What is early IBD? Prof. Laurent Peyrin-Biroulet Head, IBD Unit - - PowerPoint PPT Presentation

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)

Introduction of DMARDs

Klareskog et al. Lancet 2009

Pathological inflammatory response Immune response develops

Joint inflammation

Time

Infections Lymphomas Osteoporosis Cardiovascular complications Joint destruction Genetic and environmental factors Subclinical inflammation Criteria for diagnosis of rheumatoid arthritis fulfilled Symptoms

van der Heijde, MFM Baillier’s Clin Rheum 1996;10:435-53

Modified sharp scoring method

Schema of joint evaluation

Joint narrowing

42 joints evaluated

Erosions

44 joints evaluated

JSN: 0 = normal 1 = focal or doubtful 2 = >50% of original space left 3 = <50% of jt space or subluxation 4 = bony ankylosis or luxation Erosions: = 1 – discrete = 1 – 4 depending on surface area involved = 5 – complete collapse

Lard LR, et al. Am J Med 2001;111:446–51

Delayed DMARD* 2 4 6 8 10 12 14 6 12 18 24

Change in median sharp score

Early DMARD

*DMARD = disease-modifying anti-rheumatic drug

Joint damage as a major therapeutic goal: The example of rheumatoid arthritis

 Data at the molecular level in mice and human IBD

Spencer DM et al. Gastroenterology 2002;122:94–105

Neutralising IL-12 ameliorates the early, but not the late, phase of colitis in IL-10–/– mice

* p<0.001

Differential expression of mucosal T-cell clone IL12Rβ2 chain in early and late Crohn‟s disease

Kugathasan S. et al. Gut 2007;56:1696–1705

Late Crohn’s disease Early Crohn’s disease Infectious colitis Normal 0.2 0.4 0.6 0.8

IL12Rβ2/GAPDH

* **, ***

* p=0.03 versus normal ** p<0.05 versus normal *** p<0.05 versus late Crohn’s disease

Late Crohn’s disease

APC T Cell Foxp3- CD4+

IFN- γ IL-12 IL-1 IL-6 IL-23

Th1 Th17

IFN- γ Ltα TNF-α IL-17A IL-17F IL-22 TNF-α

Th2

IL-4 IL-5 IL-13

APC T Cell Foxp3- CD4+

IFN-γ IL-12 IL-1 IL-6 IL-23

Th1 Th17

IFN- γ Ltα TNF-α IL-17A IL-17F IL-22 TNF-α

Early Crohn’s disease

Courtesy of Julian Panès, Hospital Clinic Barcelona, Spain

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

AZA Placebo

Sustained remission up to month 18

NRI

p= 0.5

25 50 75 100

% patients LOCF

p= 0.2 67,7 57,1

25 50 75 100

% patients

44,1 38,1

25 50 75 100 125 150

2 3 4 5 6 7 8 9 10 11 12 13

P< 0.01

Visit number Mean CDAI

Mean CDAI during follow-up (as observed): The AZTEC trial

P= 0.07

Panes et al. Gastroenterology 2013

Anti-TNF therapy: earlier is better

Schreiber et al. DDW 2007

The example of adalimumab

Disease duration 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

Sandborn et al. DDW 2010

Disease duration ADA <2 years 4/9 (44) 2–5 years 4/10 (40) ≥5 years 9/43 (21)

Week 12 Mucosal healing

Data are n/N (%) Schreiber S, et al. Gastroenterol 2007;132 (Suppl 2): A147; Sandborn W, et al. Gastroenterol 2010;138 (Suppl 1): S1031

Week 56 Remission

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?

D’Haens et al. Lancet 2008; 371:660–7

0% 2% 4% 6% 8% 10% 12% 14% p=0.58

Early combined immunosuppression Conventional management Bowel resection (%)

 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

International consensus meeting (Paris, June 2011) Interim definition produced Feedback consolidated and revised definition proposed by Peyrin-Biroulet Publication of paper in Gut (2010) Launch meeting of core group (February 2011) Agreed process for developing the definition Publication of manuscript in 2012 Review of draft definition published in Gut Group proposed amendments to draft definition Group expanded to provide international membership

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

• 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.

Conclusions