USE OF IMMUNOMODULATORS FOR IBD

DANIEL H PRESENT MDCLINICAL PROFESSOR OF MEDICINEMOUNT SINAI SCHOOL OF MEDICINE

THE RIGHT WAY TO USE IMMUNOMODULATORS FOR IBD

• EARLY IN THE COURSE

• FOR BOTH CROHN’S DISEASE AND ULCERATIVE COLITIS

• SIMPLIFY ADMINISTRATION

George H. Hitchings and Gertrude B. Elion: 1988 Nobel Prize For Physiology or Medicine

For Discovery of 6-Mercaptopurine and y p pAzathioprine

Elion. Ann New York Acad Sci 1993.

Early History of 6-Mercaptopurine and Azathioprine

• 1942: Hitchings joins Wellcome L b t i t B h W llLaboratories at Burroughs Wellcome. Theorized that, since all cells require nucleic acids, it might be possible to stop the growth of rapidly dividing cells with g p y gantagonist of the nucleic acid bases

Early History of 6-Mercaptopurine and Azathioprine (Cont)

• 6-mercaptopurine subsequently widely utilized as a therapy for ALL in children

. Azathioprine was synthesized as a pro-drug for 6-MP.

Uncontrolled Studies Using Imunosupressives in Crohn’s Disease

Winkelman (1965) Nitrogen mustardWinkelman (1965) Nitrogen mustard9/13 improved1 R-V fistula closed

Brooke (1969, 1970) Azathioprine 9/24 improvedClosed fistulae

Drucker (1970) Smaller dose-slower response9/9 improved

Avery, Jones (1971) 4/10 remarkably better

Patterson (1971) 10/15 improvedPatterson (1971) 10/15 improved9 remissions

Review of literature up to 1972. Response of Crohn’s disease to immunosupressives 70/97 (72%)

The National Cooperative Crohn’s Disease Study (NCCDS)

A Retrospective Analysis• Initiation of the study in 1970• No prior controlled trials to determine efficacy

and safety of medications used in treatment a d sa e y o ed ca o s used ea eof Crohn’s disease

• Organizers selected prednisone, sulfasalazine and azathioprine as agents meriting a clinical trial

• Design attempted to model as closely as possible the process of the contemporary management of Crohn’s disease

CONTROVERSIES IN THE MANAGEMENT OF CROHN’s DISEASE

• HOW MANY PHYSICANS IN THE AUDIENCE KNOW HOW TO CALCULATE THE CDAI?CALCULATE THE CDAI?

• HOW MANY PHYSICIANS IN THE AUDIENCE USE THE CDAI TO TREAT THEIR PATIENTS?THEIR PATIENTS?

The Crohn’s Disease Activity Index

42stools 3x7days 21x2

30Taking loperamide=147Well being - 3/d=21x7=70Abd pain - 2x7=14x5=42stools - 3x7days 21x2

PROBLEM: THEIndicates -mod CDTOTAL =289 CDAI

=30Taking loperamide

PROBLEM: THE PATIENT HAS IRRITABLE BOWEL SYNDROME

EVIDENCED BASED MEDICINE USING 6MP/AZA

MISSED THE EFFICACY WITH WHAT TURNS OUT TO BE ONE OF THE MOST EFFECTIVE THERAPIES FOR IBDEFFECTIVE THERAPIES FOR IBD

ENDORSED ONE OF THE WORST THERAPIES FOR CROHN’S DISEASETHERAPIES FOR CROHN S DISEASE

Corticosteroids: Short and long term efficacy in Crohn’s disease

30-dayresponses(n=74)

Complete 58%

(n=43)

None 16%

(n=12)

Partial26%

(n=19)

1-yearProlonged response

Steroid dependent Surgery

Faubion et al, Gastroenterology 2001; 121: 255

yresponses(n=74)*

response28%

(n=21)

*One patient lost to follow*One patient lost to follow--upup

dependent32%

(n=24)

38%(n=28)

6-Mercaptopurine in Active Crohn’s Disease

50607080

6-Mercaptopurine Placebo

010203040

S O

%

SteroidSparing

OverallClinical

Improvement

AZA and 6-MP: Induction of Remission in CD

Odds Ratio of ResponseOdds Ratio of Response0.1 0.2 0.5 1 2 5 10 100

Study Year # PtsRhodes 1971 12

Klein 1974 26

Candy Part 1 1994 63Candy Part 1 1994 63

NCCDS Group 1 1979 136Phase 1

Ewe 1993 42

Present 1980 72

Willoughby Group 1 1971 12

Common odds ratio 367

Reprinted with permission from Pearson DC et al. Ann Intern Med. 1995;122:132-142.

Favors Placebo Favors Treatment

Common odds ratio 367

WHEN TO USE 6MP/AZA

TO INDUCE AND MAINTAIN REMISSIONIN ACTIVE CROHN’S DISEASE“EARLY” IN THE COURSE

STEROID SPARING

Time of Response to 6-MP

Response Cumulative Number1 month or less 4 10%2 months 19 56%3 months 5 68%3 months 5 68%4 months 5 81%5 months 2 85%6 months 3 93%Over 6 months 3 100%

TIME OF RESPONSE TO 6MP/AZA

• AT 2 MONTHS 56% OF THE IBD PATIENTS WILL HAVE RESPONDED

• OFTEN NO REASON TO RUSH TO STEROIDS OR BIOLOGICALS

Crohn’s disease is not a disease of 6 to 17 weeks.

Crohn’s disease is a disease of a lifetime.

• WHAT IS THE RUSH TO STARTBIOLOGICALS?

WHEN TO USE 6MP/AZA

• TO HEAL INTERNAL AND EXTERNAL FISTULA

• STEROIDS MUST BE DISCONTINUED IN ORDER TO OBTAIN HEALING

• “BEFORE INFLIXIMAB”

Response Of Fistulas To Aza/6-MP in Placebo Controlled Trials

• 5 placebo controlled trials reported fistula results (Present, Willoughby, Rhodes, Klein, Rosenberg)

• 22/41 (54%) patients receiving azathioprine/6-( ) p g pmercaptopurine responded compared to 6/29 (21%) treated with placebo

• Pooled odds ratio was 4.44 (95% CI 1.5-13.2) favoring fistula healingfavoring fistula healing

Pearson, Ann Int Med 1995

INTERNAL FISTULA IN CROHN’S DISEASE

• THERE ARE CURRENTLY NO CONTROLLED TRIALS LOOKING AT TREATMENT OF INTERNAL FISTULATREATMENT OF INTERNAL FISTULA WITH BIOLOGICS

Immunosuppressives in Crohn’s Disease

Fi t l H liFistula Healing

Before6-mercaptopurine

After6-mercaptopurine

Placebo-Controlled Trial Of Azathioprine Withdrawal After 42 Months Remission In

Crohn's diseaseR lR l

0,8

1,0

Remission (months)

RelapseRelapse8%8%21%21%

0 2

0,4

0,6

Months after randomization

Remission (months)mean ± SE

Azathioprine 17.3 ± 0.5Placebo 15.9 ± 0.7

0,0

0,2

0 6 12 18

Months after randomization

Lemann Gastroenterology 2002 Abstract

Endoscopic Healing In Crohn’s Disease During Treatment With Azathioprine*

60

80

100Colon (n=20)Ileum (n=13)

th H

ealin

g

20

40

% P

atie

nts

Wi

D’Haens. Gastrointest Endosc 1999. *In unblinded and uncontrolled study

0Complete Near

CompletePartial None

Extent of Endoscopic Healing

WHEN TO USE 6MP/AZA

• TO PREVENT POST OPERATIVERECURRENCE

Clinical Relapse

PREVENTION OF POST OPERATIVE RECURRENCE

• Recurrence Metronidazole- Placebo-78%• Recurrence Metronidazole- AZA -55%

• Combined therapy should be recommended in patients with enhanced i k frisk for recurrence

WHEN TO USE 6MP/AZA

PREVENT SURGERY IN PEDIATRIC CROHN’S DISEASEAZA modified the natural course of Crohn’s and early use may have a protective effect in terms y y pof need for surgery. Steroids increased the need for surgery.

Gastro-2008Gastro-2008

AZA/6-MP in Steroid Resistant UC

ents

40

50

60

70 65

% P

atie

0

10

20

30

Complete Partial Treatment

24

11

CompleteResponse

PartialResponse

TreatmentFailure

(n=68) (n=25) (n=12)

George J, et al. Am J Gastroenterol. 1996;91:1711-1714

Relapse After 6-MP Withdrawal

emis

sion

1.0

0.8

Prop

ortio

n in

Re 0.6

0.4

0.2

P

00 20 40 60 80 100 120

MonthsGeorge J. et al The long term outcome of Ulcerative Colitis treated with 6 MP Am J Gastro 91:1711-1714 1996

Breakthrough while on 6-MP

emis

sion

1.0

0.8

Prop

ortio

n in

Re 0.6

0.4

0.2

P

00 20 40 60 80 100 120

MonthsGeorge J. et al The long term outcome of Ulcerative Colitis treated with 6 MP Am J Gastro 91:1711-1714 1996

UC Maintenance With Azathioprine Controlled data:

1yr Remissionsy

40 41

64

40

50

60

70

p=nsp=0.04

23

10

20

30

40PlaceboAZA

0Jewell Hawthorne

Hawthorne AB, et al. Hawthorne AB, et al. Br Med J Br Med J 19921992

AZA=100mg; N=79AZA=2.5mg/kg; N=80

Jewell DP, et al. Jewell DP, et al. Gut Gut 19741974

AZA Is More Effective in Avoiding Steroid Requirement Than 5-ASA in the

Treatment of Steroid-Dependent UC

ts W

ithss

* (%

)

P=0.00653%

30

40

50

60

19%

AZA 5-ASA

Patie

ntSu

cces

0

10

20

30

Ardizzone S et al. Gut. 2006;55:47.

AZA 2 mg/kg/day

(n=36)

5-ASA 3.2 g/day

(n=36)

* Treatment success defined as induction of clinical and endoscopic remission and steroid discontinuation.

Treatment of steroidDependent ULC ColitisTreatment of steroidDependent ULC Colitis

• Ardizzone Gut 2006 Tested efficacy of steroid dependent UC. AZA vs 5-ASA

R i i t 6 th AZA 53%

• Ardizzone Gut 2006 Tested efficacy of steroid dependent UC. AZA vs 5-ASA

R i i t 6 th AZA 53%• Remission at 6 months AZA 53%5-ASA-21%

• Conclusion-AZA statistically more effective

• Remission at 6 months AZA 53%5-ASA-21%

• Conclusion-AZA statistically more effectiveConclusion AZA statistically more effectiveConclusion AZA statistically more effective

AZATHIOPRINE IN ULCERATIVE COLITIS

Fraser Gut 2002;50:485-9346 Patients 31 year experienceOverall Remission 58%Remission after more than6 months therapy 87%Remission at 5 years 62%

Surgery After Initiation of 6-MP Preventing colectomy

Colectomy – 11/89 (12%)

• Ulcerative Colitis - 9/68 (13%)• Proctosigmoiditis – 2/21 (10%)

George J. et al The long term outcome of Ulcerative Colitis treated with 6 MP Am J Gastro 91:1711-1714 1996

WHEN TO USE 6MP/AZA

• AFTER TREATMENT WITHCYCLOSPORINE TO PREVENTRECURRENT DISEASE

Cyclosporine in Severe UC:Probability of Avoiding

Colectomy100 y

lity

ofec

tom

y (%

)

100

60

80

CSA + 6MP/AZA

All P ti t

66%58%

Prob

abi

Avoi

ding

Col

e

40

20

All Patients

CSA alone40%

6600

Months Since Initiation of Cyclosporine36

Cohen RD, et al. Am J Gastroenterol. 1999;94:1587-1592.

WHEN TO USE 6MP/AZA

• TO PREVENT ANTIBODY FORMATION

WHEN ADMINISTERING BIOLOGICALS

Immunogenicity of Infliximab in ACCENT 1 Stratified by Dosing Regimen and

Immunosuppressionpp38

25303540

e fo

r ATI

(%)

1611

75

101520

atie

nts

Posi

tive

Sandborn. Gastroenterology editorial 2003

0Single Single + AZA Multiple Multiple + AZA

Pa

WHAT IS THE NEED AND ACCURACY OF METABOLYTE

TESTING

• Do you use 6-TG levels and when?

• Does 6-MMP level have clinical significance?

6TG AND 6MMP

• I DO NOT MEASURE 6TG-CORRELATION ABOUT 70%

I DO NOT MEASURE 6MMP I MEASURE SGOT, SGPT

TPMT ACTIVITY AND 6-TGN CONCENTRATION TESTING

• “USEFUL BUT THE OVERLAP IN RESPONSE BETWEEN PATIENTS WITH HIGH AND LOW TPMT ACTIVITY ANDHIGH AND LOW TPMT ACTIVITY AND HIGH AND LOW 6-TGN CONCENTRATIONS IS SUBSTANTIAL”

• Sandborn-Gastro and Hepatology 2007

TPMT Phenotypic Distribution12

ity.5

Uni

ts o

f Act

iv

8

6

10

TPMTL

TPMTH

TPMTH

% o

f Sub

ject

s/0.

4

6

2TPMTL

TPMTL

TPMTTPMTH

Weinshilboum RM, Sladek SL. Am J Hum Genet. 1980;32:651-662.

Erythrocyte TPMT activity (U/ml)0

05 10 15 20

FDA Directed Package Insert Changes

• The FDA Clinical Pharmacology Subcommittee of the Pharmaceutical Science Advisory Committee (October 23, 2002) and the FDA ( )Oncologic Drugs Advisory Committee (Feburary 12-13, 2003) recommended a labeling change for 6-mercaptopurine to include language recommending TPMT determination prior to treatment with 6MP or azathioprine

HOW TO USE 6MP/AZA

• In over 1000 IBD patients treated with 6MP/AZA I have never drawn a TPMT level nor has this ever resulted in a badlevel nor has this ever resulted in a bad medical outcome.

• Medico-legal issue rather than scientific• Medico-legal issue rather than scientific issue

Monitoring Thiopurines

• Traditional monitoring with CBC, Chemistries

Requires Expert Assessment

Prognosis with Thiopurines

• Additional, specialized brain centers

Navigating NYC traffic

Thiopurine Monitoring Center

Telling Clinical Anecdotes

6-MP Administration

• 6-MP initial dose = 50mg/day• 6-MP increased if no response and no

leukopenia at 4 weeks• 6-MP reduced or withheld for WBC of 3,000 or6 MP reduced or withheld for WBC of 3,000 or

less• Weekly CBC for 4 weeks and monthly thereafter• Concomitant medications(5-ASA) maintained)

5 ASA enhances 6MP response5-ASA enhances 6MP response

HOW TO USE 6MP/AZA

• Start with low dose and increase after 4 weeks as needed.

• Obtain TPMT level and start high dose 6MP/AZA if normal

6MP/AZA ADMINISTRATION

• ARE HIGHER DOSES REQUIRED TO OBTAIN A MORE RAPID RESPONSE? PROBABLY NOTPROBABLY NOT.

• WHAT IS THE RUSH?

• THESE ARE CHRONIC ILLNESSES

Xanthine Oxidase Inhibition for Preferential 6-MMP Metabolism

6-thiouric acid

XOX6-MP

HPRT6-TGNsAZA

TPMT

6-MMP

P<0.001

Steroid-sparing achieved after addition of allopurinol

17.6

12

14

16

18

20

dose

(mg)

1.84

6

8

10

12

ean

pred

niso

ne d

0

2

Pre-Allopurinol Post-Allopurinol•Seven patients were able to discontinue all steroids after the addition of allopurinol

Sparrow M, et al. Clin Gastroenterology Hep 2007 Feb;5(2):209-14.

Me

Rheumatoid Arthritis

METHOTREXATE IN ULCERATIVE COLITIS

• LIMITED DATA

• NO PROLONGED RESPONSE

METHOTREXATE FOR IBD

• Kozarek-Ann Int Med-1989• 14 CD, 7UC• Response 11/14 CD 5/7 UC• Relapse with long term use-Especially UC

METHOTREXATE IN CROHN’S DISEASE

• Lemann-Remission-72% of patients at 3 months with remission and steroid withdrawal 42% at 12 Months

• Relapse 58% at 12 months• Relapse 58% at 12 months

• Mahadevan-Remission-62%Fi t l l 25% I t 31%• Fistula closure-25%,Improvement-31%

MethotrexateActive Crohn’s DiseaseActive Crohn’s Disease

StudyStudy No.No. DurationDuration MTXMTX PlaceboPlacebo 66--MPMP PP DoseDose

FeaganFeagan 141141 16 weeks16 weeks 39%39% 19%19% 0.030.03 25 mg/wk IM25 mg/wk IM

AroraArora 3333 52 weeks52 weeks 54%54% 20%20% 0.060.06 15 mg/wk PO15 mg/wk PO

OrenOren 8484 39 weeks39 weeks 38%38% 46%46% 41%41% NSNS 12.5 mg/wk PO12.5 mg/wk PO

Feagan, Feagan, N Engl J MedN Engl J Med 19951995Arora, Arora, GastroenterologyGastroenterology 1992 (abs)1992 (abs)Oren, Oren, Am J GastroenterologyAm J Gastroenterology 19971997

Methotrexate (IM) Treatment of CD

30

40Placebo

Methotrexate 25mg weekly

P=0.025 P=0.003 P=0.92

19 1%

39.4% 39.0%35.3%

40.0%

on (%

)

0

10

20

All patients 20mg/day 20mg/day

19.1%

10.0%

> <

Rem

issi

o

p g y g y

Treatment Group

Feagan BG et al. N Engl J Med. 1995; 332:292-297

Methotrexate in IBD: Toxicity

• Major– Hepatic– Myelosuppressive– Pulmonary

• Minor– Gastrointestinal– Alopecia-inductive– Allergic

– Fertility-related– Teratogenic– Enteritic/colitic

– Neurologic

Egan LJ, Sandborn, WJ. Mayo Clinic Proc. 1996;71:69-80

Methotrexate and Pregnancy

• CONTRAINDICATED

COMMIT TRIAL

50 WEEK MULTICENTER DOUBLE• 50 WEEK,MULTICENTER,DOUBLE BLIND

• COMPARISON MTX/IFX COMBO VERSUS IFX ALONE

• IFX 5MG/KG PLUS MTX OR PLACEBO• STEROID TAPER• PRIMARY OUTCOME-FAILURE TO

ENTER A PREDNISONE FREE REMISSION

COMMIT TRIAL-RESULTS

• TREATMENT FAILURE:• MTX GROUP- 30.6% BY 50 WEEKS• PBO GROUP- 29.8% BY 50 WEEKS

P=.63 • NO CLINICAL BENEFIT BY ADDING

MTX TO INFLIXIMAB

Brian Feagan, presented at DDW 2008

Which is First Line Therapy? MTX or 6MP/AZA

D l d b N b l L t• Developed by Nobel Laureates• 9 Placebo Controlled trials • Closes fistula• Endoscopic healingp g• Prevents flare-ups long term• Prevents post operative recurrence• Effective in both UC as well as Crohn’s• Effective in combination with infliximab and• Effective in combination with infliximab and

cyclosporine

Top down vs step up strategy

Management of recent-onset Crohn’s disease: A controlled randomized trial comparing step up

and top down therapy

Newly (n=129 diagnosed Crohn’s disease )

Top down (n=65)

IFX (0/2/6) + AZA+ IFX

IFX (0/2/6) + AZA+ AZA MTX

Steroids

S

IFX + AZA

+ (episodic) IFX

Steroids

Step up (n=64)

Steroids

Steroids

Hommes et al, DDW 2005; Late-breaking abstract

Management of recent-onset Crohn’s disease

Top down(n=65)Step up(n=64)

100

75 77

6475

Patients (%)

48

21

06 Months 12 Months n=20 n=14Remission with steroid

withdrawal Endoscopic healing

(at 2 years)Hommes et al, DDW 2005; Late-breaking abstract

Toxicity of 6-MP/AZA

Immunosuppressive Therapy in IBD-Complications Directly Attributable to 6-MP

No %No. %Pancreatitis 13 3.3Bone Marrow Depression 8 2Depression 8 2Allergic Reactions 8 2Drug Hepatitis 3 0.8

• Mortality 0 (0%)• Reversability 32 (100%)

6MP/Azathioprine – Cancer in IBD

Connell Lancet 1994Connell Lancet 1994

• 755 patients – follow up 9 yrs(2 wks-29 yrs)• No significant excess of cancer in

A thi i t t d ti tAzathioprine treated patients• No non-Hodgkins lymphomas• 6MP/AZA are effective in Crohn’s and UC

and avoid surgery earlier in the course of didisease

• Risk of cancer will be increased long term because colon remains in situ

Long-term risk of malignancy with AZA in IBD

• 2204 patients (UC-1349 CD-855)• 626 received AZA, mean follow-up 13.7

yearsy• 31 cancers in 30 patients treated AZA• 77 cancers in 70 patients not treated AZA• 8 Lymphomas-3 with AZA, 5 without AZA8 Lymphomas 3 with AZA, 5 without AZA

Fraser – Alim Pharm Ther, 2002

Lymphoma in IBD With or Without 6MP/Azathioprine

• Increased risk of lymphoma reported from tertiary care centers

• No increased risk found in majority of population b d t dibased studies

Numbers of patients: CD: 6605 UC: 10391– No increased lymphoma in IBD patients– No observed increased risk of lymphoma with

AZA/6MP therapy

Lewis JD, et al. Gastroenterology. 2001 Nov;121(5):1080-7. 2. Lofltus EV, et al. Gastroenterology. 2001 Nov;121(5):1239-42.

EB Positive Lymphoma in IBD Patients Treated with

6-MP/AZA

1200 Patients-18 lymphomas– 6/18 lymphomas not treated 6-MP/AZA– 7/18 lymphomas E-B virus positive– 5/7 received 6-MP/AZA5/7 received 6 MP/AZA

Conclusion6-MP/AZA treatment of IBD is associated with a

small increased risk of EB virus positivesmall increased risk of EB virus positive lymphoma

Dayhersh, Gastro, 2002

LYMPHOMAS IN IBD

• CESAME COHORT• 800 French GI’s, 20,802 IBD patients• 60% CD -40% UC• four fold increase in lymphoproliferative• disorders in IBD patients receiving • thiopurines. 1/10,000 to 4/10,000

LYMPHOMAS IN IBD

• Siegel-Abstract DDW 2008• 8,843 patients, 18296 patient years• Results: Increased risk of NHL in CD• patients treated with anti-TNF agents• 3 fold increase ? Due to disease, or due• to treatment or other factors.

TREATMortality

Logistic Regression Data (Multivariate)

87

Odds Ratio

95% CI

Current use of infliximab 1.0 0.5-1.9

Current use of 6MP/AZA/MTX 0 7 0 4 1 3Current use of 6MP/AZA/MTX 0.7 0.4-1.3

Current use of corticosteroids 2.1 1.1-3.8*

Current use of narcotic 1 8 0 9-3 4

*p=0.001

Current use of narcotic analgesics

1.8 0.9-3.4

Lichtenstein GR, et al. Gastroenterology. 2005;128(4):A-580.

TREAT

Serious InfectionsLogistic Regression Data (Multivariate)

88

Odds Ratio

95% CI

Current use of infliximab 1.0 0.6- 1.6

Current use of 6MP/AZA/MTX 0.8 0.5- 1.2

Current use of corticosteroids 2.3 1.5- 3.5*

*p<0.001

Current use of narcotic analgesics

2.4 1.6- 3.7*

Lichtenstein GR, et al. Gastroenterology. 2005;128(4):A-580.

A Randomized, Double-Blind, Controlled Trial Comparing Infliximab and Infliximab

plus Azathioprine to Azathioprine in Patients with Crohn’s Disease Naive to

Immunomodulators and Biologic Therapy: The SONIC Trial

William Sandborn, MD; Paul Rutgeerts, MD; Walter Reinisch, MD; Gerassimos Mantzaris, MD; Asher

Kornbluth, MD; Daniel Rachmilewitz, MD; Simon Lichtiger, MD; Geert D’Haens, MD;

C Janneke van der Woude, MD; Robert Diamond, MD; Delma Broussard, MD;

Ronald Hegedus; Jean Frederic Colombel, MD

ACG 2008

Corticosteroid-Free Clinical Remission at Week 26

SONIC 90

Primary Endpoint

80

100

ents

(%) p<0.001

p=0.009 p=0.022

30.6

44.4

56.8

20

40

60

opor

tion

of P

atie

0

Pro

AZA + placebo IFX + placebo IFX+ AZA

52/170 75/169 96/169

Sandborn, WJ et al. ACG 2008.

Mucosal Healing at Week 26SONIC 91

80

100

ient

s (%

)

p<0.001

p=0 023 p=0 055

16.5

30.1

43.9

20

40

60

opor

tion

of P

ati p 0.023 p 0.055

0

Pro

AZA + placebo IFX + placebo IFX+ AZA

18/109 28/93 47/107

Sandborn, WJ et al. ACG 2008.

Conclusions

I fli i b/AZA h t t d t th i

SONIC 92

• Infliximab/AZA, when started together, was superior to AZA alone

• Infliximab monotherapy was superior to azathioprine monotherapy

I fli i b/AZA bi i h h d• Infliximab/AZA combination therapy, when started together, was superior to infliximab monotherapy

• Patients with high baseline CRP (60% of patients in this study) and/or ulcers at baseline colonoscopy had a particularly strong benefit from early infliximaba particularly strong benefit from early infliximab

• Safety was similar in all 3 arms– There was no trend toward an increased risk of

serious infections with infliximabSandborn, WJ et al. ACG 2008.

6-MP:Maintenance of Remission in Corticosteroid-Dependent CD

6 MP/ d i6-MP/prednisonePlacebo/prednisone91*

60% 4841 mg*

7930 mg

Remission at 12 months Prednisone usage at 12 months(%) (mg)

*P = 0.01.6-MP = 6-mercaptopurine.

Markowitz J et al. Gastroenterology. 1998;114(suppl A):A1032.

SUMMARYUSES OF 6MP/AZATHIOPRINE

I d d i t i i i i CD/UC• Induce and maintain remission in CD/UC• Steroid sparing in IBD• Close fistula in CD• Prevent post op recurrence in CD• Prevent post-op recurrence in CD• Maintain CSA response• Prevent antibody formation with biologicals• Prevent surgery in childhood CDPrevent surgery in childhood CD• ?First line with biologicals and/or steroids

HOW TO USE IMMUNOMODULATORS

• THANK YOU FOR YOUR ATTENTION