Inflammatory bowel diseases IBD Inflammatory bowel diseases Ulcerative

Inflammatory bowel diseases (IBD)

Inflammatory bowel diseases Ulcerative colitis Crohn’s disease

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

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

n n n n 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 The ulcerative colitis thickness of the mucosa. (After surgical resection it recurres. ) The most typical site is u the terminal ileum, u the large bowel and u other parts of the small bowel.

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

The diagnosis of the ulcerative colitis II. n Physical examination u Tenderness u Extraintestinal localization Skin F Eye F Joints F

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

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. n In more serious cases there a lot of small ulcers and spontaneous bleeding. n In the most serious cases the are large ulcerated mucosal surfaces, covered with exudate. Bleeding. n

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

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

The differential diagnosis of ulcerative colitis Irradiation colitis n Ischaemic colitis n Infectious colitis n Pseudomembranous colitis n Others n

Complications of ulcerative colitis n n Toxic megacolon The consequences of activity u u n n 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

n n n n 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. The whole. Crohn’s gastrointestinal tract and the full disease thickness of the mucosa. (After surgical resection it recurres. ) The most typical site is u the terminal ileum, u the large bowel and u other parts of the small bowel.

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

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

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

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

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

The diagnosis of the Crohn’s disease IV. n Laboratory u The sign of inflamm. (acitivity) u slight thrombocytosis, (acitivity) u elevated CRP (acitivity) u iron deficiency (occult bleeding) u low Ca (malabsorption) u pozitive Schilling test – impaired B 12 absorption u ANCA, ASCA u Combination with autoimmun diseases u Cholostasis (alk. ph. ↑, gamma. GT ↑) in case of PSC

Complications of Crohn’s disease n n Stenoses - subileus Fistula building u u External (most typically perianal) Internal F F F n n n 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

The therapy of the inflammatory bowel diseases

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

New possibilities for therapy n Biomodulation u 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 F The promotion of the antiinflammatory mediators F n Influencing the luminal factors (probiotics)

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

A sulfasalazine SULFAPYRIDIN N azo The side effects are mainly due to sulfapyridine N 5 -AMINOSALICYLACETAT The effective part

Sulfasalazine pharmacology n 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. ll=l Sulfasalazine ll Sulfapyridine l 5 -ASA l ll l l ll=l l l

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

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

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

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

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

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

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

Immun-modulants n AZA/6 MP - Imuran n Methotrexat n Cyclosporin-A

Antibiotics Metronidazol n Ciprofloxacin n

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

The theoretical possibilities of the biological treatment Nativ biological preparations ( vaccines or other preparates containing living, killed or attenuated mikroorganisms) n Recombinant peptides, proteins (growth hormon, erythropoetin etc) n Antibodies n Nuclein acids n Cell or gen therapy n 2003. Sandborn, Gastroenterology, 2002. 1592.

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

Biotechnological molecules Effect Ind. Fase Lymphocyte diff: TH 1/TH 2 anti-IF antibody IL-10 CD CD CU II. III. (-) Lymphocyte function anti-sense ICAM-1 (Isis 2302) CD CU III. (-) II. TNF-mediated inflammation Infliximab CDP 571 TNF rec. fusions protein (etanercept) p 55 TNF binding protein (onercept) Thalidomid CD, CU CD CD CD IV, III, II. (-) II. a. IF, EGF, Il-11, anti-CD 40 ligand antibody CD, CU II.

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

Infliximab – mode of action

Chimera és „human” antibodies

TNF- 17 k. D proinflammatoric cytokin n n Produced: by monocyte, makrophag, Th 1 CD 4+, NKcells, mastocytes Effects: u Influences the proliferácion F the differenciation F the function F Of nearly each cell u Acute phase reaction (inflammation) u Cytotoxicity, apoptosis u Enhancement of IL-1, IL-6 production u Systemic reaction u Tumor

Possibilities for decreasing the effect of TNF- n To block the production of TNF u Pentoxiphyllin u Thalidomide u GSC, cyclosporin n TNF monoclonal antibodies u Infliximab u CDP 571 n TNF neutralizing protein

Infliximab-Remicade n n Chimera monoclonalis Ig. G 1 TNF- antibody Effect: u Blocks the solubl TNF- u Binds the transmembran TNF- u Has an effect on the cytolysis u It has antigen properties n Indication: u Fistulazing CD u Activ, refracter CD Side effectss: upper respir. Inflamm. late hypersensitivity myalgy, arthalgy, fever, oedema

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