12 fischer best use of 5-as_as immunomodulator agents

Best use of 5-ASAs, Immunomodulator agents,

Probiotics, Diet, and Alternative therapies in IBD

Monika Fischer, MD, MSCRAssistant 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– NNT 6– Optimum dose 2.4 g of mesalamine or equivalent– Higher dose was not associated with significantly

higher remission rate at 4-8 wks

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

g/d – no difference• Recommended dose of mesalamine 2.4 g/d

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

• Up to 8% of patients are INTOLERANT to 5-ASAs

(hypersensitivity reaction, nausea, abdominal pain, diarrhea, fever, worsening UC)

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 severe active UC • Higher efficacy • 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

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 adherenceAm 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• Methotrexate• 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

80

60

40

20

0

Patients in remission (%)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Duration of trial (months)

AZA 2.5 mg/kg per day

Placebo

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

Candy S, Gut 1995

42%

7%

n=63 patients with active disease

p=0.001

100

Efficacy of 6-MP in CD maintenance after steroids in steroid naïve 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

– 15 mg/week im., 65% vs. 39% in 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

Kaplan-Meier curve: relapse rate at 18 months

8%

18%

High relapse rate after discontinuation of AZA

63%

14%

53%

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

IBD

smoking

increasing antibiotics use

improved hygiene

vaccinations

changes in the gut microbiota

westernization of diet

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

Crohn’s

UC

Dietary Intake and Risk of Developing Inflammatory Bowel

Disease

•The spread of the “Western” diet:–High in fat and protein and refined sugar but low in fruits and vegetables

• SER 2011– Diet rich in total fats, PUFAs, omega-6 fatty acids, and meats were associated with an increased risk of CD and UC

–High fiber and fruit intakes : ↓ CD risk

–High vegetable intake: ↓ UC risk

• Low levels of vitamin D: ↑ risk of both CD and UC

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

• Strong impact on the nutritional state and social life

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 intestinal barrier function and immunity

• Before surgery: Elemental diet-enteral nutrition for 2-3 weeks

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– Directly turn off effector immune 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 neededDrugs. 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 amazon.com

=$ 750/month

Complementary and alternative medicine (CAM) in IBD

• High prevalence (56%)

Aliment Pharmacol Ther. 2012 Feb;35(3):342-9.

High prevalence:Current use 17%-56% Lifetime use 74%

Gut. 2012 Apr;61(4):521-7. Mannitoba cohort

Does not appear to have major a impact on adherence to pharmacological therapy

Supplement

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