Dr Ahmad Alfadhli MD,FRCPc Haya Alhabeeb Gastroebterology Center - - PowerPoint PPT Presentation

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
• ptimal 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(Suppl1);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. Circulation2013.

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 established with increasing uptake in clinical practice

Rheumatoid arthritis1,2 Clinical remission (absence of signs and symptoms of significant inflammatory activity)

• r 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,

• r 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
• ptimise 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

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• 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 GastroenterolHepatol 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 time in many CD patients

Inflammatory activity

Surgery Stricture Stricture Fistula / abscess Onset Diagnosis

Bowel damage

Advanced disease Early disease

Clinically quiescent disease, n=21 (r=0.31)

5 10 15 20 25 30 35 40 50 100 150 200 250 300 350 400 450 500 550 600 650 700

CD endoscopic index of severity (CDEIS) CD activity index (CDAI)

*Correlation coefficient after square root transformation Cellier C, et al. Gut 1994; 35: 231-5

CLINICAL DISEASE ACTIVITY ENDOSCOPIC DISEASE ACTIVITY

All patients, N=121 Weak correlation of CDAI and CDEIS (r=0.32*; p<0.001)

Impact on social and professional life Nutrition

Disease outcomes Patient-reported outcomes

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Clinical visits Impaired QoL / disability Medication side effects Colonoscopy / imaging Anaemia Diarrhoea Cancer risk Abdominal pain Mortality Bowel damage and complications Hospitalisations Blood / faecal test monitoring Impact on work / 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
• n symptoms only
• Continued inflammation that leads

to bowel damage and disease complications

• Undertreatment of a proportion
• f 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 Aggressive disease Indolent disease

Traditional step-up Avoid intensive therapy, immunosuppression and adverse events Early intensive therapy Assure early intensive therapy to avoid complications

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

<2 Y Yea ears rs <5 Y Yea ears rs ≥5 Years

20 20 40 40 60 60 80 80 100 100

Patients with mucosal healing (%)

Week 12 mucosal healing by disease duration

NRI; N=123 patients with ulceration at baseline screening All patients (CDAI 220–450) received open-label adalimumab 160-/80-mg induction therapy at weeks 0/2 and were randomised at week 4 to receive maintenance therapy with adalimumab 40 mg every other week or placebo Mucosal healing defined as absence of mucosal ulceration Sandborn WJ, et al. J Crohn’s Colitis (Suppl) 2010;4:S36–7.

4/9 4/10 0/8 1/14 7/39 9/43

Crohn’s disease duration Adalimumab 40 mg EOW (n=62) Placebo EOW (n=61)

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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 Deep remission7-8

• 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. PanaccioneR, et al. Inflamm Bowel Dis 2013;19:1645–53.

Crohn’s disease (n=106)

Proportion of CD patients with no surgery after 1-year visit Time in years after 1-year visit

1.0 0.9 0.8 0.7 0.6 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

Proportion of UC patients with no surgery after 1-year visit Time in years after 1-year visit

1 2 3 5 7 8 4 6 1.0 0.9 0.8 0.7 0.6

Mucosal healing at 1 year No mucosal healing at 1 year

Study or subgroup MH 1 No MH 1 Weight Odds Ratio M–H, Random. 95% CI Odds Ratio M–H, Random. 95% CI Events Total Events Total

Baert 2010 24 24 22 22 Not estimable Bjorkesten2013 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 subgroup MH 1 No MH 1 Weight Odds Ratio M–H, Random. 95% CI Odds Ratio M–H, Random. 95% CI Events Total Events Total

Baert 2010 17 24 6 22 8.9% 6.48 (1.79, 23.44) Bjorkesten2013 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

0.1 0.01 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)

0.1 0.01 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 GastroenterolHepatol 2016;14:1245-55.

Study or subgroup Odds Ratio M–H, Random. 95% CI Odds 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) Cabriada2010 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) 0.1 0.01 1 10 100 Favors no MH1 Favors MH1

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

CD-related hospitalisation through week 52 IBDQ remission† at week 52

Patients in IBDQ remission† (%)

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7/11 14/53 Deep remission* (Week 12) Non-deep remission* (Week 12) 25 100 50 75

64 p<0.05

CD-related hospitalisation (%)

9

0/11 5/53 Deep remission* (Week 12) Non-deep remission* (Week 12) 25 100 50 75

EXTENDprimary 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 GastroenterolHepatol 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 GastroenterolHepatol 2016;14:1245-55;
• 5. Peyrin-Biroulet L, et al. Am J Gastroenterol2015;110:1324–38

22

Symptom improvement1 Induce and maintain Clinical remission1 Steroid-free remission1,2 Mucosal healing3-6 Clinical remission with mucosal healing Deep remission7-8

• 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. PanaccioneR, 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 treatment reduces inflammatory activity and bowel damage

Inflammatory activity Bowel damage

Pariente B, et al. Inflamm Bowel Dis 2011;17:1415–22; Colombel JF, et al. Gastroenterology2017;152:351–61.

Onset Diagnosis Early disease

Ongoing inflammatory activity and accumulation of bowel damage

Inflammatory activity

Surgery Stricture Stricture Fistula / abscess Onset Diagnosis

Bowel damage

Advanced disease Early disease

Ongoing inflammatory activity and accumulation of bowel damage

Inflammatory activity

Surgery Stricture Stricture Fistula / abscess Onset Diagnosis

Bowel damage

Advanced disease Early disease

Window of opportunity

Inflammatory activity Bowel damage

Pariente B, et al. Inflamm Bowel Dis 2011;17:1415–22; Colombel JF, et al. Gastroenterology2017;152:351–61.

WINDOW OF OPPORTUNITY

Early effective treatment reduces 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
• f 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
• f 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-BirouletL, 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(Suppl1):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 GastroenterolHepatol2014;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 faecal calprotectin 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(Suppl1):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 GastroenterolHepatol2014;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(Suppl1):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 GastroenterolHepatol2014;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
• n long-term disease outcomes, with treatment decisions based on
• bjective 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 GastroenterolHepatol 2016;14:348–54; 2. Torres J, et al. J Crohns Colitis 2016;10:1385-94;
• 3. Peyrin-Biroulet L, et al. Am J Gastroenterol2015;110:1324–38. 4. Colombel JF, et al. Gastroenterology 2017;152(Suppl 1):S155.