Transcript Update on National Psoriasis Foundation Psoriasis Score

Psoriasis OMERACT 2004
Methods to assess disease activity in
clinical trials
Gerald G Krueger MD
Professor, Cumming Presidential Endowed Chair
Dept of Dermatology University of Utah
5/2004
The challenge
1
4
6p
16
17
Qualities for Assessment of psoriasis
Investigators want
– Quick and easy to perform
– Clear definitions, reproducible
 FDA seeks
– “Static” ratings — indicating severity at the time the
patient is seen
– Results in steps (segmented).e.g. clear, mild,
moderate, severe
– Results that have clinical relevance to patient

7/18/2015
Tools to quantitate clinical
improvement in psoriasis
Clinical Assessments - Subjective
– PASI
– PGA: Dynamic + / - assisted recall; Static
– OLA
– National Psoriasis Foundation Psoriasis Score (NPF-PS)
– Lattice System-Global Psoriasis Score (LS-GPS)
– Target lesions: + / - BSA
– QOL (SF36, DLQI, others)
 Clinical Assessments - Objective
– Biopsy -- thickness, biomarkers (real time PCR, EGIR, etc)
– Photographs

PASI
E = Erythema
I = Infiltration (induration; thickness; elevation)
D = Desquamation (scale; scaling)
A = Score for % involvement in each body area
The PASI score (0-72) is calculated from the following formula:
Head (H)
0.1 (EH +IH + DH) AH
Trunk (T)
+ 0.3 (ET +ET + DT ) AT
Upper Ext. (U)
+ 0.2 (EU + IU + DU ) AU
Lower Ext. (L)
+ 0.4 (EL + IL + DL )AL
Fredriksson & Pettersson, Dermatologica 1978; 157:238
Improvement in PASI score vs time
Mean Percentage Improvement
in PASI Score From Baseline
Placebo (n=479)
Efalizumab 1 mg/kg/wk (n=763)
60
*
50
*
*
*
40
30
*
20
*
10
0
0
2
4
6
Week
*P=0.0001 vs placebo.
Gordon KB, et al. 9th IPS 2003; Poster 29.
8
10
12
Improvement in PASI 50 and 75
Percentage of Patients
70
PASI 75
60
57%*
55%*
50
PASI 75/
PASI 50
40
28%*
30
20
10
PASI 50
28%*
15%
4%
0
Placebo
(n=479)
*P<0.001 vs placebo.
Gordon KB, et al. 9th IPS 2003; Poster 29.
Efalizumab
1 mg/kg/wk
Efalizumab
2 mg/kg/wk
(n=763)
(n=409)
Alefacept 7.5 mg/week x 12
PASI < 75 is clinically meaningful
Baseline
(PASI = 14.2)
2 Weeks After Last Dose
(PASI = 9.5)
3 Months After Last Dose
(PASI = 4.8)
33% PASI Reduction
66% PASI Reduction
PASI problems





Plaque qualities (e.g., induration) not defined
Area is non-linear, uses a 1-6 scale (1 = <10% BSA, 2 = 10<30% BSA, 3 = 30-<50% BSA, 4 = 50-<70% BSA, 5 = 70<90% BSA, and 6 = 90-100% BSA)
Erythema, infiltration, scaling all weighted equally
– Plaque elevation may be more important
(FDA and investigator consensus)
Small amount of disease = less reduction than appreciated
clinically
Continuous, not in steps, PASI 50 and PASI 75 arbitrary
endpoints
PASI problems, cont’d
 Not

intuitive to physicians or patients
– PASI = 28 -- what does it mean?
– 50% or 75% reduction in PASI -- what does this
mean when recognized that score is non-linear?
Clear/almost clear not defined
– What scores = clear to almost clear?
– FDA interested in percent of patients who achieve
clear or almost clear
The NPF Psoriasis Score:
Development and Use of a New
Psoriasis Scoring System
The NPF Score
Primary End Points
Induration, Target Lesion A (0-5)
5
Induration, Target Lesion B (0-5)
5
BSA Current /Baseline (0-5)
5
Physician's Global Assessment (0-5) 5
Patient's Global Assessment (0-5)
5
Patient's Assessment of Itch (0-5)
5
Maximum Possible Score
30
Target Lesion Assessment
0.0 mm
= most heavily weighted
score
 Felt to be most important of EIS system
 Possible to improve inter-observer
reliability via NPF Reference Card
embossed with elevations that increase at
0.25 mm intervals
 Score 0 to 5
0.25 mm
Psoriasis Score
 Induration
0.50 mm
0.75 mm
1.00 mm
1.25 mm
Body Surface Area
 Percent
relative to
baseline, therefore able to
make cross-study
comparison
 Uses 1%=palm to PIP
joint system
 Does not account for
worsening of disease
BSA =
% Current
% Baseline
X 100
0 = 0% BSA remaining with
psoriasis (complete clearing
except residual discoloration)
1 = 1-20% BSA remaining
2 = 21-40% BSA remaining
3 = 41-60% BSA remaining
4 = 61-80% BSA remaining
5 = 81-100% BSA remaining
Physician’s Global
0 = cleared except residual discoloration
Assessment
 Felt
to be most important
score, but not very
dynamic alone
 EIS
scores are used by
physician to assist in
making a single PGA
score
1=majority of lesions have individual
scores for I, E, S that average 1
2 = majority of lesions have individual
scores for I, E, S that average 2
3 = majority of lesions have individual
scores for I, E, S that average 3
4 = majority of lesions have individual
scores for I, E, S that average 4
5 = majority of lesions have individual
scores for I, E, S that average 5
Patient’s Global Assessment
 Dynamic
assessment
that relies on “set
point” of individual
rather than baseline
Rank severity of psoriasis, 0 = no psoriasis, 5
= worst psoriasis has been:
0 = no psoriasis
1 = 20% as bad as my psoriasis has ever been
2 = 40% as bad as my psoriasis has ever been
3 = 60% as bad as my psoriasis has ever been
4 = 80% as bad as my psoriasis has ever been
5 = the worst my psoriasis has ever been
Patient’s Assessment of Itch
0 = No itching
 Static Assessment
 Averaged
hours
 Felt
1=Mild; only aware of itching at times, only
present when relaxing, not present when
focused on other activities
over past 24 2 = Intermediate between 1 and 3
to be significant
indicator of
improvement
3 = Moderate; often aware of itching,
annoying; sometimes disturbs sleep and
daytime activities
4 = Intermediate between 3 and 5.
5 = Severe; constant itching, distressing,
frequent sleep disturbance, interferes with
activities
Average score -- all patients
P AS I
NP F
NPF vs. PASI
3 0 .0
2 0 .0
1 5 .0
1 0 .0
5 .0
Example (Patient #6)
0 .0
1
2
3
4
Vis it #
P AS I
NP F
3
5
30
25
Prospective Trial of Acitretin
and Commercial Tanning
Score
Score
2 5 .0
20
15
10
5
0
1
2
4
Vis it #
6
7
National Psoriasis Foundation Psoriasis
Score as a tool to assess efficacy of
efalizumab (anti-CD11a) in treatment of
moderate to severe plaque psoriasis
G G Krueger, Alan Menter, Stephen Tyring,
David Harvey, Wolfgang Dummer,
Dan Henderson, Alice B Gottlieb
Responders @ 12 Weeks
Partial responders @ 12 Weeks
NPF PS Induration score during extended treatment
in subjects who were responders @ 12 weeks
Target lesion assessment +/- BSA
 Chose
two or more target lesions
– Representative of all lesions
– Representative of therapeutic target, e.g. lichenified,
intertriginous, knees, scalp, palms, soles, etc
– Assess chosen physical parameters, (E, I, S and area)
using definitions of each
 No standard definitions
 No standard scale, 0 to 3, 0 to 4, 0 to 5, 0 to 6
 BSA baseline, 1 palm = 1%
Conclusions re: Assessment of response to
therapeutic intervention
 Many
ways to assess response to Rx
 None have met the non-existent definition of what is “clinically
meaningful”
 PASI strengths: Widespread use, will distinguish active from
placebo
 PASI weaknesses: “Steps” (PASI 75, PASI 50) are artificial and
do not correspond with 75% and 50% improvement, correlate
poorly with QOL, unless trained - scores are disparate, not
effective for topical studies, not effective for systemic studies if
PASI is low, FDA dislikes it and clinicians do not use it nor
understand it
Conclusions re: Assessment of response to
therapeutic intervention, cont’d
 NPF-PS
–
–
–
–
–
strengths:
Correlates well to PASI, better than PASI to QOL
Works with low BSA (topical agents, PsA)
Has patient input
 Dynamic patient global (recall to worst ever been)
 Quantification of pruritus (most troublesome symptom),
Has defined physician global (static),
The major element -- induration of 2 target lesions -- early
change = strong predictor of response useful to assess subtle
change, easy and consistent assessment with validated
induration tool
Conclusions re: Assessment of response to
therapeutic intervention, cont’d
 NPF-PS
weaknesses:
– Not in widespread use
– “Not validated”
– “Steps” remain to be defined
– Approval agencies, e.g., FDA has not “blessed” it
– Clinicians have not been exposed to it
– Unknown = more or less acceptable than a simple
PGA
Quality of Life (QOL)
 Doesn’t
directly measure the impact of drug on
the disease
 Does measure the impact on the patient’s life
 The overall goal of therpeutic intervention is to
improve patient’s lives
 However direct measure of disease activity is the
usual primary endpoint
QOL vs Disease Severity
 Some
patients have lots of lesions but aren’t
bothered by them
 Some have very few lesions and are very bothered
by them
 QOL correlates to a degree with skin lesions, but
certainly not 100%
QOL Measures
 Non-specific
– SF-36
– Euro QOL
– Utility
 Skin specific
– DLQI
– Skindex
 Psoriasis specific
– PDI
Short Form-36
 General
health, health change,
physical functioning, limitations due
to physical health/emotional health,
social functioning, pain, energy,
emotional well-being
 Walking, climbing stairs, working
 Physical and mental dimensions
Physical Component Summary
Score of SF-36
Psoriasis: Impact on Physical Health–
Comparison With Other Diseases
60
55
55
50
45
40
47
45
45
44
43
43
42
42
41
35
35
30
Rapp SR et al. J Am Acad Dermatol. 1999;41:401.
Mental Component Summary
Score of the SF-36
Psoriasis: Impact on Mental Health–
Comparison With Other Diseases
55
50
53
52
52
52
50
49
49
46
46
45
45
40
35
35
30
Rapp SR et al. J Am Acad Dermatol. 1999;41:401.
Dermatology Life Quality Index
 Consists
of 10 questions
covering 6 domains
– Symptoms and feelings
– Daily activities
– Leisure
– Work and school
– Personal relationships
– Bother with psoriasis
treatment
 Response
options
– Very much: scored 3
– A lot: scored 2
– A little: scored 1
– Not at all: scored 0
 Range 0-30
 Lower scores = Better
QOL
Finlay AY et al. Clin Exp Dermatol. 1994;19:210.
Correlation of Change in DLQI and
Change in PASI and PGA
Correlation of
absolute changes
Correlation of
percent changes
Spearman rank correlations
PASI
PGA
0.49
0.46
0.61
0.58
Data on file, Centocor, Inc.
Efalizumab Phase III Results:
DLQI Scores at Weeks 0 & 12
Mean DLQI Score
14
12
Baseline
11.7
12.0
11.5
10
Week 12
9.9
8
6
*
*
6.1
6.1
6.3
4
2
0
Placebo
(n=170)
Efalizumab
1.0 mg/kg/wk
(n=162)
Efalizumab
2.0 mg/kg/wk
(n=166)
0 = Minimum effect on QOL; 30 = Maximum effect on QOL.
Feldman SR, et al. AAD Annual Meeting 2002; Poster.
*P<0.001 vs placebo.
34
Improvement From Baseline
In DLQI
Improvement From Baseline
in DLQI at Week 10
Mean change
Median change
12
10.3*
10
10*
8.8*
8*
8
6
4
2.6
2
0
0
Placebo
Infliximab 3mg/kg
Infliximab 5mg/kg
*p<0.001 vs placebo
Data on file, Centocor, Inc.
Summary
 QOL measures
supplement lesion measures