Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors.

Abstract

To assess the efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis (RA) and poor prognostic factors.
In this double-blind, phase IIIb study, patients with RA for 2 years or less were randomly assigned 1 : 1 to receive abatacept (approximately 10 mg/kg) plus methotrexate, or placebo plus methotrexate. Patients were methotrexate-naive and seropositive for rheumatoid factor (RF), anti-cyclic citrullinated protein (CCP) type 2 or both and had radiographic evidence of joint erosions. The co-primary endpoints were the proportion of patients achieving disease activity score in 28 joints (DAS28)-defined remission (C-reactive protein) and joint damage progression (Genant-modified Sharp total score; TS) at year 1. Safety was monitored throughout.
At baseline, patients had a mean DAS28 of 6.3, a mean TS of 7.1 and mean disease duration of 6.5 months; 96.5% and 89.0% of patients were RF or anti-CCP2 seropositive, respectively. At year 1, a significantly greater proportion of abatacept plus methotrexate-treated patients achieved remission (41.4% vs 23.3%; p<0.001) and there was significantly less radiographic progression (mean change in TS 0.63 vs 1.06; p = 0.040) versus methotrexate alone. Over 1 year, the frequency of adverse events (84.8% vs 83.4%), serious adverse events (7.8% vs 7.9%), serious infections (2.0% vs 2.0%), autoimmune disorders (2.3% vs 2.0%) and malignancies (0.4% vs 0%) was comparable for abatacept plus methotrexate versus methotrexate alone.
In a methotrexate-naive population with early RA and poor prognostic factors, the combination of abatacept and methotrexate provided significantly better clinical and radiographic efficacy compared with methotrexate alone and had a comparable, favourable safety profile.

Full text

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Clinical efficacy and safety of abatacept in
methotrexate-naive patients with early rheumatoid
arthritis and poor prognostic factors
R Westhovens,1M Robles,2A C Ximenes,3S Nayiager,4J Wollenhaupt,5P Durez,6
J Gomez-Reino,7W Grassi,8B Haraoui,9W Shergy,10S-H Park,11H Genant,12
C Peterfy,13J-C Becker,14A Covucci,14R Helfrick,14J Bathon15
1UZ Gasthuisberg, Leuven,
Belgium;2Centro Me ´dico
Toluca, Metepec, Me ´xico;
3Hospital Geral de Goia ˆnia,
Goia ˆnia, Brazil;4St Augustine’s
Hospital, Durban, South Africa;
5Klinikum Eilbek, Hamburg,
Germany;6Cliniques
Universitaires Saint-Luc,
Universite ´ Catholique de
Louvain, Brussels, Belgium;
7Hospital Clinico Universidad De
Santiago, A Coruna, Spain;
8Clinica Reumatologica,
Universita ` Politecnica delle
Marche, Ancona, Italy;9Institut
de Rhumatologie de Montre ´al,
Montreal, Quebec, Canada;
10University of Alabama,
Huntsville, Alabama, USA;11The
Catholic University of Korea,
Seoul, Korea;12University of
California, San Francisco/Synarc,
San Francisco, California, USA;
13Synarc, Inc, San Francisco,
California, USA;14Bristol-Myers
Squibb, Princeton, New Jersey,
USA;15John Hopkins University,
Baltimore, Maryland, USA
Correspondence to:
Dr R Westhovens, UZ
Gasthuisberg, Department of
Rheumatology, B-3000 Leuven,
Belgium; rene.westhovens@uz.
kuleuven.ac.be
Accepted 14 December 2008
Published Online First
4 January 2009
This paper is freely available
online under the BMJ Journals
unlocked scheme, see http://
ard.bmj.com/info/unlocked.dtl
ABSTRACT
Objectives: To assess the efficacy and safety of
abatacept in methotrexate-naive patients with early
rheumatoid arthritis (RA) and poor prognostic factors.
Methods: In this double-blind, phase IIIb study, patients
with RA for 2 years or less were randomly assigned 1 : 1
to receive abatacept (,10 mg/kg) plus methotrexate, or
placebo plus methotrexate. Patients were methotrexate-
naive and seropositive for rheumatoid factor (RF), anti-
cyclic citrullinated protein (CCP) type 2 or both and had
radiographic evidence of joint erosions. The co-primary
endpoints were the proportion of patients achieving
disease activity score in 28 joints (DAS28)-defined
remission (C-reactive protein) and joint damage progres-
sion (Genant-modified Sharp total score; TS) at year 1.
Safety was monitored throughout.
Results: At baseline, patients had a mean DAS28 of 6.3,
a mean TS of 7.1 and mean disease duration of
6.5 months; 96.5% and 89.0% of patients were RF or
anti-CCP2 seropositive, respectively. At year 1, a
significantly greater proportion of abatacept plus metho-
trexate-treated patients achieved remission (41.4% vs
23.3%; p,0.001) and there was significantly less
radiographic progression (mean change in TS 0.63 vs
1.06; p=0.040) versus methotrexate alone. Over 1 year,
the frequency of adverse events (84.8% vs 83.4%),
serious adverse events (7.8% vs 7.9%), serious infections
(2.0% vs 2.0%), autoimmune disorders (2.3% vs 2.0%)
and malignancies (0.4% vs 0%) was comparable for
abatacept plus methotrexate versus methotrexate alone.
Conclusions: In a methotrexate-naive population with
early RA and poor prognostic factors, the combination of
abatacept and methotrexate provided significantly better
clinical and radiographic efficacy compared with metho-
trexate alone and had a comparable, favourable safety
profile.
In rheumatoid arthritis (RA), persistent synovitis,
early erosions and the presence of rheumatoid
factor (RF) and anti-cyclic citrullinated peptide
(CCP) type 2 antibodies are prognostic indicators
of joint destruction and loss of function.1–3The
initiation of intensive treatment early in the course
of disease is now an accepted paradigm in the
treatment of RA, with an increasing emphasis on
tight disease control and clinical remission as a
treatment goal.4 5
Studies comparing biological agents in combina-
tion with methotrexate compared with metho-
trexate alone have demonstrated significant benefit
when treatment is initiated early.6–10These trials
have also highlighted that, although methotrexate
monotherapy can be efficacious, it does not
provide optimal disease control in a proportion of
patients.
Abatacept is a soluble, fully human, recombi-
nant fusion protein that selectively modulates the
CD80/CD86:CD28 co-stimulatory signal for T-cell
activation.11The ability of abatacept to modulate
the activation of T cells, including naive T cells,
and the role of T cells in initiating disease12
suggests that abatacept has the potential to impact
the progression of pathology early in the course of
disease.
The sustained efficacy and safety of abatacept
has previously been demonstrated in patients with
moderate-to-severe established RA who have had
an inadequate response to methotrexate13and/or
anti-tumour necrosis factor agents.14Here, we
report 1-year data from a study that assessed the
efficacy, safety and tolerability of abatacept plus
methotrexate compared with methotrexate alone,
in methotrexate-naive patients with early RA
((2 years). The patients in this study represented
a particularly poor prognosis population, because
the inclusion criteria required all patients to have
erosions and to be seropositive for RF and/or anti-
CCP2, which are associated with poor radiological
outcomes.1–3
PATIENTS AND METHODS
Patients
Eligible patients were 18 years of age or older, with
RA15for 2 years or less, at least 12 tender and 10
swollen joints, C-reactive protein (CRP) 0.45 mg/
dl or greater, RF and/or anti-CCP2 seropositivity
and radiographic evidence of bone erosion of the
hands/wrists/feet. Patients were either methotrex-
ate-naive or had previous exposure of 10 mg/week
or less for 3 weeks or less, with none administered
for 3 months before providing informed consent
(there were no requirements relating to the reason
fordiscontinuation of
therapy).
previous methotrexate
Study design
This was a multi-national, randomised, double-
blind, 2-year study (ClinicalTrials.gov identifier:
NCT00122382).Theprotocol
informed consent received institutional review
board/independent ethics committee approval,
and the study was conducted in accordance with
and patients’
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the
International Conference on Harmonisation Good Clinical
Practice. Patients, sites and the site conducting radiographic
assessment remained blinded to treatment assignments until
the end of the study.
Patients were randomly assigned 1 : 1 to receive abatacept
(,10 mg/kg according to weight range) plus methotrexate or
placebo plus methotrexate for 1 year by intravenous infusion on
days 1, 15 and 29, and every 4 weeks thereafter. Methotrexate
was initially dosed at 7.5 mg/week and subsequently increased
to 15 mg at week 4 and to 20 mg at week 8, at which dose it
was maintained until study completion. Dose reduction was
permitted to a minimum of 15 mg/week due to toxicity or
intolerability.
Women who were pregnant or breastfeeding were excluded,
and patients were required to practice effective contraceptive
measures for the study duration. Patients were excluded if they
had had active Mycobacterium tuberculosis (tuberculosis) requiring
treatment within 3 years. Patients with a positive purified
protein derivative test were eligible if treatment for latent
tuberculosis had been initiated (according to local guidelines)
and there was no evidence of active tuberculosis by chest x ray
at enrollment.
Stable low-dose oral corticosteroids ((10 mg prednisone
equivalent, daily) were permitted, plus up to two corticosteroid
‘‘pulses’’ (.10 mg prednisone or equivalent oral corticosteroids
for at least three consecutive days or injectable corticosteroids)
in any 6-month period. After 6 months, the addition of one
non-biological disease-modifying antirheumatic drug (DMARD)
was permitted.
DeclarationofHelsinki andwas consistentwith
Clinical assessments
Efficacy assessments
Co-primary endpoints
Remission at year 1, defined as a disease activity score in 28
joints (DAS28; CRP) of less than 2.6;16structural damage at year
1, measured using the Genant-modified Sharp scoring system17–19
total score (TS) with a maximum possible score of 290.
Secondary endpoints
These were assessed at year 1 and included American College of
Rheumatology (ACR) 50 responses; major clinical response
(MCR; ACR70 maintained for >6 consecutive months);
DAS28 (CRP) scores; Genant-modified Sharp erosion score
(ES; maximum possible 145) and joint-space narrowing score
(JSN; maximum possible 145); physical function (defined as an
improvement of >0.3 units from baseline in the health
assessment questionnaire disability index; HAQ-DI)20and
health-related quality of life (HRQoL) measured using the
short form (SF)-36, with an improvement of 3 units or more
considered to be clinically meaningful.21
The proportion of patients achieving ACR70 and ACR90
responses and the proportion of patients without radiographic
progression (change in TS from baseline of (0) were also
evaluated.
Safety assessments
All patients who received one dose of abatacept were evaluated,
and adverse events and serious adverse events were classified
using the Medical Dictionary for Regulatory Activities version
10.1. Autoimmune and infusional events were taken from a
predefined list of events of interest. Acute infusional events
were any adverse event occurring within 1 h after initiation of
infusion.
Statistical analysis
Power calculation
It was estimated that 500 patients randomly assigned 1 : 1 to
each group would yield 99% power and detect a 20% difference
in DAS28 (CRP)-defined remission rates at the 5% level (two-
tailed test). A response rate of 15% at year 1 in the methotrexate
group and an overall 15% dropout rate was assumed. Based on
the hierarchical testing procedure for the co-primary endpoints,
this sample size also allowed the detection of a treatment
difference of 1.6 (common SD 5) with a power of 90% for mean
change from baseline in TS.
Data analysis
Unless otherwise stated, efficacy analyses were performed on all
patients randomly assigned and treated: for DAS28 (CRP)-
defined remission, ACR and HAQ-DI responses; patients who
discontinued were considered non-responders subsequent to
discontinuation. For analysis of the co-primary endpoints,
patients who received more than one corticosteroid pulse (oral
.10 mg/day prednisone equivalent for >3 consecutive days,
intramuscularly or intravenously) during year 1, or who
received more than two intra-articular injections (corticosteroid
Figure 1
Patient disposition over 1 year. MTX, methotrexate.
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pulses counted towards the limit for intra-articular injections)
from baseline to month 6 or month 6 to year 1 were classified as
non-responders after that time. For mean change from baseline
in DAS28 (CRP), HAQ-DI and SF-36, a last observation carried
forward imputation was applied. For radiographic assessment,
all available data were included. At year 1, missing data for TS,
ES and JSN were imputed by linear extrapolation for patients
with radiographs at baseline and either month 6 or discontinua-
tion (or both). For the cumulative probability plot, the observed
cumulative proportion (scores ranked from lowest to highest
and presented as a cumulative proportion of all scores) was
plotted against the actual change from baseline.
Sensitivity analysis
For the proportion of patients without radiographic progression,
an analysis was performed in which all patients who received
additional non-biological DMARD were considered non-respon-
ders. For DAS28 (CRP)-defined remission and the proportion of
patients without radiographic progression, additional analyses
were performed in which all patients who received additional
non-biological DMARD and/or a steroid pulse were considered
non-responders. For mean change from baseline to year 1 in TS,
ES and JSN, an analysis was performed considering only
completers.
Comparisons between treatment groups
For DAS28 (CRP)-defined remission, ACR, MCR and HAQ-DI
responder rates at year 1, a continuity-corrected x2test was
used. For change from baseline for DAS28 (CRP), HAQ-DI and
SF-36, comparisons were based on an analysis of covariance
model, including treatment as the main factor and baseline
value as a covariate. A non-parametric analysis of covariance
model was used for change from baseline to year 1 in TS, ES and
JSN.
RESULTS
Baseline demographics and characteristics, and patient
disposition
Five hundred and nine patients (predominantly South American
(40.3%) and European (36.0%)) were randomly assigned to
receive abatacept plus methotrexate (n = 256) or methotrexate
alone (n = 253). Demographics and baseline clinical character-
istics were comparable between groups, with an overall mean
disease duration of 6.5 months (table 1). At baseline, patients
had a high disease activity evidenced by an overall mean DAS28
(CRP) score of 6.3, and mean tender and swollen joint counts of
31.0 and 22.4, respectively. In total, eight (3.1%) patients in the
abatacept plus methotrexate group and two (0.8%) patients in
the methotrexate alone group had received methotrexate before
Table 1
Summary of baseline demographics, clinical characteristics and concomitant medications
Abatacept +
methotrexate
(n = 256)
Placebo +
methotrexate
(n = 253)
Age in years, mean (SD)
Gender, % female
Race, % white
Geographical region, n (%)
North America, n (%)
South America, n (%)
Europe, n (%)
Rest of world, n (%)
Disease duration, mean months (SD)
Tender joints, mean (SD)
Swollen joints, mean (SD)
CRP levels, mg/dl, mean (SD)
DAS28 (CRP)*, mean (SD)
HAQ-DI (0–3){, mean (SD)
RF positive, n (%)
Anti-CCP2 positive, n (%)
RF and anti-CCP2 positive, n (%)
Total x ray score{, mean (SD) (maximum 290)
Total x ray score{, median (range)
Erosion score{, mean (SD) (maximum 145)
Erosion score{, median (range)
Joint space narrowing{, mean (SD) (maximum 145)
Joint space narrowing{, median (range)
Total patients on antirheumatic concomitant medications at randomisation, n (%)
Corticosteroids, oral and/or injectable
Corticosteroids, oral ,10 mg/day
NSAID
Other non-biological DMARD
Chloroquine
Hydroxychloroquine
Sulfasalazine
50.1 (12.4)
76.6
78.9
49.7 (13.0)
78.7
86.6
46 (18.0)
103 (40.2)
88 (34.4)
19 (7.4)
6.2 (7.5)
31.3 (14.8)
22.9 (11.3)
3.1 (3.1)
6.3 (1.0)
1.7 (0.7)
246 (96.1)
236 (92.2)
227 (88.7)
7.5 (9.7)
3.4 (0.0–57.3)
5.4 (6.1)
2.9 (0–29.1)
2.1 (4.2)
0.2 (0–28.2)
243 (94.9)
131 (51.2)
95 (37.1)
203 (79.3)
7 (2.7)
3 (1.2)
4 (1.6)
0
40 (15.8)
102 (40.3)
95 (37.5)
16 (6.3)
6.7 (7.1)
30.8 (14.0)
21.9 (10.1)
3.6 (5.0)
6.2 (1.0)
1.7 (0.7)
245 (96.8)
217 (85.8)
211 (83.4)
6.7 (8.8)
3.8 (0.0–54.6)
4.8 (5.4)
3.1 (0–36.9)
1.9 (4.0)
0.5 (0–28.0)
236 (93.3)
124 (49.0)
86 (34.0)
201 (79.4)
10 (4.0)
4 (1.6)
5 (2.0)
1 (0.4)
*n = 252 for methotrexate; {n = 254 for abatacept plus methotrexate, n = 251 for methotrexate; {n = 253 for abatacept
plus methotrexate.
CCP2, cyclic citrullinated peptide type 2; CRP, C-reactive protein; DAS28, disease activity score in 28 joints; DMARD, disease-
modifying antirheumatic drug; HAQ-DI, health assessment questionnaire disability index; NSAID, non-steroidal anti-inflammatory
drug; RF, rheumatoid factor.
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randomisation. The mean baseline TS was 7.1. A total of 491
(96.5%) and 453 (89.0%) patients was seropositive for RF and
anti-CCP2, respectively; 86.1% of patients were seropositive for
both. A total of 232 (90.6%) patients in the abatacept plus
methotrexate group and 227 (89.7%) patients in the metho-
trexate group completed year 1 (fig 1). Fewer patients receiving
abatacept plus methotrexate discontinued due to lack of
efficacy (0% vs 3.2%) or adverse events (3.5% vs 4.3%), than
those receiving methotrexate alone.
Concomitant antirheumatic medications
Concomitant medications at baseline are shown in table 1. At
month 6, the mean dose of methotrexate was 18.9 mg/week
(SD 3.2) in the abatacept plus methotrexate group and 18.9 mg/
week (SD 3.4) in the methotrexate group. At year 1 the mean
dose of methotrexate was 18.1 mg/week (SD 4.2) in the
abatacept plus methotrexate group and 19.0 mg/week (SD
2.3) in the methotrexate group. The addition of non-biological
DMARD was permitted after month 6: six (2.3%) patients in
the abatacept plus methotrexate group and 17 (6.7%) patients
in the methotrexate group received additional non-biological
DMARD. Over 1 year, 136 (53.1%) patients in the abatacept
plus methotrexate group and 136 (53.8%) patients in the
methotrexate group received oral steroids, and the mean dose
was 6.7 mg (SD 3.2) versus 8.3 mg (SD 7.1), respectively. A
total of 10 (3.9%) patients in the abatacept plus methotrexate
group and 20 (7.9%) patients in the methotrexate group
received oral steroid pulses (.10 mg); the mean dose of these
was 18.2 mg (SD 4.7) versus 27.7 mg (SD 16.7), respectively.
Efficacy
Clinical efficacy
A significantly higher proportion of patients in the abatacept
plus methotrexate group achieved DAS28 (CRP)-defined remis-
sion compared with the methotrexate group by day 57 (fig 2A),
and a significant difference was maintained up to year 1 (41.4%
vs 23.3%, respectively, at year 1; p,0.001). When patients for
whom a non-biological DMARD was initiated were considered
non-responders, the proportion of responders was 41.0% (95%
CI 35.0 to 47.0) in the abatacept plus methotrexate group
compared with 21.7% (95% CI 16.7 to 26.8) in the methotrexate
group. At year 1, disease activity was significantly reduced with
abatacept plus methotrexate compared with methotrexate
alone (adjusted mean changes from baseline in DAS28 (CRP)
were 23.22 (SE 0.09) and 22.49 (SE 0.09), respectively,
p,0.001). The proportion of patients achieving ACR50 or
ACR70 responses was significantly higher in the abatacept plus
methotrexate compared with the methotrexate group by day 57
(fig 2B and C), and a significant difference was maintained up to
year 1. For abatacept plus methotrexate compared with
methotrexate alone at year 1, the proportion of patients
achieving ACR50 was 57.4 versus 42.3% (p,0.001), ACR70
Figure 2
achieving (A) Disease activity score in 28 joints (DAS28, C-reactive protein)-defined remission; (B) American College of Rheumatology (ACR) 50; (C)
ACR70; and (D) ACR90. Data are based on the intent-to-treat population, including all patients randomly assigned and treated. Patients who
discontinued were considered non-responders. p Values represent abatacept plus methotrexate versus methotrexate alone. Error bars represent 95% CI.
*p,0.01; {p,0.05; {p,0.001.
Summary of clinical efficacy. Proportion of patients in the abatacept plus methotrexate (MTX) and methotrexate alone groups over 1 year
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42.6 versus 27.3% (p,0.001) and ACR90 16.4 versus 6.7%
(p=0.001; fig 2B–D). Over 1 year, 27.3% of patients achieved an
MCR versus 11.9% of patients receiving methotrexate alone
(p,0.001).
Radiographic progression
Baseline radiographic scores are shown in table 1. At month 6
and year 1, observed data were available for 234 (91.4%) and 218
(85.2%) patients in the abatacept plus methotrexate group and
235 (92.9%) and 223 (88.1%) patients in the methotrexate
group, respectively. Figure 3 presents mean changes in Genant-
modified Sharp scores at month 6 (based on observed data) and
year 1 (linear extrapolation applied). At year 1, changes from
baseline in TS and ES were significantly lower in the abatacept
plus methotrexate group compared with the methotrexate
group (p=0.040 and p=0.033, respectively; fig 3A and B);
mean changes in JSN scores were minimal and were comparable
between the two groups (p=0.353; fig 3C). Results were
comparable when only completers were considered at the 1-year
time point (mean changes from baseline in the abatacept plus
methotrexate vs the methotrexate groups were 0.57 vs 1.05
(p=0.020) for TS, 0.46 vs 0.89 (p=0.025) for ES and 0.11 vs
0.16 (p=0.246) for JSN, respectively). The median change from
baseline in TS, ES and JSN was 0 for both groups. The
cumulative probability plot (fig 3D) shows the distribution of
change from baseline in TS over 1 year. At year 1, the
proportion of patients with no radiographic progression (TS
(0) was 61.2% (95% CI 55.0 to 67.3) in the abatacept plus
methotrexate group versus 52.9% (95% CI 46.6 to 59.2) in the
methotrexate group, with an estimated difference of 8.3% (95%
CI 21.0 to 17.5). When patients for whom a non-biological
DMARD was initiated were considered progressors, the
proportion of patients without progression was 59.1% (95%
CI 52.9 to 65.3) compared with 48.3% (95% CI 42.1 to 54.6) for
the abatacept plus methotrexate versus methotrexate groups,
and the estimate of difference was 10.7% (95% CI 1.4 to 20.0).
When patients who received steroid pulses were also considered
progressors, the proportion of patients without progression was
58.3% (95% CI 52.1 to 64.5) compared with 47.1% (95% CI 40.8
to 53.4) and the estimate of difference was 11.2% (95% CI 1.8 to
20.5).
Physical function and HRQoL
At year 1, 184 (71.9%) patients in the abatacept plus
methotrexate group compared with 157 (62.1%) patients in
the methotrexate group achieved a change from baseline of 0.3
units or greater in HAQ-DI (p=0.024 for the abatacept plus
methotrexate versus methotrexate groups). The adjusted mean
change from baseline in HAQ-DI was 20.96 (SE 0.04) for the
abatacept plus methotrexate group and 20.76 (SE 0.04) for the
methotrexate group, and the adjusted treatment difference did
not cross zero (20.20; 95% CI 20.31 to 20.08). Significant
improvements in the SF-36 were also observed: the adjusted
mean change from baseline was 11.68 (SE 0.62) versus 9.18 (SE
0.63) for the physical component summary and 8.15 (SE 0.64)
versus 6.34 (SE 0.64) for the mental component summary
Figure 3
joint-space narrowing (JSN) and (D) cumulative probability distribution of changes from baseline in Genant-modified total Sharp scores by treatment at
year 1. p Values represent abatacept plus methotrexate (MTX) versus methotrexate alone at year 1. *Based on as-observed data. {Missing data were
imputed by linear extrapolation.
Inhibition of radiographic progression. Mean change from baseline at month 6 and year 1 for (A) total score (TS); (B) erosion score (ES); (C)
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(p=0.005 for the physical component summary and p=0.046
for the mental component summary for the abatacept plus
methotrexate versus methotrexate groups).
Safety
At year 1, the frequency of adverse events, serious adverse
events and discontinuations as a result of serious adverse events
was comparable between groups (table 2). The proportion of
adverse events that led to discontinuation was 3.1% in the
abatacept plus methotrexate group compared with 4.3% in the
methotrexate group. The most frequently reported adverse
events (.10% of patients in the abatacept plus methotrexate
group) were nausea, upper respiratory tract infection and
headache. There were six deaths; two (0.8%) in the abatacept
plus methotrexate group and four (1.6%) in the methotrexate
group. Of the two deaths in the abatacept plus methotrexate
group, one patient had pneumonia and severe gastrointestinal
bleeding and the other had an acute myocardial infarction.
The most frequent infections were upper respiratory tract
infection in 26 (10.2%) versus 26 (10.3%) patients, nasophar-
yngitis in 21 (8.2%) versus 26 (10.3%) patients and influenza in
19 (7.4%) versus 23 (9.1%) patients in the abatacept plus
methotrexate versus methotrexate groups, respectively. Serious
infections were experienced by five (2.0%) patients in the
abatacept plus methotrexate group (pneumonia, gastroenteritis,
cellulitis, pseudomonal lung infection and postoperative wound
infection, one patient each) and five (2.0%) patients in the
methotrexate group (pneumonia, three patients; gastroenteritis,
one patient; and breast cellulitis and staphylococcal infection,
both in the same patient). No patients in the abatacept plus
methotrexate group discontinued due to an infection. No
opportunistic infections or cases of tuberculosis were reported
in either group.
One malignancy was reported—pancreatic cancer in the
abatacept plus methotrexate group. The patient was 67 years of
age and had received 12 infusions of abatacept (750 mg) before
the event. The event was considered unlikely to be related to
study medication and abatacept was discontinued.
Six patients (2.3%) in the abatacept plus methotrexate group
and five patients (2.0%) in the methotrexate group had adverse
events that were recorded under the category of autoimmune
disorders. Sjogren’s syndrome, sicca syndrome, systemic lupus
erythematosus, psoriasis and atrophic gastritis occurred in one
patient in each group; erythema nodosum occurred in one
patient in the abatacept plus methotrexate group.
Sixteen patients (6.3%) in the abatacept plus methotrexate
group experienced acute infusional events compared with five
patients (2.0%) in the methotrexate group. The most common
events were dizziness (five (2.0%) vs two (0.8%) patients for
abatacept plus methotrexate vs methotrexate alone, respec-
tively); all other events were reported in two or less than two
patients in either group. All acute infusional events were mild or
moderate in intensity, except for one case of severe urticaria in
the abatacept plus methotrexate group.
Two abatacept patients became pregnant (protocol viola-
tions). One patient had received one abatacept infusion, had a
positive urine pregnancy test on day 1 and experienced a
spontaneous abortion between days 1 and 30. One patient
received nine infusions of abatacept and had a positive urine
pregnancy test on day 253. Pregnancy was confirmed by
ultrasound and was subsequently terminated by induced
abortion on day 281. Both patients were discontinued from
the study as a result of pregnancy.
DISCUSSION
This is the first trial to examine the impact of the modulation of
T-cell co-stimulation with abatacept in patients with early RA.
Both primary endpoints were met. Abatacept plus methotrexate
was significantly better at inducing DAS28 (CRP)-defined
remission and reducing radiographic progression compared with
methotrexate alone. Sensitivity analyses demonstrated that
background medications did not impact the primary endpoints.
Consistent with previous studies of abatacept in patients with
established RA,22 23
clinical responses (ACR criteria) and
clinically meaningful improvements in both physical function
and HRQoL were significantly higher in the abatacept plus
methotrexate group compared with the group receiving
methotrexate alone. In addition, the safety and tolerability of
abatacept plus methotrexate was generally comparable to
methotrexate alone.
The clinical benefits observed with abatacept plus metho-
trexate were coupled with significantly lower rates of radio-
graphic progression compared with the methotrexate-alone
group. In a patient population with established RA and an
inadequate response to methotrexate from the Abatacept in
Inadequate Responders to Methotrexate (AIM) study, the rate
of structural damage progression was significantly lower during
the second year of treatment compared with the first year.19The
2-year results from the current trial will determine whether this
effect is also observed in patients with early RA. In contrast to
the lower rates of progression in TS and ES in the abatacept plus
methotrexate group, rates of JSN progression were minimal in
both groups and were not significantly different. Consistent
with other trials in patients with early RA,6–9baseline values and
Table 2
Summary of safety at year 1
Abatacept +
methotrexate
(n = 256)
n (%)
Placebo +
methotrexate
(n = 253)
n (%)
Adverse events
Discontinuations due to adverse events
Serious adverse events
Discontinuations due to serious adverse events
Infections
Serious infections
Autoimmune events
Acute infusional events
Malignancies
Deaths
217 (84.8)
8 (3.1)
20 (7.8)
3 (1.2)
132 (51.6)
5 (2.0)
6 (2.3)
16 (6.3)
1 (0.4)
2 (0.8)
211 (83.4)
11 (4.3)
20 (7.9)
3 (1.2)
139 (54.9)
5 (2.0)
5 (2.0)
5 (2.0)
0 (0.0)
4 (1.6)
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Page 7

the progression of JSN scores were low in both treatment arms,
and it is possible that there was not enough power to detect
small differences in rates of progression between the two
groups.
On-drug remission is now an important and realistic
therapeutic goal, which is increasingly reflected in the design
of clinical trials for RA. This abatacept study and an early RA
etanercept trial10are the first studies of biological agents to use
DAS28-defined remission as a primary endpoint. Remission was
also the primary endpoint of an early RA trial comparing
combination non-biological DMARD therapy with monother-
apy,24although in that trial remission was defined using the
ACR criteria.25The clinical and radiographic efficacy benefits
reported here, including the proportion of patients achieving
DAS28 (CRP)-defined remission, are comparable with those
observed in other similar trials of early RA with biological
therapies.6–8 10This is particularly encouraging because of the
poor prognostic status of the patients in this study, as all were
required to have erosions and to be RF or anti-CCP2-
seropositive at baseline. In fact, approximately 90% of the
patients were anti-CCP2 positive. These prognostic factors all
correlate with poor long-term outcomes and an aggressive
disease course.2 3
As a result of the chronic long-term nature of RA, the safety
and tolerability of a therapeutic agent is of critical importance.
In this study, the overall frequency of adverse events and serious
adverse events (including serious infections and autoimmune
events) was similar between treatment groups, and in some
cases was numerically lower in the abatacept plus methotrexate
group. Infusional reactions occurred more frequently in the
abatacept plus methotrexate group and were mostly mild in
severity. Across both groups there were no cases of tuberculosis
or opportunistic infections. One case of cancer was reported
across treatment arms (pancreatic cancer in the abatacept plus
methotrexate group). These data are consistent with the safety
findings in previous studies of abatacept-treated patients with
RA of a longer disease duration.22 23The safety and tolerability
of abatacept plus methotrexate in this study was further
supported by a high retention rate (.90%) and a low rate of
discontinuations for safety reasons.
These data should be interpreted within the context of the
trial. As these short-term, double-blind data are restricted to
1 year, the capacity to assess longer-term structural changes
or detect infrequent safety-related events may be limited. It
will be interesting to examine this group of poor prognosis
patients over the second year of this 2-year trial in order to
monitor whether the clinical, functional and radiographic
benefits observed here are maintained or improved, as has
been observed with abatacept in patients with established
RA.13 14As this study focused on a poor prognosis patient
population who were seropositive for RF and/or anti-CCP,
seronegative patients were not included. However, it should
be noted that abatacept has previously been demonstrated to
have efficacy in patients with established RA in a number of
trials that have included both seropositive and seronegative
patients.13 14
In summary, the combination of abatacept plus methotrexate
was significantly more effective in inducing DAS28 (CRP)-
defined remission and inhibiting radiographic progression than
methotrexate alone in patients with early RA and poor
prognostic factors. Coupled with a safety and tolerability
profile comparable to methotrexate alone, these data support
the early use of abatacept in RA patients with moderate to
severe disease.
Acknowledgements: The authors would like to thank Helen Clarke, MSc, Medicus
International, for her editorial assistance.
Funding: Editorial assistance was funded by Bristol-Myers Squibb, Princeton, NJ, USA.
Competing interests: RW has received consulting fees and speaker’s bureau fees from
Bristol-Myers Squibb and Schering-Plough and research support from UCB; ACX was a
member of the national board as a consultant for Bristol-Myers Squibb (2003–7) and
Abbott (2003–5); JW has received consulting fees from Bristol-Myers Squibb; JG-R is a
member of advisory boards for Wyeth, Schering-Plough, Bristol-Myers Squibb and Roche
and has received lecture fees from Abbott, Wyeth, Roche, Bristol-Myers Squibb and
Schering-Plough; WG is a consultant for Bristol-Myers Squibb, Abbott Immunology,
GeneralElectric,EsaoteandSchering-Plough,hasreceivedhonorariumfromBristol-Myers
Squibb, Abbott Immunology, General Electric, Schering-Plough and Wyeth and has
received research support from Abbott Immunology and Wyeth; BH is a consultant and
has received a grant/research support for Abbott Canada, Amgen Canada, Bristol-Myers
SquibbCanada,RocheandSchering-Plough;WSisaspeakerandprincipalinvestigatorfor
Amgen, Wyeth, Abbott, Bristol-Myers Squibb, Centocor, Genentech and Biogen Idec; HG
is a consultant for CCBR-SYNARC, Bristol-Myers Squibb, Wyeth, Roche, Servier,
GlaxoSmithKline, Merck, Biogen Idec and Genentech and has stocks in CCBR-SYNARC;
CP is an employee and has stocks in Synarc Inc; J-CB is an employee of BMS and owns
stock options; AC and RH are employees of Bristol-Myers Squibb; JB is a consultant for
Centocor andRiley,isonthe advisory boardforAbbottandAmgen,hasreceivedresearch
support for Amgen, Biogen Idec and Bristol-Myers Squibb and has received honorarium
forAbbott,Amgen,CentocorandNovartis.MR,SN,PDandSHP havenothing todisclose.
Ethics approval: The protocol and patients’ informed consent received institutional
review board/independent ethics committee approval, and the study was conducted in
accordance with the Declaration of Helsinki and was consistent with International
Conference on Harmonisation good clinical practice.
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