Download Efficacy and safety of infliximab in patients with ankylosing

ARTHRITIS & RHEUMATISM
Vol. 52, No. 2, February 2005, pp 582–591
DOI 10.1002/art.20852
© 2005, American College of Rheumatology
Efficacy and Safety of Infliximab in Patients With
Ankylosing Spondylitis
Results of a Randomized, Placebo-Controlled Trial (ASSERT)
Désirée van der Heijde,1 Ben Dijkmans,2 Piet Geusens,3 Joachim Sieper,4
Kimberly DeWoody,5 Paul Williamson,5 Jürgen Braun,6 and the
Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab
Therapy Study Group
Spondylitis Disease Activity Index (BASDAI), night
pain, patient’s global assessment, the Bath Ankylosing
Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Metrology Index (BASMI), chest
expansion, the Mander enthesis index, the total swollen
joint index, the C-reactive protein level, and the Short
Form 36 (SF-36) health survey questionnaire. The primary end point in this study was the proportion of
patients with a 20% improvement response according
to the ASAS International Working Group criteria
(ASAS20 responders) at week 24.
Results. Of the 357 patients screened, 201 were
assigned to receive 5 mg/kg infliximab and 78 were
assigned to receive placebo. After 24 weeks, 61.2% of
patients in the infliximab group were ASAS20 responders compared with 19.2% of patients in the placebo
group (P < 0.001). Clinical benefit was observed in
patients receiving infliximab as early as week 2 and was
maintained over the 24-week study period. Patients
receiving infliximab also showed significant improvements in the BASDAI, BASFI, BASMI, chest expansion,
and physical component summary score of the SF-36.
Adverse events were reported by 82.2% of patients
receiving infliximab and by 72.0% of patients receiving
placebo; however, most adverse events in both treatment
groups were mild or moderate in severity.
Conclusion. Infliximab was well tolerated and
effective in a large cohort of patients with AS during a
24-week study period.
Objective. The signs and symptoms of ankylosing
spondylitis (AS) respond inadequately to nonsteroidal
antiinflammatory drugs, corticosteroids, and diseasemodifying antirheumatic drugs in quite a number of
patients. Tumor necrosis factor inhibitors have demonstrated success in reducing AS disease activity in a
limited number of clinical trials. The objective of this
multicenter, randomized, placebo-controlled study was
to evaluate the efficacy and safety of infliximab in
patients with AS.
Methods. Patients were randomly assigned to
receive infusions of placebo or 5 mg/kg infliximab at
weeks 0, 2, 6, 12, and 18. Efficacy was assessed using the
ASsessment in Ankylosing Spondylitis (ASAS) International Working Group criteria, the Bath Ankylosing
Supported by Centocor, Inc., Malvern, Pennsylvania.
1
Désirée van der Heijde, MD, PhD: University Hospital
Maastricht, Maastricht, The Netherlands; 2Ben Dijkmans, MD, PhD:
VU University Medical Center, Amsterdam, The Netherlands; 3Piet
Geusens, MD: Limburg Universitaire Centrum, Maastricht, The Netherlands; 4Joachim Sieper, MD: Universitaetsklinikum Benjamin
Franklin–Free University of Berlin, Berlin, Germany; 5Kimberly DeWoody, PhD, Paul Williamson, MD: Centocor, Inc., Malvern, Pennsylvania; 6Jürgen Braun, MD: Rheumazentrum Ruhrgebiet, Herne,
Germany.
Drs. van der Heijde, Dijkmans, Geusens, Sieper, and Braun
have received research support from Centocor, Inc. and have received
consulting fees or honoraria totaling less than $10,000 from Centocor,
Inc. or Schering-Plough Research Institute. In 2002, Dr. van der
Heijde gave expert testimony at the FDA hearing on inhibition of
structural damage and received a fee from Centocor, Inc. Drs.
DeWoody and Williamson own stock in Johnson and Johnson, of
which Centocor, Inc. is a subsidiary.
Address correspondence and reprint requests to Désirée van
der Heijde, MD, University Hospital Maastricht, PO Box 5800,
Maastricht 6202 AZ, The Netherlands. E-mail: [email protected].
Submitted for publication July 26, 2004; accepted in revised
form November 10, 2004.
Ankylosing spondylitis (AS) is a chronic, progressive, immune-mediated inflammatory disorder that affects 0.1–1.1% of the Caucasian adult population world582
EFFICACY AND SAFETY OF INFLIXIMAB IN AS
wide (1). Inflammation of sacroiliac joints, the spine,
and entheses leads to new bone formation, syndesmophytes, and ankylosis of joints (2–4). Patients with AS
may also have associated peripheral arthritis, enthesitis,
osteoporosis, or extraarticular involvement such as uveitis and inflammatory bowel disease (2). Compared with
the general population, patients with AS have increased
rates of work disability and unemployment (5) and a
higher mortality rate (6,7). Although the exact etiology
of AS is unknown, ⬃90% of patients with the disease
have the HLA–B27 allele (8).
Until recently, treatment options for patients
with AS have been limited to nonsteroidal antiinflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), and physical therapy. NSAIDs
are often used continuously and are not efficacious for
some patients (2,9). They relieve pain sufficiently to
allow increased spinal movement and an improved ability to exercise, but they appear to have little effect on the
underlying inflammatory process (10). DMARDs that
have shown efficacy in rheumatoid arthritis, such as
methotrexate, do not have efficacy in patients with spinal
manifestations of AS (10,11). There is evidence that
sulfasalazine may provide benefit for the peripheral
articular manifestations of AS, but it has not been shown
to be effective in treating axial disease (12–14).
Therapeutic agents that target the proinflammatory cytokine tumor necrosis factor ␣ (TNF␣) may be
the most viable alternative to existing treatment options.
Abundant TNF␣ messenger RNA and protein have
been found in the sacroiliac joints of patients with AS
(15,16). Etanercept, a dimeric fusion protein of the TNF
receptor and the Fc portion of IgG1, has been successfully used to treat patients with AS (17,18). Infliximab, a
monoclonal antibody that targets TNF␣, has also been
shown to be effective in treating patients with AS
(19–26) and other spondylarthropathies (27–32). In a
randomized, placebo-controlled, multicenter study (22),
patients who received an induction regimen of 5 mg/kg
infliximab showed significant improvement in disease
activity after 12 weeks compared with patients who
received placebo. The response was sustained over a
1-year, open-label observation period (24). Immunologic
studies conducted in a subset of patients from this trial
demonstrated that infliximab down-regulated
interferon-␥ and TNF␣ secreted by T cells (33).
Although the approved standard of care for
maintenance infliximab treatment of patients with rheumatoid arthritis is infusions every 8 weeks, there is
evidence that patients with AS would need to receive
infusions every 6 weeks. In an open-label trial, 48
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subjects with AS were treated with an induction regimen
of 5 mg/kg infliximab (26). The mean time to relapse
(defined as a loss of ⱖ50% in the global pain improvement observed at week 8) was 7 weeks (34) (median 14
weeks [26]) after the induction regimen. A second
difference from the use of infliximab for rheumatoid
arthritis is that methotrexate therapy has not been
administered concomitantly in patients with AS.
Although the results of prior studies were promising, the effect of infliximab induction and maintenance
therapy needed to be evaluated in a larger patient
population. The primary objective of the current study,
conducted by members of the Ankylosing Spondylitis
Study for the Evaluation of Recombinant Infliximab
Therapy (ASSERT) Study Group, was to assess the
reduction in the signs and symptoms of AS at week 24
after an induction regimen of 5 mg/kg infliximab followed by maintenance infusions every 6 weeks without
concomitant methotrexate therapy.
PATIENTS AND METHODS
Patients. Adult patients classified as having AS (according to the modified New York criteria [35]) for at least 3
months prior to screening, with a Bath Ankylosing Spondylitis
Disease Activity Index (BASDAI) score of ⱖ4 (range 0–10),
and with a spinal pain assessment score of ⱖ4 on a visual
analog scale (VAS; range 0–10 cm) were eligible for the study.
Patients were also required to have a normal chest radiograph
within 3 months prior to randomization and either a negative
purified protein derivative (PPD) skin test result for latent
tuberculosis (in the US and Canada) or adequate screening
with documented negative results for latent tuberculosis using
local guidelines for high-risk or immunocompromised patients
(in Europe). Patients were excluded from the study if they had
any of the following diagnoses or medical history: total ankylosis of the spine (defined by syndesmophytes present on the
lateral views of spinal radiographs at all intervertebral levels
from T6 through S1), any other inflammatory rheumatic
disease, fibromyalgia, a serious infection within 2 months prior
to randomization, tuberculosis (active or latent) or recent
contact with a person with active tuberculosis, an opportunistic
infection within 6 months of screening, hepatitis, human
immunodeficiency virus, a transplanted organ, malignancy,
multiple sclerosis, or congestive heart failure.
Patients were allowed to receive concurrent stable
doses of NSAIDs, acetaminophen (paracetamol), or tramadol
during the study. Patients were not permitted to receive
sulfasalazine or methotrexate within 2 weeks prior to screening, systemic corticosteroids within 1 month prior to screening,
anti-TNF therapy other than infliximab within 3 months prior
to screening, infliximab at any time prior to screening,
DMARDs other than sulfasalazine or methotrexate within 6
months prior to screening, or cytotoxic drugs within 12 months
prior to screening.
The study was conducted in 33 centers throughout the
584
US, Canada, and Europe. The study protocol was reviewed
and approved by the respective institutional review board or
independent ethics committee at each site. All patients provided written informed consent.
Study agents. Infliximab is a recombinant IgG1-␬
human-murine chimeric monoclonal antibody that specifically
binds to both the soluble and membrane-bound forms of
TNF␣. Both infliximab and placebo were supplied as sterile,
white, lyophilized powders in single-use 20-ml vials.
Study protocol. In this 24-week, double-blind, placebocontrolled study, patients were randomly assigned in a 3:8 ratio
to receive infusions of placebo or 5 mg/kg infliximab at weeks
0, 2, 6, 12, and 18. Patients were allocated to treatment groups
using an adaptive treatment allocation stratified by investigational site and C-reactive protein (CRP) level (within or above
3 times the upper limit of normal).
Efficacy evaluations. The primary end point was the
proportion of patients with a 20% improvement response
according to the criteria of the ASsessment in Ankylosing
Spondylitis (ASAS) International Working Group (ASAS20
responders) (36) at week 24. An ASAS20 responder was
defined as a patient who showed at least 20% improvement
from baseline and had an absolute improvement from baseline
of at least 1 unit (on a scale of 0–10) in at least 3 of the
following 4 assessment domains: patient’s global assessment,
spinal pain, function according to the Bath Ankylosing Spondylitis Functional Index (BASFI), and morning stiffness (the
average of the last 2 questions of the BASDAI). In addition,
ASAS20 responders must not have had deterioration from
baseline (defined as a worsening of ⱖ20% and an absolute
worsening of at least 1 unit [on a scale of 0–10]) in the
potential remaining assessment domain.
Secondary end points included the ASAS40 response
(40% improvement from baseline and an absolute improvement of at least 2 units [on a scale of 0–10] in at least 3 of the
4 assessment domains defined in the ASAS20 response criteria, with no deterioration from baseline in the potential
remaining assessment domain), ASAS partial remission (an
absolute score of ⬍2 in each of the above 4 ASAS assessment
domains) (36), and 20% improvement in at least 5 of the
following 6 ASAS assessment domains (an ASAS 5 of 6
response): spinal pain, patient’s global assessment, function
according to the BASFI, morning stiffness, CRP level, and the
Bath Ankylosing Spondylitis Metrology Index (BASMI) score
(37). Other secondary end points were disease activity, physical function, range-of-motion assessments, other musculoskeletal assessments, and quality of life.
Disease activity was evaluated using the BASDAI, the
night pain VAS, the patient’s global assessment, and the CRP
level. The BASDAI (score ranging from 0 to 10) is a combined
assessment of fatigue, spinal pain, joint pain, enthesitis, and
morning stiffness. In addition to the change from baseline in
the BASDAI score, the proportion of patients who had at least
50% improvement in the BASDAI score was also assessed for
each treatment group (38). Physical function was evaluated
using the BASFI (score ranging from 0 to 10), which includes
8 questions relating to the patient’s function and 2 questions
relating to a patient’s ability to cope with everyday life (39).
Range of motion was assessed using the BASMI and chest
expansion. The BASMI is an aggregate score (ranging from 0
to 10) of patient mobility assessments, including tragus-to-wall,
VAN DER HEIJDE ET AL
lumbar flexion (Schober test), cervical rotation, lumbar side
flexion, and intermalleolar distance (40). Chest expansion is
the difference between the circumference of the chest in
maximal inspiration and that in maximal expiration.
Other musculoskeletal assessments included the total
swollen joint index and the enthesis index. The swollen joint
index, an assessment tool typically used in studies of rheumatoid arthritis, is an evaluation of swelling in 44 joints, including
the elbows, wrists, metacarpophalangeal joints of the fingers
and thumbs, interphalangeal joints of the thumbs, proximal
interphalangeal joints of the fingers, shoulders, acromioclavicular joints, sternoclavicular joints, knees, ankles (mortices),
and metatarsophalangeal joints (41). The Mander enthesis
index is an assessment (score ranging from 0 to 90) of the
degree of tenderness at a variety of anatomic sites and regions
(42). The Short Form 36 (SF-36) health survey questionnaire
was used to assess quality of life (43).
Safety evaluations. Safety assessments included adverse events, infections, infusion reactions, premature discontinuation, and laboratory tests. Serum samples were assessed
at baseline and at week 24 for the presence of antinuclear
antibodies and antibodies to infliximab. Samples that tested
positive for antinuclear antibodies were also tested for antibodies to double-stranded DNA (dsDNA).
Statistical analysis. Assuming that 60% of infliximabtreated patients and 25% of placebo-treated patients achieved
the primary study end point, the study required only 40
subjects in each treatment group to achieve 90% power. The
targeted sample size for the study was 75 patients in the
placebo group and 200 patients in the infliximab group in order
to provide a sufficient number of patients for safety assessments. With this sample size, the study had ⬎99% power to
detect a treatment effect using a 2-sided chi-square test at the
␣ ⫽ 0.05 level given the abovementioned assumptions of
response rates.
All requirements for inclusion of patients in analysis
populations were prespecified. All patients were analyzed for
efficacy according to their randomly assigned treatment group,
regardless of the actual treatment they received. All patients
who received at least 1 study infusion were analyzed for safety
according to the actual treatment they received. The proportions of ASAS20 responders (primary end point) and the
proportions of patients who achieved the ASAS partial remission were analyzed using the Cochran-Mantel-Haenszel chisquare test stratified by the CRP value observed at screening
(values within versus values above 3 times the upper limit of
normal).
Patients in whom non–study-related anti-TNF therapy
was initiated or who prematurely discontinued study treatment
due to lack of efficacy were considered to be nonresponders.
Data for patients who initiated prohibited antiinflammatory
medications (e.g., systemic corticosteroids, cytotoxic drugs, or
DMARDs) or who discontinued study treatment for reasons
other than lack of efficacy (e.g., adverse events) were assessed
for treatment response based on their actual observed values at
week 24. The last observation carried forward approach was
used in the ASAS20 and ASAS partial remission analyses to
impute the missing value for patients who did not return for an
evaluation or for whom there were insufficient data for us to
assess their treatment response at week 24. Secondary efficacy
end points were not stratified by CRP level, and no adjustment
EFFICACY AND SAFETY OF INFLIXIMAB IN AS
585
was made for initiation of anti-TNF therapies, discontinuation
of treatment, or missing values. Continuous measures were
analyzed using an analysis of variance on the van der Waerden
normal scores. All statistical tests were 2-sided and were
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).
RESULTS
Data for this study were collected between November 2002 and September 2003. Overall, 279 patients
were randomly assigned to treatment with placebo (78
patients) or infliximab (201 patients). The study population, typical of patients with active AS, consisted
mostly of men (80.6%), had a median age of 40.0 years,
and had a median AS disease duration of 8.8 years
Table 1. Summary
characteristics*
of
Men, no. (%)
Caucasian, no. (%)
Age, years
Disease duration, years
History of uveitis, no. (%)
History of psoriasis,
no. (%)
History of IBD, no. (%)
HLA–B27 positive, no. (%)
BASDAI score, 0–10
BASFI score, 0–10
BASMI score, 0–10
Chest expansion, cm
Mander enthesis index,
0–90
Swollen joint index, 0–44
Night pain, 0–10 VAS
Patient’s global assessment,
0–10 VAS
CRP level, mg/dl
Screening CRP level ⱕ3
times ULN, no. (%)‡
Screening CRP level ⬎3
times ULN, no. (%)‡
SF-36 summary scores
Physical component
Mental component
baseline
demographics
and
clinical
Placebo
(n ⫽ 78)
5 mg/kg
infliximab
(n ⫽ 201)
68 (87.2)
76 (97.4)
41.0 (34.0, 47.0)
13.2 (3.7, 17.9)
25 (32.1)
5 (6.4)
157 (78.1)
197 (98.0)
40.0 (32.0, 47.0)
7.7 (3.3, 14.9)
72 (35.8)
16 (8.0)
6 (7.7)
69 (88.5)
6.5 (5.2, 7.1)
6.0 (4.1, 7.2)
4.0 (2.0, 6.0)
3.0 (2.0, 4.0)
8.0 (2.0, 16.0)
13 (6.5)
173 (86.5)†
6.6 (5.3, 7.6)
5.7 (4.5, 7.1)
4.0 (2.0, 5.0)
3.0 (2.0, 4.0)
8.0 (3.0, 15.0)
0.0 (0.0, 1.0)
6.7 (4.7, 7.9)
6.7 (5.8, 7.7)
0.0 (0.0, 1.0)
6.6 (4.8, 8.1)
6.9 (5.7, 8.0)
1.7 (0.7, 3.3)
38 (48.7)
1.5 (0.7, 3.2)
95 (47.3)
40 (51.3)
106 (52.7)
30.1 (24.9, 36.2)
45.0 (33.7, 55.5)
28.8 (23.8, 33.7)
47.6 (37.6, 54.9)
* Except where indicated otherwise, values are the median (interquartile range). IBD ⫽ inflammatory bowel disease; BASDAI ⫽ Bath
Ankylosing Spondylitis Disease Activity Index; BASFI ⫽ Bath Ankylosing Spondylitis Functional Index; BASMI ⫽ Bath Ankylosing
Spondylitis Metrology Index; VAS ⫽ visual analog scale; CRP ⫽
C-reactive protein; ULN ⫽ upper limit of normal; SF-36 ⫽ Short Form
36 health survey questionnaire.
† Only 200 patients were assessed at baseline.
‡ Normal range 0–0.5 mg/dl.
Figure 1. Patient disposition. Patients may have discontinued study
treatment but continued participation in the study. * ⫽ Of the 2
patients in the placebo group who discontinued study treatment, 1
patient discontinued participation in the study. ** ⫽ Of the 4 patients
in the infliximab group who discontinued study treatment, 2 patients
discontinued participation in the study.
(Table 1). Eighty-seven percent of patients were positive
for the HLA–B27 allele. Median scores for baseline
measurements of pain and disease activity showed that
most patients had significant AS disease activity (Table
1). Patients also had significant physical impairment at
baseline with an overall median SF-36 physical component summary score (28.9) well below that of the general
population of the US and Europe (range 49.7–52.7) (44).
However, the median SF-36 mental component summary score (47.3) was similar to that of the general
population of the US and Europe (range 47.6–54.0)
(44).
The treatment groups were well matched with
regard to demographics and baseline clinical characteristics; however, there was a higher percentage of men in
the placebo group (87.2%) compared with that in the
infliximab group (78.1%). Although the median baseline
disease duration in the placebo group was higher than
that in the infliximab group (13.2 years versus 7.7 years),
586
VAN DER HEIJDE ET AL
Figure 2. Proportion of patients who achieved A, 20% and B, 40% improvement responses over time according to the criteria of the ASsessment
in Ankylosing Spondylitis (ASAS) Working Group (see Patients and Methods for explanations of ASAS Working Group criteria). ⴱ ⫽ P ⬍ 0.001
versus placebo group.
the means were similar between treatment groups (10.1
years and 11.9 years in the infliximab and placebo
groups, respectively). The median baseline CRP level
was 1.5 mg/dl in the infliximab group and 1.7 mg/dl in the
placebo group.
The majority of patients in both treatment groups
completed the 24-week study period (Figure 1). Two
patients in the infliximab group discontinued study
infusions because of adverse events, 1 patient withdrew
due to lack of efficacy, and 1 patient was withdrawn
because of a protocol violation (positive tuberculin PPD
test result with induration of ⬎5 mm). In the placebo
group, 1 patient discontinued because of adverse events,
and 1 patient withdrew consent.
One patient was assigned to the placebo group
but received an infusion of infliximab. This patient was
included in the placebo group for the efficacy analysis
and in the infliximab group for the safety analysis. Two
other patients were assigned to the placebo group but
withdrew consent before receiving any study infusions.
These patients were included in the placebo group for
the efficacy analysis but were not included in the safety
analysis.
Efficacy. After 24 weeks, 123 of 201 patients
(61.2%) in the infliximab group were ASAS20 responders compared with 15 of 78 patients (19.2%) in the
placebo group (P ⬍ 0.001) (Figure 2A). A difference
between the treatment groups was observed as early as
week 2 and was maintained over the 24-week observa-
tion period (P ⬍ 0.001) (Figure 2A). Treatment response was observed in both CRP level strata. For
patients with baseline CRP levels ⱕ3 times the upper
limit of normal, 46.3% of 95 infliximab-treated patients
achieved an ASAS20 response compared with 21.1% of
38 placebo-treated patients (P ⫽ 0.007). For patients
with baseline CRP levels ⬎3 times the upper limit of
normal, 74.5% of 106 infliximab-treated patients
achieved an ASAS20 response compared with 17.5% of
40 placebo-treated patients (P ⬍ 0.001).
Significantly more patients in the infliximab
group were also ASAS40 responders over the 24-week
observation period compared with those in the placebo
group (P ⬍ 0.001) (Figure 2B). At week 24, 93 patients
in the infliximab group (47.0%) and 9 patients in the
placebo group (12.0%) were ASAS40 responders (P ⬍
0.001). In addition, at week 24, 97 patients in the
infliximab group (49.0%) achieved 20% improvement in
5 of the 6 ASAS assessment domains compared with 6
patients in the placebo group (8.0%) (P ⬍ 0.001) (Figure
3). Also, at week 24, 45 patients in the infliximab group
(22.4%) achieved ASAS partial remission compared
with 1 patient in the placebo group (1.3%) (P ⬍ 0.001)
(Figure 3).
Measures of disease activity (BASDAI score,
night pain, patient’s global assessment, and CRP level)
and physical function (BASFI score) were significantly
improved in the infliximab group compared with the
placebo group (Table 2). Significantly more patients in
EFFICACY AND SAFETY OF INFLIXIMAB IN AS
587
Figure 3. Proportion of patients at week 24 with 20% improvement in
5 of the 6 ASsessment in Ankylosing Spondylitis (ASAS) Working
Group response domains and proportion of patients at week 24 with
ASAS partial remission (see Patients and Methods for explanations of
ASAS Working Group criteria). ⴱ ⫽ P ⬍ 0.001 versus placebo group.
the infliximab group had at least a 50% improvement in
BASDAI score from baseline to week 24 compared with
those in the placebo group (101 patients [51.0%] versus
8 patients [10.7%], respectively). Ninety-four patients
(47.5%) in the infliximab group improved by ⱖ2 in their
BASFI score compared with 10 patients (13.3%) in the
placebo group (P ⬍ 0.001).
Patients treated with infliximab in this trial demonstrated statistically significant improvement in mea-
sures of range of motion compared with those treated
with placebo. The median improvement from baseline in
BASMI scores was 1.0 in the infliximab group and 0.0 in
the placebo group (P ⫽ 0.019) (Table 2). Patients in the
infliximab group had significantly greater improvement
in all components of the BASMI except for lumbar
flexion (Table 2). Improvement in chest expansion was
also significantly greater for patients in the infliximab
group compared with that for patients in the placebo
group (median improvement 16.7% versus 0.0%, respectively; P ⫽ 0.037). Although no significant change was
observed in the Mander enthesis index scores (P ⫽
0.800) (Table 2), there was a significant improvement
from baseline at week 24 in the enthesitis component of
the BASDAI for patients in the infliximab group (median improvement of 2.9 compared with a median
worsening of 0.2 in the placebo group; P ⬍ 0.001), as
well as a significant improvement in their median swollen joint index score (P ⫽ 0.019) (Table 2).
At week 24, patients in the infliximab group
showed a significant improvement from baseline in the
physical component summary score of the SF-36 compared with patients in the placebo group (median
change from baseline 10.2 versus 0.8, respectively; P ⬍
0.001). No significant treatment effect was observed for
the mental component summary score of the SF-36 (2.7
versus 2.0, respectively; P ⫽ 0.547); however, the patients participating in this trial had approximately normal mental component summary scores at baseline.
Table 2. Summary of median change or median percent change from baseline to week 24 in major
clinical outcomes*
Placebo
BASDAI score, 0–10
BASFI score, 0–10
BASMI score, 0–10
Tragus-to-wall
Lumbar flexion
Cervical rotation
Lumbar side flexion
Intermalleolar distance
Chest expansion, cm
Mander enthesis index, 0–90
Swollen joint index, 0–44
Night pain, 0–10 VAS
Patient’s global assessment, 0–10 VAS
CRP level, mg/dl
SF-36 summary scores
Physical component
Mental component
⫺0.4 (⫺1.4, 0.7)
0.0 (⫺1.0, 1.0)
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)
6.1 (⫺16.4, 30.0)
0.0 (⫺31.7, 25.0)
0.8 (⫺1.9, 6.0)
2.0 (⫺2.6, 7.5)
5 mg/kg infliximab
P
⫺2.9 (⫺4.9, ⫺0.9)
⫺1.7 (⫺3.6, ⫺0.6)
⫺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)
49.2 (11.4, 77.3)
⫺68.7 (⫺85.2, ⫺16.7)
⬍0.001
⬍0.001
0.019
0.013
0.749
⬍0.001
0.011
0.045
0.037
0.800
0.019
⬍0.001
⬍0.001
⬍0.001
10.2 (3.9, 17.1)
2.7 (⫺2.9, 8.8)
⬍0.001
0.547
* Values are the median (interquartile range) change from baseline except for chest expansion, patient’s
global assessment, and CRP level, which are the median (interquartile range) percent change from
baseline. See Table 1 for definitions.
588
VAN DER HEIJDE ET AL
Table 3. Incidence of adverse events through week 24*
Patients with any adverse event
Patients with any serious adverse event
Patients with any infusion reaction
Patients with any infection
Patients with any serious infection
Adverse events occurring in ⱖ5% of
patients in either treatment group
Upper respiratory tract infection
Pharyngitis
ALT level increased
Headache
Rhinitis
Diarrhea
Pain
AST level increased
Fatigue
Pruritus
Nausea
Arthritis
Rash
Placebo
(n ⫽ 75)
5 mg/kg
infliximab
(n ⫽ 202)
54 (72.0)
2 (2.7)
7 (9.3)
27 (36.0)
0 (0.0)
166 (82.2)
7 (3.5)
22 (10.9)
86 (42.6)
2 (1.0)
11 (14.7)
2 (2.7)
3 (4.0)
6 (8.0)
2 (2.7)
4 (5.3)
4 (5.3)
2 (2.7)
3 (4.0)
5 (6.7)
8 (10.7)
4 (5.3)
4 (5.3)
28 (13.9)
21 (10.4)
19 (9.4)
18 (8.9)
15 (7.4)
11 (5.4)
11 (5.4)
11 (5.4)
10 (5.0)
8 (4.0)
7 (3.5)
6 (3.0)
5 (2.5)
* Values are the number (%) of patients. ALT ⫽ alanine aminotransferase; AST ⫽ aspartate aminotransferase.
Safety. A higher proportion of patients receiving
infliximab (82.2%) experienced ⱖ1 adverse events compared with patients receiving placebo (72.0%) (Table 3).
Most adverse events in both treatment groups were mild
or moderate in severity. Forty-three percent of patients
receiving infliximab reported ⱖ1 infections compared
with 36.0% of patients receiving placebo. Eleven percent
of patients receiving infliximab reported an infusion
reaction compared with 9.3% of patients receiving placebo, and the proportion of infusions associated with
infusion reactions was low and identical between the
treatment groups (2.7%).
Seven patients (3.5%) who received infliximab
reported serious adverse events, including dizziness (1
patient); cholecystitis (1 patient); arthritis (1 patient);
leukocytosis and pneumonia (1 patient); inguinal hernia
(1 patient); hemiparesis (1 patient); and abdominal pain,
back pain, fever, and ganglioneuroma (1 patient). None
of the serious adverse events reported by patients in the
infliximab group led to discontinuation of study infusions. However, 2 patients in the infliximab group discontinued study infusions due to nonserious adverse
events, including chills (1 patient) and otitis (1 patient).
Two patients in the placebo group (2.7%) reported
serious adverse events, including pain and arthralgia (1
patient) and myelitis (1 patient). The myelitis event led
to the only adverse event–related withdrawal from the
study in the placebo group. No deaths, malignancies, or
tuberculosis events were reported in this trial.
Adverse events that were reported in at least 5%
of patients in either group occurred at comparable or
lower rates in the infliximab group compared with the
placebo group except for pharyngitis, rhinitis, and increased liver enzymes (Table 3). Nausea was reported by
3.5% of infliximab-treated patients and by 10.7% of
patients receiving placebo. Increases in levels of alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) were reported in 19 (9.4%) and 11 (5.4%) of
the infliximab-treated patients, respectively, and in 3
(4.0%) and 2 (2.7%) of the patients receiving placebo,
respectively. Twelve infliximab-treated patients (5.9%)
had postbaseline ALT or AST values that were ⱖ2 times
higher than the baseline value and ⱖ3 times higher than
the upper limit of the normal range. These criteria were
not met by patients in the placebo group. None of the
infliximab-treated patients with increased ALT or AST
values had their treatment discontinued or had their
enzyme increases reported as serious adverse events.
None of the patients in this study developed symptoms
of clinical hepatitis. As of week 24, 4 of the 12 patients
had liver enzyme levels that had returned to normal or
were decreasing.
The majority of patients in the infliximab group
(93%) had an inconclusive result for antibodies to
infliximab at week 24 due to detectable serum concentrations of infliximab, a phenomenon that has been
previously described (see refs. 45 and 46). However, 6
patients in the infliximab group (3%) had antibodies to
infliximab at week 24 with titers of 1:640 or less.
Of the 172 patients in the infliximab group and
the 65 patients in the placebo group who were negative
for antinuclear antibodies at baseline, 70 infliximabtreated patients (40.7%) were found to be positive with
a titer of 1:40 or more at week 24 compared with 6
patients (9.2%) in the placebo group. Twenty-four of
189 patients (12.7%) in the infliximab group who were
negative for antibodies to dsDNA at baseline were
found to be positive at week 24 compared with 0 of 70
patients (0%), respectively, in the placebo group. Using
a titer of 1:320 as the measure of positivity, 16 of 186
patients (8.6%) who were negative for antinuclear antibodies at baseline were found to be positive at week 24
compared with 0 of 69 patients (0%), respectively, in the
placebo group.
DISCUSSION
The results of this study indicate that patients
receiving infliximab showed substantial improvement in
EFFICACY AND SAFETY OF INFLIXIMAB IN AS
multiple measures of disease activity, physical function,
and quality of life. In addition to meeting the primary
end point of the study (an ASAS20 response), nearly
half of the patients in the infliximab group met the more
rigorous ASAS40 response criteria as well as the ASAS
5 of 6 response criteria, which have recently been shown
to be better-performing outcome measures for trials of
anti-TNF␣ therapy in patients with AS (37). In addition,
the proportion of patients in the infliximab group showing at least 50% improvement in BASDAI score at week
24 (51%) was similar to that observed by Braun et al (22)
at week 12 (53%). Finally, patients receiving infliximab
showed significant improvement in quality of life, as
assessed by the physical component summary score of
the SF-36. Although no significant improvement was
observed in the mental component summary score of the
SF-36, none was expected because patients participating
in this trial had nearly normal mental component summary scores at baseline.
The treatment groups were generally well
matched with regard to baseline characteristics. Although patients in the placebo group had longer median
disease duration at baseline (13.2 years) than those in
the infliximab group (7.7 years), the mean disease
durations were similar (11.9 years and 10.1 years, respectively). In general, patients in this trial had shorter
disease durations than those in the previous randomized
controlled trial of infliximab (⬃15 years) (22), even
though the ages of the respective patient populations
were similar (age ⬃40 years). Shorter disease duration
has recently been shown to be a strong predictor of
clinical response to anti-TNF␣ therapy in patients with
AS, presumably because irreversible structural damage
occurs as the disease progresses (47). These results
suggest that earlier treatment with anti-TNF␣ therapy
may provide a better overall prognosis for patients with
AS, and the substantial response exhibited by infliximabtreated patients with relatively short disease duration
who participated in the present study provides additional support for early treatment. However, additional
studies must be conducted in patients who are recently
diagnosed as having AS in order to determine the
appropriate time to initiate anti-TNF␣ therapy.
Infliximab-treated patients showed significant
improvement in range of motion in this study and in
the previous randomized controlled study (22). In addition to the total BASMI score and chest expansion,
patients in the infliximab group showed significant improvements in all components of the BASMI except for
lumbar flexion. However, improvements were seen in
lumbar side flexion, which may be more responsive to
589
change. Lumbar side flexion has been included as one of
the ASAS 5 of 6 response criteria because it had the
highest standardized response mean among all 5 BASMI
items (37).
Patients receiving infliximab showed significant
improvement in assessments of disease activity, physical
function, range of motion, and quality of life. However,
the results with regard to enthesitis were not consistent.
According to the enthesis question on the BASDAI,
significant improvement in enthesis pain was observed
for patients in the infliximab group. However, no significant difference between the treatment groups was observed in the Mander enthesis index scores. The Mander
enthesis index is not widely used in clinical trials or
routine clinical practice, and the feasibility of assessment
and accuracy of this index have recently been called into
question (48). It is possible that the baseline enthesis
index scores for this study population were low, thus
making it difficult for an instrument with inherent
variability to detect a change. Braun et al (22) reported
a significant improvement in the number of enthesitic
regions of infliximab-treated patients compared with
those receiving placebo. Furthermore, a significant improvement was observed in the number of infliximabtreated patients with psoriatic arthritis who had enthesopathies in the Infliximab Multinational Psoriatic
Arthritis Controlled Trial (49). Clearly, the effect of
infliximab on enthesitis in patients with AS requires
further study using a validated assessment tool that is
less cumbersome and easier to use at the bedside.
Infliximab was generally well tolerated by patients with AS who participated in this study. Twelve
patients receiving infliximab had elevations in transaminase levels; however, none of these patients showed
symptoms of hepatitis or discontinued treatment due to
the elevations. Although elevations in transaminase levels have been reported in patients with rheumatoid
arthritis after receiving infliximab (50), the clinical implications of these elevations require further exploration
in patients with AS. No patients in this study discontinued infliximab due to serious adverse events, and only 2
patients discontinued due to nonserious adverse events
(chills and otitis). The proportion of infliximab-treated
patients who were found to be newly positive for antinuclear antibodies (40.7%) was lower than the rate
reported in the product labeling (51%) (50). The incidence of infusion reactions was equivalent between the
infliximab and placebo groups, even though patients
were not receiving concomitant methotrexate. The overall adverse event profile was comparable with that
reported previously for patients with rheumatoid arthri-
590
VAN DER HEIJDE ET AL
tis (45,51,52), and no unexpected adverse events were
observed.
In conclusion, patients receiving infliximab as
monotherapy exhibited significant improvement in the
signs and symptoms of AS, physical function, and quality
of life. Additional studies must be conducted to determine the impact of infliximab treatment on early disease,
the sustainability of the treatment effect, and the safety
of infliximab therapy in patients with AS over the long
term.
ACKNOWLEDGMENTS
The authors wish to acknowledge Scott Newcomer,
MS, for his assistance in the preparation of the manuscript. We
thank the following investigators who, in addition to the
authors of this article, participated in the ASSERT trial: M.
Breban (Paris, France); G. Burmester (Berlin, Germany); M.
Clark (Chicago, IL); A. Deadhar (Portland, OR); M. Dougados (Paris, France); W. Edwards (Charleston, SC); P. Emery
(Leeds, UK); J. Gaston (Cambridge, UK); R. Inman (Toronto,
Ontario, Canada); H. Kellner (Munich, Germany); M.
Leirisalo-Repo (Helsinki, Finland); W. Maksymowych (Edmonton, Alberta, Canada); L. Moreland (Birmingham, AL); P.
Peloso (Iowa City, IA); J. Reveille (Houston, TX); C. Ritchlin
(Rochester, NY); M. Schneider (Dusseldorf, Germany); D.
Smith (Indianapolis, IN); S. Steinfeld (Brussels, Belgium); E.
Veys (Ghent, Belgium); K. de Vlam (Leuven, Belgium); H.
Zeidler (Hanover, Germany).
12.
13.
14.
15.
16.
17.
18.
19.
20.
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