Treatment Algorithms in Treatment Algorithms in Crohn’s Disease Crohn’s Disease Gary R. Lichtenstein, M.D. Gary R. Lichtenstein, M.D. Professor of Medicine Professor of Medicine University of Pennsylvania School of University of Pennsylvania School of Medicine Medicine Hospital of the University of PA Hospital of the University of PA Philadelphia Philadelphia Pennsylvania Pennsylvania
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Treatment Algorithms in Crohn’s DiseaseTreatment Algorithms in Crohn’s Disease
Gary R. Lichtenstein, M.D.Gary R. Lichtenstein, M.D.Professor of MedicineProfessor of Medicine
University of Pennsylvania School of MedicineUniversity of Pennsylvania School of MedicineHospital of the University of PAHospital of the University of PA
PhiladelphiaPhiladelphiaPennsylvaniaPennsylvania
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)
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
Long-term Evolution of Long-term Evolution of Disease Behavior in CDDisease Behavior in CD
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
Cumulative Incidence of Surgical Resection Over 1 Year in CD Cumulative Incidence of Surgical Resection Over 1 Year in CD Patients Starting CorticosteroidsPatients Starting Corticosteroids
Days
Cu
mu
lativ
e P
rob
ab
ility
(%
)
0
20
40
60
80
100
0 30 60 90 182 365
Faubion WA Jr et al. Gastroenterology. 2001;121:255.N = 77.
Prescriptions are Written on Paper…Prescriptions are Written on Paper…Not in StoneNot in Stone
Until we can predict course in Until we can predict course in individual patients…individual patients…
Advance to more potent, more toxic Advance to more potent, more toxic agents if no initial response or relapse agents if no initial response or relapse
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
• Use effective preventative strategies:Use effective preventative strategies:– 200 mg solucortef IV ADC at time of 200 mg solucortef IV ADC at time of
dosing if not on a therapeutic dose of dosing if not on a therapeutic dose of antimetabolite*antimetabolite*
– 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
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 optimization Success of algorithms depends upon optimization of each step of therapy and considerable judgment of each step of therapy and considerable judgment about each outcomeabout each outcome– Skillful application of medical therapy makes all the Skillful application of medical therapy makes all the