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
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
Intensification & Discontinuationof anti-TNF at 12 months
0
10
20
30
40
50
60
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%
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
Managing loss of response:
Verify the cause of LOR
Is it really inflammatory IBD activity ?
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
Possible mechanisms of worsening on anti-TNFs
Adapted from Allez M, J Crohn Colitis 2010
Scope, Scope and Scope…
Managing loss of response:
Start with prevention…
Scheduled vs. Episodic IFX Matters
Maser, EA, et al. Clin Gastroenterol Hepatol 2006;4:124854.
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
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
Effect of Infliximab Antibody Concentration on Duration of Response
0
20
40
60
80
100
120
140
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
Relationship Between ATI Concentration and Infusion Reactions
No Infusion Reaction Infusion Reaction
AT
I L
evel
(µ
g/m
L)
2
0
4
6
8
10
12
14
16
1820
2224
26
28
30
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.
Rapid IFX Clearance: Mechanism of Non-response in UC
Kevans D, et al. DDW 2012
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
Managing loss of response:
Dose intensification
Dose escalation results in ~60% (short-term??) response
Managing loss of response – Dose intensification
0
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%
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 ?
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
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
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
Vande Casteele N, Am J Gastroenterol 2013
Patients with sustained ATI developed significantly higher ATI levels over time compared with patients with transient ATI.
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
Managing loss of response:
Add an immunomodulator (6MP, AZA, MTX)
02468
101214161820
0 10 20 30 40
0
1
2
3
4
5
6
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
0
5
10
15
20
25
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)
Predictive Value
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
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
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
