endocarditis• Pneumonia• Tuberculosis
Rheumatic Disease• Rheumatoid Arthritis• Systemic lupus erythematosus• Mixed connective tissue disease• Polymyositis• Polyarteritis nodosa
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Differential DiagnosisInfection• Virus (HIV, hepatitis, EBV, Coxsackie)• Gonococcus• Subacute bacterial endocarditis• Pneumonia• Tuberculosis
Rheumatic Disease• Rheumatoid Arthritis• Systemic lupus erythematosus• Mixed connective tissue disease• Polymyositis• Polyarteritis nodosa
Malignancy• Leukemia• Lymphoma
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Laboratory Data
Hgb - 11.3 LFTs - wnl Hct - 34 Creatinine - 1.0 WBC - 3,200 Urinalysis - wnl Platelets - 220,000 EKG - wnl
X-rays: Chest - small pleural effusion on the right Hands/knees - swelling, no bony abnormalities
RF - 1:80 ANA - 1:160
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Serology
CH50- low
Anti-DNA - high
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Laboratory Data
Hgb - 11.3 LFTs - wnl Hct - 34 Creatinine - 1.0 WBC - 3,200 Urinalysis - wnl Platelets - 220,000 EKG - wnl
*X-rays: Chest - small pleural effusion on the right Hands/knees - swelling, erosions at MCP joints
RF - 1:80*ANA - negative
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Laboratory Data
Hgb - 11.3 LFTs - wnl Hct - 34*Creatinine - 1.8 WBC - 3,200 *Urinalysis - 2+ protein, RBCs Platelets - 220,000 EKG - wnl
X-rays: Chest - small pleural effusion on the right Hands/knees - swelling, no bony abnormalities
*RF - negative*ANA - 1:160
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Laboratory Data
Hgb - 11.3 LFTs - wnl Hct - 34 *Creatinine - 1.8*WBC - 5,600 *Urinalysis - 2+ protein, RBCs Platelets - 220,000 EKG - wnl
X-rays: Chest - small pleural effusion on the right Hands/knees - swelling, no bony abnormalities
RF - 1:80*ANA - negative
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Laboratory Data
Hgb - 11.3 LFTs - wnl Hct - 34 Creatinine - 1.0*WBC - 84,000 Urinalysis - wnl Platelets - 220,000 EKG - wnl
X-rays: Chest - small pleural effusion on the right Hands/knees - swelling, no bony abnormalities
*RF - negative*ANA - negative
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Principles of Management
Careful monitoring
Attention to psychosocial problems
Topical therapy for skin involvement
NSAIDs for arthritis/pleuritis
Treat associated medical problems
Steroids/cytotoxic drugs for refractory symptoms and/or life threatening manifestations
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Potential Biologically-Based Therapeutic
Interventions for Lupus (a partial list)
B Cell Targets• Anti-BLyS • Anti-CD20• Anti-CD22• Anti-B7• TACI-Ig
T Cell Targets• Anti-CD3• Anti-CD4• Anti-CD40L• CTLA4Ig
Cytokine Targets• Anti-IFN (a or )g• Anti-TNF-a• Anti-IL-10• Anti-IL-6R
Complement System Targets• Anti-C5• C3 convertase inhibitor (Crry-Ig)
Regulatory Cell Targets• CD4+ CD25+ T Cells
Stem Cell Transplantation
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Anti-BLyS (Belimumab)
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Summary
BLISS-52 BLISS-76
a Wallace et al. Presented at the American College of Rheumatology Annual Meeting, Nov 9, 2010, Poster 1172.
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Changes in Serologic Measures
Anti-dsDNA Median % Change
In Patients Positive at Baseline
C4 % Change Over Time
In Patients With Low Baseline C4
-43.3%-49.5%
-9.7%
38.5%
51.9%
16.7%
# p <0.001, + p <0.01, * p <0.05
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T Cell Costimulation
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Inhibition of T Cell Costimulation
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Systemic Lupus Erythematosus