Presentation
Short Description
Download Presentation...
Description
Systemic Lupus Erythematosus
Epidemiology of SLE • Prevalence - 1/2,000 people • Sex - 10:1 female predominance • Age at onset 16-55 years: 65% (F:M = 10:1) 55 years: 15% (F:M = 7:1)
• Race - more common in Blacks, Hispanics, and Asians than in Whites
Common Manifestations of SLE Constitutional Symptoms • Fatigue • Fever • Weight loss
Mucocutaneous Involvement • Photosensitive rash • Oral ulcers • Alopecia
Arthralgias/Arthritis
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
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)
Anti-dsDNA Antibodies Evidence 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
Anti-DNA Mediated Renal Injury Proposed 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)
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.
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.
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)
Antiphospholipid Antibody Syndrome (APS) • Venous thrombosis
• Arterial thrombosis • Recurrent fetal loss
• Thrombocytopenia
Prevention of Fetal Loss with Crry-Ig (Holers VM…Salmon JE: J Exp Med 195:211, 2002)
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 tolllike receptors (i.e., TLR-7 and TLR-9)
Special Serologic Studies in SLE Antinuclear Antibodies (ANA) Anti-dsDNA Antibodies
Anti-ENA Antibodies (RNP, Sm) Rheumatoid Factor (RF) Complement (C3, C4, CH50)
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
Case History Patient: 33-year-old woman Symptoms: Fatigue, myalgias/arthralgias, pleuritic chest pain Signs: T-38.5oC Nodes - mild diffuse adenopathy Lungs - dullness at right base Joints - synovitis at the wrists and MCPs; small effusions in both knees
Differential Diagnosis Infection • Virus (HIV, hepatitis, EBV, Coxsackie) • Gonococcus • Subacute bacterial endocarditis • Pneumonia
• Tuberculosis
Differential Diagnosis Infection • • • • •
Virus (HIV, hepatitis, EBV, Coxsackie) Gonococcus Subacute bacterial endocarditis Pneumonia Tuberculosis
Rheumatic Disease • Rheumatoid arthritis • Systemic lupus erythematosus
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
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
Malignancy • Leukemia • Lymphoma
Laboratory Data Hgb - 11.3 Hct - 34 WBC - 3,200 Platelets - 220,000
LFTs - wnl Creatinine - 1.0 Urinalysis - wnl EKG - wnl
X-rays: Chest - small pleural effusion on the right Hands/knees - swelling, no bony abnormalities
RF - 1:80 ANA - 1:160
Serology CH50 - low
Anti-DNA - high
Laboratory Data Hgb - 11.3 Hct - 34 WBC - 3,200 Platelets - 220,000
LFTs - wnl Creatinine - 1.0 Urinalysis - wnl EKG - wnl
*X-rays: Chest - small pleural effusion on the right Hands/knees - swelling, erosions at MCP joints
RF - 1:80 *ANA - negative
Laboratory Data Hgb - 11.3 Hct - 34 WBC - 3,200 Platelets - 220,000
LFTs - wnl *Creatinine - 1.8 *Urinalysis - 2+ protein, RBCs EKG - wnl
X-rays: Chest - small pleural effusion on the right Hands/knees - swelling, no bony abnormalities
*RF - negative *ANA - 1:160
Laboratory Data Hgb - 11.3 Hct - 34 *WBC - 5,600 Platelets - 220,000
LFTs - wnl *Creatinine - 1.8 *Urinalysis - 2+ protein, RBCs EKG - wnl
X-rays: Chest - small pleural effusion on the right Hands/knees - swelling, no bony abnormalities
RF - 1:80 *ANA - negative
Laboratory Data Hgb - 11.3 Hct - 34 *WBC - 84,000 Platelets - 220,000
LFTs - wnl Creatinine - 1.0 Urinalysis - wnl EKG - wnl
X-rays: Chest - small pleural effusion on the right Hands/knees - swelling, no bony abnormalities
*RF - negative *ANA - negative
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
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
Anti-BLyS (Belimumab)
Summary BLISS-52
a Wallace
BLISS-76
et al. Presented at the American College of Rheumatology Annual Meeting, Nov 9, 2010, Poster 1172.
Changes in Serologic Measures
-9.7%
Anti-dsDNA Median % Change In Patients Positive at Baseline -43.3% -49.5%
51.9%
C4
38.5%
% Change Over Time In Patients With Low Baseline C4
16.7%
# p
View more...
Comments