The State of the art

on treatment of
Crohn’s Disease
Hai Yun Shi, Siew Chien Ng

The Japanese Society of Gastroenterology ( July 2018)

Introduction

Genetic Environmen
Predispositi tal factors
on

Innapropriate
immune respone
 gut microbiota

Inflammatory • Chorn’s Disease ( CD )

Bowel Disease • Ulcerative Colitis ( UC )
(IBD)
Prevalence
• 0.3% in North America,
20th Century Oceania, Many countries
in Europe

• Plateaued in North
America and Europe
21th Century • Rising among industrial
countries in ASIA, Africa
and South America
 Natural History
• Crohn’s disease Progressive and
destructive disease  involve the whole
gastrointestinal tract.

• Recent Years  Immunomodulator and

biologics ↑  ↓ Surgery rates for CD
 Evolution of endpoints
and treat-to-target
• Resolution of symptoms  Primary clinical
target for CD Treatment

• Mucosal healing  Therapeutic goal in

clinical practice

Reduce risk of disease relapse, hospitilization,

and surgery.
Crohn’s Disease Activity Index (CDAI)
• The most studies endoscopic scoring systems
for :
 The Crohn’s disease Endoscopic Index
of Severity (CDEIS)
 Simple Endoscopic Score for Crohn’s
Disease SES-CD)
 ILeum Right Transverse Left and Rectum Sum
Colon Sigmoid colon

Deep ulceration
( 0 for none, 12 points
if present)
Superficial Ulceration
Endoscopic
( 0 for none, 6 points if remission :
present) CDEIS Score
Surface involved by
<3
disease
(cm on 10 cm VAS)
Surface involved by
ulceration
Total (A)
Number of segmen explore
Total A/ nmber of segmen explore (B)
If ulcerated stenosis present; add 3 (C)
If non ulcerated stenosis present, add 3 ( D)
Total CDEIS score ( B+C+D)
Simple Endoscopic Score for
Crohn’s Disease (SES-CD)

Endoscopic
remmision :
SES-CD
score < 2
Rutgeerts Score

Endoscopic
Recurrence
• A patient reported outcome (PRO) a
measurement derived directly from a
patient  any aspect of their health status,
without interpretation of their response by a
clinician or anyone else  endpoint for CD.
• There are several scale to assess patients
perspective towards the disease :
o IBDQ ( Inflammatory Bowel Disease
Questionnaire )
o FACIT-F ( Functional Assessment Chronic
Illness Therapy-Fatique)
o WPAI ( Work Productivity Activity
Impairment Questionnaire )
• Stepwise management of CD  avoidance
of the long-term bowel damage and
subsequent disability, a ‘‘treat-to-target’’
strategy has been advocated.

• The International Organization for the Study

of Inflammatory Bowel Diseases (IOIBD) 
proposed a composite target  Achieve
the resolution of abdominal pain, altered
bowel habit & Ulceration at
ileocolonoscopy.
Conventional Medication
• Aminosalicylates
o High dose measalazine  Prevent post-operative
recurrence
o Sulfasalazine  beneficial effect on peripheral
arthritis associated with CD.

• Corticosteroids
o mainstay of therapy for inducing remission in CD.
o Systemic corticosteroids  the first line treatment
to control active disease
• Thiopurines
o The European Crohn’s and Colitis
Organization (ECCO) 2016 guideline
• thiopurines  1st therapy for preventing
disease relapse in
patients who achieve
remission with
corticosteroids.
 use to prevent post-
operative recurrence
in patients with higher risk
for recurrence.

o Thiopurine withdrawal is associated with a

higher risk for relaps.
• Methotrexate
o Guidelines recommend the use of MTX as
an alternative to AZA (Azathioprine) for
the maintenance of remisssion.

o MTX is recommended in patients with

steroid-dependent, steroid-refactory, AZA-
refactory CD and also in patinets
intolerant to other immunomodulating
agents.
• Thalidomide
o Should only be considered in short-term
use among selected patients.
Anti-TNF agents
• The use of biologics in IBD started with the approval
of infliximab, which is an anti-tumor necrosis factor
(anti-TNF) agent in CD by the FDA in 1998.

• The introduction of anti-TNF has revolutionised the

therapeutic strategy of IBD, and its use continues to
increase
• ECCO guidelines  strongly in favor of early anti-TNF
use in CD therapy, especially in patients with high
disease activity & features indicating unfavorable
prognosis, including young-onset, extensive disease,
early need for corticosteroids and perianal disease
• Anti-TNF based therapy  as prophylactic
treatment after bowel resection in patients
with at least one risk factor for recurrence

• Therapeutic drug monitoring (TDM) refers to

the evaluation of drug concentration and
anti-drug antibodies during therapy
• TDM  to determine the reasons for drug
failure & guide the optimization of treatment

• Anti-TNF therapy is relatively safe in CD

treatment.

• Relapse rate after anti-TNF withdrawal is

between 30–40% at 1 year, and greater
than 50% beyond 2 years.
• Maintenance of immunomodulator
treatment after anti-TNF withdrawal reduces
the risk for relapse

• Retreatment with anti-TNF at relapse is

effective with a success rate of 88%
Other Biologics
• Vedolizumab, a monoclonal antibody to a4b7, was
approved by the US FDA for the treatment of CD in
2014.
Vedolizumab can
induce clinical
remission in 20–
30% of patients
with anti-TNF
refractory
CD after 6 weeks.
• In 2016  Ustekinumab  an antibody to
interleukin-12/23  approved by the US FDA
for the treatment of CD

• CD patients with psoriasis or those who

develop anti-TNF induced psoriasis may be
the ideal candidates for ustekinumab
therapy .
• Ustekinumab Potential to become a first-
line biologic agent for CD

• Importantly, risk of tuberculosis (TB) is low

with this drug, which may be useful in TB
endemic regions
Conclusion
• A combination of symptom control and
mucosal healing has been proposed as the
target for CD therapy.

• Corticosteroids and thiopurines remain as

the mainstay of treatment, while anti-TNF
agents are increasingly applied earlier in
disease course during the recent two
decades.
• Anti-TNF  in patients with high risk for
unfavorable prognosis.

• New biologics not only provide hope to

patients refractory to anti-TNF, but also has
potential to become first-line therapy in
selected patients due to beneficial risk
profile and long-term efficacy