marc lémann,* jean–yves mary,‡ bernard duclos,§ michel - IG-IBD

Infliximab Plus Azathioprine for Steroid-Dependent Crohn’s
Disease Patients: A Randomized Placebo-Controlled Trial
MARC LÉMANN,* JEAN–YVES MARY, ‡ BERNARD DUCLOS, § MICHEL VEYRAC,
JEAN–LOUIS DUPAS, JEAN CHARLES DELCHIER, # DAVID LAHARIE,** JACQUES MOREAU, ‡‡
GUILLAUME CADIOT, §§ LAURENCE PICON, ARNAUD BOURREILLE, IRADJ SOBAHNI, ##
JEAN–FREDERIC COLOMBEL,*** and the Groupe d’Etude Therapeutique des Affections
Inflammatoires du Tube Digestif (GETAID)*
*Department of Gastroenterology, Hôpital Saint-Louis, Paris, France; ‡ INSERM U717, Biostatistics and Clinical Epidemiology, Hôpital Saint-
Louis, Université Paris, France; § Department of Gastroenterology, Hôpital Hautepierre, Strasbourg, France; Department of Gastroenterology,
Hôpital Saint-Eloi, Montpellier, France; Department of Gastroenterology, Hôpital Nord, Amiens, France; # Department of Gastroenterology,
Hôpital Henri Mondor, Créteil, France; **Department of Gastroenterology, Hôpital Haut-Lévêque, Bordeaux, France; ‡‡ Department of
Gastroenterology, Hôpital Rangueil, Toulouse, France; §§ Department of Gastroenterology, Hôpital Robert Debré, Reims, France; Department
of Gastroenterology, Hôpital Trousseau, Tours, France; Department of Gastroenterology, Hôtel Dieu, Nantes, France; ## Department of
Gastroenterology, Hôpital Bichât, Paris, France; ***Department of Gastroenterology, Hôpital Claude Huriez, Lille, France
See editorial on page 1354; CME Quiz on page 1348.
Background & Aims: The aim of this study was to
evaluate the usefulness of short-term infliximab combined
with azathioprine (AZA) or 6-mercaptopurine
(6-MP) in steroid-dependent Crohn’s disease patients.
Methods: Patients with active disease despite prednisone
given for more than 6 months were eligible
and were stratified as follows: the failure stratum
consisted of patients receiving AZA/6-MP at a stable
dose for more than 6 months, and the naive stratum
consisted of patients not treated previously with AZA/
6-MP. Patients were randomized to infliximab 5
mg/kg or placebo at weeks 0, 2, and 6. All patients
were treated with AZA/6-MP maintained at a stable
dose throughout the 52 weeks of the study. The primary
end point was remission off steroids at week 24.
Results: Among the 113 enrolled patients (55 in the
failure stratum), 57 were assigned to infliximab. At
week 24, the success rate (intent-to-treat analysis)
was higher in the infliximab group than in the placebo
group (57% vs 29%; P .003); at weeks 12 and 52,
the corresponding rates were 75% vs 38% (P < .001)
and 40% vs 22% (P .04), respectively. In each
stratum, the success rate was significantly higher in
the infliximab group at weeks 12 and 24, and a trend
was found at week 52. In the failure stratum, only
27% of the patients in the infliximab group were still
in remission off steroids, compared with 52% in the
naive stratum. Steroid resistance was less common
and the cumulative dose of prednisone was lower in
the infliximab group. Conclusions: Infliximab plus
AZA/6-MP is more effective than AZA/6-MP alone in
steroid-dependent Crohn’s disease patients.
GASTROENTEROLOGY 2006;130:1054–1061
Corticosteroids are the first-line conventional therapy
for patients with active Crohn’s disease (CD) of
moderate to severe activity. Their efficacy, defined as
achievement of a complete clinical remission, ranges
from 48% to 92%. 1,2 This therapeutic benefit is counterbalanced
by side effects attributable to systemic action
and to inhibition of endogenous adrenal function. In
addition, 20%–40% of patients develop dependence on
corticosteroids and are exposed to prolonged treatment.
1,2 Controlled trials, 3–5 a meta-analysis, 6 and a Cochrane
review7 have shown that azathioprine (AZA) and
6-mercaptopurine (6-MP) are effective in CD both for
maintaining remission and as steroid-sparing agents in
chronic active steroid-dependent patients. A major problem
with AZA/6-MP is its delay of action, which has
been estimated to be a median of 3 months. 4 Consequently,
it often is necessary to maintain steroids for
several months, exposing patients to their side effects.
Infliximab, the chimeric monoclonal IgG1 antibody to
tumor necrosis factor (Remicade; Centocor, Malvern, PA)
has greatly improved our management of CD. The rapid
efficacy of infliximab in inducing remission in patients
with active CD was shown in placebo-controlled trials. 8,9
We hypothesized that infliximab may be useful for steroid-dependent
CD patients in combination with a slowacting
immunosuppressant (AZA/6-MP) to reduce steroid
exposure and to improve long-term remission rate.
Abbreviations used in this paper: AZA, azathioprine; CDEIS, Crohn’s
Disease Endoscopic Index of Severity; CI, confidence interval; OR, odds
ratio; 6-MP, 6-mercaptopurine.
© 2006 by the American Gastroenterological Association Institute
0016-5085/06/$32.00
doi:10.1053/j.gastro.2006.02.014

April 2006 INFLIXIMAB AND AZATHIOPRINE 1055
The aim of the present study thus was to evaluate the
usefulness of infliximab (3 infusions) combined with
AZA/6-MP compared with AZA/6-MP alone for achieving
clinical remission off steroids in steroid-dependent
CD patients.
Materials and Methods
Patients
Eligible patients were at least 18 years old and had
luminal steroid-dependent CD. The diagnosis of CD was based
on established clinical, endoscopic, radiologic, and histologic
criteria. Steroid dependency was defined as follows: (1) prednisone
had to be given for at least 6 months at a dosage 10
mg/day or more, with no interruption for more than 2 months
within the past 6 months; (2) at least 2 clinical luminal
relapses when tapering of steroids had been attempted, leading
to an increase in the dose to more than 10 mg/day; and (3) the
last attempt for steroid tapering had to be within the past 6
months. At baseline, patients had to be treated with prednisone
10 mg/day or more. Regarding AZA/6-MP status at
baseline, 2 types of patients could be included: those in the
naive stratum who did not receive AZA/6-MP in the past 2
years, and those in the failure stratum who still had clinically
active disease (Crohn’s Disease Activity Index [CDAI] 150)
despite receiving AZA/6-MP for more than 6 months at a
stable and appropriate dose (2–3 mg/kg/day for AZA and
1–1.5 mg/kg/day for 6-MP). Men and women with reproductive
potential were required to practice birth control throughout
the study and for 6 months after the last infliximab
infusion.
The exclusion criteria were as follows: (1) contraindication
to AZA/6-MP or to infliximab according to labeling recommendations;
(2) treatment with an immunosuppressive drug
other than AZA/6-MP in the past 6 months; (3) previous use
of infliximab or other anti–tumor necrosis factor drugs including
thalidomide; (4) concomitant treatment with aminosalicylates,
budesonide, topical steroids, or artificial nutrition; or
(5) presence of at least 1 of the following conditions: symptomatic
stricture, intra-abdominal abscess or infection, severe
sepsis within the past 3 months, tuberculosis (because the
bacillus Calmette-Guérin vaccination still is recommended in
France, patients with a tuberculin skin test 10 mm and a
bacillus Calmette-Guérin vaccination performed 10 years
before the tuberculin skin test were excluded), history of B or
C hepatitis, human immunodeficiency virus infection, liver
failure, pregnancy, breast-feeding, or participation in pharmaceutical
research within the past 3 months.
Study Design
This randomized, multicenter, double-blind, placebocontrolled
trial was performed at 22 sites in France; all physicians
were members of the Groupe d’Etude Thérapeutique
des Affections Inflammatoires du tube Digestif (GETAID).
The recruitment of patients took place from June 2000 to May
2002.
When the study was designed, we hypothesized that results
could be different depending on whether or not patients
received AZA/6-MP at inclusion. Patients thus were randomized
per stratum (AZA/6-MP failure or naive) and per center to
receive either infliximab or placebo in a 1:1 ratio. The randomization
was performed centrally, using permutation tables
of size 2 or 4 according to the number of patients that we
anticipated would be enrolled at each center per stratum.
The protocol was approved by the ethical committee (Comité
Consultatif de Protection des Personnes dans La Recherche
Biomédicale Paris Saint-Louis) for each participating center.
Written informed consent was obtained from all patients
before enrollment into the study.
Treatments
Infliximab/placebo. According to the randomization,
patients received at 0, 2, and 6 weeks either a 2-hour
infusion of infliximab (Remicade) administered at a dose of 5
mg/kg or an infusion of an identical placebo. Neither the
patients nor the study investigators were aware of the treatment
assigned.
Azathioprine/6-MP. All patients were treated with
AZA (2–3 mg/kg per day) or 6-MP (1–1.5 mg/kg per day).
Patients previously treated with AZA or 6-MP (failure stratum)
continued their treatment at the same dose; in the
naive-stratum patients, AZA (2–2.5 mg/kg per day) was
started 1 week after the first infliximab infusion (to differentiate
side effects related to infliximab from those related to
AZA). The AZA or 6-MP dose had to be maintained at a stable
dose throughout the study, except for patients who experienced
toxicity related to the drug. If leukopenia (1500
neutrophils/mL) or mild transaminase increases occurred (2
times the upper limit of normal value), the AZA/6-MP dose
was decreased by 50%.
Steroids. At baseline, all patients were treated with
prednisone or prednisolone at a daily dose of 10 mg or more.
In patients with active disease (CDAI, 150), the steroid daily
dose was increased by 15 mg. After 2 weeks, in patients with
a clinical remission (CDAI, 150), steroids were tapered
according to a standardized scheme (10 mg/wk to a daily dose
of 20 mg, and then 5 mg/wk). If the CDAI still was more than
150 after 2 weeks, the prednisone daily dose could be increased
to 40 mg/day or 1 mg/kg of body weight/day. Throughout the
study, in patients who experienced a relapse, steroids were
reintroduced or increased until a new remission was achieved,
and then tapered according to the same scheme.
Patients who did not reach a clinical remission after 2 weeks
with 40 mg/day or more were considered to be steroid resistant
and were classified as treatment failures; they were offered
infliximab infusion in an open-label fashion.
Other treatments. Concomitant treatment that has
been shown to facilitate steroid withdrawal in steroid-dependent
patients such as mesalamine, budesonide, artificial nutrition,
or other immunosuppressive drugs were not allowed
during the study.

1056 LEMANN ET AL GASTROENTEROLOGY Vol. 130, No. 4
Data Collection
A complete medical history and current medications
were recorded at study inclusion. Physical examination and
laboratory tests (C-reactive protein, erythrocyte sedimentation
rate, blood counts, liver tests) were performed at screening and
at each visit (weeks 0, 2, 6, 12, 24, and 52). The CDAI, 10 a
steroid side-effect score, and the cumulative doses of steroids
also were calculated at each visit. A chest radiograph and
tuberculin test were performed at inclusion and at week 24. A
colonoscopy was performed, if the patient agreed, at baseline
and at week 24, and the Crohn’s Disease Endoscopic Index of
Severity (CDEIS) was calculated. 11 Adverse events were recorded
at each visit and were classified as mild, moderate, or
severe; the relationship to study medications also was evaluated.
The CDAI10 was calculated by using patient reports of
symptoms on diary cards within the week preceding each visit.
The CDEIS was assessed according to the presence and the
extent of lesions and ulcerations (deep or superficial), and
according to the presence of ulcerated and nonulcerated strictures
on the 5 following segments: rectum, sigmoid and left
colon, transverse colon, right colon, and ileum. 11 The steroid
side-effects score was calculated as follows: 1 point was attributed
for each minor to moderate side effect including acne,
swelling of the face, buffalo hump, striae, moderate increase in
abdominal fat, insomnia or minor psychic disturbances, and
other minor side effects; and 2 points for each severe side effect
including amyotrophy and/or muscular weakness, pronounced
cushingoid obesity, severe acne, diabetes mellitus, cataract,
symptomatic bone complications, severe psychic disturbances,
high blood pressure, or other severe side effects; the score could
vary from 0 to 16.
End Points
All primary and secondary end points were prespecified.
The primary efficacy end point was the rate of success,
defined as a clinical remission (CDAI 150) 12 off steroids at
week 24. Secondary efficacy end points were as follows: (1)
success rate at week 12, (2) rate of steroid resistance, (3)
cumulative dose of prednisone at week 24, (4) steroids sideeffect
score at weeks 6, 12, and 24, (5) endoscopic improvement
between inclusion and week 24, and (6) adverse events.
A follow-up evaluation also was planned at week 52, with
assessment of the success rate. During the follow-up period
(weeks 24–52), all treatments could be given as necessary;
patients who had a relapse or received additional infusions of
infliximab were classified as treatment failures.
Statistical Analysis
The sample size calculation was based on the assumption
that infliximab would be better than placebo (1-sided
basis). We estimated that 128 patients were needed to detect
a crude difference of 20% for the primary end point between
placebo and infliximab, assuming a remission rate of 60% with
the placebo, with a power of 80%. The analysis of efficacy was
performed according to the intent-to-treat principle. All pa-
tients enrolled and not lost to follow-up evaluation were
included in the efficacy analysis, except if the CDAI was
missing. The analysis of safety was conducted including all
patients who had received at least 1 infusion of study medication.
Categoric variables were described using frequencies and
percentages and their distributions were compared between
treatment groups, globally, and per stratum by using the 2
test or the Fisher exact test. Continuous variables were summarized
using the frequency, median, and interquartile range
and their distributions were compared between treatment
groups using the Mann–Whitney test.
Success rates (the primary end point) were compared using
the 2 test (globally and per stratum); the multiple logistic
regression method also was used to estimate the odds ratio
(OR) of success with 95% confidence intervals (CIs) and to test
if the efficacy of infliximab compared with placebo was different
across strata (interaction between treatment and stratum).
Success at 12 or 52 weeks and steroid resistance were analyzed
similar to the primary end point. The cumulative dose of
prednisone, steroid side-effect score, and decrease in the CDEIS
were analyzed using the Mann–Whitney test.
Multivariate logistic regression analysis, adjusted on treatment
and stratum, with backward selection using the likelihood
ratio test, was used to look for factors measured at
baseline that were independently predictive of success at week
24. Variables were proposed to this analysis if the P value was
less than .30 in the univariate analysis. Continuous factors
were categorized as follows: each variable first was divided into
4 categories at approximately the 25th, 50th, and 75th percentiles.
If the ORs of adjacent categories were not statistically
different, these categories were grouped. If no clear pattern was
observed, the median was taken as a cut-off point. Usual
limits, such as 150 for the CDAI, also were tested. The
treatment effect and treatment-strata interaction were tested
after adjustment on independent prognostic factors. Results
were expressed as ORs with 95% CIs.
Results were considered significant when the P value was
less than .05. Data were analyzed with SPSS Software for
Windows, release 6.1 (SPSS Inc, Chicago, IL).
Results
Baseline Characteristics of Patients
The trial profile is shown in Figure 1. A total of
115 patients were randomized (56 in the failure stratum/59
in the naive stratum); 57 patients (26 in the
failure stratum) were assigned randomly to receive infliximab
and 58 patients (30 in the failure stratum) to
receive placebo. Two patients allocated to placebo treatment
(1 in each stratum) were not enrolled and did not
receive the first infusion, 1 patient because his CDAI was
less than 150 at inclusion and the other patient because
he withdrew his consent before the inclusion visit.

April 2006 INFLIXIMAB AND AZATHIOPRINE 1057
Figure 1. Flow chart of patients
randomized in the trial. The figures
in parentheses correspond
to the number of patients in the
naive stratum and the failure
stratum, respectively.
Characteristics of the 113 enrolled patients are
shown in Table 1. Comparability of the 2 treatment
groups was verified for all clinical characteristics, except
for the percentage of patients with active perianal
lesions, the CDAI level in failure stratum, and the
duration of steroid treatments in the naive stratum.
Efficacy
The numbers of patients available for efficacy
evaluation at weeks 12, 24, and 52 are shown in Figure
1. At week 24, the percentage of success (CDAI 150
and off steroids) was significantly higher in the infliximab
group than in the placebo group (57% vs 29%;
OR, 3.3; 95% CI, 1.5–7.4; P .003); the corresponding
rates were 75% vs 38% (OR, 4.9; 95% CI, 2.2–11.0; P
.001) at week 12, and 40% vs 22% (OR, 2.4; 95% CI,
1.0–5.7; P .04) at week 52 (Figure 2).
There was no significant interaction between treatment
and stratum (P .10; .32, and .82 at weeks 12,
24, and 52, respectively). The comparison of infliximab
and placebo in each stratum is indicated in Figure 3. In
the naive stratum, at week 24, the percentage of success
was significantly higher in the infliximab group than in
the placebo group (63% vs 32%; OR, 3.7; 95% CI,
1.1–11.3; P .02); the corresponding rates were 83% vs
41% (OR, 7.1; 95% CI, 2.1–24.9; P .009) at week 12,
and 52% vs 32%; (OR, 2.3; 95% CI, .7–6.9; P .14)
at week 52. In the failure stratum, the success rate also
was higher in the infliximab group than in the placebo
group at week 24 (50% vs 26%; OR, 2.9; 95% CI,
.9–9.3; P .08) and at week 12 (64% vs 34%; OR, 3.4;
95% CI, 1.1–10.3; P .03); a trend was found at week
52 (27% vs 12%; OR, 2.8; 95% CI, .6–12.4; P .16).
These results must be considered cautiously because of
the absence of demonstrable interaction.
Steroid resistance was less common in the infliximab
group than in the placebo group (5% vs 23%;
OR, 5.1; 95% CI, 1.3–19.2; P .01). The median
cumulative dose (interquartile range) of prednisone
was lower in the infliximab group at 1110 mg/24 wk
(630–1720 mg/24 wk) vs 1870 mg/24 wk (1110–
2710 mg/24 wk) (P .002). The median (interquartile
range) of the side-effect steroid score, however,

1058 LEMANN ET AL GASTROENTEROLOGY Vol. 130, No. 4
Table 1. Baseline Characteristics of the Patients Enrolled in the Trial According to Study Treatment and Stratum
was not different in the 2 treatment groups at 2.0 (.0–4.0)
vs 2.0 (1.0–4.0) at week 6 (P .65), 2.0 (.0–3.0) vs 1.0
(.0–3.0) at week 12 (P .91), and 1.0 (.0–2.0) vs .5
(.0–1.8) at week 24 (P .42). There was no significant
interaction between treatment and stratum.
Factors associated with success at week 24 in the
multivariate logistic regression analysis were a low CDAI
at baseline (OR, 4.5; 95% CI, 1.5–13.7; P .005), a
Failure stratum Naive stratum
Placebo n 29 Infliximab n 26 P Placebo n 27 Infliximab n 31 P
Sex (female) a 69 69 .95 43 39 .75
Age, yb 29 (23–33) 26 (22–37) .52 26 (22–36) 27 (22–38) .79
Disease duration, yb Disease location
7 (3–11) 5 (4–10) .97 4 (1–8) 3 (1–6) .60
a
Small bowel 11 20 .37 15 35 .74
Colon 50 32 26 13
Both 39 48 59 52
Active perianal diseasea 14 35 .07 7 32 .02
CDAIb 181 (154–259) 240 (219–281) .02 112 (42–262) 146 (90–244) .48
Duration of steroids, mob 16 (9–36) 25 (13–36) .20 15 (9–52) 9 (7–22) .03
Steroid dose, mg/dayb 30 (20–40) 33 (20–46) .32 25 (20–40) 25 (20–40) .85
Steroid dose, mg/kg/dayb .5 (.3–.7) .6 (.4–.8) .25 .4 (.3–.6) .4 (.3–.6) .77
Duration of AZA/6-MP, mob 21 (10–44) 27 (10–33) .95 0 0 -
Dosage of AZA, c mg/kg/dayb 2.4 (2.1–2.6) 2.3 (2.0–2.5) .27 2.2 (2.0–2.4) 2.2 (2.0–2.4) .94
Dosage of AZA, c mg/dayb 150 (125–150) 125 (100–150) .39 125 (100–150) 150 (125–150) .20
CDEISb (n 52) 9 (6–15) d 9 (4–14) e .63 6 (3–14) f 11 (5–16) g .50
C-reactive protein, b mg/L 8 (4–35) 19 (4–47) h .63 17 (7–31) i 20 (10–30) .36
a Percent of patients; 2 test.
b Median (interquartile range); Mann–Whitney U test.
c All patients were treated with AZA.
d n 17.
e n 9.
f n 14.
g n 12.
h n 25.
i n 26.
young age (OR, 5.9; 95% CI, 1.8–19.6; P .002), the
absence of small-bowel involvement (OR, 4.3; 95% CI,
1.5–12.2; P .004), and a long duration of steroids
before entry (OR, 5.5; 95% CI, 1.3–22.5; P .01).
After adjusting for these factors, infliximab still was
superior to placebo (OR, 5.7; 95% CI, 2.0–15.9; P
.001) and no interaction between treatment and strata
could be seen (P .63).
Figure 2. Percent of patients in
clinical remission and off steroids
at weeks 12, 24 (primary
end point), and 52 (follow-up
evaluation). The figures below
the bars correspond to the number
of patients analyzed at each
date. □, AZA/6-MP placebo;
, AZA/6-MP infliximab 5
mg/kg.

April 2006 INFLIXIMAB AND AZATHIOPRINE 1059
Figure 3. Percent of patients in
clinical remission and off steroids
in the 2 strata at weeks
12, 24 (primary end point), and
52 (follow-up evaluation). The
figures below the bars correspond
to the number of patients
analyzed at each date. □, AZA/
6-MP placebo; , AZA/6-MP
infliximab 5 mg/kg.
Endoscopy
Colonoscopy was performed at baseline in 52
patients (21 in the infliximab group and 31 in the
placebo group); 20 of them had a second colonoscopy at
week 24 (11 in the infliximab group and 9 in the placebo
group). CDEIS decrease (median [interquartile range])
from baseline to week 24 was 6.9 (4.1–9.5) in the
infliximab group and 1.2 (1.5 to 4.4) in the placebo
group (P .05). The number of patients with no ulceration
at week 24 was 3 of 11 (27%) and 3 of 9 (33%) in
the infliximab and placebo groups, respectively (P
.77).
Among the 16 patients in remission and off steroids at
week 24 (9 in the infliximab group and 7 in the placebo
group), the CDEIS decrease (median [interquartile
range]) was higher in the infliximab group than in the
placebo group, 6.9 (1.2–10.2) vs 1.2 (.0–4.0) (P .05);
the CDEIS decrease was more than 5 in 6 of the 9
patients in the infliximab group and in 0 of the 7
patients in the placebo group (P .01). The number of
patients with no ulceration at week 24 was 3 of 9 (33%)
and 3 of 7 (43%) in the infliximab and placebo groups,
respectively (P .70).
Safety
The frequency and severity of adverse events were
not different between the 2 treatment groups (Table 2).
The percent of patients who had at least 1 adverse event
was 51% (29 of 57) in the infliximab group and 50% (28
of 56) in the placebo group. The frequency of infection
was similar in the 2 treatment groups. Of note, 5 serious
adverse events were probably or possibly related to azathioprine
(Table 2). One patient in the infliximab group
had a severe reaction after the second and third infusions
(2%). No malignancy and no deaths occurred among the
study patients.
Discussion
Our study was designed to show the superiority of
treatment with a combination of AZA/6-MP with infliximab
(3 infusions at 0, 2, and 6 weeks), compared with
AZA/6-MP alone, in patients with steroid-dependent
CD. With the addition of infliximab to AZA/6-MP we
showed the following: (1) the rate of success was nearly
doubled, defined as complete clinical remission (CDAI,
150) without steroids from 38% to 75% at week 12,
from 29% to 57% at week 24, and from 22% to 40% at
52 weeks; the corresponding odds of success were increased
by a factor of about 5, 3.5, and 2.5; and (2) it
reduces exposure to steroids. Although we found that
infliximab was associated with lower steroid consumption,
steroid side effects were not decreased significantly
by infliximab.
Infliximab thus could be used as a bridge, waiting for
the delayed effect of AZA/6-MP. An important point to
consider in clinical practice, however, is whether or not
the bridge effect is holding with time. Two different
situations could be seen here. In patients with previous
failure to AZA/6-MP, a loss of efficacy was observed
gradually, and at week 52 only 27% of the patients were
still in remission off steroids in the infliximab group. In
such patients, the bridge strategy thus is questionable.
The majority of patients probably would benefit from
optimization of AZA/6-MP treatment using higher doses
adjusted to 6-thioguanine nucleotide levels (which was
not made systematically in our study), or from the switch

1060 LEMANN ET AL GASTROENTEROLOGY Vol. 130, No. 4
Table 2. Adverse Events Occurring During the Study Period:
Day 0 to Week 24
Number of events
in the infliximab
group
Number of events
in the placebo
group
Total 79 66
Mild 39 27
Moderate 36 30
Severe 4 a 9 a
Infections 18 16
Upper respiratory tract 8 11 b
Dental 2 1
Otitis 0 1
Cutaneous 3 1
Herpes virus 2 0
Urinary tract 1 1
Intestinal 1 0
Perianal abscess 0 1 c
Pelvic abscess 1 d 0
Arthralgia, myalgia 8 13 e
Abdominal pain, diarrhea 9 5
Nausea or vomiting 10 e 3
Headache 6 4
Cutaneous rash, pruritus 5 7 e
Fatigue 5 2
Reaction to infusion 2 f 0
Fever 1 4
Mild increase of
transaminase levels
1 0
Pancreatitis 0 e 2 e
Miscellaneous 14 10
a Serious adverse event in 5 cases (infliximab, n 3; placebo, n 3).
b One patient in the placebo group also had a severe pneumonitis
caused by Legionella pneumophila during the follow-up period, and
recovered with antibiotics.
c Perianal abscess occurring at week 18; surgical treatment.
d Pelvic abscess discovered at week 24; surgical treatment.
e Five patients had adverse events possibly or probably related to
azathioprine, 1 in the infliximab group (severe vomiting, week 6), and
4 in the placebo group including 1 case of arthralgia, myalgia, cough,
diarrhea, and fever (week 6), 1 case of arthralgia, fever, and cutaneous
rash (week 6), and 2 cases of pancreatitis (weeks 4 and 5); all
the patients stopped azathioprine and recovered. One additional case
of pancreatitis occurred in the infliximab group at week 23 during the
follow-up period, azathioprine was stopped but the cause remained
unclear because biliary stones also were found.
f Two severe reactions in the same patient, 1 after the second infliximab
infusion and the other after the third infusion; the patient
recovered with steroids and adrenalin.
to another immunosuppressant such as methotrexate or
to maintenance treatment with infliximab. In contrast,
among patients naive for AZA/6-MP at inclusion, despite
a similar loss of efficacy with time, more than 50%
were always in remission and off steroids at 1 year. In
such patients the strategy of using infliximab as a bridge
between steroids and AZA/6-MP could be considered.
Optimization of AZA/6-MP treatment also may have, in
this setting, improved long-term results. By comparison,
in the ACCENT 1 infliximab maintenance trial, responders
to the initial infusion of infliximab (n 335)
were randomized to infliximab (5 mg/kg) or placebo at
weeks 2 and 6, and then to infusions of infliximab 5
mg/kg, 10 mg/kg, or placebo every 8 weeks. At week 54,
the rates of remission and off steroids were 24%, 32%,
and 9%, respectively. 9 However, in this study only 29%
of patients were treated with immunosuppressants at
baseline.
A potential drawback of the bridge strategy is that the
interruption of infliximab after an induction scheme
could facilitate the development of anti-infliximab antibody,
and thus compromise a re-treatment with infliximab,
if necessary. 13,14 Unfortunately, we were not able
to assess the anti-infliximab antibody in our trial. The
risk of immunization must be weighed against the potential
for increased toxicity 15 and cost for patients receiving
regular maintenance treatment. In the present
study, the crude number and the rate of adverse events
were not different in the 2 treatment groups. However,
there is still some uncertainty regarding the long-term
safety of maintenance infliximab including infections and
the development of lymphoproliferative disorders. 16,17
In our study, the rather low effectiveness of AZA/
6-MP alone in the naive stratum for steroid-dependent
patients (32% of success at 24 and 52 weeks) compared
with previous studies 3,4,6 was probably the effect of the
stringent criterion of success that was used (ie, remission
off steroids). Moreover, all the patients included in our
study were steroid-dependent, although this was not
always the case in previous studies. On the other hand, a
remarkably high success rate (83%) was observed in the
infliximab group at week 12. This may be owing to
concurrent AZA/6-MP therapy. Two retrospective and 4
prospective studies that comprised a total of 738 patients
with active CD reported a trend toward a higher response
to infliximab in patients receiving concurrent immunosuppressants
compared with those not receiving any immunosuppressants.
18
A subgroup of patients had a colonoscopic evaluation
during our study. Despite the small number of patients,
endoscopic improvement was more pronounced in the
infliximab group than in the placebo group. When the
comparison was restricted to patients in clinical remission
and off steroids at week 24 (n 16), the superiority
of infliximab was confirmed. Even if a selection bias
cannot be ruled out, this result confirms a previous report
of mucosal healing with infliximab. 14
In conclusion, our study shows that the combination
of infliximab with azathioprine is more effective than
azathioprine alone in steroid-dependent patients to
achieve remission without steroids, and to reduce exposure
to steroids. In AZA/6-MP–naive patients, infliximab
could be used as a bridge between steroids and

April 2006 INFLIXIMAB AND AZATHIOPRINE 1061
azathioprine. If a relapse occurs, regular maintenance
therapy with infliximab should be considered. One cannot
exclude, however, that the continuation of regular
infusions of infliximab combined with AZA/6-MP could
have resulted in a better success rate in our specific study
population. This point should be tested in future studies.
In AZA/6-MP–treatment failure patients, a loss of effectiveness
was observed gradually, and the bridge strategy
cannot be recommended. Other options such as infliximab
maintenance should be considered.
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Received March 21, 2005. Accepted December 28, 2005.
Address requests for reprints to: Professor Marc Lémann, MD, PhD,
Service de Gastroentérologie, 1 avenue Claude Vellefaux, 75010,
Paris, France. e-mail: marc@lemann.com; fax: (33) 1-42-49-91-68.
Presented in part at the Digestive Disease Week, Orlando, May
17-22, 2003, and at the United European Gastroenterology Week
(1-year follow-up), Madrid, November 1-5, 2003.
Supported by Groupe d’Etude Thérapeutique des Affections Inflammatoires
du tube Digestif (GETAID), and by grants from Schering Plough, France,
with the specific help of Gérard Trape and Yves-Dominique Henry. Drugs were
provided by Schering Plough, France. All data analysis and manuscript writing
were performed independently by the GETAID, without the involvement of
representatives of Schering Plough.
In addition to the authors, the following French investigators participated in
the study: Robert Modigliani, Hôpital Saint-Louis, Paris, France; Etienne-Henry
Metman, Hôpital Trousseau Tours; Jean-Paul Galmiche, Hôtel Dieu, Nantes,
France; Jean-Pierre Gendre, Hôpital Saint-Antoine, Paris, France; Marc-André
Bigard, Hôpital Brabois, Nancy, France; Stanislas Chaussade and Vered Abitbol,
Hôpital Cochin, Paris, France; Jean-Charles Grimaud, Hôpital Nord, Marseille,
France; Gilles Bommelaer, Hotel Dieu, Clermont-Ferrand, France; Jean-
Claude Soulé, Hôpital Bichât, Paris, France; Bruno Bonaz, Hôpital Nord,
Grenoble, France; Louis Descos and Bernard Flourié, Hôpital Lyon-Sud, Lyon,
France; Eric Lerebours, Hôpital Charles Nicolle, Rouen, France; Benoit Coffin,
Hôpital Louis Mourier, Colombes, France.
The authors acknowledge Patricia Détré, Study Coordinator, for her
technical help.