Oxford Inflammatory Bowel Disease MasterClass. What is early IBD? Prof. Laurent Peyrin-Biroulet Head, IBD Unit Nancy University Hospital, France

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1 Oxford Inflammatory Bowel Disease MasterClass What is early IBD? Prof. Laurent Peyrin-Biroulet Head, IBD Unit Nancy University Hospital, France

2 Disclosures Consulting and/or lecture fees from Merck, Abbott, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Shire, Therakos, Pharmacosmos, Pilège, BMS, UCBpharma, Hospira, Takeda.

3 Experience from RA Data at the molecular level in mice and human IBD Clinical efficacy of drugs according to disease duration Defining Early Crohn s disease What about UC?

4 Experience from RA

5 Disease-modifying antirheumatic drugs (DMARDs) Immune response develops Pathological inflammatory response Joint inflammation Lymphomas Infections Cardiovascular complications Osteoporosis Time Genetic and environmental factors Symptoms Subclinical inflammation Criteria for diagnosis of rheumatoid arthritis fulfilled Joint destruction Klareskog et al. Lancet 2009 Introduction of DMARDs

6 Change in median sharp score Joint damage as a major therapeutic goal: The example of rheumatoid arthritis Modified sharp scoring method Schema of joint evaluation Joint narrowing Erosions Delayed DMARD* Early DMARD *DMARD = disease-modifying anti-rheumatic drug JSN: 42 joints evaluated 44 joints evaluated 0 = normal Erosions: = 1 discrete 1 = focal or doubtful = 1 4 depending on 2 = >50% of original space left surface area involved 3 = <50% of jt space or subluxation = 5 complete collapse 4 = bony ankylosis or luxation van der Heijde, MFM Baillier s Clin Rheum 1996;10: Lard LR, et al. Am J Med 2001;111:446 51

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8 Data at the molecular level in mice and human IBD

9 Neutralising IL-12 ameliorates the early, but not the late, phase of colitis in IL-10 / mice * p<0.001 Spencer DM et al. Gastroenterology 2002;122:94 105

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11 Differential expression of mucosal T-cell clone IL12Rβ2 chain in early and late Crohn s disease Normal Infectious colitis * Early Crohn s disease **, *** Late Crohn s disease IL12Rβ2/GAPDH * p=0.03 versus normal ** p<0.05 versus normal *** p<0.05 versus late Crohn s disease Kugathasan S. et al. Gut 2007;56:

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13 Early Crohn s disease Late Crohn s disease APC APC IFN-γ IL-12 T Cell Foxp3 - CD4 + IL-1 IL-6 IL-23 IFN- γ IL-12 T Cell Foxp3 - CD4 + IL-1 IL-6 IL-23 Th1 Th17 Th1 Th2 Th17 IFN- γ Ltα TNF-α IL-17A IL-17F IL-22 TNF-α IFN- γ Ltα TNF-α IL-4 IL-5 IL-13 IL-17A IL-17F IL-22 TNF-α Courtesy of Julian Panès, Hospital Clinic Barcelona, Spain

14 Clinical efficacy of drugs according to disease duration Defining Early Crohn s disease What about UC?

15 % patients % patients Mean CDAI Mean CDAI during follow-up (as observed): The AZTEC trial P= 0.07 P< Sustained remission up to month 18 LOCF p= ,7 57,1 Visit number NRI p= ,1 38,1 Panes et al. Gastroenterology AZA Placebo 0

16 Anti-TNF therapy: earlier is better Disease duration The example of adalimumab Placebo N=170 ADA 40 eow N=177 ADA 40 ew N=157 <2 years 4/23 (17) 13/25 (52) * 7/14 (50) 2 to <5 years 4/36 (11) 9/26 (35) * 16/31 (52)* 5 years 12/111 (11) 40/121 (33) * 42/112 (38)* * p<0.05 vs placebo Disease duration Week 56 Remission Week 12 Mucosal healing ADA <2 years 4/9 (44) 2 5 years 4/10 (40) 5 years 9/43 (21) Data are n/n (%) Schreiber S, et al. Gastroenterol 2007;132 (Suppl 2): A147; Sandborn W, et al. Gastroenterol 2010;138 (Suppl 1): S1031 Schreiber et al. DDW 2007 Sandborn et al. DDW 2010

17 Impact of disease duration on deep remission rates in CD: Lessons from the SONIC trial Peyrin-Biroulet et al. Gut 2013

18 Bowel resection (%) Has early intervention really failed? 14% 12% 10% 8% 6% 4% 2% p=0.58 0% Early combined immunosuppression Conventional management D Haens et al. Lancet 2008; 371:660 7

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21 Defining Early Crohn s disease What about UC?

22 Defining early Crohn s disease: where we were in 2010 Peyrin-Biroulet L, et al. Gut 2010;59:141 7

23 Peyrin-Biroulet L, et al. Gut 2010;59:141 7

24 Defining early CD: an international consensus in 2011 Publication of paper in Gut (2010) Launch meeting of core group (February 2011) Agreed process for developing the definition Review of draft definition published in Gut Group proposed amendments to draft definition Group expanded to provide international membership Interim definition produced Feedback consolidated and revised definition proposed by Peyrin-Biroulet International consensus meeting (Paris, June 2011) Publication of manuscript in 2012 Peyrin-Biroulet L, et al. Am J Gastroenterol 2012

25 International consensus-derived definition of early CD for disease modification trials Definition of early CD Disease duration <18 months No previous use of disease-modifying agents (immunomodulators, biologics) Covariates Bowel damage Corticosteroids use Disease location Objective signs of inflammation Clinical symptoms Peyrin-Biroulet L, et al. Am J Gastroenterol 2012

26 What about UC?

27 Is UC a progressive and destructive disease? Torres J et al. Gut 2011;Jul 11:Epub ahead of print

28 Conclusions The concept of early treatment to avoid later complications (disability and bowel damage) and the need for surgery in CD aligned to RA treatments is gaining momentum Subgroup analyses from placebo-controlled trials with anti-tnf-α agents have also suggested that patients with early CD may experience greater efficacy than patients with established disease. Recently, an international consensus has proposed The Paris Definition for Early Crohn s Disease and defined a patient with the following criteria including a patient with a diagnosis of CD less than 18 months and no previous use of DMAIDs. If accurate, then these criteria may assist in defining patients who may benefit for early aggressive treatment initiation, thus maximizing benefit and reducing disability and subsequent bowel damage. Whether the concept of early disease characteristics is valid for UC has yet to be determined.