Update IBD management vietnam

Incidence of IBD in Hong Kong: 19802014 30fold increase in three decades HK IBD RegistryIncidence of IBD in Hong Kong: 19802014 30fold increase in three decades HK IBD RegistryIncidence of IBD in Hong Kong: 19802014 30fold increase in three decades HK IBD RegistryIncidence of IBD in Hong Kong: 19802014 30fold increase in three decades HK IBD Registry

Copyright © 2016 All Rights Reserved Faculty of Medicine, The Chinese University of Hong Kong

Updates in IBD Management

Siew Ng

MBBS, FRCP (Lond, Edin), FHKAM, PhD (Lond)

Professor Department of Medicine & Therapeutics

Chinese University of Hong Kong

Copyright © 2016 All Rights Reserved Faculty of Medicine, The Chinese University of Hong Kong

Molodecky…Kaplan Gastroenterology 2012 Jan; 142(1): 46-54

The Global Map of IBD in 2015: IBD is a modern disease of modern times that is rooted in the industrialization of society

Yang Qian PLOS One 2014 Jul 16; 9(7): e101296

Incidence of IBD is 30 per 100,000

Incidence of IBD

is <5 per 100,000

Ng et al Gastroenterology 2013

Courtesy G Kaplan

ACCESS Incidence IBD In Asia-Pacific

Place Incidence

Per 100,000

95% CI

Australia 23.7 18.5-29.9 Guangzhou 3.4 2.5-4.4 Hong Kong 3.1 2.5-3.7 Macau 2.2 0.1-2.8 Sri Lanka 1.6 1.1-2.2 Singapore 1.1 0.8-1.5 Malaysia 0.9 0.4-1.9 Indonesia 0.9 0.4-1.7 Thailand 0.7 0.3-1.2

http://www.access-apibd.com/access/index.html

Ng et al Gastro 2013

NTE Cluster, North District Hospital (NDH)

NTE Cluster, Alice Ho Miu Ling Nethersole Hospital (AHNH)

NTE Cluster, Prince of Wales Hospital (PWH)

KE Cluster, Tseung Kwan

O Hospital (TKOH )

KE Cluster, United Christian Hospital (UCH)

HKE Cluster, Pamela Youde Nethersole Eastern Hospital (PYNEH)

HKW Cluster, Queen Mary Hospital (QMH)

HKE Cluster, Ruttonjee Hospital (RH)

7 Clusters 15 hospitals included – total population >7,000,000 in 2013

Hong Kong IBD Registry, N=3,000

Incidence of IBD in Hong Kong: 1980-2014

30-fold increase in three decades

Prevalence of IBD in Asia & the West

Seoul 2005 30.9 11.2 Japan 2003-2005 57.3 18.6 Hong Kong 2011-2013 34.0 21.0

North America 2001 246 162 North Europe 1987 161 54

United Kingdom 1996 122 214 New Zealand 2004 155 104

Ratio of Ulcerative colitis : Crohn’s disease

Country Ulcerative

Colitis

Crohn’s disease

UC/CD Ratio

Natural History of Ulcerative Colitis

with Standard Therapy

*Percent of patients with disease activity, in remission, or having

colectomy performed each year after diagnosis Langholz E et al Gastroenterology 1994;107:3

The way we practice in UC…

Aminosalicylates

AZA/6-MP Oral steroids

Surgery CsA or IFX

Mild to Moderate

Acute Ulcerative Colitis

Treatment Goals for UC

Induce remission (as quickly as possible)

Maintain a steroid free remission (as long as possible)

Provide therapy that has minimal toxicity

Improve quality-of-life

Achieve mucosal healing

Hierarchy of needs for the IBD patient

Corey A Siegel at DDW 2014

What is the first line treatment for mild-moderate

UC in your practice?

A Topical 5-ASA alone

B Oral 5-ASA alone

C Topical 5-ASA + Oral 5-ASA

D Topical steroids

E Systemic steroids

5-ASA in Ulcerative Colitis

Standard of care for the treatment

and maintenance of mild-to-moderate UC

(≈70% will achieve remission)

Feagan et al Cochrane Database Syst Rev 2012

Bergman et al Aliment Pharmacol Ther 2006

5-ASA in Acute Mild-to-moderate flares of UC

Pooled OR for complete remission is

2.02

How Effective are 5-ASA in Induction of Remission

• n = 622 (all 9 of the 5ASA

Treatment according to site of

disease and disease activity

Adapted from Marshall & Irvine AJG

2000

Marshall J, et al Gut 1997

Symptoms Endoscopy Histology

Rectal 5-ASA is Superior to Rectal Steroids in

Distal UC: a Meta-analysis

5-ASA better Corticosteroids better

Improvement

Remission

Marshall & Irvine Gut 1997

Combination (n=17)

Safdi M, et al Am J Gastroenterol 1997

Combined Oral and Rectal 5-ASA is

More Efficacious in Distal Active UC

Marteau P, et al Gut 2005

Combined oral and rectal 5-ASA induces a faster

improvement in Extensive Active UC

Ulcerative Colitis Management of the Acute

When treating acute ulcerative colitis

the correct dose of prednisolone is

40-60mg per day

Baron et al BMJ 1962

Case 1

22 year old student

Diagnosed with extensive UC in 2015

Presented with rectal bleed and loose stool X6 per day

Treated with oral mesalazine 2g daily

“Some” improvement

One episode of gastroenteritis 1 year ago and treated with antibiotics

Flexible Sigmoidoscopy

Histology

Case 1

22 year old student

After 3 weeks

Feels “generally well”

Occasional streaks of blood and some cramps

Still finds it difficult to attend classes

Has he achieved clinical remission?

What will you do?

a) Increase dose of mesalazine >4g per day

b) Increase dose of mesalazine and add rectal mesalazine c) Oral steroids

d) Anti-TNF agents

e) Oral tacrolimus

Rectal bleed resolved and stool frequency

returned to twice per day

Maintaining Remission in

Ulcerative Colitis

5-ASA for Maintenance of Remission in UC

Bergman et al Aliment Pharmacol Ther 2006

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7:762–769

Maintenance Therapy with Once daily dosing

Mesalazine 2G sachets (PODIUM)

More 5-ASA content per dose ….less tablets

Once per day tablet ….less often

5-ASA For Maintenance Remission in

For maintenance 3g of rectal 5-ASA per week

is recommended

D’Albasio et al AJG 1997; Piddi et al.Scand J Gastro 2004

Marteau et al Gut 1998

Ulcerative Colitis

Maintaining Remission

Mesalazine

Frequent flare-ups or chronic active disease

thiopurine (azathioprine or mercaptopurine)

Unresponsive chronic active disease

tacrolimus, anti-TNF, or vedolizumab

Ng and Kamm, Inflam Bowel Disease 2009 ECCO guidelines 2012

Therapeutic Strategies for Mild-Moderate UC

Proctitis

5-ASA suppository 1g nocte

5-ASA suppository 1g 2-3 times/day + rectal

How do you prescribe mesalazine to maintain remission in UC?

a) Once daily dosing

b) Twice daily dosing

c) Three times daily dosing

d) A combination of the above

Adherence is a Real Problem

Lowering Pill Burden and Optimizing

Daily Regimens

Increased Risk of Relapse in Patients

Kane S, et al Am J Med 2003

Recent Big News in 5-ASA Use

Higher 5-ASA content per dose

….Less tablets (better compliance)

Once per day tablet

….Less often (better compliance)

Newer formulations

….Better Release

More use of 5-ASA in UC

… Less steroids

Once daily Mesalazine Granules are Non-inferior to TID treatment in Mild-to-moderate active UC (3G daily or 1G TDS)

0 10 20 30 40 50 60 70 80 90

per protocol intention to treat

OD TID

Kruis W, et al Gut 2009;58:233–40

PATIENT COMPLIANCE better

with daily 2g regimen

Improved patient compliance correlates with better disease control

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7:762–769

2 Kane S et al Am J Med 2003;114(1):39-43

MOTUS Study

Oral mesalazine sachet

4g daily versus 2g twice daily

Clinical & Endoscopic Remission

Once daily versus multiple daily mesalamine

therapy for mild to moderate ulcerative colitis:

a meta-analysis

17 randomized studies containing 5439 patients

Once daily dose of mesalamine is as effective and

safe as multiple day dose for the induction and

maintenance treatment of mild to moderate UC

Romkens et al IBD 2012

What is Remission?

Clinical Endoscopic Histological Immunological Surrogate Markers

Remission The Benefit

In any study (inception cohort, natural history, drug intervention)

the more complete the remission

(clinical, endosc., histological, immune, biomarker)

the better the long term outcome

Treat-to-target approach feasible in UC?

Mesalazine Intensification in Quiescent UC Effect on Calprotectin

In patients with clinically quiescent UC

and increased faecal calprotectin increasing the dose of mesalazine to 4.8 per day

reduces calprotectin and lowers the relapse rate

Osterman et al (USA), Clin Gastro Hep 2014

Young age at diagnosis

Co-existing PSC (4-fold increased risk) Family history of colorectal cancer

Cancer Risk in Chinese Patients

• IBD 1990-2014 in Hong Kong

– CD: n=960

– UC: n=1,472

• gastrointestinal cancer: 25

– CD: SIR GI cancer 4.1 (2.4-6.9)

– UC: SIR GI cancer 0.8 (0.4-1.4)

– 5-ASA: multivariate HR 0.10 (0.07-0.16) – cancer

Ng S et al DDW 2016

5-ASA: chemoprophylactic

Cumulative Probability of Cancer in Ulcerative Colitis

is Significantly Lower in Patients who had

p < 0.0001

With mesalazine

Without mesalazine

With mesalazine

Without mesalazine

Ng et al DDW 2016 oral abstract

How Do You Manage Fulminant Colitis?

Use your “ Clinical Nose”

Rescue Therapy – Decisions, decisions

Infliximab Cyclosporin

n = 56 n = 55

Treatment Failure 54% p=NS 60%

Response day 7 86% 85%

Mucosal healing day 98 53% 52%

Acute Severe Ulcerative Colitis Randomised Trial: Infliximab v Cyclosporin

Laharie et al Lancet 2012

Acute Severe Ulcerative Colitis

not responding to 3-5 days IV steroids

IV Cyclosporine 2mg/kg

IV infliximab 5mg/kg

Total colectomy Ileal pouch anal anastomosis

Summary

Refractory Ulcerative Colitis

Refractory Chronic Active UC Randomised Controlled Trial of Tacrolimus

Low trough (5-10ng/ml) Placebo

p<0.001

P=0.067

Ogata et al Gut 2006

Clinical remission

UC: Infliximab v Infliximab +

New Drugs for Ulcerative Colitis

Sustained release Colonic Budesonide (MMX)

Sandborn et al Gastro 2012

New anti-TNF therapy (Golimumab)

Sandborn et al Gastro 2013

Vedolizumab (α4β7 antagonist)

Feagan et al.NEJM 2013

Tofacinitib (JAK Kinase inhibitor)

Sandborn et al NEJM 2013

Colonoscopy showed pancolitis

Histology: cryptitis is noted with increase in basal plasmacytosis

Microbiology workup negative

Case 2

Put on Mesalazine 2g BD per oral

2 months later, Clostridium difficile toxin positive

Given oral vancomycin for 2 weeks

Repeat stool tests negative for CD

Added on low dose Azathioprine

Symptoms improved, weight gain

Case 2

Poor compliance to azathioprine due to dizziness in February 2014

Disease flare up in August 2015

Bowel opening 10x per day, abdominal pain

CRP 139

Stool for CD toxin positive

Flexible Sigmoidoscopy

Copyright © 2016 All Rights Reserved Faculty of Medicine, The Chinese University of Hong Kong

What will you do?

a) Start oral vancomycin and IV metronidazole b) Start IV steroids

c) IV steroids and oral vancomycin

d) Fecal microbiota transplantation

e) Surgery

Copyright © 2016 All Rights Reserved Faculty of Medicine, The Chinese University of Hong Kong

Case 2

IV steroids, oral vancomycin and IV metronidazole

Failed response to vancomycin

Fecal microbiota transplantation was done via NJ route

Symptoms subsided and discharge with tapering dose steroid

Maintained on mesalazine 2g daily in remission

FMT

FMT

Management of Crohn’s Disease

The natural history of Crohn’s disease is: progression towards complications

Cumulative Risk of Stricturing or Penetrating

Optimising Thiopurine Luminal Crohn’s disease

Lémann M, et al Gastroenterology 2006;130:1054–61

Time after randomisation (months)

Non-inferiority hypothesis not rejected: p=0.19

Patients

(relapses) 43 40(3) 35(7) 27(9) Placebo

Azathioprine Placebo

AZA withdrawal in CD

92% 79%

Current Position of Azathioprine in

Luminal Crohn’s Disease

Steroid dependent CD (subgroup of non-severe patients) Prophylaxis of post-op recurrence

As an adjunct to anti-TNFs (combination therapy)

Risk of Surgery in Crohn’s disease Patients

with Severe Colonic Ulcerations

When to Start Anti-TNF

Patients with adverse prognostic factors

(younger, perianal lesions, extensive SB disease,

stricturing disease, deep colonic ulcers,

multiple resections)

should be

started on biologics (± immunosuppressants)

Conventional Therapy with Accelerated Step-up

No Adverse Prognostic Factors

Moderate Crohn’s disease

Thiopurine/methotrexate

~40% achieve remission at 1 year

Start anti-TNF therapy and continue thiopurine

Initial Responders

All Treated Patients

The 3 Anti-TNF Antibodies in CD

One year Remission

ACCENT 1, Hanauer et al Lancet 2002 CHARM, Colombel et al Gastroenterol 2007 PRECISE 1-4, Schreiber et al NEJM 2007

Scheduled regular anti-TNF therapy and thiopurine

oral

steroid

Reduce dose interval

of TNF

anti-Luminal Crohn’s disease (with or without perineal fistulas)

Loss of response

Switch to different biological drug

Temporarily increase dose

of anti-TNF

Increase dose

of anti-TNF

Loss of Response to Biologic

Kamm, Ng et al IBD 2011

Modern Management of Fistulising Crohn’s Disease

If complex fistula and active rectal disease

seton only

The “21st Century”

Management for Crohn’s Perianal Fistulas

Fistula closure as a therapeutic goal

Early use of biological therapy Role of imaging in monitoring treatment

Combined medical and surgery treatment

Assessment of Fistula

To assess proximal disease & extent of rectal

disease

To delineate fistula

anatomy, extent and relationship

of tracks to sphincter muscles

To include surgical

drainage and/or

seton

ENDOSCOPY MRI / AES

EUA

This should really be current practice

Trans-sphincteric fistula with supralevator extension Not healed on MRI despite external opening closure

Axial MRI

Trans-sphincteric fistula with 3 supralevator extensions Marked improvement with track resolution on MRI

Coronal MRI

Modern Management of Crohn’s Fistulas

Kamm & Ng, Clin Gastro Hepatology 2008

Accurate anal imaging (MRI, EUA, Endoscopy)

Drainage +/- seton Aggressively manage proctitis Anti-bacterial short term treatment

AZA/6-MP first line Anti-TNF often needed Consider seton removal week 4-6 MRI at 12 months to guide treatment duration

Don’t forget to optimise nutrition

Summary: Ulcerative Colitis

5-ASA is first line treatment for mild-moderate UC

Combined topical and oral preparation is superior to oral alone Improve adherence by once daily dosing

Disease monitoring with fecal calprotectin guide treatment

optimisation

Mesalazine is associated with a reduced cumulative risk of cancer

in UC

Summary: Crohn’s Disease

Scheduled anti-TNF superior to episodic treatment

Early anti-TNF use for better efficacy

Combination anti-TNF with thiopurine is the most effective

(SONIC)

Stronger and quicker induction is more effective

(“Step up vs Top Down”)

Can bridge to thiopurine and stop biologic (STORI)

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