Crohn s Disease: Should We Treat Based on Symptoms or Based on Objective Markers of Inflammation? Edward V. Loftus, Jr., M.D. Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota
Cumulative Risk of Intestinal Resection Among 314 Crohn's Disease Patients Olmsted County, Minnesota (1940-2001) 100 80 Cumulative incidence (%) 60 40 20 0 0 5 10 15 20 25 30 Years from Crohn's diagnosis No. at risk 314 156 97 62 41 23 16 1. Dhillon S et al, Am J Gastroenterol 2005 (abstract) 2. Peyrin-Biroulet L et al, Gastroenterology 2010 Suppl (abstract)
Cumulative Risk of Second Resection Among 159 Crohn's Patients Who Required Intestinal Resection Olmsted County, Minnesota 100 80 Cumulative incidence (%) 60 40 20 0 0 5 10 15 20 25 30 Years from first resection No. at risk 159 101 62 45 22 14 9 1. Dhillon S et al, Am J Gastroenterol 2005 (abstract) 2. Peyrin-Biroulet L et al, Gastroenterology 2010 Suppl (abstract)
Predictors of Disabling Crohn s Disabling At least 1 Criterion of disabling 5-yr CD course I. more than 2 steroid courses and/or steroid dependence II. further hospitalizationation for flare-up or complication III. disabling symptoms: 3 or more visits for perianal disease or extra intestinal symptoms IV. need for immunosuppressive therapy V. intestinal resection or surgical operation for perianal disease Beaugerie L et al. Gastroenterology 2006;130:650-6
Predictors of Disabling Crohn s Referred cohort of 1128 CD patients 3 factors independently predictive Disabling CD course within 5-year Initial requirement for steroids OR: 3.1 [95% CI: 2.2 4.4] Age at diagnosis below 40 OR: 2.1[95% CI: 1.3 3.6] Perianal disease at diagnosis OR: 1.8[95% CI: 1.2 2.8] Beaugerie L et al. Gastroenterology 2006;130:650-6
Predictors of Disabling Crohn s Disease: Olmsted County, 1983-96 96 Frequency of disabling CD 68/124 =54 54.8% 16.8% operated on within the first 3 months for intestinal ti resection Frequency of disabling CD 71.6% Positive Predictiv ve Value % 100 90 80 70 60 50 40 30 20 10 0 Initial steroids Age < 40 yrs at diagnosis Perianal disease at diagnosis 74.2 48.1 score 0-1 score 2-3 n = 79 n = 31 Seksik P, et al. Oral presentation during Digestive Disease Week 2007, Washington, DC
Impact of Therapy will Depend on Degree of Structural Damage & Velocity of Progression 100 High Potential Low Potential Cumu ulative Pr robability (%) 90 80 70 60 50 40 30 20 10 Penetrating Stricturing Inflammatory 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Patients at risk: Months Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.
Behavior at Crohn s Disease Diagnosis (Montreal): Olmsted County, 1970-2004 B2-4.6% (n=14) B3-14% (n=43) B1-81.4% (n=249) Thia KT et al. Am J Gastroenterol 2008 Suppl (ACG Oral)
Cumulative Probability of Change in Crohn s Disease Behavior Among B1 Disease at Diagnosis (n = 249) 1.0 0.8 0.6 0.4 0.2 0 5 10 15 20 25 30 Years from Crohn s disease diagnosis Thia KT et al. Am J Gastroenterol 2008 Suppl (ACG Oral)
Cumulative Probability of Change in Crohn s Disease Behavior From Diagnosis: Olmsted County, 1970-2004 (n = 306) 1.0 0.8 0.6 0.4 0.2 0 5 10 15 20 25 30 Years from Crohn s disease diagnosis Thia KT et al. Am J Gastroenterol 2008 Suppl (ACG Oral)
Risk Factors Associated With Complicationa Disease location Terminal ileum, HR 7.8 (95% CI 3.5-17.4) Ileocolonic, l HR 5.6 (95% CI 2.3-13.9) Upper GI, HR 9.5 (95% CI 3.0-30.1) Borderline significance Perianal disease, HR 1.69 (95% CI 0.99-2.86, p=0.051) 051) Not significantly associated Age, gender, family history, extra-gi manifestation, smoking status, and medication use Thia KT et al. Am J Gastroenterol 2008 Suppl (ACG Oral)
Advances in IBD Natural History: Predictors of More Severe Disease Crohn s disease Young age of onset (<40 years) Ileal or ileocolonic extent Fistulizing disease at diagnosis Early need for steroids Ulcerative Colitis Extensive colitis Male gender Early need for steroids Early hospitalization 1. Beaugerie L, et al. Gastroenterology 2006; Seksik P, et al. 2. Gastroenterology 2007 suppl; Ingle SB et al ACG 2007 and UEGW 2007 3. abstracts; Thia K et al. ACG 2008.
Assessment Of Efficacy Of Medical Therapy: CDAI Versus CDEIS During Treatment With Prednisolone CDAI 600 500 400 300 200 100 0 r= 0.13 ; NS 0 5 10 15 20 25 30 35 CDEIS Figure 1. Correlation of CDAI v. CDEIS at D 0 (n =142). Modigliani Gastroenterology 1990
Correlations Between hscrp, IL-6, Fecal Markers, CDAI, and Endoscopic Activity in Crohn s Disease (N=164) IL-6 Calprotectin Lactoferrin CDAI SES-CD hscrp 0.65 0.47 0.52 0.16 0.46 IL-6 0.45 0.55 0.15 0.43 Calprotectin 0.76 0.23 0.45 Lactoferrin 0.19 0.48 CDAI 0.15 Correlation coefficients highlighted g in red were significant (P<0.05). When stratified by extent, correlation coefficients were highest for colonic disease. CDAI, Crohn s Disease Activity Index; SES-CD, Simple Endoscopic Score for Crohn's Disease Jones JL et al, Clin Gastroenterol Hepatol 2008
Classification of the Sequelae of Bowel Resection for Crohn s Disease Pylorus 0 Duodenum = 8 Duodenojejunal flexure Jejunoileum = 50 5 cm from ileocecal valve Ileocecal valve Rectosigmoid junction Anus Ileocolonic junction = 10 Colon = 21 (7 x 3) Rectum = 11 50 100 Scor re Cosnes J, et al. Br J Surg. 1994;81:1627-1631.
Classification of the Sequelae of Bowel Resection for Crohn s Disease 4000 g/d Fecal Weight, 3000 2000 1000 0 20 40 60 Index Value Correlation between fecal weight and postoperative handicap index in the retrospective series. The regression equation was: y = 3793 866 log [75 x]. (n = 112, r = 0.60, P < 0.001) 001) Cosnes J, et al. Br J Surg. 1994;81:1627-1631.
Stricturing lesions Small Bowel (0-3) IPNIC Overview 0 - Normal 1 - Wall thickening <3 mm or segmental enhancement without prestenotic 2 dilatation 2 - Wall thickening 3 mm or mural stratification without prestenotic dilatation 3 - Stricture with prestenotic 3 dilatation PI s: Mark LeMann, MD, PhD & Jean-Fred Columbel, MD, PhD 1
IPNIC Overview Penetrating lesions Small Bowel (0-2) 0 - Normal 1 - Deep transmural ulceration 2 - Phlegmon or any type of fistula 1 2 PI s: Mark LeMann, MD, PhD & Jean-Fred Columbel, MD, PhD
3/18/07 7 3/27/06 6 CTE/MRE Healing ((~mucosal mucosal healing at endoscopy) g Disease Resolution of Penetrating Successful resolution with antibiotics followed by infliximab + azathioprine Bruining DH et al, Gastroenterology 2010 Suppl (abstract)
CTE/MRE Healing (~mucosal healing at endoscopy) 3/25/2005 10/11/2006 Resolution of intramural inflammation on maintenance infliximab Bruining DH et al, Gastroenterology 2010 Suppl (abstract)
Results Responders 8/17/2006 2/1/2007 Marked decrease in wall thickness and enhancement
Complementarity of Ileocolonoscopy & Enterography 63 year-old asymptomatic female with negative ileoscopy, but active TI disease by CT and MR 1. Solem CA et al. Gastrointest Endosc. 2008 Aug;68(2):255-66. 2. Siddiki H, Fidler JL et al. AJR 2009 (in press) Courtesy Dr. Jeff Fidler
Complementarity of Ileocolonoscopy & Enterography False Negative by CTE by two experienced readers False Negative by CTE by two experienced readers Several TI erosions with biopsy revealing moderate active and chronic ileitis
Problem of Penetrating Disease Large number of Crohn s patients undergoing CTE have penetrating disease 20% in our experience Ileum Fistula Abscess Abscess Bruining et al. Inflamm Bowel Dis. 2008 Dec;14(12):1701-6.
The problem of penetrating disease Clinical suspicion of a fistula or abscess % of Patien nts 35 30 25 20 15 10 5 0 No Suspicion Remote Suspicion Possible Definite Booya F et al. Abdom Imaging. 2008 Jun 13. [Epub ahead of print]
The potential benefit of imaging CTE-Related Changes Exclude Crohn s Disease Exclude Active Small Bowel Disease Add New Medication Remove Medication Surgical Referral Other Suspected Crohn s Disease (n=128) 69 (54%) 49 (38%) N/A 4 (3%) 6 (5%) 5(4%) 5 (4%) Established Crohn s Disease (n=145) 70 (48%) N/A 20 (14%) 21 (15%) 13 (9%) 5(3%) 11 (7%) 1. Bruining et al. Clinical Benefit of CT Enterography in Suspected or Established Crohn s 2. Disease: Impact on Patient Management and Physician Level of Confidence. 3. Gastroenterology 2008 Abstract
SONIC: Corticosteroid-Free Clinical Remission at Week 26 Proportion of Pa tients (% %) 100 80 60 40 20 0 p<0.001 p=0.009 p=0.022 56.8 44.4 30.6 52/170 75/169 96/169 AZA + placebo IFX + placebo IFX+ AZA Sandborn, WJ et al. ACG 2008.
SONIC: Corticosteroid-Free Clinical Remission at Week 26 by Baseline Endoscopy Status Prop portion of Patien ts (%) 100 80 60 40 20 0 p<0.001 p=0.003 p=0.117 30.4 50.5 61.3 p=0.927 p=0.372 p=0.688 40.7 33.3 40.0 p=0.003 p=0.139 21.4 38.2 p=0.074 57.1 35/115 50/99 68/111 11/27 12/36 12/30 6/28 16/28 13/34 Lesions (n=325) No Lesions (n=93) No Endoscopy or UTD* (n=90) AZA + placebo (n=170) IFX + placebo (n=169) IFX + AZA(n=169) *Unable to determine
SONIC: Corticosteroid-Free Clinical Remission at Week 26 by Baseline CRP 100 Proportio on of Pa atients (% %) 80 60 40 20 0 p=0.121 p<0.001 p=0.503 p=0.314 p=0.004 p=0.027 63.5 50.7 47.5 40.3 35.2 27.6 25/71 27/67 35/69 27/98 48/101 61/96 CRP < 0.8 mg/dl (n=207) CRP >= 0.8 mg/dl (n=295) AZA+ placebo IFX + placebo IFX + AZA
Corticosteroid-Free Clinical Remission at Week 26 Patients with CRP 0.8 mg/dl and Lesions on Baseline Endoscopy (n=204) Pro oportion of patie ents (%) 100 80 60 40 20 28.0 p<0.001 p<0.001001 56.9 p=0.169 68.8 0 21/75 37/65 44/64 AZA+ placebo IFX + placebo IFX + AZA Sandborn, WJ et al. ACG 2008.
Conclusions Should we alter the natural history of IBD? Yes Can we alter the natural history? Probably, but will likely require aggressive intervention early in the course Symptoms (CDAI) correlate poorly with endoscopy (CDEIS) and biomarkers Most patients with Crohn s disease experience a chronic progressive destructive course of disease, and morbidity is due to a combination of the disease itself as well as post-surgical changes
Conclusions Preliminary data indicate that CTE and MRE can demonstrate bowel remodeling with anti-tnf therapy, are complementary to colonoscopy, and frequently change patient management decisions Clinical i l trials and clinical i l practice may evolve to early use of anti-tnf agents alone or in combination with azathioprine and use of structural endpoints with endoscopic and radiographic endpoints