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ARTHRITIS & RHEUMATISM
Vol. 46, No. 3, March 2002, pp 755–765
DOI 10.1002/art.511
© 2002, American College of Rheumatology
Randomized Double-Blind Comparison of
Chimeric Monoclonal Antibody to Tumor Necrosis
Factor ␣ (Infliximab) Versus Placebo in
Active Spondylarthropathy
Filip Van den Bosch, Elli Kruithof, Dominique Baeten, Annemie Herssens, Filip de Keyser,
Herman Mielants, and Eric M. Veys
Objective. To confirm in a placebo-controlled trial
the safety and efficacy profile of infliximab in shortterm treatment of patients with active spondylarthropathy (SpA).
Methods. Forty patients with active SpA were
randomly assigned to receive an intravenous loading
dose (weeks 0, 2, and 6) of 5 mg/kg infliximab or
placebo. Evaluations for efficacy and safety were performed at weeks 1, 2, 6, 8, and 12. The primary end
points of this study were the improvements in patient
and physician global assessments of disease activity on
a 100-mm visual analog scale.
Results. Both primary end points improved significantly in the infliximab group compared with the
baseline value, with no improvement in the placebo
group. As early as week 2 and sustained up to week 12,
there was a highly statistically significant difference
between the values for these 2 end points in the infliximab versus the placebo group. In most of the other
assessments of disease activity (laboratory measures,
assessments of specific peripheral and/or axial disease),
significant improvements were observed in the infliximab group compared with the baseline value and
compared with placebo. Minor adverse events not causing discontinuation were equally observed in both treattocor.
ment groups. There was one severe drug-related adverse
event, in which a patient developed disseminated tuberculosis.
Conclusion. Tumor necrosis factor ␣ blockade
with infliximab in patients with active SpA was well
tolerated and resulted in significant clinical and laboratory improvements in this short-term, placebocontrolled study. However, the occurrence of tuberculosis in one patient necessitates strict inclusion criteria
and long-term followup.
The spondylarthropathies (SpA) are a group of
chronic autoimmune disorders of the joint (1). Entities
belonging to this concept are ankylosing spondylitis
(AS), reactive arthritis (ReA), psoriatic arthritis (PsA),
undifferentiated SpA (uSpA) (2), arthritis associated
with inflammatory bowel disease, and arthritis associated with acute anterior uveitis. This frequent rheumatic
condition has a global prevalence of 0.5–1%, although
there are important racial and geographic differences
and a clear predominance among men. Juveniles as well
as adults can be affected by one of the SpA.
The different types of SpA share a number of
common clinical, radiographic, and genetic features that
are clearly distinct from those of other autoimmune
arthritides, such as rheumatoid arthritis (RA). The
hallmark symptoms include sacroiliitis, spondylitis, pauciarticular synovitis, and enthesitis. In an important
number of cases, subclinical gut inflammation with
pathologic findings resembling those of Crohn’s disease
(CD) can be found, appearing in 25–75% of patients
depending upon the type of SpA (3). Some of these
patients (those with uSpA with histologic evidence of
chronic gut inflammation) may eventually develop overt
CD by the 5-year followup visit (4,5). In repeat ileo-
Supported in part by grants from Schering-Plough and Cen-
Filip Van den Bosch, MD, Elli Kruithof, MD, Dominique
Baeten, MD, PhD, Annemie Herssens, Filip de Keyser, MD, PhD,
Herman Mielants, MD, PhD, Eric M. Veys, MD, PhD: Ghent University Hospital, Ghent, Belgium.
Address correspondence and reprint requests to Filip Van
den Bosch, MD, Department of Rheumatology, Ghent University
Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. E-mail:
f.vandenbosch@pi.be.
Submitted for publication July 25, 2001; accepted in revised
form October 15, 2001.
755
756
colonoscopy studies, clinical remission of articular symptoms was consistently associated with normalization of
gut histology, while persistence of locomotor inflammation was usually associated with persistence of gut
inflammation (6).
Therapeutic options for patients with SpA are
limited. Nearly all patients take nonsteroidal antiinflammatory drugs (NSAIDs) for control of pain and stiffness.
However, their use is sometimes limited by major side
effects and drug interactions. The only diseasemodifying agent that has been demonstrated to be useful
for SpA is sulfasalazine (SSZ), which has a proven
beneficial effect on gastrointestinal symptoms in inflammatory bowel disease (7,8). Although SSZ has also been
found to have a favorable effect on articular symptoms
in SpA patients, this effect appears to be modest for
peripheral arthritis and enthesitis and nearly imperceptible for spondylitis (9,10). In patients with PsA, methotrexate (MTX) has become the most widely used
therapy (11). Although cyclosporine has a proven effect
on skin disease in psoriasis (12), the only data for its use
in PsA come from a 1-year prospective trial which
compared cyclosporine with MTX and showed that both
treatments were effective (13); however, no doubleblind, placebo-controlled trials were performed with this
agent in PsA.
Recently, the use of biologic therapies that block
tumor necrosis factor ␣ (TNF␣) has opened new perspectives for the treatment of patients with SpA. Infliximab (Remicade; Centocor, Malvern, PA) is a chimeric
anti-TNF␣ monoclonal IgG1 antibody that neutralizes
the soluble cytokine and blocks the membrane-bound
cytokine (14). Investigators in an open-label trial with
infliximab in patients with active CD despite steroid
treatment reported clinical remission with endoscopic
healing of mucosal ulcers after a single intravenous dose
(15). On the basis of two randomized, double-blind,
placebo-controlled trials (16,17), infliximab was approved by the health authorities in the US (the Food and
Drug Administration [FDA]) and Europe (the European Medicine Evaluation Agency [EMEA]) as a treatment for therapy-resistant moderate-to-severe CD and
CD with fistulas. However, studies with infliximab in
inflammatory bowel disease have not evaluated the
effect on associated rheumatologic manifestations, such
as spondylitis, synovitis, or enthesitis.
Recently, we observed a fast and significant improvement of articular as well as axial inflammation in 4
patients with SpA associated with CD treated with
infliximab (18). The observations in these patients suggested that refractory joint manifestations in CD might
VAN DEN BOSCH ET AL
be a potential indication for infliximab treatment, and
warranted further investigation of the therapeutic potential of TNF␣ blockade in patients with other subtypes of
SpA. Observations in polyarticular PsA (19,20) also
suggested a beneficial role of TNF␣ blockade in alleviating articular symptoms. Few data exist concerning the
expression of TNF␣ in joints of patients with SpA;
however, in sacroiliac joint biopsy specimens from patients with AS, an abundant TNF␣ message could be
found by in situ hybridization (21). Finally, in contrast to
SpA, the indication for TNF␣ blockade with infliximab
in RA, another form of chronic autoimmune arthritis,
has been well documented (22,23), and the drug has
been approved by the FDA and the EMEA for use in
therapy-resistant RA.
Based on these data, a pilot study was set up to
evaluate the efficacy of TNF␣ blockade with infliximab
in patients with different subtypes of active SpA (24).
This was an open-label study in 21 patients who received
a loading-dose regimen of 3 infusions of infliximab (5
mg/kg) at weeks 0, 2, and 6. All the measured variables
(global disease activity, peripheral arthritis assessments,
axial disease assessments, and skin disease) improved
significantly, with most parameters already reaching
statistical significance at day 3. The beneficial effect was
maintained up to day 84 (6 weeks after the third
infusion). Simultaneously, successful treatment with infliximab in 11 patients with AS was reported by investigators in an open-label German study (25).
We now report the results of a double-blind,
placebo-controlled trial of infliximab in patients with
different subtypes of active SpA. The study was designed
to confirm the safety and efficacy profile of infliximab in
short-term treatment of SpA.
PATIENTS AND METHODS
Study design. The study was a 12-week, monocenter,
randomized, double-blind, placebo-controlled trial. The study
protocol, the information for the patients, and the consent
form were approved by the Ethics Committee of the Ghent
University Hospital. All patients enrolled in the trial signed an
informed consent form at an initial screening visit. If eligible,
they were entered into the study within 4 weeks. No studyrelated procedures were performed before written informed
consent was obtained. The primary end points of the study
were the improvements in the patient and physician assessments of global disease activity measured on a 100-mm visual
analog scale (VAS) at week 12. These end points were chosen
because there are no validated outcome measurements for the
diseases of the SpA concept as a whole. Wherever applicable,
specific subgroup-focused measurements (e.g., in AS) were
determined, as described below under clinical evaluation. All
INFLIXIMAB VERSUS PLACEBO IN ACTIVE SpA
clinical assessments throughout the study were performed by
one investigator (FvdB). In patients with active knee arthritis,
needle arthroscopy was performed as described previously
(26); synovial biopsies were performed at baseline and at
weeks 1 and 12.
Patients. Patients had to fulfill the European Spondylarthropathy Study Group criteria for SpA (27). Patients were
at least 18 years old. For patients of childbearing potential,
both a negative pregnancy test result and adequate contraception during the study period and for 6 months after the last
infusion were criteria for entry. At the time of enrollment, all
patients had active SpA. Since there are no validated disease
activity criteria for the SpA disease concept as a whole, this was
defined as the presence of at least 1 swollen joint or 1 current
episode of active tendinitis or dactylitis and/or inflammatory
spinal pain (typical “night pain”). Disease-modifying drugs,
such as SSZ, MTX, and cyclosporine, were not allowed during
the study and were discontinued at least 4 weeks prior to
baseline.
Exclusion criteria included serious infections (e.g.,
hepatitis, pneumonia, pyelonephritis) in the previous 3
months, opportunistic infections within 2 months of screening,
documented human immunodeficiency virus infection, proven
urogenital or gastrointestinal ReA, overt CD, known malignancy, and current signs of severe, progressive, or uncontrolled
concomitant disease in the opinion of the investigator. Chest
radiography was performed at screening, and patients with
lesions suggestive of previous tuberculosis were excluded from
the study. Patients who received an investigational drug within
the previous 3 months were excluded, and previous administration of any therapeutic agent targeted at reducing levels of
TNF␣ was also a criterion for exclusion.
Concurrent medications. Patients were allowed to
continue NSAIDs and/or corticosteroids (ⱕ10 mg/day prednisolone), provided that the dosage and schedule regimen were
stable for at least 4 weeks prior to baseline and throughout the
study. No intraarticular injections of steroids were allowed
during the trial.
Randomization. A randomization list was generated by
an individual (unconnected with the study) who ensured that
equal numbers of patients with AS, PsA, and uSpA were
entered into each of the two treatment groups. Randomization
codes were provided to the hospital pharmacists, who ensured
appropriate study drug preparation. The randomization code
was concealed from study participants, the clinical observer,
and the study coordinator.
Study drug administrations. Infliximab (5 mg/kg in 250
ml 0.9% NaCl) or placebo was prepared by the hospital
pharmacy. The dose of 5 mg/kg was chosen based on the pilot
observations in patients with CD and associated SpA (18); as a
consequence, this dose was also used in the open-label pilot
trial (24). Since the present trial was designed to confirm these
results in a controlled way, the same dosage regimen was used.
Aseptic procedures were used during the preparation and
administration of the study drug. The characteristics of the
placebo and infliximab infusion bags were identical, and the
investigators and patients did not know which infusion was
being administered. The total dose was administered over a
period of at least 2 hours. A loading-dose regimen identical to
that in the open-label study (24) was used: 3 infusions were
administered at weeks 0, 2, and 6.
757
Clinical evaluation. Patients were seen for clinical
evaluation at baseline and at weeks 1, 2, 6, 8, and 12. At these
visits, the following variables were evaluated: patient global
assessment of disease activity (100-mm VAS), patient assessment of pain (100-mm VAS), physician global assessment of
disease activity (100-mm VAS), erythrocyte sedimentation rate
(ESR), and C-reactive protein (CRP) level. The clinical observer was blinded to the results of laboratory testing for
acute-phase measures (ESR and CRP level). Patients with
peripheral arthritis evaluated their own duration of morning
stiffness (in minutes) and degree of peripheral joint pain
(100-mm VAS); tender joint count (68 joints) and swollen joint
count (66 joints) were assessed by the physician. In patients
fulfilling modified New York criteria for AS (28), axial examination was performed at baseline and at weeks 2, 6, and 12.
This consisted of patient and physician assessments.
Tests scored by the patient included sleep disturbance
due to night pain (0 ⫽ not bothered, no pain at all; 1 ⫽
bothered a little, pain is present part of the time, but mild in
character; 2 ⫽ bothered a lot, steady or intermittent pain,
which usually interferes with sleep; and 3 ⫽ bothered terribly,
the night pain is constant, causes marked interference with
sleep and the patient is quite miserable), duration of morning
stiffness of the spine (in minutes), spinal pain (100-mm VAS),
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
(29), Bath Ankylosing Spondylitis Functional Index (BASFI)
(30), and Dougados Functional Index (DFI) (31). Tests performed by the physician included clinical assessment of spinal
pain (0 ⫽ no pain on firm palpation, percussion, or motion;
1 ⫽ slight pain on firm palpation, percussion, or motion; 2 ⫽
moderate pain on moderate palpation, percussion, or motion;
3 ⫽ moderate-to-severe pain on slight palpation, percussion,
or slight motion; and 4 ⫽ extreme pain with inability to
withstand even slight palpation or percussion), Bath Ankylosing Spondylitis Metrology Index (32), chest expansion, fingersto-floor test, occiput-to-wall test, modified Schober test, cervical rotation, lateral spinal flexion, intermalleolar distance, and
articular index according to Dougados (AID) (31). The extent
of skin disease in psoriasis patients was measured using the
Psoriasis Area and Severity Index (PASI) (33) at baseline and
at weeks 6 and 12.
Safety evaluation. During the infusion and for 1 hour
afterward, the patient was monitored for adverse experiences
and vital parameters (blood pressure, pulse, temperature). If
the infusion was well tolerated, the patient was discharged. At
each visit, patients were asked about side effects, and routine
laboratory tests were performed, which consisted of a full
blood count with white blood cell (WBC) differentiation and a
biochemical screening, including electrolytes, urea, creatinine,
total protein, and liver function tests. Urinalysis was performed
at screening and at the final visit. Positivity for antinuclear
antibodies (ANAs) and antibodies to double-stranded DNA
(anti-dsDNA antibodies) was determined at baseline and at
week 12. ANAs were scored by indirect immunofluorescence
on HEp-2 cells, using a semiquantitative scale from 0 to 5⫹.
Anti-dsDNA antibodies were identified by Crithidia luciliae
indirect immunofluorescence test.
Statistical analysis. The analysis was performed on the
basis of intent-to-treat. Variables were summarized by presenting the median and range. Statistical power was calculated
based on the data for the primary end points obtained in the
758
VAN DEN BOSCH ET AL
Table 1. Demographic and descriptive characteristics of the study population*
Patients†
Treatment group
Placebo
Age, years
No. men/no. women
Disease duration, years
Patient global assessment, 0–100-mm VAS
Physician global assessment, 0–100-mm VAS
Swollen joint count, 0–66
Axial night pain score, 0–3
ESR, mm/first hour
CRP level, mg/dl
HLA–B27, no. positive/no. negative
Previous DMARDs used
NSAIDs, no. using/no. not using
Corticosteroids, no. using/no. not using
Infliximab
Age, years
No. men/no. women
Disease duration, years
Patient global assessment, 0–100-mm VAS
Physician global assessment, 0–100-mm VAS
Swollen joint count, 0–66
Axial night pain score, 0–3
ESR, mm/first hour
CRP level, mg/dl
HLA–B27, no. positive/no. negative
Previous DMARDs used
NSAIDs, no. using/no. not using
Corticosteroids, no. using/no. not using
AS ⫹ PA
Total
AS
47.5 (29–66)
14/6
8 (2–34)
53.5 (24–92)
66.5 (51–94)
6 (1–17)
2 (0–3)
20 (2–107)
1.63 (0–8.37)
11/9
1 (0–3)
18/2
0/20
46.5 (29–58)
6/0
17 (6–26)
53.5 (27–69)
77 (56–78)
–
1.5 (1–3)
22.5 (12–53)
2.57 (1.75–7.13)
5/1
1 (0–2)
6/0
0/6
46 (31–66)
3/1
19 (2–34)
66.5 (45–90)
65.5 (54–94)
3 (1–11)
2 (1–2)
27 (2–107)
3.45 (0–8.37)
3/1
0.5 (0–2)
3/1
0/4
46 (26–65)
13/7
6.5 (1–20)
67 (17–96)
67.5 (59–88)
9 (1–19)
1 (0–3)
17 (1–69)
1.92 (0–6.96)
11/9
1 (0–4)
19/1
3/17
44 (40–46)
2/1
10 (5–20)
84 (37–96)
85 (72–87)
–
3 (2–3)
11 (5–40)
3.33 (0.8–4.29)
3/0
0 (0–1)
3/0
0/3
44.5 (35–60)
5/1
12 (2–19)
64 (17–83)
72 (59–88)
6.5 (1–19)
1.5 (1–2)
30 (11–69)
4.49 (1.05–6.96)
5/1
1.5 (1–2)
6/0
1/5
PsA
uSpA
47 (39–63)
4/5
5 (3–26)
47 (24–92)
65 (51–77)
8 (1–17)
2 (0–2)
8 (4–43)
0.8 (0.27–1.51)
3/6
2 (0–3)
8/1
0/9
54
1/0
5
85
83
2
2
23
2.47
0/1
2
1/0
0/1
48 (30–65)
5/4
5 (1–18)
66 (42–84)
65 (60–85)
9 (3–14)
1 (1–2)
11 (1–26)
0.96 (0–2.41)
2/7
2 (1–4)
8/1
2/7
41.5 (26–57)
1/1
2 (2–2)
80.5 (80–81)
68 (62–74)
1.5 (1–2)
1 (0–2)
21.5 (16–27)
2.18 (2.16–2.19)
1/1
1 (1–1)
2/0
0/2
* Except where otherwise indicated, values are the median (range). AS ⫽ ankylosing spondylitis; AS ⫹ PA ⫽ AS with peripheral arthritis; PsA ⫽
psoriatic arthritis; uSpA ⫽ undifferentiated spondylarthropathy; VAS ⫽ visual analog scale; ESR ⫽ erythrocyte sedimentation rate; CRP ⫽
C-reactive protein; DMARDs ⫽ disease-modifying antirheumatic drugs; NSAIDs ⫽ nonsteroidal antiinflammatory drugs.
† The placebo group had a total of 20 patients (6 with AS, 4 with AS ⫹ PA, 9 with PsA, and 1 with uSpA). The infliximab group had a total of 20
patients (3 with AS, 6 with AS ⫹ PA, 9 with PsA, and 2 with uSpA).
Table 2. Global disease assessments*
Patient global assessment, 0–100-mm VAS
Placebo
Infliximab
P, vs. placebo
Patient pain assessment, 0–100-mm VAS
Placebo
Infliximab
P, vs. placebo
Physician global assessment, 0–100-mm VAS
Placebo
Infliximab
P, vs. placebo
Night pain score, 0–3
Placebo
Infliximab
P, vs. placebo
ESR, mm/hour
Placebo
Infliximab
P, vs. placebo
CRP level, mg/dl
Placebo
Infliximab
P, vs. placebo
Baseline
(n ⫽ 40)
Week 1
(n ⫽ 40)
Week 8
(n ⫽ 39)
Week 12
(n ⫽ 38)
53.5 (24–92)
67 (17–96)
NS
64.5 (7–97)
26 (10–76)†
NS
52.5 (14–91)
30 (0–75)†
0.038
59.5 (0–94)
18 (0–66)†
ⱕ0.001
58 (2–81)
11 (1–68)†
ⱕ0.001
69 (0–100)
18 (2–78)†
ⱕ0.001
50 (16–90)
50.5 (14–95)
NS
60 (6–94)
31 (11–69)†
0.012
57 (18–93)
29 (0–71)‡
0.016
49.5 (1–91)
19 (0–68)†
0.002
58 (3–89)
15 (0–80)†
ⱕ0.001
58.5 (2–97)
18.5 (0–79)†
ⱕ0.001
66.5 (51–94)
67.5 (59–88)
NS
61.5 (15–97)
37 (10–74)†
0.009
70 (22–80)§
35 (11–65)†
ⱕ0.001
65.5 (7–93)§
18 (9–52)†
ⱕ0.001
66.5 (6–86)
14 (7–65)†
ⱕ0.001
72 (4–89)
16.5 (7–57)†
ⱕ0.001
2 (0–3)
1 (0–3)
NS
2 (0–3)
1 (0–2)
NS
2 (0–3)
1 (0–2)‡
0.006
2 (0–3)
1 (0–2)‡
0.016
2 (0–3)
1 (0–2)‡
0.01
20 (2–107)
17 (1–69)
NS
18.5 (1–113)
6 (1–40)†
0.003
15 (1–68)
3 (1–25)†
ⱕ0.001
14 (2–114)
3 (1–20)†
ⱕ0.001
20 (1–117)
3 (1–23)†
ⱕ0.001
1.9 (0–9.68)
0 (0–2.31)†
ⱕ0.001
1.6 (0–7.04)§
0.2 (0–2.63)†
0.003
1.3 (0–10.22)
0 (0–3.86)‡
ⱕ0.001
1.6 (0–8.37)
1.9 (0–6.96)
NS
1.5 (0–9.74)
0.3 (0–1.1)†
ⱕ0.001
Week 2
(n ⫽ 39)
Week 6
(n ⫽ 39)
2 (0–3)
1 (0–2)‡
0.008
17.5 (2–101)
3 (1–19)†
ⱕ0.001
1.6 (0–7.42)
0 (0–7.93)‡
ⱕ0.001
* Values are the median (range). Significance of comparisons with placebo is determined by the Mann-Whitney test. NS ⫽ not significant (see Table
1 for other definitions).
† P ⱕ 0.001 versus baseline, by Wilcoxon signed rank test.
‡ P ⱕ 0.01 versus baseline, by Wilcoxon signed rank test.
§ P ⱕ 0.05 versus baseline, by Wilcoxon signed rank test.
INFLIXIMAB VERSUS PLACEBO IN ACTIVE SpA
759
Figure 1. Patient and physician global assessments of disease activity
and C-reactive protein (CRP) levels in 40 patients with spondylarthropathy (20 treated with infliximab and 20 treated with placebo). A,
Patient global assessment on 100-mm visual analog scale (VAS). B,
Physician global assessment on 100-mm VAS. C, CRP levels in mg/dl.
Values at each point are medians. † ⫽ P ⱕ 0.05, ⴱ ⫽ P ⱕ 0.01, and
ⴱⴱ ⫽ P ⱕ 0.001 versus placebo, by Mann-Whitney test. ns ⫽ not
significant.
open-label study (24), assuming a 25% placebo response and a
0.05 Type I and Type II error. Statistical significance of the
change from baseline (intragroup analysis) was measured using
the Wilcoxon signed rank test. Comparison of the placebo and
infliximab groups was performed using the Mann-Whitney test.
P values of ⱕ0.05 were considered significant.
RESULTS
Forty patients were enrolled in the study and
subsequently randomly assigned to treatment. Table 1
shows the demographic and descriptive characteristics of
the patients in the placebo and infliximab groups. Patients were classified as having AS with only axial
disease, AS with peripheral arthritis (AS ⫹ PA), PsA,
and uSpA. The infliximab and placebo groups were well
matched at entry, with no significant differences in age,
sex ratio, disease duration, number of failed diseasemodifying antirheumatic drugs (DMARDs), the two
primary end points of the study (patient and physician
assessment of global disease activity), ESR, and CRP
level. Nearly all patients were taking NSAIDs at study
entry; 3 patients in the infliximab group were taking
low-dose prednisolone (2 with PsA, 1 with AS ⫹ PA).
HLA–B27 status was comparable in the two groups.
General assessments were performed in all patients.
Peripheral disease was evaluated in 30 patients who
presented with at least 1 swollen joint (13 in the placebo
group, 17 in the infliximab group). Axial evaluation was
performed in 21 patients fulfilling the modified New
York criteria for AS (12 in the placebo group, 9 in the
infliximab group), including 2 patients with PsA who
also fulfilled these criteria (both in the placebo group).
Global assessments. Global assessments were
performed in all patients at baseline and at weeks 1, 2, 6,
8, and 12. The results are shown in Table 2. A significant
improvement in the infliximab group (but not in the
placebo group) was observed for both primary end point
parameters (patient and physician global assessment of
disease activity), as well as for the patient assessment of
pain and the intensity of night pain. Among the laboratory variables, a significant decrease was noted for ESR
and CRP level in the infliximab group. This improvement was statistically significant (compared with the
760
VAN DEN BOSCH ET AL
Table 3. Peripheral disease assessments*
Morning stiffness, minutes
Placebo
Infliximab
P, vs. placebo
Peripheral joint pain, 0–100-mm VAS
Placebo
Infliximab
P, vs. placebo
Tender joint count, 0–68
Placebo
Infliximab
P, vs. placebo
Swollen joint count, 0–66
Placebo
Infliximab
P, vs. placebo
Baseline
(n ⫽ 30)
Week 1
(n ⫽ 30)
Week 2
(n ⫽ 29)
Week 6
(n ⫽ 29)
30 (0–300)
60 (0–300)
NS
25 (0–300)
30 (0–200)†
NS
60 (0–300)
30 (0–180)‡
NS
60 (0–300)
15 (0–180)†
NS
60 (7–95)
28.5 (3–67)†
NS
59 (10–83)
27 (0–57)‡
0.005
41 (6–87)
31 (2–60)†
NS
65.5 (11–91)
21 (2–56)†
0.001
6 (0–31)
10 (3–26)
NS
3 (0–41)
6 (0–26)‡
NS
4 (0–36)
4.5 (0–15)‡
NS
5 (0–38)
3 (0–12)‡
NS
5 (0–40)
1 (0–11)‡
0.032
6 (1–17)
9 (1–19)
NS
3 (0–16)§
3 (0–13)†
NS
3 (0–13)§
2 (0–14)‡
NS
63 (5–91)
52.5 (20–68)
NS
2 (0–18)
1 (0–8)‡
NS
Week 8
(n ⫽ 29)
60 (0–280)
30 (0–120)‡
NS
2 (0–21)
1.5 (0–8)‡
NS
Week 12
(n ⫽ 28)
60 (0–240)
17.5 (0–90)‡
0.038
70 (0–91)
19 (1–51)‡
0.002
8 (0–42)
2 (0–8)‡
0.015
3 (0–32)
1 (0–9)‡
NS
* Values are the median (range). Significance of comparisons with placebo is determined by the Mann-Whitney test. See Tables 1 and 2 for
definitions.
† P ⱕ 0.01 versus baseline, by Wilcoxon signed rank test.
‡ P ⱕ 0.001 versus baseline, by Wilcoxon signed rank test.
§ P ⱕ 0.05 versus baseline, by Wilcoxon signed rank test.
baseline value) for all of these variables from week 1
onward, with the exception of night pain, which became
significant at week 2. Moreover, for all variables, there
was a statistically significant difference between the
infliximab and placebo groups which was present from
week 2 onward. The evolution of the median value for
patient and physician global assessment of disease activity as well as that for CRP level is illustrated in Figure 1.
Peripheral assessments. The peripheral disease
assessments were performed at baseline and at weeks 1,
2, 6, 8, and 12 in 30 patients who had at least 1 swollen
joint at baseline. The results are shown in Table 3. In the
infliximab group, an improvement compared with baseline was observed for all variables. With the exception of
the swollen joint count, these improvements were statistically significant compared with the placebo group.
Individual patient values for tender and swollen joint
count at baseline and week 12 are shown in Figure 2.
Axial assessments. The questionnaires were
filled in by the patient at baseline and at weeks 1, 2, 6, 8,
and 12, and physician assessments and metrology of the
spine were performed at baseline and at weeks 2, 6, and
12. The results are shown in Tables 4 and 5, respectively.
Morning stiffness of the spine as well as functional
(BASFI, DFI) and disease activity (BASDAI) scores
improved significantly in the infliximab group compared
with baseline (Table 4). For some variables (morning
stiffness, BASDAI and BASFI scores), this improve-
Figure 2. Peripheral assessments of disease activity in 30 patients with spondylarthropathy, by treatment group. Individual patient data are
shown at baseline (week 0) and at week 12. A, Tender joint count. B, Swollen joint count. Shown are P values for week 12 versus baseline, by
Wilcoxon signed rank test.
INFLIXIMAB VERSUS PLACEBO IN ACTIVE SpA
761
Table 4. Axial disease assessments by 21 patients*
Baseline
Morning stiffness, minutes
Placebo
Infliximab
P, vs. placebo
Spinal pain, 0–100-mm VAS
Placebo
Infliximab
P, vs. placebo
BASDAI score, 0–100
Placebo
Infliximab
P, vs. placebo
BASFI score, 0–100
Placebo
Infliximab
P, vs. placebo
DFI score, 0–40
Placebo
Infliximab
P, vs. placebo
75 (5–210)
60 (0–230)
NS
63.5 (40–95)
30 (0–87)
NS
Week 1
Week 2
Week 6
75 (5–210)
25 (0–120)†
NS
75 (2–220)
15 (0–120)†
0.041
60 (5–220)
15 (0–100)†
0.049
97 (33–91)
13 (0–69)†
0.002
65.5 (17–90)
29 (0–75)
0.009
Week 8
56 (3–72)†
15 (0–64)
0.018
90 (0–220)
15 (0–60)†
0.018
Week 12
95 (10–600)
15 (0–60)†
0.006
71 (1–88)
11.5 (0–60)
0.002
53.5 (3–96)
16 (0–43)
0.002
52.7 (27.5–85.4)
58.9 (16.3–93.1)
NS
53.2 (14.6–100)
26.2 (8.7–72.6)†
0.025
56.6 (13.3–95)
24.2 (3.8–67.7)‡
0.023
50.8 (2–90.5)
16.8 (3–59.7)‡
NS
62.1 (2.1–88.5)
8.5 (0.6–47.9)†
0.002
50.1 (3.2–94.1)
26.6 (1.2–30.7)‡
0.002
58.9 (14.8–94.6)
46.5 (31.2–98.4)
NS
57.6 (8.5–92.8)
35.8 (13–91)†
NS
59.5 (4.1–92.2)
31.7 (6–90.5)†
NS
59.1 (1.4–92.5)
27.9 (0.4–87.3)‡
NS
68.4 (0.7–91)
23.2 (0.3–81.1)†
NS
71.9 (0.4–97.4)
27.4 (1.5–77.6)‡
0.041
15.3 (4–28.5)
15.5 (9.5–31.5)
NS
14 (4–28)
10 (4–29.5)†
NS
15.3 (3–28)
10.5 (1.5–29)†
NS
15.8 (1.5–24.5)
8 (1–32)†
NS
16.5 (0–25.5)
7.3 (0.5–25.5)†
NS
17.3 (0–26)
8 (1–27)‡
NS
* Values are the median (range). Significance of comparisons with placebo is determined by the Mann-Whitney test. BASDAI ⫽ Bath Ankylosing
Spondylitis Disease Activity Index; BASFI ⫽ Bath Ankylosing Spondylitis Functional Index; DFI ⫽ Dougados Functional Index (see Tables 1 and
2 for other definitions).
† P ⱕ 0.05 versus baseline, by Wilcoxon signed rank test.
‡ P ⱕ 0.01 versus baseline, by Wilcoxon signed rank test.
ment was statistically significant compared with placebo
(Table 4). The physician-assessed spinal pain score and
the AID score improved significantly in the infliximab
group compared with baseline and placebo (Table 5),
whereas in the metrologic assessments of the spine, no
significant differences (infliximab versus placebo group)
Table 5. Axial disease assessments of 21 patients by the physician*
Spinal pain score, 0–4
Placebo
Infliximab
P, vs. placebo
BASMI score, 0–10
Placebo
Infliximab
P, vs. placebo
Occiput to wall, cm
Placebo
Infliximab
P, vs. placebo
Chest expansion, cm
Placebo
Infliximab
P, vs. placebo
Fingers to floor, cm
Placebo
Infliximab
P, vs. placebo
AID score, 0–30
Placebo
Infliximab
P, vs. placebo
Baseline
Week 2
Week 6
Week 12
2 (0–3)
3 (0–4)
NS
2 (0–4)
1 (0–3)†
NS
2.5 (0–3)
1 (0–3)†
NS
3 (0–4)
1 (0–2)†
0.006
4 (2–7)
5 (2–10)
NS
4 (1–8)
4 (1–10)†
NS
4 (1–8)
4 (1–10)†
NS
4 (1–8)
4 (1–10)
NS
7.3 (3–16)
6 (3–26)
NS
7 (2.5–15)
3 (2–24)‡
NS
7.5 (2–14.5)
2 (2–26)†
NS
7.8 (2–15)
2 (1.5–25)‡
NS
3.3 (1.2–5.5)
3.5 (0.8–6.5)
NS
3.3 (2.2–5.5)
4 (1.5–6)
NS
3.5 (2–6.5)
5 (1.5–7)†
NS
4 (2.2–6)
4.5 (2–7)
NS
23 (0–45)
25 (0–63)
NS
21 (2–44)
30 (0–63)
NS
21 (0–41)
23 (0–60)
NS
4.5 (0–11)
5 (0–12)
NS
4 (0–12)
3 (0–10)
NS
5.5 (0–14)
0 (0–5)†
0.003
21.5 (0–42)
30 (0–59)
NS
7.5 (0–19)†
1 (0–7)†
0.015
* Values are the median (range). Significance of comparisons with placebo is determined by the Mann-Whitney test. BASMI ⫽ Bath Ankylosing
Spondylitis Metrology Index; AID ⫽ articular index according to Dougados (see Table 2 for other definitions).
† P ⱕ 0.05 versus baseline, by Wilcoxon signed rank test.
‡ P ⱕ 0.01 versus baseline, by Wilcoxon signed rank test.
762
VAN DEN BOSCH ET AL
Figure 3. Axial assessments of disease activity in 21 patients with spondylarthropathy, by treatment group. Individual patient data are shown
at baseline (week 0) and at week 12. A, Bath Ankylosing Spondylitis Disease Activity Index scores. B, Bath Ankylosing Spondylitis Functional
Index scores. Shown are P values for week 12 versus baseline, by Wilcoxon signed rank test.
could be detected in this short-term trial. Individual
patient values for the BASDAI and BASFI are shown in
Figure 3.
Psoriasis skin disease. The effect on skin disease
was evaluated using the PASI. No conclusions could be
drawn, since the placebo and infliximab groups were not
matched for this variable and there was already a
significant difference between the groups at baseline.
The median score in the placebo group was 8.9 (range
0.06–22.4), while that in the infliximab group was 0.235
(range 0–2.98).
Safety analysis. Two serious adverse events
(SAEs) were observed in the infliximab-treated group,
and both patients were withdrawn from the study. The
first SAE was considered to be drug related. The patient
was a 65-year-old man with PsA. All screening examinations (including chest radiograph) yielded results within
the normal range; there was no history of previous
tuberculosis in this patient. There were clear improvements in the assessments of disease activity by the
patient and physician on a 100-mm VAS from baseline
values of 42 and 78, respectively; at week 8, these values
had decreased to 10 and 13, respectively. At week 9 (3
weeks after the third infusion), the patient developed a
systemic illness with general malaise and high-peaking
fever; measures of inflammation, such as ESR and CRP
level, were markedly elevated. Further examinations
revealed nodular lesions in the spleen and liver, as well
as mediastinal lymphadenopathies. Biopsy samples of a
mediastinal lymph node, obtained through mediastinoscopy, revealed specific histologic features of tuberculosis, with the presence of acid-fast bacilli. Cultures of
gastric fluid obtained in the initial phase of the illness
were positive for Mycobacterium tuberculosis. The patient was treated with isoniazid, rifampin, pyrazinamide,
and ethambutol, and is slowly recovering.
The second SAE was considered to be procedure
related rather than drug related. The patient was a
26-year-old man with uSpA who presented with a
therapy-resistant arthritis of the right knee. One week
after the start of the blinded study drug, the patient
experienced a marked improvement in signs and symptoms (at week 1, patient global assessment dropped from
80 to 34 and physician global assessment decreased from
62 to 25 [both on a 100-mm VAS], and CRP level
decreased from 2.16 mg/dl to 0.2 mg/dl). Synovial biopsy
samples were obtained by needle arthroscopy to further
document the clinical response seen in this patient. One
day after this procedure, the patient developed an acute
exacerbation of arthritis of the right knee, with marked
systemic (CRP level 13.16 mg/dl) and local (synovial
fluid WBC count 20,800/␮l; 95% neutrophils) inflammation. Culture and polymerase chain reaction of the
synovial fluid yielded negative results. For safety reasons, this arthritis was considered a septic arthritis, and
the patient was treated with intravenous antibiotics,
recovering fully within 48 hours.
All other minor AEs were recorded and are
shown in Table 6. There were no significant differences
between the incidence of these AEs in either of the two
treatment arms. No peri-infusional AEs were observed;
vital parameters remained within normal range during
the infusions and for 1 hour afterward. Laboratory tests
were performed as described above, and no significant
changes were seen.
INFLIXIMAB VERSUS PLACEBO IN ACTIVE SpA
763
Table 6. Minor adverse events recorded from baseline to week 12
Treatment group
Infections
Common cold
Cystitis
Tooth abscess
Sore throat
Cardiovascular
Palpitations
Gastrointestinal
Nausea
Abdominal pain
Skin
Itching (no rash)
Injection-site reaction
Neurologic
Headache
Dizziness
Paresthesia
Eye
Uveitis
Conjunctivitis
Other
Fatigue
Hyperventilation
Epistaxis
Infliximab
Placebo
5
0
0
1
3
1
1
1
0
1
1
1
0
0
2
0
2
1
2
2
1
0
0
1
1
1
0
0
3
0
1
2
1
0
Detection of ANAs. At baseline, 4 patients in the
placebo group and 3 patients in the infliximab group
were ANA positive. In the placebo group, 3 of the 4
patients remained positive at week 12 (with the same
ANA fluorescence score); 1 patient had a negative test
result at week 12, and no specific reactivities to dsDNA
or extractable nuclear antigens could be determined. In
the infliximab group, 1 patient remained ANA positive
with the same ANA score, 1 patient became ANA
negative, and 1 patient had a rise in his ANA score from
2⫹ to 4⫹. Moreover, 4 patients in the infliximab group
who were ANA negative at the beginning of the study
developed a positive ANA score (ranging from 3⫹ to
4⫹) at week 12; 2 patients in this group also developed
anti-dsDNA antibodies. However, no lupus-like symptoms were observed. Nevertheless, all patients are still
being followed up.
DISCUSSION
We report here the results of the first doubleblind, placebo-controlled trial of infliximab in patients
with different subtypes of active SpA, including AS (with
or without peripheral arthritis), PsA, and uSpA. The aim
of this study was to confirm the fast and significant
improvement of global, peripheral, and axial disease
manifestations seen in a previously reported open pilot
study (24). All patients are still in followup to enable the
reporting of longer term efficacy and safety. The design
of the present trial included treatment of all patients in
one center with wide experience in the use of biologic
therapies for autoimmune arthritis, comparison of active
treatment (infliximab) with placebo in a population not
receiving other DMARDs, blinding of the clinical observer to the treatment group and the results of the
laboratory tests, and the use of a single observer for all
patients throughout the study.
The two treatment groups were well matched at
entry, both for demographic features and for baseline
clinical and laboratory measures of disease activity,
attesting to the effectiveness of the randomization procedure. Large and highly significant differences were
seen in the response rates between the infliximab and
placebo groups. When looking at the global assessments
of disease activity in these 40 patients, it is important to
note that there was virtually no placebo response in this
population. Only 3 individual patients (1 with AS, 2 with
PsA) in the placebo group displayed an improvement,
while most of them experienced stable or worsening
disease.
The sample size was calculated based on the data
from the pilot trial concerning the two primary end
points. While this number of patients was appropriate to
confirm the efficacy seen in the open-label trial, it was
not designed to yield statistically significant results in the
subgroup analysis (e.g., tender and swollen joint counts
in patients with peripheral arthritis, BASDAI and
BASFI scores in patients with AS). Therefore, the
number of patients in each subgroup is relatively small
and does not allow the drawing of definite conclusions
about the response in these subgroups. However, of the
18 patients who completed the study in the infliximab
group, 17 experienced a major improvement, suggesting
that all patients responded to the treatment equally.
The medians for patient and physician global
assessments of disease activity decreased from 67 and
67.5 to 18 and 16.5, respectively, representing improvements of 73% and 76%. Analysis of laboratory indices of
inflammation (ESR, CRP level) showed the same impressive improvement in the infliximab-treated group
compared with placebo. Other disease activity assessments for both peripheral and axial disease also showed
significant improvements in the infliximab group, but
not in the placebo group. Skin disease was not evaluated,
since the two treatment groups already differed significantly in the extent and severity of psoriasis at study
764
entry, making it impossible to draw conclusions about
the effect of the drug.
The infliximab infusions were well tolerated; no
allergic or anaphylactic reactions were observed. Two
patients in the infliximab group were withdrawn from
the trial; one was diagnosed as having disseminated
tuberculosis, while the other had an acute exacerbation
of arthritis following needle arthroscopy. As of January
2001, 33 incident cases of tuberculosis (30 in postmarketing experience) have been described in patients
treated with infliximab (data on file with Centocor).
Eleven of these 33 patients had normal pretreatment
chest radiographs, which was also the case in our patient.
Skin tests were not systematically performed and were
only available in a minority of patients. With regard to
this potentially fatal complication, a careful pretreatment screening with chest radiograph and skin test
seems appropriate.
Minor AEs not leading to discontinuation of the
trial were observed equally in the two treatment groups.
We observed the occurrence in the infliximab group (but
not in the placebo group) of ANAs in 4 patients (20%)
who were ANA negative at the start of the study; 2
patients (10%) also developed anti-dsDNA antibodies.
However, no lupus-like symptoms were observed. In RA
patients treated with infliximab, a similar occurrence of
ANAs and anti-dsDNA antibodies was observed (34).
The incidence of ANAs in the infliximab-treated patients rose from 29% pretreatment to 53% posttreatment. No RA patients were anti-dsDNA antibody positive prior to treatment with infliximab; 14% became
anti-dsDNA antibody positive posttreatment. Only 1 of
the 156 patients who were treated with infliximab developed a self-limiting clinical lupus syndrome. Fewer data
exist concerning the development of anti-dsDNA antibodies in etanercept-treated RA patients. In one study,
10 of 214 etanercept-treated patients were newly positive for anti-dsDNA antibodies (35). In a combination
study with MTX, 4 of 59 patients newly developed
anti-dsDNA antibodies after 24 weeks of treatment with
25 mg etanercept twice weekly (36). In these studies, no
symptoms suggestive of drug-induced lupus occurred,
with the exception of 1 patient who had a systemic lupus
erythematosus/RA overlap syndrome that had been
diagnosed many years before study enrollment (35).
These data confirm the findings of the open-label
trial of infliximab (24) in a similar patient group. Together with the results from previous open-label studies
with infliximab (18,19,25) and a placebo-controlled trial
of etanercept in PsA (20), they indicate that TNF␣ plays
a prominent role in the pathogenesis and disease man-
VAN DEN BOSCH ET AL
ifestations of SpA, and that blockade of this cytokine is
highly effective in reducing signs and symptoms in this
disease group as a whole. However, the mechanism by
which infliximab exerts its effect in SpA remains unknown. We previously demonstrated that the clinical
effect of TNF␣ blockade, seen in the open-label study,
was paralleled by a restoration of the impaired Th1
cytokine profile (37), pointing toward a systemic effect
of the drug. Moreover, a local biologic effect at the site
of the joint was also observed (38). As part of the
protocol of the present study, we performed needle
arthroscopy with synovial biopsy sampling in patients
with active knee arthritis. The immunohistologic features observed before and after infliximab treatment
(versus placebo) are still being analyzed; these results
will be communicated separately.
We report the results of a successful randomized,
placebo-controlled, short-term trial of infliximab in different subtypes of active SpA. The data indicate for the
first time that there may be an effective therapeutic
option in severe SpA. However, the occurrence of
tuberculosis, which was observed in one patient treated
with infliximab, necessitates strict inclusion criteria with
careful screening by chest radiograph and skin test.
Moreover, longer term experience and followup are
needed to determine the optimal maintenance regimen
(dose and interval) and to detect possible long-term side
effects.
ACKNOWLEDGMENTS
We especially thank Dr. Freddy Cornillie of Centocor.
We thank Dr. Ilse Hoffman for her help in this study, and the
following rheumatologists for referring patients: Dr. Eric
Dhondt, Dr. Rik Joos, Dr. Hilde Luyten, Dr. Stefaan Poriau,
Dr. Benedicte Vanneuville, Dr. Ann Verbruggen, Prof. Gust
Verbruggen, and Dr. Hans Zmierczak.
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