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Minimal disease activity remission and the long-term outcomes of rheumatoid arthritis.

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Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 57, No. 6, August 15, 2007, pp 935–942
DOI 10.1002/art.22895
© 2007, American College of Rheumatology
ORIGINAL ARTICLE
Minimal Disease Activity, Remission, and the
Long-Term Outcomes of Rheumatoid Arthritis
FREDERICK WOLFE,1 JOHANNES J. RASKER,2 MAARTEN BOERS,3 GEORGE A. WELLS,4
KALEB MICHAUD5
AND
Objective. To determine the prevalence of minimal disease activity (MDA) and remission in patients with rheumatoid
arthritis (RA), to assess the effect of anti–tumor necrosis factor (anti-TNF) therapy on MDA, and to determine the extent
to which MDA status improves long-term outcomes.
Methods. Using the Patient Activity Scale (PAS) as a surrogate, we assessed the prevalence of MDA and remission in
18,062 patients with RA using the newly developed Outcome Measures in Rheumatology Clinical Trials (OMERACT)
criteria for MDA.
Results. MDA was noted in 20.2% of 18,062 patients and persistent MDA, operationally defined as having MDA during
>2 consecutive 6-month observation periods, occurred in 13.5% of 7,433 patients followed longitudinally. Disease activity
at remission levels was noted in 7%. Among patients with MDA, 82% received disease-modifying antirheumatic drugs or
biologic agents. Following anti-TNF initiation, the cumulative probability of achieving MDA at 2 and 6 years was 4.1%
and 7.6%, respectively, and persistent MDA probabilities were 2.7% and 4.5%, respectively. Regardless of RA duration,
patients with MDA had substantially better outcomes, including a 10-fold reduction in work disability and an approximately 2-fold reduction in total joint replacement and mortality.
Conclusion. Remission remains uncommon in RA, and the prevalence of new remission in community practice is
substantially lower than noted in published trials of biologic therapy. On average, persons with MDA appear to have
persistently mild RA. This might be the effect of milder RA and/or more effective treatment in early RA. The PAS had
satisfactory levels of agreement with the full MDA criteria and appears suitable for use in clinical and epidemiologic
research.
KEY WORDS. Minimal disease activity; Remission; Tumor necrosis factor; Biologics; Rheumatoid arthritis.
INTRODUCTION
Remission, the absence of disease activity, is the most
desirable outcome for patients with rheumatoid arthritis
(RA), and recent advances in antirheumatic therapy appear to have made remission a realistic goal for many
1
Frederick Wolfe, MD: National Data Bank for Rheumatic
Diseases, and the University of Kansas School of Medicine,
Wichita, Kansas; 2Johannes J. Rasker, MD: University of
Twente, Enschede, The Netherlands; 3Maarten Boers, MD,
PhD: VU University Medical Centre, Amsterdam, The Netherlands; 4George A. Wells, PhD: University of Ottawa, Ottawa, Ontario, Canada; 5Kaleb Michaud, MS: National Data
Bank for Rheumatic Diseases, Wichita, Kansas, and the
Center for Primary Care and Outcomes Research, Stanford
University, Stanford, California.
Address correspondence to Frederick Wolfe, MD, National Data Bank for Rheumatic Diseases, Arthritis Research Center Foundation, 1035 N Emporia, Suite 230,
Wichita, KS 67214. E-mail: fwolfe@arthritis-research.org.
Submitted for publication August 21, 2006; accepted in
revised form February 5, 2007.
patients (1–3). However, as simple as the definition of
remission seems to be, its actual determination is difficult.
In 1981, the American College of Rheumatology (ACR;
formerly the American Rheumatism Association) published preliminary remission criteria (4). These criteria
were highly specific, but almost impossible to fulfill when
applied strictly. Although a few studies used the ACR
criteria or its modifications (5), other research opted to
define remission operationally (6 –12). With the advent of
improved RA treatment, the ability to measure remission
accurately became more important.
Among the difficulties in defining remission are several
problems. In some instances, swollen and/or painful joints
may be caused by factors other than active RA. In addition,
when erythrocyte sedimentation rate (ESR) or C-reactive
protein level (CRP) are part of a remission definition, abnormal values unrelated to RA activity could result in
exclusion of some patients from remission classification
even though they have achieved clinical remission. Remission misclassification might also occur when persons who
are in remission based on the number of swollen and
935
936
painful joints and ESR/CRP level have high levels of pain.
As with many issues in rheumatology, the ability to identify remission in the individual patient must often be
differentiated from the ability to identify remission in
groups of patients.
A modern approach probabilistically addresses remission by identifying a point on a disease activity continuum
where remission is identified with the highest level of
accuracy. Using the original Disease Activity Score (DAS),
remission has been reported as a DAS score ⬍1.6 by Prevoo et al in a study that used the original ACR criteria (4)
as an end point (6). More recently, a Disease Activity Score
in 28 joints (DAS28) ⬍2.6 was suggested as a remission
end point (13), a definition that is in accord with the
Prevoo et al definition (6). Such definitions (14) have had
wide use in the description of outcomes of clinical trials,
and results of trials of biologic agents frequently describe a
remission outcome. Probability-based remission criteria,
however, do not eliminate misclassification, but they do
allow for its quantification.
Recently Wells et al, acting on an idea from Maarten
Boers, suggested new probabilistic approaches to remission that appeared to overcome many of these problems
(15). In addition, they recognized the difficulty in agreement regarding what is actually remission, opting instead
to define minimal disease activity (MDA), which is a point
on a continuum of RA disease activity that is near remission. In addition, MDA is a point on the disease activity
spectrum that is of considerable interest itself (see Patients
and Methods section for description of MDA definition).
We used a surrogate measure of the Wells/Boers/
Outcome Measures in Rheumatology Clinical Trials
(OMERACT) definition of MDA and large data sets to explore the prevalence of remission and MDA in RA. Wells
et al and the OMERACT committee (15) suggested the need
for examining the MDA definition in external data sets. In
addition, we assessed the probability of being in an MDA
state following anti–tumor necrosis factor (anti-TNF) therapy. Finally, we described the consequence of MDA on
long-term RA outcomes.
PATIENTS AND METHODS
Patients in this study were participants in the National
Data Bank for Rheumatic Diseases (NDB) longitudinal
study of RA outcomes. NDB participants are recruited on
an ongoing basis from the practices of US rheumatologists,
and are followed prospectively with semiannual, detailed,
28-page questionnaires, as previously described (16 –18).
The analyses in this report used several subsets of NDB
participants, as will be described. During the NDB preenrollment process, patients with RA completed brief
screening questionnaires in their rheumatologists’ offices.
Patients who completed this preenrollment process (n ⫽
28,646) were then invited to participate in the (full) NDB
long-term outcome study by completing detailed semiannual questionnaires. A total of 19,052 (66.7%) patients
were fully enrolled into the longitudinal study. Of the
28,646 patients, 10,584 were identified as being enrolled
in safety registries for leflunomide and infliximab. Because
Wolfe et al
Figure 1. Disease activity among National Data Bank for Rheumatic Diseases patients with rheumatoid arthritis (RA) as determined in a randomly selected observation of the 18,062 patients.
Definitions are based on estimations from the Patient Activity
Scale (PAS). DAS ⫽ Disease Activity Score; DAS28 ⫽ Disease
Activity Score in 28 joints; MDA ⫽ minimal disease activity;
WHO ⫽ World Health Organization; ILAR ⫽ International League
of Associations for Rheumatology; OMERACT ⫽ Outcome Measures in Rheumatology Clinical Trials.
these patients were selected by the enrollment process for
the severity of their RA, they were excluded from analysis
to avoid severity bias. The remaining 18,062 patients constituted the patient group used for prevalence estimates of
MDA and the data shown in Figures 1 and 2.
Of the 18,062 patients whose data were used for the
MDA prevalence estimates, 12,682 continued in the longterm followup study. In the longitudinal analyses of this
study, this group was further restricted to include 7,433
patients who underwent at least 3 semiannual observations and who were not receiving anti-TNF therapy at the
first observation. By this restriction we were able to determine prospectively the percentage of patients who
achieved MDA status after starting anti-TNF therapy.
All NDB participants provided demographic information and completed the Health Assessment Questionnaire
(HAQ) disability index (19,20) and visual analog scales
(VAS) for pain intensity and global severity. These 3 scales
were used to calculate the Patient Activity Scale (PAS)
(21). The PAS is a 0 –10 measure of RA disease activity in
which higher values indicate greater RA disease activity.
The PAS is computed by multiplying the HAQ by 3.33 and
then dividing the sum of the VAS pain, VAS global, and
HAQ by 3. The PAS may also be computed by using the
shorter HAQ-II (22) instead of the HAQ, with essentially
identical results. HAQ-II results were not reported in the
current study. In addition to these data, patients who
enrolled in the detailed longitudinal followup study reported all medication use, joint replacement surgery, and
US Social Security disability awards. Analysis of disability awards was restricted to patients ⬍62 years of age. Data
on deaths were obtained from family and physicians, and
from yearly systematic searches of the National Death Index (23,24).
We also made use of a second data set, the Rheumatoid
Arthritis Evaluation Study (RAES) data set (25). The RAES
data set contains examination data on 619 patients re-
Minimal Disease Activity and Remission in RA
937
definitions for MDA were designed and discussed at the
OMERACT VII conference in 2004. Feedback from participants and additional on-site analyses in the cross-sectional (RAES) database allowed the formulation of 2 preliminary, equivalent definitions of MDA: one based on the
DAS28 index of disease activity and one based on meeting
cut points in 5 of the 7 World Health Organization (WHO)/
International League of Associations for Rheumatology
(ILAR) core set measures (15). We used the Wells et al
definition in our analyses of MDA.
In the first method, MDA was said to be present if the
patient satisfied at least 5 of the following 7 conditions:
VAS pain ⱕ2 (0 –10), swollen joint count ⱕ1 (0 –28), tender joint count ⱕ1 (0 –28), HAQ ⱕ0.5 (0 –3), patient global
severity ⱕ2 (0 –10), physician global disease activity ⱕ1.5
(0 –10), and ESR ⱕ20 mm/hour, or if the patient satisfied
the following conditions: had no swollen joints, no tender
joints, and an ESR ⱕ10 mm/hour. The definition was
called the core set definition because it made use of the
published core set variables for the assessment of response
in patients with RA (30,31). In the second method (the
DAS28 method), patients achieved MDA status if they had
no swollen joints, no tender joints, and an ESR ⱕ10 mm/
hour or if their DAS28 score was ⱕ2.85.
Figure 2. Percentage of patients satisfying minimal disease activity (MDA) and remission definitions according to A, duration of
rheumatoid arthritis (RA) and B, duration of RA and the use of
anti–tumor necrosis factor (anti-TNF) therapy. Each patient contributed a single random observation. For clarity and relevance,
analyses were restricted to a subset of the 18,062 patients in
Figure 1: A, the 13,128 patients with RA durations ⱕ30 years (—
⫽ MDA [core set]; – – – ⫽ remission [physician]) and B, patients
with RA durations ⱕ30 years who enrolled in the National Data
Bank for Rheumatic Diseases and provided treatment data at the
randomly selected observation (n ⫽ 7,802) (— ⫽ MDA anti-TNF
positive; – – – ⫽ MDA anti-TNF negative; ----- ⫽ remission
anti-TNF positive; – 䡠 – 䡠 ⫽ remission anti-TNF negative). MDA is
defined as a Patient Activity Scale (PAS) value ⱕ1.625 and remission at a PAS value ⱕ0.5.
cruited from the practices of Canadian and American academic and community physicians who were each asked
to examine ⬃10 consecutive patients with RA in their
clinics. In addition to the HAQ, VAS pain, and VAS global,
the RAES data set contains information on the number of
tender and swollen joints, ESR, physician global assessment, and an estimate by the physician if the patient was
in remission (had no disease activity). From these data, the
RA disease activity score (DAS28) was calculated. The
DAS28 score is a well-recognized measure of RA disease
activity (26 –29).
Wells et al described the MDA definition derived from
the OMERACT consensus conference (15). The consensus
report made use of analyses from the RAES data set. In the
Wells et al study, rheumatologists assessed 60 patient profiles describing real patients with RA seen in routine clinical practice. Based on their responses, several candidate
Relationship between MDA and clinical measures. Because the NDB data set does not contain all of the core set
or DAS28 variables, we used the PAS as a surrogate to
determine MDA. Using the RAES data set, we determined
that a PAS score ⱕ1.625 best identified MDA defined by
the core set definition. This value of the PAS correctly
identified 87% of MDA cases and had a sensitivity of
69.5%, specificity of 90.6%, odds ratio (OR) of 22.0, a
kappa value of 0.60 (95% confidence interval [95% CI]
0.52– 0.68), and a McNemar chi-square value of 0.05 (P ⫽
0.825). The area under the receiver operating characteristic
curve (AUC) for the PAS was 0.893 (the AUC was 0.859 for
the HAQ and 0.859 for VAS pain; the difference between
PAS AUC and the HAQ and pain AUC was significant at
the 0.01 level). Kappa is biased downward (prevalence
bias) and underestimates agreement when the percentage
correct is substantially greater than 50%, and was not
relevant in this context (32,33). However, kappa is presented here for completeness. The PAS score that best
described the DAS28 MDA was 1.75, percentage correct
was 79%, sensitivity was 54.0%, specificity was 85.9%,
OR was 7.4, kappa was 0.39 (95% CI 0.31– 0.48), and
McNemar chi-square was 0.19 (P ⫽ 0.662). Because PAS
determination of the DAS28 MDA had substantially reduced reliability compared with the PAS-based core set
estimate of the MDA, we chose to use the PAS-based core
set estimate of the MDA. Because all of the PAS variables
are measured in the core set and only one of the PAS
elements is measured in the DAS28, it was expected that
the PAS core set estimate of the MDA would have better
reliability than the PAS DAS28 estimate of the patient
disease activity level.
We also estimated remission in the RAES data set based
on rheumatologists’ clinical judgment. In the RAES study,
rheumatologists reported remission by indicating a global
938
Wolfe et al
disease activity score of 0 (25). For comparison purposes
only, the proportion of patients in remission using the
DAS28 remission recommendation of 2.6 (13), a value that
had an equivalent PAS score ⱕ1.25, is also shown in
Figure 1.
For clarity, we summarized the 2 data sets used in this
report. The first was the 619 patients in the RAES data set.
The purpose of using the RAES data set was to develop the
cut points in the PAS for all of the MDA and remission
criteria. The second data set, the NDB data set, made use of
2 groups. The first group comprised 18,062 patients who
were not members of safety registries and whose data were
used for prevalence estimates. The second group was a
subset of the first group and comprised 7,433 patients who
fully enrolled in the NDB, contributed at least 3 semiannual observations, and were not receiving anti-TNF therapy at their first observation.
Data were analyzed using Stata software, version 9.1
(StataCorp, College Station, TX). Differences between
groups in cross-sectional analyses were studied by logistic
regression. Longitudinal data were analyzed by Cox proportional hazards regression. Graphs of outcomes versus
disease duration were constructed using Stata’s locpoly
command (34) to produce kernel-weighted local polynomial smooths. An Epanechnikov kernel was used with a
bandwidth of 2 for Figures 2A, 2B, and 3B, except for the
MDA negative line in Figure 3B, where the bandwidth was
0.7.
RESULTS
MDA and remission in the RAES data set. The mean ⫾
SD age and disease duration of patients with RA in the
RAES data set were 58.0 ⫾ 13.5 years and 12.5 ⫾ 10.5
years, respectively, and 73% were women. Of these 619
patients, MDA occurred in 20.8% using the core set definition and 22.1% using the DAS28-based definition. Rheumatologists’ disease activity ratings of 0 or 1 on the 0 –10
scale, which may be thought to correspond to a clinical
definition of minimal activity, occurred in 22.9% of patients. In addition, remission as defined by examining
rheumatologists on clinical grounds occurred in 6.1%.
MDA and remission in the NDB. In a randomly selected
observation, MDA prevalence in 18,062 NDB patients was
20.6% and 22.5% as measured by the PAS-estimated core
set definition and the PAS-estimated DAS28 definition,
respectively (Figure 1). The remission prevalence was 7%
by the PAS estimation (PAS ⱕ0.5), which was derived
from the RAES data set remission values. When plotted
against time, remission and MDA were more common in
patients with shorter durations of RA (Figure 2A). Persistent MDA, defined as MDA for ⱖ2 semiannual periods,
occurred in 67% of patients with MDA on a single occasion, and persistent remission levels occurred in 57% of
patients who had achieved remission once.
Treatment, MDA, and remission. To evaluate the relationship between anti-TNF therapy and disease activity at
Figure 3. A, Percentage of patients who received a Social Security
disability award, had a total joint replacement, or were noted to
have died subsequently, according to minimal disease activity
(MDA) status. B, The relationship between cross-sectional MDA
status and Social Security disability award in patients with rheumatoid arthritis (RA) ⬍62 years of age. — ⫽ MDA positive; – – –
⫽ MDA negative. Data are from a randomly selected observation
from the 7,433 patients in the longitudinal analyses group.
differing durations of RA, we further restricted the randomly selected study sample of 13,128 patients shown in
Figure 2A to 7,820 patients who enrolled in the NDB and,
therefore, had treatment data available. Enrollees generally
have slightly better RA and health status than nonenrollees. As shown in Figure 2B, MDA and remission remained
more common in persons with shorter durations of RA. In
addition, there was almost no difference between MDA
and remission percentages according to treatment status.
To formally evaluate the association of anti-TNF therapy
with MDA and remission, in a random observation we
studied 7,433 NDB patients who had completed at least 3
full NDB semiannual surveys and who were not receiving
anti-TNF therapy at their first assessment. Of these, only
7.0% of patients with MDA received no RA-related treatments at all and 18.0% received no disease-modifying
antirheumatic drug (DMARD), anti-TNF, or prednisone
therapy (Table 1). MDA was less common among patients
treated with prednisone (OR 0.5, 95% CI 0.4 – 0.6), antiTNF therapy (OR 0.8, 95% CI 0.7– 0.9), and leflunomide
(OR 0.7, 95% CI 0.6 – 0.9), and more common among those
treated with hydroxychloroquine (OR 1.4, 95% CI 1.3–
1.6). These results were to be expected, because they in-
Minimal Disease Activity and Remission in RA
939
Table 1. The association between rheumatoid arthritis treatment and minimal disease activity (MDA)*
Treatment
DMARD
MTX
Prednisone
Hydroxychloroquine
Anti-TNF therapy
Leflunomide
Sulfasalazine
No treatment
No DMARD/biologic
No DMARD/biologic or prednisone
No DMARD/biologic, prednisone, or NSAID
MDA neg.
(n ⴝ 5,089)
MDA pos.
(n ⴝ 2,344)
OR (95% CI)†
P
75.0
51.1
36.5
24.0
13.6
11.0
7.2
76.7
49.2
22.2
30.7
11.2
8.2
8.4
1.1 (0.9–1.3)
0.9 (0.8–1.2)
0.5 (0.4–0.6)
1.4 (1.3–1.6)
0.8 (0.7–0.9)
0.7 (0.6–0.9)
1.2 (1.0–1.4)
0.093
0.064
⬍ 0.001
⬍ 0.001
0.002
⬍ 0.001
0.091
22.3
17.2
5.1
22.2
18.0
7.0
0.9 (0.8–1.0)
1.0 (0.9–1.2)
1.4 (1.1–1.7)
0.193
0.509
0.004
* Values are the percentage unless otherwise indicated. OR ⫽ odds ratio; 95% CI ⫽ 95% confidence interval; DMARD ⫽ disease-modifying
antirheumatic drug; MTX ⫽ methotrexate; anti-TNF ⫽ anti–tumor necrosis factor; NSAID ⫽ nonsteroidal antiinflammatory drug.
† Adjusted for availability of treatment options (secular trend).
dicate that newer and/or potentially more effective therapy is administered to patients with the most severe RA.
To be certain the anti-TNF results were valid with our
selection methods, we re-ran the anti-TNF analyses after
excluding patients who received anti-TNF therapy for ⱕ6
months. The results were similar to those described above
(OR 0.8, 95% CI 0.6 – 0.9).
To address the effect of anti-TNF therapy on remission,
we first excluded patients in remission at their first observation, leaving 6,828 patients. As shown in Figure 4, the
cumulative hazard, which may be interpreted as the estimated cumulative MDA at different points in time, indicates that the MDA percentage at 2 and 6 years for patients
treated with anti-TNF therapy was 4.1% and 7.6%, respectively. By comparison, the MDA percentage in patients not
treated with anti-TNF therapy was 5.1% and 9.3%, respectively. The patients not treated with anti-TNF therapy are
shown only for comparison purposes. Because the odds of
treatment prescription differed between the groups, no
Figure 4. The cumulative hazard of entering the minimal disease
activity (MDA) state for patients who were not in MDA and were
not receiving anti–tumor necrosis factor (anti-TNF) therapy at the
first assessment. The MDA percentage at 2 and 6 years for patients
treated with anti-TNF therapy was 4.1% and 7.6%, respectively.
By comparison, the percentage in patients not treated with antiTNF therapy was 5.1% and 9.3%, respectively. — ⫽ patients
treated with anti-TNF therapy; – – – ⫽ patients not treated with
anti-TNF therapy.
direct comparison of the effect of differing treatments on
remission could be made.
Using Cox proportional hazards regression, MDA patients in theses analyses were younger (mean ⫾ SD age
59.1 ⫾ 13.1 years versus 61.2 ⫾ 12.5 years), had more
education (13.9 ⫾ 2.4 years versus 13.2 ⫾ 2.3 years), were
more often male (28.0% versus 19.0%), had greater household income ($54,694 ⫾ $29,049 US versus $39,400 ⫾
$26,590 US), had fewer comorbid conditions (1.9 ⫾ 1.6
versus 2.7 ⫾ 1.9), and were more likely to be nonminorities (93.6% versus 91.2%) compared with patients who
were MDA negative. We also determined the MDA percentage for patients who were MDA positive at 2 consecutive semiannual periods in order to describe the durability of the MDA state. The cumulative hazard at 2 and 6
years was 2.7% and 4.5%, respectively, for the patients
treated with anti-TNF therapy and 3.2% and 5.3%, respectively, for the patients not treated with anti-TNF therapy.
MDA status and RA outcome. Patients with MDA had
good long-term outcomes (Figure 3A). In a random observation of the 7,433 patients in the longitudinal analyses,
work disability among persons younger than age 62 years
(2.4% versus 28.0%), total joint replacement (10.1% versus 22.1%), and mortality (3.3% versus 6.9%) were reduced in patients who had achieved MDA status compared with those who had not achieved MDA.
To evaluate the association of RA duration with MDA
status, we graphed the prevalence of US Social Security
disability awards against RA duration among patients
younger than age 62 years (Figure 3B). Even at RA durations as long as 30 years, work disability was ⬍8% among
patients with MDA but reached levels ⬎30% in those
without MDA in this cross-sectional analysis.
DISCUSSION
Using the proposed OMERACT WHO/ILAR core set definition, MDA was estimated to be present in 20.6% of
patients with RA. The OMERACT DAS28-based recom-
940
mendation resulted in MDA in 22.5% of patients. These
values were very close to those obtained in the RAES data
set: 20.8% using the core set definition and 22.1% using
the DAS28-based definition. In further confirmation, a
rheumatologist’s score of 0 –1 on a 0 –10 disease activity
scale (minimal disease activity) was noted to occur in
22.9%. Thus, the data from the 3 sources are in agreement;
we conclude that MDA occurs in ⬃21–22% of patients
with RA.
Remission is somewhat more difficult to quantify.
Within the 619 patients in the RAES data set, rheumatologist-defined remission occurred in 7% of cases. This definition was equivalent to a PAS ⱕ0.5, and when that
definition was applied to the NDB 7% of 18,062 patients
were found to be in remission. We estimated that remission according to the DAS28 criterion of 2.6 occurred in
15.7%. However, Wells et al suggested that the DAS remission criteria were problematic (15), and indicated that
patients with a DAS28 score ⬍2.6 can have substantial
residual disease (35).
Probability-based remission definitions are difficult and
inaccurate in individual patients, although they appear to
be appropriate at the group level. These observations concerning remission lend credence to the Wells et al approach of defining MDA as including remission (15). The
difference between MDA and remission and the fact that
MDA includes remission also indicate that it is possible to
have even better clinical status than defined by MDA.
Makinen et al have recently reviewed remission in patients with RA (7) and noted that remission prevalence
ranged from 0% to 42% in various studies. These differences might reflect treatment effect, patient selection, or
remission definition. In considering the level of disease
activity necessary to define remission and MDA, however,
we did not consider persistence of low disease activity.
Therefore, the MDA and remission percentages reported
here may be considered optimistic.
When we required MDA to occur on consecutive semiannual occasions, the MDA percentage decreased by 33%
and the remission percentage by 43%. Although it is customary to think of MDA and remission in terms of persistence, the data in this study suggest that this might not be
necessary. Patients with MDA on a single occasion had
much better outcomes than those not in MDA (Figure 3A),
including levels of work disability that were 10 times
lower and levels of total joint replacement and mortality
that were reduced 2-fold. Figure 3B can be interpreted to
indicate that patients with MDA on a single (cross-sectional) occasion always tend to persist in this low disease
activity state. Otherwise, work disability, which is a cumulative variable, would be much higher among those
with MDA on a single occasion. This interpretation, that
patients with low disease activity are determined early in
the course of RA, has been made by us previously in a
different data set (36).
One important use of MDA is to assess treatment effect.
The data in Table 1 indicate that only 18% of patients with
MDA have a DMARD/biologic-free status, but this figure is
not significantly different from the 17.2% of patients not in
MDA. If treatment-free status is related to the idea of
remission, then after extrapolating from the 20.6% with
Wolfe et al
MDA shown in Figure 1, only ⬃3.5% of patients have
treatment-free MDA. Table 1 also shows that specific drugs
do not have a clear influence on MDA status, except that
there is somewhat greater use of hydroxychloroquine and
less use of anti-TNF therapy, leflunomide, and prednisone
among patients with MDA. One possible interpretation to
these data is that patients with less severe RA who are
more likely to achieve MDA are given less potent therapies.
However, we were able to study the introduction of the
new therapy, anti-TNF therapy, and measure the prevalence of MDA following such therapy. Among patients not
previously treated with anti-TNF therapy and not currently in MDA, the percentage of patients treated with
anti-TNF therapy achieving MDA at 2 and 6 years was
4.1% and 7.6%, respectively. When consecutive semiannual periods in MDA were required, the probability of
persistent MDA status at 2 and 6 years was 2.7% and 4.5%,
respectively, for the patients treated with anti-TNF therapy.
In contrast to the MDA prevalence noted among community RA patients described above, recent clinical trials
suggest the possibility of substantial numbers of remission
among patients treated with anti-TNF therapy and suggest
that “the latest strategies and treatments enable remission
to be achieved in many more patients than formerly” (37).
For example, in the Trial of Etanercept and Methotrexate
with Radiographic Patient Outcomes (TEMPO) study, the
proportion of patients who achieved remission as defined
by a disease activity score (not DAS28) ⬍1.6 was 35% in
the combination anti-TNF/methotrexate group (38,39).
The Leeds group reported that 70% of patients with early,
poor-prognosis RA treated with infliximab plus methotrexate achieved a sustained median DAS28 score of 2.05
(remission range) (40). We did not observe improvement of
this degree among NDB patients.
We did, however, observe that patients with shorter
durations of RA had a higher rate of MDA (Figure 2A). In
Figure 2B, we observed a similar response, but this response could not be attributed to anti-TNF therapy because the early response occurred at an equal or greater
proportion in patients not treated with anti-TNF therapy
compared with those treated with anti-TNF therapy. Because the data of these figures are cross-sectional, we cannot state whether this represents better treatment in recent
years (41– 43) or a generally better response that occurs in
early RA, as we have suggested previously (36,44).
In conclusion, MDA prevalence varies slightly according to different definitions, but is between 20.6% and
22.5%. The RA remission prevalence is 7.0%. These definitions are associated with profound clinical benefit.
MDA status appears to have trait characteristics. TNF therapy is not associated with a substantial increase in MDA or
remission. PAS-based remission assessments may be a
useful tool for assessing RA status and outcome.
AUTHOR CONTRIBUTIONS
Dr. Wolfe had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of the
data analysis.
Minimal Disease Activity and Remission in RA
Study design. Wolfe, Rasker.
Acquisition of data. Wolfe, Michaud.
Analysis and interpretation of data. Wolfe, Rasker, Boers, Wells,
Michaud.
Manuscript preparation. Wolfe, Rasker, Boers, Wells, Michaud.
Statistical analysis. Wolfe, Rasker, Wells, Michaud.
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outcomes, terms, long, arthritis, activity, disease, minimax, rheumatoid, remission
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