ulcerative colitis: refining our managgpgement and...
TRANSCRIPT
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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
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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
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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
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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
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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
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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