1. Immunosuppressive Medications and IBD: Now and What’s Next
Stephen B. Hanauer, MD
University of Chicago

2. Indications for Immunosuppressives in IBD
Crohn’s Disease
Steroid-Sparing (Maintenance)
Maintenance after Biologics
Reduction of Immunogenicity
Post-Surgical Maintenance
Ulcerative Colitis
Steroid-Sparing

3. Conventional approach to Induction Therapy: step-up
Anti TNF-α therapies Surgery
Disease severity
Systemic corticosteroids
AminosalicylatesNon-systemic corticosteroids
Time
Clinical approach to use “mildest” form of drug therapy to treat patients first
Move to next step in non-responders

4. Step-up management approach
Advantages
Patients attain remission with less toxic therapies
Potentially more toxic therapies reserved for more severe or refractory disease
Minimizes risk of adverse events
Cost sparing (short-term?)
Disadvantages
Patients have to “earn” most effective treatments
Decrease in quality-of-life before patients obtain optimal therapy
Likelihood of surgery is high
Disease is not modified

5. IBDs are chronic, life-long
We cannot just look at the short-term induction therapy

6. Long-Term Therapy for IBD is Sequential
InductionMaintenance

7. Maintenance Therapy is Dictated by Induction Therapy
Induction Maintenance
Aminosalicylate
Aminosalicylate

8. Maintenance Therapy is Dictated by Induction Therapy
Induction Maintenance
Aminosalicylate (UC)
Thiopurine
Methotrexate (CD)
Corticosteroid

9. Maintenance Therapy is Dictated by Induction Therapy
Induction Maintenance
Cylcosporine
Thiopurine

10. Maintenance Therapy is Dictated by Induction Therapy
Induction Maintenance
Thiopurine
(Steroid-Naïve)
Anti-TNF
Anti-TNF
(Steroid-Refractory)

11. Maintenance Therapy is Dictated by Induction Therapy
Induction Maintenance
Natalizumab
Natalizumab

12. “Natural History” of Disease Behavior in CD
100 90
Progression Toward Surgery 80 70 60
Penetrating
Cumulative Probability (%) 50 40
Inflammatory 30
Stricturing 20 10 12 24 36 48 60 72 84 96
108
120
132
144
156
168
180
192
204
216
228
240
Months
Patients at risk:
N =
2002
552
229 95 37
Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.

13. Cumulative Probability (%)
Impact of Therapy will Depend on Degree of Structural Damage & Velocity of Progression
High Potential
Low Potential
100 90 80 70 60
Penetrating
Cumulative Probability (%) 50 40
Inflammatory 30
Stricturing 20 10 12 24 36 48 60 72 84 96
108
120
132
144
156
168
180
192
204
216
228
240
Months
Patients at risk:
N =
2002
552
229 95 37
Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.

14. Difference between Early & Late Intervention with Immunosuppressants

15. 60% exposed to IS therapy
No Change in Surgery Rates

16. % Patients Not Failing Trial Duration of Trial (months)
Efficacy of AZA as Crohn’s Disease Maintenance Therapy After Steroids in Adults*
100
AZA 2.5 mg/kg per d
Placebo 80 60 40 20
% Patients Not Failing Trial
42%
p=0.001 7% 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Duration of Trial (months)
*Remission induced by prednisolone tapered over 12 wk
Inclusion: Patients were not steroid dependent
Candy S, et al. Gut. 1995;37(4):

17. Efficacy of 6-MP as Crohn’s Disease Maintenance Therapy After Steroids in Steroid-naïve Children
91%
P<.007
Control
53%
N=55
At baseline, patients received prednisone plus either 6-MP or placebo. Steroids were tapered after induction of remission.
Markowitz J et al. Gastroenterology. 2000;119:895.

18. Dosing Considerations with Thiopurines

19. AZATHIOPRINE/ 6-MERCAPTOPURINE
6-methyl-mercaptopurine (6-MMP)
TPMT
IMDPH
GMPS
HPRT
Azathioprine mercaptopurine Thioinosinic thioguanine
(AZA) (6-MP) acid (6-TG) XO
6-thiouric acid

20. Erythrocyte TPMT Activity (UmL-1)
Distribution of Thiopurine Methyltransferase Enzyme Activity in the Population
% of Subjects/0.5 units of Activity 12
TPMTH 10 8
TPMTL
TPMTH 6 4
TPMTL 2 5 10 15 20
Erythrocyte TPMT Activity (UmL-1)
Weinshilboum. Am J Hum Genet. 1980

21. Early Evidence with Allopurinol
HEPATOXICITY
6-MMP
HPRT,IMDPH,GMPS
6-MP TG
↑↑ACTIVITY X0
6-thiouric
INACTIVE
Sparrow & Hanauer DDW 2005

22. CONTROVERSIES REGARDING THERAPEUTIC DRUG MONITORING
No Prospective Data
Time Course to AZA/6-MP Activity > 8-12 weeks
Sandborn I.V. Loading trial
Mechanisms of Action of 6-MP?
Relationship of 6-MMP to Bone Marrow 
Also of 6-Thioguanine to Bone Marrow 
Cost Effectiveness vs. Clinical Monitoring with WBC

23. Indications for Therapeutic Monitoring
Primary Dosing Regimens
Aim for target levels
Expensive
Assessment of Non-Responders or Elevated Transaminases
Consistent with current practices
May be more cost-effective
Assessment of Adherence
Pediatrics

24. SUMMARY
Pharmacogenitic Considerations are Important for IBD Therapeutics
Therapeutic Drug Monitoring May Offer Improvements If:
Prospectively Demonstrated
Superior Safety and Efficacy to Clinical and Routine Laboratory Monitoring

25. Optimizing Dose of Thiopurines Consider Pharmacology & TPMT Status
TPMT Homozygotes
Start very low (e.g. 25 mg, 2-3 times/week)
TPMT Heterozygotes
Start low dose (~1 mg/kg)
TPMT Normal
Start 2.5 mg/kg
TPMT High (abnormal LFTs, ↑6MMP)
Consider reducing dose & adding allopurinol

26. Methotrexate Maintenance after Steroids in Crohn’s Disease
100 90 80 70 60 50 40 30
Multicenter, randomized, controlled trial
76 steroid-dependent patients
In remission following methotrexate 25 mg IM x 16 weeks
Randomized to 15 mg IM or placebo x 40 weeks
65% of 45% responders=
30% overall
n=40
% Remission
65%
n=36
Methotrexate
Placebo
39%
Weeks since randomization
Feagan B, et al. N Engl J Med 2000.

27. Yin & Yang of Concomitant Immunomodulators
All biologics are immunogenic
Antibodies (at least to infliximab)
Associated with acute/delayed infusion reactions
Shorter duration of response (with episodic therapy)
Immunomodulators reduce immunogenicity across all trials
Yet…
No difference in short- or long-term responses to induction + maintenance therapy
Increase toxicity
Serious infections
Risk of neoplasia

28. Do Concomitant Immune-modulators Improve Efficacy of Infliximab in CD and UC?
Ulcerative colitis
% patients
Pts were not randomised to IMMs, biased by indication
Methods: Comparison of efficacy data with and without IMMs in IFX pivotal trials (ACCENT I, ACCENT II, ACT I and II)
Results:
Response and remission rates did not differ significantly when IFX was used with and without concomitant IMMs
While there was a trend in favor of concomitant immunomodulators in some trials, there was a trend against them in other trials
Three of the four trials showed a trend toward fewer hospitalizations when concomitant immunomodulators were used, and this trend was most pronounced in ACCENT I
Conclusion: The use of concomitant immunomodulators does not improve clinical outcomes over 54 weeks
982
Infliximab Administered as 3-Dose Induction Followed by Scheduled Maintenance Therapy in IBD: Comparable Clinical Outcomes With or Without Concomitant Immunomodulators G. R. Lichtenstein1; R. H. Diamond2; C. Wagner3; A. Olson4; R. Hegedus2; M. Bala5; W. J. Sandborn6  Background and Methods: To assess whether concomitant immunomodulator therapy with infliximab (IFX) is associated with better clinical outcomes when 3-dose induction followed by scheduled maintenance therapy is used in inflammatory bowel disease (IBD), efficacy data from pivotal trials in Crohn’s disease and ulcerative colitis (ACCENT I & II, ACT I & II) were compared. Results: As shown in the table below, response and remission rates did not differ significantly when IFX was used with and without concomitant immunomodulators. While there was a trend in favor of concomitant immunomodulators in some trials, there was a trend against them in other trials. Three of the four trials showed a trend toward fewer hospitalizations when concomitant immunomodulators were used, and this trend was most pronounced in ACCENT I (luminal Crohn’s disease (CD)). Conclusions: The use of concomitant immunomodulators in patients receiving scheduled maintenance IFX therapy for IBD does not improve clinical outcomes over 54 weeks. Whether concomitant immunomodulators would improve clinical outcomes in patients treated beyond 1 year is unknown. Hospitalization rates may be lower with the use of concomitant immunomodulators, especially in CD. The benefits and risks of these agents in combination with IFX must be carefully weighed. The use of concomitant immunomodulators in patients receiving scheduled maintenance IFX therapy for IBD should be considered optional, not mandatory. Trial Endpoint With Concomitant Immunos Without Concomitant Immunos Odds Ratio of Outcome with Concom Immunos (95% CI) Statistical Significance       ACT I Response wk 30 52% 51% 1.05 ( ) NS n=243 Response wk 54 45% 45% 1.00 ( ) NS  Remission wk 30 34% 36% 0.91 ( ) NS  Remission wk 54 34% 36% 0.92 ( ) NS  Hospitalization wk % 5.1%  NS       ACT II Response wk 30 55% 53% 1.10 ( ) NS n=241 Remission wk 30 36% 27% 1.57 ( ) NS  Hospitalizations wk % 5.8%  NS       ACCENT I Response wk 30 63% 53% 1.53 ( ) NS n=223 Response wk 54 50% 41% 1.46 ( ) NS  Remission wk 30 52% 39% 1.71 ( ) NS  Remission wk 54 37% 32% 1.24 ( ) NS  Hospitalizations wk % 5.3%  NS       ACCENT II Maint of fistula closure wk 30 60% 65% 0.80 ( ) NS n=96 Maint of fistula closure wk 54 43% 48% 0.83 ( ) NS  Hospitalizations wk % 4.6%  NS
ACT I 54 wk Response
ACT I 54 wk Remission
ACT I 54 wk Hosp
ACT II 30 wk Response
ACT II 30 wk Remission
ACT II 30 wk Hosp
All p-values = NS
Crohn’s disease
% patients
ACCENT I 54 wk Response
ACCENT I 54 wk Remission
ACCENT I 54 wk Hosp
ACCENT II 54 wk Response
ACCENT II 54 wk Response
Lichtenstein GR, et al. DDW #982
DDW Crohn’s 28

29. ACCENT I & II: Comparable clinical outcomes +/- immunomodulators (IMM)
Patients (%)
OR 1.53
Response
Remission
Patients (%)
ACCENT II
Maintenance of fistula closure
Concomitant IMM in patients receiving scheduled maintenance IFX therapy
does not improve clinical outcomes over 54 weeks
should be considered optional for IBD
Lichtenstein et al, Gastroenterology 2007; 132: A-146 (No. 982)

30. Concomitant Immunomodulators Do Not Improve the Clinical Outcomes of IFX Maintenance Therapy
Clinical Remission
(all P=NS)
Percentage of Patients
ACT II
ACT I
ACCENT I
30 Wk
54 Wk
*Clinical response: ACT I/II=decrease in Mayo score (≥30% and ≥3 points) and a decrease in rectal bleeding score (≥1 or a score of 0 or 1 at Week 8); ACCENT I=improvement of ≥70 points in CDAI score and ≥25% improvement in CDAI score. Lichtenstein GR, Diamond RH, Wagner C, et al. Gastroenterology. 2007;132:A-146. [Abstract #982]

31. CHARM: Concomitant adalimumab and immunosuppressive therapy DO NOT impact on remission at week 56
Patients in remission (%)
Placebo
100
Adalimumab 40 mg EOW, sc
Adalimumab 40 mg q-weekly, sc 50 39 37 33 13 12
With IMM
Without IMM
Week 56
Remission defined as CDAI <150
Colombel et al, Gastroenterology 2007; 132: 52

32. PRECiSE 2: Concomitant certolizmab pegol and immunosuppressive therapy DO NOT impact on Clinical response at week 26
Patients (%)
100
Certolizumab pegol (3 injections) + placebo
***
*** 64 61
Certolizumab pegol q-4w 400 mg, sc 39 33
(n=86) (n=87)
(n=124) (n=128)
With IMM
Without IMM
***p<0.001
CR100
Schreiber et al, N Engl J Med 2007; 357: 239

33. ENACT-2 Concomitant immunosuppressive DO NOT impact on Remission at 6 or 12 Months31 21 54 53 30 23 58 60 10 20 40 50 70
Percent
P≤0.009 for all comparisons with placebo
Placebo
Natalizumab
(111)
(106)
(60)
(62)
(111)
(106)
(60)
(62)
- IMM
+ IMM
- IMM
+ IMM
Month 6
Month 12
Sandborn W, Colombel J-F, Enns R, et al. Presented at: DDW 2006; May 20-25, 2006; Los Angeles, CA.

34. COMMITT: MTX plus IFX in CD (1)
Methods:
Randomized, double blind, PBO-controlled trial
Patients with active CD on corticosteroids within last 6 weeks
1:1 randomization to
IFX + PBO (n=63)
IFX + MTX (dose escalation: 10 mg,10 mg, 20 mg, 25 mg) (n=63)
Steroids withdrawn by Week 14 per protocol
IFX at 0, 2, and 6 weeks then maintenance q8W
Primary analysis: time to treatment failure
CDAI <150, no prednisone by Week 14 and maintained to Week 50
Relapse: CDAI increase of 70 points
Feagan B, et al. DDW 2008: #682C

35. COMMITT: MTX plus IFX in CD (2)
No difference in ITT analysis, duration of disease <2 years, by CDAI score
No difference in infectious AEs (58.7% MTX vs 61.9% PBO)
Feagan B, et al. DDW 2008: #682C

36. What about stopping Immunomodulators?

37. IMID: Impact of Concomitant Immunosuppression on the Outcome of Maintenance Infliximab Therapy
Week 104
Randomization
(N=80)
Continued IMM (n=40)
Discontinued IMM (n=40)
CHARM: Maintenance of Clinical Response in Crohn’s Disease With Adalimumab
Randomized Responder Population
Maintenance therapy with adalimumab for the treatment of CD was evaluated in the CHARM study.1 This was a double-blind, placebo-controlled, multicenter, 56-week study that evaluated the efficacy and safety of adalimumab for maintaining clinical remission in patients with active CD (CDAI scores of 220 – 450 points). In contrast to the ACCENT I study, where prior exposure to anti-TNF therapy was an exclusion criteria, approximately 50% of the 854 patients enrolled in the CHARM study had received prior treatment with anti-TNF antagonists. All patients received open-label induction with adalimumab 80 mg at week 0, and 40 mg at week 2. In the study design presented here, the 499 primary responders (the Randomized Responder Population) are considered—these patients had achieved a clinical response (decrease in CDAI score of ≥ 70 points from baseline) at Week 4 and were randomized to placebo, adalimumab 40 mg every other week (EOW), or adalimumab 40 mg weekly through week 56. However, both this responder group as well as the Week 4 nonresponders (Randomized Nonresponder Population) were randomized and evaluated in the CHARM study. Steroid tapering was permitted after week 8 for patients who achieved a clinical response. The coprimary endpoints of the study were remission (CDAI score < 150 points) at weeks 26 and 56.
Reference
1. Colombel JF, et al. DDW Abstract 686d.
Patients treated with AZA, 6-MP, or MTX plus IFX 5 mg/kg and in clinical remission for ≥6 months
Percentage of patients requiring a change in IFX dosing or who discontinued IFX
6-MP=6-mercaptopurine; AZA=azathioprine; IFX=infliximab; IMM=immunomodulator therapy with AZA, 6-MP, or MTX; MTX=methotrexate
Van Assche G, Paintaud G, Magdelaine C, et al. Gastroenterology. 2007;132:A-103. [Abstract #734] 37

38. IMID: Impact of Concomitant Immunosuppression on the Outcome of Maintenance Infliximab Therapy
No need for early ‘rescue’ IFX: primary endpoint
Median IFX levels, Week 8 to Week 104 combined
Cumulative survival
IFX trough levels (μg)
1.0
100
p<0.005
Log Rank (Cox): 0735; Breslow: 0.906
0.8
0.6 10
0.4
Continued
Discontinued
0.2 1
0.0 20 40 60 80
100
Continued
Discontinued
Time (weeks)
Van Asche et al, Gastroenterology 2007; 132: A-103 (No. 734)

39. Risks Associated With Long-term Use of Immunosuppressants (AZA/6-MP)1,2
Overall toxicity 15%
Pancreatitis 3.3%
Bone marrow depression (leukopenia) 2-5%
Allergic reactions 2%
Drug hepatitis 0.3%
Infectious complications 7.4%
Malignant neoplasm 3.1%
Opportunistic infections
Lymphoma
Associated with ≥fourfold increase in risk of EBV (+) lymphoma and prior treatment with AZA/6-MP
1 additional lymphoma will occur every 300 to 4,500 years after therapy with AZA or 6-MP, depending on patient age
Consistent with RA reports
Lymphoma Occurrence in IBD Patients Increased
in the 8-year Period After Introduction of AZA and 6-MP
Patients (%)
EBV=Epstein-Barr virus
Lag time observed between AZA/6-MP treatment and lymphoma development (median, 3.5 years)
1. Present DH, Meltzer SJ, Krumholz MP, et al. Ann Intern Med. 1989;111: Dayharsh GA, Loftus EV Jr, Sandborn WJ, et al. Gastroenterology. 2002;122:72-77.

40. Opportunistic infections and anti-TNF therapies :
Ex: from Risk Factors for Opportunistic Infections in IBD A Case-Control Study of 100 Patients ( )
Odds Ratio (95% CI)
P value
Any medication (5-ASA, AZA/6MP, Steroids, MTX, Infliximab)
3.50
( )
<0.0001
5-ASA
0.98
( )
0.94
Corticosteroids
3.35
( )
AZA/6MP
3.07
( )
0.0001
MTX
4.00
( )
0.26
Infliximab
4.43
( )
0.03
One medication
2.65
( )
0.0014
Two medications
9.66
(3.31–28.19)
Toruner M, et al. Gastroenterol

41. Infliximab + Azathioprine in Patients With Active Steroid Dependent Crohn’s Disease
115 pts active CD (CDAI >150) despite treatment with prednisone 10 mg/d for 6 mo
Stratified for pre-study use of AZA/ 6-MP for > 6 mo, or no prior AZA/6-MP
All treated with AZA 2 to 3 mg/kg or 6-MP 1 to 1.5 mg/kg
Randomized to infliximab 5 mg/kg or placebo at 0, 2, 6 weeks
Steroids systematically tapered
Primary endpoint: % clinical remission & off steroids at Week 24
No difference in outcome for AZA/ 6-MP treated and naive patients
P<0.001
P=0.003
P=0.04
Lemann. Gastroenterology. 2006

42. Conventional Treatment of UC: Immunomodulators
Immunomodulators are effective for maintenance of remission, but not induction
Blinded, controlled clinical trial data are limited compared to CD

43. AZA Withdrawal in Patients With UC Who Required AZA to Achieve Remission
This graph shows that relapse rates were significantly higher among patients who discontinue AZA and receive placebo when compared with patients who continue to receive AZA, indicating that AZA is more effective than placebo for maintaining remission.
This randomized, placebo-controlled trial enrolled 79 patients who had been receiving AZA for at least 6 months and who were in remission.
N=79
Randomized controlled trial of patients who had been receiving AZA for 6 months
Hawthorne AB et al. BMJ. 1992;305:20.

44. AZA vs 5-ASA for Steroid-Dependent, Active UC
This graph shows that AZA was significantly more effective than 5-ASA (Asacol) for achieving and maintaining remission in steroid-dependent UC.
72 patients with:
Active UC (Powell-Tuck Score  8 and Baron Score  2)
Steroid-dependency (at least 10 mg prednisolone/day and at least 2 unsuccessful attempts in previous 6 months to discontinue)
No concurrent meds allowed
All patients given 40 mg/d prednisolone until week 2. The dose was then tapered to 30 mg until week 4, and then 20 mg until week 8. Dose was further tapered by 5 mg per week as long as the patient was stable or had improved. If the patient worsened, the dose was raised to 40 mg day and the tapering schedule was begun again. †
N=72
*Defined as clinical remission (Powell-Tuck Index Score of 0) and endoscopic remission (Baron Index Score  1) plus steroid discontinuation Patients treated with concurrent tapering dose of steroids
† 0.8 g at breakfast and lunch and 1.6 g at dinner
Ardizzone S et al. Gut. 2006;55:47.

45. Conventional Treatment: CsA
CsA is effective for induction of remission in severe UC
CsA has demonstrated little efficacy for maintenance of remission
Use is limited due to significant safety concerns

46. Intravenous CsA: Severe Active Steroid-Refractory UC
P<.001
The left graph shows that CsA was more effective than placebo for inducing remission in patients with severe, active, steroid-refractory UC. The right graph shows that at week 2, Lichtiger scores were significantly more improved in the CsA group than in the placebo group.
This trial enrolled 20 patients with severe UC whose condition had not improved after at least 7 days of intravenous corticosteroid therapy.
A clinical response was defined as a Lichtiger score less than 10 points for 2 consecutive days. *
N=20
*Lichtiger score <10 points for 2 consecutive days
Lichtiger S et al. N Engl J Med. 1994;330:1841.

47. CsA Use in Acute UC: Long-Term Experience
Oxford 1996 to 2003
76 patients with severe UC
56 responders
to CsA
65%
90%
42%
The left graph shows that 90% of patients who had an acute attack of UC and were successfully treated with CsA relapsed by month 40. The left graph shows that 58% of patients underwent colectomy by 72 months post-treatment. These data indicate that CsA is ineffective for maintenance of remission in UC.
This trial was a retrospective trial of 76 UC patients requiring CsA between 1996 and 2003 in Oxford, England.
CsA was started on the basis of C-reactive protein (CRP) and/or stool frequency after 3 days or after 5-7 days of i.v. hydrocortisone.
54 patients received i.v. CsA (4 mg/kg)
22 received oral CsA (5 mg/kg).
74% of patients achieved initial remission.
After 1 year, 65% had relapsed, and after 3 years 90% had relapsed. After 7 years, 58% had come to colectomy.
Campbell S et al. Eur J Gastroenterol Hepatol. 2005;17:79.

48. Avoidance of Colectomy with Azathioprine After CYSA Induction
Probability of Avoiding Colectomy
Cohen, Stein, Hanauer. Am J Gastroenterol 1999;94(6):

49. Cyclosporine as a “Bridge” to Azathioprine Maintenance in UC
Study No. CYA Initial Sustained Sustained Dose Response Response Response
on AZA no AZA
Fernandez mg/kg IV / / /4
Ramkrishna mg/kg IV / / /1
Cohen mg/kg IV / / /11
Rowe mg/kg IV / / /7
Stack mg/kg IV / / /10
____ ___ ___
99/119(83%) 45/67(67%) 17/33(51%)

50. Cyclosporine Use in Acute Ulcerative Colitis: Long-Term Experience
142 patients with severe acute UC treated with IV CyA
118 (83%) responded
44 patients (31%) were on AZA, 74 (52%) were started de
novo
At 1 year, 23/44 (52%) of patients on AZA required
colectomy compared with 12/74 (16%) starting AZA
Year 1 2 3 4 5 6 7
Percent without colectomy 67 57 48 41 31 16 12
Percent in remission 35 25 18 8
Moskowitz. Gastroenterology 2005 Abstract

51. Should Biologics be used Earlier in IBD?
Anti-TNF is more efficacious than conventional therapies
Anti-TNFs are safer than conventional therapies (Corticosteroids)
May be more cost-effective (over time) than conventional therapies
Conventional Therapies Induce/Maintain Remissions in majority of patients
Majority of patients do not need cost/toxicity risks of biologics
Long-term safety experience in children & pregnancy
Can we transition back to conventional immune modulators as in RA?

52. When to Introduce Biologics?
The “Tipping Point” may be Corticosteroids?

53. Challenges of InductionMaintenance 2008: Consider the Population
Steroid-Naïve
Steroid-Induction
Thiopurine/MTX Maintenance
Anti-TNF Induction

54. Challenges of InductionMaintenance 2008: Consider the Population
Steroid-Dependent
Thiopurine/MTX Maintenance
Failure
Biologic

55. Challenges of InductionMaintenance 2008: Consider the Population
Steroid-Refractory
Immunosuppressive naïve
Anti-TNF induction Thiopurine/MTX Maintenance?
Steroid-Refractory
Despite Immunosuppressive
Anti-TNF induction & Maintenance
Stop Immunosuppressive
Fail
Anti-TNF + Switch
Fail
Switch or Natalizumab

56. Summary Immunosuppressives in IBD
Most Effective as Maintenance Therapies
After Steroids
After Biologics
After Cyclosporine (UC)
Early Aggressive Therapy is most effective
Optimal Dosing for Thiopurines Remains to be Established
Consider Pharmacogenomics
Role for Methotrexate Continues to Evolve
Cyclosporine for Severe/Fulminant UC
Monotherapy with Biologics appears effective and safe