OMERACT patient remission

Summary of research and proposal for questions the SIG can answer / end product
M. Boers 25-2-20

Background
At OMERACT 2010 the draft ACR-EULAR remission criteria were criticized during a workshop because
participants felt insufficient patient-important information was incorporated.
A working group was formed to tackle this problem.
Qualitative work (9 x focus groups across three countries) published by this group found items
important to patients with RA in considering their ‘disease as good as gone’ came under three broad
themes (for brevity participant quotes only are provided for the domains subsequently prioritized by
patients):
Symptoms: Less or no pain (“No pain is remission”; “When the disease was as good as gone I had
absolutely no symptoms; I was strong, had absolutely no pain”); Less stiffness; Less fatigue/more
energy (“For me the stiffness and fatigue. That I would just have the energy, then I would even be
prepared to put up with the pain); Less swelling; More strength; Better sleep
Impact: Physical functioning; Activities of daily living; Independence (“Independence of personal care
and independence of the jobs in the house”; “I’m happy if I can open a jar of cucumbers without going
to somebody else and asking for help”)
Normality: Being able to work; Family role; Perception of others

A prioritization survey also published by this group asked people with RA (n=274) across six countries
to rate these domains for importance (‘not important’, ‘important’, ‘essential’) in characterizing a
period of remission, and if important whether this domain needs to be ‘less’, ‘almost gone’ or ‘gone’ to
reflect remission. Participants were also asked to rate their top three most important domains. Pain,
fatigue, and independence were identified as the most important domains that patients consider to
decide whether they are in remission (‘disease activity as good as gone’).

The next phase was an ambitious longitudinal study to propose, and where necessary validate
instruments for these domains, and then decide whether information from these instruments was
such that the current ACR-EULAR definition would need to be changed.
200+ patients selected for low disease activity were studied longitudinally (plus 46 with only baseline
data). Setup was like the studies to create the ACR-EULAR remission criteria. Treatment was not
controlled.
Problems: much fewer patients than anticipated, longitudinal only from two centers, no radiograph
data, limited data (esp. longitudinal) on independence (instrument added halfway through trial in
Amsterdam where the most participants were included and followed, details below); hold on SF-36
data because of calculation problems.

Results
Pain and fatigue NRS are valid in the low disease activity setting. For the new instrument
‘independence NRS’ results are mixed, but interesting. The value of adding items to the current criteria
appears limited, but replacement of Patient Global Assessment (PtGA) for either fatigue or
independence could be further explored, as these domains appear to be a strong predictor of good
HAQ outcome. Also, comparison of discrepancy between patient-perceived and Boolean remission
reveals the latter to be more strict. Most discrepant patients are in self-perceived remission but not
Boolean remission; patients meeting Boolean but not self-perceived remission are very rare. In
patients not meeting Boolean remission it is often PtGA that fails. The mean of PtGA in such patients is
about 2 (out of 10).
Note: separate from this work, Dr Ricardo Ferreira will present a fellow poster at OMERACT with
individual patient data from 11 RCTs that suggest PtGA adds little to the other 3 remission criteria
instruments in the prediction of good radiological outcome.

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Conclusions
1. The current data is limited, but given our experience to date, this is all we are likely to get for
the coming 5-10 years. We need to make decisions now or become irrelevant.
2. With this data we can conclude that pain and fatigue (in the current core set), but also
independence, are important domains in the patient perception of (near) remission.
3. A proposal to change the current definition needs very strong arguments for several reasons.
The data presented here are in themselves insufficient for such a proposal. However, a
discussion can be started about the cutoff point for PtGA and the need to collect further data
to support substitution of PtGA for either fatigue or independence.

Proposal for SIG end product

1. Agree that decisions on the current criteria need to be taken now.
2. Agree not to change the current remission criteria now.
3. Suggest that ACR-EULAR reconsider the PtGA cutoff in the criteria.
4. Suggest that Independence is an important domain, and that the current NRS should be
further validated.
5. Nominate volunteers to take this on.

Comments discussed during call Wijnanda Hoogland, Marieke Voshaar and Maarten Boers
2020, february 14

Findings patient partners:

As presented in the summary, we are surprised about the figures with regard to self perceived
remission compared to Boolean remission. At the start, we expected patients to be less satisfied about
their health status (PtGA) compared to the opinion of the rheumatologist, but it appears to be the
other way around.
It is mostly the patients global which failes when selfperceived remission has been met by the patients
but Boolean remission not. We agree with the suggeston to reconsider the cutoff of the patients global
in the existing remission criteria. The cut-off point needs to be discussed after preferably more data
has been gathered.
The three most important domains with regard to remission according to the patients are: pain,
fatique and independence. For the measuremtent of independence it is important to consider the
difference between disease activity and the existing damage by establised RA. (This will also be
important in relation with pain, fatigue and the HAQ).

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Extended summary
Dataset: 246 patients from various sites studied cross-sectionally; 200+ patients studied longitudinally
(3 and 6 months)
Data collected:
Demographics;
Boolean remission; patient-perceived remission (single question);
core set variables;
RAID (7 items);
FACIT fatigue;
BRAF fatigue;
SF-36 (coding problems, not analyzed yet);
EQ-5D;
NRS independence:
a new NRS formulated by the research team in close consultation with patient research partners
and based on the focus group discussions, phrased as:
“Over the last week, have you been able to do things as and when you want,
without needing any kind of assistance?”, scoring 0 for no assistance to 10 for a lot of assistance.

Patients have identified pain, fatigue and independence as most important contributing factors to
decide whether they are in remission (‘disease as good as gone’).
The analyses below were intended to validate instruments for these domains in the setting
of low disease activity/remission: do they measure what they are supposed to, and do they supply
information of potential relevance to change the current ACR/EULAR remission criteria?

1. Cross-sectional studies: instruments for pain, fatigue, independence.

a. Do these instruments measure the construct: disease activity, expressed as DAS28
and SDAI?
Yes. Strong correlation in the right direction with most instruments
(so: more pain, fatigue, less independence with higher DAS or SDAI);
with exception of BRAF coping, EQ-5D anxiety: no correlation with DAS28,
weaker correlation with SDAI.
i. Comparison with other instruments listed above: equal performance.
In other words, pain, fatigue or independence instruments do not have
a stronger correlation than e.g. other items in the RAID.
b. Do these instruments discriminate between patients in and not in remission,
expressed as Boolean and as self-perceived?
Yes. Strong discrimination for both remission definitions.
i. Comparison with other instruments listed above: equal performance.
c. Additional analysis: 35% of patients are discrepant between both remission
definitions. Almost all of these (n=72, 31%) are in self-reported remission,
but not in Boolean; only 4% are in Boolean but not in self-reported remision.
In the discrepant 31% (self-report [y] Boolean [n]), the mean of all studied instruments
is much (and, with a few exceptions, strongly significantly) higher than the mean of
patients in concordant remission ((self-report [y] Boolean [y]).

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 Of special interest are the values for the instruments incorporated in the Boolean
remission definition (mean ± SD):

remission Only Patient-perceived Both Patient-perceived

and Boolean
N Mean ± SD N Mean ± SD
Patient Global (PtGA, 0-10) 72 2.1 ± 1.9 65 0.4 ± 0.5
Tender jt count (TJC, 0-28) 72 1.9 ± 3.8 65 0.1 ± 0.2
Swollen jt count (SJC, 0-28) 72 1.8 ± 2.1 65 0.1 ± 0.3
C-Reactive Protein (CRP, mg/L)* 72 6.0 ± 7.9 65 2.3 ± 1.7
* remission cutoff is 10 mg/L

Conclusion: Boolean includes almost all patients with self-perceived remission.

Roughly 80% (mean + 1SD) of patients in self-perceived remission accept higher
cutoffs for TJC, SJC and Pt Global. In fact, their mean DAS-CRP is 2.7 (SD: 1.1), near the
cutoff for minimal disease activity, compared to 1.7 (SD: 0.4) for concordant patients.
In the patients with self-perceived remission who failed only 1 Boolean criterion
(n=40), most (n=22) failed the patient global criterion
(in the other 18 pts 3 failed the TJC, 6 the SJC , and 9 the CRP criterion).

2. Longitudinal studies
Do changes in these instruments track with changes in remission status
or low/minimal disease activity status?
We chose 3 status criteria: self-reported remission y/n; and DAS28 at 2 levels:
2.60 (minimal) and 3.20 (low disease activity).
We defined two observation periods (0-3 months; 3-6 months) and made subgroups of
patients who either: remained stable in their status defined by the criterion; changed from
‘yes’ to ‘no’; or changed from ‘no’ to ‘yes’. Each patient can be present twice in the dataset:
once in each period (0-3 resp. 3-6 months). No effort has been made to account for the fact
that these two observations are not fully independent.
a. Do changes in these instruments track with stability or changes
in self-reported remission status?
NRS pain and fatigue work well (and as good as, or better than alternatives) to
discriminate changes from ‘no’ to ‘yes’ and vice versa; also, they appropriately show
no change in stable patients.
The independence NRS does not work well, but the analyses are hampered by low
patient numbers. RAID physical function and physical well-being, and to a lesser extent
EQ-5D usual activities work better as possible instruments for independence. In the 12
patients with full data on all these ‘independence measures’ these differences remain,
to a lesser extent.
Note: patient global is among the best performing instruments.
b. Do changes in these instruments track with stability or changes in DAS28 disease
activity level, with LDAS (<3.20) as cutpoint?
Most patients are stable low, and all instruments appropriately detect no change. For
change, none of the instruments work really well, but sample sizes are low. There are
max 20 patients that change status. In this setting only EQ-5D significantly detects
changes from yes to no (8 patients), and NRS pain, HAQ, RAID total and RAID physical
well-being, emotional well-being and coping detect changes from no to yes (17-20
patients).
c. Do changes in these instruments track with stability or changes in DAS28 disease
activity level, with ‘remission’/MDA status (DAS<2.60) as cutpoint?
For stable patients, HAQ shows a marginally significant change of –0.03 points
(142 patients, p=0.05), thus ‘overly sensitive’; other instruments show no signal. For
change from yes to no, sample sizes are low (5-27 patients). NRS pain discriminates
between changes in both directions. No fatigue instrument is optimal: BRAF fatigue
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 level works only in changes from yes to no, NRS fatigue and facit fatigue work only in
changes from no to yes. NRS independence does not discriminate at all. As alternative
measures, only RAID functional disability and HAQ discriminates between changes in
both directions. RAID physical well-being works only in changes from no to yes;
EQ-5D usual activities is marginal (p=0.06), only from no to yes. In other instruments,
full RAID and patient global discriminate between changes in both directions
(25-27 patients).
Conclusion: scenario b. is suboptimal and needs no further discussion (less valid cutpoint,
low sample sizes). In the other scenarios, NRS pain is fine for pain; NRS fatigue is best
overall, with some problems in scenario c. NRS independence does not work well, with low
sample sizes. Other instruments are better, with RAID subscales physical function and
physical well-being best overall.
Patient global has a very good overall performance.
3. Additional value of adding the patient perspective to the definition of remission.
As in the original ACR-EULAR development studies, ‘value’ is defined as the capability to
predict future HAQ remission as external criterion (definitions as in Felson: HAQ stable and
consistently low). Baseline levels are used to predict the presence of HAQ remission in the
subsequent 6 months.
a. Do these instruments at baseline predict HAQ remission?
Univariate logistic regression of HAQ remission (y/n).
Yes. Strong prediction in right direction.
i. Comparison with other instruments listed above: equal performance.
(Exception: BRAF coping and EQ-5D anxiety: weaker prediction.
b. Does the best instrument for pain, fatigue and independence provide information of
potential relevance to change the current ACR/EULAR remission criteria?
On the basis of all information collected so far, decide which instrument best
measures the 3 domains. Then repeat analysis under a. as multivariable backward
logistic regression, that includes those instruments, as well as Boolean, self-reported
remission.
For pain and fatigue we chose NRS. For independence we looked at NRS,
but also at RAID physical well-being and EQ-5D usual activities as alternatives. For
ACR/EULAR remission, we tested the set of components of the criteria initially entered
together; and Boolean y/n as a separate analysis.
i. HAQ remission vs remission components plus additional measures
(‘vs’ means: predicted by):
1. vs TJC, SJC, CRP, PtGA, patient perceived remission: only PtGA
(P<0.001) and trend for TJC (p=0.091) retained in model.
2. vs TJC, SJC, CRP, PtGA, Pain, Fatigue, Independence: Only
Independence NRS significant (p=0.002).
3. Replace independence NRS with RAID physical well-being and with EQ-
5D usual activities:
a. vs TJC, SJC, CRP, PtGA, Pain, Fatigue, RAID physical well-being:
only TJC and RAID phys well-being significant (0.01 and
<0.001, resp.)
b. vs TJC, SJC, CRP, PtGA, Pain, Fatigue, EQ-5D usual activities:
only EQ-5D usual activities significant (p=0.003)
Conclusion: in these analyses, only one or two variables are retained:
a component of the current remission definition or a newly added variable.
ii. HAQ remission vs remission Boolean (y/n) plus additional measures
1. vs Boolean, patient perceived remission: Boolean p=0.05, patient
perceived remission p=0.03.
2. vs Boolean, Fatigue, Independence:
Only Independence NRS significant (p=0.002).
3. Replace independence NRS with RAID physical well-being and with EQ-
5D usual activities:
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 a. vs Boolean, Pain, Fatigue, RAID physical well-being: only RAID
phys well-being significant (p=0.001)
b. vs Boolean, Pain, Fatigue, EQ-5D usual activities: only EQ-5D
usual activities significant (p=0.003)
Conclusion: in these analyses, one new variable pushes out Boolean (y/n) as
explanatory factor: either patient perceived remission (y/n), or a variable
associated with independence.
iii. Estimates of explained variability: see next page.
Note that the analyses that include independence are not directly comparable
to the other analyses, because there are much less observations.
Conclusion: some explained variability added by adding elements of patient
remission info, or replacing PtGA, but not much.
Also, note that adding a criterion, whatever the cutpoint, would make the
current criteria even more restrictive.
4. Same analyses but now with radiological damage as external criterion.
We don’t have data for this. In theory, the Dutch data have radiographs, but this is in an early
population with very low damage rates, so not enough signal to do our analyses in. Also, the
films have not yet been read.

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Table. Results of multivariable logistic regression, with
forced entry of selected variables. The two R square
columns are estimates of explained variance.
-2 Log likelihood Cox & Snell R Square Nagelkerke R Square
BOOLEAN (4x) 123 ,23 ,31
BOOLEAN (4x) + PAIN 119 ,24 ,33
BOOLEAN (4x) + FATIGUE 113 ,28 ,38
BOOLEAN (4x) + INDEPENDENCE 50 ,27 ,38
BOOLEAN (4x) + PAIN + FATIGUE 113 ,28 ,39
BOOLEAN (4x) + PAIN + INDEPENDENCE 49 ,29 ,40
BOOLEAN (4x) + FATIGUE + INDEPENDENCE 49 ,29 ,41
BOOLEAN (4x) + PAIN + FATIGUE + INDEPENDENCE 48 ,31 ,43
BOOLEAN (3x, without PtGA) + PAIN 126 ,20 ,26
BOOLEAN (3x, without PtGA) + FATIGUE 1212 ,23 ,31
BOOLEAN (3x, without PtGA) + INDEPENDENCE 51 ,27 ,37
BOOLEAN (3x, without PtGA) + PAIN + FATIGUE 119 ,25 ,34
BOOLEAN (3x, without PtGA) + PAIN + INDEPENDENCE 50 ,28 ,38
BOOLEAN (3x, without PtGA) + FATIGUE + INDEPENDENCE 50 ,28 ,39
BOOLEAN (3x, without PtGA) + PAIN + FATIGUE + INDEPENDENCE 49 ,29 ,40