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European Crohn´s and Colitis Organization - ECCO 2012Achieving Therapeutic Success in Pediatric and Adult PatientsRedefining Expectations of Infliximab Therapy in Ulcerative Colitis.

B a r c e l o n aS p a i nF e b r u a r y 1 6 t h t o 1 8 t h , 2 0 1 2

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) var-ies 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 vascu-lar 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 main-tenance 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,

Part 1

apart from concomitant treatments, received intrave-nous 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 pri-mary 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-mer-captopurine (6-MP), azathioprine (AZA); while ACT II trial patients could receive oral corticosteroids, 6-mercaptopurine, azathioprine and aminosalicy-lates (5-ASA)3.

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 muco-sal 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 percent-age 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.

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 sub-scores, risk of subsequent colectomy, symptoms, and the results of corticosteroids use were ana-lyzed 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.

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

0

20

40

80

60

100 Endoscopic Subscore of 0 or 1

Week 8 Week 30 Week 54

Pat

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5 mg/kg In�iximab Placebo 10 mg/kg In�iximab

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33.9

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24.8

50.4* 49.2*

18.2

45.5* 46.7*

75/121 72/121 30/121 61/121 60/121 22/121 55/121 57/121

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

*p<0.001

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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 endos-copy 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 signifi-cant 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.

In another study, it was shown that intestinal muco-sal healing produced by the administration of inf-liximab in patients with ulcerative colitis rendered

0

20

40

80

60

100 Patients treated with Infliximab p<0.0001

Week 30 (ACT I and ACT II)

Pat

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Endoscopic Scoring 2 (n=114)




62

46

20

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Week 8 Endoscopic

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

ACT I and ACT II Trails.Post-hoc Analysis: Patients achieving mucosal

healing are more likely to continue free of corticosteroids

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Free-colectomy survival increase in patients with ulcerative colitis treated with infliximab

0

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0.4

0.8

0.6

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Follow-up from the first administration of infliximab (Months)

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References: Ferrante M, et al. Long-term outcome after In�iximab for refractory ulcerative colitis. J Crohn´s Colitis. 2008, 2: 219-225.

Breslow: p=0.024Log Rank: p=0.027

Short-term intestinal mucosal healing

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a significant increase of colectomy-free survival6. 121 patients with refractory UC were included, of which 67% had an initial clinical response to inflix-imab. At an average of 33-month follow-up, 68% of initial patients responding to treatment had a clini-cal response, whereas 17% of the total of patients required colectomy. See Graphic 3.

In summary:

• Intestinalmucosal healing is an essentialtherapeuticobjectiveinpatientsdiagnosedwithulcerativecolitis.

• Therapywith infliximaballowspatients toachieve the intestinal mucosal healing inulcerativecolitis.

• Intestinal mucosal healing with infliximabtherapyrenderssignificantclinicalbenefitsfor patients with ulcerative colitis, suchas:

– Colectomyratereduction

– Symptomatic remission rate improve-ment

– Corticosteroidusereduction

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: 412-422.

6 Ferrante M, et al. Long-term outcome after Infliximab for refractory ulcerative colitis. J Crohn´s Colitis. 2008, 2: 219-

225.

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.

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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

European Crohn´s and Colitis Organization – ECCO 2012Achieving Therapeutic Success in Pediatric and Adult PatientsRedefining Expectations of Infliximab Therapy in Ulcerative Colitis.

B a r c e l o n aS p a i nFebruary 16th to 18th, 2 0 1 2

Part 2

Early Intervention with a Satisfactory Therapy in Ulcerative ColitisGeert D´Haens, M.D.

Academic Medical Center, Amsterdam University, Holland. Director of Imelda GI Clinical Research Centre. Imelda Hospital.

Current misunderstandings relative to ulcerative coli-tis (UC) include statements asserting that this disea-se 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 coli-tis, 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 unpre-dictable. After 10 years of disease diagnosis, colec-tomy 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 relap-ses2. In addition, relapse cumulative likelihood is of 90% after 25-year follow-up in patients with ulcera-tive 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 cumula-tive 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 colos-tomy 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 eviden-ce 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 impro-vement 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 reduc-tion in the progression to colectomy during 54-week clinical follow-up (p=0.0004)6. In addition, patients treated with infliximab with low Mayo endosco-pic 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.

Predictive factors of disabling disea-se in patients with ulcerative colitis included young age at disease diag-nosis, extended pathology (perianal disease, abdominal fistulas), disease severity, presence of gastro-duode-nal 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, sur-geries, and death7-11. Two uncertain prognosis predictors are the need of corticosteroids and the absence of smoking habit12.

There was no scientific data compa-ring 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 mode-rate to severe ulcerative colitis that did not properly respond to a therapy with corticosteroids16. This multicen-ter, double-blind, placebo-controlled trial lasted 16 weeks and included 231 patients with a diagnosis of

Clinical response in patients with ulcerative colitistreated with in iximab vs. placebo

0

20

40

80

60

100

Week 8 Week 30 Week 54

Pati

ents

(%)

33.9

6259

24.8

50.4 49.2

18.2

45.5 46.7

5 mg/kg In�iximab (n=121)Placebo (n=121) 10 mg/kg In�iximab (n=122)

ACT Study

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

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Intestinal mucosal healing in patients withCrohn’s disease treated with iniximab

0

10

20

40

30

50

60

70

Week 10 Week 54

Pati

ents

sho

win

g en

dosc

opic

he

alin

g (%

)

Single dose

Group of combined doses (5 mg/kg & 10 mg/kg maintenance in�iximab)

5 mg/kg maintenance in�iximab

10 mg/kg maintenance in�iximab

ACCENT Trial

p=0.010

p=0.007

p=0.026

31%

7%

0/17 10/32 1/11 24.8 8/15

46%

53%

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

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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-mer-captopurine, or were free from azathioprine during the previous 3 months.

Enrolled patients were randomly assigned to three therapeutic groups: a group treated with infliximab plus placebo (n=77), another group of patients trea-ted with azathioprine plus placebo (n=76), and the third group of patients treated with infliximab asso-ciated with azathioprine (n=78). The primary objecti-ve 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 azathio-prine alone (18/76) and 22% of patients treated with infliximab alone (17/77)16. See Graphic 3.

It was evidenced that 63% of patients treated with the combination of infliximab and azathioprine (49/78) achieved an intestinal mucosal healing, com-pared 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 corticos-teroid-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 pro-ved that the treatment with infliximab associated with azathioprine was superior to induce corticosteroid-free remission in patients with moderate to severe ulcerative colitis. Treatment based on the adminis-tration of infliximab is superior to induce intestinal mucosal healing. No new events altering both drugs safety have been found16.

In conclusion:

• UC colitis severity should not be underesti-mated.

• Thereisexcessmortalityandpoorlifequalityassociatedwithsurgery.

• AzathioprineinUCisonlyeffectivein25%ofpatients.

• The combined use of infliximab is morerecommendedthaninmonotherapy.

• Earlytreatmentwithbiologicsfostersmuco-sal healing and improves clinical results ofpatientswithUC.

Corticosteroid-free clinicalremission at week 16

0

20

40

80

60

100

Pati

ents

(%)

Azathioprine plusin�iximab (n=78)

Azathioprine (n=76) In�iximab (n= 77)

24%

p=0.032

p=0.813

p=0.017

22%

40%

n=18 n=17 n=31

References: Panaccione R, et al. In�iximab, Azathioprine or In�iximab + 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

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Intestinal mucosal healing at week 16

0

20

40

80

60

100

Pati

ents

(%)

Azathioprine plusin�iximab (n=78)

Azathioprine (n=76) In�iximab (n= 77)

References: Panaccione R, et al. In�iximab, Azathioprine or In�iximab + Azathioprine for treatment ofmoderate to severe ulcerative colitis: The UC SUCCESS trial. J Crohn´s Colitis. 2011, 5:S8. Abstract 13.

37%

p=0.001

p=0.028

p=0.295

55%

63%

n=28 n=42 n=49

UC SUCCESS Trial

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

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Bibliography

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): 526-535.

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

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.

European Crohn´s and Colitis Organization - ECCO 2012Achieving Therapeutic Success in Pediatric and Adult PatientsRedefining Expectations of Infliximab Therapy in Ulcerative Colitis.

Part 3

Biologic Therapy for Pediatric Patients with Ulcerative ColitisAnne 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 Crohn’s disea-se) 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 corticoste-roids 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 corticoste-roids orally on an outpatient basis (20%), and non-hospitalized patients with mild ulcerative colitis are treated with aminosalicylic acid (30%).

B a r c e l o n aS p a i nFebruary 16th to 18th, 2 0 1 2

A study assessed the efficacy of corticosteroid the-rapy in pediatric patients diagnosed with ulcerative colitis (n=62)3. As regards the immediate therapeu-tic response (one month), it was shown that 60% of patients treated with corticosteroids experienced clinical remission, 24% had a partial clinical respon-se, 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 pro-longed response, 45% of patients were dependant on corticosteroids, and 5% were submitted to surgery3.

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 corticos-teroids 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, calci-neurin 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 patients’ sex or age, or the administration of con-comitant treatment with 5-aminosalicylates (5-ASA)4. In conclusion, approximately 50% of children with ulcerative colitis beginning therapy with thiopuri-nes without concomitant or previously administered biological treatments or 5-aminosalicylates had a corticosteroid-free remission at one year of treatment without requiring rescue therapy4.

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 ulce-rative colitis refractory to corticosteroids therapy (OSDI Study – 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 corti-costeroids therapy, and received therapy with cyclos-porine (n=1), colectomy (n=3) or infliximab (n=33) within 10.5 +/- 6.4 days. Several predictors have been associated to the therapeutic intravenous cor-ticosteroids failure, like is the case of the number of bowel movements, loss of blood volume, patients’ 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 colonosco-py. 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 corti-costeroids (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 imple-mented. 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 effica-cy of infliximab in pediatric patients with moderate to severe ulcerative colitis7. This randomized, multicen-ter study included a total of 60 6-to-17-year old outpa-tients, with moderately to severely active UC (Mayo

Results in hospitalized childrenwith acute severe ulcerative colitis

0

10

20

30

Years 2006 - 2008

29%

37/128Calcineurin Inhibitors

1/37

In�iximab33/37

Colectomy3/37

Improved 1/1

Improved and medical

discharge

25/33

Colectomy8/33

Total short-term colectomy rate11/128 (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.

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Evaluation of clinical response, clinical remission andintestinal mucosal healing at eight weeks of treatment

with in�iximab in patients with ulcerative colitis

0

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30

50

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70

Clinical remissionClinical response Clinical remission measured by PUCAI

Intestinal mucosal healing

Pati

ents

(%)

8073.3

44/60

40.0

8/41 17/51

33.3

24/60

68.3: Criterion for positive response

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

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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 mercapto-purine, azathioprine, corticoids and/or 5-ASA.

The primary objective of the study was to determi-ne 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 respon-se 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.

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 ulce-rative 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 infec-tions (51%) and reactions during infusions (13%). Among serious adverse events (23%), the most fre-quent were ulcerative colitis worsening (15%), infec-tions (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 con-clusion, infliximab was effective and safe, inducing a therapeutic response at week 8 of the study in 73.3%

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..

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

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Week 54Week 30

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Clinical remission at weeks 30 and 54 of treatment with in�iximab in patients with ulcerative colitis

Remission (PUCAI)In�iximab every 12 weeksIn�iximab every 8 weeks

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

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

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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.

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 steroi-ds despite prior optimized use of aminosalicyla-tes (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.

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