INTRO - Types

Chrons

UC

Extends into the deeper

layer of the intestinal wall
and may affects mouth,
esophagus, stomach, small
intestines
Transmural inflammations
and skip lesion
50% - ileocolic, 30% ileal and
20% colic region
Regional enteritis

Causes inflammation of the

inner lining of the colon and
rectum
It is usually in the form of
characteristic ulcers or open
sores

 The World Gastroenterology

Organization indicates the following
symptoms may be associated with
inflammatory changes in the digestive
tract
Diarrhoea : with mucus or blood, occurs
at night, incontinence
Constipation: may be primary
symptoms in UC and limited to the
rectum, may lead to obstruction
Bowel movements abnormality: pain/
rectal bleeding, severe urgency or
tenesmus

Abdominal cramping and pain: commonly

present in the right lower quadrant for CD,
and periumbilical or in the left lower
quadrant in the moderate to severe UC
Nausea and vomiting : more often in CD
than UC

TREATMENT IN IBD

Strategies in treating IBD

Evolving expectations and and therapeutic strategies
The expanding role of anti TNF therapy
Rethinking our treatment approach. Step Up vs Step
Down strategies

Treatment expectations
Past expectations
Control symptoms
Improves patient
quality of life

Currents
Induction and maintenance
of remission
Mucosal healing
Closure of fistulas (CD)
Avoid surgical
intervention / decrease
hospitalizations
Decreasing likelihood of
cancer development (UC)
Minimize disease-related
and theraphy-related cx

New Paradigm for Treating Individuals with Crohns Disease and UC:
Match the aggressiveness of treatment with predicted aggressiveness of
disease, and match treatment with precise mechanism of disease
Predicted disease
Surgery
activity
Very aggressive/
Bowel rest (SB)
Get it right the
Refractory to Rx
Cyclosporine, Natalizumab
first time!
TNF antagonist
Start the correc
Moderate
treatment at d
AZA/6-MP/MTX
ly
Systemic corticosteroids
aggressiv
e/More
TNF antagonists ( early intervention?)
difficult
to treat Topical or rapidly metabolized corticosteroids

Uncomplicated/
easily treated

Antibiotics (Crohns colitis)

ASA (colitis)

ASA, aminosalicylates; AZA, azathioprine; 6-MP, 6-mercaptopurine; MTX, methotrexate

CASE OF
RECTOVAGINAL
FISTULA

 62 years old lady,underlying hypertension .

Chronic hep B-hbe ag pos-on tab tenofovir 600mg od
First presentation in 2012 with complaint of lower
abdominal pain for 6 month associated with on off
fever,altered bowel habit and brownish PV discharge

Colonoscopy 18/10/12
Inflammed and
oedematous
mucosal mass at
low rectum
fragile mucosa
Able to pass scope
till 30cm

 EUA + biopsy was done on 24/10/12 - vaginal wall fused

anteriorly and posteriorly, bleeding during touch, fistula
noted with fecal material. Biopsy taken.
CT scan 25/10/12:
Suspicious lesion at vagina or anterior rectal wall with
possible fistulous communication between the two
structure

 Diagnosis : Rectovaginal fistula most likely inflammatory

in origin
Electivelproximal transverse colostomy on 2/11/12

 However in 2013 patient developed stricture 3 cm from

the anal verge
HPE from rectal biopsy(21/3/13)-ulcerated overlying
mucosa with inflammatory cell infiltration and mild
glandular distortion and hyperplasia.
HPE rv by GI pathologist-consistent with chron disease
Referred to gastro team

THERAPY
5-ASA, steroids, surgery

Immunomodulators
(6-MP/AZA/MTX)

Biologics/simple compound (anti-TNF antibodies, anti

alpha-4 B7 integrins, anti-IL17/23, antiMadCAM/VCAM, anti-IL13,ip10, Apheresis, herbals)

Immunomodulators
AZA and 6-MP
Effective maintenance agents
Response slow (816 weeks)
Not tolerated by about 15%
of patients
Only about half of patients responsive
to AZA/6-MP for steroid refractory or
steroid-dependent disease
About 5%10% relapse despite
treatment
Safety/tolerance issues:
nausea/malaise, lymphoma risk,
opportunistic infections, pancreatitis,
myelosuppression

Rutgeerts P et al. Rev Gastroenterol Disord. 2004;4(Suppl 3):S3S9.

Nielsen OH et al. Aliment Pharmacol Ther. 2001;15:16991708.
Korelitz BI, Present DH. N Engl J Med. 1995;333:600601.

Methotrexate
An alternative for patients not
responding to or intolerant of
AZA/6-MP
Effective when given IM or SC
Response over 8 to 16 weeks
Effective maintenance agent
Safety issues: hepatic fibrosis,
interstitial pneumonitis,
teratogenicity, nausea

Altering the Natural History

of IBD
Van Assche et al. Nature Clin Gastro 2010

How important is mucosal healing

in the course of the disease?
ECCO Workshop on Mucosal Healing

Mucosal healing is associated with lower relapse rates

Mucosal healing is associated with lower
hospitalization rates
Mucosal healing is associated with less bowel damage
(fistulas) in Crohn's disease
Mucosal healing is associated with reduced need for
surgery
Mucosal lesions predict postoperative clinical
recurrence in Crohn's disease
Mucosal healing is associated with lower risk of
colorectal cancer in ulcerative colitis
Peyrin-Biroulet L et al. Journal of Crohns and Colitis 2011; 5: 477-483

Cont
She was started on tab mesalazine 1g bd with tappering
dose oral prednisolone on april 2013.
Subsequently was started on tab azathiorpine 125mg od
for steroid sparing

Patient clinically improving .

No more abdominal pain/PR bleed

8 months later
Colonoscopy on dec 2013-unable to pass through the
scope due to rectal stricture. Inflammed rectal mucosa
Rectal HPE(dec 2013)-chronic colitis consistent with
crohn disease.
MRI (january 2014)
-persistent rectovaginal fistula

WHAT DO WE DO
NEXT?

 IV infliximab 390 mg was started on May 2014 in view of

not responding with treatment.
Started with induction(at 0,2 and 6 th week) and cont with
maintainance.

 Completed 6 cycles iv inflixmab with 8 weeks apart each

cycle.
Last cycle on 15/6/15
Tab mesalazine and azathioprine were continued
She was underwent closure of colostomy and Haartman
procedure on 2/9/15

Biologic in IBD
Risk
Benefit
Infections
Better result
Lymphoma esp male Less adverse events
< 30 y.o
Multiple sclerosis
Lupus
Require lab test
every 4 months at
least

Who Should Take Biologic

Therapy?

Q: Does the patients disease severity require Biologic?

For moderate to severe IBD
Fistulizing Chrons disease
Extra intestinal manifestations
Failing conventional treatment
Consider to start early in steroid resistance/ steroid dependance or
steroid intolerance or persistent endoscopic activity

NOT if:
1.
2.
3.

4.
5.

Active (i.e. untreated) infection

Untreated malignancies (melanoma, lymphoma, renal cell Ca, lung Ca, or
presently in active chemotherapy).
Uncontrolled CHF

Neurologic disease (M.S., autoimmune neurological disease)

Fibrostenotic strictures: surgery required

Weighing the Value of Top-Down

Therapy
Benefits
Early promotion of
mucosal healing to
prevent complications
Evidence of
6-MP/AZA and
infliximab promoting
mucosal healing

Lichtenstein GR et al. Inflamm Bowel Dis. 2004;10:S2S10.

Caprilli R et al. Digestive Liver Dis. 2005;37:973979.

Disadvantages
Serious side effects
Development of
antibodies (biologics)
Cost
Majority of patients do not
require more potent
treatments initially

Individual predictive markers for

severe Crohns disease
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

Munkholm P. Scand JGastroenterol 1995;30:699700; Louis E. Gut 2003;52:5527; Lakatos P. World J Gastroenterol 2009;15:350410; Henckaerts L. Clin Gastroenterol Hepatol
2009;7:97280; Romberg MJ. Am J Gastroenterol 2009;104:37183; Chow D. Inflamm Bowel Dis 2009;15:5517; Hellers G. Gut 1980;21:5257; Beaugerie L. Gastroenterology
2006;130:6506; Loly C. Scand J Gastroenterol 2008;43:94854; Allez M. Am J Gastroenterol 2002;97:94753

Screening prior to anti-TNF therapy

Recommended screening - CXR and TST (tuberculin skin
tests)
Interferon release assays (IGRA) should be used if
available (TB spot test, Quantiferon Gold)
High rate of anergy to TST in immunosuppressed individuals
(83%) so testing should be done prior to starting therapy to
avoid confusion
Second (booster) TST 1-8 weeks later may be helpful
TST considered positive for latent TB 5mm or 15mm if
previous BCG

Anti-TNF and Tuberculosis

Those with latent TB should receive
chemoprophylaxis, at least two months before
commencing anti-TNF therapy
Standard treatment in six months of isoniazid

er JF, et al, European evidence-based Consensus on the prevention, diagnosis and management of
rtunistic infections in inflammatory bowel disease, Journal of Crohn's and Colitis (2009)

Infliximab
a chimeric (mouse/human) lgG1
monoclonal antibody that binds to
TNF-1
high specificity, affinity and
avidity2,3*
given as a single intravenous
infusion 5 mg/kg over 2-hour
period.
Induction regimen at 0, 2 and 6
weeks followed by a maintenance
regimen every 8 weeks thereafter

1. REMICADE Prescribing Information.

2. Knight DM, et al. Mol Immunol. 1993;30:144353.
3. Scallon BJ, et al. J Pharmacol Exp Ther. 2002;301:418
426.

Malaysias Indications
Inflammatory
Bowel Diseases

CD

UC Ped CD

Rheumatoid
Arthritis

Ankylosing
Spondylitis

Psoriatic
Arthritis

Psoriasis

RA

AS

PsA

Ps

Therapy with infliximab

Rapid symptomatic relief ( 60 80% of patients)
Efficacy and maintenance therapy (ACCENT I)
Mucosal healing
Acceptable safety profile
Controlled study in fistulizing Chrons (ACCENT II)

ACCENT I

ACCENT I

Percentage of Patients (%)

Maintenance of Clinical Remission

100
80

Remission Among Week 2responders

**p=0.002;
p=0.003;
(co-primary Endpoint *p<0.0001;
at Week
30
andp=0.007
Week 54)

60

45.5 **

38.9

38.4 *

40

28.3 #
20.9
13.6

20
0

Week 30
Single dose

q8 weeks Every 8 weeks

Week 54

IFX 5mg/kg q8 weeks

IFX 10mg/kg q8 weeks

Hanauer SB, et al. Lancet 2002;359:154-549.

Data on file; Centocor: ACCENT I study report

SONIC

Percentage of Patients (%)

Mucosal Healing at Week 26

Secondary Endpoint
100
p<0.001

80
p=0.02

60

p=0.06
43.9

40
20
0

30.1
16.5
18/109
AZA+PBO

28/93
IFX+PBO

47/107
IFX+AZA

Colombel JF, et al. N Engl J Med 2010;362:1383-

ACCENT II

Percentage of Patients
Responding (%)

Fistula Response at Week 54

Fistula Response at Week 54 (in Week 14-responders)

p=0.001

PBO

p=0.009

5 mg/kg IFX scheduled

Adapted from Sands BE, et al. N Engl J Med 2004;350:876-885.

ACCENT II

Effect of IFX on Hospitalizations and

Surgeries in Fistulizing CD
Patients Hospitalized
(%)
p<0.05

p<0.05

All
Randomized

Week 14responders

Patients

PBO maintenance

Cumulative Number of
Surgeries

5 mg/kg IFX maintenance

Lichtenstein GR, et al. Gastroenterology 2005;128:862-

The Pros and Cons Of Inverting The

Traditional Treatment Pyramids
Advantages

Risk

1. Early disease
stabilization/ disease
modifier
2. Minimize disease
complications
3. Reduce surgery and
hospitalization cost
4. Avoidance of steroid
toxicity

1. Prolonged
immunosupression
2. Neutralizing
antibodies
3. Increase financial
burden to the patient/
cost of treatment
4. ? Pregnancy outcomes