Treatment Algorithms in Crohn’s DiseaseTreatment Algorithms in Crohn’s Disease
Premise and PreviewPremise and Preview
In Most Clinical Scenarios ofIn Most Clinical Scenarios ofCrohn’s DiseaseCrohn’s Disease
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)
Long-term Evolution of Long-term Evolution of Disease Behavior in CDDisease Behavior in CD
Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.
24022821620419218016815614413212010896847260483624120
0
10
20
30
40
50
60
70
80
90
100
Cum
ulat
ive
Pro
babi
lity
(%)
Patients at risk:Months
2002 552 229 95 37N =
Penetrating
StricturingInflammatory
Crohn’s Disease:Crohn’s Disease:Anatomic DistributionAnatomic Distribution
Small bowelSmall bowelalonealone(33%)(33%)
Colon aloneColon alone(20%)(20%)
IleocolicIleocolic(45%)(45%)
LeastLeastMostMost
Freq of involvementFreq of involvement
Cumulative Probability of Cumulative Probability of Surgical Intervention in CDSurgical Intervention in CD
Munkholm P et al. Gastroenterology. 1993;105:1716.
Years
Pro
babi
lity
(%)
Events (no.) 122 26 15 7 7 4 8 1 8 2 2 2 3 2 1
0
20
40
60
80
100
0 2 5 8 11 14 17 20
± 2 SD
Dx
Inductive TherapiesInductive Therapiesfor Crohn’s Diseasefor Crohn’s Disease
• AminosalicylatesAminosalicylates
• AntibioticsAntibiotics
• CorticosteroidsCorticosteroids
• InfliximabInfliximab
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)
Treatment of Mild-ModerateTreatment of Mild-ModerateCrohn’s DiseaseCrohn’s Disease
NCCDS: Response to Therapy for NCCDS: Response to Therapy for Active Crohn’s DiseaseActive Crohn’s Disease
NCCDS, National Cooperative Crohn’s Disease Study.Summers RW et al. Gastroenterology 1979;77:847-869
PatientsPatients(%)(%)
Weeks after RandomizationWeeks after Randomization00 55 1010 1515
Sulfasalazine 1 g/15 kg (5 g)Sulfasalazine 1 g/15 kg (5 g)
PlaceboPlacebo
6060
5050
4040
3030
2020
1010
00
7070
13%13%
Meta-Analysis of PentasaMeta-Analysis of Pentasa®® (4g/day) (4g/day) in Active Crohn’s Diseasein Active Crohn’s Disease
P=0.005P=0.005
P=0.7P=0.7 P=0.5P=0.5
P=0.04P=0.04
Hanauer, Stromber. Clinical Gastroenterology & Hepatology 2004
P=0.005P=0.005
P=0.7P=0.7
P=0.05P=0.05P=0.04P=0.04
-80
-70
-60
-50
-40
-30
-20
-10
0
Crohn's I
n=155
Crohn’s II
n=150
Crohn's III
n=310
Overall
n=615
Ch
an
ge
fro
m b
as
eli
ne
in
CD
AI
sc
ore
Pentasa® 4 g Placebo
-60
-50
-40
-30
-20
-10
0
Crohn's I
n=155
Crohn's II
n=150
Crohn's III
n=310
Overall
n=615
Pentasa® 4 g minus Placebo
Antibiotics in Active CDAntibiotics in Active CD
0
10
20
30
40
50
60
70
Metro + CiproMetro + Cipro MetroMetro CiproCiprovs. Me-Predvs. Me-Pred vs. SASPvs. SASP vs. Mesalaminevs. Mesalamine
% R
emis
sio
n
Prantera 1996; Ursing 1982; Colombel 1999
Corticosteroids in Crohn’s DiseaseCorticosteroids in Crohn’s Disease
Faubion et al (Olmsted County, 1970-93)Faubion et al (Olmsted County, 1970-93)
““Only 43% of inception cohort everOnly 43% of inception cohort everrequired steroids”required steroids”
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 calculated92%
†
60%*
17 weeks 18 weeks 7 weeksNCCDS ECCDS GETAID
0
20
40
60
80
100 Corticosteroids
Placebo
Corticosteroid Therapy for Corticosteroid Therapy for Crohn’s DiseaseCrohn’s Disease
*30 days after initiating corticosteroid therapy
Complete Remission
58%(n = 43)
PartialRemission
26%(n = 19)
Immediate Outcome*(n = 74)
1-YearOutcome(n = 74)
Steroid Dependent
28%(n = 21)
Prolonged Response
32%(n = 24)
Surgery 38%
(n = 28)
NoResponse
16%(n = 12)
Faubion W et al. Gastroenterology 2001;121:225
Outcome of Corticosteroid Outcome of Corticosteroid Therapy for CDTherapy for CD
Remission48%
Improved 32%
No change20%
12-monthoutcomes
1-monthoutcomes
Remission54%
Relapse46%
Improved57%
Relapse43%
Munkholm. Gut 1994;35:360-362
* Remission at 12 Months = 25%
23%
75%
30%
76%
0
10
20
30
40
50
60
70
80
Smith Summers Malchow
Steroid
Placebon=59; p=NS
Corticosteroids: Corticosteroids: Maintenance of RemissionMaintenance of Remission
% P
atie
nts
in
Rem
issi
on
n=274; p=NS
n=237; p=NS
36 months 12 months 24 months
Smith RC et al. Gut. 1978;19:606.Summers RW et al. Gastroenterology. 1979;77:847.
Bergman L et al. Scand J Gastroenterol. 1976;11:651.Malchow H et al. Gastroenterology. 1984;86:249.
55%58%
Overview of Corticosteroids in CDOverview of Corticosteroids in CD
• Induce remission (NCCDS,Induce remission (NCCDS,** ECCDS, ECCDS,†† GETAIDGETAID‡‡))
• Provide rapid symptomatic relief (NCCDS,Provide rapid symptomatic relief (NCCDS,** ECCDS,ECCDS,†† GETAID GETAID‡‡))
• Frequent corticosteroid dependency with Frequent corticosteroid dependency with prolonged useprolonged use
• DO NOT maintain remissionDO NOT maintain remission• Dose- and duration-related adverse events Dose- and duration-related adverse events
with acute and chronic therapywith acute and chronic therapy
Faubion WA Jr et al. Gastroenterology. 2001;121:255.Keenan GF et al. Clin Chest Med. 1997;18:507.
Munkholm P et al. Gut. 1994;35:360.Singleton JW et al. Gastroenterology. 1979;77:870.
Steinhart AH et al. Cochrane Database Syst Rev. 2003;CD000301.
*Summers RW et al. Gastroenterology. 1979;77:847.†Malchow H et al. Gastroenterology. 1984;86:249.‡Modigliani R et al. Gastroenterology. 1990;98:811.
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
Maintenance TherapyMaintenance Therapyfor Crohn’s Disease: Issuesfor Crohn’s Disease: Issues
• Definition of remissionDefinition of remission– Clinical, endoscopic, radiologic, laboratoryClinical, endoscopic, radiologic, laboratory
• Induction therapyInduction therapy– 5-ASA, steroids, antibiotics, immunomodulators5-ASA, steroids, antibiotics, immunomodulators– SurgerySurgery
• Disease location Disease location • Disease behaviorDisease behavior
– Inflammatory, fibrostenotic, fistulizingInflammatory, fibrostenotic, fistulizing
• SmokingSmoking
Months after RandomizationMonths after Randomization
Summers. Gastroenterology 1979
NCCDS - Response to Therapy for NCCDS - Response to Therapy for Crohn’s Disease Remission MaintenanceCrohn’s Disease Remission Maintenance
Oral Budesonide as Maintenance Oral Budesonide as Maintenance Therapy for CDTherapy for CD
Adapted from Greenberg GR et al. Gastroenterology 1996;110:45-51
PP == nsns
Budesonide 6 mgBudesonide 6 mg
Budesonide 3 mgBudesonide 3 mg
PlaceboPlacebo
DaysDays00 100100 200200 300300
Cu
mu
lati
ve p
rob
abili
ty
Cu
mu
lati
ve p
rob
abili
ty
of
rem
issi
on
of
rem
issi
on
00
0.50.5
11
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%
Antibiotics
1. Metronidazole• MOA:
– It is thought that metronidazole may have anti-inflammatory effects as well as antibacterial effects.
• Dosing:– Metronidazole is most useful in treating fistulizing
CD in doses ranging from 1 g/day to 2 g/day. Treatment of 2 months or longer is necessary for fistula healing.
– Discontinuing metronidazole therapy often results in an exacerbation of the fistula drainage.
Antibiotics
2. Ciprofloxacin:– Recently, ciprofloxacin in doses of 1–1.5 g/day has
been used as an alternative to metronidazole.
– Ciprofloxacin has not been well studied as monotherapy. In small studies, it appears to be mainly effective in treating perianal and fistulizing CD. It may be useful in combination with metronidazole.
– One study suggested that this combination could be an alternative treatment to steroids in treating the acute phase of CD.
Budesonide
• Highly potent glucocorticoid.• First pass metabolism in the liver , resulting in a systemic bioavailability of 10–15%.
• Low corticosteroid-related adverse effects, including adrenal suppression, (due to the low systemic bioavailability).
• Approved in the U.S. in 2001 for pts with mild to moderate, active CD involving the ileum and/or ascending colon.
Budesonide
• A recently published meta-analysis (total 621 enrolled pts)
Suggests that budesonide is not as effective as standard doses of the steroids in inducing remission.
* Budesonide induced remission in 50–70% of pts with active disease in the ileum or in the right ileocolonic area.
* Older steroids induced remission in 60–73% of pts.• This indicates that budesonide is not superior to older agents in inducing remission for active CD but may be an alternative to mesalamine in these patients.
““Evidence-Based” Approach of Evidence-Based” Approach of Sandborn and FeaganSandborn and Feagan
Mild-Moderate Mild-Moderate Crohn’s DiseaseCrohn’s Disease
Left-sided disease restricted to colon Disease involving the ileumLeft-sided disease restricted to colon Disease involving the ileum and/or ascending colonand/or ascending colon
SulfasalazineSulfasalazine16 weeks16 weeks
Budesonide capsulesBudesonide capsules8-16 weeks8-16 weeks
Sulfa-allergic/failed treatment Failed treatmentSulfa-allergic/failed treatment Failed treatment
Conventional steroidsConventional steroids
>60%>60% 45% acute45% acute80% 1 year80% 1 year
Sandborn, Feagan, 2003
TopicsTopics
• Antimetabolite therapyAntimetabolite therapy
• Anti-inflammatory cytokinesAnti-inflammatory cytokines
• TNF blockade TNF blockade
0
20
40
60
80
% R
esp
on
se
0 10
Weeks
Prednisone Placebo AZA
P=0.17
NCCDS DataNCCDS Data
AZA: Induction of RemissionAZA: Induction of Remission
AZA and 6-MP: Induction of AZA and 6-MP: Induction of Remission in CDRemission in CD
Pearson DC et al. Ann Intern Med 1995;122:132-142.
Azathioprine and 6-Mercaptopurine Azathioprine and 6-Mercaptopurine in IBD: Toxicityin IBD: Toxicity
• CommonCommon– Gastrointestinal Gastrointestinal
intoleranceintolerance– MyalgiaMyalgia
• UncommonUncommon– Bone marrow Bone marrow
suppressionsuppression– PancreatitisPancreatitis– Allergic reactions Allergic reactions – Hepatic toxicityHepatic toxicity
Present DH. Gastroenterol Clin North Am 1989;18:57-71
– Opportunistic Opportunistic infection infection
– Neoplasm Neoplasm
MethotrexateMethotrexate
Feagan. N Eng J Med. 1995;332(5):292-7
% R
esp
on
se
% R
esp
on
se
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: Time to RelapseMethotrexate: Time to Relapse%
Re m
issi
on
% R
e mis
sio
n
Weeks Since RandomizationWeeks Since Randomization
P P =0.044=0.044
MethotrexateMethotrexate
PlaceboPlacebo
Feagan BG. N Engl J Med 2000;342(22):1627-32
Methotrexate in IBD: ToxicityMethotrexate in IBD: Toxicity
• MajorMajor– HepaticHepatic– MyelosuppressiveMyelosuppressive– PulmonaryPulmonary– Fertility-relatedFertility-related– TeratogenicTeratogenic– Enteritic/coliticEnteritic/colitic
Egan LJ, Sandborn WJ. Mayo Clin Proc 1996;71:69-80
• MinorMinor– GastrointestinalGastrointestinal– Alopecia-inductiveAlopecia-inductive– AllergicAllergic– NeurologicNeurologic
CyclosporineCyclosporine
Cyclosporine in CDCyclosporine in CD
Feagan BG. Inflammatory Bowel Dis 1995;1:335-339
Biologic TherapyBiologic Therapy
Infliximab: Mechanism of ActionInfliximab: Mechanism of Action
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
Median Time to Loss of ResponseMedian Time to Loss of ResponseThrough Week 54Through Week 54
Week 2 RespondersWeek 2 Responders
ACCENT I
Hanauer S, Feagan B. Lancet. 2002;359:1541-9
Clinical Remission at Week 54*Clinical Remission at Week 54*
*Week-2 responders
0
10
20
30
40
50
Single Dose(n=110)
Pro
po
rtio
n o
f P
atie
nts
(%
)
5 mg/kgq 8 wk(n=113)
10 mg/kgq 8 wk(n=112)
P<0.001
P=0.007 P=NS
14%
28%
38%
ACCENT IACCENT I
Hanauer SB, et al. Lancet 2002
REMICADEREMICADE®® (infliximab) in Patients (infliximab) in Patients with Fistulizing Crohn’s Diseasewith Fistulizing 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.
Fistula Response at Week 54Fistula Response at Week 54
23%27%
49%
40%
0
20
40
60
80
100
Fistula Response Complete Response
Placebo maintenance 5 mg/kg infliximab maintenance
P=0.014
Pat
ien
ts i
n R
esp
on
se (
%)
P=0.002
Sands BE, et al NEJM 2004
ACCENT IIACCENT II
Among Patients Responding at Weeks 10 and 14Among Patients Responding at Weeks 10 and 14
41/8324/89 41/8324/89
Fistula Response at Week 54Fistula Response at Week 54
23%27%
49%
40%
0
20
40
60
80
100
Fistula Response Complete Response
Placebo maintenance 5 mg/kg infliximab maintenance
P=0.014
Pat
ien
ts i
n R
esp
on
se (
%)
P=0.002
Sands, B et al. NEJM 2004
ACCENT IIACCENT II
Among Patients Responding at Weeks 10 and 14Among Patients Responding at Weeks 10 and 14
41/8324/89 41/8324/89
Incidence of Antibodies-to-Infliximab (ATI) Incidence of 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
Infliximab and Antibody FormationInfliximab and Antibody Formation
• Cohort study (n = 125): mean of 3.9 infusions / Cohort study (n = 125): mean of 3.9 infusions / 10 months10 months
• 61% of patients developed ATI61% of patients developed ATI
• Antibody formation inversely associated with serum Antibody formation inversely associated with serum infliximab concentrationinfliximab concentration
• ATI formation > 8 ug predicted shorter duration of ATI formation > 8 ug predicted shorter duration of response (35 vs. 71 days) – present in 37%response (35 vs. 71 days) – present in 37%
• Approximately 2.5 times as likely to form ATI if Approximately 2.5 times as likely to form ATI if concomitant antimetabolite therapy was not usedconcomitant antimetabolite therapy was not used
Baert et al. N Engl J Med 2003;348:7
Prevention of ATIs Prevention of ATIs
• Avoid intermittent therapyAvoid intermittent therapy
• Use effective preventative strategies:Use effective preventative strategies:MTX/AZA for chronic useMTX/AZA for chronic use
* Farrell R. Gastroenterology 2003;124(4):917-24
CD: Mild to ModerateCD: Mild to ModerateActive symptoms/
flare
Budesonide
Observe Taper
Consider budesonidetitrated to symptoms
or6-MP/AZA
orMTX
Not confined to
Prednisone
Taper
6-MP/AZAor
MTX
Consider 5-ASAConsider Abx
ObserveNo flare No flare
Flare
Response
No response
Exclude entericpathogen
Flare
Response
Ileal/ R colonileal/ R colon
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
InfliximabInfliximabInfliximab indicated
• Exclude enteric pathogen
• Exclude abscess, stricture
• Exclude latent/active TB
Infliximab 5 mg/kg wks 0, 2, 6
• Consider steroid pre-treatment
• Consider 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 infliximab
5 mg/kg q 8 wksLoss of response
Inadequate response
Inadequate response
(Start 6-MP/AZA or MTX)
FistulaFistulaFistula
Diagnosticevaluation
Fistula type
Not superficial
Superficial
• Antibiotics• Consider
fistulotomy
Observe
FailureFailure
FailureDefinitivesurgery Maintain
6-MP/AZAand/or infliximab
Failure
Tacrolimus• Seton
• Antibiotics
• 6-MP/AZA ± infliximab
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