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Efficacy and safety of infliximab in patients with ankylosing spondylitis over a two-year period.

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Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 59, No. 9, September 15, 2008, pp 1270 –1278
DOI 10.1002/art.24001
© 2008, American College of Rheumatology
ORIGINAL ARTICLE
Efficacy and Safety of Infliximab in Patients With
Ankylosing Spondylitis Over a Two-Year Period
JÜRGEN BRAUN,1 ATUL DEODHAR,2 BEN DIJKMANS,3 PIET GEUSENS,4 JOACHIM SIEPER,5
PAUL WILLIAMSON,6 WEICHUN XU,6 SUDHA VISVANATHAN,6 DANIEL BAKER,6 NEIL GOLDSTEIN,6
DÉSIRÉE VAN DER HEIJDE,7 AND THE ANKYLOSING SPONDYLITIS STUDY FOR THE EVALUATION OF
RECOMBINANT INFLIXIMAB THERAPY STUDY GROUP
Objective. To assess safety and efficacy of infliximab in patients with ankylosing spondylitis (AS) through 102 weeks.
Methods. Patients (n ⴝ 279) with active AS were randomized to either group 1 (n ⴝ 78; placebo through week 24 and then
infliximab 5 mg/kg from weeks 24 through 96) or group 2 (n ⴝ 201; infliximab 5 mg/kg through week 96). The primary
efficacy end point at week 24 (>20% improvement in the ASsessment in Ankylosing Spondylitis International Working
Group criteria [ASAS20]) was assessed with an intent-to-treat analysis of observed data.
Results. More patients in group 2 than group 1 achieved the ASAS20 response at week 24 (61.2% versus 19.2%; P <
0.001). By week 102, groups 1 and 2 were similar with regard to ASAS20 response (72.1% versus 73.9%); ASAS40
responses at week 102 were 45.9% versus 59.4%. No new safety issues were discerned.
Conclusion. Infliximab demonstrated sustained efficacy and safety over 2 years in this large cohort of patients with active AS.
Ankylosing spondylitis (AS) is an immune-mediated rheumatic disease characterized by inflammatory back pain
due to sacroiliitis, spondylitis, and enthesitis. Traditional
therapies for AS may have limited efficacy for some patients (1–3). Owing to the pivotal role of tumor necrosis
factor ␣ (TNF␣) in AS pathogenesis (4,5), drugs targeting
TNF␣ have emerged as alternatives for patients with unremitting disease (6 –9). Infliximab 5 mg/kg administered
every 6 weeks was evaluated in 279 patients with AS
in the Ankylosing Spondylitis Study for the Evaluation
of Recombinant Infliximab Therapy (ASSERT), and was
found to be well tolerated and significantly more effective
than placebo in improving signs and symptoms of disease through week 24 (8). In an ASSERT substudy involving 266 patients with evaluable magnetic resonance
imaging (MRI) data, patients treated with infliximab
showed significant decreases in spinal inflammation versus placebo (10). The ASSERT study continued through
102 weeks; the 2-year safety and efficacy findings are presented.
ClinicalTrials.gov identifier: NCT00207701.
1
Jürgen Braun, MD: Rheumazentrum Ruhrgebiet, Herne,
Germany; 2Atul Deodhar, MD: Oregon Health and Science
University, Portland; 3Ben Dijkmans, MD, PhD: VU University Medical Centre and Jan van Breemen Institution, Amsterdam, The Netherlands; 4Piet Geusens, MD: University
Hasselt, Hasselt, Belgium and University Hospital, Maastricht, The Netherlands; 5Joachim Sieper, MD: Universitaetsklinikum Benjamin Franklin, Free University of Berlin,
Berlin, Germany; 6Paul Williamson, MD, Weichun Xu, PhD,
Sudha Visvanathan, PhD, Daniel Baker, MD, Neil Goldstein,
MD: Centocor, Inc., Malvern, Pennsylvania; 7Désirée van
der Heijde, MD, PhD: Leiden University Medical Center,
Leiden, The Netherlands.
Drs. Braun, Dijkmans, and Geusens have received research support from Centocor and have received consulting
fees or honoraria (less than $10,000 each) from Centocor
and the Schering-Plough Research Institute. Dr. Deodhar
has received research support from Centocor and has received speaking fees and honoraria (more than $10,000
each) from Centocor and Genentech. Dr. Sieper has received
research support from Centocor, has received consultant
fees, speaking fees, and/or honoraria (less than $10,000
each) from Schering-Plough, Abbott, and Wyeth, and gave
expert testimony for Schering-Plough and received a fee.
Drs. Williamson, Xu, Visvanathan, and Baker own stock in
Johnson & Johnson, of which Centocor is a subsidiary, and
are employees of Centocor. Dr. Goldstein is a paid consultant for Centocor. Dr. van der Heijde has received research
support from Centocor, has received consultant fees, speaking fees, and/or honoraria (less than $10,000 each) from
Abbott, Amgen, Centocor, Schering-Plough, UCB, Wyeth,
Roche, Pfizer, Chugai, and Novartis, and in 2002 gave expert
testimony at the FDA hearing on inhibition of structural
damage and received a fee from Centocor.
Address correspondence to Jürgen Braun, MD, Rheumazentrum Ruhrgebiet, Landgrafenstr 15, 44652 Herne, Germany. E-mail: j.braun@rheumazentrum-ruhrgebiet.de.
Submitted for publication January 16, 2008; accepted in
revised form May 19, 2008.
INTRODUCTION
1270
Two Years of Infliximab in Ankylosing Spondylitis
1271
Figure 1. Patient treatment and disposition.
PATIENTS AND METHODS
Patients. Patient eligibility for the ASSERT study has
been previously described (8). Briefly, study participants
had AS according to the modified New York criteria (11)
for at least 3 months prior to screening, a Bath Ankylosing
Spondylitis Disease Activity Index (BASDAI) score ⱖ4
(range 0 –10; a combined assessment of fatigue, spinal
pain, joint pain, enthesitis, and morning stiffness), and a
spinal pain assessment score ⱖ4 on a visual analog scale
(VAS; range 0 –10 cm) (8). Institutional review boards/
independent ethics committees reviewed and approved
the study protocol. All patients provided written informed
consent.
Study protocol. In this double-blind, placebo-controlled study, patients were randomly assigned (3:8) to 1 of
2 groups (8). Patients in group 1 (the placebo/infliximab
group) received placebo through week 24 and infliximab
as an induction regimen at weeks 24, 26, and 30, followed
by dosing every 6 weeks. Patients in group 2 (the infliximab 5 or 7.5-mg/kg group) received infliximab (5 mg/kg)
through week 96 (with a placebo infusion at week 26 to
maintain the blind). Starting at week 36, patients in group
2 with a BASDAI score ⱖ3 at both the current and prior
visits could increase the dose of infliximab to 7.5 mg/kg. In
both groups, infusions were given at weeks 0, 2, and 6, and
then every 6 weeks through week 96 (see exceptions in
Figure 1).
Efficacy evaluations. Clinical response assessments
were performed prior to any study agent infusion at weeks
0, 2, 6, 12, 18, 24, and 30, and then every 6 weeks through
week 102. The primary study end point was achievement
of ⱖ20% improvement (and an absolute improvement
from baseline of at least 10 units on a scale of 0 –100) in at
least 3 of 4 assessment domains of the ASsessment in
Ankylosing Spondylitis International Working group cri-
teria (ASAS20) (12) at week 24 (8): patient’s global assessment, spinal pain, physical function according to the Bath
Ankylosing Spondylitis Functional Index (BASFI), and
morning stiffness (the average of the last 2 questions of the
BASDAI). These ASAS20 responders also must not have
had deterioration from baseline (i.e., worsening ⱖ20%,
and an absolute worsening ⱖ10 units on a scale of 0 –100)
in the potential remaining assessment domain. ASAS20
response was also assessed at week 102. The proportions
of patients achieving partial remission (i.e., a score ⬍20 on
a scale of 0 –100 mm in each of the 4 ASAS domains
described above) and meeting the ASAS40 (12) and
ASAS5/6 (13) response criteria were also determined.
Disease activity was also evaluated using the BASDAI
(14), a night pain VAS, and C-reactive protein (CRP) level.
Physical function was evaluated using the BASFI (score
range 0 –10; includes 8 questions relating to the patient’s
function and 2 relating to the patient’s ability to cope with
everyday life) (15). Range of motion was assessed using the
Bath Ankylosing Spondylitis Metrology Index (BASMI; an
aggregate score of patient mobility assessments, including
tragus-to-wall, lumbar flexion [Schober test], cervical rotation, lumbar side flexion, and intermalleolar distance, assessed on a scale from 0 –2 for each assessment and then
summed for the aggregated 0 –10 score) (16) and chest
expansion (the difference between the circumference of
the chest in maximal inspiration and that in maximal
expiration). Other joint assessments included the total
swollen joint (17) and enthesis (18) indices. Quality of life
was assessed with the Short Form 36 (SF-36) health survey
questionnaire (19).
Safety evaluations. Safety assessments, including documentation of adverse events, infections, and infusion reactions, were made at each visit. Samples for clinical laboratory tests were collected at weeks 0, 2, 6, 12, 18, 24, 26,
and 30, and then every 6 weeks through week 102. Serum
samples were collected for assessment of antinuclear an-
1272
Braun et al
tibodies (ANAs) and antibodies to infliximab (20) at weeks
0, 24, 54, 78, 96 (antibodies to infliximab only), and 102.
Samples positive for ANAs were also tested for antibodies
to double-stranded DNA (dsDNA).
Statistical analyses. The sample size justification for
the ASSERT study was provided previously (8). Efficacy
analyses were based on randomized treatment groups, and
patients who received ⱖ1 study infusion were included in
safety analyses by actual treatment received.
The proportion of ASAS20 responders (primary end
point) was analyzed using the Cochran-Mantel-Haenszel
chi-square test stratified by screening CRP level (within
normal range versus ⱖ3 times the upper limit of normal).
Analyses for the primary end point at week 24 utilized an
intent-to-treat (ITT) analysis, and subsequent analyses of
ASAS20 data through week 102 utilized observed data.
With the exception of partial remission, all other efficacy
analyses did not employ stratification by CRP level, and as
supportive analyses, they generally included only patients
with a nonmissing outcome. The proportions of patients
with ASAS20 and ASAS40 responses in addition to
achievment of partial remission were determined by ITT
analyses with last observation carried forward (LOCF)
methodology. Continuous measures were analyzed using
an analysis of variance on the van der Waerden normal
scores. All statistical tests were 2-sided and performed at
␣ ⫽ 0.05 with no statistical adjustments for multiple comparisons. All analyses and summaries were conducted using SAS software, version 8.2 (SAS Institute, Cary, NC).
Baseline patient and disease characteristics. Overall,
279 patients were randomized to either placebo followed
by infliximab (78 patients) or infliximab 5 or 7.5 mg/kg
(201 patients). Most patients had significant AS disease
activity (Table 1). One hundred six (52.7%) of 201 patients
escalated the infliximab dose from 5 to 7.5 mg/kg at week
36 or later (Figure 1). Sixty-one (78.2%) patients who were
randomized to placebo and 166 (82.6%) randomized to
infliximab completed the study through 102 weeks.
Figure 2. The proportion of patients achieving A, ⱖ20% improvement in the ASsessment in Ankylosing Spondylitis International Working Group criteria (ASAS20), or B, partial remission,
observed data. Open circles represent the placebo/infliximab
5-mg/kg group, open squares represent the infliximab 5-mg/kg
group, and solid squares represent the infliximab 5 or 7.5-mg/kg
group. For A, the numbers of patients contributing data at weeks
2, 6, 12, 18, 24, 36, 54, 78, and 102 are as follows. Placebo/
infliximab: 76, 76, 75, 75, 75, 72, 67, 64, and 61, respectively;
infliximab 5 mg/kg: 95, 95, 94, 93, 92, 91, 84, 82, and 80, respectively; infliximab 5-7.5 mg/kg: 106, 105, 105, 106, 106, 106, 92, 87,
and 85, respectively. For B, the numbers of patients contributing
data at weeks 2, 6, 12, 18, 24, 36, 54, 78, and 102 are as follows.
Placebo/infliximab: 76, 76, 75, 75, 75, 72, 67, 64, and 61, respectively; infliximab 5 or 7.5 mg/kg: 201, 200, 199, 199, 198, 197, 176,
169, and 165, respectively.
Efficacy. To provide an appropriate frame of reference,
the previously reported week 24 efficacy data are presented along with the week 102 data (Table 1 and Figures
2 and 3). Despite significant differences for most efficacy
parameters at week 24, the treatment groups were generally comparable by week 102, indicating sustained benefit
of infliximab through 1.5 or 2 years of therapy.
ASAS20 responders. At week 24, 61.2% of infliximabtreated patients achieved an ASAS20 response versus
19.2% of placebo-treated patients (P ⬍ 0.001; CochranMantel-Haenszel chi-square test, stratified by screening
CRP level). As of week 36, following crossover from placebo to infliximab at week 24, ASAS20 response was similar between treatment groups, with ⬎70% of patients in
each group achieving ASAS20 response at week 102 (Figure 2A). The proportions of patients achieving partial remission were similar between the treatment groups from
weeks 36 through 102 (Figure 2B). Consistent results were
observed when employing ITT with LOCF methodology in
the ASAS20 response and partial remission analyses (data
not shown).
Among the 201 patients randomized to infliximab 5
mg/kg, 95 (47.3%) achieved and maintained ASAS20 response to infliximab 5 mg/kg throughout the 2-year period.
The remaining 106 (52.7%) patients escalated to 7.5 mg/kg
at week 36 or later. The percentage of patients achieving an
ASAS20 response increased from 34.0% to 60.0% from
weeks 2 to 102 among patients who qualified for dose
escalation, but the overall percentage with improvement at
week 102 was ⬃30% lower than in patients who did not
require dose escalation (of whom 89% achieved an
ASAS20 response). Of note, the majority of ASAS20 nonresponders at week 102 (38 [63.3%] of 60) had at least 1
ASAS20 response during the 2-year study. Among patients
RESULTS
4.0 (2.0, 5.0)
15.0 (12.0, 20.0)
2.5 (1.5, 4.0)
45.0 (30.0, 60.0)
8.8 (5.5, 14.0)
99.5 (79.0, 112.0)
3.0 (2.0, 4.0)
8.0 (3.0, 15.0)
0.0 (0.0, 1.0)
6.6 (4.8, 8.1)
1.5 (0.7, 3.2)
28.8 (23.8, 33.7)
47.6 (37.6, 54.9)
4.0 (2.0, 6.0)
15.0 (12.0, 20.5)
3.0 (1.5, 4.0)
47.0 (30.0, 60.0)
10.0 (5.3, 13.0)
102.0 (74.0, 120.0)
3.0 (2.0, 4.0)
8.0 (2.0, 16.0)
0.0 (0.0, 1.0)
6.7 (4.7, 7.9)
1.7 (0.7, 3.3)
30.1 (24.9, 36.2)
45.0 (33.7, 55.5)
Infliximab 5
mg/kg (n ⴝ 201)
0.8 (⫺1.9, 6.0)
2.0 (⫺2.6, 7.5)
0.0 (⫺1.0, 0.0)
0.0 (⫺1.0, 1.0)
0.4 (⫺0.2, 1.0)
0.0 (⫺7.0, 5.0)
0.3 (⫺1.0, 2.7)
0.0 (⫺9.0, 7.0)
0.0 (⫺25.0, 42.9)
⫺3.0 (⫺8.0, 0.0)
0.0 (0.0, 1.0)
⫺0.3 (⫺1.7, 0.9)
0.0 (⫺31.7, 25.0)
Placebo
(n ⴝ 78)
8.3 (2.5, 17.7)
2.3 (⫺3.6, 11.9)
⬍ 0.001
0.547
10.2 (3.9, 17.1)
2.7 (⫺2.9, 8.8)
⫺1.0 (⫺2.0, 0.0)
⫺0.5 (⫺2.0, 1.0)
0.5 (0.0, 1.0)
6.0 (0.0, 19.0)
1.5 (⫺0.3, 3.5)
8.0 (⫺3.0, 19.0)
33.3 (⫺16.7, 100.0)†
⫺4.0 (⫺13.0, 0.0)
0.0 (⫺1.0, 0.0)
⫺3.3 (⫺5.8, ⫺1.2)
⫺58.8 (⫺78.9, 0.0)†
0.019
0.013
0.749
⬍ 0.001
0.011
0.045
0.037
0.800
0.019
⬍ 0.001
⬍ 0.001
⫺1.0 (⫺1.0, 0.0)
⫺0.5 (⫺2.0, 0.7)
0.5 (⫺0.3, 1.0)
5.0 (⫺2.0, 15.0)
2.0 (⫺0.3, 4.5)
3.5 (⫺5.0, 12.0)
16.7 (⫺16.7, 66.7)
⫺3.0 (⫺9.0, 0.0)
0.0 (⫺1.0, 0.0)
⫺2.9 (⫺5.6, ⫺0.8)
⫺68.7 (⫺85.2, ⫺16.7)
Placebo/infliximab
(n ⴝ 78)
P
12.4 (4.8, 19.5)
2.4 (⫺2.8, 10.4)
⫺1.0 (⫺2.0, 0.0)
⫺1.0 (⫺3.0, 0.0)
1.0 (0.0, 2.0)
10.0 (0.0, 19.0)
2.2 (⫺1.0, 5.0)
9.0 (⫺2.0, 20.0)
34.8 (0.0, 100.0)†
⫺4.0 (⫺10.0, 0.0)
0.0 (⫺1.0, 0.0)
⫺4.0 (⫺6.4, ⫺1.8)
⫺64.5 (⫺84.9, ⫺20.0)†
Infliximab 5 or 7.5
mg/kg (n ⴝ 201)
Week 102
Infliximab 5
mg/kg (n ⴝ 201)
Week 24
* Values are the median (interquartile range) baseline value or change from baseline, except for chest expansion and CRP level, which are the median (interquartile range) percent change from baseline.
BASMI ⫽ Bath Ankylosing Spondylitis Metrology Index; VAS ⫽ visual analog scale; CRP ⫽ C-reactive protein; SF-36 ⫽ Short-Form 36 health assessment questionnaire; PCS ⫽ physical component
summary; MCS ⫽ mental component summary.
† Actual mean ⫾ SD values for chest expansion at week 102 were 4.4 ⫾ 2.4 and 4.4 ⫾ 1.9 for the placebo/infliximab and infliximab 5 or 7.5-mg/kg groups, respectively; and for CRP level were 1.0 ⫾
1.3 and 0.7 ⫾ 0.8 for the placebo/infliximab and infliximab 5 or 7.5-mg/kg groups, respectively.
BASMI (0–10)
Tragus-to-wall, cm
Lumbar flexion, cm
Cervical rotation, degrees
Lumbar side flexion, cm
Intermalleolar distance, cm
Chest expansion, cm
Mander enthesis index, 0–90
Swollen joint index, 0–44
Night pain, 0–10 VAS
CRP level, mg/dl
SF-36 summary score
PCS score
MCS score
Placebo
(n ⴝ 78)
Baseline
Table 1. Summary of baseline and median change or median percent change in randomized patients from baseline to weeks 24 and 102 in additional clinical outcomes*
Two Years of Infliximab in Ankylosing Spondylitis
1273
1274
Figure 3. Mean ⫾ SD values over time for A, the Bath Ankylosing
Spondylitis Functional Index (BASFI), B, the Bath Ankylosing
Spondylitis Disease Activity Index (BASDAI), and C, the Bath
Ankylosing Spondylitis Metrology Index (BASMI). Open circles
represent the placebo/infliximab 5-mg/kg group, solid squares
represent the infliximab 5 or 7.5-mg/kg group. The numbers of
patients contributing BASFI data at weeks 2, 6, 12, 18, 24, 36, 54,
78, and 102 are as follows. Placebo/infliximab: 76, 76, 75, 75, 75,
72, 67, 64, and 61, respectively; and infliximab 5 or 7.5 mg/kg:
201, 201, 199, 199, 198, 197, 176, 169, and 166, respectively. The
numbers of patients contributing BASDAI data at weeks 2, 6, 12,
18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 96, and 102 are as
follows. Placebo/infliximab: 76, 76, 75, 75, 75, 73, 72, 72, 70, 67,
65, 65, 65, 64, 62, 61, 63, and 61, respectively; infliximab 5 or 7.5
mg/kg: 201, 200, 199, 199, 198, 197, 197, 190, 188, 176, 178, 174,
172, 169, 168, 168, 167, and 165, respectively. The numbers of
patients contributing BASMI data at weeks 24, 54, 78, and 102 are
as follows. Placebo/infliximab: 76, 75, 67, 64, and 61, respectively; infliximab 5 or 7.5 mg/kg: 199, 176, 168, and 166, respectively.
randomized to infliximab, 47 (39.2%) and 31 (25.8%) of
120 patients who achieved an ASAS20 response at week
24 had BASDAI scores ⱖ3 and ⱖ4, respectively, for 2
consecutive visits after week 24.
In an assessment of ASAS20 response among patients
receiving infliximab 7.5 mg/kg for ⱖ12 weeks following
dose escalation (n ⫽ 91), 43 (47.3%) achieved an ASAS20
response following dose escalation. Ninety of these patients had ASAS20 response data at week 24 (41 achieved
response and 49 did not). Interestingly, 31 (75.6%) of 41
Braun et al
patients were among those achieving an ASAS20 response
at week 24, while 12 (24.5%) of 49 were not ASAS20
responders at week 24, indicating that patients not responding to infliximab 5 mg/kg by week 24 had a lower
likelihood of responding to a higher dose of infliximab
than patients who initially responded but then lost response. Similar findings were observed when assessing
this subgroup for a BASDAI score ⬍2 following dose escalation. While only 9 (8.7%) of the 104 patients who
escalated the infliximab dose and had BASDAI data at
week 24 achieved a BASDAI ⬍2, 8 (32.0%) of 25 patients
who had a BASDAI ⬍3 at week 24 achieved a BASDAI ⬍2
following escalation to infliximab 7.5 mg/kg, versus only 1
(1.3%) of 79 with a BASDAI ⱖ3 at week 24.
ASAS40 and ASAS5/6 response criteria. At week 102,
98 (59.4%) of 165 patients receiving infliximab 5 mg/kg
followed by 5 or 7.5 mg/kg achieved an ASAS40 response,
versus 28 (45.9%) of 61 patients receiving placebo/infliximab 5 mg/kg. Respective findings employing ITT and
LOCF methodology were 105 (52.2%) of 201 versus 33
(42.3%) of 78. Similarly, 90 (54.5%) of 165 infliximab 5 or
7.5-mg/kg patients versus 29 (47.5%) of 61 placebo/infliximab patients achieving ASAS40 response at week 102
also met the ASAS5/6 criteria at week 102.
Quality of life. Median changes from baseline to week
24 in the physical component summary (PCS) score of the
SF-36 were 10.2 and 0.8 for the infliximab and placebo
groups, respectively (P ⬍ 0.001). Following crossover to
active treatment at week 24, placebo/infliximab patients
had a substantial and sustained increase in quality of life.
Median changes from baseline to week 102 for the infliximab 5 or 7.5-mg/kg and placebo/infliximab groups were
12.4 and 8.3, respectively, for the PCS score, and 2.4 and
2.3, respectively, for the mental component summary
score.
Physical function. Median changes in BASFI score at
week 24 were –1.7 and 0.0 for the infliximab and placebo
groups, respectively (P ⬍ 0.001). At week 36, following
crossover from placebo to infliximab, the median change
from baseline was –1.3. At week 102, further improvement
was observed in the infliximab 5 or 7.5-mg/kg group
(⫺2.5), whereas improvement in the placebo/infliximab
group was comparable to that achieved at week 24 in the
infliximab 5 or 7.5-mg/kg group (⫺1.9) (Figure 3A). Notably, 46.8% of patients in the infliximab 5 or 7.5-mg/kg
group maintained ⱖ2 units of improvement from baseline
in BASFI score at week 24. At week 102, 80.9% of these
patients maintained this response.
Disease activity. At week 24, 49.0% of patients in the
infliximab group achieved a BASDAI score ⬍3 (indicating
low disease activity) versus 18.7% of patients in the placebo group (P ⬍ 0.0001). At week 102, the placebo/infliximab group began to approach the degree of benefit observed in the infliximab 5 or 7.5-mg/kg group, with 59.0%
and 61.8% of patients in these groups, respectively,
achieving a BASDAI score ⬍3 (Figure 3B).
Median improvement in night pain from baseline to
week 24 was significantly greater in the infliximab group
(⫺2.9) versus placebo (⫺0.3; P ⬍ 0.001). At week 102, the
median improvement from baseline in night pain in the
placebo/infliximab group approached that observed in the
Two Years of Infliximab in Ankylosing Spondylitis
1275
Table 2. Summary of safety findings in treated patients through week 102*
Infliximab through 102 weeks
Weeks
Average weeks of
Followup
Treatment
Patients with any adverse event
Patients with any serious adverse event
Patients with any malignancy
Patients with any infection
Patients with any serious infection
Patients with any infusion reaction†
Infusions with any infusion reaction
Patients with serious infusion reactions
Possible delayed hypersensitivity reaction‡
Possible anaphylactic reaction§
Patients with antibodies to infliximab
Infusion reactions by antibody-toinfliximab status
Positive
Negative
Inconclusive
Patients with lupus erythematosus
syndrome
Patients with newly positive ANA titers
ⱖ1:40
Patients with newly positive ANA titers
ⱖ1:320
Patients with newly positive anti-dsDNA
Placebo
(n ⴝ 76)
Placebo/5 mg/
kg
(n ⴝ 74)
5 or
7.5 mg/kg
(n ⴝ 201)
Combined
(n ⴝ 275)
0–24
24–102
0–102
-
25.3
18.3
57 (75.0)
2 (2.6)
0 (0.0)
29 (38.2)
0 (0.0)
7 (9.2)
10/260 (2.6)
0 (0.0)
0 (0.0)
0 (0.0)
-
70.2
60.1
72 (97.3)
15 (20.3)
1 (1.4)
60 (81.1)
3 (4.1)
9 (12.2)
14/869 (1.6)
2 (2.7)
1 (1.4)
0 (0.0)
5/63 (7.9)
94.2
84.2
196 (97.5)
34 (16.9)
2 (1.0)
158 (78.6)
8 (4.0)
43 (21.4)
78/3,388 (2.3)
0 (0.0)
0 (0.0)
0 (0.0)
18/176 (10.2)
87.8
77.7
268 (97.5)
49 (17.8)
3 (1.1)
218 (79.3)
11 (4.0)
52 (18.9)
92/4,257 (2.2)
2 (0.7)
0 (0.0)
0 (0.0)
23/239 (1.0)
-
3/5 (60.0)
1/7 (14.3)
4/51 (7.8)
2 (2.7)
11/18 (61.1)
4/15 (26.7)
21/143 (14.7)
2 (0.9)
14/23 (60.9)
5/22 (22.7)
25/194 (12.9)
4 (1.4)
8/73 (11.0)
40/67 (59.7)
119/193 (61.7)
159/260 (61.2)
1/73 (1.4)
17/67 (25.4)
74/193 (38.3)
91/260 (35.0)
0/73 (0.0)
14/67 (20.9)
63/193 (32.6)
77/260 (29.6)
* Values are the number (percentage) of patients. ANA ⫽ antinuclear antibodies; anti-dsDNA ⫽ antibodies to double-stranded DNA. See Patients and
Methods for detailed definitions of adverse events.
† Any adverse event that occurred during, or within 1 hour after, study drug infusion.
‡ An adverse event of myalgia and/or arthralgia with fever and/or rash occurring 1–14 days after an infusion of study drug.
§ An adverse event of anaphylactoid reaction, laryngeal edema, pharyngeal edema, or a symptom complex characterized by urticaria and/or
angioedema with bronchospasm, circulatory failure, myocardial ischemia, arrhythmia, hypotension, or dyspnea occurring within 24 hours following
the start of study drug infusion.
infliximab 5 or 7.5-mg/kg group (⫺3.3 and ⫺4.0, respectively). The median percent reductions in CRP at week 102
were comparable between groups: 64.5% and 58.8% for
the infliximab 5 or 7.5-mg/kg and placebo/infliximab
groups, respectively.
Range of motion. Median changes from baseline to
week 24 in BASMI score were ⫺1.0 for the infliximab
group versus 0.0 for placebo (P ⫽ 0.019). At week 102,
median changes from baseline in BASMI were –1.0 for
both the infliximab 5 or 7.5-mg/kg group and the placebo/
infliximab group (Table 1, Figure 3C). Approximately 63%
of patients in both treatment groups achieved an improvement ⱖ1 unit in BASMI score at week 102. Respective
median percent changes from baseline in chest expansion
for the infliximab and placebo groups were 16.7% and
0.0% at week 24 (P ⫽ 0.037) and 34.8% and 33.3% at week
102 (Table 1).
Safety. The average lengths of followup for treatment
with placebo, placebo/infliximab, and infliximab 5 or 7.5
mg/kg were 25.3 weeks, 70.2 weeks, and 94.2 weeks, respectively (Table 2).
Adverse events. Through week 102, 97.5%, 97.3%,
and 75.0% of patients in the infliximab 5 or 7.5-mg/kg,
placebo/infliximab, and placebo groups, respectively, had
adverse events. The most frequently reported adverse
event was upper respiratory tract infection (48.7% of
infliximab-treated patients). Among the 106 patients who
escalated the infliximab dose from 5 to 7.5 mg/kg, 87.7%
experienced an adverse event during the study. Similarly,
their most common event was upper respiratory tract infection (31.1%).
Serious adverse events were reported for similar proportions of patients across the treatment groups. Through
week 102, the most frequently reported serious adverse
event was arthritis, occurring in 5 (1.8%) of the 275 infliximab-treated patients. Only 1 case of arthritis occurred
after dose escalation to infliximab 7.5 mg/kg.
No patient died during the 102-week study. A patient
with lung cancer (diagnosed after escalation to infliximab
7.5 mg/kg) was discontinued from the study, and subsequently died due to ventricular fibrillation during chemotherapy for the tumor. Two additional malignancies were
diagnosed during the study: squamous cell skin carcinoma
1276
in a placebo/infliximab patient (after crossover to infliximab), and breast cancer in an infliximab-treated patient
(after escalation to 7.5 mg/kg). One placebo/infliximab patient developed nonseminoma testicular carcinoma after
study completion (not included in Table 2).
Eleven patients had a serious infection: 3 (4.1%) placebo/infliximab (following crossover to infliximab) and 8
(4.0%) infliximab 5 or 7.5-mg/kg (4 after escalation to 7.5
mg/kg). Pneumonia was the most frequently reported serious infection, occurring in 3 (1.5%) infliximab-treated
patients (2 after escalation). There were no serious infections in placebo patients through week 24. There were also
no reports of tuberculosis or serious opportunistic infections; however, 2 patients (placebo/infliximab) had results
of purified protein derivative (PPD) testing convert to positive findings. One patient had no clinical or radiographic
evidence of active tuberculosis, but due to the positive
PPD conversion latent tuberculosis was suspected, and the
patient received prophylactic treatment with isoniazid.
This patient completed study treatment. The PPD conversion in the second patient was noted 48 days after the
week 48 infliximab infusion, during patient hospitalization for a suspected lupus-like syndrome. Treatment was
not specified, and the patient discontinued the study agent
due to other adverse events. Three patients had oral Candida infections. Several superficial fungal infections were
reported in infliximab-treated patients, including fungal
dermatitis in 15 (5.5%) and moniliasis in 13 (4.7%) patients in the combined infliximab group. One infliximab
patient had herpes zoster.
Serious neurologic events occurred in 1 (1.3%) placebo
patient (myelitis), 1 (1.4%) placebo/infliximab patient
(coma and convulsions), and 3 (1.5%) infliximab 5 or
7.5-mg/kg patients (hemiparesis, neuroma, optic neuritis).
Optic neuritis was reported after dose escalation to infliximab 7.5 mg/kg. The patient with hemiparesis (unrelated
to study agent) was subsequently noted to have had a
cerebrovascular accident with slight left-sided sensorimotor loss from which he recovered. All of these neurologic
events had resolved at the time of the last followup visit.
One patient in the placebo/infliximab group had a possible delayed hypersensitivity reaction (1 week after crossover to infliximab) reported as fever and myalgia. This
patient had antibodies to infliximab and discontinued
study agent infusions at week 30 due to bronchospasm and
receipt of etanercept. Neither possible anaphylactic reactions nor congestive heart failure were reported.
Autoantibodies (ANA and anti-dsDNA). Among patients who were negative for ANA at baseline, newly positive ANAs (titer ⱖ1:40) were detected in 8 (11.0%) placebo patients, 40 (59.7%) placebo/infliximab patients, and
119 (61.7%) infliximab patients. For newly positive ANAs
(titer ⱖ1:320), respective occurrences were 1 (1.4%), 17
(25.4%), and 74 (38.3%) patients. Among patients who
were negative for anti-dsDNA at baseline, newly positive
findings were detected in no patients who received placebo only, 14 (20.9%) patients in the placebo/infliximab
group, and 63 (32.6%) patients in the infliximab 5 or
7.5-mg/kg group.
Four patients had lupus erythematosus syndrome (Table
2): 2 in the placebo/infliximab group (after crossover to
Braun et al
infliximab) and 2 in the infliximab 5 or 7.5-mg/kg group. In
the placebo/infliximab group, 1 patient had severe arthralgia of multiple joints after crossover that resulted in study
agent discontinuation (arthralgia resolved), and another
had swelling and pain of finger joints after crossover. This
patient completed study treatment, at which time the
swelling had resolved, but the pain was ongoing. In the
infliximab group, 1 patient had drug-induced systemic
lupus erythematosus (SLE) during treatment with the
5-mg/kg dose (resolved without treatment, and the patient
completed treatment with infliximab 5 mg/kg followed by
7.5 mg/kg), and a second patient discontinued treatment
with infliximab 7.5 mg/kg due to pleurisy, pericarditis,
pulmonary embolism (resolved), and SLE and antiphospholipid syndrome (ongoing at time of discontinuation).
Two patients had uveitis after escalation to infliximab 7.5
mg/kg.
Immunogenicity and infusion reactions. Through week
24, 6 (3.0%) of 199 infliximab patients with appropriate
samples had antibodies to infliximab. Through week 102,
the incidences of antibodies to infliximab were 5 (7.9%) of
63, 5 (6.0%) of 83, and 13 (14.0%) of 93, respectively, for
placebo/infliximab 5-mg/kg treatment (weeks 24 –102), infliximab 5-mg/kg treatment (weeks 0 –102), and infliximab
7.5-mg/kg treatment (weeks 36 –102). For the placebo/infliximab group (weeks 24 –102), 7 (11.1%) of 63 patients
were antibody negative, versus 7 (8.4%) of 83 for the
infliximab 5-mg/kg group (weeks 0 –102) and 8 (8.6%) of
93 for the infliximab 7.5-mg/kg group (weeks 36 –102).
Among the 7 patients who were antibody positive at week
24, 6 were positive and 1 was negative at week 102. The
majority of patients who were antibody negative at week
24 (n ⫽ 68) were classified as inconclusive at week 102
(n ⫽ 52). Seven patients were antibody negative at week 24
but positive at week 102. The majority of patients who
were classified as antibody inconclusive at week 24 (n ⫽
163) had the same status at week 102 (n ⫽ 142). Of the
patients classified as inconclusive at week 24, 10 were
antibody positive and 11 were antibody negative at week
102.
Infusion reactions occurred in 7 (9.2%) placebo patients,
9 (12.2%) placebo/infliximab patients, and 43 (21.4%) infliximab 5 or 7.5-mg/kg patients. The respective numbers
of infusions with an infusion reaction were 10 (2.6%), 14
(1.6%), and 78 (2.3%). Similar findings were observed in
patients who escalated the infliximab dose to 7.5 mg/kg;
i.e., 12 (11.3%) of these 106 patients had an infusion
reaction and 23 (2.7%) of the 863 infusions were associated with an infusion reaction. Two (2.6%) patients in the
placebo/infliximab group had serious infusion reactions
after crossover to infliximab (bronchospasm in 1 patient
and bronchospasm, orbital edema, flushing, and vertigo in
the other). Seven patients discontinued study agent due to
infusion reactions. Among patients with samples for antibody to infliximab determinations, 4 patients who were
classified as antibody positive and 1 who was classified as
antibody negative discontinued due to an infusion reaction. Through week 102, patients positive for antibodies to
infliximab had the highest occurrence of infusion reactions (Table 2).
Two Years of Infliximab in Ankylosing Spondylitis
Laboratory abnormalities. Very few patients had a
markedly abnormal change in hematology laboratory values. Markedly abnormal increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total
bilirubin (defined as ⬎75 IU/liter for ALT/AST or ⬎1.5
mg/dl for bilirubin, all in conjunction with an increase of
ⱖ100%), occurred in 67 (24.5%), 31 (11.3%), and 6 (2.2%)
infliximab patients, respectively. Elevated liver function
tests were generally transient, and no clinically significant
sequelae associated with abnormal liver function were
observed. There were no cases of liver failure. Only 1
patient (placebo/infliximab) had concurrent markedly abnormal ALT and bilirubin levels. However, the peak bilirubin was only 1.9 mg/dl. One (1.3%) patient in the placebo/infliximab group had a markedly abnormal ALT
elevation. No patient had both an ALT ⱖ3 times the upper
limit of normal and a total bilirubin ⱖ2 times the upper
limit of normal.
DISCUSSION
ASSERT was a multicenter, randomized, double-blind,
placebo-controlled study of 279 patients with AS. Efficacy
and safety findings through week 24 have been reported
(8), as have MRI assessments of spinal inflammation (10).
In the current evaluation, no new safety findings were
observed with the extension of infliximab treatment (5 or
7.5 mg/kg every 6 weeks) through 2 years, and the improvements in signs and symptoms, physical function,
range of motion, and quality of life observed at week 24
were maintained through week 102 among these AS patients receiving infliximab for 2 years. The placebo patients who began infliximab at week 24 (received active
treatment for 1.5 years) showed comparable improvement
in the signs and symptoms of AS, physical function, and
quality of life. These clinical efficacy findings are important given the severity of disability that can occur in patients with AS who are treated with nonsteroidal antiinflammatory drugs alone (21–23), and are consistent with
previous reports of open-label infliximab treatment of 70
AS patients, in whom infliximab therapy produced rapid
and significant improvements in the BASDAI score that
were durable through 1 (24), 2 (25), and 3 (26) years of
therapy.
BASFI scores clearly indicate that infliximab treatment
resulted in continuous improvement in physical function
over time. Axial metrology is also an important tool reflecting the potential of infliximab to effectively treat AS.
In our evaluation of the BASMI, ⬃63% of patients receiving infliximab achieved an improvement ⱖ1 unit in
BASMI score at week 102.
Starting with the week 36 infusion, patients initially
randomized to receive infliximab 5 mg/kg who had a BASDAI score ⱖ3 at both the current and prior visits could
increase the infliximab dose to 7.5 mg/kg. The clinical
efficacy data derived from this trial following dose escalation provide no rationale for increasing the infliximab dose
in patients with AS based on the escalation criteria employed. Specifically, among the subgroup of patients
whose infliximab dose was escalated from 5 to 7.5 mg/kg at
1277
week 36 or later, ⬃30% fewer patients achieved the
ASAS20 at each time point versus infliximab-treated patients not escalating the dose. Antibodies to infliximab
developed in patients requiring dose escalation, but the
increase to 7.5 mg/kg could not compensate for the accelerated infliximab clearance induced by the antibodies
formed against infliximab. These findings of reduced efficacy in conjunction with antibody to infliximab development in AS patients are consistent with a previous evaluation in 8 men with AS (only 2 were receiving concomitant
disease-modifying antirheumatic drugs) (27). Findings in
our study may also be partly the result of some patients at
each measurement period having received an increased
dose for only a short period of time, because dose escalation could have occurred at any point from week 36 onward. Data derived from infliximab clinical trials have
indicated that antibody development was lower among
rheumatoid arthritis and Crohn’s disease patients receiving immunosuppressant therapies such as 6-mercaptopurine/azathioprine or methotrexate (28). Because methotrexate has not shown efficacy in AS, combination therapy
was not evaluated in this study. However, in light of the
above antibody findings, it is of interest that 2 recent
studies showed no better efficacy of infliximab in combination with methotrexate in patients with AS (29,30). Also
related to the antibody to infliximab data, it could be
useful to assess whether reductions in the interval between infliximab doses may be more appropriate than
increasing the dose in nonresponders. Further analyses are
necessary to make firm conclusions about the role of antibodies to infliximab in patients with AS.
As noted, infliximab 5 or 7.5 mg/kg every 6 weeks
demonstrated a favorable safety profile in this 2-year
study of patients with AS. In the evaluation of safety
data, it is important to note the variable lengths of
followup for patients receiving placebo (25.3 weeks),
placebo followed by infliximab (70.2 weeks), and infliximab 5 or 7.5 mg/kg (94.2 weeks). As was observed
through week 24 (8), adverse events related to the respiratory system were the most frequently reported through
week 102. Serious infections were uncommon, and there
were no reports of active tuberculosis or serious opportunistic infections. Three patients had malignancies, but
none had lymphoma. One of these patients (with lung
cancer) died from an arrhythmia during chemotherapy
after study withdrawal.
Taken together, these long-term findings indicate that
infliximab has beneficial efficacy and is safe in patients
with active AS over 2 years.
ACKNOWLEDGMENTS
The authors wish to thank Michelle Perate, MS and Mary
Whitman, PhD, of Centocor, Inc., for writing support.
AUTHOR CONTRIBUTIONS
Dr. Braun had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of the
data analysis.
Study design. Braun, Williamson, Baker, van der Heijde.
1278
Acquisition of data. Braun, Deodhar, Dijkmans, Sieper, Baker, van
der Heijde.
Analysis and interpretation of data. Braun, Deodhar, Dijkmans,
Geusens, Sieper, Xu, Visvanathan, Baker, Goldstein, van der
Heijde.
Manuscript preparation. Braun, Deodhar, Dijkmans, Geusens,
Sieper, Visvanathan, Baker, Goldstein, van der Heijde.
Statistical analysis. Williamson, Xu.
Braun et al
15.
16.
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