optimizing management using the treat to target approach...ibd’treatmentgoalsare’evolving’...

Optimizing management using the treat to target approach

Subrata Ghosh, FRCP, FRCPE, FRCPC, FCAHS Professor of Medicine, Microbiology and Immunology

Head of the Department of Medicine University of Calgary, CANADA

Beirut Symposium September 2014

Disclosures

•  Speaker honorarium: Abbvie, Janssen, Ferring

•  Steering commi9ees: Janssen, Abbvie, Novo Nordisk, BMS, Pfizer

• Research support: Abbvie

• Advisory boards: Janssen, Shire, Abbvie, Takeda

Inflammation Drives Disease Progression

Triggering Event

Immune inflammatory response- Innate & Adaptive

Immune cell activation

Proinflammatory cytokines- TNF

Fibrogenesis, collagen production, activation of tissue metalloproteinases, and production of

other inflammatory mediators

Tissue damage Chronicity

INFL

AM

MAT

ION

Treat to Target Algorithm in RA

IBD treatment goals are evolving

1.  Colombel JF et al. N Engl J Med 2010;362:1383–95. 2.  Baert FJ et al. Gastroenterology 2010;138:463–68. 3.  Sandborn WJ et al. J Crohn’s Coli7s 2010;4:S36:PO69 at ECCO. 4.  Louis E et al. Gastroenterology 2012;142:63–70. 5.  Colombel JF et al. J Crohn’s Coli7s 2010;4:S11:OP31 at ECCO

Treatment strategies need to evolve as

treatment goals evolve

Adapted from IOIBD

Deep remission5

Mucosal healing1-4

Steroid-free remission

Clinical remission

Improved symptoms

Change course of disease

PotenYal benefits and risks of treaYng to a goal

Benefits

  Improved outcomes resulYng from be\er disease control achieved through disease monitoring

  Disease modificaYon: reducYon of damage

Risks

  Over-‐treatment: cost and safety

  Increased complexity of treatment algorithms

  Risk of immunogenicity (targets leading to interrupted mAb therapy)

  Added risk from endoscopic procedures or invasive tests

Improving Outcomes in Immune Mediated Inflammatory Diseases

•  Diagnose early

•  Predict disease course and outcome

•  Treat Early with effecYve therapy

•  OpYmize therapy

•  Treat to target

•  Understand remission

•  Sustain remission

Choose early the paNents for the most effecNve treatment

Crohn’s disease: effect of disease duraNon on treatment efficacy

PaNents in remission, week 56: <2 years placebo n=4/23, adalimumab n=20/39; 2 to <5 years placebo n=4/36, adalimumab n=25/57; ≥5 years placebo n=12/111, adalimumab n=82/233. Data are from randomised responders

PaNents received inducNon therapy of adalimumab 80 mg (week 0) followed by 40 mg (week 2) and were randomised at week 4

Week 56

0

20

40

60

80

100

Remission

(%)

23 n= 39 <2 years

17%

51%

36 57 2 to <5 years

11%

44%

111 233 ≥5 years

11%

35%

p=0.014 p=0.001 p<0.001

Placebo All adalimumab

Time from diagnosis to anY-‐TNF

CHARM: effect of disease duraYon on remission

Adapted from Schreiber S et al. Gastroenterol 2007;132(4 Suppl 2):A-‐147

Reference Predictors Outcome

Munkholm PL . Gastroenterology 1993

Extensive (>100cm), gastroduodenal or jejunal disease

Mortality

Franchimont D. Eur J Gastroenterol Hepatol 1998

Smoking, coliYs, non-‐fibrostenoYc type, young age at diagnosis

CorYcodependency

Lichtenstein G. Am J Gastroenterol 2006

Disease severity, ileal disease, corYcosteroid use

Stenosis or obstrucYon

Beaugerie L. Gastroenterology 2006

Need for steroids, perianal disease, age at diagnosis <40 yrs

Disabling disease (>2 steroids, IMs, hospitalisaYon, surgery within 5yr)

Loly C. Scand J Gastroenterol 2008

Age <40, stricturing disease or intra-‐abdominal fistulae, perianal disease, fever, weight loss >5 kg, high platelet count

Severe disease (>2 resecYons or >70 cm, stoma, complex perianal disease 5 yr)

Who to treat: predictors of poor outcomes in CD

PredicYng severe Crohn’s disease: deep ulcers at colonoscopy

Probability of colectomy in patients with or without deep ulcers covering >10% of at least 1 colonic segment

Adapted from Allez M et al. Am J Gastroenterol 2002;97:947‒953

Bars represent 95% confidence intervals. In univariate analysis, presence of deep ulcers at index colonoscopy were associated with a significantly higher risk of colectomy (p<0.0001)

Deep ulcers n=53 No deep ulcers n=49

% c

olec

tom

y

0

10

20

30

40

50

60

70

1 year 3 years 8 years

31%

6%

43%

8%

62%

18%

(19/26)

(p=0.0028)

(7/23)

Complete absence of lesions at 2 years

SUTD

•  Early disease duration, naive to immunomodulators

D’Haens G, et al. Lancet 2008;371:660-667.

EXTEND: early adalimumab associated with higher rates of mucosal healing than later use

p=0.029 for ADA vs placebo for duraYon <5 years vs ≥5years All paYents (n=135) received open-‐label ADA 160/80mg inducYon at Weeks 0/2 and 129 paYents were randomised at Week 4 to maintenance therapy with ADA 40 mg eow or placebo.

0

7

18

44 40

21

0 5

10 15 20 25 30 35 40 45 50

<2 years 2 to <5 years ≥5 years

Adalimumab, induction-only (placebo)

Adalimumab, every other week

Patie

nts

with

muc

osal

hea

ling

at w

eek

12 (%

)

1/14 7/39 4/9 4/10 9/43

Sandborn WJ, et al. J Crohn’s Coli7s 2010;4:S36: P060 at ECCO 2010

CumulaYve Probability of Abdominal Surgery

Crohn’s disease Phenotype at anti-TNF start

B1= inflammatory; B2= stricturing; B3=penetrating. L1=terminal ileal.

Moran GW et. al. Clin Gastroenterol Hepatol 2014 (epub ahead of print)

Thiopurines: personalized medicine model in IBD

Crohn’s disease: SONIC comparing AZA with IFX/both: Mucosal healing at wk 26†‡

0

5

10

15

20

25

30

35

40

45

50

AZA n=109

IFX n=93

IFX+AZA n=107

16.5%

30.1%

43.9%

P≤0.001

P=0.023

P=0.055

†Mucosal healing defined as the absence of mucosal ulceration at Wk 26; residual erythema and/or edema may be present.

‡Includes subjects with evidence of ulceration at baseline that were eligible for the mucosal healing analysis at Wk 26.

Colombel JF et al NEJM 2010

Managing loss of response: therapeuYc drug levels

Primary non-‐responder Secondary loss of response

PharmacokineYc failure

Pharmacodynamic failure

Immunogenicity failure

OpYmize Biologic – dose escalaYon

Measuring drug levels is more cost effecYve than Empiric dose escalaYon

0

2000

4000

6000

8000

10000

Study week Co

st per paY

ent, €

mea

n 0 4 8 12

*

*

*

IFX intensificaYon

Algorithm

Steenholdt C et. al. Gut 2014; 63:919-927.

Symptoms and inflammatory load: The concept of Treat to Target (T-T)

Symptoms

Tissue damage

We currently underestimate treatment need

Paradigm shift

Inflammation

Treatment threshold

Aim to keep your paYents in this health state

Asthma: PEFR

RA: low DAS, Sharp score

IBD: Lemann score, Mucosa

Overt inflammation

No inflammation

  178 CD paYents with clinical remission defined by SIBDQ scores in a prospecYve registry

  Silent (asymptomaYc) CD paYents feel well but have an elevated CRP

–  Represent up to 24% of CD paYents in clinical remission

–  May benefit from further evaluaYon or closer monitoring to prevent disease related complicaYons and hospitalizaYon

–  HospitalisaYons tend to be for surgical intervenYon for ileal disease

‘Silent’ Crohn’s paYents (asymptomaYc with elevated CRP) have a 6-‐fold higher risk of hospitalisaYons

Chi Square=32.23; P-value<0.001

37% were hospitalized

7% were hospitalized

0.00

0.25

0.50

0.75

1.00

% H

ospi

taliz

atio

n-Fr

ee

0 200 400 600 800Days After Clinic Visit

Normal CRP Elevated CRP

Majority of hospitalisations in asymptomatic patients with elevated CRP occur within the first 12 months of the clinic visit when CRP

elevation was detected

Vargas EJ, et al. Presented at DDW Orlando, USA, May 20, 2013. Abstract 557.

OR 6.82, 95% CI 2.50-18.58; P<0.0001

Benefits of objecYve monitoring in inflammatory bowel disease: CRP

CorrelaYon between faecal calprotecYn, lactoferrin and endoscopic acYvity in CD

Sipponen T et al. Inflamm Bowel Dis 2008;14:40-‐46.

•  Has the therapy induced mucosal healing?

A combinaYon of faecal calprotecYn and hs-‐CRP to predict mucosal healing

A subanalysis of the STORI trial

Lémann M et al. UEGW 2010, Barcelona, Spain, October 23–27:OP370.

*Defined as CDEIS≤3 Hs-CRP, high-sensitivity CRP

78%

39%

82% 74%

53% 72%

SensiYvity

Specificity

hs-‐CRP <5 mg/L Calpro ≤250 µg/g hs-‐CRP <5 mg/L and Calpro ≤250 µg/g

PredicYon of relapse by faecal calprotecYn levels

Tibble JA et al. Gastroenterology 2000;119:15–22.

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Prop

orYon

of p

aYen

ts witho

ut a re

lapse

0 2 4 6 8 10 12 Time (months)

CD calprotecYn <50 mg/L

CD calprotecYn >50 mg/L

•  Is this paYent about to flare despite maintenance therapy?

Long-term mucosal healing reduces resection & colectomy rates: UC and CD

Frøslie KF et al. Gastroenterology. 2007;133(2):412-422.

Ulcerative colitis Crohn’s disease

Pts with MH at 1 year

Pts without MH at 1 year

P=0.10 P=0.02

Pts with MH at 1 year

Pts without MH at 1 year

Time in Years After 1-Year Visit

Prop

ortio

n of

CD

Pat

ient

s N

ot R

esec

ted

Prop

ortio

n of

UC

Pat

ient

s N

ot C

olec

tom

ised

Time in Years After 1-Year Visit

The consequences of failing to achieve mucosal healing •  Development of more serious disease and complications

- increased need for steroids and surgery •  Necessitate more intensive treatment strategies

SIMPLE ENDOSCOPIC SCORE FOR CROHN’S DISEASE (SES-‐CD):

.

SIZE OF ULCER

Score 1 -‐Aphthous Ulcer (01-‐05 cm) Score 2 -‐Large Ulcer 05-‐2cm Score 3-‐ Very large Ulcer >2cm

ULCERATED SURFACE

AFFECTED SURFACE

PRESENCE OF NARROWINGS

Score 1< 10% Score 2 10-‐30% Score 3 >30%

Score1 <50% Score 2 50-‐75% Score 3 >75%

Can be passed Cannot be passed

Leh colon

Transverse colon

Right colon

Rectum

ILEUM

Possible treatment goal: mucosal healing

•  Working definiNon for mucosal healing: –  CD: absence of ulcers >5 mm

•  AlternaNve: quanNtaNve endpoints (CDEIS, SES-‐CD) – More responsive to change –  Complex as a treatment goal

•  Evidence for the working definiNon for mucosal healing? –  AssociaNon with relevant long-‐term outcomes –  No evidence for treaNng to these goals

Imaging as a subsYtute to endoscopy

REACT Trial: Algorithm-‐based Treatment

Khanna R, et al. Presented at DDW; May 4, 2014 Abstract 1053.

Therapeutic Algorithm for CD •  Center-‐level cluster randomisaYon to early

combined immunosuppression algorithm or current best pracYce

•  CD paYents recruited from 40 centers (N=1982) •  Regular clinical review at 4 weeks and then

Q12 weeks •  Used algorithm to treat to target •  Followed for 24 months

•  Primary endpoint: clinical remission (HBI <5 & no steroids) at 12 months

Primary endpoint (symptomatic remission) was not met

Algorithm based treatment: REACT CLUSTER RANDOMIZED STUDY

  Primary endpoint (symptomaNc remission) was not met

–  Possibly related to low mean baseline HBI (4.1)

–  ProporNon of paNents in Early Combined Immunosuppression and ConvenNonal Management groups who received combined anNmetabolite/anN-‐TNF by 12 months was 15.1% and 6.5% (P<.001) and 19.7% and 9.6% by 24 months (P<.001)

  Community-‐based data indicate that a symptom-‐based convenNonal approach to CD management may not be opNmal and Early Combined Immunosuppression may be more effecNve in prevenNng CD-‐related complicaNons

HospitalizaYon, Surgery or Serious Disease-‐Related ComplicaYons

P<0.001

Khanna R, et al. Presented at DDW; May 4, 2014 Abstract 1053.

Algorithm based treatment: REACT CLUSTER RANDOMIZED STUDY

Crohn’s disease –Remission and targets

Clinical remission

Endoscopic remission

QoL Remission

Imaging remission

Histologic remission

CRP remission

Fecal markers remission

Cytokine remission

Treatment goal: sustained deep remission

1. Colombel JF, et al. J Crohns Coli7s 2010; 4:S11; 2. Colombel JF, et al. Gut 2010;59(Suppl 3):A80

*Deep remission defined as clinical remission (CDAI <150) and complete mucosal healing in EXTEND. Note: 1-‐year data are exploratory, as the primary efficacy endpoint of mucosal healing at Week 12 was not reached (p=0.34). All paYents (n=135) received adalimumab 160/80 mg inducYon therapy before being randomised (n=129) to adalimumab 40 mg eow or to placebo CDAI: Crohn’s disease acYvity index; eow: every other week

Placebo Adalimumab 40 mg eow

0

5

10

15

20

25

Week 12

6/61 10/62

10

16

p=0.34

12/62 0/61

19 p<0.001

Week 52

PaYen

ts in

deep

remission

* (%

)

EXTEND: deep remission at 12 and 52 weeks in paYents with moderate to severe Crohn’s disease1

Achieving deep remission at Week 12 was associated with be\er outcomes at Week 52 (p<0.05 versus not achieving deep remission at Week 12)2

•  Be\er QoL •  Less acYvity impairment

•  Less hospitalizaYon

Clinical and deep remission rates in a real-‐life sexng

Remission rates in CD paYents (n=183) receiving anY-‐TNF maintenance therapy in Finland (median 23 months)

Clinical remission defined as no clinical symptoms; Deep remission defined as no clinical symptoms and endoscopic remission (CD: SES-‐CD 0–2) Molander P, et al. J Crohns Coli7s 2012; doi: 10.1016/j.crohns.2012.10.018

Remission

rate (%

)

Clinical remission Deep remission

64

43

0

20

40

60

80

100

CD paYents (n=183)








•  Sustain remission (maintain goal)

Long term maintenance of clinical remission and response over 4 years: ADHERE study

Panaccione R et. al. APT 2013;38:1236

Predictors of relapse ayer stopping anY-‐TNF: Real-‐life experience

Molnar T et.al. Aliment Pharm Ther 2013

AnY-‐TNF therapy was restarted a median of 6 months ayer disconYnuaYon in almost half of Crohn’s disease pa7ents who had been in clinical remission following one year of an7-‐TNF therapy

Scheme of monitoring

CEUS, contrast-‐enhanced ultrasonography; CRP, C-‐reacYve protein. F-‐CalP, faecal calprotecYn

Baseline assessment: CRP, F-‐CalP, CEUS, MR enterography, colonscopy

AnY-‐TNF inducYon

Not in symptomaYc remission SymptomaYc remission

Treat to target ●  CRP every 4 weeks ●  F-‐CalP every 4 weeks ●  Colonoscopy week 12, 52 ●  CEUS week 12, 24, 53

Assessment ●  CRP ●  F-‐CalP ●  CEUS ●  Colonoscopy

No evidence of inflammaYon – ConYnue scheduled maintenance

ConYnued inflammaYon – Escalate therapy

AcYve inflammaYon – Modify or change Rx

Monitoring in IBD

Key Dos

  Measure and record baseline parameters to ensure you can track disease acYvity

  Adopt appropriate monitoring for different paYent situaYons

  Regularly monitor disease acYvity using objecYve markers e.g. CRP, faecal markers

  Measure and record precise, standardised descripYons of endoscopic lesions including type, locaYon, depth and extent

  Aim for Yght control of disease acYvity through sustained inhibiYon of inflammaYon

IBD Ahead: OpYmised monitoring; Dusseldorf, 23–24 September 2011.

Key Don’ts

  Rely on symptoms to monitor disease acYvity

  Assume symptoms relate to acYve disease

  Take short-‐cuts: be thorough in understanding disease acYvity in each of your paYents with IBD

  Be saYsfied with poor recording or descripYon of lesions with endoscopy

Calgary IBD Clinic algorithm

Diagnosis Early IBD Diagnosis

Risk straNficaNon

Safety opNmizaNon

Minimize steroid use

MILD DISEASE

AnNbioNcs 5-‐ASA Budesonide NutriNonal Rx

AVOID SYSTEMIC STEROIDS

Accelerated step-‐up

SEVERE DISEASE

Early combinaNon Rx

MODERATE DISEASE

Average outcome Fistulizing Abscess

Avoid steroids Start biologics

Predicted poor outcome

How should we change our pracYce ?

•  Symptom control is not adequate as Treat to Target –objecNve evaluaNon of disease control is required.

•  Use of our most effecNve therapy to minimize or abolish damage should be the driving theme of our strategy.

•  One size does not fit all – straNfy our paNents to tailor therapy.

optimizing management using the treat to target approach...ibd’treatmentgoalsare’evolving’...

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