Robert N. Baldassano, MD Colman Professor of Pediatrics
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What do we do when the patient loses their response to an anti-TNF: Minor tweaks or
major treatment changes?
Robert N. Baldassano, MD
Colman Professor of PediatricsUniversity of Pennsylvania, Perelman School of Medicine
Director, Center for Pediatric IBDThe Children's Hospital of Philadelphia
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What is secondary loss of response ?
Symptoms only“(1) an increase in the PCDAI of >15 points from the reference PCDAI at week 10 at 2 consecutive visits at least 7 days apart, or (2) the PCDAI was higher than 30 points at any scheduled or unscheduled visit” (Hyams J, Gastro 2007) “Patients who initially respond to anti-TNF therapy and
subsequently lost clinical response…with a rise of >70 points of CDAI” (Allez M, ECCO Workshop, J Crohn Colitis 2010)
“Symptoms plus evidence of inflammation” (Regueiro M, Inflam Bowel Dis 2007)
Symptoms +inflammation
“Withdrawal of infliximab and switch of medical therapy or need for surgery” (de Ridder, Inflam Bowel Dis 2008)“Recurrent symptoms necessitating
adalimumab dose escalation”Karmiris K, Gastro 2009
Symptoms +Treatment change
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Intensification & Discontinuationof anti-TNF at 12 months
0
10
20
30
40
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CZP (W
ELCOME)*
CZP (PRECIS
E II)*
IFX (
ACCENT I)
IFX (
REACH)
IFX (
PIBDCRG
)
IFX (
Pittsb
urgh)
IFX (
London)
ADA (CHARM
)
ADA (Rotte
rdam
)
ADA (New
-York
)
Dose escalation
Drug discontinuation
Ben-Horin S, Aliment Pharmacol Ther 2011
At 12 months:Dose escalation - 23-46% Drug discontinuation - 5-13%
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Cumulative rate of loss of responseover time to anti-TNF treatment
(adalimumab)
Alimentary Pharmacology & TherapeuticsVolume 33, Issue 9, pages 987-995, 2011
2/3 of patients who lose response to anti-TNF do so within the first 12 months of therapy
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Managing loss of response:
Verify the cause of LOR
Is it really inflammatory IBD activity ?
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Uncontrolled IBD inflammation : (Low drug level) Loss of anti-TNF activity due to anti-drug antibodies Relentless TNF-mediated flare ‘consuming’ all anti-TNF Ab Loss of anti-TNF activity due to non-immune drug clearance Non-adherence to therapy
Uncontrolled IBD inflammation: (Adequate drug level) Shift of disease pathway away from TNF to other mediators
Non-IBD related inflammation: (Adequate drug level, High CRP) Infection ! Other (vasculitis, ischemia)
Non-inflammatory mechanisms (Adequate drug level, Normal CRP) Fibrostenotic strictures Cancer IBS Miscellaneous (Amyloidosis, BOG, Bile salt diarrhea, etc)
Possible mechanisms of worsening on anti-TNFs
Adapted from Allez M, J Crohn Colitis 2010
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Possible mechanisms of worsening on anti-TNFs
Adapted from Allez M, J Crohn Colitis 2010
Scope, Scope and Scope…
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Managing loss of response:
Start with prevention…
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Scheduled vs. Episodic IFX Matters
Maser, EA, et al. Clin Gastroenterol Hepatol 2006;4:124854.
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Maser, EA, et al. Clin Gastroenterol Hepatol 2006;4:124854.
Clinical Remission CRP < 5 mg/dlEndoscopic
Improvement >75%
P<0.001 P<0.001 P<0.001
% o
f pati
ents
IFX Trough Levels are Important
Outcomes at 1 year on scheduled infliximab therapy
**
*
Trough Trough Trough
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Higher trough levels associated with better response
1.0
3.8
0
2
4
6
8
10
IFX + Placebo (n=73) IFX + AZA (n=76)
Colombel JF, et al. N Engl J Med. 2010;362:1383-1395
HYPOTHESIS: Optimizing levels with anti-TNF monotherapy could be an alternate to dual therapy
SONIC Trial
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Effect of Infliximab Antibody Concentration on Duration of Response
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Negative 1.8–8.0 µg/mL 8.0–20.0 µg/mL >20.0 µg/mL
Concentration of Antibodies to Infliximab
Day
s U
nti
l S
ub
seq
uen
t In
fusi
on P < 0.001
Baert F et al. N Engl J Med. 2003;348:601.
28 days
61 days
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Relationship Between ATI Concentration and Infusion Reactions
No Infusion Reaction Infusion Reaction
AT
I L
evel
(µ
g/m
L)
2
0
4
6
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1820
2224
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ATI levels 8.0 µg/mLMore likely to experience infusion reactions (relative risk, 3.9; 95% CI 1.3 to 11.7; P = 0.04)
Miele E et al. J Pediatr Gastroenterol Nutr. 2004;38:502.
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Rapid IFX Clearance: Mechanism of Non-response in UC
Kevans D, et al. DDW 2012
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Undetectable Serum IFX Trough Predictiveof Colectomy in UC
55%
17%
P<0.001
Cole
ctom
y(%
pati
ents
)
Seow CH et al, Gut 2010;59:49-54
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Managing loss of response:
Dose intensification
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Dose escalation results in ~60% (short-term??) response
Managing loss of response – Dose intensification
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20
40
60
80
100
% re
gain
ed re
spon
se
Ben-Horin S, Aliment Pharmacol Ther 2011
At 12 months:Regained response - 50-70%
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Diverse Protocols Abound
Infliximab Adalimumab5mg/kg/6weeks 40mg/EW
7.5mg/kg/8weeks 80mg/EOW
10mg/kg/8weeks 40mg/10 days
5mg/kg/4weeks
Re-induction followed by de-escalation
How to intensify ?
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Month
Number at risk 168 119 110 93 86 75 62
Res
po
nse
ra
te t
o e
scal
ati
on
(%
)
Combined sustained response: 47% at 12 months
Month
Number at risk 168 119 110 93 86 75 62
Res
po
nse
ra
te t
o e
scal
ati
on
(%
)
Month
Number at risk 168 119 110 93 86 75 62
Res
po
nse
ra
te t
o e
scal
ati
on
(%
)
Combined sustained response: 47% at 12 months
10mg/kg/8w
5mg/kg/4wP=0.2
Katz L, Inflamm Bowel Dis, 2012
Double dose (10mg/kg/8w) is at least as effective as interval halving (5mg/kg/4w) in loss of response to Infliximab
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0 2 6 14 22 wks.0
3
10
µg/mL increased toxicity?
The therapeutic window concept
Nesterov I. J Rheumatol 2005
loss of efficacy
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Antibody to IFX Can Be Transient
• 90 adult IBD patients– 1,232 serum samples
• 59% developed ATI– By study design
• ATI was transient in 28%
Vande Casteele N et al. Am J Gastroenterol 2013
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Vande Casteele N, Am J Gastroenterol 2013
Patients with sustained ATI developed significantly higher ATI levels over time compared with patients with transient ATI.
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Vande Casteele N, Am J Gastroenterol 2013
Trou
gh le
vel o
f Infl
ixim
ab (μ
g/m
l)
Dose-intensification must increaseIFX trough level to regain response
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Managing loss of response:
Add an immunomodulator (6MP, AZA, MTX)
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02468
101214161820
0 10 20 30 40
0
1
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7
Infliximab anti-infliximab antibodies (ATI)
Conc
entr
ation
(mcg
/ml)
Start MTX
10 20 30 40 50
Patient 1
Weeks
0
5
10
15
20
25
Infliximab anti-infliximab antibodies (ATI) 0 10 20 30 40 50 60
Start AZA
Patient 3
Start 6-MP
Patient 2
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Start AZA
0 10 20 30 40 50
Patient 4
Conc
entr
ation
(mcg
/ml)
Weeks
Ben Horin S, Clin Gastroenterol Hepatol 2013
Adding immunomodulator to revert immunogenicity
Weeks
Weeks
Weeks Weeks
Conc
entr
ation
(mcg
/ml)
Conc
entr
ation
(mcg
/ml)
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Predictive Value
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Infliximab Trough May Predict Sustained Response in Crohn Disease
• Retrospective adult cohort 84 patients
– IFX trough level measured at 14 or 22 wks
• Sustained clinical response• IFX Trough level > 3 μg/ml
• Increase in ATI• IFX Trough level < 3 μg/ml
Bortlik M et al. J Crohns Colitis 2012
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IFX Trough Levels• Greatest predictor of IFX failure
– Any IFX trough < 0.91 μg/ml
• IFX trough <2.2 μg/ml at week 14 predicts– Develop ATI (p<0.0001)– Discontinue IFX for LOR/hypersensitivity (p=0.003)
• When escalating therapy– ATI > 9.1 U/mL risk of failure (LR 3.6)– Patients with success had increase in IFX levels
Vande Casteele N et al. Am J Gastroenterol 2013; epub ahead of print
Authors suggest:dose escalation if IFX trough <2.2 at week 14dose escalation can be attempted with low level ATI
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Proposed Treatment Algorithm
Positive ATI (detectable antibody) > 9
≤ 9
Change to another anti-TNF
Increase infliximabor add IM no
success
If persistent disease,change to Rx with different mechanism of action (non- anti-TNF agent)
Therapeutic IFX conc(>3 mcg/ml trough level)
Active disease onEndoscopy/radiology
Inactive disease onEndoscopy/radiology
Change to Rx with different mechanism of action (non- anti-TNF agent)
Investigate for alternate etiology of symptoms
Sub-therapeutic IFX(<3 mcg/ml trough level)
Increase infliximaband/or add IM
If persistent disease, change to another anti-TNF
Adapted from Afif W et al. Am J Gastroenterol 2010; 105:1133-1139