201506012 1430 lazarev ibd how to · pdf file6/11/2015 1 june 12, 2015 1 ibd: how to diagnose...
TRANSCRIPT
6/11/2015
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June 12, 2015
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IBD: How to Diagnose and Treat
Mark Lazarev, MD Assistant Professor of Medicine, Johns Hopkins University School of Medicine
Disclosures
• I do not have any relevant financial relationships with any commercial interests.
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Talk outline
• Overview of IBD– Best approach to diagnosis
• Crohn’s disease– Current approach to therapy– Drug levels - using our biologics in a smarter
way – New therapies in the pipeline
• Ulcerative colitis– Integrating vedolizumab in your practice– New drugs in the pipeline
IBD overview
• Chronic inflammatory condition of the GI tract – affects up to 1.4 million persons in the US
• Generally presents in patients in their teens or 20s
• Predisposing factors:– Genetics– Bacteria– Triggers – GI infections, NSAIDs, antibiotics
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Diagnosis in IBD
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Diagnosing IBD: Laboratory data
• Complete blood count (CBC)– Anemia, inflammation, infection
• ESR, C-reactive protein– Markers of inflammation
• Metabolic panel– Dehydration, electrolyte depletion, liver
abnormalities
• Stool studies– Infection, inflammation
Diagnostic tools for IBD
• Ileocolonoscopy
• Small bowel imaging– Small bowel series
– Computed tomography
– Magnetic resonance imaging
– Capsule endoscopy
• Serum biomarkers
• Fecal biomarkers
Diagnosing IBD: Endoscopy - CD
Ulcers in Crohn’s disease
Strictures in Crohn’s disease
Anastomoses in Crohn’s disease
de Chambrun GP, et al. Nat Rev Gastroenterol Hepatol. 2010;7:15‐29.
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de Chambrun GP, et al. Nat Rev Gastroenterol Hepatol. 2010;7:15‐29.
Diagnosing IBD: Endoscopy ‐ UC
• Erythema
• Decreased vascular pattern
• Mild friability
1 = MILD
• Marked erythema
• Absent vascular pattern
• Friability
• Erosions
2 = MODERATE
• Marked erythema
• Absent vascular • markings
• Granularity
• Friability
• Spontaneous bleeding
• Ulcerations
3 = SEVERE
• No friability or granularity
• Intact vascularpattern
0 = NORMAL
Slide courtesy of A. Kornbluth
Methods for assessing structural features in IBDAdvantages Disadvantages
Ileocolonoscopy Validated, widely availableSensitive to changesPrognostic value
Limited to luminal structuresIncomplete examinations 20%
- SBFT Widely availableDetection penetrating/stricturingcomplications
Patient toleranceRadiation exposureBowel transit timeNo information about extraenteric disease, misses mild disease
- CT Widely available, reproducible Less interobserver variation Fast studyExtraenteric structures
Radiation exposure and overuseMisses mild disease
- MRI High sensitivity & specificityReproducible over timeExtraenteric structuresNo radiationBetter for perianal disease
Limited availabilityHeterogeneity in image acquisition and interpretationHave to lie still for appropriate breath-holding sequencesMisses mild disease
- WCE Detects more small bowel lesions than cross-sectional imagingWidely available
Heterogeneity in interpretationLower specificity for Crohn’s diseaseCapsule retention
Small bowel series Small bowel series
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Small bowel seriesMURAL HYPERENHANCEMENT INCREASED MURAL THICKNESS
MURAL STRATIFICATION(laminated appearance of thickenedsmall bowel)
COMB SIGN – dilated vasa recta in the mesenteric vasculature
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T1 Coronal plane. MRI Endoscopy
Ordas I. DDW 2010. Abs # 546
MR Small bowel CD
Normal small bowel , good distention of bowel loops
Thickened terminal ileum
MR Small bowel CD
Capsule endoscopy in IBD
Villous appearance (normal vs edematous), patchy or diffuse
Ulceration – number; extent; size, shape
Stricture – number, ulcerations, traversable
Gralnek, et al. APT 2008; 27: 146-154
Antibody AntigenNon-IBD
(%)CD (%) UC (%)
ASCASaccharomyces
cerevisiae5% 55–65% 5-15%
pANCA –antineutrophil cytoplasmic
antibody
Histone H1, bacterial antigen?
<5% 2–25% 50–65%
Anti-ompC E. Coli <5% 40–50% 2%
Anti - 2 Pseudomonas fluorescens
5-10% 54% 10%
Anti-Flagellin cBIR 8-10% ~50% 6%
Serum Biomarkers Associated with IBD
Slide adapted from Mark Silverberg MD
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Stool studies as an assessment of activity
• What is the most sensitive test for assessing active disease in Crohn’s and UC– A) ESR
– B) CRP
– C) Fecal calprotectin
– D) Stool lactoferrin
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Fecal markers – stacking up to CRP
Mosli et al. Am J Gastroenterol May 12, 2015 22
Sensitivity Specificity
CRP – IBD 0.49 (0.34-0.64) 0.92 (0.72-0.98)
FC - IBD 0.88 (0.84-0.90) 0.73 (0.66-0.79)
FC - UC 0.88 (0.84-0.92) 0.79 (0.68-0.87)
FC - CD 0.87 (0.82-0.91) 0.67 (0.58-0.75)
SL - IBD 0.82 (0.73-0.88) 0.79 (0.62-0.89)
Crohn’s disease
– Current approach to therapy
– Drug levels - using our biologics in a smarter way
– New therapies in the pipeline
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Crohn’s disease treatment options
Least
MostBiologic therapies (Infliximab, Adalimumab,
Certolizumab pegol, Natalizumab)
Methotrexate
6-Mercaptopurine/ Azathioprine
Corticosteroids
Antibiotics
Severe
Moderate
Mild
Level of aggressiveness
Disease severity
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Patient factors favoring top-down therapy
• Age < 40
• Early penetrating disease or perianal complications
• Early need for steroids
• Presence of anti-microbial antibodies
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SONIC 27
0
20
40
60
80
100
Pe
rce
nt
of
pa
tien
ts (
%)
AZA + placebo IFX + placebo IFX+ AZA
p<0.001
p=0.025 p=0.002
Corticosteroid-Free Clinical Remission at Week 50
* Patients who did not enter the Study Extension had Week 26 values carried forward
48/170 67/169 94/169
28.2
39.6
55.6
All Randomized Patients (N=508)*
Rutgeerts P et al. N Engl J Med. 2005;353:2462-2476.
Is there a role for thiopurinemonotherapy?
• There is further data that thiopurinesplay a limited role as a stand-alone agent early in diagnosis – AZTEC trial– 156 adults with recent CD diagnosis
randomized to azathioprine at 2.5mg/kg/d vs. placebo – otherwise only steroids allowed
– At 76 wks, rate of cortisteroid-free remission was 44.1% vs. 36.5%
Panes et al. Gastroenterology 2013;145;766-74 28
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Whom to choose for combination therapy
• Need to weigh a number of factors– Disease severity and extent– Men vs. women – HSTCL
• Consider combination with methotrexate in men– Advanced age– Concerns with adherence
• Ultimately if disease is severe, it’s important to be aggressive upfront, and then peel away medication after remission is achieved
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Smarter use of biologics –employing levels
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Clinical impact of serum anti–TNF-a levels
Reference Study Design NAnti-TNF
Clinical Impact of Serum Anti-TNFand Drug Level
Li , 2010SubanalysisCLASSIC I/II
258/CD ADL
Week 4 serum TL predicted clinical remission in CLASSIC I but no dose-exposure-response relationship identified in CLASSIC II
Karmiris , 2009 Prospective
168/CD ADL Low serum TL predicted LOR
Mazor, 2013 Retrospective
121/CD ADL
Serum TL >5 μg/mL associated with higher clinical remission rates and normal CRP
Sandborn, 2012
SubanalysisPRECISE (open-label)
203/CD CZP
Drug plasma concentrations positively correlated with clinical remission
Roblin,2014
Cross-sectional
40 CD/UC ADL
Higher serum TL (median 6.5 μg/mL) associated with clinical remission and mucosal healing
Sandborn, 2014
Prospective PURSUIT
625/UC GOL
Drug concentration quartile at week 6 positively predicted improvement in Mayo score and rates of clinical response and remission
Sandborn, 2014
Prospective PURSUIT
157/UCGOL
Drug concentration quartile positively predicted higher rates of clinical remission
Therapeutic Drug monitoring vs. usual care
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A Prospective Controlled Trough Level Adapted InfliXImab Treatment (TAXIT) Trial
Cohort CD and UC on IFX maintenance 263 patients
Control group (115): therapy based on clinical symptom & CRP
Study group (136/148 ): therapy based on TLI (3-7 μg)
(77%) were ATI positive
All patients were
optimized 3-7μg/ml
TLI
Casteele et al. Gastroenterology 2015;148(7):1320-9
TAXIT results
• 68 patients in each arm escalated or deescalated
• Dose escalation resulted in a significant drop in CRP & HBI.
• Dose de-escalation did not effect CRP, HBI or partial MAYO score.
Casteele et al. Gastroenterology 2015;148(7):1320-9
TAXIT (cont.)
• Primary endpoint – clinical and biological remission (CRP<5mg/L) at week 52
• Higher % in therapeutic range for TLI at 52 weeks for TLI dosing vs. clinical dosing (78 vs. 56%, p<0.001)– Clinical dosing group had greater proportion of
undetectable TLI
• Primary endpoint not different – 69% vs. 72%
Casteele et al. Gastroenterology 2015;148(7):1320-9
• There is probably a role for a one time optimization for patients on maintenance infliximab– May be extrapolated to adalimumab
• At this point, cannot support serial measures of TLI in clinical care
• More trials necessary to optimize use of biologics to balance clinical efficacy and costs
TAXIT conclusions
Casteele et al. Gastroenterology 2015;148(7):1320-9
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Randomised, single-blind, multicentre Danish study in CD (n=69)
Individualised therapy vs dose intensification in patients with CD who lose response to anti-TNF
Steenholdt C , et al. Gut 2013; gutjnl-2013-305279 [ePub ahead of print]
Co-primary clinical endpoint in intention-to-treat and per protocolpopulations. Dashed lines illustrate the predefined non-inferiority margin
0%-25%-50% 25% 50%
True difference
IFX intensificationbetter
Algorithmbetter
Per protocol
Intention-to-treat
Patients with secondary IFX failure were randomised to IFX dose intensification (5 mg/kg every 4 weeks) or interventions based on serum IFX and IFX antibody
levels
Co-primary economic endpoint in per protocol populations.Data are average treatment per patient
IFXintensification
0 4 8 12
Study week
0
2
4
6
8
10
Co
st p
er p
atie
nt,
€m
ean
Algorithm
*
**p<0.001
Crohn’s disease – New and upcoming drugs
• New for Crohn’s– Vedolizumab – alpha-4, beta-7 inhibitor –
approved for moderate to severe CD
• Upcoming– ustekinumab – IL-12/23 inhibitor –
completing phase III
– Mongersen – oral SMAD7 inhibitor – phase II complete
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• Vedolizumab
Source: Gastroenterology 2009; 136:1182-1197 (DOI:10.1053/j.gastro.2009.02.001 )
Vedolizumab (Anti‐Alpha 4 Beta 7 Integrin) For Moderately‐to‐Severely Active Crohn’s Disease: Results at Week 6 in 368
Patients
P=0.02
P=0.23
Δ 7.81.2, 14.3
Δ 5.7–3.6, 15.095% CI:
Induction ITT Population
Patients, %
Sandborn et al NEJM 2013369:711-21
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Vedolizumab (Anti‐ 47 Integrin) For Maintenance of Response in Moderately‐to‐Severely Active Crohn’s Disease: Results at Week 52 in
461 Patients
Patients, %
*
*
Δ17.4 Δ14.7 Δ13.4 Δ15.3 Δ7.2 Δ2.0Δ15.9 Δ12.9
*P<0.05 **P<0.01 †CS tapering began in responders at 6 weeks; for others, as soon as a clinical response was achieved.
Maintenance ITT Population
*
**
****
Sandborn et al NEJM2013369:711-21
Mongersen
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Percentage of patients who were in remission at day 15 (CDAI <150) and who remained in remission for at least 2 weeks
Monteleone G, et al. NEJM, March 19, 2015
Ulcerative colitis
– Integrating vedolizumab in your practice
– New drugs in the pipeline
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Study Design
• Phase 3
• Randomized, double-blind
• Placebo-controlled trial
• 211 medical centers in 34 countries
• 2008 to 2012
Inclusion Criteria
• 18 to 80 years
• Active UC– Mayo 6-12
– Endo subscore ≥ 2
– Minimal extent to 15cm
• Unsuccessful treatment with other agents– Steroids, IM, anti-TNFs
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Vedolizumab (Anti-Alpha 4 Beta 7 Integrin) For Moderately-to-Severely Active Ulcerative Colitis: Results at Week 6 in 374 Patients
P<0.001
P=0.0009
P=0.0012
Feagan et al. N Engl J Med 2013;369:699-710
Vedolizumab (Anti- 47 Integrin) For Maintenace of Response in Moderately-to-Severely Active Ulcerative Colitis: Results at Week 52 in 373 Patients
Feagan et al. N Engl J Med 2013;369:699-710
Safety
• No PML!
Vedolizumab – practical applications in UC
• In my practice:– Biologic naïve patients
• Moderate disease, steroid dependent – infliximab vsvedolizumab
• Severe disease – infliximab +/- thiopurine– For secondary non-responders consider a second anti-
TNF – For primary non-responders, failure of 2 or more anti-
TNFs, or adverse reactions to anti-TNFs, there is a role for vedolizumab
– Currently no role for hospitalized refractory patients• Further study needed – infliximab vs. vedolizumab
in UC
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UC - Upcoming drugs
• Etrolizumab – Subcutaneous α4 β7, αE β7 inhibitor – Phase III
• Tofacitinib – Oral janus kinase 1 and 3 inhibitor – Phase III completing
• Ozanimod – Oral sphingosine-1-phosphate receptor inhibitor – Phase II complete*– Selectively retains activated lymphocyte in
lymph node– Fingolimod approved for MS
* Sandborn et al. Gastroenterology 2015; 148(4):Supplement 1, S-93 53