Inflammatory bowel diseases (IBD)

1. Inflammatory bowel diseases (IBD)

2. Inflammatory bowel diseases Ulcerative colitis Crohn’s disease

3. Infammatory bowel diseases (IBD) Ulcerative colitis Crohn’s disease Inflammation of all layers of the g.i. tract Inflammation and ulcers only in the mucosa of the colon Ileitis Ileocolitis Colitis

4. Extraintestinal symptomes /localisation • Joints - arthritis • Skin – erythema nodosum, pyoderma gangrenosum • Eye - iridocyclitis • Liver – cholostatic liver diseases (primary sclerozing cholangitis)

5. The ulcerative colitis • The Crohn’s disease is a chronic disease with changing, relapsing course. • The etiology is unknown. • Immunological factors are involved in the pathogenesis. • The genetical background is not completely understood but partly cleared • It localizes the whole gastrointestinal tract and the full thickness of the mucosa. • (After surgical resection it recurres.) • The most typical site is • the terminal ileum, • the large bowel and • other parts of the small bowel.

6. The diagnosis of the ulcerative colitis I. • History • Diarrhea (during the night as well) • Bleeding (fresh, bright, evtl. purulent) • Pain – tenesmus • Fever • Weight loss

7. The diagnosis of the ulcerative colitis II. • Physical examination • Tenderness • Extraintestinal localization • Skin • Eye • Joints

8. The diagnosis of the ulcerative colitis III. • Ultrasonography • Endoscopy • Histology • Endoscopic scores • Disease activity scores

9. The endoscopic characteristics of the ulcerative proctocolitis • In case of a mild inflammation the vascular pattern disappears, and the mucosal surface is granular. Touching the mucosa it bleeds. • In more serious cases there are a lot of small ulcers and spontaneous bleeding. • In the most serious cases the are large ulcerated mucosal surfaces, covered with exudate. Bleeding.

10. Localisation of ulcerative colitis • The rectum in almost always involved • The recto-sigmoid localization is frequent • Left sided colitis • Right sided colitis • Pancolitis

11. The diagnosis of the ulcerative colitis IV. • Laboratory • The sign of inflamm. (acitivity) • slight thrombocytosis, (acitivity) • elevated CRP (acitivity) • iron deficiency (occult bleeding) • Low se.protein, albumin (detoriated condition – very bad sign) • ANCA, ASCA • Combination with autoimmun diseases • Cholostasis (alk.ph. ↑, gammaGT ↑) in case of PSC

12. The differential diagnosis of ulcerative colitis • Irradiation colitis • Ischaemic colitis • Infectious colitis • Pseudomembranous colitis • Others

13. Complications of ulcerative colitis • Toxic megacolon • The consequences of activity • Bleeding - always in case of activity • Perforation - rare • Malignancy – colorectal cancer. Only in cases of pancolitis or involvement of the majority of the colon. There is no increased risk if the disease localizes on the rectum –i.e. proctitis). The risk of cancer increases 10 years after the beginining of the disease. • Primary sclerotising cholangitis – later cholangiocarcinoma

14. The Crohn’s disease • The Crohn’s disease is a chronic disease with changing, relapsing course. • The etiology is unknown. • Immunological factors are involved in the pathogenesis. • The genetical background is not completely understood but partly cleared • It localizes the whole gastrointestinal tract and the full thickness of the mucosa. • (After surgical resection it recurres.) • The most typical site is • the terminal ileum, • the large bowel and • other parts of the small bowel.

15. The diagnosis of the Crohn’ I. • History • Diarrhea (during the night as well partly activity, partly bile acid colitis) • Bleeding (differently from the ulcerative colitis the bleeding is exceptional – mainly if the large bowel is involved) • Pain – the site is not typical but can reflect the localization of the disease (i.e. ileocoecal) • Increased peristalsis – in case of stenosis • Malabsorption • Fever • Weight loss

16. The diagnosis of the Crohn’s disease II. • Physical examination • Tenderness • Abdominal mass • Increased peristalsis • Extraintestinal localization • Skin • Eye • Joints • Fistulas (most typical perianal)

17. The diagnosis of the Crohn’s disease III. • Ultrasonography • Endoscopy • Histology • Double contrast enterography • CT scan • Immunscintigraphy • Disease activity scores

18. The endoscopic characteristics of the Crohn’s disease • „Aphtoid” lesions • Huge ulcers surrounded, by relative normal mucosa „skipped lesions”. • Stenoses are more frequent (compared with the ulc. colitis). • The terminal ileum can be involved.

19. Localisation of Crohn’s disease • The terminal ileum • The terminal ileum + right side of the colon • The colon • Other parts of the small bowel • Any part of the gastrointestinal tract

20. The diagnosis of the Crohn’s disease IV. • Laboratory • The sign of inflamm. (acitivity) • slight thrombocytosis, (acitivity) • elevated CRP (acitivity) • iron deficiency (occult bleeding) • low Ca (malabsorption) • pozitive Schilling test – impaired B12 absorption • ANCA, ASCA • Combination with autoimmun diseases • Cholostasis (alk.ph. ↑, gammaGT ↑) in case of PSC

21. Complications of Crohn’s disease • Stenoses - subileus • Fistula building • External (most typically perianal) • Internal • recto-vaginal, • recto-vesical – faecal urin • entero-colic – malabsorption • Abscesses • Bleeding • Perforation - rare • Malignancy – colorectal cancer. Only in cases of colonic localization. • Primary sclerotising cholangitis – later cholangiocarcinoma

22. The therapy of the inflammatory bowel diseases

23. Symptomatic acting drogs Against diarrhea spamolytics cholestyramin 5-ASA preparates sulfasalazine olsalazine oral 5-ASA (mesalamine) and azo-analoges local 4-ASA and 4-ASA Corticosteroids oral corticosteroids parenteral preparates parenteral ACTH local corticosteroids Immunmodulant drogs Antibiotics Metronidazol ciproflaxin Others nicotin heparin Drogs used in the medical therapy of IBD

24. New possibilities for the therapy • Biomodulation • Background – the way of action is the correction of the imbalance between the proinflammatoric (pl.TNF-, IL-2) and antiinflammatoric (pl. IL-10, IL-12) cytokines by • Inhibition of the inflammatory mediators • The promotion of the antiinflammatory mediators • Influencing the luminal factors (probiotics)

25. Aminoszalicylic acid • Oral, suppositoria, enema • The site of the action of the oral preparates can be influanced by using different formulations • Formulations Azo binding - sulfasalazin (Salazopyrin, Dipentum) Other formul. - mesalazine (Pentasa, Salofalk)

26. A sulfasalazine N N SULFAPYRIDIN 5-AMINOSALICYL- ACETAT azo The side effects are mainly due to sulfapyridine The effective part

27. Sulfasalazine pharmacology ll=l Sulfasalazine ll Sulfapyridine • Sulfasalazine gets into the large bowel without absorption, After the bacterial splitting of the azo binding the sulfapyridine part excrets with the urine. The 5-ASA remains in the gastrointestinal tract. l 5-ASA l l l ll l l ll=l l l

28. The indications of sulfasalazine treatment • Ulcerative proctocolitis • The mild or moderately active form • The maintenance of remission • Crohn’s disease • The mild or moderately active form • The maintenance of remission • The prevention of postoperative relapses

29. Sulfasalazine toxicity • Frequent side effects: dyspepsia, nausea, loss of appetite, headache • Allergic reactions: rushes, fever, arthralgy • Haematologic changes: • mild: haemolysis, neutropenie, folic acid def. • sever: haemolysis, agranulocytosis • Sever toxic reactions: pulmonary, liver, pancreas, skin, neurologic

30. Sulfasalazine analogs ll=l Oral preparates Rectal preparates Sulfapyridine 5-ASA l Sustained release 5-ASA mesalamine l = l Carrier molecule 4-ASA balsalazine l = l Olsalazine

31. Olsalazine l l = N N Bacterial spliting l l + 5-ASA 5-ASA

32. Steroids • Systemic acting • oral preparates, • suppositoria, • enemas (the most frequently used is metilprednisolone) (not used for long lasting therapy – side effects) • Locally acting (fast metabilising) • oral, • enemas (budenoside is the most frequently used - relatively safe)

33. Indications Proctitis and left-sided colitis Preparations Systemic acting Week systemic effects (partly absorbing) No systemic effect („first pass”metabolism in the liver) hydrocortison prednisolon metasulfo-benzoate budesonide Locally acting corticosteroids

34. Oral Indications Preparations Parenteral Moderately severe and severe ulceratve colitis and Crohn’s disese prednisolone methylprednisolone Other corticosteroides Severe or toxic ulcerative colitis or Crohn’s disease Systemic acting corticosteroids

35. Immun-modulants • AZA/6MP - Imuran • Methotrexat • Cyclosporin-A

36. Antibiotics • Metronidazol • Ciprofloxacin

37. The „biologic” treatment • The „biologic treatment” are targetted on a specific site of the inflammatory cascade (cytokin or kemokin effector molecules). • They influence the activation of the immune system.

38. The theoretical possibilities of the biological treatment • Nativ biological preparations ( vaccines or other preparates containing living, killed or attenuated mikroorganisms) • Recombinant peptides, proteins (growth hormon, erythropoetin etc) • Antibodies • Nuclein acids • Cell or gen therapy

39. Possible „biological” therapies • Rekombinant cytokines • Rekombinant immunoadhaesines • Oligopeptid receptor agonists, antagonists • Antisense oligonucleotids • Chimera- or human monoklonal antibodies

40. Biotechnological molecules

41. The role of pro-inflammatoric cytokines in Crohn’s disease The inflammation and injury ov mucosa IL-6 Plasma cell B sejt Plasma cell T cell activation IL-8 Humoral immune response Antigen presenting cell TNFa IL-1 GM-CSF Antigen Leukotriens, superoxidoks, nitrit oxid and prostaglandins Inflammatory cell adhaesion

42. Infliximab – mode of action

43. Chimera és„human” antibodies

44. TNF-17 kD proinflammatoric cytokin • Produced: by monocyte, makrophag, Th1 CD4+, NK-cells, mastocytes • Effects: • Influences • the proliferácion • the differenciation • the function Of nearly each cell • Acute phase reaction (inflammation) • Cytotoxicity, apoptosis • Enhancement of IL-1, IL-6 production • Systemic reaction • Tumor

45. Possibilities for decreasing the effect of TNF- • To block the production of TNF • Pentoxiphyllin • Thalidomide • GSC, cyclosporin • TNF monoclonal antibodies • Infliximab • CDP571 • TNF neutralizing protein

46. Infliximab-Remicade • Chimera monoclonalis IgG1 TNF- antibody • Effect: • Blocks the solubl TNF- • Binds the transmembran TNF-  • Has an effect on the cytolysis • It has antigen properties • Indication: • Fistulazing CD • Activ, refracter CD Side effectss: upper respir. Inflamm. late hypersensitivity myalgy, arthalgy, fever, oedema

47. The treatment strategy of sever Crohn’s disease • Iv. steroid • oral 5-ASA • AZA/6MP • Antibiotics • TNF- α antibody • Complication - surgery