“setting the stage for psa” history, purpose, accomplishments and goals of asas robert landewé...

““Setting the stage for PsA”Setting the stage for PsA”

History, purpose, accomplishments and goals of ASASHistory, purpose, accomplishments and goals of ASAS

Robert LandewéRobert Landewé

MaastrichtMaastricht T The Netherlandshe Netherlands, ,

What I will do What I will do

• Briefly reviewing the history and the current Briefly reviewing the history and the current organisation of ASAS organisation of ASAS

• Discuss a few relevant “accomplishments” by ASASDiscuss a few relevant “accomplishments” by ASAS

RheumatologyRheumatology

• deals with chronic muskoloskeletal conditionsdeals with chronic muskoloskeletal conditions

• long-term courselong-term course

• outcome charactererised by pain, disability, outcome charactererised by pain, disability, deformity, early death, huge costs, etc.deformity, early death, huge costs, etc.

Ankylosing spondylitsAnkylosing spondylits

• Chronic inflammatory condition affecting the spine and Chronic inflammatory condition affecting the spine and peripheral jointsperipheral joints

• Tendency to ankylosis of the spine (“bamboo-spine”)Tendency to ankylosis of the spine (“bamboo-spine”)

• Classification criteria including clinical and radiographic Classification criteria including clinical and radiographic criteriacriteria

• Strong genetic linkage (HLA-B27)Strong genetic linkage (HLA-B27)

• Spectrum of spondylo-arthropathies, with diseases Spectrum of spondylo-arthropathies, with diseases sharing the same clinico-pathophysiological propertiessharing the same clinico-pathophysiological properties

Therefore...Therefore...

• Assessment is crucial Assessment is crucial – to classify for diagnostic purposesto classify for diagnostic purposes– to prognosticateto prognosticate– to measure the course of the diseaseto measure the course of the disease– to assess outcometo assess outcome

History of ASAS working groupHistory of ASAS working group

• ASAS: Assessments in Ankylsoing SpondylitisASAS: Assessments in Ankylsoing Spondylitis

• 1995 started by Sjef van der Linden and Désirée van 1995 started by Sjef van der Linden and Désirée van der Heijde in Maastricht, as an informal societyder Heijde in Maastricht, as an informal society

• Lack of standardisation in outcome measures in ASLack of standardisation in outcome measures in AS


• Steering committee: Maxime Dougados, Nick Steering committee: Maxime Dougados, Nick Bellamy, Andrei Calin, Asim KhanBellamy, Andrei Calin, Asim Khan

• Participants from >20 countriesParticipants from >20 countries – clinicians, – clinicians, epidemiologists, patients, representatives epidemiologists, patients, representatives pharmaceutical companiespharmaceutical companies


• Biannual meetings in connection with ACR and Biannual meetings in connection with ACR and EULAR, separate workshops, also in collaboration EULAR, separate workshops, also in collaboration with OMERACTwith OMERACT

• Several investigative initiatives:Several investigative initiatives:– Definitions of core sets for SMARD, DC-ART, clinicalDefinitions of core sets for SMARD, DC-ART, clinical

record keepingrecord keeping– ASAS responder criteria for NSAIDsASAS responder criteria for NSAIDs– Validation of responder criteria by Delphi exerciseValidation of responder criteria by Delphi exercise– ASAS remission criteriaASAS remission criteria– Defining criteria for TNF-blocking drugs in ASDefining criteria for TNF-blocking drugs in AS


• Growing interest in the work of ASASGrowing interest in the work of ASAS

• Increase in amount of work, increase in costsIncrease in amount of work, increase in costs

• More formal organisation desirableMore formal organisation desirable

EULAR 2002 StockholmEULAR 2002 Stockholm

• Executive committeeExecutive committee

• Advisory boardAdvisory board

• Project leadersProject leaders

• MembersMembers

• Corporate membersCorporate members

Members of the executive committee:Members of the executive committee:– Désirée van der Heijde (president)Désirée van der Heijde (president)– Maxime Dougados (vice-president)Maxime Dougados (vice-president)– John Davis (secretary)John Davis (secretary)– Jochen Sieper (treasurer)Jochen Sieper (treasurer)– Jürgen BraunJürgen Braun– Sjef van der LindenSjef van der Linden



Members of advisory board:Members of advisory board:– Members of the executive committeeMembers of the executive committee– Nick BellamyNick Bellamy– Andrei CalinAndrei Calin– Asim KhanAsim Khan– Herman MielantsHerman Mielants– Ruben Burgos-VargasRuben Burgos-Vargas– Representatives of agenciesRepresentatives of agencies– Representatives of Asia and AfricaRepresentatives of Asia and Africa– Total up to 15Total up to 15


Executive committeeExecutive committee will meet at least twice a year, organise will meet at least twice a year, organise workshops for the members, and is directly involved in the workshops for the members, and is directly involved in the projects performed within ASASprojects performed within ASAS

Advisory boardAdvisory board will meet at least once a year, give advice to the will meet at least once a year, give advice to the executive committee and to others (such as agencies, executive committee and to others (such as agencies, pharmaceutical companies)pharmaceutical companies)

The EC and AB will remain in the present composition for the next 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 three years. Before the end of the third year, the EC will make a proposal on the continuation.proposal on the continuation.


Projectleaders:Projectleaders: • All members can make a proposal for an ASAS study to All members can make a proposal for an ASAS study to

the executive committee. the executive committee. • The member who made the proposal will be the project The member who made the proposal will be the project

leader for that specific project.leader for that specific project.


MembersMembers::

• Persons with a proven interest in ASPersons with a proven interest in AS

• Persons who would like to become a member of Persons who would like to become a member of ASAS should write a CV with a focus on the interest ASAS should write a CV with a focus on the interest in AS. Thin AS. Thisis should be submitted together with two should be submitted together with two accompanying letters from ASAS members.accompanying letters from ASAS members.

• The decision on membership will be taken by the ABThe decision on membership will be taken by the AB


Corporate members:Corporate members:

• All pharmaceutical companies are entitled to All pharmaceutical companies are entitled to become a corporate member. become a corporate member.

• They have to pay a yearly fee They have to pay a yearly fee

• Two representatives of that company are invited at Two representatives of that company are invited at the ASAS workshops.the ASAS workshops.

Mission StatementMission Statement

To support and To support and ppromote the study of ankylosing romote the study of ankylosing spondylitisspondylitis

This includes:This includes:– increasing awareness and early diagnosis of the increasing awareness and early diagnosis of the

diseasedisease– development and validation of assessment toolsdevelopment and validation of assessment tools– the evaluation of treatment modalities in order to the evaluation of treatment modalities in order to

promote clinical research, with the ultimate goal to promote clinical research, with the ultimate goal to improve outcome of the diseaseimprove outcome of the disease

AccomplishmentsAccomplishments

Core sets and domainsCore sets and domains

Disease activityDisease activitySigns & symptoms of ASSigns & symptoms of AS

At the basis:At the basis: • More than 120 instruments on a variety of signs & symptoms in AS More than 120 instruments on a variety of signs & symptoms in AS

published in the literaturepublished in the literatureDevelopment of a core set for endpoints in different settings:Development of a core set for endpoints in different settings:• 12 domains (eg. Fatigue, pain, spinal mobility)12 domains (eg. Fatigue, pain, spinal mobility)• Definition of 3 core-set settings: Definition of 3 core-set settings:

– SMARD/physical therapy SMARD/physical therapy – DCARTDCART– Clinical record keepingClinical record keeping

Selection of instruments:Selection of instruments:• Instruments were presented to ASAS members for a judgment on Instruments were presented to ASAS members for a judgment on

feasibility feasibility andand relevance relevance (cut-off: 50%) (cut-off: 50%)

Disease activityDisease activitySigns & symptoms of ASSigns & symptoms of AS

• ……..• All information was presented in an ASAS-workshopAll information was presented in an ASAS-workshop• Discussion and voting on instruments per domain per core setDiscussion and voting on instruments per domain per core set

ASAS/OMERACT ASAS/OMERACT core domains for core domains for Ankylosing Ankylosing SpondylitisSpondylitis

SM-ARD/Physical Therapy

Clinical Record Keeping

DC-ART

physical functionspinal stiffness

pain

spinal mobility

patient global assessment

peripheral joints/entheses

acutephase

reactants

fatigue

spine radiograph

hip radiograph

van der Heijde et al J Rheumatol 1999;26:951-4van der Heijde et al J Rheumatol 1999;26:951-4

Updated core setUpdated core setDomain Instrument

Function BASFI or FI Dougados

Pain VAS-last week-spine-at night-due to AS

and VAS-last week-spine-due to AS

Spinal

mobility

chest expansion

and modified Schober

and occiput to wall

and (lateral spinal flexion or BASMI)

Patient global VAS-last week

van der Heijde et al J Rheumatol 1999;26:951-4; van der Heijde et al J Rheumatol 1999;26:951-4;

Updated core setUpdated core set

van der Heijde et al J Rheumatol 1999;26:951-4; van der Heijde et al J Rheumatol 1999;26:951-4;

Domain Instrument

Peripheral joints/

entheses*

number of swollen joints (44 joint count)/

validated enthesitis score

X-ray spine/hips* AP+Lat Lumbar

and Lat Cervical spine

and X-pelvis (SI and Hips)

Stiffness Duration of morning stiffness-spine-last week

Acute phase

reactants*

ESR

Fatigue Fatigue question BASDAI

AchievementsAchievements

• Uniformity of clinical researchUniformity of clinical research

• Comparability of studiesComparability of studies

• Matrix for the pharmaceutical industries and Matrix for the pharmaceutical industries and regulatory authorities with respect to drug regulatory authorities with respect to drug developmentdevelopment– COX-II inhibitorsCOX-II inhibitors– TNF-blocking drugs TNF-blocking drugs

AccomplishmentsAccomplishments

Improvement criteria to be used in Improvement criteria to be used in

SMARD-trialsSMARD-trials

Development of improvement criteriaDevelopment of improvement criteria

Statistical approachStatistical approach

• 5 randomized NSAID-placebo controlled trials5 randomized NSAID-placebo controlled trials

• Short-term (up to 6 weeks)Short-term (up to 6 weeks)

• Flare designFlare design

• Axial diseaseAxial disease

• 684 patients treated with NSAIDs684 patients treated with NSAIDs

• 346 patients treated with placebo346 patients treated with placebo

Development of improvement criteriaDevelopment of improvement criteria

• SMARD core set was defined (5 domains)SMARD core set was defined (5 domains)

• Definition of most reliable and sensitive instruments Definition of most reliable and sensitive instruments within each domain (response statistics)within each domain (response statistics)

• Development of 20 single- and multiple-domain criteria Development of 20 single- and multiple-domain criteria setssets

• Discriminatory capacity (NSAIDs vs placebo) of selected Discriminatory capacity (NSAIDs vs placebo) of selected candidate response criteria in 2/3 of the samplecandidate response criteria in 2/3 of the sample

• Validation in remaining 1/3 of the sampleValidation in remaining 1/3 of the sample

Domains and instruments of Domains and instruments of improvement criteriaimprovement criteria

• Patient global - Patient global - VASVAS

• Pain - Pain - VASVAS

• Function – Function – BASFIBASFI

• Stiffness – average of Stiffness – average of morning stiffnessmorning stiffness durationduration and and intensityintensity (BASDAI q 5 and 6) OR (BASDAI q 5 and 6) OR durationduration of of morning stiffness (120 minutes = maximum)morning stiffness (120 minutes = maximum)

• Spinal mobility – chest expansionSpinal mobility – chest expansion, modified , modified Schober, fingers to floorSchober, fingers to floor

Ultimate choiceUltimate choice

Patient globalPatient global

PainPain

FunctionFunction

StiffnessStiffness

Improvement of 20% AND 10 units in at least 3 domainsImprovement of 20% AND 10 units in at least 3 domains

No worsening in remaining domainNo worsening in remaining domain

Anderson et al Arthritis Rheum 2001:44:1876-886Anderson et al Arthritis Rheum 2001:44:1876-886

Performance of improvement criteriaPerformance of improvement criteria

• NSAIDsNSAIDs 49% responders 49% responders

• Placebo 24% respondersPlacebo 24% responders

Nb 1: in a flare designNb 1: in a flare design

Nb 2: statistically derivedNb 2: statistically derived

Cross-validationCross-validation

• Against the expert’s opinionAgainst the expert’s opinion– In 3 Delphi rounds with 55 true “paper patients” from a large In 3 Delphi rounds with 55 true “paper patients” from a large

multicenter trial NSAIDs vs. placebomulticenter trial NSAIDs vs. placebo– Participants were asked to decide upon response (yes vs. no)Participants were asked to decide upon response (yes vs. no)– Analysis on which domains contributed most to the expert’s Analysis on which domains contributed most to the expert’s

opinionopinion– Provisional response criteria that best met the expert’s opinionProvisional response criteria that best met the expert’s opinion

• Against the “end of trial judgment” by pt/phAgainst the “end of trial judgment” by pt/ph– Improved vs. not improvedImproved vs. not improved

Van Tubergen et al, Ann Rheum Dis 2003;62:215Van Tubergen et al, Ann Rheum Dis 2003;62:215



ASAS-ICASAS-IC

YesYes NoNo

ConsensusConsensus

byby

expertsexperts

YesYes

NoNo

2121 2121

00 1313


• ASAS-IC were far more conservative than the ASAS-IC were far more conservative than the experts in adjudicating response to individual experts in adjudicating response to individual patientspatients

• Only improvement in pain, (and patient global) Only improvement in pain, (and patient global) appeared contributive in the expert’s decision appeared contributive in the expert’s decision

• Expert’s considered “worsening” unimportantExpert’s considered “worsening” unimportant



• ASAS-IC are strict, and highly specificASAS-IC are strict, and highly specific

• Eperts consider “pain” as the dominant domainEperts consider “pain” as the dominant domain




• Development of a set of improvement criteria based Development of a set of improvement criteria based on the opinion of the experts on the opinion of the experts – No “worsening” includedNo “worsening” included– Prominent place for “pain” and “global”Prominent place for “pain” and “global”

• Performance was tested in the original NSAIDs Performance was tested in the original NSAIDs cohort.cohort.



• All new criteria sets discriminated well between All new criteria sets discriminated well between placebo and active treatmentplacebo and active treatment

• Most new sets discriminated better than the ASAS-Most new sets discriminated better than the ASAS-ICIC

• But: all new criteria sets gave placebo response But: all new criteria sets gave placebo response between 30 and 42% between 30 and 42%



ASAS-ICASAS-IC

YesYes NoNo

End ofEnd of

trialtrial

YesYes

NoNo

62% 38%62% 38%

11%11% 89%89%


• ASAS-IC are highly specific, but not very sensitive if ASAS-IC are highly specific, but not very sensitive if compared to the eperts opnion and the end-of-trial compared to the eperts opnion and the end-of-trial patient/physician’s opinionpatient/physician’s opinion

• Recommended to use in RCTs, not in clinical Recommended to use in RCTs, not in clinical practicepractice

SummarySummary

• History, organisation, mission of ASASHistory, organisation, mission of ASAS

• Few examples of important achievementsFew examples of important achievements

• Reached by concerted actions and consensusReached by concerted actions and consensus

Current statusCurrent status

• ASAS started as an informal group of scientists interested in ASAS started as an informal group of scientists interested in outcome and ASoutcome and AS

• ASAS is now widely considered the platform for clinical ASAS is now widely considered the platform for clinical research and drug-development in AS/SpA by many parties:research and drug-development in AS/SpA by many parties:– InvestigatorsInvestigators– PatientsPatients– Pharmaceutical industriesPharmaceutical industries– Regulatory authoritiesRegulatory authorities

“setting the stage for psa” history, purpose, accomplishments and goals of asas robert landewé...

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