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Jill Buyon, M.D.

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Conclusion: these tests had limited utility in predicting or excluding lupus flares ... (514 patients followed at the Toronto Lupus Clinic 1991-1995) ... – PowerPoint PPT presentation

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Title: Jill Buyon, M.D.


1
Presented by Jill Buyon, M.D. at the September
29, 2003 meeting of the Arthritis Advisory
Committee
2
High
Low
3
The Enduring Role of anti-dsDNA and Complement
Proteins in Diagnostic Testing(Back to Basics)
  • anti-dsDNA abs specific to SLE
  • anti-dsDNA abs can deposit in the glomerulus
  • (high avidity, IgG, cationic, fix complement)
  • Evidence of complement consumption indicates
    immune complex-driven inflammation
  • genetic alterations in early complement proteins
    of classical pathway) are associated with SLE
  • Association between genetic polymorphisms in FcgR
    alleles (IIa) and renal disease


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Classical Pathway
Alternative Pathway
C3 -- C3a C3b (spontaneous)
DNA-IgG anti-dsDNA C1
-- C1 esterase activity
C3b B
C4 --C1-- C4a C4b
C2 --C1-- C2a C2b
C3bB
C3
D
P
C4b,2b
C3b,Bb
C3b,Bb,P
Ba
(stable)
C3a
C3a
chemotactic factor anaphylotoxin
C3b
C3b
C5
C4b,2b,3b
C3b,Bb,3b
C5a
C5a
chemotactic factor anaphylotoxin
C5b
C5b
C6
C6
C7
C7
C8
C8
C9
Glomerulonephritis Fetal loss
C9
MAC
MAC
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Neutrophil activation
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CR3
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ICAM-1
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C3a C5a
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Resting PMN
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Resting EC
Endothelial cell activation (priming)
IL-1ß TNF? C1q C3a C5a C5b-9 aEC aPL
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E-selectin
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Leukothrombosis
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Vaso-occlusive plug
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7
Playing Rules for Evaluation of the Biomarker f
Define Assay for Measurement Assay Binding Isotyp
e DNA Sens/Spec Crithidia high low affinity
abs IgM or IgG dsDNA specsens Farr high affinity
abs IgM and IgG ss and dsDNA ELISA high low
affinity abs IgM or IgG ss or dsDNA sensspec
anti-DNA abs
Complement Assay Component Specimen Me
asurement Immunochemical Native C3,
C4 serum Nephelometry Functional integrity
CH50 EDTA plasma RBC lysis Catabolic state
Activation C3a EDTA plasma ELISA
Define parameters of change for these candidate
biomarkers
8
Does the candidate biomarker
  • predict flare?
  • associate with flare?
  • respond to therapy in parallel with favorable
    clinical outcome?

An association between a factor and the risk
of a disease does not guarantee that
drug-induced changes in that factor will produce
a corresponding change in the risk.
9
Percent of Visits with Flares, Categorized by
Prior and Concurrent Changes in Levels of
Anti-dsDNA (Total 574 visits, overall flare rate
19) Ho et al, AR, 2001
Prior between visits 2 months and 1 month
before visit with flare Concurrent
between previous 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. Prior h DNAabs Critidia
2 dilutions (72 visits) 39 0.001 Concurrent
i DNAabs ELISA (89 visits) 30 0.002 Concurrent
i DNAabs Crithidia (112 visits) 29 0.0002

10
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 increases
pretest likelihood of disease (10 is high)
sensitivity 1-specificity LR for association of
flare and hdsDNA abs by Crithidia 2.7
LR for a negative test To determine the post
test probability of disease
after a negative result (0.10 is low)
1-sensitivity specificity LR for association
of flare and hdsDNA abs by Crithidia -.081
Conclusion these tests had limited utility in
predicting or excluding lupus flares
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Clinically Active Serologically Quiescent (CASQ)
SLE
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(514 patients followed at the Toronto Lupus
Clinic 1991-1995)
62 patients had CASQ 43 with CNS, renal and/or
vasculitis
58 patients had followup after last CASQ defining
visit
9 remained CASQ for 3 yrs
23 became inactive
5 became serologically active but clinically
stable (SACS)
21 became clincially and serologcially active
Gladman et al , J Rheum, 2003
12
Evaluation of the Sensitivity and Specificity of
C3, C4, CH50, anti-dsDNA and C3a for Detection of
Lupus Flares within 3 months (Tseng et al, Arth
Rheum suppl, 2001)
  • Cohort Patients enrolled in Safety of Estrogen
    in Lupus Erythematosus National Assessment
    (SELENA)
  • randomized double-blind placebo controlled trial
  • 496 female patients enrolled from 9/96 3/02
  • SLE patients given either HRT/placebo or
    OCP/placebo for 1 year
  • Analytes measured C3, C4, CH50, C3a and
    anti-dsDNA
  • baseline, q monthly x 3, and then q 3 months
    over a
  • 12 month period
  • Disease activity SELENA SLEDAI and PGA
  • Outcomes Severe flares, Mild/moderate flares

13
Approach
Previous visit must have occurred within 3
months from date of measurement
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Definition of flares
Severe Flare Change in SLEDAI to 12 New/worse
CNS SLE Vasculitis Nephritis Myositis Pl
t
Requiring Doubling of Prednisone Prednisone
0.5mg/kg/d Hospitalization New Cytoxan,
Azathioprine or Methotrexate Increase in
PGA to 2.5
  • Mild or Moderate Flare
  • Change of SLEDAI 3
  • New/worse Lupus rash Nasopharyngeal
    ulcers Pleuritis Pericarditis Arthritis
    Fever (SLE)
  • Any h in Prednisone to
  • Added NSAIDS or Plaquenil for disease activity
  • Physician Global Assessment (PGA) increase 1.0,
    and

15
Patients Available for Evaluation and Outcomes
  • 496 Total Patients (328 HRT patients 168 OCP
    patients)  
  • 428 patients had C3a and/or CH50 available
  • 496 patients had C3, C4, anti-dsDNA available
  • 2. Flares (including multiple flares in
    patients)
  • 491 mild/moderate flares
  • 39 severe flares

16
Sensitivity and Specificity of Analytes to
Predict Flares
Limitations/ Implications Utility of analytes
improved if definition of positive tests less
stringent.
Analytes q 3 months insufficient, monthly may
improve prediction of flares.
Absence of abnormal analytes does
not equate with clinical stability\ but
presence may be predictive of
flares. A priori treatment
of patients with abnormal analytes may be
appropriate since few
patients would be unnecessarily exposed.
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Serologically Active, Clinically Stable SLE
Objective To evaluate steroid treatment in
averting flares when elevations of plasma C3a
are accompanied by rising anti-dsDNA titers in
stable or inactive patients
Principal Investigator Steve Abramson Collabora
tors Chung-E Tseng Jill P.
Buyon Michael Belmont
Betty Diamond Meggan Mackay
  • Inclusion Criteria
  • Anti-DNA abs present within 2 years
  • Prednisone
  • No active infection
  • Stability of disease and medications for 2
    months

18
  • Study Design
  • Patients followed monthly for 12-18 months
  • History and physical, analytes, and SLEDAI
  • Randomization Criteria
  • Rise of C3a ( 50 and absolute level ? 500
    ng/ml)
  • Rise of anti-DNA (25) from visit within 1-2
    months
  • Absence of clinical activity

Placebo
Prednisone 30 mg X 2 wks 20 mg X 1
wk 10 mg X 1wk
19
Flow Chart of Patients Followed in the
Observational Study (up to 18 months)
180
NON-RANDOMIZED
RANDOMIZED(Serological flare, clinically stable)
139
41
Completed no serological or clinical flare
Stopping point
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92
Clinicalflare
No clinicalflare
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30
Clinical flare with or without serologic flare
Voluntarydrop out
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Severe
Protocol Violation
Mild to Moderate
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Asian 17 African-American 22 Hispanic
46 Caucasian 15
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Exclusioncriteria
5
9
20
Analysis of Severe Flares ? 90 Days
Severe Flare No Flare
Prednisone
0 21
6 14
Placebo
Fishers exact test 0.009
21
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, pancytopen
ia
1 pleural effusion
Placebo
Prednisone (no severe flares) 30mg X 1wk 30mg X
1wk 20mg X 1wk 10mg X 1wk
22
Summary of Results of Outcome Variables by
Treatment Groups
23
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
Rand
Clinical Flare
-2 -1 0 1 2 3
24
Anti-DNA abs and C as Candidate Biomarkers for
Clinical Trials in SLE
Clinical laboratory correlation in SLE is a
heterogeneous relationship Unanswered
Questions 1. Are these serologic parameters
useful as predictors of flare and/or in
assessment of flare and response to therapy? 2.
Which tests are best and are combinations
superior? 3. What is the optimal time interval
in which to study a patient? 4. What is the
outcome being measured i.e. definitions of flare,
and in what organ, renal could be most relevant?

25
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 necessarily ii hhh active
nephritis i hhh active extrarenal iii h act
ive nephritis and extrarenal
" One easily believes what one earnestly hopes
for " The Roman dramatist Terrence
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