Induction and Maintenance Therapies: Lessons from PROTECT Joel R. Rosh, MD Director, Pediatric...
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Transcript of Induction and Maintenance Therapies: Lessons from PROTECT Joel R. Rosh, MD Director, Pediatric...
Induction and Maintenance Therapies: Lessons from PROTECT
Joel R. Rosh, MDDirector, Pediatric Gastroenterology
Goryeb Children's Hospital/Atlantic Health Professor of Pediatrics
Icahn School of Medicine at Mount Sinai
Disclosures
• Grant Support: – Abbvie, Astra-Zeneca, Janssen
• Consultant:– Abbvie, Given, Janssen, Soligenix
• Honoraria/Speakers’ Bureau– Abbott Nutrition, Abbvie, Prometheus
Incidence of IBD is Increasing Dramatically WorldwideSartor, Nature Clin Prac, 2006
Key Point 1:
IBD is a Complex Disorder that May Require a Genetically Susceptible Host with an Appropriate Environmental Trigger(s)
Key Point 2:
IBD Results from an Exaggerated Mucosal Immune Response to Commensal Microorganisms
Pathogenesis of IBD
GWAS Studies Have Identified over 180 Inflammatory Bowel Disease Susceptibility Loci
Lees C W et al. Gut doi:10.1136/gut.2009.
EVOLVING CLASSIFICATION(Diabetes as the Model)
ULCERATIVE COLITIS• Mucosal• Continuous
CROHNS DISEASE• Transmural• Discontinuous• OralPeri-anal
Inde
term
inat
e Co
litis
IBD 1 IBD 2 IBD 3 IBD 4 IBD5
IMM
UNE
RESPONSE
ENVIRONMENTAL
FACTORS TREATMENT
GENET
IC
SUSC
EPTIB
ILITY
HOST GENETICS
GENE EXPRESSION
MICROBIOMESMOKING
DIET
INNATE RESPONSE
PHARMACOGENOMICS
SURGERY
BIOLOGICS
STRESSNSAIDS
ADHERENCE
ADAPTIVE RESPONSE
IBD patients may have unique signatures that predict complicated or treatment refractory disease
FAMILY HISTORY
Large bowel Small bowelIBD
SEROLOGICAL RESPONSE
Clinical features: age, location, endoscopy, histology, etc.
MONITORING
IBD: Therapeutic Themes
• Correct diagnosis!• Induction therapies• Maintenance therapies• “Step in” is better than “step up”• Optimization of therapy• Treat the whole patient
IBD: Therapeutic Themes
• Correct diagnosis!• Induction therapies• Maintenance therapies• “Step in” is better than “step up”• Optimization of therapy• Treat the whole patient
IBD: Therapeutic Themes
• Correct diagnosis!• Induction therapies• Maintenance therapies• “Step in” is better than “step up”• Optimization of therapy• Treat the whole patient
IBD: Therapeutic Themes
• Correct diagnosis!• Induction therapies• Maintenance therapies• “Step in” is better than “step up”• Optimization of therapy• Treat the whole patient
28%21%
39%
51%
0%
20%
40%
60%
80%
100%
Week 30 Response Week 30 Remission
28%
17%
54%
40%
0%
20%
40%
60%
80%
100%
Week 26 Response Week 26 Remission
29%36%
48%
63%
0%
20%
40%
60%
80%
100%
Week 26 Response Week 26 Remission
30%37%
55%
67%
0%
20%
40%
60%
80%
100%
Week 36 Response Week 36 Remission
Infliximab Week 2 RespondersACCENT 1
Adalimumab Week 4 RespondersCHARM
Certolizumab Week 6 RespondersPRECiSE 2
Natalizumab Week 10 RespondersENACT-2
Placebo
Infliximab Adalimumab
Placebo eow
Placebo
Certolizumab
Placebo
Natalizumab
Pa
tien
ts (
%)
Pa
tien
ts (
%)
Pa
tien
ts (
%)
Pa
tien
ts (
%)
Adapted from Hanauer SB et al. Lancet. 2002;359(9317):1541-1549 (ACCENT 1), Colombel J-F et al. Gastroenterology. 2007;132(1):52-65 (CHARM), Schreiber S et al. N Engl J Med. 2007;357(3):239-250 (PRECiSE 2), and Sandborn WJ et al. N Engl J Med 2005;353:1912-1925 (ENACT-2)..
28%21%
39%
51%
0%
20%
40%
60%
80%
100%
Week 30 Response Week 30 Remission
28%
17%
54%
40%
0%
20%
40%
60%
80%
100%
Week 26 Response Week 26 Remission
29%36%
48%
63%
0%
20%
40%
60%
80%
100%
Week 26 Response Week 26 Remission
30%37%
55%
67%
0%
20%
40%
60%
80%
100%
Week 36 Response Week 36 Remission
Infliximab Week 2 RespondersACCENT 1
Adalimumab Week 4 RespondersCHARM
Certolizumab Week 6 RespondersPRECiSE 2
Natalizumab Week 10 RespondersENACT-2
Placebo
Infliximab Adalimumab
Placebo eow
Placebo
Certolizumab
Placebo
Natalizumab
Pa
tien
ts (
%)
Pa
tien
ts (
%)
Pa
tien
ts (
%)
Pa
tien
ts (
%)
Adapted from Hanauer SB et al. Lancet. 2002;359(9317):1541-1549 (ACCENT 1), Colombel J-F et al. Gastroenterology. 2007;132(1):52-65 (CHARM), Schreiber S et al. N Engl J Med. 2007;357(3):239-250 (PRECiSE 2), and Sandborn WJ et al. N Engl J Med 2005;353:1912-1925 (ENACT-2)..
IBD: Therapeutic Themes
• Correct diagnosis!• Induction therapies• Maintenance therapies• “Step in” is better than “step up”• Optimization of therapy• Treat the whole patient:
– The best combination therapy!
IBD: Therapeutic Themes
• Correct diagnosis!• Induction therapies• Maintenance therapies• “Step in” is better than “step up”• Optimization of therapy• Treat the whole patient:
– The best combination therapy!– Start with how we speak
Predicting Response tO
STandardized PEdiatric Colitis Therapy
1U01 DK 095745-01
Disease Location at BaselineN=379 Enrolled with UC
LocationAssessed
Out of N=379
MacroscopicDisease
Microscopic Disease
onlyCecum 343(90.5%) 232(67.6%) 26(7.6%)Ascending Colon 347(91.6%) 233(67.1%) 35 (10.1%)Transverse Colon 354(93.4%) 287(81.1%) 17(4.8%)Descending Colon 371(97.9%) 343(92.5%) 8(2.2%)Sigmoid 376(99.2%) 372(98.9%) 1(0.3%)Rectum 376(99.2%) 373(99.2%) 3(0.8%)
Non-Classical Features at Diagnosis N=379 Enrolled with UC
Non-classical Feature %Relative rectal sparing 33(8.7%)Macroscopic patchiness 35(9.2%)Periappendiceal inflammation 27(7.1%)Backwash ileitis 28(7.4%)Microscopic gastritis 212(55.9%)Non-spec macro gastritis 102(26.9%)
Diagnosis of UC
MildPUCAI 10-34
Moderate/SeverePUCAI 35-64
Severe/Fulminant ≥65
Pathway A: Mesalamine
Response No Response
Remission Flare
Pathway B: PO Steroids
Response No Response
Pathway CAdd Mesalamine
WeanPrednisone
Remission
MaintainanceMesalamine
C.I. Anti-TNF
Flare: Early (<6 mon)Late (≥ 6 mon)
IM/Anti-TNF
Hospital
Pathway D: IV Steroids
Response≤14 days
No Response
C.I. Anti-TNF
S
Flare5-ASA intolerance1
StopMesalamine
C.I. = calcineurin inhibitorAnti-TNF = anti-TNFαIM = ImmunomodulatorS= Surgery(1) Paradoxical worsening with mesalamine
IM/Anti-TNFMaintenance
MaintainanceMesalamine
Early
Late
Pathway F
Pathway G
Pathway E
Initial Therapy By PUCAI:Need to “Right Fit”
2 patients with UC did not receive medical therapy. One had a colectomy and one decided to treat UC with diet.2 patients had missing data2 received both Pentasa and steroids at time 0
Baseline PUCAI Pentasa Oral Steroids
IV Steroids
Mild (n=90) 78 (87%) 9 (10%) 2 (2.0%)
Moderate (n=164) 48 (29%) 81 (49%) 30 (18%)
Severe (n=119) 2 (2%) 33 (28%) 81 (68%)
n=379
Initial Therapy By PUCAI:Need to “Right Fit”
2 patients with UC did not receive medical therapy. One had a colectomy and one decided to treat UC with diet.2 patients had missing data2 received both Pentasa and steroids at time 0
Baseline PUCAI Pentasa Oral Steroids
IV Steroids
Mild (n=90) 78 (87%) 9 (10%) 2 (2.0%)
Moderate (n=164) 48 (29%) 81 (49%) 30 (18%)
Severe (n=119) 2 (2%) 33 (28%) 81 (68%)
n=379
Initial Therapy By PUCAI:Need to “Right Fit”
2 patients with UC did not receive medical therapy. One had a colectomy and one decided to treat UC with diet.2 patients had missing data2 received both Pentasa and steroids at time 0
Baseline PUCAI Pentasa Oral Steroids
IV Steroids
Mild (n=90) 78 (87%) 9 (10%) 2 (2.0%)
Moderate (n=164) 48 (29%) 81 (49%) 30 (18%)
Severe (n=119) 2 (2%) 33 (28%) 81 (68%)
n=379
24022821620419218016815614413212010896847260483624120
0
10
20
30
40
50
60
70
80
90
100
Cu
mu
lati
ve P
rob
abil
ity
(%)
Patients at risk: Months2002 552 229 95 37N =
Penetrating
Cosnes J et al. Inflamm Bowel Dis. 2002;8:244-250.
High Potential Low Potential
InflammatoryStructuring
Impact of Therapy Depends on Degree of Structural Damage and Velocity of Progression
Slide Courtesy of the GI Health Foundation
Consensus Predictors of Poor Outcome*
• Deep colonic ulcerations on endoscopy • Persistent severe disease despite adequate induction
therapy • Extensive (pan-enteric) disease • Marked growth retardation (> -2.5 height Z scores), • Severe osteoporosis • Stricturing or penetrating disease (B2 and/or B3
disease behavior) at onset • Severe perianal disease
*Ruemmele et al. J Crohn’s Colitis ECCO/ESPGHAN Working Group 2014;8:1179
Optimizing Outcomes:TREAT TO TARGET:
• Regular assessment of disease activity using objective clinical and biologic outcome measures
• Adjust treatment if not accomplishing the goal
• Enables better outcomes in RA, hypertension, diabetes, hypercholesterolemia
Bouguen, Clin Gastroenterol Hepatol ePub 2013 Sep 10, PMID 24036054
LOSS OF RESPONSE TO ANTI-TNF THERAPIES: “GIST”
Ben-Horin, Aliment Pharmacol Ther 2011;33:987
Strategies to Optimize Durable Biologic Response
• Regularly scheduled maintenance• Concomitant immunomodulator
– ?duration
• Monitoring drug/antibody levels– “treat to trough”
Proactive Testing in Pediatric IBD:Week 14 IFX Levels and Outcomes
Week 54 Outcome (Yes v. No) Median IFX Level (ug/mL)
Persistent Remission 4.7 versus 2.6*
Clinical Remission 3.2 versus 2.2
Clinical & Laboratory Remission 4.2 versus 3.0
Sustained Durable RemissionWeek 14 to 54
5.5 versus 3.1*
Sustained Durable RemissionWeek 22 to 54
5.1 versus 3.0*
(n=58)
* p<0.05 Singh et al. Inflamm Bowl Disease 2014;20:1708
IS MUCOSAL HEALING ACHIEVABLE?
Bouguen, Clin Gastroenterol Hepatol 2014;12:978-85.
IS MUCOSAL HEALING ACHIEVABLE?
Bouguen, Clin Gastroenterol Hepatol 2014;12:978-85.
67 CD patients underwent 161 endoscopies
Summary:Inflammatory Bowel Diseases
• Chronic intestinal inflammation from a dysregulated immune response to the enteric microbiome in a genetically predisposed host
• A family of diseases currently simplified to two umbrella terms: Crohn’s disease and ulcerative colitis
• Accurate diagnosis and staging requires clinical suspicion and appropriate confirmatory testing.
Summary:Inflammatory Bowel Diseases
• Pyramid approach does not change the natural history and disabling outcomes of surgery, hospitalization, lowered QOL.
• Personalized approach of Risk stratification and “treat to target” are emerging as best practices.
• Therapeutic drug monitoring and optimization of therapy are critically important goals in the biologic era.
• Treatment of the whole patient will result in best overall outcomes.
Backup Slides
RISK Study: The Microbiome shifts in pediatric Crohn’s disease: Decreased diversity, losses and gains
Microbiome was profiled in 800 RISK subjects
enrolled at 28 pediatric centers in US/CAN
500 cases + 300 controls
Gevers et al. Cell Host Micro 2014;15:382
The relative goodness of fit of the models, P <0.0043 Clinical variables only Clinical, expression and microbialC statistics (AUC) 0.705 0.760
A multi’omic model is superior in predicting surgery and steroid free remission in comparison to clinical factors alone.
Multiple regression analysis including clinical, gene expression, and microbial variables. p-value OR CIAge≥10 vs. <10 0.8868 0.944 0.430, 2.075Ileal DU vs. no DU
PCDAI>30 0.6244 0.771 0.271, 2.188PCDAI≤30 0.0029 4.713 1.701, 13.057
Anti-TNF therapy 0.0020 5.181 1.828, 14.706APOA1 expression level > 80th percentile 0.0152 3.058 1.241, 7.576
Blautia Abundant (>70th percentile) vs non-abundant
Veillonella abundant 0.5183 1.634 0.368, 7.25Veillonella non-abundant 0.0028 0.231 0.089,0.604
Haberman et al JCI 2014PRO-KIIDS RISK Study
0
20
40
60
80
100
Perc
ent o
f pati
ents
(%)
AZA + placebo IFX + placebo IFX+ AZA
p<0.001
p=0.025 p=0.002
SONIC: Steroid Free Remission
48/170 67/169 94/169
28.2
39.6
55.6
All Randomized Patients (N=508)*
Colombel JF, et al. N Engl J Med 2010; 362:1383
Vedolizumab: Primary Maintenance Endpoint For Adult Crohn’s Disease
Clinical Remission0%
5%
10%
15%
20%
25%
30%
35%
40%
22%
39%
36%
VDZ / VDZ Q8w (n=154)VDZ / VDZ Q4w (n=154)
VDZ / Placebo (n=153)p<0.01
=17%
=15%
Patients %
(95% CI)
p<0.001
Predictors of Disabling Crohn’s
• Initial requirement for steroidsOR: 3.1 [95% CI: 2.2 – 4.4]
• Age at diagnosis below 40OR: 2.1 [95% CI: 1.3 – 3.6]
• Perianal disease at diagnosisOR: 1.8 [95% CI: 1.2 – 2.8]
Referred cohort of 1128 CD patients 3 factors independently predictive
disabling CD course within 5-year
Beaugerie L et al. Gastroenterology 2006;130:650-6
Progressive Bowel Damage in CD
Pariente et al. Inflamm Bowel Dis 2011
ProactiveEffective Medical Therapy
Reactive Maximal Medical Therapy
Early Surgery
Physical & Psychosocial Growth & Development
What you see onthe outside does not always indicatewhat is going oninside
Months
No
lo
ss o
f re
sp
on
se
100
80
60
40
20
00 12 24 36 48
Loss of Response After Immunomodulator Withdrawal
TL=trough levelsDrobne D et al. DDW 2011; Abstract 279
Loss of Response after Immunomodulator Withdrawal
TL detectable & CRP <5 mg/L
TL detectable & CRP >5 mg/L
TL undetectable & CRP >5 mg/L
Slide Courtesy of the GI Health Foundation
IS MUCOSAL HEALING ACHIEVABLE?
HR 2.35 (95%CI 1.15-4.97) HR 4.28 (95%CI 1.9-11.5)
Bouguen, Clin Gastroenterol Hepatol 2014;12:978-85.
SUGGESTED ALGORITHM
Bouguen, Clin Gastroenterol Hepatol ePub 2013 Sep 10, PMID 24036054
IBD:Management Goals
Relievesymptoms
Treat inflammation
Treatcomplications
Address psychosocial
issues
Identify dysplasiaand detect
cancerImprove daily
functioning
Replenish nutritional
deficits
Minimize treatment toxicity
Maintain remission
EstablishDiagnosisEstablishDiagnosis