Jean-Fr d ric COLOMBEL

1. 12/07/2012

2. Anti-TNF et rectocolite hémorragique  Jean-Frédéric Colombel CHU Lille

3. Histoire naturelle de la RCH Ulcerative colitis (UC) is a chronic inflammatory disease that commonly exhibits a cyclical disease course. A population-based study in Copenhagen County, Copenhagen, aimed to assess UC disease course on a short- and long-term basis. A total of 11611 UC patients were followed from diagnosis up to 25 years after diagnosis. As many as 90% of these patients with UC experienced intermittent periods of active disease, despite receiving maintenance pharmacologic therapy. Maintenance therapy included 5-ASAs and steroids to treat flares.1 This graph shows the 5-year disease course, beginning 3 years after diagnosis, in 600 patients with UC receiving 5-aminosalicylates (5-ASAs) for maintenance therapy and steroids for flares. Each year, 25% of patients were in remission, 57% had intermittently active disease, and 18% had active disease. Of the 57% of patients with cyclical relapses and remission, 28% had ?3 years between relapses, and 29% had <3 years between relapses during this time period.1 1. Langholz E, Munkholm P, Davidsen M, Binder V. Course of ulcerative colitis: analysis of changes in disease activity over years. Gastroenterology. 1994;107:3-11. Reprinted with permission from the American Gastroenterological Association.Ulcerative colitis (UC) is a chronic inflammatory disease that commonly exhibits a cyclical disease course. A population-based study in Copenhagen County, Copenhagen, aimed to assess UC disease course on a short- and long-term basis. A total of 11611 UC patients were followed from diagnosis up to 25 years after diagnosis. As many as 90% of these patients with UC experienced intermittent periods of active disease, despite receiving maintenance pharmacologic therapy. Maintenance therapy included 5-ASAs and steroids to treat flares.1 This graph shows the 5-year disease course, beginning 3 years after diagnosis, in 600 patients with UC receiving 5-aminosalicylates (5-ASAs) for maintenance therapy and steroids for flares. Each year, 25% of patients were in remission, 57% had intermittently active disease, and 18% had active disease. Of the 57% of patients with cyclical relapses and remission, 28% had ?3 years between relapses, and 29% had <3 years between relapses during this time period.1 1. Langholz E, Munkholm P, Davidsen M, Binder V. Course of ulcerative colitis: analysis of changes in disease activity over years. Gastroenterology. 1994;107:3-11. Reprinted with permission from the American Gastroenterological Association.

4. Approche actuelle du traitement de la RCH Current “Step-Up” Treatment Approach Historically, a step-up approach has been taken to the treatment of Crohn’s disease (CD). Antibiotics and aminosalicylates are used initially to control mild disease symptoms. Corticosteroids are introduced to treat moderate-to-severe disease. Immunosuppressants, eg, azathioprine (AZA) or 6-mercaptopurine (6-MP), may be given to improve response to or allow withdrawal of steroids. Surgery and bowel rest, considered options of last resort, are generally reserved for patients who are unresponsive to corticosteroids. This traditional approach may achieve some of the stated treatment goals, but long-term maintenance of disease control remains a challenge.Current “Step-Up” Treatment Approach Historically, a step-up approach has been taken to the treatment of Crohn’s disease (CD). Antibiotics and aminosalicylates are used initially to control mild disease symptoms. Corticosteroids are introduced to treat moderate-to-severe disease. Immunosuppressants, eg, azathioprine (AZA) or 6-mercaptopurine (6-MP), may be given to improve response to or allow withdrawal of steroids. Surgery and bowel rest, considered options of last resort, are generally reserved for patients who are unresponsive to corticosteroids. This traditional approach may achieve some of the stated treatment goals, but long-term maintenance of disease control remains a challenge.

6. L’infliximab dans la RCH :Quelles sont les questions importantes ? Quelle est l’efficacité du traitement en terme de : Induction et maintien d’une réponse et d’une rémission ? Amélioration de la Qualité de vie ? Cicatrisation endoscopique ? Sevrage en corticoides ? Réduction du risque de colectomie ? Quels sont les effets secondaires ? Quelles sont les indications ?

7. L’infliximab dans la RCH : essais randomiséspré-2005

9. Malades 364 malades dans chaque étude (ACT1 et ACT2) Malades avec RCH active : Mayo score de 6 à 12 points Sous-score endoscopique =2 Traitements : Traitement concomitant par (= 1) : Corticoides, azathioprine/6-MP, ou aminosalicylés (ACT 2) Antécédents d’échec ou d’intolérance à (= 1) : Corticoides, azathioprine/6-MP, ou aminosalicylés (ACT 2) 364 patients with active colitis were enrolled at 55 sites. The inclusion criteria included: 1. Evidence of moderate to severe disease, indicated by a Mayo score of 6 to 12 points, with an endoscopic subscore of at least 2. The Mayo score is an assessment of ulcerative colitis activity, the total Mayo score ranging from 0 to 12 points, higher scores indicating more severe disease. The Mayo score is a composite of four measurements including stool frequency, rectal bleeding, findings of flexible proctosigmoidoscopy, and physician's global assessment . (Schroeder KW et al. N Engl J Med 1987;317:1625-9) 2. AND either concurrent treatment with corticosteroids, azathioprine, 6-MP, or aminosalicylates OR failure to tolerate or respond to at least one of the aforementioned therapies. The difference between the patient population of ACT 1 and ACT 2 lies in the broader patient base in ACT 2, as it allowed for the inclusion of patients who were also being treated with aminosalicylates or had failed to respond or tolerate such treatment. 364 patients with active colitis were enrolled at 55 sites. The inclusion criteria included: 1. Evidence of moderate to severe disease, indicated by a Mayo score of 6 to 12 points, with an endoscopic subscore of at least 2. The Mayo score is an assessment of ulcerative colitis activity, the total Mayo score ranging from 0 to 12 points, higher scores indicating more severe disease. The Mayo score is a composite of four measurements including stool frequency, rectal bleeding, findings of flexible proctosigmoidoscopy, and physician's global assessment . (Schroeder KW et al. N Engl J Med 1987;317:1625-9) 2. AND either concurrent treatment with corticosteroids, azathioprine, 6-MP, or aminosalicylates OR failure to tolerate or respond to at least one of the aforementioned therapies. The difference between the patient population of ACT 1 and ACT 2 lies in the broader patient base in ACT 2, as it allowed for the inclusion of patients who were also being treated with aminosalicylates or had failed to respond or tolerate such treatment.

10. Fréquence des selles 0 (normal) à 3 (5 ou plus au delà du n.habituel) Saignement rectal 0 (absent) à 3 (évacuation de sang pur) Rectosigmoidoscopie 0 (normal) à 3 (anomalies sévères) Appréciation globale par le médecin 0 (normal) à 3 (maladie sévère) The individual components of the Mayo Score are assigned scores of 0 through 3, with worsening disease represented by higher scores: Stool frequency 0 (normal) to 3 (5 or more over normal) Rectal bleeding 0 (no blood) to 3 (blood alone passed) Findings of flexible sigmoidoscopy 0 (normal) to 3 (severe active disease) Physician’s global assessment 0 (normal) to 3 (severe disease) The total Mayo Score ranges from 0-12 points Clinical remission: =2 points with no individual subscore > 1 Mildly active disease: 3-5 points Moderately active disease: 6-10 points Severely active disease: 11-12 points The individual components of the Mayo Score are assigned scores of 0 through 3, with worsening disease represented by higher scores: Stool frequency 0 (normal) to 3 (5 or more over normal) Rectal bleeding 0 (no blood) to 3 (blood alone passed) Findings of flexible sigmoidoscopy 0 (normal) to 3 (severe active disease) Physician’s global assessment 0 (normal) to 3 (severe disease) The total Mayo Score ranges from 0-12 points Clinical remission: =2 points with no individual subscore > 1 Mildly active disease: 3-5 points Moderately active disease: 6-10 points Severely active disease: 11-12 points

11. Sous-score endoscopique du score Mayo These photos correspond to the Mayo Endoscopy subscores: 0=Normal or inactive disease 1=Mild disease (erythema, decreased vascular pattern, mild friability) 2=Moderate disease (marked erythema, absent vascular pattern, friability, erosions) 3=Severe disease (spontaneous bleeding, ulceration)These photos correspond to the Mayo Endoscopy subscores: 0=Normal or inactive disease 1=Mild disease (erythema, decreased vascular pattern, mild friability) 2=Moderate disease (marked erythema, absent vascular pattern, friability, erosions) 3=Severe disease (spontaneous bleeding, ulceration)

12. All patients were randomized into three treatment arms of placebo, 5 mg/kg infliximab, or 10 mg/kg infliximab in a 1:1:1 ratio. They received infusions at Week 0, 2, and 6, and then every 8 weeks thereafter through Week 46 for a total of eight infusions. The primary endpoint was clinical response measured at Week 8. The major secondary endpoints were measured at Week 30, followed by the Final evaluation at Week 54.All patients were randomized into three treatment arms of placebo, 5 mg/kg infliximab, or 10 mg/kg infliximab in a 1:1:1 ratio. They received infusions at Week 0, 2, and 6, and then every 8 weeks thereafter through Week 46 for a total of eight infusions. The primary endpoint was clinical response measured at Week 8. The major secondary endpoints were measured at Week 30, followed by the Final evaluation at Week 54.

13. All patients were randomized into three treatment arms of placebo, 5 mg/kg infliximab, or 10 mg/kg infliximab in a 1:1:1 ratio. They received infusions at Week 0, 2, and 6, and then every 8 weeks thereafter through Week 46 for a total of eight infusions. The primary endpoint was clinical response measured at Week 8. The major secondary endpoints were measured at Week 30, followed by the Final evaluation at Week 54.All patients were randomized into three treatment arms of placebo, 5 mg/kg infliximab, or 10 mg/kg infliximab in a 1:1:1 ratio. They received infusions at Week 0, 2, and 6, and then every 8 weeks thereafter through Week 46 for a total of eight infusions. The primary endpoint was clinical response measured at Week 8. The major secondary endpoints were measured at Week 30, followed by the Final evaluation at Week 54.

14. Définition des critères Réponse clinique Diminution du score Mayo =30% & =3 points et baisse du sous-score de saignement =1 ou sous-score de 0 ou 1 Rémission clinique Score Mayo =2 points, sans sous-score >1 Cicatrisation endoscopique Sous-score endoscopique de 0 ou 1 The primary endpoint of clinical response measured at Week 8 was defined as: A decrease in the Mayo score by at least 30% and at least 3 points, and A decrease in the rectal bleeding subscore of at least 1, or a rectal bleeding subscore of 0 or 1. The major secondary endpoints measured at Week 8 were defined as: The achievement of clinical remission denoted by a Mayo score of less than or equal to 2 points with no individual subscore greater than 1 The major secondary endpoints measured at Week 30 were defined as: The achievement of clinical remission denoted by a Mayo score of less than or equal to 2 points with no individual subscore greater than 1. The achievement of mucosal healing defined as an endoscopy subscore of 0 or 1.The primary endpoint of clinical response measured at Week 8 was defined as: A decrease in the Mayo score by at least 30% and at least 3 points, and A decrease in the rectal bleeding subscore of at least 1, or a rectal bleeding subscore of 0 or 1. The major secondary endpoints measured at Week 8 were defined as: The achievement of clinical remission denoted by a Mayo score of less than or equal to 2 points with no individual subscore greater than 1 The major secondary endpoints measured at Week 30 were defined as: The achievement of clinical remission denoted by a Mayo score of less than or equal to 2 points with no individual subscore greater than 1. The achievement of mucosal healing defined as an endoscopy subscore of 0 or 1.

15. Caractéristiques des malades The median disease duration of ulcerative colitis for all 364 patients was 4.7 years. The median age was 40 years old. The percent of patients refractory to corticosteroids was 31% The median CRP score was 8 mg/L which was slightly higher than the normal which is usually considered to be approximately 6 mg/L. The median Mayo score was 8. The percent of patients with extensive disease (e.g. pancolitis) was about half, at 46% of the patients.The median disease duration of ulcerative colitis for all 364 patients was 4.7 years. The median age was 40 years old. The percent of patients refractory to corticosteroids was 31% The median CRP score was 8 mg/L which was slightly higher than the normal which is usually considered to be approximately 6 mg/L. The median Mayo score was 8. The percent of patients with extensive disease (e.g. pancolitis) was about half, at 46% of the patients.

16. Réponse clinique à la 8ème semaine

17. Rémission clinique à la 8ème semaine

18. Maintien de la réponse clinique aux 8ème, 30ème et 54ème (ACT1) semaines

19. Maintien de la rémission clinique aux 8ème, 30ème et 54ème (ACT1) semaines

20. Rémission clinique + sevrage en corticoides In patients who were receiving corticosteroids at baseline, there was a significant difference in the proportion of patients who both achieved clinical remission and were off corticosteroids at Week 30 in the patients infused with 5 mg/kg infliximab vs. those receiving placebo. 24% of the patients receiving 5 mg/kg vs. 10% of the placebo patients,a significant difference (p=0.030). There was a trend of a higher percentage of those patients receiving 10 mg/kg of infliximab vs. placebo 19% vs. 10% of the placebo patients.In patients who were receiving corticosteroids at baseline, there was a significant difference in the proportion of patients who both achieved clinical remission and were off corticosteroids at Week 30 in the patients infused with 5 mg/kg infliximab vs. those receiving placebo. 24% of the patients receiving 5 mg/kg vs. 10% of the placebo patients,a significant difference (p=0.030). There was a trend of a higher percentage of those patients receiving 10 mg/kg of infliximab vs. placebo 19% vs. 10% of the placebo patients.

21. Cicatrisation endoscopique à la 8ème semaine

23. Maintien de la cicatrisation endoscopique There was a significant difference in the proportion of patients who experienced mucosal healing (defined as an endoscopic subscore of 0 or 1) in the infliximab-treated patients compared to the placebo-treated patients at both Week 8 and Week 30. 60% of the patients receiving 5 mg/kg and 62% receiving 10 mg/kg achieved mucosal healing at Week 8 vs. 31% of the placebo patients. 46% of the patients receiving 5 mg/kg and 57% receiving 10 mg/kg achieved mucosal healing at Week 30 vs. 30% of the placebo patients. Data similar to that found in ACT 1.There was a significant difference in the proportion of patients who experienced mucosal healing (defined as an endoscopic subscore of 0 or 1) in the infliximab-treated patients compared to the placebo-treated patients at both Week 8 and Week 30. 60% of the patients receiving 5 mg/kg and 62% receiving 10 mg/kg achieved mucosal healing at Week 8 vs. 31% of the placebo patients. 46% of the patients receiving 5 mg/kg and 57% receiving 10 mg/kg achieved mucosal healing at Week 30 vs. 30% of the placebo patients. Data similar to that found in ACT 1.

24. Amélioration de la qualité de vie

25. Réduction du nombre d’hospitalisations

26. Effets secondaires

27. Effets secondaires notables Infections TB (1 malade dans le groupe 10 mg/kg group) Histoplasmose (1 malade décédé dans la phase d’extension groupe 5mg/kg) Pneumopathie (8 malades) 2 dans le groupe 5 mg/kg 6 dans le groupe 10 mg/kg Effets secondaires neurologiques Névrite optique (2 malades : groupe 5 mg/kg et 10mg/kg phase d’extension) Neuropathie multifocale (1 malade : groupe 5mg/kg)

28. Effets secondaires notables Immunogénicité ATI : 6% des malades Pas de relation ATI/réponse (faible effectif) Réactions immédiates à la perfusion ~~ 10% des malades Relation ATI et réactions à la perfusion Cancers/lymphomes Groupe placebo : cancer baso-cellulaire (1) Groupe 5mg/kg : cancer du rectum (1), cancer de la prostate (1), dysplasie colique (1) Groupe 10mg/kg : cancer baso-cellulaire (1)

32. Conclusions L’Infliximab est efficace dans le traitement de la rectocolite hémorragique Formes modérées à sévères Colites graves L’Infliximab est globalement bien toléré dans la rectocolite hémorragique Infliximab induces and maintains Clinical response Clinical remission Mucosal healing Infliximab enables patients with active ulcerative colitis to discontinue corticosteroids and achieve remission. Infliximab is generally well tolerated with a safety profile consistent with infliximab prescribing information.Infliximab induces and maintains Clinical response Clinical remission Mucosal healing Infliximab enables patients with active ulcerative colitis to discontinue corticosteroids and achieve remission. Infliximab is generally well tolerated with a safety profile consistent with infliximab prescribing information.

33. Approche actuelle du traitement de la RCH Current “Step-Up” Treatment Approach Historically, a step-up approach has been taken to the treatment of Crohn’s disease (CD). Antibiotics and aminosalicylates are used initially to control mild disease symptoms. Corticosteroids are introduced to treat moderate-to-severe disease. Immunosuppressants, eg, azathioprine (AZA) or 6-mercaptopurine (6-MP), may be given to improve response to or allow withdrawal of steroids. Surgery and bowel rest, considered options of last resort, are generally reserved for patients who are unresponsive to corticosteroids. This traditional approach may achieve some of the stated treatment goals, but long-term maintenance of disease control remains a challenge.Current “Step-Up” Treatment Approach Historically, a step-up approach has been taken to the treatment of Crohn’s disease (CD). Antibiotics and aminosalicylates are used initially to control mild disease symptoms. Corticosteroids are introduced to treat moderate-to-severe disease. Immunosuppressants, eg, azathioprine (AZA) or 6-mercaptopurine (6-MP), may be given to improve response to or allow withdrawal of steroids. Surgery and bowel rest, considered options of last resort, are generally reserved for patients who are unresponsive to corticosteroids. This traditional approach may achieve some of the stated treatment goals, but long-term maintenance of disease control remains a challenge.

34. AMM de l’Infliximab dans la RCH Remicade est indiqué dans le traitement de la rectocolite hémorragique active, modérée à sévère chez les patients qui n’ont pas répondu de manière adéquate à un traitement conventionnel comprenant les corticoïdes et l’azathioprine ou la 6-mercaptopurine, ou chez lesquels ce traitement est mal toléré ou contre-indiqué.

35. 12/07/2012