1. A personalized approach to choosing therapies in IBD: Can we do this smarter?
Stephen B. Hanauer, MD

2. 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

3. Goals of therapy 2013 Induce (clinical) remission Maintain remission
Mucosal healiing
Maintain remission
Prevent complications
Disease
Therapy
Optimise timing of surgery

4. Distribution of UC Disease Severity at Presentation
100
Fulminant disease (9%) 80
N=1161 60
Moderate to higher activity (71%)
Patients With UC (%) 40
Key Point:
Population data suggest that most patients present initially with “moderate to higher” disease activity.
Background:
Langholz et al studied a cohort of 1,161 UC patients in Copenhagen County and estimated that most (71%) presented with “moderate to higher” disease activity.
“Moderate to higher” disease activity defined as more than 4 bowel movements daily and/or presence of blood/pus and/or systemic symptoms.
20% of patients presented with low activity and 9.1% presented with fulminant disease during the first year of diagnosis.
Reference: Langholz E, Munkholm P, Nielsen OH, et al. Incidence and prevalence of ulcerative colitis in Copenhagen County from 1962 to Scand J Gastroenterol 1991;26: 20
Low activity (20%)
Disease Activity
Langholz EP et al. Scand J Gastroenterol. 1991;26:

5. Moderate-high activity (20%)
Course of UC
Disease Course One Year After Diagnosis
Colectomy Rate (%)
Years 40 30 20 10 5 15
No symptoms
(50%)
Low activity
(30%)
Moderate-high activity (20%)
100 80 60 40 20
Disease activity
Patients With UC (%)
Hendriksen C et al, Gut. 1985;26:

6. Predictors of Poor Response or Colectomy1-5
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
BPM=beats per minute; CRP=c-reactive protein; ESR=erythrocyte sedimentation rate.
1. Lindgren SC et al. Eur J Gastroenterol Hepatol. 1998;10: ; 2. Gonzalez-Lama Y et al. Hepatogastroenterology. 2008;55: ; 3. Suzuki Y et al. Dig Dis Sci. 2006;51: ; 4. Cacheux W et al. Am J Gastroenterol 2008;103: Ananthakrishnan AN et al. Am J Gastroenterol. 2008;103:2789–2798.

7. Inflammatory activity (CDAI, CDEIS, CRP)
Inflammatory activity and progression of bowel damage in a theoretical patient with Crohn’s Disease
Stricture
Surgery
Bowel damage
Fistula/abscess
Inflammatory activity (CDAI, CDEIS, CRP)
Stricture
Curatio Fact Check
**PERMISSION NEEDED FOR HANDOUT**-
This is an adaptation of Figure 1, page 1420 of Pariente 2011.
Pariente B et al. Inflamm Bowel Dis. 2011;17(6):1415.
Disease onset
Diagnosis
Early disease
Pariente B et al. Inflamm Bowel Dis. 2011;17(6):1415. 7 7 7 7

8. Relationship Between Clinical Symptoms and Endoscopic Indices at Presentation of Acute CD
600
500
400
Crohn’s Disease Activity Index
( CDAI )
300
200
100
R=0.13; NS 5 10 15 20 25 30 35
Crohn’s Disease Endoscopic Index of Severity (CDEIS)
Modigliani R et al. Gastroenterology. 1990;98:811.

9. CDAI vs CRP ULN Gastroenterology, 1990. 98(4): 811-18 100 10 1 0.1
Baseline CDAI
150
200
250
300
350
400
450
500
Log CRP mg/L
0.01
0.1 1 10
100
ULN
Gastroenterology, (4):

10. Example of sequential therapies for IBD
Disease severity
at presentation
Natalizumab
Anti-TNF/
Thiopurine/MTX (CD)
Severe
Anti-TNF
Aminosalicylate (UC)/
Thiopurine/MTX (CD)
Corticosteroid
Moderate
Aminosalicylate
Aminosalicylate
This is a new slide from Dr Hanauer.
Induction
Maintenance
Mild
Step-up according to severity at presentation or failure at prior step

11. 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

12. 60% exposed to IS therapy
No Change in Surgery Rates

13. 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)
Clinical factors for prognosis “ are not highly accurate predictors for use on the individual patient level”
Lichtenstein, G.R. Gastro and Hep.; 6, , 2010.
Note: although smoking did not reach statistical significance in the Beaugerie study cited in the slide there is evidence that smoking leads to a poorer prognosis for CD as summarized below:
“Research shows that current and former smokers have a higher risk of developing Crohn's disease than nonsmokers. Among people with Crohn’s disease, smoking is linked with a higher rate of relapse, repeat surgery, and the need for drug therapy. Women have a higher risk of relapsing and needing surgery and treatment than men whether they are current or former smokers. Why smoking increases the risk of Crohn's disease is unknown, but some researchers believe that smoking might lower the intestines defenses, decrease blood flow to the intestines, or cause immune system changes that result in inflammation.” (accessed July 16, 2010)
P values reflect non-disabling vs. disabling CD
Beaugerie L et al Gastroenterology. 2006;130: 13

14. Treatment of “Early Crohn’s” Disease is More Effective than “Late Disease”

15. CHARM: Remission by Disease Duration with Adalimumab at Week 26
Placebo
All adalimumab
% Remission
Hanauer - 26
985
<2 years
N = 23, N = 39
<2-5 years
N = 36, N = 57
≥ 5 years
N = 111, N = 233
*P = .002, **P < .001, †P = .014, ‡P = .001 all vs placebo
Schreiber S, et al. Am J Gastroenterol 105(7): 15

16. EXTEND: disease duration and deep remission* rates40
Placebo 33
Adalimumab 40 mg eow 30
Patients in deep remission* at Week 52 (%) 20 18 16 10
0/9
3/9
0/15
2/11
0/41
7/44
The same trend exists for disease duration and deep remission in EXTEND: patients appear to be more likely to achieve deep remission if they receive treatment early in their disease course.
<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 16 16 16 16

17. Do we need a target if we want to prevent disease progression in IBD?
Symptoms
Biologic activity
CRP
Calprotectin
Endoscopic activity
Transmural activity
Histological activity

18. Rheumatoid arthritis progression
Early RA
Intermediate
Late
Inflammation
Disability
Radiographs
© ACR
Severity (arbitrary units)
RA Progression
The relationship between the development of radiographic joint destruction in RA and its long-term consequences for the patient is not well understood, but one view of the disease process is that inflammatory joint symptoms are the main determinant of disability early in the disease, while joint destruction dominates in late disease.
Presentations and discussions at OMERACT IV (the 4th International Consensus Conference on Outcome Measures in Rheumatoid Arthritis Clinical Trials) are consistent with this view, suggesting a high correlation between inflammation and disability in early RA, but that the strength of this relationship declines over time.
Discussions at OMERACT IV also indicated that fluctuations in disability become less pronounced in later-stage RA and more closely correlated with radiographic evidence of joint damage.
Kirwan JR. Links between radiological change, disability, and pathology in rheumatoid
arthritis. J Rheumatol. 2001;28: 5 10 15 20 25 30
Duration of disease (years)
Graph: Adapted from Kirwan JR. J Rheumatol 2001;28:881-6 Photo: Copyright © American College of Rheumatology

19. 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’ 19

20. Treat-to-target approach has been adopted in other therapy areas
Treatment targets
Diabetes
<7% HbA1c
Hypertension
BP: 140/90 mmHg (135/80 mmHg for diabetic patients)
LDL-cholesterol: 70 mg/dL (to lower incidence of cardiac events)
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

21. 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

22. Patients in remission* (%) disease activity score
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
p<0.0001
Patients in remission* (%)
disease activity score
Mean reduction in
*Remission was defined as disease activity score <1.6.
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.
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.

23. Mean radiographic progression rate
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
p=0.03
Mean radiographic progression rate
All patients had recent onset rheumatoid arthritis (complaints <1 year at study entry)
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
Van Tuyl LH, et al. Ann Rheum Dis. 2008;67:1574–7.
Symmons D, et al. Health Technol Assess 2005;9:1–78.

24. Treatment of early RA with anti-TNF may prevent progression of structural damage
Baseline
102 Weeks
Safe analysis: no joint progression seen as indicated in Sharp score . There may be possible re-calcification upon IFX treatment (compare top bone, bottom right corner in baseline versus 102 weeks).
 Total Sharp score = -10.5

25. Mucosal Healing Predicts Sustained (2-year) Clinical Remission in Early CD
Simple endoscopic score 0
Simple endoscopic score 1-9
% of patients in Remission
W1133 Filip J Baert et al.
AIMS: At present no clinical data are available supporting the relevance of mucosal healing in Crohn’s disease (CD). We already reported that early combined immunosuppression (CIS) with infliximab (IFX) and azathioprine (AZA) led to significantly higher rates of complete ulcer healing after 2 years (yrs) compared to conventional management (CM) including corticosteroids. This study focused on the value of endoscopy performed after 2 yrs of treatment to predict clinical outcome in the following 2 yrs.
METHODS: 133 newly diagnosed CD pts at 21 centers were randomized to treatment with CIS (3 infusions of IFX with AZA) or to CM with corticosteroids, to be repeated as clinically necessary. In the CIS group, patients with a relapse were given repeated IFX. In the CM group, AZA was added in case of corticosteroid dependency and IFX was only given after failure of AZA. Nineteen pts dropped out of the study before 1 yr. A subset of 44 pts (24 CIS, 20 CM) underwent an ileocolonoscopy at 2 yrs. Endoscopic CD activity was scored with the Simple Endoscopic Score for CD (SES-CD). All centers reconsented their pts for an additional 2 yrs of clinical follow-up. Fishers exact two sided test was used for comparison.
RESULTS: At the time of analysis year 4 data were available in 42/44 pts (23 CIS, 19 CM). A SES-CD score = 0 at yr 2 predicted a stable clinical remission in the following 2 yr period in 15/22 pts (68%) compared to 7/19 (35%) pts with endoscopic activity (SES-CD 2-9) (P = .004). In all but two pts this remission was sustained without IFX during y 3 and 4. In addition, only 1/22 pt with an SES-CD = 0 developed a new or had persistent active fistula versus 5/19 with an SES-CD 2-9 (P = .079). Although clinical remission rates were higher in the CIS group when SES-CD score of 0 was achieved (13/17, 76%) compared to the CM group (2/5,40%), significance was not reached probably due to low numbers (P = .27). Two of four pts (50%) with CIS with SES score 2-9 also reached a 2 y sustained clinical remission without IFX compared to 1/14 (7%) pts treated with CM. No significant differences in medication use were observed between the two groups during year 3-4.
CONCLUSIONS: For the first time in CD, this study provides evidence that complete mucosal healing leads to significant higher clinical remission rates 2 years down the line. These data further support a top down approach in early CD to alter the disease course.
Baert FJ, et al. Gastroenterology. 2010;138: 25

26. Is a treat-to-target approach feasible in IBD?
Labs (CRP) ?
Symptoms
QoL
Biologic
(Deep remission)
Disease modification
Mucosal healing
Hospitalisations
surgery

27. 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)

28. 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

29. Cumulative probability (%)
Impact of therapy will depend on degree of structural damage and speed of progression
100 90 80 70
Penetrating 60 50
Cumulative probability (%) 40 30
Stricturing
Inflammatory 20 10 12 24 36 48 60 72 84 96
108
120
132
144
156
168
180
192
204
216
228
240
Months
Patients at risk:
N =
2002
552
229 95 37
Cosnes J et al. Inflamm Bowel Dis. 2002;8: 29

30. 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

31. Goals of therapy Future goals Current Disease modification
Prevent disease progression & complications
Neoplasia
Strictures / fistulae
Surgery
Disability
Pharmacoeconomics
Direct / indirect costs
Current
Induce (clinical) remission
Maintain (clinical) remission
Prevent complications
Therapy
Optimise timing of surgery

32. Evolving Goals of Therapy for IBD: Sustained Deep Remission
Clinical Parameters
Outcomes
Response
Improved symptoms
Improved QoL
Remission
No symptoms
Decreased hospitalisation
Normal labs
Deep remission
Normal endoscopy
Avoidance of surgery
Dr Remo Panaccione presented this theoretical model during an Abbott symposium at the ECCO 2010 meeting.
The goals of Crohn’s disease management – together with the corresponding clinical parameters and outcomes – have evolved.
Dr Panaccione suggested that we may be able to sustain these outcomes, and proposed sustained deep remission as potential new treatment goal.
Mucosal healing
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 32 32

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

34. 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:

35. Sustained Clinical Response to IFX
IFX Trough Levels at the Beginning of Maintenance Therapy
Bortlik M, et al. J Crohn’s Colitis dx.doi.org/ /j.crohns

36. 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
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########## Presentation updated on 1/09/2013 by DFisher7 ##########
########### Presentation 'New Cleveland Clinic_FINAL.pptx' updated on January 09, 2013 ###########
Author: DFisher7 Intended Use: Unsolicited Not for Dissemination Approval Date: Not Approved Review By: Not Determined
*************** User Comments **************
*Slides were generated by Jay Popp, reviewed and approved by Jim Barrett and Mike Safdi. *
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Presenter: MA Personnel Intended for: HCP
########### Presentation 'DDW 2012_dissemination IFX_Final.pptx' created on June 04, 2012 ###########
Author: Dfisher7 Intended Use: Unsolicited for Dissemination Approval Date: 6/04/ Review By: 6/04/2013
*Slides were reviewed and approved by Dusti Fisher, Jay Popp, and Rob Tamburri
Reinisch W, et al. Gastroenterology. 2012;142(5):Supp 1,S-114.

37. 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