Dr Ahmad Alfadhli MD,FRCPc

Haya Alhabeeb Gastroebterology Center

Mubarak Alkabeer Hospital

What is a treat-to-target approach?Lessons from other therapy areas

Rationale for a treat-to-target approach in IBD: Disease course modification as a realistic goal in IBD

Implementation of a treat-to-target approach in IBD

Evidence for a treat-to-target approach in IBD:REACT, POCER and now CALM

Summary

Aim: To avoid development of serious complications and disability in patients with chronic conditions

Concept: Treating to a pre-defined treatment target that is associated with optimal long-term outcomes (goal-oriented approach)

Strategy: Ongoing and regular monitoring of the target and/or surrogate marker, with optimisation of treatment when the target is not met

Additional principles: All components target, treatment and monitoring are tailored to the needs of

the individual patient De-escalation of therapy may be considered when treatment goals are achieved

Bouguen G et al. Clin Gastroenterol Hepatol 2015;13:1042-50; McKloskey et al. Int J Clin Rheumatol 2015;10:1-4.

A T2T approach involves pre-defining a treatment target, in consultation with the patient,

continuously monitoring disease activity,and modifying treatment until the target is reached

T2T is well established in clinical practice

BP, blood pressure; HbA1c, glycated haemoglobin; LDL-C, Low-density lipoprotein cholesterol

1. ADA. Diabetes Care 2017;40(Suppl 1);S1-S132; 2. ESC. Eur Heart J 2013;34:3035-87; 3. Mancia G et al. J Hypertens. 2013;31:1281–1357; 4. James PA et al. JAMA. 2014;311:507–520; 5. Catapano AL, et al. European Heart Journal 2016;37:2999–3058.

*2013 AHA/ACC guideline on blood cholesterol made no recommendations for specific LDL-cholesterol or non-HDL targets. Stone NJ, et al. Circulation 2013.

Dyslipidaemia5*

LDL-C <3 mmol/L (low/moderate CV risk patients), <2.6 mmol/L (high CV risk patients), <1.8 mmol/L (very high CV risk patients)

Hypertension3,4

BP <140/90 mmHg(in most hypertensive patients)

Diabetes1,2

HbA1c <7%(more or less stringent goals may be appropriate for individual patients)

T2T concept is well establishedwith increasing uptake in clinical practice

Rheumatoidarthritis1,2

Clinical remission (absence of signs and symptoms of significant inflammatory activity)

or low disease activity

1. Smolen JS et al. Ann Rheum Dis 2010;69:631–7; 2. Smolen JS et al. Ann Rheum Dis 2015;0:1–13. doi:10.1136/annrheumdis-2015-207524

T2T recommendations exist,with emerging evidence

Psoriasis

Body surface area (BSA) ≤1%3

Reduction in Psoriasis Area Severity Index (PASI) ≥75% from treatment initiation4

Physician global assessment (PGA) score 05

Psoriatic arthritis1,2

Remission / inactive disease of musculoskeletal involvement, with consideration of extra-articular manifestations,

or low/minimal disease activity

1. Smolen JS, et al. Ann Rheum Dis 2014;73:6-16; 2. Gossec L, et al. Ann Rheum Dis 2016;75:499-510; 3. Armstrong AW, et al. J Am Acad Dermatol 2017;76:291-98.; 4. Mrowietz U, et al. Arch Dermatol Res 2011;303:1-10; 5. Gulliver W, et al. J Cutaneous Med Surg 2015;19:22-27

Therapeutic advances have improved treatment outcomes and led to the proposal of stringent treatment targets

Treatment algorithms are based on treatment targets

Frequent monitoring allows treatment optimisation within specific timeframes

Treatment targets should be tailored to the individual patient to optimise outcomes and minimise risk

Target choice and therapeutic changes should be shared physician–patient decisions

Information technology (electronic data capture, interactive algorithms and score calculation) can help integrate T2T into routine clinical practice

Disease course modification as a realistic goal in IBD

CD and UC are chronic progressive conditions, with a major clinical and patient burden

Ongoing inflammatory activity results in the accumulation of bowel damage, which leads to complications and disability

10

1. Pariente B, et al. Inflamm Bowel Dis 2011;17:1415–22; 2. Duveau N, et al. J Crohns Colitis 2015; 9(Suppl1):S57; 3. Bhagya Rau B, et al. J Clin Gastroenterol 2016;50:476-82; 4. Giletta C, et al. Clin Gastroenterol Hepatol 2015;13:633-40

Theoretical patient with Crohn’s disease1 Clinical evidence in Crohn’s disease

Over median 23 months, bowel damage increased in >1/3 of patients2

Over 5 years, bowel damage increased in 48% of patients3

At 2–10 years post diagnosis, >50% had substantial damage4

Bowel damage(measured by the Lémann Index)

increases over timein many CD patients

Infl

amm

ato

ryac

tivi

ty

Surgery

Stricture

Stricture

Fistula / abscess

Onset Diagnosis

Bo

wel

dam

age

Advanced diseaseEarly disease

Clinically quiescent disease,

n=21(r=0.31)

0

5

10

15

20

25

30

35

40

0 50 100 150 200 250 300 350 400 450 500 550 600 650 700

CD

en

do

sco

pic

in

dex

of

seve

rity

(C

DEI

S)

CD activity index (CDAI)

*Correlation coefficient after square root transformation

Cellier C, et al. Gut 1994; 35: 231-5

CLINICAL DISEASE ACTIVITY

END

OSC

OP

IC D

ISEA

SE A

CT

IVIT

Y

All patients, N=121Weak correlation of CDAI and CDEIS

(r=0.32*; p<0.001)

Impact onsocial and

professional life Nutrition

Disease outcomes Patient-reported outcomes

12

Clinicalvisits

ImpairedQoL /

disability

Medicationside effects

Colonoscopy /imaging

Anaemia

Diarrhoea

Cancerrisk

Abdominalpain

Mortality

Boweldamage and

complications

Hospitalisations

Blood /faecal testmonitoring

Impact onwork / school

Fatigue

Surgery

Poor growth /weight loss

Bouguen G, et al. Clin Gastroenterol Hepatol 2015;13:1042-50.

A traditional step-up approach can result in:

Treatment step-up that is based on symptoms only

Continued inflammation that leads to bowel damage and disease complications

Undertreatment of a proportion of patients

Patients at high risk of developing poor outcomes receiving effective intervention too late

5-ASA (in UC)

STEROIDS

THIOPURINES

BIOLOGICS

SURGERY

Need to determine as early as possible who is at a high risk of developing disease complications

Simple demographic and clinical features can help identify high-risk patients at diagnosis and throughout the disease course1

Aggressivedisease

Indolentdisease

Traditional step-upAvoid intensive therapy, immunosuppression andadverse events

Early intensive therapyAssure early intensive

therapy to avoid complications

1. Torres J, et al. J Crohns Colitis 2016;10:1385-1394

<2 Years <5 Years ≥5 Years0

20

40

60

80

100

Pat

ien

ts w

ith

mu

cosa

lh

eal

ing

(%)

Week 12 mucosal healing by disease duration

NRI; N=123 patients with ulceration at baseline screeningAll patients (CDAI 220–450) received open-label adalimumab 160-/80-mg induction therapy at weeks 0/2and were randomised at week 4 to receive maintenance therapy with adalimumab 40 mg every other week or placeboMucosal healing defined as absence of mucosal ulceration

Sandborn WJ, et al. J Crohn’s Colitis (Suppl) 2010;4:S36–7.

4/9 4/100/8 1/14 7/39 9/43

Crohn’s disease duration

Adalimumab 40 mg EOW (n=62)Placebo EOW (n=61)

16

More effective treatments Treatment optimisation Earlier intervention

Symptom improvement1

Induce and maintain

Clinical remission1

Steroid-free remission1,2

Mucosal healing3-6

Clinical remission

with mucosal healing

Deepremission7-8

1. Colombel JF, et al. Gastroenterology 2007;132:52–65.2. Colombel JF, et al. Dig Dis 2012(Suppl. 3):107–11.3. Colombel JF, et al. N Engl J Med 2010;362:1383–95.4. Baert FJ, et al. Gastroenterology 2010;138:463–68.

5. Sandborn WJ, et al. J Crohn’s Colitis 2010;4:S36.6. Louis E, et al. Gastroenterology 2012;142:63–70.7. Colombel JF, et al. J Crohn’s Colitis 2010;4:S11.8. Panaccione R, et al. Inflamm Bowel Dis 2013;19:1645–53.

Crohn’s disease (n=106)

Pro

po

rtio

n o

f C

D p

atie

nts

wit

h n

o s

urg

ery

afte

r 1

-yea

r vi

sit

Time in years after 1-year visit

1.0

0.9

0.8

0.7

0.6

0 1 2 3 4 5 6 7

Mucosal healing at 1 year

No mucosal healing at 1 year

Ulcerative colitis (n=338)

Mucosal healing status at 1 year and risk of surgery

Froslie KS, et al. Gastroenterology 2007;133:412–22

Pro

po

rtio

n o

f U

C p

atie

nts

wit

h n

o s

urg

ery

afte

r 1

-ye

ar v

isit

Time in years after 1-year visit

0 1 2 3 5 7 84 6

1.0

0.9

0.8

0.7

0.6

Mucosal healing at 1 year

No mucosal healing at 1 year

Study or subgroupMH 1 No MH 1

WeightOdds Ratio

M–H, Random. 95% CIOdds Ratio

M–H, Random. 95% CIEvents Total Events Total

Baert 2010 24 24 22 22 Not estimable

Bjorkesten 2013 10 10 26 32 10.0% 5.15 (0.27, 99.79)

Froslie 2007 47 53 70 88 89.9% 2.01 (0.74, 5.45)

Total (95% CI) 87 118 142 100.0% 2.22 (0.86, 5.69)

Total events 81

Study or subgroupMH 1 No MH 1

WeightOdds Ratio

M–H, Random. 95% CIOdds Ratio

M–H, Random. 95% CIEvents Total Events Total

Baert 2010 17 24 6 22 8.9% 6.48 (1.79, 23.44)

Bjorkesten 2013 8 10 20 32 5.0% 2.40 (0.44, 13.23)

Cohen 2014 3 3 3 4 1.2% 3.00 (0.09, 102.05)

Czaja-Bulsa 2012 2 2 5 8 1.3% 3.18 (0.12, 87.92)

Dai 2014 65 78 21 31 15.9% 2.38 (0.91, 6.22)

Froslie 2007 22 53 22 88 27.6% 2.13 (1.03, 4.41)

Fukuchi 2014 5 5 13 17 1.5% 3.67 (0.17, 80.21)

Grover 2014 7 15 10 11 1.6% 20.29 (1.01, 406.33)

Reinisch 2015 54 70 27 53 24.4% 3.25 (1.50, 7.06)

Rutgeerts 2010 10 20 14 42 12.4% 2.00 (0.67, 5.93)

Total (95% CI) 280 308 100.0% 2.80 (1.91, 4.10)

Total events 193 131

Association of MH at first endoscopic assessment (MH1) with long-term clinical remission (CR)

Association of MH1 with CD-related surgery-free rate

Favors no MH1 Favors MH1

0.10.01 1 10 100

Heterogeneity. τ2=0.00; χ2=4.57; df=9 (p=0.87); I2=0%; Test for overall effect: Z=5.26 (p<0.00001)

0.10.01 1 10 100

Favors no MH1 Favors MH1

Heterogeneity. τ2=0.00; χ2=0.35; df=1 (p=0.55); I2=0%; Test for overall effect: Z=1.65 (p=0.10)

Shah SC, et al. Aliment Pharmacol Ther 2016:43(3):317–33

Mucosal healing was also associated with avoidance of colectomy, and steroid-free remission

CR, clinical remission; MH1, mucosal healing at the first endoscopic evaluation after initiation of UC therapy

Shah SC, et al. Clin Gastroenterol Hepatol 2016;14:1245-55.

Study or subgroupOdds Ratio

M–H, Random. 95% CIOdds Ratio

M–H, Random. 95% CI

Biologic therapy (N=891)

Arias 2015 6.10 (2.83, 13.17)

Armuzzi 2013 2.94 (1.36, 6.38)

Colombel 2011 7.48 (4.48, 12.47)

Dai 2014 0.50 (0.15, 1.63)

Gustavsson 2010 11.15 (0.47, 266.66)

Tursi ADA 2014 Not estimable

Tursi IFX 2014 1.65 (0.71, 3.83)

Subtotal (95% CI) 3.02 (1.35, 6.74)

Non-biologic therapy (N=490)

Cabriada 2010 64.00 (3.38, 1210.55)

Froslie 2007 1.56 (1.01, 2.41)

Paoluzi 2002 7.50 (1.39, 40.43)

Yamamoto 2010 49.17 (13.99, 172.83)

Subtotal (95% CI) 11.79 (1.39, 100.11)

TOTAL (95% CI) 4.50 (2.12, 9.52)

0.10.01 1 10 100Favors no MH1 Favors MH1

Hospitalisation and IBDQ remission at week 52 in patients who achieved deep remission with adalimumab at week 12

CD-related hospitalisationthrough week 52

IBDQ remission†

at week 52

Pat

ien

ts i

n IB

DQ

re

mis

sio

n†

(%)

26

7/11 14/53

Deepremission*

(Week 12)

Non-deepremission*

(Week 12)

0

25

100

50

7564

p<0.05

CD

-rel

ated

ho

spit

alis

atio

n (

%)

9

0/11 5/53

Deepremission*

(Week 12)

Non-deepremission*

(Week 12)

0

25

100

50

75

EXTEND primary efficacy endpoint of mucosal healing at week 12 was not reached (p=0.34) *Deep remission defined as clinical remission (CDAI <150) and complete mucosal healing†IBDQ remission defined as IBDQ score ≥170

Colombel JF, et al. Clin Gastroenterol Hepatol 2014;12:414–22.e5; Colombel JF, et al. Gut 2010;59(Suppl 3):A80

Ongoing inflammatory activity in the gut results in the accumulation of bowel damage in CD, which leads to complications and disability1

There is often a disconnection between clinical symptoms and underlying mucosal inflammation in CD2

Several studies have shown the importance of mucosal healing for long-term outcomes in CD3 and UC4

Recommended treatment targets in CD and UC now include both clinical remission and endoscopic remission5

1. Pariente B, et al. Inflamm Bowel Dis 2011;17:1415–22; 2. Cellier C, et al. Gut 1994; 35: 231-5; 3. Shah SC, et al. Aliment Pharmacol Ther 2016:43(3):317–33; 4. Shah SC, et al. Clin Gastroenterol Hepatol 2016;14:1245-55;5. Peyrin-Biroulet L, et al. Am J Gastroenterol 2015;110:1324–38

22

Symptom improvement1

Induce and maintain

Clinical remission1

Steroid-free remission1,2

Mucosal healing3-6

Clinical remission

with mucosal healing

Deepremission7-8

1. Colombel JF, et al. Gastroenterology 2007;132:52–65.2. Colombel JF, et al. Dig Dis 2012(Suppl. 3):107–11.3. Colombel JF, et al. N Engl J Med 2010;362:1383–95.4. Baert FJ, et al. Gastroenterology 2010;138:463–68.

5. Sandborn WJ, et al. J Crohn’s Colitis 2010;4:S36.6. Louis E, et al. Gastroenterology 2012;142:63–70.7. Colombel JF, et al. J Crohn’s Colitis 2010;4:S11.8. Panaccione R, et al. Inflamm Bowel Dis 2013;19:1645–53.

Prevent:• Intestinal

damage• Neoplasia• Disability• Surgery• Mortality• Cost of care

Disease modification?

More effective treatments Treatment optimisation Earlier intervention

Early effective treatmentreduces inflammatory activity

and bowel damage

Infl

amm

ato

ryac

tivi

ty

Bo

wel

dam

age

Pariente B, et al. Inflamm Bowel Dis 2011;17:1415–22; Colombel JF, et al. Gastroenterology 2017;152:351–61.

Onset Diagnosis Early disease

Ongoing inflammatory activity and accumulation of

bowel damage

Infl

amm

ato

ryac

tivi

ty

Surgery

Stricture

Stricture

Fistula / abscess

Onset Diagnosis

Bo

wel

dam

age

Advanced diseaseEarly disease

Ongoing inflammatory activity and accumulation of

bowel damage

Infl

amm

ato

ryac

tivi

ty

Surgery

Stricture

Stricture

Fistula / abscess

Onset Diagnosis

Bo

wel

dam

age

Advanced diseaseEarly disease

Window of opportunity

Infl

amm

ato

ryac

tivi

ty

Bo

wel

dam

age

Pariente B, et al. Inflamm Bowel Dis 2011;17:1415–22; Colombel JF, et al. Gastroenterology 2017;152:351–61.

WINDOW OFOPPORTUNITY

Early effective treatmentreduces inflammatory activity

and bowel damage

Onset Diagnosis Early disease

CD and UC are chronic progressive diseases ongoing inflammation drives accumulation of bowel damage, leading to complications and disability

Early intervention is important to avoid complications in patients at high risk of progression

Control of symptoms is essential, but does not alter the natural history of IBD

Today’s treatments can treat beyond symptoms and heal the intestinal mucosa Mucosal healing is associated with improved long-term outcomes

Available biomarkers provide adjunctive measures of inflammation

Tools are available to measure bowel damage and assess the long-term effectiveness of new treatments and algorithms

Bouguen G, et al. Clin Gastroenterol Hepatol 2015;13:1042-50;. Pariente B, et al. Gastroenterology 2015;148:52–63; Peyrin-Biroulet L, et al. Gut 2012;61:241-47.

How can we ensure optimal and timely use of available treatments, for good disease control and improved outcomes?

Need for a target-driven treatment strategy

REACT, POCER and now CALM

1. Colombel JF, et al. Gastroenterology 2017;152(Suppl 1):S155; 2. Khanna R, et al. Lancet 2015;386;1825-34; 3. De Cruz P, et al. Lancet 2015:11;385:1406-17; 4. Bouguen G et al. Clin Gastroenterol Hepatol 2014;12:978–85.

Higher rate of mucosal healing and deep remission in early Crohn’s disease

when treating to a target of biomarkers levels (CRP and faecal calprotectin), compared with symptom-driven clinical management (CALM)1

Lower rate of hospitalisation, surgery and complications in patients with established Crohn’s disease

with use of an early combined immunosuppression algorithmic approach, treating to the target of clinical remission, compared with a conventional approach (REACT)2

Lower rate of endoscopic recurrence in postoperative Crohn’s disease

with early colonoscopy and treatment step-up for endoscopic recurrence, compared with risk-stratified drug therapy alone (POCER)3

In algorithm-driven, prospective treatment studies with adalimumab,the T2T approach has been associated with a:

• CALM is the first study to demonstrate that a T2T approach(using the CRP and faecalcalprotectin targets) leads to superior endoscopic and deep remission outcomes in CD compared with symptom-driven care

• Managing only the clinical symptoms of CD does not adequately control underlying inflammation

• Escalation of adalimumab treatment did not lead to increased safety signals

In algorithm-driven, prospective treatment studies with adalimumab,the T2T approach has been associated with a:

1. Colombel JF, et al. Gastroenterology 2017;152(Suppl 1):S155; 2. Khanna R, et al. Lancet 2015;386;1825-34; 3. De Cruz P, et al. Lancet 2015:11;385:1406-17; 4. Bouguen G et al. Clin Gastroenterol Hepatol 2014;12:978–85.

Higher rate of mucosal healing and deep remission in early Crohn’s disease

when treating to a target of biomarkers levels (CRP and faecal calprotectin), compared with symptom-driven clinical management (CALM)1

Lower rate of hospitalisation, surgery and complications in patients with established Crohn’s disease

with use of an early combined immunosuppression algorithmic approach, treating to the target of clinical remission, compared with a conventional approach (REACT)2

Lower rate of endoscopic recurrence in postoperative Crohn’s disease

with early colonoscopy and treatment step-up for endoscopic recurrence, compared with risk-stratified drug therapy alone (POCER)3

In REACT, early combined immunosuppression (ECI) with adalimumab with treatment decisions based on symptoms was associated with significantly lower rates of surgery, hospitalisation and complications than conventional management in patients with a median Crohn’s disease duration of >12 years

No significant difference between treatment approaches for symptomatic remission at 12 months, although the remission rate was consistently higher in the ECI group through follow-up Symptoms may not be the most relevant outcome in CD

No difference in safety outcomes between treatment approaches Rates of serious infection were low

Data support the use of an aggressive algorithmic approach in community GI practice to decrease the risk of serious CD-related complications and surgery

Khanna R, et al. Lancet 2015;386;1825-34; Singh S, Loftus EV. Lancet 2015;386(10006):1800-2.

In algorithm-driven, prospective treatment studies with adalimumab,the T2T approach has been associated with a:

1. Colombel JF, et al. Gastroenterology 2017;152(Suppl 1):S155; 2. Khanna R, et al. Lancet 2015;386;1825-34; 3. De Cruz P, et al. Lancet 2015:11;385:1406-17; 4. Bouguen G et al. Clin Gastroenterol Hepatol 2014;12:978–85.

Higher rate of mucosal healing and deep remission in early Crohn’s disease

when treating to a target of biomarkers levels (CRP and faecal calprotectin), compared with symptom-driven clinical management (CALM)1

Lower rate of hospitalisation, surgery and complications in patients with established Crohn’s disease

with use of an early combined immunosuppression algorithmic approach, treating to the target of clinical remission, compared with a conventional approach (REACT)2

Lower rate of endoscopic recurrence in postoperative Crohn’s disease

with early colonoscopy and treatment step-up for endoscopic recurrence, compared with risk-stratified drug therapy alone (POCER)3

POCER investigated T2T with a target of normal mucosal endoscopy

Treating patients with postoperative CD according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, was superior to standard care

Treatment intensification at 6 months brings some patients into remission 1 year later

Clinical risk factors predicted recurrence, but patients at low risk also need monitoring

Early endoscopic remission did not guarantee long-term endoscopic remission, and ongoing monitoring is still needed

Faecal calprotectin is a good marker for monitoring for recurrence

De Cruz P, et al. Lancet 2015;385:1406–17; Wright EK, et al. Gastroenterology, 2015;148:938-47.

T2T has been shown to improve long-term patient outcomes in several chronic, progressive diseases

In IBD, a T2T approach may prevent the development of disease complications, surgery, bowel damage and disability, and may therefore achieve the ultimate target of improved patient QoL

Treatment targets in CD and UC have been defined, based on patient-reported outcomes and endoscopic remission, and may be tailored to the individual patient and their disease

Evidence for a T2T approach in IBD is accumulating from algorithm-driven prospective studies

Ongoing and future studies will evaluate the impact of a T2T approach on long-term disease outcomes, with treatment decisions based on objective measures of inflammation

Remember: Ultimate target is to return to normal life

Think about long-term outcomes1

Diagnose early

Assess prognosis to identify patients needing early intervention2

Adopt a treat-to-target approach, based on CALM algorithms4

Rapid step-up approach

Optimised therapy

Tight monitoring of objective signs of inflammation (mucosal healing, or surrogate markers like FCP or CRP)

1. Peyrin-Biroulet L, et al. Clin Gastroenterol Hepatol 2016;14:348–54; 2. Torres J, et al. J Crohns Colitis 2016;10:1385-94;3. Peyrin-Biroulet L, et al. Am J Gastroenterol 2015;110:1324–38. 4. Colombel JF, et al. Gastroenterology 2017;152(Suppl 1):S155.