Post on 11-May-2015
“Top Down” therapy is NOT the best strategy for treating Crohn’s Disease –
David G. Binion, M.D.
Co-Director, Inflammatory Bowel Disease CenterDirector, Translational Inflammatory Bowel Disease Research
Visiting Professor of MedicineDivision of Gastroenterology, Hepatology and Nutrition
University of Pittsburgh School of MedicineUPMC Presbyterian Hospital
Pittsburgh, PA, USA
Disclosure Grant Support
National Institutes of Health Crohn’s and Colitis Foundation of America Centocor Elan Biogen
Honoraria/consulting Centocor, Prometheus Laboratories, Abbott
laboratories, UCB Pharma, Salix Pharmaceuticals, Elan Biogen
Off label discussion of Drugs
Overview:
I. Evolution of Crohn’s disease (CD) therapy
II. New biologic agents for CD Anti-TNF-alpha agents Anti-IL-12/anti-IL23 Natalizumab
III. The “Top down vs step up” protocol for CD.
IV. Is “Top down” therapy a good idea for all CD patients? Heterogeneity of CD Disease modifying therapy in early CD
V. A rational approach for biologic therapy in IBD Who should be treated with biologics Risk/benefit assessment
I. Evolution of Crohn’s disease therapy
Crohn’s Disease: 1960’s historical perspective
Treatment limited to sulfasalazine and prednisone. No need for algorithm, because
limited options available
Biologic era in IBD management:Healing of refractory ulceration/fistula with Infliximab
van Dullemen HM et al. Gastroenterology. 1995;109:129.
Pretreatment 4 Weeks posttreatment
PretreatmentPretreatment 2 Weeks2 Weeks
10 Weeks10 Weeks 18 weeks18 weeks
Present DH, et al. N Engl J Med. 1999;340:1398–1405.
Drug therapy for Crohn’s disease - 2008
First line therapy
5-ASAbalsalazidebudesonideantibiotics(metronidazole,Cipro, rifaximin, amoxicillin,minocycline,tetracycline)
Immunomodulators/Second line therapy
corticosteroidsbudesonideazathioprine/6-MPmethotrexate
Biologic Therapy
infliximabadalimumabcertolizumab pegolnatalizumab
InvestigationalImmunomodulators
mycophenolate mofetilleflunamideFK 506thioguaninestem cell transplant
Biologics - in development
mesenchymal stem cellsabataceptthalidomideanti IL-12 (ABT-874)Trichuris suisprobiotic therapyvisilizumab (anti-CD3)Adacolumn (leukocytopharesis)golimumabfontalizumab
Nutritional therapy
elemental dietTPN
II. New biologic agents for IBD
Anti-TNF-alpha agents
Anti-IL-12/anti-IL23
Natalizumab
Molecular and cellular mechanisms in IBD
Sands BE. Inflammatory Bowel Dis.1997;3:95.
Nonspecific injuryand repair
NOROM
Proteases
PGE2
PAF
ThromboxaneLTB4
Growth factors Trefoil proteins
T-cellactivation
Pro-inflammatorycytokines
RestingMo
ActivatedMo
ActivatedPMN
Selectins
PMN
Integrins
Monocyte
MAdCAM-1
Lymphocyte
ICAM-1
Adhesionand recruitment
IL-8 IL-1IL-12/23
IFN-
TNF-
Th1 Th2 IL-10
IL-4
CD40CD40L
IL-2CD4+
T cell
NaiveT cell
B cell
CD4+ T cellsand T-helpersubsets
MHCClass II
B7
TCR
CD4CD28
CTLA4
Molecular and cellular mechanisms in IBD
Sands BE. Inflammatory Bowel Dis.1997;3:95.
Nonspecific injuryand repair
NOROM
Proteases
PGE2
PAF
ThromboxaneLTB4
Growth factors Trefoil proteins
T-cellactivation
Pro-inflammatorycytokines
RestingMo
ActivatedMo
ActivatedPMN
Selectins
PMN
Integrins
Monocyte
MAdCAM-1
Lymphocyte
ICAM-1
Adhesionand recruitment
IL-8 IL-1IL-12/23
IFN-
TNF-
Th1 Th2 IL-10
IL-4
CD40CD40L
IL-2CD4+
T cell
NaiveT cell
B cell
CD4+ T cellsand T-helpersubsets
MHCClass II
B7
TCR
CD4CD28
CTLA4
Biologics Under Investigation in IBD
_ Anti-TNF Strategies– Chimeric antibodies
– “Humanized” antibodies
– “Fully human” antibodies
– Antibody fragments
– Antisense compound
– TNF-BP1
– Thalidomide
_ Cytokine strategies– Il-1ra (anakinra)– Antibodies to Il-4, Il-6, Il-8, Il-12, Il-15, Il-
16, Il-18, Il-23– Il-10, Il-11
_ Anti-cell adhesion molecules– Antibodies to ICAM-1, VCAM-1, VLA-4,
-4 (natalizumab), 47– Antisense compound to ICAM-1– Anti NF-B, anti-OX40, anti-ZAP
_ Other approaches– rhuGrowth hormone, KGF- (failed in UC
trial), rosiglitizone, PAF inhibitor, EGF, RDP, Nu-286 (Wnt agonist)
Chimeric monoclonal Chimeric monoclonal antibody (75% humanantibody (75% human
IgGIgG11 isotype) isotype)
InfliximabInfliximab
IgGIgG11
ConstructConstruct of Anti-TNF- of Anti-TNF-αα Biologic Agents Biologic AgentsConstructConstruct of Anti-TNF- of Anti-TNF-αα Biologic Agents Biologic Agents
Mouse Mouse HumanHumanPEG, polyethylene glycol.PEG, polyethylene glycol.
Humanized Fab’Humanized Fab’fragment (95% humanfragment (95% human
IgGIgG11 isotype) isotype)
Certolizumab PegolCertolizumab Pegol
PEGPEG
PEGPEG
VHVHVLVL
CCHH11
No FcNo Fc
Human recombinant Human recombinant antibody (100% humanantibody (100% human
IgGIgG11 isotype) isotype)
AdalimumabAdalimumab
IgGIgG11
Clinical Response and Remission with Infliximab
Targan SR, et al. N Engl J Med. 1997;337:1029-1035.
4%
16%
48%
81%
0
20
40
60
80
100
4-week ClinicalResponse
4-week ClinicalRemission
Placebo (n=25)
REMICADE 5 mg/kg(n=27)
P<0.001
P<0.001
% P
ati
ents
ACCENT I: Maintenance Infliximab for CD in Randomized Responders (N = 335)
Hanauer SB, et al. Lancet. 2002;359:1541–1549.
Week 30
Week 54
% o
f P
atie
nts
% o
f P
atie
nts
Placebo
Infliximab10 mg/kg
Infliximab
5 mg/kg
Clinical Remission
60
40
20
0
Clinical Response
60
40
20
0
p < 0.0001
p = 0.0002
60
40
20
0
p < 0.0001
p = 0.0001
p = NS
p = NS
26
4760
15
3646
p = 0.002
p = 0.003
60
40
20
0
p < 0.0001
p = 0.007
p = NS
p = NS
25
3945
14
2838
CLASSIC I: Results at Week 4
* p < 0.05 vs placebo; †p = 0.001 vs placebo; ‡p = 0.007 vs placebo.Clinical remission = CDAI < 150; Clinical response = 70 or 100 is a ≥ 70 or ≥ 100 point decrease in CDAI from baseline.Hanauer S, et al. Gastroenterology. 2006;130:323–33.
Placebo Adalimumab 40/20
Adalimumab 80/40 Adalimumab 160/80
18
24
36
12
5459
37 3440
50
% o
f P
atie
nts
*
*
25
0
10
20
30
40
50
60
70
59
Clinical Remission
Clinical Response
70
Clinical Response
100
*‡
†
CHARM: Clinical Remission of CD Over Time With Adalimumab
Randomized Responders (n = 499)
* *
* **
* * * *
*
**
* * * * **
†
% o
f P
atie
nts
Weeks
47
40
41
36
1712
*p < 0.001 vs placebo; †p = 0.005 vs placebo.EOW = every other week; remission = CDAI < 150.Colombel JF, et al. DDW 2006, Abstract 686d.
0
10
20
30
40
50
60
0 10 20 30 40 50 60
Placebo Adalimumab 40 mg EOW Adalimumab 40 mg weekly
26 56
Placebo q 4 wk (N = 212)
Certolizumab pegol 400 mg q 4 wk (N = 216)
*
*
0
20
40
60
80
Clinical Response (decrease in CDAI ≥ 100
points)
Clinical Remission(CDAI < 150 points)
% o
f P
atie
nts
*p < 0.001 vs placebo.Schreiber S, et al. Gut. 2005;54(Suppl VII):A82.
36
63
29
48
PRECiSE 2: Clinical Response and Remission at Week 26 in Patients With CD
Randomized Responders (N = 428)
Overview of Results of Long-Term Anti-TNF Trials
Response† Remission Response‡ Remission Response‡ Remission
Remission = CDAI score < 150† Decrease in CDAI score of 70 points and 25%‡ Decrease in CDAI score of 100 points
27.0
51.0
21.0
39.0
Pat
ien
ts (
%)
Hanauer SB et al. Lancet. 2002;359:1541–1549.Colombel J et al. Gastroenterology. 2006;131:950.Schreiber S et al. Gut. 2005;54(Suppl VII):A82.
Week 26–30
26.0
52.0
17.0
40.0
62.8
36.2
47.9
28.6
Infliximab 5 mg/kg
ACCENT 1 n = 113
CHARMn = 172
PRECiSE 2 n = 215
Adalimumab 40 mg EOW Certolizumab pegol 400 mg every 4 weeks
Placebo Placebo Placebo
*P = .0002; **P = .003; ***P < .001
*
**
***
***
***
***
0
20
40
60
80
100
Natalizumab as Maintenance Therapy for Crohn’s Disease: ENACT-2 Trial
Sandborn WJ et al. N Engl J Med. 2005;353:19121925.
Natalizumab 300 mg
Placebo
Pat
ien
ts (
%)
Response≥ 70-point decrease
in CDAI
RemissionCDAI ≤ 150
PP < .05 < .05 PP < .05 < .05 PP < .05 < .05 PP < .05 < .05
Mean CDAI Scores Over 24 Months of Continuous Treatment With Natalizumab
Panaccione R, et al. Am J Gastroenterol. 2006;101(Suppl 2):S450. Abstract 1152.
Mea
n C
DA
I S
core
350
300
250
200
150
100
50
0
All patients (n = 87)Prior exposure to anti-TNF (n = 22)Prior failure of anti-TNF (n = 11)
291.5298.2301.5
90.079.589.5
72.157.864.5
71.964.094.6
Months
OLEBaseline
ENACT-2
Baseline
ENACT-1
Baseline
2724211812963
Summary: Anti-TNF-Summary: Anti-TNF-αα Therapy in IBD Therapy in IBD
_ Effective therapy for Effective therapy for induction and remission of induction and remission of active CD and fistulizing active CD and fistulizing CD (infliximab) CD (infliximab)
_ In the current management In the current management paradigm, reserved for paradigm, reserved for patients with more severe patients with more severe diseasedisease
_ Mucosal healing with long-Mucosal healing with long-term therapy (infliximab)term therapy (infliximab)
_ Safety issuesSafety issues– InfectionsInfections– Reactivation of latent TBReactivation of latent TB– Possible lymphoma riskPossible lymphoma risk– Hepatosplenic T-cell lymphoma Hepatosplenic T-cell lymphoma
in young patients on infliximab in young patients on infliximab plus concomittant azathioprine (n plus concomittant azathioprine (n = 8)= 8)
_ ImmunogenicityImmunogenicity– Infliximab:Infliximab: Infusion reactions Infusion reactions
contributing to loss of responsecontributing to loss of response– Other anti-TNF-Other anti-TNF-αα agents: agents:
Immunogenicity occurs; Immunogenicity occurs; significance is uncertainsignificance is uncertain
Patients With CD Who Developed HSTCL While Receiving Infliximab and Immunomodulators
_ 8 cases of HSTCL have been reported in CD patients receiving infliximab plus azathioprine or 6-mercaptopurine
– AZA or 6-MP use for 3 to 7 years prior to starting IFX
_ 7 males; 1 female_ Age range: 12 to 31 years_ Duration of CD: 2 to 8 years_ T-cell receptor type at presentation: 3 αβ; 5 γδ_ HSTCL occurred at varying times after IFX exposure--
– 5 years after 1 dose of IFX 5 mg/kg (1 case)– 2-3 years after 1-3 doses of IFX 5 mg/kg (3 cases)– 2-5 years after 10-20 doses of IFX 5-10 mg/kg (4 cases)
_ Outcome: 6 patients died; 1 responded to chemo; 1 starting chemo
_ Incidence – approximately 1 in 1000
HSTCL = Hepatosplenic T-cell lymphoma.Thayu M, et al. J Pediatr Gastroenterol Nutr. 2005;40:220–222; Centocor press release, May 2006.
Natalizumab: Safety_ Most common AEs (≥ 10% of patients) were headache,
nausea, and nasopharyngitis_ 8–14% of patients discontinued treatment due to AEs_ 6 cases of progressive multifocal leukoencephalopathy
(PML) have been reported – 35,000 patients treated to date
_ Patients in all clinical trials have been re-evaluated for PML2,3
– 89% of eligible clinical trial patients participated (N = 3389)– No additional, confirmed cases of PML were identified in > 3000 patients– PML was excluded in all but 1 patient, where repeat MRI and CSF were
not available– Estimated risk of PML in this population:
• < 1 per 1000 patients (0.1%; 95% CI: 0.2–2.8 per 1000)3
• Incidence in CD: 1 in 1275• Incidence in MS: 2 in 2248• In outpatient use < 1 in 3 - 6000 patients
1. Sandborn WJ, et al. N Engl J Med. 2005;353:1912–1915; 2. Sandborn WJ, et al. DDW 2006, Abstract 492;3. Yousry T A, et al. N Engl J Med. 2006; 354:924–933.
III. Step-up vs Top-down Approach
D’Haens GR, et al. Lancet 2008. 371: 660-7.
New Approaches to Therapeutic Intervention in Crohn’s Disease?
The “Step-up” vs “Top-down” Trial
Corticosteroids
Corticosteroids
Corticosteroids
+ (episodic) IFX
IFX +
AZA
+ AZA/MTX
+ IFX
AZA, azathioprine; IFX, infliximab; MTX, methotrexate.AZA, azathioprine; IFX, infliximab; MTX, methotrexate.
Assessment of Top-Down Versus Step-Up Strategies in CD
• Newly diagnosed CD of < 4 years’ duration (N = 129)
• Naive to immunomodulators and biologics
Step-up (n = 64)
Steroids
+ IFX
+ AZA MTX
Steroids
Steroids
Top-down(n = 65)IFX (Wk 0, 2, 6)
+ AZA
IFX + AZA
+ (episodic) IFX
Steroids
CDAI < 150 Points AND No Steroids AND No Surgery
Weeks
% o
f P
atie
nts
Step-upTop-down
*
0
20
40
60
80
100
0 20 40 60 80 100
Co-primary endpoints6 & 12 months
†*
* P < 0.01; † P < 0.05D’Haens GR, et al. Lancet 2008. 371: 660-7.
Top-Down Versus Step-Up TrialClinical Results at 2 Years
D’Haens GR, et al. Lancet 2008. 371: 660-7.
Reduction and Disappearance of Ulcers
% o
f P
atie
nts
88
71
47
30
p < 0.001
p < 0.001
0
20
40
60
80
100
Reduction Disappearance
Step-upTop-down
Patients Receiving Immunosuppressants
Weeks
% o
f P
atie
nts
Patients Receiving Infliximab
0
50
100
0 20 40 60 80 100
Step-upTop-down
0
50
100
% o
f P
atie
nts
80%
20%
What does mucosal healing in Crohn’s disease mean clinically?
Endoscopic Healing and Reduced Hospitalizations and Surgeries: Infliximab maintenance for Crohn’s disease
0%
8%
0
10
20
30
40
50
Hospitalization Surgery
Patients with no healing(n=74)
Rat
e o
f H
osp
ital
izat
ion
s an
d S
urg
erie
s (%
)
0%
Patients with healing at 1 visit (10 or 54 wk) (n=16)
Patients with healing at both 10 and 54 wks
Rutgeerts P et al. Gastroenterology. 2002;123(suppl):43.M2138.
25%
46%
0%(34*) (4*) (6*)
*Number per 100 patients
Infliximab: ACCENT IInfliximab: ACCENT I
Weighing the Value of Top-Down Therapy
• Maintenance of Maintenance of remissionremission
• Improved function and Improved function and QOLQOL
• Early promotion of Early promotion of mucosal healing to mucosal healing to prevent complicationsprevent complications
• Side effectsSide effects
• CostCost
• Majority of patients may Majority of patients may not require more potent not require more potent treatments initiallytreatments initially
• Under-treatment of Under-treatment of most severe patients most severe patients with episodic strategy?with episodic strategy?
Benefits Disadvantages
Lichtenstein GR, et al. Inflamm Bowel Dis. 2004;10:S2–S10.Caprilli R, et al. Digestive Liver Dis. 2005;37:973–979.
IV. Is “Top-down” treatment a good idea for managing all patients with
Crohn’s disease?
Natural History of Crohn’s disease
Heterogeneity of Crohn’s disease. Severe CD phenotypes.
1998 - Tale of 2 boys
Patient -1 12 year old boy
with weight loss and diarrhea
Diagnosis – Crohn’s disease of ileum and colon
Treated with steroids + immune modifiers
Patient -2 13 year old boy
with weight loss and diarrhea
Diagnosis – Crohn’s disease of ileum and colon
Treated with steroids + immune modifiers
With permission, S Kugathasan MD
2003 - Tale of 2 boysPatient -1 He had been in clinical
remission for first 2 years Relapse required a short
course of steroids Normal growth and timely
puberty He has been in remission
since then Repeat colonoscopy – all
lesions were healed.
Patient -2 Became steroid dependent; no
response to most meds. Allergic to biologic therapy retreatment following episodic dosing.
1st surgery in 6 months Recurrence of Crohn’s Delayed puberty Stunted growth More steroids, tube feeding Bowel perforation needed 2nd
surgery Further hospitalization and TPN 3rd surgery for ‘ostomy’ Doing OK, hoping to get his
bowel reconnected in futureWith permission, S Kugathasan MD
Probability of Surgery for Crohn’s Disease
Years After Diagnosis
Patients (%)
1 Surgery
2Surgeries
≥ 3Surgeries
NoSurgery
5 37 7 5 51
10 39 11 12 39
15 34 14 22 30
Munkholm P et al. Gastroenterology. 1993;105:1716–1723.
severemoderate mild
Probability of Surgery for Crohn’s Disease
Years After Diagnosis
Patients (%)
1 Surgery
2Surgeries
≥ 3Surgeries
NoSurgery
5 37 7 5 51
10 39 11 12 39
15 34 14 22 30
Munkholm P et al. Gastroenterology. 1993;105:1716–1723.
Can we predict these subgroups at the time of diagnosis?
Must we wait to have multiple surgeries to define severe disease?
Estimate of Work Capacity: 10 Years Following Diagnosis
Fully capable Partially capable IncapableYears
% P
atie
nts
Binder V et al. Gut. 1985;26:146.
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10
30% of CD ptswith disability
Heterogeneity of Crohn’s disease
Predictability of the postoperative course of Crohn's disease.
Rutgeerts P, Geboes K, Vantrappen G, Beyls J, Kerremans R, Hiele M.
Gastroenterology. 1990;99:956-963
Rutgeerts Endoscopic Scoring System – neoterminal ileum
I,1 I,3
I,4
Actuarial analysis of symptomatic recurrence in patients stratified according to severity of endoscopic lesions
Rutgeerts P, et al. Gastroenterology. 1990;99:956-963
Actuarial analysis of symptomatic recurrence in patients stratified according to severity of endoscopic lesions
Severe Crohn’ssubgroup – rapidpost-operativesymptomaticrecurrence
Rationale for disease modifying therapy in Crohn’s disease.
What can our pediatric gastroenterology colleagues teach
us about Crohn’s disease?
Early disease –Inflammation
Late disease –Tissue remodelingTime
Efficacy of AZA as Maintenance Therapy
in Patients with Active CD*
Duration of Trial (months)
* Remission induced by prednisolone tapered over 12 wk Candy S, et al. Gut. 1995;37:674.
80
60
40
20
0
% P
atie
nts
No
t Fa
iling
Tri
al
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
AZA 2.5 mg/kg/d (n=33)
Placebo (n=30)
100
P=0.001
BiologicTherapypatients
Duration of Remission With 6-MP in Children With Newly Diagnosed CD
1.00
0.75
0.50
0.25
0.000 100 200 300 400 500 600
Days from Start of Remission
Fra
ctio
n i
n R
emis
sio
n
6-MP
Controls
P < .007
Markowitz J et al. Gastroenterology. 2000;119:895.
REACH: Response and Remission Rates to Infliximab in Pediatric Patients With Moderate-to-Severe CD
88
64
33
59 56
24
0
20
40
60
80
100
Week 10 Week 54 q8 Week 54 q12
Response Remission
% o
f P
atie
nts
n = 99 n = 66 n = 29n = 33 n = 17 n = 12
p = 0.002p < 0.001
*
Clinical Remission Clinical Response
Hanauer SB, et al. Lancet. 2002;359:1541–1549.
ACCENT IWeek 54
Placebo
Infliximab 5 mg/kg
60
40
20
0
p = 0.0001
15
36
60
40
20
0
p = 0.007
14
28
Changes in PCDAI Score Following Infliximab Infusion
(10 Weeks)
0
20
40
60
80
100
PC
DA
I S
core
0 2 4 6 8 10 12
Weeks Following Infliximab Infusion
Kugathasan S et al. Am J Gastroenterol. 2000;95:3189.
94% responserate
Mucosal and histologic healing after infliximab in Early CD
0 8 16 24 32 40 56
Duration of Response Following Initial Infliximab Infusion: Early vs. Late CD
% P
atie
nts
Wit
ho
ut
Rel
apse
640
25
50
75
Late CD (n=8)
Early CD (n=6)
48
Weeks Following Infliximab Infusion
100
Kugathasan S et al. Am J Gastroenterol. 2000;95:3189.
PRECiSE 2: Week 26 Clinical Response or Remission by Duration of Crohn’s Disease
*P < 0.01; †P < 0.05; ‡P < 0.001 vs placebo.Sandborn WJ, et al. Am J Gastroenterol. 2006;101(Suppl 2):S394. Abstract 1109.
Placebo
Certolizumab
68
55
4744
37 3629
24
< 1 1 to < 2 2 to < 5 ≥ 5
90
75
6257
37
50
3633
0
20
40
60
80
100
< 1 1 to < 2 2 to < 5
Pat
ien
ts (
%)
≥ 5
Duration of Crohn’s Disease (years)
Response Remission
*
††
‡
‡
n = 54 42 100 229 54 42 100 229
Biologic induction for all Crohn’s disease patients implies episodic dosing for those who will require
longterm maintenance.
Why is episodic dosing of biologic therapy problematic in IBD?
Maintenance Treatment
Serum Concentrations of Infliximab:All Randomized Patients
Antibodies to Infliximab Through Week 54
• 14% of patients were antibody to infliximab (+)
0
2
4
6
8
10
12
14
16
18
20
nu
mb
er
of
pa
tie
nts
0 10 20 30 40 50 60 70 80 90 100 110 120 130
number of weeks between 1st and 2nd infusions of infliximab
Outcome of 86 infliximab second infusions
Acute systemic reaction
Delayed systemic reaction
Kugathasan S et al. Am J Gastroenterol. 2002; 97: 1408-14.
Analysis of longterm infliximab performance in Crohn’s disease
2nd Analysis: Last maintenance infusion
Past Episodic group
Scheduled group
Both groups received ≥ 24 months maintenance
start
infliximab
last
infliximab
Mean 40 months
Mean 50
months
Fewer patients hospitalized & undergoing surgery on SCHEDULED infliximab
Before infliximab Therapy
% o
f P
atie
nts
Past Episodic (n=24)Scheduled (n=28)p =NS p =NS
46 46
6158
0
10
20
30
40
50
60
70
Hospitalization Surgery
At last infliximab infusion
p < 0.001 p < 0.001
67
21
7
67
Hospitalization Surgery
Fewer TOTAL hospitalizations & surgeries on scheduled infliximab
Before Infliximab Therapy
Nu
mb
er
of
Ev
en
ts
Past Episodic (n=24)Scheduled (n=28)p =NS p =NS
1714
55 55
0
10
20
30
40
50
60
Hospitalization Surgery
At last infliximab infusion
7
p < 0.001 p < 0.001
32
2
28
Hospitalization Surgery
110 surgeriesin 52 pts
Durability of infliximab in Crohn’s disease
50% of CD patients have discontinued infliximab by 6 years of maintenance therapy (n = 153)
Gonzaga J et al. Gastroenterology 2008; 134: A665.
V. A rational approach for biologic therapy in Crohn’s disease
Crohn’s disease - medical management algorithm:No partial obstruction or abscess detected
Moderate
AZA/6MP/MTX to induce/maintain remission
AZA/6MP/MTX maintenance
Corticosteroid taper
breakthrough
SevereMild
5-ASA,Budesonideor antibiotics
Inadequate response toAZA/6MP/MTX
infliximab, adalimumab,certolizumab, natalizumabmaintenance
No
Yes
unable to taperCorticosteroids
Surgical patients
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
Sandborn, WJ et al. ACG 2008.
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
Sandborn, WJ et al. ACG 2008.
Duration of Remission With 6-MP in Children With Newly Diagnosed CD
1.00
0.75
0.50
0.25
0.000 100 200 300 400 500 600
Days from Start of Remission
Fra
ctio
n i
n R
emis
sio
n
6-MP
Controls
P < .007
Markowitz J et al. Gastroenterology. 2000;119:895.
Summary and conclusions - I
Multiple biologic agents targeting TNF-, IL-12/23 and 4 integrin are being developed for Crohn’s disease.
Rapid, effective therapy to induce remission has long-term benefit, specifically for mucosal healing in CD.
Precedent for disease modifying therapy exists with pediatric CD patients.
Summary and conclusions - II
Antibody based biologic therapy for CD is not flexible. Re-starting therapy is associated with immunogenicity, allergy and diminished efficacy.
Rapid identification of the high risk subgroup of patients (approximately 25% of CD) who will ultimately require biologic therapy for long-term maintenance of remission remains the ultimate goal.
Risk-benefit assessment will favor use of biologic agents in the severe Crohn’s disease subgroups.