Clinical and imaging efficacy of infliximab in HLA-B27-Positive patients with magnetic resonance imaging-determined early sacroiliitis.
ABSTRACT To evaluate the efficacy of infliximab in HLA-B27-positive patients with magnetic resonance imaging (MRI)-determined early sacroiliitis, using both clinical and MRI assessments.
Forty patients with recent-onset inflammatory back pain, as assessed by the Calin criteria, HLA-B27 positivity, clinical disease activity as measured by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), pain and morning stiffness, and magnetic resonance imaging (MRI)-determined sacroiliac joint bone edema were randomized in a double-blind manner to receive infliximab 5 mg/kg or placebo at 0, 2, 6, and 12 weeks. MRI scans were performed at baseline and 16 weeks and scored by 2 observers (blinded to both the order of the scans and to treatment group), using the Leeds scoring system. Clinical assessments included the BASDAI, the Bath Ankylosing Spondylitis Functional Index (BASFI), the Ankylosing Spondylitis Quality of Life (ASQoL) instrument, the ASsessment in Ankylosing Spondylitis International Working Group criteria (ASAS) for improvement, and markers of inflammation.
The mean reduction in the total MRI score from week 0 to week 16 was significantly greater in infliximab-treated patients compared with placebo-treated patients (P = 0.033). On average, significantly more lesions resolved in the infliximab group (P < 0.001), while significantly more new lesions developed in the placebo group (P = 0.004). Significantly greater improvement in the infliximab group versus the placebo group was also observed for changes from week 0 to week 16 in the BASDAI (P = 0.002), BASFI (P = 0.004), and ASQoL (P = 0.007) scores. Responses according to the ASAS criteria for 40% improvement, the ASAS criteria for 20% improvement in 5 of 6 domains, and ASAS partial remission were achieved by 61%, 44%, and 56% of infliximab-treated patients, respectively. Infliximab was well tolerated, and no serious adverse events were observed.
Infliximab was an effective therapy for early sacroiliitis, providing a reduction in disease activity by week 16. This study is the first to show that infliximab is effective for reducing clinical and imaging evidence of disease activity in patients with MRI-determined early axial spondylarthritis.
- SourceAvailable from: Jean-François ChenotZeitschrift für Rheumatologie 09/2014; 73 Suppl 2:78-96. · 0.46 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Ankylosing spondylitis (AS) is a chronic inflammatory disease with prominent involvement of the spine and sacroiliac joints which frequently leads to significant spine deformity and disability. The development of effective therapies for AS, particularly with anti-tumor necrosis factor agents, has resulted in improved symptoms and functions for many patients, and clinical research increasingly suggests that effective therapy can also prevent destruction in the spine and other structures. Recent focus of disease classification in AS has emphasized that many individuals with features of inflammatory back pain but no visible changes on plain x-rays have active inflammatory disease when imaged with magnetic resonance imaging (MRI). Recent studies indicate that individuals with "non-radiographic" spondylitis can also respond to anti-inflammatory therapies. Several new agents are also showing promise for treatment of AS. These developments represent a significant advance in the management of this debilitating condition.F1000prime reports. 09/2014; 6:78.
- Arthritis & Rheumatology 08/2013; 65(8). · 7.48 Impact Factor
ARTHRITIS & RHEUMATISM
Vol. 60, No. 4, April 2009, pp 946–954
© 2009, American College of Rheumatology
Clinical and Imaging Efficacy of Infliximab in
HLA–B27–Positive Patients With Magnetic
Resonance Imaging–Determined Early Sacroiliitis
Nick Barkham, Helen I. Keen, Laura C. Coates, Philip O’Connor, Elizabeth Hensor,
Alexander D. Fraser, Lorna S. Cawkwell, Alexander Bennett,
Dennis McGonagle, and Paul Emery
Objective. To evaluate the efficacy of infliximab in
HLA–B27–positive patients with magnetic resonance
imaging (MRI)–determined early sacroiliitis, using
both clinical and MRI assessments.
Methods. Forty patients with recent-onset inflam-
matory back pain, as assessed by the Calin criteria,
HLA–B27 positivity, clinical disease activity as mea-
sured by the Bath Ankylosing Spondylitis Disease Ac-
tivity Index (BASDAI), pain and morning stiffness, and
magnetic resonance imaging (MRI)–determined sacro-
iliac joint bone edema were randomized in a double-
blind manner to receive infliximab 5 mg/kg or placebo
at 0, 2, 6, and 12 weeks. MRI scans were performed at
baseline and 16 weeks and scored by 2 observers
(blinded to both the order of the scans and to treatment
group), using the Leeds scoring system. Clinical assess-
ments included the BASDAI, the Bath Ankylosing
Spondylitis Functional Index (BASFI), the Ankylosing
Spondylitis Quality of Life (ASQoL) instrument, the
ASsessment in Ankylosing Spondylitis International
Working Group criteria (ASAS) for improvement, and
markers of inflammation.
Results. The mean reduction in the total MRI
score from week 0 to week 16 was significantly greater in
infliximab-treated patients compared with placebo-
treated patients (P ? 0.033). On average, significantly
more lesions resolved in the infliximab group (P <
0.001), while significantly more new lesions developed in
the placebo group (P ? 0.004). Significantly greater
improvement in the infliximab group versus the placebo
group was also observed for changes from week 0 to
week 16 in the BASDAI (P ? 0.002), BASFI (P ? 0.004),
and ASQoL (P ? 0.007) scores. Responses according to
the ASAS criteria for 40% improvement, the ASAS
criteria for 20% improvement in 5 of 6 domains, and
ASAS partial remission were achieved by 61%, 44%, and
56% of infliximab-treated patients, respectively. Inflix-
imab was well tolerated, and no serious adverse events
Conclusion. Infliximab was an effective therapy
for early sacroiliitis, providing a reduction in disease
activity by week 16. This study is the first to show that
infliximab is effective for reducing clinical and imaging
evidence of disease activity in patients with MRI-
determined early axial spondylarthritis.
Ankylosing spondylitis (AS), the prototype spon-
dylarthritis (SpA), is increasingly recognized as an im-
portant and potentially treatable condition. AS is more
common than previously estimated, with some studies
suggesting a prevalence similar to that of rheumatoid
European Clinical Trials (EudraCT) Database: 2004-001880-
23, DDX No MS8000MN/13157.
Supported by Centocor, which also provided the study drug.
Nick Barkham, MBChB, MRCP, Helen I. Keen, MBBS,
FRACP, Laura C. Coates, MBChB, Philip O’Connor, FRCR, Eliza-
beth Hensor, PhD, Alexander D. Fraser, MD, FRCPI, Lorna S.
Cawkwell, MRCP, Alexander Bennett, MBChB, MRCP, Dennis
McGonagle, PhD, MRCPI, Paul Emery, MA, MD, FRCP: University
of Leeds, Leeds, UK.
Dr. Barkham has received speaking fees and a travel grant
(less than $10,000 each) from Centocor; the University of Leeds unit
within which he works has received research funding from Centocor.
Dr. Keen has received a travel grant from Schering-Plough (less than
$10,000). Dr. Coates has received consulting fees, speaking fees,
and/or honoraria from Schering-Plough (less than $10,000). Dr. Emery
has received consulting fees, speaking fees, and/or honoraria from
Schering-Plough, Centocor, Wyeth/Amgen, Abbott, Roche, and
Bristol-Myers Squibb (less than $10,000 each).
Address correspondence and reprint requests to Paul Emery,
MA, MD, FRCP, Academic Unit of Musculoskeletal Disease, Chapel
Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK. E-mail:
Submitted for publication May 13, 2008; accepted in revised
form December 30, 2008.
arthritis (1). Importantly, AS affects individuals at a time
when they are economically active (most commonly in
the third decade of life), and the disease has a major
impact on their ability to work (2).
Anecdotal evidence has suggested that patients
who are treated early, i.e., before radiographic changes
are apparent, have a better outcome (3). However, the
current diagnosis of AS according to the modified New
York criteria (4) relies on radiographically detectable
damage. Therefore, the definitive diagnosis of AS is
often delayed by up to a decade, because this is the
length of time that may be required for structural
changes to develop (5).
The limitations of radiography have been par-
tially addressed by the advent of fat-suppressed mag-
netic resonance imaging (MRI), which can be used to
diagnose axial SpA at a stage when radiographic findings
remain normal (6). Histologic studies have confirmed
that these early MRI changes are caused by osteitis at
the sacroiliac joints (7,8) and typically evolve into radio-
graphic AS over several years (9).
One of the great challenges in caring for patients
with AS is early and accurate diagnosis. The Calin
criteria for diagnosis of early inflammatory back pain
(10) lack sensitivity and specificity (11,12). A recently
proposed modification of the clinical criteria (13) has
been shown to have much greater sensitivity and speci-
ficity but has not been tested in early disease. In
addition, the serum level of markers of inflammation are
not consistently elevated in these patients and thus are
not reliable surrogate markers for diagnosis (14,15).
Based on the strong association between HLA–
B27 positivity and AS, testing patients with early inflam-
matory back symptoms for HLA–B27 is useful for early
diagnosis as well as for predicting persistent disease that
may be associated with ocular and cardiac manifesta-
tions (16). Indeed, the combination of the Calin criteria
for inflammatory back pain, HLA–B27 positivity, and
MRI-defined early sacroiliitis identifies a group of pa-
tients who could experience progression to AS in ?90%
of cases (17).
The advent of anti–tumor necrosis factor (anti-
TNF) antibodies in the field of rheumatology has pro-
vided new therapeutic options for patients with AS. The
efficacy of anti-TNF therapies in AS has been confirmed
in numerous trials (18–21). However, until now, there
has been no evidence to justify treatment of MRI-
determined early axial SpA with anti-TNF agents, be-
cause all of the randomized controlled trials conducted
to date (18–21) have used diagnosis according to the
definite modified New York criteria (4) for inclusion. In
the present study, we combined the Calin criteria for
inflammatory back pain, HLA–B27 positivity, and MRI-
defined early sacroiliitis to identify a homogeneous
cohort of patients with early axial SpA in whom disease
would likely progress to AS and randomized these
patients to receive infliximab therapy or placebo, in
order to ascertain the effectiveness of anti-TNF therapy
in patients with preradiographic axial SpA.
PATIENTS AND METHODS
The trial was conducted at the Leeds Teaching Hospi-
tals Trust, Leeds, UK. The local ethics committee approved
the study, and written informed consent was obtained from all
patients prior to screening.
Inclusion and exclusion criteria. Eligible patients had
a combination of inflammatory back pain, according to the
Calin criteria (10), for the previous 3 months to 3 years (Table
1), were positive for HLA–B27, and had MRI evidence of
sacroiliitis. All eligible patients had active disease, as defined
by at least 2 of the following: a Bath Ankylosing Spondylitis
Disease Activity Index (BASDAI) score of ?40, a pain score of
?40 on a 100-mm visual analog scale, and early morning
stiffness lasting ?45 minutes. From studies of infliximab
treatment in established AS with MRI outcome (22), we
calculated that at the 5% significance level with 80% power
detecting a 50% difference between the placebo and treatment
groups in the mean changes from baseline to the end point, 20
patients were required in each group.
To identify 40 patients with MRI-determined sacroiliac
joint bone edema, 49 patients with symptoms and HLA–B27
positivity were screened and underwent MRI. The MRIs were
reviewed by musculoskeletal radiologists for the presence of
sacroiliac joint bone marrow edema representative of active
sacroiliitis. Nine patients had no evidence of sacroiliac joint
bone edema on MRI and were therefore not randomized into
the study. Other exclusion criteria were past or current tuber-
the criteria described by Calin et al (ref. 10)*
Working definition of inflammatory back pain, according to
Age at onset of back discomfort, years
Persistence of back discomfort, months
Associated with morning stiffness
Response to exercise
* A score of ?4 indicates the presence of inflammatory back pain.
INFLIXIMAB FOR EARLY SACROILIITIS 947
culosis, congestive heart disease, treatment with systemic glu-
cocorticoids in the previous month, and treatment of the
sacroiliac joints with intraarticular glucocorticoids within the
previous 3 months.
Treatment protocol. Patients fulfilling the inclusion
criteria were randomized to receive infusions of placebo or
infliximab (5 mg/kg) at 0, 2, 6, and 12 weeks. Treatment with
oral nonsteroidal antiinflammatory drugs remained unchanged
throughout the study. Intraarticular steroid therapy was not
allowed, nor was the introduction of oral glucocorticoids or
disease-modifying antirheumatic drugs.
Study assessments. The efficacy of therapy was deter-
mined by evaluating changes in MRI and clinical/functional
assessments. The primary study end point was the change in
the total MRI score (sum of the 8 sacroiliac joint regions) from
week 0 to week 16. Safety was assessed by monitoring patients
for the occurrence of adverse events and by collecting samples
for clinical laboratory testing at each visit.
MRI protocol and scoring. MRI scans were performed
at baseline (week 0) and week 16, using the commercially
available 1.5T Gyroscan ACS-NT system (Philips, Best, The
Netherlands). Patients were examined in the supine position,
with a flat-surface coil positioned under the sacrum. T1-
weighted turbo spin-echo (TSE) and STIR TSE fat-suppressed
coronal oblique sequences of the sacroiliac joints and T2-
weighted spectral presaturation with inversion recovery sagit-
tal sequences of the whole spine were obtained. The MRI
parameters were as follows: for T1-weighted oblique se-
quences of the sacroiliac joint, repetition time (TR) 892 msec,
time to echo (TE) 14 msec, matrix 384 ? 512 pixels, field of
view (FOV) 320 mm, slice thickness 4.0 mm, slice gap 0.4 mm,
number of signals averaged (NSA) 3, and acquisition time 5
minutes 44 seconds; for STIR TSE, TR 2,500 msec, TE 10
msec, matrix 382 ? 512 pixels, FOV 320 mm, slice thickness 4.0
mm, slice gap 0.8 mm, NSA 2, and acquisition time 4 minutes
The pretreatment and posttreatment scans were scored
together simultaneously by 2 independent observers (DM and
LCC) who were blinded to both the order of the scans and to
treatment group, using a previously reported scoring system
(3,22). Observer disagreement was resolved by consensus.
Regions of MRI-determined sacroiliitis, as defined on T2-
weighted fat-suppressed images as bone marrow edema (iden-
tified by a high or intermediate marrow signal), were scored.
For scoring purposes, the sacroiliiac joint was split into 8
regions, as previously described (22). Briefly, a line was drawn
across the upper third of the sacroiliac joint, and the upper
right iliac, upper right sacral, upper left sacral, and upper left
iliac regions were evaluated. The 4 corresponding lower re-
gions were similarly evaluated. Each region was scored for
bone edema as follows: 0 ? absent, 1 ? mild, 2 ? moderate,
and 3 ? extensive. The scores were based on both the extent of
osteitis and its severity (or intensity). An overall score of
inflammatory activity was calculated as the sum of scores for
bone marrow edema, for a total possible maximal score of 12
per joint (24 per patient). To assess the degree of change
between scans, paired scoring was performed for every lesion
using this system with, for example, resolution of a severe
lesion improving from a score of 3 to a score of 0. In the spine,
bone marrow lesions were defined as described above and
were recorded as present or absent in the vertebral body,
posterior elements including spinous processes and facet
joints, and paraspinal soft tissues. A total count of lesions per
spinal area for each patient was performed. Change was
assessed as resolution of the baseline lesions.
Radiographic assessments. Radiography of the sacro-
iliac joints was not routinely performed as part of the study
protocol. However, the majority of patients did undergo
radiography of the sacroiliac joints just prior to being screened
for the study. These radiographs were reviewed by indepen-
dent radiologists/rheumatologists who were blinded to the
treatment group and MRI findings.
Clinical and functional assessments. At each visit, dis-
ease activity was assessed with the BASDAI (23), the physi-
cian’s global assessment of disease activity, and the swollen and
tender joint counts (n ? 28) to assess peripheral involvement.
The Bath Ankylosing Spondylitis Functional Index (BASFI)
(24), the disability index of the Health Assessment Question-
naire (HAQ) (25), and the Ankylosing Spondylitis Quality of
Life instrument (ASQoL) (26) were used to assess function,
disability, and quality of life at each visit. Also at each visit,
spinal mobility was assessed by the measurement of chest
expansion and the Schober test of lumbar flexion. Samples
were collected at each visit for determination of the erythro-
cyte sedimentation rate (ESR) and the C-reactive protein
(CRP) level, both of which are markers of inflammation. The
ASsessment in Ankylosing Spondylitis International Working
Group criteria for 40% improvement (ASAS40) (27), 20%
improvement in 5 of 6 domains (27), and for partial remission
(28) were applied to these clinical data.
Statistical analysis. Data were summarized and tested
according to distribution and type. Means and standard devi-
ations are presented for normally distributed continuous data,
and Student’s t-tests were used to compare the 2 treatment
groups. Medians and interquartile ranges were presented for
non-normally distributed and ordinal data, which were com-
pared with nonparametric Mann-Whitney U tests. Nominal
data were summarized as the number (%) and compared with
Pearson’s chi-square tests, continuity-corrected as appropriate
if the expected cell count dropped below 5. All tests were
performed at the 5% level of significance. Corrections for
multiple testing within each family of statistical tests were
applied for secondary outcomes, according to Holm’s modifi-
cation of the Bonferroni adjustment. The following thresholds
for statistical significance of secondary outcomes were derived:
for the Mann-Whitney U test, 0.007; for Student’s t-test, 0.025;
for the chi-square test, 0.017. All analyses were performed
using SPSS software version 15.1.1 (SPSS, Chicago, IL).
Patient demographics. Forty patients were ran-
domized (20 to infliximab treatment and 20 to the
placebo group). One patient (in the placebo group)
withdrew consent at 12 weeks and discontinued partici-
pation in the study. This patient was included in the
analysis of efficacy, because it was performed on an
intent-to-treat basis. The remaining 39 patients com-
pleted the study. The randomized treatment groups
948BARKHAM ET AL
were similar with regard to baseline demographic and
disease characteristics (Table 2). Despite an average
duration of back pain of ?1–1.5 years, patients had
evidence of active disease (mean BASDAI score ?5.5),
causing significant impairment of functional ability and
quality of life. Associated extraarticular features in-
cluded iritis in 6 patients (15%), psoriasis in 4 patients
(10%), and inflammatory bowel disease in 1 patient
(2.5%). Three patients (7.5%) had a family history of
AS, 6 patients (15%) had a family history of psoriasis,
and 4 patients (10%) had a family history of inflamma-
tory bowel disease.
MRI findings. Thirty-nine patients (20 in the
infliximab group and 19 in the placebo group) had MRI
performed at baseline and week 16. One patient did not
have a repeat scan at 16 weeks because he had with-
drawn consent at 12 weeks; the last observation carried
forward was used for analysis in his case. All patients had
lesions on baseline MRI scans consistent with active
disease, when reviewed by musculoskeletal radiologists
prior to entry into the study. When blinded paired
scoring of the scans was performed after the study, 3
patients (all in the placebo group) had a baseline MRI
score of 0. The remainder of the patients all had scores
of grade 1 or higher. Seventy percent of the patients had
bilateral sacroiliitis. The median total MRI score for the
sacroiliac joints at baseline was 3.5 (interquartile range
[IQR] 2, 8), and the median changes at week 16 were 0
(IQR –2.00, 1.50) in the placebo group and ?2.00 (IQR
?6.25, 0.00) in the infliximab group (for the primary end
point, Mann-Whitney U asymptotic z ? ?2.17, P ?
0.033). None of the patients in the infliximab group had
an increase in the total MRI score, whereas 5 patients in
the placebo group did have such an increase.
At baseline, 75 and 60 abnormal sacroiliac joint
lesions were observed in the infliximab group and the
placebo group, respectively. Among the abnormal base-
line joint regions (score ?1), 47 (62.7%) in the inflix-
imab group resolved completely, versus 20 (29.4%) in
the placebo group (Pearson’s ?2? 15.84, 1 df, P ?
0.001). When considering joint regions with moderate or
high levels of inflammation (MRI score ?2) at baseline
(24 in the placebo group and 22 in the infliximab group),
6 (22.2%) in the placebo group resolved completely,
compared with 17 (77.3%) in the infliximab group
(Pearson’s ?2? 14.75, df ? 1, P ? 0.001).
Considering those regions with no MRI abnor-
mality at baseline (MRI score ? 0), 92 sacroiliac joint
regions in the placebo group (57.5%) were normal,
compared with 85 sacroiliac joint regions in the inflix-
imab group (53.1%) (P ? 0.431, by chi-square test).
Among these normal joint regions, new lesions devel-
oped in 11 (12.0%) in the placebo group compared with
1 (1.2%) in the infliximab group (Pearson’s ?2? 8.12,
1 df, P ? 0.004).
Patients with moderate or extensive bone marrow
edema (at least 1 sacroiliac region with a score of grade
?2) were compared with those with mild edema only (all
regions scoring grade 1). In the placebo group, there was
no significant difference in the MRI response (change in
total lesion score) between patients with mild baseline
bone edema (median 1, IQR ?2, 3) and those with
moderate or extensive edema (median ?0.5, IQR
?5.25, 0; P ? 0.475, by Mann-Whitney U test). In the
infliximab group, patients with mild baseline bone
edema showed significantly less improvement in the
total MRI score (median 0.0, IQR ?2.0, 0.0) than those
with moderate or extensive edema (median ?7, IQR
?12, ?2; P ? 0.002).
Although all patients manifested baseline sacro-
iliac joint inflammation, only 9 patients (22.5%; 5 in the
infliximab group and 4 in the placebo group) had
inflammation detectable on spinal MRI scans. Among
patients with spinal inflammation, an average of 3 (range
1–6) spinal lesions were present. Three of the 5
infliximab-treated patients with spinal lesions had com-
plete resolution (10 of 12 lesions resolved), compared
Baseline characteristics of the patients*
(n ? 20)
(n ? 20)
No. of men/no. of women
Age, mean years
Mean duration of back pain, months
Mean BASFI score
Mean BASDAI score
HAQ score (range 0–3)
ASQoL score (range 0–18)
Chest expansion, mm
Lumbar flexion, mm
Concomitant NSAID use, no. (%)
Mean number of SI joint lesions
* Except where indicated otherwise, values are the median. For
C-reactive protein (CRP), n ? 18 patients in the placebo group and 19
patients in the infliximab group. For the Bath Ankylosing Spondylitis
Disease Activity Index (BASDAI) score, n ? 19 patients in the placebo
group. No significant differences between placebo and infliximab were
observed for any of the variables. BASFI ? Bath Ankylosing Spondy-
litis Functional Index; HAQ ? Health Assessment Questionnaire;
ASQoL ? Ankylosing Spondylitis Quality of Life; NSAID ? nonste-
roidal antiinflammatory drug; SI ? sacroiliac; MRI ? magnetic
INFLIXIMAB FOR EARLY SACROILIITIS 949
with 1 of 4 patients in the placebo group (4 of 14 lesions
resolved) (P ? 0.016).
Plain radiography findings. In 34 of 40 patients,
plain radiographs of the sacroiliac joints were obtained
at baseline. Sixteen (47%) of the 34 radiographs were
entirely normal, 14 (41%) of the 34 radiographs showed
minor abnormalities not sufficient to make a diagnosis
according to the modified New York criteria, and 4
(12%) of the 34 radiographs fulfilled the modified New
York criteria for a radiographic diagnosis of AS.
Results of clinical and functional assessments.
The week 16 findings for clinical and functional assess-
ments are summarized in Table 3. The mean reduction
in the BASDAI score at 16 weeks was significantly
greater in the infliximab group (?3.41) than in the
placebo group (?0.75) (P ? 0.002). Functional ability,
as assessed by the BASFI score, also improved to a
significantly greater extent in the infliximab group
(mean reduction ?2.70) compared with the placebo
group (mean reduction ?0.47) (P ? 0.004). There was
no significant difference between treatment groups in
CRP level reductions; however, baseline CRP levels of
11.5 mg/liter in the placebo group and 5.0 mg/liter in the
infliximab group likely precluded detection of a
treatment-related difference. There was a trend toward
a larger reduction in the HAQ disability index score
among infliximab-treated patients (?0.44) compared
with placebo-treated patients (?0.13), but this differ-
ence did not reach significance (P ? 0.065). There was,
however, significant improvement in quality of life by 16
weeks, as measured by the ASQoL score, in infliximab-
treated patients (?6.18) compared with placebo-treated
patients (?1.00) (P ? 0.007).
In terms of the composite ASAS response crite-
ria, significantly larger proportions of infliximab-treated
patients than placebo-treated patients met the ASAS40
criteria (61.1% versus 17.6%; P ? 0.009) for improve-
ment at week 16 (Table 3.) In addition, more than half
of infliximab-treated patients (55.6%) met the ASAS
partial remission criteria at week 16, compared with
12.5% of placebo-treated patients (P ? 0.009) (Table 3).
There was no significant difference in the placebo
or treatment arm in changes in the BASDAI score
between patients with mild baseline MRI bone edema
(score ?1) and those with moderate or severe baseline
MRI bone edema (P ? 0.68 in the placebo group and
P ? 0.71 in the infliximab group). In the infliximab
group, a higher proportion of patients with an elevated
line CRP level (n ? 9) achieved all of the ASAS
composite measures, compared with those patients (n ?
9) with a normal baseline CRP level (for ASAS20, 8
patients versus 6 patients; for ASAS50, 7 patients versus
4 patients; for ASAS70, 6 patients versus 4 patients).
However, this difference was not shown to be statistically
significant, due to the small numbers of patients in these
Adverse events. Study medication was well toler-
ated, and no serious adverse events were observed. An
allergy to infliximab, characterized by a rash and bron-
chospasm, developed in 1 patient in the infliximab
group. This patient discontinued infliximab therapy at
week 6 but continued in the study and had a followup
MRI performed at week 16.
TNF blockade has been a crucial advance in the
treatment of AS in recent years. However, previous
Results of clinical and functional assessments at week 16*
(n ? 20)
(n ? 20)P
BASDAI score, mean ? SD
BASFI score, mean ? SD
C-reactive protein, mg/liter
HAQ disability index score
Lumbar flexion, cm
ASAS40 response, no./no. tested (%)
ASAS5/6 response, no./no. tested (%)
ASAS partial remission, no./no. tested (%)
?0.75 ? 2.42
?0.47 ? 2.25
?1.5 (?6.6, 0.5)
?0.13 (?0.38, 0.00)
0.000 (?1.000, 1.500)
0.00 (?0.50, 1.00)
?1.00 (?4.50, 0.75)
?3.41 ? 2.53
?2.70 ? 2.36
?4.0 (?10.0, 0.0)
?0.44 (?0.93, ?0.13)
1.000 (0.000, 1.875)
0.50 (0.00, 1.00)
?6.18 (?10.00, ?2.25)
* Except where indicated otherwise, values are the median (interquartile range). For the Bath Ankylosing Spondylitis Disease
Activity Index (BASDAI), chest expansion, and lumbar flexion, n ? 19 patients in the placebo group. For C-reactive protein,
n ? 18 patients in the placebo group and 19 patients in the infliximab group. BASFI ? Bath Ankylosing Spondylitis Functional
Index; HAQ ? Health Assessment Questionnaire; ASQoL ? Ankylosing Spondylitis Quality of Life; ASAS40 ? ASsessment
in Ankylosing Spondylitis International Working Group criteria for 40% improvement.
950BARKHAM ET AL
studies have been limited to patients in whom the
diagnosis of AS was confirmed by the definite modified
New York criteria, which rely on the presence of radio-
graphic structural changes, which can take several years
to develop. In this study, we used stringent inclusion
criteria to identify a homogeneous cohort of HLA–B27–
positive patients with MRI-determined sacroiliitis who
have early axial SpA and a high likelihood of eventually
progressing to radiographically defined AS. In this co-
hort, infliximab therapy resulted in significant sup-
pression of MRI-determined inflammation relative to
placebo, with a significant reduction in the total MRI
score, increased resolution of inflammatory lesions, and
decreased progression of new inflammatory lesions at
week 16 (Figure 1). These results are consistent with
those seen in patients with established AS (18,22,29).
Additionally, we observed impressive clinical responses
to infliximab therapy, with improvement in disease ac-
tivity, functional status, and quality of life seen at
When comparing our findings with those derived
from a study of infliximab in established AS (20), the
proportion of patients reaching the ASAS partial remis-
sion criteria was far higher (55.6% versus 22.4%), sug-
gesting a clear benefit for early treatment of apparently
more reversible disease. Previous studies in established
AS have shown that patients with a shorter disease
duration have a better response to anti-TNF agents (30),
suggesting that very early treatment before damage is
evident on radiographs will lead to improved responses.
Therefore, this study confirms the efficacy of infliximab
in early axial SpA and suggests that these patients may
respond more favorably to infliximab treatment than
patients with radiographically evident, established AS
As noted, the lack of a significant treatment
effect on reductions in CRP levels is likely attributable
to a low median baseline CRP level of 5 mg/liter in the
infliximab group. It is known that CRP levels can be
variable in AS, with some patients showing very little
systemic inflammatory response (14,15). It appears that
in the early stages of disease that characterized our study
cohort, a higher proportion of patients will have normal
levels of markers of inflammation, and that these mark-
ers cannot be relied on to aid diagnosis or guide therapy.
The results suggested a better response in those individ-
uals with an elevated baseline CRP level; however,
patients with a normal CRP level did respond to inflix-
imab, with two-thirds of patients achieving an ASAS20
These patients represent a select group of those
presenting with inflammatory low back pain, having a
relatively brief symptom duration and active disease
both clinically and on MRI. Their disease was impacting
their functional ability and quality of life, and no current
proven treatment options were available to them. Given
that the average age of the patients was younger than 30
years, the majority were working full-time. However,
many were struggling to cope because of their disease.
Until now, there has been no evidence to guide the
treatment of such patients. Current guidelines on the
treatment of AS are all based on a diagnosis according to
definite New York criteria, which require radiographic
evidence of disease (31). This study provides novel data
on the clinical and MRI-determined efficacy of TNF
blockade in HLA–B27–positive patients with active sac-
roiliitis. Of note, patients with HLA–B27–positive in-
flammatory back pain without MRI-defined osteitis
were excluded from this study. The role of anti-TNF
agents in such patients early in the course of disease
requires separate evaluation.
Several recent studies have examined the impact
of anti-TNF agents on radiographic changes in AS
(32,33). This research has not provided convincing evi-
dence of slowing of radiographic progression, despite
anti-TNF treatment for up to 4 years. Explanatory
theories suggest that inflammation and bony progression
are 2 independent pathways, and that suppression of
inflammation may not prevent spinal ankylosis (34). The
impact of TNF blockade on new bone formation in the
spine has been controversial, and it has been suggested
that once inflammation has started, the bony progres-
sion cannot be halted with suppression of TNF alone. If
this is the case, early intervention, when only sacroiliitis
is present, may prevent the development of osteitis at
other sites and subsequent bone growth and fusion at
Interestingly, despite the short duration of symp-
toms among patients in this study, 4 patients already met
the modified New York criteria for a diagnosis of AS.
This has been observed in other cohorts of patients with
early inflammatory low back pain (35) and reflects the
fact that some patients do have rapidly progressive
A recent study by Haibel et al (36) examined the
efficacy of adalimumab in the treatment of patients with
axial SpA without radiographically defined sacroiliitis.
Although that study showed efficacy for anti-TNF ther-
apy in this group of patients, there are substantial
differences in the population treated in that study com-
pared with the population treated in the current study.
The mean duration of symptoms in the patients receiv-
INFLIXIMAB FOR EARLY SACROILIITIS951
ing active treatment in the study by Haibel et al (7 years
[range 2–16 years]) was significantly longer than that in
our cohort and cannot really be regarded as representing
early disease. The inclusion criteria for the study by
Haibel et al required the presence of 2 of the following
3 features: inflammatory back pain, HLA–B27 positivity,
and bone edema on MRI. Of the patients treated with
adalimumab in that study, only 14% had the combina-
tion of HLA–B27 positivity and abnormal MRI results.
The study population had a relatively high proportion of
female patients (59%) and a lower prevalence of HLA–
B27 positivity (59%), which is consistent with an undif-
ferentiated SpA cohort rather than an AS cohort. For
these reasons, we believe that the study by Haibel and
colleagues represents treatment of a heterogeneous
group of patients with SpA, many of whom would not be
expected to experience progression to AS. We believe
that patients in our cohort, all of whom were HLA–B27
positive and had abnormal MRI results, are more rep-
resentative of those with early AS.
In conclusion, this study is the first to demon-
strate that infliximab is effective for reducing clinical and
imaging evidence of disease activity in a cohort of
patients in whom progression to radiographic AS is
highly likely. The findings of this study highlight the
need for a diagnosis of AS that is not based on radio-
graphic criteria and suggest that there is a place for
anti-TNF therapy in early axial SpA. However, because
SpA occurs in young people, and the long-term risks of
malignancy following anti-TNF therapy are currently
Figure 1. Magnetic resonance images of the sacroiliac joints of a patient before (A) and after (B) receiving
infliximab therapy. The extensive bone marrow edema that was observed in both sacroiliac joints before
treatment was resolved in the posttreatment scan.
952 BARKHAM ET AL
unknown, a careful consideration of potential risks and
benefits should be made before beginning anti-TNF
therapy for any patient. Further research is needed to
determine whether this early treatment will halt radio-
graphic progression at the sacroiliac joints and else-
where. If early treatment of axial SpA will also prevent
loss of work participation and result in sustained im-
provement in the quality of life, these patients merit
Dr. Emery 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
Study design. Barkham, O’Connor, Fraser, Cawkwell, Emery.
Acquisition of data. Barkham, Keen, Coates, Fraser, Cawkwell,
Analysis and interpretation of data. Barkham, Keen, Coates,
O’Connor, Hensor, McGonagle, Emery.
Manuscript preparation. Barkham, Keen, Coates, McGonagle,
Statistical analysis. Hensor.
Radiographic scoring. Bennett.
ROLE OF THE STUDY SPONSOR
Centocor had no role in the study design or in the collection,
analysis, or interpretation of the data, the writing of the manuscript, or
the decision to submit the manuscript for publication. Publication of
this article was not contingent upon approval by Centocor.
1. Braun J, Bollow M, Remlinger G, Eggens U, Rudwaleit M, Distler
A, et al. Prevalence of spondylarthropathies in HLA–B27 positive
and negative blood donors. Arthritis Rheum 1998;41:58–67.
2. Barkham N, Kong KO, Tennant A, Fraser A, Hensor E, Keenan
AM, et al. The unmet need for anti-tumour necrosis factor
(anti-TNF) therapy in ankylosing spondylitis. Rheumatology
3. Marzo-Ortega H, McGonagle D, O’Connor P, Emery P. Efficacy
of etanercept in the treatment of the entheseal pathology in
resistant spondylarthropathy: a clinical and magnetic resonance
imaging study. Arthritis Rheum 2001;44:2112–7.
4. Van der Linden S, Valkenburg HA, Cats A. Evaluation of
diagnostic criteria for ankylosing spondylitis: a proposal for mod-
ification of the New York criteria. Arthritis Rheum 1984;27:361–8.
5. Feldtkeller E, Khan MA, van der Heijde D, van der Linden S,
Braun J. Age at disease onset and diagnosis delay in HLA-B27
negative vs. positive patients with ankylosing spondylitis. Rheuma-
tol Int 2003;23:61–6.
6. Braun J, Bollow M, Eggens U, Konig H, Distler A, Sieper J. Use
of dynamic magnetic resonance imaging with fast imaging in the
detection of early and advanced sacroiliitis in spondylarthropathy
patients. Arthritis Rheum 1994;37:1039–45.
7. Bollow M, Fischer T, Reisshauer H, Backhaus M, Sieper J, Hamm
B, et al. Quantitative analyses of sacroiliac biopsies in spondylo-
arthropathies: T cells and macrophages predominate in early and
active sacroiliitis—cellularity correlates with the degree of en-
hancement detected by magnetic resonance imaging. Ann Rheum
8. Marzo-Ortega H, O’Connor P, Emery P, McGonagle D. Sacroiliac
joint biopsies in early sacroiliitis. Rheumatology (Oxford) 2007;46:
9. Oostveen J, Prevo R, den Boer J, van de Laar M. Early detection
of sacroiliitis on magnetic resonance imaging and subsequent
development of sacroiliitis on plain radiography: a prospective,
longitudinal study. J Rheumatol 1999;26:1953–8.
10. Calin A, Porta J, Fries JF, Schurman DJ. Clinical history as a
screening test for ankylosing spondylitis. JAMA 1977;237:2613–4.
11. Gran JT. An epidemiological survey of the signs and symptoms of
ankylosing spondylitis. Clin Rheumatol 1985;4:161–9.
12. Underwood MR, Dawes P. Inflammatory back pain in primary
care. Br J Rheumatol 1995;34:1074–7.
13. Rudwaleit M, Metter A, Listing J, Sieper J, Braun J. Inflammatory
back pain in ankylosing spondylitis: a reassessment of the clinical
history for application as classification and diagnostic criteria.
Arthritis Rheum 2006;54:569–78.
14. Dougados M, Gueguen A, Nakache JP, Velicitat P, Zeidler H,
Veys E, et al. Clinical relevance of C-reactive protein in axial
involvement of ankylosing spondylitis. J Rheumatol 1999;26:
15. Spoorenberg A, van der Heijde D, de Klerk E, Dougados M,
de Vlam K, Mielants H, et al. Relative value of erythrocyte
sedimentation rate and C-reactive protein in assessment of disease
activity in ankylosing spondylitis. J Rheumatol 1999;26:980–4.
16. Freeston J, Barkham N, Hensor E, Emery P, Fraser A. Ankylosing
spondylitis, HLA-B27 positivity and the need for biologic thera-
pies. Joint Bone Spine 2007. E-pub ahead of print.
17. Rudwaleit M, van der Heijde D, Khan MA, Braun J, Sieper J. How
to diagnose axial spondyloarthritis early. Ann Rheum Dis 2004;63:
18. Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, et al.
Treatment of active ankylosing spondylitis with infliximab: a
randomised controlled multicentre trial. Lancet 2002;359:1187–93.
19. Gorman JD, Sack KE, Davis JC Jr. Treatment of ankylosing
spondylitis by inhibition of tumor necrosis factor ?. N Engl J Med
20. Van der Heijde D, Dijkmans B, Geusens P, Sieper J, DeWoody K,
Williamson P, et al, and the Ankylosing Spondylitis Study for the
Evaluation of Recombinant Infliximab Therapy Study Group.
Efficacy and safety of infliximab in patients with ankylosing
spondylitis: results of a randomized, placebo-controlled trial
(ASSERT). Arthritis Rheum 2005;52:582–91.
21. Van der Heijde D, Kivitz A, Schiff MH, Sieper J, Dijkmans BA,
Braun J, et al. Efficacy and safety of adalimumab in patients
with ankylosing spondylitis: results of a multicenter, randomized,
double-blind, placebo-controlled trial. Arthritis Rheum 2006;54:
22. Marzo-Ortega H, McGonagle D, Jarrett S, Haugeberg G,
Hensor E, O’Connor P, et al. Infliximab in combination with
methotrexate in active ankylosing spondylitis: a clinical and imag-
ing study. Ann Rheum Dis 2005;64:1568–75.
23. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P,
Calin A. A new approach to defining disease status in ankylosing
spondylitis: the Bath Ankylosing Spondylitis Disease Activity
Index. J Rheumatol 1994;21:2286–91.
24. Calin A, Garrett S, Whitelock H, Kennedy LG, O’Hea J, Mallorie
P, et al. A new approach to defining functional ability in ankylos-
ing spondylitis: the development of the Bath Ankylosing Spondy-
litis Functional Index. J Rheumatol 1994;21:2281–5.
25. Pincus T, Summey JA, Soraci SA Jr, Wallston KA, Hummon NP.
Assessment of patient satisfaction in activities of daily living using
a modified Stanford Health Assessment Questionnaire. Arthritis
26. Doward LC, Spoorenberg A, Cook SA, Whalley D, Helliwell PS,
Kay LJ, et al. Development of the ASQoL: a quality of life
instrument specific to ankylosing spondylitis. Ann Rheum Dis
INFLIXIMAB FOR EARLY SACROILIITIS953
27. Brandt J, Listing J, Sieper J, Rudwaleit M, van der Heijde D,
Braun J. Development and preselection of criteria for short term
improvement after anti-TNF ? treatment in ankylosing spondylitis.
Ann Rheum Dis 2004;63:1438–44.
28. Anderson JJ, Baron G, van der Heijde D, Felson DT, Dougados
M. Ankylosing Spondylitis Assessment Group preliminary defini-
tion of short-term improvement in ankylosing spondylitis. Arthritis
29. Braun J, Baraliakos X, Golder W, Brandt J, Rudwaleit M, Listing
J, et al. Magnetic resonance imaging examinations of the spine in
patients with ankylosing spondylitis, before and after successful
therapy with infliximab: evaluation of a new scoring system.
Arthritis Rheum 2003;48:1126–36.
30. Rudwaleit M, Listing J, Brandt J, Braun J, Sieper J. Prediction of
a major clinical response (BASDAI 50) to tumour necrosis factor
? blockers in ankylosing spondylitis. Ann Rheum Dis 2004;63:
31. Braun J, Pham T, Sieper J, Davis J, van der Linden S, Dougados
M, et al, for the ASAS Working Group. International ASAS
consensus statement for the use of anti-tumour necrosis factor
agents in patients with ankylosing spondylitis. Ann Rheum Dis
32. Baraliakos X, Listing J, Brandt J, Haibel H, Rudwaleit M, Sieper
J, et al. Radiographic progression in patients with ankylosing
spondylitis after 4 yrs of treatment with the anti-TNF-? antibody
infliximab. Rheumatology (Oxford) 2007;46:1450–3.
33. Baraliakos X, Listing J, Rudwaleit M, Brandt J, Sieper J, Braun J.
Radiographic progression in patients with ankylosing spondylitis
after 2 years of treatment with the tumour necrosis factor ?
antibody infliximab. Ann Rheum Dis 2005;64:1462–6.
34. Lories RJ, Derese I, De Bari C, Luyten FP. Evidence for uncou-
pling of inflammation and joint remodeling in a mouse model of
spondylarthritis. Arthritis Rheum 2007;56:489–97.
35. Puhakka KB, Jurik AG, Schiottz-Christensen B, Hansen GV,
Egund N, Christiansen JV, et al. MRI abnormalities of sacroiliac
joints in early spondylarthropathy: a 1-year follow-up study. Scand
J Rheumatol 2004;33:332–8.
36. Haibel H, Rudwaleit M, Listing J, Heldmann F, Wong RL,
Kupper H, et al. Efficacy of adalimumab in the treatment of axial
spondylarthritis without radiographically defined sacroiliitis: re-
sults of a twelve-week randomized, double-blind, placebo-con-
trolled trial followed by an open-label extension up to week
fifty-two. Arthritis Rheum 2008;58:1981–91.
954 BARKHAM ET AL