Download A personalized approach to choosing therapies in IBD

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
Distribution of UC Disease Severity
at Presentation
100
Fulminant
disease (9%)
Patients With UC (%)
80
60
N=1161
Moderate to
higher activity
(71%)
40
20
Low activity
(20%)
0
Disease Activity
Langholz EP et al. Scand J Gastroenterol. 1991;26:1247-1256.
4
Course of UC
Disease Course One
Year After Diagnosis
40
Moderate-high activity
(20%)
30
Low activity
(30%)
20
Colectomy Rate (%)
80
60
40
20
Patients With UC (%)
100
10
No symptoms
(50%)
0
0
0
Disease activity
Hendriksen C et al, Gut. 1985;26:158-163.
5
10
15
20
Years
5
Predictors of Poor Response or Colectomy1-5
• Serum albumin
• Stool frequency
• ESR >30 mm/h
• Percentage of bloody stools
• Bandemia
• Body temperature >37.5°C
• Prolonged flare
• Heart rate >90 bpm
• Active infection
• Increased CRP
• Hospitalization setting
• Toxic megacolon
• Severe endoscopic lesions
• Low hemoglobin <10.5 g/dL
• Disease duration
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.
6
Inflammatory activity and progression of
bowel damage in a theoretical patient with
Crohn’s Disease
Stricture
Bowel damage
Fistula/abscess
Stricture
Disease
onset
Diagnosis
Pariente B et al. Inflamm Bowel Dis. 2011;17(6):1415.
Early
disease
Inflammatory activity
(CDAI, CDEIS, CRP)
Surgery
Crohn’s Disease Activity Index
( CDAI )
Relationship Between Clinical Symptoms
and Endoscopic Indices at Presentation of
Acute CD
600
500
400
300
200
100
R=0.13; NS
0
0
5
10
15
20
25
30
35
Crohn’s Disease Endoscopic Index of Severity
(CDEIS)
Modigliani R et al. Gastroenterology. 1990;98:811.
CDAI vs CRP
100
10
Log CRP mg/L
ULN
1
0.1
0.01
150
200
250
300
350
400
450
500
Baseline CDAI
Gastroenterology, 1990. 98(4): 811-18
Example of sequential therapies for
IBD
Disease severity
at presentation
Natalizumab
Anti-TNF
Severe
Corticosteroid
Moderate
Aminosalicylate
Mild
Anti-TNF/
Thiopurine/MTX (CD)
Aminosalicylate (UC)/
Thiopurine/MTX (CD)
Aminosalicylate
Induction
Maintenance
Step-up according to severity
at presentation or failure at prior step
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
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)
P values reflect non-disabling vs. disabling CD
Beaugerie L et al Gastroenterology. 2006;130:650-656.
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Treatment of “Early Crohn’s”
Disease is More Effective than
“Late Disease”
CHARM: Remission by Disease Duration
with Adalimumab at Week 26
Placebo
% Remission
70
59*
60
50
41**
40
40
25
30
20
All adalimumab
17
14
10
0
<2 years
N = 23, N = 39
<2-5 years
N = 36, N = 57
*P = .002, **P < .001, †P = .014, ‡P = .001 all vs placebo
Schreiber S, et al. Am J Gastroenterol 105(7): 1574-1582.
≥ 5 years
N = 111, N = 233
Patients in deep
remission* at Week 52 (%)
EXTEND: disease duration and deep
remission* rates
40
Placebo
Adalimumab 40 mg eow
33
30
18
20
16
10
0/9
3/9
0/15
2/11
0/41
7/44
0
<2 years
2 to <5 years
≥5 years
Disease duration
*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
Do we need a target if we want to
prevent disease progression in IBD?
Transmural
activity
Histological activity
Biologic activity
● CRP
● Calprotectin
Endoscopic activity
Rheumatoid arthritis progression
Severity (arbitrary units)
Early RA
Intermediate
Late
Inflammation
Disability
Radiographs
© ACR
0
5
10
15
20
Duration of disease (years)
Graph: Adapted from Kirwan JR. J Rheumatol 2001;28:881-6
Photo: Copyright © American College of Rheumatology
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30
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
Treatment targets
Diabetes
•
<7% HbA1c
Hypertension
•
•
Rheumatoid
arthritis
•
•
Remission
Low disease activity
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
BP: 140/90 mmHg
(135/80 mmHg for
diabetic patients)
LDL-cholesterol:
70 mg/dL
(to lower
incidence of
cardiac events)
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 care1–7
• TICORA study (n=111): outcome measures were significantly better with
intensive management than with routine care 2
p<0.0001
3
1.9
2
p<0.0001
100
3.5
Patients in
remission* (%)
Mean reduction in
disease activity score
4
1
0
80
65
60
40
16
20
0
Intensive
management
Routine care
Intensive
management
*Remission was defined as disease activity score <1.6.
1.
2.
3.
4.
Fransen J, et al. Ann Rheum Dis. 2005;64:1294–8.
Grigor C, et al. Lancet. 2004;364:263–9.
Stenger AA, et al. Br J Rheumatol. 1998;37:1157–63.
Verstappen SM, et al. Ann Rheum Dis. 2007;66:1443–9.
5.
6.
7.
Van Tuyl LH, et al. Ann Rheum Dis. 2008;67:1574–7.
Edmonds J, et al. Ann Rheum Dis. 2007;66(Suppl. II):325.
Symmons D, et al. Health Technol Assess 2005;9:1–78.
Routine care
Potential benefits of treating to target
in rheumatoid arthritis patients (cont.)
• Targeted treatment slows joint damage more than usual care1–5
• Stenger, et al. study (n=228): mean radiographic progression over
2 years was significantly lower with targeted therapy than with usual
care1
Mean radiographic
progression rate
40
p=0.03
30
35
26
20
10
0
Early 'aggressive'
treatment
Conventional treatment
All patients had recent onset rheumatoid arthritis (complaints <1 year at study entry)
1.
2.
3.
Stenger AA, et al. Br J Rheumatol. 1998;37:1157–63.
Verstappen SM, et al. Ann Rheum Dis. 2007;66:1443–9.
Edmonds J, et al. Ann Rheum Dis. 2007;66(Suppl. II):325
4.
5.
Van Tuyl LH, et al. Ann Rheum Dis. 2008;67:1574–7.
Symmons D, et al. Health Technol Assess 2005;9:1–78.
Treatment of early RA with anti-TNF
may prevent progression of structural
damage
Baseline
102 Weeks
 Total Sharp score = -10.5
Mucosal Healing Predicts Sustained (2-year)
Clinical Remission in Early CD
% of patients in Remission
Simple endoscopic score 0
80
70
60
50
40
30
20
10
0
Simple endoscopic score 1-9
70.8
62.5
27.3
18.2
Remission of Steroids
Baert FJ, et al. Gastroenterology. 2010;138:463-468.
Off Steroids and No
Anti-TNF
Is a treat-to-target approach feasible in
IBD?
Symptoms
QoL
Labs (CRP)
?
Biologic
Mucosal healing
Hospitalisations
surgery
(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
Impact of therapy will depend on degree of
structural damage and speed of
progression
100
Cumulative probability (%)
90
80
70
Penetrating
60
50
40
30
Stricturing
Inflammatory
20
10
0
0
12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240
Patients at risk:
2002
N=
Cosnes J et al. Inflamm Bowel Dis. 2002;8:244-250.
Months
552
229
95
37
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 targeted approach
Goals of therapy
Future goals
Current
• Induce
(clinical) remission
• Maintain
(clinical) remission
• Prevent complications
– Therapy
• Optimise timing of surgery
• Disease modification
– Prevent disease
progression &
complications
•
•
•
•
Neoplasia
Strictures / fistulae
Surgery
Disability
• Pharmacoeconomics
– Direct / indirect costs
Evolving Goals of Therapy for IBD:
Sustained Deep Remission
Goal
Response
Remission
Clinical Parameters
Outcomes
Improved symptoms
Improved QoL
No symptoms
Normal labs
Deep remission
Normal endoscopy
Mucosal healing
Decreased
hospitalisation
Avoidance of surgery
Minimal/no disability
SUSTAINED
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
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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.
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Sustained Clinical Response to IFX
IFX Trough Levels at the Beginning of Maintenance Therapy
Bortlik M, et al. J Crohn’s Colitis. 2012.
dx.doi.org/10.1016/j.crohns.2012.10.019.
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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
Serum IFX Concentrations (g/mL)/ Proportion of Patients (%)
1st Quartile
2nd Quartile
3rd Quartile
4th 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
Reinisch W, et al. Gastroenterology.
2012;142(5):Supp 1,S-114.
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
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