Disclosures New Paradigms, New None Management: Our Changing - PDF document

10/20/16 Disclosures New Paradigms, New • None Management: Our Changing Understanding of Ulcerative Colitis and Diverticulitis Jonathan P . Terdiman, MD Professor of Clinical Medicine and Surgery Director, Gastroenterology Service Hospitalized UC Patient| 2 UC: History In Hospital • 20 year old woman, college student • Dehydrated – IV fluids, VS normalize • Developed bloody diarrhea during midterm examinations. 10+ BMs per day and night • Diet: Clear liquids • Roommate brings her to ED • CT scan – Pale – LB wall thickening and fat stranding, no dilation of the colon – Tachycardic (> 120), BP 85/45, afebrile • Stools collected for infectious agents – Abdominal pain, Tender in LLQ, focal rebound - for culture, E.coli 0157, O&P, C diff – Bloody bowel movements in ED – WBC 16K, Hct 22%, crp 70 mg/L • Admitted to Hospital Hospitalized UC Patient| 3 Hospitalized UC Patient| 4 1

10/20/16 Predicators of Poor Response or Surgery Classification of UC Severity • Stool frequency • Serum albumin >10 stools/day, continuous Fulminant • >8 or >5 after 3 days IV rx. • ESR > 30 mm/h bleeding, toxicity, abdominal • Percentage bloody stools • Bandemia tenderness/distension, transfusion requirement, colonic dilation on x-ray • Body temperature > 37.5 • Prolonged flare Severe >6 bloody stools/day + fever, tachycardia, anemia, • Heart rate >90 bpm • Active infection or ­ ESR CRP (>25, >45 mg/L) • Hospitalization setting • Moderate ≥4 stools/day, minimal Transverse colon > 5 cm • Disease duration • signs of toxicity Low hemoglobin <10.5 g/dL • <4 stools/day ± blood, Mild normal ESR, no signs of Lindgren SC et al. Eur J Gastroenterol Hepatol 1998;10(10):831-5. Gonzalez-Lama Y et al. Hepatogastroenterol 2008;55(86-87):1609-14. Suzuki Y et al Dig Dis Sci 2006;51(11):2031-8. Cacheux W. et al. A,m J Gastroenterol toxicity 2008;103(3):637-42. Ananthakrishnan AN et al. A, J Gastroenterol 2008;103(11):2789-98. Hospitalized UC Patient| 6 Kornbluth A, Sachar DB. Am J Gastroenterol . 2010;105:501. Flexible Sigmoidoscopy Endoscopic Severity: UC Mild Moderate Severe • Limited to rectosigmoid • No prep • Mucosa: • Edema, Erythema • Diffuse Ulceration • Granular mucosa • Coarsely granular • Frank ulcerations • Pattern • Edematous • Small ulcerations • Spontaneous hemorrhage • Loss of normal • Friable – Circumferential, continuous, no skip vascular pattern areas Sutherland LR, et al. Gastroenterology. 1987;92:1894-1898. Hospitalized UC Patient| 7 Hospitalized UC Patient| 8 2

10/20/16 Endoscopic Severity Predicts Colectomy Infections in UC • No broad spectrum antibiotics Moderate Severe • C. difficile endoscopic colitis endoscopic colitis 100 100 – Oral vanco first line (40 v 10% Colectomy (%) Colectomy (%) colectomy rate) – 40% rule: 40% of UC flares, 40% no prior abx, 40% colectomy rate 8% 93% 30% 26% 17% 77% • CMV 0 0 Deep/ Mucosal Large Well-like Superficial Deep but extensive detachment mucosal ulcers ulcers nonextensive – IHC + up to 20-30% of severe UC ulcers abrasions ulcers > 50% → colectomy >20% → colectomy – Bystander versus pathogen Carbonnel F et al. Dig Dis Sci. 1994;39:1550. – Treat both, avoid CsA Hospitalized UC Patient| 9 Hospitalized UC Patient| 10 Meanwhile, back in the hospital … IV Corticosteroids: Effective in Severe UC Outcomes: Severe UC by Day 15 % Remission or Substantial • No progression of exam, VS stable, no need for 93% 100% further transfusion 78% 69% 70% 65% 80% 53% Response 60% • PPD placed, Hep serologies sent 40% 20% • IV steroids started, solumedrol 1 mg/kg (40 mg) 0% daily Dexa HC 400mg M-pred M-pred HC 400 mg M-pred 64 100mg x3 40mg 0.75-1..0 mg mg/kg Daily Dose Sood, A et al. J Clin Gastroenterol 2002;35(4):328-31. Panes, J et al. Gastroenterology 2000;119:903-8. Mantzaris, GJ et al. Scand J Gastroenterol 2001;36:971-4. Mantzaris, GJ et al. Am J Gastroenterol 1994;89:43-6. D’Haens G et al. Gastroenterology 2001;120:1323-9. Chapman et al. Gut 1986;27:1210-2 Hospitalized UC Patient| 11 Hospitalized UC Patient| 12 3

10/20/16 Steroid Failure: Day 3 assessment Hospital Day 3 • Patient with minimal response • Still multiple poorly –formed, bloody bowel movements, cramps (> 10) • Hgb < 7, 2 units of blood given, CRP > 50, xray with T colon at 4 cm • Options? 1) Wait longer on IV steroids 2) Start cyclosporin or tacrolimus 3) Start infliximab 4) Operation Hospitalized UC Patient| 13 IV Cyclosporin: Highly Effective CSA: Colectomy Avoidance with AZA Outcomes: Severe UC by Day 15 91% 100% 86% 82% 79% % Response 69% 80% 64% 56% 60% 40% 20% 0% 4mg/kg 4mg/kg 5mg/kg 4mg/kg 4mg/kg 4mg/kg 4mg/kg Daily Dose Lichtiger et al. N Engl J Med 1994;330:1841-5. Stack WA et al. Aliment Pharmacol Ther 1998;12:973-8. Van Gossum A et al. Acta Gastroenterol Belg 1997;60:197-200. Cohen RD et al. Am J Gastroenterol 1999;94:1587-92. Wenzl HH et al. Z Gastroenterol 1998;36:287-93. D’Haens G et al. Gastroenterology 2001;120:1323-9 Hyde GM et al. Eur J Gastroenterol Hepatol 1998;10:411-3. Actis GC et al. BMC Gastro 2007;7:13-19 Hospitalized UC Patient| 15 Hospitalized UC Patient| 16 4

10/20/16 Infliximab: IV steroid-refractory UC CSA vs. IFX: Severe IV Steroid-Refractory UC • 23 GETAID and 6 ECCO centres Colectomy 80% 1.0 Infliximab • 111 pts failing 5 days IV steroids : : Lichtiger score>10 67% 70% Placebo Probability Not Operated 0.8 • Patients randomized to either i.v.: 60% Infliximab • Cys 2mg/kg/d x 1 week , then oral CSA x 91 days 50% 0.6 Placebo • IFX 5mg/kg at weeks 0-2-6 40% P =0.0038 (log rank – test) 29% 0.4 • All patients started on azathioprine 2.5 mg/kg/d 30% • Steroids tapered 20% 0.2 10% • Failure : 0.0 0% • No response day 7 0 30 60 90 • Absence Remission Day 98 Time in Days • Relapse Day 7 – 98 No. of Patients at Risk Infliximab 24 17 17 17 • Severe AE or Death Placebo 21 7 7 7 • Colectomy Jarnerot G, et al. Gastroenterol. 2005;128(7):1805-1811. Hospitalized UC Patient| 17 Hospitalized UC Patient| 18 IFX vs CsA ( Narula, et al. Am J Gastroenterol 2016; 111:477–491) CSA vs. IFX: Severe IV Steroid-Refractory UC Treatment Failure * 100% Response: Day 7 Colectomy rates at 12 months 100% 85.4% 85.7% 80% p=0.49 60% 80% p=0.97 54% 60% 60% 40% 40% 20% 20% 0% 0% Cys (n=55) IFX (n=56) Cys (n=55) IFX (n=56) * Failure: Response: Lichtiger score < 10 and decrease ≥ 3 points as compared to baseline • No response day 7 • Absence Remission Day 98 • Relapse Day 7 – 98 • Severe AE or Death Laharie et al. 2011 • Colectomy Hospitalized UC Patient| 19 Hospitalized UC Patient| 20 5

10/20/16 IFX vs CsA ( Narula, et al. Am J Gastroenterol 2016; 111:477–491) BOTH Cyclosporin and Infliximab? • Drug adverse events • Never together. Too much risk (20-30% SAE) • Some Exceptions: 1. Cyclosporin: effective, but then has allergic reaction to azathioprine / 6-MP. (wash out for 48-72 hours) 2. Cyclosporin: intolerable side-effect (wash out for 48- 72 hours) 3. Infliximab: Once given NO CsA Hospitalized UC Patient| 21 Hospitalized UC Patient| 22 Infliximab: Not always successful Infliximab failure….Why? • Randomized Placebo-Controlled Trial Results • Infliximab 5mg/kg @ weeks 0, 2 • Placebo • IFX: Detected in all pts stool. Week 6 Results • Highest in the first days post infusion. P= 0.76 50% 39% • Nonresponders, had much P= 0.96 30% 40% 30% 26% high amounts of drug lost in 30% Infliximab stool. 20% Placebo 10% 0% UCCS <3 Baron = 0 • No difference in IBDQ or EuroQol Scores Brandse JF, et al. Presented at DDW; May ,2013. Abstract 157. Probert CSJ et al. Gut 2003;52:998-1002. Hospitalized UC Patient| 23 Hospitalized UC Patient| 24 6

10/20/16 Higher Trough Levels: Better Outcomes Accelerated Infliximab Dosing: Success ? • 125 Steroid-Refractory UC pts Steroid-free Remission by IFX Trough Status • Retrospective 100 P<0.001 • IFX “Infliximab”; ATI “Antibody to • 50 hospitalized UC pts Remission (%) 80 69.4 Infliximab” Patients in • Corticosteroid refractory 60 • Trough Infliximab >2 µg/ml • Standard dose infliximab: 5mg/kg Weeks 0,2,6, 40 then q8 w • Remission: OR 10 (3,35) 17.5 20 • Accelerated dose: 3 doses within median 24 days • Colectomy: 0.18 (0.07, 0.44) 0 Serum IFX Serum IFX 100% ≤ 2µg/ml > 2µg/ml Steroid-free Remission by IFX/ATI Status 100 80% P<0.001 Colectomy by IFX Trough Status Patients in Remission (%) P=0.073 80 100 P<0.001 60% Accelerated Normal 70.0 40% Colectomy (%) 80 60 40% 60 55.5 40 40 20% 6.7% P=0.84 28.5 17.7 20 16.6 20 13.0 0 0% Serum IFX Serum IFX ≤ 2µg/ml > 2µg/ml Colectomy During 0 IFX+ IFX+ IFX- IFX- Induction ATI- ATI+ ATI- ATI+ Murthy S, et al. 2012 Gibson DJ et al. Clin Gastroenterol Hepatol 2014 Hospitalized UC Patient| 25 Hospitalized UC Patient| 26 Colectomy for severe UC • Colectomy – Surgical consult by day 3 for refractory patients – Toxic megacolon, perforation, refractory bleeding – Failure of medical therapy at 7-10 days • Total abdominal colectomy with Hartmann – Mortality < 1% – Laparoscopic or robotic – J pouch in 3 stages if eligible, but NOT during acute illness Hospitalized UC Patient| 27 7