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 Pediatrics
University of Pennsylvania, Perelman School of Medicine
Director, Center for Pediatric IBD
The Children's Hospital of Philadelphia
What is secondary loss of response ?
“(1) an increase in the PCDAI of >15 points from
Symptoms only
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”
“Patients who initially respond to anti-TNF therapy and
(Hyams J, Gastro 2007)
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”
“Recurrent symptoms necessitating
adalimumab dose escalation”
Karmiris K, Gastro 2009
(de Ridder, Inflam Bowel Dis 2008)
Symptoms +
Treatment change
Intensification & Discontinuation
of anti-TNF at 12 months
60
Dose escalation
50
Drug discontinuation
At 12 months:
40
Dose escalation - 23-46%
Drug discontinuation - 5-13% 30
20
10
D
A
A
D
A
(
A New
(R -Y
A ott ork
D er )
A
da
(
IF CH m
A )
IF X
X (L R M
o
IF (Pit nd o )
X ts
n
(P bu )
r
I
IF BD g h)
IF X CR
C X (RE G)
ZP (A A
C C
C (P CE H)
ZP R
EC N T
(W IS I )
EL E
C I I)*
O
M
E)
*
0
Ben-Horin S, Aliment Pharmacol Ther 2011
Cumulative rate of loss of response
over time to anti-TNF treatment
(adalimumab)
2/3 of patients who lose response to anti-TNF do so within
the first 12 months of therapy
Alimentary Pharmacology & Therapeutics
Volume 33, Issue 9, pages 987-995, 2011
Managing loss of response:
Verify the cause of LOR
Is it really inflammatory IBD activity ?
Possible mechanisms of worsening on anti-TNFs
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)
Adapted from Allez M, J Crohn Colitis 2010
Possible mechanisms of worsening on anti-TNFs
Scope, Scope and Scope…
Adapted from Allez M, J Crohn Colitis 2010
Managing loss of response:
Start with prevention…
Scheduled vs. Episodic IFX Matters
Maser, EA, et al. Clin Gastroenterol Hepatol 2006;4:124854.
IFX Trough Levels are Important
Outcomes at 1 year on scheduled infliximab therapy
Clinical Remission
CRP < 5 mg/dl
Endoscopic
Improvement >75%
*
*
% of patients
*
P<0.001
Trough
P<0.001
Trough
P<0.001
Trough
Maser, EA, et al. Clin Gastroenterol Hepatol 2006;4:124854.
SONIC Trial
Higher trough levels associated with better response
10
8
6
3.8
4
2
1.0
0
IFX + Placebo (n=73)
IFX + AZA (n=76)
HYPOTHESIS: Optimizing levels with anti-TNF
monotherapy could be an alternate to dual therapy
Colombel JF, et al. N Engl J Med. 2010;362:1383-1395
Days Until Subsequent Infusion
Effect of Infliximab Antibody Concentration
on Duration of Response
P < 0.001
140
120
100
80
61 days
60
40
28 days
20
0
Negative
1.8–8.0 µg/mL
8.0–20.0 µg/mL
>20.0 µg/mL
Concentration of Antibodies to Infliximab
Baert F et al. N Engl J Med. 2003;348:601.
ATI Level (µg/mL)
Relationship Between ATI Concentration and
Infusion Reactions
30
28
26
24
22
20
18
16
14
12
10
8
6
4
2
0
ATI levels 8.0 µg/mL
More likely to experience
infusion reactions
(relative risk, 3.9; 95% CI
1.3 to 11.7; P = 0.04)
No Infusion Reaction
Infusion Reaction
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 Predictive
of Colectomy in UC
P<0.001
Colectomy
(% patients)
55%
17%
Seow CH et al, Gut 2010;59:49-54
Managing loss of response:
Dose intensification
(
A New
(R -Y
AD otte ork
A rd )
(C am
IF HA )
IF X M RM
IF X ( ad )
X
Lo ri d
(
IF Pit nd o
X ts
n
(P bu )
r
I
IF BD g h)
IF X ( CR
CZ X ( RE G )
P AC AC
CZ (P CE H)
P RE NT
(W CI
I
EL SE )
CO I I)*
M
E)
*
A
% regained response
At 12 months:
Regained response - 50-70%
AD
AD
Managing loss of response – Dose intensification
Dose escalation results in ~60% (short-term??) response
100
80
60
40
20
0
Ben-Horin S, Aliment Pharmacol Ther 2011
How to intensify ?
Diverse Protocols Abound
Infliximab
5mg/kg/6weeks
Adalimumab
40mg/EW
7.5mg/kg/8weeks
80mg/EOW
10mg/kg/8weeks
40mg/10 days
5mg/kg/4weeks
Re-induction followed by de-escalation
Response rate to escalation (%)
Double dose (10mg/kg/8w) is at least as effective as interval
halving (5mg/kg/4w) in loss of response to Infliximab
Combined sustained response: 47% at 12 months
10mg/kg/8w
P=0.2
5mg/kg/4w
Month
Number at risk 168
119
110
93
86
75
62
Katz L, Inflamm Bowel Dis, 2012
The therapeutic window concept
increased toxicity?
µg/mL
10
3
loss of efficacy
0
0
2
6
14
22 wks.
Nesterov I. J Rheumatol 2005
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
Patients with sustained ATI developed significantly
higher ATI levels over time compared with patients with
transient ATI.
Vande Casteele N, Am J Gastroenterol 2013
Trough level of Infliximab (μg/ml)
Dose-intensification must increase
IFX trough level to regain response
Vande Casteele N, Am J Gastroenterol 2013
Managing loss of response:
Add an immunomodulator (6MP, AZA, MTX)
(mcg/ml)
Concentration
Concentration (mcg/ml)
Adding immunomodulator to revert
immunogenicity
Patient 2
Patient 1
7
Start
MTX
6
5
4
3
2
1
0
10
Weeks Weeks
20
Infliximab
30
40
50
anti-infliximab antibodies (ATI)
20
18
16
14
12
10
8
6
4
2
0 Weeks 0
(mcg/ml)
Concentration
(mcg/ml)
Concentration
Start
AZA
20
20
15
15
10
10
5
5
0
20
30
40
25
25
Weeks
10
Patient 4
Patient 3
Weeks
Start
6-MP
0
10
Infliximab
20
30
40
50
60
anti-infliximab antibodies (ATI)
0
Weeks 0
Start
AZA
10
20
30
40
50
Ben Horin S, Clin Gastroenterol Hepatol 2013
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
Authors suggest:
dose escalation if IFX trough <2.2 at week 14
dose escalation can be attempted with low level ATI
Vande Casteele N et al. Am J Gastroenterol 2013; epub ahead of print
Proposed Treatment Algorithm
≤9
Positive ATI
(detectable antibody) > 9
Therapeutic IFX conc
(>3 mcg/ml trough level)
Sub-therapeutic IFX
(<3 mcg/ml trough level)
Increase infliximab
or add IM
no
If persistent disease,
change to Rx with different
mechanism of action
(non- anti-TNF agent)
success
Change to another
anti-TNF
Active disease on
Endoscopy/radiology
Change to Rx with different
mechanism of action
(non- anti-TNF agent)
Inactive disease on
Endoscopy/radiology
Investigate for
alternate etiology of
symptoms
Increase infliximab
and/or add IM
If persistent disease,
change to another
anti-TNF
Adapted from Afif W et al. Am J Gastroenterol 2010;
105:1133-1139