Introduced by Jill Buyon, M.D. at the September 29, 2003 meeting of the Arthritis Advisory Committee

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Low. High. The Enduring Role of hostile to dsDNA and Complement Proteins in Diagnostic Testing (Back to Basics) . hostile to dsDNA abs particular to SLEanti-dsDNA abs can store in the glomerulus(high enthusiasm, IgG, cationic, fix supplement) Evidence of supplement utilization shows insusceptible complex-driven irritation hereditary changes in ahead of schedule supplement proteins of traditional pathway) are connected with

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Displayed by Jill Buyon, M.D. at the September 29, 2003 meeting of the Arthritis Advisory Committee

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High Low

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The Enduring Role of against dsDNA and Complement Proteins in Diagnostic Testing (Back to Basics) hostile to dsDNA abs particular to SLE hostile to dsDNA abs can store in the glomerulus (high ardentness, IgG, cationic, settle supplement ) Evidence of supplement utilization shows insusceptible complex-driven irritation hereditary adjustments in early supplement proteins of established pathway) are related with SLE Association between hereditary polymorphisms in Fc g R alleles (IIa) and renal sickness

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Classical Pathway Alternative Pathway C3 - > C3a + C3b (unconstrained) DNA-IgG against dsDNA + C1 - > C1 esterase movement C3b + B C4 - C1- - > C4a + C4b C2 - C1- - > C2a + C2b C3bB C3 D P C4b,2b C3b,Bb,P C3b,Bb + Ba (stable) C3a chemotactic consider anaphylotoxin C3b C5 C4b,2b,3b C3b,Bb,3b C5a chemotactic figure anaphylotoxin C5b + C6 + C6 C7 C8 Glomerulonephritis Fetal misfortune C9 MAC

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Neutrophil enactment CR3 . . ICAM-1 . . . . . . . . . C3a C5a . . . . . . . . Resting PMN . . . . . . . . . . . . . . . . . Resting EC Endothelial cell actuation (preparing) IL-1ß TNF  C1q C3a C5a C5b-9 aEC aPL . . . . . . . . . . . . . . . . . . . . E-selectin . Leukothrombosis . . . . . . . . . . . . . . . . . . . . . . . Vaso-occlusive fitting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Playing Rules for Evaluation of the Biomarker f Define Assay for Measurement Assay Binding Isotype DNA Sens/Spec Crithidia high + low partiality abs IgM or IgG dsDNA spec>sens Farr high proclivity abs IgM and IgG ss and dsDNA ELISA high + low fondness abs IgM or IgG ss or dsDNA sens>spec hostile to DNA abs Complement Assay Component Specimen Measurement Immunochemical Native C3, C4 serum Nephelometry Functional respectability CH 50 EDTA plasma RBC lysis Catabolic state Activation C3a EDTA plasma ELISA Define parameters of progress for these applicant biomarkers

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Does the hopeful biomarker: anticipate flare? connect with flare? react to treatment in parallel with great clinical result? A relationship between a variable and the danger of an ailment does not ensure that medication initiated changes in that element will deliver a comparing change in the hazard.

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Percent of Visits with Flares, Categorized by Prior and Concurrent Changes in Levels of Anti-dsDNA (Total 574 visits, general flare rate = 19%) Ho et al, AR, 2001 Prior: between visits 2 months and 1 month before visit with flare Concurrent: between past visit and current visit Flare P (SLEDAI > 3) Prior h DNAabs ELISA >10% (70 visits) 30% 0.007 Prior h DNAabs ELISA >25% (45 visits) 29% N.S. Earlier h DNAabs Critidia >2 weakenings (72 visits) 39% 0.001 Concurrent i DNAabs ELISA (89 visits) 30% 0.002 Concurrent i DNAabs Crithidia (112 visits) 29% 0.0002

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Reanalysis of Ho and Petri Data: Likelihood Ratio Kavanaugh et al, Arth Rheum, 2001 LR for a positive test: Extent to which a positive test improves pretest probability of ailment (10 is high) affectability 1-specificity LR for relationship of flare and h dsDNA abs by Crithidia = 2.7 LR for a negative test: To decide the post test likelihood of infection after a negative outcome (0.10 is low) 1-affectability specificity LR for relationship of flare and h dsDNA abs by Crithidia = - .081 Conclusion: these tests had restricted utility in anticipating or barring lupus flares

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Clinically Active Serologically Quiescent (CASQ) SLE 1 (514 patients took after at the Toronto Lupus Clinic 1991-1995) 62 patients had CASQ : 43 with CNS, renal and additionally vasculitis 58 patients had followup after last CASQ characterizing visit 9 remained CASQ for 3 yrs 23 got to be distinctly dormant 5 turned out to be serologically dynamic however clinically steady (SACS) 21 turned out to be clincially and serologcially dynamic Gladman et al , J Rheum, 2003

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Evaluation of the Sensitivity and Specificity of C3, C4, CH50, hostile to dsDNA and C3a for Detection of Lupus Flares inside 3 months (Tseng et al, Arth Rheum suppl, 2001) Cohort : Patients enlisted in Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA) randomized twofold visually impaired fake treatment controlled trial 496 female patients selected from 9/96 – 3/02 SLE patients given either HRT/fake treatment or OCP/fake treatment for 1 year Analytes measured : C3, C4, CH50, C3a and against dsDNA gauge, q month to month x 3, and after that q 3 months over a 12 month time frame Disease movement : SELENA SLEDAI and PGA Outcomes: Severe flares, Mild/direct flares

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Approach * Previous visit more likely than not happened inside 3 months from date of estimation

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Definition of flares Mild or Moderate Flare Change of SLEDAI >3 New/more terrible: Lupus rash Nasopharyngeal ulcers Pleuritis Pericarditis Arthritis Fever (SLE) Any h in Prednisone to < 0.5mg/kg/d Added NSAIDS or Plaquenil for illness action Physician Global Assessment (PGA) increment >1.0, and < 2.5 Severe Flare Change in SLEDAI to > 12 New/more terrible: CNS SLE Vasculitis Nephritis Myositis Plt<60,000 Hemolytic iron deficiency Requiring: Doubling of Prednisone Prednisone >0.5mg/kg/d Hospitalization New Cytoxan, Azathioprine or Methotrexate Increase in PGA to >2.5

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Patients Available for Evaluation and Outcomes 496 Total Patients (328 HRT patients + 168 OCP patients) :  428 patients had C3a and additionally CH50 accessible 496 patients had C3, C4, hostile to dsDNA accessible 2. Flares (counting numerous flares in patients): 491 mellow/direct flares 39 extreme flares

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Sensitivity and Specificity of Analytes to Predict Flares Limitations/Implications U tility of analytes enhanced if meaning of positive tests less stringent. Analytes q 3 months inadequate, month to month may enhance expectation of flares. Nonappearance of unusual analytes does not liken with clinical stability\ but rather nearness might be prescient of flares. From the earlier treatment of patients with irregular analytes might be suitable since couple of patients would be superfluously uncovered.

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Serologically Active, Clinically Stable SLE Objective : To assess steroid treatment in deflecting flares when heights of plasma C3a are joined by rising hostile to dsDNA titers in steady or inert patients Principal Investigator : Steve Abramson Collaborators : Chung-E Tseng Jill P. Buyon Michael Belmont Betty Diamond Meggan Mackay Inclusion Criteria Anti-DNA abs display inside 2 years Prednisone <15 mg  No dynamic contamination Stability of sickness and drugs for 2 months

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Study Design Patients took after month to month for 12-year and a half History and physical, analytes, and SLEDAI Randomization Criteria Rise of C3a (> half and supreme level  500 ng/ml) Rise of hostile to DNA (>25%) from visit inside 1-2 months Absence of clinical movement Prednisone : 30 mg X 2 wks 20 mg X 1 wk 10 mg X 1wk Placebo

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Flow Chart of Patients Followed in the Observational Study (up to year and a half) 180 NON RANDOMIZED (Serological flare, clinically steady) 139 41 Completed no serological or clinical flare Stopping point 47 92 Clinical flare No clinical flare 11 30 Clinical flare with or without serologic flare Voluntary drop out 11 21 Severe Protocol Violation Mild to Moderate 6 Asian 17% African-American 22% Hispanic 46% Caucasian 15% 7 Exclusion criteria 5 9

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Analysis of Severe Flares  90 Days Severe Flare No Flare Prednisone 0 21 6 14 Placebo Fisher's correct test = 0.009

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Randomization: Timing and Clinical Features of the 6 Severe Flares Randomization C3a 1 month 2 month 3 month Anti-DNA 3 renal 1 CNS 1 pyoderma gangrenosum, pancytopenia 1 pleural emission Placebo Prednisone (no serious flares) 30mg X 1wk 30mg X 1wk 20mg X 1wk 10mg X 1wk

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Summary of Results of Outcome Variables by Treatment Groups

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Placebo C3a 2000 1000 0 -2 -1 0 1 2 3 2072 • Placebo DNA 984 618 434 378 128 -2 -1 0 1 2 3 Serial Measurements of Analytes in Representative Patients From Placebo and Prednisone Groups 1500 1000 500 0 1500 1000 500 0 Prednisone C3a Rand Clinical Flare Rand 500 250 0 -2 -1 0 1 2 3 Prednisone DNA Rand Clinical Flare -2 -1 0 1 2 3

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Anti-DNA abs and C as Candidate Biomarkers for Clinical Trials in SLE Clinical research center connection in SLE is a heterogeneous relationship Unanswered Questions 1. Are these serologic parameters valuable as indicators of flare and additionally in evaluation of flare and reaction to treatment? 2. Which tests are ideal and are blends predominant? 3. What is the ideal time interim in which to concentrate a patient? 4. What is the result being measured i.e. meanings of flare, and in what organ, renal could be generally pertinent?

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TABLE 13.4, p252... Dubois Textbook, Chapter: Complement and SLE, Schur and Glickstein Ability of Immune Tests to Predict Clinical Exacerbations in SLE C3 Anti-DNA Clinical Evidence i hh none fundamentally ii hhh dynamic nephritis i hhh dynamic extrarenal iii h dynamic nephritis and extrarenal " One effortlessly accepts what one sincerely seeks after " The Roman writer Terrence

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