1. Prevention of Postoperative Crohn’s disease
Miguel Regueiro, M.D.
Professor of Medicine
Associate Chief for Education
Clinical Head and Co-Director, IBD Center
University of Pittsburgh School of Medicine

2. 50-65% of CD pts still go to surgery despite earlier and more IMM/antiTNF usage
IN 2014:
CD treatment relies on initiation of med rx in response to ds – in many, the tissue damage may be irreversible…therefore…

3. Surgery is still required in IBD
…and should not be considered a failure…..it is how we medically prevent/manage postop CD that is the trick.

4. The Natural Course of postop CD
Recurrence is clinically silent initially
Histologic
Endoscopic
Radiologic
Clinical
Surgical
30% 3 yr
60% 5 yr
Within
1 week
70-90%
by 1 yr
Tissue damage
50% by 5 yrs
Surgery
[1] D’Haens G, Geboes K, Peeters M, et al. Gastroenterology 1998;114:
[2] Olaison G, S medh K, Sjodahl R. Gut 1992;33:
[3] Rutgeerts P, Geboes K, Vantrappen G, et al Gastroenterology 1990;99:
[4] Sachar DB. Med Clin North Am 1990;74:

5. Endoscopic Recurrence
Endoscopic Remission
i0: no lesions
i1: < 5 aphthous lesions
i2: > 5 aphthous lesions with normal intervening mucosa
i3: diffuse aphthous ileitis with diffusely inflamed mucosa
i4: diffuse inflammation with large ulcers, nodules, and/or narrowing
Endoscopic Recurrence
Rutgeerts P, Geboes K, Vantrappen G, et al Gastroenterology 1990;99:

6. >70% of Pts Have i2,3,4 Recurrence 1 Year after Surgery – Rutgeerts et al Gastro 1990
i0 and i1 remission
-low likelihood of progression i4
i,3
i2,i3,i4 recurrence
Likely progression
to another surgery

7. More Questions than Answers
Algorithm for post-op CD management
More Questions than Answers
???
5-ASA?
Antibiotics?
Steroids?
6MP/AZA?
What about anti-TNFs/Biologics?
How should we follow these patients?
When to Colonosocope?
Are there predictors of disease recurrence?

8. Medications for Preventing Postoperative Crohn’s Disease

9. Summary of Postop RCTs 5ASA, Nitroimidazoles, AZA/6MP
Postop Prevention RCTs
Clinical Recurrence
Endoscopic recurrence
Placebo
25% – 77%
53% - 79%
5 ASA
24% - 58%
63% - 66%
Budesonide
19% - 32%
52% - 57%
Nitroimidazole
7% - 8%
52% - 54%
AZA/6MP
34% – 50%
42 – 44%
Regueiro M. Inflammatory Bowel Diseases. 2009

10. Out of these options…the best seems to be….

11. Metronidazole 250mg TID x 3 m then AZA 2.5mg/kg
p=0.05
D’Haens G, Norman M, Van Assche G, et al. Gastroenterology 2007;132:289

12. Limitation of the studies: the best we can expect are endoscopic recurrence rates of ~45%
This means that despite postop meds, nearly half of CD pts will have also have a clinical recurrence and require future surgery

13. What about Postop antiTNF?
Recently: A lot of discussion and focus on postop antiTNFs – is it worth the hype?

14. Pittsburgh Likes Hype

15. RCT: Infliximab Prevents Crohn’s Disease Recurrence after Ileal Resection
Regueiro M, Schraut W, Baidoo L, Kip KE, Sepulveda AR, Pesci M, Harrison J, Plevy SE.
Gastroenterology 2009;136:

16. Randomized, two-armed, double-blind, placebo-controlled trial
Sample size power calculation
Assuming 80.0% recurrence in placebo group, 20.7% recurrence in infliximab group 24 total pts needed (2-sided type I error rate of 0.05)
24 patients randomly assigned to infliximab 5mg/kg or placebo within 4 weeks of surgery (0,2,6, and every 8 weeks for one year)

17. Infliximab vs placebo p=0.0006
1/11
11/13
Endoscopic Recurrence defined as endoscopic scores of i2, i3, or i4.

19. This is only one small study, we need more data….
#24
The Pittsburgh Postop Bus

20. antiTNF Control PO- Endo Recur 0% 100% (5ASA) 9% 85% (PBO) 21%
Sorrentino1 (MTX/IFX v 5ASA 2yr) 0%
100% (5ASA)
Regueiro2 (IFX vs PBO RCT 1 yr) 9%
85% (PBO)
Yoshida3 (IFX vs PBO Open 1 yr)
21%
81% (5ASA)
Armuzzi8 (IFX vs AZA Open 1 yr)
40% (AZA)
Fernandez-Blanco 4 (ADA)
10%
N/A
Papamichael5 (ADA 6m)
Savarino6 (ADA 3yr)
Aguas7 (ADA 1 yr)
De Cruz9 (ADA vs AZA 6mos) 6%
38% (AZA)
Savarino10 (ADA vs AZA vs 5ASA 2 yrs)
65% (AZA), 83%(5ASA)

21. Anti-TNF Postop References
Sorrentino et al. Arch Intern Med 2007
Regueiro et al. Gastroenterol 2009
Yoshida et al. Inflamm Bowel Ds 2011
Fernandez-Blanco et al. Gastroenterol 2010A
Papamichael et al. JCrohnsColitis 2012
Savarino et al. Europ Journal Gastro Hep 2012
Aguas et al. World J Gastro 2012
Armuzzi et al. JCrohnsColitis 2013
DeCruz et al. Gastro 2012A
Savarino et al. Am Journal Gastro 2014

22. Antitumor necrosis factor [alpha] is more effective than conventional medical therapy for the prevention of postoperative recurrence of Crohn's disease: a meta-analysis.
Nguyen, Douglas; Solaimani, Pejman; Nguyen, Emily; Jamal, Mohammad; Bechtold, Matthew
European Journal of Gastroenterology & Hepatology. 26(10): , October 2014.

23. Clinical Remission 1 yr postop

24. Endoscopic Remission 1 yr postop

25. Histologic Remission 1 yr postop

26. Comparison of the effectiveness of infliximab and adalimumab in preventing postop recurrence in patients with Crohn’s disease (Tursi A et al. Tech Coloproctol 2014)

27. What about long-term postoperative Crohn’s ds?
Most studies stop at one year

28. Infliximab Maintenance Prevents Endoscopic and Surgical Crohn’s Disease Recurrence: Long-term Outcomes from the Randomized Controlled Postoperative Prevention Study
Regueiro M, Kip K, Baidoo L, Swoger J, Schraut W. Clinical Gastroenterology and Hepatology 2014

29. Long-term outcomes in patients assigned to placebo or infliximab after surgery
1 year
End RCT
IFX
Status
> 5 years
After Surgery
Time 0
Surgery
IFX (11)
PBO (13)
Figure 1

30. Long-term outcomes in patients assigned to placebo or infliximab after surgery
1 year
End RCT
IFX
Status
> 5 years
After Surgery
Time 0
No Recurrence*
No Surgery
Cont. IFX (3)
Recurrence (1)
Remission (10)
Surgery
IFX (11)
Recurrence (8)
Surgery (5)
Stop IFX (8)
PBO (13)
*1 IFX patient i3 at 1 year after surgery, remained i3 through 6 years
+All 5 patients had been i3 or i4 and all progressed to surgery
^This pt had been i1 at end of RCT but progressed to i4 and another surgery
Figure 1

31. Long-term outcomes in patients assigned to placebo or infliximab after surgery
1 year
End RCT
IFX
Status
> 5 years
After Surgery
Time 0
Surgery
IFX (11)
Recurrence (5)+
Surgery (5)
Start IFX (12)
Recurrence(11)
Remission (2)
PBO (13)
No IFX (1)
Recurrence and
Surgery^
*1 IFX patient i3 at 1 year after surgery, remained i3 through 6 years
+All 5 patients had been i3 or i4 and all progressed to surgery
^This pt had been i1 at end of RCT but progressed to i4 and another surgery
Figure 1

32. How should we manage a Crohn’s ds pt who recently had surgery?
Take into account risk factors for postop recurrence

33. Active cigarette smoking
Relative Risk Factors
Early age of surgery (<30)
Short time to first surgery
Ileocolonic disease
Active cigarette smoking
Progressed to surgery despite immunomodulators
Penetrating (fistulizing) disease
History of prior resection

34. My Approach – Almost All of my patients start a med after surgery
…but NOT necessarily an antiTNF - take into account Risk Factors for Recurrence

35. Risk of Post-Op Recurrence
Low
Moderate
High
No Meds
6MP or AZA ± metronidazole
Anti-TNF
Colonoscopy 6-12 months post-op
Colonoscopy 6-12 months post-op
No Recurrence
Recurrence
No Recurrence
Recurrence
Colonoscopy every 1-3 yrs
Immunomodulator or anti-TNF
Colonoscopy every 1-3 yrs
 anti-TNF or Δ biologics
Penetrating disease, > 2 surgeries
<10yrs CD, long stricture or inflammatory CD
Long-standing CD, 1st surgery, short stricture

36. Coming Next Year
The PREVENT Study

37. Thank you!