Prognostication in IBD: Can We Really Predict the Future or Are We Just Describing the Past? Raymond Cross, MD, MS, AGAF Associate Professor of Medicine Director of the Inflammatory Bowel Disease Program University of Maryland School of Medicine 7/19/14

Current Need for Risk Stratification in IBD IBD, especially CD, are heterogeneous diseases Not appropriate to treat every patient the same Despite improved outcomes with early biologic therapy with IS, this approach may not be appropriate for every patient Overtreatment of patients with mild disease Increased rates of adverse events (albeit small) Cost There is often a poor correlation between symptoms and disease activity Personalized approaches which include risk stratification are needed to individualize therapy

What clinical variables are associated with adverse outcomes in IBD?

Clinical Predictors of Complicated Clinical Course in CD 5-year clinical course after diagnosis Variable Nondisabling, % (n=166) Disabling, % (n=957) P-value* Age at onset <40 years* 77.1 87.7 .0004 ≥40 years 22.9 12.3 Location of disease Small bowel only 44.6 32.8 .002 Small bowel + colon 25.9 39.4 Colon only 29.5 27.8 Smoking status Smoker 50.3 57.4 .09 Ex- or nonsmoker 49.7 42.6 Perianal lesions at diagnosis Yes* 17.5 26.4 .01 No 82.5 73.6 Required steroids for tx first flare 37.3 65.2 .0001 62.7 34.8 Beaugerie L, et al. Gastroenterology. 2006 4

Predictors of Complicated CD Complicated CD defined as either stricturing or penetrating disease Patients with complicated CD were Younger at diagnosis (24 years vs. 33 years, p<.001) Current smokers (36% vs. 15%, p<.01) Ileal disease (39% vs. 19%, p<.01) Exposed to steroids in 1st year after diagnosis (77% vs. 56%, p<.01) Less likely to be exposed to biologics (6% vs. 20%, p=.01) Patil, S., et al. (2012). Gastroenterology 142(5): S667-S667

Variables Significantly Associated with Early Surgery in Crohn’s Disease Factor Odds Ratio 95% CI Oral corticosteroid use in 1st 6 months vs. none 3.79 (1.90-7.55) Current smoker vs. nonsmoker 3.09 (1.47-6.51) Ileal localization only vs. all others 2.22 (1.30-3.81) Nausea/vomiting vs. none 2.07 (1.04-4.10) Abdominal pain vs. none 1.82 (1.05-3.18) Colonic localization only 0.27 (0.13-0.56) Sands B., et al. Am J Gastroenterol. 2003. 6

Clinical Predictors of Severe and “Very Severe” Crohn’s Disease Severe CD (58% of subjects) Age <40 years at onset Presence of perianal lesions at diagnosis Very severe CD (37% of subjects) Stricturing or intra-abdominal fistulizing at diagnosis Fever at diagnosis Weight loss >5 kg at diagnosis Increased platelet count at diagnosis -Criteria for severe CD same as those defined by Beaugerie -Very severe CD defined as: >70 cm intestinal resection; >2 intestinal resections; colectomy; stoma; complex perianal disease *P<0.001; †P<0.01; ‡P<0.05 Loly, C., et al. (2008). Scand J Gastroenterol 7

Variables Associated with Severe CD Early age at diagnosis Early treatment with corticosteroids Perianal involvement Smoking Disease location Ileal vs. colonic Upper GI tract involvement? Complicated disease at diagnosis

Are biologic markers associated with a more severe disease course in IBD?

High Fecal Calprotectin is Associated with Risk of Relapse in IBD 43 CD 37 UC In remission for 1-4 months 25 (58%) relapsed over period of 12 months 19 (51%) relapsed over period of 12 months Proportion of patients without a relapse 1 UC calprotectin <50mg/L UC calprotectin >50 mg/L CD calprotectin <50 mg/L CD calprotectin >50 mg/L RR 10.6 (CD) RR 13.4 (UC) 3 6 9 12 RR, relative risk Tibble, JA., et al. Gastroenterology. 2000 Time (months) 10

FCP as Marker of Disease Activity in Patients Taking Infliximab for UC UC patients in remission on IFX 5 mg/kg q8w (n=113) FCP measured monthly for 1 year Deep remission = normal endoscopy at baseline and week 52 + Mayo score < 3 27% were in deep remission FCP levels highly correlate with disease activity FCP <50 mg/kg at all time points in patients in deep remission Median FCP 477 mg/kg in patients with a flare Two consecutive levels >300 mg/kg predicted a flare De Vos M et al. ECCO 2012. Abstract no OP 07.

FCP and Fecal Lactoferrin Predict Endoscopic Disease Activity FCP and FL correlate significantly with the Crohn’s Disease Index of Severity (CDEIS) Measure Sensitivity Specificity PPV NPV CDAI>150 27% 94% 91% 40% CRP>5mg/l 48% FCP >200mcg/g 70% 92% 61% FL >10mcg/g 66% 59% Sipponen T, et al. Inflamm Bowel Dis 2009

Antibody Responses to Microbial Antigens Predict Clinical Outcomes Variable Small bowel disease Fibrostenosis Internal perforating Small bowel surgery UC-like Anti-I2 NS 0.027 0.01 Anti-OmpC <0.006 ASCA 0.023 <0.001 <0.001¥ pANCA 0.013¥ <0.002¥ NOD2 0.003 <0.008¥ ¥negative association Mow, W. S, et al. (2004). Gastroenterology

Risk of Disease Progression Increases With Increased Immune Responses CLINICAL PHENOTYPE NUMBER OF ANTIBODIES TOWARD MICROBIAL ANTIGENS* P trend ODDS RATIO (3 vs 0) 95% CI (3 vs 0) 1 2 3 Fibrostenosing (%) 23.0 50.0 66.7 72.0 <0.001 8.6 4.0–18.9 Internal perforating (%) 27.9 27.5 42.5 58.7 3.7 1.8–7.6 Small bowel surgery (%) 57.5 *Number of antibodies is the cumulative total of microbial antigen responses to I2, OmpC (outer membrane porin C), and ASCA (anti-Saccharomyces cerevisiae). Results are irrespective of pANCA and NOD/CARD15 status. Mow, W. S, et al. (2004). Gastroenterology 14

Increased Immune Reactivity is Associated with Complications in CD Mow WS, et al. Gastroenterology. 2004

Immunoreactivity Predicts Rapid Progression to Complications and Surgery Dubinsky MC, et al. Clin Gastroenterol Hepatol. 2008

Requirement for Surgery in CD According to NOD2/CARD15 Gene Status Results of Kaplan-Meier Analysis: Probability of Remaining Free of Surgery According to NOD2/CARD15 Gene Status Presence of NOD2/CARD15 variants was associated with: More frequent surgery for stricture Earlier requirement of surgery More frequent surgical recurrence Earlier requirement for reoperation Months 20 80 100 120 40 60 0.0 1.00 0.6 0.2 Cumulative Survival 0.4 0.8 No variant NOD2/CARD15 gene variants Alvarez-Lobos M, et al. Ann Surg. 2005

Incidence of Pouchitis According to Level of pANCA Fleshner PR, et al. Gut. 2001 K25RGU121005

Time after IPAA (months) Effect of Anti-CBir1 Expression and pANCA Level on Cumulative Incidence of Chronic Pouchitis Time after IPAA (months) Fleshner PR, et al. Clin Gastroenterol Hepatol. 2008

Biologic Markers Can Predict Relapse and Complications in IBD FCP correlates with endoscopic disease activity Persistently elevated levels predict relapses Qualitative and quantitative responses to microbial antigens are associated with complications in CD and UC Mutations in NOD2 are associated with higher rates of surgery

Can therapeutic drug levels predict future outcomes?

Detectable IFX Trough Levels are Associated with Improved Outcomes Maser, E. A., et al. (2006). Clin Gastroenterol Hepatol

Detectable IFX Trough Levels are Associated with Improved Outcomes CRP 2.0 in patients with detectable trough vs. 11.8 in those with negative levels Maser, E. A., et al. (2006). Clin Gastroenterol Hepatol

Use of Therapeutic Drug Levels to Guide Changes in Therapy Response to Test Clinical Response P value Detectable HACA Increase IFX 17% P<0.004 Change Anti-TNF 92% Subtherapeutic concentration 86% P<0.016 33% Afif W., et al. Am J Gastroenterol 2010

Trough and ATI Predict Persistence with IFX in IBD Vande Casteele N. Am J Gastroenterol 2013

Trough and ATI Predict Persistence with IFX in IBD ATI were present in 59% of patients; 72% were persistent and 28% were transient Vande Casteele N. Am J Gastroenterol 2013

Trough and ATI Predict Persistence with IFX in IBD IFX trough level < 2.2 ug/ml at week 14 predicted IFX LOR and hypersensitivity reaction ATI were present in 59% of patients; 72% were persistent and 28% were transient Vande Casteele N. Am J Gastroenterol 2013

Trough Levels of IFX Predict Outcomes in UC Seow, C. H., et al. (2009). Gut.

Can endoscopic findings predict the subsequent disease course?

Definition of Mucosal Healing Definitions of MH not uniform Interobserver variability Reasonable definition would be total disappearance of all mucosal ulcers Erythema and distorted mucosal vascular pattern not included Is improvement in endoscopic activity just as important?

Risk of Colectomy According to the Presence of Severe Endoscopic Lesions Probability of Colectomy (%) *Extensive and deep ulcerations on index colonoscopy. Allez M, et al. Am J Gastroenterol. 2002 K25RGU121005 31

Long-term Outcomes Following Mucosal Healing: Norway No mucosal healing Froslie KF, et al. Gastroenterology 2007

MH After Therapy Predicts Improved Outcomes Baert, F., et al. (2009). Gastroenterology.

Is Complete MH Needed in CD? Schnitzler, F., et al. Inflamm Bowel Dis 2009

Curatio PowerPoint Template 12/27/2018 10:11 AM EXTEND: Patients Who Achieved Deep Remission* with ADA at Week 12 and Hospitalization Rates All-cause hospitalization through Week 52 CD-related hospitalization through Week 52 20 20 17 15 15 All hospitalization (%) 10 CD-related hospitalization (%) 10 9 5 5 0/11 9/53 0/11 5/53 Deep remission* (Week 12) Non-deep remission* (Week 12) Deep remission* (Week 12) Non-deep remission* (Week 12) * Deep remission defined as clinical remission (CDAI <150) and complete mucosal healing in EXTEND Colombel JF et al. Gut. 2010;59(Suppl 3):A80.

Long Term Outcomes Following MH in Patients with UC Adapted from Froslie KF, et al. Gastroenterology 2007

MH after Steroids Associated with Improved Clinical Outcomes in UC Variable CR & ER CR only No response General relapse 83% 92% 100% Systemic relapse 55% 72% 91% Hospitalization 25% 49% 64% Immune suppressant 5% 26% 54% Colectomy 3% 18% 17% *Mean follow up 51months §76% followed for 5 years Ardizzone, S.,et al. (2011). Clin Gastroenterol Hepatol

Week 8 Endoscopy Correlates With Steroid-free Remission Rates at Week 30 in ACT 1 and ACT 2 Week 8 Mayo endoscopy score Median steroid dose Steroid-free remission rates P value IFX Arm 46 <0.0001 1 4.5 34 2 10 11 3 6.5 Colombel, JF, et al. Gastroenterology 2011

MH and Time to Colectomy in IFX-treated Patients 0 = NORMAL 1 = MILD 2 = MODERATE 3 = SEVERE Colombel JF et al. Gastroenterology. 2011

MH is Associated with Improved Outcomes Achieving MH (or improvement in endoscopic activity) is associated with decreased: Flares Surgery Hospitalizations Should MH be the target of treatment? Cannot achieve MH in a significant proportion Partial MH may be good enough Limited prospective studies evaluating outcomes in those treated with MH as treatment target

Conclusion Currently available clinical, biologic, genetic and endoscopic markers are helpful to identify patients at risk for complications of IBD In the future, improved diagnostics will help identify at-risk (at-higher risk) IBD patients that will benefit from aggressive medical intervention Anticipate that diagnostics will also help to identify the best (or worse) treatment for a patient