1. PsA: Review of Available Assessment Instruments and Lessons from Trial Results Part II Christian Antoni Friedrich Alexander University Erlangen-Nürnberg Department of Medicine III

2. 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

3. Antoni N.Y. 8/03 The IMPACT Trial Centers Kalden/AntoniErlangen, Germany Burmester/SchneiderBerlin, Germany Smolen/EbnerVienna, Austria Kirkham London, United Kingdom Keystone/GladmanToronto, Canada Kavanaugh/TutuncuSan Diego, California Weisman/WallaceLos Angeles, California Furst/MolitorSeattle, Washington WassenbergRatingen, Germany

4. Antoni N.Y. 8/03 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

5. Antoni N.Y. 8/03 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

6. Antoni N.Y. 8/03 Patient Population Psoriasis duration (mean)18.8 years –Mean age at diagnosis26.7 years Arthritis duration (mean)11.0 years –Mean age at diagnosis 34.4 years Concomitant DMARDs treatment (69/101 patients) –Leflunomide6 –Sulfasalazine8 –Methotrexate56 –Mean DMARD 1.85 all patients 2.09 Infliximab 1.86 Placebo

7. Antoni N.Y. 8/03 Mean Baseline Activity PlaceboInfliximab Tender-joint count2024 Swollen-joint count1415 Physician global (0-100)5354 Patient global (0-100) 5752 Patient pain (0-100)5754 HAQ disability index (0-3)1.191.14 CRP (mg/L)2123

8. Antoni N.Y. 8/03 Baseline PASI PlaceboInfliximab n = 52n = 52 Subjects with Any Skin n= 42n= 42 Involvement Subjects with PASI >2.5n = 18n = 21 Mean Baseline 7.96 (2.7-27.9) 8.88 (2.8-26.1)

9. Antoni N.Y. 8/03 Week 16 Results: PASI PlaceboInfliximab Mean PASI Baseline 7.968.88 Mean PASI Week 16 8.711.62 % Change of Mean-29.6%81.5%* > 75% Improvement1 subjects 14 subjects (0.05%) (67%)** *p<0.001 **p<0.0001

10. Antoni N.Y. 8/03 Week 50 Results: PASI Placebo + InfliximabInfliximab Mean PASI Baseline 7.968.88 Mean PASI Week 50 2.481.73 % Change of Mean47.6%72.1%* > 75% Improvement8 subjects 12 subjects (44%) (57%)** *p<0.001 **p<0.0001

11. 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

12. Antoni N.Y. 8/03

13. Intra and Inter Observer Variability Intra-rater variability shows good correlation Hernandez-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

14. Antoni N.Y. 8/03 Count vs. Score Tenderness

15. Antoni N.Y. 8/03 Count vs. Score Swelling

16. Antoni N.Y. 8/03 Week 16 Results: ACR 20, 50, 70 counts vs. score Percent of Patients Responding *p<0.0001

17. Antoni N.Y. 8/03 Outline Baseline characteristics of actual trial patients Joint count vs. joint score Used and not used assessment instruments: –Clegg Criteria –ACR –DAS and DAS28 –HAQ and SF36 –RADAI MRI and Ultrasound

18. Antoni N.Y. 8/03 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)

19. Antoni N.Y. 8/03 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

20. Antoni N.Y. 8/03 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

21. Antoni N.Y. 8/03 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)

22. Antoni N.Y. 8/03 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)

23. 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

24. Antoni N.Y. 8/03 Rheumatoid Arthritis: Patient 3 infliximab

25. Antoni N.Y. 8/03 20% ACR20 vs DAS28: same improvement, different level of disease activity

26. Antoni N.Y. 8/03 26.3 ACR AUC 6.1 ACR AUC Same level of disease activity, different baseline value AUC ACR influence of baseline

27. Antoni N.Y. 8/03 Week 16 Results PsARC *p<0.0001 Percent of Patients

28. Antoni N.Y. 8/03 Week 16 Results: ACR 20, 50, 70 Percent of Patients Responding *p<0.0001

29. Antoni N.Y. 8/03 Week 16 Results Proportion of DAS 28 Responders Patients with a Good or Moderate DAS28 Response at Week 16 Percent of Patients

30. Antoni N.Y. 8/03 Week 16 Results Proportion of DAS Original Responders Patients with a Good or Moderate DAS Response at Week 16 Percent of Patients

31. Antoni N.Y. 8/03 20 questions in eight categories of function: The Health Assessment Questionnaire (HAQ) Functional Disability Index (FDI) n dressing n arising n eating n walking n hygiene n reach n grip n activities aids, devices or help by another person

32. Antoni N.Y. 8/03 Reduction of Efficacy parameters at week 16 ACR individual parameters Parameterbaselineweek 16change % Placebo/Infliximab Tender joint score:25/3127/14-30/62 Swollen joint score:17/1716/54/68 Patient Global VAS:56/5258/25-10/49 Patient VAS of pain:57/5458/22-3/55 Physician Global VAS:53/5553/20-5/61 HAQ:1.19/1.141.2/0.68/47 CRP:12/1211/2-23/62

33. Antoni N.Y. 8/03 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

34. Antoni N.Y. 8/03 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

35. Antoni N.Y. 8/03 SF-36 RA Comparison European cohorts

36. Antoni N.Y. 8/03 Patient vs. physician assessment of the patient’s health today RA? Best imaginable Worst imaginable Mean=3.8 +/- 2.1Mean=5.0 +/- 2.4

37. Antoni N.Y. 8/03 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

38. Antoni N.Y. 8/03 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)

39. Antoni N.Y. 8/03 Mean RADAI RA by Country N=5173, mean = 4.11

40. Antoni N.Y. 8/03 RADAI vs. Tender joints in RA N=5084

41. Antoni N.Y. 8/03 RADAI vs HAQ in RA

42. 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

43. Antoni N.Y. 8/03

46. correlation MRI with joint counts Correlation with % change of Gadolinium uptake Tender Joint Scorer = 0,62p = 0,04 Swollen Joint scorer = 0,772p = 0,008 Physician evaluation of disease activity r = 0,82p = 0,006 Patient evaluation of disease activity r = 0,74p = 0,009 Morning stiffnessr = 0,639p = 0,027

47. Antoni N.Y. 8/03 Infliximab Reduces Inflammation in Psoriatic Arthritis MRI Scan of wrist – Gadolinium Uptake Week 0 Week 10 Antoni C et al. EULAR 2000.