4. COLOSCOPY UC Early Stage
Hyperemia
Petechial Bleeding
 Fragiability

5. COLOSCOPY CD Early Stage
Aphtoid
Mucosal Lesions
(Ulcers)

6. COLOSCOPY UC Floride (Acute) Stage
Confluating
(Continious)
Ulcerations
Pseudopolyposis

7. COLOSCOPY CD Floride (Acute) Stage
Couble-stone relief
Fissura
Fistula
Solitary ulcers

8. COLOSCOPY UC Late (chronic) Stage
Pseudopolyps
Loss of haustra
Carcinoma

9. COLOSCOPY CD Late (chronic) Stage
Stenosis
Fistula
Pseudopolyps
Diverticula

10. Radiology / CD Couble stone Aphtoid ulcers Pseudodiverticula Fistula
Polymorph ulcers

11. Activity Index Basedon - Clinical Activity - Endoscopical Activity
- Histological Activity
- Laboratory Activity

12. Activity Index /CD

13. Activity Index /UC

14. Differential Diagnosis

15. Prognosis / UC 80% chronic intermittant 15% chronic continious
10% acute fulminant
The longer the chronicity
The worse is the prognosis.

16. Prognosis / CD “ No absolute cure” İn 1 year 70% Remission
MILD
MODERATE 30% Remission
İn 1 year 70% Remission
In 2 years 50% Remission
70% - Surgical Intervention
POSTOP Refall 1 year 70%
2 years 50%

17. Summary -Prognosis / UC
High Rezidive – Quotient
Good if isolated Procto- sigmoiditis
Pancolitis  HIGH – Risk
Pancolitis  often OP.

18. Summary - Prognosis / CD
High – Rezidive Quotient
Complications  OP

19. Goals of Therapy for IBD
Inducing remission
Maintaining remission
Restoring and maintaining nutrition
Maintaining patient’s quality of life
Surgical intervention (selection of optimal time for surgery)

20. Pharma-Information Oral Aminosalicylates Topical Aminosalicylates
Corticosteroids
Immunsuppressiva
Antibiotics
Biologic agents (anti TNF-alfa)

21. Oral Aminosalicylates
SULFASALACIN  COLON
- Sulfapyridine – Carrier +
- 5-ASA – Antiinflammatuar
5-ASA : 3-6 g/d INHIBITION
- cyclooxygenase
- lipooxygenase
O2-Radical - neutrophil
Clearance
NK-ABsynthesis
depression

22. Sulfasalacin
Sulfapyridine - AZO-BINDING ASA
Azoreductase
COECUM

23. Oral Aminosalicylates
B. MESALAMIN  Ileum
5-ASA Colon
2 g/d Eudragit
Capsel

24. Topical Aminosalicylates
5-ASA – FOAM
SUPPOSITOIRES

25. CORTICOSTEROIDS ORAL IV use TOPICAL Prednisone 60/50/40......10 mg Or
Less side effected new forms
Budesonid 9 mg/d
(Endocort / Budenofalk)

26. CORTICOSTEROIDS Inhibition of : Proinflammatory Cytokines
Supportion of protective CK.
(IL-4, IL 10)
Inhibition of Inflammation Mediators
(PAF)

27. Corticosteroids in CD: Induction of Remission
p not calculated
92%†
100
Corticosteroids
82%*
Placebo 80
60%* 60
38%
% Patients 40
30% 20
NCCDS
ECCDS
GETAID
17 weeks
18 weeks
7 weeks
Clinical Remission
*Randomized controlled trial
†Multicenter prospective trial
Malchow H et al. Gastroenterology. 1984;86:249.
Modigliani R et al. Gastroenterology. 1990;98:811.
Summers RW et al. Gastroenterology. 1979;77:847.

28. Remission Rates in Acute Crohn’s Studies with Budesonide CIR
Remission rates at
8 weeks (%) 70 60 50 40 30 20 10
Bud CIR Bud CIR Placebo Pentasa® Prednisolone
9 mg QD 4.5 mg BID 2 g BID 40 mg
Greenberg 1994; Rutgeerts 1994; Thomsen 1998

29. Immunsuppressiva A. Azathiopyrin (AZT) 6-Mercaptopurin
- Cell replication ]
B. Methotrexat (MTX)
- Antimetabolite
- Inhibition of
Dihydrofolacid reductase +
Lymphocytic Proliferation
C. Cyclosporin
- Immunmodulater
- T-Cell depression

30. Antibiotics
Metronidazol

31. Therapeutic Pyramid for Active Crohn’s Disease
Surgery
Severe
Immunomodulators
Infliximab
(Prednisone) ?
Moderate
Corticosteroids
The therapeutic pyramid for Crohn’s disease is based upon clinical trials. Controlled release budesonide has been advocated for mild-moderate disease in countries where it is available. Infliximab has been efficacious independent of concomitant medications.
(Budesonide)
Mild
Aminosalicylates/Antibiotics

32. Outcomes for Mild-Moderate Disease

33. Biologic agents
İnfliximap
adaluminap

34. Infliximab: Mechanism of Action

35. Healing of Colonic Ulceration with Infliximab
Pretreatment
4 weeks post-treatment
Van Dullemen HM et al. Gastroenterology 1995;109:

36. REMICADE® (infliximab) in Patients with Fistulizing Crohn’s Disease
Present, et al.
REMICADE® (infliximab) in Patients with Fistulizing Crohn’s Disease
Complete Response: All Fistulas Closed
P=0.04
P=0.001 *
*Placebo=Conventional Therapy
Present D, et al. N Engl J Med. 1999;340:

37. Incidence of Antibodies-to-Infliximab (ATI) Maintenance Studies*
Antibody-to-Infliximab (ATI) Status
The most frequent AEs (by preferred term) in infliximab-treated patients in all studies
were upper respiratory tract infections (27.9%), headache (25.7%), nausea (20.6%),
abdominal pain (20.5%), pain (13.9%), pharyngitis (13.5%), arthralgia (13.0%), rash
(12.9%), fatigue (11.9%), sinusitis (11.7%), vomiting (11.6%) fever (11.5%), diarrhea
and dizziness (each 10.8%), and coughing (10.0%).
% of Pts with ATI
% of Patients Inconclusive†
% of Pts without ATI
ACCENT I CD
n = 514
Week 72
ACCENT II CD
n = 258
Week 54
ATTRACT RA
n = 295
Week 102
ASPIRE RA
n = 629
Week 54
p. 94 and 95 of ASPIRE ISS
Maintenance Studies
* pts with evaluable samples
† pts with long-lasting serum concentrations of infliximab and never ATI (+)
ASPIRE: Integrated Safety Summary, Sep. 18, 2003

38. Infliximab Infliximab indicated Exclude enteric pathogen
Exclude abscess, stricture
Exclude latent/active TB
(Start 6-MP/AZA or MTX)
Response
Observe up to 8 wks
Infliximab 5 mg/kg wks 0, 2, 6
Consider steroid pre-treatment
Consider acetaminophen, diphenhydramine pre-treatment
Recurrent sx ≤ 4 wks
Recurrent sx > 4 - < 8 wks
Recurrent sx ≥ 8 wks
Once a decision to treat with infliximab has been made, infectious complications need to be first guarded against by diagnosing and treating enteric pathogens, abscess, tuberculosis, or other infectious issues. Concurrent treatment with an immune modulator is desirable to minimize risk of antibodies to infliximab and subsequent loss of response. Similarly, once a course of treatment has been begun, maintenance dosing at regular intervals of 8 weeks or less should ensue, again to minimize the formation of antibodies to infliximab. Patients who do not respond to 5 mg/kg may respond to dose escalation, while patients who require treatment intervals of less than 8 weeks may be maintained at shorter intervals.
Inadequate response
Maintain infliximab 5 mg/kg q 4-8 wks
Infliximab 10 mg/kg
Inadequate response
Inadequate response
Surgery or investigational Rx
Escalate dose or shorten interval
Maintain infliximab 5 mg/kg q 8 wks
Loss of response

39. Medical Management / CD
Long-term Therapy :
A – IMMUNSUPPRESSIVA
A2T : 25/50 MG Tbl. +
- CS for Relapsing Falls
B – SURGERY
Remissions – maintenance
- 5.ASA : 2 g/d  2 years

40. Methotrexate

41. Historical Overview
1948 – first “designer drug” specific antagonist of folic acid
1950’s – serendipitous discovery of activity in psoriasis
1960’s – widely used for psoriasis – hepatotoxic
1966 – Enderlin reported use in RA
1985 – Wienblatt defines pharmacokinetics in RA
– treatment of choice for RA

42. MTX Results: Remission50
P =0.025
% Response 25
19.1%
39.4%
Placebo
MTX
Feagan. N Eng J Med. 1995;332(5):292-7

43. Methotrexate in IBD: Toxicity
Major
Hepatic
Myelosuppressive
Pulmonary
Fertility-related
Teratogenic
Enteritic/colitic
Minor
Gastrointestinal
Alopecia-inductive
Allergic
Neurologic
Egan LJ, Sandborn WJ. Mayo Clin Proc 1996;71:69-80

44. CD: Moderate to Severe Moderate CD Severe CD Observe Taper PO Steroids
Adequate response
Adequate response
Success
Observe
Taper
PO Steroids
IV Steroids
Inadequate response
Inadequate response
Failure
6-MP/AZA
Consider infliximab + 6-MP/AZA or MTX
Consider surgery
Adequate response
Inadequate response/intolerant
Maintain 6-MP/AZA or MTX
Adequate response
Consider change to MTX
Inadequate response/intolerant
Patients with more active symptoms may require a course of oral or intravenous steroids. Patients who are unable to successfully taper steroids, or who do not respond fully should be considered for 6-mercaptopurine, azathioprine, or methotrexate. Patients who do not fully respond to optimized dosing with these agents may be considered for infliximab, surgery, or investigational therapy.
Maintain infliximab + 6-MP/AZA or MTX
Adequate response
Add infliximab
Inadequate response/intolerant
Surgery or investigational therapy

45. Medical Management / UC
Refractory States or Chronic active Forms
Immunsuppressiva
A2T :
+ ? Cs
OP  Proctocolectomy
(= Definitive Cure)

46. Ulcerative Colitis
Remissions – Maintenance
5-ASA  2 gr/d

47. OP – Indications / CD Bleeding Ileus Stenosis Fistula Carcinom
Perforation
Abcess

48. OP – Indications / UC
Toxic Megacolon
Perforation
Severe Bleeding