Treatment Algorithms in Ulcerative ColitisTreatment 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
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)
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).
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.
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.
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.
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 ±
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.
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.
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%
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
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
> 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
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
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
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
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).
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
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
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)
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
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
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®®
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
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
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™
Sulfasalazine Dose/ToxicitySulfasalazine Dose/Toxicity
1G 2G 3G 4G
100%100%
ResponseResponse
ToxicityToxicity
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
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
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
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
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).
Marteau, P et al. Gut 2005;54:960-965
Remission and improvement rates
Maintenance Therapies for Maintenance Therapies for Ulcerative ColitisUlcerative Colitis
• AminosalicylatesAminosalicylates
• Azathioprine/6-MPAzathioprine/6-MP
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
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
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
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
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
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.
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.
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.
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.
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
)
**
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
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)
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
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.
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
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.
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.
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
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
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.
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.
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.
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.
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
*
*
*
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
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
*
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
*
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*
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
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
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