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ARTHRITIS & RHEUMATISM

Vol. 50, No. 11, November 2004, pp 34323443


DOI 10.1002/art.20568
2004, American College of Rheumatology

Combination of Infliximab and Methotrexate Therapy for


Early Rheumatoid Arthritis
A Randomized, Controlled Trial
E. William St.Clair,1 Desiree M. F. M. van der Heijde,2 Josef S. Smolen,3 Ravinder N. Maini,4
Joan M. Bathon,5 Paul Emery,6 Edward Keystone,7 Michael Schiff,8 Joachim R. Kalden,9
Ben Wang,10 Kimberly DeWoody,10 Roberta Weiss,10 and Daniel Baker,10
for the Active-Controlled Study of Patients Receiving Infliximab for the Treatment of
Rheumatoid Arthritis of Early Onset Study Group
Objective. To compare the benefits of initiating
treatment with methotrexate (MTX) and infliximab
(antitumor necrosis factor [anti-TNF] monoclonal
antibody) with those of MTX treatment alone in patients with rheumatoid arthritis (RA) of <3 years
duration.

Methods. RA patients were eligible if they had


active disease and no prior treatment with MTX or a
TNF inhibitor. One thousand forty-nine patients were
randomly assigned in a 4:5:5 ratio to 3 treatment
groups: MTXplacebo, MTX3 mg/kg infliximab, and
MTX6 mg/kg infliximab. MTX dosages were rapidly
escalated to 20 mg/week, and infliximab or placebo
infusions were given at weeks 0, 2, and 6, and every 8
weeks thereafter through week 46.
Results. At week 54, the median percentage of
American College of Rheumatology improvement
(ACR-N) was higher for the MTX3 mg/kg infliximab
and MTX6 mg/kg infliximab groups than for the
MTXplacebo group (38.9% and 46.7% versus 26.4%,
respectively; P < 0.001 for both comparisons). Patients
in the MTX3 mg/kg infliximab and MTX6 mg/kg
infliximab groups also showed less radiographic progression than those receiving MTX alone (mean SD
changes in van der Heijde modification of the total
Sharp score at week 54: 0.4 5.8 and 0.5 5.6 versus
3.7 9.6, respectively; P < 0.001 for each comparison).
In addition, physical function improved significantly
more in the MTX3 mg/kg infliximab and MTX6
mg/kg infliximab groups than in the MTXplacebo
group. Infliximab therapy was associated with a significantly higher incidence of serious infections, especially
pneumonia.
Conclusion. For patients with active RA in its
early stages, combination therapy with MTX and infliximab provides greater clinical, radiographic, and functional benefits than treatment with MTX alone.

Supported by Centocor, Inc., a subsidiary of Johnson &


Johnson.
1
E. William St.Clair, MD: Duke University Medical Center,
Durham, North Carolina; 2Desiree M. F. M. van der Heijde, MD:
University Hospital Maastricht, Maastricht, The Netherlands; 3Josef S.
Smolen, MD: Medical University of Vienna, Vienna, Austria; 4Ravinder N. Maini, MD: Kennedy Institute of Rheumatology, London, UK;
5
Joan M. Bathon, MD: Johns Hopkins University, Baltimore, Maryland; 6Paul Emery, MD: University of Leeds, Leeds, UK; 7Edward
Keystone, MD: Center for Advanced Therapeutics, Mt. Sinai Hospital,
Toronto, Ontario, Canada; 8Michael Schiff, MD: Denver Arthritis
Clinic, Denver, Colorado; 9Joachim R. Kalden, MD: Institute for
Clinical Immunology, Erlangen, Germany; 10Ben Wang, PhD, Kimberly DeWoody, PhD, Roberta Weiss, MD, Daniel Baker, MD:
Centocor, Inc., Malvern, Pennsylvania.
Drs. St.Clair, van der Heijde, Smolen, Maini, Bathon, Emery,
Keystone, and Kalden have received consultancies and/or honoraria
from Centocor, Inc., totaling less than $10,000 per year. In 2002, Drs.
van der Heijde and Maini gave expert testimony to the FDA hearing
on inhibition of structural damage and received a fee. The Kennedy
Institute of Rheumatology has a patent and a research and licensing
agreement from Centocor, Inc., under which it has received royalties
for the use of infliximab in rheumatoid arthritis. As a coinventor, Dr.
Maini receives a percentage of these royalties under the Kennedy
Institutes formula for the division of royalties. Drs. Maini, Wang,
DeWoody, Weiss, and Baker own stock in Johnson & Johnson, of
which Centocor, Inc., is a subsidiary.
Address correspondence and reprint requests to Josef S.
Smolen, MD, Division of Rheumatology, Department of Medicine III,
Medical University Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail: josef.smolen@wienkav.at.
Submitted for publication March 9, 2004; accepted in revised
form June 30, 2004.
3432

INFLIXIMAB THERAPY FOR RHEUMATOID ARTHRITIS

Rheumatoid arthritis (RA) is a chronic, inflammatory polyarthritis with frequent progression to joint
destruction and disability (1). Often, only a brief period
of time elapses between the onset of joint inflammation
and the development of bone erosions and cartilage
injury (24). These pathologic events are at least in part
dependent on increased expression of tumor necrosis
factor (TNF) (5). In support of this premise, clinical
trials have shown that TNF blocking agents, such as
etanercept, infliximab, and adalimumab, significantly
reduce joint inflammation, slow radiographic progression of joint damage, and improve physical function in
advanced RA (610).
Early treatment with a TNF blocking agent may
be an effective strategy for suppressing joint inflammation and preventing subsequent joint damage in RA. In
a 1-year controlled trial, 25-mg twice weekly injections of
etanercept, a soluble TNF receptor Fc fusion protein,
more rapidly controlled the signs and symptoms in
patients with RA of 3 years duration compared with
methotrexate (MTX) therapy, but its use alone was no
better than MTX for slowing radiographic progression
of joint destruction, as determined by the primary
radiographic end point (11). However, it was determined
in a subanalysis that patients who received etanercept
had lower erosion scores than those who received MTX
(11). In the 2-year, open-label, completer-only followup
study, the patients receiving etanercept had higher
American College of Rheumatology (ACR) response
rates and less radiographic progression of joint damage
than those receiving MTX alone (12). Current evidence
further indicates that aggressive disease-modifying antirheumatic drug (DMARD) therapy in early RA, particularly with 2- and 3-drug combinations of DMARDs,
produces greater clinical, radiographic, and functional
benefits than less intensive regimens (1318). However,
these studies have not evaluated, in comparison with
MTX therapy, the relative efficacy of a combination
strategy incorporating a potent anti-TNF drug.
We therefore compared the treatment benefits of
the combination of MTX and infliximab with those of
MTX alone in patients with RA of 3 years duration.
PATIENTS AND METHODS
Patients. Patients eligible for this trial were at least 18
years old but no older than 75 years, met the 1987 revised
criteria of the ACR (formerly, the American Rheumatism
Association) for the classification of RA (19), and had persistent synovitis for 3 months and 3 years, 10 swollen joints,
and 12 tender joints. In addition, eligible patients had one or
more of the following: a positive test result for serum rheuma-

3433

toid factor, radiographic erosions of the hands or feet, or a


serum C-reactive protein (CRP) level 2.0 mg/dl.
Patients were excluded if they had any prior treatment
with MTX, had received other DMARDs within 4 weeks of entry
(or leflunomide within the past 6 months), or had been treated
with infliximab, etanercept, adalimumab, or other anti-TNF
agent. Three or fewer prestudy doses of MTX were allowed to
enhance enrollment of patients who might have been started on
this medication recently by their physicians. Because MTX therapy generally requires a minimum of 68 weeks to achieve a
clinical effect, we reasoned that 3 or fewer doses probably would
not bias the selection of patients on the basis of a treatment
response. Other exclusion criteria were infection with human
immunodeficiency virus, hepatitis B virus, or hepatitis C virus as
well as a history of active or past tuberculosis, congestive heart
failure, or lymphoma or other malignancy within the past 5 years
(excluding excised skin cancers).
Study protocol. The protocol was approved by an
institutional review board at each study center and was carried
out in accordance with the Helsinki Declaration and all
subsequent revisions. In addition to the authors of this article,
the members of the Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis
of Early Onset Study Group are listed in Appendix A. Patients
were enrolled between July 21, 2000 and February 28, 2002
and randomly assigned to receive 1 of the following 3 treatments in a 4:5:5 ratio: MTX plus placebo, MTX plus 3 mg/kg
infliximab, or MTX plus 6 mg/kg infliximab. Patient allocation
to a treatment group was performed using a dynamic process in
which patients were randomly assigned to 1 of the 3 treatment
groups by the Interactive Voice Response System (IVRS). The
IVRS assigned a treatment group to patients such that the
numbers of patients in the 3 treatment groups were as balanced as possible within each investigational site, while maintaining 300 (placebo arm) or 375 (the 2 infliximab arms)
patients per treatment group.
Infliximab (Remicade; Centocor, Malvern, PA) was
supplied in 20-ml vials containing 100 mg of the lyophilized
concentrate; placebo was supplied in an identical manner
except that it did not contain infliximab. Oral MTX was started
at 7.5 mg/week and escalated in a graduated manner (2.5
mg/week every 12 weeks) to 15 mg/week by week 4 and 20
mg/week by week 8, with at least 5 mg/week of oral folic acid.
The MTX dosage could be tapered only for toxicity. An
algorithm was used to make dosage adjustments for mild,
moderate, and severe suspected MTX-related toxicity. If toxicity did not improve after withholding MTX therapy for 4 weeks,
then the MTX and study drug infusions were permanently
discontinued. The study drugs were also stopped if the dosage of
MTX dropped below 7.5 mg/week for 4 weeks. Infliximab or
placebo infusions were given at weeks 0, 2, and 6, and every 8
weeks thereafter through week 46. Oral corticosteroids (10
mg/day prednisone or its equivalent) and nonsteroidal antiinflammatory drugs were maintained at baseline dosages. Other
DMARDs were not permitted during the study.
Joint examinations were performed by an independent
assessor who had no knowledge of the patients treatment
assignment. Other assessments included the patients selfevaluation of pain, patients and evaluators global disease
assessment, patients self-evaluation of fatigue, patients selfevaluation of functional status using the Disability Index of the

3434

Health Assessment Questionnaire (HAQ) (20), and patients


self-evaluation of quality of life using the Medical Outcomes
Study Short Form 36 (SF-36) (21).
Blood samples were obtained for measuring the erythrocyte sedimentation rate and serum CRP levels, as well as for
determining the presence of antinuclear antibodies (ANAs),
antidouble-stranded DNA (anti-dsDNA) antibodies, and antibodies to infliximab (22). For antiinfliximab antibody assays,
the results were considered to be inconclusive if the sample
was negative but contained detectable concentrations of infliximab (the presence of infliximab in the serum is known to
interfere with the interpretation of the assay for antibodies to
infliximab). Radiographs of the hands and feet were obtained
within 4 weeks of the first dose of study drug and at weeks 30
and 54, or upon premature withdrawal of the patient from the
study.
The protocol was amended on February 22, 2001 to
include mandatory tuberculosis screening for study patients.
All study patients in the US and Canada received a purified
protein derivative (PPD) tuberculin skin test, and investigators
followed the American Thoracic Society/Centers for Disease
Control and Prevention guidelines for immunocompromised
patients. Outside the US and Canada, local country guidelines
were followed for screening, diagnosis, and treatment of latent
tuberculosis.
Study end points. Signs and symptoms. The primary
end point for reduction of signs and symptoms was the
percentage of ACR improvement (ACR-N) from baseline to
week 54. The ACR-N is defined as the minimum of the
following 3 items: the percentage change from baseline in the
number of tender joints, the percentage change from baseline
in the number of swollen joints, and the median of the
percentage change from baseline for the patients global
assessment, physicians global assessment, pain, disability, and
serum levels of CRP (11). A negative ACR-N indicates
worsening of disease activity from baseline.
The reduction in signs and symptoms was also evaluated using the ACR 20% criteria for clinical improvement
(ACR20) (23). Improvement of 50% (ACR50), 70% (ACR70),
and 90% (ACR90) was similarly defined using these criteria. A
major clinical response was defined as an ACR70 response for
6 consecutive months. Clinical improvement was also assessed
using the Disease Activity Score in 28 joints (DAS28), a
validated composite index with measures of joint tenderness
and swelling, global disease activity, and serum levels of
acute-phase reactants (2426).
Radiographic changes. The primary end point for radiographic progression of joint damage was the change from
baseline to week 54 in the van der Heijde modification of the
total Sharp score (vdH-S) (27). Two readers scored the
radiographs independently without knowledge of treatment assignment, clinical response, or the order of the radiographs. For
each set of radiographs, the mean score of the 2 readers was used
for the analyses. Radiographic progression of disease was defined
as an increase from baseline in the vdH-S that was larger than the
smallest detectable difference (SDD). The SDD was 9.03 for this
trial and reflects that component of a measure that was statistically attributable to error from the measurement process (28,29).
Physical function. The primary end point for improvement in physical function was the change from baseline in
HAQ scores averaged over weeks 3054; this time period was

ST.CLAIR ET AL

prespecified so that treatment comparisons were made during


the time when MTX had reached peak efficacy. This effect was
evaluated with changes in quality of life, as measured by the
SF-36.
Statistical analysis. The statistical analyses of the 3
coprimary end points were performed hierarchically in a
predefined order to control for Type I error. First, a 2-sided
t-test on the van der Waerden normal score (30) was performed for the ACR-N. The test was positive if the global test
showed statistical significance for the combined MTX
infliximab groups compared with the MTX-alone group and at
least one of the MTXinfliximab groups showed statistically
significant improvement over the MTX-alone group (both at
the 0.05 level). Two-sided t-tests were then sequentially
performed for the primary radiographic and functional end
points. Nominal 2-sided P values were reported for secondary
analyses.
Patients were assigned an ACR-N value of 0 if they
received prohibited medications, had 2 joint injections or
surgeries, withdrew due to lack of efficacy, or withdrew before
week 30 without followup measurements. The actual ACR-N
value at week 54 was used for subjects who discontinued
treatment because of study drug toxicity but continued to be
followed up to determine drug efficacy. A last observation
carried forward principle was used to handle missing data
between weeks 30 and 54. Data obtained prior to week 30 were
not carried over for the week 54 analysis. Patients with no data
after week 30 had values set to 0. If a patient had evaluable
radiographs either at baseline or at week 54 and at one other
time point, the value was estimated using linear extrapolation.
Two sensitivity analyses were performed to assess the
robustness of the ACR-N end point. The first analyzed ACR-N
at week 54, with ACR-N set to 0 for subjects who discontinued
the study medication because of an adverse event. The second
sensitivity analysis analyzed ACR-N at week 54 using the
actual ACR-N regardless of the use of study-prohibited medications, surgical procedures, or treatment discontinuations. If
a patients radiographs were missing at baseline and week 54,
the change from baseline was estimated using the percentile of
the entire patient population. Missing values were not imputed
for the erosion and joint space narrowing scores when analyzed
separately. If the baseline HAQ score was missing or no HAQ
scores were obtained at and after week 30, the area under the
curve of the HAQ change from baseline and from week 30 to
week 54 was estimated using the percentile of the entire
patient population.
A sample size of 1,050 patients provided 90% power
(under 0.05 each) to detect a significant difference
between treatment groups in signs and symptoms, assuming a
mean of 50% improvement in the ACR-N for the MTX
placebo group and a mean of 60% improvement in the ACR-N
for either MTXinfliximab treatment group. This study also
provided 90% power for detecting a difference in the
changes of the vdH-S between the MTXinfliximab groups and
the MTXplacebo group, assuming a progression of 2.0 vdH-S
units for the MTXplacebo group and a 65% reduction in
damage for the groups receiving MTX and infliximab.
Role of the funding source. Representatives of the
sponsor assisted in the statistical design and data analysis of
this trial. Otherwise, the study sponsor had no role in the data

INFLIXIMAB THERAPY FOR RHEUMATOID ARTHRITIS

3435

Figure 1. Flow of participation in the present study. All patients received concomitant methotrexate. The
randomized study population consisted of 1,049 patients from 122 sites in North America and Europe. Prior to
unblinding, 45 patients were excluded from the efficacy analysis because the data on case report forms at 2 sites
could not be verified by source documents. Note that patients who discontinued study treatment could have
completed their participation in the study through the last followup visit and could have been evaluated for study
drug safety and efficacy at week 54.

interpretation, the content of this article, or the decision to


submit the manuscript for publication.

RESULTS
One thousand forty-nine patients were randomized to receive study medication as depicted in Figure 1.
Prior to unblinding, 45 patients at 2 sites were excluded
from the efficacy analysis (16 in the MTXplacebo
group, 14 in the MTX3 mg/kg infliximab group, and 15
in the MTX6 mg/kg infliximab group) because their
study data could not be verified with source documents.
Patients who discontinued study treatment might have
completed study participation through the last followup
visit, and therefore data for these patients were evaluated for safety and efficacy at week 54.
Characteristics of the patients. The analyses
were based on evaluable data for 1,004 patients. The
characteristics of the 1,004 study patients with RA were
similar among the 3 treatment groups, with a mean
disease duration of 0.8 years for the MTX3 mg/kg

infliximab group and 0.9 years for each of the other 2


groups (Table 1). The magnitudes of the joint counts,
pain ratings, global assessments, and HAQ scores indicated that the study patients had a moderate level of
disease activity. Only 7 (2.5%), 5 (1.4%), and 7 (1.9%)
patients in the MTXplacebo, MTX3 mg/kg infliximab,
and MTX6 mg/kg infliximab groups, respectively, had
received 13 doses of MTX prior to baseline, as permitted in the protocol design.
Maintenance of MTX therapy and withdrawals.
Most patients among the 3 treatment groups were able
to have their MTX dosages escalated to 20 mg/week and
to have this dosage maintained through their last evaluation (217 [72.8%] in the MTXplacebo group, 260
[69.7%] in the MTX3 mg/kg infliximab group, and 254
[67.2%] in the MTX6 mg/kg infliximab group). The
remaining patients either did not reach 20 mg/week or
could not maintain the target dosage of 20 mg/week
through week 54. MTX toxicity was the primary reason
for failure to reach or maintain 20 mg/week of MTX in

3436

ST.CLAIR ET AL

Table 1. Baseline patient characteristics*

Age, mean SD years


Women, %
Glucocorticoid therapy, %
NSAID therapy, %
DMARD naive, %
Duration of disease, mean SD years
Positive test for serum rheumatoid factor, %
Erosion score 0, %
Tender joint count, mean SD
Swollen joint count, mean SD
HAQ score, mean SD
SF-36 score, mean SD#
Physical component
Mental component
ESR, mean SD mm/hour
CRP level, mean SD mg/dl
Total radiographic score**
Mean SD
Median (IQR)
Range
Erosion score
Mean SD
Median (IQR)
Range
JSN score
Mean SD
Median (IQR)
Range

MTX placebo
(n 282)

MTX 3 mg/kg infliximab


(n 359)

MTX 6 mg/kg infliximab


(n 363)

50 13
75
38
82
65
0.9 0.7
71
80
34 15
22 11
1.5 0.6

51 12
71
37
85
71
0.8 0.7
71
84
32 15
21 10
1.5 0.7

50 13
68
39
82
68
0.9 0.8
73
83
33 15
22 11
1.5 0.6

29.5 7.7
44.7 11.9
43 28
2.6 2.9

28.8 7.7
45.4 11.5
45 29
2.9 3.3

29.3 8.2
44.2 11.9
44 27
3.0 3.4

11.3 15.9
5.1 (1.4, 14.6)
0.0102.7

11.6 15.2
5.2 (1.8, 15.1)
0.081.3

11.2 15.2
5.3 (1.7, 14.6)
0.0102.7

8.25 12.3
3.0 (0.5, 10.5)
0.072.3

8.75 12.1
3.8 (1.0, 11.0)
0.057.3

8.27 11.8
3.8 (1.0, 10.8)
0.076.8

3.0 4.8
1.0 (0.0, 3.9)
0.030.4

2.9 4.4
1.0 (0.0, 3.8)
0.024.6

2.9 5.2
1.0 (0.0, 3.6)
0.043.8

* MTX methotrexate; NSAID nonsteroidal antiinflaminatory drug; DMARD disease-modifying antirheumatic drug; HAQ Health
Assessment Questionnaire; SF-36 Short-Form 36 health survey; ESR erythrocyte sedimentation rate; CRP C-reactive protein; IQR
interquartile range; JSN joint space narrowing.
Scores can range from 0 to 280.
Sixty-six joints were assessed.
Sixty-eight joints were assessed.
Scores range from 0 (no difficulty) to 3 (unable to perform this activity).
# Scores were grouped into physical and mental summary components and compared with normalized scores for the general US population, for
which the mean SD is 50 10. Higher scores indicate a better quality of life.
** Scores can range from 0 to 448, with higher scores indicating more joint damage. There were 279 patients in the MTX placebo group, 355 in
the MTX 3 mg/kg infliximab group, and 360 in the MTX 6 mg/kg infliximab group.
Scores can range from 0 to 168.

31 (39%), 45 (40%), and 41 (33%) patients in the


MTXplacebo, MTX3 mg/kg infliximab, and MTX6
mg/kg infliximab groups, respectively. Including all randomized patients, the mean SD dosages of MTX at
week 54 were 15.1 8.0 mg/week, 15.5 7.6 mg/week,
and 14.9 7.7 mg/week for the MTXplacebo, MTX3
mg/kg infliximab, and MTX6 mg/kg infliximab groups,
respectively, indicating similar MTX dosing among the
treatment groups. For this calculation, the MTX dose
was set at 0 for withdrawals before week 54.
Premature discontinuation by patients occurred
in similar proportions among the 3 treatment groups
(Figure 1). However, more patients from the MTX
placebo group than from the MTX3 mg/kg infliximab
and MTX6 mg/kg infliximab groups withdrew due to

lack of efficacy (9.6% versus 1.9% and 3.3%, respectively). In contrast, withdrawals because of adverse
events were more frequent in the MTX3 mg/kg infliximab and MTX6 mg/kg infliximab groups than in the
MTXplacebo group (9.5% and 9.6% versus 3.2%,
respectively).
Clinical efficacy. The patients receiving MTX3
mg/kg infliximab and MTX6 mg/kg infliximab achieved
a significantly higher median (interquartile range [IQR])
ACR-N (38.9% [0.0, 77.3] and 46.7% [0.0, 82.1], respectively) than those in the MTXplacebo group (26.4%
[0.0, 64.3]) (P 0.001 for both comparisons). Two
sensitivity analyses (see Patients and Methods) showed
statistically significant differences favoring the infliximab treatment groups, attesting to the robustness of

INFLIXIMAB THERAPY FOR RHEUMATOID ARTHRITIS

Figure 2. Comparison of American College of Rheumatology 20%


criteria for clinical improvement (ACR20), ACR50, ACR70, and
ACR90 responses. Shown are the percentages of patients with ACR
responses at week 54. In these secondary analyses, there were 274
patients in the methotrexate (MTX)placebo group, 351 in the
MTX3 mg/kg infliximab group, and 355 in the MTX6 mg/kg
infliximab group. Patients were excluded from these analyses if they
had no baseline observations. Patients were considered to be ACR20
nonresponders if they received prohibited medications, had 2 joint
injections or surgeries, or withdrew due to lack of efficacy. Missing
values between weeks 30 and 54 were replaced with the last observation carried forward. If such a value was not available, then that
component of the ACR response criteria was assigned a value of 0%
improvement. P 0.028; P 0.001; P 0.001; and
P 0.002 versus MTXplacebo group.

this result. There were no significant differences in


clinical efficacy between the 3 mg/kg and 6 mg/kg
infliximab dosage groups. ACR20, ACR50, and ACR70
response rates were significantly higher in the MTX3
mg/kg infliximab and MTX6 mg/kg infliximab groups
than in patients receiving MTX alone, while the ACR90
response rate was significantly higher in the MTX6
mg/kg infliximab group than in the MTXplacebo group
(Figure 2). The proportions of patients achieving a
sustained ACR70 response for at least 6 months were
also greater in the MTX3 mg/kg infliximab and MTX6
mg/kg infliximab groups (12.4% and 17.3%, respectively) than in the MTXplacebo group (7.7%) (P 0.06
and P 0.001, respectively). In addition, greater reductions in DAS28 scores and higher remission rates were
observed in the groups receiving the MTXinfliximab
combinations (Figures 3 and 4).
Radiographic evaluation of joint damage. From
baseline to week 54, the mean SD change in the
vdH-S was significantly less for the patients receiving
MTX3 mg/kg infliximab and MTX6 mg/kg infliximab
(0.4 5.8 and 0.5 5.6, respectively) than it was for
those receiving MTX alone (3.7 9.6) (P 0.001 for
each comparison) (Table 2). Radiographic progression
of joint damage was not significantly different between
the 2 infliximab dosage groups. The separate analysis of
the erosion and joint space narrowing scores also favored those receiving the MTXinfliximab combinations

3437

over those receiving MTX alone (Table 2). The proportions of patients with radiographic progression exceeding the SDD (increase in vdH-S 9.03) were lower in
the MTX3 mg/kg infliximab and MTX6 mg/kg infliximab groups (14/359 [3.9%] and 7/363 [1.9%], respectively) than in the MTXplacebo group (31/282 [11.0%])
(P 0.001 for both comparisons).
Improvement in physical function. HAQ scores
improved more in the MTX3 mg/kg infliximab and
MTX6 mg/kg infliximab groups than in the group receiving MTX alone. The mean SD and median (IQR)
decreases from baseline in HAQ scores from weeks
3054 averaged over time were 0.80 0.65 and 0.78
(0.38, 1.18) for the MTX3 mg/kg infliximab group and
0.88 0.65 and 0.79 (0.48, 1.34) for the MTX6 mg/kg

Figure 3. Analysis of Disease Activity Score in 28 joints (DAS28)


values. The DAS28 values at baseline and week 54 are shown for the
3 treatment groups. In this secondary analysis, there were 235 patients
in the methotrexate (MTX)placebo group, 294 in the MTX3 mg/kg
infliximab group, and 289 in the MTX6 mg/kg infliximab group.
Patients with missing DAS28 values at baseline or week 54 were
excluded from this analysis. The DAS28 value was calculated as
follows: 0.56 the square root of the tender joint count 0.28 the
square root of the swollen joint count 0.7 ln erythrocyte sedimentation rate 0.014 patients global assessment of disease activity.
The DAS28 value was set to baseline whenever a prohibited medication was taken or surgery occurred, or if the patient withdrew from the
study due to lack of efficacy. The mean SD (solid horizontal lines
and bars) and median (interquartile range [IQR]) (dashed horizontal
lines and boxed areas) DAS28 values at baseline were 6.7 1.0 and 6.8
(6.1, 7.4) for the MTXplacebo group, 6.6 1.1 and 6.8 (5.9, 7.4) for
the MTX3 mg/kg infliximab group, and 6.7 1.0 and 6.8 (6.1, 7.4) for
the MTX6 mg/kg infliximab group. The mean SD and median
(IQR) DAS28 values at week 54 were 4.6 1.8 and 4.7 (3.1, 5.9) for
the MTXplacebo group, 4.0 1.8 and 3.7 (2.8, 5.2) for the MTX3
mg/kg infliximab group, and 3.7 1.8 and 3.5 (2.3, 4.9) for the MTX6
mg/kg infliximab group. For comparisons of the change between
baseline and week 54: P 0.001 for MTX3 mg/kg infliximab versus
MTXplacebo; P 0.001 for MTX6 mg/kg infliximab versus MTX
placebo.

3438

ST.CLAIR ET AL

Figure 4. DAS28 remission rates. The percentages of patients achieving remission of their disease according to the DAS28 at week 54 are
shown for the 3 treatment groups. In this secondary analysis, there
were 240 patients in the MTXplacebo group, 302 in the MTX3
mg/kg infliximab group, and 300 in the MTX6 mg/kg infliximab
group. Patients were excluded from this analysis if they had missing
values at week 54. A DAS28 value 2.6 was considered to indicate
remission of disease (23). For comparisons of rates of remission: P
0.065 for MTX3 mg/kg infliximab versus MTXplacebo; P 0.001 for
MTX6 mg/kg infliximab versus MTXplacebo. See Figure 3 for
definitions.

infliximab group compared with 0.68 0.63 and 0.75


(0.22, 1.04) for the MTXplacebo group (median decreases of 0.78 versus 0.75 and 0.79 versus 0.75; P 0.03
and P 0.001, respectively). From baseline to week 54,
more patients in the MTX3 mg/kg infliximab and
MTX6 mg/kg infliximab groups improved their HAQ
scores by at least 0.22 units (273/359 [76.0%] and
274/363 [75.5%], respectively) than those in the MTX
placebo group (184/282 [65.2%]) (P 0.003 and P
0.004, respectively). Of note, 0.22 is the minimum level

of improvement considered to be clinically significant


(31).
Improvement in the SF-36 physical component
summary score also favored the combination of MTX
infliximab over MTX therapy alone. From baseline to
week 54, the mean SD and median (IQR) increases in
the physical component summary score of the SF-36
were 11.7 11.6 and 10.9 (2.6, 19.8) for the MTX3
mg/kg infliximab group and 13.2 12.0 and 11.8 (4.4,
21.2) for the MTX6 mg/kg infliximab group, but only
10.1 11.4 and 8.9 (1.4, 18.9) for the MTXplacebo
group (median increases of 10.9 versus 8.9 and 11.8
versus 8.9; P 0.10 and P 0.003, respectively).
Adverse events. Table 3 shows the frequencies of
adverse events during this study. One or more infusion
reactions occurred in 79 patients (21%) from the
MTX3 mg/kg infliximab group and in 56 patients (15%)
from the MTX6 mg/kg infliximab group compared with
only 20 patients (7%) receiving MTX alone. Two patients (0.5%) in each of the MTXinfliximab groups had
infusion reactions classified as serious by the investigators according to the regulatory definition. Anaphylactic
reactions were predefined in the protocol as the occurrence of urticaria and bronchospasm, dyspnea, or hypotension. Three patients from the MTX6 mg/kg infliximab group had reactions meeting the definition of
anaphylactoid; they were not among those classified as
experiencing serious infusion reactions.
The proportion of patients with 1 serious adverse events was higher in the MTXinfliximab groups

Table 2. Change in radiographic scores*

Change in van der Heijde modification of the total Sharp


score from baseline to week 54
Mean SD
Median (IQR)
P
Change in erosion score from baseline to week 54
Mean SD
Median (IQR)
P
Change in JSN score from baseline to week 54
Mean SD
Median (IQR)
P

MTX placebo
(n 282)

MTX 3 mg/kg infliximab


(n 359)

MTX 6 mg/kg infliximab


(n 363)

3.7 9.6
0.43 (0.0, 4.5)

0.4 5.8
0.0 (0.8, 1.3)
0.001

0.5 5.6
0.0 (1.0, 1.3)
0.001

3.0 7.8
0.3 (0.0, 3.8)

0.3 4.9
0.0 (0.8, 1.3)
0.001

0.1 4.2
0.0 (1.0, 1.0)
0.001

0.6 2.1
0.0 (0.0, 0.4)

0.1 1.6
0.0 (0.0, 0.0)
0.001

0.2 1.4
0.0 (0.0, 0.20)
0.130

* See Table 1 for definitions.


Values were imputed by linear extrapolation.
Versus MTX placebo.
Scores were analyzed separately without imputation rules, decreasing the numbers of patients available for these subanalyses (see Patients and
Methods). There were 226 patients analyzed in the MTX placebo group and 306 analyzed in each of the MTX infliximab groups.

INFLIXIMAB THERAPY FOR RHEUMATOID ARTHRITIS

Table 3.

3439

Adverse events in patients receiving at least 1 dose of study drug*


MTX placebo
(n 291)

Adverse events occurring at a rate


of 10%
URI
Nausea
Headache
Sinusitis
Pharyngitis
Patients with 1 serious adverse
event
Pneumonia
Fever
Myocardial infarction
Asthma
Tuberculosis
Infusion reaction

MTX 3 mg/kg
infliximab (n 372)

MTX 6 mg/kg
infliximab (n 377)

60 (21)
53 (18)
31 (11)
24 (8)
17 (6)
32 (11)

94 (25)
73 (20)
43 (12)
46 (12)
33 (9)
52 (14)

106 (28)
65 (17)
42 (11)
38 (10)
40 (11)
51 (14)

0 (0)
0 (0)
2 (0.7)
0 (0)
0 (0)
0 (0)

8 (2)
0 (0)
1 (0.3)
2 (0.5)
3 (0.8)
2 (0.5)

11 (3)
5 (1.3)
4 (1.1)
2 (0.5)
1 (0.3)
2 (0.5)

* Values are the number (%) of treated patients. MTX methotrexate; URI upper respiratory tract
infection.
Includes 2 patients with cardiac failure in the MTX 3 mg/kg infliximab and MTX 6 mg/kg infliximab
groups. These events were not judged to be serious by the investigator.
Four patients in the MTX 6 mg/kg infliximab group were diagnosed as having malignancies. These
malignancies included endometrial cancer at week 3, pancreatic cancer with metastasis at week 18,
adenocarcinoma of the colon at week 52, and acute myeloid leukemia at week 52. Four patients died,
including 1 from respiratory failure attributed to MTX-related lung toxicity (in the MTX placebo
group), 1 from an upper gastrointestinal bleed (in the MTX placebo group), 1 from cardiac arrest (in
the MTX 3 mg/kg infliximab group), and 1 from metastatic pancreatic cancer (in the MTX 6 mg/kg
infliximab group).

(14%) than in the MTXplacebo group (11%) (Table 3).


Serious infections occurred more commonly in patients
receiving MTX3 mg/kg infliximab (21 patients [5.6%])
or MTX6 mg/kg infliximab (19 patients [5.0%]) than in
those receiving MTX alone (6 patients [2.1%]) (P 0.02
and P 0.04, respectively) (Table 4). Among the serious
infections, pneumonia occurred more frequently in the
infliximab-treated patients than in those treated with
MTX alone (15/749 [2.0%] versus 0/291 [0.0%]). Most of
these cases were community-acquired pneumonias that
responded appropriately to antibiotic therapy.
Among the cases of pneumonia, active tuberculosis was diagnosed in 4 patients from the infliximab
Table 4.

treatment groups (1 in the US and 3 in Europe; 2 cases


occurred after the third infusion, 1 after the fourth
infusion, and 1 after the eighth infusion). Two of these
patients had had a negative PPD skin test result at the
screening visit. The other 2 patients had not received the
PPD skin test at study entry because they had enrolled
before the implementation of the protocol amendment
that required PPD skin testing. Three of the patients
were diagnosed as having pulmonary tuberculosis based
on a positive sputum culture. The other patient was
suspected of having tuberculosis because of a history of
fever and weight loss and recent conversion of a PPD
skin test result from negative to positive. None of these

Serious infections observed in 0.5% of patients who received at least 1 dose of study drug*
MTX placebo MTX 3 mg/kg infliximab
MTX 6 mg/kg
(n 291)
(n 372)
infliximab (n 377)

Patients with 1 serious infection


Pneumonia
Tuberculosis
Sepsis
Bronchitis
Septic bursitis

6 (2.1)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)

21 (5.6)
6 (1.6)
3 (0.8)
2 (0.5)
2 (0.5)
0 (0.0)

* Values are the number (%) of treated patients. MTX methotrexate.


P 0.02 versus MTX placebo.
P 0.04 versus MTX placebo.

19 (5.0)
9 (2.4)
1 (0.3)
1 (0.3)
0 (0.0)
2 (0.5)

3440

ST.CLAIR ET AL

patients were considered by the investigator to have


extrapulmonary tuberculosis. All of these patients were
withdrawn from the study, discontinued their infliximab
infusions, and were successfully treated with appropriate
antituberculosis medications. Malignancy was diagnosed
in 4 patients during the trial, all of whom were in the
MTX6 mg/kg infliximab group (see footnote in Table
3). Four patients died during the study: 2 were in the
MTXplacebo group, and 1 was in each of the MTX
infliximab dose groups. One of the patients in the
MTXplacebo group died of respiratory failure attributed to MTX-related lung toxicity (see footnote in Table
3).
Autoimmunity. Similar to findings in previous
studies, infliximab therapy was associated with the development of ANAs. Overall, 118 of 298 patients
(39.6%) in the MTX3 mg/kg infliximab group, 106 of
309 patients (34.3%) in the MTX6 mg/kg infliximab
group, and 29 of 256 patients (11.3%) in the MTX
placebo group became newly positive for ANAs during
the study (P 0.001 for both comparisons with the
MTXplacebo group). This analysis was restricted to
those subjects with blood samples available at each time
point. Serum anti-dsDNA antibodies appeared in 71 of
298 patients (23.8%) and 64 of 309 patients (20.7%) in
the MTX3 mg/kg infliximab and MTX6 mg/kg infliximab groups, respectively, while only 1 of 256 patients
(0.4%) receiving MTX alone developed anti-dsDNA
antibodies (P 0.001 for both comparisons with the
MTXplacebo group). One patient in the MTX6 mg/kg
infliximab group developed a skin rash and ANA positivity, but tested negative for serum anti-dsDNA antibodies; this event was classified by the investigator as
drug-induced lupus.
Immunogenicity. Serum antibodies to infliximab
were detected at some time in 46 of 317 patients (14.5%)
and 21 of 312 patients (6.7%) in the MTX3 mg/kg
infliximab and MTX6 mg/kg infliximab groups, respectively. Negative test results were obtained after the last
infusion in 142 of 317 patients (44.8%) and 110 of 312
patients (35.3%) in the MTX3 mg/kg infliximab and
MTX6 mg/kg infliximab groups, respectively. The results were inconclusive for the remaining samples.
DISCUSSION
This study demonstrates that treatment of early
RA with the combination of MTX and infliximab improves the signs and symptoms of disease activity, inhibits the radiographic progression of joint damage, and
improves physical function better than MTX therapy

alone over 1 year. The primary and major secondary


efficacy analyses were consistent in showing the superiority of the combination of MTX and infliximab over
MTX alone.
In a previous study, infliximab at 3 mg/kg and 10
mg/kg given every 48 weeks for up to 2 years produced
significant clinical, radiographic, and functional benefits
in RA when added to background MTX therapy
(8,9,32). Since that study population consisted of partial
responders to MTX therapy, the analysis could only
show the incremental benefits of infliximab over placebo. In contrast, the parallel design of the present study
allows for the benefits of the MTXinfliximab combination to be distinguished from those of MTX alone, which
is a widely accepted standard of care for the initial
treatment of moderate-to-severe RA. An unbiased comparison of efficacy between these treatment groups
requires that patients not have been previously exposed
to these medications. Our design allowed up to 3 doses
of MTX prior to randomization, which might have
biased the results. However, only 1.42.5% of the study
population had received any previous doses of MTX.
Thus, our results reflect the superiority of the combination of infliximab and MTX therapy over MTX alone in
a treatment-naive population. In patients with more
advanced RA, results from a recent trial show the
advantages of the combination of etanercept and MTX
over either drug alone in terms of reducing disease
activity, slowing radiographic progression of joint damage, and improving physical function (33).
The safety profile of the MTXinfliximab combination was similar to that observed in previous infliximab trials (8,9,22,32) except for an increased risk of
serious infections in the MTXinfliximab groups compared with MTX therapy alone. In particular, we found
a higher incidence of pneumonia in patients receiving
the MTXinfliximab combinations than in those receiving MTX monotherapy. The 2.0% incidence of pneumonia in the MTX3 mg/kg infliximab group in the present
study is similar to the 1.9% incidence of pneumonia in
the MTXinfliximab groups (3 mg/kg or 10 mg/kg infliximab dosages) in the largest study previously conducted
(32). However, caution must be used in comparing the
rates of adverse events between these 2 studies due to
differences in the patient populations.
The 4 cases of tuberculosis in the infliximab
treatment groups are consistent with previous reports
indicating an increased risk for reactivation of latent
tuberculosis with anti-TNF therapy (34). Two of the
patients in the trial developed tuberculosis despite a
negative PPD skin test result at screening. In RA,

INFLIXIMAB THERAPY FOR RHEUMATOID ARTHRITIS

false-negative PPD skin test results may arise from


impaired delayed-type hypersensitivity (35,36).
The 4 cases of noncutaneous malignancy observed in the present study all occurred in the 6 mg/kg
infliximab treatment group. In a recent summary, the
incidences of nonlymphomatous malignancies, excluding
nonmelanoma skin cancers, were not significantly different in infliximab-treated patients from clinical studies
compared with the general population (37). None of the
patients in the present study was diagnosed as having
lymphoma.
The optimal approach for treating RA in its early
stages is not known with certainty. MTX is often used as
the initial DMARD for patients with moderate-tosevere disease activity, and our results underscore the
clinical efficacy of this approach. In a previous study,
etanercept therapy was associated with significantly less
radiographic progression over 2 years than MTX alone
(12). Therefore, for some patients, early treatment with
a TNF antagonist may afford superior protection
against the development of radiographic damage compared with the use of MTX as a single DMARD. In the
present trial, 1 of 3 patients in the MTXinfliximab
groups achieved an ACR70 response compared with 1
of 5 patients in the MTX-alone group. Similarly, 1 of
9 patients in the MTX-alone group had significant
radiographic progression over 1 year (an increase from
baseline in the vdH-S larger than the SDD of 9.03)
compared with 1 of 30 patients in the MTXinfliximab
groups. Further studies are needed to determine which
subsets of patients with early RA may benefit most from
the combination regimen.
Our study may have limitations. The ACR-N was
chosen as a primary outcome for the present study. It is
a continuous variable and allows for the use of a smaller
sample size than a design employing the dichotomous
ACR20 responder index. The ACR20 is a validated end
point for evaluating the clinical effects of DMARD
therapy for RA. The ACR-N utilizes the same disease
measures for evaluating signs and symptoms as the
ACR20 responder index, and it may therefore be expected to have similar validity as a treatment end point.
Furthermore, the ACR-N was analyzed conservatively in
our study, using a negative change score for worsening of
signs and symptoms. This methodologic approach may
partly explain the relatively low ACR-N values (compared with the ACR20 responses) across the treatment
groups. Regardless, the coprimary analysis using
ACR-N as an end point was entirely consistent with the
2 sensitivity analyses and the secondary analyses of

3441

ACR20, ACR50, and ACR70 responses as well as


DAS28 responses.
The possibility that our results may not generalize to the population of RA patients as a whole is
another consideration. Our study population had
moderate-to-severe disease activity, with one or more
factors indicating a poor prognosis: serum rheumatoid
factor positivity, erosive disease, or elevated serum CRP
level (3840). Sokka and Pincus have reported that only
31% of patients from a private rheumatology practice
would have been eligible for the early RA trial of
etanercept versus MTX (41), which has inclusion criteria
similar to those of the present study. Thus, the results
from these 2 trials may not generalize to patients with
less severe RA. Also, patients who were excluded from
this trial (as they would have been from most other
trials) because of older age or serious comorbid illnesses
might have had more treatment-related complications
than were observed in this study.
This study has shown that patients with active RA
in its early stages can benefit from aggressive therapy
using a TNF inhibitorbased combination regimen.
However, these results also show that a significant
proportion of patients with early RA can achieve disease
control for 1 year by taking MTX alone. Thus, for the
individual patient, the potential incremental benefits of
the combination approach must be carefully weighed
against the possibility of greater toxicity. These results
nevertheless show that the combination of MTX and
infliximab produces clinical, radiographic, and functional benefits exceeding those of MTX alone and may
ultimately prove to be a highly effective strategy for
preventing joint damage and functional disability in
patients at high risk for disease progression.
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APPENDIX A: THE ACTIVE-CONTROLLED STUDY OF


PATIENTS RECEIVING INFLIXIMAB FOR THE
TREATMENT OF RHEUMATOID ARTHRITIS OF
EARLY ONSET STUDY GROUP
Members of the Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early
Onset Study Group, in addition to the authors of this article, are as
follows: Austria: Dr. Gabriele Eberl, MD, Krankenhaus Lainz (Vienna); Dr. Klaus Machold, Allgemeines Krankenhaus Wien (Vienna).
Belgium: Professor Jean-Pierre Devogelaer, Clinique Universitaire St.
Luc (Brussels); Dr. Piet Geusens, Biomedisch Onderzoek Centrum
(Diepenbeek); Dr. R. Westhovens, Universitair Ziekenhuis Gasthuisberg (Leuven). Canada: Wiliam Martin, MD, University of Calgary
(Calgary, Alberta); Boulos Haraoui, MD, Institut de Rhumatologie de
Montreal (Montreal, Quebec); Carter Thorne, MD, The Arthritis
Program Research Group (Newmarket, Ontario); Robert McKendry,
MD, Ottawa Hospital (Ottawa, Ontario); Andre-Damien Beaulieu,
MD, Laval University Hospital (Sainte Foy, Quebec); Majed Khraishi,
MD, St. Clares Mercy Hospital (St. Johns, Newfoundland); Mary
Bell, MD, Sunnybrook and Womens College Health Sciences Centre
(Toronto, Ontario); Janice Canvin, MD, Hani El-Gabalawy, MD,
University of ManitobaArthritis Centre (Winnipeg, Manitoba).
France: Professor Bernard G. Combe, Hopital Lapeyronie (Montpellier); Dr. Yves Maugars, CHU Hotel Dieu (Nantes); Professor Liana
Euller-Ziegler, Hospital de LArchet (Nice); Professor Maxime Dougados, Professor Andre Kahan, Groupe Hospitalier Cochin (Paris).
Germany: Dr. Andrea Rubbert, Universitatsklinikum Ko
ln (Cologne);
Dr. Hubert Nu
lein, PhD, Stadtisches Klinikum (Dresden); Dr. Maria
Stoyanova-Scholz, Klinikum Duisburg (Duisburg); Dr. Gernot Keyer,
Martin-Luther-Universitat (Halle); Professor Holm Hantzschel, Universitatsklinik Leipzig (Leipzig); Dr. Michael Schwarz-Eywill, des
Evangelischen Krankenhauses (Oldenburg); Dr. Constanze Richter
(Stuttgart); Dr. Tony Hans-Peter, Universitat Wu
rzburg (Wurzburg).
Ireland: Dr. Oliver Fitzgerald, St. Vincent University Hospital (Dublin). Israel: Professor Abraham Menahim Nahir, Rambam Medical
Center (Haifa); Professor Michael Yaron, Ichilov Hospital (Tel Aviv).
Italy: Professor Francesco Trotta, Ospedale SantAnna (Ferrara);
Professor Marco Matucci Cerinic, Universita di Firenze (Florence);
Professor Flavio Fantini, Istituto Ortopedico Gaetano Pini (Milan);
Professor Silvano Todesco, Policlinico Universitario (Padua); Professor Stefano Bombardieri, Ospedale Santa Chiara (Pisa). The Netherlands: Dr. Robert Landewe, Atrium Medisch Centrum (Heerlen); Piet
van Riel, MD, PhD, Academisch Ziekenhuis Nijmegen (Nijmegen).
Norway: Dr. Anne Glenns, Diakonhjemmets Sykehus (Oslo). Spain:
Dr. Raimon Sala San-Marti, Hospital Clinic of Barcelona (Barcelona);
Dr. Jose M. Alvaro-Gracia, Hospital de la Princesa (Madrid); Dr.
Emilio Martin Mola, Hospital Universitario La Paz (Madrid); Dr.
Vicente Rodriguez Valverde, Hospital Universitario Marques de
Valdecilla (Santander); Dr. Juan J. Gomez-Reino, Hospital Clinico
Universitario (Santiago). Sweden: Professor Lars Klareskog, Professor
Ronald van Vollenhoven, Karolinska Sjukhuset (Stockholm). United
Kingdom: Dr. Andrei Calin, Royal National Hospital for Rheumatology Diseases (Bath); Dr. Simon Bowman, Birmingham Heartlands

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Hospital (Birmingham); Dr. John Kirwan, University of Bristol (Bristol); Professor Brian Hazleman, Addenbrookes Hospital (Cambridge);
Dr. Rob Moots, University Hospital Aintree (Liverpool); Dr. David
Doyle, Whipps Cross Hospital (London); Dr. Karl Gaffney, Norfolk
and Norwich University Hospital (Norwich); Professor Paul Wordsworth, Nuffield Orthopaedic Centre (Oxford). United States: David
McLain, MD, Alabama Research Center (Birmingham, AL); William
Shergy, MD, Rheumatology Associates of North Alabama (Huntsville,
AL); Christopher Adams, MD, Little Rock Diagnostic Clinic (Little
Rock, AR); Paul Caldron, DO, Arizona Arthritis Research (Paradise
Valley, AZ); Benjamin Harris, MD (Phoenix, AZ); Sanford Roth, MD
(Phoenix, AZ); John Tesser, MD, Phoenix Center for Clinical Research (Phoenix, AZ); David Yocum, MD, University of Arizona
Health Science Center (Tucson, AZ); Arthur Kavanaugh, MD, University of CaliforniaSan Diego Division of Rheumatology (La Jolla,
CA); Daniel Wallace, MD (Los Angeles, CA); Irene Tong, MD
(Pasadena, CA); Kathryn Hobbs, MD, Christopher Striebich, MD,
University of Colorado Hospital (Aurora, CO); Deborah Desir, MD,
Arthritis and Osteoporosis Center (Hamden, CT); Brian Peck, MD
(Waterbury, CT); Howard Offenberg, MD, Radiant Research (Daytona Beach, FL); Mitchell Lowenstein, MD (Palm Harbor, FL);
Jeffrey Kaine, MD, Sarasota Arthritis Research Center (Sarasota, FL);
Michael Burnette, MD, Tampa Medical Group (Tampa, FL); Jeffrey
Miller, MD (Tampa, FL); Craig Wiesenhutter, MD, Coeur DAlene
Arthritis Clinic (Coeur DAlene, ID); Margaret Michalska, MD,
RushPresbyterianSt. Lukes Medical Center (Chicago, IL); Michael
Stack, MD, Indiana Internal Medicine Associates (Indianapolis, IN);
James Anderson, MD, Heartland Research Associates (Wichita, KS);
Richard Lies, MD, Wichita Clinic (Wichita, KS); Michael H. Edwards,
MD, University Medical Associates (Louisville, KY); Seth Lourie, MD
(Greenbelt, MD); Herbert Baraf, MD, Center for Rheumatology and
Bone Research (Wheaton, MD); Larry Anderson, MD, Charles Radis,
DO, Rheumatology Associates (Portland, ME); Richard Martin, MD,
Arthritis Education and Treatment Center (Grand Rapids, MI); Justus
Fiechtner, MD, MPH (Lansing, MI); David Zoschke, MD, Arthritis
and Rheumatology Consultants (Edina, MN); John Ervin, MD, The
Center for Pharmaceutical Research (Kansas City, MO); Suthin
Songcharoen, MD (Jackson, MS); Elliot Kopp, MD, C.A.R.E. Center
(Raleigh, NC); Melvin Churchill, MD, Arthur Weaver, MD, Arthritis
Center of Nebraska (Lincoln, NE); Marc Goldberg, MD, New Jersey
Physicians (Passaic, NJ); Joel Kremer, MD, Center for Rheumatology
(Albany, NY); Michael Luggen, MD, Deaconess Arthritis Center
(Cincinnati, OH); Alan Safdi, MD, Consultants for Clinical Research
(Cincinnati, OH); Christine Codding, MD, nTouch Research (Oklahoma City, OK); Gary Sultany, MD (Portland, OR); Alan Kivitz, MD
(Duncansville, PA); Marlin Wenger, MD, Lancaster Rheumatology
Research (Lancaster, PA); John Abruzzo, MD, Thomas Jefferson
University Hospital (Philadelphia, PA); Robert Griffin, Jr., DO (West
Reading, PA); Charles Pritchard, MD, Rheumatic Disease Associates,
Ltd. (Willow Grove, PA); Paul Wheeler, MD (Nashville, TN); Andrew
Chubick, MD (Dallas, TX); Stanley Cohen, MD, Radiant Research
(Dallas, TX); John Cush, MD, Presbyterian HospitalDallas (Dallas,
TX); David Karp, MD, The University of Texas Southwestern Medical
Center at Dallas (Dallas, TX); Francis Burch, MD, San Antonio
Center for Clinical Research (San Antonio, TX); Joel Rutstein, MD,
Arthritis Diagnostic and Treatment Center (San Antonio, TX); Christopher Wise, MD, Virginia Commonwealth University (Richmond,
VA); Garry Bayliss, MD (Salem, VA); Scott Baumgartner, MD,
Physicians Clinic of Spokane (Spokane, WA); Robert Ettlinger, MD
(Tacoma, WA); John Fahey, MD (Milwaukee, WI); Allan Goldman,
MD, The Rheumatic Disease Center (Milwaukee, WI).