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Systemic Lupus Erythematosus

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) <16 years: 20% (F:M = 2:1) >55 years: 15% (F:M = 2:1) Race - more common in Blacks and Asians than in Whites.

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Systemic Lupus Erythematosus

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  1. Systemic Lupus Erythematosus

  2. Epidemiology of SLE • Prevalence - 1/2,000 people • Sex - 10:1 female predominance • Age at onset 16-55 years: 65% (F:M = 10:1) <16 years: 20% (F:M = 2:1) >55 years: 15% (F:M = 2:1) • Race - more common in Blacks and Asians than in Whites

  3. Common Manifestations of SLE Constitutional Symptoms • Fatigue • Fever • Weight loss Mucocutaneous Involvement • Photosensitive rash • Oral ulcers • Alopecia Arthralgias/Arthritis

  4. 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

  5. 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)

  6. 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

  7. 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)

  8. 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.

  9. 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.

  10. Antiphospholipid AntibodiesaPL 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)

  11. Antiphospholipid Antibody Syndrome (APS) • Venous thrombosis • Arterial thrombosis • Recurrent fetal loss • Thrombocytopenia

  12. Prevention of Fetal Loss with Crry-Ig(Holers VM…Salmon JE: J Exp Med 195:211, 2002)

  13. 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)

  14. Special Serologic Studies in SLE Antinuclear Antibodies (ANA) Anti-dsDNA Antibodies Anti-ENA Antibodies (RNP, Sm) Rheumatoid Factor (RF) Complement (C3, C4, CH50)

  15. 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 ACR Criteria For SLE

  16. 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

  17. Differential Diagnosis Infection • Virus (HIV, hepatitis, EBV, Coxsackie) • Gonococcus • Subacute bacterial endocarditis • Pneumonia • Tuberculosis

  18. Differential Diagnosis Infection • Virus (HIV, hepatitis, EBV, Coxsackie) • Gonococcus • Subacute bacterial endocarditis • Pneumonia • Tuberculosis Rheumatic Disease • Rheumatoid arthritis • Systemic lupus erythematosus

  19. 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

  20. 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

  21. 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

  22. Serology CH50 - low Anti-DNA - high

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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 Potential Biologically-Based Therapeutic Interventions for Lupus (a partial list)

  29. Anti-BLyS(Belimumab)

  30. Summary BLISS-52 BLISS-76 a Wallace et al. Presented at the American College of Rheumatology Annual Meeting, Nov 9, 2010, Poster 1172.

  31. -9.7% -43.3% -49.5% 51.9% 38.5% 16.7% Changes in Serologic Measures Anti-dsDNA Median % Change In Patients Positive at Baseline C4 % Change Over Time In Patients With Low Baseline C4 # p <0.001, + p <0.01, * p <0.05

  32. T Cell Costimulation

  33. Inhibition of T Cell Costimulation

  34. Systemic Lupus Erythematosus

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