PowerPoint Presentation · active CD of any location. Their use in isolated perianal CD is not...

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24 yrs old female

Watery diarrhea and abdominal pain for 6 months

Severe loss of weight (height-1.6m, weight- 36 kg)

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The importance of stratification & accurate prognosis prediction

Medicine of the present:one treatment fits all

Medicine of the future:personalised diagnosis and therapy

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Why should we use predictive factors in IBD prognosis?

Prediction: profiling in order to take the best therapeutic decision

• Assessing prognosis at an early stage is essential for the development of an appropriate management plan

Indolent AggressiveStep-up

Avoid intensive therapy,immunosuppression, adverse events

Top-downAssure early intensive therapy

to avoid complications

Courtesy of Tine Jess, National Health Surveillance and Research, Denmark

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When should we start to assess risk? As soon as possible

Surgery

Stricture

Stricture

Fistula/abscess

Dig

est

ive

dam

age

Disease onset Diagnosis Early disease

Window ofopportunity?

Adapted from Pariente B, et al. Inflamm Bowel Dis 2011;17:1415–22

Inflam

mato

ryactivity

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Why should we use prognostic factors?

It’s all about selecting the right treatment for the right patient at the right time

Low risk of progression

High risk of progression

Top-down strategy will over-treat and exposepatients to costs and risks of immunosuppression

Step-up therapy might postpone adequate therapy in patients with aggressive disease resulting in avoidable disease progression and morbidity

Billiet T. Curr Gastroenterol Rep. 2014 Nov;16(11):416

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Which are the predictors? (CD)

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Munkholm P. Scand JGastroenterol 1995;30:699–700; Louis E. Gut 2003;52:552–7; Lakatos P. World J Gastroenterol 2009;15:3504–10; Henckaerts L. Clin Gastroenterol Hepatol2009;7:972–80; Romberg MJ. Am J Gastroenterol 2009;104:371–83; Chow D. Inflamm Bowel Dis 2009;15:551–7; Hellers G. Gut 1980;21:525–7; Beaugerie L. Gastroenterology 2006;130:650–6; LolyC. Scand J Gastroenterol 2008;43:948–54; Allez M. Am J Gastroenterol 2002;97:947–53

Marker Predicted outcome

Ileal location Complications, surgery

Location proximal to the last third of ileum Relapses, surgery

Colonic or rectal disease Perianal disease

Anal lesions Disabling disease

Stricturing penetrating behaviour at diagnosis Surgery

Age <40 years Disabling disease

Smoking Relapses, complications

Deep colonic ulcers Surgery

CARD15 variants Complications, surgery

IBD5/OCTN variants Perianal disease

Anti-glycan antibodies Complications, surgery

Anti-bacterial antibodies Complications, surgery

CARD, caspase activating recruitment domain; OCTN, organic cation/l-carnitine transporter

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Which are the predictors? (UC)

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Marker Predicted outcome

Extensive colitis Colectomy, cancer, mortality

Colitis extension Colectomy

Sclerosing cholangitis Cancer

Extra-intestinal manifestations Colectomy

Young age Colectomy, cancer

Non-smoking Relapses, colectomy

Systemic inflammation Colectomy

No response to first line therapy Colectomy

No mucosal healing 1 year after diagnosis Colectomy

HLA variants Colectomy

ANCA No response to anti-TNF

HLA, human leukocyte antigen; ANCA, anti-neutrophil cytoplasmic antibodies

Langholz E et al. Gastroenterology 1992;103:1444–51; Devroede GJ et al. N Engl J Med 1971;285:17–21; Ekbom A et al. Gastroenterology 1992;103:954–60; Gower-Rousseau C et al. Am J Gastroenterol2009;104:2080–8; Szamosi et al. Eur J Gastroenterol 2010;22:872–9; Bojic D et al. Inflamm Bowel Dis 2009;15:823–8; Solberg IC et al. Scand J Gastroenterol2009;44:431–40

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Which prognostic factors to use?

Clinical (age, extent, behaviour, symptoms)

Endoscopic (mucosal healing)

Imaging

Faecal (calprotectin)

Serological and laboratory markers(CRP, ASCA, ANCA, OmpC)

Genetic (>100, primarily NOD2/CARD15)

ANCA: anti-neutrophil cytoplasmic antibodies; ASCA:anti-Saccharomyces cerevisiae antibodies; OmpC, outer membrane protein C precursor

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Moving towards disease modification in inflammatory bowel disease (IBD) therapy

Targeting early Crohn’s disease (CD): an opportunity to change the disease course for a long-term disease evolution

Disease duration (years)

Dia

gno

sis

of

Cro

hn

’sd

ise

ase

InflammationDamageDisability

Allen PB, Peyrin-Biroulet L. Curr Opin Gastroenterol 2013;29:397–404

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Moving towards disease modification in IBD therapy

Diagnosis ofCrohn’s disease

Window of opportunity:18 months

Disease duration (years)

Initiationof DMAIDs

Steroids + azathioprine if no poor prognostic factors, no severe disease, no disease complications(if persistent objective signs of inflammation at 6 months, initiation of a biologics-based strategy)ORBiologics-based therapy as first-line therapy

Inflammation

Damage

Disability

A window of opportunity: the concept of disease-modifying anti-inflammatorybowel disease drugs (DMAIDs) early in the disease course to change the naturalhistory of Crohn’s disease

Allen PB, Peyrin-Biroulet L. Curr Opin Gastroenterol 2013;29:397–404

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That window of opportunity is not for all……

Between 20-40% are primary non responders, ~50% lose the initial response

Risk for surgery under anti-TNF:Stricturing - adjusted HR, 6.17 (95% CI, 2.81– 13.54)Penetrating - adjusted HR, 3.39 (95% CI, 1.45–7.92)

“…. delayed treatment increases rates of treatment failure”

Patients with stricturing or penetrating disease do not respond to anti-TNF

Assa A J et. al.; Crohns Colitis. 2013Ben-Horin S. ; Nat Rev Gastroenterol Hepatol. 2014Grover Z et al.; J Crohns Colitis. 2014Peyrin-Biroulet L et al.; Clin Gastroenterol Hepatol. 2008

Moran G.W., Clinical Gastroenterology and Hepatology 2014

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A retrospective case –control study, Israeli IDF soldiers who developed IBD (N=32)1

The PREDICTS Study, US military personnel who developed CD (N=100)2

1. Israeli E. et al., GUT 2005; 2. Choung R. S. et al., APT 2016

31.3% of Crohn’s disease (CD) patients were ASCA positive before diagnosis, mean interval ~38 months

Serologic markers may appear before the onset of IBD

Median 6 years (IQR 5.6–8.2)Higher rates of ABs before diagnosis in complicated vs. non-complicated CD

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“Ultra rapid” complications occur in 34% of patients already within 6 months from diagnosis

No. patients Reason for admission surgery

28 Inflammatory exacerbation 1 Colectomy

2 SB obstruction 1 Ileocecetomy

3 Abdominal abscess 1 Ileocecetomy

6 Perianal complication 3 Perianal abscess drainage

Diagnosis Inclusionup to 6 months from

diagnosis

6 months 12 months 18 months 24 months

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Complications appeared within the first 6 months

Patients at risk:76 52 29

Days since diagnosis

6 months since diagnosis

• Complicators had a non-inflammatory phenotype, and early use of steroids, 5ASA, and antibiotics

• Non- inflammatory phenotype adjuster RR - 9.0 (p=0.004)

• Steroids shortly after diagnosis adjusted RR 9.5 (p=0.002)

• Each decrease of 1 unit of albumin level increases risk by 5% (p=0.021)

• Each increase in 1 year of age at diagnosis increases risk by 5% (p=0.045)

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We compared the efficacy of early treatment (within 6 months after diagnosis) with azathioprine versus conventional management of patients at high risk for disabling disease.

We performed an open-label trial of adults with a diagnosis of CD for less than 6 months who were at risk for disabling disease. From July 2005 to November 2010, patients at 24 French centers were randomly assigned to treatment with

azathioprine (2.5 mg ∙ kg) or conventional management

azathioprine only in cases of corticosteroid dependency, chronic active disease with frequent flares, poor response to corticosteroids, or development of severe perianal disease).

METHODS: We performed a prospective double-blind trial of adult patients with a recent (<8 weeks) diagnosis of Crohn’s disease. Patients were randomly assigned to groups given

azathioprine (2.5mg/ kg, n=68) or placebo (n = 63)

at 31 hospitals from February 2006 to September 2009.

Corticosteroids but no other concomitant medications were allowed for control of disease activity. The primary measure of efficacy was sustained corticosteroid-free remission.

RESULTS:

After 76 weeks of treatment, 30 patients treated with azathioprine (44.1%) and 23 given placebo (36.5%) were in sustained corticosteroid-free remission (difference of 7.6%; 95% confidence interval, 9.2 to 24.4%; P = .48).

The rates of relapse (defined as Crohn’s Disease Activity Index score >175) and corticosteroid requirements were similar between groups.

A post hoc analysis of relapse, defined as a Crohn’s Disease Activity Index score >220, showed lower relapse rates in the azathioprine group than in the placebo group (11.8% vs 30.2%; P = .01).

Serious adverse events occurred in 14 patients in the azathioprine group (20.6%) and 7 in theplacebo group (11.1%) (P = .16).

A larger percentage of patients in the azathioprine group had adverse events that led to study drug Discontinuation (20.6%) than in the placebo group (6.35%) (P = .02).

CONCLUSIONS: In a study of adults with Crohn’s disease, early azathioprine therapy was no more effective than placebo to achieve sustained corticosteroid freeremission but was more effective in preventing moderate to severe relapse in a post hoc analysis.

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British Society of Gastroenterology Guidelines:

Corticosteroids are potent anti-inflammatory agents for moderate to severe relapses of both ulcerative colitis and Crohn’s disease. They have no role in maintenance therapy for either disease.

Two commonly used regimens are:

A starting dose of 40 mg prednisolone per day, reducing by

5 mg/d at weekly intervals, or (for moderate disease).

20 mg/d for 4 weeks then reduce by 5 mg/day at weekly

intervals.

Mowat C. et al, 2011, Gut. 60(5):571-607Mowat C. et al, 2011, Gut. 60(5):571-607

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British Society of Gastroenterology Guidelines

Escalation of therapy should be considered in the following situations:

any patient who has a severe relapse or frequently relapsing disease

those who require two or more corticosteroid courses within a 12 month period

those whose disease relapses as the dose of steroid is reduced below 15 mg

relapse within 6 weeks of stopping corticosteroids

Mowat C. et al, 2011, Gut. 60(5):571-607Mowat C. et al, 2011, Gut. 60(5):571-607

Physician perspectives on unresolved issues in the use of conventional therapy in Crohn's disease: Results from an international survey and discussion programme

M. Ferrante et al.Journal of Crohn's and Colitis (2012) 6, 116–131

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Question 1: Introduction of corticosteroids


When should we introduce corticosteroids,

and for how long?

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100% of the GEs believe that patients who do not respond within 2–4 weeks had

best be further investigated and other therapeutic options considered.

Answer 1: Introduction of corticosteroids

1. Systemic corticosteroids are best used for moderately to severely

active CD of any location. Their use in isolated perianal CD is not supported.

2. Budesonide is preferred to systemic corticosteroids for mildly to moderately active ileocaecal disease and right colonic

disease, but is not universally available. In countries where budesonide is not available, early introduction of immunomodulators (and/or anti-TNF therapy) for their corticosteroid-sparing properties is appropriate.

3. The duration of initial treatment with systemic corticosteroids at

full dose depends on the response of the patient.

There is no clear evidence that continuing the full dose

(40–60 mg prednisone or equivalent) beyond weeks 1–3 influences remission rates.

Patients who do not respond within 2–4 weeks had best be further investigated and other therapeutic options considered.

100% agreement after 2nd voteM. Ferrante et al.Journal of Crohn's and Colitis (2012) 6, 116–131

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Question 2: Dosing strategy for corticosteroids

What is the best dosing strategy for the use of corticosteroids in patients with

Crohn’s disease, in terms of: starting and maximum doses, duration, dose

escalation/de-escalation (when? rate?), formulation, avoiding side-effects?

What duration of corticosteroid treatment is linked to the occurrence of side

effects?


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94% of the GEs agreed that corticosteroids should be taper after no more than 3–4 weeks

Answer 2: Dosing strategy for corticosteroids

1. The optimal initial dose of oral systemic corticosteroids in CD ranges from 40 to 60 mg/day to 1 mg/kg/day. For IV hydrocortisone, the optimal starting dose is 300–400 mg/day.

2. The optimal starting dose of budesonide is 9 mg/day.

3. Tapering of corticosteroids is generally initiated within a week of starting therapy, and after no more than 3–4 weeks. Treatment should not exceed 12 weeks except in exceptional

circumstances.

Early introduction of immunomodulators or anti-TNF

therapy is appropriate.

4. No data are available to allow evaluation of any benefit of

intentional dose escalation of corticosteroids.

M. Ferrante et al.Journal of Crohn's and Colitis (2012) 6, 116–13194% agreement after 2nd vote

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94% of the GEs agreed that the best way to prevent corticosteroid-induced side effects is to avoid prolonged or repetitive use

Answer 2: Dosing strategy for corticosteroids cont’

5. Systemic corticosteroids and budesonide are ineffective as maintenance therapy.

It is strongly recommended to taper all corticosteroids to zero and switch appropriate patients to immunomodulator (or anti-TNF) therapy.

6. Corticosteroids have been shown to increase the risk of serious, opportunistic infections and

mortality, both independently or in combination with immunomodulators and anti-TNF agents.

7. The best way to prevent corticosteroid-induced side effects is to avoid prolonged or repetitive

use and to switch appropriate patients to immunomodulator therapy and/or anti-TNF

therapy.

94% agreement after 2nd voteM. Ferrante et al.Journal of Crohn's and Colitis (2012) 6, 116–131

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Pariente B, et al. Inflamm Bowel Dis 2010; epub 28 Nov 2010

Inflammation is ongoing and resulting tissue damage is cumulative

Progression of digestive damage and

inflammatory activity in a theoretical

patient with Crohn’s disease

Pre-clinical Clinical

Infla

mm

ato

ry a

ctiv

ity

(CD

AI, C

DE

IS, C

RP

)

Surgery

Stricture

Stricture

Fistula / abscess

Disease

onset

Diagnosis Early

disease

Dig

esti

ve d

am

ag

e

CDAI: Crohn’s disease activity index; CDEIS: Crohn’s disease endoscopic index of severity; CRP: C-reactive protein

IBD treatment goals are evolving

Deep remission5

Mucosal healing1 -4

Steroid-free remission

Clinical remission

Improved symptoms

.1Colombe!JF et al. N Engl JMed 2010;362:1383-95.

.2Baert Fl et al. Gastroenterology 2010;138:463-68.

.3Sandborn WJ eta!. JCrohn's Colitis 2010;4:S36:P069 at ECCO.

.4Louis Eet al. Gastroenterology 2012;142:63-70.

.5Colombe!JF et al.J Crohn's Colitis 2010;4:S11:0P31 at ECCO.

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Mucosal healing is associated with lower risk of surgery: IBSEN cohort

Treatment goals in IBD: can mucosal healing alter outcome?

Crohn’s disease

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

IBSEN group: 227 incident CD and 513 incident UC patients assessed at 1 and 5 years

Pro

po

rtio

n o

f C

D p

atie

nts

wit

h n

o s

urg

ery

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

Ulcerative colitis

Pro

po

rtio

n o

f U

C p

atie

nts

wit

h n

o s

urg

ery

Time in years after 1-year visit

1.00

0.98

0.96

0.92

0.90

0 1 2 3 5 7 8

0.94

4 6

Mucosal healing at 1 year

No mucosal healing

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Treating-to-target (mucosal healing) in CD based on endoscopy

Endoscopic outcomes in consecutive CD patients (with baseline endoscopic lesions and subsequent endoscopies) referred to a single IBD centre between Jan 2011 and Dec 2012

Patients with CD (n=67) underwent ≥2 consecutive assessments for endoscopic disease activity, with adjustment of medical therapy to the target of mucosal healing

Endoscopy at referralAbsence of MH (n=67)

48 adjustments in medical therapy

Med

ian

tim

e2

4 w

ks(1

8–3

8)

Med

ian

tim

e2

3 w

ks(1

5–3

2)

Med

ian

tim

e2

5 w

ks(1

4–4

4)

MH (n=28 patients)

89% following treatmentadjustment (n=25)Endoscopy 2

No MH (n=39 patients)

59% following treatmentadjustment (n=23)


Endoscopy 3

No MH (n=11 patients)



MH (n=5 patients)


Endoscopy 4

MH (n=5 patients)


MH (n=1 patient)


Bouguen G et al. Clin Gastroenterol Hepatol 2014;12:978–85.

Cumulative risk of surgery in Crohn’s

Munkholm P, Gastroenterology 1993

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Mucosal healing (MH): an important target in IBD

• An achievable, monitorable goal, associated with better outcomes

• Requires early introduction of effective therapy in high-risk patients

• MH is associated with lower relapse rates in CD and UC

• MH is associated with lower hospitalisation and reduced need for surgery rates

• Mucosal lesions predict postoperative clinical recurrence in CD

• Mucosal lesions predict relapse after anti-TNF withdrawal

• MH is associated with lower risk of colorectal cancer in UCBouguen G, et al. Clin Gastroenterol Hepatol 2014 [Epub ahead of print]; Rutgeerts P, et al, Gastroenterology 1990;99:956-963; Neurath M, Travis S. Gut 2012;61:1619-35; Yokoyama K, et al. Gastroenterol Res Pract. 2013;192794. doi: 10.1155/2013/192794

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Symptom monitoring in IBD is not enough…

• No correlation between symptoms, endoscopic findings and disease course

• Overall accuracy of clinical symptoms relative to endoscopic inflammation is 56%

• A need for biomarkers – what defines a good biomarker in IBD?

− A marker of disease activity

− Predicts imminent relapse

− Predicts post-operative recurrence

− Predicts response to therapy

− Assists in treatment optimisation

Jones J, et al. Clin Gastroenterol Hepatol 2008;6:1218-1224Peyrin-Biroulet L, et al. Clin Gastroenterol Hepatol 2013;pii:S1542-3565(13)01086-0 Solberg IC, et al. Clin Gastroenterol Hepatol 2007;5:1430-1438;Thiu KT, et al. Gastroenterology 2010;139:1147-1155

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Algorithms in IBD:The future

Future

• Patient profiling

• Predictors of disease course I prognosis

• Predictors of drug response

• Established targets

• Systematic monitoring to ensure targets met

Summary• There is no robust or simple model that will tell us how to

treat our patients with IBD

• Several clinical, biological, and endoscopic markers have been

associated with different risks and complications of the disease

• Selecting patients for an appropriate treatment strategy is

critical to achieving optimal disease control

• Therapeutic strategies should be tailored to the individual

patient with the goal of optimising outcomes

• Employing strategies to identify patients early for treatment

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