Medical Management of Inflammatory Bowel Disease

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1 Medical Management of Inflammatory Bowel Disease John K. Marshall MD MSc FRCPC AGAF Division of Gastroenterology McMaster University John K. Marshall: Conflicts of Interest Speaker: AbbVie, Allergan, Ferring, Janssen, Procter & Gamble, Shire, Takeda Consultant: AbbVie, Allergan, Astra-Zeneca, Boehringer-Ingelheim, Celgene, Celltrion, Cubist, Ferring, Hospira, Janssen, Merck, Pfizer, Procter & Gamble, Shire, Takeda Research: AbbVie, Boehringer-Ingelheim, Celgene, Centocor, Genentech, Hoffman La Roche, Pfizer, Qu Biologics, Shire Inflammatory Bowel Disease Ulcerative Colitis Crohn s Disease Evolving strategies: New therapies Treatment monitoring Disease monitoring Bressler B, Marshall JK, et al. Gastroenterology 2015;148: Toronto Consensus Clinical Practice Guidelines The goal of therapy in treating ulcerative colitis is a durable, steroid-free complete* remission. Goals of Care: Inflammatory Bowel Disease Prevent Surgery Heal the Mucosa Normalize Quality of Life Limit Disability Avoid Steroids * Both clinical and endoscopic 1985 Relieve Symptoms 2015 Bressler B, Marshall JK, et al. Gastroenterology 2015;148:

2 Audience Question #1: What are the components of the Mayo Score for ulcerative colitis activity? 1. Weight, stool frequency, rectal bleeding and physician global assessment 2. Weight, stool frequency, rectal bleeding and C- reactive protein 3. Stool frequency, rectal bleeding, physician global assessment, endoscopy 4. Stool frequency, urgency, rectal bleeding and physician global assessment 5. Stool frequency, urgency, rectal bleeding and endoscopy Parameter Stool frequency Rectal bleeding Physician s global assessment Endoscopy findings 4-5 = Mild 6-9 = Moderate = Severe Normal for patient None Mayo Score Score more than normal Streaks less than 50% of time 3-4 more than normal Obvious blood most of the time 5 more than normal Blood alone passed Normal Mild Moderate Severe Normal or inactive disease Erythema, vascular pattern, mild friability Marked erythema, friability, erosions Spontaneous bleeding, ulceration Schroeder K. N Engl J Med 1987;317: Occupational Hazard Clinician s Guide to Fecal Calprotectin 60% of neutrophil cytosol protein Fecal concentration correlates with inflammation Stable for up to one week at room temperature FC Level Interpretation Suggested Action < μg/g μg/g > 250 μg/g Quiescent disease is likely Inflammation is possible Active inflammation is likely Continue therapy Further testing required to confirm inflammation Optimize therapy to address ongoing inflammation Bressler B. Can J Gastroenterol Hepatol 2015;29: Management of Mild-Moderate UC: The Toronto Consensus Optimizing 5ASA Therapy Dose optimization: g/day Combination therapy: Oral/Rectal Once daily administration Monitor compliance Bressler B, Marshall JK, et al. Gastroenterology 2015;148:

3 CONTRIBUTE: Budesonide MMX for 5ASA Failure N=448 (ITT analysis) with mild-moderate UC (UCDAI 4-10) inadequately controlled with oral 5-ASA randomized 1:1 to add B-MMX 9 mg PO OD or placebo for 8 weeks 50% Management of Moderate-Severe UC: The Toronto Consensus 40% * 30% 20% 10% 7.5% * 13.0% 12.3% * 20.0% 17.5% 27.0% Placebo B-MMX * p<0.05 0% Clinical and Endoscopic Score 0 Endoscopic Remission Histologic Healing Rubin DT. ECCO 2015 [OP011] Bressler B, Marshall JK, et al. Gastroenterology 2015;148: Anti-TNF Monoclonal Antibodies Humira TM Phage Display Synthetic MAb 160mg/80mg SC then 40mg SC q2weeks Simponi TM Transgenic Human MAb 200mg/100mg SC then 100mg SC Q4weeks Remicade TM Chimeric Recombinant MAb 5mg/kg wk 0/2/6 IV then 5mg/kg Q8weeks (Cimzia TM ) PEG-Fab Fragment CD and UC UC only CD and UC CD only (USA) Derkx B. Lancet 1993;342:173-4 Therapeutic Drug Monitoring: Secondary Loss of Response New Therapeutic Target: Leukocyte Trafficking Serum Drug Concentration Low / Subtherapeutic High / Therapeutic Anti-Drug Antibody at Trough Low / Undetectable High / Detectable Intensify therapy (increase dose or shorten interval) Change to treatment with a different mechanism of action Switch within class to another anti-tnf agent? switch to different MOA? Vedolizumab (anti α4β7) Natalizumab (anti α4) Etrolizumab (anti β7) PF (anti MAdCAM) Colombel JF. Inflamm Bowel Dis 2012;18: Rutgeerts P. Gastroenterology 2009;136:

4 GEMINI I: Vedolizumab in UC Week 52 of Maintenance Phase Management of Steroid-Refractory UC: The Toronto Consensus Patients, % Patients With Prior TNFα Antagonist Failure (n=81) PBO VDZ Q8W 5 37 Clinical Remission Maintenance ITT Population 16 Durable Clinical Response Patients With No Prior TNFα Antagonist Therapy (n=151) Results are based on pre-defined exploratory analyses 19 Clinical Remission Durable Clinical Response Feagan BG. N Engl J Med 2013;369: Bressler B, Marshall JK, et al. Gastroenterology 2015;148: Digestive damage Progression of Crohn s Disease Disease Diagnosis onset Pre-clinical Stricture Fistula/abscess Early disease Clinical Stricture Surgery Inflammatory activity (CDAI, CDEIS, CRP) Audience Question #2: Which is true regarding 5-aminosalicylic acid therapy for Crohn s disease? 1. 5-ASA is ineffective for both induction and maintenance of remission 2. 5-ASA is effective for induction of remission but not for maintenance of remission 3. 5-ASA is ineffective for induction of remission but effective for maintenance of remission 4. 5-ASA efficacy in Crohn s disease is dosedependent 5. 5-ASA is only effective for small bowel disease Pariente B. Inflamm Bowel Dis 2011;17: ASA Ineffective for Crohn s Disease: Meta-Analyses Induction of response/remission: Meta-analysis of 3 pivotal Pentasa TM trials 1 found CDAI to be 45 on therapy vs. 18 on placebo (p=0.04) Cochrane review 2 found low- and high-dose 5-ASA to be no better than placebo for inducing response or remission Oral budesonide is a better option 3 Maintenance of Response/Remission: Cochrane review 4 found pooled OR for maintaining medical remission with oral 5-ASA vs. placebo in 6 trials was 1.00 ( ) at 12 months 1 Hanauer SB. Clin Gastroenterol Hepatol 2004;2: Lim WC. Cochrane Database Syst Rev 2016;7:CD Moja L. Aliment Pharmacol Ther 2015;41: Akobeng AK. Cochrane Database Syst Rev 2005;CD Immunomodulators for Crohn s Disease Methotrexate 25mg SC/PO weekly 15mg SC/PO weekly Level I evidence for induction and maintenance Avoid use in young women of reproductive age Thiopurines (azathiopurine, 6-MP) mg/kg/d (AZA) or mg/kg/d (6MP) New evidence questions efficacy in early disease AZTEC (Spanish multicentre trial) RAPID (French multicentre trial) Concern for toxicity Lymphoproliferative disorders (Health Canada warning) Non-melanoma skin cancer Myelosuppression 4

5 CESAME Cohort (N=19,486): Risk of LD on Thiopurines by Age Annual incidence rate (/1000 patient-years) Thiopurine therapy Ongoing Discontinued Never received <50 years years >65 years No. LD Patient-years 13,595 7,924 15,732 2,3251,524 4, ,375 Beaugerie L. Lancet 2009;374: SONIC Trial: Week 26 Steroid-Free Remission Primary endpoint Proportion of Patients (%) p=0.009 p< p=0.022 AZA + placebo IFX + placebo IFX+ AZA 57 52/170 75/169 96/169 Colombel JF. N Engl J Med 2010;362: Risk Factors for Poor Prognosis in Crohn s Disease Unfavourable location Upper GI, mid small bowel, rectum Unfavourable behaviour Fistulization, early stricture, early steroids Deep ulcers at endoscopy Unfavourable patient Young age, smoker, hospitalized Biomarkers (?) Post-Surgical Prophylaxis: A Reasonable Approach Discussion smoking cessation with all Consider metronidazole for all (12 weeks?) Risk stratify for recurrence Low No therapy Medium Azathioprine High TNF inhibition Consider pre-operative therapy success/failure If already on TNF inhibitor then continue If progressed despite AZA then consider TNF inhibition Assess endoscopically/radiologically after 6-12 months Step up if evidence of recurrence IBD Therapeutic Pipelines Take Home Points Crohn s Disease Ulcerative Colitis Sustained steroid-free complete remission is the preferred goal of care when treating IBD Fecal calprotectin is a novel surrogate measure for mucosal healing in IBD 5-ASA is effective for UC but not for Crohn s disease Budesonide MMX is as novel alternative for UC Risk-benefit balance of thiopurines is controversial Anti-TNFα and anti-α4β7 integrin MAb are biologic therapeutic options for UC and Crohn s disease The development pipeline for IBD is promising Amiot A, Peyrin-Biroulet L. Therap Adv Gastroenterol 2015;8:

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