2 Epidemiology of SLE Prevalence - 1/2,000 people Sex - 10:1 female predominanceAge 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
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 involvementSerum levels correlate with disease activityConcentration is enriched in glomerular eluatesSome monoclonal anti-dsDNA can produce lupus nephritis
11 Anti-DNA Mediated Renal Injury Proposed Mechanisms Deposition of circulating immune complexesBinding 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.
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 AntibodiesAnti-ENA Antibodies (RNP, Sm)Rheumatoid Factor (RF)Complement (C3, C4, CH50)
20 Case History Patient: 33-year-old woman Symptoms: Fatigue, myalgias/arthralgias,pleuritic chest painSigns: T-38.5oCNodes - mild diffuse adenopathyLungs - dullness at right baseJoints - synovitis at the wrists and MCPs;small effusions in both knees
27 Laboratory Data Hgb - 11.3 LFTs - wnl Hct - 34 Creatinine - 1.0 WBC - 3,200 Urinalysis - wnlPlatelets - 220,000 EKG - wnl*X-rays: Chest - small pleural effusion on the rightHands/knees - swelling, erosions at MCP jointsRF - 1:80*ANA - negative
28 Laboratory Data Hgb - 11.3 LFTs - wnl Hct - 34 *Creatinine - 1.8 WBC - 3,200 *Urinalysis - 2+ protein, RBCsPlatelets - 220,000 EKG - wnlX-rays: Chest - small pleural effusion on the rightHands/knees - swelling, no bony abnormalities*RF - negative*ANA - 1:160
29 Laboratory Data Hgb - 11.3 LFTs - wnl Hct - 34 *Creatinine - 1.8 *WBC - 5,600 *Urinalysis - 2+ protein, RBCsPlatelets - 220,000 EKG - wnlX-rays: Chest - small pleural effusion on the rightHands/knees - swelling, no bony abnormalitiesRF - 1:80*ANA - negative
30 Laboratory Data Hgb - 11.3 LFTs - wnl Hct - 34 Creatinine - 1.0 *WBC - 84,000 Urinalysis - wnlPlatelets - 220,000 EKG - wnlX-rays: Chest - small pleural effusion on the rightHands/knees - swelling, no bony abnormalities*RF - negative*ANA - negative
31 Principles of Management Careful monitoringAttention to psychosocial problemsTopical therapy for skin involvementNSAIDs for arthritis/pleuritisTreat associated medical problemsSteroids/cytotoxic drugs for refractory symptoms and/or life threatening manifestations
32 Potential Biologically-Based Therapeutic Interventions for Lupus (a partial list) B Cell TargetsAnti-BLySAnti-CD20Anti-CD22Anti-B7TACI-IgT Cell TargetsAnti-CD3Anti-CD4Anti-CD40LCTLA4IgCytokine TargetsAnti-IFN (a or g)Anti-TNF-aAnti-IL-10Anti-IL-6RComplement System TargetsAnti-C5C3 convertase inhibitor (Crry-Ig)Regulatory Cell TargetsCD4+ CD25+ T CellsStem Cell Transplantation
34 SummaryBLISS-52BLISS-76a Wallace et al. Presented at the American College of Rheumatology Annual Meeting, Nov 9, 2010, Poster 1172.
35 Changes in Serologic Measures -43.3%-49.5%-9.7%38.5%51.9%16.7%# p <0.001, + p <0.01, * p <0.05Anti-dsDNAMedian % ChangeIn Patients Positive at BaselineC4% Change Over TimeIn Patients With Low Baseline C4