1. Best use of 5-ASAs,
Immunomodulator agents,
Probiotics, Diet, and Alternative
therapies in IBD
Monika Fischer, MD, MSCR
Assistant Professor of
Clinical Medicine

2. •
All recommendations in this lecture are based
on the American College of Gastroenterology
IBD Task Force guidelines published in April
2011

3. IBD The therapy of IBD is complex
and getting even more
complicated…

5. 5-ASAs: strong recommendation for
induction of remission in UC
•
Induction:
–
11 RCTs, 2086 patients with mild-to-moderately
active UC
–
40% achieved remission vs. 20% in the placebo
group
–
NNT 6
–
Optimum dose 2.4 g of mesalamine or equivalent
–
Higher dose was not associated with significantly

6. 5-ASAs are effective at preventing
relapse in quiescent UC
•
Strong recommendation based upon high quality
of evidence
•
11 RTCs, 1502 patients
•
NNT 4 (95% CI: 3-7)
•
40% relapsed vs. 63% in the placebo group over
6-12 months
•
Similar efficacy between different 5-ASA
preparations
•
Only one RTC to compare high > 2.5 g/d vs. 2-2.5

7. Safety of 5-ASAs
•
Generally no greater side-effects than placebo
•
Very rare, BUT serious side-effects:
–
Interstitial nephritis (1:400 per year, not dose
dependent)
–
Pancreatitis
–
Pneumonitis
–
Pericarditis
–
Hepatitis
World J Gastrointest Pharmacol Ther. 2010 December 6; 1(6): 132-134.

8. 0nce-daily dosing of 5-ASAs
•
Should be offered in a once-a day dosing
regimen
•
Not only the delayed-release formulations
(MMX) but the older forms of 5-ASAs with
adequate effects
•
Better compliance
•
Higher efficacy Gastroenterology. 2010;138:1286-1296
Clin Gastroenterol Hepatol. 2009;7:762-769.
•
Better outcomes World J Gastroenterol. 2011 August 14; 17(30): 3467-3478.

9. The combined approach with oral
plus topical 5-ASA as first-line
therapy in mildly- to moderately
severe efficacy UC
•
Higher active
•
Ensures high concentrations along the entire
length of the colon
•
Increasing the dose to >2.5 g/day will result
in higher concentration in the right colon
BUT will not change the concentration in the
rectosigmoid colon Am J Gastroenterol 2012; 107:167–176

10. Oral vs. topical 5-ASA in UC
maintenance
•
Oral 5-ASA + topical mesalamine is superior
in preventing relapse in left-sided and
extensive colitis
•
Topical 5-ASAs is superior to oral therapy for
maintenance of left-sided UC
•
But, 80% of patients favor oral treatment
alone
•
Patient preference highly impacts adherence
Am J Gastroenterol 2012; 107:167–176

11. 5-ASAs are no longer
recommended for Crohn’s
induction of maintenance
•
Metaanalysis of 3 RTCs of mesalamine 4g/d in
615 pts with active CD : reduction of CDAI by 18
points
–
0-600 scale, 70-100 point reduction required to establish
clinical efficacy!
•
Cochrane database review for induction 2010:
–
Sulfasalazine shows modest efficacy for the
treatment of active Crohn's disease. Little if any
benefit for 5-ASAs Clin Gastroenterol Hepatol. 2004;2:379-388

12. 5-ASAs are no longer
recommended for Crohn’s
•
maintenance of remission
Cochrane database review for maintenance
2005:
–
not superior to placebo, no further RTCs are
needed
•
SER/meta-analysis 2011: 5-ASAs not effective
in induction or maintenance of remission, but
further trials maybe helpful
Am J Gastroenterol. 2012 Feb;107(2):167-76

13. The Prevention of Colitis-Related
Cancer
by 5-ASAs
•
“An Appealing Hypothesis that Remains Unproven”
•
Observational studies with conflicting results
•
None of the studies have conclusively shown any
impact of 5-ASAs on CRC risk
•
None of the studies of sufficient quality for a
definitive answer
Am J Gastroenterol. 2011 Apr;106(4):737-40

14. Immunomodulators
•
Thiopurine analogs: azathioprine and 6-MP
•
Methotrexate
•
Calcineurin inhibitors: tacrolimus and
cyclosporine

15. Immunosupressive therapy for UC
•
6-MP and AZA recommended for maintenance
BUT not for induction of remission:
–
3 RTCs, 127 pts, NNT 4, annual relapse rate of
39% in the AZA vs. 66% in the placebo group
•
AZA withdrawal trial of 79 pts in stable
remission for 1 year: 36% on AZA relapsed vs.
59% stopped at 12 months
•
MTX is not recommended for induction or
maintenance, but results based on 2 RTCs
.
using ONLY 12.5 and 15 mg oral dose weekly

16. Role of Thiopurines in Crohn’s
disease
•
6-MP, AZA are recommended for
maintenance but NOT for induction of
remission

17. Efficacy of AZA in Crohn’s Disease
Maintenance Therapy After Steroids
Patients in remission (%)
100
AZA 2.5 mg/kg per day
80 Placebo
n=63 patients with active
60 disease
42%
40
20
7%
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
p=0.001 Duration of trial (months)
*Remission induced by prednisolone tapered over 12 wks
Inclusion: Patients were not steroid dependent
Candy S, Gut 1995

18. Efficacy of 6-MP in CD maintenance
after steroids in steroid naïve children
Markowitz J, Gastroenterology. 2000

19. Role of MTX in the therapy of CD
•
Intramuscular MTX is effective in inducing
remission in steroid refractory patients
–
25 mg/ week for 16 weeks, 39% vs. 19% in remission
•
Methotrexate at a weekly oral dose of 12.5 mg
was not better than 6-mercaptopurine
•
MTX is recommended for maintenance of
remission NEJM. 1995 Feb 2;332(5):292-7 NEJM. 2000 Jun 1;342(22):1627-32.

20. Intramuscular MTX is effective in
inducing remission in steroid
refractory pts (25 mg weekly for 16
weeks) High- prednisone stratum:
on > 20 mg/d > 2 weeks
before randomization
Low-prednisone stratum:
on ≤ 20 mg/d > 2 weeks
before randomization
NEJM. 1995 Feb
2;332(5):292-7

21. Optimal dosing of thiopurines is
•
crucial is a form of
Underdosing of thiopurines
undertreatment
•
AZA : 2.5 mg/kg per day
•
6-MP: 1.5 mg/kg per day)
•
Dose should be modified based upon TPMT
enzyme activity
•
Intermediate metabolizers usually have great
response to AZA/6-MP ( high 6-TGNs!)

22. Monitoring for myelopsuppression
•
Thiopurine methyltransferase (TPMT)
screening cannot substitute for regular
monitoring because the majority of cases of
myelotoxicity are not TPMT-related

23. 6-MP as an alternative to
azathioprine
•
10-15% patients have GI (nausea, vomiting,
abdominal pain) intolerance to Imuran
•
> 50% of these patients 6-MP is well-tolerated
or vice versa
•
6-MP is a safe alternative in patients with
hepatotoxicity due to AZA
World J Gastroenterol. 2011 August 14; 17(30): 3467-3478.

24. Withdrawal of immunomodulators
in patients with stable remission
•
A retrospective study published in 1996 has
suggested that withdrawal of azathioprine
might be possible in patients who have been
in complete remission without steroids for
longer than 3.5 years
The Lancet, Volume 347, Issue 8996, Pages 215 - 219, 27 January 1996

25. AZA maintenance should be continued > 3.5 years
8%
18%
Kaplan-Meier curve: relapse rate at 18 months

26. High relapse rate after
discontinuation of AZA
14%
53%
63%
Kaplan-Meier curve: relapse rate Clin Gastroenterol Hepatol. 2009 Jan;7(1):80-5

27. Withdrawal of immunomodulators
in patients with stable remission
•
Thiopurines should probably be continued
indefinitely
•
Withdrawal is associated with a high risk of
relapse even after stable remission for several
years

28. Role of intestinal microbiota, diet,
and probiotics in the treatment of
IBD

29. Current understanding of IBD pathophysiology
vaccinations
s oking
m
increasing
antibiotics use changes in the
gut microbiota
IBD
improved
hygiene
westernization of
diet

30. Crohn’s
Increasing
incidence
rates of
Crohn’s and
UC world-
wide
UC

31. Dietary Intake and Risk of
Developing Inflammatory Bowel
Disease
•
The
Am J Gastroenterol 2011;106:563–573

32. Diet as a form of treatment in CD and
UC
•
No data to support a specific diet in CD
or UC
•
60% of IBD patients believe that food is a
risk factor for relapse and 2/3 of patients
avoid certain foods they like to avoid a
flare :
Vegetables, fruits, meat, peanuts, cereals, milk, yeast, eggs, tea, coffee,
and chocolate
Inflamm Bowel Dis. 2012 Mar 29

33. Diet in special situations
•
Elemental diet in active CD in children
•
Low residue diet in stricturing CD or severe UC is
beneficial
•
Total gut rest (?) : TPN in case of bowel obstruction
or very severe colitis
•
Crucial role of enteral feeding in maintenance of

34. Crohn’s disease patients have unique
and less diverse microbial flora: cause
or effect?
Nature. 2010 Mar
4;464(7285):59-65.
Gut microbiome in CD , UC and healthy subject

35. Antibiotics in CD
•
800 mg rifaximin-ER bid for 12 weeks induced
remission with few adverse events in patients
with moderately severe active CD
•
RCT, 402 pts, 4 arms: placebo, 400 mg bid, 800
mg bid and 1200 bid
•
62% in the 800 mg bid rifaximin vs. 43% in the
placebo group in remission at 12 weeks
(P = .005)
Gastroenterology. 2012 Mar;142(3):473-481

36. Probiotics
•
Alter the composition of the gut microbiota
–
Bacteriocin production
–
Altering pH
•
Alter the epithelial barrier function
–
Production of SCFA
–
Block attachment of pathogenic bacteria to gut
epithelium
•
Downregulation of inflammation
–
Activate regulatory T cells

37. Probiotics in IBD
•
Great therapeutic potential
•
Have not been realized in clinical trials
•
“medical food” by the FDA
–
Manufacturers only needs to proof safety
•
Maybe wrong bacteria are used?

38. Role of Probiotics in CD and UC
•
No evidence to support the use of probiotics
in CD
•
Promising results for
–
E. coli Nissle in inactive UC
–
VSL#3 in active UC
–
VSL #3 in inactive pouch patients BUT
further studies needed
Drugs. 2012 Apr 16;72(6):803-23

39. Role of probiotic in UC
•
Recommended only as adjunctive therapy
•
Consider cost!
•
Recommended dose
900 billion CFU qid =
$ 25/day on amazon.com
=$ 750/month

40. Complementary and alternative
medicine (CAM) in IBD
•
High prevalence (56%) High prevalence:
Current use
17%-56%
Lifetime use 74%
Does not appear to
have major a impact
on adherence to
pharmacological
therapy
Aliment Pharmacol Ther. 2012 Feb;35(3):342-9.
Gut. 2012 Apr;61(4):521-7. Mannitoba cohort

41. Supplement

42. Recommendation by ACG IBD Task
Force for therapy in active UC to
induce remission

43. Recommendation in quiescent UC
to prevent relapse

44. Recommendation in active CD to
induce remission

45. Recommendation in quiescent CD
to prevent relapse