Oxford Inflammatory Bowel Disease MasterClass What is “early IBD”? Prof. Laurent Peyrin-Biroulet Head, IBD Unit Nancy University Hospital, France
Disclosures Consulting and/or lecture fees from Merck, Abbott, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Shire, Therakos, Pharmacosmos, Pilège, BMS, UCB- pharma, Hospira, Takeda.
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?
Experience from RA
Disease-modifying antirheumatic drugs (DMARDs) Immune response develops Pathological inflammatory response Joint inflammation Lymphomas Cardiovascular Infections complications Osteoporosis Time Genetic and Symptoms Joint destruction environmental factors Subclinical Criteria for diagnosis of inflammation rheumatoid arthritis fulfilled Introduction of DMARDs Klareskog et al. Lancet 2009
Joint damage as a major therapeutic goal: The example of rheumatoid arthritis Delayed DMARD* Early DMARD Modified sharp scoring method *DMARD = disease-modifying anti-rheumatic drug Schema of joint evaluation 14 Joint narrowing Erosions Change in median sharp score 12 10 8 6 42 joints evaluated 44 joints evaluated JSN: 0 = normal Erosions: = 1 – discrete 4 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 2 4 = bony ankylosis or luxation 6 18 24 12 van der Heijde, MFM Baillier’s Clin Rheum 1996;10:435 -53 Lard LR, et al. Am J Med 2001;111:446 – 51
Data at the molecular level in mice and human IBD
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
Differential expression of mucosal T-cell clone IL12R β2 chain in early and late Crohn‟s disease Normal Infectious colitis * ** , *** Early Crohn’s disease Late Crohn’s disease 0 0.2 0.4 0.6 0.8 IL12R β 2/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;56:1696 – 1705
Late Crohn’s disease Early Crohn’s disease APC APC T Cell Foxp3 - CD4 + T Cell Foxp3 - CD4 + IL-1 IL-1 IFN- γ IFN- γ IL-6 IL-6 IL-12 IL-12 IL-23 IL-23 Th17 Th1 Th17 Th1 Th2 IL-17A IL-17A IL-4 IFN- γ IFN- γ IL-17F IL-17F IL-5 Lt α Lt α IL-22 IL-22 IL-13 TNF- α TNF- α TNF- α TNF- α Courtesy of Julian Panès, Hospital Clinic Barcelona, Spain
Clinical efficacy of drugs according to disease duration Defining Early Crohn’s disease What about UC?
Mean CDAI during follow-up (as observed): The AZTEC trial 150 125 Mean CDAI 100 75 P= 0.07 50 P< 0.01 25 0 2 3 4 5 6 7 8 9 10 11 12 13 Visit number Sustained remission up to month 18 100 100 NRI LOCF p= 0.5 p= 0.2 75 75 67,7 % patients % patients 57,1 50 50 44,1 38,1 25 25 0 0 AZA Placebo Panes et al. Gastroenterology 2013
Anti-TNF therapy: earlier is better The example of adalimumab Week 56 Remission Disease Placebo ADA 40 eow ADA 40 ew duration N=170 N=177 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 Schreiber et al. DDW 2007 Week 12 Mucosal healing Disease duration ADA <2 years 4/9 (44) 2 – 5 years 4/10 (40) ≥5 years 9/43 (21) Sandborn et al. DDW 2010 Data are n/N (%) Schreiber S, et al. Gastroenterol 2007;132 (Suppl 2): A147; Sandborn W, et al. Gastroenterol 2010;138 (Suppl 1): S1031
Impact of disease duration on deep remission rates in CD: Lessons from the SONIC trial Peyrin-Biroulet et al. Gut 2013
Has early intervention really failed? 14% p =0.58 12% Bowel resection (%) 10% 8% 6% 4% 2% 0% Early combined Conventional immunosuppression management D’Haens et al. Lancet 2008; 371:660 – 7
Defining Early Crohn’s disease What about UC?
Defining early Crohn’s disease: where we were in 2010 Peyrin-Biroulet L, et al. Gut 2010;59:141 – 7
Peyrin-Biroulet L, et al. Gut 2010;59:141 – 7
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
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
What about UC?
Is UC a progressive and destructive disease? Torres J et al. Gut 2011;Jul 11:Epub ahead of print
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.
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