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Inflammatory bowel diseases (IBD). Inflammatory bowel diseases. Ulcerative colitis. Crohn’s disease. 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.

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Inflammatory bowel diseases ibd

Inflammatory bowel diseases

Ulcerative colitis

Crohn’s disease


Inflammatory bowel diseases ibd

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


Extraintestinal symptomes localisation
Extraintestinal symptomes /localisation

  • Joints - arthritis

  • Skin – erythema nodosum, pyoderma gangrenosum

  • Eye - iridocyclitis

  • Liver – cholostatic liver diseases (primary sclerozing cholangitis)


The ulcerative colitis
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.


The diagnosis of the ulcerative colitis i
The diagnosis of the ulcerative colitis I.

  • History

    • Diarrhea (during the night as well)

    • Bleeding (fresh, bright, evtl. purulent)

    • Pain – tenesmus

    • Fever

    • Weight loss


The diagnosis of the ulcerative colitis ii
The diagnosis of the ulcerative colitis II.

  • Physical examination

    • Tenderness

    • Extraintestinal localization

      • Skin

      • Eye

      • Joints


The diagnosis of the ulcerative colitis iii
The diagnosis of the ulcerative colitis III.

  • Ultrasonography

  • Endoscopy

  • Histology

  • Endoscopic scores

  • Disease activity scores


The endoscopic characteristics of the ulcerative proctocolitis
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.


Localisation of ulcerative colitis
Localisation of ulcerative colitis

  • 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
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


The differential diagnosis of ulcerative colitis
The differential diagnosis of ulcerative colitis

  • Irradiation colitis

  • Ischaemic colitis

  • Infectious colitis

  • Pseudomembranous colitis

  • Others


Complications of ulcerative colitis
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


The crohn s disease
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.


The diagnosis of the crohn i
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


The diagnosis of the crohn s disease ii
The diagnosis of the Crohn’s disease II.

  • Physical examination

    • Tenderness

    • Abdominal mass

    • Increased peristalsis

    • Extraintestinal localization

      • Skin

      • Eye

      • Joints

    • Fistulas (most typical perianal)


The diagnosis of the crohn s disease iii
The diagnosis of the Crohn’s disease III.

  • Ultrasonography

  • Endoscopy

    • Histology

  • Double contrast enterography

  • CT scan

  • Immunscintigraphy

  • Disease activity scores


The endoscopic characteristics of the crohn s disease
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.


Localisation of crohn s disease
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


The diagnosis of the crohn s disease iv
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


Complications of crohn s disease
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



Drogs used in the medical therapy of ibd

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


New possibilities for the therapy
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)


Aminoszalicylic acid
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)


A sulfasalazine
A sulfasalazine

N

N

SULFAPYRIDIN

5-AMINOSALICYL-

ACETAT

azo

The side effects are mainly due to sulfapyridine

The effective part


Sulfasalazine pharmacology
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


The indications of sulfasalazine treatment
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


Sulfasalazine toxicity
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


Sulfasalazine analogs
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


Olsalazine
Olsalazine

l

l

=

N

N

Bacterial spliting

l

l

+

5-ASA

5-ASA


Steroids
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)


Locally acting corticosteroids

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


Systemic acting corticosteroids

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


Immun modulants
Immun-modulants

  • AZA/6MP - Imuran

  • Methotrexat

  • Cyclosporin-A


Antibiotics
Antibiotics

  • Metronidazol

  • Ciprofloxacin


The biologic treatment
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.


The theoretical possibilities of the biological treatment
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


Possible biological therapies
Possible „biological” therapies

  • Rekombinant cytokines

  • Rekombinant immunoadhaesines

  • Oligopeptid receptor agonists, antagonists

  • Antisense oligonucleotids

  • Chimera- or human monoklonal antibodies



The role of p ro inflammator ic cytokines in c rohn s disease
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


Inflammatory bowel diseases ibd

Infliximab – mode of action


Chime ra s h uman antibodies
Chimera és„human” antibodies


Tnf 17 kd proinflammatoric cytokin
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


Possibilities for decreasing the effect of tnf
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


Infliximab remicade
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


The treatment strategy of sever crohn s disease
The treatment strategy of sever Crohn’s disease

  • Iv. steroid

  • oral 5-ASA

  • AZA/6MP

  • Antibiotics

  • TNF- α antibody

  • Complication - surgery