Transcript Antibiotic treatment of Crohn’s Disease: Does it Work?

Arie Levine
Pediatric Gastroenterology Unit
Wolfson Medical Center
Oxidative Burst
NCF4 NCF2
Treatment
Darfeuille Michaud

Defective apoptosis T cells (Bax/ BCL2 ratios )

Defective apoptosis in dendritic cells with NOD2 mutations
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Increased Survivin –HSP90( anti-apoptotic molecule) in mucosal T
cells in Crohn’s disease
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Apoptosis pharmoacogenetic indices predict response to therapy
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Response to thiopurines correlated with apoptosis effect
Ina et al. J Immunol 1999;163:1081–90
Zelinkova et al Inflamm Bowel Dis 2008 ;14:186-94
De Souza et al Gastroenterology 2012
Hlavaty et al Inflamm Bowel Dis 2007;13:372-9
Cosu etal JCC 2012 epub
Genetic
Defect
Bacterial
Clearance
Bacterial
Infiltration
of the
Epithelium
+
+
Environment
Unknown
factors
Defect of
apoptosis
of
Activated
T Cells
Abnormal
Stimulation
regulation
of the
of the
adaptive
immune
immune
system
system
Tissue
Intestinal
damage
tissue
enabling
damage
bacterial
penetration
Genetic
Defect
Bacterial
Clearance
Bacterial
Infiltration
of the
Intestines
+
+
Environment
Unknown
factors
Defect of
apoptosis
of
Activated
T Cells
Abnormal
Stimulation
regulation
of the
adaptive
of the
immune
immune
system
system
Tissue
Intestinal
damage
tissue
enabling
damage
bacterial
penetration

Decrease bacterial triggering through all 3
compartments ( refuges)
 Luminal
 Biofilm
 Intracellular
 Simultaneous apoptosis

Decreases bacterial triggering through all 3
compartments ( refuges)
 Luminal
 Biofilm
 Intracellular



Promotes prolonged apoptosis of activated T
cells
AIEC sensitive
Reduces epithelial permeability by up
regulating Claudins Occludins and JAM A

All patients treated identically, all patients seen at
week 0,4 and 8 weeks with PCDAI and CRP

Weeks 0-4

Weeks 4-8

Primary end point remission ( PCDAI <7.5 without
height or <10), variables associated with remission

Secondary end point was normalization of CRP at
week 8 ( <0.5 mg/dL)
 Azithromycin 7.5-10 mg /kg /day 5 days a week (max 500mg)+
Metronidazole 15-20 mg/kg daily (max 1000 mg)
 Azithromycin 7.5-10 mg /kg /day 3 days a week + Metronidazole
15-20 mg/kg daily
Variable
No Remiss P Value
N=11
Total
cohort
N=32
Remission
N=21
Baseline
PCDAI
28 ± 10
25 ± 10
34 ± 6
P=0.004
Baseline CRP
3.2 ± 2.7
2.7 ± 2.9
4.2 ± 2.1
P=0.16
Baseline ESR
44 ± 19
44 ± 20
46 ± 17
NS
Baseline
albumin
3.8 ± 0.6
3.8 ± 0.6
3.7 ± 0.4
NS
Baseline
hemoglobin
11.3 ± 1.2
11.1 ± 1.2
11.7 ± 1
NS
L1 Montreal
25%
29%
18%
NS
L2
22%
33%
0%
NS
L3
44%
33%
64%
P=0.14
L4
41%
21%
64%
P=0.07
L3+L4
13%
5%
27%
P=0.11
(66%)
(34%)

PCDAI dropped from 28 ± 10 to 8.6 ± 8.3
 (P<0.001)

CRP declined from 3.2 ± 2.7 to 1.2 ± 2.6
mg/dL
 (P=0.04)


ESR from 44 ± 19 to 26 ± 12 (P<0.001)
CRP wk 8 normal 54% of patients with
elevated CRP baseline

We hypothesize that a 2-month antibiotic
course of Azithromycin combined with
Metronidazole is effective for inducing
remission in active pediatric Crohns disease
(CD). We also hypothesize that Azithromycin
combined with Metronidazole is superior to
the Metronidazole alone , and that remission
will be accompanied by normalization of CRP
in a high proportion of patients with active
CD.
Group 1:
Group 2:
Oral Metronidazole
Oral Metronidazole
+
10mg/kg X2/day (maximum 1000mg)
for 8 weeks.
10mg/kgX2/day (maximum 1000mg
day) for 8 weeks
Oral
Azithromycin 7.5
mg/kg once daily (maximum
500mg) 5 consecutive days a week for
the first 4 weeks and 3 consecutive
days a week for the last 4 weeks
N=70
1. Children 5-17 years of age.
2. Diagnosis of active Crohn's Disease.
3. Patients with a PCDAI≥10 ≤40 (mild to
moderate disease).
4. Have involvement of the colon and/or
terminal ileum..
5. The CRP ≥ 0.6 mg/dL.
6. Duration of disease since diagnosis < 3 years.
Primary :
Response rate at 8 weeks defined as a drop in
PCDAI of at least 12.5 points (or remission
without steroids, intention to treat principle)
Secondary:
1. CS free remission rate at 8 weeks.
2. Normalization of CRP ( CRP ≤0.5 mg/dL)
3. Mean Fecal calprotectin at 8 weeks .
4. CS free remission at 12 weeks
1.
2.
3.
Fecal samples for microbiome at baseline 8 and
12 weeks
Does Microbiome predict response ?
Is response dependent on changing microbiome?
*Analysis of Microbiome from samples and Bioinformatics
will be performed in Boston.

Clinical
◦ Offer alternative therapy that does not require
immune suppression
◦ Does treating upstream event ( trigger for
inflammation) early in disease change natural
history

Translational
◦ Can we identify a component in the microbiome
which is present before therapy, changes in
responders?
Sites in Boston, Edmonton, 6 sites in Europe
and 4 in Israel 
