5-ASA Therapy, Steroids and Antibiotics in

Inflammatory Bowel Disease

David T. Rubin, MDAssociate Professor of Medicine

Co-Director, Inflammatory Bowel Disease CenterU i it f Chi M di l C tUniversity of Chicago Medical Center

Relevant DisclosuresP t d G bl Ph ti l• Procter and Gamble Pharmaceuticals: consulting and grant support

• Salix Pharmaceuticals: grant support• Shire Pharmaceuticals: consulting

Treatment Goals 2008… and beyondCURRENTCURRENT• Early accurate diagnosis• Rapid effective induction of remission • Stable steroid-free maintenance of remission• Prevention of complications

Disease related– Disease related– Therapy related

• Improved quality of life

NEAR FUTURE….• Incorporation of mucosal healing into plans for better outcomesIncorporation of mucosal healing into plans for better outcomes• Understanding of the “right” therapy at the “right” time (use of

prognostic markers and individualized therapies early in disease course)

Outdated “Therapeutic Pyramids”Ulcerative ColitisCrohn’s Disease Ulcerative Colitis

Surgery

Crohn’s Disease

SurgeryInfliximab Severe

Fulminant

Systemic Corticosteroids

Cyclosporine

InfliximabMTX

AZA/6-MPSystemic Steroids

Moderate

Aminosalicylates

BudesonideAntibiotics

5-ASAMild

“Conventional” Therapeutic ApproachS it d f t di t t fi t li th i• Severity and safety dictate first line therapies

– NOT prognosis or likelihood of response• Patients have to prove they need something

“stronger” or “riskier”• The chronicity of the disease is sometimes an

afterthought– Induction therapy dictates choice of

maintenance therapyBetter long term outcomes are an added– Better long term outcomes are an added bonus

• Usually less expensive (in the short run)

5-ASA Therapy in IBD• Effective in induction and maintenance of

mild-moderate UC– May have benefit in mild CD- insufficient

evidence • E l ti f lti l d d t• Evolution from multiple doses per day to

single dose• Simplified dosing regimen = increased patient

adherence• Topical therapy plus oral therapy is betterTopical therapy plus oral therapy is better

than oral alone• Unclear whether switching is effective• Chemopreventive benefits

Details of Mesalamine Delivery Systems

5-ASA 5-ASAN=N5-ASAN N

N=N

SulfasalazineNHSO2

Sulfapyridine

COOH

CH

Olsalazine

MesalamineControlled-release capsules

Su apy d e

5-ASA5-ASA 5-ASA

Balsalazide disodiumcapsules

(ABA)

NaOOC

OH5-ASA

MesalamineRectal suspension enema/

suppositoryMesalamine

Gastro-resistant/pH(Lialda)

MesalamineDelayed-release capsules

(Asacol)

(ABA)inert

carrier

OH

EthylcelluloseMicrospheres

Eudragit S MMX technology

5-ASA

5-ASA

Oral Mesalamine for mild-to-moderate UC

R (%)*Response (%)*Study Disease Status Placebo Mesalamine (g)

0.8 1.6 2.4 4.8Schroeder1

(6 weeks)Active 18

(n=38)27

(n=11)74

(n=38)Sninsky2

(6 weeks)Active 23

(n=52)43**

(n=53)49***

(n=53)Hanauer3

(6 months)Maintenance 48

(n=87)63†

(n=90)70††

(n=87)

1Schroeder, et al. N Engl J Med. 1987. 2Sninsky, et al. Ann Internal Med. 1991.

3Hanauer, et al. Ann Internal Med. 1996.

*Response defined as Schroeder: Combined complete and partial response Sninsky: Patients who improved and were in remission Hanauer: Maintenance of remission

**P=0.03, ***P=0.003, †P=0.05, ††P=0.005

1.00

Granulated Mesalamine: ITT PopulationKaplan-Meier Plot of Relapse-Free Duration

Granulated Mesalamine 1.5 g/d

Placebo

ty

0.75

Prob

abili

t

0.25

0.50

p<0.05

Days

0 100 200 300

Lichtenstein, et al. ACG 2008.

Delayed-Release Mesalamine:Dose Response at Week 6

ASCEND II1 ASCEND III2

Trea

tmen

t W

eek

6 (%

)

Mild UC (n=110)

5972P<0.05

60708090

100

66 70P=NS

Trea

tmen

t W

eek

6 (%

)Moderate UC (n= 772)

60708090

100

Moderate UC (n= 254)

3340P=NS

Patie

nts

With

TSu

cces

s at

W

2.4 g/day 4.8 g/day D l d R l M l i *

0102030405060

* Asacol®

Patie

nts

With

TSu

cces

s at

W

2.4 g/day 4.8 g/day D l d R l M l i *

0102030405060

Delayed-Release Mesalamine*

2. Sandborn WJ et al. DDW 2008.

Delayed-Release Mesalamine*

1. Hanauer SB et al. Am J Gastroenterol. 2005;100:2478.

Kamm et al1

Dose Response at Week 8: Delayed Release Mesalamine in Mild to Moderate UC

100 Kamm et al1

Lichtenstein et al2

s in

Clin

ical

En

dosc

opic

n at

Wee

k 8

(%)

41 41P=0.01* P=0.007*

405060708090

100

* P-values represent active treatment vs. placebo† Lialda™

2.4 g/day

Patie

ntan

d E

Rem

issi

on

Placebo

22

4.8 g/day

13

3429

P<0.001* P=0.009*

010203040

1. Kamm MA et al. Gastroenterology. 2007;132:66. 2. Lichtenstein GR et al. Clin Gastroenterol Hepatol.2007;5:95.

Delayed Release Mesalamine†

Treatment of Distal UC: Oral and Topical Mesalamine Therapy

100 Oral (2.4 g/d)Rectal (4 g/d)Combined

*

port

ing

edin

g (%

)

100

60

80

Patie

nts

Rep

No

Rec

tal B

lee

40

20

6 Weeks0

*P<0.002 vs oral alone, P=0.04 vs topical alone.

Adapted from Safdi M et al. Am J Gastroenterol. 1997;92:1867.

Mesalamine 4 g total PO

Extensive Mild/Moderate UC: Oral and Rectal Mesalamine Therapy

89

62

nts

(%)

Mesalamine 4 g total PO (in divided doses; 2 g BID) + mesalamine enema 1 g HS (N=71)

P=NS

P=0.0008

Mesalamine 4 g total PO (in divided doses; 2 g BID) + placebo enema HS (N=56)

60708090

100

44

34

No.

of P

atie

n P=NS

102030405060

Remission Improvement

Week 4

Marteau P et al. Gut. 2005;54:960.

0

Meta-Analysis of Mesalamine* (4 g/day) in Active Crohn’s Disease

0 0

40

-30

-20

-10

0

m B

asel

ine

Sco

re

30

-20

-10

0

P=0.7 P=0.05

P=0.04

80

-70

-60

-50

-40

Cha

nge

From

in C

DA

I

P=0.005

P=0.7

P=0.05

P=0.04

60

-50

-40

-30

P=0.005

*Controlled-release capsules Hanauer S et al. Clin Gastroenterol Hepatol. 2004;2:379.

Mesalamine* 4 g Placebo

Crohn’s In=155

Crohn’s IIn=150

Crohn’s IIIn=310

Overalln=615

Mesalamine* 4 g minus placebo

Crohn’s In=155

Crohn’s IIn=150

Crohn’s IIIn=310

Overalln=615

-80 -60

Mesalamine Maintenance ofRemission in Crohn’s Disease

Study Year Pts (n)

McLeod 1995 163Brignola 1995 87Sutherland 1997 66Overall 411

Thomson 1990 248Prantera 1992 125

Caprilli 1994 95

Brignola 1992 44Gendre 1993 161Bresci 1994 66Thomson 1995 286Arber 1995 59Modigliani 1996 85Sutherland 1997 180De Franchis 1997 117

Favors Treatment Favors ControlRisk Difference 95% CI

Overall 1,371De Franchis 1997 117

-0.5 0.50.40.30.20.10.0-0.1-0.2-0.3-0.4

Adapted from Cammà C et al. Gastroenterology. 1997;113:1465-1473 with permission from American Gastroenterological Association.

Does It Matter Which Aminosalicylate Is Used?

• D li t f di• Deliver to area of disease• Insurance and adherence issues• Don’t settle for less than remission!• Rationale that delivery system may make a difference,

but untested/unprovenbut u tested/u p o e• Oral aminosalicylates share more than

they differ– Pharmacokinetics– Clinical efficacy– Adverse events

• Different for prodrugs– Sulfapyridine– Looser stools

• Monitor renal function for all

Corticosteroid Therapy in IBDEff ti i UC d CD• Effective in UC and CD

• The need (or choice) of steroids is a prognostic marker

– May represent a “tipping point” needing other therapies for maintenancetherapies for maintenance

– Have an exit strategy!• Systemic corticosteroids demonstrate

substantial toxicity at higher doses and for longer periods of timelonger periods of time

• The development of non-systemic steroid formulations provide benefit with less toxicity

Corticosteroid Therapy

St d Di St id/ D R (%)*Study Disease State

Steroid/ Dose Response (%)*

Steroid PlaceboTruelove1

(6 weeks)Active Cortisone ≥

100 mg69

(n=109)41

(n=101)

Lennard-Jones2

(6 months)

Maintenance Prednisone 15 mg

38 (n=34)

40 (n=35)

Truelove3

(5 days)Severely

activePrednisolone

60 mg73 N/A

(5 days) active 60 mg (Total n=49)

1Truelove, et al. Br Med J. 1955;2:1041.2Lennard-Jones, et al. Lancet. 1965;1:188.

3Truelove, et al. Lancet. 1974;1:1067.

*Response defined as Truelove: Patients who improved and were in remission Lennard-Jones: Maintenance of remissionTruelove: Patients in remission

NCCDS: Response to Therapy for Crohn’s Disease Remission Maintenance

100

90

80

Prednisone 1/4 mg/kg (20 mg)

Placebo

Sulfasalazine 1/2 g/kg (2.5 g)Azathioprine 1 mg/kg (75 mg)

70

50

60

0

Months After Randomization2418126

Summers RW et al. Gastroenterology. 1979;77:847.

Corticosteroids: Short- and Long-Term Efficacy in UC

1-Month Outcomes*(n=63)

Complete Remission

54%(n=34)

Partial Remission

30%(n=19)

No Response 16%

(n=10)

1-YearOutcomes

Steroid Dependent

Prolonged Response Surgery

( ) ( )

*30 days after initiating corticosteroid therapy Faubion W, et al. Gastroenterology. 2001;121:255.

Outcomes(n=63)

Dependent22%

(n=14)

Response49%

(n=31)

29%(n=18)

Corticosteroids: Short- and Long-Term Efficacy in Crohn’s Disease

30-DayResponses(n=74)

None 16% (n=12)

Complete 58%(n=43)

Partial26%(n=19)

1-YearResponses

Prolonged response

Steroid dependent Surgery

38%

Faubion WA Jr. et al. Gastroenterology. 2001;121:255.

Responses(n=74)*

*1 patient lost to follow-up

p28%(n=21)

p32%(n=24)

38%(n=28)

Mortality Associated with Current and Recent Corticosteroid Use – Adjusted HR (95% CI)

2.813

4

5

atio

2.49

1

2

3

Haz

ard

Ra

Lewis JD, et al. Am J Gastroenterol. 2008;103:1428-1435.

0 95% CI: (2.26-3.5) 95% CI: (1.65-3.75)

Recent Use of Corticosteroids

Current Use of Corticosteroids

Oral Budesonide: Efficacy as Maintenance Therapy

Prob

abili

tyss

ion

Budesonide 6 mgBudesonide 3 mgPlacebo

1.00.9

0.70.8

0.6

Cum

ulat

ive

Pof

Rem

is

0.4

0.2

0.5

0.3

0.10.0

Time (Days)

300100 2000

Adapted from Greenberg GR et al. Gastroenterology. 1996;110:45-51 with permission from American Gastroenterological Association.

Antibiotic Therapy in IBD• Less rigorously studied• Less rigorously studied• Crohn’s disease:

– Infectious complications– Peri-anal disease– Crohn’s colitis– Crohn s colitis – Prevention of post-op recurrence – Small bowel bacterial overgrowth

• Ulcerative colitis:– No convincing evidence of primary efficacyg p y y– Prophylaxis when on cyclosporine therapy

• Pouchitis

Therapy of Active Crohn’s Disease150150 p= 05

AI

AI 5050

100100

150150PlaceboMetronidazolep=NS

p=.005

p=.05

Cha

nge

in C

DA

Cha

nge

in C

DA

--5050

00

No difference in clinical remission rates.No difference in clinical remission rates.Sutherland L, et al. Sutherland L, et al. Gut.Gut. 1991;32(9):10711991;32(9):1071--1075.1075.

CC

--100100Small intestineSmall intestinen=24n=24

Small/LargeSmall/Largeintestineintestinen=31n=31

Large intestineLarge intestinen=8n=8

Antibiotics in Active CD

emis

sion

(%)

40

50

60

70

0

Patie

nts

in R

e

10

20

30

0Metro + Ciprovs Me-Pred1

Ciprovs Mesalamine3*

Metrovs SASP2

1. Prantera C et al. Am J Gastroenterol. 1996;91:328.2. Ursing B et al. Gastroenterology. 1982;83:550.

3. Colombel JF et al. Am J Gastroenterol. 1999;94:674.Metro, metronidazole; Me-Pred, methylprednisolone;Cipro, ciprofloxacin; SASP, sulfasalazine

*Mesalamine controlled-release capsules

Ornidazole Post-op Prophylaxisin Crohn’s Disease

p=0.09

p=0 02 p=NSp=S54%

48%45%

79%

59%60

80

100OrnidazolePlacebo

rren

ce

p=.046

p=.036

p= 002p=.1

p=.27

p=0.02

p=<0.044

p=NS35%

27%

8%

34%

%45%37%

0

20

40

% o

f Rec

ur p=.002

N=800

3 Months 12 Months 12 Months 24 Months 36 Months

Endoscopic Clinical

Rutgeerts P, et al. Gastroenterology. 2005 Apr;128(4):856-61.

Antibiotics in Pouchitis

• Uncontrolled trials:• Uncontrolled trials: – Oral metronidazole or ciprofloxacin: 96% response1

– Local metronidazole (40-160 mg/d per rectum): 11/11 patients responded2

– Oral rifaximin (1 g BID) + ciprofloxacin (500 mg bid): 86% f 386% improvement in refractory disease3

• Controlled trial: metronidazole (400 mg PO TID):↓ stool frequency, no change endoscopy4

1. Hurst RD, et al. Arch Surg. 1996;131:497-500.2. Nygaard K, et al. Scand J Gastroenterol. 1994;29:462-467.3. Gionchetti P, et al. Gastroenterology. 1997;119:A981.4. Madden MV, et al. Dig Dis Sci. 1994;39:1193-1196.

Conclusions: 5-ASA, Steroids and Antibiotics in IBD

• 5 ASA th i ff ti f i d ti d• 5-ASA therapy is effective for induction and maintenance of UC, limited in CD

– Topical therapy is effective for distal and additive in extensive UC.– There does not appear to be a dose-response for oral 5-ASA in UC.– Simplified dosing regimens and delivery systems have provided

many options for patients and providers.y p p p• Corticosteroids remain effective induction agents in

UC and CD– Should be considered markers of disease prognosis and paired

with effective maintenance strategies.– Limited by toxicity- non-systemic steroids provide new options.

B d t tibi ti h i t t l i• Broad-spectrum antibiotics have an important role in infectious complications of IBD and for pouchitis

– Despite interest in the “infectious cause of IBD” this remains elusive.