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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