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ARTHRITIS & RHEUMATISM
Vol. 63, No. 12, December 2011, pp 3702–3711
DOI 10.1002/art.30634
© 2011, American College of Rheumatology
Joint Damage in Rheumatoid Arthritis Progresses in
Remission According to the Disease Activity Score in
28 Joints and Is Driven by Residual Swollen Joints
Daniel Aletaha and Josef S. Smolen
residual joint swelling (n ⴝ 92, 80.7%) had less radiographic progression over 1 year than those with residual
joint swelling (n ⴝ 22, 19.3%) (mean ⴞ SD SHS
progression 0.2 ⴞ 2.6 versus 2.2 ⴞ 4.2; P ⴝ 0.11).
Likewise, the proportion of patients with a total SHS
progression of >0.5/year was significantly lower among
those without joint swelling than among those with joint
swelling (27.2% versus 50.0%; P ⴝ 0.039). DAS28 remitters without joint swelling showed progression comparable to that in the total group of remitters by the
Simplified Disease Activity Index (remission defined as
<3.3) and Clinical Disease Activity Index (remission
defined as <2.8), namely, 0.2 versus ⴚ0.07 versus 0.16,
respectively (P ⴝ 0.66).
Conclusion. Radiographic progression with nonbiologic treatment is minimal only when patients in
DAS28 remission have no persistent residual joint
swelling. Under these conditions, progression is comparable to that in patients with disease in remission
according to other disease activity indices.
Objective. Remission has been defined as the
ultimate target for patients with rheumatoid arthritis.
The Disease Activity Score in 28 joints (DAS28) has
been criticized for the amount of disease activity that
remains in patients despite their achieving DAS28 remission. This study was undertaken to investigate the
significance of residual inflammation in remission in
relation to radiographic progression.
Methods. We pooled 1-year clinical data, kindly
provided by the respective sponsors, on 864 patients in
methotrexate monotherapy arms of recent pivotal trials.
We identified patients who had attained persistent
DAS28 remission from month 6 through month 12 (a
DAS286–12 of <2.6). Among these patients we then
assessed radiographic progression in total Sharp/van
der Heijde scores (SHS) from baseline to 12 months
between those with residual joint swelling (defined as a
swollen joint count from month 6 through month 12
[SJC6–12] of >2) and those without residual joint
swelling (defined as an SJC6–12 of <2).
Results. One hundred fourteen patients (13.2%)
achieved a DAS286–12 of <2.6, of whom those without
Rheumatoid arthritis (RA) is an inflammatory
joint disease with joint destruction being its most essential hallmark. Joint damage in RA involves both cartilage and bone. While cartilage damage is due to activation of chondrocytes and matrix metalloproteinases (1),
bone destruction is a consequence of the activity of
osteoclasts (2,3). However, all of these events are driven
by the inflammatory response. Indeed, previous studies
have revealed that joint damage is related to the level of
the acute-phase response and swollen joint counts
(SJCs), both at the start of therapy and cumulatively
over time, but not to tender joint counts (TJCs) or other
clinical variables (4–6). As a consequence, scoring on
composite indices of disease activity is also related to the
extent of joint damage (5).
While physical disability is one of the most
important outcomes to prevent in patients with RA, the
This is a publication of the Joint and Bone Center for
Diagnosis, Research and Therapy of Musculoskeletal Disorders of the
Medical University of Vienna.
Supported by the European Union Seventh Framework Programme (Coordination Theme 1 [Health], project Masterswitch;
HEALTH-F2-2008-223404).
Daniel Aletaha, MD, Josef S. Smolen, MD: Medical University of Vienna, Vienna, Austria.
Dr. Aletaha has received consulting fees, speaking fees,
and/or honoraria from Abbott, Pfizer, MSD, UCB, and Roche (less
than $10,000 each). Dr. Smolen has received consulting fees, speaking
fees, and/or honoraria from Abbott, Amgen, Bristol-Myers Squibb,
Pfizer, MSD, Roche, and UCB (less than $10,000 each).
Address correspondence to Daniel Aletaha, MD, Division of
Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
E-mail: [email protected]
Submitted for publication October 14, 2010; accepted in
revised form August 16, 2011.
3702
JOINT DAMAGE PROGRESSION IN DAS28 REMISSION
interest in joint damage relates to the fact that permanent RA-related disability is greatly due to joint destruction (7–9). Clinical remission will not only reverse
disability that is related to activity, but will also halt
progression of joint destruction, especially if sustained
over time (10,11). Therefore, remission will also prevent
the accrual of irreversible disability.
Only recently has remission become an achievable goal (12,13), and only few trials have employed
remission as a primary end point (14,15). While there
are several definitions of remission (16,17), remission as
defined by the Disease Activity Score in 28 joints
(DAS28) (18) is most frequently reported in clinical
trials (14,19). However, DAS28 remission has been
under scrutiny over recent years, since a large proportion of patients with DAS28 remission have significant
residual SJCs (20–23). While stringent remission criteria, such as those of the Simplified Disease Activity
Index (SDAI) (24) or Clinical Disease Activity Index
(CDAI), allow for the presence of a maximum of 2
swollen joints in the state defined as remission, DAS28
remission allows for the presence of even more than a
dozen swollen joints (20,21). This residual joint activity
in DAS28 remitters has now also been confirmed by
sonographic joint assessment (23). Moreover, DAS28
remission rates exceed rates of patients meeting the
American College of Rheumatology 70% improvement
criteria (ACR70 response rates) (25) in many trials and
even ACR50 response rates in some trials (14). This
indicates a limited stringency of the state of remission
when defined by the DAS28.
Nonetheless, a DAS28 of ⬍2.6 clearly constitutes
a desirable state spanning from no disease activity to
relatively low disease activity. This range between no
residual activity and little residual activity is of particular
interest, as it is unclear how much residual disease
activity is tolerable to prevent radiographic damage and,
consequently, the associated functional disability. In the
present study we evaluated whether DAS28 remission is
a sufficiently stringent goal regarding the major shortterm outcome of RA, namely, progression of joint
damage.
PATIENTS AND METHODS
Data sources. We were kindly provided with random
80–90% patient-level data by the sponsors of the following
trials: the ASPIRE (Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis
of Early Onset) trial of infliximab plus methotrexate (MTX)
versus MTX alone in MTX-naive patients with early RA of ⱕ3
years (26); the PREMIER trial of adalimumab versus MTX
3703
versus the combination of adalimumab and MTX in patients
with early, aggressive RA who did not have previous MTX
treatment (27); the ERA (Early RA) trial of etanercept versus
MTX (28); the TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) study, which compared etanercept monotherapy, etanercept plus MTX, and
MTX monotherapy (29); and trials of leflunomide (LEF)
compared with sulfasalazine or MTX (30–33). All patients
had active RA at entry into these studies and were required to
have 6–10 swollen joints and at least 6–12 tender joints. With
the exception of the ASPIRE trial, elevations in acute-phase
reactants were also required for enrollment (C-reactive protein
[CRP] level ⱖ1.5–2.0 mg/dl or erythrocyte sedimentation
rate [ESR] ⱖ28 mm/hour). Sharp or modified Sharp/van der
Heijde scores (SHS) (34) were available for radiographic
analysis in all trials. Patient demographics have been presented
in the respective reports.
Data preparation. We analyzed patient data from all
MTX monotherapy trial arms (ASPIRE, ERA, PREMIER,
TEMPO, and LEF trials), which were the active comparators
in all of these trials. Patients treated with MTX monotherapy
were selected because we used radiographic progression as the
outcome of interest, which would be retarded or halted on
treatment with tumor necrosis factor (TNF) inhibitors plus
MTX even at states of disease activity higher than remission
(35–37). For completeness, we also evaluated and present the
results on this combination group. We identified and pooled
patients with complete clinical data at baseline and at 6, 9, and
12 months, as well as complete radiographic data at baseline
and at 12 months (n ⫽ 864). If needed, data obtained within
4 weeks after the above-mentioned time points were allowed
as substitutes for the 6-, 9-, and 12-month time points.
Outcome measures. We evaluated the baseline characteristics for this cohort, including SJCs and TJCs on a
28-joint scale, patient’s and evaluator’s global assessments of
disease activity on a 0–100-mm visual analog scale, ESR in
mm/hour, CRP level in mg/dl, Health Assessment Questionnaire (HAQ) score (38), and total SHS. Based on the individual instruments for the assessment of disease activity we
calculated values for 3 composite indices: the DAS28 (0.56 ⫻
⻫[TJC28] ⫹ 0.28 ⫻ ⻫[SJC28] ⫹ 0.70 ⫻ ln[ESR] ⫹ 0.014 ⫻
global health) (18); the SDAI (SJC ⫹ TJC ⫹ patient’s global
assessment ⫹ evaluator’s global assessment ⫹ CRP level) (24);
and the CDAI (SJC ⫹ TJC ⫹ patient’s global assessment ⫹
evaluator’s global assessment) (5,24). Customarily, we used the
patient’s global assessment as the global health measurement
for the DAS28 (in mm); patient’s global assessment and
evaluator’s global assessment in the SDAI and CDAI were
measured in cm (with 1 decimal). The CRP level in the SDAI
was measured in mg/dl. Radiographs were scored according to
the total Sharp score or total SHS. The definition of remission
was ⬍2.6 for the DAS28, ⱕ2.8 for the CDAI, and ⱕ3.3 for the
SDAI.
Main analyses. We identified patients who attained
persistent DAS28 remission, defined as an average DAS28 at
the 6-, 9-, and 12-month visits of ⬍2.6 (a DAS286–12 of ⬍2.6);
the period of 6 months and the average score (instead of
requiring a DAS28 ⬍2.6 at all visits) were used to allow for
slight fluctuations of disease activity (compensation of higher
levels with lower levels of disease activity) and to achieve
patient numbers that would provide sufficient power for our
3704
ALETAHA AND SMOLEN
Table 1.
Baseline characteristics of the patient population (n ⫽ 864)
Age, years
Disease duration, years
Women
Rheumatoid factor positive
Swollen joint count, 0–28
Tender joint count, 0–28
Patient’s global assessment of disease activity, 0–100 mm
Evaluator’s global assessment of disease activity, 0–100 mm
C-reactive protein, mg/dl
Erythrocyte sedimentation rate, mm/hour
Disease Activity Score in 28 joints
Simplified Disease Activity Index
Clinical Disease Activity Index
Health Assessment Questionnaire score, 0–3
Sharp/van der Heijde score
analysis. Conversely, DAS28 nonremission was defined as a
DAS286–12 of ⱖ2.6. For each patient, we calculated mean SJC
for the 6–12-month period and then divided the patients into
2 groups, those with residual joint swelling (defined as an
SJC6–12 of ⱖ2) and those without (defined as an SJC6–12
of ⬍2). This cut point was chosen because ⬃75% of surveyed
rheumatologists would not tolerate more than 2 swollen joints
as being compatible with remission (39), which was recently
also confirmed by another survey performed in the course of
developing the new ACR/European League Against Rheumatism remission definition (40,41). As will be shown in the
Results, the mean SJC was 0.4 in patients with SJC6–12 ⬍2.
In patients with persistent DAS28 remission
(DAS286–12 ⬍2.6), we used the chi-square statistic to compare
the proportions of patients with (SJC6–12 ⱖ2) and without
(SJC6–12 ⬍2) residual joint swelling who experienced radiographic progression, defining progression as an increase in
total SHS of ⬎0.5 from baseline to 12 months (42). We also
compared the radiographic progression (total SHS) from
baseline to 12 months between the 2 patient populations by
evaluating the median (quartiles) of radiographic progression
using the Wilcoxon test (2 groups) and the Kruskal-Wallis test
(⬎2 groups). We used probability plots to depict the progression in the different groups. We subsequently performed the
same comparative analysis of the effect of residual joint
swelling in the subgroup of patients whose disease was not in
remission (“DAS28 nonremitters,” i.e., patients with a
DAS286–12 of ⱖ2.6). For some of the trials, radiographic data
were available also at 6 months, which allowed us to match the
clinical and the radiographic time periods using both average
DAS28 and average SJC, as well as radiographic progression
from month 6 to month 12.
We also wished to compare the results obtained in
DAS28 remitters without residual joint swelling to results
obtained in patients with disease in remission by the SDAI or
CDAI. By definition, the latter groups would fulfill the criterion of SJC6–12 ⬍2, as the SDAI/CDAI definitions do not
allow for more than 2 swollen joints in a state of remission.
Persistent SDAI/CDAI remissions were defined in a manner
analogous to the DAS28, as SDAI6–12 and CDAI6–12. While
the patients studied here primarily were treated with MTX, we
Mean ⫾ SD or percent
Median (range)
53 ⫾ 13
2.4 ⫾ 3.4
75
71
13.9 ⫾ 6.4
16.0 ⫾ 6.9
62 ⫾ 21
63 ⫾ 17
3.6 ⫾ 3.9
47 ⫾ 26
6.6 ⫾ 1.1
46 ⫾ 15
42 ⫾ 14
1.49 ⫾ 0.65
21 ⫾ 31
54 (18–82)
1 (0–18)
–
–
13 (0–28)
15 (0–28)
65 (3–100)
62 (10–100)
2 (0–26)
42 (2–150)
7 (3–9)
45 (5–91)
41 (4–74)
2 (0–3)
10 (3–331)
also repeated this main analysis (comparing average progression between DAS28 remitters with and without residual joint
swelling) in the 2 other treatment groups, pooled TNF inhibitor monotherapy or TNF inhibitor plus MTX.
Sensitivity analyses. Since the main results of the TNF
inhibitor monotherapy group were similar to those in the MTX
monotherapy group, we pooled these groups for all subgroup/
sensitivity analyses as described below to achieve sufficient
power. In the main analysis we defined sustained remission as
an average DAS28 of ⬍2.6. As this theoretically allows disease
activity to be above the cut point of 2.6 on at least some
occasions, we performed an additional analysis in which we
required disease to be in remission at all 3 visits (at 6, 9, and 12
months). Since we based the choice of cut point for presence or
absence of joint swelling (SJC6–12 ⬍2 or ⱖ2) on a survey, we
evaluated additional cut points to ensure that the observed
results were not completely inherent to that definition. In this
sensitivity analysis, we simply repeated the main analysis in
DAS28 remitters first defining residual joint swelling by a cut
point of 1 (⬍1 and ⱖ1) and then by a cut point of 3, instead of
the cut point of 2 that we used in the rest of the study. We
finally evaluated whether the observed differences in radiographic progression related more to differences in progression
of erosions or differences in progression of joint space narrowing.
All analyses were performed using SPSS software,
version 16.0 and the SAS package, version 9.1.3. P values less
than 0.05 were considered significant.
RESULTS
Differences in values of disease activity core set
variables among patients in DAS28 remission with and
without residual joint swelling. Table 1 presents the
baseline characteristics of the 864 MTX-treated patients
that we studied. Of these, 114 (13.2%) achieved a state
of DAS28 remission (DAS286–12 ⬍2.6; mean ⫾ SD
2.0 ⫾ 0.4), among whom 22 (19.3%) showed residual
joint swelling (SJC6–12 ⱖ2); the median SJC6–12 in this
JOINT DAMAGE PROGRESSION IN DAS28 REMISSION
3705
Table 2. Average values of core set variables during months 6–12 among patients in persistent DAS28
remission (mean DAS28 ⬍2.6 during months 6–12)*
Core variable
SJC ⬍2 (n ⫽ 92)
SJC ⱖ2 (n ⫽ 22)
P
SJC, 0–28
TJC, 0–28
PGA, 0–100 mm
EGA, 0–100 mm
CRP, mg/dl
ESR, mm/hour
DAS28
SDAI
CDAI
HAQ score, 0–3
0.4 ⫾ 0.5
0.7 ⫾ 1.1
9.8 ⫾ 11.4
7.8 ⫾ 8.1
0.62 ⫾ 0.59
12.0 ⫾ 8.1
2.0 ⫾ 0.5
3.5 ⫾ 2.4
2.9 ⫾ 2.4
0.21 ⫾ 0.36
3.6 ⫾ 1.32
0.8 ⫾ 1.0
13.4 ⫾ 10.3
13.1 ⫾ 8.7
0.51 ⫾ 0.41
6.4 ⫾ 3.6
2.1 ⫾ 0.3
7.5 ⫾ 2.5
7.0 ⫾ 2.4
0.21 ⫾ 0.29
⬍0.0001
0.74
0.16
0.008
0.42
⬍0.002
0.27
⬍0.0001
⬍0.0001
0.992
* Values are the mean ⫾ SD. DAS28 ⫽ Disease Activity Score in 28 joints; SJC ⫽ swollen joint count;
TJC ⫽ tender joint count; PGA ⫽ patient’s global assessment of disease activity; EGA ⫽ evaluator’s
global assessment of disease activity; CRP ⫽ C-reactive protein; ESR ⫽ erythrocyte sedimentation rate;
SDAI ⫽ Simplified Disease Activity Index; CDAI ⫽ Clinical Disease Activity Index; HAQ ⫽ Health
Assessment Questionnaire.
Structural progression as a function of DAS28
remission status and joint swelling. Table 3 shows that
the proportion of patients without progression of joint
damage (change in score ⬍0.5) was significantly higher
in DAS28 remitters without residual joint swelling than
in those with residual swelling. In accordance with these
data, the medians tended to be lower in the former
group than in the latter (P ⫽ 0.1); comparing the means
by t-test also revealed a significant difference among the
groups (data not shown). Taken together, these results
imply that DAS28 remission alone, even over a period of
6 months, is not sufficient to halt radiographic progression; patients need to be further evaluated for the level
of residual joint swelling, which is a key driver of
progression, even if the DAS28 is ⬍2.6.
The importance of joint swelling is further supported by the investigation of patients who did not
achieve DAS28 remission. Among these patients with a
mean DAS286–12 of ⱖ2.6, those without joint swelling
experienced only little progression of joint destruction
group was 3.7, with 25% of patients exceeding 4 swollen
joints to a maximum of 6. Patients in DAS28 remission
without residual joint swelling had significantly lower
disease activity levels by SDAI and CDAI than did those
with swelling (mean ⫾ SD SDAI 3.5 ⫾ 2.4 versus 7.5 ⫾
2.5, mean ⫾ SD CDAI 2.9 ⫾ 2.4 versus 7.0 ⫾ 2.4; P ⬍
0.0001 for both). These higher levels were not solely due
to the differences in SJC, but were also a consequence of
higher levels of evaluator’s global assessment and, by
trend, of patient’s global assessment (Table 2). Interestingly, TJCs were similar between these 2 groups, and
ESR was even significantly lower in patients with higher
joint counts (P ⬍ 0.002); in other words, because the
ESR is highly weighted in the DAS28, and SJC and
patient’s global assessment have only low weights (43), a
lower level of ESR (even within the normal range)
allowed for much higher levels of SJC and patient’s
global assessment, while a disease activity state reflected
by a DAS28 ⬍2.6 was still maintained. HAQ scores at 1
year were similar in both groups.
Table 3. Average increase in total SHS and percent of those with progression of joint damage (change in SHS ⬎0.5) over year
1 in the methotrexate-treated patient groups of the analyzed trials*
Patients with
progression, %
Patients in DAS28 remission
SJC ⬍2
SJC ⱖ2
Patients not in DAS28 remission
SJC ⬍2
SJC ⱖ2
P†
27
50
0.039
40
56
⬍0.001
Total SHS increase,
mean ⫾ SD
Total SHS increase,
median (IQR)
0.2 ⫾ 2.6
2.2 ⫾ 4.2
0 (0, 0.5)
0.6 (⫺0.3, 4.5)
1.1 ⫾ 4.2
2.8 ⫾ 11.5
0 (1.0, 1.5)
0.9 (0, 4.0)
P‡
0.110
⬍0.001
* SHS ⫽ Sharp/van der Heijde score; IQR ⫽ interquartile range; DAS28 ⫽ Disease Activity Score in 28 joints; SJC ⫽ swollen
joint count.
† By chi-square test.
‡ By Wilcoxon test.
3706
ALETAHA AND SMOLEN
Figure 1. Structural progression as a function of Disease Activity Score in 28 joints
(DAS28) remission (REM) status and residual joint swelling. DAS28 remission is
defined as a mean DAS28 at the 6-, 9-, and 12-month visits of ⬍2.6 (DAS28
nonremission [NONREM] is defined as a mean DAS28 of ⱖ2.6), while the presence or
absence of residual joint swelling is defined as a mean swollen joint count over the same
period of ⱖ2 or ⬍2, respectively. Analyses were performed in the patient group treated
with methotrexate. The graph shows individual data points for the 4 groups, using
probability plots of radiographic progression according to residual swelling. P ⫽ 0.11 for
comparison of groups with disease in remission; P ⫽ 0.0003 for comparison of groups
with disease not in remission, by Wilcoxon test.
when compared to nonremitters with joint swelling
(Table 3). Similarly, the proportion of patients with
radiographic progression was significantly higher in
those with than in those without residual joint swelling.
In fact, as can be appreciated from Table 3 and Figure 1,
progression was similar in individuals with residual joint
swelling regardless of whether patients were in DAS28
remission or not (median progression 0.63 versus 0.91,
respectively). Importantly, among patients without residual joint swelling there was no difference in radiographic progression between those who attained DAS28
remission and those who did not. This further supports
the notion that the reduction in SJC rather than the
DAS28 remission state is important in interfering with
progression of joint damage.
When we evaluated radiographic progression between 6 months and 12 months (instead of between 0
months and 12 months), we found a similar result.
DAS28 remitters over the same period (mean
DAS286–12 ⬍2.6, as used in the main analysis) without
residual joint swelling (SJC6–12 ⬍2) also had a lower rate
of progression compared to those with residual joint
swelling (15.2% versus 38.9%; P ⫽ 0.022) and a lower
average/median progression (mean ⫾ SD 0 ⫾ 0.8 versus
0.7 ⫾ 2.5) (median 0.0 versus 0.3) (P ⫽ 0.042 by
Wilcoxon test).
Comparative analyses using other scores. Remission was then defined by the SDAI and CDAI criteria.
Fifty-two patients (6.0%) had SDAI remission (SDAI
ⱕ3.3; mean ⫾ SD 1.8 ⫾ 0.8), with a mean ⫾ SD SJC of
0.3 ⫾ 0.4 for the 6–12-month period; 60 patients (6.9%)
had CDAI remission (CDAI ⱕ2.8; mean ⫾ SD 1.4 ⫾
0.8), with a mean ⫾ SD SJC of 0.4 ⫾ 0.5. The mean ⫾
SD SJCs in these patient groups were therefore very
JOINT DAMAGE PROGRESSION IN DAS28 REMISSION
3707
Figure 2. Comparative analyses using other scores. Radiographic progression in different groups is presented in a manner analogous to that in Figure 1. There is no difference
in progression between patients in remission (REM) according to the Disease Activity
Score in 28 joints (DAS28), Simplified Disease Activity Index (SDAI), and Clinical
Disease Activity Index (CDAI) if patients with DAS28 remission are limited to those
without residual joint swelling. P ⫽ 0.66 across all 3 groups, by Kruskal-Wallis test. Color
figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.
com/journal/10.1002/(ISSN)1529-0131.
similar to that seen in the subgroup of patients with
DAS28 remission and SJC ⬍2 (0.4 ⫾ 0.5) (Table 2). In
contrast to the DAS28-based definition of remission, no
patient in SDAI or CDAI remission can possibly have
more than 2 swollen joints, simply by the nature of the
respective formula and cut points. Consequently, the
average number of swollen joints of all patients in
DAS28 remission (mean ⫾ SD SJC6–12 1.0 ⫾ 1.0) was
significantly higher than that of all patients in either
SDAI or CDAI remission (P ⬍ 0.0001 for both comparisons), as was the mean TJC, patient’s global assessment,
and evaluator’s global assessment (P ⬍ 0.0001 for each)
(detailed data not shown).
Similarly, while HAQ scores were low among
patients in DAS28 remission (mean ⫾ SD 0.21 ⫾ 0.35),
they were considerably lower among patients in SDAI
remission (0.09 ⫾ 0.18) (P ⫽ 0.0023) and CDAI remission (0.12 ⫾ 0.26) (P ⫽ 0.057). Given that the majority
of the analyzed patients had early disease and therefore
mostly fully reversible impairment of physical function,
this implies that physical function essentially normalizes
in SDAI and CDAI remission, while there is a slight
residual disability in DAS28 remission, potentially reflecting the higher joint counts and global assessments as
shown above. Finally, among patients in SDAI and
CDAI remission, joint damage progressed by a mean ⫾
SD of only ⫺0.07 ⫾ 0.56 and 0.16 ⫾ 0.49, respectively—
degrees almost identical to that seen in the subgroup of
DAS28 remitters who had no residual joint swelling
(P ⫽ 0.66) (Figure 2 and Table 4), and the proportion of
3708
ALETAHA AND SMOLEN
Table 4. Analysis using other treatment groups, cut points, and radiographic time points, and using the radiographic
subscales*
Analysis type,
swelling status (n)
Main analysis (base case)§
No swelling (92)
Swelling (22)
Anti-TNF¶
No swelling (59)
Swelling (16)
Anti-TNF ⫹ MTX#
No swelling (201)
Swelling (31)
Increased stringency of remission**
No swelling (81)
Swelling (17)
SJC cut point ⫽ 1††
No swelling (114)
Swelling (75)
SJC cut point ⫽ 3‡‡
No swelling (165)
Swelling (24)
Erosion score§§
No swelling (151)
Swelling (38)
JSN score¶¶
No swelling (151)
Swelling (38)
Patients with progression
(change in SHS ⬎0.5), %
P†
Total SHS increase,
mean ⫾ SD
Total SHS increase,
median (IQR)
P‡
27
50
0.039
0.2 ⫾ 2.6
2.2 ⫾ 4.2
0 (0, 0.5)
0.6 (⫺0.3, 4.5)
0.110
27
63
0.008
⫺1.4 ⫾ 7.3
0.5 ⫾ 0.9
0 (⫺1.0, 0.5)
0.5 (0.0, 1.0)
0.009
31
29
0.796
⫺0.1 ⫾ 3.1
⫺0.5 ⫾ 2.4
0 (⫺1.0, 0.6)
0 (⫺1.4, 0.6)
0.600
25
53
0.020
0.0 ⫾ 2.7
0.6 ⫾ 2.5
0 (⫺0.3, 0.3)
0.5 (0, 1.0)
0.103
28
40
0.087
⫺0.6 ⫾ 5.6
0.8 ⫾ 3.1
0 (0, 0.5)
0 (⫺0.3, 1.0)
0.185
30
50
0.055
⫺0.3 ⫾ 5.0
1.4 ⫾ 2.8
0 (⫺0.3, 0.5)
0.4 (0, 1.9)
0.028
27
50
0.007
⫺0.1 ⫾ 3.2
1.1 ⫾ 3.0
0 (0, 0.5)
0.4 (0, 1.0)
0.007
9
29
0.001
⫺0.3 ⫾ 2.1
0.3 ⫾ 1.7
0 (0, 0)
0 (0, 0.5)
0.104
* One or more items of the main analysis are modified in each analysis. IQR ⫽ interquartile range.
† By chi-square test.
‡ By Wilcoxon test.
§ Methotrexate (MTX) subgroup; total Sharp/van der Heijde score (SHS); remission defined as a Disease Activity Score in 28
joints (DAS28) from month 6 through month 12 of ⬍2.6; swollen joint count (SJC) cut point ⫽ 2; total of 864 patients; 114
patients (13%) in DAS28 remission.
¶ Anti–tumor necrosis factor (anti-TNF) subgroup; total of 407 patients; 75 patients (18%) in DAS28 remission.
# Anti-TNF plus MTX subgroup; total of 740 patients; 232 patients (31%) in DAS28 remission.
** Pooled MTX only/anti-TNF only; all visits in DAS28 remission; total of 1,271 patients; 98 patients (8%) in DAS28 remission.
†† Pooled MTX only/anti-TNF only; SJC cut point ⫽ 1; total of 1,271 patients; 189 patients (15%) in DAS28 remission.
‡‡ Pooled MTX only/anti-TNF only; SJC cut point ⫽ 3; total of 1,271 patients; 189 patients (15%) in DAS28 remission.
§§ Pooled MTX only/anti-TNF only; erosion score used instead of total SHS; total of 1,271 patients; 189 patients (15%) in
DAS28 remission.
¶¶ Pooled MTX only/anti-TNF only; joint space narrowing (JSN) score used instead of total SHS; total of 1,271 patients; 189
patients (15%) in DAS28 remission.
patients with progression did not differ significantly
among these 3 groups (32.7% versus 35.0% versus
27.2%, SDAI remitters, CDAI remitters, and DAS28
remitters without swelling, respectively; P ⫽ 0.56 by
chi-square test).
Analysis of patients treated with TNF inhibitors.
TNF inhibitors in combination with MTX have a considerable impact on radiographic progression, a major
reason for the selection of the MTX-treated patients as
the analysis group for identifications of associations.
Indeed, in the group receiving MTX in combination with
a TNF inhibitor (n ⫽ 740), there was virtually no
difference from the results obtained in the MTX monotherapy group (base case), since progression was totally
halted in both DAS28 remission groups (Table 4). In
contrast, analysis of the smaller subgroup of patients
treated with TNF blocker monotherapy (n ⫽ 407)
showed associations with progression similar to those
seen with MTX monotherapy (Table 4), revealing a
significant difference in the proportion of patients with
progression (27% versus 63%; P ⬍ 0.01) and in average
progression between patients with and those without
joint swelling in DAS28 remission (mean ⫾ SD 0.5 ⫾ 0.9
versus ⫺1.4 ⫾ 7.3, respectively) (median 0.5 versus 0,
respectively) (P ⬍ 0.01 by Wilcoxon test); this is consistent with previous observations that monotherapy
with TNF inhibitors has less effect on structural damage
than does therapy combining TNF blockers with MTX
(27–29).
Additional analyses. Effects of stringent definition
of sustained remission. In our main analysis, we used the
average DAS28 from 6–12 months to assess remission.
JOINT DAMAGE PROGRESSION IN DAS28 REMISSION
When using an “all-in-remission” definition (i.e., all
visits with DAS28 ⬍2.6), a significantly higher proportion of patients with residual joint swelling still had
progression as opposed to those without residual joint
swelling (52.9% versus 24.7%; P ⫽ 0.02) (Table 4).
Modifying the cut point for “absence of joint swelling.” An additional sensitivity analysis showed that a
similar association of residual joint swelling with radiographic joint progression in DAS28 remitters could be
seen if a cut point of 1 or 3 was used (instead of the cut
point of 2) for defining presence or absence of residual
swelling. In both analyses, the results of the main
analysis were generally confirmed (Table 4).
Erosion and joint space narrowing subscales of
radiographic scores. Finally, we performed a separate
analysis of joint space narrowing and erosions to learn if
the residual swelling would affect one feature of joint
damage more than the other. As shown in Table 4, the
lower progression in DAS28 remitters without joint
swelling was generally confirmed for both features,
erosions and joint space narrowing.
DISCUSSION
In the present study we showed that ⬃1 in 5 RA
patients who achieved sustained DAS28 remission with
MTX treatment had average residual SJCs of ⱖ2, some
even up to an average number of 6 swollen joints. The
hypothesis that the DAS28 does not provide sufficiently
stringent remission criteria was further substantiated by
the fact that among patients in DAS28 remission who
had residual joint swelling, joint damage progressed
significantly despite a state of DAS28 remission over 6
months. Regardless of the definition of nonswelling,
radiographic progression in DAS28 remission was minimized only if patients were in the nonswelling group.
This was also the case for patients in remission by the
SDAI and CDAI, who by definition had joint counts of
ⱕ2. The same observations were made in patients
remaining in DAS28 remission from month 6 to month
12, whether radiographic progression was assessed for
the whole first year or only for the 6–12-month period.
This indicates that not only the initial period of higher
disease activity, but also the period during which the
residual swelling occurred, was important. Not only do
these data support the well-known notion that joint
swelling is a crucial feature of RA and a highly important
prognostic factor for radiographic progression (4,6), but
they also suggest that the presence of joint swelling even
trumps the prognostic value of achieving remission, at
least by the most commonly used index, the DAS28.
Interestingly, while disability as assessed by the
3709
HAQ decreased to ⬃0.1 among patients in SDAI/CDAI
remission, it was—although still low—significantly
higher in DAS28 remission, i.e., ⬃0.2. A similar observation has also been made for the EuroQol 5-domain
instrument (44) value, which differed significantly from
the general population among RA patients in DAS28
remission, while values were normalized among those in
CDAI remission (45).
Therapy with TNF blockers plus MTX led to
similar inhibition of joint damage whether patients in
DAS28 remission did or did not have residual joint
swelling; this is consistent with earlier observations on
the reduction of the dependence of joint damage on the
inflammatory response (dissociation) upon therapy with
TNF inhibitor plus MTX (35,37). Importantly, in the
small group of patients treated with TNF inhibitor
monotherapy, there was still an observable difference,
which suggests that such dissociation does not take place
upon TNF inhibition without the use of MTX.
Several limitations of our study need to be borne
in mind when interpreting the data. First, this was a post
hoc analysis in which the outcomes assessed did not
constitute primary end points, although the data came
from patients enrolled in randomized controlled trials
who were starting MTX therapy. Second, the MTX trial
arms from several studies were pooled. However, this
was necessary to obtain a critical number of patients in
DAS28, SDAI, and CDAI remission; moreover, it may
not necessarily be disadvantageous to evaluate patients
coming from trials with slightly different inclusion criteria and different populations, as the heterogeneity adds
to the generalizability of the results. Further, the sensitivity analyses using more or less stringent cut points for
joint counts further supported our findings, although
some of these analyses showed differences only by trend
due to low numbers and consequently low power.
Undoubtedly, it is of utmost importance to
achieve a good clinical state, ideally remission, in patients with RA, and it has been shown that this is more
effective for reducing progression of joint damage and
restoring physical function than just achieving improvement, even by an ACR70 response (46). Indeed, clinical
remission should ideally be accompanied by structural
and functional remission (i.e., no progression of joint
damage and maximal reduction of physical disability).
However, in our study, we have shown not only that a
large proportion of patients in DAS28 remission have a
significant number of residual swollen joints, but also
that this is in particular a determinant of progression of
joint damage. In accordance with observations that
DAS28 remission rates often exceed the proportions
of patients attaining ACR70 and even ACR50 responses
3710
ALETAHA AND SMOLEN
(14,27,47,48), these data indicate that more stringent
criteria are needed for the definition of remission, and
these have in fact been published very recently (40,41).
Importantly, in this definition the present SDAI and
CDAI cutoffs for remission have been maintained.
The conclusion from our study is that DAS28
remission is strict with regard to serologic markers of
inflammation but less strict with regard to clinical markers of inflammation, the latter of which seem to carry
greater significance regarding structural progression.
Our study confirms that patients in DAS28 remission
but with residual joint swelling do not experience slowing or arrest of structural progression.
7.
8.
9.
10.
11.
ACKNOWLEDGMENTS
We thank Abbott, Amgen, Centocor, and Wyeth,
which was acquired by Pfizer in October 2009, for kindly
providing the data from their clinical trials.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Aletaha 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.
Study conception and design. Aletaha, Smolen.
Acquisition of data. Aletaha, Smolen.
Analysis and interpretation of data. Aletaha, Smolen.
12.
13.
14.
15.
16.
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