1. You Can Never Stop a Biologic
Scott D Lee MD
Associate Professor of Medicine
Director, Clinical Inflammatory Bowel Diseases Program
University of Washington
Seattle, WA
March 23rd, 2013

2. Diagnosed with moderate to severe disease
General Considerations in IBD Patients Started and Maintained on Biologics
Diagnosed with moderate to severe disease
At risk for complications of IBD
Have had significant improvement
Discontinued or on significantly less steroids
Do not have related limiting side effects
Have not develop contraindication
Cancer
Active infection
Demyelinating disease

3. Proportion of Patients (%) Remission defined as: CDAI <150 points
ACCENT I
Week 54 Remission after Response to Infliximab Discontinued vs Continued Therapy
P<0.001
P=0.021
Proportion of Patients (%)
Single Dose (n=102)
5 mg/kg q 8 wks (n=104)
10 mg/kg q 8 wks (n=105)
Remission defined as: CDAI <150 points

4. Proportion of Patients (%)
ACCENT I
Week 54 Steroid Free Remission After Response to Infliximab Discontinued vs Continued Therapy
Single Dose
5 mg/kg q 8 wks
10 mg/kg q 8 wks
Proportion of Patients (%)
P=0.005
P=0.059
P=NS
6/54
14/56
18/53

5. Infliximab Antibody Formation Discontinued vs Continued Therapy
ACCENT I
Proportion of Patients with ATI*
Through Week 54
Proportion of Patients (%)
Episodic
Strategy
Maintenance
q 8 weeks
10 mg/kg
Maintenance q 8 weeks
5 mg/kg
P=0.003
P=0.42
This slide highlights the effect of immunosuppression and episodic treatment on ATI development in the ACCENT  trial. In patients receiving REMICADE episodically, the rate of ATI development without immunosuppression was 38% compared with 16% in patients receiving immunomodulators. This difference was statistically significant. With maintenance dosing, the rate of ATI development was lower and the effect of immunomodulators was less pronounced. In the 5 mg/kg every 8 week group, 7% of patients receiving immunomodulators developed ATI compared with 11% of patients not receiving immunosuppressants and in the 10 mg/kg q 8 week group, 4% of patients receiving immunomodulators developed ATI compared with 8% of patients not receiving immunosuppressants. The differences ATI’s in the maintenance groups between patients receiving and not receiving immunomodulators were not statistically significant.
Hanauer S, et al., Clin Gastroenterol Hepatol. 2004;2:542–553.

6. Duration of Response by Antibody Level
Antibody Formation and Effect on Response with Episodic Treatment with Infliximab
Duration of Response by Antibody Level
Days of Response
37% of Patients
(n=46)
140
120
100 40 20 80 60
Negative
g/mL
>20.0
71 days of clinical response
to Infliximab therapy
35 days of clinical response to Infliximab therapy
63% of Patients
(n=79)
The median duration of response by antibody level is shown here. The box plots represent the 1st and 3rd quartiles in each group, while the T-bars represent the rest of the data with a maximum of 1.5 times the interquartile range. Patients who were negative for antibodies to infliximab or had low titer antibodies (1.7 – 7.9 µg/mL) had a median of 71 days of clinical response to REMICADE therapy. Patients who developed antibodies to infliximab with titers of 8.0 µg/mL or higher had a median of 35 days clinical response to REMICADE therapy.
Baert F, et al. N Engl J Med. 2003;348:

7. Continued Therapy Is Associated with Fewer Hospitalizations
ACCENT I
Continued Therapy Is Associated with Fewer Hospitalizations
Episodic Strategy
5 mg/kg Scheduled Strategy
10 mg/kg Scheduled Strategy
Combined Schedule Strategy
Week 54
P=0.047
P=0.023
P=0.014 10 20 30 40 50
Number of Hospitalizations per 100 Patients
Rutgeerts P et al. Gastroenterology. 2004;126:
Rutgeerts P et al. Gastroenterology. 2004;126:

8. Continued Therapy Is Associated With Fewer Intra-Abdominal Surgeries
ACCENT 1
Continued Therapy Is Associated With Fewer Intra-Abdominal Surgeries
Episodic Strategy
5 mg/kg Scheduled Strategy
10 mg/kg Scheduled Strategy
Combined Schedule Strategy
Week 54
P = 0.04
P = 0.07
P = 0.01 10 20 30 40 50
Proportion of Patients With Surgeries
Rutgeerts P et al. Gastroenterology. 2004;126:
Rutgeerts P et al. Gastroenterology. 2004;126:

9. UC Response and Remission IFX Discontinued vs Continued Therapy
ACT 1
Remission
Response
100 50
†P<0.001 90 † 45 † †
‡P<0.01 39 † 80 † 40 ‡ 37 69 34 70 62 † 35 32 ‡ 60 52 30 51
Percent of Patients 50
Percent of Patients 25 37 40 20 30 16 15 30 15
Clinical response was defined as a decrease in the Mayo score by 30% and 3 points AND a decrease in the rectal bleeding subscore of 1 or a rectal bleeding subscore of 0 or 1. 20 10 10 5
8 Weeks
30 Weeks
8 Weeks
30 Weeks
Placebo infusions
5 mg/kg infliximab
10 mg/kg infliximab
Rutgeerts P. N Engl J Med. 2005;353:
Rutgeerts P. N Engl J Med. 2005;353:

10. Early Use of AZA After First Steroid Induction
EFFICACY OF AZA THERAPY
Early Use of AZA After First Steroid Induction
150
125
Mean CDAI
100 75
P= 0.07 50
P< 0.01 25 2 3 4 5 6 7 8 9 10 11 12 13
Visit number
Sustained remission up to month 18
NRI
p= 0.5 25 50 75
100
% patients
LOCF
p= 0.2
67,7
57,1
44,1
38,1
AZA
Placebo
Sans M. Gastroenterology 2011 (Abstract)

11. Week 50 Steroid Free Remission AZA vs IFX vs Dual Therapy
SONIC
Week 50 Steroid Free Remission AZA vs IFX vs Dual Therapy
All Randomized Patients (N=508)*
p<0.001
p=0.028
p=0.035
41/170
59/169
78/169
Colombel JF et al. NEJM 2010.

12. Mucosal Healing at Week 26 AZA vs IFX vs Dual Therapy
SONIC
Mucosal Healing at Week 26 AZA vs IFX vs Dual Therapy
100
p<0.001 80
p=0.023
p=0.055 60
Proportion of Patients (%) 44 40 30 16 20
18/109
28/93
47/107
AZA + placebo
IFX + placebo
IFX+ AZA

13. Mucosal Healing Predicts Sustained Clinical Remission in Early CD
Mucosal Healing is Predictive of Sustained Remission
Mucosal Healing Predicts Sustained Clinical Remission in Early CD
Simple endoscopic score 0
Simple endoscopic score 1-9
100 80 * ** ** 60
% of patients 40 20
Remission at year 3+4
Remission off steroids at year 3+4
Remission off steroids at year 3+4
and no
flare during year
3+4
* P < 0.05; ** P < 0.01 (Fischer’s exact)
Baert FJ, et al. Gastroenterology 2010 . 13

14. Risk of Lymphoma Associated with Immunomodulators
RISK OF THERAPY - MALIGNANCY
Risk of Lymphoma Associated with Immunomodulators
19,486 IBD patients
30.1% currently receiving thiopurines
14.4% discontinued thiopurines
55.5% never exposed to thiopurines
Receiving thiopurines vs. never exposed
HR 5.28 ( )
Exposure
Rate per 10,000 pt-years
95% CI
Current use
9 .0
Discontinued
2.0
Never exposed
2.6
Beaugerie et al, Lancet 2009;7:374.

15. Meta-Analysis Of Lymphoma Rate Associated With Anti-TNF Agents
RISK OF THERAPY - MALIGNANCY
Meta-Analysis Of Lymphoma Rate Associated With Anti-TNF Agents
8905 patients representing 20,602 pt-years of exposure
13 Non-Hodgkin lymphomas  6.1/10,000 pt years
This HR is very similar to SIR with thiopurines
Mean age 52, 62% male
10/13 exposed to IM* (This is really a risk of combo Rx)
Lymphoma SIR does not appear increase with addition of anti-TNF
Lymphoma SIR appears to be dependent on thiopurine use
NHL rate per 10,000
SIR
95% CI
SEER all ages
1.9 -
IM alone
6.1
3.23
Anti-TNF + IM vs SEER
Anti-TNF+ IM vs IM alone
1.7
*not reported in 2
Siegel et al, CGH 2009;7:874.

16. Anti-TNF Meta-Analysis And Malignancies
RISK OF THERAPY - MALIGNANCY
Anti-TNF Meta-Analysis And Malignancies
Controls
Anti-TNF
-0.14% ( , P=0.39)
Risk difference
Difference in effect: treatment minus placebo (CI 95%)
Peyrin-Biroulet et al CGH 2008;6:664. 16

17. Discontinued biologic vs continued use leads to:
Conclusions
Discontinued biologic vs continued use leads to:
Higher recurrence rates of disease activity
Lower likelihood of steroid free remission
Increased risk of antibody formation
Antibody formation leads to loss of response
Continued biologic therapy vs Thiopurines is:
More effective maintenance therapy
Thiopurines appear to be the primary risk of lymphoma
Results in higher rates of mucosal healing
Once biologic therapy it should not be stopped as the risks outweigh the benefits
A transition to thiopurines as maintenance is less effective and potentially higher risk