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“Best
Best of DDW
DDW”
Inflammatory Bowel
B
Disease
Post-DD
DW 2010
Laguna Niguel,
N
CA
Southern Califoornia Society of
Gastroen
nterology
“A taste off N’awlins”
Top
pics
• Etiology of IBD
• 5ASA and colorectal cancer
c
• Optimizing use of anti--TNF drugs
– Crohn
Crohn’s
s disease
– Ulcerative colitis
– Special
p
Considerationss – Elderly,
y, pregnancy
p g
y
• New drugs / Pipeline
• Predicting outcomes
Etiologic Theories
T
in
Inflammatory Bowel
B
Disease
Genetic
Predisposition
IBD
Mucosal Immune
System
(Innate/Adaptive
Immune
Dysfunction)
Environmental
gers
Trigg
Courtesy of S. Targan
Etiologic Theories
T
in
Inflammatory Bowel
B
Disease
Intestinal infection
“Hygiene
yg
hypothesis”
yp
IBD
“Refrigerator
Theory”
Smoking
Environmental
gers
Trigg
“Stress”
NSAIDS
“Doc, is there anything
a
I was
exposed to
o as a child
that gave me IBD?”
Are there any modiffiable environmental
risk factors
f
s ffor IBD?
Do Antibiotic
cs in Infancy
Increase the Risk
k of Pediatric IBD?
• Population-based case
e-control study in
Manitoba
• Antibiotic exposure in 1st year of life ’96 – ‘06
– 24 Cases: IBD (up to age
a 11); 79% CD
– 240 Controls: Matched
d to age, sex, region
• Average
g # abx rx = 2.6
6 ((cases)) vs 0.9 ((ctrl))
– Most common reason: Otitis media
– OR 5.8 (1.7 – 19.9)
Shaw et al. DDW 2010. Abstract 95
Does Eatting Meat
Increase the Risk of IBD?
• Propective cohort of 67,581 French women
– Self-administered diet surveyss every 2 years for avg. 10.4 yr
– Validated
V lid t d IBD di
diagnoses
OR
95% CI
P value
Total Protein Intake
3.31
1.41 – 7.77
0.007
Animal Protein Intake
3.03
1.45 – 6.34
0.005
•Association seen with meat, fish but not eggs, dairy
•Associations
Associations with both CD and U
UC but ‘dose
UC,
dose-effect
effect’ only seen in UC
Jantchou et al. DDW 2010. Abstract # 98
Current Therap
pies and Goals
• Induce remission
quickly
• Maintain
M i t i remission
i i
• Improved quality of life
• Modify
M dif llong tterm
outcomes
– Minimize hospitalization
p
and
surgery
– Minimize steroid exposure
– Decrease disability
•
•
•
•
•
•
Aminosalicyclates
Corticosteroids
Immunomodulators
g
Biologics
Antibiotics
Supportive agents
37 ym with UC
U pancolitis
doing well on 6MP
Should he be on 5-ASA for
chemoprevention off colorectal cancer?
5ASA Does NO
OT Prevent CRC
• Manitoba IBD database – 8939 subjects
• Study I – Assess CRC rissk in users vs. non-users
• Study II – Assess 5ASA use
u in all 87 CRC cases
– No difference in 5ASA use
e in cases vs controls
5ASA use
HR for CRC 95% CI
P-value
1 yr
1.5
0.89 – 2.53
0.13
5 yr
2.7
1.19 – 6.18
0.02
Bernstein et al DDW 2010. #254
5ASA DOES Prevent CRC
• CESAME cohort – 19,486 su
ubjects
j
enrolled 2004-7
– 74 cases before and 79 cases after enrollment
– 5ASA and IM use ‘the year of the
t cancer’ assessed
– IM do not prevent CRC: 0.71 (0
0.39 – 1.27) p=0.25
Group (number of cancers)
All patients (n=153)
UC (n=95)
Crohn's disease ((n=58))
Pts at high risk* (n=94)
Pts not at high risk (n=59)
5-ASA
5
0.55 [0.34-0.89]
[
0.52 [0.29-0.95]
[
0.62 [[0.27-1.40]]
0.46 [0.24-0.85]
[
0.75 [0.34-1.66]
[
p-value
p=0.01
p=0.03
p=0.25
p
p=0.01
p=0.48
*high risk = disease >10 yrs, colon >50% involved
Carrat et al. DDW 2010#255
18 yf,
f hi
history
t
off perianal
p i
l CD,
CD doing
d i
well on infliximab,, starting
g college
g in
the fall.
“Doc
Doc, can I switch to
t a self-injectible?
self injectible?”
If a patient
ti t is
i in
i remission,
i i
iis it ok
k tto
switch biolog
gic therapy?
Switch to Adalimumab in
i CD Pts Controlled by
Maintenance IFX: Prospectiv
p
ve Randomized Switch Study
y
Group A:
ADA
50%
80 mg
m SC → 40 mg SC EOW
L
LOR
Ö Interval decrease (EW)
N=36
INTOLERANCE
or
COMPLETE LOR
IFX maintenance
≥ 6 months
Symptom control
CDAI <200
50%
Group B: IFX
L
LOR
Ö Interval decrease/
Dose increase (10 mg/kg)
5 mg/kg
/k q6-8
6 8 wks
k
N=37
54 weeks
V Assche et al, DDW 2010, Oral # 645.
Van
Switch to Adalimumab in
i CD Pts Controlled by
ve Randomized Switch Study
Maintenance IFX: Prospectiv
udy terminated early)
Results Overview (Stu
Group B
IFX
Group A
ADA
p=0.006
p=0.003
14%
28%
2%
84%
53%
19%
stable
t bl
dose escallation
early termination
Van Assche et al, DDW 2010, Oral # 645
Switch to Adalimumab in CD Pts Controlled by
Maintenance IFX: Prospectiv
ve Randomized Switch Study
• Majority preferred ADA
A for maintenance, but
significant proportion returned
r
to IFX due to
intolerance to ADA
• Electively switching ptts to a 2nd anti-TNF not
recommended
Van Assche et al, DDW 2010, Oral # 645.
24 yff on adalimu
d li mab
b 40
40mg every
other week, sh
howing signs of
clinical atttenuation.
How can we optimize adalimumab dosing?
Recapturing respons
se to ADA with microreinduction in patients
p
with CD
• Retrospective, single center, n=20
n
• CD p
patients on ADA underwen
nt micro-reinduction (mRI)
(
)
• 80 mg dose EW for 2 weeks for loss of response
• 12/20 ((60%)) p
patients subjectiv
j
velyy improved
p
at week 12
– mRI may allow recapture off response to ADA treatment
without p
permanent dose esccalation
Cassani et al. DDW 2010; Abstract W1315
Infliximab for Ulcerative
U
Colitis
CLINICAL REMISSION
R
AT
WE
EEK 8
Rutgeerts et al. NEJM 2005
Infliximab as a res
scue therapy for IV
steroid reffactory UC
IFX is approved for mod to severe UC, but
b limited data on its use as rescue
therapy for steroid refactory hospitalized
d patients
Colectomy Ra
ate
Colectomy free survival
1N=132,
72 males
Mean age 39
3 pts
t lost
l t to
t f/u
f/
Wk 8: 21/132 (16%)
Wk 52: 28/129
9 (22%)
Wk52: 101/129 (78%)
13% IFX monotherapy
50% AZA monotherapy
th
32% IFX+ AZA
N=20, 10 males
Mean age 30
2 pts lost to f/u
1 yr: 5/18 (28%
%)
3/5 had conco
omittant C.
difficile
2 yr:13/18 (72%)
50% required IFX dose
optimization
25% IFX + IMM
2
Conclusions: IFX is effective rescue therapy fo
or colectomy free survival, pair with immunmodulators
1. Monterubbianesi et al DDW 2010 W1257
2. Venu et al DDW 2010 W1296
Efficacy and safety of In
nfliximab rescue therapy
after cyclosporin failure
e in steroid refactory UC
•
•
•
51 IV steroid refactory UC pts treate
ed with IFX after CSA failure (78% IV
CSA, 22% oral CSA)
Median time from last CSA to first IFX 12 days
Results: 15 (29.4%) went for colectomy over median 5 weeks
Remission
R
Response
Colectomy
IFX #1
#1, nn=51
6 (12%)
39 (76%))
6 (12%)
IFX #3
#3, n=39
23(59%)
12(31%)
4 (10%)
•Adverse event rate 25%: 6 infections, 1 leukopenia, 1 bowel perforation, 1
fever, 1 death (40 yr m, surgery 10d affter 1st IFX, died of pneumonia)
•Conclusion: Rate of adverse events and
a mortality,
mortality decision of sequential
CSA-IFX should be individualized
Chaparro et al. DDW 2010 W1274
Does adalimuma
ab ‘work’
ab
work for UC?
Adalimumab for Induction
n of Clinical Remission in
M d
Moderately
t l to
t Severely
S
l Active
A ti Ul
Ulcerative
ti Colitis
C liti
Primary Endpoint: Clinical Remission at
a Week 8
Proportio
on of Patients (%)
20
*
18 5
18.5
15
†
10
9.2
10
5
24/130
12/130
13/130
Placebo
A
ADA
80/40
0
ADA 160/80
*pp=0.031
0.031 vs. placebo
† p=0.833
vs. placebo
Reinisch et al, DDW 2010, Oral # 847t
Ulcerative
e Colitis
CLINICAL REMISSION AT
WEEK 8
CLINICAL REMISSION AT
WEEK 8
Reinisch et al, DDW 2010, # 847t
Rutgeerts et al. NEJM Feb 2005
Secondary Endpoints
Placebo
(N=130)
ADA 80/40
(N=130)
ADA 160/80
(N=130)
Clinical response
44.6%
51.5%
54.6%
Mucosal healing
41 5%
41.5%
37 7%
37.7%
46 9%
46.9%
Rectal bleeding
subscore ≤ 1
66.9%
70.0%
77.7%*
PGA subscore ≤ 1
46.9%
53.8%
60.0%†
Stool frequency
subscore ≤ 1
37.7%
36.2%
49.2%‡
*p=0.052, †p=0.035, ‡p=0.061 vs. placebo.
Reinisch et al, DDW 2010, Oral # 847t
Are there imporrtant differences
among the 3 anti-TNFs?
Placentall transfer.. %
Ex-Vivo placental transfe
er of Anti-D IgG antibody
certolizum
mab pegol
g
Anti-D IgG
G
Certolizumab p
pegol
g by
y Bioassay
y
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
1
2
3
4
P
Placentas
5
6
Certolizumab pegol was detected in the
e fetal circuit of 2 placentas
placentas, certolizumab
pegol in these samples (0.15% and 0.009%) was lower than the amount of anti-D
IgG (0.60% and 0.39%, respectively)
Porter et al. DDW 2010. Abstract W1208
What drugs
s are being
studied for
f IBD?
“N
“Negativ
tive Trials”
Ti l ”
• Abatacept (anti-CTLA4, Orencia
O
®) for CD
– Phase III RCT study termin
nated early due to lack of
efficacy in induction phase
e (12 weeks)
• VSL #3
– Placebo-Controlled trial forr maintenance of remission in
30 patients on stable 5ASA
A or IM
– At 1 year, 9 flares total (8 in VSL#3, 1 in placebo)
• Rituximab (anti
(anti-CD20,
CD20, Rituxan ®) for UC (phase II)
– Primary endpoint remission at 4 weeks
– 3/16 rituximab vs 1/8 place
p ebo ((NS))
– Role for higher dose?
Hanauer
a aue et a
al DDW 2010
0 0 #6
#649
9
Willert et al DDW 2010 T1235
Leiper et al DDW 2010 648
Low-Dose Naltrexone
• Endogenous opioids “play a role” in “healing of tissues”
• Randomized, DB, placebo-c
p
controlled trial of LDN
4.5mg/d in adults with CDAI >220, single crossover
a baseline, Weeks 12 and 24
• Colonoscopies performed at
• Primary outcomes: CDAI, endoscopic
e
and histologic
inflammatory scores
• 40 patients enrolled
Low Dose Naltrexone
Low-Dose
• CDAI scores decreased significantly
sg
y from baseline
(p<0.001) in those treated
d with LDN
– 82% of LDN-treated patien
nts had at least a 70-point drop
i th
in
the CDAI score
– Unclear what placebo resp
ponse was (not in abstract)
– Endoscopy and histology sscores improved in LDN
LDN-treated
treated
patients (p=0.002)
• Unconventional presenta
p
tion of data
– CDAI scores at week 0 vs week 12 was primary endpoint
– NO DIRECT COMPARISO
ON TO PLACEBO group
Smith J et al. DDW 2010 Abstract # 646
“The
The Piipeline
ipeline”
CCX282-B (T
Traficet-EN ®)
• Oral CCR9 antagonist for mod
derate-to-severe Crohn’s
• Methods: Randomized, double
e-blind, placebo-controlled trial
• Maintenance 36 weeks after 12-week induction and 4-week
open-label
– Endpoints: CDAI response and Remission at 36 weeks
• Results: 241 pts randomized
Remission (%)
100
Placebo (n=146
6) CCX282-B (n=95)
80
60
50 47
44 47
40
4
42
50
49
38
47
31
20
P=0.01
0
Wk 4
Wk 12
W 20
Wk
Wk 28
Wk 36
Keshav et al DDW 2010 #647
HMPL00
04 in UC
Andrographiis Paniculata
• Indigenous medicinal plant from
Southeast Asia
• Anti-inflammatory
A ti i fl
t
properties,
ti
use
ed
d
for thousands of years; mixture of
o
active compounds
p
• Mouse data (prelim) with reduce
ed
intestinal inflammation, IL6, TNF
Fa
• Double
D bl bli
blind
d phase
h
II RCT ffor mildmild
moderate UC, 223 patients
• Remission and mucosal healing at
week 8 (dose-dependent respon
nse)
Sandborn et al DDW 2010 #847
Should we be thinking
t
g about
biologics differently in
special pop
pulations?
What are the risks of biologic
b
therapy in the
eldeerly?
What are the risks of biolo
ogic therapy on pregnancy
and the first year of life
fe in an exposed infant?
Elderly and Immunosuppressive
medications
• Elderly patients, 5 time
es more likely to have
infectious complication
p
ns if on
immunomodulators1
• Older age not associated with adverse events
from biologic therapy iin IBD2
1.Lin et al. DDW 2010 W1201
2.Bushan A DDW 2010 #413
Impact of IBD medicatio
on exposure on newborn
develo
opment
PIANO registry interim analysis of 521 patients
353 completed pregnancy, 339 live births
Newborns reaching development milestones
Drug
g exposure
p
(Denverr Childhood Developmental Score)
Month 4
Month 9
Month 12
Control n=136
89 (92.8%)
69 (90.6%)
56 (86.1%)
IS (AZA/6-MP) n=79
53 (93.2%)
41 (82.3%)**
33 (84.2%)
Anti-TNF n=124
88 (94.8%)
60 (91.3%)
39 (89.6%)
* 39 women took both an IS and an anti-TNF agent
** p=0.04 – IS may result in a statistically lower number of newbo
orns reaching developmental milestones at Month 9
Mahadevan et al. DDW 2010; Abstract 764
Patients with Corticosteroid
d-free Clinical Remission (Panel A) and
Mucosal Healing (Panel B) at Week 26
SON
NIC
• 508 adults with CD
• Naïve to IM and biologics
• Randomized to
– AZA 100
– IFX 5mg/kg
– AZA + IFX
• Followed 1 yr with CDAI,
colonoscopy,
l
d
drug llevels
l
Colombel et al. NEJM Feb 2010
Who should be
b treated a la
SON
NIC?
Can we predict wh
ho is most likely to
benefit from this tre
eatment approach?
Probabillity of no
on-progre
essive C
CD
Antibody Sum Predict Earlier
Surgery in Cro
ohn’s Disease
1.00
N= 189
N= 243
0.75
N 47
N=
P<0.0001
0.50
N= 174
ab_sum=0
_
ab_sum=1
ab_sum=2
ab_sum=3
0.25
0.00
0
25
50
75
100
125
150
175
Time to su
urgery (months)
Dubinsky, M., et al Clin Gastroenterol Hepatol. 2008 Jul 9 .
Predicting Prognosis
s of Crohn’s Disease
( k Wh
(aka.
Who should
h ld gett ‘Top
‘T Down’
D
’ therapy?)
th
?)
• 619 CD patients asses
ssed for clinical
and NOD2 mutations
predictors,, serologies
p
g
QSS
Very Low (6-11)
(6 11)
Low (12-14)
Medium ((15-17))
High (18-20)
Very High (21-24)
n
88(14%)
130 (21%)
168 ((27%)
148 (24%)
85 (14%)
Complications
23%
46%
55%
79%
79%
Surgery
10%
22%
35%
49%
64%
Lichtenstein et al. DDW 2010 #207
Shifting Treatm
ment Paradigms
Better Drug Levels
Lower Antibody
Levels
Muco
osal
Healling
Early
Treatment
Conco
omitant
Anti--TNF
And
d IM
Anti-TNFs and Mucosal
M
Healing
• MUSIC – Certolizumab le
eads to mucosal healing
– 89 pts, CDEIS 14.5 Æ 8.3 (wk 10) and 9.6 (wk 54)
• EXTEND – Adalimumab leads to mucosal healing
– Those with early healing (S
SES < 5 at week 12) had
significantly better CDAI sccores and remission at week 52
• Higher infliximab trough le
evels are associated with
mucosal healing in Crohn
n’s
n
s disease
– Serum samples in 210 pattients treated with IFX
Van Moerkercke W et al DDW 2010 #405
Colombel et al. DDW 2010 S1045, T1239
Rutgeerts et al DDW 2010 644
Infliximab an
nd ATI levels
• Many patients ‘attenuate’ to infliximab over time
– Antibodies to IFX, increase
ed drug clearance
• Drug trough levels are hig
gher in those who maintain
response (and ATI are low
wer)
• Assays available to meassure drug and ATI levels
– Cutoff levels not determine
ed
• Methods: Retrospectivelyy classified CD/IFX
– Maintenance Responders, Secondary NR, Primary NR
o
cut-off levels
– ROC curves to determine optimal
Steenholdt et al. DDW 2010 #1270
“My
My patient los
st effect to IFX”
IFX
How to interrpret ‘levels’
Hig
gh
anti-Drug Antibodies
A
(>10 U
U/mL)
Low
anti-Drug Antibodies
(<10 U/mL)
Low Infliximab Level
((<0.5 ug/mL)
g
)
High Infliximab Level
(>0.5 ug/mL)
Steenholdt et al. DDW 2010 #1270
“My
My patient los
st effect to IFX”
IFX
Treatment Algorithm
Hig
gh
anti-Drug Antibodies
A
(>10 U
U/mL)
Low Infliximab Level
((<0.5 ug/mL)
g
)
Low
anti-Drug Antibodies
(<10 U/mL)
Problem: Ellimination of
IFX due to antibodies
Solution: Change to
another antiTNF
g Infliximab Level
High
(>0.5 ug/mL)
Steenholdt et al. DDW 2010 #1270
“My
My patient los
st effect to IFX”
IFX
Treatment Algorithm
Low Infliximab Level
((<0.5 ug/mL)
g
)
Hig
gh
anti-Drug Antibodies
A
(>10 U
U/mL)
Low
anti-Drug Antibodies
(<10 U/mL)
Problem: Ellimination of
IFX due to antibodies
Solution: Change to
another antiTNF
Problem:
Pharmacokinetic
Solution: Increase IFX
dose or frequency
g Infliximab Level
High
(>0.5 ug/mL)
Steenholdt et al. DDW 2010 #1270
“My
My patient los
st effect to IFX”
IFX
Treatment Algorithm
Low Infliximab Level
((<0.5 ug/mL)
g
)
g Infliximab Level
High
(>0.5 ug/mL)
Hig
gh
anti-Drug Antibodies
A
(>10 U
U/mL)
Low
anti-Drug Antibodies
(<10 U/mL)
Problem: Ellimination of
IFX due to antibodies
Solution: Change to
another antiTNF
Problem:
Pharmacokinetic
Solution: Increase IFX
dose or frequency
Problem:
Pharmacodynamic
Solution: Review
history,
y, change
g class
Steenholdt et al. DDW 2010 #1270
“My
My patient los
st effect to IFX”
IFX
Treatment Algorithm
Hig
gh
anti-Drug Antibodies
A
(>10 U
U/mL)
Low
anti-Drug Antibodies
(<10 U/mL)
Low Infliximab Level
((<0.5 ug/mL)
g
)
Problem: Ellimination of
IFX due to antibodies
Solution: Change to
another antiTNF
Problem:
Pharmacokinetic
Solution: Increase IFX
dose or frequency
g Infliximab Level
High
(>0.5 ug/mL)
Problem: ???
Solution: Repeat
R
test
Problem:
Pharmacodynamic
Solution: Review
y, change
g class
history,
Steenholdt et al. DDW 2010 #1270
Summary “Themes”
Themes
DDW 2010
• Ongoing controversies
s
– IFX for hospitalized UC
C
– Who to treat with ‘Top Down’ approach
– Should one continue 5ASA purely for
chemoprevention
• Anti
Anti-TNFs
TNFs are not omn
ni equivalent
ni-equivalent
– UC, pregnancy
Summary “Themes”
Themes
DDW 2010
• Optimize what we hav
ve, because we don’t
have a lot of drugs
g
– Don’t switch if doing we
ell
– Consider ‘micro-reindu
micro reindu
uction’ for adalimumab
uction
attenuators
– Drug
g levels can help
p decision making
g for
infliximab attenuation