““Imaging in PsA”Imaging in PsA”
Robert LandewéRobert Landewé
MaastrichtMaastricht T The Netherlandshe Netherlands, ,
Imaging modalitiesImaging modalities
• MRIMRI
• USUS
• Plain X-raysPlain X-rays
Why Imaging modalitiesWhy Imaging modalities
• Prognostic reasonsPrognostic reasons
• Set a disease controlling claimSet a disease controlling claim
• Follow therapeutic eficacyFollow therapeutic eficacy
• etc. etc.
ImagingImaging
• TechniqueTechnique
• Scoring methodsScoring methods
OMERACTOMERACTRARA
• TruthTruth
• FeasibilityFeasibility
• Validity Validity
TruthTruth
• X-rays: yesX-rays: yes
• MRI: ?MRI: ?
• US: ?US: ?
ReliabilityReliability
ReproducibilityReproducibility
• X-rays: yesX-rays: yes
• MRI: ?MRI: ?
• US: ?US: ?
Sensitivity-to-changeSensitivity-to-change
• X-rays: yesX-rays: yes
• MRI: yesMRI: yes
• US: ?US: ?
FeasibilityFeasibility
• X-rays: yesX-rays: yes
• MRI: noMRI: no
• US: ?/noUS: ?/no
PsAPsA
• ErosionsErosions
• Joints space narrowingJoints space narrowing
• PeriosteitisPeriosteitis
• AnkylosisAnkylosis
• ......
Scoring methods for RAScoring methods for RA
• ErosionsErosions
• Joints space narrowingJoints space narrowing
• PeriosteitisPeriosteitis
• AnkylosisAnkylosis
• Scored in joints with a high propensity for damageScored in joints with a high propensity for damage
RA vs PsARA vs PsA
RARA
• PolyarticularPolyarticular
• Hands & feetHands & feet
• Relation with large jointsRelation with large joints
• Relation with funtionRelation with funtion
PsAPsA
• Oligoarticular, asymm.Oligoarticular, asymm.
• Hands & feet ?Hands & feet ?
• Relation with large joints ?Relation with large joints ?
• Relation with function ?Relation with function ?
RA-scoring methods in PsA ?RA-scoring methods in PsA ?
• Great chance of missing relevant informationGreat chance of missing relevant information
• Lack of sensitivity to changeLack of sensitivity to change
• Lack of discriminationLack of discrimination
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.
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.
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
History of ASAS working groupHistory of ASAS working group
• 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
History of ASAS working groupHistory of ASAS working group
• 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
History of ASAS working groupHistory of ASAS working group
• 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
EULAR 2002 StockholmEULAR 2002 Stockholm
EULAR 2002 StockholmEULAR 2002 Stockholm
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
EULAR 2002 StockholmEULAR 2002 Stockholm
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.
EULAR 2002 StockholmEULAR 2002 Stockholm
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.
EULAR 2002 StockholmEULAR 2002 Stockholm
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
EULAR 2002 StockholmEULAR 2002 Stockholm
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
Cross-validationCross-validation
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
Cross-validationCross-validation
• 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
Van Tubergen et al, Ann Rheum Dis 2003;62:215Van Tubergen et al, Ann Rheum Dis 2003;62:215
Cross-validationCross-validation
• 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
Van Tubergen et al, Ann Rheum Dis 2003;62:215Van Tubergen et al, Ann Rheum Dis 2003;62:215
Cross-validationCross-validation
Van Tubergen et al, Ann Rheum Dis 2003;62:215Van Tubergen et al, Ann Rheum Dis 2003;62:215
• 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.
Cross-validationCross-validation
Van Tubergen et al, Ann Rheum Dis 2003;62:215Van Tubergen et al, Ann Rheum Dis 2003;62:215
• 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%
Cross-validationCross-validation
Van Tubergen et al, Ann Rheum Dis 2003;62:215Van Tubergen et al, Ann Rheum Dis 2003;62:215
ASAS-ICASAS-IC
YesYes NoNo
End ofEnd of
trialtrial
YesYes
NoNo
62% 38%62% 38%
11%11% 89%89%
Cross-validationCross-validation
• 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
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