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


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

IBD The therapy of IBD is complex and getting even more complicated‌

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


Optimum dose 2.4 g of mesalamine or equivalent

Higher dose was not associated with significantly

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

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)




Hepatitis World J Gastrointest Pharmacol Ther. 2010 December 6; 1(6): 132-134.

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

Better outcomes

Gastroenterology. 2010;138:1286-1296 Clin Gastroenterol Hepatol. 2009;7:762-769. World J Gastroenterol. 2011 August 14; 17(30): 3467-3478.

The combined approach with oral plus topical 5-ASA as first-line therapy in mildly- to moderately Higher efficacy severe active UC •

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 Am J Gastroenterol 2012; 107:167–176 rectosigmoid colon

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

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

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

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

Immunomodulators •

Thiopurine analogs: azathioprine and 6-MP


Calcineurin inhibitors: tacrolimus and cyclosporine

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

Role of Thiopurines in Crohn’s disease


6-MP, AZA are recommended for maintenance but NOT for induction of remission

Efficacy of AZA in Crohn’s Disease Maintenance Therapy After Steroids Patients in remission (%) 100

AZA 2.5 mg/kg per day 80



n=63 patients with active disease


40 20 0

0 p=0.001

7% 1










Duration of trial (months)

*Remission induced by prednisolone tapered over 12 wks Inclusion: Patients were not steroid dependent




14 15

Candy S, Gut 1995

Efficacy of 6-MP in CD maintenance after steroids in steroid na誰ve children

Markowitz J, Gastroenterology. 2000

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.

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

Optimal dosing of thiopurines is crucial Underdosing of thiopurines is a form of 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!)

Monitoring for myelopsuppression •

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

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.


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

AZA maintenance should be continued > 3.5 years

8% 18%

Kaplan-Meier curve: relapse rate at 18 months

High relapse rate after discontinuation of AZA 14%

53% 63%

Kaplan-Meier curve: relapse rate

Clin Gastroenterol Hepatol. 2009 Jan;7(1):80-5

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

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

Current understanding of IBD pathophysiology


smoking increasing antibiotics use

changes in the gut microbiota IBD

improved hygiene

westernization of diet



Increasing incidence rates of Crohn’s and UC worldwide

Dietary Intake and Risk of Developing Inflammatory Bowel Disease

The Am J Gastroenterol 2011;106:563–573

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

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

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

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

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

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?

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

Role of probiotic in UC •

Recommended only as adjunctive therapy

Consider cost!

Recommended dose 900 billion CFU qid = $ 25/day on =$ 750/month

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


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

Recommendation in quiescent UC to prevent relapse

Recommendation in active CD to induce remission

Recommendation in quiescent CD to prevent relapse

12_Fischer_Best use of 5-ASAs Immunomodulator agents