1. CASE DISCUSSION:
Crohn's disease patient with bad perianal disease- are new therapies any help?
Alana Wichmann, APN, MSN, FNP, Advanced Practice Nurse, University of Chicago, Inflammatory Bowel Disease Center
David A. Schwartz MD, FACG, AGAF, Professor of Medicine/Director, IBD Center, Vanderbilt University

2. New therapies in perianal Crohn’s disease
49 year old White male with a history of ileocolonic Crohn's presents with a two month history of perianal discomfort, rectal drainage, bloating and abdominal discomfort with obstructive symptoms. He has been well on 5-ASA up until he developed these symptoms.
A colonoscopy is done and demonstrates fibrotic valve and severe ulceration and erythema, unable to intubate the terminal ileum. Colon otherwise normal.
PE: normal, except....
New therapies in perianal Crohn’s disease

3. New therapies in perianal Crohn’s disease
MRE is performed and notes a simple perianal fistula, no abscess, confirms 4 cm of “string sign” in ileum.
New therapies in perianal Crohn’s disease

4. New therapies in perianal Crohn’s disease
He undergoes an ileocecectomy. Post-operatively, you decide to start which therapy:
Ciprofloxacin and metronidazole
Anti-TNF with azathioprine
Azathioprine with metronidazole
Anti-Integrin therapy
New therapies in perianal Crohn’s disease

5. Simple vs. Complex Fistulas
New therapies in perianal Crohn’s disease

6. History and physical exam
Endoscopy to assess activity of Crohn’s disease
Imaging study (EUS or MRI) to delineate perianal disease process
Exam under anesthesia (EUA)
Simple fistula without
rectal inflammation
Simple fistula with
rectal inflammation
Complex fistula
Seton placement
Antibiotics, AZA/6-MP, & Anti-TNF
Antibiotics and AZA/6-MP
Consider anti-TNF
Antibiotics,
AZA/6MP & Anti-TNF
(consider monitoring healing with repeat imaging study)
(consider monitoring healing
with repeat imaging study)
Treatment
Failure
Treatment
Success
Treatment
Failure
Treatment
Success
Treatment
Failure
Treatment
Success
1. Fistulotomy
2. Consider fibrin glue, fistula plug or endorectal advancement flap
3. If 1 or 2 fails, treat as complex fistulizing process
Continue maintenance
AZA/6-MP
& Anti-TNF
(if started)
Continue maintenance
AZA/6-MP
& Anti-TNF
Treat as complex fistulizing process 1. 2.
Consider Tacrolimus in selected pts
Proctectomy
1. Remove seton
2. Continue
maintenance AZA
6-MP & Anti-TNF

7. History and physical exam
Endoscopy to assess activity of Crohn’s disease
Imaging study (EUS or MRI) to delineate perianal disease process
Exam under anesthesia (EUA)
Simple fistula without
rectal inflammation
Simple fistula with
rectal inflammation
Complex fistula
Seton placement
Antibiotics, AZA/6-MP, & Anti-TNF
Antibiotics and AZA/6-MP
Consider anti-TNF
Antibiotics,
AZA/6MP & Anti-TNF
(consider monitoring healing with repeat imaging study)
(consider monitoring healing
with repeat imaging study)
Treatment
Failure
Treatment
Success
Treatment
Failure
Treatment
Success
Treatment
Failure
Treatment
Success
1. Fistulotomy
2. Consider fibrin glue, fistula plug or endorectal advancement flap
3. If 1 or 2 fails, treat as complex fistulizing process
Continue maintenance
AZA/6-MP
& Anti-TNF
(if started)
Continue maintenance
AZA/6-MP
& Anti-TNF
Treat as complex fistulizing process 1. 2.
Consider Tacrolimus in selected pts
Proctectomy
1. Remove seton
2. Continue
maintenance AZA
6-MP & Anti-TNF

8. Azathioprine / 6 - MP
The 5 Controlled trials were summarized in a meta-analysis1
22 / 41 (54%) of patients who received AZA /6-MP responded vs. 6 / 29 (21%) who received placebo.
Pooled odds ratio was 4.44 in favor of fistula healing
1-Pearson et al. Ann Intern Med. 1995

9. AZA Improves Fistula Healing at Week 20
Dejaco, APT 2003

10. New therapies in perianal Crohn’s disease
You use metronidazole for three months initially as a “bridge” to full weight-based dosing of azathioprine and he reports feeling well.
Resolution of perianal pain and drainage after approximately 6 months of therapy.
New therapies in perianal Crohn’s disease

11. New therapies in perianal Crohn’s disease
A colonoscopy is performed and demonstrates Rutgeerts i1 recurrence at the anastomosis. What would be the next step?
Continue azathioprine and do nothing further
Withdraw therapy since he is feeling better
Switch to infliximab 5 mg/kg every 8 week maintenance with azathioprine
Start vedolizumab and antibiotic therapy
New therapies in perianal Crohn’s disease

12. New therapies in perianal Crohn’s disease
MRI to Monitor Therapy
41 pts, serial MRIs, 3 years follow-up
Patients with early response (6 weeks) had 5x ↑ rate of remission (p=0.004)
Improvement plateaued at 1 year
15 patients achieved healing on MRI
5/7 (71%) who continued the TNF after achieved mri healing maintained remission
Only 3/8 (38%) maintained remission off of the TNF
New therapies in perianal Crohn’s disease
Tozer et al. , IBD 2012

13. New therapies in perianal Crohn’s disease
Despite weight-based dosing of the azathioprine, he develops irritation and drainage recurs in his perianal area.
He is commenced on infliximab 5 mg/kg every 8 weeks with the azathioprine. Initially, he is doing well but 5 months into therapy he reports recurrence of perianal pain and drainage.
An MR Enterography is performed which notes previously diagnosed perianal fistula in addition to a new fistulous tract on the right side of the perineum that travels in a cephalad direction with a branch heading medially, and an apparent connection with the anal canal located directly posterior. No abscess is seen
New therapies in perianal Crohn’s disease

14. New therapies in perianal Crohn’s disease

15. New therapies in perianal Crohn’s disease
Infliximab trough levels are also performed and infliximab drug level is 24, antibody level 0. What is your next plan of action?
Switch to adalimumab plus azathioprine
Exam under anesthesia
Increase infliximab to 7.5 mg/kg every 8 weeks
Switch to anti-integrin therapy such as natalizumab or vedolizumab.
New therapies in perianal Crohn’s disease

16. What are the latest advances for treatment of perianal disease?
New therapies in perianal Crohn’s disease

17. Perianal Crohn’s Disease: Latest Advances in Treatment
David A. Schwartz, MD
Director, Inflammatory Bowel Disease Center
Professor of Medicine
Vanderbilt University Medical Center

18. New therapies in perianal Crohn’s disease
Outline
Importance of imaging –
Initial Assessment
Monitor healing and guide treatment
Benefits of Setons
Possible new treatments on the horizon
New therapies in perianal Crohn’s disease

19. What Happens When Fistulas are Missed at Time of EUA?
-In 52% of patients needed repeat surgery in cases where surgery and MRI disagreed
-Fistula recurrence was always at site predicted by MRI
Buchanan et al, Lancet 2002

20. Study Results
A prospective triple blinded study compared EUS, MRI and EUA in 32 patients with suspect perianal Crohn’s disease.1
All three methods showed excellent accuracy in assessing these patients
EUS – 91% (95% CI 75% - 98%)
EUA – 91% (95% CI 75% - 98%)
MRI – 87% (95% CI 69% - 96%)
Combining either of the imaging modalities with EUA increased the accuracy to 100%
1- Schwartz et al., Gastro 2001

21. MRI to Guide Therapy with Infliximab or Adalimumab
Medical therapy was increased if no or partial response seen on MRI
Ng et al. Am J Gastro 2009

22. Utilizing EUS to Improve Fistula Healing%
Schwartz et al, IBD 2005

23. 2 Randomized Prospective Studies Looking at EUS to Improve Outcomes
Initial Prospective Pilot Study
Recent Follow-up Prospective Study
1-Spradlin, Schwartz Am J Gatro 2008
2- Wiese,Schwartz Am J Gastro 2011 (ab)

24. Does Controlling Fistula Healing Make a Difference?
Requeiro et al, IBD 2003

25. Comparison of Healthcare Utilization in Patients with CD Perianal Fistulas Treated with Biologics with or without Setons
Schwartz et al. ECCO 2013

26. With & Without Seton
Without Seton
With Seton
Seton

27. Anti-TNF  Antibody

28. Infliximab for Crohn’s Perianal Fistulas
Primary endpoint; > 50% reduction in open fistulas
Initial Fistula Response to Infliximab
N=94 %
p = 0.041
p < 0.001
Present et al. , NEJM 1999

29. Anti-TNF Maintenance Therapy for CD Related Fistulas
Adalimumab
Infliximab
Certolizumab
N=28
1-Sands et al. , NEJM 2004
2-Colombel, Gut 2009
3- Schreiber S, et al. APT, 2011

30. Vedolizumab
Sandborn et al. , NEJM 2013

31. Adipose Derived Stem Cells – Fistula Healing at Week 24
Portilla et al, Int J of Colorectal Dis , 2013