ARTHRITIS & RHEUMATISM
Vol. 54, No. 1, January 2006, pp 26–37
© 2006, American College of Rheumatology
The PREMIER Study
A Multicenter, Randomized, Double-Blind Clinical Trial of Combination Therapy
With Adalimumab Plus Methotrexate Versus Methotrexate Alone or Adalimumab
Alone in Patients With Early, Aggressive Rheumatoid Arthritis Who Had Not
Had Previous Methotrexate Treatment
Ferdinand C. Breedveld,1Michael H. Weisman,2Arthur F. Kavanaugh,3Stanley B. Cohen,4
Karel Pavelka,5Ronald van Vollenhoven,6John Sharp,7John L. Perez,8and
George T. Spencer-Green,8for the PREMIER Investigators
Objective. To compare the efficacy and safety of
adalimumab plus methotrexate (MTX) versus MTX
monotherapy or adalimumab monotherapy in patients
with early, aggressive rheumatoid arthritis (RA) who
had not previously received MTX treatment.
Methods. This was a 2-year, multicenter, double-
blind, active comparator–controlled study of 799 RA
patients with active disease of <3 years’ duration who
had never been treated with MTX. Treatments included
adalimumab 40 mg subcutaneously every other week
plus oral MTX, adalimumab 40 mg subcutaneously
every other week, or weekly oral MTX. Co-primary end
points at year 1 were American College of Rheumatology
50% improvement (ACR50) and mean change from
baseline in the modified total Sharp score.
Results. Combination therapy was superior to
both MTX and adalimumab monotherapy in all out-
comes measured. At year 1, more patients receiving
combination therapy exhibited an ACR50 response
(62%) than did patients who received MTX or adali-
mumab monotherapy (46% and 41%, respectively; both
P < 0.001). Similar superiority of combination therapy
was seen in ACR20, ACR70, and ACR90 response rates
at 1 and 2 years. There was significantly less radio-
graphic progression (P < 0.002) among patients in the
combination treatment arm at both year 1 and year 2
(1.3 and 1.9 Sharp units, respectively) than in patients
in the MTX arm (5.7 and 10.4 Sharp units) or the
adalimumab arm (3.0 and 5.5 Sharp units). After 2
years of treatment, 49% of patients receiving combina-
tion therapy exhibited disease remission (28-joint Dis-
ease Activity Score <2.6), and 49% exhibited a major
clinical response (ACR70 response for at least 6 contin-
uous months), rates approximately twice those found
Supported by Abbott Laboratories.
1Ferdinand C. Breedveld, MD: Leiden University Medical
Center, Leiden, The Netherlands;2Michael H. Weisman, MD: Cedars-
Sinai Medical Center, Los Angeles, California;3Arthur F. Kavanaugh,
MD: University of California San Diego Center for Innovative Ther-
apy, La Jolla;4Stanley B. Cohen, MD: University of Texas Southwest-
ern Medical Center, Dallas;5Karel Pavelka, MD: Institute of Rheu-
matology, Prague, Czech Republic;6Ronald van Vollenhoven, MD:
Karolinska Hospital, Stockholm, Sweden;7John Sharp, MD: Univer-
sity of Washington, Seattle;8John L. Perez, MD, George T. Spencer-
Green, MD, MS: Abbott Laboratories, Parsippany, New Jersey.
Dr. Breedveld has received consulting fees or honoraria (less
than $10,000 per year) from Centocor, Schering-Plough, Amgen/
Wyeth, and Abbott. Dr. Weisman has received consulting fees or
honoraria (less than $10,000 per year) from Abbott, Bristol-Myers
Squibb, Centocor, Amgen/Wyeth, Roche, Human Genome Sciences,
Elan/Biogen, Regeneron, and Genentech. Dr. Kavanaugh has per-
formed clinical studies for Abbott, Amgen, Centocor, Biogen-Idec,
Bristol-Myers Squibb, and Genentech. Dr. Cohen has received con-
sulting fees or honoraria (less than $10,000 per year) from Abbott,
Genentech, Biogen IDEC, Scios, Amgen, Sanofi-Aventis, Chelsea
Therapeutics, and Xencor. Dr. van Vollenhoven has received consult-
ing fees or honoraria (less than $10,000 per year) from Abbott,
Centocor, Schering-Plough, and Wyeth. Dr. Sharp has received con-
sulting fees or honoraria (more than $10,000 per year) from Abbott,
Amgen, Aventis, Centocor, Fujisawa, and Wyeth and consulting fees
or honoraria (less than $10,000 per year) from Bristol-Myers Squibb
and Schering. Dr. Perez is a member of Abbott’s stock retirement plan.
Dr. Spencer-Green owns stock in Abbott.
Address correspondence and reprint requests to Ferdinand C.
Breedveld, MD, Department of Rheumatology, Leiden University
Medical Centre, Albinusdreef 2, C4-R Postbox 9600, Leiden 2300 RC,
The Netherlands. E-mail: email@example.com.
Submitted for publication March 31, 2005; accepted in revised
form September 21, 2005.
among patients receiving either monotherapy. The ad-
verse event profiles were comparable in all 3 groups.
Conclusion. In this population of patients with
early, aggressive RA, combination therapy with adali-
mumab plus MTX was significantly superior to either
MTX alone or adalimumab alone in improving signs
and symptoms of disease, inhibiting radiographic pro-
gression, and effecting clinical remission.
Rheumatoid arthritis (RA) is a chronic inflam-
matory disorder characterized by progressive inflamma-
tory synovitis and destruction of articular cartilage and
marginal bone (1). Joint erosions can be seen within 6
months of disease onset in the majority of patients, and
occur more rapidly in the first year compared with late
disease (2,3). Although most conventional disease-
modifying antirheumatic drug (DMARD) therapies
have been shown to slow joint destruction, radiographic
progression does not stop (3–9). Historical studies have
demonstrated that moderate disability within 2 years of
diagnosis is not uncommon, and after 10 years, up to
30% of patients may be unable to work (10,11). Remis-
sion rarely occurs (5,12).
There is little evidence that current therapies can
reverse the sequelae of RA once they occur. Radio-
graphic damage progresses in a linear manner after the
first year, and if radiographic repair occurs, it is uncom-
mon (13). Improvement in disability, as measured by
Health Assessment Questionnaire (HAQ) disability in-
dex (DI) scores (14), can be demonstrated in the short
term with DMARD therapy, but the magnitude of this
improvement is substantially greater in patients with
early disease compared with those whose disease is more
advanced (15–20). Longitudinal studies of RA patients
show that there is a progressive decline in HAQ scores
with time (17,21). In patients with late disease, disability
correlates with radiographic evidence of joint damage
(9,11,22). Like radiographic progression, disability is
also progressive, and once joint damage has occurred
and patients have become disabled, there is a low
likelihood of full recovery (10,23).
Early intervention that prevents irreversible dam-
age would appear to offer the best opportunities for
achievement of favorable outcomes in patients with
early, aggressive RA. In early intervention studies in
which radiographic progression has been measured, this
therapeutic window can be as short as months (24–27).
In addition to early therapy, combination treatment,
rather than monotherapy, has been shown to result in
more favorable short-term and long-term outcomes
(24,28–30). This has been shown with traditional
DMARDs as well as with biologic therapies (31,32).
Although few studies have investigated outcomes with a
5–10-year horizon, extrapolation of findings in short-
term (1–2-year) studies suggests that early, aggressive
combination treatment has the highest likelihood of
preventing the long-term sequelae of RA. No single
study has compared the efficacy of anti–tumor necrosis
factor (anti-TNF) therapy alone, MTX therapy alone, or
the combination of MTX and anti-TNF therapy in
patients with early RA who had never been treated with
MTX. The present study was undertaken to compare the
efficacy of early intervention with combination therapy
(adalimumab plus MTX) versus either MTX mono-
therapy or adalimumab monotherapy in patients with
PATIENTS AND METHODS
This clinical trial, termed the PREMIER study, was
sponsored by Abbott Laboratories and conducted at 133
investigational sites (11 in Australia, 85 in Europe, and 37 in
North America). PREMIER study investigators are listed in
Appendix A. An independent data safety monitoring board,
composed of external medical expert consultants, reviewed the
safety and progress of the study regularly. A central institu-
tional review board or independent ethics committee at each
participating site approved the study, and all patients provided
written informed consent.
To be eligible for the study, patients had to be 18 years
of age or older and had to have disease that fulfilled the
American College of Rheumatology (ACR; formerly, the
American Rheumatism Association) 1987 revised criteria for
the classification of RA (33), with a disease duration of ?3
years. In addition, they had to have had ?8 swollen joints, ?10
tender joints, and an erythrocyte sedimentation rate of ?28
mm/hour or C-reactive protein (CRP) concentration of ?1.5
mg/dl, and had to either be rheumatoid factor positive or have
had at least 1 joint erosion. Patients who had received treat-
ment with MTX, cyclophosphamide, cyclosporine, azathio-
prine, or ?2 other DMARDs were excluded. Patients were
screened for tuberculosis (TB) prior to receiving study drug
(with a purified protein derivative [PPD] at North American
and Australian sites and by chest radiography at European
sites). Patients who were, in the investigators’ opinions, at high
risk for TB were allowed to enroll in the study and take
concomitant isoniazid (INH; up to 300 mg/day).
The study was a multicenter, randomized, double-
blind, active comparator–controlled, phase III clinical trial.
Patients were randomized to 1 of 3 treatment groups: adali-
mumab 40 mg subcutaneously every other week plus weekly
oral MTX (20 mg/week); adalimumab 40 mg subcutaneously
every other week (adalimumab plus placebo); or weekly oral
MTX (MTX plus placebo). Hence, all patients received an
injection (adalimumab or placebo) and an oral medication
(MTX or placebo). In addition, all patients received concom-
itant folic acid at a dosage of 5–10 mg/week. The study
included a screening period, as well as a 4-week washout
ADALIMUMAB PLUS MTX TREATMENT OF RA27
period for patients taking other DMARDs. A blinded, 2-year
treatment period was chosen to more completely assess antic-
ipated treatment effects over time.
For patients in whom response according to the ACR
20% improvement criteria (ACR20) (34) was not achieved at
week 16 or later, the protocol mandated that the injectable
study medication (adalimumab or placebo) be increased to
weekly dosing after the dosage of the oral study medication
(MTX or placebo) had been optimized. Dosage escalation was
permitted at week 16 or later, but “de-escalation” back to
every-other-week injectable drug was not permitted. For pa-
tients randomized to receive MTX monotherapy, this decrease
in the dosing interval resulted in a dosage escalation of
placebo, and for those randomized to receive either combina-
tion therapy or adalimumab monotherapy, this resulted in a
dosage escalation of adalimumab.
MTX was initiated at a dosage of 7.5 mg/week for the
first 4 weeks of the study. If the MTX was well-tolerated and
the patient continued to have any swollen or tender joints, the
dosage was increased to 15 mg/week during weeks 4–8, and to
20 mg/week at week 9. In cases of typical MTX toxicities (e.g.,
increased aspartate transaminase or alanine transaminase, or
gastrointestinal adverse effects), the MTX dosage could be
reduced to as low as 7.5 mg/week. If MTX had to be reduced
to ?7.5 mg/week, the patient was withdrawn from the study.
The co-primary efficacy end points at year 1 were 1)
the percentage of patients in whom an ACR50 response was
achieved (35) and 2) the mean change from baseline in the
modified total Sharp score (36), comparing the combination
therapy group versus the MTX monotherapy group. An
ACR50 response was chosen as a primary end point to reflect
the expectations of achieving a higher magnitude of clinical
improvement now seen with the use of TNF inhibitors, which
were not available when the ACR definition of improvement
was developed. The ACR50 was defined in a manner analo-
gous to the ACR definition of improvement (34,35,37). Pa-
tients were considered to have achieved an ACR50 response if
the following 3 criteria were met: 1) ?50% improvement from
baseline in the tender joint count; 2) ?50% improvement from
baseline in the swollen joint count; and 3) ?50% improvement
from baseline in at least 3 of the following 5 parameters:
patient’s assessment of pain, patient’s global assessment of
disease activity, physician’s global assessment of disease activ-
ity, patient’s assessment of physical function (HAQ DI), and
acute-phase reactant value (CRP).
ACR responses were calculated using an intention-to-
treat analysis, for which patients who discontinued the study
prior to reaching the end point were considered to be nonre-
sponders. The study had 80% power to detect a difference of
at least 13% in ACR response rates between adalimumab plus
MTX combination therapy and MTX monotherapy.
Change from baseline in the modified total Sharp
score was used to evaluate inhibition of progression of joint
structural damage. The maximum possible value for the total
Sharp score was 398 (38). Single-emulsion radiographs of the
hands (posteroanterior view) and feet (anteroposterior view)
were obtained and digitized for blinded reading. Four readers
with no knowledge of the treatment allocations were used for
this study, with 2 of these readers reviewing the radiographs of
each patient and assessing joint erosions (0–5 scale) and joint
space narrowing (0–4 scale), using the modified total Sharp
score. During the readings, a computer randomly displayed
patient images. Images from multiple time points were dis-
played simultaneously to allow for comparative assessment,
and the readers were blinded with regard to the time point at
which the displayed images had been obtained.
Additional secondary efficacy end points included the
percentage of patients in whom clinical remission was achieved
(defined as a 28-joint Disease Activity Score [DAS28]  of
?2.6), improvement in physical function (as measured by the
change from baseline in the HAQ DI), percentage of patients
in whom an ACR20, ACR50, ACR70, or ACR90 response was
achieved at year 2, change from baseline in the modified total
Sharp score at year 2, and maintained clinical response
through 104 weeks, defined as an ACR70 response for ?6
continuous months (4,17,34,35,37,40,41).
Safety assessments, including the monitoring of ad-
verse events (AEs) and measurements of laboratory para-
meters, were carried out at regular intervals during the course
of the study. AEs that were recorded as “serious” were those
that met regulatory guidance or required prolonged hospital-
ization, were life-threatening or resulted in death, caused
significant or permanent disability, or in the opinion of the
investigator, were significant medical events.
Statistical analyses for dichotomous variables were
conducted using Pearson’s chi-square test for ACR response
and the Mann-Whitney U test for radiographic progression.
All statistical tests were 2-sided. P values less than 0.05 were
considered significant. All patients who were randomized and
received at least 1 injection of study medication were included
in the efficacy and safety analyses.
Demographic and baseline clinical characteristics
of the patients reflected a population with early RA and
were comparable among the 3 treatment groups. In each
treatment group, the mean duration of RA at baseline
was ?1 year. Moreover, 57% of the study patients had
had RA for ?6 months. Similar percentages of patients
in each treatment group had previously received treat-
ment with a DMARD (other than MTX). Among all
patients who previously took DMARDs, 41% had re-
ceived antimalarial agents, and 39% had received sul-
fasalazine. Approximately one-third of patients in each
treatment group were taking corticosteroids at baseline.
The mean corticosteroid dosage (prednisone equivalent)
was 6.7 mg/day in the combination treatment arm, 6.7
mg/day in the adalimumab monotherapy arm, and 6.4
mg/day in the MTX monotherapy arm. There were
small, statistically significant baseline differences among
treatment groups in the HAQ DI (P ? 0.012), patient’s
global assessment of disease activity (P ? 0.048), pa-
tient’s assessment of pain (P ? 0.041), and joint erosion
score (P ? 0.030). Mean baseline total Sharp score and
joint space narrowing scores were higher in the MTX
monotherapy arm than in either of the adalimumab
28BREEDVELD ET AL
arms, but these differences did not reach statistical
significance. In post hoc analyses, adjustment for these
baseline imbalances had no effect on the statistical
significance of the differences at end point among the 3
treatment arms. Comparably small numbers of patients
had no erosions at baseline (7% of patients in the
combination therapy group, 6% in the adalimumab
group, and 5% in MTX group).
A total of 799 patients not previously treated with
MTX were enrolled in the study, and 539 completed 2
years of treatment. Significantly more patients who
received combination therapy (75.7% [203 patients])
completed the 2-year, double-blind treatment period,
compared with patients who received monotherapy with
either adalimumab (60.9% [167 patients]) or MTX
(65.8% [169 patients]) (P ? 0.001 across treatment
arms). A total of 32 patients in the combination therapy
group (11.9%), 26 patients in the adalimumab mono-
therapy group (9.5%), and 19 patients in the MTX
monotherapy group (7.4%) withdrew because of an
adverse event, but these differences were not statistically
significant (P ? 0.21). Only 13 patients in the combina-
tion therapy group (4.9%) withdrew as a result of lack of
efficacy, versus 52 (19.0%) in the adalimumab mono-
therapy group and 46 (17.9%) in the MTX monotherapy
ACR response. Following 1 year of treatment, an
ACR50 response (the primary end point) had been
achieved in 62% of patients who had received combina-
tion therapy, compared with 41% of patients who had
received adalimumab monotherapy and 46% of patients
who had received MTX monotherapy (P ? 0.001 for
both comparison treatments versus combination ther-
apy) (Figure 1). There was no statistically significant
difference between the adalimumab and MTX mono-
therapy treatment groups. At year 2, ACR50 responses
were sustained in the combination treatment group, and
continued to be clinically and statistically superior to
Baseline characteristics according to treatment group*
Adalimumab plus MTX
(n ? 268)
(n ? 274)
(n ? 257)
No. (%) female/male
Years of RA
Years of RA, no. (%)
Previously took DMARDs, no. (%)
Taking corticosteroids, no. (%)
Tender joint count, 0–68
Swollen joint count, 0–66
C-reactive protein, mg/dl
Physician’s global assessment of disease activity,
Patient’s global assessment of disease activity,
Patient’s assessment of pain, 100-mm VAS†
Joint space narrowing score
Estimated annual TSS progression,
TSS duration of RA
51.9 ? 14.0
193 (72.0)/75 (28.0)
52.1 ? 13.5
212 (77.4)/62 (22.6)
52.0 ? 13.1
190 (73.9)/67 (26.1)
0.7 ? 0.80.7 ? 0.80.8 ? 0.9
30.7 ? 14.2
21.1 ? 11.2
3.9 ? 4.2
1.5 ? 0.6
65.1 ? 17.6
31.8 ? 13.6
21.8 ? 10.5
4.1 ? 3.9
1.6 ? 0.6
67.6 ? 18.6
32.3 ? 14.3
22.1 ? 11.7
4.0 ? 4.0
1.5 ? 0.6
65.6 ? 17.7
66.8 ? 22.167.8 ? 23.363.0 ? 25.0
62.5 ? 21.3
6.3 ? 0.9
64.6 ? 23.6
6.4 ? 0.9
59.6 ? 24.3
6.3 ? 0.9
18.1 ? 20.1
11.0 ? 12.3
7.1 ? 9.6
18.8 ? 19.0
11.3 ? 11.3
7.5 ? 9.4
21.9 ? 22.2
13.6 ? 13.6
8.2 ? 10.7
* Except where indicated otherwise, values are the mean ? SD. RA ? rheumatoid arthritis; DMARDs ? disease-modifying antirheumatic drugs;
HAQ ? Health Assessment Questionnaire; DI ? disability index; VAS ? visual analog scale; DAS28 ? 28-joint Disease Activity Score; TSS ? total
† P ? 0.05 among treatment arms.
‡ n ? 267 in the adalimumab plus methotrexate (MTX) group, 271 in the adalimumab monotherapy group, and 251 in the MTX monotherapy group.
ADALIMUMAB PLUS MTX TREATMENT OF RA 29
responses in both the adalimumab and MTX mono-
therapy treatment groups (P ? 0.001). Similar statisti-
cally significant patterns were observed for ACR20,
ACR70, and ACR90 responses.
Radiographic progression. There was signifi-
cantly less radiographic disease progression at 6 months,
1 year, and 2 years among patients who had received
combination therapy (Figure 2) compared with those in
either monotherapy arm. At year 1, patients treated with
combination therapy had a mean increase in total Sharp
score (a co-primary end point) of 1.3 Sharp units,
compared with 3.0 units in those receiving adalimumab
monotherapy (P ? 0.002), and 5.7 units in those receiv-
ing MTX monotherapy (P ? 0.001). At year 2, patients
treated with adalimumab plus MTX continued to have
significantly less radiographic progression (mean change
1.9 Sharp units) compared with those treated with either
adalimumab monotherapy (5.5 units) or MTX mono-
therapy (10.4 units) (P ? 0.001 for both comparisons).
Adjustment by linear regression for the higher mean
baseline erosion score among patients in the MTX arm
did not alter the statistical findings. Although ACR
responses were comparable in the 2 monotherapy arms,
there was significantly less progression in the adali-
mumab monotherapy arm compared with the MTX
monotherapy arm at 6 months (2.1 versus 3.5), 1 year
(3.0 versus 5.7), and 2 years (5.5 versus 10.4) (all P ?
There was significantly less change from baseline
in erosion scores among patients receiving combination
therapy at 6 months, 1 year, and 2 years (0.6, 0.8, and 1.0,
respectively) than in patients receiving adalimumab
monotherapy (1.3, 1.7, and 3.0, respectively) or MTX
monotherapy (2.4, 3.7, and 6.4, respectively) (P ? 0.001
for all comparisons). Similarly, the combination therapy
group had significantly less change in joint space nar-
rowing scores at 6 months, 1 year, and 2 years (0.2, 0.5,
and 0.9, respectively) compared with patients receiving
adalimumab monotherapy (0.8, 1.3, and 2.6, respec-
tively) or MTX monotherapy (1.0, 2.0, and 4.0, respec-
tively) (P ? 0.001 for all comparisons).
During year 2, radiographic progression among
patients who were treated with MTX monotherapy
occurred at approximately the same rate as seen during
Figure 2. Mean change from baseline in total Sharp scores over time,
by treatment group. ? ? P ? 0.001 versus adalimumab alone and
versus methotrexate (MTX) alone; § ? P ? 0.001 versus MTX alone;
?? ? P ? 0.002 versus adalimumab alone and P ? 0.001 versus MTX
Figure 1. American College of Rheumatology 20% response (ACR20), ACR50, ACR70, and ACR90 at years 1 and 2, by treatment group. § ?
P ? 0.001 versus adalimumab (ADA) alone and P ? 0.022 versus methotrexate (MTX) alone; † ? P ? 0.001 versus ADA alone and P ? 0.002 versus
MTX alone; # ? P ? 0.043 versus ADA alone; ? ? P ? 0.001 versus ADA alone and versus MTX alone.
30BREEDVELD ET AL
year 1 (5.7 Sharp units from baseline to year 1 and 4.7
units from year 1 to year 2), while patients who received
combination therapy had less than half the progression
in year 2 than they had experienced in year 1 (1.3 units
from baseline to year 1 and 0.6 units from year 1 to year
The percentage of patients with no radiographic
progression (change in total Sharp score ?0.5 from
baseline) was higher in the combination arm (64% at
year 1 and 61% at year 2) than in the adalimumab
monotherapy arm (51% and 45%; P ? 0.01) or the MTX
monotherapy arm (37% and 34%; P ? 0.01). The
difference in these percentages between the adali-
mumab monotherapy arm and MTX monotherapy arm
was also statistically significant (P ? 0.01).
Clinical remission. DAS28. Following 1 year of
treatment, clinical remission (defined as DAS28 ?2.6)
(32) was achieved in 43% of patients receiving combi-
nation therapy, compared with 23% of patients receiving
adalimumab monotherapy and 21% of patients receiving
MTX monotherapy (both P ? 0.001) (Figure 3). Simi-
larly, following 2 years of treatment, clinical remission
had been attained in 49% of patients receiving combi-
nation therapy, compared with 25% of patients receiving
adalimumab monotherapy and 25% of patients who had
received MTX monotherapy (both P ? 0.001).
Major clinical response. After 2 years of treat-
ment, 49% of patients receiving combination therapy
exhibited a major clinical response, compared with 25%
and 27% of patients, respectively, in the adalimumab
and MTX monotherapy groups (P ? 0.001).
HAQ DI. Following 1 year of treatment, patients
receiving combination therapy had significantly greater
improvement in the HAQ DI (mean ? SD ?1.1 ? 0.6
units) compared with patients receiving adalimumab
monotherapy (?0.8 ? 0.7 units; P ? 0.002) and MTX
monotherapy (?0.8 ? 0.6 units; P ? 0.001). Improve-
ment in the HAQ DI at year 2 among patients in the
combination treatment arm (?1.0 ? 0.7 units) was
statistically superior to that among patients in the MTX
monotherapy arm (?0.9 ? 0.6 units; P ? 0.05) but not
the adalimumab monotherapy arm (?0.9 ? 0.7 units;
P ? 0.058). At year 2, significantly more patients in the
combination therapy arm (72%) had achieved improve-
ment in the HAQ DI of ?0.22 units from baseline
compared with the adalimumab monotherapy arm
(58%) or the MTX monotherapy arm (63%) (both P ?
0.05).Thirty-three percent of patients in the combination
therapy arm compared with 19% in each of the mono-
therapy arms had HAQ DI scores of 0 at year 2 (P ?
Dosage adjustment. As described above, the dos-
age of MTX could be adjusted if toxicity or intolerance
developed. The mean MTX dosage was 16.9 mg/week in
the MTX monotherapy group and 16.3 mg/week in the
combination therapy group. At year 1, 69% of patients
in the combination therapy arm and 82% of patients in
the MTX monotherapy arm were taking MTX at a
dosage of 20 mg weekly. At year 2, 64% of patients in the
combination therapy arm and 80% of patients in the
MTX monotherapy arm were taking 20 mg of MTX
Figure 3. Clinical remission (28-joint Disease Activity Score ?2.6) at year 1 and year 2 and major clinical response (ACR70 response achieved and
sustained continuously for ?6 months) at year 2, by treatment group. ? ? P ? 0.001 versus adalimumab alone and versus MTX alone. See Figure
1 for definitions.
ADALIMUMAB PLUS MTX TREATMENT OF RA 31
Increased dosing with injectable study medica-
tion (adalimumab or placebo) to weekly injections was
mandated by the study protocol for those patients in
whom an ACR20 response had not been achieved in 2
consecutive visits after week 16. Twenty-nine of 268
patients in the combination therapy group (11%), 69 of
274 patients in the adalimumab monotherapy group
(25%), and 52 of 257 patients in the MTX monotherapy
group (20%) underwent dosage escalation during year 1.
Of these dosage escalators, 12 of 29 in the combination
therapy arm (41%), 20 of 69 in the adalimumab alone
arm (29%), and 25 of 52 in the MTX alone arm (48%)
had not achieved an ACR20 response any time prior to
dosage escalation. Weekly dosing had a minimal effect
on improving efficacy parameters in these patients (Ta-
ble 2). Similar results were seen following dosage esca-
lation in patients who had achieved a prior ACR re-
sponse (data not shown). The percentage of patients
who had not achieved an ACR20 response and became
ACR50 responders after dosage escalation in year 1 was
similar in those receiving active injectable drug (1% of
the patients in the combination therapy arm and 1% in
the adalimumab monotherapy arm) and those receiving
injectable placebo drug (1% in the MTX monotherapy
arm). Thus, there was no impact on the primary efficacy
end point. Similarly, dosage escalation had a minimal
effect on the percentage of patients who achieved an
ACR20 response, ACR70 response, DAS28 remission,
or major clinical response.
Safety. The percentages of patients with reported
AEs were comparable in the combination therapy, adali-
mumab monotherapy, and MTX monotherapy groups
(262 of 268 patients [97.8%], 262 of 274 patients
[95.6%], and 245 of 257 patients [95.3%], respectively).
No statistically significant differences were observed
across treatment groups in the percentages of patients
who experienced serious AEs (P ? 0.192).
The overall rate of infectious AEs did not differ
significantly among the 3 treatment groups (123, 110,
and 119 events per 100 patient-years in the combination
therapy, adalimumab monotherapy, and MTX mono-
therapy groups, respectively) (Table 3). The rate of
serious infections in the adalimumab monotherapy
group was significantly lower than that in the combina-
tion treatment group, but not significantly different
compared with the MTX monotherapy group. In the
combination therapy arm, 9 serious infections were
reported, including 3 pulmonary infections (including 1
case of pleural TB) and 1 case each of sinus infection,
wound infection, septic arthritis, infected hygroma, cel-
lulitis, and urinary tract infection. In the adalimumab
monotherapy arm, the 3 serious infections included 1
Percentage of patients who became responders at years 1 and 2 after increasing the frequency of injections to weekly*
Year 1Year 2 Year 1Year 2 Year 1Year 2
Major clinical response†
* ACR20 ? American College of Rheumatology 20% improvement (see Table 1 for other definitions).
† ACR70 improvement for ?6 continuous months.
Patients with treatment-emergent adverse events*
Adalimumab plus MTX
(n ? 268, patient-
years ? 482)
(n ? 274, patient-
years ? 435)
(n ? 257, patient-
years ? 429)
Serious adverse events
Infectious adverse events
* Values are the number of events per 100 patient-years. MTX ? methotrexate.
† P ? 0.05 versus adalimumab monotherapy.
32BREEDVELD ET AL
case each of pneumonia, cellulitis, and septic arthritis. In
the MTX monotherapy arm, the 7 serious infections
consisted of 2 cases of pneumonia and 1 each of septic
arthritis, sinusitis, abscess, bacteremia, and parotitis.
There was 1 death from infection in the MTX mono-
therapy arm, in a 58-year-old man in whom pneumonia
developed 25 days after MTX treatment began.
Thirty patients in the study were identified by the
investigator as being at high risk for TB and received
prophylactic therapy (primarily INH) prior to the initi-
ation of study medication. One patient in the adali-
mumab plus MTX treatment group developed pleural
TB. She was a 78-year-old woman in Belgium who had
no PPD test performed, had a negative chest radiogra-
phy result at baseline, and did not receive INH prophy-
laxis. She recovered with treatment. No other opportu-
nistic infections were seen.
One patient in the adalimumab monotherapy
group developed a lupus-like reaction with positive
antinuclear antibody and was withdrawn from the study.
No demyelinating events were observed.
Ten malignancies were found among patients in
the study. Two were observed in the combination treat-
ment arm (ovarian and prostate), 4 in patients who had
received adalimumab monotherapy (breast, colon, mul-
tiple myeloma, and metastatic cancer with unknown
primary site), and 4 in patients who had received MTX
(lymphoma, melanoma, prostate, and breast).
The standardized mortality ratio (SMR) was cal-
culated by using the World Health Organization mortal-
ity data for the US published in 1997, categorized by age
and sex. Six patients died during the study: 1 patient in
the combination treatment arm died (of ovarian cancer),
4 patients in the adalimumab monotherapy arm died (1
sudden death at home in a patient with chronic obstruc-
tive pulmonary disease and pulmonary hypertension, 1
died of metastatic liver cancer [unknown primary site], 1
died of metastatic colon cancer, and 1 died of liver
failure [the patient had preexisting cirrhosis]), and 1
patient in the MTX monotherapy arm died (of pneumo-
nia). The overall SMR in the PREMIER study was 0.463
(95% confidence interval 0.169–1.007).
The findings presented here demonstrate that
combination therapy with adalimumab plus MTX was
superior to either adalimumab monotherapy or MTX
monotherapy in the treatment of adult patients with
recently diagnosed moderate-to-severe RA not previ-
ously treated with MTX. The superiority with respect to
ACR responses, inhibition of radiographic progression,
improvement in the HAQ, and measures of clinical
remission was seen after both 1 year and 2 years of
therapy. Substantially more patients receiving combina-
tion therapy had no radiographic progression compared
with those receiving MTX monotherapy.
This study confirms the effectiveness of combina-
tion therapy over monotherapy, as has been shown in
other published studies (31,32,42–44). However, unlike
the Trial of Etanercept and Methotrexate with Radio-
graphic Patient Outcomes study (31), it was carried out
in RA patients who had early, aggressive disease and had
not previously been treated with MTX. Unlike the Early
Rheumatoid Arthritis (etanercept monotherapy) (ERA)
(44) and Active-Controlled Study of Patients Receiving
Infliximab for the Treatment of Rheumatoid Arthritis of
Early Onset (32) studies, the PREMIER study included
3 treatment arms (combination therapy, anti-TNF ther-
apy alone, and MTX alone, in patients with early, rapidly
progressive RA studied for 2 years).
DAS remission, defined as a DAS28 of ?2.6,
represents very low disease activity (40). With the
DAS28 as a measure of clinical remission, nearly half of
the patients (49%) who had received combination ther-
apy achieved a DAS28 of ?2.6 at 2 years, approximately
twice the number in either monotherapy arm. As an-
other measure of the magnitude of the response in the
combination therapy arm, a maintained clinical response
(defined in Food and Drug Administration [FDA] guid-
ance as achieving an ACR70 response and maintaining it
for ?6 consecutive months) was achieved by 49% of the
patients who received combination therapy. This per-
centage is also approximately twice the rate seen in
patients who had received either adalimumab mono-
therapy (25%) or MTX monotherapy (27%).
An unusual finding at baseline was the magnitude
of radiographic damage present in patients who had an
average disease duration of ?1 year. The mean baseline
radiographic scores were numerically higher in the MTX
arm than in either of the adalimumab arms, although
this reached statistical significance only for erosion
scores. However, the estimated duration of disease prior
to study entry was slightly higher in the MTX arm (0.8
years) than the adalimumab arms (0.7 years for both),
which could partly explain this difference.
The projected annual progression in the total
Sharp score (calculated by dividing the baseline total
Sharp score by the mean duration of disease at baseline)
in this early RA population was 25.9 units, and was
similar across all 3 treatment arms. This is significantly
greater than the rate that has been estimated to take
ADALIMUMAB PLUS MTX TREATMENT OF RA 33
place in an RA population treated with traditional
DMARDs (4,8,45), and reflects a population with very
aggressive disease. This is likely a result of the selection
criterion that required the presence of rheumatoid fac-
tor or erosive disease at baseline. As such, this popula-
tion is unique in that it represents a subset of patients
with particularly aggressive RA who are at high risk for
radiographic progression, and may not be generalizable
to all patients with early RA. Sokka and Pincus have
suggested that many patients followed up by rheuma-
tologists may have disease that is less severe than that in
patients studied in clinical trials (46). However, the
results from this study demonstrate that in patients with
early RA who are identified by the practicing rheuma-
tologist as having active disease with evidence of aggres-
sive radiographic progression, early use of combination
therapy with a TNF inhibitor is appropriate.
Furthermore, blinded randomized controlled tri-
als such as this do not necessarily follow the paradigm
that a clinician might follow in managing a patient with
RA since, during the course of a clinical trial, all RA
treatments, except as noted, cannot be changed. In
routine clinical practice, flares of disease would likely be
managed by adjusting medication dosages or changing
medications. In a randomized trial such as this one, such
changes would mandate discontinuation because of pro-
tocol violation or treatment failure. Thus, there may be
an underestimate of the benefits of a specific treatment
in a controlled trial, because patients in clinical practice
might be able to continue treatment with modest med-
ication adjustments. In the conservative analysis used in
this study, these patients were classified as nonre-
sponders and were not further analyzed.
While the ACR, DAS28, and HAQ responses
were all statistically similar between the adalimumab
and MTX monotherapy arms in this study, there was
significantly less radiographic progression among pa-
tients in the adalimumab monotherapy arm at both year
1 and year 2. This suggests that there may be separate
mechanistic pathways, one that mediates improvement
in signs and symptoms and is similarly responsive to
either TNF inhibition or MTX therapy, and another that
mediates joint damage and is more responsive to TNF
inhibition than to MTX therapy. This observation is
similar to that seen in the ERA trial, which compared
MTX monotherapy with etanercept therapy, and in
which ACR responses were similar between treatment
arms, but with a trend toward less radiographic progres-
sion in the etanercept arm (44). However, combination
therapy was not studied in that trial.
All treatments were generally safe and well-
tolerated in this study, with rates and types of AEs
similar across all 3 treatment groups and comparable
with reported findings in controlled trials of other TNF
antagonists (31,32,38,44). The rate of serious infections,
defined as infectious events that met FDA criteria for
seriousness (generally requiring hospitalization), was
higher in the combination therapy arm than in the
adalimumab monotherapy arm, but was not statistically
different from that in the MTX treatment arm. How-
ever, the study was not powered to detect differences in
uncommon events such as serious infections, which
occurred at a rate of ?5% in this study, and the results
must be interpreted in this context. The actual rate of
serious infections (2.9 events per 100 patient-years) was
similar to rates reported in patients with early RA
treated with etanercept (2.6 per 100 patient-years) but
lower than the rates reported in patients with long-
standing RA treated with either adalimumab or etaner-
cept (4.8–6.0 per 100 patient-years) (38,42–44,47).
While direct comparisons among different trials cannot
be made with precision, these observations suggest that
RA patients with early disease may have a lower rate of
serious infections than patients with long-standing dis-
Important safety considerations with the use of
TNF antagonists have been identified, including serious
infections, opportunistic infections (including TB), ma-
lignancies, demyelinating disease, lupus-like reactions,
and congestive heart failure (48–60). Cases of TB have
been reported with all TNF antagonists and are believed
to represent reactivation of latent disease (56,61–63).
Screening prior to initiation of anti-TNF therapy is
effective in identifying patients at risk and reducing the
rate of TB reactivation, and is recommended by rheu-
matologists and health care authorities, including the
Centers for Disease Control and Prevention (61,64). In
the present study, there was 1 case of TB, in a patient
who recovered with treatment, but no other opportunis-
tic infections were seen. Higher rates of lymphoma have
been seen in RA patients compared with the general
population (60). In this study, there was 1 case of
lymphoma in the MTX monotherapy arm, and none in
the other treatment arms. One case of lupus-like reac-
tion occurred in the combination treatment arm, and
symptoms resolved when the study drug was discontin-
ued. No cases of demyelination were observed.
This study demonstrates the magnitude of re-
sponse that can be achieved in treating an early, MTX-
naive RA population with aggressive combination ther-
apy and establishes the superiority of combination
therapy to either MTX monotherapy or adalimumab
34 BREEDVELD ET AL
monotherapy. Furthermore, the results of this study
demonstrate that increasing the dosage of adalimumab
from 40 mg every other week to 40 mg weekly in ACR
nonresponders does not provide substantial additional
measurable benefit to the patient, whether the adali-
mumab is taken alone or in combination with MTX. For
those patients who are able to tolerate MTX, combina-
tion therapy provides substantial improvement over
either adalimumab monotherapy or MTX monotherapy.
For the patient with early, aggressive and erosive RA,
treatment with combination therapy is superior to treat-
ment with MTX alone.
1. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet 2001;358:
2. Van der Heidje D, van Leeuwen MA, van Riel PL, van de Putte L.
Radiographic progression on radiographs of hands and feet during
the first 3 years of rheumatoid arthritis measured according to
Sharp’s method (van der Heijde modification). J Rheumatol
3. Lindqvist E, Jonsson K, Saxne T, Eberhardt K. Course of radio-
graphic damage over 10 years in a cohort with early rheumatoid
arthritis. Ann Rheum Dis 2003;62:611–6.
4. Hulsmans HM, Jacobs JW, van der Heidje DM, van Albada-
Kuipers GA, Schenk Y, Bijlsma JW. The course of radiologic
damage during the first six years of rheumatoid arthritis. Arthritis
5. Lindqvist E, Saxne T, Geborek P, Eberhardt K. Ten year outcome
in a cohort of patients with early rheumatoid arthritis: health
status, disease process, and damage. Ann Rheum Dis 2002;61:
6. Pincus T, Ferraccioli G, Sokka T, Larsen A, Rau R, Kushner I, et
al. Evidence from clinical trials and long-term observational
studies that disease-modifying anti-rheumatic drugs slow radio-
graphic progression in rheumatoid arthritis: updating a 1983
review. Rheumatology (Oxford) 2002;41:1346–56.
7. Sokka T, Hannonen P. Utility of disease modifying antirheumatic
drugs in sawtooth strategy: a prospective study of early rheumatoid
arthritis patients up to 15 years. Ann Rheum Dis 1999;58:618–22.
8. Wolfe F, Sharp JT. Radiographic outcome of recent-onset rheu-
matoid arthritis: a 19-year study of radiographic progression.
Arthritis Rheum 1998;41:1571–82.
9. Welsing PM, Landewe RB, van Riel PL, Boers M, van Gestel AM,
van der Linden S, et al. The relationship between disease activity
and radiologic progression in patients with rheumatoid arthritis: a
longitudinal analysis. Arthritis Rheum 2004;50:2082–93.
10. Sokka T, Kautiainen H, Mottonen T, Hannonen P. Work disability
in rheumatoid arthritis 10 years after the diagnosis. J Rheumatol
11. Welsing PM, van Gestel AM, Swinkels HL, Kiemeney LA, van
Riel PL. The relationship between disease activity, joint destruc-
tion, and functional capacity over the course of rheumatoid
arthritis. Arthritis Rheum 2001;44:2009–17.
12. Prevoo ML, van Gestel AM, van ’t Hof MA, van Rijswijk MH, van
de Putte LB, van Riel PL. Remission in a prospective study of
patients with rheumatoid arthritis: American Rheumatism Asso-
ciation preliminary remission criteria in relation to the disease
activity score. Br J Rheumatol 1996;35:1101–5.
13. Sharp J, van der Heidje D, Boers M, Boonen A, Bruynesteyn K,
Emery P, et al. Repair of erosions in rheumatoid arthritis does
occur: results from 2 studies by the OMERACT Subcommittee on
Healing of Erosions. J Rheumatol 2003;30:1102–7.
14. Fries JF, Spitz PW, Kraines RG, Holman HR. Measurement of
patient outcome in arthritis. Arthritis Rheum 1980;23:137–45.
15. Baumgartner SW, Fleischmann R, Moreland L, Schiff M, Marken-
son J, Whitmore J. Etanercept (Enbrel) in patients with rheuma-
toid arthritis with recent onset versus established disease: improve-
ment in disability. J Rheumatol 2004;31:1532–7.
16. Hawley DJ, Wolfe F. Sensitivity to change of the Health Assess-
ment Questionnaire (HAQ) and other clinical and health status
measures in rheumatoid arthritis: results of short-term clinical
trials and observational studies versus long-term observational
studies. Arthritis Care Res 1992;5:130–6.
17. Wolfe F, Pincus T. The level of inflammation in rheumatoid
arthritis is determined early and remains stable over the longterm
course of the illness. J Rheumatol 2001;28:1817–1824.
18. Pincus T, Sokka T. Quantitative measures and indices to assess
rheumatoid arthritis in clinical trials and clinical care. Rheumatol-
ogy (Oxford) 2004;30:725–51.
19. Pincus T, Strand V, Koch G, Amara I, Crawford B, Wolfe F, et al.
An index of the three core data set patient questionnaire measures
distinguishes efficacy of active treatment from that of placebo as
effectively as the American College of Rheumatology 20% re-
sponse criteria (ACR20) or the Disease Activity Score (DAS) in a
rheumatoid arthritis clinical trial. Arthritis Rheum 2003;48:
20. Pincus T, Sokka T. Partial control of core data set measures and
Disease Activity Score (DAS) measures of inflammation does not
prevent long-term joint damage: evidence from longitudinal ob-
servations over 5-20 years. Clin Exp Rheumatol 2002;20(5 Suppl
21. Krishnan E, Fries J. Reduction in long-term functional disability in
rheumatoid arthritis from 1977 to 1998: a longitudinal study of
3035 patients. Am J Med 2003;115:371–6.
22. Van der Heidje D. Impact of rheumatoid arthritis on physical
function during the first five years: no longer a question mark?
Rheumatology (Oxford) 2000;39:579–580.
23. Sokka T, Pincus T. Markers for work disability in rheumatoid
arthritis. J Rheumatol 2001;28:1718–22.
24. Landewe RB, Boers M, Verhoeven AC, Westhovens R, van de
Laar MA, Markusse HM, et al. COBRA combination therapy in
patients with early rheumatoid arthritis: long-term structural ben-
efits of a brief intervention. Arthritis Rheum 2002;46:347–56.
25. Mottonen T, Hannonen P, Korpela M, Nissila M, Kautiainen H,
Ilonen J, et al. Delay to institution of therapy and induction of
remission using single-drug or combination–disease-modifying an-
tirheumatic drug therapy in early rheumatoid arthritis. Arthritis
26. Tsakonas E, Fitzgerald AA, Fitzcharles MA, Cividino A, Thorne
JC, M’Seffar A, et al. Consequences of delayed therapy with
second-line agents in rheumatoid arthritis: a 3 year followup on
the hydroxychloroquine in early rheumatoid arthritis (HERA)
study. J Rheumatol 2000;27:623–9.
27. O’Dell JR. Treating rheumatoid arthritis early: a window of
opportunity? [editorial]. Arthritis Rheum 2002;46:283–5.
28. O’Dell JR, Leff R, Paulsen G, Haire C, Mallek J, Eckhoff PJ, et al.
Treatment of rheumatoid arthritis with methotrexate and hydroxy-
chloroquine, methotrexate and sulfasalazine, or a combination
of the three medications: results of a two-year, randomized,
double-blind, placebo-controlled trial. Arthritis Rheum 2002;
29. O’Dell J, Haire E, Erikson N, Drymalski W, Palmer W, Eckhoff P,
et al. Treatment of rheumatoid arthritis with methotrexate alone,
sulfasalazine and hydroxychloroquine, or a combination of all
three medications. N Engl J Med 1996;334:1287–91.
30. Pincus T, O’Dell JR, Kremer JM. Combination therapy with
ADALIMUMAB PLUS MTX TREATMENT OF RA35
multiple disease-modifying antirheumatic drugs in rheumatoid
arthritis: a preventive strategy. Ann Intern Med 1999;131:768–74.
31. Klareskog L, van der Heidje D, de Jager JP, Gough A, Kalden J,
Malaise M, et al. Therapeutic effect of the combination of
etanercept and methotrexate compared with each treatment alone
in patients with rheumatoid arthritis: double-blind randomised
controlled trial. Lancet 2004;363:675–81.
32. St.Clair EW, van der Heidje DM, Smolen JS, Maini RN, Bathon
JM, Emery P, et al. Combination of infliximab and methotrexate
therapy for early rheumatoid arthritis: a randomized, controlled
trial. Arthritis Rheum 2004;50:3432–43.
33. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF,
Cooper NS, et al. The American Rheumatism Association 1987
revised criteria for the classification of rheumatoid arthritis.
Arthritis Rheum 1988;31:315–24.
34. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D,
Goldsmith C, et al. American College of Rheumatology prelimi-
nary definition of improvement in rheumatoid arthritis. Arthritis
35. Felson DT, Anderson JJ, Lange ML, Wells G, LaValley MP.
Should improvement in rheumatoid arthritis clinical trials be
defined as fifty percent or seventy percent improvement in core set
measures, rather than twenty percent? Arthritis Rheum 1998;41:
36. Van der Heijde DM. How to read radiographs according to the
Sharp/van der Heijde method. J Rheumatol 1999;26:743–5.
37. Pincus T, Sokka T, Kavanaugh A. Relative versus absolute goals of
therapies for RA: ACR 20 or ACR 50 responses versus target
values for near remission of DAS or single measures. Clin Exp
Rheumatol 2004;22(5 Suppl 35):S50–6.
38. Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y,
Teoh Ls, et al. Radiographic, clinical, and functional outcomes of
treatment with adalimumab (a human anti–tumor necrosis factor
monoclonal antibody) in patients with active rheumatoid arthritis
receiving concomitant methotrexate therapy: a randomized, pla-
cebo-controlled, 52-week trial. Arthritis Rheum 2004;50:1400–11.
39. Prevoo MLL, van ’t Hof MA, Kuper HH, van Leeuwen MA, van
de Putte LB, van Riel PL. Modified disease activity scores that
include twenty-eight-joint counts: development and validation in a
prospective longitudinal study of patients with rheumatoid arthri-
tis. Arthritis Rheum 1995;38:44–8.
40. Fransen J, Creemers MCW, van Riel PL. Remission in rheuma-
toid arthritis: agreement of the disease activity score (DAS28) with
the ARA preliminary remission criteria. Rheumatology (Oxford)
41. Food and Drug Administration. Guidance for industry clinical
development programs for drugs, devices, and biological products
for thetreatment of rheumatoid arthritis (RA). URL: http://
42. Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE.
Predictors of infection in rheumatoid arthritis. Arthritis Rheum
43. Genovese MC, Bathon JM, Fleischmann RM, Moreland LW,
Martin RW, Whitmore JB, et al. Longterm safety, efficacy, and
radiographic outcome with etanercept treatment in patients with
early rheumatoid arthritis. J Rheumatol 2005;32:1232–42.
44. Bathon JM, Martin RW, Fleischmann R, Tesser JR, Schiff M,
Keystone E, et al. A comparison of etanercept and methotrexate in
patients with early rheumatoid arthritis. N Engl J Med 2000;343:
45. Strand V, Landewe R, van der Heidje D. Using estimated yearly
progression rates to compare radiographic data across recent
randomised controlled trials in rheumatoid arthritis [abstract].
Ann Rheum Dis 2002;61(Suppl 2):ii64.
46. Sokka T, Pincus T. Most patients receiving routine care for
rheumatoid arthritis in 2001 did not meet inclusion criteria for
most recent clinical trials or American College of Rheumatology
criteria for remission. J Rheumatol 2003;30:1138–46.
47. Moreland LW, Cohen SB, Baumgartner SW, Tindall EA, Bulpitt
K, Martin R, et al. Long-term safety and efficacy of etanercept
in patients with rheumatoid arthritis. J Rheumatol 2001;28:
48. Robinson WH, Genovese MC, Moreland LW. Demyelinating and
neurologic events reported in association with tumor necrosis
factor ? antagonism: by what mechanisms could tumor necrosis
factor ? antagonists improve rheumatoid arthritis but exacerbate
multiple sclerosis? [review]. Arthritis Rheum 2001;44:1977–83.
49. Spencer-Green G, Warren MS, Whitmore J, Djian J, Pedersen R.
Effects of etanercept (ENBREL) in patients with chronic heart
failure: results of RENAISSANCE and RECOVER trials [ab-
stract]. Arthritis Rheum 2002;46 Suppl 9:S520.
50. Mohan A, Cote T, Siegel J, Braun M. Infectious complications of
biologic treatments of rheumatoid arthritis. Curr Opin Rheumatol
51. Ellerin T, Rubin RH, Weinblatt ME. Infections and anti–tumor
necrosis factor ? therapy [review]. Arthritis Rheum 2003;48:
52. Wolfe F, Michaud K, Anderson J, Urbansky K. Tuberculosis
infection in patients with rheumatoid arthritis and the effect of
infliximab therapy. Arthritis Rheum 2004;50:372–9.
53. Khanna D, McMahon M, Furst DE. Safety of tumour necrosis
factor-? antagonists. Drug Safety 2004;27:307–24.
54. Imperato AK. Long-term risks associated with biologic response
modifiers used in rheumatic diseases. Curr Opin Rheumatol
55. Khanna D, McMahon M, Furst DE. Anti–tumor necrosis factor ?
therapy and heart failure: what have we learned and where do we
go from here? [review].Arthritis Rheum 2004;50:1040–50.
56. Mohan A, Cote T, Block J, Manadan A, Siegel J, Braun M.
Tuberculosis following the use of etanercept, a tumor necrosis
factor inhibitor. Clin Infect Dis 2004;39:295–9.
57. Ormerod LP. Tuberculosis and anti-TNF-? treatment [editorial].
58. Wolfe F, Michaed K. Lymphoma in rheumatoid arthritis: the
effect of methotrexate and anti–tumor necrosis factor therapy in
18,572 patients. Arthritis Rheum 2004;50:1740–51.
59. Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM.
Tumor necrosis factor antagonist therapy and lymphoma develop-
ment: twenty-six cases reported to the Food and Drug Adminis-
tration. Arthritis Rheum 2002;46:3151–8.
60. Gridley G, McLaughlin JK, Ekbom A, Klareskog L, Adami HO,
Hacker D, et al. Incidence of cancer among patients with rheu-
matoid arthritis. J Natl Cancer Inst 1993;85:307–11.
61. Centers for Disease Control and Prevention (CDC). Tuberculosis
associated with blocking agents against tumor necrosis factor-?—
California, 2002-2003. MMWR Morb Mortal Wkly Rep 2004;53:
62. Hamilton CD. Tuberculosis in the cytokine era: what rheumatolo-
gists need to know [editorial]. Arthritis Rheum 2003;48:2085–91.
63. Keane J, Gershon S, Wise RP, Mirabile L, Kasznica J, Schwieterman
WD, et al. Tuberculosis associated with infliximab, a tumor necrosis
factor ?-neutralizing agent. N Engl J Med 2001;345:1098–104.
64. Winthrop K, Siegel J. Tuberculosis cases associated with inflix-
imab and etanercept. Clin Infect Dis 2004;39:1256–7.
APPENDIX A: PREMIER STUDY INVESTIGATORS
PREMIER study investigators, in addition to the authors of
this article, are as follows: Australia, P. Bird, J. Bleasel, R. Buchanan,
R. Day, M. Handel, P. Hanrahan, G. Jones, G. Littlejohn, G. Major, P.
Nash, K. Pile, M. Rischmueller, P. Vecchio; Austria, J. Hermann, K.
Machold; Belgium, T. Appelboom, J. Devogelaer, P. Geusens, M.
36 BREEDVELD ET AL
Malaise, L. Verbruggen, E. Veys, R. Westhovens; Canada, C. Atkins,
M. Bell, W. Bensen, J. Canvin, A. Cividino, B. Haraoui, E. Keystone,
M. Khraishi, A. Russell, K. Shojania, M. Starr, H. Tannenbaum, G.
Thomson, J. Thorne, J. Uddin; Czech Republic, P. Bradna, O. Mayer;
Denmark, H. Bliddal, N. Daugaard-Peters, K. Hørslev-Petersen; Fin-
land, M. Kauppi, M. Leirisalo-Rapo, R. Niemela ¨; France, M. Boissier,
M. Dougados, A. Perdriger, J. Sany, J. Sibilia, J. Tebib; Germany, R.
Alten, G. Burmester, T. Do ¨rner, F. Emmrich, G. Gromnica-Ihle, J.
Kalden, J. Kekow, B. Lang, J. Meier, H. Peter, R. Rau, M. Schatten-
kirchner, H. Stahl, B. Volz, S. Wassenberg; Ireland, B. Bresnihan, M.
Molloy; Italy, L. Bambara, M. Cutolo, G. Ferraccioli, G. Valentini;
The Netherlands, D. van der Heijde, P. van Riel, M. van Rijswijk;
Norway, O. Fo ¨rre, T. Kvien; the Slovak Republic, J. Rovensky ´; Spain,
J. Crespillo, S. de Vita, J. Go ´mez-Reino, G. Herrero-Beaumont, J.
Jover, J. Marenco, E. Pascual, X. Tena, J. Tornero, G. Vidal; Sweden,
M. Ahlmen, J. Bratt, R. Ha ¨llgren, R. Oding, S. Rantapa ¨a ¨-Dahlqvist, P.
Seideman; Switzerland, J. Chamot; UK, P. Emery, B. Hazelman, B.
Kirkham, P. Maddison, D. Walker, R. Williams; US, R. Arthur, H.
Baraf, C. Birbara, M. Burnette, W. Chase, M. Churchill, Jr., F. Dietz,
W. Eider, R. Ettlinger, N. Gaylis, G. Halter, R. Harrell, P. Howard, A.
Jaffer, J. Kaine, H. Kenney, A. Kivitz, S. Klein, J. Kremer, C. Ludivico,
D. MacPeek, W. Maier, R. Malamet, M. Pickrell, M. Schiff, D. Sikes,
S. Solomon, E. Spencer-Smith, E. Tindall, J. Trice, J. Uhl, F. Well-
borne, S. Wolfe, T. Zizic.
ADALIMUMAB PLUS MTX TREATMENT OF RA37