COLOSCOPYCOLOSCOPYUC Early StageUC Early Stage

HyperemiaHyperemiaPetechial Petechial

BleedingBleeding FragiabilityFragiability

COLOSCOPYCOLOSCOPYCD Early StageCD Early Stage

AphtoidAphtoidMucosal Mucosal

LesionsLesions

(Ulcers)(Ulcers)

COLOSCOPYCOLOSCOPYUC Floride (Acute) StageUC Floride (Acute) Stage

ConfluatingConfluating(Continious)(Continious)

UlcerationsUlcerationsPseudopolypoPseudopolypo

sissis

COLOSCOPYCOLOSCOPYCD Floride (Acute) StageCD Floride (Acute) Stage

Couble-stone Couble-stone reliefrelief

FissuraFissuraFistulaFistulaSolitary ulcersSolitary ulcers

COLOSCOPYCOLOSCOPYUC Late (chronic) StageUC Late (chronic) Stage

PseudopolypsPseudopolypsLoss of haustraLoss of haustraCarcinomaCarcinoma

COLOSCOPYCOLOSCOPYCD Late (chronic) StageCD Late (chronic) Stage

StenosisStenosisFistulaFistulaPseudopolypsPseudopolypsDiverticulaDiverticula

Radiology / Radiology / CDCD

Couble stoneCouble stoneAphtoid ulcersAphtoid ulcersPseudodiverticulaPseudodiverticulaFistulaFistulaPolymorph ulcersPolymorph ulcers

Activity IndexActivity Index

BasedonBasedon - Clinical Activity- Clinical Activity

- Endoscopical Activity- Endoscopical Activity

- Histological Activity- Histological Activity

- Laboratory Activity- Laboratory Activity

Activity Index /CDActivity Index /CD

Activity Index /UCActivity Index /UC

Differential DiagnosisDifferential Diagnosis

Prognosis / UCPrognosis / UC

80% chronic intermittant80% chronic intermittant15% chronic continious15% chronic continious10% acute fulminant10% acute fulminant

The longer the chronicityThe longer the chronicityThe worse is the prognosis.The worse is the prognosis.

Prognosis / CDPrognosis / CD

“ “ No absolute cure”No absolute cure” MILDMILD MODERATEMODERATE 30% Remission30% Remission İn 1 yearİn 1 year 70% Remission 70% Remission In 2 yearsIn 2 years 50% Remission 50% Remission• 70% - Surgical Intervention70% - Surgical Intervention

POSTOPPOSTOP RefallRefall 1 year 70%1 year 70%2 years 50%2 years 50%

Summary -Prognosis / UCSummary -Prognosis / UC

High Rezidive – QuotientHigh Rezidive – Quotient Good if isolated Procto- Good if isolated Procto-

sigmoiditissigmoiditis Pancolitis Pancolitis HIGH – RiskHIGH – Risk PancolitisPancolitis often OP.often OP.

Summary - Prognosis / CDSummary - Prognosis / CD

High – Rezidive QuotientHigh – Rezidive Quotient Complications Complications OPOP

Goals of Therapy for IBDGoals of Therapy for IBD

Inducing remissionInducing remission Maintaining remissionMaintaining remission Restoring and maintaining nutritionRestoring and maintaining nutrition Maintaining patient’s quality of lifeMaintaining patient’s quality of life Surgical intervention (selection of optimal time Surgical intervention (selection of optimal time

for surgery)for surgery)

Pharma-InformationPharma-Information

1)1) Oral AminosalicylatesOral Aminosalicylates2)2) Topical AminosalicylatesTopical Aminosalicylates3)3) CorticosteroidsCorticosteroids4)4) ImmunsuppressivaImmunsuppressiva5)5) AntibioticsAntibiotics6)6) Biologic agents (anti TNF-alfa)Biologic agents (anti TNF-alfa)

Oral AminosalicylatesOral AminosalicylatesA.A. SULFASALACINSULFASALACIN COLONCOLON

- Sulfapyridine – - Sulfapyridine – CarrierCarrier++- 5-ASA- 5-ASA – Antiinflammatuar – Antiinflammatuar

5-ASA :5-ASA : 3-6 g/d 3-6 g/d INHIBITIONINHIBITION - cyclooxygenase- cyclooxygenase - lipooxygenase- lipooxygenase O2-Radical O2-Radical - neutrophil - neutrophil Clearance Clearance NK-ABsynthesisNK-ABsynthesis depressiondepression

SulfasalacinSulfasalacin

SulfapyridineSulfapyridine - AZO-BINDING- - AZO-BINDING- 5-ASA 5-ASA

AzoreductaseAzoreductase

COECUMCOECUM

Oral AminosalicylatesOral Aminosalicylates

B. MESALAMIN B. MESALAMIN IleumIleum 5-ASA5-ASA ColonColon2 g/d2 g/d EudragitEudragitCapselCapsel

Topical AminosalicylatesTopical Aminosalicylates

5-ASA – FOAM5-ASA – FOAM

SUPPOSITOIRESSUPPOSITOIRES

CORTICOSTEROIDSCORTICOSTEROIDS

ORALORALIVIV useuseTOPICALTOPICALPrednisonePrednisone 60/50/40......10 mg60/50/40......10 mg

OrOrLess side effected new formsLess side effected new formsBudesonidBudesonid 9 mg/d9 mg/d(Endocort / Budenofalk(Endocort / Budenofalk))

CORTICOSTEROIDSCORTICOSTEROIDS

Inhibition of :Inhibition of : Proinflammatory Proinflammatory CytokinesCytokines

Supportion of protective CK. Supportion of protective CK. (IL-4, IL 10)(IL-4, IL 10)

Inhibition of Inflammation MediatorsInhibition of Inflammation Mediators(PAF)(PAF)

Corticosteroids in CD:Corticosteroids in CD:Induction of RemissionInduction of Remission

*Randomized controlled trial†Multicenter prospective trial

Malchow H et al. Gastroenterology. 1984;86:249.Modigliani R et al. Gastroenterology. 1990;98:811.

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

Clinical Remission

% P

atie

nts

30%

82%*

38%

p not calculated 92%†

60%*

17 weeks 18 weeks 7 weeksNCCDS ECCDS GETAID

0

20

40

60

80

100 CorticosteroidsPlacebo

Remission Rates in Acute Crohn’s StudiesRemission Rates in Acute Crohn’s Studieswith Budesonide CIRwith Budesonide CIR

Bud CIRBud CIR Bud CIRBud CIR PlaceboPlacebo Pentasa Pentasa®® Prednisolone Prednisolone 9 mg QD9 mg QD 4.5 mg BID4.5 mg BID 2 g BID2 g BID 40 mg 40 mg

Remission rates atRemission rates at8 weeks (%)8 weeks (%)

Greenberg 1994; Rutgeerts 1994; Thomsen 1998

0

10

20

30

40

50

60

70

ImmunsuppressivaImmunsuppressivaA.A. Azathiopyrin (AZT)Azathiopyrin (AZT)6-Mercaptopurin6-Mercaptopurin- Cell replication ]- Cell replication ]B.B. Methotrexat (MTX)Methotrexat (MTX)- Antimetabolite- Antimetabolite- Inhibition of- Inhibition of Dihydrofolacid reductaseDihydrofolacid reductase++ Lymphocytic ProliferationLymphocytic ProliferationC.C. CyclosporinCyclosporin- Immunmodulater- Immunmodulater- T-Cell depression- T-Cell depression

AntibioticsAntibiotics

• MetronidazolMetronidazol

Therapeutic PyramidTherapeutic Pyramidfor Active Crohn’s Diseasefor Active Crohn’s Disease

SevereSevere

ModerateModerate

Aminosalicylates/AntibioticsAminosalicylates/Antibiotics

CorticosteroidsCorticosteroids

ImmunomodulatorsImmunomodulators

SurgerySurgery

InfliximabInfliximab

??(Prednisone)(Prednisone)

MildMild

(Budesonide)(Budesonide)

Outcomes for Mild-Moderate DiseaseOutcomes for Mild-Moderate Disease

Mild-Moderate Disease

AminosalicylateResponse 40-50%

Antibiotic(Colonic Disease)Response 40-50%

Budesonide(Ileum-Right Colon)Response 50-65%

PlaceboResponse 30-40%

Biologic agentsBiologic agents

•İnfliximapİnfliximap•adaluminapadaluminap

Infliximab: Mechanism of Infliximab: Mechanism of ActionAction

Healing of Colonic UlcerationHealing of Colonic Ulcerationwith Infliximabwith Infliximab

Van Dullemen HM et al. Gastroenterology 1995;109:129-135

PretreatmentPretreatment 4 weeks 4 weeks post-treatmentpost-treatment

REMICADEREMICADE®® (infliximab) in Patients with (infliximab) in Patients with Fistulizing Crohn’s DiseaseFistulizing Crohn’s Disease

Complete Response: All Fistulas ClosedComplete Response: All Fistulas Closed

P=0.001

P=0.04

*Placebo=Conventional Therapy*

Present, et al.

Present D, et al. N Engl J Med. 1999;340:1398-1405.

Incidence of Incidence of Antibodies-to-Infliximab (ATI) Antibodies-to-Infliximab (ATI) Maintenance Studies*Maintenance Studies*

Maintenance StudiesMaintenance Studies

% of Pts without ATI% of Pts without ATI% of Pts with ATI% of Pts with ATI % of Patients Inconclusive% of Patients Inconclusive††

* pts with evaluable samples* pts with evaluable samples

ACCENT I ACCENT I CDCD

n = 514n = 514Week 72Week 72

16

2758

ACCENT IIACCENT IICDCD

n = 258n = 258Week 54Week 54

17

52

31

ATTRACTATTRACTRARA

n = 295n = 295Week 102Week 102

9

56

36

Antibody-to-Infliximab (ATI) StatusAntibody-to-Infliximab (ATI) Status

†† pts with long-lasting serum concentrations of infliximab and never ATI (+)pts with long-lasting serum concentrations of infliximab and never ATI (+)

11

49

40

ASPIREASPIRERARA

n = 629n = 629Week 54Week 54

ASPIRE: Integrated Safety Summary, Sep. 18, 2003

InfliximabInfliximabInfliximab indicated

Exclude enteric pathogenExclude abscess, strictureExclude latent/active TB

Infliximab 5 mg/kg wks 0, 2, 6Consider steroid pre-treatmentConsider acetaminophen,

diphenhydramine pre-treatment

Infliximab 10 mg/kg

Surgery or investigational Rx

Observe up to 8 wks

Recurrent sx≤ 4 wks

Recurrent sx> 4 - < 8 wks

Recurrent sx≥ 8 wks

Response

Maintain infliximab5 mg/kg q 4-8 wks

Inadequate response Escalate dose or

shorten intervalMaintain infliximab5 mg/kg q 8 wksLoss of

response

Inadequate response

Inadequate response

(Start 6-MP/AZA or MTX)

Medical Management / CDMedical Management / CD

Long-term Therapy :Long-term Therapy :

AA – IMMUNSUPPRESSIVA – IMMUNSUPPRESSIVAA2T :A2T : 25/50 MG Tbl25/50 MG Tbl..++- CS- CSfor Relapsing Fallsfor Relapsing Falls

B – B – SURGERYSURGERYRemissions – Remissions – maintenancemaintenance

- 5.ASA :- 5.ASA : 2 g/d 2 g/d 2 years2 years

MethotrexateMethotrexate

Historical OverviewHistorical Overview1948 1948 –– first “designer drug” specific first “designer drug” specific

antagonist of folic acidantagonist of folic acid1950’s 1950’s –– serendipitous discovery serendipitous discovery

of activity in psoriasisof activity in psoriasis1960’s 1960’s –– widely used for psoriasis widely used for psoriasis ––

hepatotoxichepatotoxic1966 1966 –– Enderlin reported use in RA Enderlin reported use in RA1985 1985 –– Wienblatt defines Wienblatt defines

pharmacokinetics in RApharmacokinetics in RA1980-2000 1980-2000 –– treatment of choice treatment of choice

for RAfor RA

Feagan. N Eng J Med. 1995;332(5):292-7

% R

espo

nse

% R

espo

nse

0 0

25 25

19.1%19.1% 39.4%39.4%

P P =0.025=0.025

PlaceboPlacebo MTXMTX

5050

MTX Results: RemissionMTX Results: Remission

Methotrexate in IBD: ToxicityMethotrexate in IBD: Toxicity

MajorMajorHepaticHepaticMyelosuppressiveMyelosuppressivePulmonaryPulmonaryFertility-relatedFertility-relatedTeratogenicTeratogenicEnteritic/coliticEnteritic/colitic

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

MinorMinorGastrointestinalGastrointestinalAlopecia-inductiveAlopecia-inductiveAllergicAllergicNeurologicNeurologic

CD: Moderate to SevereCD: Moderate to SevereModerate CD

Observe TaperSuccess

PO Steroids

6-MP/AZA

Consider change to MTX

Add infliximab

Surgery or investigational

therapy

Severe CD

IV Steroids

Adequate response

Inadequate response

Consider infliximab+ 6-MP/AZA or MTX

Consider surgery

Adequate response

Failure

Maintain6-MP/AZA or MTX

Maintaininfliximab +

6-MP/AZA or MTX

Adequate response

Adequate response

Adequate response

Inadequate response

Inadequate response/intolerant

Inadequate response/intolerant

Inadequate response/intolerant

Medical Management / UCMedical Management / UC

Refractory States or Chronic Refractory States or Chronic active Formsactive Forms ImmunsuppressivaImmunsuppressiva

A2T :A2T :+ ?+ ?CsCsOPOP ProctocolectomyProctocolectomy

(= Definitive Cure)(= Definitive Cure)

Ulcerative ColitisUlcerative Colitis

Remissions – MaintenanceRemissions – Maintenance

5-ASA5-ASA 2 gr/d2 gr/d

OP – Indications / CDOP – Indications / CD

BleedingBleeding IleusIleusStenosisStenosisFistulaFistulaCarcinomCarcinomPerforationPerforationAbcessAbcess

OP – Indications / UCOP – Indications / UC

Toxic MegacolonToxic MegacolonPerforationPerforationSevere BleedingSevere Bleeding