1. Immunomodulators and Biologics
Maria T. Abreu, MD
University of Miami Miller School of Medicine
Miami, Florida
criterio de valoración
Buenas noches. Primero quiero darle las gracias a la asociacion nacional de gastroenterologia Mexicana por haber me (EXTENDIDO) esta invitacion y a los representates de Schering Plough division Undra Jorge Pirod y Susana Martinez que me organizaron este viaje. Finalmente le doy las gracias al Doctor Rafael Perez Huacuja que con otros colegas esta iniciando estudios importantes en Mexico para identificar casos de enfermedad inflamatoria intestinal. Para me es un gran placer poder compartir con ustedes los avances que se han llevada a cabo en el tratamiento de las enfermedades inflamatoria intestinales.
NEXT SLIDE:
Para empesar, yo ejerso en el hospital Cedars-Sinai en Los Angeles. Aqui tenemos un centro de EII con una clinica adonde tratamos aproximada mente 3,000 pacientes con EII. Tambien tenemos laboratorios scientificos para hacer investigaciones en EII.

2. What is there left to talk about…
Are there any new tools for clinicians?
What do we know?
Are UC and Crohn’s disease treatment different?
Picking the patient based on disease burden

3. Maintenance of remission off steroids Mucosal healing (histology)
and/or
Mucosal healing (histology)
Induction of remission
IBD
Maintenance of remission

4. What do we know: Guiding principles
Combination therapy is better than monotherapy
Early therapy is better than late therapy (esp Crohn’s disease)
Well timed surgery is ok

5. Biologics in IBD Infliximab approved for Crohn’s disease
1998
Certolizumab Pegol for Crohn’s disease (2008)
Adalimumab for Crohn’s disease
(2002)
Initial cA2 (infliximab) paper
(1995) NEJM 1997
Infliximab for ulcerative colitis (2005)
Natalizumab for Crohn’s disease (2008)
Nobel prize in 1988

6. First-line Biologic Agents for the Treatment of CD
Humanized Fab’ fragment (95% human IgG1 isotype)
Certolizumab Pegol
PEG VH VL
CH1
No Fc
Chimeric monoclonal antibody (75% human IgG1 isotype)
Infliximab
IgG1
Human recombinant antibody (100% human IgG1 isotype)
Adalimumab
IgG1
Mouse
Human
PEG, polyethylene glycol.

7. SONIC AZA 2.5mg/kg IFX 5mg/kg IFX + AZA
Moderate-to-severe CD in patients with no prior exposure to biologic agents or immunomodulators
Excluded intermediate TPMT activity
Average disease duration 2.3 years
AZA 2.5mg/kg
IFX 5mg/kg
IFX + AZA
1° endpoint: Induction + maintenance of steroid-free remission
2° endpoint: Mucosal healing

8. Clinical Remission Without Corticosteroids at Week 26
SONIC 8
Clinical Remission Without Corticosteroids at Week 26
Primary Endpoint
100
p<0.001 80
p=0.009
p=0.022 57 60
Proportion of Patients (%) 45 40 30
criterio de valoración 20
52/170
75/169
96/169
AZA + placebo
IFX + placebo
IFX+ AZA
Colombel, J.F., et al., N Engl J Med. 362(15): p

9. Mucosal Healing at Week 26
SONIC 9
Mucosal Healing at Week 26
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
Colombel, J.F., et al., N Engl J Med. 362(15): p

10. Patients Enrolled in the Extension (N=280)
Corticosteroid-Free Clinical Remission at Week 50
Patients Enrolled in the Extension (N=280)
p=0.010
p=0.324
p=0.065
41/75
59/97
78/108
Percent of Patients (%)

11. SONIC: IFX Trough Levels at Week 30* are Higher with Concomitant AZA
Median Serum Trough Levels (mg/ml)
(N=97)
(N=109)
* Patients who had 1 or more PK samples obtained after their first study agent administration were included in the analysis
Sandborn, W. et al. NEJM, 2010

12. Trough Concentration of Infliximab is Higher With Concurrent Methotrexate
Infliximab plus
6.35
µG/L
3.75
MTX+IFX
IFX alone
Feagan B et al. DDW Abs no. 682C.

13. Are UC and Crohn’s disease treatments different?

14. Sequential Therapies for UC
Disease Severity
at Presentation
Colectomy
Anti-TNF
Cyclosporine
Anti-TNF
Thiopurine
Severe
Moderate
Mild
Aminosalicylate
Thiopurine
Corticosteroid
Aminosalicylate
Aminosalicylate
Induction
Maintenance
Therapy is stepped up according to severity at presentation or failure at prior step

15. IBD has common genetic origins
CD Genes
UC Genes
ECM1
NKX2-3
IFNG
IL26
ORMDL3
RNF186
OTUD3
PLA2G2E
IL19
FCGR2A
FCGR2C
REL
CCDC139
PUS10
MST1
CEP72
TPPP
IL23R
CDKAL1
NKX2-3
PTPN2
MST1
BTLN2
IL10
NOD2
ATG16L1
IRGM
PTGER4
CCR6
ITLN1
STAT3
IL12B
JAK2
LYRM4
IL18RAP
Genes in common
Brant SR. Gastroenterology. 2009;136:396.
McGovern D et al. Nat Genet. 2010;42:332.

16. UC SUCCESS Failing corticosteroids AZA 2.5mg/kg IFX 5mg/kg IFX + AZA
Moderate-to-severe UC (Mayo score ≥6)
Failing corticosteroids
No prior exposure to biologic agents; no current immunomodulators
AZA 2.5mg/kg
IFX 5mg/kg
IFX + AZA
1° endpoint: Steroid-free remission at week 16 (total Mayo score ≤2)

17. Infliximab, Azathioprine, or Infliximab + Azathioprine for UC: The UC Success Trial
Objective
To assess the best treatment strategy in patients with moderate-severe UC who are failing corticosteroids
Patients (N=231)
Severe UC (Mayo score ≥6)
Failing corticosteroids
Naive to azathioprine or had stopped ≥3 months prior to entry
Treatments
AZA 2.5 mg/kg + placebo
IFX 5 mg/kg + placebo
IFX 5 mg/kg + AZA 2.5 mg/kg
At week 8, nonresponders in the AZA arm were eligible for IFX 5 mg/kg at weeks 8, 10, and 14
Primary end point
Steroid-free remission at week 16 (total Mayo score ≤2)
Panccione R et al. DDW 2011; Abstract 835

18. UC SUCCESS study * Patients (%)
*P<.05 compared to IFX; #P<.05 compared to AZA
Panccione R et al. DDW 2011; Abstract 835

19. Conclusions
IFX+AZA was superior to AZA and IFX monotherapy in inducing steroid-free remission in patients with moderate-severe UC
Patients treated with IFX both as monotherapy and in combination with AZA are more likely to achieve response and mucosal healing than those treated with AZA monotherapy

20. Why do immunomodulators alone not look so good?
Take longer to work
Studies have excluded intermediate metabolizers
Weight-based dosing underestimates dose about half the time1
Morales A et al Inflamm Bowel Dis Apr;13(4):380-5.

21. 6-MP: Corticosteroid withdrawal and/or maintenance of remission*
3/53
22/58
5/39
23/44
Complete fistula closure
Complete steroid d/c
Disappearance of symptoms
Present DH, et al. N Eng J Med. 1980;302:981-7.

22. AZA: Corticosteroid withdrawal and maintenance of remission
100
Placebo (n=30)
AZA 2.5 mg/kg per day (n=33) 80 60
Percent of Patients Not Failing Trial
42% 40
P=.001
35% 20
This trial enrolled 63 patients with active CD. Patients were tapered off prednisolone for 12 weeks while at the same time entering into this into a randomised, double-blind, 15-month trial. At 12 weeks, there was no difference in the rates of remission between the 2 groups, but by 15 months there was a highly significant difference. 7% 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Duration of Trial (months)
Remission induced by prednisolone 1mg/kg tapered over 12 wk
Permitted CDAI <175 as definition of remission at month 15
Candy S et al. Gut. 1995;37:674.

23. Comparing across studies AZA or 6-MP

24. Response-guided therapy
Mucosal healing +
Histologic healing =
Deep remission

25. Mucosal healing in IBD : effect of different therapies
Crohn UC
5-ASA No +
Steroids
Azathioprine
Methotrexate ?
Infliximab
+ (Sonic trial)
Certolizumab
+ (Music trial)
Adalimumab
+ (Extend trial)
Natalizumab
Enteral nutrition -

26. Early mucosal healing a favorable prognostic factor
Insert figure from the Gastroenterology paper from ACT

27. Early mucosal healing a favorable prognostic factor in UC
ACT 1 and ACT 2
Early mucosal healing a favorable prognostic factor in UC
P<0.0001
Patients in Corticosteroid-free remission %
Infliximab-treated patients
Week 8 endoscopy
Week 8
endoscopic score
Colombel JF et al. Gastroenterology Jun 29. [Epub ahead of print].
4/15/2017

28. Patients with mucosal healing at week 12 (%)
The best opportunity to induce mucosal healing is early in Crohn’s disease (EXTEND study)
Adalimumab, induction-only (placebo) 50 44 45 40 40
Adalimumab, every other week 35 30
Patients with mucosal healing at week 12 (%) 25 21 18 20 15 10 7 5
4/9
1/14
4/10
7/39
9/43
<2 years
2 to <5 years
5 years
p=0.029 for adalimumab vs placebo for disease duration <5 years vs. ≥5years
All patients (n=135) received open-label adalimumab 160-/80-mg induction therapy at Weeks 0/2 and 129 patients were randomised at Week 4 to maintenance therapy with adalimumab 40 mg every other week or placebo
Sandborn WJ, et al. J Crohn’s Colitis 2010; 4:S36 (Abstract P060)

29. New tools for guiding therapy

30. Maser EA et al. Clin Gastroenterol Hepatol. 2006;4:1248-1254.
Detectable levels of infliximab at trough are associated with better outcomes
Clinical Remission
C-reactive Protein
Endoscopic Change
*P<.001 *
*P<.001
*P<.001 * *
Undetectable
2.0 ug/ml
Undetectable
2.0 ug/ml
Undetectable
2.0 ug/ml
Maser EA et al. Clin Gastroenterol Hepatol. 2006;4: 30 30

31. Clinical outcomes in UC patients treated with infliximab correlate with detectable trough levels76 69 28 15
P< 0.001
Patients developed undetectable levels of infliximab and then developed ATIs
Clinical outcomes according to the presence and absence of a detectable trough serum infliximab concentration. The proportion of patients with (A) clinical remission defined as a Mayo score of 0 and discontinuation of prednisone for ⩾4 weeks; (B) endoscopic improvement defined as a reduction in the follow-up endoscopic score of at least 1 point from the baseline to the follow-up evaluation; and (C) colectomy. 55 7
Seow C H et al. Gut 2010;59:49-54

32. Infliximab Serum Levels are Related to Mucosal Healing
Methods
Analysis of serial serum samples
Patients
Crohn’s disease on infliximab (N=215)
P=.042
6.05
Trough infliximab concentration (μg/mL)
curación de la mucosa
INTRODUCTION: The importance of mucosal healing as a treatment goal in Crohn’s disease has increasingly been recognized. Infliximab (IFX) is a very efficacious treatment and has shown to induce rapid and profound healing. Mucosal healing is associated with deep clinical remission, reduction of hospitalisations and surgical rates. Nevertheless, primary and secondary failure occurs. Secondary loss of response is at least in part explained by immunogenicity leading to lower trough levels of the drug. Little is known about the importance of trough levels in optimizing therapy. We wanted to study whether IFX trough levels are important to achieve mucosal healing and if they are related to the degree of healing. AIMS & METHODS: We studied serial serum samples in 215 patients with Crohn’s disease, all in whom clinical and endoscopic data before and after start of IFX therapy were present. For 191 patients, serum was available at time t0 (before the start of IFX), t1 (2 to 6 weeks after the first infusion) and t2 (at the time of the endoscopy). IFX trough levels were determined by an in-house developed ELISA method, in which 1:150 diluted serum samples were applicated to TNF alpha coated plates. On each plate, an internal standard curve was introduced and a polyclonal HRP-conjugated goat anti-human antibody was used for detection. Endoscopic healing was defined as complete (disappearance of all lesions), partial (clear endoscopic improvement but still ulceration present) or no healing. Data were analysed using non-parametric Kruskal Wallis en Mann Witney test. RESULTS: Complete healing was observed in 39% of patients, partial in 20% and no healing in 41% of patients. Patients who showed (partial or complete) healing had significantly higher IFX trough levels compared to patients without healing (median 5.44 µg/mL; P – P versus 0.85 µg/mL;P – P respectively; p=0.026). Furthermore, a dose-dependent effect was observed with the highest trough levels detected in patients with complete healing (median 6.05 µg/mL; P – P ) followed by partial healing (median 3.29 µg/mL; P – P ) and absence of healing (0.85 µg/mL; P – P ; p= 0.042). CONCLUSION: Infliximab trough levels are strongly related with the degree of mucosal healing. In this study, we showed that patients with complete healing under IFX have significantly higher trough levels than patients without healing. Measurement of infliximab trough levels is therefore useful in optimizing therapy since they may allow dose adjustment in patients with low drug levels.
3.29
0.85
Van Moerkercke B et al. GASTRO Abstract No. OP327. 32

33. All anti-TNFs are immunogenic— esp as monotherapy
Patients, %
Episodic Maintenance
Scheduled Maintenance
IMS-
IMS+
Infliximab1 (CD 5 mg/kg)
(CD 10 mg/kg)
38%
16%
11% 8% 7% 4%
Infliximab2 (UC 5 mg/kg)
(UC 10 mg/kg)
No data
19% 9% 2%
Certolizumab3 (PRECiSE I)
10%
Certolizumab4 (PRECiSE II)
24%
12%
Adalimumab5 (RA, all doses)
28%
8% (latest JAMA)
Adalimumab6 (CLASSIC II) 0%
IMS = immunosuppressant.
Hanauer SB et al. Clin Gastroenterol Hepatol. 2004;2: ; 2. Sandborn WJ et al. DDW 2007 Poster and abstract T1273; 3. Sandborn WJ et al. N Engl J Med. 2007;357: ; 4. Schreiber S et al. N Engl J Med. 2007;357: ; 5. Adalimumab [package insert]. Abbott Laboratories. July 2007; 6. Sandborn WJ et al. Gut. 2007;56:
7. JAMA, April 13, 2011—Vol 305, No. 14 33 33 33

34. When to Switch? The RA Experience
Relationship between infliximab and anti-infliximab (ATI) levels and clinical outcome A B C
1.5 months
3 months 60 50 40 30 20 10
P=.0005
P=.0001
P=.001 25 20 15 10 5
P=.009
P=.0399
Anti-infliximab antibody (%)
S-infliximab (µg/ml)
P=.0025
P=.016
Relationships of infliximab and anti-infliximab antibody levels to clinical outcome:
A. Trough tumor necrosis factor binding capacity due to infliximab in sera obtained immediately before the third drug infusion (at 1.5 months). Bioavailability of infliximab before the third infusion varied considerably from patient to patient, and a substantial number of patients with low serum levels of infliximab at this early time point (1.5 months) experienced response failure within the observation period. P values were determined by Mann-Whitney rank sum test and are versus patients who did not experience treatment failure with infliximab at the standard dose throughout the observation period.
B. Anti-infliximab antibody levels (% bound cpm) in sera obtained before the fourth infliximab infusion (at 3 months). Detection of anti-infliximab antibodies at an early time point (3 months) was associated with later dose increases necessitated by inadequate clinical response. In fact, antibodies had not been detectable at 3 months in any of the patients who exhibited good response to standard therapy
C. Anti-infliximab antibody levels (% bound cpm) in sera obtained before the fourth infliximab infusion (at 3 months). Early formation of anti-infliximab antibodies was also associated with subsequent discontinuation of therapy. This was the case both in general (discontinuation for any reason) and when discontinuation was due to treatment failure or infusion reactions. The same trend was seen when sera were investigated for the presence of antibodies after 6 months of therapy, whereas after 1.5 months too few patients were antibody positive for meaningful comparison.
P values were determined by Mann-Whitney rank sum test and are versus patients who continued to receive infliximab at the standard dose (B) and
versus patients who did not discontinue infliximab therapy within the first 18 months (C). Each circle represents an individual patient; bars show the
median and interquartile range.
No failure
< 6 months
> 12 months
Any
Therap.
failure
Infusion
reaction
Standard
therapy
Dose
increase
within 18 months
Ongoing
< 12 months
Therapeutic failure
Reason to stop therapy
within 18 months
Bendtzen K et al. Arthritis Rheum. 2010;54:

35. Median adalimumab concentrations stratified by ada Abs
Geertje M. Bartelds, et al. JAMA, April 13, 2011—Vol 305, No. 14

36. Clinical Outcomes in UC Patients Treated With Infliximab Correlate With Detectable Trough Levels76 69 28 15
P< 0.001
Clinical outcomes according to the presence and absence of a detectable trough serum infliximab concentration. The proportion of patients with (A) clinical remission defined as a Mayo score of 0 and discontinuation of prednisone for ⩾4 weeks; (B) endoscopic improvement defined as a reduction in the follow-up endoscopic score of at least 1 point from the baseline to the follow-up evaluation; and (C) colectomy. 55 7
Seow C H et al. Gut 2010;59:49-54

37. Adalimumab Trough Levels Predict Long-term Response
1.0
30.00
Mann-Whitney p=.016
Log Rank: p=0.1
0.8
20.00 8
ADA TR wk 12 (µg/mL)
0.6
Patients with sustained clinical responses(%)
8.9
0.4
10.00
1.6
0.2
0.00
ADA TR>0.33 µg/mL, n=104
Concomitant medication at initiation of adalimumab therapy (%)  Corticosteroids41 (24.4)  Azathioprine/6-mercaptopurine41 (24.4)  Methotrexate21 (12.5) Indication for adalimumab treatment in relation to infliximab failure (%)  Intolerance of infliximab54 (32)  No response to infliximab11 (6.5)  Loss of response to infliximab97 (58)
Continue (n=46)
Discontinue (n=15)
ADA TR>0.33 µg/mL, n=16
0.0 30 60 90
120
150
180
210
240
ADA discontinuation by wk 24
Sustained clinical response (weeks)
Karmiris K et al. Gastroenterology Nov;137(5): 37

38. Afif W et al. Am J Gastroenteterol. 2010;105:1133-1139.
Clinical Utility of Measuring Anti-TNF and Human Anti-Chimeric Antibodies
Objective
Evaluate clinical utility of measuring HACA and infliximab concentrations
Patients (N=155)
CD (78%) or UC (20%)
Methods
HACA and infliximab concentrations measured in 155 patients
Indications for testing included loss of response (49%), partial response (22%), possible autoimmune reaction (10%)
Afif W et al. Am J Gastroenteterol. 2010;105:

39. Clinical Outcomes in Patients With Detectable HACA (n=35)*
92%
P<.004
Complete/partial response (%)
17%
Anti-TNF changed (11/12)
Infliximab increased (1/6)
* 6 discontinued IFX, 3 continued same dose 3, 3 proceeded to surgery, patients could not be assessed

40. Clinical Outcomes in Patients With Sub-therapeutic Concentrations (n=69)*
86%
P<.016
Complete/partial response (%)
33%
Infliximab increased (25/29)
Anti-TNF changed (2/6)
* 10 continued same dose, 9 discontinued IFX, 8 proceeded to surgery and 7 patients could not be assessed

41. Potential Treatment Algorithm Based on Therapeutic Anti-TNF Agent Concentrations
if no response, change to Rx with different mechanism of action (non anti-TNF agent)
change to another anti-TNF agent
Positive HACA
increase IFX dose
Afif W et al. Am J Gastroenteterol. 2010;105:

42. Algorithm Based on Therapeutic Anti-TNF Agent Concentrations
Sub-therapeutic IFX concentration
increase infliximab dose or frequency
If no response, change to different anti-TNF agent or change mechanism of action
change to Rx with different mechanism of action (non anti-TNF agent)
endoscopy/CTE with active disease
* Therapeutic IFX concentration
endoscopy/CTE with inactive disease
investigate for alternate etiology of symptoms
Afif W et al. Am J Gastroenteterol. 2010;105:

43. Multivariate analysis
Infections and mortality in the TREAT registry: 15,000 patient-years of experience
Multivariate analysis
4.5
Mortality
Serious infections 4
3.5 3
2.5 *
IFX
Odds ratio
AZA 6-MP MTX
AZA 6-MP MTX ** 2
IFX
1.5
Steroid use is associated with an increased odds ratio suggesting higher risk of mortality or serious infections. Neither infliximab nor immunosuppressants were associated with an increased risk of mortality or serious infections.
The incidence of serious infections was 1.29 per 100 patient-years within 3 months of an infliximab infusion versus 0.68 in patients not within 3 months of an infliximab infusion (relative risk [RR]=1.9, 95% confidence interval [CI]=1.34–2.70, p < 0.001). However, logistic regression showed that infliximab was not an independent predictor of serious infections (RR=1.40, 95% CI=0.95–2.07). The only factor independently associated with serious infections was current use of steroids (RR=2.01, CI=1.4–2.91, p < ). Neither current use of infliximab nor current use of immunosuppressants was significantly associated with the development of serious infection.2
The TREAT registry has driven rapid withdrawal of steroid therapy.
However, it is noteworthy that serious infection rates for inflximab are creeping up and may catch steroids.
Steroids
Steroids 1
0.5
*p=0.001
**p<0.0001
IFX = infliximab; AZA = azathioprine; MTX = methotrexate
Lichenstein GR, et al. Gastroenterology 2006;130(suppl 4):A-71
Lichtenstein GR, et al. Clin Gastroenterol Hepatol 2006;4:621–630 43 43

44. Risk Factors for Opportunistic Infections in IBD: A Case-Control Study
100 cases of opportunistic ınfections
Odds Ratio (95% CI)
P value
1 medication
2.7 (1.5–4.8)
0.0014
2 medications
9.7 (3.3–28.2)
<
3 medications
Infinite
Overall P <
Steroids alone
2.2 (1.1–4.8)
0.037
6-MP/AZA alone
2.5 (1.2–5.1)
0.015
IFX alone
11.2 (0.8–153.3)
0.07
6-MP/AZA + steroids
15.7(4.1–59.5)
6-MP/AZA + IFX
1.6 (0.1–18.7)
0.71
6-MP/AZA + IFX + steroids
0.0003
Steroids alone 2.2 (1.1–4.8) 0.037
6MP/AZA alone 2.5(1.2–5.1) 0.015
IFX alone (0.8–153.3) 0.07
6MP/AZA – steroids 15.7(4.1–59.5) <0.0001
6MP/AZA – IFX 1.6 (0.1–18.7) 0.71
6MP/AZA – IFX – steroids infinite
6-MP = 6-mercaptopurine; AZA = azathioprine; IBD = inflammatory bowel disease; IFX = infliximab. Toruner M, et al. Gastroenterology 2008;134:

45. Clinical Remission With Anti–TNF-α Agents
Adalimumab 160/80 mg
Placebo
100
52% 75
72%
Patient Remission (%)
48% 50
28%
36% 25
21%
12% 7%
Anti –
TNF α -
Secondary *
Naive Patients
Anti –
TNF α - †
* Anti–TNF-α-naive group: placebo, n=74; adalimumab, n=76; P=.004
†Secondary anti–TNF-α group: placebo, n=12; adalimumab, n=34; P<.001
Hanauer SB et al. Gastroenterology. 2006;130(2):323
Sandborn WJ et al. Ann Intern Med. 2007;146(12):829 45

46. SONIC: Corticosteroid-Free Clinical Remission at Week 26
Primary Endpoint
100
43%
P<0.001 80
P=0.006
P=0.022 60
56.8
Proportion of Patients (%)
44.4 40
30.6 20
52/170
75/169
96/169
AZA + placebo
IFX + placebo
IFX+ AZA
Colombel J-F et al. N Engl J Med Apr 15;362(15):

47. How do you pick the right patients for these interventions?

48. Picking therapy based on patient
Severity of Inflammation
Symptoms
Location
Limited ileal disease
Mild—bothered but functions at a normal capacity
Superficial ulcerations
Deep ulcerations/inflamma-tory stricture
Extensive small bowel involvement
Moderate (affects daily life)
Fibrotic stricture
Extensive colonic involvement
Internal perforating disease (+/- abscess)
Severe (close to or needing hospitalization)
Perianal perforating
Rectal disease

49. Risk of NH Lymphoma with anti-TNF + IM treatment for Crohn’s Disease Meta-analysis Results
8905 patients representing 20,602 pt-years of exposure
13 Non-Hodgkin’s lymphomas 
Mean age 52, 62% male
10/13 exposed to IM* (really a study of combo Rx)
6.1 per 10,000 pt-years
NHL rate per 10,000
SIR
95% CI
SEER all ages
1.9 -
IM alone
3.6
Anti-TNF + IM vs SEER
6.1
3.23
Anti-TNF+ IM vs IM alone
1.7
Siegel et al, CGH 2009;7: *not reported in 2

50. Risk of Developing NH Lymphoma
Patient receiving anti-TNF + Immunomodulator Therapy for 1 year
Risk with combination therapy
Risk without medication
Risk with IM monotherapy
Siegel et al, CGH 2009;7:874.

51. Who needs combination therapy? When can we use sequential monotherapy?
Anti-TNFs
Biologics (immunogenic)
Immunomodulators:
Thiopurines
MTX
Mechanistic synergy
Higher levels of biologic
Moderate-to-severe disease
Steroid-refractory disease
Severe prognostic markers
A lot to lose

52. Who needs combination therapy? When can we use sequential monotherapy?
Anti-TNFs
Biologics (immunogenic)
Immunomodulators:
Thiopurines
MTX
Steroid-refractory disease
Mild course/ prognostic markers
Hi-risk for complications from combo therapy?
Steroid-dependent disease
(applies to both CD/UC)

53. So how do we reconcile these?
Combination therapy is most effective at inducing & maintaining (1 year) remissions in IS naïve patients
Steroids + Biologic
Biologic + Immune Suppressants
Prolonged immune suppression adds no benefit if patients are already failing therapy
Possible short-term benefits of reducing immunogenicity?

54. Is it practical to start IMM with biologics at the same visit?
Time consuming discussions
Each need their own tests prior to starting

55. Key Takeaways
Patients should be risk stratified for disease severity and potential for long-term complications of their IBD
Combination therapy better than monotherapy for most patients
Still role for immunomodulators in steroid-dependent disease
Mucosal healing should be a goal
Therapeutic drug monitoring is useful and may become more widely available

56. Knowing Which Therapy Combinations Work Best
5-ASAs
Immuno- modulators
Experimental Therapies
Biologics
Steroids
biologics, 5-asa, immunomodulators, steroids, experimental