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, 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 – NNT 6 – 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) – Pancreatitis – Pneumonitis – Pericarditis – 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 Gastroenterology. 2010;138:1286-1296 Clin Gastroenterol Hepatol. 2009;7:762-769.• Better outcomes World J Gastroenterol. 2011 August 14; 17(30): 3467-3478.
The combined approach with oralplus topical 5-ASA as first-linetherapy in mildly- to moderatelysevere 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
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 Crohns 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 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
Efficacy of 6-MP in CD maintenanceafter 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 NEJM. 1995 Feb 2;332(5):292-7 NEJM. 2000 Jun 1;342(22):1627-32.
Intramuscular MTX is effective in inducing remission in steroidrefractory 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 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!)
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 vaccinationss oking m increasingantibiotics use changes in the gut microbiota IBD improvedhygiene westernization of diet
Crohn’s Increasing incidence rates of Crohn’s and UC world- wideUC
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 uniqueand 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 amazon.com =$ 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