Transcript
Page 1: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Treatment Algorithms in Ulcerative ColitisTreatment Algorithms in Ulcerative Colitis

Page 2: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Premise and PreviewPremise and Preview

In Most Clinical Scenarios ofIn Most Clinical Scenarios ofUlcerative ColitisUlcerative Colitis

Therapy is SequentialTherapy is Sequential

Page 3: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

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 Surgical intervention (selection of optimal time for surgery)time for surgery)

Page 4: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis
Page 5: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Inflammatory Bowel Disease

• UC is limited to the mucosa of the large bowel.• CD is transmural and may affect any portion of the

GI tract.• Some patients exhibit signs and symptoms of both

and up to 25% of patients with IBD do not separate cleanly into either classification.

• UC and CD can exhibit extraintestinal manifestations (i.e., symptoms that involve organs other than the intestines).

Page 6: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Environmental Risk Factors

• Smoking UC , CD. • CHO & sugar CD.• Oral contraceptives CD. - The relative risk of CD is reported to be (8.0) in women who

have used oral contraceptives for > 5 yrs - Relative risk of (1.2) in women who have not used oral

contraception.• Breastfeeding CD.• diarrheal illness during infancy UC.• NSAIDs CD. ( 5-fold)• IBD is not caused by stress. stress may alter the immune

system and increase the susceptibility to disease.

Page 7: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Epidemiology

• Northern countries have the incidence of IBD; Southern European countries have a incidence.

• In the U.S., incidence of IBD is reported to be in African

Americans than in Caucasians.• Migrants who move from an area of lower incidence to an area

of higher incidence develop a higher incidence of IBD.

• UC and CD are more frequent in populations of higher socioeconomic class.

• IBD the highest peak occurring in people age 15–30 yrs of age & a smaller peak occurring in people 60–80 yrs of age.

Page 8: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Anatomic Comparison of UC to CD

Ulcerative Colitis Crohn’s Disease

• Continuous superficial layers of the bowel, not associated with granulomas.

• Limited to the colorectal area ( proctitis or the entire colon ).

• Crypt abscesses [accumulations of polymorphonuclear neutrophil cells], necrosis of the epithelium, edema, hemorrhage, & surrounding accumulations of chronic inflammatory cells.

• The mucosa: friable, granular, and erythematous.

• Discontinuous ulceration transmural, patchy , granulomatous inflammation.

• Involve the entire GI tract from the mouth to the anus.

• Involve fistula formation, & perianal.

• The inflammatory infiltrate consists: T & B lymphocytes, macrophages,& plasma cells.

Page 9: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis
Page 10: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

The Sigmoidoscopic / Colonoscopic

Abnormality UC CD

Mucosal granularity + ±

Mucosal friability + ±

“Cobblestoning” - +

Thick interhaustral septum + +

Pseudopolyps + +

Strictures + ++

Mucosal bridging + ±

Ulcers In abnormal mucosal In normal mucosa

Mucosal involvement Contiguous, circumferential Discontinuous, not circumferential

Rectum Involved ±

Vascular patter Distorted ±

Page 11: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Ulcerative Colitis

• Symptoms of UC:1. Constipation.

2. Rectal bleeding.

3. Urgency.

4. Diarrhea.

5. Abdominal discomfort.

6. Decreased appetite, & weight loss.

7. Bloody stools.

Page 12: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Remission & Relapse of UC

• Completely relapse-free course is only 18.4% after 5 yrs & Completely relapse-free course is only 10.6% after 25 yrs.

• The probability of unrelenting disease is 0.1%.

• The annual chance of experiencing a year in remission after a relapse is 30%.

Factors associated with a relapse: 1. Aspirin & other NSAIDs. 2. Respiratory illness.

3. Enteric infection (e.g. ,Campylobacter jejuni)

4. Antibiotics, oral contraceptives, & psychological stress.

Page 13: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Complication of U.C.

1. Massive hemorrhage. 2. Toxic megacolon.3. Perforation. 4. Strictures. 5. Sclerosing cholangitis, Cholangiocarcinoma.6. Extraintestinal symptoms [ acute arthropathy sacroiliitis,

ankylosing spondylitis, ocular complications,& hepatobiliary disease].

7. Colon cancer.• The cancer risk is highest in patients with UC > 10 years.• The annual incidence of colon cancer in patients with UC of

> 10 years is 0.8–1%

Page 14: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Referral Population Cohort:Referral Population Cohort:Disease Distribution at PresentationDisease Distribution at Presentation

nn == 11161116

37%37%

17%17%

46%46%

Farmer RG, Easley KA, Ranking GB. Dig Dis Sci 1993;38(6):1137-1146

Page 15: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Classification of Severity of IBDClassification of Severity of IBD

Variable Mild Disease Severe Disease Fulminant Disease

Stools < 4/day > 6/day > 10/day

Blood in stool Intermittent Frequent Continuous

Temperature Normal > 37.5°C > 37.5°C

Pulse Normal >90 beats/minute >90 beats/minute

Hemoglobin Normal <75 of normal value Transfusion required

ERS ≤ 30 mm/hour >30 mm/hour >30 mm/hour

Colonic features on radiograph

Normal Air, edematous wall,

thumbprintingDilatation of colon (>5.0 cm diameter)

Clinical signsMinimal

tendernessAbdominal tenderness

Increased abdominal distension, tenderness

Page 16: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

> 30> 30> 30> 30< 30< 30ESR ESR

Transfusion requiredTransfusion required<75% of normal<75% of normalNormalNormalHemoglobinHemoglobin

> 90> 90> 90> 90NormalNormalPulsePulse

> 37.5> 37.5> 37.5> 37.5NormalNormalTemperature (C)Temperature (C)

ContinuousContinuousFrequentFrequentIntermittentIntermittentBlood in stoolBlood in stool

>10>10>6>6<4<4Stools (#/day)Stools (#/day)

MILDMILDSEVERESEVERE

FULMINANTFULMINANT

Colitis Activity AssessmentColitis Activity Assessment

Page 17: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

UC: Natural HistoryUC: Natural History

0

20

40

60

80

100

Disease Activity

Pa

tien

ts w

ith

UC

(%

)

Disease Severity at PresentationDisease Severity at Presentation

Mild Activity (20%)

Moderate Activity(71%)

Severe Activity (9%)

Mild Activity:Mild Activity: < 4 stools daily< 4 stools dailyNo systemic disturbanceNo systemic disturbanceESR: NlESR: Nl

Moderate Activity:Moderate Activity: > 4 stools daily > 4 stools dailyMinimal systemic effectsMinimal systemic effects

Severe Activity:Severe Activity: >> 6 stools daily 6 stools daily

Bloody stoolsBloody stools FeverFever

TachycardiaTachycardiaAnemiaAnemiaESR > 30 mm/hrESR > 30 mm/hr

Hendriksen C, Kreiner S, Binder V. Gut 1985;26:158-163

Page 18: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

UC Natural HistoryUC Natural History

0%

10%

20%

30%

40%

0 5 10 15 20Years

Col

ecto

my

Rat

e (%

)

0%

20%

40%

60%

80%

100%

Disease Activity

Pat

ient

s w

ith U

C (%

)

.

No Symptoms(50%)

Low Activity(30%)

Moderate-High Activity (20%)

10%10%

23%23%

31%31%

Disease course one year after diagnosisDisease course one year after diagnosis

Page 19: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Natural Course of Ulcerative ColitisNatural Course of Ulcerative Colitis

Langholz E et al.Scand J Gastroenterol. 1996;31:260-266.Based on a multivariate analysis.

Proctitis Left-Sided Pan-colitis

Progression

Surgery

Regression

Page 20: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Treatment of IBDTreatment of IBD

Pharmacological Management:Pharmacological Management:1.1. Aminosalicylates.Aminosalicylates.

2.2. Cortisone or Steroids. Cortisone or Steroids.

3.3. Immunomodulatory and Immunomodulatory and Immunosuppressive Agents Immunosuppressive Agents [Azathioprine and 6-MP, [Azathioprine and 6-MP, Methotrexate, Cyclosporine]Methotrexate, Cyclosporine]

4.4. Infliximab.Infliximab.

5.5. Antibiotics.Antibiotics.

6.6. Miscellaneous Therapies (Heparin).Miscellaneous Therapies (Heparin).

Page 21: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Therapeutic Pyramid for Therapeutic Pyramid for Active UCActive UC

SevereSevere

ModerateModerate

MildMild

Systemic CorticosteroidsSystemic Corticosteroids

AminosalicylatesAminosalicylates

SurgerySurgery

Oral SteroidsOral SteroidsAZA/6-MPAZA/6-MP

CyclosporineCyclosporine

Infliximab Infliximab

Page 22: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Sequential IndicationsSequential Indications

Induction of remissionInduction of remission• Treatment of acute diseaseTreatment of acute disease

Maintenance of remissionMaintenance of remission • Medical maintenanceMedical maintenance• Steroid-sparing Steroid-sparing

Page 23: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Ulcerative Colitis: Ulcerative Colitis: Induction of RemissionInduction of Remission

• Mild diseaseMild disease– AminosalicylateAminosalicylate

• Topical therapy (distal disease)Topical therapy (distal disease)• Oral therapy (extensive disease)Oral therapy (extensive disease)

Page 24: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Generic Name Trade Name Formulation Site of Release

Balsalazide

Up to 6.75 g/dayColazal

4-aminobenzoyl-β -alanine carrier

Colon

Mesalamine

Up 4 g/dayPentasa

Ethylcellulose covering individually coated

microgranules

Duodenum,jejunum,

ileum,colon

Mesalamine

Up to 4.8 g/dayAsacol

pH dependent, releasing drug at pH ≥ 7

Terminal ileum,colon

Mesalamine

Up to 4 g/dayRowasa Liquid enema

Below the splenic flexure

Mesalamine

Up to 500 mg 2 times/day

Rowasa Canasa

SuppositoryRectum

Colon

Olsalazine

Up to 3 g/day bDipentum

Two molecules of mesalamine

Colon

Sulfasalazine

Up to 6 g/dayAzulfidine Sulfapyridine carrier Colon

Page 25: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Chemical Structure of 5-Aminosalicylate Chemical Structure of 5-Aminosalicylate (Mesalamine) and Its Pro-Drugs: Sulfasalazine, (Mesalamine) and Its Pro-Drugs: Sulfasalazine,

Balsalazide, and OlsalazineBalsalazide, and Olsalazine

5-aminosalicylic acid5-aminosalicylic acid SulfasalazineSulfasalazine

BalsalazideBalsalazide OlsalazineOlsalazine

Page 26: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Oral 5-ASA Release SitesOral 5-ASA Release Sites

StomachStomach

Small Small IntestineIntestine

Large Large IntestineIntestine

Azo bondAzo bond

AZO-AZO-COMPOUNDSCOMPOUNDS

Mesalamine in Mesalamine in microgranulesmicrogranules

PentasaPentasa® ®

MesalamineMesalaminew/ eudragit-Sw/ eudragit-S

AsacolAsacol®®

Page 27: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Comparative Doses:Comparative Doses:Mild to Moderate UCMild to Moderate UC

RecommendedRecommended

Treatment DoseTreatment Dose

EquivalentEquivalent

5-ASA dose5-ASA dose

SulfasalazineSulfasalazine 3-4 grams3-4 grams 1.2-1.6 grams1.2-1.6 grams

MesalamineMesalamine 2.4 grams2.4 grams 2.4 grams2.4 grams

BalsalazideBalsalazide 6.75 grams6.75 grams 2.4 grams2.4 grams

Page 28: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

5-ASA Delivery Systems5-ASA Delivery Systems

PENTASA®

ASACOL®®

SASP/OLS/BALS

ENEMA

SUPP

JEJUNUM / ILEUM / ASC / DES / SIG / RECTJEJUNUM / ILEUM / ASC / DES / SIG / RECT

Page 29: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

SPD476 uses MMX technology to deliver SPD476 uses MMX technology to deliver 5-ASA to the entire colon5-ASA to the entire colon

Gastro-resistant layer Hydrophilic polymers

5-ASA Lipophilic excipients

• Delayed and extended drug release Delayed and extended drug release

formulation containing 1.2g 5-ASAformulation containing 1.2g 5-ASA• Highest 5-ASA drugHighest 5-ASA drug

loading per tabletloading per tablet

MMX = MMX Multi Matrix System™

Page 30: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Sulfasalazine Dose/ToxicitySulfasalazine Dose/Toxicity

1G 2G 3G 4G

100%100%

ResponseResponse

ToxicityToxicity

Page 31: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Aminosalicylate Dosing for ReductionAminosalicylate Dosing for Reductionof Signs/Symptomsof Signs/Symptoms

Dose-Response without IntoleranceDose-Response without Intolerance

% R

esp

on

se

Schroeder, Tremaine, Ilstrup, 1997; Hanauer, 1993; Sninsky, 1991

0

10

20

30

40

50

60

70

80

PLACEBO 1.6G 2G 2.4G 4G 4.8G

Page 32: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

ASCEND I & II:ASCEND I & II:Pooled DataPooled Data

• Two Phase III, multi-center, randomized, double-blind Two Phase III, multi-center, randomized, double-blind controlled studiescontrolled studies

• 423 analyzable patients with moderately active UC 423 analyzable patients with moderately active UC randomized to oral mesalamine – 4.8 g/day (800 mg randomized to oral mesalamine – 4.8 g/day (800 mg tablets) or 2.4 g/day (400 mg tablets) x 6 weekstablets) or 2.4 g/day (400 mg tablets) x 6 weeks

• Treatment with 4.8 g/day provided a statistically significant Treatment with 4.8 g/day provided a statistically significant efficacy benefit over 2.4 g/day in moderately active diseaseefficacy benefit over 2.4 g/day in moderately active disease

• Both doses of mesalamine had similar safety profiles, and Both doses of mesalamine had similar safety profiles, and both were well toleratedboth were well tolerated

Hanauer et al. DDW 2005

Page 33: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

ASCEND I & II:ASCEND I & II:Treatment Success at Weeks 3 & 6Treatment Success at Weeks 3 & 6

PP=0.0034=0.0034 PP=0.058=0.058

n=223 n=223n=198 n=200

**

Pooled Data: Moderately Active UCPooled Data: Moderately Active UC

58%53%

72%

62%

00

2020

4040

6060

8080

Week 3Week 3 Week 6Week 6

% o

f P

atie

nts

Im

pro

ved

% o

f P

atie

nts

Im

pro

ved

2.4 g/day2.4 g/day

4.8 g/day4.8 g/day

Page 34: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Oral (2.4 g) vs. Rectal (4 g)Oral (2.4 g) vs. Rectal (4 g)Mesalamine for Distal UCMesalamine for Distal UC

% R

esp

on

se%

Res

po

nse

Safdi. Am J Gastroenterol 1997

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

1 week1 week 2 weeks2 weeks 3 weeks3 weeks 6 weeks6 weeks

Oral Oral

RectalRectal

CombinedCombined

Page 35: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Addition of Rectal Mesalamine to Oral Addition of Rectal Mesalamine to Oral Mesalamine in Mesalamine in PanPancolitiscolitis

Marteau, P et al. Gut 2005;54:960-965Marteau, P et al. Gut 2005;54:960-965

Percentage of patients achieving remission (ulcerative Percentage of patients achieving remission (ulcerative colitis disease activity index (UCDAI) of 0 or 1) or colitis disease activity index (UCDAI) of 0 or 1) or

improvement (decrease in UCDAI >2 points). improvement (decrease in UCDAI >2 points).

Page 36: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Marteau, P et al. Gut 2005;54:960-965

Remission and improvement rates

Page 37: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Maintenance Therapies for Maintenance Therapies for Ulcerative ColitisUlcerative Colitis

• AminosalicylatesAminosalicylates

• Azathioprine/6-MPAzathioprine/6-MP

Page 38: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Aminosalicylate:Aminosalicylate: Maintenance Therapy Maintenance Therapy

• SulfasalazineSulfasalazine– Dose-response limited by intoleranceDose-response limited by intolerance– Conventional dose-reduction based Conventional dose-reduction based

on balance of efficacy/toxicityon balance of efficacy/toxicity

Page 39: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Oral Mesalamine DosingOral Mesalamine Dosingfor UC Maintenancefor UC Maintenance

% R

emis

sio

n%

Rem

issi

on

MonthsMonths

Hanauer. Ann Intern Med 1996

PLCBPLCB

00

2020

4040

6060

8080

100100

120120

11 22 33 44 55 66 77 88 99 1010 1111 1212

1.6 g1.6 g

0.8 g0.8 g

Page 40: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Oral vs. Topical MesalamineOral vs. Topical Mesalaminefor Maintenance of Distal UCfor Maintenance of Distal UC

% R

emis

sio

n%

Rem

issi

on

MonthsMonths

D’Albasio. Am J Gastroenterol 1997

4 g QOD enema4 g QOD enema

1.6 g/day oral1.6 g/day oral

00

2020

4040

6060

8080

100100

120120

22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424

Page 41: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Frequency of Topical Mesalamine for Frequency of Topical Mesalamine for Maintenance of Distal UCMaintenance of Distal UC

Miner. Gastroenterol 1994;106:A736

% R

emis

sio

n

0

10

20

30

40

50

60

70

80

90

6 wks 12 wks 24 wks

QHS

QOD

Q3D

Placebo

Page 42: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Combined Oral + Topical Mesalamine for Combined Oral + Topical Mesalamine for Maintenance of Distal UCMaintenance of Distal UC

D’Albasio. Am J Gastroenterol 1997

MonthsMonths

% R

emis

sio

n%

Rem

issi

on

00

2020

4040

6060

8080

100100

120120

11 22 33 44 55 66 77 88 99 1010 1212

Oral 1.6 g + topicalOral 1.6 g + topical2/wk2/wk

Oral 1.6 gOral 1.6 g

Page 43: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Outcome Azathioprine n=25

Placebo n=25

Remission

Complete

Partial

17

14

3

16

10

6Relapse 3* 6Withdrawn

Side effects

Poor compliance

5

3*

2

3

0

3

*P<0.05

AZA in Severe UC: 1 Yr Placebo-AZA in Severe UC: 1 Yr Placebo-Controlled Trial - ResultsControlled Trial - Results

Sood A, et al. Indian J Gastroenterology. 2000;19:14-16.

Page 44: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Aminosalicylates Side effects:

Dose-dependent side effects:

1. Headache.

2. Dyspepsia.

3. N, V, anorexia.

4. Alopecia.

Idiosyncratic reactions:

1. Hypersensitivity reactions (rash).

2. Dronchospasm.

3. Hemolytic anemia.

4. Agranulocytosis

5. Hepatitis, pancreatitis.

6. Male infertility.

7. Interstitial nephritis.

Page 45: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

CorticosteroidCorticosteroid

M.O.A:

1. Anti-inflammatory effects and suppress the immune system.

2. production of some pro-inflammatory cytokines

3. Directly inhibit many leukocyte functions.

Dose: prednisone (40–60 mg/day), hydrocortisone(100 mg q 6–8 hrs), methylprednisolone (40-60 mg/day), Budesonide (9-15 mg/day).

Adverse Reactions: sleep disturbances, mood alterations, adrenal suppression, glaucoma, cataracts, osteoporosis.

Monitoring Parameters: BP, Blood glucose, electrolytes, Ca+2 correct level.

Page 46: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Azathioprin and 6-MPAzathioprin and 6-MP

M.O.A:

1. Inhibiting the synthesis of protein, (RNA,DNA).

2. Direct anti-inflammatory properties

3. Inhibit cytotoxic T cell and natural killer cell function.

Dose: azathioprine (1.5–3.0 mg/kg/day),

6-MP (1–1.5 mg/kg/day).

Adverse Reactions: leukopenia, pneumonia, thrombocytopenia, pancreatitis, lymphoma, bone marrow toxicity.

Monitoring Parameters: CBC, Platelet counts, total bilirubin, alkaline phosphatase, TPMT phenotype before therapy.

Page 47: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Controlled Trial of AZA in Management Controlled Trial of AZA in Management of Chronic UC - Resultsof Chronic UC - Results

Rosenberg J, et al. Gastroenterology. 1975;65:96-99.

P=NS

**P<0.05 compared to placebo and baseline

Total General Health Score* Reduction of Prednisone Dose (mg/day)

*Combined scores for the number of bowel movements, state of health, findings on proctoscopy and rectal biopsy.

Mea

n T

ota

l S

core

Re

du

cti

on

of

Pre

dn

iso

ne

Do

se

(m

g/d

ay

)

**

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Controlled Trial of AZA in Management Controlled Trial of AZA in Management of Chronic UC - Resultsof Chronic UC - Results

23.2 22.2

13.6

2.3

0

5

10

15

20

25

30

Placebon=20

Azathioprinen=24

Mea

n A

ctiv

ity

Sco

re

P<0.001

7.7 8.1

5.3

4.2

0123456789

10

Placebon=20

Azathioprinen=24

Red

uct

ion

of

Pre

dn

iso

ne

Do

se

(mg

/day

)

*p=NS

Mean Activity Score at Baseline and 6 Months

Reduction of Prednisone Dose (mg/day) at Baseline and 6 Months

*p<0.001

Kirk A, et al. British Medical Journal. 1982;284:1291-2.

*Comparison between azathioprine and placebo at 6 Months

Page 49: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Methotrexate for Active UC and Induction Methotrexate for Active UC and Induction of Remissionof Remission

Oren R, et al. Gastroenterology. 1996;110:1416.

0102030405060708090

100

Percent of Patients in 1st Remission

Placebo

Methotrexate 12.5 mg/wk PO

% P

atie

nts

49% 47%

n=37

n=30P=NS

Time to first remission for MTX was 4.1 months vs. placebo (3.4 months)

Page 50: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Complications of Surgery: Ileal Pouch-Complications of Surgery: Ileal Pouch-Anal Anastomosis (IPAA)Anal Anastomosis (IPAA)

– Pelvic sepsis– Leakage – Incontinence– Intestinal obstruction– Anastomotic strictures– Sexual dysfunction– Pouchitis– Female infertility

Lichtenstein G. The Clinician’s Guide to Inflammatory Bowel Disease. SLACK;2003:127–129.

Potential short-term complications

Potential long-term complications

Page 51: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Complications of UC SurgeryComplications of UC Surgery

• Mortality (<0.5%)1

• 3-10 stools/24 hrs so bowel pattern not normal1

• Impotence (1.5%)2

• Pouchitis (10-60%)1

• Small bowel obstruction (20%)1

• Decrease in female fertility (56-98%)3-5

• Pouch-vaginal fistula (4%)1

1Sagar PM, Pemberton JH. In Satsangi J, Sutherland L, et al, eds. Inflammatory Bowel Diseases. Spain: Elsevier Limited; 2003:491 511.

2Pemberton JH, et al. Ann. Surg. 1987;206(4):504-513. 3Olsen, KO, et al. Gastroenterology. 2002;122:15-19.

4Johnson P, et al. Dis Colon Rectum. 2004;47;1119–1126. 5Gorgun E, et al. Surgery. 2004;136(4):795–803.

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Delaney CP, et al. Ann Surg. 2003;238:221-228.

Ileal Pouch –Functional OutcomeIleal Pouch –Functional Outcome

Age in Years

10 year postoperative <45 46-55 56-65 >65# of BM / 24 Hours 5.5 5.7 6.2 4.6

Never Incontinent (%) 56 46 42 33

Nocturnal Seepage (%) 39 48 39 60

Majority of patients had UC other diseases included Crohn’s disease, indeterminate colitis, familial polyposis, and cancer

Page 53: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Ileal Pouch: Cumulative Incidences Ileal Pouch: Cumulative Incidences PregnancyPregnancy

MonthsControls (n=914)

Before Colectomy

(n=84)

After IPAA

(n=149)12 75% 78% 18%*24 82% 85% 27%*60 88% 90% 36%*

*P<0.001 vs. Controls

Olsen KO, et al. Gastroenterology. 2002;122:15-19.

Page 54: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

54IN

0559

4?

CyclosporineCyclosporine

• Dose: IV 4mg/kg/day , PO 6-8 mg/kg/day.

• Adverse Reactions: nephrotoxicity, bone marrow suppression, hyperlipidemia, hypertension, neurotoxicity, hepatotoxicity.

• Monitoring Parameters: Cyclosporine blood level 300 ng/ml and 400 ng/ml, cholesterol levels, srcr, BUN, BP.

Page 55: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

20Patients

2

81

9

11

Cyclosporine in Patients withCyclosporine in Patients withSevere Ulcerative ColitisSevere Ulcerative Colitis

Cyclosporine

No Response: surgery

Response

Elective colectomy

Oral Cyclosporine

Lichtiger S et al. NEJM 1994

Page 56: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

IV Cyclosporine: Major ToxicityIV Cyclosporine: Major Toxicity

Renal insufficiency Renal insufficiency 23%23%

InfectionInfection 20%20%

SeizuresSeizures 3%3%

DeathsDeaths 2%2%

AnaphylaxisAnaphylaxis 1%1%

Sternthal J et al. Gastroenterol 1996

Page 57: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

InfliximabInfliximab

M.O.A:

1. Its a chimeric monoclonal antibody.

2. High-affinity to binds with TNF-α on the surface of macrophages and T cells which increases the destruction of those cells.

3. Its neutralizes the pro-inflammatory actions of TNF-α

Dose: given as a single 5 mg/kg IV over 2 hours. (5 mg/kg at zero,2 and 6 wks followed by a dose of 5 mg/kg every 8 wks

Adverse Reactions: sepsis, malignancies, hematologic disorders, autoimmune disorders, precipitate tuberculosis (TB) . transient infusion reaction.

Page 58: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Study DesignStudy Design• Multicenter, randomized, double-blind, placebo-Multicenter, randomized, double-blind, placebo-

controlled, parallel-treatment group trial controlled, parallel-treatment group trial • Conducted globally at 62 sitesConducted globally at 62 sites• 364 subjects with moderately to severely active 364 subjects with moderately to severely active

ulcerative colitis were randomized and treated: ulcerative colitis were randomized and treated: – 121 in the placebo treatment group121 in the placebo treatment group

– 121 in the REMICADE121 in the REMICADE®® (infliximab) 5 mg/kg treatment (infliximab) 5 mg/kg treatment groupgroup

– 122 in the 122 in the REMICADEREMICADE 10 mg/kg treatment group 10 mg/kg treatment group

ACT 1

Data on File, Centocor, Inc.

Page 59: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Patient PopulationPatient Population• Subjects with:Subjects with:

– Moderately to severely active ulcerative colitis Moderately to severely active ulcerative colitis (UC):(UC):

• Mayo score Mayo score 6 points (on 12 point scale) 6 points (on 12 point scale)• Endoscopy subscore Endoscopy subscore 2 points 2 points

• Subjects must meet at least 1 of the Subjects must meet at least 1 of the following criteria:following criteria:– Current treatment with ≥ 1 of the following:Current treatment with ≥ 1 of the following:

• Oral corticosteroids, 6‑mercaptopurine (6-MP), or Oral corticosteroids, 6‑mercaptopurine (6-MP), or azathioprine (AZA) azathioprine (AZA)

– Have failed to successfully taper, tolerate, or Have failed to successfully taper, tolerate, or respond to corticosteroids within the past 18 respond to corticosteroids within the past 18 monthsmonths

– Have failed to tolerate or respond to 6-MP or Have failed to tolerate or respond to 6-MP or AZA within the previous 5 yearsAZA within the previous 5 years

ACT 1

Data on File, Centocor, Inc.

Page 60: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Study DesignStudy Design

• Infusions

ACT 1

Randomization of patients

Final Evaluation

Week 0

Week 2

Week 6

Week 8

Week 14

Week 22

Week 30

Visits

Week 46

Week 54

REMICADE® (infliximab)

5 mg/kgREMICADE® (infliximab)

5 mg/kgPlacebo

REMICADE 10 mg/kg

•••

•••

•••

Primary endpoint (clinical response)Major secondary endpoints (clinical remission, mucosal healing)

Major secondary endpoints (clinical response, clinical remission)• • •

••

••

••

••

••

••

Week 38

Data on File, Centocor, Inc.

Page 61: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Clinical Response at Week 8 and Week 30Clinical Response at Week 8 and Week 30

ACT 1

Intent-to-treat AnalysisPatients in all groups with baseline medication were continued on stable doses

REMICADE US Package Insert.

*p<0.001†p<0.01

*

*

*

Page 62: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Clinical Response at Week 8 by Clinical Response at Week 8 by Corticosteroid Refractory StatusCorticosteroid Refractory Status

ACT 1

Data on File, Centocor, Inc.Data on File, Centocor, Inc.

62

†p=0.010‡p=0.005*p<0.001

35.3 37.9

77.4*

66.7*67.7

59.3

0102030405060708090

100

Corticosteroid Refractory Subjects

Noncorticosteroid RefractorySubjects

Pro

po

rtio

n o

f P

atie

nts

(%

) †p=0.010‡p=0.005*p<0.001

n=12/34 n=24/31 n=21/31 n=33/87 n=60/90 n=54/91

Page 63: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Clinical Remission at Week 8 and Week 30Clinical Remission at Week 8 and Week 30ACT 1

REMICADE US Package Insert.

Intent-to-treat AnalysisPatients in all groups with baseline medication were continued on stable doses

15 16

393432

37

0

10

20

30

40

50

60

70

80

90

100

Week 8 Week 30

Pro

po

rtio

n o

f P

ati

en

ts (

%)

Placebo Infusion 5 mg/kg REMICADE® (infliximab) 10 mg/kg REMICADE

† **

*p<0.001†p<0.01

*

Page 64: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Mucosal Healing at Week 8 and Week 30Mucosal Healing at Week 8 and Week 30

ACT 1

REMICADE US Package Insert.

Intent-to-treat AnalysisPatients in all groups with baseline medication were continued on stable doses

3425

62

5059

49

0

10

20

30

40

50

60

70

80

90

100

Week 8 Week 30

Pro

po

rtio

n o

f P

ati

en

ts (

%)

Placebo Infusion 5 mg/kg REMICADE® (infliximab) 10 mg/kg REMICADE

**

*

*p<0.001

*

Page 65: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Clinical Remission Clinical Remission Without Corticosteroids at Week 30Without Corticosteroids at Week 30

ACT 1

Data on File, Centocor, Inc.

65

10

22

0

5

10

15

20

25

30

Pro

po

rtio

n o

f P

atie

nts

(%

)

Placebo Combined REMICADE® (infliximab)

*p = 0.039*

Page 66: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis
Page 67: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Ulcerative Colitis: Mild to ModerateUlcerative Colitis: Mild to ModerateAcute flare

Exclude entericpathogen

Extensive

Oral 5-ASA

Responseadequate

Responseinadequate

Maintainoral 5-ASA

Response adequate Consider

increased dose

Responseinadequate

Oral steroid

Response inadequate

Oral 5-ASA Response inadequate

Consider rectal therapy(5-ASA and/or steroid)

Patient willing totake rectal therapy

Patient unwilling to take rectal

therapy

Responseadequate

Maintain

L sided

Page 68: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Ulcerative Colitis: Moderate to SevereUlcerative Colitis: Moderate to Severe

Moderate

Oral steroid

Taper

Successful

Maintain on5-ASA and

observe

Inadequate response

Adequate response

Unsuccessful

IV Steroid

6MP/AZA

Success

Maintain6-MP/AZA

Response

Failure

ConsiderCyA

No response

Colectomy

Inadequate response

Severe

Infliximab

Response

Maintaininfliximab

No response

Page 69: Treatment Algorithms in Ulcerative Colitis Treatment Algorithms in Ulcerative Colitis

Final PointsFinal Points• There is no “one size fits all” to IBD therapyThere is no “one size fits all” to IBD therapy

– Therapy and decision making are tailored to the Therapy and decision making are tailored to the individualindividual

• Algorithms are based upon available evidenceAlgorithms are based upon available evidence– Evidence is in constant fluxEvidence is in constant flux

• Success of algorithms depends upon Success of algorithms depends upon optimization of each step of therapy and optimization of each step of therapy and considerable judgment about each outcomeconsiderable judgment about each outcome– Skillful application of medical therapy makes all the Skillful application of medical therapy makes all the

difference in outcomesdifference in outcomes


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