Approaches to Inflammatory Bowel Disease

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1 2:15 3pm Best Approach to Inflammatory Bowel Disease SPEAKER Maria Abreu, MD Presenter Disclosure Information The following relationships exist related to this presentation: Maria Abreu, MD, receives consulting fees for AbbVie Laboratories, Prometheus Labs, Sanofi Aventi, Takeda, UCB, Pfizer Janssen, Mucosal Health Board, GSK Holding Americas, Inc. Hospira Inc., Shire Pharmaceuticals, Salix Pharmaceuticals Inc., and Ferring Pharmaceuticals. She also serves on the Scientific Advisory Board for Asana Medical Inc. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Learning Objectives Approaches to Inflammatory Bowel Disease Maria T. Abreu, MD University of Miami Miller School of Medicine Miami, Florida Translate the concepts related to pathogenesis of inflammatory bowel disease (IBD). Employ strategies for implementing first-line therapy for IBD. Manage side effects and develop preventive care plans for IBD patients on immunomodulatory or biologic therapy. The Spectrum of IBD UC CD DIAGNOSIS OF IBD Indeterminate colitis

2 Diagnosis of IBD Genetic testing Radiology History/ and Physical Endoscopy IBD Pathology The First Goal of Management in IBD: Obtain a Clear and Accurate Diagnosis In 2015, should include disease extent and current severity and some element of longitudinal prognosis Serologic testing The Challenges to Diagnosis in IBD Lack of knowledge about the disease and its various manifestations (primary care). Lag time of presymptomatic disease before presentation. Inaccurate classification system Overlap of phenotypes between ulcerative colitis (UC) and Crohn s disease (CD) Variations of existing disease presentations Diagnosis of IBD is Based on the Gold Standard of Clinical, radiographic, endoscopic, and histologic findings + Serologic and genetic testing Clinical: Clues From the History How did the symptoms start? Acute onset or insidious over time What do they mean by diarrhea, abdominal pain, or bleeding? You may be surprised! Think about red flags Waking at night, weight loss, anemia Family history Family history of CD had a hazard ratio (HR) of 8.4 (95%, confidence interval [CI] ) 1 Will this be self-limited? Medication effect or infection Clinical: Clues From the Exam Extraintestinal manifestations Red eyes, aphthous ulcers, joint and skin effects May precede GI symptoms Fullness or mass on abdominal exam Perianal disease Fissure, abscess, fistula, skin tags 1. Melmed GY et al. Dis Colon Rectum. 2008;51:100.

3 Considerations in the Differential Diagnosis of IBD Infectious colitis (including Clostridium difficile) Ischemic colitis Drug-induced (NSAID) enterocolitis Solitary rectal ulcer syndrome Radiation enterocolitis Diversion colitis Endometriosis Malignancy Functional (IBS) Diverticular disease Adapted from Forcione DG, Sands BE. In: Sartor RB, NSAID, Sandborn nonsteroidal WJ. Kirsner s anti-inflammatory Inflammatory drug Bowel Diseases. 6th ed. New York: Saunders; 2004: Symptoms of Ulcerative Colitis Depend on Extent and Severity of Inflammation Rectal bleeding and urgency to evacuate Diarrhea Abdominal cramping Extraintestinal symptoms Joint pain/swelling Eye inflammation Skin lesions Common Symptoms of Crohn s Disease Diarrhea Abdominal pain and tenderness Loss of appetite and weight Fever Fatigue Rectal bleeding and anal ulcers Stunted growth in children Patients (%) Small-Bowel Imaging in Crohn s Disease: Prospective Blinded 4-Way Study With Consensus Reference Standard CTE Sensitivity Specificity (n=41) (n=27) (n=36) (n=38) CTE and CE were equally sensitive but CE was less specific than the other 3 modalities Accuracy CE IleocolonoscopySBFT CTE, CT enterography; CE, capsule endoscopy Solem CA et al. Gastrointest Endosc. 2008;68:255. Antibody DNase Sensitive panca ASCA IBD Specific Serologic Immune Markers Antigen Histone H1, bacterial antigen? Saccharomyces cerevisiae (oligomannans) Non- IBD (%) CD (%) UC (%) <5% 10 25% 50 65% 5% 55 65% 5% OmpC E. Coli <5% 38 50% 2% Anti- 2 Pseudomonas fluorescens <5% 54% 2% Anti-Flagellin CBir 1 Antigen 8-14% 50% 6% Anti-ALCA IgG Anti-ACCA IgA laminaribioside Glc(β1,3)Glc(β) Chitobioside GlcNAc(β1,4)GlcNAc(β) 2% 27% 9% 12% 25% 25% Additional Diagnostic Tests and Techniques Chromoendoscopy for dysplasia detection. Fecal markers of inflammation. Small intestinal ultrasonography. PET scans. Therapeutic monitoring using metabolites and drug levels.

4 Summary of IBD Diagnosis Overdiagnosis of IBD can be as large a problem as underdiagnosis. A careful history and physical exam in combination with radiographic, endoscopic, and histologic findings is necessary. The first colonoscopy is the most important. Serologic and genetic markers are currently adjunctive. Think about how a test will help you before you do it. TREATMENT OF IBD Therapeutic Pyramid for IBD Induction of remission IBD Maintenance of remission off steroids and/or Mucosal healing Induction of Remission/ Active Disease Experimental therapies Tacrolimus Cyclosporine Vedolizumab Anti-TNF Maintenance of Remission Vedolizumab anti-tnf Methotrexate (CD) Maintenance of remission Corticosteroids 5-ASA 6-MP/AZA 5-ASA Stomach Small Intestine Large Intestine 5-ASA Release Sites Mesalamine (Pentasa ) Mesalamine in microgranules Mesalamine (Asacol Lialda Apriso ) Mesalamine w/ eudragit-s Mesalamine with MMX delivery Azo bond Sulfazalazine (Azulfidine ) Olsalazine (Dipentum ) Balsalazide (Colazal ) Mesalamine suppositories (Rowasa Canasa ) Patients (%) 5-ASA Dose Escalation: 2.4 g/day vs. 4.8 g/day in Select Patient Subsets with Moderate UC Treatment success at week 6 in patients having taken previous UC therapy: ASCEND III 70% 64% 0 n=323 n=338 Previous n=188 n=192 Previous n=157 n=157 Previous n=234 n=230 Previous Use of Oral 5-ASA Rectal Therapies Steroids 2 Medications P=0.07 P=0.06 P=0.05 *P= g/d more effective than 2.4 g/day in select patient subsets Sandborn WJ, et al. Gastroenterology. 2009;137(6): % 70% 54% 64% 2.4 g/day 4.8 g/day 58% * 70% *Asacol Included oral 5-ASAs, rectal therapies, steroids, or immunomodulators

5 Once daily mesalamine better than twice a day for clinical & endoscopic remission Immediate and Prolonged Outcomes of Corticosteroid Therapy in CD Patients with UC-DAI 1 at week 8 (%) Difference: 13% 95% CI: 2.7, 28.2; P=0.105 Difference: 10% 95% CI: 3.4, 24.1; P=0.140 Pentasa BD Pentasa OD 30-Day Responses (n=74) Complete 58% (n=43) Partial 26% (n=19) None 16% (n=12) treatment with 4g OD was non-inferior to treatment with 2g BD (week 8 remission rate) 1-Year Responses (n=74)* Steroid Dependent 32% (n=24) Prolonged Response 28% (n=21) Surgery 38% (n=28) Flourié B, et al. Al Pharm & Ther 2013 Faubion WA. Gastroenterology 2001;121,2: * One patient lost to follow-up Immunomodulators: Thiopurines and Methotrexare Long-term (maintenance) treatments. Primarily for patients unable to get off steroids. Requires regular monitoring of blood counts and metabolite levels (thiopurines). Azathioprine (AZA) AZA 6-MMP TPMT 6-MP XO Rac 1 Co-stimulation 6TG 6TG-MP 6TG-DP 6TGTP CD28 CD3 T-cell Tiede I et al. J Clin Invest. 2003; 111: Neurath M et al. Clin Gastroenterol Hepatol. 2005;3: TPMT Phenotypic Distribution %of subjects/0.5 units of activity TPMT L TPMT L TPMT L TPMT H TPMT H TPMT H Erythrocyte TPMT activity (U/ml) Weinshilboum RM, Sladek SL. Am J Hum Genet. 1980;32: Infliximab IgG 1 Chimeric monoclonal antibody (75% human IgG 1 isotype) Mouse Human PEG, polyethylene glycol. Biologic Agents for CD or UC Adalimumab Golimumab IgG 1 Human recombinant antibody (100% human IgG 1 isotype) Certolizumab Pegol PEG VL No Fc PEG VH CH 1 Humanized Fab fragment (95% human IgG 1 isotype) Vedolizumab IgG 1 Humanized IgG 1

6 SONIC Moderate-to-severe CD in patients with no prior exposure to biologic agents or immunomodulators Excluded intermediate TPMT activity Average disease duration 2.3 years AZA 2.5mg/kg IFX 5mg/kg IFX + AZA 1 endpoint: Induction + maintenance of steroid-free remission 2 endpoint: Mucosal healing SONIC Clinical Remission Without Corticosteroids at Week 26 Primary Endpoint Proportion of Patients (%) 100 p< p=0.009 p= /170 75/169 96/169 AZA + placebo IFX + placebo IFX+ AZA Colombel, J.F., et al., N Engl J Med (15): p Reasons for Complications in the Established IBD Patient Complications of the disease Complications of the treatment RISKS OF THERAPY Mortality associated with current and recent corticosteroid use adjusted HR (95% CI) TOXICITY OF MEDICATIONS They almost never happen, but good to be informed. Hazard Ratio 95% CI: ( ) 95% CI: ( ) Current use of corticosteroids Recent use of corticosteroids Lewis JD, et al. Am J Gastroenterol. 2008;103:

7 Infections and mortality in the TREAT registry: 15,000 patient-years of experience Risk factors for opportunistic infections in IBD: A case-control study Odds ratio IFX Mortality AZA 6-MP MTX Multivariate analysis Steroids * IFX *p=0.001 Serious infections **p< AZA 6-MP MTX ** Steroids IFX = infliximab; AZA = azathioprine; MTX = methotrexate 100 cases of opportunistic ınfections Odds Ratio (95% CI) P value 1 medication 2.7 ( ) medications 9.7 ( ) < medications Infinite Overall P < Steroids alone 2.2 ( ) MP/AZA alone 2.5 ( ) IFX alone 11.2 ( ) MP/AZA + steroids 15.7( ) < MP/AZA + IFX 1.6 ( ) MP/AZA + IFX + steroids Infinite Lichenstein GR, et al. Gastroenterology 2006;130(suppl 4):A-71 Lichtenstein GR, et al. Clin Gastroenterol Hepatol 2006;4: MP = 6-mercaptopurine; AZA = azathioprine; IBD = inflammatory bowel disease; IFX = infliximab. Toruner M, et al. Gastroenterology 2008;134: Risk of Lymphoma Associated with Immunomodulators 19,486 IBD patients 30.1% currently receiving thiopurines 14.4% discontinued thiopurines 55.5% never exposed to thiopurines Exposure Rate per 10,000 pt-years 95% CI Current use Discontinued Never exposed Receiving thiopurines vs. never exposed HR 5.28 ( ) Beaugerie L et al. Lancet. 2009;374: Risk of NH Lymphoma with anti-tnf + IM treatment for Crohn s Disease Meta-analysis Results 8905 patients representing 20,602 pt-years of exposure 13 Non-Hodgkin s lymphomas 6.1 per 10,000 pt-years Mean age 52, 62% male 10/13 exposed to IM* (really a study of combo Rx) NHL rate per 10,000 SIR 95% CI SEER all ages IM alone Anti-TNF + IM vs SEER Anti-TNF+ IM vs IM alone Siegel et al, CGH 2009;7: *not reported in It is a subgroup of patients at higher risk for infections and lymphomas Older Average age = 63 (systematic review); 67 (Mayo) Multiple co-morbidities Concomitant steroids and/or narcotics Long-standing disease Young healthy patients are not in the clear, but probably much less at risk. Thromboembolic Risk in Hospitalized IBD Patients Single center study: 173 patients experienced 200 thromboembolic events over an 11-year period DVT 48%; PE 12%; thrombophlebitis 12%; mesenteric venous thrombosis 4%; coronary ischemia 6%; stroke/tia 5% Identified Number of patients, Risk Factor Proportion of patients Prothrombotic State total tested = 44 (%) Surgery (IBD related / 30% / 6% Antiphospholipid Ab 3 (7) unrelated) Factor VIII mutation 3 (7) Malignancy (past or current) 17% Hyperhomocysteinem 3(7) Estrogen use 9% ia Personal / family history of 20% / 25% Lupus anticoagulant 9 (20) TE Protein S deficiency 2 (5) Smoking 11% Prophylaxis was documented in only 40% of inpatients Total prior to the diagnosis 20 (45) of Prothrombotic state 12% (20 of 44 patients the thromboembolic event tested) Siegel, CGH 2006; Colombel, Gastro 2004; Lichtenstein CGH 2006; Toruner, Gastro 2008 Levy A, et al. Presented at DDW; May 20, Abstract Mo1242.

8 What should doctors do to minimize risk Routine laboratory monitoring Age and risk: older men and younger men and thiopurines Vaccinate patients: Seasonal flu HPV (young women) Pneumococcal vaccine Avoid live vaccines if already on immunomodulators: Varicella MMR Skin exams yearly Develop a simple checklist Finding the Right Mechanism for the Right Patient Adhesion Molecule IBDInhibitors Anti-IL-12/23 The Future is Bright TNF inhibitors