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Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis.

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ARTHRITIS & RHEUMATISM
Vol. 58, No. 10, October 2008, pp 3063–3070
DOI 10.1002/art.23901
© 2008, American College of Rheumatology
Radiographic Findings Following Two Years of Infliximab
Therapy in Patients With Ankylosing Spondylitis
Désirée van der Heijde,1 Robert Landewé,2 Xenofon Baraliakos,3 Harry Houben,4
Astrid van Tubergen,2 Paul Williamson,5 Weichun Xu,5 Daniel Baker,5 Neil Goldstein,6
Jürgen Braun,3 and the Ankylosing Spondylitis Study for the Evaluation of Recombinant
Infliximab Therapy Study Group
Objective. To evaluate the effect of infliximab on
progression of structural damage over 2 years in patients with ankylosing spondylitis (AS).
Methods. In the Ankylosing Spondylitis Study for
the Evaluation of Recombinant Infliximab Therapy
(ASSERT), a randomized, double-blind, placebo-
controlled trial of the efficacy of infliximab compared
with placebo, 279 patients with active AS received either
placebo through week 24 and then infliximab 5 mg/kg
from week 24 through week 96 (n ⴝ 78) or infliximab 5
mg/kg from baseline through week 96, administered
every 6 weeks after a loading dose (n ⴝ 201; these
patients were the focus of the radiographic analyses).
Radiographic findings in patients from the ASSERT
trial were indistinguishable from those in a historical
control cohort of patients who had no prior use of
anti–tumor necrosis factor agents (from the Outcome in
Ankylosing Spondylitis International Study [OASIS]
database; n ⴝ 192). Radiographic progression of structural damage from baseline to the 2-year followup was
scored using the modified Stoke Ankylosing Spondylitis
Spine Score (mSASSS). All images were scored in one
batch.
Results. Median changes in the mSASSS from
baseline to year 2 were 0.0 for both the OASIS and the
ASSERT cohorts (P ⴝ 0.541). Mean changes in the
mSASSS were also similar between the OASIS and
ASSERT cohorts (mean ⴞ SD change over 2 years 1.0 ⴞ
3.2 and 0.9 ⴞ 2.6, respectively). In addition, results from
sensitivity analyses did not show a statistically significant difference in the mSASSS between the OASIS and
ASSERT cohorts.
Conclusion. AS patients who received infliximab
from baseline through week 96 did not show a statistically significant difference in inhibition of structural
damage progression at year 2, as assessed using the
mSASSS scoring system, when compared with radiographic data from the historical control OASIS cohort.
Improvements in clinical outcomes and spinal inflammation have been previously demonstrated with the use
of infliximab therapy.
Supported by Centocor, Inc. (Malvern, Pennsylvania) and
Schering-Plough Corporation (Kenilworth, New Jersey). Centocor
Ortho Biotech Services, LLC, paid AMTEC Maastricht BV (clinical
trial center owned by the University Hospital Maastricht) for the use
of the Outcome in Ankylosing Spondylitis International Study database in the present analysis.
1
Désirée van der Heijde, MD, PhD: Leiden University Medical Center, Leiden, The Netherlands; 2Robert Landewé, MD, PhD,
Astrid van Tubergen, MD, PhD: University Hospital Maastricht,
Maastricht, The Netherlands; 3Xenofon Baraliakos, MD, Jürgen
Braun, MD: Rheumazentrum Ruhrgebiet, and Ruhr University,
Herne, Germany; 4Harry Houben, MD, PhD: Atrium Medical Center,
Herleen, The Netherlands; 5Paul Williamson, MD, Weichun Xu, PhD,
Daniel Baker, MD: Centocor Research and Development, Inc.,
Malvern, Pennsylvania; 6Neil Goldstein, MD: Precision Research,
Malvern, Pennsylvania.
Dr. van der Heijde has received consulting fees, speaking fees,
and/or honoraria from Abbott Laboratories, Amgen, Aventis, BristolMyers Squibb, Centocor, Pfizer, Roche, Schering-Plough, UCB,
Wyeth, and Chugai (less than $10,000 each), and research grants from
Centocor and Wyeth. Dr. Landewé has received consulting fees,
speaking fees, and/or honoraria from Abbott, Amgen, Bristol-Myers
Squibb, Centocor, Schering-Plough, UCB, and Wyeth (less than
$10,000 each), and research grants from Abbott, Centocor, ScheringPlough, and Wyeth. Dr. Houben has received consulting fees from
Centocor (less than $10,000). Drs. Williamson, Xu, and Baker own
stock in Johnson and Johnson, of which Centocor is a subsidiary. Dr.
Goldstein has received consulting fees from Centocor (more than
$10,000). Dr. Braun has received consulting fees, speaking fees, and/or
honoraria from Abbott, Centocor, Schering-Plough, and Wyeth (less
than $10,000 each), and research grants from Centocor, ScheringPlough, and Abbott.
Address correspondence and reprint requests to Désirée van
der Heijde, MD, PhD, Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
E-mail: d.vanderheijde@kpnplanet.nl.
Submitted for publication February 20, 2008; accepted in
revised form June 20, 2008.
3063
3064
Ankylosing spondylitis (AS) is a chronic, progressive inflammatory disease characterized by inflammatory back pain, due to sacroiliitis, spondylitis, and enthesitis, that affects young men and women, commonly
starting in the second and third decades of life (1).
Traditional therapies for AS, including nonsteroidal
antiinflammatory drugs (NSAIDs), disease-modifying
antirheumatic drugs, and physical therapy, have limited
efficacy (2,3). In contrast, the anti–tumor necrosis factor
(anti-TNF) agents infliximab (3,4), etanercept (5,6), and
adalimumab (7) have shown strong clinical efficacy in
short- and intermediate-term evaluations.
Recently, the effects of infliximab were evaluated
in 279 patients with AS in the Ankylosing Spondylitis
Study for the Evaluation of Recombinant Infliximab
Therapy (ASSERT), a multicenter, randomized, doubleblind, placebo-controlled trial of the efficacy of infliximab (Remicade) compared with placebo in patients
with AS receiving standard antiinflammatory drug therapy. At week 24 of treatment with 5 mg/kg infliximab,
administered once every 6 weeks, infliximab was found
to be well tolerated and significantly more effective than
placebo in improving the signs and symptoms of disease
(4). In a substudy of 266 patients with AS, images of the
spine obtained by magnetic resonance imaging (MRI) at
baseline and at week 24 were evaluable, and patients
who received infliximab showed a significant decrease in
spinal inflammation as detected by MRI, compared with
patients receiving placebo (8). This reduction was still
present at the 2-year followup (9).
Whereas MRI evaluations are useful in assessing
active spinal lesions, chronic spinal changes in AS are
mainly assessed by conventional radiography (10). The
modified Stoke Ankylosing Spondylitis Spine Score
(mSASSS) has been identified as the most sensitive
scoring method when evaluating chronic spinal changes
on conventional radiographs (10,11). In AS, spinal radiographic progression develops relatively slowly and
may be detectable only after a minimum of 2 years in a
considerable number of patients. Thus, it is ethically
difficult to justify a radiographic study in AS that
prospectively incorporates a control arm for 2 years, if
patients in the active treatment arm already show major
clinical improvement shortly after the TNF blocker has
been initiated (12).
As a result, the radiographic data obtained from
the ASSERT trial were compared with the radiographic
data obtained in a prospective followup study, the
Outcome in Ankylosing Spondylitis International Study
(OASIS), with the provision that the radiographs were
scored in one batch and in a blinded manner. Results of
VAN DER HEIJDE ET AL
these comparisons of mSASSS findings are presented
herein.
PATIENTS AND METHODS
ASSERT study. Criteria for inclusion and exclusion of
patients in the ASSERT study have been described previously
(4). In this double-blind, placebo-controlled clinical trial, patients were randomly assigned in a 3:8 ratio to 1 of 2 treatment
groups. Patients in 1 group received placebo through week 24
and then infliximab 5 mg/kg from week 24 through week 96
(designated the placebo/infliximab group; n ⫽ 78), and patients in the other group received infliximab 5 mg/kg from
baseline through week 96 (designated the infliximab 5 mg/kg
group; n ⫽ 201). Patients in the latter group had their dose
increased to 7.5 mg/kg starting with the week 36 infusion based
on their disease activity (designated the infliximab 7.5 mg/kg
group). Infusions were administered at weeks 0, 2, and 6 as the
initial loading dose and then every 6 weeks through week 96.
Radiographs of the lateral cervical and lumbar spine were
obtained from patients at baseline and at year 2 or at the time
of withdrawal from the ASSERT trial if a patient was withdrawn from treatment after the week 54 infusion. The 201
patients who were originally assigned to receive infliximab
5 mg/kg were the focus of these radiographic analyses.
OASIS database. The OASIS database is a prospectively defined and prospectively collected data set that contains
information on ⬃200 patients with AS, who received the best
standard of care available at the time of their visits to multiple
international centers. None of the OASIS patients were
treated with anti-TNF therapy during the first 4 years of data
collection. Information collected included, among other variables, radiographic images of the lateral cervical and lumbar
spine, demographic data, and indices of pain and spinal
mobility. Radiographic data obtained from OASIS patients at
baseline and after 2 years of followup are included in the
present analysis. All patients included in the OASIS cohort
who had complete radiographs but did not have complete
spinal ankylosis (n ⫽ 192) were the primary population used
for comparison in the present study. In addition, a subset of
patients from the OASIS database who would have satisfied
the ASSERT eligibility criteria were identified; these 70 patients were termed the OASIS match population.
Radiographic evaluations. Lateral radiographic views
of the cervical and lumbar spine were scored using the
mSASSS scoring system (10). The total mSASSS (13) is the
sum (range 0–72) of the numerical scores for the anterior site
of the cervical spine from the lower border of C2 to the upper
border of T1, and the anterior site of the lumbar spine from the
lower border of T12 to the upper border of S1. Each corner of
the vertebrae is scored as follows: 0 ⫽ normal; 1 ⫽ presence of
erosions, sclerosis, or squaring; 2 ⫽ presence of syndesmophytes; and 3 ⫽ presence of bridging syndesmophytes.
Investigators at Bio-Imaging Technologies (Newtown,
PA and Leiden, The Netherlands) digitized all radiographs
from the OASIS and ASSERT cohorts; blinding was done to
conceal patient identity as well as the origin and time point of
each radiograph. All radiographs were mixed and transferred
electronically, in one batch, to the 2 readers. The serial
radiographs were grouped per patient, with blinding for time
TWO-YEAR RADIOGRAPHIC OUTCOMES OF INFLIXIMAB IN AS
Table 1.
3065
Baseline characteristics of the ASSERT and OASIS patient populations*
Male
Age, years
Mean ⫾ SD
Median
Disease duration, years
Mean ⫾ SD
Median
HLA–B27 positive§
Concomitant NSAID use
BASDAI (range 0–10)
Mean ⫾ SD score
Median score
BASFI (range 0–10)
Mean ⫾ SD score
Median score
BASMI (range 0–10)
Mean ⫾ SD score
Median score
Uveitis at baseline
Psoriasis at baseline
OASIS cohort‡
ASSERT cohort
(n ⫽ 201)†
Primary (n ⫽ 192)
Match (n ⫽ 70)
157 (78.1)
130 (67.7)
47 (67.1)
39.6 ⫾ 10.6
40.0
44.0 ⫾ 12.5
43.2
44.2 ⫾ 12.5
43.9
10.2 ⫾ 8.7
7.8
173 (86.5)
185 (92.0)
11.3 ⫾ 8.6
9.9
152 (84.0)
145 (75.5)
9.9 ⫾ 8.8
8.0
59 (84.3)
56 (80.0)
6.5 ⫾ 1.5
6.6
3.5 ⫾ 2.1
3.2
5.7 ⫾ 1.3
5.3
5.7 ⫾ 1.9
5.7
3.5 ⫾ 2.6
3.3
4.9 ⫾ 2.3
5.0
4.1 ⫾ 2.1
4.0
72 (35.8)
16 (8.0)
3.0 ⫾ 2.3
3.0
28 (14.6)
9 (4.7)
3.4 ⫾ 2.4
3.0
11 (15.7)
3 (4.3)
* Except where indicated otherwise, values are the number (%) of patients. NSAID ⫽ nonsteroidal
antiinflammatory drug; BASDAI ⫽ Bath Ankylosing Spondylitis Disease Activity Index; BASFI ⫽ Bath
Ankylosing Spondylitis Functional Index; BASMI ⫽ Bath Ankylosing Spondylitis Metrology Index.
† The Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy (ASSERT)
population comprised patients who were originally assigned to infliximab 5 mg/kg.
‡ The Outcome in Ankylosing Spondylitis International Study (OASIS) primary population comprised a
major secondary analysis of the ASSERT trial. The OASIS match population, i.e., the subset of patients
from the OASIS database who would have satisfied the ASSERT eligibility criteria, comprised one of
several sensitivity analyses conducted.
§ Data shown are for 200 patients in the ASSERT population, 181 patients in the OASIS primary
population, and 70 patients in the OASIS match population.
sequence. Two independent readers (XB and HH) and an
adjudicator (AvT) who were unaware of the OASIS radiographic data met to discuss scoring rules, to improve the
consistency in scoring of radiographic changes. The 2 readers
performed the independent assessment of the radiographs for
the entire population (ASSERT and OASIS). The adjudicator
only evaluated the data from patients whose “change score”
differed between the readers by a predefined threshold of at
least 5 units.
The total mSASSS at each time point was calculated.
The difference between the scores at 2 time points (for
example, the 2-year mSASSS minus the baseline mSASSS) was
defined as the change score for that patient. The proportions
of patients exhibiting at least 1-point, 2-point, 3-point, and
4-point increases (worsening) in the mSASSS from baseline to
year 2 were also determined.
Statistical analysis. All requirements for inclusion in
the study populations were prespecified. Change in total
mSASSS from baseline to year 2 was compared between
patients in the OASIS cohort and patients in the ASSERT
cohort who were randomly assigned to the infliximab arm at
baseline, with baseline mSASSS used as a covariate. This end
point of change in mSASSS in the ASSERT cohort was
analyzed using analysis of covariance, with the van der Waerden test to determine normally distributed scores.
To evaluate the consistency of the overall mSASSS
results, the median difference and 95% confidence interval
were determined for subgroups that had been prespecified in
the analysis plan, including those based on demographics (sex,
age), disease characteristics at baseline (HLA–B27 status), and
measures of disease activity at baseline (C-reactive protein
level, Bath Ankylosing Spondylitis Disease Activity Index
[BASDAI] [14], Bath Ankylosing Spondylitis Functional Index
[BASFI] [15], Bath Ankylosing Spondylitis Metrology Index
[16] [scale of 0–10 for each Bath Index], and patient’s global
assessment of disease activity on a 0–100-mm visual analog
scale). In addition, sensitivity analyses were conducted to
evaluate the robustness of the data comparisons between the 2
patient cohorts. In particular, changes from baseline mSASSS
to year 2 mSASSS, using the baseline mSASSS as a covariate,
were assessed using the OASIS match population for comparison with the ASSERT population.
Using the main scores from the 2 readers for the
radiographs from all patients and the reread radiographic data
from 10% of the randomly selected patients, an interreader
intraclass correlation coefficient (ICC) and a read–reread
(intrareader) ICC were estimated for determinations of the
mSASSS at baseline and at year 2. Also, changes in the
mSASSS from baseline to year 2 were compared between
readers.
3066
VAN DER HEIJDE ET AL
Table 2. Comparison of scoring of radiographic structural damage
progression between the ASSERT and OASIS patient populations*
No. of patients in subset
Radiographic mSASSS
(range 0–72)
Baseline
No. evaluated
Mean ⫾ SD score
Median score
Year 2
No. evaluated
Mean ⫾ SD score
Median score
Change in mSASSS‡
No. of patients evaluated
Mean ⫾ SD change score
Median change score
Interquartile range
Range
P vs. ASSERT
OASIS cohort†
ASSERT
cohort
Primary
Match
201
192
70
190
17.7 ⫾ 17.9
10.8
176
15.8 ⫾ 18.1
8.8
65
17.5 ⫾ 19.1
9.7
156
18.1 ⫾ 17.5
11.5
165
16.6 ⫾ 18.4
9.0
61
18.4 ⫾ 19.0
10.1
156
0.9 ⫾ 2.6
0.0
⫺0.5, 1.2
⫺6.6, 12.2
–
165
1.0 ⫾ 3.2
0.0
0.0, 1.3
⫺3.1, 25.7
0.541
61
1.2 ⫾ 3.9
0.0
⫺0.2, 1.5
⫺2.3, 25.7
0.683
tion more closely resembled those of the patients in the
ASSERT population at baseline (Table 1).
Change in mSASSS in overall, subgroup, and
sensitivity analyses. Median changes in the mSASSS
from baseline to year 2 were 0.0 for both the OASIS and
the ASSERT cohorts (P ⫽ 0.541). Mean changes were
also similar between the cohorts (Table 2 and Figure
1A). In addition, the results of all subgroup analyses
showed no statistically significant differences in the
mSASSS between the cohorts (Figure 2).
* mSASSS ⫽ modified Stoke Ankylosing Spondylitis Spine Score (see
Table 1 for other definitions).
† The primary OASIS population comprised a major secondary analysis of the ASSERT trial. The OASIS match population, i.e., the
subset of patients from the OASIS database who would have satisfied
the ASSERT eligibility criteria, comprised one of several sensitivity
analyses conducted.
‡ Change in the mSASSS through year 2 was assessed using baseline
mSASSS as the covariate.
All statistical tests were 2-sided and were performed at
an alpha level of 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
Patient and disease characteristics at baseline.
Characteristics of the patients in the OASIS primary
population were generally similar to those of the patients in the ASSERT population, with the following
exceptions. Higher proportions of patients in ASSERT
than in OASIS were taking NSAIDs (92.0% versus
75.5%), had uveitis (35.8% versus 14.6%), and had
psoriasis (8.0% versus 4.7%) at baseline. Also, patients
in the ASSERT cohort, compared with the OASIS
primary population, appeared to have greater disease
activity and more limited physical function at baseline
(mean BASDAI 6.5 versus 3.5; mean BASFI 5.7 versus
3.5) (Table 1). The mSASSS values at baseline were
similar among the groups (Table 2). As expected, characteristics of the patients in the OASIS match popula-
Figure 1. Cumulative probability plots for the change in total modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) through year
2 among patients with ankylosing spondylitis treated with infliximab
from the Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy (ASSERT) cohort compared with the
Outcome in Ankylosing Spondylitis International Study (OASIS)
primary cohort (A) and the OASIS match cohort (B).
TWO-YEAR RADIOGRAPHIC OUTCOMES OF INFLIXIMAB IN AS
3067
Figure 2. Differences between patient cohorts in the change in total
mSASSS from baseline to year 2 (broken vertical bars) and associated
95% confidence intervals (95% CI) (horizontal bars) for subgroups
defined by baseline demographics (A), disease characteristics (B), and
disease severity (C). VW ⫽ van der Waerden (test for normal scores);
CRP ⫽ C-reactive protein; BASDAI ⫽ Bath Ankylosing Spondylitis
Disease Activity Index; BASFI ⫽ Bath Ankylosing Spondylitis Functional Index; BASMI ⫽ Bath Ankylosing Spondylitis Metrology Index;
VAS ⫽ visual analog scale (of disease activity). See Figure 1 for other
definitions.
The results from all sensitivity analyses performed, including those using the OASIS match population for comparison (Table 2 and Figure 1B) as well as
the analysis of results without the use of adjudication
(n ⫽ 15), confirmed the lack of a significant difference in
the mSASSS between the OASIS and the ASSERT
cohorts. In addition, results of post hoc analyses that
controlled for patient’s age and disease duration showed
that these variables had no effect on the difference in the
mSASSS between the OASIS and ASSERT cohorts
(P ⫽ 0.65).
Increase in mSASSS from baseline. Approximately one-third of patients in both the ASSERT cohort
(34.0%) and the OASIS cohort (35.2%) had at least a
1-point increase (worsening) in the mSASSS from baseline to year 2. The study populations were also similar
with regard to the proportions of patients who had at
least a 2-point increase (19.9% versus 17.6%), 3-point
increase (14.7% versus 10.3%), and 4-point increase
(10.9% versus 7.3%) from baseline. In all cases, the
observed differences between the infliximab and placebo
treatment groups were not significant.
Consistency across readers. We observed a high
correlation of 0.91 between the 2 readings for the week
0 measurement of total mSASSS, a high correlation of
0.92 between the 2 readings for the year 2 measurement
of total mSASSS, and a moderately high correlation of
0.62 for the assessment of change in mSASSS from
baseline. Data analyzed by each reader independently
yielded results that were consistent with the primary
analysis results expressed as the average of the 2 readings.
DISCUSSION
In the present evaluation of radiographic data
from the ASSERT study, in which we used the mSASSS
scoring system to determine changes in structural damage to the spine, patients with AS who received infliximab from week 0 through week 96 did not show a
3068
statistically significant difference in inhibition of structural damage progression at year 2 when compared with
the historical control OASIS cohort. The OASIS population was utilized as a historical control group for the
ASSERT study because radiographic progression in the
spine develops relatively slowly and may be detectable
only after a minimum of 2 years in a substantial number
of patients, and therefore maintaining a placebo control
group for 2 years is not appropriate, particularly in view
of the established efficacy of anti-TNF therapy in improving the signs and symptoms of AS (11). Specifically,
sustained efficacy has been shown after 2 years of
infliximab treatment in 279 patients with active AS, with
more than 70% of patients achieving an Assessment of
SpondyloArthritis (international Society) criteria for
20% improvement response by week 102 (17).
Of particular relevance, the comparison with a
historical control group was made under a special condition, whereby the OASIS radiographs were randomized and merged with the ASSERT radiographs. Subsequently, all radiographs were scored simultaneously
without indication of film origin. In addition, the study
was sufficiently powered (73%) to detect a difference of
0.8 in the mSASSS between 2 groups with sample sizes
of 177 (ASSERT cohort receiving infliximab only) and
176 (OASIS primary cohort) and a standard deviation of
2.9. However, some limitations to these analyses remain,
including the fact that the 2 cohorts of patients were not
randomized as one unit, and that patients in the OASIS
and ASSERT groups differed at baseline in several
clinical disease indices. However, results of the many
subgroup analyses performed did not show inhibition of
radiographic progression in the infliximab-treated patients.
Moreover, the only known predictor of radiographic progression is the presence of structural damage, which was included as a covariate in this analysis.
Although it is known that physical function is determined by both disease activity and structural damage, it
is unknown what effect a small progression in the
mSASSS over a 2-year period could have on long-term
function. Furthermore, TNF blockers impart major direct gains on both disease activity and function.
As an additional limitation, the mSASSS method
of scoring radiographic images assesses the anterior sites
of the lumbar and cervical spine (10). Thus, only part of
the structural damage that may occur in a patient with
AS is being evaluated, with exclusion of the posterior
sites of the vertebrae, the facet joints, and the thoracic
spine. Nevertheless, the validated mSASSS is the preferred method and accepted standard for scoring radio-
VAN DER HEIJDE ET AL
graphic progression in AS (10,18). Because this was
applied to both the active treatment and control groups,
it is unlikely that our results were affected by the lack of
assessment of other potential sites of progression.
With regard to reader agreement, we observed
high correlations (0.91 and 0.92, respectively) between
the 2 readings for both the week 0 and year 2 total
mSASSS, and a moderate correlation (0.62) between the
2 readings for the change in total mSASSS from baseline. The relatively lower ICC of change scores is well
known and is inherent in the use of the ICC statistic,
which is not always the most appropriate statistic if only
small change scores in a minority of patients are observed. These findings were consistent with the reader
agreement previously observed in studies using MRIbased scoring methods in AS patients (19). Moreover,
the analysis of the data by each reader separately
revealed the same results as when results were analyzed
as the average score from the 2 readers.
Results from our analysis were consistent with
those from a previous study of infliximab in AS that
showed limited inhibition of radiographic progression,
as assessed by the mSASSS scoring system, after 2 years
of therapy (1). In that previous study, the mean ⫾ SD
change in the mSASSS from baseline to year 2 was 0.4 ⫾
2.7 among 41 patients who received infliximab 5 mg/kg
every 6 weeks, compared with 0.7 ⫾ 2.8 in the 41
patients who received no controlled intervention (P not
significant). It should be noted that in both the previous
study and the present analysis, patients’ radiographs
were blinded for time sequence in the process of
mSASSS scoring, a reading method that has been associated with documentation of significantly less progression, i.e., less reader bias, than when readers are aware
of the chronology of the radiographs (20). However, the
origin of the treatment group (and therefore the treatment) was known to the reader.
In a third study that assessed the effect of infliximab on structural changes in AS over 4 years, using the
mSASSS scoring method, there was less radiographic
progression in the infliximab-treated patients (change in
mSASSS within 4 years 1.6) as compared with published
data from the OASIS cohort (change in mSASSS within
4 years 4.4) (21). However, in that study, mSASSS values
for the control group were derived from published
OASIS data and were scored chronologically, and the
cohorts were each scored by a different reader. Moreover, both readers were aware of the patients’ treatment.
Taken together, these factors limit the usefulness of the
results of these preliminary data derived in the context
TWO-YEAR RADIOGRAPHIC OUTCOMES OF INFLIXIMAB IN AS
of a less rigorous study design without a direct comparator.
In a study utilizing MRI assessments to monitor
disease progression, treatment with infliximab was
shown to result in improvement in spinal inflammation
in patients with AS (22). Similarly, treatment with the
anti-TNF agent etanercept was found, by MRI, to lead
to improvement in spinal inflammation in patients with
AS; however, inhibition of radiographic progression was
not detected following treatment with etancercept in
these patients (23–25). Moreover, the disease progression observed in both the etanercept treatment group
and the OASIS control group in that trial was consistent
and numerically similar to the progression that we
observed in patients treated with infliximab in this study,
validating the comparison between the ASSERT (infliximab only) and OASIS populations (24).
The pathologic characteristics of AS may explain
why anti-TNF therapy does not appear to have a major
effect on radiographic progression. The hallmark of AS
is bone formation rather than bone resorption, leading
to the fusion of joints and intervertebral spaces and to
the development of bridging syndesmophytes (26). In
predominantly destructive diseases like rheumatoid arthritis, the proinflammatory effects of TNF coincide
with osteoclast activation and subsequent bone erosion,
and there is a clear longitudinal relationship between
clinical disease activity and subsequent radiographic
damage (27,28). In contrast, data from the OASIS
cohort have demonstrated no relationship between radiographic progression and clinical disease activity parameters in AS (26). Thus, although anti-TNF therapy
plays an important role in treating AS by significantly
improving the clinical symptoms, effective targets for
inhibiting structural remodeling in AS still need to be
developed.
AUTHOR CONTRIBUTIONS
Dr. van der Heijde 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. Van der Heijde, Landewé, Williamson, Baker, Braun.
Acquisition of data. Van der Heijde, Landewé, Baraliakos, Houben,
van Tubergen, Baker, Braun.
Analysis and interpretation of data. Van der Heijde, Landewé,
Houben, Williamson, Baker, Goldstein, Braun, Michelle Perate, MS
(nonauthor; Centocor, Inc.), Mary Whitman, PhD (nonauthor; Centocor, Inc.).
Manuscript preparation. Van der Heijde, Landewé, Houben, van
Tubergen, Williamson, Baker, Goldstein, Braun.
Statistical analysis. Xu.
3069
ROLE OF THE STUDY SPONSOR
Centocor and Schering-Plough funded this study. The
ASSERT study group supervised the study and assisted with study
design. Data were collected by the investigators and entered into a
Centocor database. Centocor statisticians and programmers conducted
the analyses, and the authors, assisted by a medical writer, prepared
this manuscript. All authors reviewed and approved the manuscript
content before submission and jointly agreed to submit the final
version of the manuscript.
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