2Epidemiology 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
9Target 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)
10Anti-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
11Anti-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)
12Autoantibodies 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.
13Autoantibodies 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.
16Prevention of Fetal Loss with Crry-Ig (Holers VM…Salmon JE: J Exp Med 195:211, 2002)
17Other 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)
20Case 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
27Laboratory 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
28Laboratory 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
29Laboratory 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
30Laboratory 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
31Principles 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
32Potential 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
34SummaryBLISS-52BLISS-76a Wallace et al. Presented at the American College of Rheumatology Annual Meeting, Nov 9, 2010, Poster 1172.
35Changes 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