ECCO 2012 Congress - Barcelona

Barcelona

Spain

February 16th to 18th, 2012

Part 1

European Crohn´s and Colitis Organization ECCO 2012 Achieving Therapeutic Success in Pediatric and Adult Patients

Redefining Expectations of Infliximab Therapy in Ulcerative Colitis.

Importance of intestinal mucosal healing in ulcerative colitis Dr. Jean-Frédéric Colombel.

Professor of Hepato-Gastroenterology, Lille University, France. President of ECCO (European Crohn´s and Colitis Organization) The definition of intestinal mucosal healing in patients diagnosed with ulcerative colitis (UC) varies in the different clinical studies conducted up to present times. Several parameters are usually used, such as the Rachmilewitz Index (inferior to 2 and/ or inferior to 4), modified Sutherland Index (inferior to 1), the Baron Scale (inferior to 1), and the Mayo endoscopic subscore (value between 0 and 1). Mayo endoscopic subscore introduces four lesion grades characterizing ulcerative colitis1. Grade 0 defines the normal intestinal mucosa or inactive disease; grade

1 determines a mild disease (erythema, reduced vascular patter, and mild friability); grade 2 defines a moderate disease (marked erythema, absent vascular pattern, erosions, friabilty); and grade 3 consists of a severe disease with spontaneous bleeding and ulcers1. According to ECCO (European Crohn and Colitis Organization) clinical practice guidelines, UC remission is defined as a complete resolution of symptoms and endoscopic healing of the intestinal mucosa2.

Two clinical studies have been conducted to assess the efficacy of infliximab as induction and maintenance treatment in adult patients with ulcerative colitis (ACT I and ACT II – Active Ulcerative Colitis Trial)3. Both studies included 364 patients with a moderately to severely active ulcerative colitis, who,

apart from concomitant treatments, received intravenous placebo or infliximab (5 or 10 mg/kg) at week 0, 2, and 6, and then every eight weeks up to week 46 of ACT I trial or week 22 of ACT II trial. The primary objectives of both studies were to assess the clinical response in week 8 of the study. Patients of ACT trials had ulcerative colitis for more than three months confirmed by a biopsy at baseline, an active colitis confirmed by a score higher than or equal to 2 in the Mayo endoscopic subscore, and a score of 6-12 (inclusive) in the Mayo endoscopic subscore at baseline. Differences between both studies are based on the concomitant medication received by patients. ACT I trial patients could receive as concomitant medication oral corticosteroids, 6-mercaptopurine (6-MP), azathioprine (AZA); while ACT II trial patients could receive oral corticosteroids, 6-mercaptopurine, azathioprine and aminosalicylates (5-ASA)3.

Graphic 1

It was observed that, at week 8 of ACT I trial, 62% of patients treated with 5 mg/kg infliximab presented a score of 0-1 in the endoscopic scoring (intestinal mucosal healing), while 59% of patients treated with 10 mg/kg infliximab achieved such result, compared with 33.9% of patients treated with placebo. At week 30 of this study, 50.4% of patients treated with 5 mg/kg infliximab and 49.2% of patients that received 10 mg/kg infliximab remained within mucosal healing criteria, against the 24.8% of patients treated with placebo. In the follow-up period, at week 54 of the study, approximately the same percentage of patients of both active groups presented a score of 0-1 in the endoscopic scoring (45.5% of the group treated with 5 mg/kg infliximab and 46.7% of the group treated with 10 mg/kg infliximab, against 18.2% of the group that received placebo)3. See Graphic 1.

It was found that patients achieving an intestinal mucosal healing were more likely to experience corticosteroid-free symptomatic remission. At week 30, 62% of patients with a score of 0 at week 8 were corticosteroid-free, as well as the 46% who had a score of 1, 20% with a score of 2, and 10% with a score of 3 (p<0.0001). See Graphic 2.

In addition, 46%, 34%, 11% and 6.5% of patients, respectively, were in corticosteroid-free symptomatic remission (p<0.0001) with infliximab treatment.

A correlation between the low score at week 8 with infliximab and a reduced likelihood of colectomy at week 54 of follow-up (p=0.0004) were also observed.

This tendency was not observed in patients receiving placebo.

This study concluded that the grade of intestinal mucosal healing after eight weeks of therapy with infliximab was correlated with an improvement of clinical results, including the incidence of colectomy.

Short-term and long-term intestinal mucosal healing.

ACT I Trial Endoscopic Subscore of 0 or 1

100 Patients percentage (%)

A post hoc analysis of ACT I and II trials assessed the association between early improvement (based on endoscopy) and subsequent clinical results4.

Patients were categorized into four subgroups based on scores of the Mayo endoscopic subscore at week 8, 30 and 54 of the ACT I trail. Endoscopic subscores, risk of subsequent colectomy, symptoms, and the results of corticosteroids use were analyzed at week 8. Both in week 30 (ACT I and ACT II trials combined) and in week 54, the percentage of patients under corticosteroid-free symptomatic remission was assessed. In addition, in week 54, the cumulative incidence of colectomy (ACT I and ACT II trials combined) was assessed4.

80 62*

60

*p<0.001 59* 50.4*

40

33.9

45.5*

46.7*

24.8

20 0

49.2*

18.2 41/121 75/121 72/121

Week 8 Placebo

30/121 61/121 60/121

22/121 55/121 57/121

Week 30

Week 54

5 mg/kg Infliximab

10 mg/kg Infliximab

References: Rutgeerts P, Sandborn W, Feagan B, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Eng J Med. 2005, 353: 2462-2476.

Mucosal healing is correlated to a better long-term UC evolution. This was shown by a Norwegian cohort study5, in which a follow-up with basal endoscopy was carried out, at the year at 5 years, in 495 patients with intestinal inflammatory disease.

It was observed that patients presented a mucosal healing at the year of treatment, presented a significant reduction of the need of colectomy at 5 years (p=0.02 for UC), as well as a reduced inflammatory activity and use of corticosteroids.

Patients free of corticosteroids (%)

Graphic 2

In another study, it was shown that intestinal mucosal healing produced by the administration of infliximab in patients with ulcerative colitis rendered

a significant increase of colectomy-free survival6.

121 patients with refractory UC were included, of which 67% had an initial clinical response to infliximab. At an average of 33-month follow-up, 68% of initial patients responding to treatment had a clinical response, whereas 17% of the total of patients required colectomy. See Graphic 3.

In summary: â&#x20AC;˘ Intestinal mucosal healing is an essential therapeutic objective in patients diagnosed with ulcerative colitis.

ACT I and ACT II Trails.

Post-hoc Analysis: Patients achieving mucosal healing are more likely to continue free of corticosteroids Patients treated with Infliximab p<0.0001

100 80 62

60

46

40 20

20 10

0 Week 30 (ACT I and ACT II) Endoscopic Scoring 0 (n=120)

Endoscopic Scoring 1 (n=175)

Endoscopic Scoring 2 (n=114)

Endoscopic Scoring 3 (n=57)

Week 8 Endoscopic Scoring

Colectomy-free survival

Graphic 3

References: Colombel JF, Rutgeerts P, Reinisch W, et al. Early mucosal healing with Infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology. 2011, 141(4): 1194-1201.

Free-colectomy survival increase in patients with ulcerative colitis treated with infliximab 1 0.8 0.6 0.4 Breslow: p=0.024 Log Rank: p=0.027

0.2

Short-term intestinal mucosal healing

Present Absent

0 0

12

24 36 48 60 72 Follow-up from the first administration of infliximab (Months)

84 n=70

References: Ferrante M, et al. Long-term outcome after Infliximab for refractory ulcerative colitis. J Crohn´s Colitis.

2008, 2: 219-225.

• Therapy with infliximab allows patients to achieve the intestinal mucosal healing in ulcerative colitis.

• Intestinal mucosal healing with infliximab therapy renders significant clinical benefits for patients with ulcerative colitis, such as: – Colectomy rate reduction – Symptomatic remission rate improvement – Corticosteroid use reduction

Bibliography: 1. Schroeder K, Tremaine W, et al. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Eng J Med. 1987, 317: 1625-1629.

2. Stange EF, Travis SPL, Vermeire S, et al. European consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. J Crohn´s Colitis. 2008, 2:1-23.

3. Rutgeerts P, Sandborn W, Feagan B, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Eng J Med. 2005, 353: 2462-2476.

4. Colombel JF, Rutgeerts P, Reinisch W, et al. Early mucosal healing with Infliximab is associated with improved long-term clinical outcomes in ulcerative colitis.

Gastroenterology. 2011, 141(4): 1194-1201.

5. Froslie KF, Jahnsen J, Moum B, et al. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology. 2007, 133: 412422.

6 Ferrante M, et al. Long-term outcome after Infliximab for refractory ulcerative colitis. J Crohn´s Colitis. 2008, 2: 219225.

By virtue of the fact that this material has been intellectually and exclusively produced by its authors, the editors and sponsors are not responsible of scientific exactness, precision and validity of the information, opinions and conclusions expressed therein.

Material elaborated by Circle Press based on their attendance to the Symposium and exclusively directed to Physicians.

REM0412CCACT-GAS

Cover photo: Shutterstock

This promotional material has been revised and approved by the Regulatory Affairs and Medical Departments from Janssen. Venezuela: Janssen Cilag C.A. Rif. J-30042532-0.

Barcelona

Spain

February 16th to 18th, 2012

Part 2

European Crohn´s and Colitis Organization – ECCO 2012 Achieving Therapeutic Success in Pediatric and Adult Patients

Redefining Expectations of Infliximab Therapy in Ulcerative Colitis.

Early Intervention with a Satisfactory Therapy in Ulcerative Colitis Geert D´Haens, M.D. Academic Medical Center, Amsterdam University, Holland. Director of Imelda GI Clinical Research Centre. Imelda Hospital.

Current misunderstandings relative to ulcerative colitis (UC) include statements asserting that this disease is a “benign pathology”, that ulcerative colitis can be cured only by colectomy, that the administration of anti-TNF monoclonal antibodies is less effective in the treatment of ulcerative disease than in Crohn’s disease, and that the intestinal mucosal healing is not so important in ulcerative colitis1.

With respect to the natural course of ulcerative colitis, approximately half of patients experience clinical

remission at any moment of the disease evolution and 90% experience an intermittent course of the pathology2. Relapses of ulcerative colitis are unpredictable. After 10 years of disease diagnosis, colectomy rate is of approximately 24%. Between three and seven years from the disease diagnosis, 25% of patients with ulcerative diagnosis achieve disease remission, and 57% experience intermittent relapses2. In addition, relapse cumulative likelihood is of 90% after 25-year follow-up in patients with ulcerative colitis. It is worth to mention that the likelihood of patients to maintain work capabilities is of 92.8% after ten years of disease diagnosis2. The cumulative likelihood of colorectal cancer development in patients with ulcerative colitis increases with time, specially from ten years of disease diagnosis (2% at 10 years, 8% at 20 years, and 18% at 30 years

from ulcerative colitis diagnosis)3. It was observed that the global prevalence of colorectal cancer in any patient with ulcerative colitis is of approximately 3.7%. Colorectal cancer incidence rate is of 3 every 1.000 patients per year of disease duration3.

In relation to the statement asserting that ulcerative colitis can be “cured” by means of colectomy, it is known that 25% of patients who underwent surgery suffered obstructive complications, 50% of patients had colostomy bag infections, a bowel movement frequency of 6-8 times a day with a “normal colostomy bag”, and frequent night fecal incontinence1.

Another misunderstanding in UC is that anti-TNF antibodies are less effective in UC than in Crohn’s disease (CD). This is not true, because it can be evidenced in the results of ACT trials4 that clinical response with 5 mg/kg and 10 mg/kg infliximab as maintenance treatment was of about 50 % at week

8, 30, and 54 (see Graphic 1), similar to the evidence shown in the ACCENT I trial5, in which patients with CD received different maintenance doses of infliximab (see Graphic 2).

Intestinal mucosal healing after treatment with infliximab is essential for its correlation to an improvement of clinical results, including colectomy6. A study showed that patients with ulcerative colitis treated with infliximab had low values in the Mayo endoscopic score, and this is correlated to a reduction in the progression to colectomy during 54-week clinical follow-up (p=0.0004)6. In addition, patients treated with infliximab with low Mayo endoscopic scores had symptomatic improvement and a reduction of corticosteroids use in week 30 and 54 of the study (p<0.0001). In conclusion, the grade of intestinal mucosal healing after eight weeks of treatment with infliximab has been correlated to a clinical improvement, especially in colectomy rate6.

Graphic 1

Clinical response in patients with ulcerative colitis treated with infliximab vs. placebo

ACT Study 100

Patients (%)

80 62

60

59 50.4

40

33.9

49.2

45.5

46.7

24.8

20

18.2

0 Week 8 Placebo (n=121)

Week 30

Week 54

5 mg/kg Infliximab (n=121)

10 mg/kg Infliximab (n=122)

References: Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis.

N Eng J Med. 2005, 353: 2462-2476.

Graphic 2

Intestinal mucosal healing in patients with Crohn’s disease treated with infliximab

ACCENT Trial Patients showing endoscopic healing (%)

70 p=0.007

60

p=0.026

50 40

Single dose 53%

46% p=0.010 31%

30

5 mg/kg maintenance infliximab

20 10 0

Group of combined doses (5 mg/kg & 10 mg/kg maintenance infliximab)

7% 0/17

10/32

Week 10

1/11

24.8

8/15

10 mg/kg maintenance infliximab

Week 54

References: Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with Infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn´s disease. Gastrointest Endosc. 2006, 63: 433-442.6)

Predictive factors of disabling disease in patients with ulcerative colitis included young age at disease diagnosis, extended pathology (perianal disease, abdominal fistulas), disease severity, presence of gastro-duodenal or jejunal lesions, among others.

The possible consequences of the presence of these “poor prognosis” factors can be the dependence on corticosteroids, stenosis or intestinal obstruction, hospital admissions, surgeries, and death7-11. Two uncertain prognosis predictors are the need of corticosteroids and the absence of smoking habit12.

There was no scientific data comparing the therapeutic strategies based on the administration of infliximab and the monotherpay with azathioprine in patients with moderate to severe ulcerative colitis. In addition, there were limited data on azathioprine efficacy in these patients’ population.

And there were no data comparing monotherapy with infliximab against treatment with infliximab associated with azathioprin14, 15.

UC SUCCESS Trail assessed the efficacy and safety of associating infliximab and azathioprine compared to monotherapy with infliximab and azathioprine in patients with moderate to severe ulcerative colitis that did not properly respond to a therapy with corticosteroids16. This multicenter, double-blind, placebo-controlled trial lasted 16 weeks and included 231 patients with a diagnosis of

It was evidenced that 63% of patients treated with the combination of infliximab and azathioprine (49/78) achieved an intestinal mucosal healing, compared to 55% of patients treated with infliximab alone (42/77) and 37% of patients treated with azathioprine monotherapy (28/76). See Graphic 4.

In a sub-analysis of the study, it was observed that 56% of patients treated with the combination of infliximab and azathioprine (44/78) had a corticosteroid-free intestinal mucosal healing at week 16 of the study, compared to 52% of patients treated with infliximab alone (40/77) and 36% of patients treated with azathioprine alone (27/76)16.

In summary, the clinical UC SUCCESS Trial has proved that the treatment with infliximab associated with azathioprine was superior to induce corticosteroidfree remission in patients with moderate to severe ulcerative colitis. Treatment based on the administration of infliximab is superior to induce intestinal mucosal healing. No new events altering both drugs safety have been found16.

Graphic 3

Corticosteroid-free clinical remission at week 16 p=0.017

Patients (%)

80 p=0.032

60 p=0.813 40%

40 24%

22%

20 0

n=18

n=17

n=31

Azathioprine (n=76) Infliximab (n= 77) Azathioprine plus infliximab (n=78) References: Panaccione R, et al. Infliximab, Azathioprine or Infliximab + Azathioprine for treatment of moderate to severe ulcerative colitis: The UC SUCCESS trial. J Crohn´s Colitis. 2011, 5:S8. Abstract 13.

UC SUCCESS Trial

Graphic 4

Enrolled patients were randomly assigned to three therapeutic groups: a group treated with infliximab plus placebo (n=77), another group of patients treated with azathioprine plus placebo (n=76), and the third group of patients treated with infliximab associated with azathioprine (n=78). The primary objective was corticosteroid-free clinical remission at week 16 of the study. The secondary objective consisted in intestinal mucosal healing at week 16 of the study.

It was observed that 40% of patients treated with the combination of infliximab and azathioprine (31/78) presented a corticosteroid-free clinical remission, compared to 24% of patients treated with azathioprine alone (18/76) and 22% of patients treated with infliximab alone (17/77)16. See Graphic 3.

UC SUCCESS Trial

100

Intestinal mucosal healing at week 16 p=0.295

100 p=0.001

80 Patients (%)

moderate to severe ulcerative colitis (defined by a Mayo endoscopic score of 6 to 12), who had failed corticosteroids treatment16. It was necessary that patients had not undergone prior treatments with infliximab or other anti-TNFs, azathioprine / 6-mercaptopurine, or were free from azathioprine during the previous 3 months.

p=0.028

60

63% 55%

40

37%

20 0

n=28

n=42

n=49

Azathioprine (n=76) Infliximab (n= 77) Azathioprine plus infliximab (n=78) References: Panaccione R, et al. Infliximab, Azathioprine or Infliximab + Azathioprine for treatment of moderate to severe ulcerative colitis: The UC SUCCESS trial. J Crohn´s Colitis. 2011, 5:S8. Abstract 13.

In conclusion: • UC colitis severity should not be underestimated.

• There is excess mortality and poor life quality associated with surgery.

• Azathioprine in UC is only effective in 25% of patients.

• The combined use of infliximab is more recommended than in monotherapy.

• Early treatment with biologics fosters mucosal healing and improves clinical results of patients with UC.

Bibliography

REM0412CCACT-GAS

1. Ochsenkuhn T and D´Haens G. Current misunderstandings in the management of ulcerative colitis. Gut. 2011, 60(9): 1294-1299.

2. Langholz E, Munkholm P, Davidsen M, et al. Course of ulcerative colitis: analysis of changes in disease activity over years. Gastroenterology. 1994, 107(1): 3-11.

3. Eaden JA, Abrams KR, et al. The risk of colorrectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001, 48(4): 526535.

4. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Eng J Med. 2005, 353: 2462-2476.

5. Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with Infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn´s disease. Gastrointest Endosc.

2006, 63: 433-442.

6. Colombel JF, Rutgeerts P, Reinisch W, et al. Early mucosal healing with Infliximab is associated with improved long-term clinical outcomes in ulcerative colitis.

Gastroenterology. 2011, 141: 1194-1201.

7. Munkholm PL, Langhorz E, Davidsen M, et al. Intestinal cancer risk and mortality in patients with Crohn´s disease.

Gastroenterology. 1993, 105: 1716-1723.

8. Franchimont DP, Louis E, Croes F, et al. Clinical pattern of corticosteroid dependent Crohn´s disease. Eur J Gastro and Hepatol. 1998, 10: 821-5.

9. Lichtenstein GR, Olson A, Travers S, et al. Factors associated with the development of intestinal strictures or obstructions in patients with Crohn´s disease. Am J Gastroenterol. 2006, 101: 1030-1038.

10. Beaugerie L, Seksik P, Gendre JP, et al. Predictors of Crohn´s disease. Gastroenterology. 2006, 130(3): 650-6.

11. Louis E. Gastroenterology. 2007, 132: suppl 2: A-17.

12. Cosnes J, Gower-Rousseau C, et al. Epidemiology and natural history of Inflammatory Bowel Diseases.

Gastroenterology. 2011, 140(6): 1785-1794.

13. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine or combination therapy for Crohn´s disease. N

This promotional material has been revised and approved by the Regulatory Affairs and Medical Departments from Janssen.

Venezuela: Janssen Cilag C.A. Rif. J-30042532-0

Eng J Med. 2010, 362: 1383-1395.

14. Mantzaris GJ, Sfakianakis M, et al. A prospective randomized observer-blind 2-year trial of azathioprine monotherapy versus azathioprine and olsalazine for the maintenance of remission of steroid-dependent ulcerative colitis. Am J Gastroenterol. 2004, 99(6): 1122-1128.

15. Sood A, Midha V, et al. Long term results of use of azathioprine in patients with ulcerative colitis in India. World J Gastroenterol. 2006, 12(45): 7332-7336.

16. Panaccione R, et al. Infliximab, Azathioprine or Infliximab + Azathioprine for treatment of moderate to severe ulcerative colitis: The UC SUCCESS trial. J Crohn´s Colitis. 2011, 5:S8. Abstract 13.

By virtue of the fact that this material has been intellectually and exclusively produced by its authors, the editors and sponsors are not responsible of scientific exactness, precision and validity of the information, opinions and conclusions expressed therein.

Material elaborated by Circle Press based on their attendance to the Symposium and exclusively directed to Physicians.

Cover photo: Shutterstock

Barcelona

Spain

February 16th to 18th, 2012

Part 3

European Crohn´s and Colitis Organization ECCO 2012 Achieving Therapeutic Success in Pediatric and Adult Patients

Redefining Expectations of Infliximab Therapy in Ulcerative Colitis.

Biologic Therapy for Pediatric Patients with Ulcerative Colitis Anne M. Griffiths, M.D. Head of Gastroenterology Division, SickKids Hospital, Toronto University, Canada.

Professor of Pediatrics, Toronto University, Canada.

Associated Scientist of Genetics and Genome Biology.

Pathologies included in the so-called inflammatory bowel disease (ulcerative colitis and Crohnâ&#x20AC;&#x2122;s disease) are complex polygenic pathologies that constitute one of the major causes of morbidity in Europe and North America. The clinical onset of ulcerative colitis (UC) is different in the pediatric population and the adult population. Ulcerative colitis in children is more extended in 82% of the cases and generates proctitis, In a Canadian study, which included 99 hospitalized children diagnosed with severe ulcerative colitis, demographic and clinical characteristics were eva-

luated in this type of patients2. 49% of patients were 2 to 7-year-old males. In addition, 90% of patients presented extended ulcerative colitis and 49% had an early onset of the disease. It was observed that the hospital admission risk in children with ulcerative colitis was of 28%. It was also observed that children with this condition frequently experienced at least one exacerbation of the disease during its normal course.

Additionally, the response to intravenous corticosteroids is poor in this type of patients2.

Treatment of pediatric patients with a first onset of ulcerative colitis depends on its severity. Those patients hospitalized with an acute severe ulcerative colitis frequently receive intravenous corticosteroids (15%). Non-hospitalized patients with moderate to severe ulcerative colitis usually receive corticosteroids orally on an outpatient basis (20%), and nonhospitalized patients with mild ulcerative colitis are treated with aminosalicylic acid (30%).

A study assessed the efficacy of corticosteroid therapy in pediatric patients diagnosed with ulcerative colitis (n=62)3. As regards the immediate therapeutic response (one month), it was shown that 60% of patients treated with corticosteroids experienced clinical remission, 24% had a partial clinical response, and only 16% of patients did not present any therapeutic response. At one year of the beginning of corticosteroid therapy, 50% of patients had a prolonged response, 45% of patients were dependant on corticosteroids, and 5% were submitted to surgery3.

Percentage of patients with Graphic 1 therapeutic corticosteroid failure

A study evaluated the efficacy of thiopurines in children diagnosed with ulcerative colitis. In this prospective observational study, 394 patients with a recent diagnosis of ulcerative colitis under 16 years of age were included4. 50% of these patients were treated with thiopurines (n=197), 84% of these patients were concomitantly treated with corticosteroids and 60% with 5-aminosalicylates (5-ASA).

The primary objective of the study was to determine the inactive corticosteroid-free disease at the year following the beginning of treatment with thiopurines, without requiring rescue therapy (infliximab, calcineurin inhibitors, or colectomy). It was observed that 49% of patients had a corticosteroid-free remission and without requiring the administration of a rescue therapy. Corticosteroid-free remission rate at one year of thiopurine treatment was not affected, whether by early beginning of thiopurine therapy (less than three months) or a later therapy (longer than three months from diagnosis). In addition, it was also not affected by patientsâ&#x20AC;&#x2122; sex or age, or the administration of concomitant treatment with 5-aminosalicylates (5-ASA)4.

In conclusion, approximately 50% of children with ulcerative colitis beginning therapy with thiopurines without concomitant or previously administered biological treatments or 5-aminosalicylates had a corticosteroid-free remission at one year of treatment without requiring rescue therapy4.

30

Results in hospitalized children with acute severe ulcerative colitis 29% 1/37 1/1 37/128

20

10

0 Years 2006 - 2008

Calcineurin Inhibitors

Improved

33/37 Infliximab

Improved and medical discharge

3/37

8/33

Colectomy

Colectomy

25/33

Total short-term colectomy rate 11/128 (8.6%)

References: Turner D, Mack D, et al. Severe pediatric ulcerative colitis: a prospective multicenter study of outcomes and predictors of response. Gastroenterology. 2010, 138: 2282-2291.

The unmet needs in the treatment of pediatric patients diagnosed with ulcerative colitis include the disease being dependant on corticosteroids and the disease being refractory to corticosteroids therapy. A clinical study was conducted to assess the efficacy and safety of infliximab in pediatric patients with ulcerative colitis refractory to corticosteroids therapy (OSDI Study â&#x20AC;&#x201C; Outcomes in children hospitalized with Severe Colitis)5. This prospective multicenter study included 128 patients hospitalized due to severe ulcerative colitis. The clinical and laboratory data, as well as the Pediatric Ulcerative Colitis Activity Index (PUCAI), were collected during admission. Patients were followed during a year after medical discharge5.

29% of patients of this study failed intravenous corticosteroids therapy, and received therapy with cyclosporine (n=1), colectomy (n=3) or infliximab (n=33) within 10.5 +/- 6.4 days. Several predictors have been associated to the therapeutic intravenous corticosteroids failure, like is the case of the number of bowel movements, loss of blood volume, patientsâ&#x20AC;&#x2122; age and disease onset. Short-term colectomy rate was of 8.6% (11/128) and the long-term rate was of 19% at one year of medical discharge. It was observed that 25 of the 33 children with ulcerative colitis treated with infliximab responded satisfactorily5. See Graphic 1.

In conclusion, infliximab is an effective therapy in pediatric patients with ulcerative colitis refractory to corticosteroid therapy.

The Pediatric Ulcerative Colitis Activity Index (PUCAI) is a predictor of therapeutic failure to corticosteroids.

It is a valid instrument to measure ulcerative colitis activity in children and teenagers without the need of determining intestinal mucosa lesions by colonoscopy. This index assesses the disease impact by means of a score of several signs and symptoms present in patients: abdominal pain, rectal bleeding, consistency of bowel movement, number of bowel movements during one day and bowel movements at night. A score inferior to 10 in PUCAI determines ulcerative colitis remission; values between 10 and 30 reflect a mild activity of the disease; between 35 and 60, a moderate activity; and between 65 and 85, a severe activity of the pathology6, 7. PUCAI determined in day 3 of admission of a patient with a score higher than 45 predicts a therapeutic failure of intravenous corticosteroids (negative predictive value: 94%, positive predictive value: 43%, p<0.001)6. When determining PUCAI and obtaining a score higher than 70, a rescue therapy (positive predictive value: 100%, negative predictive value: 79%, p<0.001)6 should be implemented. The strict development of pediatric ulcerative colitis activity index represents a sensitive, highly credible, valid, and non-invasive index.

A Phase III clinical trial assessed the safety and efficacy of infliximab in pediatric patients with moderate to severe ulcerative colitis7. This randomized, multicenter study included a total of 60 6-to-17-year old outpatients, with moderately to severely active UC (Mayo

It was observed that 73.3% of patients treated with infliximab presented a clinical response to therapy (IC95%=62.1%-84.5%), 68.3% presented a healed intestinal mucosa, 40% presented a clinical remission, and 33.3% of patients treated with infliximab had a clinical remission measured through the pediatric ulcerative colitis activity index (PUCAI)7. See Graphic 2.

At week 30 of the study, it was observed that 40% of patients treated with 5 mg/kg infliximab every eight weeks experienced clinical remission of ulcerative colitis, compared to 19% of patients that received 5 mg/kg infliximab every twelve weeks. In addition, 38.1% of patients treated with infliximab every eight weeks had clinical remission at week 54 of the study, while only 18.2% of patients receiving the drug every twelve weeks had clinical remission7. See Graphic 3.

In relation to infliximab safety profile in this study, adverse events more frequently reported were infections (51%) and reactions during infusions (13%).

Among serious adverse events (23%), the most frequent were ulcerative colitis worsening (15%), infections (pneumonia), neutropenia and pancreatitis. It is worth to mention that no deaths, malign tumor onset, serious neurologic events, opportunistic infections or tuberculosis were evidenced in this study7. In conclusion, infliximab was effective and safe, inducing a therapeutic response at week 8 of the study in 73.3%

Graphic 2

These results are comparable to those achieved in ACT clinical trials conducted in adult patients with ulcerative colitis. At week 54 of the study, the double of patients had a clinical remission after eight-week treatment with infliximab, compared to twelve-week therapies. In pediatric clinical practice, it is necessary to synchronize therapy with anti-TNF antibodies in

Evaluation of clinical response, clinical remission and intestinal mucosal healing at eight weeks of treatment with infliximab in patients with ulcerative colitis 80

73.3

70

68.3 : Criterion for positive response

Patients (%)

60 50

40.0

40

33.3

30 20 10 8/41

44/60

0

17/51

24/60

Clinical response Clinical remission Clinical remission Intestinal mucosal measured by PUCAI healing References: Hyams J, Damaraju L, Blank M, et al. Induction and maintenance therapy with Infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol. 2011. Doi 10.161.

Clinical remission at weeks 30 and 54 of treatment with infliximab in patients with ulcerative colitis Infliximab every 8 weeks Infliximab every 12 weeks

Remission (PUCAI)

45 40

40.0

38.1

35 Patients (%)

The primary objective of the study was to determine the therapeutic response at week 8 of the study (reduction in the Mayo endoscopic score higher than or equal to 30% and higher than or equal to 3 points, and reduction in rectal bleeding subscores greater than 1 and in absolute subscores equal to or inferior to 1). Maintenance objectives included achieving a pediatric ulcerative colitis activity index (PUCAI) inferior to 10 points, defining clinical remission. All 60 patients included in this study were administered with 5 mg/kg infliximab at weeks 0.2 and 6. At week 8 of the study, patients experiencing a response were randomly assigned to two groups of treatment treated with 5 mg/kg infliximab every eight weeks (n=22) and another group treated with 5 mg/kg infliximab every twelve weeks (n=23). Both groups were assessed at week 54. Patients not experiencing a response to infliximab were discontinued from treatment7.

Outlined baseline characteristics of patients included in the study were an average of 14.5 years of age, 1.35 year-long disease, a Mayo endoscopic score of 8 points, a pediatric ulcerative colitis activity index (PUCAI) of 55 points and a extended disease of 76.7%. Among the medication used by patients, we can outline corticosteroids (61.7 %), azathioprine, methotrexate and 6-mercaptopurine (53.3%), and finally, aminosalicylates (53.3%)7.

of pediatric patients with moderately to severely active ulcerative colitis, who had not responded to conventional treatments. Global disease remission rate at week 54 of the study for all enrolled patients was of 28.6%, and a more effective remission rate was evidenced when administering infliximab every eight weeks..

Graphic 3

score of 6 to 12) with an endoscopic Mayo subscore of >2 at 2 weeks prior to inclusion, and with current failure or failure history or intolerance to 6 mercaptopurine, azathioprine, corticoids and/or 5-ASA.

30 25 20

p=NS 19.0

p=NS

8/20 4/21

8/21 4/22

Week 30

Week 54

18.2

15 10 5 0

References: Hyams J, Damaraju L, Blank M, et al. Induction and maintenance therapy with Infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol. 2011. Doi 10.161.

pediatric patients with ulcerative colitis. Indications of therapy with anti-TNF antibodies include acute severe ulcerative colitis refractory to steroids (second-line treatment), ulcerative colitis dependant on steroids despite prior optimized use of aminosalicylates (5-ASA) and thiopurines, ulcerative colitis that responds to steroids but depends on these drugs (alternative to thiopurines), and outpatients with poor response to oral corticosteroids.

Bibliography: 1. Van Limbergen J, Russell RK, Drummond HE, et al.

Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology. 2008, 135(4): 1114-1122.

2. Turner D, Walsh CM, Benchimol EI, et al. Severe pediatric ulcerative colitis: incidence, outcomes and optimal timing for second-line therapy. Gut. 2008, 57: 331-338.

3. Hyams J. Clin Gastro Hepatol. 2008.

4. Hyams J, Lerer T, Mack D, et al. Outcome following thiopurine use in children with ulcerative colitis: a prospective multicenter registry study. Am J Gastroenterol.

2011, 106(5): 981-987.

5. Turner D, Mack D, et al. Severe pediatric ulcerative colitis: a prospective multicenter study of outcomes and predictors of response. Gastroenterology. 2010, 138: 2282-2291.

6. Turner D, Otley AR, Mack D, et al. Development, validation and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology. 2007, 133: 423-432.

7. Hyams J, Damaraju L, Blank M, et al. Induction and maintenance therapy with Infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol. 2011. Doi 10.161.

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