1. Measures and markers of prediction in Inflammatory Bowel Disease Julian Panes Department of Gastroenterology Hospital Clínic, Barcelona

2. Julián Panés Professor of Gastroenterology Research contracts:Abbvie, Boehringer Ingelheim, Genentech, MSD, Pfizer, Roche Consulting:Abbvie, BMS, Boehringer Ingelheim, Genentech, MSD, Novo-Nordisk, NSP, Pfizer, Roche, Topivert, Tygenics, Employment in industry:None Stockholder of a healthcare company: None Owner of a healthcare company: None Other:None Disclosure of potential conflicts of interest

3. Why assess prognosis initially? Assessing prognosis at an early stage is essential for the development of an appropriate management plan Avoid intensive therapy, immunosuppression, adverse events Assure early intensive therapy to avoid complications IndolentAggressive

5. Solberg IC, et al. Clin Gastroenterol Hepatol 2007;5:1430–8 IBSEN: disease course in Crohn’s disease over 10 years Disease activity 010 Years 0 45%19% 3% 32% Patterns of severity of bowel symptoms in CD

6. Disease characteristics associated with higher relapse rates Age Use of systemic steroids 1 st flare Cumulative rate (%) of patients relapsing Solberg IC, et al. Clin Gastroenterol Hepatol 2007;5:1430–8 p=0.03p=0.02 p=0.008

7. Phenotype at diagnosis and recurrence rates in Crohn’s disease Ten year clinical follow-up project 13 centers from 7 EU countries 358 CD patients classified for phenotype at diagnosis 262 (73.2%) a first clinical recurrence 113 (31.6%) a first surgical intervention Wolters FL et al. Gut 2006;55:1124–30. Colonic disease (L2) Age > 40 Upper GI Disease (L4) 1 Surgery Clinical recurrence 20.50.2 Proportion in each group 5.6% 32.6% 42.2%

8. Aggressive course Crohn’s disease Munkholm P. et al. Scand J Gastroenterol 1995:30:699-706 D12348 Years after diagnosis active p <0.001 45% 50% 5% inactive Courtesy of Pia Munkholm

9. Indolent course Crohn’s disease D12348 Years after diagnosis active inactive 8% 48% 44% Munkholm P. et al. Scand J Gastroenterol 1995:30:699-706 Courtesy of Pia Munkholm

10. Long term disease behaviour in CD Ileal Colon Ileocolon Proximal Penetrating Stricturing Inflammatory Louis E et al Gut 2001; 49:777-32 Disease behaviorDisease location Percent

11. Factors influencing the development of stricturing or penetrating pattern in Crohn’s disease % Louis E et al Gut 2001; 49:777-32 Diagnosis After 10 years

12. Predictors of «disabling» (severe) CD Derivation cohort – Retrospective – 262 for prevalence seen from diagnosis – 1123 patients (factors) Validation cohort – Prospective – 302 patients Definition disabling (any) – ≥ 2 steroid courses – steroid dependence – hospitalization – chronic (>12 mo) symptoms – need immunosuppressants – need surgery 64.9% - 80.5% CI 59.1% - 92.2% PPVDerivationValidation 2 factors0.910.84 3 factors0.930.91 Beaugerie L et al. Gastroenterology 2006;130:650–6. Independent factors at diagnosis Steroid requirement Age < 40 Perianal Disease 12345

13. Predictors of very severe Crohn’s Disease Criteria: >70 cm resection, >2 resections, colectomy, stoma, complex perianal disease Prevalence: 18% of patients at 5 years Independent predictors at diagnosis: – Age <40 – Stricturing or intra-abdominal penetrating – Fever – Loss of >5 kg – Increased platelet counts Loly C, et al. Scand J Gastroenterol. 2008 43:948-54

14. Serum Immune Responses and Disease Progression in Pediatric CD 196 pediatric CD patients Penetrating or stricturing disease: 38 (19%) at diagnosis; 58 (30%) at the end of follow-up. Median follow-up period within the study: 18 months Immune Responses: ASCA, anti-OmpC, anti-I2, pANCA Odds of having B2/B3 ≥ 1 Immune Response: OR=5.5 [1.3–23.6] 4 Immune Responses: OR=11.0 [1.5–80.4] Dubinsky MC et al Am J Gastroenterol 2006; 101:360–7 0 0.25 0.5 0.75 1 0 all negative 20406080100120 1-3 positive Time to disease progression (months) 140 Probability of non-progressive CD p=0.03 n=70 n=93 Number immune responses

15. Serological Makers in the Prediction of Complications and Surgery in Pediatric CD 139 patients. Age 11.1±3.4 yr. Complications (fistula / abscess): 31 patients during follow-up First Surgery: 35 patients duging follow up ASCA and pANCA measurements every 3 months Amre DK et al Am J Gastroenterol 2006; 101:645–52 0 500 1000 1500 2000 Days 0 20 40 60 80 100 Proportion free of first complication 0 500 1000 1500 2000 Days 0 20 40 60 80 100 Proportion free of first surgery ASCA negative ASCA positive logrank test p<0.001

16. The prognostic power of the NOD2 genotype for complicated CD: a meta-analysis 49 studies, 8893 subjects, 2897 with NOD2 mutations Adler J et al. Am J Gastroenterol 2011; 106:699-712 0,811,21,41,61,82 Complicated Disease Stricturing Penetrating Perianal Surgery RR (95% CI) p 1.17 (1.10, 1.24) < 0.001 1.33 (1,15, 1.55) < 0.001 1.16 (1.05, 1.28) < 0.003 1.03 (0.92, 1.16) 0.6 1.58 (1.38, 1.80) < 0.001

17. Risk factors for surgery VariableRR Age at diagnosis 0-140.8 (0.6 - 0.96) 15-291 45-691.2 (1.0 – 1.4) Disease location Colorectal1 Ileocolonic1.7 (1.4 – 2.0 Ileocecal3.2 (2.7 – 3.6) Small bowel3.2 (2.5 – 4.0) Perianal fistulas No1 Yes1.2 (1.04 – 1.3) Retrospective. 1936 patients. Diagnosed 1955 -1989. Final evaluation 1993-4 Median follow-up 14.9 yr. Complete in 99.2% cases Bernell O et al. Ann Surg 2000;231:38–45. 0 3 6 9 12 15 Years 0 20 40 60 80 100 Cumulative risk of surgery (%)

18. Henriksen M, et al. Gut 2008;57:1518–1523 CRP>23 mg/L at diagnosis in extensive UC and risk for colectomy in 5 years (n=129) CRP a Marker of Disease Outcome? 1 Percent 0 10 20 30 40 50 234 6 7 4 26 CRP>53 mg/L at diagnosis in L1 CD and risk for surgery in 5 years (n=46) 1 Percent 0 20 40 60 80 100 234 36 44 50 82 Quartile

19. Risk of Early Surgery for Crohn’s Disease Retrospective 331 patients new diagnosis CD followed since diagnosis 69 (20.1%) surgery within 3 yr Sands BE et al. Am J Gasroenterol 2003;981:2712–8. Independent risk factors Multivariate analysis Smoking OR 3.42 (1.54–6.35) Colonic localization OR 0.36 (0.22–0.57) * * No Yes Any SB Colon only Smoking Disease location % operated

20. Significance of granulomas in incident CD cases 188 consecutive incident CD cases Epithelioid gralulomas: – 69 (37%) – 46 (25%) at diagnosis

21. Severity of Endoscopic Lesions and Long Term Outcome in CD Allez M et al. Am J Gastroenterol 2002;97:947–53. Colectomy Patients: 102 (all colonoscopies 1990-1996) Severe Endoscopic Lesions: Deep ulcerations > 10% surface of one segment Prevalence: 52%

22. 0,2,4,6,8 1 % patients wihout surgery 020406080100120 Months p =0.0089 Wild type NOD2/CARD15 Variants Álvarez-Lobos M et al. Ann Surg 2005;242: 693–700 Surgery-free survival in Crohn’s disease according to NOD2/CARD15 variants

23. Need of reoperation Genetic factors: NOD-2 0,2,4,6,8 1 0102030405060 Months p =0.03 Wild type CARD15 Variants Survival free of reoperation after first surgery Álvarez-Lobos M et al. Ann Surg 2005;242: 693–700

24. Predictors CD summary RelapseComplicatio ns Surgery Age++++ Location++++++ B2, B3 at diagnosis +++ Smoking+ N flares+++ CRP+ Perianal++ Steroids+++ Genetics++

25. 25 Disease Course in UC Solbert IG, et al. Scand J Gastroenterol, 2009; 44: 431-40 Remission after initial activity 55% 05 yrs Increase in severity 1% 05 yrs Chronic contiuous 6% 05 yrs Chronic intermitent 37% 05 yrs younger age at diagnosis (p<0.009)

26. Clinical course of UC during the first year after diagnosis Age on risk of relapse Disease extent on therapeutic requirements Moum B et al Scand J Gastroenterol 1997; 32:1005-12 p=0.005 p=0.011 p=0.03

27. Aggressive course, I Ulcerative colitis D12348 Years after diagnosis active p <0.001 32% 61% 6% inactive Langholz E et al. Gastroenterology. 1994;107:3.

28. Indolent course, III Ulcerative colitis D12348 Years after diagnosis 6% 46% 48% Langholz E et al. Gastroenterology. 1994;107:3. active inactive

29. 29 Colonoscopy for Predicting Disease Outcome of Moderate-to-Severe UC After Steroid Treatment Parente F, et al. Am J Gastroenterol 2010;105:1150–1157 Baron at 15 months Baron at 3 months 0–12–3OR 0–184%40%1 2–316%60% 5.22 (1.55–17.6) 3 months 20 40 60 80 100 0 9 months15 months Baron 3 mo 0–1 Baron 3 mo 2–3 cumulative probability of endoscopic remission

30. Early mucosal healing and long-term remission in UC Colombel JF et al. Gastroenterology 2011;141:1194–201. ACT 1/2: steroid-free remission at Week 30 with infliximab Remission was defined as a total Mayo score ≤2, with no individual subscore >1 ACT 1/2 subanalysis; primary endpoint was clinical response at Week 8 (p<0.001); patients randomised to placebo or infliximab induction and maintenance therapy at Week 0 0 (n=120) 46 60 100 0 20 40 80 Patients (%) p<0.0001 1 (n=175) 34 2 (n=114) 11 3 (n=57) 6.5 Endoscopic score at Week 8

31. 31 Predictors of Relapse in UC Hazard ratio (95% CI) P value Age0.4 a (0.2–0.7)0.003 Basal plasmacytosis 4.5 (1.7–11.9)0.003 No. of prior relapses (women) 1.6 b (1.2–1.9)<0.001 No. of prior relapses (men) 0.93 (0.7–1.3)0.64 Bitton A, et al. Gastroenterology 2001;120:13–20 0 0.25 0.5 0.75 1 0 Absence Proportion of patients in remission 24681012 Presence Basal Plasmacytosis Months on study a Per decade. b No significant differences in WBC, Hb, and albumin.

32. Cumulative rate of colectomy 32 0 5 10 15 20 25 Proportion of UC patients not colectomised 02411 Time since diagnosis (years) 681097531 Solbert IG, et al. Scand J Gastroenterol, 2009; 44: 431-40 Colectomy at 10 years 9.8 %

33. 33 Szamosi T, et al. Eur J Gastro 2010;22:872–879 Smoking and Need for Surgery in UC pLogRank=0.042 0 0.2 0.4 0.6 0.8 1.00 Survival without colectomy 0.00100.00200.00300.00400.00 Follow-up (months) No-smoking Smoking Censored

34. 34 ESR and disease extend at diagnosis: Markers of colectomy risk Solbert IG, et al. Scand J Gastroenterol, 2009; 44: 431-40 0.5 0.6 0.7 0.8 0.9 1.0 Fraction of patients not operated 02410 Time to operation (years) 68 ESR > 30 mm/h ESR ≤ 30 mm/h 12 ESR > 30 mm: HR: 2.94 (95%CI: 1.58 – 5.46), p=0.001 Extensive colitis: HR: 2.98 (95%CI: 1.25 – 7.08), P=0.013

35. 35 Henriksen M, et al. Gut 2008;57:1518–1523 CRP: A Marker of Disease Outcome in UC P=0.02 0.5 0.6 0.7 0.8 0.9 1.0 Fraction of patients not operated 02410 Time to operation (years) 68 C-reactive protein levels >23 mg/l (75% percentile) C-reactive protein levels ≤23 mg/l

36. Serologic Markers in UC? 36 Solberg IC, et al. Inflamm Bowel Dis 2009;15:406 – 14 Male gender : OR: 0.52 (95%CI: 0.32 – 0.82), P=0.005 Azathioprine use: OR: 4.23 (95%CI: 1.73 – 10.02), P<0.001 0.80 0.84 0.88 0.92 0.96 1.00 Proportion of UC patients not colectomised 02411 Time since diagnosis (years) 681097631 Log rank-test, P=0.52 pANCA negative pANCA positive OR=odds ratio; pANCA= Anti-neutrophil cytoplasmic antibody

37. 37 Predictors for mucosal healing: Education longer than 12 years and extensive disease at diagnosis Froslie KF, et al. Gastroenterology 2007;133:412–422 Mucosal Healing and Need for Surgery (IBSEN) P=0.02 0.90 0.92 0.94 0.96 0.98 1.00 Proportion of UC patients not colectomised 012345678 Time in years after 1 year visit

38. Relationship Between Histologic Inflammation and Colectomy Risk? University of Chicago IBD Endoscopy Database used to identify patients with UC Out of 106 patients (median age: 27 years, median duration of disease: 13.5 years) studied In Cox modeling with time-varying covariates – 1-point increase in inflammation grade * resulted in a statistically significant increase in risk of colectomy (Hazard ratio =1.90, 95% CI 1.02–3.51; P=0.042) – The grade of histologic inflammation was not correlated with number of endoscopies, clinic encounters, radiological exams or steroid exposure Rubin DT, et al. DDW 2007. Abstract #103. * 6-point grading of histologic inflammation.

39. Progression of UC disease extent over 5 years Progresion of disease extent: 41/146 (28%)28/90 (31%) Henriksen M, et al. Inflamm Bowel Dis 2006;12:543–50 Number of patients with progresion Norwegian IBSEN cohort study, 1990–1994 (n=454) Disease extent after 5 years: Proctosigmoiditis Left-sided colitis Extensive colitis

40. Extension progression (n=63) Extensive stable (n=63) P N bowel movements 8.9  4.55.8  3.7 0.02 CRP (mg/dl) 5.1  6.92.3  3.6 0.01 ESR (mm/h) 46.0  30.329.8  25.5 0.03 Albumin (g/L) 38.2  6.941.2  7.7 0.03 Hemoglobin (g/L) 119.2  18.2123.9  20.1 ns Steroid refractory/dependent (%)46270.026 Cyclosporine (%)23.811.30.054 Infliximab (%)6.31.6ns Hospitalization (%)46.620.60.002 Hospital stay (days) 7.4  11.23.5  9.3 0.04 Surgery (%)19.04.80.015 Comparison of cases with disease progression and controls with stable extensive disease Clinical characteristics of UC at time of progression from distal to extensive colitis Etchevers J et al. Inflamm Bowel Dis. 2009;15:1320-5 Cyclosporine is not approved for treatment of ulcerative colitis

41. 41 Polygenic Multifactorial Model Predicting Medically Refractory UC Haritunians T, et al. Inflamm Bowel Dis 2010;16:1830–1840 0 20 40 60 80 100 Proportion (%) Risk-A 0.9% (n=109) Risk-B 17.2% (n=373) Risk-C 74.3% (n=268) Risk-D 100% (n=50) 0 0.2 0.4 0.6 0.8 1.0 Cumulative Probability of Avoiding Colectomy (MR-UC) 10202430405060 Risk-A; n=109 Risk-B; n=373 Risk-C; n=268 Risk-D; n=50 Time to Surgery (months)

42. Predictors UC summary RelapseTherapy requirements SurgeryCancer Age++/- Disease extent+++++ CRP /ESR++ Steroids 1st flare+++ Smoking+ (-) Mucosal healing++++ N flares+ Progression of extension ++ Genetics+/-

43. Age Disease extension / Location (CD: perianal) Steroid requirement Biomarkers Smoking Mucosal healing Sustained remission Predicting IBD at diagnosis