Marcellus Simadibrata Kolopaking MD PhD FACG FASGE FINASIM

Division Gastroenterology Department Internal Medicine Faculty

Medicine Universitas Indonesia / RS Dr. Cipto Mangunkusumo Jakarta

Dry Workshop Management treatment of IBD. Sabtu 24 Maret 2018. Aula

lantai 6 RSPAD Gatot Subroto Jakarta Pusat
Outline
 Introduction
 Management of Inflammatory Bowel Disease:
Indonesian Consensus.
 Biologic Treatment in IBD
 Adalimumab Treatment in IBD
 Indication and Contraindication
 Side effects
 Conclusion
Introduction-1
 Inflammatory bowel disease (IBD) is a chronic
inflammatory disease of the gastrointestinal tract.
 Divided into ulcerative colitis (UC), Crohn's disease
(CD) and Indeterminate Colitis(IC); different
- Clinically
- Endoscopically
- Histopathologically
Introduction-2
 The management of IBD include
Nonpharmacological(including nutrition),
Pharmacological, surgery.
 The pharmacological conventional medicine already
been used such as anti inflammatory agents,
corticosteroids, immunomodulators, but the outcome
still not good/optimal.
 Now we have biologic agents to optimize the response
of therapy such as adalimumab.
 Definition
 Ulcerative colitis (UC) is a chronic inflammatory
condition causing continuous mucosal inflammation
of the colon without granulomas on biopsy, affecting
the rectum and a variable extent of the colon in
continuity, which is characterised by a relapsing and
remitting course.
 Crohn's disease is a lifelong disease arising from an
interaction between genetic and environmental
factors, but observed predominantly in developed
countries of the world.
ECCO. J Crohn’s and Colitis. 2012.09.003 965-990
 Diagnosis of IBD
 Diagnosis IBD is made upon history
taking/anamnesis, physical examination, supporting
examination including endoscopy and imaging
studies.
 Diagnosis Criteria: Asian Pacific consensus, ECCO
consensus/guideline, World Gastroenterology
Organization(WGO), Indonesian Gastroenterology
Society(ISG) National Consensus on IBD.
Management of Inflammatory Bowel
Disease: Indonesian Consensus
 Non-pharmacology: Nutrition, general condition
improvement, Education.
 Pharmacology: anti inflammatory agents(mesalamine,
sulfasalazine etc), corticosteroid(methylprednisolone,
budesonide etc.), immunomodulators(6
mercaptopurine, azathioprine, methotrexate etc).
 Surgery.
Symptoms / Patient-reported outcomes

Mucosal lesions Biomarkers

endoscopy (CRP)
MRI
calprotectin
Disease modification in IBD: Window of Opportunity for Intervention
From clinical response to deep remission

1976 1981 1989 2000 2009 2017

CDAI CRP CDEIS Calprotectin MaRIA

(MRI) CDAI
+
CRP
+
CDEIS
+
Calpro.
+
MaRiA

Placebo effect
Algorithm of Indonesian Consensus 2013 on the management of
IBD for new patient
Algorithm of Indonesian Consensus 2013 on the management of
Ulcerative Colitis in primary care
Algorithm of Indonesian Consensus 2013 on the management of
Crohn’s Disease in primary care
 Biologic Treatment in IBD-1

1. ANTI-TUMOR NECROSIS FACTOR AGENTS(Anti

TNF):

 Adalimumab (Humira®)
 Certolizumab pegol (Cimzia®)
 Golimumab (Simponi®)
 Infliximab (Remicade®)
 Infliximab-dyyb (Inflectra®)

Crohn’s & Colitis Foundation. http://www.crohnscolitisfoundation.org/resources/biologic-therapies.html

 Biologic Treatment in IBD-2
2. INTEGRIN RECEPTOR ANTAGONISTS:

 Natalizumab (Tysabri®)

 Vedolizumab (Entyvio™)

Crohn’s & Colitis Foundation. http://www.crohnscolitisfoundation.org/resources/biologic-therapies.html

Adalimumab Treatment in IBD
 Indication of Adalimumab
Crohn Disease
 Indicated for reduction of signs and symptoms and induction and
maintenance of clinical remission in adults with moderately to severely
active Crohn disease who have had inadequate response to conventional
therapy; may be used in patients who have lost response to or are
intolerant of infliximab
 Induction: 160 mg SC either as 4 injections of 40 mg on day 1 or as 2
injections of 40 mg daily on 2 consecutive days, then 80 mg SC 2 weeks
later (day 15)
 Maintenance (beginning Week 4 [Day 29]): 40 mg SC q2wk
 Dosing considerations
 Some patients may require weekly 40-mg dose for maintenance
(Inflamm Bowel Dis 2011 Jan 17(1):141-51; Am J Gastroenterology
2009;104:465-83)

Ulcerative Colitis
 Indicated for treatment of ulcerative colitis unresponsive to
immunosuppressants (eg, corticosteroids, azathioprine, 6-
mercaptopurine [6-MP])
 Induction: 160 mg SC either as 4 injections of 40 mg on day 1 or as 2
injections of 40 mg daily on 2 consecutive days, then 80 mg SC 2 weeks
later (day 15)
 Maintenance (beginning Week 4 [Day 29]): 40 mg SC q2wk
 Continue maintenance dose only if evidence of clinical remission is
apparent by 8 weeks of therapy
Contra indication and Warnings /precautions of
Adalimumab
 CONTRAINDICATIONS: None
 WARNINGS / PRECAUTIONS:
• Serious infections: Do not start HUMIRA during an active infection. If an infection
develops, monitor carefully, and stop HUMIRA if infection becomes serious
• Invasive fungal infections: For patients who develop a systemic illness on HUMIRA,
consider empiric antifungal therapy for those who reside or travel to regions
where mycoses are endemic
• Malignancies: Incidence of malignancies was greater in HUMIRAtreated patients than
in controls
• Anaphylaxis or serious allergic reactions may occur
• Hepatitis B virus reactivation: Monitor HBV carriers during and several months after
therapy. If reactivation occurs, stop HUMIRA and begin anti-viral therapy
• Demyelinating disease: Exacerbation or new onset, may occur
• Cytopenias, pancytopenia: Advise patients to seek immediate medical attention if
symptoms develop, and consider stopping HUMIRA
• Heart failure: Worsening or new onset, may occur
• Lupus-like syndrome: Stop HUMIRA if syndrome develops
Adverse reactions and Drug interactions

 ADVERSE REACTIONS:
Most common adverse reactions (incidence >10%):
infections (e.g. upper respiratory, sinusitis),
injection site reactions, headache and rash.
 DRUG INTERACTIONS:
- Abatacept: Increased risk of serious infection
- Anakinra: Increased risk of serious infection
- Live vaccines: Avoid use with HUMIRA
RISKS & SPECIAL CONSIDERATIONS

 Side Effects & Intolerance. Redness, itching, bruising, pain, or swelling at the injection
site. Other side effects may include: headache, fever, chills, hives and other
rashes. Occasional severe allergic reactions may occur.
 Infections. may become reactivated including tuberculosis (TB) and chronic Hepatitis
B virus. Further, to help prevent infections, influenza vaccinations.
 Cancer Risk. Increase in the incidence of lymphoma, an uncommon cancer. The risk is
highest in patients using anti-TNF medications in combination with another
immunosuppressant, such as azathioprine (Imuran®).
 Liver Problems. Biologic therapies have been rarely associated with changes in liver
function, jaundice.
 Arthritis. New joint pain.
 Lupus-like Reaction. Rarely can cause a lupus-like reaction (LLR) which may present
with symptoms such as a rash, joint pain, muscle ache, and/or fever. LLR may require a
course of corticosteroids.
 Other Considerations. heart failure, hepatitis or multiple sclerosis before taking these
treatments.
 REACT: overview
 Aim: To assess efficacy of an early combined immunosuppression (ECI)
treatment algorithm for CD vs conventional management at community GI
practices in Canada and Belgium
 Primary outcome measure: symptomatic remission (HBI<4 no
corticosteroids) at practice level at 1 year
 Additional outcome measures included major adverse outcomes (surgery
or hospitalization for CD, or serious disease-related complication) and
serious drug-related adverse events
 Study design:
 Open-label cluster RCT
 41 gastroenterology practices randomised 1:1 to implement ECI algorithm
or to continue with their usual care for CD management
 with minimisation for country and practice size
 Up to 60 consecutive adult patients were assessed within each practice
Khanna R, et al. Lancet 2015;386;1825-34.
REACT: ECI algorithm
 REACT: baseline characteristics
Early combined Conventional
immunosuppression management
Mean (SD) Mean (SD)
Practice characteristics
No. of patients per site 51.6 (11.8) 49.9 (12.9)
Country, % based in Canada, % 86 89
Patient characteristics
Age, years 44.1 (3.8) 44.1 (2.7)
Male, % 42.2 (8.2) 43.1 (6.9)
Disease duration, months 149.0 (40.0) 158.1 (29.2)
Current smoker, % 25.0 (8.2) 18.0 (6.2)
Medications, %
Corticosteroids 19.2 (8.6) 17.5 (13.6)
Antimetabolites (not with anti-TNF) 32.8 (16.0) 28.3 (14.7)
TNF-antagonists (not with antimetabolite) 19.7 (14.8) 21.0 (15.6)
Combined antimetabolite/TNF-antagonists 12.1 (7.6) 13.1 (13.8)
Previous surgery for Crohn’s, % 45.4 (13.3) 49.3 (12.9)
Disease location, %
Colon 24.0 (9.2) 20.1 (5.2)
Small bowel 32.3 (10.7) 36.7 (15.6)
Both 43.7 (13.4) 43.2 (14.3)
Fistula, active, % 6.6 (4.0) 8.2 (4.4)
Harvey-Bradshaw Index (HBI) score 4.0 (1.0) 4.1 (1.15)
SF-36® mental component summary score 44.6 (3.3) 45.9 (1.8)
SF-36® physical component summary score 46.0 (2.1) 45.5 (2.2)
EQ-5D™ score 0.81 (0.04) 0.81 (0.03)

Khanna R, et al. Lancet 2015;386;1825-34.

 REACT: time to initiation of treatments
40 Corticosteroids 40 Antimetabolites
CM 21.2% ECI 21.0% CM 15.6% ECI 26.7%

Patients (%)
Patients (%)

30 30
HR (95% CI) = 0.97 (0.77, 1.21) HR (95% CI) = 1.84 (1.39, 2.44)
20 20

10 10
p=0.777 p<0.001
0 0
0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24
Time (months) Time (months)
Combination therapy with
40 TNF antagonists 40 antimetabolites and TNF antagonists
CM 17.4% ECI 27.4% CM 9.6% ECI 19.7%

Patients (%)
Patients (%)

30 30
HR (95% CI) = 1.72 (1.34, 2.22) HR (95% CI) = 2.29 (1.73, 3.04)
20 20

10 10
p<0.001 p<0.001
0 0
0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24
Time (months) Time (months)
Conventional management (CI) Early combined immunosuppression (ECI)
Khanna R, et al. Lancet 2015;386;1825-34.
 REACT: major adverse outcomes at 24 months
Surgery 40 Serious complication
40

Complications (%)
HR (95% CI) = 0.73 (0.61, 0.87) 30.9%
HR (95% CI) = 0.69 (0.50, 0.97) 30
Surgeries (%)

30
20 24.3%
20
9.5% 10
10
6.6% p<0.001
p=0.0314 0
0 0 3 6 9 12 15 18 21 24
0 3 6 9 12 15 18 21 24 Time (months)
Time (months)
Hospitalisation Hospitalisation, surgery or serious disease-
40 40 related complication
34.7%
Hospitalized (%)

Hospitalisation, surgery
HR (95% CI) = 0.84 (0.65,1.08) HR (95% CI) = 0.73 (0.62, 0.86)
30 30

or complications (%)
27.4%
20 15.6% 20

10 12.9% 10
p=0.16 p<0.001
0 0
0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24
Time (months) Time (months)
Conventional management (CI) Early combined immunosuppression (ECI)
Khanna R, et al. Lancet 2015;386;1825-34.
 REACT: serious disease and drug-related complications and mortality
Early Combined
Conventional
Immunosuppress
Management P Value
ion
N (%)
N (%)
Worsening Crohn’s disease

Abscess 32 (3.0) 33 (3.7) 0.36

Fistula 29 (2.7) 39 (4.3) 0.03
Stricture/bowel obstruction 67 (6.2) 82 (9.1) 0.01
Serious worsening disease 98 (9.0) 96 (10.7) 0.65
Serious extra-intestinal 47 (4.3) 50 (5.6) 0.37
manifestations
Serious drug-related complications 10 (0.9) 10 (1.1) 0.84
Deaths
Cardiovascular 2 (0.2) 5 (0.5)
Thromboembolic 1 (0.1) 1 (0.1)
Cancer 3 (0.3) 2 (0.2)
Infection 1 (0.1) 1 (0.1)
Other 0 (0.0) 1 (0.1)
Total R, et al. Lancet 2015;386;1825-34.
KhannaMortality 7 (0.7) 10 (1.1)
a. P Value from Cox analysis 0.33a
 CRP: prediction of hospitalisation in ‘silent’ Crohn’s disease

 178 patients with clinical remission defined by sIBDQ

scores in a prospective registry

Hospitalisations in asymptomatic patients

1.0 7% 6-fold
Hospitalization-free (%)

Objective
evidence of were hospitalised higher risk of
inflammation 0.75 hospitalisation
manifested by
CRP elevation
37% with elevated
suggests a 6-
fold higher were hospitalised CRP
0.50
risk for
hospitalisatio Normal CRP
n during the
ensuing two
Elevated CRP
years
0.25

Chi Square = 32.23; p<0.001

0.0
0 200 400 600 800
sIBDQ, short inflammatory bowel disease questionnaire Days after clinic visit
Vargas EJ, et al. Gastroenterology 2013;144(Suppl 1):S-102
J-F Colombel,1 R Panaccione,2 P Bossuyt,3 M Lukas,4 F Baert,5 T Vanasek,6 A Danalioglu,7 G Novacek,8 A Armuzzi,9
X Hebuterne,10 S Travis,11 S Danese,12 W Reinisch,8 WJ Sandborn,13 P Rutgeerts,14 D Hommes,15 S Schreiber,16 E
Neimark,17 B Huang,17 Q Zhou,17 J Petersson,17 K Wallace,17 AM Robinson,17 RB Thakkar,17 G D’Haens18
1Icahn School of Medicine at Mount Sinai, New York, USA, 2University of Calgary, Calgary, Canada, 3Imelda General Hospital,
Bonheiden, Belgium, 4Charles University, Prague, Czech Republic, 5AZ Delta Roeselare-Menen, Belgium, 6Hepato-
Gastroenterologie HK, s.r.o., Hradec Králové, Czech Republic, 7Bezmialem Vakif University, Istanbul, Turkey, 8Medical University
of Vienna, Vienna, Austria, 9Presidio Columbus, Fondazione Policlinico Gemelli Università Cattolica, Rome, Italy, 10Service de
Gastroentérologie et Nutrition Clinique, Nice, France; Université de Nice-Sophia-Antipolis, Nice, France, 11Oxford University
Hospitals, Oxford, UK, 12Istituto Clinico Humanitas, Milan, Italy, 13University of California San Diego, La Jolla, CA, USA,
14University of Leuven, Leuven, Belgium, 15University of California, Los Angeles, CA, USA, 16University Hospital Schleswig-

Holstein, Kiel, Germany, 17AbbVie Inc., North Chicago, IL, USA, 18Academic Medical Center, Amsterdam, Netherlands

Digestive Disease Week 2017

Chicago, IL, May 6-9
 Background

 In patients with Crohn’s disease (CD), it is unknown if treatment

escalation decisions based on close monitoring of biomarkers of
inflammation (serum C-reactive protein and fecal calprotectin)
lead to improved outcomes in patients with CD
 This approach may be defined as “treat to target”
 CALM is a prospective, open-label, multicenter, active-controlled,
Phase 3 study designed to evaluate 2 treatment algorithms in
patients with CD:
 Clinical management (CM)
 Treat to target (T2T)
 Therapy was escalated according to pre-specified failure criteria
Methods: Study Design
 Methods: Failure Criteria

Lab visits Clinical Management Treat to Target

Week -1 CDAI decrease < 70 points CDAI ≥ 150

(prior to compared to BL or CDAI > 200 CRP ≥ 5mg/L
randomization) FC ≥ 250 g/g
Prednisone use at week 0

Weeks 11, 23, CDAI decrease < 100 points CDAI ≥ 150
and 35 compared to BL or CDAI ≥ 200 CRP ≥ 5mg/L
FC ≥ 250 g/g
Prednisone use a week prior to visit Prednisone use a week prior to visit
 Methods: Key Inclusion/Exclusion Criteria

 Inclusion criteria:

 Adults (18-75 years old) with ileal, colonic (including rectal) or ileocolonic CD

 Moderate to severe CD with or without systemic corticosteroids* (CS):

 Baseline CDAI ≥ 220 and ≤ 450 (no CS at baseline)
 Baseline CDAI ≥ 200 and ≤ 450 (≤ 20 mg CS at baseline)
 Baseline CDAI > 150 and ≤ 450 (> 20 mg CS for ≥ 7 days before baseline)

 Active endoscopic CD (total CD Endoscopic Index of Severity [CDEIS] > 6 and sum of
CDEIS subscores > 6 in ≥ 1 segment with ulcers)

 CRP ≥ 5 mg/L and/or FC ≥ 250 μg/g at screening

 Exclusion criteria:
 Previous or current biologic or immunomodulator use Prednisone or equivalent.

 More than 2 previous courses of CS or currently receiving CS for > 3 months before
screening
 Methods: Endpoints
 Primary Endpoint:
 Proportion of patients with mucosal healing (CDEIS < 4) and no deep ulcerations 48 weeks after
randomization
 Select Secondary Endpoints (all assessed at 48 weeks after randomization):
 Deep remission (CDAI < 150, CDEIS < 4, and no deep ulcers, absence of draining fistula,
discontinuation of steroids ≥ 8 weeks)
 Biologic remission (FC < 250 g/g, CRP < 5mg/L, and CDEIS < 4)
 Mucosal healing (CDEIS < 4)
 Mucosal healing in all segments (CDEIS < 4 and CDEIS < 4 in each segment)
 Complete endoscopic remission (CDEIS = 0)
 Endoscopic Response (CDEIS decrease > 5)
 Steroid-free remission (CDAI <150 and discontinuation of steroid use ≥ 8 weeks) over time

 Statistical Analysis:
 Missing values after randomization were imputed using non-responder imputation (NRI); patients
who moved to a rescue group were considered a failure for endpoints
 Endpoints were analyzed using Cochran-Mantel-Haenszel test stratified by smoking status (yes/no)
and weight (<70/70 kg) at screening
 Results: Patient Disposition

Study
Randomization
Completion
N = 460
Patients
n = 122 n = 93 (76.2%)
Screened
Clinical Clinical Discontinuation: n = 29
Management Management (23.8%)
• AE: 12 (9.8)
N = 244 • Withdrew Consent: 3
Patients (2.5)
• Lost of Follow-up: 1 (0.8)
Randomize • Lack of Efficacy: 12 (9.8)
• Other: 1 (0.8)
d
n = 90
n = 122
(73.8%)
Treat to Target Discontinuation: n = 32
Treat to Target (26.2%)
• AE: 16 (13.1)
• Withdrew Consent: 4
(3.3)
• Lost of Follow-up: 2 (1.6)
• Lack of Efficacy: 5 (4.1)
• Other: 5 (4.1)

AE, adverse event

 Results: Baseline Characteristics
Clinical Management Treat to Target
n=122 n=122
Female (%) 56.6 59.0
White (%) 92.6 92.6
Age, year (mean) 31.1 32.1
Weight, kg (mean) 66.3 66.3
Disease duration, year (mean) 0.86 1.04
CDAI (mean) 267.7 273.3
CDEIS (mean) 14.26 13.38
Disease Location (%)
Ileal 11.5 17.2
Colonic 30.3 27.9
Ileal-colonic 53.3 52.5
FC (%)
< 250 g/g 13.9 20.0
≥ 250 g/g 86.1 80.0
CRP (%) 16.1 13.6
< 5 mg/L 15.6 22.1
 5 mg/L 84.4 77.9
Smoker (%) 27.0 25.4
IBDQ (mean) 130.9 127.4
Results: Primary Endpoint at 48 Weeks After
Randomization
CDEIS < 4 AND NO DEEP ULCERATIONS
Results: Secondary Endpoints at 48 Weeks After
Randomization
 Results: Steroid-free Remission

CDAI < 150 AND DISCONTINUATION OF STEROID USE FOR AT LEAST 8 WEEKS
 Results: Treatment Option Over Time

PATIENTS WHO COMPLETED THE STUDY AND DID NOT MOVE TO THE RESCUE GROUP
 Serious Infections
Clinical Management Treat to Target
n = 122 n = 122
n (%) n (%)
Abdominal abscess 0 2 (1.6)
Abscess 1 (0.8) 1 (0.8)
Anal abscess 4 (3.3) 0
C. difficile infection 0 2 (1.6)
Erysipelas 1 (0.8) 0
Salmonella gastroenteritis 1 (0.8) 0
Viral gastroenteritis 1 (0.8) 0
Nasal vestibulitis 1 (0.8) 0
Pneumonia 0 1 (0.8)
Pulmonary TB 0 1 (0.8)
Rotavirus infection 1 (0.8) 0
Sepsis 1 (0.8) 0
Urinary tract infection 1 (0.8) 0
Viremia 1 (0.8) 0
 Reasons for Escalation in T2T Arm

Proportion of patients violating each success

criterion*

Escalated CRP, n CDAI, n Prednisone

Lab visit FC, n (%)
Patients, n (%) (%) Use, n (%)

Week 11 64 62 (96.9) 26 (40.6) 16 (25.0) 9 (14.1)

Week 23 56 53 (94.6) 30 (53.6) 15 (26.8) 4 (7.1)

Week 35 33 31 (93.9) 16 (48.5) 5 (15.2) 3 (9.1)

*Patients are counted under each reason.

 Reasons for Escalation in CM Arm

Proportion of patients violating each

success criterion*

Escalated Prednisone Use, n

Lab visit CDAI, n (%)
Patients, n (%)

Week 11 24 12 (50.0) 16 (66.7)

Week 23 9 4 (44.4) 6 (66.7)

Week 35 7 7 (100.0) 0 (0)

*Patients are counted under each reason.

 Conclusions CALM

• This is the first study to demonstrate a T2T approach, using biomarkers of

inflammation, serum C-reactive protein and fecal calprotectin, leads to
superior endoscopic and clinical outcomes in CD compared with symptom-
driven care

• Managing patients with CD by clinical symptoms alone may not adequately

control underlying inflammation

• The T2T approach did not lead to increased safety signals

 Prospective RCT on fecal calpro guided 5ASA dose escalation in UC
Subject disposition
Intervention: FC>300ug/g, ASA increased

Randomized
n=109

Intervention group Control group

n=65 n=44
Excluded
n= 14 Excluded
Protocol violation n=4
(n=5) Protocol violation (n=4)
<9 samples (n=9) Intervention group Control group
n=51 n=40

FC < 300 µg/g FC > 300 µg/g FC > 300 µg/g FC < 300 µg/g
n=23 n=28a n=28 n=12

No relapse Relapse Relapse No relapse

n=20 n=8 n=16 n=12

Lasson et al. UEG Journal 2015,vol3(1) 72-79

Prospective RCT on FC guided 5ASA dose escalation in UC
 Prospective RCT on fecal calpro guided 5ASA dose escalation in UC

Active Intervention vs control: subjects with active DE stayed in remission

Proportion of patients without a relapse
longer 1.0

─── Active Intervention

0.8 – – – Controls

0.6

0.4

0.2 p = 0.13

0.0
0 5 10 15 20

Time
(months)
Lasson et al. UEG Journal 2015,vol3(1) 72-79
 Conclusions T2T

• CD is a progressive inflammatory disease associated

leading to chronic inflammation and bowel damage
• There is a window of opportunity to treat early
• Tight monitoring for inflammation and control to achieve
biologic /mucosal healing improved outcomess
 Challenges in T2T

• We need to make T2T real for Drs and patients

• All modalities of monitoring are important, including
symptoms, CRP, FC, Endoscopy, MRI
• BUT FC is most sensitive and easy
• In JAPAC most drs treat to symptoms, and even then not
to target
• We need to educate