1

Ulcerative Colitis: Refining our Management and Incorporating g p g

Newer Concepts

Asher Kornbluth, MDClinical Professor of Medicine

The Henry D. JanowitzThe Mt. Sinai School of Medicine

Refining our Management and Incorporating Newer Concepts in UC:

Objectives

• Fine tuning our use of 5 ASA drugs• Fine tuning our use of 5-ASA drugs• Anti-TNF treatment in UC: Traditional

Uses, Additional Uses• Approaches to dysplasia diagnosis and

managementg

2

Refining our Management and Incorporating Newer Concepts in UC:

Objectives

• Fine tuning our use of 5 ASA drugs• Fine tuning our use of 5-ASA drugs• Anti-TNF treatment in UC: Traditional

Uses, Additional Uses and Unknown Uses• Approaches to dysplasia diagnosis and

managementg

Delayed-Release Mesalamine* in Moderate UC: Overall Improvement for 2.4 g/day vs 4.8 g/day

100100

nt ) nt )

ASCEND II1 ASCEND III2Moderate UC (n=772)Moderate UC (n=254)

102030405060708090

102030405060708090

atie

nts

With

Tre

atm

enSu

cces

s at

Wee

k 6

(%)

atie

nts

With

Tre

atm

enSu

cces

s at

Wee

k 6

(%

5972P

3

Delayed-Release Mesalamine* 2.4 g/day vs 4.8 g/day in Select Patient Subsets With Moderate UC

Treatment success at week 6 in patientshaving taken previous UC therapy: ASCEND III

80 2.4 g/day4.8 g/day

70% 70% 70%*

60

40

20

0

Patie

nts

(%) 64%

70%

n=323 n=338

61%

70%

n=188 n=192

54%

64%

n=157 n=157

58%

n=234 n=230

70%

0Previous

Oral 5-ASAP=0.07

PreviousRectal Therapies

P=0.06

PreviousSteroidsP=0.05

Previous Use of≥2 Medications†

*P=0.01

*Asacol†Included oral 5-ASAs, rectal therapies, steroids, orimmunomodulators Sandborn WJ, et al. Gastroenterology 2009;137:1934.

4.8 g/d more effective than 2.4 g/day in select patient subsets.

12 Month Maintenance of Remission Rates With MMX-Mesalamine: QD vs. BID Dosing

Kamm MA, et al. Gut 2008; 57: 893-902

4

Maintenance Efficacy with QD dosing at 6 monthswith Extended-Release 5-ASA

Extended-release mesalamine1 1.5 g/Day Placebo

Difference(95% CI)

17%

Difference(95% CI)

12%) 100 17% 12%P

5

QD is as effective as BID Dosing in Maintaining Remission

With pH-Release Mesalamine

90.5% 91.8%*ng

th

s 100tie

nts

(%) R

emai

nin

Rem

issi

on a

t 6 M

on

20

40

60

80

QD(n=473)

BID(n=474)

Frequency of Delayed-ReleaseMesalamine† Dosing

*95% CI for BID-QD dosing, -2.3, 4.9†Asacol 400 mg tablet Sandborn WJ, et al. Gastroenterology 2010;138:1286-96.

Pa in R

0

5-ASAs in UC: Take Home Messages

• 4 8 gm/d of greater benefit c/w 2 4 gm/d in• 4.8 gm/d of greater benefit c/w 2.4 gm/d in selected subsets of patients with moderate disease

• New agents for maintenance designed for once daily dosing

• Once daily dosing of “older” agents may be as effective as “traditional” split dosing of these agents

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Refining our Management and Incorporating Newer Concepts in UC:

Objectives

• Fine tuning our use of 5-ASA drugs• Anti-TNF treatment in UC: Traditional

Uses, Additional Uses• Approaches to dysplasia diagnosis and

management

Infliximab Induction and Maintenance Therapy in Patients With UC: Clinical Remission

ACT 1 ACT 2Placebo IFX 5 mg/kg IFX 10 mg/kg

6

11

34

2628

36

10152025303540

15 16 17

3934 3532

3734

1015202530354045

Patie

nts

(%)

Placebo IFX 5 mg/kg IFX 10 mg/kg

**

††

† † ††

†

†

*P≤0.003 vs placebo†P

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Poor Correlation Between Mucosal Healing vsClinical Remission in UC

Week 8 Week 30 Week 54Mucosal Healing = Mayo Score 0 or 1

*

*

*

*

*

*

*P ≤ .001 vs placebo based on a two-sided Cochran-Mantel-Haenszel chi-square test.

Rutgeerts P, et al. N Engl J Med 2005;353:2462.

Predictors of Colectomy in Severe Colitis: Poor Prognostic Endoscopic features

Extensive Loss of Mucosal Layer*Deep Ulcers

Well-like Ulcers Large Mucosal Abrasions

*With or without residual mucosal areas.

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Severity of Disease Correlates with Colectomy

Severe Endoscopic Colitis(n = 46)

Moderate Endoscopic Colitis(n = 39)

93% underwentcolectomy

23% underwentcolectomy

Carbonnel F, et al. Dig Dis Sci 1994;39:1550-1557.

Mucosal healing with Infliximab Reduces Colectomy Rates

Colombel JF, et al. Gastro 2011, June 30, epub ahead of print

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Presence of Detectable Trough Infliximab Levels Increases Remission and Reduces

Colectomy

Seow CH, et al. Gut 2010;59:49-54

CsA vs IFX in IV Steroid-Refractory UC: The CYSIF

StudyFirst randomized controlled study comparing CsA toFirst randomized, controlled study comparing CsA to IFX in IV steroid-refractory severe acute UC

• n=111: 55 received CsA, 56 received IFX

C i d i• Co-primary endpoints• Colectomy at day 7 in hospital• Colectomy at day 98

Laharie D, et al. To be presented at DDW 2011; May 9, 2011;Chicago, IL. Abstract 619.

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CYSIF: Primary Objectives =Treatment Failure at Day 7

Difference Cys vs. IFX: -0.3% (95%CI: -13.3 to 12.8%)

p=0.97

85.4% 85.7%

40%

60%

80%

100%

Response: Lichtiger score < 10 and decrease ≥ 3 points as compared to baseline

0%

20%

Cys (n=55) IFX (n=56)

CYSIF: Primary Objectives =Treatment Failure at Day 98

p=0.4960%54%

40%

60%

80%

100% Difference Cys vs. IFX failure rates: -6.4% (95%CI: - 24.8 to 12.0%)

0%

20%

Cys (n=55) IFX (n=56)

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1.0

CSA vs Infliximab: Time to Colectomy

ival Colectomy rate

p=0.66IFX: 21± 5%Cys: 18 ± 5%

olec

tom

y-fr

ee s

urvi

Cys

IFX

0.2

0.4

0.8

0.6

Co

0 14 28 42 56 70 84 98Days since randomization

% of patients 56 53 50 46 46 46 45 41at risk 55 52 50 46 45 45 45 42

Acute Salvage With CsA After IFX Failure and Vice Versa: Mt. Sinai Experience

RemissionResponse

80

100

40%

20%

33%

23%Pat

ient

s (%

)

20

40

60

80

Maser EA, et al. Clin Gastroenterol Hepatol 2008;6:1112.

*Acute salvage therapy defined as having received the alternatedrug within 4 weeks of discontinuing the first agent.

IFX Salvage*(n=10)

CSA Salvage*(n=9)

0

12

Serious Adverse EventTotal = 16% (3/19)

Other Immune Suppression

Drug Sequence MedicationInterval

Is it Safe to Use Cyclosporine After Infliximab Failure (Within 1 Month)

and Vice-Versa

Death; gram negative sepsis

Azathioprine,Prednisone

IFX-Salvage 1 day

Pancreatitis followed by Enterococcus, and Klebsiella bacteremia

None CSA-Salvage 4 weeks

Klebsiella bacteremia

Herpes Esophagitis Prednisone taper (20 mg)

CSA-Salvage 5 days

Maser EA, et al. Clin Gastroenterol Hepatol 2008;6:1112.

Acute Salvage With CsA After IFX Failure and Vice Versa: GETAID Experience

hout

y

0.8

1

0 84

Prop

ortio

n W

ithC

olec

tom

y

0

0.2

0.4

0.6

12 24 36 48 60 72

Leblanc S, et al. Am J Gastroenterol 2011;106:771.GETAID, Groupe d’Etude Therapeutique des Affections Inflammatoires du Tube Digestif

Months Since Second Treatment

Number at risk 86 23 16 8 6 3 2

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Anti-TNF treatments in UC: Take Home Messages

• Mucosal healing leads to reduced colectomy rates• Mucosal healing leads to reduced colectomy rates• Measurement of serum infliximab trough level

may guide future infliximab dosing• Infliximab as effective as cyclosporine in patients

with severe IV steroid-refractory UCRi k f l th ith CSA ft i fli i b• Risk of salvage therapy with CSA after infliximaband vice-versa, associated with significant risk and should be used very judiciously

Refining our Management and Incorporating Newer Concepts in UC:

Objectives • Fine tuning our use of 5-ASA drugs• Infliximab: Traditional Uses, Additional

Uses and Unknown Uses• Approaches to dysplasia diagnosis and

management

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5-ASA May Protect Against Dysplasia or CRC in UC Patients

Study type Author (Year) Number OR (95% CI)Any cancer or dysplasiaStudy type Author (Year) Number

Moody (1996)* 10/0Lashner (1997) 4/25

Lindberg (2001)* 7/43

Pinczowski (1994) 102/0 Eaden (2001) 102/0 Rubin (2003) 8/18

Van Staa (2003) 76/0 Bernstein (2003) 11/0

Rutter (2004)* 14/54

OR (95% CI)0.1 (0.0–0.3)1.0 (0.3–2.7)0.6 (0.2–1.7)

0.4 (0.2–0.7)0.5 (0.2–1.0)0.3 (0.1–0.9)0.5 (0.4–0.9)1.2 (0.3–4.6)2.1 (0.6–6.9)

Cohort

Case-Control

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( )Adjusted summary odds ratio

P value for homogeneity

( )

0.51 (0.4–0.7); P=0.39

0.01 0.10 1.0 10LowerRisk

Higher Risk

Reprinted by permission from Macmillan Publishers Ltd: Am J Gastroenterol 100(6):1345-1353, copyright 2005 (http://www.nature.com/ajg/index.html).

*Only unadjusted odds ratio reported.

Reduced Risk of CRC with Thiopurine Use:

Results of the CESAME Study

Colorectal CancerMultivariate Analysis

of Thiopurine Therapyn SIR 95% CI HR 95% CI

IBD, total population 19,486 2.0 1.4–2.7 0.57 0.24–1.32

Long-standing, extensive IBD (>10 years duration and >50% cumulative colonic extent)

2,841 6.3 4.0–9.6 0.28(P=0.03) 0.1–0.9

Beaugerie L et al. Presented at: Digestive Disease Week, 2009; Chicago, IL; June 1, 2009. Abstract 281.

Patients with long-standing extensive colitis who received thiopurine therapy had a 3.5-fold

decreased risk of colorectal advanced neoplasia.CI, confidence interval; HR, hazard ratio; SIR, standardized incidence ratio

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Ursodeoxycholic Acid in UC and PSCCross-sectional study: • UDCA decreased prevalence of dysplasia1UDCA decreased prevalence of dysplasia

OR 0.18 (0.05–0.61)P=0.005

Randomized placebo-controlled trial: • UDCA vs placebo: dysplasia/cancer2

RR 0 26 (0 06 0 92)

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RR=0.26 (0.06–0.92) P=0.034

1. Tung B, et al. Ann Intern Med 2001;134:89. 2. Pardi D, et al. Gastroenterology 2003;124:889.

Histological Inflammation Is a Risk for Neoplasia in UC

Author (Year) Design Patients Inflammation

Risk(OR or HR)

Rutter Case 68 cases Histologic OR 4 69*Rutter(2004)

Case-control 136 controls

Histologic OR 4.69* (2.10–10.48)

Gupta (2007) Cohort

418 patients65 with any neoplasia

15 with advanced neoplasia

Pathology reports:any neoplasia

Pathology reports without

polypectomy:

HR 1.4

HR 3.0neoplasia p yp yany neoplasia

Rubin (2006)

Case-control

56 cases 90 controls Average histologic

OR 2.8†(1.4–5.2)

Rutter M, et al. Gastroenterology 2004;126:451.Gupta R, et al. Gastroenterology 2007;133:1099.

Rubin D, et al. Gastroenterology 2006;130:A2. Abstract 14.

*P

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Chromoendoscopy in IBD

Without dye spray After dye spray

Kiesslich R, et al. Gastroenterology 2003;124:880-888.

Prospective, Controlled Studies Comparing Chromoendoscopy to

White Light: Dysplasia Yield

St d# of

P ti t

Number of Lesions per Patient by Ch

Number of Lesions per Patient by

Whit Li htDifference

( f ld)Study Patients Chromo White-Light (x-fold)Kiesslich et al (2003) 165 0.381 0.124 3.07

Hurlstone et al (2004) 324 0.259 0.068 3.81

Rutter et al (2004) 100 0.090 0.020 4.50

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Kiesslich et al (2007) 153 0.210 0.044 4.75

Marion et al (2008) 102 0.157 0.029 5.66

Neurath M, Kiesslich R. Nature Clinical Practice Gastroenterology & Hepatology 2009;6:134.

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Management of Polypoid Dysplasia

Patient Population NMean

Follow-Up Outcomes (% patients)Chronic UC or Crohn’s colitis 48 4.1 48% further polypswith dysplastic polyps and no dyplasia in flat mucosa1

years 0 cancer

Chronic UC with adenoma-like mass (ALM)2

24 42.4 months

58% further adenoma-like DALMS4% LGD0 adenocarcinoma

Chronic UC with sporadic d t id f

10 41.2 th

50% further adenomasadenoma outside area of colitis

months 0 LGD0 adenocarcinoma

Non-UC with sporadic adenoma

49 37 months 39% further adenomas

1. Rubin PH, et al. Gastroenterology 1999;117:1295-1300. 2. Engelsgjerd M, et al. Gastroenterology 1999;117:1288-1294.

E d i l t

Management of Polypoid Dysplasia

• Polypectomy complete

Endoscopic polypectomy (without surgical resection) is adequate treatment for

adenoma-like polyps in UC patients.

• The base of the polyp separately biopsied and foundto have no dysplasia.

• There should be no dysplasia elsewhere in the colon.

IF:

1. Rubin PH, et al. Gastroenterology 1999;117:1295-1300. 2. Engelsgjerd M, et al. Gastroenterology 1999;117:1288-1294.

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Dysplasia and CRC Diagnosis and Managment: Take Home Messages

• Probable chemopreventive benefits of 5-ASA and thiopurines in UC and ursodeoxycholic acidand thiopurines in UC, and ursodeoxycholic acid in UC/PSC

• Increased chronic inflammation increases dysplasia and CRC risk

• Chromoendoscopy increases yield of detecting dysplasia compared to white light colonoscopydysplasia compared to white light colonoscopy

• Adenomas that are resected in their entirety, without adjacent or remote dysplasia, can be followed closely without colectomy