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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)

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Presentation on theme: "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)"— Presentation transcript:

1 Systemic Lupus Erythematosus

2 Epidemiology of SLE Prevalence - 1/2,000 people Sex - 10:1 female predominance Age at onset 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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4 Common Manifestations of SLE Constitutional Symptoms Fatigue Fever Weight loss Mucocutaneous Involvement Photosensitive rash Oral ulcers Alopecia Arthralgias/Arthritis

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8 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

9 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)

10 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

11 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)

12 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.

13 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.

14 Antiphospholipid Antibodies aPL antibodies bind complexes of phospholipids and plasma proteins: Prothrombin-activator complex (activated factor X, factor V, prothrombin, calcium, phospholipid)  2 -glycoprotein I (a naturally occurring anticoagulant)

15 Antiphospholipid Antibody Syndrome (APS) Venous thrombosis Arterial thrombosis Recurrent fetal loss Thrombocytopenia

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

17 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)

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

19 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

20 Case History Patient:33-year-old woman Symptoms:Fatigue, myalgias/arthralgias, pleuritic chest pain Signs:T-38.5 o C Nodes - mild diffuse adenopathy Lungs - dullness at right base Joints - synovitis at the wrists and MCPs; small effusions in both knees

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

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

23 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

24 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

25 Laboratory Data Hgb LFTs - wnl Hct - 34 Creatinine 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

26 Serology CH50- low Anti-DNA- high

27 Laboratory Data Hgb LFTs - wnl Hct - 34 Creatinine 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

28 Laboratory Data Hgb LFTs - wnl Hct - 34*Creatinine 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

29 Laboratory Data Hgb LFTs - wnl Hct - 34*Creatinine *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

30 Laboratory Data Hgb LFTs - wnl Hct - 34 Creatinine *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

31 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

32 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 (  or  Anti-TNF-  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

33 Anti-BLyS (Belimumab)

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

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

36 T Cell Costimulation

37 Inhibition of T Cell Costimulation

38 Systemic Lupus Erythematosus


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