A personalized approach to choosing therapies in IBD: Can we do this smarter?

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Feb 22, 2014 (3 years and 3 months ago)

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A personalized approach to choosing
therapies in IBD: Can we do this
smarter?



Stephen B. Hanauer, MD




Treating IBD beyond symptoms



Personalised
’ management for IBD will depend on:


Disease severity at presentation


Clinical and biologic prognostic factors


Achievement of clinical and biologic remission


Maintenance of clinical and biologic remission


Patient adherence


Therapeutic monitoring


Pharmacoeconomics

Goals of therapy 2013



Induce
(clinical)
remission


Mucosal
healiing


Maintain

remission


Prevent complications


Disease


Therapy


Optimise timing of surgery

0

20

40

60

80

100

Low activity

(20%)

Moderate to

higher activity

(71%)

Fulminant

disease (9%)

Patients With UC (%)

Disease Activity

Distribution of UC Disease Severity

at Presentation

N=1161

Langholz

EP et al.
Scand

J
Gastroenterol
.

1991;26:1247
-
1256.

4

Course of UC




Disease Course One

Year After Diagnosis

No symptoms

(50%)

Low activity

(30%)

Moderate
-
high activity
(20%)

100

80

60

40

20

0

Disease activity

Colectomy
Rate
(%)

Years

40

0

30

20

10

0

5

10

15

20

Patients With UC (%)

Hendriksen

C et
al,
Gut
. 1985;26:158
-
163.

5

Predictors of Poor Response or Colectomy
1
-
5


Serum albumin


ESR >30 mm/h


Bandemia


Prolonged flare


Active infection


Hospitalization setting


Severe endoscopic lesions


Disease duration



Stool frequency


Percentage of bloody stools


Body temperature >
37.5
°
C


Heart rate >90 bpm


Increased CRP


Toxic
megacolon


Low hemoglobin <10.5 g/
dL


6

BPM=beats per minute; CRP=c
-
reactive protein; ESR=erythrocyte sedimentation rate.

1. Lindgren SC et al.
Eur

J
Gastroenterol

Hepatol
.
1998;10:831
-
835; 2. Gonzalez
-
Lama Y
et
al.
Hepatogastroenterology
.

2008;55:1609
-
1614; 3. Suzuki Y et al.
Dig Dis
Sci.

2006;51:2031
-
2038; 4.
Cacheux

W et
al.
Am J
Gastroenterol

2008;103:637
-
642. 5.
Ananthakrishnan

AN et al.
Am J
Gastroenterol
.

2008;103:2789

2798.

Inflammatory activity and progression of

bowel damage in a theoretical patient with
Crohn’s Disease

Pariente B
et al.
Inflamm

Bowel

Dis.

2011;17(6):1415.

Inflammatory

activity


(CDAI, CDEIS, CRP)

Surgery

Stricture

Stricture

Fistula/abscess

Disease

onset

Bowel damage

Diagnosis

Early

disease

Relationship Between Clinical Symptoms
and Endoscopic Indices at Presentation of
Acute CD

R=0.13; NS

Crohn

s⁄楳 ase Ac瑩v楴y 䥮摥d

( CDAI )

Crohn

猠䑩s敡獥 䕮E潳o潰楣i䥮摥d 潦⁓ov敲楴y
(CDEIS)

0

0

100

200

300

400

500

600

5

10

15

20

25

30

35

Modigliani R et al.
Gastroenterology.

1990;98:811.

ULN

Baseline CDAI

150

200

250

300

350

400

450

500

Log CRP mg/L

0.01

0.1

1

10

100

CDAI vs CRP

Gastroenterology, 1990. 98(4): 811
-
18

Step
-
up
according to
severity

at
presentation or failure at prior step

Example of sequential therapies for
IBD

Aminosalicylate


Corticosteroid


Anti
-
TNF


Disease
severity


at
presentation

Severe

Natalizumab

Aminosalicylate

(UC)/

Thiopurine
/MTX (CD)

Aminosalicylate

Anti
-
TNF/

Thiopurine
/MTX (CD)


Induction

Maintenance

Moderate

Mild

Step
-
up / sequential management
approach

Perceived advantages


Patients attain remission with less toxic therapies


Potentially more toxic therapies reserved for more severe or
refractory disease


Minimises risk of adverse events


Cost sparing
(short
-
term?)

Perceived
disadvantages


Patients have to ‘earn’ most effective treatments


Decrease in quality
-
of
-
life before patients obtain optimal therapy


Likelihood of surgery may not be altered


Disease may not be modified







60% exposed to IS therapy


No Change in Surgery Rates

P values reflect non
-
disabling vs. disabling CD

Beaugerie

L et
al
Gastroenterology.
2006;130:650
-
656.


Clinical
Predictors for
Disabling

Crohn’s
Disease



Age of onset (
P
=.0004)


Small bowel disease location (
P
=.002)


Perianal lesions at diagnosis (
P
=.01)


Need for steroids at first flare (
P
=.0001)


Current smoker (
P
=.09
)

13

Treatment of

Early Crohn

s


Disease is More Effective than

Late Disease


CHARM: Remission by Disease Duration
with Adalimumab at Week 26

17
25
14
59*
40
41**
0
10
20
30
40
50
60
70
*P

= .002, **P

< .001,

P = .014,

P = .001 all vs placebo

Schreiber S, et al. Am J
Gastroenterol

105(7): 1574
-
1582.



Placebo

All adalimumab

% Remission

<2 years

N = 23, N = 39

<2
-
5 years


N = 36, N = 57

≥ 5 years

N = 111, N = 233

EXTEND: disease duration and deep
remission* rates

Placebo

Adalimumab 40 mg eow

Patients in deep

remission* at Week 52 (%)

0

10

30

40

33

<2 years

20

0/15

18

2 to <5 years

0/41

16

≥5 years

0/9

3/9

2/11

7/44

*Deep remission defined as clinical remission (CDAI <150) and complete mucosal healing in EXTEND

p
<0.001 for adalimumab vs placebo, adjusted for baseline disease duration (Cochran
-
Mantel
-
Haenszel test)

All patients (n=135) received adalimumab 160/80mg induction therapy, before randomisation (n=129) to

adalimumab 40mg eow or to placebo

CDAI: Crohn’s disease activity index; eow: every other week

Colombel

JF,
et al
. Gastroenterology 132:52
-
65: 2007

Disease duration

Do we need a target if we want to
prevent disease progression in IBD?

Transmural

activity

Histological activity

Biologic activity


CRP


Calprotectin

Endoscopic activity

Severity (arbitrary units)

0

Duration of disease (years)

5

10

15

20

25

30

Graph: Adapted from
Kirwan

JR.
J
Rheumatol

2001;28:881
-
6

Photo: Copyright
©

American College of Rheumatology

© ACR

Rheumatoid arthritis progression

Early
RA

Intermediate

Late

Inflammation

Disability

Radiographs

Similarities between

other therapy areas and IBD?

Hypertension, type 2 diabetes and rheumatoid
arthritis


Chronic progressive diseases


Failure to treat early and effectively can lead to serious
complications and disability


Disease management has evolved over time


Significant advances in treatment


Insights into the importance of early and optimised therapy


Focus on a

treat to target


approach to achieve


tight control


Treat
-
to
-
target approach has been adopted

in other therapy areas

Diabetes


<7% HbA1c

Rheumatoid

arthritis


Remission


Low disease activity

Hypertension


BP: 140/90 mmHg
(135/80 mmHg for
diabetic patients)


LDL
-
cholesterol:
70

mg/
dL


(to lower
incidence of
cardiac events)



Treatment targets

Diabetes
:
ADA. Diabetes Care 2011;34(Suppl. 1):S1

98;
Hypertension
: ESH/ESC Task Force.
Eur

Heart J 2007;28:1462

536;

Rheumatoid arthritis:
Smolen

JS, et al. Ann Rheum
Dis

2010;69:631

7

Potential wider implications of a

adopting a treat
-
to
-
target approach


Treatment algorithms are based on treatment targets


e.g. achieve ‘absence of disease activity’ in 3

6 months in RA


Frequent monitoring is recommended so that
treatment can be optimised


e.g. HbA1c monitoring every 3 months in patients with diabetes


Modification of the target for high
-
risk patient groups


e.g. lower blood
-
pressure target of 130/80 mmHg in patients with both
hypertension and type 2 diabetes


Risk of ‘tight target’ in ICU setting


Early disease states are recognised


e.g. pre
-
hypertension, pre
-
diabetes

Diabetes
:
ADA. Diabetes Care 2011;34(Suppl. 1):S1

98;
Hypertension
: ESH/ESC Task Force.
Eur

Heart J 2007;28:1462

536;

Rheumatoid arthritis:
Smolen

JS, et al. Ann Rheum
Dis

2010;69:631

7

Potential benefits of treating to target

in rheumatoid arthritis patients


Targeted treatment reduces disease activity more than usual care
1

7


TICORA study (n=111): outcome measures were significantly better with
intensive management
than with routine care
2

1.
Fransen

J, et al. Ann Rheum Dis. 2005;64:1294

8.

2.
Grigor

C, et al. Lancet. 2004;364:263

9.

3.
Stenger

AA, et al. Br J
Rheumatol
. 1998;37:1157

63.

4.
Verstappen

SM, et al. Ann Rheum Dis. 2007;66:1443

9.

5.
Van
Tuyl

LH, et al. Ann Rheum Dis. 2008;67:1574

7.

6.
Edmonds J, et al. Ann Rheum Dis. 2007;66(Suppl. II):325.

7.
Symmons

D, et al. Health
Technol

Assess 2005;9:1

78.

65

16

0
20
40
60
80
100
Intensive
management
Routine care
Patients in
remission* (%)

*Remission was defined as disease activity score <1.6.

3.5

1.9

0
1
2
3
4
Intensive
management
Routine care
Mean reduction in

disease activity score

p
<0.0001

p
<0.0001

Potential benefits of treating to target

in rheumatoid arthritis patients
(cont.)


Targeted treatment slows joint damage more than usual care
1

5


Stenger
,
et al.

study (n=228): mean radiographic progression over

2 years was significantly lower with targeted therapy than with usual
care
1

1.
Stenger

AA, et al. Br J
Rheumatol
. 1998;37:1157

63.

2.
Verstappen

SM, et al. Ann Rheum Dis. 2007;66:1443

9.

3.
Edmonds J, et al. Ann Rheum Dis. 2007;66(Suppl. II):325

4.
Van
Tuyl

LH, et al. Ann Rheum Dis. 2008;67:1574

7.

5.
Symmons

D, et al. Health
Technol

Assess 2005;9:1

78.

26

35

0
10
20
30
40
Early 'aggressive'
treatment
Conventional treatment
Mean radiographic
progression rate

p
=0.03

All patients had recent onset rheumatoid arthritis (complaints <1 year at study entry)

Baseline

102 Weeks

Treatment of early RA with anti
-
TNF
may prevent progression of structural
damage




T潴慬⁓桡牰a
獣潲攠

-
㄰⸵

Mucosal Healing Predicts Sustained (2
-
year)
Clinical Remission in Early CD


Baert

FJ, et al. Gastroenterology. 2010;138:463
-
468.

Simple endoscopic score 0

Simple endoscopic score 1
-
9

% of patients in Remission

70.8

62.5

27.3

18.2

0
10
20
30
40
50
60
70
80
Remission of Steroids
Off Steroids and No
Anti-TNF
Is a treat
-
to
-
target approach feasible in
IBD?

Symptoms

QoL

Labs (CRP)


?

Mucosal healing

Hospitalisations

surgery

Biologic

(Deep remission)

Disease modification


What are the components of deep
remission?


Inflammatory symptoms


Laboratory evidence of inflammation


CRP,
calprotectin
, etc.


Endoscopic healing


Histologic healing (e.g. UC)


Stabilization of Imaging (structural damage)

What is disease modification in IBD?


Symptom resolution


Stabilised

QoL and PRO


Reduced disease/therapy complications


Structural damage


EIMs


Neoplasia


Reduced disability


Improved
pharmacoeconomics


Direct/indirect costs

240

228

216

204

192

180

168

156

144

132

120

108

96

84

72

60

48

36

24

12

0

0

10

20

30

40

50

60

70

80

90

100

Cumulative
probability
(%)

Patients at risk:

Months

2002

552

229

95

37

N =

Penetrating

Stricturing

Inflammatory

Impact of therapy will depend on degree of
structural damage and speed of
progression

Cosnes

J et al.
Inflamm

Bowel Dis
. 2002;8:244
-
250.

Summary


Current therapeutic strategies for IBD do not
modify long
-
term sequelae


Therapies based on symptoms not prognosis


Similar to other chronic diseases treating to
prognostic markers can improve long
-
term
outcomes


Prospective studies are needed to confirm:


Prognostic criteria


Relevance of individual (composite) targets


Impact on long
-
term outcomes
(
benefits/risks)


Socioeconomic values of
t
argeted approach



Goals of therapy

Current


Induce

(clinical)
remission


Maintain

(clinical)
remission


Prevent complications


Therapy


Optimise timing of surgery

Future goals


Disease modification


Prevent disease
progression &
complications


Neoplasia


Strictures / fistulae


Surgery


Disability


Pharmacoeconomics


Direct / indirect costs

Response

Remission

Deep remission

Goal

Clinical Parameters

Improved symptoms

No symptoms

Normal labs

Mucosal healing

Outcomes

Improved
QoL

Decreased

hospitalisation

Avoidance of surgery

SUSTAINED

Minimal/no disability

Normal endoscopy

QoL
=quality of life

Modified from
Panaccione

R. Presented at:
European Crohn’s and Colitis Organization (ECCO) Fifth Annual Congress.
Prague, Czech Republic; February 2010

Evolving Goals of Therapy for IBD:

Sustained Deep Remission

32

Maintenance with Biologics will
be Optimized by Pharmacology &
Determination of Trough Levels

Factors that Influence the PK of TNF
Antagonists

Impact on TNF antagonist PK

Presence of ADAs

Decreases drug concentration

Increases clearance

Worse

clinical outcomes

Concomitant use of
immunosuppressives

Reduces ADA formation

Increases

drug concentration

Decreases drug clearance

Better clinical outcomes

Low serum albumin concentration

Increases drug clearance

Worse clinical

outcome

High baseline CRP

concentration

Increase drug clearance

High baseline TNF concentration

May decrease drug concentration by
increasing clearance

High body size

May increase drug clearance

Sex

Males have higher clearance

Ordas

I et. al.
Clin

Gastroenterol

Hepatol
.
2012; 10:1079
-
1087.

34

Sustained Clinical Response to IFX

IFX Trough Levels at the Beginning of Maintenance Therapy

35

Bortlik

M, et al.
J Crohn’s Colitis
. 2012.

dx.doi.org/10.1016/j.crohns.2012.10.019.

Infliximab Concentration and Clinical Outcome in Patients
With UC


Results


The proportion of pts achieving clinical remission increased with
increasing quartiles of IFX concentrations


Similar trends were observed for clinical response and MH

Reinisch

W, et al.
Gastroenterology.
2012;142(5):Supp 1,S
-
114.

Serum

IFX Concentrations (



)⼠偲opo牴楯渠o映fa瑩敮瑳t(┩

1
st

Quartile

2
nd

Quartile

3
rd

Quartile

4
th

Quartile

p
-
values

Clinical remission at
Wk 8

<21.3

26.3

≥ 21.3
-
<33.0

37.9

≥33.0
-
<47.9

43.9

>47.9

43.1

p=0.0504

Clinical Remission at
Wk 30

<0.11

14.6

≥0.11
-
<2.4

25.0

≥2.4
-
<6.8

59.6

>6.8

52.1

p<0.0001

Clinical Remission at
Wk 54

<1.4

2.1

≥1.4
-
<3.6

55

≥3.6
-
<8.1

79.0

>8.1

60

p=0.0066

Summary



Personalized management for IBD

depends on:


Disease severity at presentation


Clinical and biologic prognostic factors


Achievement of clinical and biologic remission


Maintenance of clinical and biologic remission


Patient adherence


Therapeutic monitoring

37