IBD management

1. Recent advances in management of
Inflammatory bowel diseases
Subhash Nandwani

2. Aminosalicylates
FOR CROHN’S DISEASE
• Sulfasalazine – useful for inducing remission
• Mesalamine – role uncertain
• For maintenance – 5-ASA compounds not
useful

3. Aminosalicylates
• FOR ULCERATIVE COLITIS
• Sulfasalazine and Mesalamines – useful in
inducing remission and maintenance of it

4. Glucocorticoids
• Effective both in CD and UC for inducing
remission
• They are not effective for maintenance of
remission.

5. Budesonide
• Preferred over prednisolone in localised mild
ileocaecal crohn’s
• Less effective than conventional steroids in
severe disease
• Not effective for maintenance of remission

6. Thiopurines
• Azathioprine and 6-mercaptopurine
FOR CROHN’S DISEASE
• 50 % patients respond and 1/2 -2/3 of them
will maintain that response
FOR ULCERATIVE COLITIS
• use of azathioprine is largely based on its
estabilished efficacy in CD rather any proven
benefit in UC

7. methotrexate
FOR CROHN’S DISEASE
• MTX 25 mg/wk IM, induced remission in 40%
vs 20% in placebo at 8 weeks
• MTX 15 mg/wk IM / SC for 1-4 yrs. 65%
maintenaned remission vs 40% in placebo
group
• Oral MTX was not found effective
• Used as alternative to thiopurines

8. methotrexate
FOR ULCERATIVE COLITIS
• Not effective

9. antibiotics
FOR CROHN’S DISEASE
• Metronidazole – useful in healing perineal
fistulas. Benefit not seen in active luminal
crohn’s disease.
• Ciprofloxacin –showed benefit in perianal
fistula and in treatment of luminal disease.
• Rifaximin 800 mg bd Vs placebo : 62% vs 43%
remission at 12 wks (p=0.005)

10. antibiotics
FOR ULCERATIVE COLITIS
• Antibiotics not effective in UC except in
suppurative complications

11. cyclosporine
FOR CROHN’S DISEASE
• Only high doses are effective at unacceptably
high cost of side effects. Other less hazardous
medications are preferred.
FOR ULCERATIVE COLITIS
• Only 1 study showed response in 9 of 11
patients in 7 days with IV cyclosporine
4mg/kg/day
• 50% patients required colectomy in 6 months

12. cyclosporine
• Cyclosporine can be considered as bridge
therapy in steroid refractory UC while waiting
for elective surgery or onset of action of
azathioprine

13. Mycophenolate mofetil
• Pharmacodynamics similar to azathioprine,
but more rapid onset of action
• Efficacy inferior to azathioprine, < 50%
remission rate

14. Tacrolimus
FOR CROHN’S DISEASE
• Preliminary data suggest benefit in steroid
resistant disease.
• Also may be effective as topical agent for oral
and perianal ulcerating disease.
FOR ULCERATIVE COLITIS
• Limited data
• Not accepted as standard therapy

15. Thalidomide
• Efficacy seen in small studies in CD

16. Biological therapy

17. Biological therapy for IBD
Biological therapy is the use of biological agents,
which are so termed because of their protein
origin (e.g., antibodies and cytokines)

18. Anti- TNF antibodies
Infliximab
Adalimumab
Golimumab
Certolizumab pegol

19. Biological therapy - indications
• steroid refracory
• Steroid dependent
• Steroid intolerant

20. Biological therapy
• All have similar response rate of 60% and 40%
of responders maintain that for 1 year
• Infliximab and cyclosporine showed similar
efficacy in severe UC
• serious infections in 2-4% patients
• Pyogenic complications of crohn’s should be
treated first
• Screen for TB before starting therapy

21. Biological therapy
• Anti TNF therapy is more effective when
treatment is initiated early in the disease
• Clinical remission rates approached 60% in
patients who had CD for <2 years, compared
to 40% in patients who had a longer duration
of disease
• Combination therapy with infliximab and
azathioprine is more effective than either
alone

22. Adalimumab
Ref: - Triantafillidis et al. Drug Design, Development and Therapy 2011; 5: 185- 210

23. Adalimumab
• Advantages over infliximab:
– induces remissions more frequently than placebo
in adult patients with CD who cannot tolerate IFX
or are symptomatic despite receiving IFX therapy
– Less immunogenic
• Prospective, randomized head to head studies
comparing IFX to ADA required.
Ref: - Triantafillidis et al. Drug Design, Development and Therapy 2011; 5: 185- 210

24. Golimumab
• Latest approval, May 2013
• Moderate to severe Ulcerative colitis (UC) with an
inadequate response or intolerant to prior treatment
or requiring continuous steroid therapy

25. Golimumab
Ref: - Full Prescribing information. Drugs at FDA.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125289s094lbl.pdf

26. Golimumab
• Resembles adalimumab
• Not a huge advance, but offers another option in
its class
• ?? May be superior to other anti-TNF-α
antibodies in terms of its ability to inhibit both
TNF-α-mediated cytotoxicity and TNF-α-mediated
endothelial cell activation.
Ref: - Gastroenterology & Hepatology 2012; 8 (8)

27. Certolizumab pegol
• Approved in April 2008
• Reducing signs and symptoms of Crohn’s disease
and maintaining clinical response in adult
patients with moderately to severely active
disease who have had an inadequate response to
conventional therapy.

28. Certolizumab pegol
• Approved in April 2008
• Reducing signs and symptoms of Crohn’s disease and
maintaining clinical response in adult patients with
moderately to severely active disease who have had
an inadequate response to conventional therapy.
StudyCD1StudyCD2
Ref: - Full Prescribing information. Drugs at FDA.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125160s215lbl.pdf

29. Induction therapy
Chronic maintenance
therapy
Infliximab
5 mg/kg i.v. infusion, at
0, 2 and 6 weeks
5 mg/kg i.v. infusion
every 8 weeks
Adalimumab
160 mg s.c. at week 0,
then 80 mg at week 2
40 mg s.c. every 2 weeks
Golimumab
200 mg s.c. at week 0,
then 100 mg at week 2
100 mg s.c. every 4
weeks
Certolizumab pegol
400 mg s.c. at 0, 2 and 4
weeks
400 mg s.c. every 4
weeks
Anti- TNF antibodies:
Treatment protocol
- Treatment should be given as a planned course of treatment until treatment failure
(including the need for surgery), or until 12 months after the start of treatment,
whichever is shorter.
- Should only be continued if there is clear evidence of ongoing active disease as
determined by clinical symptoms, biological markers and investigation, including
endoscopy if necessary.Ref:- NICE technology appraisal guidance 187, 2011

30. Anti adhesion molecules

31. Anti- integrin therapy
Gut-homing
effector memory
cell
Natalizuma
b

32. Anti adhesion molecules
• Natalizumab : inhibits lymphocyte trafficking
into site of inflammation
• Vedolizumab : gut selective, no effect on CNS

33. natalizumab
• Humanized monoclonal antibody against α4-
integrin, Inhibits leukocyte migration into
inflammed tissue
• it also inhibits lymphocyte trafficking into CNS
• Risk of progressive multifocal
leukoencephalopathy (PML) caused by
infection with John Cunningham virus (JCV)
• Check anti JCV virus antibodies before
treatment

34. natalizumab
• Approved by FDA in 2008 for moderate to
severe crohn’s refractory to prior treatment,
including anti-TNF
• However, it should not be used in combination
with immunosuppressants or inhibitors of
TNF-α.

35. vedolizumab
• Gut selective anti adhesion molecule
• Anti integrin molecule, similar to natalizumab,
but no effect on brain so no risk of PML
• Approved by FDA in 2014 for Crohn’s disease
and ulcerative colitis

36. Anti interleukins

37. Anti interleukins : ustekinumab
• Human anti IL-12/IL-23 monoclonal antibody
• Study in severe crohn’s disease: 40% response
rate at 6 wks vs 24% in placebo

38. Janus Kinase (JAK) inhibitor

39. Janus kinase (JAK) signal inhibitors
• As most of the available biological therapies
are directed at the blockage of only one
cytokine, it seems reasonable to believe that
the modulation of a common cytokine
downstream pathway could represent an
attractive therapeutic approach.
J Med Chem. 2010;53:8468–8484

40. Janus Kinase (JAK) inhibitor
• JAK family of kinases mediate signal
transduction activity for multiple cytokines
• Tofacitinib: oral JAK inhibitor showed promise
for UC and CD with response rates 30-80%

41. Epidermal growth factor (EGF)
Stimulates cell proliferation in GIT
EGF enema – effective in left sided mild to
moderate UC

42. rosiglitazone
• Peroxisome proliferator receptor agonist
• 44% response vs 23% in placebo in UC at 12
weeks
• Use restricted to patients who have failed or
cannot tolerate standard medical therapy

43. Probiotics
• To modulate intestinal immune response in
IBD
• Disappointing results in CD
• Mixed results in UC

44. Fecal microbiota transplant
• Extreme form of probiotic treatment
• Few reports
• Good results

45. Porcine whipworm
• Trichuris suis: promising effect, 43% vs 17% in
placebo at week 12 in UC
• good safety and toleralability

46. Nutritional therapy
• Defined enteral or polymeric diets useful in
children with CD in whom steroids are
undesirable, no role in adults.

47. Nutritional therapy
• Dietary pattern has effect on intestinal
microbial enterotype
• Alteration of microbiome with diet may be a
strategy to prevent or manage crohn’s disease

48. Cytapharesis
• To reduce peripheral blood leukocytes
• Not effective

49. • Autologous hematopoietic stem cell transplantation
(HSCT) as a therapy for experimental colitis shows
that immunosuppressive therapy followed by cell
transplantation might be an efficient approach for
IBD control.
• In those HSCT studies, cyclophosphamide or total
body irradiation were used as immunosuppressive
therapy, followed by bone marrow transplantation to
restore the immune compartment and, presumably,
self-tolerance.
Cellular therapy for IBD
Braz J Med Biol Res. 2015 Feb; 48(2): 96–107.

50. Out of 12 patients , 5 achieved a clinical and endoscopic
remission within 6 months after HSCT.
Impact of Autologous HSCT in
crohn’s disease
Gut. 2008;57:211–217.

51. Mesenchymal stem cells (MSC)
infusion therapy
• Injection of MSC into fistulas secondary to CD
results in closure of the lesions in most cases.
• It also showed complete fistula closure
Gut. 2011;60:788–798.

52. IBD: Pathogenesis & targets

53. Novel agents….
ᵡApilimod
mesylate
(IL-12, IL- 23)
√Ustekinumab
(p40 subunit of IL-
12/23)
ᵡBriakinumab
(p40 subunit of IL
12/23)
√Basiliximab
(CD25 of IL-
ᵡDacilizumab
(CD25 of IL-2√Fontolizuma
b
(IFN-γ)
Sirukumab (IL-6);
Tocilizumab (IL-
6R)
Anrukinzumab (IL-
13)ᵡSecukinumab (IL-
17)√Vidofludimus
(release of IL-
17)
ᵡIL-10, IL-11,
IFN-β
√Visilizumab
(CD3 TCR)
ᵡRituximab
(CD20)
ᵡSargramostim
(GM-CSF)
Filgrastin
(rGSF)
Thiazolidinedion
es
√GED-0507-
34
ᵡAlicaforsen (ICAM-1)
√Alicaforsen enema
Etrolizumab (α4β7)
PF-547659 (MAdCAM )
Anti-
adhesion
(anti-
integrin)
Anti-
IL
JAK3
inhibitors
Anti-
inflamm
-atory
cytokine
s
Inductio
n of T-
cell
apoptos
is
Growth
factors
PPAR-γ
agonists
III
II
I

54. Conclusion
 A number of new drugs and technologies are at
various stages of development and investigation.
 Of these, few will prove to be effective or safe
enough to make a major impact.

55. Thank you