who should receive early anti-tnf therapy: with what benefits and risks?
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
Who should receive early anti-TNF therapy: With what benefits and risks?
Ted Denson, MDCincinnati Children’s Hospital Medical CenterUniversity of Cincinnati College of Medicine
Disclosures• Grant support: NIH & CCFA• Adapted from NASPGHAN 2013 talk by Jeff Hyams
IBD: Treatment Goals
• 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
• 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
Dis
ease
Sev
erity
Thiopurines ThiopurinesCorticosteroids Enteral Nutrition
Methotrexate
Anti-TNF
Surgery
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
88
64
33
59 56
24
0102030405060708090
100
Week 10 Week 54 q8 Week 54 q12
Response Remission
*Reduction from baseline of ≥ 15 points in PCDAI score and a PCDAI score ≤ 30.†PCDAI score ≤ 10.
% o
f Pat
ient
s
n = 99 n = 66 n = 29n = 33 n = 17 n = 12
p = 0.002
p < 0.001
* †
Hyams et al. Gastroenterology 2007;132:863-873
Imagine Trial
ADA-EXP LD ADA-EXP HD ADA -N LD ADA-N HD05
101520253035404550
52 Week Remission
Remission
17% 19% 28% 45%
P=0.8
P=0.065
Hyams et al. Gastroenterology 2012;143:365EXP= IFX experienced, N=IFX naïve
2008-2012: 552 childrenNewly 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 onlyn = 68
No early immunotherapy
n = 236
Early IM onlyn=248
Propensity Score Matching
Anti-TNFα onlyn = 68
No early immunotherapy n = 68
IM onlyn = 68
Additional Treatment Characteristics of Study Triads
Early Therapy n=204
Agents used in 1st 3 months
Additional agents 3-6 months
Additional agents 6-12 months
Total other agents 3-12 months
Anti-TNFα only n=68
67 IFX1 ADA
0 Thio4 MTX
1 Thio2 MTX
1 Thio6 MTX
IM onlyN=68
54 Thio14 MTX
6 IFX0 ADA
13 IFX1 ADA
19 IFX1 ADA
No immuno-therapyN=68
48 5-ASA8 EEN
11 Thio8 MTX7 IFX1 ADA1 IFX + IM2 ADA + IM
3 Thio5 MTX4 IFX1 ADA4 IFX + IM
14 Thio13 MTX11 IFX2 ADA5 IFX+IM2 ADA+IM
Hyams et al. Gastroenterology 2013
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%)
CS-free, Surgery free
(p=0.0003)
12 Month Outcomes For The Three Early Therapy Approaches: PCDAI≤10
Without Resection (n=204 for 68 propensity score matched triads)
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 z-score
Weight z-score
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-therapy (n=68)
-0.32 (1.1)-0.06 (1.1)
-0.67 (1.1) -0.68 (1.1)
Difference between groups
P=0.6P=0.039
P=0.8 P=0.8
*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 non-response 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• 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
Bodger et al Alimen Pharm Ther 2009
Surgical care: ~44% of lifetime costsICER: incremental cost-effectiveness ratioQALY: quality-adjusted life-years
Is the Reward Worth the Risk?
REWARD
RISK REWARD
RISK
DO IT DON’T DO IT
Crohn’s Disease Progresses on “Conventional Therapy” in Children: 1988-2002
Vernier-Massouille et al. Gastroenterology 2008;135:1106
Inflammatory
Stricturing
Penetrating
34% at 5 yrs
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
Study:Genetic makeup
Bacteria in bowel
Immune reactivity
Environmental Exposures
1100 children with Crohn’s at diagnosis
3 years160 – 200 patients with complication / surgery
CCFA Sponsored Clinical Research Network:PRO-KIIDS: Aim to Discover and Validate New Diagnostic & Prognostic Tools
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