IBD: Whats new? Whats important? Dr. Chadwick Williams Assistant - PowerPoint PPT Presentation

IBD: What’s new? What’s important? Dr. Chadwick Williams Assistant Professor, Dalhousie University Dartmouth General Hospital, Dartmouth NS CSIM 2019 - Halifax

CSIM Annual Meeting 2019 Conflict Disclosures Definition: A Conflict of Interest may occur in situations where the personal and professional interests of individuals may have actual, potential or apparent influence over their judgment and actions. “I have the following conflicts to declare or I have no conflicts to declare” Company/Organization Details Advisory Board or equivalent Key Opinion Leader Abbvie, Janssen, Takeda Speakers bureau member Presentation of national and international Abbvie, Janssen, Takeda conference reviews to regional group Payment from a commercial - organization. (including gifts or other consideration or ‘ in kind ’ compensation) Grant(s) or an honorarium - Patent for a product referred to or - marketed by a commercial organization. Investments in a pharmaceutical - organization, medical devices company or communications firm. Participating or participated in a Abbvie, Janssen REACT 2, CONSTRUCT clinical trial

What keeps me up at night? • Thursday night football • American news • They want to get rid of cows! • Mucosal healing*

Learning Objectives • Review the distinctions between Crohn’s disease (CD) and ulcerative colitis (UC) • Learn role and limitations of fecal calprotectin and other diagnostic testing • Review the most current pharmacologic and non-pharmacologic IBD management strategies and potential common serious adverse effects of therapy

Fair Warning • IBD review for the internist • Interactive and case-based • Not a deep data dive

Crohn ’ s disease and UC are chronic diseases • genetics and environmental factors • Complications ‒ significant morbidity • no cure • multiple effective therapies available

Incidence varies but where is it highest? 1. Eastern & Nordic European countries 2. Western Canada 3. Atlantic Canada 4. Midwest US 5. South East Asia G Kaplan et al J CAG 2019, 2(S1) S6-S16

Case 1 • 36 yr old man with non-bloody diarrhea X 3 mos • Abdominal pain and mouth ulcers • Perianal tract draining • Hemoglobin 101, ferritin 15 and CRP 35 • FHx of IBD • Active cigarette smoker

Is this presentation more consistent with CD or UC? Why? • Predominantly non-bloody diarrhea and abdo pain • Weight loss • Perianal disease • Active smoker*

Case 2 • 21 year old female with rectal bleeding for 2 months but no significant abdominal pain • Urgency and tenesmus • Pains of feet , knees, hands and lower back • Reddened right eye

Is this presentation more consistent with CD or UC? Why? • Ulcerative colitis (but could also be Crohn’s colitis)

Crohn’s versus ulcerative colitis Crohn’s Ulcerative Colitis Disease distribution / Can affect anywhere from Colon and always starts distally mouth to anus ‒ can be (rectum) - confluent Disease extent patchy Transmural Yes (can present with No penetrating complications) inflammation Perianal Disease Yes No Extraintestinal Yes (usually if there is Yes significant colonic manifestations involvement) Histology Possible presence of Granulomas rarely seen granulomas

Return to Case 1 • 36 yr old man with non-bloody diarrhea X 3 mos • Abdominal pain and mouth ulcers • Perianal tract draining • Hemoglobin 101, ferritin 15, CRP 35 • FHx of IBD • Active cigarette smoker

What other investigations would you order? • Calcium, vitamin D, vitamin B12 • Viral hepatitis serologies (and vaccinate if not immune) • Baseline fecal calprotectin (-/+ in this case) • Imaging options (XR, CT, MR, US, perianal assessment) • endoscopy • TST, CXR

Game Changer

Fecal calprotectin is a diagnostic game changer Clinical Utility Correlates well with endoscopy (POCER) • Protein released at the gut mucosa by leukocytes in response to inflammation • Highly sensitive inflammatory marker (96% in adults) • Useful IBD screening tool • Useful tool for monitoring IBD patients (can predict relapse) • Reduction in need for endoscopy Wright et al, Gastroenterology . 2015 May;148(5):938-947 N Walsham and R Sherwood Clin and Exp Gastro 2016;9:21-29 P van Rheneen BMJ 2010;341:c3369

Small bowel follow through is no longer SOC for small bowel assessment • Options include CTE and MRE (plus capsule endoscopy and SBUS if available) • MRE nudges out CTE for sensitivity and specificity plus avoids radiation risk • Rapid access is an issue • MR is a superior modality for perianal disease (although CT is adequate to r/o perianal abscess) K. Haas et al World J Radiol 2016;28(8):124-31

Small bowel ultrasound is under-utilized • Effective tool for identifying small bowel inflammation • PPV 97%, NPV 94% • Non-invasive, inexpensive, no radiation • Requires specialized training • SOC in many European institutions and training programs but limited use in Canada and US F Castiglione et al Inflamm Bowel Dis 2013; 19:991-8

Case 1 - continued • MR enterography and MR pelvis ‒ 10 cm of terminal ileitis with skip lesions and no obstruction. Rectosigmoid colon inflammation with a simple and short anorectal fistula. No abscess • Fecal calprotectin ‒ 945 mcg/g • Colonoscopy ‒ ileitis and proctitis with deep ulcerations in both locations • Viral studies, TST and CXR normal

What is the best treatment for this patient? Consider surgery now? 1. Short course of steroid 2. Course of steroid plus azathioprine 3. Steroid course, 5ASA plus biologic agent 4. Steroid course, biologic agent plus azathiopine 5. None of the above

There are a growing number of options for IBD but • GIs are not rheumatologists or dermatologists... • IBD ain’t viral hepatitis...we have no panacea

More than just symptoms Targets of therapy in IBD • Clinical remission (resolution of symptoms) • Improved function and QOL • Endoscopic healing • Histologic healing*

We will focus on newer therapeutic agents but... • Frequent and prolonged steroid therapy is a major problem • 5ASA therapy in Crohn’s disease is a major problem • The role of immunomodulators (methotrexate and azathioprine) is evolving Lim and Hanauer Cochrane Review Jul 2010 Ford et al Cochrane Review Apr 2011

Anti-TNF antagonism • First class of biologics used in IBD • Monoclonal antibodies to TNF (an important proinflammatory cytokine) • Infliximab IV, adalimumab SC, golimumab SC (only indicated in UC) • Well tolerated but important AEs: TB reactivation, lupus-like syndrome, demyelination, infection Targan et al: N Engl J Med 1997; 337(15):1029-35 Sands et al. N Eng J Med 2004;350:876-885 Colombel et al: N Engl J Med 2010; 362:1383-95

Targan et al NEJM 1997;337:1029-35 Colombel et al: N Engl J Med 2010; 362:1383-95 Sands et al. N Eng J Med 2004;350:876-885 Sandborn et al Gastro 2014; 146(1):96-109

Integrin blockade • Vedolizumab-eh • IV monoclonal antibody to α 4 β 7 / MadCAM1 adhesion complex • Gut specific endothelial blockade to leukocytes • Favorable side effect profile: nasopharyngitis, slight increase of serious infections W. Sandborn NEJM 2013; 369(8):711-21

Vedolizumab showed efficacy in Crohn’s disease and ulcerative colitis • GEMINI I showed drug efficacy in UC but suggested a more sluggish onset of action compared to other biologics • GEMINI II failed to meet induction dual primary endpoint • Maintenance primary endpoint met resulting in Crohn’s disease indication W Sandborn NEJM 2013; 369(8):711-21

IL 12/23 antagonism • Ustekinumab approved for moderate to severe Crohn’s • Anti IL 12/23 monoclonal antibody • Induction ‒ IV weight based • Maintenance ‒ 90mg SC every 8 weeks • Favorable side effect profile • No AE signal compared to placebo (except allergy to ustekinumab)

UNITI-1 CR UNITI-2 CR UNITI ‒ MAINTENANCE OUTCOMES (52 WEEKS) Feagan B et al N Engl J Med. 2016 Nov 17;375(20):1946-1960

JAK inhibition • Tofacitinib is a small molecule (Janus kinase inhibitor mainly JAK 1 and JAK 3) • Downregulation of IL 6 = reduction in inflammation • Oral twice daily dosing • Induces rapid remission and sustained response in ulcerative colitis • no risk of antigenicity • AE: infection, dysplipidemia (no increased risk of CV events) W Sandborn et al NEJM 2017;376:1723-36

How to choose? • Consider disease characteristics • Fistula (antiTNF) • EIMs (antiTNF, MTX, sulfasalazine) • Patient characteristics (MS, CHF) • Patient preference • compliance • Safety • Future ‒ refined MOAs, new MOAs, personalized therapies (serology, genome, cytokine expression)

Return to the case... • Young male with ileo-colonic Crohn’s disease with deep ulcerations • Uncomplicated fistulizing disease • Treated initially with short course of budesonide, azathioprine 2.5mg/kg daily, infliximab (only agent with data in fistulizing disease) • That was 2012...nowadays I approach this differently