psa: review of available assessment instruments and lessons from trial results part ii christian...

PsA: Review of Available Assessment Instruments and

Lessons from Trial Results

Part IIChristian Antoni

Friedrich Alexander University

Erlangen-Nürnberg

Department of Medicine III

Antoni N.Y. 8/03 Antoni N.Y. 8/03

Outline

• Baseline characteristics of actual trial patients

• Joint count vs. joint score

• Used and not used assessment instruments

• MRI and Ultrasound


The IMPACT Trial Centers

• Kalden/Antoni Erlangen, Germany

• Burmester/Schneider Berlin, Germany

• Smolen/Ebner Vienna, Austria

• Kirkham London, United Kingdom

• Keystone/Gladman Toronto, Canada

• Kavanaugh/Tutuncu San Diego, California

• Weisman/Wallace Los Angeles, California

• Furst/Molitor Seattle, Washington

• Wassenberg Ratingen, Germany


IMPACT Inclusion Criteria• > 18 years old

• PsA with peripheral polyarticular involvement for >6 months

• Typical psoriatic arthritis presentation with /without active skin lesions

– Arthritis der DIP-Gelenke an Händen und Füßen– Arthritis mutilans mit Sakroilitis– Symmetrische Arthritis, klinisch wie die RA imponierend

aber ohne RF– Asymmetrische Oligoarthritis mit Beteiligung der kleinen

Gelenke (Wurstfinger)– Ankylosierende Spondylitis mit oder ohne periphere

Arthritis(Moll and Wright 1973)

• Negative for RF


IMPACT Inclusion Criteria

• Active disease (5 joints and ESR>28, or CRP> 15, or morning stiffness > 45 minutes)

• At least 1 DMARD failure

• Stable DMARD dosing > 4 weeks, if applicable

• Stable prednisone <10 mg/day for 2 weeks

• Stable NSAIDS for 2 weeks


Patient Population

• Psoriasis duration (mean) 18.8 years– Mean age at diagnosis 26.7 years

• Arthritis duration (mean) 11.0 years– Mean age at diagnosis 34.4 years

• Concomitant DMARDs treatment (69/101 patients)– Leflunomide6– Sulfasalazine 8– Methotrexate 56– Mean DMARD

• 1.85 all patients• 2.09 Infliximab• 1.86 Placebo


Mean Baseline ActivityMean Baseline Activity

Placebo Infliximab

Tender-joint count 20 24

Swollen-joint count 14 15

Physician global (0-100) 53 54

Patient global (0-100) 57 52

Patient pain (0-100) 57 54

HAQ disability index (0-3) 1.19 1.14

CRP (mg/L) 21 23


Baseline PASI

Placebo Infliximab

n = 52 n = 52

Subjects with Any Skin n= 42 n= 42 Involvement

Subjects with PASI >2.5 n = 18 n = 21

Mean Baseline 7.96 (2.7-27.9) 8.88 (2.8-26.1)


Week 16 Results: PASI

Placebo Infliximab

Mean PASI Baseline 7.96 8.88

Mean PASI Week 16 8.71 1.62

% Change of Mean -29.6% 81.5%*

> 75% Improvement 1 subjects 14 subjects (0.05%) (67%)**

*p<0.001

**p<0.0001


Week 50 Results: PASI

Placebo + Infliximab Infliximab

Mean PASI Baseline 7.96 8.88

Mean PASI Week 50 2.48 1.73

% Change of Mean 47.6% 72.1%*

> 75% Improvement 8 subjects 12 subjects (44%) (57%)**

*p<0.001

**p<0.0001


Outline






Intra and Inter Observer Variability

Intra-rater variability shows good correlationHernandez-Cruz B, Clin Exp Rheum 199

“inter-rater agreement hardly exceeds the chance level when degree of tenderness is independently assessed”

Hart 1985, Lewis 1988, Thompson 1991, Scott 1992


Count vs. Score Tenderness

studymedN

Obs Variable Mean Std Dev Minimum Maximum Median

Placebo 52 jlstcountjlstscorejl16tcountjl16tscorejl50tcountjl50tscore

19.745098025.117647121.734693927.36734696.34615386.8076923

11.507985315.301826113.756476524.34534007.77094798.8274049

5.00000005.00000005.00000005.0000000

00

64.000000079.000000066.0000000

126.000000030.000000039.0000000

19.000000022.000000019.000000021.00000002.50000002.5000000

Infliximab 52 jlstcountjlstscorejl16tcountjl16tscorejl50tcountjl50tscore

23.862745130.921568610.686274513.98039227.07692318.0769231

13.614726724.172582113.460297521.852679610.945222213.2322336

7.00000007.0000000

0000

64.0000000142.0000000

61.0000000119.0000000

46.000000056.0000000

22.000000025.00000006.00000006.00000003.50000004.0000000


Count vs. Score Swelling

studymedN

Obs Variable Mean Std Dev Minimum Maximum Median

Placebo 52 jlsscountjlssscorejl16scountjl16sscorejl50scountjl50sscore

13.921568617.078431413.795918416.12244902.90384623.0961538

7.44269618.7540691

10.321861114.94522314.97546775.3035675

5.00000005.0000000

0000

42.000000051.000000047.000000087.000000026.000000026.0000000

12.000000015.000000011.000000012.00000001.00000001.0000000

Infliximab 52 jlsscountjlssscorejl16scountjl16sscorejl50scountjl50sscore

14.705882417.17647064.94117655.05882353.65384623.7307692

7.54266309.59730356.83055426.97255125.94050446.0297153

5.00000005.0000000

0000

34.000000044.000000028.000000029.000000028.000000028.0000000

13.000000014.00000003.00000003.00000001.00000001.0000000


Week 16 Results: ACR 20, 50, 70counts vs. score

9,613

0 0 0 0

53

3329*

48*

7167*

0

20

40

60

80

100

ACR 20 ACR20S

ACR 50 ACR50S

ACR 70 ACR70S

Placebo Infliximab

Per

cen

t o

f P

atie

nts

Res

po

nd

ing

*p<0.0001*p<0.0001


Outline• Baseline characteristics of actual trial

patients


• Used and not used assessment instruments:– Clegg Criteria– ACR– DAS and DAS28– HAQ and SF36– RADAI



Combined Indices

• Paulus Criteria (Arthritis. Rheum. 1990)

• ACR Preliminary Definition of Improvement in Rheumatoid Arthritis (Arthritis. Rheum. 1995)

• EULAR Criteria, "Disease Activity Index" DAS (J Rheumatol 1993)

• PsARC or Clegg Criteria (Arhtritis Rheum 1996)


Clegg or PsARC Criteria

• Improvement is defined as:

• Improvement in 1 out of 4 criterias including one out of JTS or JSS

– 30% improvement in TJS– 30% improvement in JSS– Patient Global on a Liquert scale (1 out of 4)– Doctors global on a Liquert scale (1 out of 4)

• For improved cases non of the 4 criteria is allowed to worse by the defined changes


ACR20 Criteria of Improvement

20% improvement in swollen and tender joints

and

20% improvement in 3 of the 5 assessments:

– patient’s assessment of pain (VAS)

– patient’s globa assessment of disease activity (VAS)

– evaluator’s global assessment of disease activity (VAS)

– patient’s assessment of physical function (HAQ)

– CRP or ESR


Disease Activity Score (DAS)

• Composite Index incorporating:– ESR– Swollen joint count– Ritchie Index of articular tenderness (score)– Assessment of patient’s general health

• DAS28 (28 joint count) as reliable as DAS (53/44 joint count)


DAS 28

• Tender joint count (28)

• Swollen joint count (28)

• ESR

• Patient Global (0-100 mm)

• DAS = 0,555 (28 TJC.)+ 0,284

(28 SJC.) + 0,70 In (ESR) + 0,0142 (patient global)

090401.1 Lindenbaum-On-screen 23

EULAR Response Criteria

DAS28 at Endpoint

Improvement in DAS or DAS28 from Baseline

3.2

> 3.2 and 5.1

> 5.1

> 1.2 > 0.6 and 1.2 0.6

Good

Moderate

None


Rheumatoid Arthritis: Patient 3

infliximabinfliximab


20%

20%

ACR20 vs DAS28:same improvement, different level

of disease activity


26.3 ACR AUC

6.1 ACR AUC

Same level of disease activity, different baseline value

AUC ACR influence of baselineAUC ACR influence of baseline


Week 16 Results PsARC

18,4

78.0*

0

20

40

60

80

100

Placebo Infliximab

*p<0.0001

Per

cen

t o

f P

atie

nts


Week 16 Results: ACR 20, 50, 70

9,60 0

28.9*

48.0*

67.3*

0

20

40

60

80

100

ACR 20 ACR 50 ACR 70

Placebo Infliximab

Per

cen

t o

f P

atie

nts

Res

po

nd

ing

*p<0.0001*p<0.0001


Week 16 Results Proportion of DAS 28 Responders

23,1

84,6

0

20

40

60

80

100

Placebo Infliximab

Patients with a Good or Moderate DAS28 Response at Week 16

Per

cen

t o

f P

atie

nts


Week 16 Results Proportion of DAS Original Responders

19,2

76,9

0

20

40

60

80

100

Placebo Infliximab

Patients with a Good or Moderate DAS Response at Week 16

Per

cen

t o

f P

atie

nts


20 questions in eight categories of function:

The Health Assessment Questionnaire (HAQ)

Functional Disability Index (FDI)

n dressingn arisingn eatingn walking

n hygienen reachn gripn activities

aids, devices or help by another person


Reduction of Efficacy parameters at week 16Reduction of Efficacy parameters at week 16

ACR individual parameters

Parameter baseline week 16 change %

Placebo/Infliximab

Tender joint score: 25/31 27/14 -

30/62

Swollen joint score: 17/17 16/5 4/68

Patient Global VAS: 56/52 58/25 -10/49

Patient VAS of pain: 57/54 58/22 -3/55

Physician Global VAS: 53/55 53/20 -5/61

HAQ: 1.19/1.14 1.2/0.6 8/47

CRP: 12/12 11/2 -23/62


Medical Outcomes Study Short-Form-36 (SF-36)

• Generic health status measure containing 36 items on 8 different aspects of health

1 – physical functioning

2 – physical role

3 – mental health

4 – emotional health

5 – bodily pain

6 – social functioning

7 – generic health

8 – vitality


SF-36• Most widely used generic measure of health status

• Numerous methods of scoring and analysing the data

• Can be used in comparisons– between patients and the general population,

– between severity groups and over time

• scores can be linked to a range of interpretations, including distribution and norm or anchor based


SF-36 RA Comparison European cohorts


Patient vs. physician assessment of the patient’s health today RA?

Best imaginable Worst imaginable

Mean=3.8 +/- 2.1 Mean=5.0 +/- 2.4


RADAI

n Self Description The RADAI is a useful method as a complement to

physician’s assessments in long-term observation studies

n Rationale for use The questionnaire is short, easy to use, valid,

reliable, and sensitive to change in disease activity

EULAR Handbook of Clinical Assessment P-47


Fransen et al. 2000 (observational study in 584 patients

with rheumatoid arthritis)

n good test-retest-correlation (0.81 - 0.85)

n weak correlation with the ESR (0.27)

n correlation with tender joint count 0.55

n correlation with physician´s global assessment 0.59

n correlation with DAS28: 0.56

Rheumatoid Arthritis Disease Activity Index (RADAI)


Mean RADAI RA by CountryN=5173, mean = 4.11


RADAI vs. Tender joints in RAN=5084


RADAI vs HAQ in RA


Outline






correlation MRI with joint counts

Correlation with % change of Gadolinium uptake

• Tender Joint Score r = 0,62 p = 0,04

• Swollen Joint score r = 0,772 p = 0,008

• Physician evaluation of disease activityr = 0,82 p = 0,006

• Patient evaluation of disease activityr = 0,74 p = 0,009

• Morning stiffness r = 0,639 p = 0,027


Infliximab Reduces Inflammation in Psoriatic Arthritis

Infliximab Reduces Inflammation in Psoriatic Arthritis

MRI Scan of wrist – Gadolinium UptakeMRI Scan of wrist – Gadolinium UptakeMRI Scan of wrist – Gadolinium UptakeMRI Scan of wrist – Gadolinium Uptake

Week 0Week 0 Week 10Week 10

Antoni C et al. EULAR 2000.Antoni C et al. EULAR 2000.

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