INFLAMMATORY BOWEL DISEASE is is a spectrum of Remitting, Relapsing, Chronic Inflammatory intestinal, conditions causing significant GI symptoms that include diarrhoea, abdominal pain, bleeding, anemia and weight loss. It is divided into two major subtypes: Ulcerative colitis and Crohn’s disease

1. DR PRERANA KADAM
GUIDE: DR SMITA TIWARI
SHORT TALK
Dr. Prerana Manik Kadam 1

2. INFLAMMATORY BOWEL DISEASE
It is a spectrum of
• Remitting
• Relapsing
• Chronic
• Inflammatory intestinal conditions
• Causes significant GI symptoms that include
diarrhoea, abdominal pain, bleeding, anaemia
and weight loss.
Divided into two major subtypes:
Ulcerative colitis and Crohn’s disease
Dr. Prerana Manik Kadam 2

3. CASE STUDY
Name of the patient : Ramesh Sinha
Age /Sex : 40
yrs/Male
Occupation : Auto driver
Address : Karwan
C/C: Patient came to the hospital with
h/o “Bloody stools” 2 episodes ,
h/o “loose motions” 3 episodes ,
h/o “Abdominal pain” intermittently worsening
since 4 days
h/o “Vomiting” 1 episode
h/o “Fever” since 4 days
Family history : No h/o colorectal cancer, TB,
similar complaints
Dr. Prerana Manik Kadam 3

4. Past history :
h/o similar complaints in the past, after stressful
long working hours
No h/o recent and past medical problems -
intestinal infection, perineal, perianal disease
No h/o major surgeries in the past.
No h/o TB and known TB contacts
No h/o weight loss
No h/o nocturnal awakenings and sweating
Personal history:
Non smoker, not an alcoholic
Consumes fast food and fried diet daily both
veg and non-veg
No h/o recent travel
Not on any other medication at present eg
antibiotics, NSAIDs , corticosteroids
CASE STUDY
Dr. Prerana Manik Kadam 4

5. CASE STUDY
O/E: GC fair
Pt Febrile, Temp: 38 °C
BP : 126/82 mm of Hg
HR : 110/ min
SPO2 : 99% on RA
CNS : Pt oriented to time, place and person
R/S : AEEBS
P/A : Soft , distended
No guarding, rigidity
Tenderness present
PR : Painful
Provisional diagnosis : Amoebiasis ?
Hemorrhoids ? Fissure ? Ulcerative colitis?
Crohn’s disease?
Dr. Prerana Manik Kadam 5

6. CASE STUDY
Dr. Prerana Manik Kadam 6

7. CASE STUDY
MICROBIOLOGICAL INVESTIGATION :
No organism on stool culture
Direct microscopy of stool :
Stool with blood and mucus
COLONOSCOPY :
Flexible colonoscopy :
1. Colonoscopy reveals “Erythema” with
“Erosions” noted in rectum and “Loss of
vascular pattern”
2. Multiple polypoid lesions noted in sigmoid
colon throughout the procedure mucosa is
darker red with mucus, blood and pus in lumen
Dr. Prerana Manik Kadam 7

8. CASE STUDY
Dr. Prerana Manik Kadam 8

9. CASE STUDY
DIFFERENTIAL DIAGNOSIS
• Ulcerative colitis
• Crohn’s disease
• Infections of the colon (especially with
Clostridium difficile, Campylobacter, and
Escherichia coli O157:H7 species,
amoeba, and cytomegalovirus)
• Ischemic colitis
• Radiation colitis
• NSAIDs
Pain,
Gastrointestinal
Bleeding And
Intestinal
Ulcerations
Dr. Prerana Manik Kadam 9

10. Toxic megacolon
Peritonitis
Long standing ulcer
Cholangitis
Ulcerative
colitis
Crohn’s
disease
Stricture
Perforation
Deep ulcer
Rectal bleeding
Perianal
Manifestation
Loss of appetite
Fever
Malabsorption
INTESTINAL COMPLICATIONS
Dr. Prerana Manik Kadam 10

11. EXTRAINTESTINAL COMPLICATIONS
Dr. Prerana Manik Kadam 11

12. PATHOPHYSIOLOGY
• An aberrant immune response to the commensal microbiota of the gut in
genetically susceptible individuals
• Dysbiosis of the microbiome in IBD
• Histologically,
Superficial lesions
Lymphocytes and neutrophils
Transmural lesions
Lymphocytes and macrophages
Granuloma formation
Submucosal fibrosis
Ulcerative colitis Crohn’s disease
Dr. Prerana Manik Kadam 12

13. Bacterial antigens in the
intestinal lumen
Interactions
Immune cells in the
intestinal wall
Proposed pathogenesis
Target sites for
pharmacological
intervention.
Dr. Prerana Manik Kadam 13

14. • Bimodal peak in age of onset : 15
and 40 years and 50 and 80 years
• 5-15 per 100,000
• Jewish Ashkenazi population.
• NOD2/CARD15 on chromosome
16 and IL23R on chromosome 1
– high incidence (50%) in
monozygotic twins.
• Cigarrete smoking : high-risk
factor
• Bimodal peak in age of onset : 15
and 40 years and 50 and 80 years
• 5-25 cases per 100,000
• Whites eastern Europe, Jewish
Ashkenazi population.
• Critical genes were CXCL10,
VCAM1, CXCL9, MMP9, IDO1,
and CCR7
Ulcerative colitis Crohn’s Disease
Dr. Prerana Manik Kadam 14

15. TREATMENT
GOALS
Choice of treatment - extent and severity of
disease
disease course and patient response.
Treatment:
Medical
Surgical
• Control acute exacerbations
• Induce and maintain remission
• Treat specific complications
• Improve the quality of life
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16. Extent and Severity – Mayo score
Dr. Prerana Manik Kadam 16

17. CLASSIFICATION OF DRUGS TO TREAT IBD
■ Mesalamine-Based
Therapy
■ Glucocorticoids
■ Immunomodulatory
Agents
■ Biological Therapies
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18. Sulfasalazine and 5-aminosalicylates (5-ASAs)
(given orally, 1st line therapy)
• Induction : 3-4g/day
• Remission : 1.5- 2g/day in divided doses
or once daily dosing
- Takes 2-4 weeks for action
- Effective in 60% or more in 4 weeks
AMINOSALICYTATES
Current Status :
~ Mild to moderately active UC
~ Severe UC as adjunct with
corticosteroid
~Not used in Crohn’s disease as
Sulfasalazine releases 5-ASAs in
colon.
Dose
Dr. Prerana Manik Kadam 18

19. Sulfasalazine : combination of sulfapyridine (an
antibiotic) and 5‐aminosalicylic acid (an
anti‐inflammatory agent) joined by Azo Bond
• To preserve benefit of 5-ASA
• Reduce side effect of sulfa component
Second-generation 5-ASA compounds were
developed.
The active moiety was not sulfapyridine but the
5‐ASA component.
Dr. Prerana Manik Kadam 19

20. Inhibition of cytokines
Inhibition of COX and LOX pathways, so PG and leukotreine
production is suppressed
Inhibition of the production of ILs , TNF-α, PAF
Inhibition of generation of PPAR-γ and nuclear transcription
factor (NF-κB) pivotal to production of inflammatory mediators.
T cell proliferation, activation and differentiation inhibited
Increases scavenging of free radicals and oxidants.
Mechanism of action of 5-ASA
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21. Adverse Effects
Related primarily to the sulfa
moiety
Sulfasalazine inhibits intestinal
folate absorption.
Reversibly decreases the number
and motility of sperm
Allergic reactions include rash,
fever, Stevens-Johnson syndrome,
hepatitis, pneumonitis, haemolytic
anaemia, and bone marrow
suppression.
Nephrotoxicity:
Nephrotic syndrome due to
minimal-change nephropathy;
resolving with drug withdrawal
and high-dose oral
corticosteroids. Tubulointerstitial
nephritis- idiosyncratic reaction
Pancreatitis, hepatotoxicity, bone
marrow suppression and anaemia.
Dr. Prerana Manik Kadam 21

22. Oral Therapy + 5-ASA Enema
5-ASA Enema
Current Status :
~ Distal UC
~ Refractory cases
~ Proctitis
~ Mild-to-moderate/Severe UC
~ All extensive UC patients-
Pancolitis
Route depends on site of disease
Distal colonic disease
Or
Rectal involvement
Dr. Prerana Manik Kadam 22

23. SULFASALAZINE OLSALAZINE BALSALAZIDE
5 ASA + SULFAPYRIDINE 5ASA + 5ASA 5ASA + Inert compound
Colonic action Most reliable delivery of 5-
ASA
Carrier poorly absorbed
A/e sulfapyridine Initially aggravates diarrhoea Safer alternative
Second Generation 5-ASAs
Dr. Prerana Manik Kadam 23

24. 5-ASA treatment : Summary
Mesalamine (5-ASA)
• Mild-to-moderate ulcerative
colitis
• Combination with
glucocorticoids for severe
ulcerative colitis
• Primarily topical with limited
effects on deeper tissue
inflammation
• Absorbed in jejunum, so utility in
more distal disease is limited
• Suppository for rectal disease
Sulfasalazine
• Mild-to-moderate ulcerative
colitis
• Combination with
glucocorticoids for severe
ulcerative colitis
• Prodrug, delivers 5-ASA to more
distal GI regions.
• Sulfapyridine released; may cause
adverse effects in patients sensitive
to sulfa drugs
Drugs Therapeutic Uses Clinical Pharmacology
Dr. Prerana Manik Kadam 24

25. Olsalazine
• Mild-to-moderate ulcerative
colitis
• Combination with
glucocorticoids for severe
ulcerative colitis
• Prodrug with two azo-linked 5-
ASA molecules
• Eliminates the side effects
associated with the sulfapyridine
moiety of sulfasalazine
Balsalazide
• Mild-to-moderate ulcerative
colitis
• Combination with
glucocorticoids for severe
ulcerative colitis
• Prodrug with a 5-ASA
molecule linked to an inert,
unabsorbable second moiety
Drugs Therapeutic Uses Clinical Pharmacology
Dr. Prerana Manik Kadam 25

26. • Route : oral, rectal, or iv.
~ Oral Prednisolone, budesonide,
beclamethasone dipropionate
~ IV Prednisolone, Methylprednisolone,
Hydrocortisone
~ Enema / foam Hydrocortisone
GLUCOCORTICOIDS
Current Status :
~ Non responders to 5-ASA
~Moderately severe cases for
induction and remission in both
UC and Crohn’s disease
~Severe/Acute flareups
Dr. Prerana Manik Kadam 26

27. Steroid Responsiveness
Glucocorticoid responsive : improve clinically within 1-2 weeks; tapered or
discontinued – maintain remission
Glucocorticoid dependent : respond to steroids but relapse when tapered or
discontinued
Glucocorticoid resistant : do not improve even with prolonged high dose steroids
Dr. Prerana Manik Kadam 27

28. Mechanism of action
Induction of annexins in macrophages, endothelium and fibroblasts.  Annexins inhibit phospholipase A2, decreased
production of PGs, LTs & PAF.
Negative regulation of COX-2  decreased PG production.
Negative regulation of genes for cytokines in macrophages, endothelial cells and lymphocytes  decreased
production of IL-1, IL-2, IL-3, IL-6, TNFα, y interferon, fibroblast proliferation and T-lymphocyte function are
suppressed
Decreased production of acute phase reactants from macrophages and endothelial cells  Complement function is
interfered
Decreased production of CAM in endothelial cells expression of transcription factors  Adhesion and localization of
leukocytes is interfered
Decreased production of collagenase  Prevention of tissue destruction
Dr. Prerana Manik Kadam 28

29. • Oral Prednisolone 40-60mg/day reduced to 5mg/week
taper over 8-12 week
• IV Methylprednisolone 60mg daily or Hydrocortisone
100mg 6 hrly
• Rectal once daily Enterofoam 10%
Steroids can be given
For maximum 12 weeks
Adverse effects increase beyond that
Dose
Dr. Prerana Manik Kadam 29

30. • Increased risk of infection
• Cushingoid features
• Psychiatric problems
• Cataracts
• Glaucoma
• Impaired wound healing
• Metabolic bone disease
• Skin thinning
• HPA axis suppression
• Abrupt withdrawal- adrenal insufficiency
Adverse Effects
Dr. Prerana Manik Kadam 30

31. IMMUNOSUPPRESSANTS
• Long term management especially Crohn’s disease
• 60% Crohn’s disease and substantial UC patients
• Not useful in acute exacerbations – long latency of
action
• Good remission maintaining property
• Steroid sparing property
Dr. Prerana Manik Kadam 31

32. THIOPURINES
(6-mercaptopurine and azathioprine)
Current Status :
~ Severe IBD
~ Steroid resistant or dependent
patients
~ Frequent Flareups
~Not for acute disease – long
latency
~ Delay recurrence of Crohn’s
disease after Sx resection
~ Fistulating Crohn’s disease
• Azathioprine 1.5- 2.5 mg/kg
• Mercaptopurine 1.5 – 2 mg/kg
In both Crohn’s disease and ulcerative
colitis
Dose
Dr. Prerana Manik Kadam 32

33. Mechanism of action
Inhibit the conversion of
inosine monophosphate
to adenine and guanine
nucleotides
The building blocks for RNA
and DNA.
There is
inhibition of purine
synthesis.
They also get incorporated
into RNA and DNA which
becomes dysfunctional.
Selectively affects
differentiation and
function of T cells and
inhibits cytolytic
lymphocytes.
CMI is primarily
depressed.
Azathioprine and 6-MP are oxidised and their metabolism is inhibited by allopurinol;
dose has to be reduced to 1/4th or ½ if allopurinol is given concurrently
Dr. Prerana Manik Kadam 33

34. Three fates of Mercaptopurine
(Courtesy: Goodman and Gillman Edition 13)
Relative differences in
response is due to
differences in TPMT
activity
TPMT : Thiopurine S-methyltransferase
HGPRT : Hypoxanthine-guanine
phosphoribosyltransferase
XO : Xanthine oxidase
Dr. Prerana Manik Kadam 34

35. Bone marrow
suppression
Hepatotoxicity
Increased risk of
cancer
– Non Hodgkins
lymphoma
Idiosyncratic
Pancreatitis 5%
Arthralgia
Rash
Fever
Nausea Vomiting
Dose related Idiosyncratic
Adverse effects – 10% of Pts
Dr. Prerana Manik Kadam 35

36. METHOTREXATE
Current Status :
~ Severe Crohn’s disease
~ Unresponsive or intolerant to
Azathioprine
~ Steroid resistant or dependent
IBD
~ UC -- poor efficacy
25mg/week parenterally
Induction : 25mg weekly
Remission : 15 mg weekly
Dose
Dr. Prerana Manik Kadam 36

37. Folic acid analogue
Dihydrofolate reductase enzyme inhibitor
Blocks the conversion of DHFA to THFA
THFA – required for one carbon transfer reactions in purine synthesis and
amino acid interconversions in DNA synthesis
DHFA inhibits thymidylate synthase which is required for DNA, RNA and
protein synthesis
Causes cell death – specifically in S phase
Mechanism of action
Dr. Prerana Manik Kadam 37

38. Possible Anti-inflammatory Action
Dihydrofolate reductase, thereby blocking DNA synthesis and causing
cell death.
Purine metabolism
T cell activation
Cytokine production
ICAM
IL receptor binding
Inhibits
Dr. Prerana Manik Kadam 38

39. Macrocytosis
Stomatitis Punctate cutaneous eruptions
Headache Inability to concentrate
Alopecia
Fever
Adverse effects
Dr. Prerana Manik Kadam 39

40. CYCLOSPORINE
Current Status :
~ Induction and maintenance of
remission in Severe UC
~ Severe UC not responding to
steroids
2-4 mg /kg/day iv
Calcineurin inhibitor and a potent immunomodulator
Dose
Dr. Prerana Manik Kadam 40

41. Mechanism of action
(Courtesy: Goodman and Gillman Edition 13)
Dr. Prerana Manik Kadam 41

42. • Adverse effects
Infection, seizures, hypertension, nephrotoxicity, peripheral neuropathy
and hyperkalaemia.
• Other uses
Most frequently after organ transplantation.
Oral cyclosporine less effective - limited intestinal absorption.
‘Bridge therapy’
controls symptoms for 7-10 days till Azathioprine works
Dr. Prerana Manik Kadam 42

43. BIOLOGICS
Dr. Prerana Manik Kadam 43

44. TNF-α INHIBITORS
• Infliximab is a chimeric antibody (25%
mouse,75% human)
• Adalimumab is a fully humanized antibody.
• Certolizumab pegol is a humanized fragment
antigen binding that is “pegylated” (i.e., bound
to a polyethylene glycol polymer to increase
serum half-life of the parent compound).
Dr. Prerana Manik Kadam 44

45. Current Status
Infliximab : (Response 2-4
weeks)
Severe Active Crohn’s
disease
Fistulating Crohn’s disease
– helps in closure
Severe UC not improved
with iv steroids or
Immunosuppressants or when
latter is inappropriate
Reserve drug for refractory
cases
Decreases acute flare-ups
Steroid resistant: induction
of remission and mucosal
healing
Azathioprine + Infliximab
Adalimumab and
Certolizumab pegol:
(Response 2-8 weeks)
Severe and Refractory IBD
Moderately severe disease
induction and maintenance in
Crohn’s disease
Dr. Prerana Manik Kadam 45

46. TNFa is secreted by activated macrophages ,immune cells to act on TNF
receptors (TFR1, TFR2) - located on the surface of neutrophils,
fibroblasts, endothelial cells as well as found in free soluble form in serum
and serous fluids.
TNFa inhibitors bind and neutralize both soluble and membrane-bound
TNF-α
TNF-α amplifies immune inflammation by releasing other cytokines
and enzymes like collagenases and metalloproteinases
Mechanism of action
Dr. Prerana Manik Kadam 46

47. • Infused iv every 2-8 weeks – decreases acute flareups and helps in fistula
closure.
• Response occurs in 2-4 weeks
• Therapy is continued till the response is maintained.
Infliximab:
Substantial toxicity
Acute reactions Decrease its clinical efficacy
Antibodies formation
Lowering of resistance to infection
Dose and frequency
Dr. Prerana Manik Kadam 47

48. Screening for latent tuberculosis and hepatitis B infection is essential prior to
starting treatment with anti‐TNF biologics.
Potential reactivation of TB
PPD test for latent TB  +ve  treat with prophylactic INH
 Increased incidence of NHL
Acute (fever, chills, urticaria, or even anaphylaxis)
 Serum sickness–like reactions - after infliximab infusion.
Infliximab increased incidence of respiratory infections
Adverse effects
Dr. Prerana Manik Kadam 48

49. USTEKINUMAB
Current Status :
~ Originally developed for Psoriasis
~ Induction and maintenance therapy
-moderate to severely active UC -
who had failed to respond or were
intolerant to steroids,
immunomodulators, anti-TNF
therapy or vedolizumab
•8-week induction therapy
•44-week maintenance
therapy
130mg or 6mg/kg
Dose
Anti interleukin monoclonal antibody
Dr. Prerana Manik Kadam 49

50. Anti interleukin monoclonal antibody
targets P450 subunit
common to pro-inflammatory cytokines IL23 and IL12
Prevent activation of receptors on lymphocytes
Mechanism of action
Dr. Prerana Manik Kadam 50

51. VEDOLIZUMAB
Current Status :
~ Induction and
maintenance of remission in
both moderate to severe
Crohn’s disease and UC
•Induction 300mg at
0,2,6 weeks
•Maintenance every 8
weeks
Humanised monoclonal antibody binds to and inhibits α4β1 and α4β7
integrin subunit on lymphocytes
Dose
Dr. Prerana Manik Kadam 51

52. Vedolizumab is a monoclonal antibody to the α4β7 integrin
Blocks the binding of α4β7 to the mucosal addressin cell adhesion molecule-1
(MAdCAM-1)
Blocks lymphocyte movement to the gut
Thus preventing immune response
Mechanism of action
Dr. Prerana Manik Kadam 52

53. Adverse effects
Headache Hypersensitivity
Arthralgia
Nasopharyngitis
Fatigue
Dr. Prerana Manik Kadam 53

54. NATALIZUMAB
Current Status :
~ Induction and
maintenance of
response in CD
a/w a risk of rare but usually fatal
progressive multifocal
leukoencephalopathy (PML),
particularly in those who are seropositive
for the JC virus or have prior exposure to
immunosuppressive therapy.
Humanised monoclonal antibody binds to and inhibits α4‐integrin
Dr. Prerana Manik Kadam 54

55. Proctocolectomy and Brooke
ileostomy
Proctocolectomy and Kock pouch
 Abdominal colectomy and ileorectal
anastomosis
Total proctocolectomy with ileal
pouch–analanastomosis (IPAA)
• Pouchitis is nonspecific inflammation
of the ileal pouch reservoir
• Most important long-term
complication of total proctocolectomy
SURGICAL PROCEDURES
Dr. Prerana Manik Kadam 55

56. • Dysbiosis of the intestinal microbiome -
key factor in the development of IBD
• Antibiotics : Metronidazole,
ciprofloxacin, amoxicillin-clavulanate,
and piperacillin-tazobactam
• Probiotics - mixtures - beneficial
lyophilized bacteria – oral preparations
in market egs: Vibact, Acigut, Sporolac.
Manipulating the Intestinal Microbiome
To treat IBD
A balance :
Mucosal
epithelium
Normal gut
Flora
Immune
response
Dr. Prerana Manik Kadam 56

57. IBD - dysbiosis of the intestinal
microbiome
Methods to re-establish normal
microflora in patients.
Faecal transplant Instillation of a
preparation of faeces from a
healthy donor into the colon
By enema or colonoscopy.
Effective therapy for antibiotic resistant Clostridium
difficile infection
Faecal Transplant as Therapy in IBD
Dr. Prerana Manik Kadam 57

58. Analgesic, anticholinergic, and antidiarrheal – reduce symptoms and improve
quality of life.
Oral iron, folate, and vitamin B12
Loperamide or diphenoxylate - reduce the frequency of bowel movements and
relieve rectal urgency.
Cholestyramine - treat bile salt induced colonic secretion - limited ileocolic
resection patients
Supportive Therapy in IBD
Dr. Prerana Manik Kadam 58

59. Mesalamine and glucocorticoids are FDA category B drugs that are used
frequently in pregnancy and generally are considered safe.
Methotrexate is absolutely contraindicated in pregnant patients.
Anti–TNF-α drugs, particularly Infliximab and Adalimumab, have been assessed
for their safety, and found safe.
Therapy of IBD During Pregnancy
Dr. Prerana Manik Kadam 59

60. IBD requires prolonged treatment for remission and maintenance.
Drugs used have their own set of adverse effects whose severity may affect
the lifestyle of patient.
Better treatment with fewer adverse effects offering good prolonged
remission is thus needed.
CONCLUSIONS
Dr. Prerana Manik Kadam 60

61.  Brunton LL, Hilal-Dandan R, Knollmann BC. As Bases Farmacológicas da Terapêutica de Goodman e Gilman-13. Artmed
Editora; 2018 Dec 19.
 Tripathi KD. Essentials of medical pharmacology. JP Medical Ltd; 2013 Sep 30.
 Satoskar RS, Bhandarkar SD, Ainapure SS. Pharmacology and pharmacotherapeutics. Indian Journal of Pharmacology.
1997 Sep 1;29(5):330
 Lamb, C. A., Kennedy, N. A., Raine, T., Hendy, P. A., Smith, P. J., Limdi, J. K., Hayee, B., Lomer, M., Parkes, G. C.,
Selinger, C., Barrett, K. J., Davies, R. J., Bennett, C., Gittens, S., Dunlop, M. G., Faiz, O., Fraser, A., Garrick, V., Johnston,
P. D., Parkes, M., … Hawthorne, A. B. (2019). British Society of Gastroenterology consensus guidelines on the
management of inflammatory bowel disease in adults. Gut, 68(Suppl 3), s1–s106. https://doi.org/10.1136/gutjnl-2019-
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 Joana Torres, Stefanos Bonovas, Glen Doherty, Torsten Kucharzik, Javier P Gisbert, Tim Raine, Michel Adamina, on behalf
of the European Crohn’s and Colitis Organisation [ECCO], ECCO Guidelines on Therapeutics in Crohn's Disease: Medical
Treatment, Journal of Crohn's and Colitis, Volume 14, Issue 1, January 2020, Pages 4–22, https://doi.org/10.1093/ecco-
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62. Dr. Prerana Manik Kadam 62