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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-
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ST.CLAIR ET AL
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.
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
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ST.CLAIR ET AL
MTX placebo
(n 282)
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.
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
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
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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.
MTX placebo
(n 282)
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
Table 3.
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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).
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)
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)
19 (5.0)
9 (2.4)
1 (0.3)
1 (0.3)
0 (0.0)
2 (0.5)
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ST.CLAIR ET AL
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7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
ST.CLAIR ET AL
3443
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).