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Evaluation of the preliminary definitions of minimal disease activity and remission in an early seropositive rheumatoid arthritis cohort.

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Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 57, No. 3, April 15, 2007, pp 440 – 447
DOI 10.1002/art.22619
© 2007, American College of Rheumatology
ORIGINAL ARTICLE
Evaluation of the Preliminary Definitions of
Minimal Disease Activity and Remission in an
Early Seropositive Rheumatoid Arthritis Cohort
DINESH KHANNA,1 MYUNGSHIN OH,2 DANIEL E. FURST,2 VEENA RANGANATH,2
RICHARD H. GOLD,2 JOHN T. SHARP,3 GRACE S. PARK,2 EDWARD C. KEYSTONE,4 AND
HAROLD E. PAULUS,2 FOR THE WESTERN CONSORTIUM OF PRACTICING RHEUMATOLOGISTS
Objective. To evaluate published proposed definitions of minimal disease activity (MDA) and remission in patients with
early rheumatoid arthritis (RA).
Methods. The cohort comprised disease-modifying antirheumatic drug (DMARD)–naive patients with early seropositive
active RA (n ⴝ 200) treated with traditional DMARDs in the prebiologic era. MDA definitions included Disease Activity
Score in 28 joints (DAS28) <2.85, or achieving 5 of 7 World Health Organization (WHO)/International League of
Associations for Rheumatology (ILAR) core set measure thresholds as proposed by the Outcome Measures in Rheumatology Clinical Trials. Other MDA definitions included Simplified Disease Activity Index (SDAI) score <11 and Clinical
Disease Activity Index (CDAI) score <10. Remission definitions included American College of Rheumatology (ACR)
remission, DAS28 <2.6, DAS28 <2.4, achieving all 7 WHO/ILAR core set measure thresholds, SDAI <3.3, and CDAI <2.8.
Physical function was assessed using the Health Assessment Questionnaire (HAQ) disability index (DI) and radiographic
progression was assessed using the Sharp score.
Results. At baseline, no patients were in MDA or remission. Depending on the MDA definition, 20 –32%, 27–32%, and
30 – 48% were in MDA at 6, 12, and 24 months, respectively. Depending on the remission definition, 0.7–15%, 0 –24%, and
0 –33% were in remission at 6, 12, and 24 months, respectively. For example, at 6 months, lowest (highest) responses for
MDA were seen with DAS28 <2.85 (SDAI <11) and for remission with ACR remission criteria (DAS28 <2.6). Patients who
achieved either MDA or remission had lower HAQ DI and radiographic scores compared with patients who achieved
neither.
Conclusion. Our study demonstrated that different proportions of patients were classified as MDA or remission depending on the definition used. This has implications in predefining MDA or remission for a clinical trial or to establish goals
for optimum management of RA in clinical practice.
KEY WORDS. Rheumatoid arthritis; Low disease activity; Clinical remission; Minimal disease activity.
Rheumatoid arthritis (RA) is a chronic arthritis associated
with disability and decrement in quality of life. New therapeutics have revolutionized the treatment of RA, and the
goal of therapy has become to maintain patients in a low
disease activity status or remission (1,2). The Outcome
Measures in Rheumatology Clinical Trials (OMERACT)
group has recently proposed preliminary definitions of
minimal disease activity (MDA), i.e., low disease activity
Dr. Khanna’s work was supported in part by a National
Institutes of Health K–12 BIRWCH grant (HD-051953).
1
Dinesh Khanna, MD, MSc: the University of Cincinnati
and the Veterans Affairs Medical Center, Cincinnati, Ohio;
2
MyungShin Oh, PhD, Daniel E. Furst, MD, Veena Ranganath, MD, Richard H. Gold, MD, Grace S. Park, MPH, Harold E. Paulus, MD: David Geffen School of Medicine, University of California, Los Angeles; 3John T. Sharp, MD:
University of Washington, Seattle; 4Edward C. Keystone,
MD: Mount Sinai Hospital, University of Toronto, Toronto,
Ontario, Canada.
Members of the Western Consortium of Practicing Rheumatologists are as follows: Robert Shapiro, Maria W. Greenwald, H. Walter Emori, Fredrica E. Smith, Craig W. Wiesenhutter, Charles Boniske, Max Lundberg, Anne MacGuire,
Jeffry Carlin, Robert Ettlinger, Michael H. Weisman, Elizabeth Tindall, Karen Kolba, George Krick, Melvin Britton,
Rudy Greene, Ghislaine Bernard Medina, Raymond T.
Mirise, Daniel E. Furst, Kenneth B. Wiesner, Robert F.
Willkens, Kenneth Wilske, Karen Basin, Robert Gerber, Gerald Schoepflin, Marcia J. Sparling, George Young, Philip J.
Mease, Ina Oppliger, Douglas Roberts, J. Javier Orozco Al-
INTRODUCTION
440
Remission and Minimal Disease Activity in Early RA
state in RA (3). MDA is defined as a disease state that is
“between high disease state and remission” (3). By definition, anyone in remission is also in MDA. In another study,
Aletaha et al proposed definitions for MDA and remission
(4) based on the Disease Activity Score in 28 joints
(DAS28), Simplified Disease Activity Index (SDAI), and
Clinical Disease Activity Index (CDAI) (5). We assessed
preliminary definitions of MDA and remission in a disease-modifying antirheumatic drug (DMARD)–naive cohort with early, seropositive, active RA.
PATIENTS AND METHODS
Patients. Patients included in this study were a subset
of a group of patients with early RA participating in a
long-term observational study by the Western Consortium
of Practicing Rheumatologists, which is a regional consortium of rheumatology practices in the western US and
Mexico. The study was reviewed and approved by the
University of California Los Angeles institutional review
board.
The consortium and its practices have been detailed in
previous publications (6,7). In brief, patients in this subset
had a diagnosis of early RA (median of 5.2 months since
symptom onset), had no previous DMARD treatment, were
rheumatoid factor (RF) seropositive (median 214 IU/ml),
had ⱖ6 swollen joints and ⱖ9 tender joints, and had at
least 2 sets of scored joint radiographs. Patients with
symptom onset ⬎14 months or negative RF were excluded.
The consortium rheumatologists assessed patient disease
status at study entry (baseline), 6 months, 1 year, and
yearly thereafter. Using standard methods, detailed physician assessment included all of the core set outcome measures required to calculate DAS28 score, including complete tender and swollen joint counts and acute-phase
reactant measures, as well as 0 –10-cm visual analog scales
(VAS) for physician global assessment and patient VAS
assessments of disease activity, fatigue, stiffness, and pain.
The DAS28 was calculated according to the published
algorithm using the swollen and tender joint count of 28
joints, patient’s global assessment, and erythrocyte sedimentation rate (ESR) in mm/hour (8,9). At each scheduled
physician visit, blood specimens were collected for C-reactive protein level; ESR was determined when clinically
indicated in the rheumatologist’s office or local laboratory.
cala, John Seaman, Martin Berry, Ken J. Bulpitt, Grant Cannon, Gregory Gardner, Allen Sawitzke, Andrew Lun Wong,
Daniel O. Clegg, Timothy Spiegel, Wayne Jack Wallis, Mark
Wener, Robert Fox.
Dr. Keystone has received honoraria (more than $10,000
each) as a consultant to Abbott and Amgen. Dr. Paulus has
received consultancy fees and/or honoraria (less than
$10,000) from Amgen and has served as a member of the
Targeted Genetics Data and Safety Monitoring Board.
Address correspondence to Dinesh Khanna, MD, MSc,
Division of Immunology, Department of Medicine, University of Cincinnati, 231 Albert Sabin Way, ML 0563, PO Box
670563, Cincinnati, OH 45267-0563. E-mail: dinesh.khanna
@uc.edu.
Submitted for publication March 15, 2006; accepted in
revised form August 4, 2006.
441
Patients were asked to complete a detailed self-report
mailed questionnaire at study entry and every 6 months
thereafter for the duration of the study. In these questionnaires, patients reported changes in demographics, health,
medication, pain, and fatigue, and completed the Health
Assessment Questionnaire (HAQ) disability index (DI).
Study assessments included radiographs of the hands,
wrists, and forefeet. Standard posteroanterior radiographs
including both hands and wrists and anteroposterior radiographs including both forefeet were obtained at entry, 6
months, and yearly thereafter in the rheumatologists’ offices or at the radiology facility usually used by the rheumatologists. Two experienced readers (JTS and RHG)
scored all available radiographs for erosions (on a scale
from 0 to 5) and joint space narrowing (on a scale from 0 to
4); the total score was the sum of the erosion and joint
space narrowing scores. After a brief training session in
which the readers discussed the scoring scale and reviewed a small group of radiographs to be sure they agreed
on the features to be scored, the radiographs were scored
independently using the method described by Sharp et al
(10,11) to score 17 joints of each hand and wrist for erosions and 16 for joint space narrowing, and 6 joints of each
forefoot for erosions and joint space narrowing. Maximum
possible scores for the hands/wrists were 170 for erosion
and 128 for joint space narrowing (total score 298), for the
feet were 60 for erosion and 48 for joint space narrowing
(total score 108), and for both hands/wrists and feet were
230 for erosion and 176 for joint space narrowing (total
score 406). Radiographs were read in patient sets and were
randomized and blinded for sequence. The independent
scores of readers 1 and 2 for each radiograph were averaged, and this average was used for the analysis. Sclerosis
or healing of erosions was not scored. For each patient
with ⱖ2 radiographic observations, the slope of the least
squares regression line was calculated to estimate the annualized progression rates of erosion score, joint space
narrowing score, and total Sharp score, assuming that progression remained relatively constant during the time interval of the observations.
Patients could be treated with ⱖ1 DMARD at any time
after the baseline evaluation. At 2 years of followup, the
cumulative patient-years of DMARD use by these 200 patients, individually or in combination, were 187.5 years for
methotrexate, 95.7 years for antimalarials, 27 years for
sulfasalazine, 2.3 years for etanercept, 1.25 years for infliximab, 13.5 years for intramuscular gold, 2 years for azathioprine, 129.8 years oral prednisone, and 5.5 years for
other DMARDs. At some time during the course of the 2
years, ⬃28% were receiving double combination DMARD
therapy (combinations of either methotrexate, sulfasalazine, or hydroxychloroquine) and 5% were receiving triple
therapy (methotrexate, sulfasalazine, and hydroxychloroquine). Nonsteroidal antiinflammatory drugs were used or
changed as clinically indicated at the discretion of the
physicians.
Preliminary definitions of MDA. The OMERACT group
has proposed preliminary definitions (3) for achieving
MDA. For the first definition, patients with no tender
442
Khanna et al
Table 1. Various definitions of minimal disease activity (MDA) and remission*
Disease activity measure
TJC ⫽ 0; SJC ⫽ 0; ESR ⱕ10
DAS28 ESR 4-item ⫽ 0.56(公TJC28) ⫹ 0.28(公SJC28) ⫹ 0.70 ⫻
ln(ESR) ⫹ 0.014(GH)
WHO core set measures thresholds
TJC28 ⱕ1; SJC28 ⱕ2; HAQ DI ⱕ0.5; ESR ⱕ20; GH VAS ⱕ2; MD
global VAS ⱕ1.5; patient pain VAS ⱕ2
CDAI ⫽ TJC28 ⫹ SJC28 ⫹ GH (10 cm) ⫹ MD global (10 cm)
SDAI ⫽ TJC28 ⫹ SJC28 ⫹ GH (10 cm) ⫹ MD global (10 cm) ⫹
CRP
ACR remission thresholds
AM stiffness ⱕ15; fatigue ⫽ 0; joint pain ⫽ 0; SJC ⫽ 0; TJC ⫽
0; ESR ⬍30 for women, ⬍20 for men
MDA
(reference)
Remission
(reference)
All required
ⱕ2.85 (3)
5 of 7 (3)
—
⬍2.4 (4)
⬍2.6 (12)
7 of 7 (3)
ⱕ10 (5)
ⱕ11 (5)
ⱕ2.8 (5)
ⱕ3.3 (5)
—
5 of 6 (13)
* TJC ⫽ tender joint count; SJC ⫽ swollen joint count; ESR ⫽ Westergren erythrocyte sedimentation rate (mm/hour); DAS28 ⫽ Disease Activity Score
in 28 joints; TJC28 ⫽ Tender Joint Count for 28 joints; SJC28 ⫽ Swollen Joint Count for 28 joints; GH ⫽ patient global assessment; WHO ⫽ World Health
Organization; HAQ DI ⫽ Health Assessment Questionnaire disability index; VAS ⫽ visual analog scale; MD global ⫽ physician global assessment;
CDAI ⫽ Clinical Disease Activity Index; SDAI ⫽ Simplified Disease Activity Index; CRP ⫽ C-reactive protein; ACR ⫽ American College of
Rheumatology; AM stiffness ⫽ morning stiffness in minutes.
joints and no swollen joints and an ESR ⱕ10 mm/hour are
considered to be in MDA. If patients do not meet this
criterion, they are still considered to be in MDA if either
their DAS28 score is ⱕ2.85 or they meet 5 of the 7 World
Health Organization (WHO)/International League Against
Rheumatism (ILAR) core set measure thresholds, i.e., pain
ⱕ2 (0 –10 scale), swollen joint count ⱕ1 (out of 28), tender
joint count ⱕ1 (out of 28), HAQ DI score ⱕ0.5 (range 0 –3),
physician global assessment ⱕ1.5 (0 –10 scale), patient
global assessment ⱕ2 (0 –10 scale), and ESR ⱕ20 mm/
hour. Aletaha and Smolen have proposed definitions
based on the CDAI and SDAI (5). According to the definitions, CDAI scores ⱕ10 and SDAI scores ⱕ11 are considered as MDA (Table 1).
Preliminary definitions of remission. DAS28 score
⬍2.6 was proposed as a definition of remission by Prevoo
et al in 1995 (12). Aletaha and colleagues recently used
paper patient profiles and expert opinion of 35 rheumatologists (4) to develop a stricter definition for remission:
DAS28 score ⬍2.4. Aletaha and Smolen also proposed
CDAI score ⱕ2.8 and SDAI score ⱕ3.3 as definitions of
being in remission (5). We also assessed a core set– based
definition of remission, i.e., achieving 7 of 7 WHO/ILAR
core set thresholds, as proposed by the OMERACT group
(3). These remission definitions were compared with the
American College of Rheumatology (ACR; formerly the
American Rheumatism Association) remission definition
(13), which involves meeting 5 of the following 6 criteria
for at least 2 consecutive months: morning stiffness ⱕ15
minutes, no fatigue, no joint pain (by history), no swollen
joint count, no tender joint count, and ESR ⬍30 mm/hour
for women or ⬍20 mm/hour for men. We modified the
ACR remission criteria by assessing remission cross-sectionally, i.e., at single points in time, rather than over a
consecutive 2-month period (Table 1).
Table 2. Baseline characteristics of the study population (n ⴝ 200)*
Variables
Mean ⴞ SD
Median (25th, 75th percentile)
Age, years
Disease duration, months
Patient global assessment (0–10)
Physician global assessment (0–10)
Patient pain assessment (0–10)
ESR, mm/hour
HAQ (0–3)
Tender joint count (0–28)
Swollen joint count (0–28)
DAS28/ESR 4 item
SDAI (0–86)
CDAI (0–76)
Total Sharp score
Erosion score
Joint space narrowing score
51.38 ⫾ 12.91
5.94 ⫾ 3.29
4.30 ⫾ 2.33
5.19 ⫾ 2.08
5.13 ⫾ 2.42
42.67 ⫾ 24.66
1.20 ⫾ 0.71
13.97 ⫾ 7.63
13.33 ⫾ 7.13
5.48 ⫾ 1.02
41.09 ⫾ 16.49
38.27 ⫾ 15.36
6.36 ⫾ 8.66
2.15 ⫾ 3.96
4.21 ⫾ 6.22
50.85 (42.12, 61.72)
5.28 (3.40, 8.13)
4.62 (2.15, 6.27)
5.30 (3.40, 6.70)
5.28 (3.30, 6.93)
38.00 (26.00, 55.00)
1.25 (0.63, 1.63)
13.00 (8.50, 20.00)
12.00 (8.00, 19.00)
5.54 (4.78, 6.24)
38.75 (28.65, 51.95)
36.01 (26.65, 48.51)
3.67 (1.25, 8.25)
0.75 (0.17, 2.50)
2.00 (0.67, 5.75)
* See Table 1 for definitions.
Remission and Minimal Disease Activity in Early RA
443
Table 3. Proportion of patients in minimal disease activity (MDA) state at 0, 6, 12, and 24 months*
Baseline
(n ⴝ 200)
6 months
(n ⴝ 152)
12 months
(n ⴝ 142)
24 months
(n ⴝ 101)
Definition
MDA
No
MDA
MDA
No
MDA
MDA
No
MDA
MDA
No
MDA
SJC ⫽ 0, TJC ⫽ 0, and ESR ⱕ10
(definition 1)
5 of 7 WHO/ILAR core sets
DAS28 ⱕ2.85
SDAI ⱕ11
CDAI ⱕ10
0
200
4 (3)
148
3 (2)
139
3 (3)
98
0
0
0
0
200
200
200
200
35 (23)
31 (20)
48 (32)
46 (30)
117
121
104
106
38 (27)
38 (27)
46 (32)
46 (32)
104
104
96
96
30 (30)
35 (35)
45 (45)
48 (48)
71
66
56
53
* Values are the number or number (percentage). ILAR ⫽ International League of Associations for Rheumatology; see Table 1 for additional definitions.
Statistical analysis. For each definition, the Wilcoxon
rank sum test was performed to compare 2 groups (patients
classified as MDA versus those not MDA and patients
classified as in remission versus those not in remission).
Agreement between different definitions of MDA and remission was assessed using the kappa statistic and was
interpreted as proposed by Altman (14): 0.20 indicates
poor agreement, 0.20 – 0.40 indicates fair agreement, 0.40 –
0.60 indicates moderate agreement, 0.60 – 0.80 indicates
good agreement, and 0.80 –1.00 indicates excellent agreement. We analyzed the data using SAS software, release
8.02 (SAS Institute, Cary, NC). P values less than 0.05 were
considered indicative of statistical significance.
RESULTS
At baseline, 200 patients had sufficient available data to
assess DAS28 score, the 7 core set measures (VAS pain,
swollen joint count, tender joint count, HAQ DI score,
physician global assessment, patient global assessment,
and ESR) (Table 2), morning stiffness, VAS fatigue, and
radiographs. The majority of the patients were women
(77%) and had moderate patient-reported disability (median HAQ DI score 1.25) and high disease activity (median
DAS28 score 5.54). At 6, 12, and 24 months after baseline,
152, 142, and 101 patients, respectively, had complete
core set measures, morning stiffness, and VAS fatigue
along with Sharp scores of paired radiographic data.
Minimal disease activity and remission. The proportions of patients in MDA as defined by no tender joints and
no swollen joints and an ESR ⱕ10 mm/hour were as follows: 3%, 2%, and 3% at 6, 12, and 24 months, respectively (Table 3). For patients who did not achieve MDA as
described above, the 2 other definitions (DAS28 score
ⱕ2.85 and 5 of 7 WHO/ILAR core set criteria thresholds)
were assessed. For the 5 of 7 WHO/ILAR core set criteria
definition (including patients who also achieved MDA by
no tender joints and no swollen joints and an ESR ⱕ10
mm/hour), 23%, 27%, and 30% of patients achieved MDA
at 6, 12, and 24 months, respectively (Table 3, Figure 1).
The proportions of patients achieving MDA as defined by
DAS28 score ⱕ2.85 (including patients who achieved
MDA by no tender joints and no swollen joints and an ESR
ⱕ10 mm/hour) were very similar: 20%, 27%, and 35% at
6, 12, and 24 months, respectively. The proportions of
patients in MDA at 6, 12, and 24 months using the definition SDAI score ⱕ11 were 32%, 32%, and 45%, respectively, and using the definition CDAI score ⱕ10 were 30%,
32%, and 48%, respectively.
At baseline, as expected, no patients were in MDA or
remission. At months 6, 12, and 24, 15%, 24%, and 33%
were in remission using DAS28 score ⬍2.6, respectively
(Table 4). In comparison, 13%, 19%, and 25% were in
remission using DAS28 score ⬍2.4 and 3%, 4%, and 6%
were in remission using the 7 of 7 core set criterion at 6,
12, and 24 months, respectively. For ACR remission criteria, 0.7%, 0%, and 0% were in remission at 6, 12, and 24
months, respectively. The proportions of patients in remission at 6, 12, and 24 months for SDAI score ⱕ3.3 were
11%, 11%, and 15%, respectively, and for CDAI score
ⱕ2.8 were 12%, 11%, and 17%, respectively.
We assessed agreement at the 6-month, 12-month, and
24-month time points among the different definitions. The
agreement between different definitions of MDA was good
to excellent (range 0.67– 0.97) (Table 5). However, agreement among the definitions of remission ranged from poor
to excellent (range 0.07– 0.97) (Table 6). For example, the
ACR remission definition had poor agreement with DAS28
score ⬍2.4, DAS28 score ⬍2.6, CDAI score ⱕ2.8, and SDAI
Figure 1. Proportions of patients (n ⫽ 152) with minimal disease
activity (MDA) or remission at month 6, using various definitions
of MDA and remission. SJC ⫽ swollen joint count; TJC ⫽ tender
joint count; ESR ⫽ erythrocyte sedimentation rate; DAS ⫽ Disease
Activity Score; WHO ⫽ World Health Organization; ILAR ⫽ International League of Associations for Rheumatology; CDAI ⫽
Clinical Disease Activity Index; SDAI ⫽ Simplified Disease Activity Index; ACR ⫽ American College of Rheumatology.
444
Khanna et al
Table 4. Proportion of patients in remission at baseline, 6, 12, and 24 months*
Baseline (n ⴝ 200)
Definition
Remission
No
remission
DAS28 ⬍2.6
DAS28 ⬍2.4
7 of 7 WHO/ILAR core
sets
ACR remission (5 of 6
items)
SDAI ⱕ3.3
CDAI ⱕ2.8
0
0
0
200
200
200
0
0
0
6 months (n ⴝ 152)
12 months (n ⴝ 142)
24 months (n ⴝ 101)
No
remission
Remission
No
remission
Remission
No
remission
23 (15)
20 (13)
5 (3)
129
132
147
34 (24)
27 (19)
5 (4)
108
115
137
33 (33)
25 (25)
6 (6)
68
76
95
200
1 (0.7)
151
0
142
0
101
200
200
17 (11)
18 (12)
135
134
15 (11)
16 (11)
127
126
15 (15)
17 (17)
86
84
Remission
* Values are the number or number (percentage). ILAR ⫽ International League of Associations for Rheumatology; see Table 1 for additional definitions.
score ⱕ3.3, and only a fair agreement with the 7 of 7
WHO/ILAR core sets.
Using the various proposed definitions, the HAQ DI
status and radiographic scores of patients who achieved
MDA (or remission) compared with patients who did not
are presented in Tables 7 and 8. Patients classified as being
in MDA (or remission) had lower median HAQ DI and
radiographic scores compared with patients who were not
in MDA or remission, except for a few outlier comparisons
when only ⱕ2 patients achieved MDA or remission.
DISCUSSION
This study evaluated several published proposed definitions of MDA states and remission in a cohort of patients
with early, seropositive RA. With the advent of new therapies, the goal of current RA treatment is to achieve MDA
and remission (15–17). As pointed out by the OMERACT
group, with the recent advances in RA therapy, “the proportion of patients achieving a satisfactory state of MDA is
becoming an important measure with which to compare
different treatment strategies” (3). Our cohort comprised
patients with early, seropositive RA, defined as active
disease by ⱖ6 swollen joints and ⱖ9 tender joints, who
were treated with traditional DMARDs before the biologic
era.
Although the clinical concepts of treatment-induced remission, spontaneous remission (persisting without treatment), and MDA state (very good, but not quite remission)
in RA are easily understood and increasingly realistic
goals of modern treatment regimens (16,18), this study
clearly illustrates the lack of consensus in attempts to
quantitatively define these concepts. In our observational
cohort, the proportions of patients who were classified as
being in remission or MDA varied widely among the published proposed definitions (Figure 1).
Depending on the MDA definition used, 20 –32% of
patients were in MDA at 6 months, 27–32% were in MDA
at 12 months, and 30 – 48% were in MDA at 24 months. For
the MDA definitions, the lowest response rates were seen
Table 5. Agreement between the different definitions of low disease activity at 6 months*
5 of 7 WHO/ILAR core sets
DAS28 <2.85
SDAI <11
1
0.69 (good)
0.69 (good)
0.68 (good)
1
0.68 (good)
1
0.67 (good)
0.97 (excellent)
5 of 7 WHO/ILAR
core sets
DAS28 ⱕ2.85
SDAI 11
CDAI <10
* ILAR ⫽ International League of Associations for Rheumatology; see Table 1 for additional definitions.
Table 6. Agreement between the different definitions of remission at 6 months*
DAS28
<2.6
DAS28 ⬍2.6
DAS28 ⬍2.4
7 of 7 WHO/ILAR core sets
ACR remission (5 of 6 items)
SDAI ⱕ3.3
1
DAS28 <2.4
0.92 (excellent)
1
7 of 7
WHO/ILAR
core sets
0.32 (fair)
0.20 (fair)
1
ACR
remission
0.07 (poor)
0.08 (poor)
0.33 (fair)
1
SDAI <3.3
CDAI <2.8
0.48 (moderate)
0.48 (moderate)
0.23 (fair)
0.10 (poor)
1
0.52 (moderate)
0.46 (moderate)
0.31 (fair)
0.09 (poor)
0.97 (excellent)
* Degree of agreement indicated by kappa values: ⬍0.2 ⫽ poor agreement; 0.2– 0.4 ⫽ fair agreement; ⬎0.4 – 0.6 ⫽ moderate agreement; ⬎0.6 – 0.8 ⫽
good agreement; ⬎0.8 –1.0 ⫽ excellent agreement. Parentheses indicate the range of values at the 6-month, 12-month, and 24-month assessments.
ILAR ⫽ International League of Associations for Rheumatology; see Table 1 for additional definitions.
Remission and Minimal Disease Activity in Early RA
445
Table 7. Effects of minimal disease activity (MDA) state on HAQ score status and radiographic score*
6 months (n ⴝ 152)
12 months (n ⴝ 142)
24 months (n ⴝ 101)
Definition
MDA
No MDA
MDA
No MDA
MDA
No MDA
SJC ⫽ 0, TJC ⫽ 0, and ESR
ⱕ10 (definition 1),
no. (%)
HAQ
Total Sharp score
5 of 7 WHO/ILAR core sets,
no. (%)
HAQ
Total Sharp score
DAS28 ⱕ2.85, no. (%)
HAQ
Total Sharp score
SDAI ⱕ11, no. (%)
HAQ
Total Sharp score
CDAI ⱕ10, no. (%)
HAQ
Total Sharp score
4 (3)
148
3 (2)
139
3 (3)
98
0.25 (0.0, 0.5)
15.50 (6.0, 18.3)
30 (30)
0.56 (0.1, 1.1)
8.63 (4.0, 17.5)
71
0.00 (0.0, 0.1)
5.50 (3.0, 12.5)
35 (35)
0.13 (0.0, 0.5)
5.00 (1.5, 13.5)
45 (45)
0.13 (0.0, 0.5)
5.63 (2.0, 13.5)
48 (48)
0.13 (0.0, 0.7)
6.00 (3.0, 15.5)
1.00 (0.4, 1.5)†
12.00 (5.0, 18.8)
66
0.94 (0.4, 1.4)†
12.38 (5.5, 18.8)‡
56
1.00 (0.4, 1.5)†
12.50 (5.5, 18.5)‡
53
1.00 (0.4, 1.5)†
12.38 (5.5, 18.1)
0.25 (0.0, 0.8) 0.75 (0.3, 1.2)
1.75 (0.8, 2.8) 5.50 (2.0, 10.5)
35 (23)
117
0.13 (0.0, 1.1) 0.50 (0.0, 1.1)
8.00 (0.0, 16.0) 6.50 (3.5, 13.5)
38 (27)
104
0.00 (0.0, 0.3)
2.75 (0.8, 5.5)
31 (20)
0.00 (0.0, 0.5)
2.75 (0.5, 7.0)
48 (32)
0.25 (0.0, 0.8)
3.50 (1.3, 7.8)
46 (30)
0.25 (0.0, 0.8)
3.25 (1.0, 7.5)
0.06 (0.0, 0.4)
4.25 (2.3, 10.5)
38 (27)
0.13 (0.0, 0.8)
4.25 (2.0, 9.5)
46 (32)
0.13 (0.0, 0.4)
4.25 (2.0, 7.0)
46 (32)
0.13 (0.0, 0.4)
4.38 (2.0, 7.0)
0.88 (0.5, 1.4)†
6.50 (2.0, 14.3)†
121
0.88 (0.4, 1.4)†
6.00 (2.5, 12.0)‡
104
0.88 (0.5, 1.4)†
6.88 (2.0, 11.5)
106
0.88 (0.5, 1.4)†
6.88 (2.3, 11.5)
0.81 (0.1, 1.4)†
7.63 (3.5, 15.0)
104
0.75 (0.1, 1.3)†
7.63 (3.5, 15.0)‡
96
0.88 (0.1, 1.4)†
9.00 (4.0, 15.5)‡
96
0.81 (0.1, 1.4)†
9.00 (3.5, 15.0)‡
* Values are the median (25th, 75th percentile) unless otherwise indicated. ILAR ⫽ International League of Associations for Rheumatology; see Table
1 for additional definitions.
† P ⬍ 0.01 for MDA versus no MDA at months 6, 12, or 24.
‡ P ⬍ 0.05 for MDA versus no MDA at months 6, 12, or 24.
with DAS28 score ⱕ2.85 (20% at 6 months and 27% at 12
months) and 5 of 7 WHO/ILAR criteria (30% at 24
months), and the highest response rates were seen with
SDAI score ⱕ11 (32% at 6 and 12 months) and CDAI score
ⱕ10 (48% at 24 months). Similarly, for the remission
definitions, the lowest responses rates were seen with the
ACR remission criteria (0.7%, 0%, and 0% at 6, 12, and 24
months, respectively) and the highest response rates were
seen with DAS28 score ⬍2.6 (15%, 24%, and 33% at 6, 12,
and 24 months, respectively).
Table 8. Effects of remission state on HAQ score status and radiographic score*
6 months (n ⴝ 152)
Definition
Remission
No remission
DAS28 ⬍2.6, no. (%)
HAQ
Total Sharp score
DAS28 ⬍2.4, no. (%)
HAQ
Total Sharp score
7 of 7 WHO/ILAR core
sets, no. (%)
HAQ
Total Sharp score
ACR remission, no.
(%)
HAQ
Total Sharp score
SDAI ⱕ3.3, no. (%)
HAQ
Total Sharp score
CDA1 ⱕ2.8, no. (%)
HAQ
Total Sharp score
23 (15)
0.00 (0.0, 0.3)
2.13 (0.5, 7.0)
20 (13)
0.00 (0.0, 0.4)
2.13 (0.5, 6.8)
5 (3)
129
0.88 (0.3, 1.3)†
5.50 (2.3, 11.8)‡
132
0.88 (0.3, 1.3)†
5.50 (2.0, 11.5)‡
147
0.00 (0.0, 0.3)
2.88 (1.6, 5.5)
1 (0.7)
0.75 (0.3, 1.3)†
5.50 (2.0, 10.5)
151
0.00 (0.0, 0.0)
8.00 (8.0, 8.0)
17 (11)
0.25 (0.0, 0.8)
2.75 (0.5, 8.0)
18 (12)
0.25 (0.0, 0.8)
2.63 (0.5, 7.5)
0.75 (0.3, 1.1)
5.25 (2.0, 10.5)
135
0.75 (0.3, 1.3)‡
5.50 (2.0, 10.5)
134
0.75 (0.3, 1.3)‡
5.50 (2.0, 10.5)
12 months (n ⴝ 142)
Remission
24 months (n ⴝ 101)
No remission
Remission
No remission
34 (24)
0.13 (0.0, 0.6)
4.00 (1.8, 5.5)
27 (19)
0.13 (0.0, 0.6)
4.13 (1.8, 7.5)
5 (4)
108
0.75 (0.1, 1.3)†
7.63 (4.0, 15.5)‡
115
0.63 (0.1, 1.3)†
7.50 (3.5, 15.0)‡
137
33 (33)
0.13 (0.0, 0.5)
5.00 (2.0, 11.3)
25 (25)
0.13 (0.0, 0.4)
5.13 (3.5, 13.5)
6 (6)
68
0.88 (0.3, 1.4)†
12.38 (5.4, 19.1)‡
76
0.81 (0.3, 1.3)†
12.00 (4.5, 18.8)
95
0.00 (0.0, 0.0)
2.00 (1.3, 4.5)
0 (0)
0.50 (0.1, 1.1)†
6.75 (3.5, 13.8)
142
0.00 (0.0, 0.1)
2.75 (1.3, 6.0)
0 (0)
0.63 (0.1, 1.3)†
11.00 (4.5, 17.8)‡
101
15 (11)
0.13 (0.0, 0.6)
4.00 (1.3, 5.5)
16 (11)
0.19 (0.0, 0.5)
4.25 (1.6, 10.8)
0.50 (0.0, 1.1)
6.50 (3.5, 13.5)
127
0.50 (0.1, 1.3)†
7.13 (3.5, 13.8)
126
0.56 (0.1, 1.3)‡
7.00 (3.5, 13.5)
15 (15)
0.00 (0.0, 0.4)
6.00 (1.5, 11.0)
17 (17)
0.00 (0.0, 0.3)
5.00 (1.3, 11.0)
0.50 (0.1, 1.1)
8.75 (4.5, 17.5)
86
0.63 (0.1, 1.3)†
10.04 (4.5, 18.6)
84
0.69 (0.2, 0.3)†
11.63 (4.5, 18.8)‡
* Values are the median (25th, 75th percentile) unless otherwise indicated. ILAR ⫽ International League of Associations for Rheumatology; see Table
1 for additional definitions.
† P ⬍ 0.01 for remission versus no remission at months 6, 12, or 24.
‡ P ⬍ 0.05 for remission versus no remission at months 6, 12, or 24.
446
The higher proportions of patients achieving MDA at
month 24 may be due to selection bias because patients
with more active disease might have dropped out of the
consortium. Considering the various definitions for remission, the proportions of patients meeting criteria with
DAS28 score ⬍2.4, DAS28 score ⬍2.6, SDAI score ⱕ3.3, or
CDAI score ⱕ2.8 were between 11% and 15% at 6 months,
11% and 24% at 12 months, and 15% and 33% at 24
months. There is currently an effort to revise the definitions of remission. Patients who achieve remission as defined by DAS28 score ⬍2.6 may still have substantial
disease activity (19), and as stated by Aletaha and colleagues, “even the new, more stringent DAS28 cutoff value
of 2.4 allows for the presence of up to 12 swollen joints in
our patients” (4). In contrast, the definitions of remission
using the SDAI and CDAI only permit 2 swollen or 2
tender joints or 1 tender and 1 swollen joint. The ACR
remission criteria and 7 of 7 WHO/ILAR criteria were
stricter: 0.7% and 3% at 6 months, 0% and 4% at 12
months, and 0% and 6% at 24 months, respectively,
achieved these criteria for remission. As the definition of
remission undergoes refinement, our data suggest that
OMERACT’s first definition of achieving MDA (no tender
joints or swollen joints and an ESR ⱕ10 mm/hour) may be
better used as a definition of remission (only 2–3%
achieved remission at different time points). Supporting
the MDA and remission definitions, patients who achieved
either MDA or remission by most definitions had lower
HAQ DI and radiographic scores at months 6, 12, and 24
compared with patients who did not achieve MDA or
remission (except for the ACR remission criteria and 7 of 7
WHO/ILAR criteria, which were attained by only a few
patients).
Our study has several strengths. First, the patients enrolled in the cohort were DMARD naive at entry and had
active disease as defined by ⱖ6 swollen and 9 tender joint
counts. No patient was in MDA or remission at baseline,
providing face validity to the definitions. Second, after
entering the cohort almost all patients were started on
traditional DMARDs by their rheumatologists. The proportions of patients achieving MDA and remission using different definitions provide a benchmark for comparison
with future cohorts. However, our study has limitations.
Because missing data were not imputed, fewer baseline
patients were able to be evaluated at 6, 12, and 24 months.
This restricted our ability to assess MDA and remission in
all 200 patients during each time point. However, this
should not invalidate our conclusions, because our goal
was to evaluate the preliminary definitions of MDA and
remission. Biologic agents had not been approved when
these patients were studied (1993–1997); the proportions
of patients achieving MDA or remission may be larger
now. In addition, our findings may not be generalizable to
other RA patient populations, e.g., patients with seronegative RA, less active RA, or longer disease duration.
In conclusion, we assessed the definitions of MDA and
remission in a cohort of patients with early, active, seropositive RA. If these criteria are used as secondary outcomes in clinical trials, it is essential that the selected
definition of MDA or remission is fully described because
the proportion of patients so classified varies widely de-
Khanna et al
pending on the definition selected. Much more work will
be needed to reach consensus on single uniform definitions of MDA and remission. Agreement on easily measured uniform definitions is particularly desirable at this
time because it may provide an attainable goal for optimal
management of RA in clinical practice. Use of these uniform definitions of MDA and remission in clinical trials
may help to determine the most beneficial regimens for
management of the various stages of RA.
AUTHOR CONTRIBUTIONS
Dr. Khanna 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. Khanna, Furst, Paulus.
Acquisition of data. Gold, Sharp, Park, Paulus.
Analysis and interpretation of data. Khanna, Furst, Ranganath,
Park, Paulus.
Manuscript preparation. Khanna, Furst, Ranganath, Sharp, Keystone, Paulus.
Statistical analysis. Khanna, Oh.
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