Ra Acr:eular 2010 PDF

2010ACR/EULARClassification
CriteriaforRheumatoidArthritis
PublishedintheSeptember2010
IssuesofA&R andARD
PhasesoftheProject
Phase 1 Phase 2
Data analysis Consensus process
Predictors of MTX Determinants of high

initiation probability of RA
Phase 3
Integration of 1 and 2
Increase feasibility
Final Criteria
Phase1
DataDrivenApproach
Phase1:PatientsandMethods
Patients EARLYARTHRITISCOHORTS
3115patients from9cohorts
Inflammatoryarthritis (nootherdefinitediagnosis)of
<3years
NopreviousDMARD/MTXtreatment
Methods PREDICTORSOFMTXTREATMENT
Step1:Univariateregressionanalysis ofallpossible
variables
Step2:Principalcomponentanalysis:identifythemes
Step3:Multivariateregressionanalysis withall
relevantthemes
Phase1:ThreeAnalyticSteps
Identify significant
variables at baseline
Univariate Regression Analysis
Gold standard: MTX
STEP 1 treatment at one year
Identify sets of
Principal Component Analysis variables representing
the same theme
STEP 2
Identify independent
Multivariate regression Analysis effects of variables and
their relative contribution
STEP 3 (weight)
STEPS1and2:PredictorsofMTXinitiation
Loadings on Factors 1-6
FactorNo(Eigenvalue) 1 (5.33) 2 (1.91) 3 (1.62) 4 (1.15) 5 (0.99) 6 (0.94)
Anit-Citrullinated peptide AB (0,1,2) .104 .064 .035 .079 .094 .878
Rheumatoid factor (0,1,2) .105 .013 .064 .053 .117 .878
CRP (0,1,2) -.004 .101 -.049 .847 .004 .055
ESR (tertiles) .012 .026 -.042 .847 -.042 .121
HAQ (tertiles) .103 .180 .343 .555 .062 -.074
SJC (1,2-6,7-28) .612 .356 .198 .075 .526 .125
MCP swelling (yes/no) .839 .103 .282 .017 .149 .158
PIP swelling (yes/no) .287 .138 .082 -.003 .852 .176
Wrist swelling (yes/no) .165 .865 .140 .119 .055 .102
MTP swelling (yes/no) .055 .047 .024 .009 .022 .127
Tender Joint count (1, 2-6, 7-28) .268 .204 .767 .058 .384 .047
MCP tenderness (yes/no) .509 .014 .723 -.003 .108 .094
PIP tenderness (yes/no) .103 .045 .550 -.048 .710 .098
Wrist tenderness (yes/no) .001 .658 .599 .036 .001 .048
Symmetrical MCP swelling .826 .205 .095 .039 .163 .062
Symmetrical wrist swelling .229 .785 -.024 .133 .194 -.037
Loadings: 0 0.199 0.2 0.399 0.4 0.599 0.6 0.799 0.8 1

STEP2:RelevantThemestoPredictMTXTreatment
Factor Loadingvariables Theme Representedby
1 SJC,MCPSW,MCPSWSym MCP MCPswelling
involvement
2 WristSW,WristTD, Wrist Wristswelling
WristSWSym involvement
3 TJC,MCPTD,PIPTD Hand/finger PIPorMCPorwrist
tenderness tenderness
4 CRP,ESR Acutephase AbnormalCRPor
response abnormalESR
5 PIPSW,PIPTD PIP PIPswelling
involvement
6 ACPApos.,RFpos. Serology Pos.ACPAorpos.RF
Phase1:Results
Variable Comparison P OR (95% CI) Weight
Swollen MCP Pres vs. abs 0.003 1.46 (1.14 to 1.88) 1.5
Swollen PIP Pres vs. abs 0.001 1.51 (1.19 to 1.91) 1.5
Swollen wrist Pres vs. abs <0.001 1.61 (1.28 to 2.02) 1.5
Hand tenderness Pres vs. abs <0.001 1.80 (1.33 to 2.44) 2
Mod. vs. normal 0.172 1.24 (0.91 to 1.70) 1
Acute phase
High vs. normal 0.001 1.68 (1.23 to 2.28) 2
Mod. vs. normal <0.001 2.22 (1.81 to 3.28) 2
Serology
High vs. normal <0.001 3.85 (2.96 to 5.00) 4
Phase1:Conclusion
Swellingofsmalljointregions (PIP,MCP,wrist)has
independenteffect
Tenderness mightbealsobeconsideredasjoint
involvement
Symmetrical involvementdoesnot seemtohavea
significant incrementaleffectoverunilateralinvolvement
Abnormalacutephaseresponse hasaconsiderableeffect
Serology hasaconsiderableeffect,andshowsadose
responserelationshipoftitres
PhasesoftheProject
Phase 1 Phase 2

Phase 3
Final Criteria
Phase2
ConsensusApproach
Phase2:Methods
Rankingofpatientprofiles byexpertsfortheir
probabilitytodevelopRA
Evidencebaseddiscussionondiscrepancies inthe
ranking
Specifying targetpopulation
Developingpositiveandnegativedeterminants forrisk
ofRA(informedbyPhase1data)
Groupingthesedeterminantsintodomainsand
categories
Weighting ofeachcategoryusingdecisionanalytic
software
Phase2:Overview
Expert panel
Phase2:Overview
Expert panel
Submit case scenarios of early

undifferentiated inflammatory arthritis
Rank the case scenarios on
probability of developing
persistent erosive RA
Phase2:Overview
Expert panel

Discussion on reasons for

Phase 1 data
discordance among physicians
+ Positive factors - Negative factors
Specify target population

Phase2:Overview
Expert panel

Discussion on reasons for

Phase 1 data
+ Positive factors - Negative factors
Identifying domains and categories

Phase2:Overview
Expert panel

Discussion on reasons for Phase 1 data

+ Positive factors
- Negative factors
Identifying domains and categories
Deriving weights
Tentative Criteria
Phase2:Results
PhasesoftheProject
Phase 1 Phase 2

Phase 3
Final Criteria
Phase3
IntegrationofFindings
fromPhases1and2
OptimizingFeasibility
Exact Rescaled Rounded to
(0-100) (0-10) 0.5 (0-10)
JOINT INVOLVEMENT
1 medium-large 0 0 0
>1-10 medium-large, asymmetric 10.2 1.02 1
>1-10 medium-large, symmetric 16.1 1.61 1.5
1-3 small 21.2 2.12 2
4-10 small 28.8 2.88 3
>10, including at least one small joint 50.8 5.08 5
SEROLOGY (RF or ACPA)
0 (<ULN) 0 0 0
+ (ULN to 3xULN) 22.0 2.20 2
++ (>3xULN) 33.9 3.39 3.5
ACUTE PHASE REACTANTS (ESR or CRP)
Normal 0 0 0
Abnormal 5.9 0.59 0.5
SYMPTOM DURATION
<6 weeks 0 0 0
6 weeks 9.3 0.93 1
(0-100) (0-10) 0.5 (0-10)
JOINT INVOLVEMENT
1-3 small 21.2 2.12 2
4-10 small 28.8 2.88 3
0 (<ULN) 0 0 0
+ (ULN to 3xULN) 22.0 2.20 2
++ (>3xULN) 33.9 3.39 3.5
Normal 0 0 0
Abnormal 5.9 0.59 0.5
SYMPTOM DURATION
<6 weeks 0 0 0
6 weeks 9.3 0.93 1
(0-100) (0-10) 0.5 (0-10)
JOINT INVOLVEMENT
1-3 small 21.2 2.12 2
4-10 small 28.8 2.88 3
0 (<ULN) 0 0 0
+ (ULN to 3xULN) 22.0 2.20 2
++ (>3xULN) 33.9 3.39 3.5
Normal 0 0 0
Abnormal 5.9 0.59 0.5
SYMPTOM DURATION
<6 weeks 0 0 0
6 weeks 9.3 0.93 1
FinalCriteria
TargetPopulationoftheCriteria
Two requirements:
(1) Patient with at least one joint with definite clinical
synovitis (swelling)
(2) Synovitis is not better explained by another
disease
Differential diagnoses differ in patients with different presentations.
If unclear about the relevant differentials, an expert rheumatologist
should be consulted.
2010ACR/EULAR
ClassificationCriteriaforRA
JOINTDISTRIBUTION(05)
SEROLOGY(03)
SYMPTOMDURATION(01)
ACUTEPHASEREACTANTS(01)
2010ACR/EULAR
1largejoint 0
210largejoints 1
13smalljoints(largejointsnotcounted) 2
>10joints(atleastonesmalljoint) 5
SEROLOGY(03)
SYMPTOMDURATION(01)
2010ACR/EULAR
1largejoint 0
210largejoints 1
SEROLOGY(03)
NegativeRFAND negativeACPA 0
LowpositiveRFOR lowpositiveACPA 2
HighpositiveRFOR highpositiveACPA 3
SYMPTOMDURATION(01)
2010ACR/EULAR
1largejoint 0
210largejoints 1
SEROLOGY(03)
SYMPTOMDURATION(01)
<6weeks 0
6weeks 1
2010ACR/EULAR
1largejoint 0
6 = definite RA
210largejoints 1
>10joints(atleastonesmalljoint) 5 What if the score is <6?
SEROLOGY(03)
NegativeRFAND negativeACPA 0 Patient might fulfill the criteria
HighpositiveRFOR highpositiveACPA 3 Prospectively over time
(cumulatively)
SYMPTOMDURATION(01)
<6weeks 0
Retrospectively if data on all
6weeks 1
four domains have been
ACUTEPHASEREACTANTS(01) adequately recorded in the past
NormalCRPAND normalESR 0
AbnormalCRPOR abnormalESR 1
Classificationvs.Diagnosis
Wedonthavediagnosticcriteria forRA
Typicallyinrheumaticdiseases,criteriaarelabeledas
classificationcriteria
Thesearehelpfulindefininghomogeneoustreatment
populations forstudypurposes
Aclinicaldiagnosis hastobeestablishedbythe
physician(rheumatologist)
Itincludesmanymoreaspectsthancanbeincludedin
formalcriteria
Formalclassificationcriteriamightbeaguide toestablisha
clinicaldiagnosis
Classificationvs.Diagnosis
Classification for studies Clinical Diagnosis
Disease
No disease
Target Population Target Population
Usually well defined, smaller Less well defined, larger
AlgorithmtoClassificationofRAIncluding
Radiographs
1swollenjoint,
6/10onthe
whichis
whichisnot bestexplainedby Yes
scoringsystem?
Yes RA
anotherdisease?
No Documentresultof
thescoringsystem
Longstanding
inactivedisease Yes
suspected?
Yes
No Performradiographic
No assessment
Radiographs
Yes Erosionstypicalfor
already available
RApresent?
No No
NotRA
Summary:
RadiographicAssessment
WHENTOPERFORM HOWTOUSE
GENERALPRINCIPLES Thepresenceoftypicalerosionsallow
classificationofRAevenwithout
Radiographsarenotrequired inthe fulfillmentofthescoringsystem
ACR/EULAR2010classificationcriteria
Thescoringresultshouldneverthelessbe
Radiographsshouldnotbetaken forthe
documentedinclinicalstudies/trials
merepurposeofclassification
EXCEPTIONS Currently,thereisnoexactdefinitionof
typicalerosions
1.Radiographsshouldbetaken inthe
unclassifiedpatientinwhomlongstanding Thereisworkinprogresstodevelopthe
inactivediseaseissuspected(likelyfailed respectivedefinitions
classificationfalsely)
2.Ifradiographsarealreadyavailable inan
earlyarthritispatient,theirinformationcanbe
usedforclassificationpurposes.
(e.g.,radiographstakenbyGPbeforereferral)
Definitions
Definitions
1largejoint 0
210largejoints 1
Definition of JOINT INVOLVEMENT
- Any swollen or tender joint (excluding DIP
of hand and feet, 1st MTP, 1st CMC)
SEROLOGY(03)
NegativeRFAND negativeACPA 0 - Additional evidence from MRI / US
LowpositiveRFOR lowpositiveACPA 2 may be used for confirmation of the
HighpositiveRFOR highpositiveACPA 3 clinical findings
SYMPTOMDURATION(01)
<6weeks 0
6weeks 1
6 = definite RA
Definitions
1largejoint 0
210largejoints 1
Definition of SMALL JOINT
SEROLOGY(03)
NegativeRFAND negativeACPA 0 MCP, PIP, MTP 2-5, thumb IP, wrist
HighpositiveRFOR highpositiveACPA 3 NOT: DIP, 1st CMC, 1st MTP
SYMPTOMDURATION(01)
<6weeks 0
6weeks 1
6 = definite RA
Definitions
1largejoint 0
210largejoints 1
410smalljoints(largejointsnotcounted) 3 Definition of LARGE JOINT
Shoulder, elbow, hip, knee, ankles
SEROLOGY(03)
SYMPTOMDURATION(01)
<6weeks 0
6weeks 1
6 = definite RA
Definitions
1largejoint 0
210largejoints 1
>10joints(atleastonesmalljoint) 5 Definition of >10 JOINTS
SEROLOGY(03)
- At least one small joint
- Additional joints include:
temporomandibular,
SYMPTOMDURATION(01)
<6weeks 0
sternoclavicular,
6weeks 1 acromioclavicular, and
ACUTEPHASEREACTANTS(01) others (reasonably expected in RA)
6 = definite RA
Definitions
1largejoint 0
210largejoints 1
410smalljoints(largejointsnotcounted) 3 Definition of SEROLOGY
Negative: ULN (for the respective lab)
SEROLOGY(03)
NegativeRFAND negativeACPA 0 Low positive: >ULN but 3xULN
HighpositiveRFOR highpositiveACPA 3 High positive: >3xULN
SYMPTOMDURATION(01)
<6weeks 0
6weeks 1
6 = definite RA
Definitions
1largejoint 0
210largejoints 1
Definition of SYMPTOM DURATION
>10joints(atleastonesmalljoint) 5 Refers to the patients self-report on the maximum
SEROLOGY(03) duration of signs and symptoms of any joint that is
NegativeRFAND negativeACPA 0 clinically involved at the time of assessment.
SYMPTOMDURATION(01)
<6weeks 0
6weeks 1
6 = definite RA
AlgorithmforClassification
START >10 joints Branch 1
(eligible patient)
Yes
No
4-10 small joints Branch 2

Yes
No
1-3 small joints Branch 3

Yes
No
2-10 large joints

Yes
Branch 4
No
RA
Branch#1:PolyarticularPresentation
Branch #1 Serology:
10 joints Low/high positive?
No
Yes
Duration:
6 weeks?
No Yes
APR: Abnormal?
No Yes
RA RA
Branch#2:Presentationwith
Oligo/PolyarticularSmallJoints
Branch #2 Serology:
4-10 small joints high positive?
No
Serology:
low positive?
Yes
Yes
No Duration:
6 weeks?
Yes
No
APR:
RA Abnormal? Yes RA
Mono/OligoarticularSmallJoints
Branch #3 Serology:
1-3 small joints High positive?
No
Yes
Serology:
Low positive?
Yes
No
Duration: Duration:
6 weeks? 6 weeks?
No
No
Yes Yes
APR:
RA No Yes RA
abnormal?
Oligo/PolyarticularLargeJoints
Branch #4 Serology: ++
2-10 large joints
Yes
No Duration: 6
weeks
No Yes
APR:
RA No
Abnormal
Yes RA
START >10 joints (at least
(eligible patient) one small joint)
Rheumatoid arthritis
No Yes
No classification of rheumatoid arthritis
4-10 small joints

Serology:
+/++
No Yes
Serology: No Yes
1-3 small joints
++
No Yes
No Yes Duration:
2-10 large Serology:
6 weeks
(no small) joints ++
Serology:
No Yes +
No Yes
Serology: Duration:
+ 6 weeks No Yes
Serology: No Yes
++ No Yes
Duration: APR:
No Yes 6 weeks Abnormal
No Yes Duration:
6 weeks
Duration:
6 weeks No Yes
No Yes
No Yes
No Yes
APR: APR: APR:

Abnormal Abnormal Abnormal
Yes No Yes No Yes

No
RA RA RA RA RA RA RA RA
Example:FalsePositiveClassification
JOINTSDISTRIBUTION(05)
CASE SCENARIO
1largejoint 0
210largejoints 1 Inflammatory Osteoarthritis
410smalljoints(largejointsnotcounted) 3 - One clinically inflamed OA joint
>10joints(atleastonesmalljoint) 5 (PIP 3 right hand)
SEROLOGY(03)
- Tenderness of all DIPs, PIPs,
thumb IPs, CMC 1, and knees
HighpositiveRFOR highpositiveACPA 3 - Seronegative
SYMPTOMDURATION(01)
<6weeks 0
- Long standing disease
6weeks 1 - Normal acute phase
If OA is clinically apparent, then this
patient would not be in the target
population of the criteria
6 = definite RA
Example:FalseNegativeClassification
JOINTSDISTRIBUTION(05)
CASE SCENARIO
1largejoint 0
210largejoints 1 Early seronegative RA
- Swollen and tender MCP 1-3 on
both sides
SEROLOGY(03)
NegativeRFAND negativeACPA 0 - Seronegative
- 2 weeks duration
SYMPTOMDURATION(01) - Elevated CRP levels
<6weeks 0
6weeks 1
This patient might fulfill the criteria at a
ACUTEPHASEREACTANTS(01) subsequent visit (be classified
NormalCRPAND normalESR 0 prospectively)
6 = definite RA
ImportantNotes
CriteriaareclassificationcriteriaNOTdiagnosticcriteria
Inclinicalpracticetheymayinformthephysiciansdiagnosis
Forthepurposeofclassification,radiographsshouldonlybe
performed
Forpatientswithlongstandinginactive(burntout)disease,whoare
NOTyetformallyclassifiedordiagnosed,andwhowouldfailtoclassify
asRAaccordingtothescoringsystem,giventheirjointinactivity
Thetermerosions,typicalforRAstillneedstobepreciselydefined
(size,site,number)
Noexhaustivelistofexclusionsisdefined
Differentialdiagnosisisresponsibilityofthephysician(influencedby
age,gender,population,etc.)
Limitsfalsepositiveclassification
FutureProspects
8797% ofpatientsstartedonMTXwithinone
year werepositivelyclassifiedasRA in
independentcohortsatbaseline
Formalexternalvalidation studiesareongoing
ComparingproportionsfulfillingACR1987and
ACR/EULAR2010criteria
Identifyingsensitivity,specificity,PPV,NPVetc.in
independentsettings
Summary
NewclassificationcriteriaforRA havebeen
establishedbyaninternationaltaskforce
Criteriaaremeanttobeusedforpatientswith
clinicalsynovitisinatleastonejoint
Theclassificationcriteriaarenotdiagnosticcriteria,
buttheycaninformthediagnosis,whichultimately
hastobemadebytherheumatologist
Validationinindependentcohorts isalreadyongoing

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2010ACR/EULARClassification

Predictors of MTX Determinants of high

Loadings: 0 0.199 0.2 0.399 0.4 0.599 0.6 0.799 0.8 1

Predictors of MTX Determinants of high

Submit case scenarios of early

Submit case scenarios of early

Discussion on reasons for

Specify target population

Submit case scenarios of early

Discussion on reasons for

Specify target population

Identifying domains and categories

Rank the case scenarios on

Discussion on reasons for Phase 1 data

Specify target population

Identifying domains and categories

Predictors of MTX Determinants of high

4-10 small joints Branch 2

1-3 small joints Branch 3

2-10 large joints

4-10 small joints

APR: APR: APR:

Yes No Yes No Yes

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