Transcript Redefining remission in rheumatoid arthritis a joint ACR

Redefining remission
in rheumatoid arthritis
a joint
ACR/EULAR/OMERACT
initiative
Maarten Boers
Department of Clinical Epidemiology
and Biostatistics
VU University Medical Center Amsterdam
Outline
Background/Task
Decisions and research agenda
made at ACR 2007
Progress to date
redefining remission in RA
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Remission team
George Wells, Ottawa
Josef Smolen, Vienna
Lilian van Tuyl, Amsterdam
Bin Zhang, Boston
Julia Funovits, Vienna
ACR-EULAR ad hoc committee (40+ members)
co-chairs:
Maarten Boers, Amsterdam
David Felson, Boston
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Background
Increasing numbers of patients reach remission
Abundance of remission definitions
‘strict’ definitions: ACR, CDAI/SDAI, PAS/RAPID3
‘loose’ definitions: DAS, DAS28, mACR,
SJC0/TJC0/ESR10, MDA
Need for a uniform definition (RA trials, practice)
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OMERACT Filter
to select measures
To be applicable in its intended setting,
a measure must be
truthful
discriminative
feasible
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OMERACT Filter
Truth
free from bias
criterion, construct validity
relevant
content, face validity
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OMERACT Filter
Discrimination
able to distinguish between states
that are of interest:
at one time point
at different time points
reliability, reproducibility,
sensitivity to change
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OMERACT Filter
Feasibility
time
costs
interpretability
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Etymology
Remittere (L):
to send back; to decrease; to relax...
Remission
(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.
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Concept: key points
State, not change or transition
Pattern of transitions interesting research area
Time spent in state not part of concept
Absence of disease activity
How to be sure?
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Concept: key points
State, not change or transition
Absence of disease activity
Related but not identical:
Cure: disease does not return
Arrest: disease process is stopped
Intermission: period of no activity
between two periods of active disease
Antithetical
Relapse: return of disease activity
Flare: substantial increase of disease activity
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Current definitions: Pinals
(1981)
5 or more must be fulfilled
for at least 2 consecutive months:
Morning stiffness not exceeding 15 minutes
No fatigue
No joint pain (by history)
No joint tenderness or pain on motion
No soft tissue swelling in joints
or tendon sheaths
ESR (W) <30 mm/h (f); <20 mm/h (m)
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Pinals
3 groups classified according to the
rheumatologist: complete remission, partial
remission, active disease
Sensitivity 72%, specificity 90%
against partial remission
Using 4 out of 6: sens 90%, spec 62%
Read the discussion!
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Pinals
“A major obstacle to developing criteria for
remission in RA is the difficulty in ascertaining
the absence of inflammation by methods that
are reliable and also convenient in clinical
settings...”
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Pinals
“A major obstacle...”
“Substantial variation appears to exist
in the concept of remission within the group
of participating rheumatologists...”
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DAS/DAS28
DAS: Ritchie joint index and 44 swollen joint ct
DAS28: 28 tender & swollen joint count
Both use a ‘general health’ VAS (0-100)
DAS28 = 0.56 sqrt (TJC) + 0.28 sqrt (SJC)
+ 0.70 ln (ESR) + 0.014 GH.
DAS28 remission: 2.6
DAS remission: 1.6
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DAS28 remission (1996)
Validation against ARA criteria in Nijmegen
obs. data, moderately active disease
‘mACR’:
Fatigue not assessed
Remission defined as
4 out of 5 remaining criteria
3 months instead of 2 months period;
single visit data used
Sens and Spec against mACR 87%
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SDAI/CDAI remission (2005)
SDAI = (28TJC) + (28SJC) + MDGA + PGA + CRP
CDAI = (28TJC) + (28SJC) + MDGA + PGA
SDAI remission = 3.3
CDAI remission = 2.8
Developed in patient profile exercise
and validated in observational datasets
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PAS/RAPID3 (2005)
PAS = 1/3 [(HAQ * 3.33) + pain + PGA]
PAS remission: 1.25 (judgment)
RAPID3 = 1/3 [(HAQ * 3.33) + pain + PGH]
RAPID3 remission: 1.0 (judgment)
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MDA
(minimal disease activity; 2003)
State of disease activity deemed a useful target
of treatment by patient and physician, given
current treatment possibilities and limitations.
Derived from profile exercises at OMERACT
Initial ‘remission’ decision node:
TJC = 0, SJC = 0, ESR = 10 or less
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MDA (minimal disease activity)
Initial ‘remission’ decision node:
TJC = 0, SJC = 0, ESR = 10 or less.
If not in remission, choose system:
DAS 2.85 or less
5 out of 7 core set criteria
Pain  2
SJC  1
TJC  1
HAQ  0.5
MDGA  1.5
PGA  2
ESR  20
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Remission in Kansas
ESR missing in about 50% of 849 patients
Kappa’s between def’s 0.09 - 0.51
40
30
20
10
5
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2.
8
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QUEST-RA
5519 patients from 62 sites in 22 countries
Tetrachor. correlation between def’s 0.63-0.91
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Vienna
948 patients in obs database,
most with low disease activity
Kappa’s between def’s 0,36 - 0,89
40
30
20
10
<
5
.6
,C
R
P
Š2
28
=
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Background: Conclusion
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’
These and DAS28 remission criterion
resemble DAS28 MDA
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Task
A joint ACR / EULAR / OMERACT initiative to:
Study current remission definitions
Explore the theoretical concept of remission
Re-define remission in RA
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Decisions made at ACR 2007*
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.
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Decisions made at ACR 2007 (2)
Measurement issues
Definition 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
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Decisions made at ACR 2007 (3)
Potential setting and use
A remission definition for practice settings
is needed and part of the task
Trial and practice definitions
should be closely linked
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Research agenda – ACR 2007
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
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Research agenda – ACR 2007 (2)
Measurement issues
What 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?
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Research agenda – ACR 2007 (3)
Potential settings and uses
Are 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?
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Progress to date
Challenges*
No good previous example on how to do this...
Initial delays caused by difficulties in obtaining datasets
Trial datasets only contain information on the core set
No observational datasets in current exercise
Systematic review of evidence
for validity of current definitions
Formulation of candidate definitions
Cutpoints chosen from survey by Aletaha
Sparse and comprehensive combinations
of core measures
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Progress to date
Challenges*
Systematic review of evidence
for validity of current definitions
Formulation of candidate definitions
Validation:
How well does presence of remission by
this candidate definition predict a good outcome?
stability in damage
stability in physical function
Further validation:
analyses in subsets of patients with a poor prognosis
good outcome defined as stability
in BOTH damage and function
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Progress to date
Challenges*
Systematic review of evidence
for validity of current definitions
Formulation of candidate definitions
Validation:
Further validation:
Committee survey on acceptable levels
of residual activity in measures
Determination of residual disease activity
in candidate definitions
This Saturday: selection of short list/provisional def.
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Systematic review of evidence
for validity of current definitions
Search: 1138 records, 14 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.
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Formulation of candidate definitions
indices: DAS28, CDAI, SDAI
original cut points
plus stricter cut points for DAS28
plus more relaxed cut points for CDAI/SDAI
core set: TJC, SJC, CRP/ESR
+/– other measures
at cut points 0 and 1
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Validation:
Gold standard outcome between y1 and y2:
no damage progression (SvdH =< 0)
HAQ good (=<0.5) and no deterioration (=<0)
Does presence of remission
by definition # at 6 months lead to increased
prevalence of the gold standard outcome?
Answer: yes, better for HAQ than damage,
but no choice between definitions possible
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Challenges
Lack of damage progression frequently seen
in patients not in remission, and even more so
in intensive treatment & biological trials...
Normal HAQ difficult to attain in longstanding
disease (irreversibility and comorbidity)
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Datasets
Randomized controlled trials
ASPIRE, ERA, PREMIER, TEMPO (MTX,
biologicals; 1-2 years)
Extension trials
PREMIER (5 years; no treatment assignment,
from year 3 onward all patients received
adalimumab)
COBRA
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Likelihood Ratio – PREMIER/ERA/TEMPO
Remission
Criteria
HAQ
6mo
HAQ
12 mo
SHARP
6mo
SHARP
12mo
DAS28 <
2.0
2.3
2.6
1.5
1.8
<
2.2
2.5
2.9
1.6
1.7
<
2.6
2.6
3.6
1.8
2.2
CDAI <= 2.8
4.5
5.3
1.9
1.4
<= 3.5
2.9
4.2
2.1
1.7
<= 4.0
2.6
3.3
1.8
1.8
<= 3.3
3.9
5.4
2.2
1.7
<= 4.0
2.9
4.3
2.2
1.8
<= 5.0
2.6
3.7
2.0
1.8
SDAI
SJC28 =
0
1.7
2.4
1.2
1.4
TJC28 =
0
2.1
1.5
1.8
2.0
CRP
<= 1
1.2
1.2
1.2
1.1
Pain
=
4.2
5.5
1.5
1.6
0
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Residual disease activity
1
2
3
4
5
6
core set measure: 30-40 (CRP 60-70)
measures:
20-30
measures:
15-20
measures:
10-15
measures:
8-12
measures:
<10
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Further validation:
Repeat exercise in poor prognosis patients
RF/aCCP+, damage at baseline
Repeat exercise in MTX treated patients
Redefine outcome: no damage progression
AND HAQ good & stable
Does presence of remission
by definition # at 6 months lead to increased
prevalence of the gold standard outcome?
Answer: yes, better for HAQ than damage,
but no choice between definitions possible
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Face validity
Describe the residual disease activity
that each definition allows in term of:
Swollen joint count
Tender joint count
ESR / CRP
Physician global assessment
Patient global assessment
Pain
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Committee survey
Two questions:
If this were the ONLY measure to define remission,
what is the maximum level of disease activity
you are willing to accept?
If there were other measures in the definition
and these all point to remission,
what is the maximum level of disease activity
you are willing to accept in this measure?
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Methods
25 respondents
VAS scales from 0 to 100
75th percentiles
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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
75th percentiles; VAS 0 to 100
Physician global
10
mm
Patient global
20
mm
Pain
20
mm
HAQ
0.5 points
Fatigue
25
mm
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If there were other measures in the definition
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
75th percentiles;VAS 0 to 100
Physician global
20
mm
Patient global
30
mm
Pain
30
mm
HAQ
1.0 points
Fatigue
40
mm
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Cut 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
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Residual disease activity
Strict cutpoints
TJC28
SJC28
CRP
PhG
PtG
Pain
TJC+SJC+CRP
1
1
10
60
80
81
TJC+SJC+CRP+PhG
1
1
10
10
73
77
TJC+SJC+CRP+PtG
1
1
10
20
10
15
TJC+SJC+CRP+pain
1
1
10
40
60
10
TJC+SJC+CRP+PhG+PtG
1
1
10
10
10
27
TJC+SJC+CRP+PhG+pain
1
1
10
10
47
10
TJC+SJC+CRP+PtG+pain
1
1
10
20
10
10
TJC+SJC+CRP+PhG+PtG+pain
1
1
10
10
10
10
DAS28<2.6
7
21
25
50
80
95
SDAI ≤ 3.3
2
2
27
20
23
27
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Residual disease activity
Middle cutpoints
TJC28
SJC28
CRP
PhG
PtG
Pain
TJC+SJC+CRP
2
1
10
60
80
88
TJC+SJC+CRP+PhG
2
1
10
10
73
88
TJC+SJC+CRP+PtG
2
1
10
48
20
49
TJC+SJC+CRP+pain
2
1
10
50
60
20
TJC+SJC+CRP+PhG+PtG
2
1
10
10
20
37
TJC+SJC+CRP+PhG+pain
2
1
10
10
47
20
TJC+SJC+CRP+PtG+pain
2
1
10
30
20
20
TJC+SJC+CRP+PhG+PtG+pain
2
1
10
10
20
20
DAS28<2.6
7
21
25
50
80
95
SDAI ≤ 3.3
2
2
27
20
23
27
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Residual disease activity
Relaxed cutpoints
TJC28
SJC28
CRP
PhG
PtG
Pain
TJC+SJC+CRP
3
2
14
60
90
88
TJC+SJC+CRP+PhG
3
2
14
20
73
88
TJC+SJC+CRP+PtG
3
2
14
54
30
49
TJC+SJC+CRP+pain
3
2
14
54
70
30
TJC+SJC+CRP+PhG+PtG
3
2
14
20
30
49
TJC+SJC+CRP+PhG+pain
3
2
14
20
70
29
TJC+SJC+CRP+PtG+pain
3
2
14
54
30
30
TJC+SJC+CRP+PhG+PtG+pain
3
2
14
20
30
29
DAS28<2.6
7
21
25
50
80
95
SDAI ≤ 3.3
2
2
27
20
23
27
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Residual disease activity
Strict cutpoints
TJC28
SJC28
CRP
PhG
PtG
Pain
TJC+SJC+CRP
1
1
10
60
80
81
TJC+SJC+CRP+PhG
1
1
10
10
73
77
TJC+SJC+CRP+PtG
1
1
10
20
10
15
TJC+SJC+CRP+pain
1
1
10
40
60
10
TJC+SJC+CRP+PhG+PtG
1
1
10
10
10
27
TJC+SJC+CRP+PhG+pain
1
1
10
10
47
10
TJC+SJC+CRP+PtG+pain
1
1
10
20
10
10
TJC+SJC+CRP+PhG+PtG+pain
1
1
10
10
10
10
DAS28<2.6
7
21
25
50
80
95
SDAI ≤ 3.3
2
2
27
20
23
27
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Residual disease activity
Middle cutpoints
TJC28
SJC28
CRP
PhG
PtG
Pain
TJC+SJC+CRP
2
1
10
60
80
88
TJC+SJC+CRP+PhG
2
1
10
10
73
88
TJC+SJC+CRP+PtG
2
1
10
48
20
49
TJC+SJC+CRP+pain
2
1
10
50
60
20
TJC+SJC+CRP+PhG+PtG
2
1
10
10
20
37
TJC+SJC+CRP+PhG+pain
2
1
10
10
47
20
TJC+SJC+CRP+PtG+pain
2
1
10
30
20
20
TJC+SJC+CRP+PhG+PtG+pain
2
1
10
10
20
20
DAS28<2.6
7
21
25
50
80
95
SDAI ≤ 3.3
2
2
27
20
23
27
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Percentage in remission
Total
DMARD
mono
Biological
mono
Combi
number of patients
1230
380
330
520
TJC+SJC+CRP+PhG
14
10
9
26
TJC+SJC+CRP+PtG
12
9
7
22
TJC+SJC+CRP+PhG+PtG
10
8
7
20
TJC+SJC+CRP+PhG+pain
10
8
6
20
TJC+SJC+CRP+PhG+PtG+pain
9
7
6
18
TJC+SJC+CRP+PhG+PtG+pain
15
10
9
25
DAS28 < 2.6
21
19
17
35
SDAI
14
10
8
26
≤ 3.3
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Last Saturday
TJC+SJC+CRP+PtG got highest marks
5 def’s to remain for further testing in
observational datasets
agenda at OMERACT 10
presentation of final validation exercises
stability/reliability
start development of patient ‘absence of disease’
definition and measurement
collaborate with OMERACT RA Flare group
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Conclusion
Process characteristic of OMERACT*
Data-driven consensus
OMERACT Filter of Truth, Discrimination,
Feasibility
Continuum of remission,
minimal disease activity, active disease
along the same feasible scale
Strong impetus to start development of patient
definition in collaboration with RA flare group
OMERACT 10 in Borneo May 3-8, 2010: www.omeract.org
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