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Step Up versus Top Down Therapy for IBD
Gary R. Lichtenstein, MDProfessor of Medicine
Director, Center for IBDUniversity of PA School of Medicine
Hospital of the University of PA Philadelphia, PA
Current “Therapeutic Pyramid” for Crohn's disease
Severe
Moderate
MildAdapted from: Hanauer et al, Am J Gastroenterol 2001; 96: 635
BudesonideAntibiotics
5-ASA
MTXAZA / 6-MP
Systemic steroids
Surgeryanti-TNF-α
Rationale for early use of biological therapies in Crohn’s disease
• Target important mediators of inflammatory response i.e., greater specificity than existing therapies
• Useful for active disease and for maintenanceof remission
• Highly effective for management of fistulae
• Potential to alter the long-term course (disease modification)
Rutgeerts et al, Gastroenterology 2004; 126: 1593
Top down vs step up strategyWhat are the long-term considerations?
Long-Term Evolution of Crohn's Disease is Structural Damage
Cosnes et al, Inflamm Bowel Dis 2002; 8: 244
24022821620419218016815614413212010896847260483624120
0
20
40
60
80
100
Cumulative probability (%)
Patients at risk: Months2002 552 229 95 37n=
Penetrating
StricturingInflammatory
Role of Glucocorticoids inMild-to-Moderate Disease
• Effective induction agents, but do not modify disease
• Prednisolone* High clinical response rates (92%), but only about
one third of patients have mucosal healing No correlation between clinical activity index and
endoscopic assessment
• Limited maintenance efficacy Only about one third of patients have prolonged
response 1 year after first course
• Long-term toxicity; potential for dependency• Budesonide allows longer therapy but has not
changed long-term outcomes*Modigliani R et al. Gastroenterology. 1990;98:811818.Reviewed in Rutgeerts P et al. Rev Gastroenterol Disord. 2004;4(suppl 3):S3S9.
Predictors of Disabling Disease:Requirement for Steroids Is Turning Point
Beaugerie L et al. Gastroenterology. 2006;130:650–656.
5-year clinical course after diagnosis
VariableNondisabling, %
(n = 166)Disabling, %
(n = 957) P value
Age at onset < 40 years ≥ 40 years
77.122.9
87.712.3
.0004
Location of disease Small bowel only Small bowel + colon Colon only
44.625.929.5
32.839.427.8
.002
Smoking status Smoker Ex or nonsmoker
50.349.7
57.442.6
.09
Perianal lesions at diagnosis Yes No
17.582.5
26.43.6
.01
Required steroids for first flare Yes No
37.362.7
65.234.8
.0001
Cumulative incidence of surgical resection over 1 yr in Crohn's disease pts starting corticosteroids
Faubion et al, Gastroenterology 2001; 121: 255
38% of patients required surgery within 12 mos.
n=77n=77 Days
Cumulative probability (%)
30 60 90 182 3650
100
80
60
40
20
Efficacy of AZA as Crohn’s Disease Maintenance Therapy After Steroids*
80
60
40
20
0
Patients not failing trial (%)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Duration of trial (months)
AZA 2.5 mg/kg per day
Placebo
*Remission induced by prednisolone tapered over 12 wks Inclusion: Patients were not steroid dependent
Candy et al, Gut 1995; 37: 674
42%
7%
n=63 patients with active disease
p=0.001
100
Treatment with azathioprine is 35% (42–7%) more effective in maintaining remission
Feagan et al, N Engl J Med 2000; 342: 1627
Methotrexate maintenance after steroids in Crohn’s disease
• Multi-center, randomized, controlled trial
• 76 steroid-dependent patients
• In remission following methotrexate 25 mg IM x 16 weeks
• Randomized to 15 mg IM or placebo x 40 weeks
Weeks since randomization
100
90
80
70
60
50
40
30
Remission (%)
MethotrexatePlacebo
n=40
n=36
0 4 8 12 16 20 24 28 32 36 40
65%
39%
65% of 39% responders = 26% overall
p=0.04
Do immunosuppressives change the course of Crohn’s disease?
Cosnes et al, Gut 2005; 54: 237
No change in operative rates
Patients operated on (%)
Months after diagnosis
78–82 (n=34)
p=0.81
50
40
30
20
10
00 12 24 36 48 60
93–97 (n=176)
83–87 (n=46)
88–92 (n=102)
98–02 (n=102)
ACCENT I: Maintenance of clinical response in week 2 responders
Hanauer et al, Lancet 2002; 359: 1541
+++p<0.001, 10 mg q-8wks vs single infusion ++p=0.001, 5 mg q-8wks vs single infusion
***p<0.001, 10 mg q-8wks vs single infusion **p=0.002, 5 mg q-8wks vs single infusion
***
Single infusion
Infliximab 5 mg/kg q-8wks
Infliximab 10 mg/kg q-8wks
110 113 112 110 113 112
+++
++**
2717
5143
5953
Week 30 Week 54
Patients who maintained response (%)
0
100
n=
Step-Up and Top-Down Therapy for Crohn’s Disease
Anti TNF
AZA/MTX
Steroids
5-ASA/SPS
Anti TNF
AZA/MTX
Steroids
Combination
Step-up therapy
Top-downtherapy
Lichtenstein GR et al. Inflamm Bowel Dis. 2004;10:S2–S10.
Step-Up vs Top-Down:Study Design
D’Haens G et al Lancet 2008;371:660-667
133 Crohn’s patients, CDAI > 220Diagnosed < 4 years ago
Never treated with glucocorticoids (GCs), immunomodulators, or infliximab (IFX)
Step up Top down
Budesonide 9 mg/dayor
Prednisone 40 mg/day
IFX at weeks 0, 2, and 6+
AZA 2–2.5 mg/kg/day
AZA if repeated need for GCs, dependency
IFX for immunosuppression failure
Repeat IFX for relapse
GCs for failure to respond to IFX
Management of Recent-Onset CD: A controlled, randomized trial comparing
step up and top down therapy
Newly diagnosed* Crohn’s disease (n=130)
Step up (n=65)
Steroids
Top down (n=65)
IFX (0/2/6) + AZA
+ IFX
+ AZA MTX
Steroids
Steroids
IFX + AZA
+ (episodic) IFX
Steroids
*within 4 yearsD’Haens G et al Lancet 2008;371:660-667
Management of Recent Onset Crohn’s Disease
Top down(n=65)
Step up(n=65)
0
100
6 months 12 months n=20
75
48
77
64
75
21
n=14
Remission with steroid withdrawal
Endoscopic healing (at 2 years)
Patients (%)p=0.006 p=0.15 p=0.002
D’Haens G et al Lancet 2008;371:660-667
Endoscopy before treatment
Infliximab: Endoscopic HealingInfliximab: Endoscopic Healing
Rutgeerts P, et al Gastro Endoscopy 2006
Endoscopy after treatment at weeks 0, 2 & 6
Infliximab: Endoscopic HealingInfliximab: Endoscopic Healing
Week 10 ResultsWeek 10 Results
Rutgeerts P, et al Gastro Endoscopy 2006
Step-Up vs Top-Down Trial: Relapse Rate
Weeks following randomization
P = .018
Top down
Su
bje
cts
no
t fa
ilin
g (
%)
0
20
40
60
80
100
14
Year 1
14
Step up
Year 2
20 26 32 38 44 50 56 62 68 74 80 86 92 98 104
D’Haens G et al Lancet 2008;371:660-667
Top Down vs. Step Up Secondary Endpoint: Mean Number of Days of Steroid Use
0.545.6
70.2
79.7
0
10
20
30
40
50
60
70
80
90
Year 1 Total (Years 1 + 2)
Days
Top Down Step Up
*Preliminary data
D’Haens G et al Lancet 2008;371:660-667
0
10
20
30
40
50
60
70
80
90
100
1-8 9-16 17-24 25-32 33-40 41-48 49-56 57-64 65-72 73-80 81-88 89-96 97-104
Week
% o
f P
atie
nts
Top Down Step Up
†Numbers for the top down group indicate patients who required episodic IFX
Top Down vs. Step Up Secondary Endpoint: Proportion of Patients
Receiving Infliximab
*Preliminary data D’Haens G et al Lancet 2008;371:660-667
PRECiSE 1
Certolizumab Pegol Study Designs
CZP 400 mg sc (Wk. 0, 2, 4 then Q4W to week 24)
Placebo (Wk 0,2,4 the Q4W to week 24)
Doses
Weeks 0 2 4 6 8 12 16 20 24 26(6&26)
Co-primary endpoint Co-primary
endpoint
Responders(CDAI ↓ ≥100 pts)
Nonresponders Discontinue
CZP 400 mg sc Q4W to week 24
Placebo Q4W to week 24
PRECiSE 2
Doses
Weeks 0 2 4 6 8 12 16 20 24 26
Open Label
(CZP 400 mg)
Primary endpoint
CDAI 220-450
Stratified for:• CRP <10 mg/L or 10 mg/L• Baseline IS and steroids
Schreiber S, et al. NEJM 2007Sandborn WJ, et al. NEJM 2007
Sandborn et al, NEJM 2007
Certolizumab pegol 3 inj, placebo maintenance, SC
Certolizumab pegol 3 inj, 400 mg q-4weekly, SC
Early intervention with biologics enhances efficacy: PRECiSE 2
***p<0.001**p<0.01*p<0.05
Any <1 1–<2 2–<5 ≥5
Response(≥100 pt
DecreaseCDAI)
n= 210 215 35 19 22 20 55 45 98 131
Patients (%)
36.2
***62.8
**89.5
*62.2 ***
57.3
37.150
75
36.4 32.7
CD duration (yr)
0
100
Remission (CDAI ≤150)
Patients (%)
Any <1 1–<2 2–<5 ≥5n= 210 215 35 19 22 20 55 45 98 131
28.6
***47.9
*68.4
46.7 ***44.3
37.1 36.4
55
29.123.5
CD duration (yr)
0
100
Week 26
Placebo (n=170) Placebo
Baselin
e / Week 0
N=
854*
Week 4
n=
778
Week 56
‡
40 mg eow Open-label
40 mg eow (n=172)
40 mg ew (n=157)
Flare / Nonresponse
40 mg ew Open-label
Week 26
‡ 40 mg eow
40 mg ew
Week 240 mg
80 mg
Open label Randomized, double-blind, placebo-controlled
Week 4 stratified
by CR-70 response†
Week 12
CHARM: Study Design
*Previous anti-TNF: 49.6%†CDAI decrease ≥ 70 points from baseline ‡Two co-primary endpoints: Clinical remission (CDAI <150) at Weeks 26 and 56 in Week 4 CR-70 responders vs placebo
Flare / Nonresponse
Colombel JF, et al. Gastroenterol. 2007;132:52–65
Screening period
14 days
CHARM: Adalimumab in early Crohn’s disease
Adalimumab 40 mg q-weekly SC (n=157)
Placebo (n=170)
Adalimimab 40 mg EOW SC (n=172)
Week 26
Patients in remission CDAI <150 (%)
17 2514
56
35 37 454564
0
100
<2 years 2 to <5 years ≥5 years
* *
* *
Patients in remission CDAI <150 (%)
17 11 11
52
35 33 385250
0
100
<2 years 2 to <5 years ≥5 years
*
* ***
Week 56
Disease duration
Disease duration
Schreiber et al, Gastroenterology 2007; 132: A147 (Abstract 985)
*p<0.05
Preliminary Data
Patient PopulationSONIC
• Subjects 21 years of age or older with:– Moderate-to-Severe Crohn’s disease (CD)
• CDAI 220 and 450
– No prior exposure to biologic agents or immunomodulators
– Normal TPMT
Sandborn, WJ et al. ACG 2008.Preliminary Data
Study DesignSONIC
Week 0*
Week 2
Week 6
Week 14
Week 22
Week 30
Visits
Week 46
Week 38
Week 54
•••
• Infusions
Primary Endpoint (Corticosteroid-free Remission at Week 26)
Secondary Endpoint (Week 50)
• • •
Randomization of patients
Mai
nE
xte
ns
ion
Week 26*
Week 50
Azathioprine 2.5 mg/kg + placeboinfusions
Infliximab 5 mg/kg+ placebo capsules
Infliximab 5 mg/kg+ Azathioprine
2.5 mg/kg
• • •
• • •
* Endoscopy performed at Weeks 0 & 26
•••
• • •
• • •
Week 10
Week 18
Week 42
•••
Sandborn, WJ et al. ACG 2008.Preliminary Data
Corticosteroid-Free Clinical Remission at Week 26
SONIC
Primary Endpoint
30.6
44.4
56.8
0
20
40
60
80
100
Pro
po
rtio
n o
f P
atie
nts
(%
)
AZA + placebo IFX + placebo IFX+ AZA
p<0.001
p=0.009 p=0.022
52/170 75/169 96/169
29
Sandborn, WJ et al. ACG 2008.Preliminary Data
Mucosal Healing at Week 26
SONIC
16.5
30.1
43.9
0
20
40
60
80
100
Pro
po
rtio
n o
f P
atie
nts
(%
)
AZA + placebo IFX + placebo IFX+ AZA
p<0.001
p=0.023 p=0.055
18/109 28/93 47/107
30
Sandborn, WJ et al. ACG 2008.Preliminary Data
Corticosteroid-Free Clinical Remission Through Week 26
SONIC
*p<0.05 IFX+AZA vs AZA+PBO, IFX+PBO vs AZA+PBO
†p<0.05 IFX+AZA vs IFX+PBO
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Week
AZA + placebo IFX + placebo IFX + AZA
Pro
po
rtio
n o
f P
atie
nts
(%
)
**
** *
*
* *
†
31
Sandborn, WJ et al. ACG 2008.Preliminary Data
Anti-TNF-α is most effective therapy
to date, so why not use first?
Hospitalization accounts for >50% of healthcare costs in Crohn's disease*
Feagan et al, Am J Gastroenterol 2000; 95: 1955
Inpatient (57%)
Outpatient (24%)
MD Office (8%)
Medications (4%)
Emergency Room (2%)
Home Care (3%)
SNF (2%)
Other (1%)
In-patient
*Data from patients with a CD-related medical claim (10/94–09/95) included in a
1994 integrated claims databasen=607
Influence of anti-TNF-α (infliximab) on resources in Crohn's disease: UK study
• 1093 fewer bed days • Fewer investigations
(OR 0.39; 95% CI 0.29–0.52)• Out-patient (OP) visits unchanged
(standard follow-up)
Jewell et al, Gastroenterology 2004; 126: S1218Jewell et al, Data submitted for publication
• Number of abdominal operations halved
• 33 fewer examinations under anesthesia (EUA) (OR 0.34; 95% CI 0.20–0.59)
OperationsHospitalization
0
400
800
1200
1600
Bed days OP visits Investigations
6-mo pre IFX treatment 6-mo post IFX treatment
0
10
20
30
40
50
60
EUA Operations
n=205
Rates of Hospitalization and Surgery:The ACCENT I Trial
7.4
2.63.1
0
2
4
6
8
10
Pat
ien
ts w
ith
h
osp
ital
izat
ion
(%
)
Pat
ien
ts w
ith
in
tra-
abd
om
inal
su
rger
y (%
)
Episodic 5 mg/kg scheduled 10 mg/kg scheduled(n = 188) (n = 192) (n = 193)
P = .04
P = .07
P = .047
P = .023
Rutgeerts P et al. Gastroenterology. 2004;126:402413.
Rates of Hospitalizations and Surgeries:The ACCENT II Trial
Pro
po
rtio
n o
f p
atie
nts
h
osp
ital
ized
(%
)
Week 14 respondersn = 195
Nu
mb
er o
f su
rger
y/p
roce
du
res
per
100
pat
ien
ts P < .01 P < .05
Infliximab 5 mg/kg Placebo
Randomizedn = 282
Week 14 responders n = 195
Randomizedn = 282
Lichtenstein GR et al. Gastroenterology. 2005;128:862-869.
TREAT™ Registry Data: Safety of infliximab (IFX) and other Crohn’s
disease therapies
• Only prednisone and narcotics associated with increased risk of mortality and serious infections
• Continuous + intermittent IFX-treated patients have similar rates of mortality as patients not treated with IFX
Lichtenstein GR et al, Gastroenterology 2007; 132: A-178 (No. S1124)
***p≤0.001
Incidence per 100 patient-years
Rate within 3 monthsof IFX infusion
Rate outside 3 monthsof IFX infusion
IFX-treated
Non-IFX treated
Serious infections Malignancy Lymphomas
RR 1.77CI 1.27–2.46
RR 0.74CI 0.49–1.12
RR 1.08CI 0.22–2.992
0
0.67
1.19
0.390.53
0.04 0.05
***
Preliminary Data
Current and future therapeutic paradigms in Crohn's disease
Goals induce remission maintain remission prevent complications optimize surgical outcomes improve quality-of-life
Current* Step up approach Conservative use of immunomodulators
Additional goals disease modification mucosal healing pharmacoeconomics disease prevention improve quality-of-life
Future Top down approach Earlier use of immunomodulators
*Hanauer et al, Am J Gastroenterol 2001; 96: 635Preliminary Data
Learnings from RA / BEST trial
BEST Study: Early rheumatoid arthritis
• Multicenter randomized controlled trial comparing 4 treatment strategies
No progression in Total Sharp Score
Group 1 Group 2 Group 3 Group 4
100
80
60
40
20
0
Goekoop-Ruiterman et al, Arthritis Rheum 2005; 52: 3381
Clinical and radiographic outcomes were assessed at baseline, 3 months, 1 year
508 patients randomized to 1 of 4 treatment strategies
Patients (%)
Sequential monotherapy
Step-up combination therapy
Initial combination therapy with taperedhigh dose prednisone
Initial combination therapy with infliximab
Have We Truly Evolved ?
Vermiere et al, Aliment Pharmacol Ther 2006; 25: 3
Response
Continue Tx and observe
Response
Taper & stop Tx Observation
Relapse within 1yr?
Steroids + AZA or MTX
No response
AZA or MTX? Surgery
Relapse
Anti-TNF-No response
No response
Colonic(± small intestine) Small intestine
Smoking cessationSulfasalazine ± antibiotics
Smoking cessationBudesonide / corticosteroids
Patient Mild presentation Inflammatory disease No perianal disease No extraintestinal manifestations Non-smoking
Management plan: Low risk of progression
Adapted from Vermiere et al, Aliment Pharmacol Ther 2006; 25: 3
Patient Young age at onset (<18 yr) Non-inflammatory disease behavior Extensive disease (small/large bowel) Early steroid need Extraintestinal manifestations Active smoker
Response
Taper and stop steroids and continue immunosuppressants
Smoking cessationBudesonide / corticosteroids + AZA or MTX
No response
Anti-TNF-
Response
Maintenance
No response
Switch anti-TNF-
Surgery
Management plan: Intermittent to High Risk of Progression
Summary
• Preliminary studies have provided some evidence that reversing the treatment paradigm from a "step up" to a "top down" approach may positively alter the natural history of CD
• Evidence suggests that early use of biologic therapy is effective in improving quality-of-life and helping patients to achieve and maintain remission
Current Management Recommendation for
patients with Crohn’s Disease
• Top-down approach is preferred
– Less clinical relapse
– Less Steroid use
– Better mucosal healing
– Fewer • hospitalizations • Surgeries
– Likely to have fewer strictures
Current Management Recommendation for
patients with Crohn’s Disease
• Top-down approach is not preferred
– Overtreatment of approximately 30% of patients
– Uncertain safety difference
– ? More or less benefit if given as routine maintenance
STEP UP
TOP DOWN