“Setting the stage for PsA” History, purpose, accomplishments and goals of ASAS

1. “Setting the stage for PsA”History, purpose, accomplishments and goals of ASAS Robert Landewé Maastricht The Netherlands,

2. What I will do • Briefly reviewing the history and the current organisation of ASAS • Discuss a few relevant “accomplishments” by ASAS

3. Rheumatology • deals with chronic muskoloskeletal conditions • long-term course • outcome charactererised by pain, disability, deformity, early death, huge costs, etc.

4. Ankylosing spondylits • Chronic inflammatory condition affecting the spine and peripheral joints • Tendency to ankylosis of the spine (“bamboo-spine”) • Classification criteria including clinical and radiographic criteria • Strong genetic linkage (HLA-B27) • Spectrum of spondylo-arthropathies, with diseases sharing the same clinico-pathophysiological properties

5. Therefore... • Assessment is crucial • to classify for diagnostic purposes • to prognosticate • to measure the course of the disease • to assess outcome

6. History of ASAS working group • ASAS: Assessments in Ankylsoing Spondylitis • 1995 started by Sjef van der Linden and Désirée van der Heijde in Maastricht, as an informal society • Lack of standardisation in outcome measures in AS

7. History of ASAS working group • Steering committee: Maxime Dougados, Nick Bellamy, Andrei Calin, Asim Khan • Participants from >20 countries – clinicians, epidemiologists, patients, representatives pharmaceutical companies

8. History of ASAS working group • Biannual meetings in connection with ACR and EULAR, separate workshops, also in collaboration with OMERACT • Several investigative initiatives: • Definitions of core sets for SMARD, DC-ART, clinicalrecord keeping • ASAS responder criteria for NSAIDs • Validation of responder criteria by Delphi exercise • ASAS remission criteria • Defining criteria for TNF-blocking drugs in AS

9. History of ASAS working group • Growing interest in the work of ASAS • Increase in amount of work, increase in costs • More formal organisation desirable

10. EULAR 2002 Stockholm • Executive committee • Advisory board • Project leaders • Members • Corporate members

11. EULAR 2002 Stockholm Members of the executive committee: • Désirée van der Heijde (president) • Maxime Dougados (vice-president) • John Davis (secretary) • Jochen Sieper (treasurer) • Jürgen Braun • Sjef van der Linden

12. EULAR 2002 Stockholm Members of advisory board: • Members of the executive committee • Nick Bellamy • Andrei Calin • Asim Khan • Herman Mielants • Ruben Burgos-Vargas • Representatives of agencies • Representatives of Asia and Africa • Total up to 15

13. EULAR 2002 Stockholm Executive committee will meet at least twice a year, organise workshops for the members, and is directly involved in the projects performed within ASAS Advisory board will meet at least once a year, give advice to the executive committee and to others (such as agencies, pharmaceutical companies) The EC and AB will remain in the present composition for the next three years. Before the end of the third year, the EC will make a proposal on the continuation.

14. EULAR 2002 Stockholm Projectleaders: • All members can make a proposal for an ASAS study to the executive committee. • The member who made the proposal will be the project leader for that specific project.

15. EULAR 2002 Stockholm Members: • Persons with a proven interest in AS • Persons who would like to become a member of ASAS should write a CV with a focus on the interest in AS. This should be submitted together with two accompanying letters from ASAS members. • The decision on membership will be taken by the AB

16. EULAR 2002 Stockholm Corporate members: • All pharmaceutical companies are entitled to become a corporate member. • They have to pay a yearly fee • Two representatives of that company are invited at the ASAS workshops.

17. Mission Statement To support and promote the study of ankylosing spondylitis This includes: • increasing awareness and early diagnosis of the disease • development and validation of assessment tools • the evaluation of treatment modalities in order to promote clinical research, with the ultimate goal to improve outcome of the disease

18. Accomplishments Core sets and domains

19. Disease activitySigns & symptoms of AS At the basis: • More than 120 instruments on a variety of signs & symptoms in AS published in the literature Development of a core set for endpoints in different settings: • 12 domains (eg. Fatigue, pain, spinal mobility) • Definition of 3 core-set settings: • SMARD/physical therapy • DCART • Clinical record keeping Selection of instruments: • Instruments were presented to ASAS members for a judgment on feasibility and relevance (cut-off: 50%)

20. Disease activitySigns & symptoms of AS • …. • All information was presented in an ASAS-workshop • Discussion and voting on instruments per domain per core set

21. DC-ART Clinical Record Keeping SM-ARD/Physical Therapy physical function spinal stiffness patient global assessment fatigue acutephase reactants spinal mobility pain hip radiograph peripheral joints/entheses spine radiograph ASAS/OMERACT core domains for Ankylosing Spondylitis van der Heijde et al J Rheumatol 1999;26:951-4

22. Updated core set van der Heijde et al J Rheumatol 1999;26:951-4;

23. Updated core set van der Heijde et al J Rheumatol 1999;26:951-4;

24. Achievements • Uniformity of clinical research • Comparability of studies • Matrix for the pharmaceutical industries and regulatory authorities with respect to drug development • COX-II inhibitors • TNF-blocking drugs

25. Accomplishments Improvement criteria to be used in SMARD-trials

26. Development of improvement criteria Statistical approach • 5 randomized NSAID-placebo controlled trials • Short-term (up to 6 weeks) • Flare design • Axial disease • 684 patients treated with NSAIDs • 346 patients treated with placebo

27. Development of improvement criteria • SMARD core set was defined (5 domains) • Definition of most reliable and sensitive instruments within each domain (response statistics) • Development of 20 single- and multiple-domain criteria sets • Discriminatory capacity (NSAIDs vs placebo) of selected candidate response criteria in 2/3 of the sample • Validation in remaining 1/3 of the sample

28. Domains and instruments of improvement criteria • Patient global - VAS • Pain - VAS • Function – BASFI • Stiffness – average of morning stiffnessduration and intensity (BASDAI q 5 and 6) OR duration of morning stiffness (120 minutes = maximum) • Spinal mobility – chest expansion, modified Schober, fingers to floor

29. Ultimate choice Improvement of 20% AND 10 units in at least 3 domains Patient global Pain Function Stiffness No worsening in remaining domain Anderson et al Arthritis Rheum 2001:44:1876-886

30. Performance of improvement criteria • NSAIDs 49% responders • Placebo 24% responders Nb 1: in a flare design Nb 2: statistically derived

31. Cross-validation • Against the expert’s opinion • In 3 Delphi rounds with 55 true “paper patients” from a large multicenter trial NSAIDs vs. placebo • Participants were asked to decide upon response (yes vs. no) • Analysis on which domains contributed most to the expert’s opinion • Provisional response criteria that best met the expert’s opinion • Against the “end of trial judgment” by pt/ph • Improved vs. not improved Van Tubergen et al, Ann Rheum Dis 2003;62:215

32. Cross-validation ASAS-IC Yes No 21 21 0 13 Yes No Consensus by experts Van Tubergen et al, Ann Rheum Dis 2003;62:215

33. Cross-validation • ASAS-IC were far more conservative than the experts in adjudicating response to individual patients • Only improvement in pain, (and patient global) appeared contributive in the expert’s decision • Expert’s considered “worsening” unimportant Van Tubergen et al, Ann Rheum Dis 2003;62:215

34. Cross-validation • ASAS-IC are strict, and highly specific • Eperts consider “pain” as the dominant domain Van Tubergen et al, Ann Rheum Dis 2003;62:215

35. Cross-validation • Development of a set of improvement criteria based on the opinion of the experts • No “worsening” included • Prominent place for “pain” and “global” • Performance was tested in the original NSAIDs cohort. Van Tubergen et al, Ann Rheum Dis 2003;62:215

36. Cross-validation • All new criteria sets discriminated well between placebo and active treatment • Most new sets discriminated better than the ASAS-IC • But: all new criteria sets gave placebo response between 30 and 42% Van Tubergen et al, Ann Rheum Dis 2003;62:215

37. Cross-validation ASAS-IC Yes No Yes No • 62% 38% • 11% 89% End of trial Van Tubergen et al, Ann Rheum Dis 2003;62:215

38. Cross-validation • ASAS-IC are highly specific, but not very sensitive if compared to the eperts opnion and the end-of-trial patient/physician’s opinion • Recommended to use in RCTs, not in clinical practice

39. Summary • History, organisation, mission of ASAS • Few examples of important achievements • Reached by concerted actions and consensus

40. Current status • ASAS started as an informal group of scientists interested in outcome and AS • ASAS is now widely considered the platform for clinical research and drug-development in AS/SpA by many parties: • Investigators • Patients • Pharmaceutical industries • Regulatory authorities