ARTHRITIS & RHEUMATISM

Vol. 48, No. 1, January 2003, pp 35–45

DOI 10.1002/art.10697
© 2003, American College of Rheumatology

Adalimumab, a Fully Human Anti–Tumor Necrosis Factor ␣

Monoclonal Antibody, for the Treatment of
Rheumatoid Arthritis in Patients Taking
Concomitant Methotrexate

The ARMADA Trial

Michael E. Weinblatt,1 Edward C. Keystone,2 Daniel E. Furst,3 Larry W. Moreland,4

Michael H. Weisman,5 Charles A. Birbara,6 Leah A. Teoh,7
Steven A. Fischkoff,7 and Elliot K. Chartash7

Objective. To evaluate the efficacy and safety of
adalimumab (D2E7), a fully human monoclonal tumor
necrosis factor ␣ antibody, in combination with metho-
trexate (MTX) in patients with active rheumatoid ar-
thritis (RA) despite treatment with MTX.
Methods. In a 24-week, randomized, double-blind,
placebo-controlled study, 271 patients with active RA
were randomly assigned to receive injections of adali-
1
Michael E. Weinblatt, MD: Brigham and Women’s Hospital,
Boston, Massachusetts; 2Edward C. Keystone, MD: Mount Sinai
Hospital, Toronto, Ontario, Canada; 3Daniel E. Furst, MD: University
of California, Los Angeles; 4Larry W. Moreland, MD: The University
of Alabama at Birmingham; 5Michael H. Weisman, MD: Cedars Sinai
Medical Center, Los Angeles, California; 6Charles A. Birbara, MD:
University of Massachusetts City Campus, Worcester; 7Leah A. Teoh,
MA, Steven A. Fischkoff, MD, Elliot K. Chartash, MD: Abbott
Laboratories, Parsippany, New Jersey.
The Anti–Tumor Necrosis Factor Research Study Program of
the Monoclonal Antibody Adalimumab (D2E7) in Rheumatoid Ar-
thritis (ARMADA) trial was supported by Abbott Laboratories and
Knoll Pharmaceuticals. Dr. Weinblatt has also received honoraria as a
member of the scientific advisory board and as a consultant to Abbott
Laboratories and Knoll Pharmaceuticals. Dr. Keystone has also re-
ceived honoraria as a consultant and speaker for Abbott Laboratories
and Knoll Pharmaceuticals. Dr. Furst has also received honoraria as a
member of the scientific advisory board and speaker for Abbott
Laboratories and Knoll Pharmaceuticals. Dr. Moreland has also
received honoraria as a consultant to Abbott Laboratories and Knoll
Pharmaceuticals. Dr. Weisman has also received honoraria as a
consultant to Abbott Laboratories and Knoll Pharmaceuticals.
Address correspondence and reprint requests to Michael E.
Weinblatt, MD, Rheumatology and Immunology, Brigham and Wom-
en’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail:
mweinblatt@partners.org.
Submitted for publication May 22, 2002; accepted in revised
form September 3, 2002.
35
mumab (20 mg, 40 mg, or 80 mg subcutaneously) or
placebo every other week while continuing to take their
long-term stable dosage of MTX. The primary efficacy
end point was the American College of Rheumatology
criteria for 20% improvement (ACR20) at 24 weeks.
Results. An ACR20 response at week 24 was
achieved by a significantly greater proportion of pa-
tients in the 20-mg, 40-mg, and 80-mg adalimumab plus
MTX groups (47.8%, 67.2%, and 65.8%, respectively)
than in the placebo plus MTX group (14.5%) (P <
0.001). ACR50 response rates with the 20-mg, 40-mg,
and 80-mg adalimumab dosages (31.9%, 55.2%, and
42.5%, respectively) were significantly greater than that
with placebo (8.1%) (P ⴝ 0.003, P < 0.001, and P <
0.001, respectively). The 40-mg and 80-mg doses of
adalimumab were associated with an ACR70 response
(26.9% and 19.2%, respectively) that was statistically
significantly greater than that with placebo (4.8%) (P <
0.001 and P ⴝ 0.020). Responses were rapid, with the
greatest proportion of adalimumab-treated patients
achieving an ACR20 response at the first scheduled visit
(week 1). Adalimumab was safe and well tolerated;
comparable numbers of adalimumab-treated patients
and placebo-treated patients reported adverse events.
Conclusion. The addition of adalimumab at a
dosage of 20 mg, 40 mg, or 80 mg administered subcu-
taneously every other week to long-term MTX therapy in
patients with active RA provided significant, rapid, and
sustained improvement in disease activity over 24 weeks
compared with MTX plus placebo.
36
Over the last decade, methotrexate (MTX) has
become the treatment of choice for rheumatoid arthritis
(RA) (1,2), providing initial improvement within weeks
(3) and maximal benefits generally by 6 months (4).
However, many patients continue to have some degree
of disease activity despite receiving therapeutic doses of
MTX. Even when they respond fully to MTX therapy,
patients experience less than 50% improvement (5). To
enhance the clinical response, MTX is frequently com-
bined with one or more other traditional disease-
modifying antirheumatic drugs (DMARDs) (5,6).
Elucidation of the pathophysiology of RA has led
to the development of biologic DMARDs that bind to
and inactivate the proinflammatory cytokine tumor ne-
crosis factor ␣ (TNF␣). Primarily produced by activated
monocytes and macrophages, TNF␣ mediates both in-
flammatory synovitis and articular matrix degradation
(7). Among its diverse pathologic effects, TNF␣ induces
the production of other proinflammatory cytokines,
stimulates endothelial cells to express adhesion mole-
cules that attract leukocytes into affected joints, in-
creases the rate of synthesis of metalloproteinases by
synovial macrophages, fibroblasts, osteoclasts, and chon-
drocytes, and inhibits the synthesis of proteoglycans in
cartilage (7). Two TNF␣ blockers are commercially
available for treating RA: infliximab (8), a chimeric
(75% human and 25% mouse peptide sequences) mono-
clonal antibody to TNF␣, and etanercept (9), a recom-
binant human TNF receptor (p75)–Fc fusion protein.
Adalimumab (D2E7; Abbott Laboratories, Abbott Park,
IL), the first fully human (100% human peptide se-
quences) therapeutic monoclonal antibody that blocks
TNF␣, is currently being evaluated in clinical trials for
the treatment of RA (10–14).
Genetically engineered through phage display
technology, adalimumab is indistinguishable in structure
and function from natural human IgG1 (10). Clinical
trials have been conducted for more than 4 years with
adalimumab as monotherapy and as combined therapy
with MTX to monitor the long-term efficacy and safety.
Results from these studies have demonstrated the ability
of adalimumab to control the signs and symptoms of
RA, as measured by a good clinical response and
inhibition of disease progression (11–14), with 42% of
patients demonstrating no radiologic progression after 2
years of treatment (14). The present study, the Anti-
TNF Research Study Program of the Monoclonal Anti-
body Adalimumab [D2E7] in Rheumatoid Arthritis
(ARMADA) trial, was a 24-week study conducted to
evaluate the efficacy and safety of adalimumab admin-
WEINBLATT ET AL
istered subcutaneously every other week to patients with
active RA despite long-term therapy with MTX.
PATIENTS AND METHODS
Patients. Eligible patients were 18 years of age or older
and had RA that was diagnosed according to the 1987 revised
criteria of the American College of Rheumatology (ACR;
formerly, the American Rheumatism Association) (15). Active
disease was defined as the presence of at least 9 tender joints
(of 68 joints evaluated) and 6 swollen joints (of 66 joints
evaluated). Additionally, participants must have been treated
with MTX for a minimum of 6 months and must have been
taking a stable weekly dose (12.5–25 mg, or 10 mg if intolerant
to higher doses) for at least 4 weeks before entering the study.
All participants must have failed treatment with at least 1
DMARD besides MTX, but no more than 4 DMARDs.
Exclusion criteria consisted of standard exclusion cri-
teria used in trials of other biologics in patients with RA. In
addition, patients who had received treatment with anti-CD4
therapy or TNF␣ antagonists, had a history of active listeriosis
or mycobacterial infection, and had a major episode of infec-
tion requiring hospitalization or treatment with intravenous
antibiotics within 30 days or oral antibiotics within 14 days
prior to screening were also excluded.
Monoclonal antibody. Adalimumab is an IgG1 made
by phage display technology with amino acid sequences only
from the human germline, making it indistinguishable in
structure and function from natural human IgG1 (10). Adali-
mumab has high specificity and affinity for TNF␣ (Kd ⫽ 6 ⫻
10⫺10M) and not TNF␤ (lymphotoxin) (10). Adalimumab has
a terminal half-life comparable to that of human IgG1 (⬃2
weeks) (10).
Study protocol. This study was a 24-week, randomized,
double-blind, placebo-controlled trial of adalimumab with
concomitant MTX therapy and was performed at 35 sites
throughout the US and Canada. All patients gave their written
informed consent, and the Institutional Review Board at each
study site approved the trial. After screening and baseline
assessments, which included chest radiographs and tuberculin
skin testing, study visits were conducted weekly during the first
month, every other week during the second month, and
monthly thereafter. Patients were randomized to receive pla-
cebo or adalimumab at a dosage of 20 mg, 40 mg, or 80 mg
subcutaneously every other week as 2 injections of 1.6 ml per
injection. Patients were instructed in self-injection techniques.
All DMARDs, except MTX, were discontinued 4
weeks before the study. In addition to MTX, concomitant RA
therapies permitted during the study included salicylates,
nonsteroidal antiinflammatory drugs, and corticosteroids
(maximum daily dose of 10 mg of oral prednisone or equiva-
lent). Dosage tapering or changes in the route of administra-
tion of the concomitant medications were not permitted during
the study. Folic acid or leucovorin was permitted. High-
potency opioid analgesics (e.g., methadone, hydromorphone,
or morphine) were prohibited; other analgesics were allowed,
although not within 12 hours of study visits.
Efficacy assessments. The primary efficacy end point
was the ACR20 response (16). Secondary efficacy end points
included the ACR50 and the ACR70 response rates (16) and
ADALIMUMAB AND CONCOMITANT MTX TREATMENT FOR RA
improvements in ACR core set of disease activity measures for
RA clinical trials (17), as follows: tender joint count, swollen
joint count, patient’s assessment of pain, patient’s global
assessment of disease activity, physician’s global assessment of
disease activity, the Disability Index of the Health Assessment
Questionnaire (HAQ) (18), and serum levels of C-reactive
protein. Other secondary efficacy end points were the score on
the Short Form 36 (SF-36), which is a 36-item health survey
(19), and the fatigue scale of the Functional Assessment of
Chronic Illness Therapy (FACIT) (20). Serum concentrations
of the cartilage destruction markers pro–matrix metallopro-
teinase 1 (proMMP-1) and proMMP-3 were obtained during
the study.
Patients who failed to meet or to maintain an ACR20
response but had received study drug (adalimumab or placebo)
for at least 16 weeks were eligible to remain in the study or to
roll over to an open-label continuation study with adalimumab.
Patients who rolled over into the open-label continuation study
after 16 weeks were considered completers. All patients who
did not complete 24 weeks of the study were considered ACR
nonresponders in the primary and secondary analyses of week
24 data. Patients who achieved and maintained an ACR20
response for ⱖ16 weeks continued in the study until they had
completed 24 weeks of treatment, at which time they were
eligible to enter the open-label continuation study.
Safety assessments. Safety was assessed on the basis of
adverse events reported by patients and findings of physical
examination and laboratory evaluations. Serum levels of anti-
adalimumab antibodies, antinuclear antibodies (ANA), and
anti–double-stranded DNA (anti-dsDNA) antibodies (by ra-
dioimmunoassay; performed automatically if ANA titers were
elevated from baseline) were monitored at baseline and at
weeks 4, 12, and 24. Serum levels of anti-adalimumab antibod-
ies were measured by double-capture enzyme-linked immu-
nosorbent assay; titers ⬎20 ng/ml were considered positive,
and samples had ⬍50% suppression with the addition of
human serum.
Statistical analysis. To detect a difference of 35% in
ACR20 response rates between any of the tested doses of
active drug and placebo, assuming a placebo response rate of
20% and 90% power, a sample size of 67 patients was
calculated to be required for each of the 4 treatment arms.
Statistical significance was set at P ⱕ 0.05 for all tests. The
study was not powered to show a difference among adali-
mumab treatment groups. Randomization was done using a
block size of 8. Only centers that enrolled multiples of 8
patients would have equal numbers of patients in each treat-
ment group.
Demographic and baseline characteristics were com-
pared among all dosage groups, as determined using the
Kruskal-Wallis test for continuous variables and the chi-square
test for discrete variables. Efficacy end points were analyzed on
an intent-to-treat basis and included all patients who received
at least 1 dose of study drug (adalimumab or placebo).
Fulfillment of the ACR20, ACR50, and ACR70 criteria was
based on changes observed from baseline to week 24. Patients
who dropped out before week 24 and patients who did not
achieve an ACR20 response were classified as nonresponders.
Differences in the percentage of patients achieving an
ACR20 response at week 24 (the primary efficacy end point)
were compared between each of the adalimumab dosage
37
groups and the placebo group by use of Dunnett’s test.
Differences in the percentages of patients achieving ACR50
and ACR70 responses at week 24 (secondary efficacy end
points) were compared between each of the adalimumab
dosage groups and the placebo group by use of an unadjusted
t-test, without correction for multiple comparisons. Differ-
ences in the change from baseline to the last observation
carried forward (LOCF) to week 24 in other secondary efficacy
end points were compared between each of the adalimumab
dosage groups and the placebo group by use of analysis of
covariance, with baseline as the covariate and without correc-
tion for multiple comparisons. The significance of the change
from baseline in efficacy end points within each treatment
group was assessed using the corresponding 95% confidence
interval (if “0” was not contained in the interval, the change
was considered significant).
Adverse events were analyzed by frequency and per-
centage and were compared between the adalimumab and
placebo groups by use of Pearson’s chi-square test, without
correction for multiple comparisons. To adjust for the higher
rate of withdrawals and shorter amount of treatment time in
the placebo group, adverse events were also analyzed by the
total number of patients experiencing a particular adverse
event per total years of treatment (number of patients/patient-
year).
RESULTS
Disposition of the patients. A total of 336 RA
patients were screened, and 271 patients met the entry
criteria and were randomized to 4 treatment groups: 62
(22.9%) in the placebo group, 69 (25.5%) in the 20-mg
adalimumab group, 67 (24.7%) in the 40-mg adali-
mumab group, and 73 (26.9%) in the 80-mg adalimumab
group. Among the 271 patients that entered the study,
161 completed the 24 weeks. Ninety-two patients who
did not achieve an ACR20 response elected to enter the
open-label continuation study between weeks 16 and 24.
Of these 92 rollover patients, 23, 27, and 27 were in the
adalimumab 20 mg, 40 mg, and 80 mg groups, respec-
tively, and 35 were in the placebo group. In addition, 18
patients withdrew from the study prematurely because
of adverse events (n ⫽ 7), withdrawal of consent (n ⫽ 5),
lack of efficacy (n ⫽ 3), protocol violation (n ⫽ 1), or
loss to followup (n ⫽ 2). All of the 18 patients who
withdrew from the study did so before week 16 and were
not eligible to roll over into the open-label extension
trial.
Demographic and baseline characteristics. There
were no statistically significant differences in the demo-
graphic and baseline characteristics among the treat-
ment groups (Table 1). Most of the study patients were
women (n ⫽ 208 [76.8%]). The overall mean age of the
study patients was 55.5 years. The overall mean duration
of disease activity was 12.3 years. At baseline, the mean
38 WEINBLATT ET AL

Table 1. Demographic and baseline characteristics in the 271 rheumatoid arthritis patients studied*
Adalimumab dosage (every other week)

Placebo 20 mg 40 mg 80 mg
Characteristic (n ⫽ 62) (n ⫽ 69) (n ⫽ 67) (n ⫽ 73)
Age, years 56.0 ⫾ 10.8 53.5 ⫾ 12.4 57.2 ⫾ 11.4 55.5 ⫾ 11.7
Sex, % female 82.3 75.4 74.6 75.3
Disease duration, years 11.1 ⫾ 8.0 13.1 ⫾ 8.1 12.2 ⫾ 11.1 12.8 ⫾ 9.9†
Tender joint count (0–68 joints) 28.7 ⫾ 15.2 28.5 ⫾ 14.4 28.0 ⫾ 12.7 30.3 ⫾ 15.7
Swollen joint count (0–66 joints) 16.9 ⫾ 9.5 17.6 ⫾ 8.7 17.3 ⫾ 8.6 17.0 ⫾ 8.2
Patient’s assessment of pain (0–100-mm 57.2 ⫾ 21.0 55.1 ⫾ 20.6 53.0 ⫾ 22.0 55.0 ⫾ 23.7
VAS)‡
Patient’s global assessment of disease 58.0 ⫾ 23.2 57.6 ⫾ 21.6 56.9 ⫾ 21.1 58.8 ⫾ 24.9
activity (0–100-mm VAS)§
Physician’s global assessment of disease 58.9 ⫾ 15.3 60.5 ⫾ 17.3 58.7 ⫾ 15.8 62.6 ⫾ 14.7
activity (0–100-mm VAS)§
HAQ Disability Index (0–3 scale)¶ 1.64 ⫾ 0.63 1.52 ⫾ 0.62 1.55 ⫾ 0.61 1.55 ⫾ 0.66
C-reactive protein, mg/dl (normal ⬍0.8) 3.1 ⫾ 3.9 2.8 ⫾ 3.1 2.1 ⫾ 1.8 2.8 ⫾ 2.7
Rheumatoid factor, IU/liter 321.2 ⫾ 518.2# 264.6 ⫾ 462.7 269.3 ⫾ 390.0 318.8 ⫾ 536.0
Methotrexate dosage, mg/week 16.5 ⫾ 5.0 16.9 ⫾ 4.4 16.4 ⫾ 4.1 17.2 ⫾ 4.7
No. of previous DMARDs 3.0 3.0 2.9 3.1

* There were no statistically significant differences in any demographic or baseline characteristic across all dosage groups combined, by
Kruskal-Wallis test for continuous variables and chi-square test for discrete variables; statistical significance was set as P ⱕ 0.05. Except where
indicated otherwise, values are the mean ⫾ SD. DMARDs ⫽ disease-modifying antirheumatic drugs.
† n ⫽ 72.
‡ The visual analog scale (VAS) for pain ranges from 0 ⫽ no pain to 100 ⫽ severe pain.
§ The VAS for global assessment of disease activity ranges from 0 ⫽ no disease activity to 100 ⫽ extreme disease activity.
¶ The Health Assessment Questionnaire (HAQ) scale ranges from 0 ⫽ no difficulty to 3 ⫽ unable to perform activity.
# n ⫽ 61.

tender joint count was 28.9, the mean swollen joint count
was 17.2, and the mean Disability Index score of the
HAQ was 1.56. All groups were similar with respect to
concomitant diseases.
The mean (⫾SD) weekly dose of MTX at the
start of the study was 16.8 ⫾ 4.4 mg in the adalimumab-
treated patients and 16.5 ⫾ 5.0 mg in the placebo-
treated patients. The majority of patients received oral
doses of MTX (64.6% [135 of 209] of adalimumab-
treated patients and 62.9% [39 of 62] of placebo-treated
patients). The mean number of DMARDs used pre-
viously, including MTX, among both the adalimumab-
treated and placebo-treated patients was 3.0. The previ-
ous DMARDs commonly used included hydroxychloro-
quine in 184 patients (67.9%), parenteral gold in 132
patients (48.7%), and sulfasalazine in 91 patients (33.6%).
There was a small percentage of patients who stopped
using a DMARD (i.e., hydroxychloroquine, sulfasalazine,
auranofin, azathioprine, cyclosporine, or leflunomide) on
the day of screening, including 11% of patients random-
ized to the placebo group, 12% of patients randomized
to 20 mg of adalimumab, 15% of patients randomized to

Table 2. Patients with ACR20, ACR50, and ACR70 responses at week 24*
Adalimumab dosage (every other week)
Placebo
Response criteria met (n ⫽ 62) 20 mg (n ⫽ 69) 40 mg (n ⫽ 67) 80 mg (n ⫽ 73)
ACR20 9 (14.5) 33 (47.8) 45 (67.2) 48 (65.8)
P† ⬍0.001 ⬍0.001 ⬍0.001
ACR50 5 (8.1) 22 (31.9) 37 (55.2) 31 (42.5)
P‡ 0.003 ⬍0.001 ⬍0.001
ACR70 3 (4.8) 7 (10.1) 18 (26.9) 14 (19.2)
P‡ NS ⬍0.001 0.020

* Values are the number (%) of patients who met the American College of Rheumatology criteria for
20%, 50%, and 70% improvement (ACR20, ACR50, and ACR70, respectively) at week 24. Patients who
did not complete the 24-week study were defined as nonresponders. NS ⫽ not significant.
† Adalimumab versus placebo, by Dunnett’s test; statistical significance was set at P ⱕ 0.05.
‡ Adalimumab versus placebo, by unadjusted t-test; statistical significance was set at P ⱕ 0.05.
ADALIMUMAB AND CONCOMITANT MTX TREATMENT FOR RA 39

40 mg of adalimumab, and 18% of patients randomized

to 80 mg of adalimumab. In these patients, a washout
period of at least 4 weeks was required before the study
drug could be started. Prednisone was used concomi-
tantly by 46.4% (n ⫽ 97) of adalimumab-treated patients
and 58.1% (n ⫽ 36) of placebo-treated patients, with
doses ranging from 1 mg/day to 10 mg/day.
ACR20 responses. Patients receiving adalimumab
plus MTX demonstrated significant and rapid improve-
ment in disease activity compared with those receiving
placebo plus MTX. At week 16, the point at which
nonresponders could roll over into the continuation
study, ACR20 responders consisted of 21% of the
patients treated with placebo, 52% of those treated with
20 mg of adalimumab, 70% of those treated with 40 mg
of adalimumab, and 62% of those treated with 80 mg of
adalimumab. In the primary analysis, patients who did
not complete the 24 weeks were classified as nonre-
sponders, irrespective of clinical response.
Treatment with adalimumab given every other
week plus MTX given weekly was found to be statisti-
cally superior to placebo plus MTX in terms of the
ACR20 response rates at week 24 (P ⬍ 0.001 for each
adalimumab dosage group versus the placebo group)
(Table 2). The ACR20 response rate at week 24 was
comparable between the 40-mg (67.2%) and 80-mg
(65.8%) dosages of adalimumab, but slightly lower for
the 20-mg dosage (47.8%), as compared with the pla-
cebo group (14.5%) (Table 2). The sample size did not
allow statistically meaningful comparisons between
adalimumab doses.
ACR50 and ACR70 responses. Each adalimumab
dosage plus MTX group was statistically superior to the
placebo plus MTX group for ACR50 response rates at
week 24 (P ⫽ 0.003, P ⬍ 0.001, and P ⬍ 0.001,
respectively) (Table 2). The 40-mg and 80-mg adali-
mumab dosages were associated with ACR70 response
rates (26.9% and 19.2%, respectively) that were signifi-
cantly greater than the response associated with placebo
(4.8%) (P ⬍ 0.001 and P ⫽ 0.020, respectively) (Table 2
and Figure 1).
Onset and maintenance of response. Onset of Figure 1. Percentages of rheumatoid arthritis patients who met the
response was noted after 1 week of treatment (Table 3). American College of Rheumatology criteria for 20%, 50%, and 70%
improvement (ACR20, ACR50, and ACR70, respectively) during
The proportions of patients attaining an ACR20 re-
treatment with methotrexate (MTX) plus either placebo or adali-
sponse at week 1 in the 20-mg, 40-mg, and 80-mg mumab at a dosage of either 20 mg, 40 mg, or 80 mg administered
adalimumab dosage plus MTX groups were 26.1%, subcutaneosly every other week (EOW).
25.4%, 31.5%, respectively, compared with 6.5% in the
placebo plus MTX group. The proportion of
adalimumab-treated patients achieving a first-time percentage of patients achieving an ACR20 response
ACR20 response was greatest at week 1, the first increased from week 1 through week 12 and continued
scheduled visit. In each adalimumab dosage group, the at that level through week 24 (Figure 1). The ACR50
40 WEINBLATT ET AL

Table 3. Time to ACR20 response*

Adalimumab dosage (every other week)

Visit Placebo (n ⫽ 62) 20 mg (n ⫽ 69) 40 mg (n ⫽ 67) 80 mg (n ⫽ 73)

Week 1 4 (6.5) 18 (26.1) 17 (25.4) 23 (31.5)
Week 2 8 (12.9) 13 (18.8) 8 (11.9) 8 (11.0)
Week 3 9 (14.5) 6 (8.7) 9 (13.4) 15 (20.5)
Week 4 6 (9.7) 5 (7.2) 9 (13.4) 4 (5.5)
Week 6 2 (3.2) 6 (8.7) 3 (4.5) 5 (6.8)
Week 8 2 (3.2) 2 (2.9) 2 (3.0) 2 (2.7)
Week 12 1 (1.6) 5 (7.2) 3 (4.5) 3 (4.1)
Week 16 1 (1.6) 3 (4.3) 1 (1.5) 2 (2.7)
Week 20 0 0 1 (1.5) 0

* Values are the number (%) of patients who first met the American College of Rheumatology criteria for
20% improvement (ACR20) at each time point.

Table 4. Response of American College of Rheumatology core components at week 24*

Adalimumab dosage (every other week)

Criterion Placebo (n ⫽ 62) 20 mg (n ⫽ 69) 40 mg (n ⫽ 67) 80 mg (n ⫽ 73)

Tender joint count (0–68 joints)
Baseline value 28.7 ⫾ 15.2 28.5 ⫾ 14.4 28.0 ⫾ 12.7 30.2 ⫾ 15.7
Absolute change ⫺5.3 ⫾ 12.1 ⫺14.4 ⫾ 15.1 ⫺14.4 ⫾ 18.4 ⫺16.8 ⫾ 13.8
Percentage change ⫺18.5 ⫺50.2 ⫺51.4 ⫺55.6
P† ⬍0.001 ⬍0.001 ⬍0.001
Swollen joint count (0–66 joints)
Baseline value 16.9 ⫾ 9.5 17.6 ⫾ 8.7 17.3 ⫾ 8.6 17.0 ⫾ 8.2
Absolute change ⫺2.9 ⫾ 10.5 ⫺7.7 ⫾ 10.0 ⫺10.4 ⫾ 10.0 ⫺10.8 ⫾ 8.4
Percentage change ⫺17.8 ⫺43.8 ⫺60.7 ⫺62.9
P† 0.002 ⬍0.001 ⬍0.001
Patient’s assessment of pain (0–100-mm VAS)‡
Baseline value 57.2 ⫾ 21.0 55.1 ⫾ 20.6 53.0 ⫾ 22.0 55.0 ⫾ 23.7
Absolute change ⫺8.6 ⫾ 22.5 ⫺24.8 ⫾ 24.2 ⫺25.1 ⫾ 33.1 ⫺27.6 ⫾ 24.7
Percentage change ⫺15.0 ⫺45.0 ⫺47.2 ⫺50.2
P† ⬍0.001 ⬍0.001 ⬍0.001
Patient’s global assessment of disease activity
(0–100-mm VAS)§
Baseline value 58.0 ⫾ 23.2 57.6 ⫾ 21.6 56.9 ⫾ 21.1 58.8 ⫾ 24.9
Absolute change ⫺8.6 ⫾ 25.1 ⫺27.1 ⫾ 24.6 ⫺29.7 ⫾ 31.8 ⫺32.0 ⫾ 25.9
Percentage change ⫺14.7 ⫺46.9 ⫺52.4 ⫺54.4
P† ⬍0.001 ⬍0.001 ⬍0.001
Physician’s global assessment of disease activity
(0–100-mm VAS)§
Baseline value 58.9 ⫾ 15.3 60.5 ⫾ 17.3 58.7 ⫾ 15.8 62.6 ⫾ 14.7
Absolute change ⫺6.8 ⫾ 24.5 ⫺30.3 ⫾ 22.6 ⫺31.1 ⫾ 24.9 ⫺38.0 ⫾ 22.6
Percentage change ⫺11.6 ⫺50.1 ⫺53.0 ⫺60.5
P† ⬍0.001 ⬍0.001 ⬍0.001
Disability Index of the HAQ (0–3 scale)¶
Baseline value 1.64 ⫾ 0.63 1.52 ⫾ 0.62 1.55 ⫾ 0.61 1.55 ⫾ 0.66
Absolute change ⫺0.27 ⫾ 0.57 ⫺0.54 ⫾ 0.58 ⫺0.62 ⫾ 0.63 ⫺0.59 ⫾ 0.53
Percentage change ⫺16.5 ⫺35.5 ⫺40.0 ⫺38.1
P† 0.004 ⬍0.001 0.001
C-reactive protein, mg/dl (normal ⬍0.8)
Baseline value 3.1 ⫾ 3.9 2.8 ⫾ 3.1 2.1 ⫾ 1.8 2.8 ⫾ 2.7
Absolute change 0.1 ⫾ 2.4 ⫺1.4 ⫾ 2.9 ⫺1.6 ⫾ 1.6 ⫺1.3 ⫾ 3.5
Percentage change 3.2 ⫺50.0 ⫺71.4 ⫺42.9
P† ⬍0.001 ⬍0.001 ⬍0.001

* Except where indicated otherwise, values are the mean ⫾ SD. Values for absolute change from baseline represent the last observation carried
forward to week 24. A negative absolute change or a negative percentage change indicates an improvement in the response criterion.
† Absolute change for adalimumab versus placebo treatment, by analysis of covariance with baseline as the covariate; statistical significance was set
at P ⱕ 0.05.
‡ The visual analog scale (VAS) for pain ranges from 0 ⫽ no pain to 100 ⫽ severe pain.
§ The VAS for global assessment of disease activity ranges from 0 ⫽ no disease activity to 100 ⫽ extreme disease activity.
¶ The Health Assessment Questionnaire (HAQ) scale ranges from 0 ⫽ no difficulty to 3 ⫽ unable to perform activity.
ADALIMUMAB AND CONCOMITANT MTX TREATMENT FOR RA
Figure 2. Serum concentrations (last observation carried forward) of
the cartilage destruction markers pro–matrix metalloproteinase 1
(proMMP-1) and proMMP-3 during treatment with methotrexate
(MTX) plus either placebo or adalimumab at a dosage of 20 mg, 40
mg, or 80 mg administered subcutaneously every other week (EOW).
ⴱ ⫽ P ⱕ 0.01 and †⫽ P ⱕ 0.02 versus placebo at week 24, by analysis
of covariance, with baseline as the covariate and without correction for
multiple comparisons.
and ACR70 responses increased through week 24 for all
adalimumab groups (Figure 1).
ACR core component responses. Each adali-
mumab dosage plus MTX group was associated with a
statistically significant improvement over baseline, com-
pared with the placebo plus MTX group, in each of the
7 ACR core components at week 24 (LOCF) (Table 4).
Mean tender joint counts decreased by 50.2%, 51.4%,
and 55.6% with the 20-mg, 40-mg, and 80-mg adali-
mumab dosages, respectively, and by 18.5% with pla-
cebo. Likewise, the mean swollen joint counts decreased
41
by 43.8%, 60.7%, and 62.9% with the 20-mg, 40-mg, and
80-mg adalimumab dosages, respectively, and by 17.8%
with placebo. The Disability Index of the HAQ de-
creased by at least 0.54 (absolute change) for each
dosage of adalimumab, compared with a decrease of
0.27 for placebo. C-reactive protein levels decreased by
50.0%, 71.4%, and 42.9% with the 20-mg, 40-mg, and
80-mg adalimumab dosages, respectively, and increased
by 3.2% with placebo.
SF-36 scores. After 24 weeks of treatment
(LOCF), there were statistically significant increases
(improvements) over baseline (5% level of significance)
in the mean SF-36 scores for 7 of 8 domains, 8 of 8
domains, and 8 of 8 domains with the 20-mg, 40-mg, and
80-mg dosages of adalimumab plus MTX, respectively,
in comparison with statistically significant increases in 4
of 8 domains with placebo plus MTX (data not shown).
Changes of 5–10 points in individual domain scores have
been associated with meaningful clinical improvements
and can be considered to represent minimum clinically
important differences (21). After 24 weeks of treatment
(LOCF), all adalimumab treatment groups combined
achieved a minimum clinically important mean increase
over baseline (ⱖ10 points) in 6 domains (physical func-
tion, physical role, bodily pain, vitality, social function,
and emotional role). In contrast, placebo-treated pa-
tients reached a minimum clinically important mean
increase over baseline (ⱖ10 points) in 2 domains (phys-
ical role and emotional role).
FACIT fatigue scale scores. After 24 weeks of
treatment (LOCF), there were statistically significant
differences in the mean increases (improvements) over
baseline in FACIT fatigue scale scores in the 40-mg and
80-mg adalimumab dosages plus MTX groups (8.5 and
9.5) versus the placebo plus MTX group (3.0) (P ⫽ 0.001
and P ⬍ 0.001) (data not shown). Similar results were
obtained in comparisons of all adalimumab dosage
groups combined (8.0) versus placebo (3.0) (P ⬍ 0.001).
Serum levels of proMMP-1 and proMMP-3. Af-
ter 24 weeks of treatment (LOCF), there were statisti-
cally significant decreases in serum levels of proMMP-1
compared with baseline with the 20-mg, 40-mg, and
80-mg dosages of adalimumab plus MTX (⫺21.6, ⫺33.6,
and ⫺20.1 ng/ml, respectively) (P ⱕ 0.002). In contrast,
serum levels of proMMP-1 increased with placebo plus
MTX (increased by 4.3 ng/ml). Likewise, after 24 weeks
of treatment (LOCF), there were statistically significant
decreases in serum levels of proMMP-3 compared with
baseline with the 20-mg, 40-mg, and 80-mg doses of
adalimumab (⫺33.9, ⫺30.7, and ⫺27.0 ng/ml, respec-
tively) (P ⱕ 0.001). Serum levels of proMMP-3 also
42 WEINBLATT ET AL

Table 5. Changes in laboratory values at week 24* showed increases, and the platelet count showed a
Adalimumab (every other Placebo decrease.
week) (n ⫽ 209) (n ⫽ 62) Adverse events. Adalimumab was well tolerated.
Hematocrit, % The numbers of patients with treatment-emergent ad-
Baseline value 37.7 ⫾ 3.6 37.4 ⫾ 3.7 verse events were similar between the adalimumab plus
Absolute change 1.2 ⫾ 2.7† ⫺0.1 ⫾ 2.3 MTX group (2.16/patient-year) and the placebo plus
Hemoglobin, gm/dl
Baseline value 12.7 ⫾ 1.3 12.5 ⫾ 1.3 MTX group (2.33/patient-year) (Table 6). A total of
Absolute change 0.6 ⫾ 0.9† 0.2 ⫾ 0.8 15.3% of the adalimumab-treated patients and 3.2% of
Lymphocytes, % placebo-treated patients reported adverse events cate-
Baseline value 20.3 ⫾ 9.0 20.0 ⫾ 10.3
Absolute change 7.6 ⫾ 7.5† 0.2 ⫾ 6.2 gorized as “injection site reaction” according to the
Platelets, ⫻103/mm3 Hoechst Adverse Reaction Terminology System
Baseline value 308.9 ⫾ 99.0 311.7 ⫾ 113.3 (HARTS) body system coding dictionary; these adverse
Absolute change ⫺45.6 ⫾ 60.2† 16.9 ⫾ 44.6
events included pain, erythema, localized rash (injection
* Values are the mean ⫾ SD. Values for absolute change from site reaction), and hemorrhage at the injection site. The
baseline represent the last observation carried forward to week 24.
† P ⱕ 0.05 versus baseline, based on 95% confidence intervals. majority of these injection site reactions were mild or
moderate.
The number and rate of the most common ad-
decreased with placebo (⫺0.1), although this change was verse events are listed in Table 6. Infections occurred at
not significant. a similar rate in the adalimumab-treated (1.55/patient-
Comparisons of these changes in each adali- year) and the placebo-treated (1.38/patient-year) pa-
mumab dosage plus MTX group versus placebo plus tients. Adverse events were classified as infections if in
MTX group were also significant for serum levels of the interpretation of the investigator, there was a good
proMMP-1 (P ⱕ 0.01) as well as proMMP-3 (P ⱕ 0.02) possibility that the symptom(s) was caused by an infec-
(Figure 2). tious organism. The most common infections were rhi-
Laboratory tests. Statistically significant changes nitis, upper respiratory tract infection, and flu syndrome.
in laboratory values over baseline were observed at most Two adalimumab-treated patients developed serious in-
measurement times among the adalimumab plus MTX– fections (pneumonia) that were treated with antibiotics;
treated patients (Table 5). The hematocrit value, hemo- both patients remained in the study. One patient taking
globin concentration, and percentage of lymphocytes adalimumab developed a new malignancy (adenocarci-

Table 6. Adverse events*

Adalimumab dosage (every other week)

20 mg 40 mg 80 mg Placebo
(27.4 patient-years) (28.2 patient-years) (31.4 patient-years) (21.0 patient-years)
(n ⫽ 69) (n ⫽ 67) (n ⫽ 73) (n ⫽ 62)

No. (%) No. per No. (%) No. per No. (%) No. per No. (%) No. per
Adverse event of patients patient-year of patients patient-year of patients patient-year of patients patient-year
Rhinitis 16 (23.2) 0.58 17 (25.4) 0.60 17 (23.3) 0.54 12 (19.4) 0.57
Upper respiratory tract 14 (20.3) 0.51 10 (14.9) 0.36 16 (21.9) 0.51 6 (9.7) 0.29
infection
Nausea 13 (18.8)† 0.47 3 (4.5) 0.11 7 (9.6) 0.22 4 (6.5) 0.19
Flu syndrome 8 (11.6) 0.29 10 (14.9) 0.36 5 (6.8) 0.16 5 (8.1) 0.24
Headache 7 (10.1) 0.26 4 (6.0) 0.14 21 (10.0) 0.32 6 (9.7) 0.29
Injection site pain‡ 6 (8.7) 0.22 7 (10.4) 0.25 8 (11.0) 0.26 2 (3.2) 0.10
Accidental injury 4 (5.8) 0.15 10 (14.9) 0.36 6 (8.2) 0.19 7 (11.3) 0.33
Diarrhea 6 (8.7) 0.21 7 (10.4) 0.25 4 (5.5) 0.13 5 (8.1) 0.24
Rash 7 (10.1) 0.26 3 (4.5) 0.11 5 (6.8) 0.16 3 (4.8) 0.14
Injection site reaction‡ 3 (4.3) 0.11 1 (1.5) 0.04 8 (11.0)† 0.26 0 0
Dizziness 8 (11.6)† 0.29 2 (3.0) 0.7 1 (1.4) 0.03 1 (1.6) 0.05

* Shown are adverse events that occurred in ⱖ10% of patients in any treatment group. “No. per patient-year” represents the number of patients
experiencing the particular adverse event per total years of treatment.
† P ⱕ 0.05 versus placebo, by Pearson’s chi-square test without correction for multiple comparisons.
‡ Injection site pain and injection site reaction (indicating a localized rash) are both adverse event terms that are categorized as “injection site
reaction” according to the Hoechst Adverse Reaction Terminology System (HARTS) body system coding dictionary.
ADALIMUMAB AND CONCOMITANT MTX TREATMENT FOR RA
noma of the colon). No drug-related toxicity occurred,
as indicated by changes in hematologic and clinical
chemistry evaluation findings.
Seven patients withdrew from the study because
of adverse events: 4 receiving 20 mg of adalimumab (skin
hypertrophy, pruritus, injection site reaction, and cough
with asthenia), 1 receiving 80 mg of adalimumab (ade-
nocarcinoma of the colon), and 2 receiving placebo
(avascular necrosis of the femur and allergic reaction).
During the study, serum samples obtained from 3
patients tested positive for anti-adalimumab antibodies
(1 each taking placebo, 20 mg of adalimumab, and 80 mg
of adalimumab). The patients in the placebo and the
20-mg adalimumab groups who were positive for anti-
adalimumab antibodies did not achieve an ACR20 re-
sponse, but the patient in the 80-mg adalimumab group
achieved an ACR70 response.
At week 24, 18 of the 162 adalimumab-treated
patients (11.1%) and 3 of the 49 placebo-treated pa-
tients (6.1%) who were negative for the presence of
ANA at baseline converted to ANA positive. The dif-
ferences between treatment groups were not statistically
significant. At week 24, 18 of the 41 adalimumab-treated
patients (43.9%) and 3 of the 9 placebo-treated patients
(33.3%) who were positive for the presence of ANA at
baseline converted to ANA negative. At week 24, 8 of
the 204 adalimumab-treated patients (3.9%) but none of
the 58 placebo-treated patients who were negative for
the presence of anti-dsDNA antibodies at baseline con-
verted to anti-dsDNA positive. No patients developed
symptoms of lupus-like syndrome.
DISCUSSION
This trial was conducted to test whether admin-
istration of adalimumab to patients who were not re-
sponding adequately to MTX would achieve additional
benefit and whether the adalimumab plus MTX combi-
nation would be safe and well tolerated. In this group of
patients, the addition of adalimumab (subcutaneously
every other week) to the MTX (orally or subcutaneously
every week) therapy achieved significant, rapid, and
sustained responses. Of the 271 patients who entered the
study, 161 completed 24 weeks of treatment. Ninety-two
of the remaining 110 patients completed at least 16
weeks of therapy, were defined as nonresponders, and
then entered the open-label rollover study. Eighteen
patients did not complete at least 16 weeks of the study
because of adverse events (n ⫽7), withdrawal of consent
(n ⫽ 5), lack of efficacy (n ⫽ 3), protocol violation (n ⫽
1), and lost to followup (n ⫽ 2).
The 20-mg, 40-mg, and 80-mg adalimumab dos-
43
age plus MTX groups achieved statistically superior
ACR20 and ACR50 response rates compared with the
placebo plus MTX group. Furthermore, ACR70 re-
sponse rates among those who received 40 mg and 80 mg
of adalimumab were statistically significantly greater
than the ACR70 response rate among those who re-
ceived placebo. The placebo response rate for this study
was lower than the rate observed in other studies using
MTX partial responders, but the reason for this obser-
vation is not clear. The onset of response with adali-
mumab was rapid, with the greatest proportion of
adalimumab-treated patients achieving an ACR20 re-
sponse at week 1, the first evaluation.
Each adalimumab group was associated with a
statistically significant improvement compared with pla-
cebo in each of the ACR core components, including
tender and swollen joint counts. The significant im-
provements in the Disability Index of the HAQ suggest
that the addition of adalimumab to MTX treatment
improved functional capacity and reduced disability
within 6 months or less. Changes in SF-36 scores and
FACIT fatigue scores indicate that health-related qual-
ity of life also improved with the addition of adali-
mumab. Statistically significant decreases in serum levels
of proMMP-1 and proMMP-3 were also observed.
ProMMP-1 and proMMP-3 are possible biochemical
markers of cartilage destruction that are cleaved to
produce MMP-1 (fibroblast or tissue collagenase) and
MMP-3 (stromelysin 1), the active MMPs (22). MMP-3,
in turn, participates in the activation of MMP-1 (22).
Recently, it was shown that high serum levels of
proMMP-3 are associated with greater articular damage
and the presence of the shared epitope in RA patients
(23). Significant improvement in levels of acute-phase
reactants, including C-reactive protein, increases in he-
matocrit and hemoglobin concentrations, and a decrease
in platelet counts, were also observed with adalimumab
plus MTX compared with placebo plus MTX.
Taken together, these findings indicate that ad-
dition of adalimumab to MTX therapy substantially and
rapidly improves standard measures of disease activity,
including signs and symptoms, the acute-phase response,
functional parameters, fatigue scales, and quality of life
scores in RA patients not adequately responding to
therapy with MTX alone.
Adalimumab given subcutaneously every other
week was well tolerated in these patients. The majority
of adverse events were mild or moderate, and treatment-
emergent adverse events were reported in comparable
numbers of patients treated with adalimumab plus MTX
and placebo plus MTX. The rate of infections was
comparable between the 2 groups, occurring in 1.55
44
patients/patient-year in the adalimumab groups and in
1.38 patients/patient-year in the placebo group. The
most common infections were of the upper respiratory
tract. No opportunistic infections, including tuberculo-
sis, were observed during this study. Other common
adverse events included injection-site reactions, which
occurred in 15.3% and 3.2% of adalimumab- and
placebo-treated patients, respectively. Similar propor-
tions of adalimumab- and placebo-treated patients con-
verted from ANA negative to ANA positive and vice
versa. Although conversion to positivity for anti-dsDNA
antibodies occurred slightly more frequently in the ac-
tive treatment arms, no cases of lupus-like syndromes
were noted.
The mean dosage of MTX at the start of this
study (16.7 mg/week) was considered an adequate dose
for defining continued disease activity in patients receiv-
ing long-term therapy. This dosage equates to 10 mg/m2,
which is the therapeutic range for MTX in the treatment
of RA (24).
Limitations of the current study include the lack
of another active-DMARD arm, so that the response to
adalimumab could be compared with the response to
other known therapies. A randomized active-
comparator trial involving adalimumab alone, adali-
mumab plus MTX, and MTX alone in patients with early
RA is currently under way and will provide further
insight into the utility of adalimumab in the treatment of
RA.
Other treatment approaches have been effective
in RA patients who are partially responsive to MTX,
including combinations of MTX with traditional
DMARDs (cyclosporine, sulfasalazine, hydroxychloro-
quine, or leflunomide) or biologic DMARDs (infliximab
or etanercept) (25). Introduction of adalimumab, a
biologic DMARD and the first fully human anti-TNF␣
monoclonal antibody, increases the range of possible
therapeutic combinations.
This clinical trial demonstrated that adalimumab
(20 mg, 40 mg, or 80 mg subcutaneously every other
week) with concomitant MTX therapy is more effective
than MTX plus placebo at reducing the signs and
symptoms of RA. All 3 regimens of adalimumab plus
MTX were well tolerated. Our findings suggest that
adalimumab may be a new therapeutic option for pa-
tients with longstanding, active RA who have had an
inadequate response to MTX.
ACKNOWLEDGMENTS
The authors wish to thank the following principal
investigators: C. Aranow (Brooklyn, NY), M. Atkinson (Cal-
WEINBLATT ET AL
gary, Alberta, Canada), A. Beaulieu (Ste. Foy, Quebec, Can-
ada), W. Bensen (Hamilton, Ontario, Canada), K. Bulpitt (Los
Angeles, CA), B. Caciolo (St. Louis, MO), J. Caldwell (Gaines-
ville, FL), J. Canvin (Winnipeg, Manitoba, Canada), A. Ci-
vidino (Hamilton, Ontario, Canada), C. DeAbate (New Or-
leans, LA), R. Dore (Anaheim, CA), M. Genovese (Palo Alto,
CA), B. Haroui (Montreal, Quebec, Canada), T. Kelly (Las
Vegas, NV), M. Khraishi (St. John’s, Newfoundland, Canada),
A. Klinkhoff (Vancouver, British Columbia, Canada), R. Laut-
zenheiser (Indianapolis, IN), M. Lowenstein (Palm Harbor,
FL), D. MacPeek (Toms River, NJ), J. Markenson (New York,
NY), M. Michalska (Chicago, IL), A. Safdi (Cincinnati, OH),
D. Sikes (Zephyr Hills, FL), M. Schiff (Denver, CO), S.
Silverman (Beverly Hills, CA), M. Starr (Pointe-Claire, Que-
bec, Canada), D. Wallace (Los Angeles, CA), C. Weisenhutter
(Coeur D’Alene, ID), and C. Wise (Richmond, VA). The
investigators wish to thank all of the study coordinators as well
as the patients who participated in the study and completed the
evaluations despite their severe RA.
REFERENCES
1. Kremer JM. Safety, efficacy, and mortality in a long-term cohort of
patients with rheumatoid arthritis taking methotrexate: followup
after a mean of 13.3 years. Arthritis Rheum 1997;40:984–5.
2. Weinblatt ME, Maier AL, Fraser PA, Coblyn JS. Longterm
prospective study of methotrexate in rheumatoid arthritis: conclu-
sion after 132 months of therapy. J Rheumatol 1998;25:238–42.
3. Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE,
Glass DN, et al. Efficacy of low-dose methotrexate in rheumatoid
arthritis. N Engl J Med 1985;312:818–22.
4. Kremer JM, Lee JK. The safety and efficacy of the use of
methotrexate in long-term therapy for rheumatoid arthritis. Ar-
thritis Rheum 1986;29:822–31.
5. Kremer JM. Rational use of new and existing disease-modifying
agents in rheumatoid arthritis. Ann Intern Med 2001;138:695–706.
6. O’Dell J. Conventional DMARD options for patients with a
suboptimal response to methotrexate. J Rheumatol Suppl 2001;
62:21–6.
7. Choy EH, Panayi GS. Cytokine pathways and joint inflammation
in rheumatoid arthritis. N Engl J Med 2001;344:907–16.
8. Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen
JS, et al. Randomised double-blind comparison of chimeric mono-
clonal antibody to tumour necrosis factor ␣ (cA2) versus placebo
in rheumatoid arthritis. Lancet 1994;344:1105–10.
9. Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleisch-
mann RM, Weaver AL, et al. Treatment of rheumatoid arthritis
with a recombinant human tumor necrosis factor receptor
(p75)-Fc fusion protein. N Engl J Med 1997;337:141–7.
10. Salfeld J, Kaymakçalan Z, Tracey D, Roberts A, Kamen R.
Generation of fully human anti-TNF antibody D2E7 [abstract].
Arthritis Rheum 1998;41 Suppl 9:S57.
11. Kempeni J. Preliminary results of early clinical trials with the fully
human anti-TNF␣ monoclonal antibody D2E7. Ann Rheum Dis
1999;58 Suppl 1:170–2.
12. Kempeni J. Update on D2E7: a fully human anti-tumour necrosis
factor ␣ monoclonal antibody. Ann Rheum Dis 2000;59 Suppl
1:144–5.
13. Barrera P, Joosten LA, den Broeder AA, van de Putte LB, van
Riel PL, van den Berg WB, et al. Effects of treatment with a fully
human anti-tumour necrosis factor ␣ monoclonal antibody on the
local and systemic homeostasis of interleukin 1 and TNF␣ in
patients with rheumatoid arthritis. Ann Rheum Dis 2001;60:660–9.
14. Den Broeder AA, Joosten LA, Saxne T, Heinegård D, Fenner H,
ADALIMUMAB AND CONCOMITANT MTX TREATMENT FOR RA
Miltenburg AM, et al. Long term anti-tumour necrosis factor
alpha monotherapy in rheumatoid arthritis: effect on radiological
course and prognostic value of markers of cartilage turnover and
endothelial activation. Ann Rheum Dis 2002;61:311–8.
15. 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.
16. 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
Rheum 1995;38:727–35.
17. Felson DT, Anderson JJ, Boers M, Bombardier C, Chernoff M,
Fried B, et al. The American College of Rheumatology prelimi-
nary core set of disease activity measures for rheumatoid arthritis
clinical trials. Arthritis Rheum 1993;36:729–40.
18. Fries JF, Spitz PW, Young DY. The dimensions of health out-
comes: the Health Assessment Questionnaire, Disability and Pain
scales. J Rheumatol 1982;9:789–93.
19. Ware JE Jr, Sherbourne CD. The MOS 36-item Short-Form
health survey (SF-36). 1. Conceptual framework and item selec-
tion. Med Care 1992;30:473–83.
45
20. Cella D, Webster K. Linking outcomes management to quality-of-
life measurement. Oncology (Huntingt) 1997;11:232–35.
21. Kosinski M, Zhao SZ, Dedhiya S, Osterhaus JT, Ware JE Jr.
Determining minimally important changes in generic and disease-
specific health-related quality of life questionnaires in clinical
trials of rheumatoid arthritis. Arthritis Rheum 2000;43:1478–87.
22. Nagase H, Suzuki K, Morodomi T, Enghild JJ, Salvesen G.
Activation mechanisms of the precursors of matrix metalloprotein-
ases 1, 2 and 3. Matrix 1992;1 Suppl:237–44.
23. Cheung NT, Dawes PT, Poulton KV, Ollier WE, Taylor DJ,
Mattey DL. High serum levels of pro-matrix metalloproteinase-3
are associated with greater radiographic damage and the presence
of the shared epitope in patients with rheumatoid arthritis.
J Rheumatol 2000;27:882–7.
24. Furst DE, Koehnke R, Burmeister LF, Kohler J, Cargill I.
Increasing methotrexate effect with increasing dose in the treat-
ment of resistant rheumatoid arthritis. J Rheumatol 1989;16:
313–20.
25. American College of Rheumatology Subcommittee on Rheuma-
toid Arthritis Guidelines. Guidelines for the management of
rheumatoid arthritis: 2002 update. Arthritis Rheum 2002;46:
328–46.