Dr Vaishali Bhardwaj M.D. D.M - PowerPoint Presentation

Slide1

Dr

Vaishali

Bhardwaj

M.D. D.M

DM Gastroenterology G B pant Hospital Delhi.

2013-2014 Assistant Professor GB Pant Hospital

.

2014-Present Assistant Professor &Head Department Of Gastroenterology PGIMER RML Hospital

She

has various publications

and has presented

papers in both

National

and

International conferences

.

She has been awarded Young Investigator Award twice at

AOCC.

Area of

intrest

:

Heaptology

&IBD.

Slide2

IBD “STATE OF ART”

Dr

Vaishali

Bhardwaj

M.D.D.M(Gastroenterology)

Head Department Of Gastroenterology

PGIMER RML Hospital New Delhi

Slide3

Introduction

Chronic Inflammatory diseases of Bowel

Slide4

We’ve come a long way

…

Crohn’s and UC

are described

IBD is recognized

Prednisone

Mesalamine

Remicade (Infliximab)

Azathioprine

Methotrexate

Humira (Adalimumab)

Cimzia

(Certolizumab pegol)

Tysabri

(Natalizumab)

1700-1900

1930

1940

1950

1960

1970

1980

1990

2000

2010

2020

Slide5

Idiopathic, chronic, relapsing, inflammatory conditions that are immunologically mediated

Heterogeneous diseases characterized by various genetic abnormalities that lead to overly aggressive T-cell responses to a subset of

commensal

enteric bacteria.

Environmental factors precipitate the onset or reactivation of disease.

Slide6

Introduction

Ulcerative Colitis

Affects rectum & extends proximally to variable extent of colon

Affects only mucosa in continuous pattern

Characterised by-

Rectal bleeding

,

Frequent stools,

Mucus discharge, Tenesmus

& Lower abdominal pain.

Crohns Disease

Chronic inflammation potentially involving any location of GIT .

Transmural

& often discontinuous. Characterised by-

FatigueDiarrhea

with or without gross blood, Pain, weight loss, fever.

Slide7

The famous SPM Triad

Slide8

Triad for IBD Pathogenesis

Slide9

Genetics in IBD

Family History Significantly positive

Particular ethnic groups with highly conserved genetic material more at risk

GWAS identified- 118 genetic risk loci

28 common for UC and CD

Khor

B.

Gardet

A, et al. Nature 2011

Slide10

Role of Genetics in IBD

Crohn’s

Disease

71 risk loci

50-54% concordance in monozygotic twins

4% in

dizygotic

twins

First degree relative-10x

Ulcerative Colitis

47 risk loci

10-15% concordance in monozygotic twins

No concordance in

dizygotic

First degree relative-2x

Khor B. Gardet A, et al. Nature 2011

Slide11

Genes

Name

Region

CD

UC

Function

Innate immunity related

NOD2

16q12

Yes No

Senses bacterial peptidoglycan to activate cell signallingATG16L1

2q37Yes No

Component of autophagy complex

IRGM5q33Yes

+/-Role in autophagy, required in IFN y related clearance of intracellular pathogens

IL 23 – Th17 related IL23R1p31

Yes Yes

Unique component of heterodimeric IL23 receptorIL12B (p40)

5q33Yes Yes

Component of IL23, common to IL12STAT317q21

Yes Yes Major STAT downstream of various cytokines including IL-6,10,17,21,22,23

Others

PTGER45p13Yes

NoReceptor for inflammatory mediator PGE2

SLC22A45q31Yes

+/-Plasma membrane polyspecific organic anion transporter

MHC6p21

YesYes Distinct MHC class II

asso. between UC and CDIL10

1q32+/-Yes

Immunosuppressive cytokine, central role in regulating intestinal inflammationINFG

12q15No Yes

Critical cytokine in innate and adaptive immunity against intracellular pathogens

Slide12

NOD2

NOD2 :

2 CARD domains, a central NBD and a LRR domain

LRR domain recognizes bacterial MDP :

regulates

NF

kb

activation and production of pro-inflammatory cytokines

3 variants in LRR domain : significant association with CD but no association with UC

Slide13

Role of NOD2 IBD Pathogenesis

Exact mechanism unclear –

proposed loss or gain of function

Carriers of 1 NOD2 high risk variant : 2-4 fold increase risk of CD

2 NOD2

high risk variants

: 20-40 fold increased risk

Association with

Ileal

disease

Younger onset

Stricturing

phenotype

Slide14

Autophagy

Genes

Results in

lysosomal

degradation of organelles, unfolded proteins, or foreign extracellular material

Key process required for maintaining cellular homeostasis after infection, mitochondrial damage, or ER stress

Defects in

autophagy

shown to result in pathological inflammation

Autophagy

- important role in human inflammatory disorders

by direct elimination of intracellular bacteria

activation of PRR

signaling

involved in gut homeostasis and CD pathogenesis

Slide15

Autophagy

Slide16

Microbiome

Illusion for researchers

Gut contains –

10

14

microorganisms

500 species

Lot of them still unexplored

Crucial role in normal homeostasis as well as disease

Slide17

10

11

 cells/g

- Ascending

colon

;

10

7–8

 

Distal

Ileum & 10

2–3 

Proximal Ileum & Jejunum.

Slide18

Composition

Bacteriodes

Firmicutes

90%

Proteobacteria

Actinobacteria

Fusobacteria

Slide19

Microbiome

IBD :

dysregulated

immune response to

microbiota

Theory

:

luminal bacteria provide stimulus for an inflammatory response

Evidence

CD diversion of

feaces

induces remission and infusion of

feaces reactivates the disease

D’Haens GR et al. Gastroenterology 1998

UC with active disease, antibiotics reduced mucosal inflammation

Casellas F, Inflamm

Bowel Dis 1998

Slide20

Differences in Normal and Diseased Bowel

Healthy subjects

IBD subjects

High biodiversity

Low biodiversity

Stable

microbiota

Dysbiosis

Increased gut

commensals

Increased gut pathogensHigher firmicutesLower firmicutes

Slide21

Dysbiosis

Slide22

IBD,s are

chronic,Life

-long

We cannot just look at the short term induction therapy.

Slide23

Goals of Therapy in the Inflammatory Bowel Diseases

Symptom Improvement

Improve the Future

Reduce Hospitalization

Reduce need for surgery

Reduce social &occupational burden

Mucosal Healing

Targeted Therapy Against Inflammation in IBD

Improve Safety and Tolerability of Medications

Slide24

Rogler

et al. Role of biological therapy for inflammatory bowel disease in developing countries. Gut

2012

Slide25

Choice of Medical Therapy

Slide26

Current “Therapeutics Pyramid”

Crohn,s Disease

Ulcerative colitis

Slide27

Step Up Management Approach

Slide28

Strategies & Targets of IBD Therapy

Classic Anti

inflammtory

&

Immunosupressants

Immunomodulators & Inhibitors of CascadesElimination of Antigen processing & presentation.

Inhibition Of CD4 cell activation.

Induction Of apoptosis

Generation of regulatory T cells&

effector cells.

Inhibition of recruitment ,migration & Adhesion.Inhibition of GALT activation.Repair &restitution of barrier function.

Slide29

Slide30

When to Introduce Biologics??

The “Tipping Point “ may be Corticosteroids?

Slide31

Mucosa

Submucosa

Blood Vessels

IBD Immunology 101

Slide32

IBD Immunology 101

Mucosa

Submucosa

Blood Vessels

Slide33

ANTI-TNF-

α

ANTIBODIES

Best

studied pro-inflammatory

cytokine

Produced

by mononuclear

cells

Synthesis

is induced through activation of cellular receptors, e.g., TLR4Activation of TLR4 signaling induces activation of

NF-κB and

MAPKDifferentiation of macrophages as well as inducing expression of pro-inflammatory cytokines, e.g., TNF-

α, interleukin (IL)-6 and IL-12

Slide34

Chimeric

monoclonal antibody (75% human

IgG

1

isotype

)

Infliximab

IgG

1

Construct of Anti-TNF-

α

Biologic Agents

Mouse

Human

PEG, polyethylene glycol.

Humanized

Fab

’

fragment (95% human

IgG

1

isotype

)

Certolizumab

Pegol

PEG

PEG

VH

VL

C

H

1

No Fc

Human recombinant antibody (100% human

IgG

1

isotype

)

Adalimumab

IgG

1

Slide35

Infliximab

Chimeric

monoclonal antibody directed against tumor necrosis factor

a.

Active Ulcerative colitis Trials 1 & 2 (ACT 1, ACT 2)

In each study, 364 patients with moderate-to-severe UC despite treatment with concurrent medications received placebo or

infliximab

(5 mg or 10 mg per kilogram of body weight)

i.v

at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2) Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2

Rutgeerts

P et al. Infliximab

for Induction and Maintenance Therapy for Ulcerative Colitis. N Engl

J Med .

Slide36

Patients with moderate-to-severe active ulcerative colitis treated with

infliximab

at weeks 0, 2, and 6 and every eight weeks thereafter were more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo

Slide37

A

dalimumab

Adalimumab

(ADA) is a fully humanized, ,

IG G1

monoclonal

antibody,binds

high affinity &

specificity human TNF.

ADA is administered subcutaneously

Effective in inducing & maintaining remission moderate-to-severe Crohn’s disease& moderate-to-severe ulcerative colitis.

Can be used in pt refractory to IFX

No antibody formation

Slide38

C

ertolizumab

P

egol

Pegylated

conjugated Fab against

TNF Does not contain an

Fc portion

Golimumab

Human monoclonal antibody that targets TNF with a higher affinity than adalimumab

.

Slide39

Anti-TNF a Risks

Immunogenecities

(all

biologicals

)

IFX specific

Infusion reactions

Class effects

Drug induced lupus

Injection site reactions (

Ada ,C

pegol)

NHL (IFX+AZA)Serious infection -3%

Oppourtunistic infection Demyelination

Slide40

Slide41

Anti-adhesion therapies

Chemokine Antagonists

Anti-Integrin blockade

Interleukin and Cytokine Antagonists

IL-12/23 pathways

Blockade

of

Intracellular

Inflammation

Control

JAK-STAT Kinase Pathways

Targets for Therapy

Slide42

Chemokine CCR-9

Chemokines

are selectively released to activate elements of inflammatory response

Chemokine CCR9 has many function in intestinal inflammation

Attracts T and B-cells to the site of inflammation

CCR9 Binds to intestinal endothelium to help pull T-cells into the intestine

Activates endothelial

Integrins

, permitting other inflammatory cells to enter the gut.

Blockade of Cell Adhesion and Homing Cytokines

Slide43

CCL-25 Ligand

CCR9 Receptor

Blockade of Cell Adhesion and Homing Cytokines

Slide44

Compound

CCX282-B

Anti-chemokine CCR9 medication

In Phase III Testing in Large Crohn’s Population

Taken in pill form twice a day

For Study in Crohn’s Disease

Blockade of Cell Adhesion and Homing Cytokines

Slide45

Block WBC Binding to

Integrins

Anti-Integrin Coating

Blockade of Adhesion Molecules:

Vedolizumab

Slide46

Vedolizumab

rhuMAb

Beta7

PF-00547659 (MAdCAM-1 Antagonist)

Leading Anti-

Integrins

In Development

Blockade of Adhesion Molecules:

Vedolizumab

Slide47

Blockade of Adhesion Molecules:

Vedolizumab

Vedolizumab

Vedolizumab

–

antibody

against

one

type

of

integrin

Prevents binding of White Blood Cells (WBC)

in the intestineSpecific to the Intestine

Being Studied in both Ulcerative Colitis and Crohn’s

Given via IV infusion

(in the

vein) once

a month

Slide48

rhuMAb

Beta7

Cheroutre

and

Madakamutil

, Nat Rev

Immunol

2004

Blockade of Adhesion Molecules:

rhuMAb

Beta7

Slide49

IL-12/23

Ligand

IL-12

Receptor

Blockade of Cell-Activating Signals

T-cell

T-cells

ACTIVATED

Dendritic cell

IL-17

Interferon

Slide50

U

stekinumab

U

stekinumab

–

antibody

blocking

IL-12/23

Interleukins

Blocks IL-12/23 mediated Activation of T-

cells, Agents normalize IL-12/23 mediated signaling, cellular activation, and and cytokine

production, thereby reducing inflammation

Currently

approved for treatment of

Psoriasis (

tradename: Stelera

®)IV induction then Subcutaneous every 4 weeks.

Blockade of Cell-Activating Signals:

ustekinumab

Slide51

IL-12/23

Ligand

IL-12

Receptor

Blockade of Cellular Inflammation Controls

T-cell

JAK

Interleukins

Interleukins Attach to Receptors

JAK Binds to Activated Receptors

JAK then Signals DNA

Cell produces

mediators

of

inflammation

Slide52

Modulates

signaling for

several types of interleukins,

Janus Kinases (JAK-1,2,3) mediate cellular response to many cytokines

.

JAK proteins are a MAJOR mechanism of directing the changes in cellular function to cause inflammation

.

Oral medication, Daily

For Crohn’s Disease and Ulcerative Colitis

Tofacitinib

(CP-690550)

Dampening Cytokine Response: JAK-Inhibitors

Slide53

Slide54

Exciting Agents Early in Development

Slide55

Fecal

Microbiota

Transplantation

FMT is introduction of fecal suspension derived from a healthy donor into GI Tract of diseased individual.

FMT is no longer considered an alternative or last resort rather is gaining mainstream acceptance as valuable therapy with biological plausibility.

FMT Transplant Material (TM)

medically classified a human tissue is derived from healthy donor with no risk factors for transmissible disease/ any issue that may alter the cellular

composition,esp

antibiotic use.

Slide56

Donor stool is delivered within few hours of passage undergoes -

Dilution with normal saline

Homogenization with a blender to achieve natural slurry

Filtration to remove particulate material.

Some institution use

cryoprotection

by freezing at -80 c till use.

Slide57

Route of administration varies

Naso

-Duodenal

Colonoscopy

Enema

Enteric coated capsule

Slide58

Use in IBD is still in infancy .

Mixed results are shown in various systemic reviews and RCT,s showing remission rates of 35%-40% in moderately active disease.

Factors that could potentially determine final outcome -

Host genotype

Disease duration

Antibiotic use associated with IBD onset

Certain type of IBD associated

Dysbiosis

Donor characteristics

Slide59

Currently FMT in IBD is restricted to investigational settings and several large clinical trials are underway.

Slide60

Thank you