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Clinical remission andor minimal disease activity in patients receiving adalimumab treatment in a multinational open-label twelve-week study.

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Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 59, No. 1, January 15, 2008, pp 32– 41
DOI 10.1002/art.23247
© 2008, American College of Rheumatology
ORIGINAL ARTICLE
Clinical Remission and/or Minimal Disease
Activity in Patients Receiving Adalimumab
Treatment in a Multinational, Open-Label,
Twelve-Week Study
GERD R. BURMESTER,1 GIANFRANCO FERRACCIOLI,2 RENÉ-MARC FLIPO,3
INDALECIO MONTEAGUDO-SÁEZ,4 KRISTINA UNNEBRINK,5 SONJA KARY,5
AND
HARTMUT KUPPER5
Objective. To evaluate the effect of adalimumab treatment on clinical remission and/or minimal disease activity (MDA)
in 6,610 patients with active rheumatoid arthritis (RA) who were enrolled in the Research in Active RA trial, a
multinational, open-label, 12-week study with an optional extension period.
Methods. Clinical remission was defined as a Disease Activity Score in 28 joints (DAS28) <2.6, Simplified Disease
Activity Index (SDAI) score <3.3, or Clinical Disease Activity Index (CDAI) score <2.8. MDA required absence of tender
and swollen joints plus erythrocyte sedimentation rate (ESR) <10 mm/hour; DAS28 score <2.85; or achievement of 5 of
7 core criteria for pain, swollen/tender joints, physical function, physician/patient global assessment, and ESR. Time to
and time in remission/MDA and response predictors were analyzed using Kaplan-Meier estimates and Cox proportional
hazards regression analysis, respectively.
Results. A total of 38%, 24%, and 27% of patients achieved remission defined as DAS28 <2.6, SDAI <3.3, and CDAI <2.8,
respectively. MDA was observed in 45% of patients by DAS28 <2.85, in 43% by the core set of criteria, and in 13% by
absence of tender/swollen joints plus ESR <10 mm/hour. Median times in continuous remission and MDA were 3.4 and
4.4 months, respectively. Predictors for remission (DAS28 <2.6) and MDA (DAS28 <2.85) were male sex; younger age;
concomitant disease-modifying antirheumatic drug use; lower baseline DAS28, CRP concentration, and Health Assessment Questionnaire disease index score; <1 comorbidity; and tumor necrosis factor antagonist naivety.
Conclusion. During adalimumab treatment, 25% of patients experienced clinical remission and nearly half achieved
MDA. To our knowledge, this analysis represents the largest prospective clinical trial data set to be assessed using
Outcome Measures in Rheumatology Clinical Trials MDA criteria.
INTRODUCTION
Since the introduction of biologic response modifiers that
inhibit tumor necrosis factor (TNF), the expectations of
medical treatment for active rheumatoid arthritis (RA)
have changed markedly. Several clinical trials have demonstrated the efficacy of TNF antagonists (adalimumab,
etanercept, and infliximab) in significantly reducing disClinicalTrials.gov identifier: NCT00448383.
Supported by a grant from Abbott GmbH & Co. KG, Ludwigshafen, Germany. Dr. Burmester’s work was supported
by Abbott, Schering-Plough, Wyeth, and Roche.
1
Gerd R. Burmester, MD: Charité University Medicine
Berlin, Berlin, Germany; 2Gianfranco Ferraccioli, MD:
Catholic University of Rome, Rome, Italy; 3René-Marc
Flipo, MD: University Hospital, Lille, France; 4Indalecio
Monteagudo-Sáez, MD: Hospital General Universitario Gregorio Marañón, Madrid, Spain; 5Kristina Unnebrink, PhD,
Sonja Kary, MD, MA, Hartmut Kupper, MD: Abbott GmbH &
Co. KG, Ludwigshafen, Germany.
32
ease activity and limiting progression of joint destruction
and subsequent disability in patients with RA (1– 4). Appropriate management of RA requires more than the assessment of relative improvement or change in signs and
symptoms. Being able to assess the actual state of disease
Dr. Burmester has received consultant fees, speaking
fees, and honoraria (more than $10,000 each) from Abbott,
Schering-Plough, Wyeth, and Roche. Dr. Ferraccioli has received consultancy fees and speaking fees (less than $10,000
each) from Abbott, Wyeth, and Schering-Plough. Dr. Unnebrink holds stock options in Abbott. Dr. Kary is a contractor
for Abbott (Germany). Dr. Kupper holds stock options in
Abbott.
Address correspondence to Gerd R. Burmester, MD, Department of Rheumatology and Clinical Immunology,
Charité University Medicine Berlin, Charitéplatz 1, 10117
Berlin, Germany. E-mail: gerd.burmester@charite.de.
Submitted for publication March 19, 2007; accepted in
revised form June 15, 2007.
Clinical Remission and MDA in RA
activity is important in making informed treatment decisions (5–9).
The general therapeutic goal in RA is to obtain a state of
low disease activity, or even clinical remission, thereby
preventing further joint destruction with optimal treatment. Historically, several criteria for assessing clinical
remission have been developed (10,11). The definition and
therapeutic usefulness of clinical remission or of low disease activity/minimal disease activity (MDA) is complex
and recently has been the subject of intense discussion
(12–19). One well-established definition is achievement of
a disease activity score ⬍2.6 based on the erythrocyte
sedimentation rate (ESR) and Disease Activity Score in 28
joints (DAS28) assessment (5,20,21). Because the DAS28
threshold can be achieved by patients who may be quite
symptomatic in the few joints that are swollen, a more
restrictive DAS28 score limit of ⬍2.4 has been proposed
but not widely accepted (22,23). Furthermore, 2 other criteria for identifying clinical remission, Simplified Disease
Activity Index (SDAI) and Clinical Disease Activity Index
(CDAI) cut points of ⱕ3.3 and ⱕ2.8, respectively, are also
being investigated and applied in clinical practice
(22,24,25).
The concept of MDA, which aims for an acceptable state
of RA that is near remission and is adequate for many
patients, has been developed by the Outcome Measures in
Rheumatology Clinical Trials (OMERACT) MDA working
group (26). By definition, the OMERACT MDA criteria
include clinical remission as well as a state of low disease
activity. In a stepwise process, the proposed OMERACT
definition for identifying MDA first considers all patients
who have a tender joint count (TJC) of 0 and a swollen
joint count (SJC) of 0 plus an ESR ⱕ10 mm/hour; this state
of RA is, in fact, clinical remission. In the second step,
patients are considered in MDA either when a DAS28
score ⱕ2.85 is achieved or, alternatively, when 5 of the 7
following core criteria are met: pain score ⱕ2 on a 0 –10
visual analog scale (VAS), SJC ⱕ1 in a 28-joint assessment,
TJC ⱕ1 in a 28-joint assessment, Health Assessment Questionnaire (HAQ) disability index (DI) score ⱕ0.5 on a 0 –3
scale, physician global assessment of disease activity ⱕ1.5
on a 0 –10 VAS, patient global assessment of disease activity ⱕ2 on a 0 –10 VAS, and ESR ⱕ20 mm/hour.
The recently completed Research in Active RA (ReAct)
trial provides a large database of 6,610 patients who received adalimumab, a fully human monoclonal antibody
against TNF, in an open-label study designed to mimic
rheumatologic care in typical clinical practices (27,28). We
analyzed the percentage of patients in the ReAct trial who
achieved remission or MDA by different scores, the time
until remission or MDA after the initiation of adalimumab
treatment, and the time in sustained remission or MDA.
Also, we investigated possible predictors for achievement
and maintenance of clinical remission and MDA.
MATERIALS AND METHODS
Ethics. The ReAct trial was conducted in accordance
with principles of the Declaration of Helsinki and the
International Conference on Harmonization Guidelines for
33
Good Clinical Practice, and compliance with all local laws
and customs was ensured by the investigators. Written
informed consent was obtained from each participant before initiation of any study-related procedures.
Patients. The study was conducted in adult patients
with RA as defined by the 1987 revised criteria of the
American College of Rheumatology (formerly the American Rheumatism Association) (29). Eligible patients had
RA for ⱖ3 months; a DAS28 score ⱖ3.2, indicating at least
moderate disease activity (20); and treatment failure with
at least 1 traditional disease-modifying antirheumatic drug
(DMARD). Patients were allowed to continue their current
antirheumatic therapy if the treatment regimen was not
modified until week 12. Previous or concurrent treatment
with alkylating agents was not allowed.
Study design. All patients self-administered a subcutaneous injection of adalimumab 40 mg (Abbott Laboratories, Abbott Park, IL) every other week during this 12week, open-label, multicenter study. After the initial
12-week phase, patients could enter an optional extension
until adalimumab became commercially available. Subsequently, patients could also enter an ongoing postmarketing observational study for up to 5 years. Patients who had
received adalimumab without combination DMARD use
and did not achieve at least a moderate response according
to the European League Against Rheumatism response criteria (30) at week 12 could change to weekly injections of
adalimumab. Efficacy and routine safety evaluations were
conducted at weeks 2, 6, and 12, and every 8 weeks thereafter.
Statistical analysis. Clinical remission was defined as
achieving a DAS28 score ⬍2.6, an SDAI score ⱕ3.3, or a
CDAI score ⱕ2.8. The SDAI consists of the sum of the
number of tender and swollen joints, a global assessment
of disease activity by both the patient and the clinician
(10-cm VAS), and C-reactive protein (CRP) concentration
in mg/dl (22). The CDAI refers to the same clinical variables as the SDAI but omits the CRP component.
MDA was evaluated using the preliminary OMERACT
definition as described by Wells and colleagues (26), although we did not perform the analyses in 2 consecutive
steps. All patients were entered into the evaluation of
actual clinical remission, defined as no tender or swollen
joint counts and an ESR ⬍10 mm/hour. Irrespective of the
result of this analysis, all patients were also included in
the analyses of MDA by either a DAS28 score ⱕ2.85 or 5 of
the 7 core set criteria as described earlier.
All measures were assessed at week 12 and at the last
individual observation for each patient, irrespective of the
point in time when the patient discontinued the study. In
addition, outcome criteria were assessed at any individual
time point during the treatment period. The percentage of
patients who fulfilled each outcome criterion was calculated using the total number of patients who had the required data available at the defined time points (observed
values) as the denominator. In addition, the percentage of
patients achieving remission or MDA at any time during
34
treatment was stratified by baseline patient characteristics
and treatment conditions.
Analyses of time to remission and time to MDA and of
time in remission and time in MDA (in patients who had
achieved remission) were limited to the respective DAS28
criteria. Kaplan-Meier survival estimates were used to
evaluate the median time from the first adalimumab injection to remission and to MDA. If remission or MDA had
not been achieved at the time of the last visit, the observation was censored in the Kaplan-Meier analysis. For
patients who reached remission, both the time in remission and the time in at least MDA after remission were
analyzed using Kaplan-Meier methods. The time in remission and the time in at least MDA were calculated from
time of remission to the first visit where remission (or
MDA) was lost (the “event” in the Kaplan-Meier analysis)
or to the last available visit. If remission (or MDA) was
ongoing at the time of the last visit, the observation was
censored in the Kaplan-Meier analysis.
Predictors of achievement and maintenance of remission or MDA were identified using Cox proportional hazards regression analysis. Again, remission and MDA for
this analysis were defined by the DAS28 criterion exclusively. Baseline characteristics entered into the model as
possible predictors were DAS28 score (ⱕ5.1, ⬎5.1–7, ⬎7),
CRP concentration (⬍20, ⱖ20 mg/liter), physical function
(HAQ DI score ⬍1, 1–⬍1.5, 1.5–⬍2, ⱖ2), rheumatoid factor (RF; positive/negative), age (⬍40 years, 40 –ⱕ65 years,
⬎65–ⱕ75 years, ⬎75 years), sex (male/female), smoking
history (never/ever), duration of RA (ⱕ1 year, ⬎1–2 years,
⬎2–5 years, ⬎5–10 years, ⬎10 years), number of previously failed DMARDs (1, 2, 3, 4, ⱖ5), history of treatment with etanercept and/or infliximab (yes/no), concomitant use of DMARDs (yes/no), concomitant use of glucocorticoids (yes/no), number of comorbidities (ⱕ1, ⬎1), and
time to remission (for sustained remission/MDA only)
(31–35). Finally, in a descriptive analysis, the DAS28
values for patients who achieved remission were followed
up to the last observation of each patient at study discontinuation.
RESULTS
A total of 6,610 patients were enrolled in the ReAct trial:
81% were female, 73% were RF positive, 74% were taking
at least 1 concomitant DMARD, and 71% were receiving
glucocorticoids. Additional baseline characteristics included a mean age of 54 years, mean disease duration of 11
years, mean DAS28 score of 6.0, and mean HAQ DI score of
1.64 (27). During the complete adalimumab treatment period, the mean exposure to adalimumab was 33.3 weeks
(maximum of 95.6 weeks), resulting in 4,210 patient-years
of adalimumab exposure. At week 12, 93% of enrolled
patients continued in the study. The overall withdrawal
rate was 20.8%, with 6.8% of patients withdrawing due to
lack of effectiveness (27). The number of patients in the
ReAct trial gradually decreased as adalimumab was approved for commercial use in participating countries. After 1 year, 1,257 patients remained in the study. The baseline characteristics of patients who discontinued the study
Burmester et al
Figure 1. Clinical remission and minimal disease activity (MDA)
at various time points in the Research in Active Rheumatoid
Arthritis (ReAct) trial. A, Percentage of patients achieving clinical
remission measured by Disease Activity Score in 28 joints
(DAS28), Simplified Disease Activity Index (SDAI), and Clinical
Disease Activity Index (CDAI). B, Percentage of patients achieving
MDA measured by Outcome Measures in Rheumatology Clinical
Trials criteria. Open bars ⫽ week 12; shaded bars ⫽ last observation; solid bars ⫽ any time. TJC ⫽ tender joint count; SJC ⫽
swollen joint count; ESR ⫽ erythrocyte sedimentation rate.
before week 52 were very similar to the baseline characteristics of patients who remained in the study after 1 year.
Statistically significant but clinically irrelevant differences
between the ⱖ1-year treatment subset versus the ⬍1-year
treatment subset were concomitant DMARD use (77% versus 73%), HAQ DI score (1.7 versus 1.6), mean number of
previous DMARDs (3.1 versus 2.7), mean duration of RA
(11 years versus 10 years), and mean age (54 years versus
53 years).
The median DAS28 score of all enrolled patients at their
last visit was 3.6; the first quartile DAS28 score at the last
visit was 2.6, indicating that one-quarter of all patients
discontinued the study nearly in remission. In the extension phase, 414 (6%) of 6,610 patients, most of whom were
Clinical Remission and MDA in RA
35
Table 1. Observed percentages of patients in remission or in minimal disease activity measured by various scores at any time
during adalimumab treatment*
Clinical remission
Subgroup
All patients (n ⫽ 6,473)‡
Baseline DAS28 score
ⱕ5.1 (n ⫽ 1,266)
⬎5.1 (n ⫽ 5,207)
⬎7.0 (n ⫽ 1,275)
Baseline C-reactive protein, mg/liter
⬍20 (n ⫽ 3,837)
ⱖ20 (n ⫽ 2,562)
Baseline HAQ DI score, 0–3
⬍1 (n ⫽ 1,092)
1–⬍1.5 (n ⫽ 1,334)
1.5–⬍2 (n ⫽ 1,711)
ⱖ2 (n ⫽ 2,313)
Previous DMARD use, no.
ⱕ3 (n ⫽ 4,068)
⬎3 (n ⫽ 2,210)
Previous etanercept and/or infliximab use
Yes (n ⫽ 878)
No (n ⫽ 5,595)
Duration of rheumatoid arthritis, years
ⱕ5 (n ⫽ 1,973)
⬎5 (n ⫽ 4,466)
Rheumatoid factor
Positive (n ⫽ 4,714)
Negative (n ⫽ 1,748)
Age, years
⬍40 (n ⫽ 980)
40–ⱕ65 (n ⫽ 4,046)
⬎65–ⱕ75 (n ⫽ 1,222)
⬎75 (n ⫽ 225)
Sex
Male (n ⫽ 1,246)
Female (n ⫽ 5,227)
Comorbidities, no.§
ⱕ1 (n ⫽ 3,991)
⬎1 (n ⫽ 2,482)
Concomitant DMARD use, no.
0 (n ⫽ 1,672)
ⱖ1 (n ⫽ 4,801)
ACR50 response at week 6
Yes (n ⫽ 1,699)
No (n ⫽ 4,345)
Minimal disease activity
DAS28
<2.6
SDAI
<3.3
CDAI
<2.8
No TJC or SJC and
ESR <10 mm/hour
DAS28
<2.85
5 of 7 core
criteria†
38
24
27
13
45
43
63
32
18
37
21
14
39
24
16
25
11
6
72
39
24
62
38
26
44
29
28
19
29
23
16
10
51
37
46
38
58
47
37
25
42
31
22
14
43
34
24
17
23
16
13
8
65
54
44
32
67
54
41
27
42
31
28
17
31
19
16
10
49
34
48
34
26
40
13
26
15
29
7
14
31
48
27
45
43
36
30
22
33
24
17
12
49
44
48
40
37
42
23
27
26
29
12
17
44
49
42
44
51
39
29
26
34
24
20
17
37
26
21
19
23
13
8
7
58
46
36
28
57
43
35
27
46
36
27
24
30
26
19
12
52
44
48
42
43
31
27
20
30
21
16
9
50
38
48
35
28
42
18
27
20
29
9
15
35
49
34
46
63
29
49
14
54
17
26
9
72
36
74
32
* DAS28 ⫽ Disease Activity Score in 28 joints; SDAI ⫽ Simplified Disease Activity Index; CDAI ⫽ Clinical Disease Activity Index; TJC ⫽ tender joint
count; SJC ⫽ swollen joint count; ESR ⫽ erythrocyte sedimentation rate; HAQ DI ⫽ Health Assessment Questionnaire disability index; DMARD ⫽
disease-modifying antirheumatic drug; ACR50 ⫽ American College of Rheumatology 50% improvement criteria (44).
† Fulfillment of 5 of the following 7 core criteria: pain score ⱕ2 (0 –10 visual analog scale), swollen joint count ⱕ1 (0 –28 joints), tender joint count
ⱕ1 (0 –28 joints), HAQ DI score ⱕ0.5 (0 –3), physician global assessment of disease activity ⱕ1.5 (0 –10), patient global assessment of disease activity
ⱕ2 (0 –10 visual analog scale), and ESR ⱕ20 mm/hour.
‡ n ⫽ number of patients with available DAS28 data; other subgroups have slightly different numbers of patients and are not shown but can be provided
upon request.
§ Includes valvular heart disease, congestive heart failure, ischemic heart disease, hypertension, liver disease, peptic ulcer disease, kidney disorder,
diabetes mellitus, hyperlipidemia, hypothyroidism, osteoarthritis, osteoporosis, cerebral vascular accident, depression, asthma, emphysema/chronic
obstructive pulmonary disease, past tuberculosis, past pneumonia, and drug allergies/reactions.
receiving adalimumab monotherapy, underwent dose escalation to adalimumab 40 mg weekly. For these patients,
the first quartile DAS28 score 16 weeks after dose increase
was 3.4, indicating that only some of these patients experienced remission/MDA after dose increase.
Clinical remission and MDA at various time points. At
week 12, a total of 1,187 (20%) of 6,051 patients were in
remission as measured by a DAS28 score ⬍2.6, and 1,494
(25%) of 6,051 were in a state of MDA as measured by a
DAS28 score ⱕ2.85. Compared with week 12, higher per-
36
Burmester et al
Figure 2. Inverted Kaplan-Meier curves of time to first occurrence of clinical remission
(Disease Activity Score in 28 joints [DAS28] ⬍2.6; median 10.4 months) and of minimal
disease activity (MDA; DAS28 score ⱕ2.85; median 8.2 months). * Number of patients still
under observation excluding those who already achieved remission. ⫹ Number of patients
still under observation excluding those who already achieved MDA. Solid line ⫽ time to
MDA; broken line ⫽ time to remission.
centages of patients achieved both definitions of response
at the last observation (25% and 31%, respectively) and at
any time during adalimumab treatment (38% and 45%,
respectively) (Figure 1).
With respect to clinical remission by the SDAI score
ⱕ3.3 and CDAI score ⱕ2.8 definitions, 11% of patients met
the threshold for each measure of remission at week 12.
Similar to the DAS28 results, the percentages of patients
meeting the SDAI and CDAI remission criteria increased at
the last observation and at any time during the study
(Figure 1A). MDA was observed in 43% of patients according to the core set of criteria at any time during adalimumab treatment, compared with 24% and 30% at week
12 and the last observation, respectively. Absence of tender/swollen joints plus ESR ⱕ10 mm/hour resulted in the
lowest percentage of patients achieving MDA at all time
points (5% of all patients at week 12, 7% of all patients at
the last observation, and 13% at any time) (Figure 1B). In
addition, the remission and MDA data as achieved at any
time during the study were stratified by baseline patient
and treatment characteristics (Table 1). Irrespective of the
assessment method, patients with lower baseline DAS28
score, HAQ DI score, CRP concentration, age, and number
of previous DMARDs and who were TNF antagonist naive
and RF negative were more likely to achieve remission/
MDA. These univariate analyses were then scrutinized
using the Cox proportional hazards regression model.
Time to clinical remission or time to MDA and predictors for response. For all patients enrolled, the KaplanMeier estimates were 10.4 months (95% confidence interval [95% CI] 10.1–11.7) for median time to remission and
8.2 months (95% CI 7.2– 8.3) for MDA (Figure 2). In the
38% and 45% of all patients who achieved remission or
MDA during adalimumab therapy, the median time to
response was 2.8 months for both measures (mean 3.7
months and 3.4 months, respectively). We identified the
following predictors for clinical remission response by
Cox regression: lower baseline HAQ DI score, lower baseline DAS28 score, younger age, male sex, concomitant
DMARD treatment, lower CRP concentration, ⱕ1 comorbidity, and no previous TNF antagonist treatment (Table
2). The predictors for MDA were identical with the addition of a weak positive impact of never smoking and fewer
previous DMARDs (data not shown).
Time in clinical remission or time in MDA and predictors of maintenance. Overall, of the patients who
achieved remission (DAS28 score ⬍2.6) during adalimumab treatment, 47% discontinued the study in a state
of remission and 55% discontinued the study in MDA
after a period of continuous remission or MDA. The
Kaplan-Meier estimate for median time in continuous remission was 3.4 months (95% CI 3.2–3.7) (Figure 3). Similarly, the median time that patients remained in at least
continuous MDA following remission was 4.4 months
(95% CI 4.1–5.1). Twenty-five percent of patients remained in remission for at least 8.7 months (95% CI 7.3–
12.5).
The analysis of predictors for sustained remission, measured as hazard ratios for loss of remission, revealed that
the following factors were associated with a longer duration of remission: male sex, no previous TNF antagonist
treatment, younger age, and short time to clinical remission (Table 3). Additional factors predicting a longer time
in at least MDA after clinical remission (measured as time
to loss of MDA) were smoking (never), ⱕ1 comorbidity,
and low baseline HAQ DI score and DAS28 score, whereas
age had no significant impact on time in MDA after remission (data not shown).
Finally, the DAS28 values of those patients who experienced clinical remission (DAS28 score ⬍2.6) at any time
during adalimumab treatment were evaluated until patients discontinued the study. This patient subset entered
the study with a mean and median DAS28 score of 5.6. The
mean and median DAS28 scores at the last observation
were 2.5 and 2.3, respectively, indicating that more than
50% of this subset discontinued the study in a state of
clinical remission. At 8, 16, 24, and 32 weeks after the first
assessment of clinical remission, the observed mean and
Clinical Remission and MDA in RA
37
Table 2. Predictors of time to clinical remission (DAS28 score <2.6)*
Possible confounder
Baseline DAS28
⬎7 vs ⱕ5.1
⬎5.1–ⱕ7 vs ⱕ5.1
Baseline C-reactive protein, mg/liter
ⱖ20 vs ⬍20
Baseline HAQ DI score, 0–3
ⱖ2 vs ⬍1
1.5–⬍2 vs ⬍1
1–⬍1.5 vs ⬍1
Previous DMARD use, no.
ⱖ5 vs 1
4 vs 1
3 vs 1
2 vs 1
Previous etanercept and/or infliximab use
Yes vs no
Duration of rheumatoid arthritis, years
⬎10 vs ⱕ1
⬎5–10 vs ⱕ1
⬎2–5 vs ⱕ1
⬎1–2 vs ⱕ1
Rheumatoid factor
Positive vs negative
Age, years
⬎75 vs ⬍40
⬎65–ⱕ75 vs ⬍40
40–ⱕ65 vs ⬍40
Sex
Male vs female
Comorbidities, no.‡
⬎1 vs ⱕ1
Concomitant DMARD use, no.
ⱖ1 vs 0
Concomitant glucocorticoids (maximum
dosage 10 mg/day)
Yes vs no
Smoking history
Ever vs never
Hazard ratio
95% CI
P
0.265
0.504
0.225–0.311
0.459–0.553
⬍0.0001†
⬍0.0001
⬍0.0001
0.838
0.769–0.913
0.603
0.739
0.870
0.533–0.683
0.659–0.829
0.778–0.974
0.879
1.056
1.034
1.100
0.754–1.025
0.921–1.212
0.916–1.168
0.983–1.231
0.825
0.709–0.960
0.884
0.901
0.846
1.056
0.720–1.085
0.732–1.109
0.687–1.041
0.837–1.332
0.942
0.861–1.031
0.611
0.676
0.779
0.461–0.810
0.584–0.783
0.701–0.865
0.1943
⬍0.0001†
0.0006
⬍0.0001
⬍0.0001
1.284
1.160–1.422
⬍0.0001
0.853
0.780–0.932
0.0005
1.340
1.209–1.484
⬍0.0001
1.047
0.959–1.144
0.3034
1.076
0.987–1.174
0.0973
⬍0.0001
⬍0.0001†
⬍0.0001
⬍0.0001
0.0157
0.0443†
0.1004
0.4354
0.5872
0.0967
0.0126
0.0725†
0.2377
0.3248
0.1144
0.6462
* 95% CI ⫽ 95% confidence interval; see Table 1 for additional definitions.
† Overall P value for all subcategories.
‡ Includes valvular heart disease, congestive heart failure, ischemic heart disease, hypertension, liver
disease, peptic ulcer disease, kidney disorder, diabetes mellitus, hyperlipidemia, hypothyroidism, osteoarthritis, osteoporosis, cerebral vascular accident, depression, asthma, emphysema/chronic obstructive
pulmonary disease, past tuberculosis, past pneumonia, and drug allergies/reactions.
median DAS28 scores in 2,049, 1,639, 1,235, and 862
patients, respectively, were 2.5 and 2.4 at each time point.
DISCUSSION
The database from the ReAct trial presented an excellent
opportunity to investigate the effectiveness of adalimumab
on achievement of clinical remission and MDA in patients
with severe RA (mean baseline DAS28 score 6.0) (26,27).
Limitations of the study, including an open-label design
and a relatively short study duration, are balanced by a
large data set that was obtained in a study designed to
reflect usual clinical practice. In the current analyses, we
focused on the clinical aspects of remission or MDA dur-
ing adalimumab therapy and did not attempt to validate
the various assessment methods. A separate evaluation of
the various methodologic approaches will be published
separately.
Regardless of the assessment method, the percentage of
patients who met the remission or MDA requirements
increased after week 12. Dose escalation was rare during
the study and had no impact on the overall rate of remission/MDA. In general, clinical remission rates using the
SDAI and CDAI definitions were similar to each other but
were more restrictive than the DAS28 definition. We also
applied the new OMERACT concept of MDA, which encompasses a restrictive parameter (absence of tender/swollen joints plus normal ESR) that is indicative of remission,
38
Burmester et al
Figure 3. Kaplan-Meier curves for time in continuous remission (Disease Activity Score in
28 joints [DAS28] ⬍2.6; median 3.4 months) or in minimal disease activity (MDA; DAS28
score ⱕ2.85; median 4.4 months). * Number of patients still under observation excluding
those who already experienced loss of remission. ⫹ Number of patients still under observation excluding those who already experienced loss of MDA. Solid line ⫽ time in MDA
after remission; broken line ⫽ time in remission.
as well as 2 other definitions for an acceptable state of low
disease activity in which future joint damage can be prevented (26). The core set of MDA criteria tended to produce response profiles similar to the DAS28 score ⱕ2.85
requirement, whereas the strictest MDA definition yielded
fewer responders than the DAS28 definition of clinical
remission. Wells and colleagues (36) evaluated MDA outcomes in 2 abatacept studies. In their study of TNF antagonist–naive patients with RA, a lower percentage of patients
in MDA were reported at week 12 compared with our
study; however, this comparison is limited by differences
in study design (36).
Overall, results from the ReAct trial were consistent
with previous placebo-controlled, randomized clinical trials of adalimumab as a treatment for RA (37–39). The
remission rates documented for clinical studies of etanercept (40 – 42) and infliximab (4) are similar to or somewhat
lower than those observed in the ReAct trial; however,
differences in study design limit our ability to directly
compare the results of our study with results from randomized controlled studies. The 1-year remission rate associated with biologic treatment was 16% in the German biologics register (pooled data of 4 biologics, with 15% of
patients receiving adalimumab) (34). No data on remission
during adalimumab treatment have been published by the
British biologic register, but the remission rates for etanercept and infliximab were lower than in clinical studies
(32,33). The baseline characteristics of patients in the ReAct trial were similar to the patients in the German register
(34), whereas patients in the British register had notably
higher disease activity and worse physical function
(32,33). In general, a comparison between the studies is
limited by both different response assessments and different statistical methods used to assess predictors.
However, the results of our univariate subgroup analyses are similar overall to previously reported findings for
both biologic registry and clinical trial data (31–35,43).
Irrespective of the assessment method, patients with moderate RA activity achieved higher rates of remission/MDA
compared with patients with more severe RA. Moreover,
the percentage of patients meeting the most restrictive
MDA definition was substantially higher in patients who
were less disabled at baseline. In addition, patients who
achieved a rapid response to adalimumab treatment
achieved higher rates of clinical remission/MDA compared with nonresponders.
Although the median time to remission or MDA was ⬃3
months in patients who experienced remission/MDA,
other results, including the relatively low rate of remission/MDA observed in the analyses of week 12 data, indicate that many patients experienced remission or MDA
later in the course of adalimumab treatment.
Among other factors, younger age, male sex, less severe
RA, and concomitant DMARD therapy increased the likelihood of achieving clinical remission or MDA, whereas
the number of previous DMARDs, the duration of RA,
concomitant glucocorticoid therapy, and smoking history
had no influence. Overall, these findings were consistent
with the results published in the British register (33).
However, we did not assess the impact of nonsteroidal
antiinflammatory drug use in our analysis.
Remission is, in general, difficult to maintain in patients
with RA, particularly in patients with long-established
and severe RA (19). The mean adalimumab treatment duration of approximately 8 months in the ReAct trial restricts the evaluation of maintenance of remission/MDA,
but this period is comparable with published data (34,42).
In the German register, 7.7% of patients treated with antiTNF with a DAS28 score ⬍2.6 achieved this value after 6
months of treatment (34). In the Trial of Etanercept and
Methotrexate with Radiographic Patient Outcomes, 18%
of patients with a DAS28 score ⬍2.6 sustained this level of
response after 6 months of treatment with etanercept and
methotrexate (42). In the ReAct trial, approximately 50%
of patients who achieved remission experienced sustained
remission for a median of 3.4 months, and 25% experienced sustained remission for 7.5 months. We analyzed
the time in MDA after remission because MDA is consid-
Clinical Remission and MDA in RA
39
Table 3. Predictors of time to loss of clinical remission (DAS28 score >2.6)*
Possible confounder
Hazard ratio
95% CI
P
Time to remission (per month)
Baseline DAS28 score
⬎7.0 vs ⱕ5.1
⬎5.1–ⱕ7 vs ⱕ5.1
Baseline C-reactive protein, mg/liter
ⱖ20 vs ⬍20
Baseline HAQ DI score, 0–3
ⱖ2 vs ⬍1
1.5–⬍2 vs ⬍1
1–⬍1.5 vs ⬍1
Previous DMARD use, no.
ⱖ5 vs 1
4 vs 1
3 vs 1
2 vs 1
Previous etanercept and/or infliximab use
Yes vs no
Duration of rheumatoid arthritis, years
⬎10 vs ⱕ1
⬎5–10 vs ⱕ1
⬎2–5 vs ⱕ1
⬎1–2 vs ⱕ1
Rheumatoid factor
Positive vs negative
Age, years
⬎75 vs ⬍40
65–ⱕ75 vs ⬍40
40–ⱕ65 vs ⬍40
Sex
Male vs female
Comorbidities, no.‡
⬎1 vs ⱕ1
Concomitant DMARD use, no.
ⱖ1 vs 0
Concomitant glucocorticoid use (maximum
dosage 10 mg/day)
Yes vs no
Smoking history
Ever vs never
1.024
1.003–1.046
1.177
1.122
0.939–1.476
0.984–1.278
0.946
0.842–1.064
1.213
1.134
1.018
1.019–1.444
0.966–1.331
0.868–1.195
1.008
0.995
0.929
0.869
0.820–1.241
0.824–1.202
0.785–1.100
0.743–1.017
1.336
1.097–1.629
1.211
1.302
1.188
1.225
0.907–1.643
0.964–1.757
0.879–1.607
0.879–1.709
1.096
0.967–1.243
1.581
1.301
1.280
1.084–2.306
1.056–1.603
1.100–1.489
0.711
0.614–0.824
⬍ 0.0001
1.065
0.942–1.205
0.3136
0.975
0.844–1.126
0.7280
1.114
0.982–1.263
0.0924
1.104
0.980–1.243
0.1030
0.0243
0.1813†
0.1576
0.0857
0.3544
0.0950†
0.0302
0.1252
0.8250
0.3691†
0.9364
0.9604
0.3949
0.0794
0.0041
0.4865†
0.1884
0.0855
0.2627
0.2312
0.1525
0.0063†
0.0174
0.0136
0.0014
* 95% CI ⫽ 95% confidence interval; see Table 1 for additional definitions.
† Overall P value for all subcategories.
‡ Includes valvular heart disease, congestive heart failure, ischemic heart disease, hypertension, liver
disease, peptic ulcer disease, kidney disorder, diabetes mellitus, hyperlipidemia, hypothyroidism, osteoarthritis, osteoporosis, cerebral vascular accident, depression, asthma, emphysema/chronic obstructive
pulmonary disease, past tuberculosis, past pneumonia, and drug allergies/reactions.
ered an acceptable state from both a patient and physician
perspective. Half of the patients maintained at least MDA
for a median of 4.4 months. However, approximately onequarter of the patients discontinued in a state of remission
or MDA and could not be evaluated for long-term outcomes. The maintenance of remission was strongly dependent on male sex and, to a lesser degree, on a short time to
remission, the absence of previous TNF antagonist therapy, and younger age. By comparison, sustained MDA was
dependent not on age but on smoking history (never).
Consistent with previous reports, we found a strong relationship between male sex and achievement and maintenance of remission (32,43).
To our knowledge, this analysis represents the largest,
prospective clinical trial data set to be characterized using
the OMERACT criteria for MDA. Because remission is
difficult to maintain, the MDA data demonstrating the
benefit of adalimumab treatment should be of value to
rheumatologists treating patients with RA.
Depending on the assessment method, clinical remission was achieved in approximately one-quarter to more
than one-third of patients with active RA during adalimumab therapy in the ReAct trial. Nearly half of the patients experienced MDA as defined by OMERACT methods. Initiation of adalimumab treatment in combination
with DMARDs in patients who are less disabled and have
developed few comorbidities substantially increases the
likelihood of remission/MDA. Overall, more than half of
40
Burmester et al
the patients who had experienced remission at any time
during the study remained in remission at study end.
Throughout the complete course of adalimumab therapy,
at least MDA was sustained for a median of 4.4 months in
patients who achieved remission.
9.
10.
ACKNOWLEDGMENTS
Abbott thanks the physicians and staff members of all
study centers for having participated in ReAct. We thank
Dr. Uemit Oezer for medical support, Dr. David Webber
and Ina Reinhardt for study management, and Dana L.
Randall, MS, PharmD, for editorial assistance.
AUTHOR CONTRIBUTIONS
Dr. Burmester 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 design. Burmester, Unnebrink, Kupper.
Acquisition of data. Burmester, Monteagudo-Sáez, Unnebrink.
Analysis and interpretation of data. Burmester, Ferraccioli,
Flipo, Monteagudo-Sáez, Unnebrink, Kary, Kupper.
Manuscript preparation. Burmester, Flipo, Monteagudo-Sáez,
Unnebrink, Kary, Kupper.
Statistical analysis. Flipo, Unnebrink.
ROLE OF THE STUDY SPONSOR
Abbott GmbH & Co. KG collaborated with Drs. Burmester, Ferraccioli, Flipo, and Monteagudo-Sáez to design and conduct the
study. All authors analyzed the data, reviewed the manuscript
critically for important intellectual content, approved the final
draft, and agreed to its submission.
.
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