Controversies and challenges in
the clinical care of patients with
IBD:
You can’t always get what you
want!
Stephen B. Hanauer, MD
University of Chicago Medicine
Conflicts of Interest




Abbott
Janssen
UCB
Prometheus
What I want for
Hanukkah/Christmas
 Cost-effective therapeutic drug
monitoring for biologics
 Ability to dose-adjust biologics
 A reliable surrogate for mucosal healing
Therapeutic Drug
Monitoring
Clinical Gastroenterology and Hepatology
Volume 10, Issue 10 , Pages 1079-1087, October 2012
Therapeutic Drug Monitoring of Tumor Necrosis Factor
Antagonists in Inflammatory Bowel Disease
Ingrid Ordás, Brian G. Feagan, William J. Sandborn
50.0
10.0
5.0
1.0
Adalimumab 160 mg (day 1), 80 mg (day 8)
and 40 mg ev ery tw o w eek s
Adalimumab 40 mg ev ery tw o w eek s
0.5
Simulated anti-TNF biologic conc
Inflix imab 5 mg/k g at day 1, day 15, day 43 and ev ery 8 w eek s
Inflix imab 3 mg/k g at day 1, day 15, day 43 and ev ery 8 w eek s
0
20
40
60
Time (day s )
80
100
120
Effects of absent blood levels
 Disease recurs (or no primary response)
 Development of antibodies
(immunogenicity)
 Secondary loss of response
Factors Affecting the Pharmacokinetics of
Monoclonal Antibodies
IMPACT on PK
Presence of ADAs
Decreases serum [mAbs]
Three fold-increased clearance
Worse clinical outcomes
Concomitant use of IS
Reduces formation
Increases serum [mAbs]
Decreases mAbs clearance
Better clinical outcomes
High Baseline [TNF-α]
May decrease [mAbs] by increasing clearance
Low Albumin
High Baseline CRP
Body size
Gender
Increases clearance
Worse clinical outcomes
Increases clearance
High BMI may increase clearance
Males have higher clearance
Ordas I, Feagan B, Mould D, Sandborn WJ. Clin Pharmacol Ther 2012
Effect of Trough Serum Infliximab Concentrations
on Clinical Outcome at >52 Weeks
Trough serum infliximab
Detectable
100
Undetectable
Patients with endoscopic improvement >75% (%)
Patients in remission (%)
100
82
88
p<0.001
33
p<0.001
6
0
100
0
Patients with CRP <5 mg/dL (%)
76
100
Patients with complete endoscopic remission (%)
p<0.001
47
32
p=0.03
19
0
Maser et al. Clin Gastroenterol Hepatol. 2006; 4:1248-54
0
Lower Adalimumab Trough Levels Results in a Lower
Rate of Sustained Clinical Response
Karmaris Gastro 2009;137:1628–1640
100
90
80
70
60
50
40
30
20
10
0
P< 0.001
Endoscopic Improvement
(% of patients)
Remissison
(% of patients)
Clinical outcomes in UC patients treated
with infliximab correlate with detectable
trough levels
69
15
Detectable
Colectomy (% of patients)
(% of patients)
Undetectable
P< 0.001
100
90
76
80
70
60
50
40
28
30
20
10
0
Undetectable
P< 0.001
100
90
80
70
60
55
50
40
30
20
7
10
0
Undetectable
Seow C H et al. Gut 2010;59:49-54
Detectable
Detectable
ACT 1+2: Proportion of Patients with Ulcerative Colitis
Treated with Infliximab Achieving Clinical Remission by
Serum Infliximab Concentration
IFX Conc.
(% patients)
Week 8
Week 30
Week 54
1st
Quartile
2nd
Quartile
3rd
Quartile
4th
Quartile
<21.3μg/mL
≥21.3-<33μg/mL
≥33-<47.9μg/mL
>47.9μg/mL
(26.3%)
(37.9%)
(43.9%)
(43.1%)
<0.11μg/mL
≥0.11-<2.4μg/mL
≥2.4-<6.8μg/mL
>6.8μg/mL
(14.6%)
(25.5%)
(59.6%)
(52.1%)
<1.4μg/mL
≥1.4-<3.6μg/mL
≥3.6-<8.1μg/mL
>8.1μg/mL
(21.1%)
(55.0%)
(79.0%)
(60.0%)
Reinish W, Sandborn WJ et al., Digestive Disease Week 2012; Abstract # 566
P-values
P=0.0504
P<0.0001
P=0.0066
Guidance for Patients Losing
Response:
Based on mAb Blood Levels and antimAbs
Potential Treatment Algorithm Based on
Therapeutic Anti-TNF Agent Concentrations
change to another
anti-TNF agent
Positive
AntimAb
if no response,
change to Rx with
different mechanism
of action
(non anti-TNF agent)
Increase mAb dose
Afif W et al. Am J Gastroenteterol. 2010;105:1133-1139.
Potential Treatment Algorithm Based on
Therapeutic Anti-TNF Agent Concentrations
Sub-therapeutic
mAb
concentration
Increase mAb
dose or
frequency
change to
different antiTNF agent
Afif W et al. Am J Gastroenteterol. 2010;105:1133-1139.
If no response,
change to different
anti-TNF agent
if no response, change to
Rx with different
mechanism of action
(non anti-TNF agent)
Potential Treatment Algorithm Based on
Therapeutic Anti-TNF Agent Concentrations
* Therapeutic
mAb
concentration
endoscopy/CTE
with active
disease
endoscopy/CTE
with inactive
disease
change to Rx with
different mechanism
of action
(non anti-TNF agent)
investigate for alternate
etiology of symptoms
* Patients should have endoscopic or radiologic imaging
Afif W et al. Am J Gastroenteterol. 2010;105:1133-1139.
Clinical Utility of Measuring IFX and
HACA Levels in Patients with IBD
Clinical outcomes in patients with
detectable HACA (N = 35)*
Clinical outcomes in patients with
sub-therapeutic concentrations (N
= 69)*
100
100
92
P<0.004
80
60
40
17
20
Complete / Partial
Response (%)
Complete / Partial
Response (%)
P<0.016
86
80
60
40
40
20
0
0
Anti-TNF changed
(11/12)
Infliximab
increased (1/6)
* 6 discontinued IFX, 3 continued same dose 3, 3
proceeded to surgery, 5 patients could not be
assessed
Afif W, et al. Am J Gastroenterol 2010 May;105(5):1133-9.
Anti-TNF changed
Infliximab
(2/6)
increased (25/29)
* 10 continued same dose, 9 discontinued IFX, 8
proceeded to surgery and 7 patients could not be
assessed
Prospective studies of maintaining
trough levels and cost effectiveness in
progress
What about dose adjustments?
Major issue (hassle factor) with 3rd
Party Payors
Efficacy of Intensification Regimes:
Experience of a Single Referral Centre
 Objective:
 To evaluate the efficacy of intensification regimes of
infliximab (IFX) and adalimumab (ADA) in patients with IBD
with regard to therapeutic response and ability to return to
normal dosing
 Methods:
 Retrospective review for intensification of therapeutic
regimes of biological therapy in patients with IBD treated in
center with IFX or ADA between October 2007 and
September 2010
19
Lukas M, et al. DDW 2011. Abstract Mo1239.
Anti-TNF Therapy for CD:
Dose Escalation and Early Discontinuation
Infliximab (n=199)
Adalimumab
(n=136)
10.9 yrs
15 yrs
% on combined IS
64%
93%
1st anti-TNF used
--
37.5%
Required dose escalation
38%
39%
Required dose escalation
by 1 yr
14%
32%
Mean disease duration
Predictors for dose
escalation
 by longer disease
duration
Stopped therapy by 1 yr*
Reasons for stopping
therapy
 by stricturing
phenotype;  by prior
anti-TNF exposure
29%
Treatment failure,
ADRs/drug allergy
13%
Treatment failure,
ADRs/drug allergy
*Patients on combined IS therapy were less likely to stop therapy at 1 yr.
Naik AS et al. Gastroenterology 2009;136(Suppl 1):A-654.
Loss of Response to Adalimumab
Dose Increase – CHARM Study
27 % over 1 year
Approximately half of these maintain benefit
and continue at the increased dose
Colombel JF et al. Gastroenterology. 2007;132:52
EMEA website
Influence of Trough Adalimumab Serum Levels and
AAA on Long-term Outcome in Crohn’s Disease
 Study design: Patients with
CD were treated adalimumab
in a single tertiary center
 N=176 patients
 Follow-up: Median f/u 2 years
 Efficacy
 71% response @ 4 wks
 67% response @ 12 wks
 65.4% (102/156) receiving
maintenance therapy
required dose escalation at
end of f/u period
 9.2% of patients developed
AAA
Karmaris Gastro 2009;137:1628–1640
Patients with sustained clinical response
without dose escalation
TR before & after escalation (µg/ml)
Adalimumab Trough Levels
and clinical response to dose escalation
25
20
Mann-Whitney: p<0.0001 
15
10
5

5.9
0.0
0
absent CR (n=9)
at least partial CR (n=24)
CRto 40ew es calation
Karmaris Gastro 2009;137:1628–1640
Efficacy of Intensification Regimes:
Experience of a Single Referral Centre
 Results:
IFX
ADA
341
111
Intensification
47 (14%)
14 (13%)
Interval ↓
33 (70%)
100%
Dose ↑
6 (13%)
n/a
Both
8 (17%)
n/a
Median time to intervention
6 mo (3-21)
3 mo (1-7)
Response after interval ↓
22/33 (67%)
5/14 (36%)
Return to normal dosing
50%
40%
Courses of therapy
 Conclusions:
 Intensification of biological therapy restored clinical response in 54%

of therapeutic interventions, with shortening of interval in IFX
treatment being the most effective
Approximately in half of the cases the normal dosing regime was
possible to restore
24
Lukas M, et al. DDW 2011. Abstract Mo1239.
WE NEED A COST-EFFECTIVE
BIOMARKER FOR MUCOSAL HEALING
25
Correlations Between hsCRP, IL-6,
Fecal Markers, CDAI, and Endoscopic
Activity in Crohn’s Disease (N=164)
hsCRP
IL-6
Calprotectin
Lactoferrin
CDAI
SES-CD
0.65
0.47
0.52
0.16
0.46
0.45
0.55
0.15
0.43
0.76
0.23
0.45
0.19
0.48
IL-6
Calprotectin
Lactoferrin
CDAI
Correlation coefficients highlighted in red were significant (P < 0.05).
When stratified by extent, correlation coefficients were highest for colonic disease.
hs-CRP = high-sensitivity C-reactive protein; IL-6 = interleukin 6; CDAI, = Crohn’s Disease Activity Index; SES-CD, =
Simple Endoscopic Score for Crohn's Disease.
Jones JL, et al. Clin Gastroenterol Hepatol. 2008;6:1218-1224.
0.15
Use of fecal calprotectin as marker of disease
activity in patients under maintenance
treatment with infliximab for ulcerative colitis
• N=113 UC patients on IFX 5mg/kg in stable remission with 5mg/kg IFX q8.
Fecal calprotectin (FC) measured monthly for 1 year
Deep remission (DR) = normal endoscopy at BL and wk 52 + Mayo score < 3
Active disease = clinical Mayo score or endoscopic score >2 at wek52
median FC < 50 mg/kg at
all measured time points.
# of Patients
% of Patients
–
–
–
25
Median FC 477 mg/kg. Increase in FC observed
already 3mo before. Two consecutive FC
measurements >300 mg/kg predicted flare
FC levels highly correlate with disease activity in pts on IFX maintenance therapy for UC.
DR is associated with very low levels of FC. A flare is associated with high levels (median >300 mg/kg).
Two consecutive cp levels of >300 mg/kg predict a flare.
De Vos et al. ECCO 2012, abstract OP 07
Close monitoring of CRP and fecal calprotectin
levels to predict relapse in Crohn's disease
patients. A sub-analysis of the STORI study
• N= 113 CD patients in corticosteroid-free remission for ≥ 6mos on IFX and
immunosuppressants (IS) .
- IFX discontinued , CRP and calprotectin measured every 2 mos through
18 mos or clinical relapse.
P = 0.001
P = 0.07
• CRP > 5mg/l and Calpro >250μg/g were associated with relapse in short term
• After discontinuation of IFX in CD patients, elevated levels of CRP and calpro
were associated with increased risk of short term relapse, even with high
variability of markers during follow-up
de Suray, et al. ECCO 2012, abstract P274
Fecal lactoferrin level is an indicator of
mucosal healing
 85 pts monitored for the complete 12-months
 49 pts experienced sustained remission defined by
CAI
 44 achieved mucosal healing based on Endoscopy Score
0–1
 41 did not show any signs of acute histological activity
(Riley Score)
 FLA was the only biomarker to show a median
level above cut-off for active disease defined
by endoscopy as well as histology for pts in
sustained clinical remission
29
Langhorst J., et al. ECCO 2012. Abstract P095.
Fecal lactoferrin level is an indicator of
mucosal healing
 Fecal lactoferrin (FLA) level is an indicator of mucosal healing in patients with

ulcerative colitis: A prospective 12-month monitoring study
85 pts monitored for the complete 12-months
 36 pts suffered a flare
 49 pts experienced sustained remission defined by CAI.
Flare
Remission
P-value
Median FLA levels (µg/g)
40
5
<0.0001
Median CRP levels (mg/dl)
0.6
0.1
<0.001
Median WBC levels
7.6
6.0
0.01
Mucosal activity
Mucosal healing
Median FLA levels (µg/g)
37
5
0.09
Median CRP levels (mg/dl)
0.1
0.2
0.882
Median WBC levels
6.0
5.9
0.787
Histologic activity
No histologic activity
Median FLA levels (µg/g)
14.4
4.6
0.198
Median CRP levels (mg/dl)
0.2
0.1
0.948
Median WBC levels
6.0
6.0
P-value
P-value
0.759
30
Langhorst J., et al. ECCO 2012. Abstract P095.
Calprotectin and Disease Activity
Author
Patient Assessment Lactoferrin
Calprotectin CRP
popula endoscopic
(Sensitivity / (Sensitivity / (Sensitivity /
tion
disease
Specificity) Specificity) Specificity)
activity
Roseth(2004)
Solem (2005)
CD
and
UC
CD
Siponnen (2008)
CD
Study
specific index
CDEIS
77% / 100%
Siponnen (2008)
CD
CDEIS
66%-71% /
83%-92%
70%-91% /
44%-92%
Siponnen (2010)
CD
SES-CD
80% / 67%
80% / 89%
D’Inca (2007)
CD
SES-CD
77% / 80%
81% / 80%
D’Inca (2007)
UC
Mayo score
75% / 60%
78% / 70%
Schoepfer (2009)
UC
Rachmilewitz
Index
86% - 93% /
71% - 88%
Schoepfer (2010)
CD
CDEIS
89% / 58%
Farup
method
Lewis JD. Gastroenterology 2011;13:
100% / 100%
54% / 75%
87% / 100%
48% / 91%
68%/58%
Predictive Value of Calprotectin for
Clinical Relapse
Tibble JA et al. Gastroenterology 2000:119:15-22
Calprotectin to Predict Relapse
Author
Gisbert*
Tibble
Tibble
Costa
Costa
D’Inca
Sipponen
Walkiewicz
Patients
UC
UC
CD
UC
CD
UC
UC+CD
CD
Duration
of
remission
at entry
>6 mos.
1-4 mos.
1-4 mos.
1-12 mos.
1-12 mos.
3-36 mos.
> 3mos
(51% >12
months)
Not stated
* NPV 100% at 12 weeks
Lewis JD. Gastroenterology 2011;13
Elevated
Level
>150μg/g
>50μg/g
>50μg/g
>150μg/g
>150μg/g
>130μg/g
>100μg/g
Relapse
Rate with
Low
Calpro
9%
10%*
15%
10%
57%
30%
25%
Relapse
Rate with
High
Calpro
31%
85%*
85%
81%
87%
79%
39%
>400μg/g
11%
56%
Monitoring Inflammation
 Can Fecal Calprotectin
 detect subclinical inflammation?
 predict future flares?
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
CD and UC in clinical remission
Cutoff of 167
Prediction of future flares
100%
72%
69%
75%
Sensitivity
Specificity
3 months
Gisbert, IBD 2009; 15: 1190.
1 year
You Can’t Always Get What you
Want….