Redefining remission in rheumatoid arthritis a joint ACR/EULAR/OMERACT initiative Maarten Boers Department of Clinical Epidemiology and Biostatistics VU

Redefining remissionRedefining remissionin rheumatoid arthritisin rheumatoid arthritis

a joint a joint ACR/EULAR/OMERACT ACR/EULAR/OMERACT

initiativeinitiative

Maarten BoersMaarten BoersDepartment of Clinical EpidemiologyDepartment of Clinical Epidemiology

and Biostatisticsand BiostatisticsVU University Medical Center VU University Medical Center

AmsterdamAmsterdam

redefining remission in RA 2

OutlineOutline

Background/TaskBackground/Task

Decisions and research agenda Decisions and research agenda made at ACR 2007made at ACR 2007

Progress to dateProgress to date


Remission teamRemission team

George Wells, OttawaGeorge Wells, OttawaJosef Smolen, ViennaJosef Smolen, ViennaLilian van Tuyl, AmsterdamLilian van Tuyl, AmsterdamBin Zhang, BostonBin Zhang, BostonJulia Funovits, ViennaJulia Funovits, ViennaACR-EULAR ad hoc committee (40+ members)ACR-EULAR ad hoc committee (40+ members)

co-chairs: co-chairs: Maarten Boers, AmsterdamMaarten Boers, AmsterdamDavid Felson, BostonDavid Felson, Boston


BackgroundBackground

Increasing numbers of patients reach remissionIncreasing numbers of patients reach remissionAbundance of remission definitionsAbundance of remission definitions

‘strict’ definitions: ACR, CDAI/SDAI, PAS/RAPID3‘loose’ definitions: DAS, DAS28, mACR,

SJC0/TJC0/ESR10, MDA

Need for aNeed for a uniform definition (RA trials, practice) uniform definition (RA trials, practice)


OMERACT Filter OMERACT Filter to select measuresto select measures

To be applicable in its intended To be applicable in its intended setting, setting,

a measure must bea measure must be

truthfultruthful

discriminativediscriminative

feasiblefeasible


OMERACT FilterOMERACT Filter

TruthTruth

free from biasfree from biascriterion, construct validity

relevantrelevantcontent, face validity



DiscriminationDiscrimination

able to distinguish between able to distinguish between states states that are of interest:that are of interest:

at one time pointat different time pointsreliability, reproducibility, sensitivity to change



FeasibilityFeasibility

timetimecostscostsinterpretabilityinterpretability


EtymologyEtymology

Remittere Remittere (L): (L): to send back; to decrease; to relax...to send back; to decrease; to relax...RemissionRemission

(med dictionary):An abatement or lessening of the manifestations of a disease.(Wiki):The state of absence of disease activity in patients with a chronic illness, with the possibility of return of disease activity.


Concept: key pointsConcept: key points

State, not change or transitionState, not change or transitionPattern of transitions interesting research areaTime spent in state not part of concept

Absence of disease activityAbsence of disease activityHow to be sure?


Concept: key pointsConcept: key points

State, not change or transitionState, not change or transitionAbsence of disease activityAbsence of disease activityRelated but not identical:Related but not identical:

Cure: disease does not returnArrest: disease process is stoppedIntermission: period of no activity between two periods of active disease

AntitheticalAntitheticalRelapse: return of disease activityFlare: substantial increase of disease activity


Current definitions: Pinals Current definitions: Pinals (1981)(1981)

5 or more must be fulfilled 5 or more must be fulfilled for at least for at least 2 consecutive months2 consecutive months::

Morning stiffness not exceeding 15 minutesNo fatigueNo joint pain (by history)No joint tenderness or pain on motionNo soft tissue swelling in joints or tendon sheathsESR (W) <30 mm/h (f); <20 mm/h (m)


PinalsPinals

3 groups classified according to the 3 groups classified according to the rheumatologist: complete remission, rheumatologist: complete remission, partial remission, active diseasepartial remission, active diseaseSensitivity 72%, specificity 90% Sensitivity 72%, specificity 90% against partial remissionagainst partial remissionUsing 4 out of 6: sens 90%, spec 62%Using 4 out of 6: sens 90%, spec 62%Read the discussion!Read the discussion!


PinalsPinals

““A major obstacle to developing criteria A major obstacle to developing criteria for remission in RA is the difficulty in for remission in RA is the difficulty in ascertaining the absence of inflammation ascertaining the absence of inflammation by methods that are reliable and also by methods that are reliable and also convenient in clinical settings...”convenient in clinical settings...”


PinalsPinals

““A major obstacle...”A major obstacle...”““Substantial variation appears to exist Substantial variation appears to exist in the concept of remission within the in the concept of remission within the group group of participating rheumatologists...”of participating rheumatologists...”


DAS/DAS28DAS/DAS28

DAS: Ritchie joint index and 44 swollen DAS: Ritchie joint index and 44 swollen joint ctjoint ctDAS28: 28 tender & swollen joint countDAS28: 28 tender & swollen joint countBoth use a ‘general health’ VAS (0-100)Both use a ‘general health’ VAS (0-100)

DAS28 = 0.56 sqrt (TJC) + 0.28 sqrt (SJC) DAS28 = 0.56 sqrt (TJC) + 0.28 sqrt (SJC) + 0.70 ln (ESR) + 0.014 GH.+ 0.70 ln (ESR) + 0.014 GH.DAS28 remission: 2.6DAS28 remission: 2.6DAS remission: 1.6DAS remission: 1.6


DAS28 remission (1996)DAS28 remission (1996)

Validation against ARA criteria in Validation against ARA criteria in Nijmegen Nijmegen obs. data, moderately active diseaseobs. data, moderately active disease‘‘mACR’:mACR’:

Fatigue not assessedRemission defined as 4 out of 5 remaining criteria

3 months instead of 2 months period;3 months instead of 2 months period;single visit data usedsingle visit data usedSens and Spec against mACR 87%Sens and Spec against mACR 87%


SDAI/CDAI remission (2005)SDAI/CDAI remission (2005)

SDAI = (28TJC) + (28SJC) + MDGA + PGA + SDAI = (28TJC) + (28SJC) + MDGA + PGA + CRPCRPCDAI = (28TJC) + (28SJC) + MDGA + PGACDAI = (28TJC) + (28SJC) + MDGA + PGASDAI remission = 3.3SDAI remission = 3.3CDAI remission = 2.8CDAI remission = 2.8

Developed in patient profile exercise Developed in patient profile exercise and validated in observational datasetsand validated in observational datasets


PAS/RAPID3 (2005)PAS/RAPID3 (2005)

PAS = 1/3 [(HAQ * 3.33) + pain + PGA]PAS = 1/3 [(HAQ * 3.33) + pain + PGA]PAS remission: 1.25 (judgment)PAS remission: 1.25 (judgment)

RAPID3 = 1/3 [(HAQ * 3.33) + pain + RAPID3 = 1/3 [(HAQ * 3.33) + pain + PGH]PGH]RAPID3 remission: 1.0 (judgment)RAPID3 remission: 1.0 (judgment)


MDA MDA (minimal disease activity; (minimal disease activity;

2003)2003)State of disease activity deemed a useful State of disease activity deemed a useful target of treatment by patient and target of treatment by patient and physician, given current treatment physician, given current treatment possibilities and limitations.possibilities and limitations.Derived from profile exercises at Derived from profile exercises at OMERACTOMERACTInitial ‘remission’ decision node: Initial ‘remission’ decision node: TJC = 0, SJC = 0, ESR = 10 or lessTJC = 0, SJC = 0, ESR = 10 or less


MDA (minimal disease MDA (minimal disease activity)activity)

Initial ‘remission’ decision node: Initial ‘remission’ decision node: TJC = 0, SJC = 0, ESR = 10 or less.TJC = 0, SJC = 0, ESR = 10 or less.If not in remission, choose system:If not in remission, choose system:

DAS 2.85 or less5 out of 7 core set criteria

Pain 2SJC 1TJC 1HAQ 0.5MDGA 1.5PGA 2ESR 20


Remission in KansasRemission in Kansas

ESR missing in about 50% of 849 patientsESR missing in about 50% of 849 patientsKappa’s between def’s 0.09 - 0.51Kappa’s between def’s 0.09 - 0.51

0

10

20

30

40

CDAI Š

2.8

MDGA Š

1

PAS

II Š1

.25

SJC,

TJC

=0

DAS2

8 Š2

.6

SJC,

TJC

=0,

ESR

Š10

PAS

II Š2

.2

MDA, 5

/7 C

ore

MDA, D

AS28

Š2.8

5


QUEST-RAQUEST-RA

5519 patients from 62 sites in 22 5519 patients from 62 sites in 22 countriescountriesTetrachor. correlation between def’s 0.63-Tetrachor. correlation between def’s 0.63-0.910.91

0

10

20

30

40


ViennaVienna

948 patients in obs database, 948 patients in obs database, most with low disease activitymost with low disease activityKappa’s between def’s 0,36 - 0,89Kappa’s between def’s 0,36 - 0,89

0

10

20

30

40

SDAI Š

3.3

CDAI Š

2.8

ACR 4/5

#fa

tigu

e

DAS28

Š2.

6

SJC,T

JC =

0, C

RP <5


Background: ConclusionBackground: Conclusion

ACR, CDAI/SDAI, PAS/RAPID3 ‘strict’ACR, CDAI/SDAI, PAS/RAPID3 ‘strict’Applying the 2 month duration requirement in the ACR criteria probably decreases prevalence by at least 50%

mACR and SJC0/TJC0/ESR10 ‘lax’mACR and SJC0/TJC0/ESR10 ‘lax’These and DAS28 remission criterion These and DAS28 remission criterion resemble DAS28 MDAresemble DAS28 MDA


TaskTask

A joint ACR / EULAR / OMERACT initiative A joint ACR / EULAR / OMERACT initiative to:to:

Study current remission definitionsExplore the theoretical concept of remission

Re-define remission in RA


Decisions made at ACR 2007*Decisions made at ACR 2007*

Conceptual issues:Conceptual issues:A strict definition:

no clinical disease

lack of damage progression over time

Not in the definition:Long term outcomes (phys. function, damage):used to determine validity of a new definition

Therapy

*Van Tuyl, LHD et al. Arthritis Rheum (AC&R) 2009;61:704-10.


Decisions made at ACR 2007 Decisions made at ACR 2007 (2)(2)

Measurement issuesMeasurement issuesDefinition should include as a minimum:

Tender joint count (full joint count preferred)

Swollen joint count (idem)

An acute phase reactant

Definition should not include:Duration of remission


Decisions made at ACR 2007 Decisions made at ACR 2007 (3)(3)

Potential setting and usePotential setting and useA remission definition for practice settings is needed and part of the taskTrial and practice definitions should be closely linked


Research agenda – ACR 2007Research agenda – ACR 2007

Conceptual issues:Conceptual issues:Assessment of reliability/reproducibility of the remission definition Predictive validity of candidate definition against X-rays and physical function Relationship between remission and MDA and longer term outcome (function, disability) The role of new imaging (eg. US and MRI) in the definition, measurement, assessment and monitoring of the remission


Research agenda – ACR 2007 Research agenda – ACR 2007 (2)(2)

Measurement issuesMeasurement issuesWhat disease activity measures to include? Exact question in physician and patient globals? What about between-physician variability? Do we need 28 joints or more? Should we give priority to specific joints? Should we ask patients directly if they feel they are in remission? For patients in remission at one time point, what is the likelihood to be in remission at adjacent time points?


Research agenda – ACR 2007 Research agenda – ACR 2007 (3)(3)

Potential settings and usesPotential settings and usesAre there equivalent measures, easier to use in practice, which give the same information? Can the practice setting definition include fewer measures whilst retaining a strong resemblance to the trial definition?



Challenges*Challenges*No good previous example on how to do this...Initial delays caused by difficulties in obtaining datasetsTrial datasets only contain information on the core setNo observational datasets in current exercise

Systematic review of evidence Systematic review of evidence for validity of current definitionsfor validity of current definitionsFormulation of candidate definitions

Cutpoints chosen from survey by AletahaSparse and comprehensive combinations of core measures



Challenges*Challenges*Systematic review of evidence Systematic review of evidence for validity of current definitionsfor validity of current definitionsFormulation of candidate definitionsValidation:How well does presence of remission by this candidate definition predict a good outcome? predict a good outcome?

stability in damagestability in physical function

Further validation:Further validation:analyses in subsets of patients with a poor prognosisgood outcome defined as stability in BOTH damage and function



Challenges*Challenges*Systematic review of evidence Systematic review of evidence for validity of current definitionsfor validity of current definitionsFormulation of candidate definitionsValidation:Further validation:Further validation:Committee survey on acceptable levels Committee survey on acceptable levels of residual activity in measuresof residual activity in measuresDetermination of residual disease activity Determination of residual disease activity in candidate definitionsin candidate definitionsThis Saturday: selection of short list/provisional This Saturday: selection of short list/provisional def.def.


Systematic review of evidence Systematic review of evidence for validity of current definitionsfor validity of current definitions

Search: 1138 records, 14 studies (!)Search: 1138 records, 14 studies (!)In all included studies: In all included studies:

Relationship between remission and long term structural damage or disability Patients in remission (various definitions) showed less deterioration of function and radiographic progression compared to patients not in remission.

*Van Tuyl, LHD et al. Arthritis Rheum (AC&R) 2009;in press.


Formulation of candidate definitions

indices: DAS28, CDAI, SDAIindices: DAS28, CDAI, SDAIoriginal cut points plus stricter cut points for DAS28plus more relaxed cut points for CDAI/SDAI

core set: TJC, SJC, CRP/ESR core set: TJC, SJC, CRP/ESR +/– other measures+/– other measures

at cut points 0 and 1


Validation:

Gold standard outcome between y1 and y2:Gold standard outcome between y1 and y2:no damage progression (SvdH =< 0)HAQ good (=<0.5) and no deterioration (=<0)

Does presence of remission Does presence of remission by definition # at 6 months lead to increased by definition # at 6 months lead to increased prevalence of the gold standard outcome?prevalence of the gold standard outcome?

Answer: yes, better for HAQ than damage, Answer: yes, better for HAQ than damage, but no choice between definitions possiblebut no choice between definitions possible


ChallengesChallenges

Lack of damage progression frequently Lack of damage progression frequently seen seen in patients not in remission, and even in patients not in remission, and even more so in intensive treatment & more so in intensive treatment & biological trials...biological trials...Normal HAQ difficult to attain in Normal HAQ difficult to attain in longstanding disease (irreversibility and longstanding disease (irreversibility and comorbidity)comorbidity)


DatasetsDatasets

Randomized controlled trialsRandomized controlled trialsASPIRE, ERA, PREMIER, TEMPO (MTX, biologicals; 1-2 years)

Extension trialsExtension trialsPREMIER (5 years; no treatment assignment, from year 3 onward all patients received adalimumab)

COBRACOBRA


Likelihood Ratio – Likelihood Ratio – PREMIER/ERA/TEMPOPREMIER/ERA/TEMPO

Remission Remission CriteriaCriteria

HAQHAQ6mo6mo

HAQHAQ12 mo12 mo

SHARPSHARP6mo6mo

SHARPSHARP12mo12mo

DAS28DAS28 < < 2.02.0 2.32.3 2.62.6 1.51.5 1.81.8

< < 2.22.2 2.52.5 2.92.9 1.61.6 1.71.7

< < 2.62.6 2.62.6 3.63.6 1.81.8 2.22.2

CDAICDAI <= <= 2.82.8 4.54.5 5.35.3 1.91.9 1.41.4

<= <= 3.53.5 2.92.9 4.24.2 2.12.1 1.71.7

<= <= 4.04.0 2.62.6 3.33.3 1.81.8 1.81.8

SDAISDAI <= <= 3.33.3 3.93.9 5.45.4 2.22.2 1.71.7

<= <= 4.04.0 2.92.9 4.34.3 2.22.2 1.81.8

<= <= 5.05.0 2.62.6 3.73.7 2.02.0 1.81.8

SJC28SJC28 = = 00 1.71.7 2.42.4 1.21.2 1.41.4

TJC28TJC28 = = 00 2.12.1 1.51.5 1.81.8 2.02.0

CRPCRP <= <= 11 1.21.2 1.21.2 1.21.2 1.11.1

PainPain = = 00 4.24.2 5.55.5 1.51.5 1.61.6


Residual disease activityResidual disease activity

1 core set measure: 30-40 (CRP 60-70)1 core set measure: 30-40 (CRP 60-70)2 measures: 2 measures: 20-3020-303 measures: 3 measures: 15-2015-204 measures: 4 measures: 10-1510-155 measures: 5 measures: 8-128-126 measures: 6 measures: <10 <10


Further validation:Further validation:

Repeat exercise in poor prognosis patientsRepeat exercise in poor prognosis patientsRF/aCCP+, damage at baseline

Repeat exercise in MTX treated patientsRepeat exercise in MTX treated patientsRedefine outcome: no damage progression AND Redefine outcome: no damage progression AND HAQ good & stableHAQ good & stable

Does presence of remission Does presence of remission by definition # at 6 months lead to increased by definition # at 6 months lead to increased prevalence of the gold standard outcome?prevalence of the gold standard outcome?Answer: yes, better for HAQ than damage, Answer: yes, better for HAQ than damage, but no choice between definitions possible but no choice between definitions possible


Face validityFace validity

Describe the residual disease activity Describe the residual disease activity that each definition allows in term of:that each definition allows in term of:

Swollen joint countTender joint countESR / CRPPhysician global assessmentPatient global assessmentPain


Committee survey Committee survey

Two questions:Two questions:If this were the ONLY measure to define If this were the ONLY measure to define remission, remission, what is the what is the maximummaximum level of disease activity level of disease activity you are willing to accept?you are willing to accept?

If there were other measures in the definition If there were other measures in the definition and these all point to remission, and these all point to remission, what is the what is the maximummaximum level of disease activity level of disease activity you are willing to accept in this measure?you are willing to accept in this measure?


MethodsMethods

25 respondents25 respondentsVAS scales from 0 to 100VAS scales from 0 to 1007575thth percentiles percentiles


If this were the ONLY measure :If this were the ONLY measure :

TJC28 2 joints

TJC full 2 joints

SJC28 1 joints

SJC full 1 joints

ESR 25 mm

CRP 10 Mg/l

Physician global

10 mm

Patient global 20 mm

Pain 20 mm

HAQ 0.5

points

Fatigue 25 mm

75th percentiles; VAS 0 to 100


If there were other measures in the If there were other measures in the definition and these all point to remissiondefinition and these all point to remission

::

TJC28 3 joints

TJC full 3 joints

SJC28 2 joints

SJC full 2 joints

ESR 30 mm

CRP 15 Mg/l

Physician global

20 mm

Patient global 30 mm

Pain 30 mm

HAQ 1.0

points

Fatigue 40 mm

75th percentiles; VAS 0 to 100


Cut pointsCut points

strict middle

relaxed

TJC28 ≤1 ≤2 ≤3 joints

SJC28 ≤1 ≤1 ≤2 joints

ESR ≤20 ≤25 ≤30 mm

CRP ≤10 ≤10 ≤15 mg/l

Physician global

≤10 ≤10 ≤20 mm

Patient global ≤10 ≤20 ≤30 mm

Pain ≤10 ≤20 ≤30 mm


Residual disease activityResidual disease activityStrict cutpoints TJC28 SJC28 CRP PhG PtG Pain

TJC+SJC+CRP 11 11 1010 6060 8080 8181

TJC+SJC+CRP+PhG 11 11 1010 1010 7373 7777

TJC+SJC+CRP+PtG 11 11 1010 2020 1010 1515

TJC+SJC+CRP+pain 11 11 1010 4040 6060 1010

TJC+SJC+CRP+PhG+PtG 11 11 1010 1010 1010 2727

TJC+SJC+CRP+PhG+pain 11 11 1010 1010 4747 1010

TJC+SJC+CRP+PtG+pain 11 11 1010 2020 1010 1010

TJC+SJC+CRP+PhG+PtG+pain

11 11 1010 1010 1010 1010

DAS28<2.6 77 2121 2525 5050 8080 9595

SDAI ≤ 3.3 22 22 2727 2020 2323 2727


Residual disease activityResidual disease activityMiddle cutpoints TJC28 SJC28 CRP PhG PtG Pain

TJC+SJC+CRP 22 11 1010 6060 8080 8888

TJC+SJC+CRP+PhG 22 11 1010 1010 7373 8888

TJC+SJC+CRP+PtG 22 11 1010 4848 2020 4949

TJC+SJC+CRP+pain 22 11 1010 5050 6060 2020





22 11 1010 1010 2020 2020

DAS28<2.6 77 2121 2525 5050 8080 9595

SDAI ≤ 3.3 22 22 2727 2020 2323 2727


Residual disease activityResidual disease activityRelaxed cutpoints TJC28 SJC28 CRP PhG PtG Pain

TJC+SJC+CRP 33 22 1414 6060 9090 8888

TJC+SJC+CRP+PhG 33 22 1414 2020 7373 8888

TJC+SJC+CRP+PtG 33 22 1414 5454 3030 4949

TJC+SJC+CRP+pain 33 22 1414 5454 7070 3030





33 22 1414 2020 3030 2929

DAS28<2.6 77 2121 2525 5050 8080 9595

SDAI ≤ 3.3 22 22 2727 2020 2323 2727


Residual disease activityResidual disease activityStrict cutpoints TJC28 SJC28 CRP PhG PtG Pain

TJC+SJC+CRP 11 11 1010 6060 8080 8181

TJC+SJC+CRP+PhG 11 11 1010 1010 7373 7777

TJC+SJC+CRP+PtG 11 11 1010 2020 1010 1515

TJC+SJC+CRP+pain 11 11 1010 4040 6060 1010





11 11 1010 1010 1010 1010

DAS28<2.6 77 2121 2525 5050 8080 9595

SDAI ≤ 3.3 22 22 2727 2020 2323 2727


Residual disease activityResidual disease activityMiddle cutpoints TJC28 SJC28 CRP PhG PtG Pain

TJC+SJC+CRP 22 11 1010 6060 8080 8888

TJC+SJC+CRP+PhG 22 11 1010 1010 7373 8888

TJC+SJC+CRP+PtG 22 11 1010 4848 2020 4949

TJC+SJC+CRP+pain 22 11 1010 5050 6060 2020





22 11 1010 1010 2020 2020

DAS28<2.6 77 2121 2525 5050 8080 9595

SDAI ≤ 3.3 22 22 2727 2020 2323 2727


Percentage in remissionPercentage in remission

TotalDMARD mono

Biological mono

Combi

12301230 380380 330330 520520

TJC+SJC+CRP+PhG 1414 1010 99 2626

TJC+SJC+CRP+PtG 1212 99 77 2222

TJC+SJC+CRP+PhG+PtG 1010 88 77 2020

TJC+SJC+CRP+PhG+pain 1010 88 66 2020


99 77 66 1818


1515 1010 99 2525

DAS28 < 2.6 2121 1919 1717 3535

SDAI ≤ 3.3 1414 1010 88 2626

number of patients


Last SaturdayLast Saturday

TJC+SJC+CRP+PtG got highest marks5 def’s to remain for further testing in observational datasetsagenda at OMERACT 10

presentation of final validation exercisesstability/reliabilitystart development of patient ‘absence of disease’ definition and measurement

collaborate with OMERACT RA Flare group


ConclusionConclusion

Process characteristic of OMERACT*Process characteristic of OMERACT*Data-driven consensusData-driven consensusOMERACT Filter of Truth, Discrimination, FeasibilityOMERACT Filter of Truth, Discrimination, FeasibilityContinuum of remission, Continuum of remission, minimal disease activity, active disease minimal disease activity, active disease along the same feasible scalealong the same feasible scaleStrong impetus to start development of patient definition in Strong impetus to start development of patient definition in collaboration with RA flare groupcollaboration with RA flare group

OMERACT 10 in Borneo May 3-8, 2010: www.omeract.org

Documents

Redefining remission in rheumatoid arthritis a joint ACR/EULAR/OMERACT initiative Maarten Boers Department of Clinical Epidemiology and Biostatistics VU