1. Dr Vaishali Bhardwaj M.D. D.M
DM Gastroenterology G B pant Hospital Delhi.
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.

2. IBD “STATE OF ART” Dr Vaishali Bhardwaj M.D.D.M(Gastroenterology)
Head Department Of Gastroenterology
PGIMER RML Hospital New Delhi

3. Introduction Chronic Inflammatory diseases of Bowel IBD
Crohn’s Disease
Ulcerative Colitis
Microscopic Colitis
Chronic Inflammatory diseases of Bowel
Broad group of Disease

4. Remicade (Infliximab)
We’ve come a long way…
1930
1940
1950
1960
1970
1980
1990
2000
2010
2020
Azathioprine
Methotrexate
IBD is recognized
Prednisone
Crohn’s and UC
are described
Mesalamine
Remicade (Infliximab)
Humira (Adalimumab)
Giovanni Battista Morgagni in 1761 provided description of intestinal inflammation.
Burrill Bernard Crohn Dr. Leon Ginzburg and Dr. Gordon Oppenheimer landmark paper describing Crohns.
1859 smuel wilkis ulcerative colitis.
Nana savrtz 5 asa.,azad khan first time used in uc ,brookes introduced AZA.van deventer introduced infx to IBD.
Cimzia
(Certolizumab pegol)
Tysabri
(Natalizumab)

5. 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.

6. Introduction Ulcerative Colitis Crohns Disease
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.
Chronic inflammation potentially involving any location of GIT .
Transmural & often discontinuous.
Characterised by-
Fatigue
Diarrhea with or without gross blood,
Pain, weight loss, fever.

7. The famous SPM Triad Host Enviromment Agent
All of us remember from our MBBs days the complex traid in pathogenesis of disease.

8. Triad for IBD Pathogenesis
Genetics
Immune
Dysfunction
Microbiome &
Environmental

9. Khor B. Gardet A, et al. Nature 2011
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

10. Khor B. Gardet A, et al. Nature 2011
Role of Genetics in IBD
Crohn’s Disease
Ulcerative Colitis
71 risk loci
50-54% concordance in monozygotic twins
4% in dizygotic twins
First degree relative-10x
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

11. Innate immunity related NOD2
Genes
Name
Region CD UC
Function
Innate immunity related
NOD2
16q12
Yes No
Senses bacterial peptidoglycan to activate cell signalling
ATG16L1
2q37
Component of autophagy complex
IRGM
5q33
+/-
Role in autophagy, required in IFN y related clearance of intracellular pathogens
IL 23 – Th17 related
IL23R
1p31
Unique component of heterodimeric IL23 receptor
IL12B (p40)
Component of IL23, common to IL12
STAT3
17q21
Major STAT downstream of various cytokines including IL-6,10,17,21,22,23
Others
PTGER4
5p13
Receptor for inflammatory mediator PGE2
SLC22A4
5q31
Plasma membrane polyspecific organic anion transporter
MHC
6p21
Distinct MHC class II asso. between UC and CD
IL10
1q32
Immunosuppressive cytokine, central role in regulating intestinal inflammation
INFG
12q15
Critical cytokine in innate and adaptive immunity against intracellular pathogens

12. NOD2 NOD2 : 2 CARD domains, a central NBD and a LRR domain
LRR domain recognizes bacterial MDP : regulates NFkb activation and production of pro-inflammatory cytokines
3 variants in LRR domain : significant association with CD but no association with UC
Nucleotide binding oligomerization domain 2./CARD 15 is caspase recuritment domain .
One frameshift mutation leading to early truncation of protein,2 missense mutation

13. 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 : fold increased risk
Association with
Ileal disease
Younger onset
Stricturing phenotype
Gene product of nod2 is cytosolic protein that function as intracellular sensor of bacteria..
This protein binds to MDP component of bacterial peptidoglycan.
Mutation in nod2 –momonuclear cells decreased activation of nfkbeta

14. 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
The term autophagy, or “self-eating,” results in the lysosomal degradation of organelles, unfolded proteins, or foreign extracellular material (Figure 2). It is a key process required for maintaining cellular homeostasis after infection, mitochondrial damage, or ER stress. Defects in autophagy have been shown to result in pathological inflammation and GWAS have linked two key genes in autophagy, ATG16L1 and IRGM, to CD[13,76]. An ATG16L1 hypomorphic mouse line that expresses about 1% of the normal level of ATG16L1 was shown to have Paneth cell granule abnormalities that are similar to those found in ileal resections in patients with CD that also carry the ATG16L1 gene variant[77]. While these hypomorphic ATG16L1 mice do not develop spontaneous colitis, they were found to have an increased susceptibility to DSS colitis[42]. However, when rederived virus free, these mice lost the Paneth cell pathology and ability to develop DSS induced colitis, which could be reversed by norovirus infection[42]. A recent study has reported that the ATG16L1 and NOD2 pathways may be interrelated[ 78]. In 2010, Cooney et al[78] demonstrated that NOD2 stimulation is capable of initiating autophagy in DCs and that for effective autophagy to occur, both intact NOD2 and ATG16L1 functions are required. IRGM belongs to a family of interferon-inducible immunity related GTPases (IRGs) that encodes a protein involved in multiple autophagocytic pathways including intracellular clearance of pathogens[79]. IRGM has been shown to play a role in autophagy during both Salmonella typhimurium and Mycobacterium bovis infections[79,80]. Another study in CD patients has demonstrated that autophagy is also important in the clearance of AIEC and that IRGM and ATG16L1

15. Autophagy
Figure 2 Autophagy. A small volume of cytoplasm is enclosed by the autophagic
isolation membrane, which forms the autophagosome. The outer membrane
of the autophagosome then fuses with the lysosome where the cytoplasm derived
materials are degraded

16. Microbiome Illusion for researchers Gut contains – 1014 microorganisms
500 species
Lot of them still unexplored
Crucial role in normal homeostasis as well as disease

17. Absolute numbers vary greatly, ranging from
1011 cells/g - Ascending colon ; 107–8  Distal Ileum & 102–3  Proximal Ileum & Jejunum.

18. Composition
Bacteriodes
Firmicutes %
Proteobacteria
Actinobacteria
Fusobacteria

19. 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

20. Differences in Normal and Diseased Bowel
Healthy subjects
IBD subjects
High biodiversity
Low biodiversity
Stable microbiota
Dysbiosis
Increased gut commensals
Increased gut pathogens
Higher firmicutes
Lower firmicutes

21. Dysbiosis

22. IBD,s are chronic,Life-long We cannot just look at the short term induction therapy.

23. 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
The goal of therapy in IBD is to Induce Remission ;to maintain remission to maintain adequate nutrition ,minimize disease and treatment related complications.and improve QOL.

24. Rogler et al. Role of biological therapy for inflammatory bowel disease in developing countries. Gut 2012

25. Choice of Medical Therapy
severity
Mild,
Moderate
Severe
Disease distribution
E1,E2,E3 Disease
Prior Therapy
Side effects
Complication
Response

26. Current “Therapeutics Pyramid”
Ulcerative colitis
Surgery
Infliximab(SEVERE)
MTX
AZA/6-MP
Systemic Steroids (Moderate)
Budenoside
Antibiotics
5-ASA (MILD)
Surgery
Cyclosporin
Systemic Steroids
Infliximab
Aminosaliysalates
Crohn,s Disease
Concept obsufactes induction maintanence stratgies.

27. Step Up Management Approach
Remission achieved with less toxic drugs.
Toxic therapy reserved for severe or refractory disease.
Minimalize risk of adverse events
Cost sparing??
Pateint need to “earn “most “ effective treatment.
Decrease in QOL before pateint obtain optimal therapy
High likelihood of surgery
Disease is not modified.

28. Strategies & Targets of IBD Therapy
Classic Anti inflammtory &Immunosupressants
Immunomodulators & Inhibitors of Cascades
Elimination 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.

30. When to Introduce Biologics??
The “Tipping Point “ may be Corticosteroids?

31. IBD Immunology 101
Mucosa
Submucosa
Blood Vessels

32. IBD Immunology 101
Mucosa
Submucosa
Blood Vessels

33. ANTI-TNF-α ANTIBODIES
Best studied pro-inflammatory cytokine
Produced by mononuclear cells
Synthesis is induced through activation of cellular receptors, e.g., TLR4
Activation of TLR4 signaling induces activation of NF-κB and MAPK
Differentiation of macrophages as well as inducing expression of pro-inflammatory cytokines, e.g., TNF-α, interleukin (IL)-6 and IL-12

34. Construct of Anti-TNF-α Biologic Agents
Chimeric monoclonal antibody (75% human IgG1 isotype)
Infliximab
IgG1
Human recombinant antibody (100% human IgG1 isotype)
Adalimumab
IgG1
Humanized Fab’ fragment (95% human IgG1 isotype)
Certolizumab Pegol
PEG VH VL
CH1
No Fc
Mouse
Human
PEG, polyethylene glycol.

35. 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 .

36. 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

37. Adalimumab
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

38. Certolizumab Pegol Pegylated conjugated Fab against TNF
Does not contain an Fc portion
Golimumab
Human monoclonal antibody that targets TNF with a higher affinity than adalimumab.

39. 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

41. Anti-adhesion therapies
Targets for Therapy
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

42. Chemokine CCR-9 Blockade of Cell Adhesion and Homing Cytokines
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.

43. Blockade of Cell Adhesion and Homing Cytokines
CCL-25 Ligand
CCR9 Receptor

44. Compound CCX282-B Blockade of Cell Adhesion and Homing Cytokines
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

45. Block WBC Binding to Integrins
Blockade of Adhesion Molecules: Vedolizumab
Block WBC Binding to Integrins
Anti-Integrin Coating

46. Leading Anti-Integrins In Development
Blockade of Adhesion Molecules: Vedolizumab
Leading Anti-Integrins In Development
Vedolizumab
rhuMAb Beta7
PF (MAdCAM-1 Antagonist)

47. Vedolizumab Blockade of Adhesion Molecules: Vedolizumab
Vedolizumab – antibody against one type of integrin
Prevents binding of White Blood Cells (WBC) in the intestine
Specific to the Intestine
Being Studied in both Ulcerative Colitis and Crohn’s
Given via IV infusion (in the vein) once a month

48. rhuMAb Beta7 Blockade of Adhesion Molecules: rhuMAb Beta7
Cheroutre and Madakamutil, Nat Rev Immunol 2004

49. Blockade of Cell-Activating Signals
IL-12
Receptor
IL-12/23
Ligand
T-cell
Interferon
Dendritic cell
IL-17
T-cells
ACTIVATED

50. Blockade of Cell-Activating Signals: ustekinumab
Ustekinumab – 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.

51. Blockade of Cellular Inflammation Controls
Interleukins
Interleukins Attach to Receptors
IL-12
Receptor
JAK Binds to Activated Receptors
JAK
IL-12/23
Ligand
JAK then Signals DNA
Cell produces mediators
of inflammation
T-cell

52. Tofacitinib (CP-690550) Dampening Cytokine Response: JAK-Inhibitors
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

54. Exciting Agents Early in Development

55. 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.

56. 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.

57. Route of administration varies
Naso -Duodenal
Colonoscopy
Enema
Enteric coated capsule

58. 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

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

60. Thank you