Who should receive early anti-TNF
therapy: With what benefits and
risks?
Ted Denson, MD
Cincinnati Children’s Hospital Medical Center
University of Cincinnati College of Medicine
Disclosures
• Grant support: NIH & CCFA
• Adapted from NASPGHAN 2013 talk by Jeff Hyams
IBD: Treatment Goals
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Clinical remission: no disease activity
Excellent quality of life
Intestinal healing
Normal growth and development
Prevent surgeries and hospitalizations
Minimal side effects
Acceptable financial cost
Therapeutic Options
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Option 1: Prednisone followed by 5-ASA
Option 2:Prednisone followed by 6-MP/Aza
Option 3: Prednisone followed by methotrexate
Option 4: Exclusive enteral nutrition followed by
IM
Option 5: Anti-TNFα monotherapy
Option 6: Anti-TNFα plus thiopurine
Option 7: Anti-TNF α plus methotrexate
Option 8: Intensive helminth therapy
Label for Infliximab Therapy in Children
• Approved for pediatric use in 2006
• Infliximab is indicated for reducing signs and
symptoms and inducing and maintaining
clinical remission in pediatric patients with
moderately to severely active Crohn’s disease
(CD) who have had an inadequate response to
conventional therapy.
Accelerated Step-up Therapy for CD
Disease Severity
Surgery
Anti-TNF
Methotrexate
Thiopurines
Corticosteroids
Thiopurines
Enteral Nutrition
Focus Questions
• How should we position anti-TNFα therapy in
2013? Rescue (i.e., after conventional therapy)
vs. primary (at diagnosis)
• Can we identify patients who will receive the
greatest benefit from early anti-TNFα therapy?
• What are the risks of early anti-TNFα therapy?
• Should we give monotherapy or combination
therapy? Do benefits outweigh risks?
• Can we stop anti-TNFα therapy?
REACH: Response and Remission
% of Patients
Response *
100
90
80
70
60
50
40
30
20
10
0
Remission
†
p = 0.002
88
p < 0.001
59
64
56
33
24
n = 99
n = 66
Week 10
n = 33
n = 29
Week 54 q8
n = 17
n = 12
Week 54 q12
*Reduction from baseline of ≥ 15 points in PCDAI score and a PCDAI score ≤ 30.
†PCDAI score ≤ 10.
Hyams et al. Gastroenterology 2007;132:863-873
Imagine Trial
52 Week Remission
50
45
40
35
30
25
20
15
10
5
0
P=0.065
P=0.8
Remission
17%
ADA-EXP LD
19%
ADA-EXP HD
EXP= IFX experienced, N=IFX naïve
28%
ADA -N LD
45%
ADA-N HD
Hyams et al. Gastroenterology 2012;143:365
2008-2012: 552 children
Newly Diagnosed with Crohn’s Disease
Enrolled in CCFA RISK Study
Crohn’s disease: 552 children with
complete data and 1 yr f/u
Anti-TNFα only
n = 68
Early IM only
n=248
No early
immunotherapy
n = 236
Propensity Score Matching
Anti-TNFα only
n = 68
IM only
n = 68
No early immunotherapy
n = 68
Additional Treatment Characteristics of Study
Triads
Early
Therapy
n=204
Agents
used in 1st
3 months
Additional
agents 3-6
months
Additional Total other
agents 6agents 3-12
12 months months
Anti-TNFα 67 IFX
only n=68 1 ADA
0 Thio
4 MTX
1 Thio
2 MTX
1 Thio
6 MTX
IM only
N=68
54 Thio
14 MTX
6 IFX
0 ADA
13 IFX
1 ADA
19 IFX
1 ADA
No
immunotherapy
N=68
48 5-ASA
8 EEN
11 Thio
8 MTX
7 IFX
1 ADA
1 IFX + IM
2 ADA + IM
3 Thio
5 MTX
4 IFX
1 ADA
4 IFX + IM
14 Thio
13 MTX
11 IFX
2 ADA
5 IFX+IM
2 ADA+IM
Hyams et al. Gastroenterology 2013
12 Month Outcomes For The
Three Early Therapy Approaches: PCDAI≤10
Without Resection
(n=204 for 68 propensity score matched triads)
CS-free, Surgery free
Treatment
Yes (n=136)
No (n=68)
Early anti-TNFα
only (n=68)
58 (85%)
10 (15%)
Early IM only
(n=68)
41 (60%)
27 (40%)
No early
immunotherapy
(n=68)
37 (54%)
31 (46%)
(p=0.0003)
No difference between early IM and no early IM
Hyams et al. Gastroenterology 2013
Growth Parameters of Study Triads at
Diagnosis/One Year
Early
Therapy
Height zscore
Weight zscore
BMI z-score
Anti-TNFα
only (n=68)
-0.16 (1.1)
+0.14 (0.4)*
-0.56 (1.4)
-0.79 (1.5)
IM only
(n=68)
-0.29 (1.1)
-0.02 (0.4)
-0.72 (1.3)
-0.81 (1.3)
No immuno- -0.32 (1.1)
therapy
-0.06 (1.1)
(n=68)
-0.67 (1.1)
-0.68 (1.1)
Difference
between
groups
P=0.8
P=0.8
P=0.6
P=0.039
*p=0.002, anti-TNFα group only
What Does That Mean?
• In clinically similar populations of children with Crohn’s
disease, early (<3 mon) therapy with anti-TNFα was
superior to early IM or no early immunotherapy
despite later addition of those agents: PCDAI
remission, CRP, growth
• There was no particular clinical or laboratory
characteristic that helped predict response or nonresponse to an initial therapeutic decision
• It doesn’t mean that everyone should get anti-TNFα
therapy, rather that we need to better define further
characteristics of patients, such as genetics, serology,
microbiome. Confirmatory studies will be required.
Pooled Adverse Events for Pediatric IFX and ADA
Dubinsky et al IBD 2013
Infliximab Black Box Warning
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WARNING: SERIOUS INFECTIONS and MALIGNANCY
SERIOUS INFECTIONS
Increased risk of serious infections leading to hospitalization or death, including
tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as
histoplasmosis) and infections due to other opportunistic pathogens.
Discontinue infliximab if a patient develops a serious infection.
Perform test for latent TB; if positive, start treatment for TB prior to starting
infliximab. Monitor all patients for active TB during treatment, even if initial
latent TB test is negative.
MALIGNANCY
Lymphoma and other malignancies, some fatal, have been reported in children
and adolescent patients treated with tumor necrosis factor (TNF) blockers,
including infliximab.
Postmarketing cases of fatal hepatosplenic T-cell lymphoma (HSTCL) have been
reported in patients treated with TNF blockers including infliximab. All infliximab
cases were reported in patients with Crohn’s disease or ulcerative colitis, the
majority of whom were adolescent or young adult males. All had received
azathioprine or 6-mercaptopurine concomitantly with infliximab at or prior to
diagnosis.
T-Cell NHL Reported to FDA AERS with
TNF-α Inhibitors: The REFURBISH
Study
Deepak et al. Am J Gastroenterol 2013:108:99
The Option Grid for Shared Decision Making
Dubinsky et al IBD 2013
UK Markov Model for Cost Effectiveness of
Anti-TNF Therapy
Bodger et al Alimen Pharm Ther 2009
Anti-TNF is Cost Effective for up to 4 Years
Surgical care: ~44% of lifetime costs
ICER: incremental cost-effectiveness ratio
QALY: quality-adjusted life-years
Bodger et al Alimen Pharm Ther 2009
Is the Reward Worth the Risk?
REWARD
RISK
RISK
REWARD
DO IT
DON’T DO IT
Crohn’s Disease Progresses on
“Conventional Therapy” in Children:
1988-2002
Inflammatory
34% at 5 yrs
Stricturing
Penetrating
Vernier-Massouille et al. Gastroenterology
2008;135:1106
Infliximab Reduces Risk for Surgery
Gupta et al Gastroenterology 2006
Higher Anti-microbial Serologies (QSS) are Associated
with Increased Risk for Complications
Dubinsky et al Clin Gastro Hep 2008
Systems Dynamics Model for Disease Complications
Siegel et al IBD 2011
Benefit of Early anti-TNF May Increase as QSS Increases
Siegel et al IBD 2011
Patient Decision Aid
Siegel et al IBD 2011
CCFA Sponsored Clinical Research Network:
PRO-KIIDS: Aim to Discover and Validate
New Diagnostic & Prognostic Tools
1100 children with Crohn’s at
diagnosis
Study:
Genetic makeup
Bacteria in bowel
Immune reactivity
Environmental Exposures
3 years
160 – 200 patients with
complication / surgery
Take home messages
• Anti-TNFα therapy is highly successful in inducing and
maintaining remission in most pediatric patients with
CD
• Select the correct patient to treat. Rescue vs. primary
• Patients with significant growth failure and higher risk
of disease complications may derive greater relative
benefit
• Consider anti-TNF withdrawal once treatment goals are
met (catch-up growth, mucosal healing) in carefully
selected patients: biologic exit strategy