Transcript measeeadv

GRAPPA
Examples of Work Projects
Philip Mease
Examples of GRAPPA Work Projects
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Classification and diagnosis of PsA (CASPAR)
Evaluation of PsA composite outcomes
Determination of minimal clinically important
difference of function in PsA
“Participation” measure
Determination of patient global assessment
Axial assessment
Enthesial assessment
Dactylitis assessment
PsA treatment guidelines
PsA: Classification Schema
Moll & Wright, Vasey and Espinosa, Fournie,
Bennett, Gladman, McGonagle
 CASPAR (Philip Helliwell)
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Psoriatic arthritis – disease
classification and diagnosis
Psoriatic arthritis
 Inflammatory arthritis
– Oligoarticular, polyarticular, DIP, axial, mutilans
Psoriasis
 (Usually) negative rheumatoid factor
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Moll and Wright
Psoriatic arthritis – disease
classification and diagnosis
New classification criteria are required:
 Reduce contamination with other conditions
 More precise epidemiology
 Improved prognostic information
 Facilitate research into aetiology and
pathophysiology
CASPAR – development and validation
of classification criteria for PsA
A prospective multicentre international case
control study
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600 consecutive patients
with PsA
600 next available controls
with inflammatory arthritis
and inflammatory
osteoarthritis (OA)
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At least 50% with RA
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Matched for disease duration
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Standardized proforma
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Clinical and historic data
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Radiographic data
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DNA samples
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Serum sample
CASPAR – validation of classification
criteria for PsA
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Analysis by:
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– Univariate analyses
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– Comparison of existing
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criteria
– Conditional logistic
regression
– Latent class analysis
– Classification and
regression trees
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International study
All major ‘players’
Consensus criteria
Based on sound
methodology
(cf RA and ESSG)
Clinical features
Case
Control
35
30
%
25
20
15
10
5
0
Dactylitis
Enthesitis
DIP involvement
CASPAR – individual features
Diagnostic Odds Ratio (DOR)
 Ratio of odds of positivity in disease relative to
odds of positivity in non-disease
 DOR = true positive / false negative ÷ false
positive / true negative
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– Sensitivity / (1-sens) ÷ (1-specificity) / specificity
– LR*(+) / LR(-)
*LR = Likelihood Ratio
Glas et al. J Clin Epid 2003; 56:1129–35
Psoriasis
Psoriasis
DOR = 581
Nail dystrophy
DOR = 59
Family history of psoriasis DOR = 9.2
Dactylitis
Dactylitis
DOR = 19.3
DIP disease
DIP disease
DOR = 6.4
Clinical enthesitis
Any tender enthesis
DOR = 3.8
Inflammatory heel pain
DOR = 2.7
Outcome Measurements in PSA
preliminary results from IMPACT
and Etanercept PhaseII trials
OMERACT 7
C. Antoni
J. Fransen
W. Uter
P. Mease on behalf of
GRAPPA
Methods
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Data resources
– Etanercept PhaseII week 0-12 n=60
– IMPACT week 0-16 n=104
Combined SAS data base Erlangen
 Analysis
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– ROC receiver operating characteristic in combined
data base
– Responsiveness analysis in seperated data bases
(standardised response mean SRM; t-value; chisquare)
ROC changes
DAS28 4 Variables
youden
.784
cutoff1
1.27
sens
.880
spec
.904
ROC changes
68 Tender Joint Count
youden
.513
cutoff1
6.00
sens
.753
spec
.759
ROC changes
66 swollen joint count
youden
.464
cutoff1
6.00
sens
.654
spec
.810
ROC changes
CRP
youden
.324
cutoff1
-.10
sens
.935
spec
.389
Discrimination IMPACT
Criterium
EULAR28
Good + moderate
Good
EULAR28 (DAS28 crp)
Good + moderate
Good
Placebo (n=52) Drug (n=52)
%improved
%improved
26%
0%
92%
60%
30%
7%
88%
52%
2 MH
53.4
p-value
<0.0001
35.4
<0.0001
48.6
<0.0001
EULAR
Good + moderate
Good
26%
0%
88%
63%
ACR20
ACR50
ACR70
10%
0%
0%
67%
48%
29%
36.2
32.6
17.4
<0.0001
<0.0001
<0.0001
PsARC
30%
82%
27.9
<0.0001
Discrimination Etanercept
Criterium
EULAR28
Good + moderate
Good
Placebo (n=30) Drug (n=30)
%improved %improved 2 MH
15%
8%
EULAR28 (DAS28 crp)
Good + moderate 15%
Good
4%
p-value
26.2
<0.0001
23.3
<0.0001
22.9
<0.0001
93%
52%
86%
39%
EULAR
Good + moderate
Good
12%
4%
81%
44%
ACR20
ACR50
ACR70
15%
4%
0%
73%
50%
13%
19.6
14.8
3.8
<0.0001
0.0001
0.05
PsARC
33%
90%
19.3
<0.0001
Inflammatory Enthesopathy
Enthesitis
 Periosteal
new
bone formation
 Subchondral
bone
inflammation and
resorption
Bone
McGonagle D. Arthritis Rheum. 1999. 42:1080-1086.
MASES Index
..
..
.. ..
13 sites
0 = no pain
...
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Heuft-Dorenbosch Ann Rheum Dis 2003
1 = pain
MCID Background
Key question: In a given disease parameter,
how much change is clinically important to
the patient as opposed to “statistically
significantly different”
 > 20 different methodologies to measure
minimal clinically important difference
 MCID for RA for Health Assessment
Questionnaire (HAQ) is 0.22 (out of total of
3.0)
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How Much Improvement in
Functional Status Is Considered
Important by Patients With Active
Psoriatic Arthritis: Applying the
Outcome Measures in Rheumatoid
Arthritis Clinical Trials (OMERACT)
Group Guidelines
Philip Mease1 Rita Ganguly2, L. Wanke3, Amitabh Singh2
1Seattle
Rheumatology Associates, Seattle, WA; 2Wyeth Research,
Collegeville, PA; 3Amgen, Thousand Oaks, CA
Methods (derived from Etanercept
Phase III trial in PsA)
Patient Rating-Based MCID
Not At
All
Important
How important to you is the amount of
change in your physical limitations (such
as limitations in walking, standing,
gripping reaching, etc.)
1
Extremely
Important
2
3
4
5
Minimally Important
6
7
Very Important
Mean change from baseline
in HAQ Disability Score for
those who improved
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Methods
Data-Driven Approach MCID
 Upper bound of 95% confidence interval of standard
error of measurement (SEM) for HAQ
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SEM =
σ
baseline HAQ
1- rbaseline
HAQ
where σ=standard deviation
r = Cronbach’s alpha coefficient
Results
Threshold
95%
for delta in Confidence Type of MCID
HAQ Scores Interval
SEM-Based MCID
Patient Rating-Based MCID
Patient Rating-Based Major
Clinically Important Difference
0.40
0.30
N.A.
0.24-0.35
2.2.5
2.1.5
0.65
0.57-0.72
2.1.5
Participation
Measurement of“Participation” in all aspects
of life: work, family, social, religious, etc.
 Mandate from WHO International
Classification of Function (ICF) group
regarding all disease groups
 Seen as involvement in a life situation,
not merely the execution of a task or action
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Action Plan
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Agreement that this is a worthwhile project
Identify rheumatology and dermatology leaders: Will Taylor, Henning
Boehncke
Project1: Map items from existing measurement tools to ICF
categories
Project2: Delphi exercise (includes non-rheumatologists, non-medical
health professionals)
Project3: Patient survey using ICF checklist (funding required for
training and patient assessments); validate WHODAS at same time
Project4: 3-day consensus development meeting possibly adjacent to
EULAR 2006 (Netherlands)
Project5: Further patient survey to validate the core-set
(?) Project6: Development of the core-set into a psychometrically
sound measurement tool
Patient Global Question
Please place a mark on each line below to indicate your answer to
each question relating to the past week (or 3 days?/ or day of
assessment?)
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Global
In all the ways in which your PSORIASIS and ARTHRITIS, as
a whole, affects you, how would you rate the way you feel at
this time? (10 cm line)
(from “wellness” to “the worse I can feel”)
Joints
In all the ways your ARTHRITIS affects you, how would you
rate the way you feel at this time? (10 cm line)
Skin
In all the ways your PSORIASIS affects you, how would you
rate the way you feel at this time? (10 cm line)
Biomarkers in PsA and Psoriasis
Goal: Standardization of histologic and
immunohistochemical analyses used in skin
synovial biopsies before and after treatment
with various agents
 Committee lead: Oliver Fitzgerald (Dublin)
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Immunohistochemistry
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Inflammatory cells
– CD3, CD38, CD55, CD68, granzyme B
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Adhesion molecules
– ICAM-1, VCAM-1, E-selectin
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Angiogenesis
– vWF, VEGF, v3, bFGF
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Matrix metalloproteinases
– MMP1, MMP3, MMP13, TIMP
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Cytokines
– IL-1, TNF, IL-6, IL-18
GRAPPA PsA Treatment Guidelines
Peripheral
Arthritis
Skin and
Nail Disease
Axial
Disease
Dactylitis
Enthesitis
Initiate
Therapy
Initiate
Therapy
Initiate
Therapy
Initiate
Therapy
Initiate
Therapy
NSAIDs,
IA steroids,
DMARDs
(MTX, CsA,
SSZ, LEF),
Biologics
(anti-TNF)
Topicals
PUVA/UVB
DMARDs
(MTX, CsA)
Biologics
(anti-TNF, etc)
NSAID
PT
Biologics
(anti-TNF)
NSAID
Injection
Biologics
(anti-TNF)
NSAID
Injection
Biologics
(anti-TNF)
Reassess Response to
Therapy and Toxicity
GRAPPA=Group for Research and Assessment of Psoriasis and Psoriatic Arthritis;
NSAIDs=nonsteroidal anti-inflammatory drugs; IA=intra-articular; DMARDs=disease-modifying
antirheumatic drugs; MTX=methotrexate; CsA=cyclosporin A; SSZ=sulfasalazine;
LEF=leflunomide; anti-TNF=tumor necrosis factor inhibitor; PUVA=psoralen plus ultraviolet light
A; UVB=ultraviolet light B; PT=physiotherapy.
Quality of evidence
Evidence
Recommendation
1A meta-analysis of RCT
1B one or more RCT
2A one or more CT
2B well-designed studies
Grade A
Grade B
3
non-experimental studies
Grade C
4
expert opinions,
clinical experience
Grade D
Soriano ER, McHugh GRAPPA, San Antonio, 2004 MJ.
Level evidence:
effect size, side-effect profile
SSZ
MTX
CyA
LFN
Gold
AZA
ETN
INF
Evidence
symptom
control
1A
2B
1B
1B
-1A
2B
1B
1B
Effect size
SE
NE
ME
LE
SE
ME
HE
HE
Evidence Xray
-3
-3
3
4
-3
–
1B
–
Toxicity
Low
Low
High
Low
Med
Low
Low
Low
Recomm.
grade?
A-B
B
A-B
A
-A
B
A
A
Means evidence against. NE: negligible effect; SE: Small effect;
ME: Medium effect; LE: Large effect; HE: Huge effect
A few unanswered questions
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Why do skin and joint disease coexist in PsA?
What is behind the difference in clinical expression
between SpAs and RA
What is the enthesopathy process trying to teach us
about the central pathophysiology of the SpAs and
how does this influence our assessment and therapy?
What implication will differential cellular activity and
cytokine expression have on our approach to therapy
of SpAs?
Are the lessons being learned about the ability to
inhibit disease progression in RA transferable to
SpAs?