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

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