Inflammatory Inflammatory bowel diseasesbowel diseases

(IBD)(IBD)

Inflammatory bowel diseases

Ulcerative colitis

Crohn’s disease

Ulcerative colitisUlcerative colitis Crohn’s diseaseCrohn’s disease

Inflammation and ulcers Inflammation and ulcers only in the mucosa of the only in the mucosa of the

coloncolon

Inflammation of all layers of Inflammation of all layers of the g.i. tractthe g.i. tract

Infammatory bowel diseases (IBD)

IleitisIleitis IleocolitisIleocolitis ColitisColitis

Joints - arthritisJoints - arthritis Skin – erythema nodosum, pyoderma Skin – erythema nodosum, pyoderma

gangrenosumgangrenosum Eye - iridocyclitisEye - iridocyclitis Liver – cholostatic liver diseases Liver – cholostatic liver diseases

(prima(primaryry sclero sclerozzing cholangitising cholangitis))

Extraintestinal symptomes /localisation

Extraintestinal symptomes /localisation

The ulcerative colitisThe 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.

HistoryHistory Diarrhea (during the night as well)Diarrhea (during the night as well) Bleeding (fresh, bright, evtl. Bleeding (fresh, bright, evtl. ppurulent)urulent) Pain – tenesmusPain – tenesmus FeverFever Weight lossWeight loss

The diagnosis of the ulcerative colitis I.

The diagnosis of the ulcerative colitis I.

Physical examinationPhysical examination TendernessTenderness Extraintestinal localizationExtraintestinal localization

SkinSkin EyeEye JointsJoints

The diagnosis of the ulcerative colitis II.

The diagnosis of the ulcerative colitis II.

UltrasonographyUltrasonography EndoscopyEndoscopy HistologyHistology

Endoscopic scoresEndoscopic scores Disease activity scoresDisease activity scores

The diagnosis of the ulcerative colitis III.

The diagnosis of the ulcerative colitis III.

The endoscopic characteristics of the ulcerative proctocolitis

The endoscopic characteristics of the ulcerative proctocolitis

In case of a mild inflammation the In case of a mild inflammation the vascular pattern disappears, and vascular pattern disappears, and the mucosal surface is granular. the mucosal surface is granular. Touching the mucosa it bleeds.Touching the mucosa it bleeds.

In more serious cases there are a In more serious cases there are a lot of small ulcers and lot of small ulcers and spontaneous bleeding.spontaneous bleeding.

In the most serious cases the are In the most serious cases the are large ulcerated mucosal surfaces, large ulcerated mucosal surfaces, covered with exudate. Bleeding.covered with exudate. Bleeding.

Localisation of ulcerative colitisLocalisation of ulcerative colitis

The rectum in almost The rectum in almost always involvedalways involved

The recto-sigmoid The recto-sigmoid localization is frequentlocalization is frequent

Left sided colitisLeft sided colitis Right sided colitisRight sided colitis PancolitisPancolitis

LaboratoryLaboratory The sign of inflamm. (acitivity)The sign of inflamm. (acitivity) slight thrombocytosis, (acitivity)slight thrombocytosis, (acitivity) elevated CRP (acitivity)elevated CRP (acitivity) iron deficiency (occult bleeding)iron deficiency (occult bleeding) Low se.protein, albumin (detoriated condition – very Low se.protein, albumin (detoriated condition – very

bad sign)bad sign) ANCA, ASCAANCA, ASCA Combination with autoimmun diseasesCombination with autoimmun diseases Cholostasis (alk.ph. ↑, gammaGT ↑) in case of PSCCholostasis (alk.ph. ↑, gammaGT ↑) in case of PSC

The diagnosis of the ulcerative colitis IV.The diagnosis of the ulcerative colitis IV.

The differential diagnosis of ulcerative colitisThe differential diagnosis of ulcerative colitis

Irradiation colitisIrradiation colitis Ischaemic colitisIschaemic colitis Infectious colitisInfectious colitis Pseudomembranous Pseudomembranous

colitiscolitis OthersOthers

Toxic megacolonToxic megacolon The consequences of activityThe consequences of activity

Bleeding - always in case of activity Bleeding - always in case of activity Perforation - rarePerforation - rare

Malignancy – colorectal cancer. Only in cases of pancolitis Malignancy – colorectal cancer. Only in cases of pancolitis or involvement of the majority of the colon. There is no or involvement of the majority of the colon. There is no increased risk if the disease localizes on the rectum –i.e. increased risk if the disease localizes on the rectum –i.e. proctitis). The risk of cancer increases 10 years after the proctitis). The risk of cancer increases 10 years after the begbegiinining of the disease.nining of the disease.

Primary sclerotiPrimary sclerotisising cholangitis – later ng cholangitis – later cholangiocarcinomacholangiocarcinoma

Complications of ulcerative colitisComplications of ulcerative colitis

The Crohn’s diseaseThe 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.

HistoryHistory Diarrhea (during the night as wellDiarrhea (during the night as well partly activity, partly partly activity, partly

bile acid colitis)bile acid colitis) Bleeding (differently from the ulcerative colitis the Bleeding (differently from the ulcerative colitis the

bleeding is exceptional – mainly if the large bowel is bleeding is exceptional – mainly if the large bowel is involved)involved)

Pain – the site is not typical but can reflect the Pain – the site is not typical but can reflect the localization of the disease (i.e. ileocoecal)localization of the disease (i.e. ileocoecal)

Increased peristalsis – in case of stenosisIncreased peristalsis – in case of stenosis MalabsorptionMalabsorption FeverFever Weight lossWeight loss

The diagnosis of the Crohn’ I.The diagnosis of the Crohn’ I.

Physical examinationPhysical examination TendernessTenderness Abdominal massAbdominal mass Increased peristalsisIncreased peristalsis Extraintestinal localizationExtraintestinal localization

SkinSkin EyeEye JointsJoints

Fistulas (most typical perianal)Fistulas (most typical perianal)

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

UltrasonographyUltrasonography EndoscopyEndoscopy

HistologyHistology Double contrast enterographyDouble contrast enterography CT scanCT scan ImmunscintigraphyImmunscintigraphy

Disease activity scoresDisease activity scores

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

The endoscopic characteristics of the Crohn’s disease

The endoscopic characteristics of the Crohn’s disease

„„Aphtoid” lesionsAphtoid” lesions Huge ulcers Huge ulcers

surrounded, by surrounded, by relative normal relative normal mucosa „skipped mucosa „skipped lesions”.lesions”.

StenosStenosees are more s are more frequent (compared frequent (compared with the ulc. colitis).with the ulc. colitis).

The terminal ileum The terminal ileum can be involved.can be involved.

Localisation of Crohn’s diseaseLocalisation of Crohn’s disease

The terminal ileumThe terminal ileum The terminal ileum + The terminal ileum +

right side of the colonright side of the colon The colonThe colon Other parts of the Other parts of the

small bowelsmall bowel Any part of the Any part of the

gastrointestinal tractgastrointestinal tract

LaboratoryLaboratory The sign of inflamm. (acitivity)The sign of inflamm. (acitivity) slight thrombocytosis, (acitivity)slight thrombocytosis, (acitivity) elevated CRP (acitivity)elevated CRP (acitivity) iron deficiency (occult bleeding)iron deficiency (occult bleeding) low Ca (malabsorption)low Ca (malabsorption) pozitive Schilling test – impaired Bpozitive Schilling test – impaired B1212 absorption absorption ANCA, ASCAANCA, ASCA Combination with autoimmun diseasesCombination with autoimmun diseases Cholostasis (alk.ph. ↑, gammaGT ↑) in case of PSCCholostasis (alk.ph. ↑, gammaGT ↑) in case of PSC

The diagnosis of the Crohn’s disease IV.The diagnosis of the Crohn’s disease IV.

Stenoses - subileusStenoses - subileus Fistula building Fistula building

External (most typically perianal)External (most typically perianal) Internal Internal

recto-vaginal, recto-vaginal, recto-vesical – faecal urinrecto-vesical – faecal urin entero-colic – malabsorptionentero-colic – malabsorption

AbscessesAbscesses BleedingBleeding Perforation - rarePerforation - rare Malignancy – colorectal cancer. Only in cases of colonic Malignancy – colorectal cancer. Only in cases of colonic

localization. localization. Primary sclerotising cholangitis – later cholangiocarcinomaPrimary sclerotising cholangitis – later cholangiocarcinoma

Complications of Crohn’s diseaseComplications of Crohn’s disease

The therapy of the inflammatory bowel diseases

The therapy of the inflammatory bowel diseases

Drogs used in the medical therapy of IBDDrogs used in the medical therapy of IBD

Symptomatic acting drogsSymptomatic acting drogs Against dAgainst diarrheaiarrhea spamolyticsspamolytics cholestyramincholestyramin

5-ASA preparates5-ASA preparates sulfasalazinesulfasalazine olsalazineolsalazine oral 5-ASA (mesalamine) and oral 5-ASA (mesalamine) and

azo-analogesazo-analoges local 4-ASA and 4-ASAlocal 4-ASA and 4-ASA

CorticosteroidsCorticosteroids oral corticosteroidsoral corticosteroids parenteral preparatesparenteral preparates parenteral ACTHparenteral ACTH local corticosteroidslocal corticosteroids

Immunmodulant drogsImmunmodulant drogs AntibioticsAntibiotics

MetronidazolMetronidazol ciproflaxinciproflaxin

OthersOthers nicotinnicotin heparinheparin

New possibilities for the therapyNew possibilities for the therapy

Biomodulation Biomodulation Background – the way of action is the correction of Background – the way of action is the correction of

the imbalance between the proinflammatoric the imbalance between the proinflammatoric (pl.TNF-(pl.TNF-, IL-2) and antiinflammatoric (pl. IL-10, , IL-2) and antiinflammatoric (pl. IL-10, IL-12) cytokines byIL-12) cytokines by Inhibition of the inflammatory mediators Inhibition of the inflammatory mediators The promotion of the antiinflammatory mediatorsThe promotion of the antiinflammatory mediators

Influencing the luminal factors (probiotics)Influencing the luminal factors (probiotics)

Aminoszalicylic acidAminoszalicylic acid

Oral, suppositoria, enemaOral, suppositoria, enema The site of the action of the oral preparates can be The site of the action of the oral preparates can be

influanced by using different formulationsinfluanced by using different formulations FormulationsFormulations

Azo bindingAzo binding - sulfasalazin (Salazopyrin, - sulfasalazin (Salazopyrin, Dipentum)Dipentum)

Other formul. - mesalazine (Pentasa, Salofalk)Other formul. - mesalazine (Pentasa, Salofalk)

A sulfasalazineA sulfasalazine

NN NNazoazo

5-AMINOSALICYL-5-AMINOSALICYL-ACETATACETAT

SULFAPYRIDINSULFAPYRIDIN

The effective partThe effective partThe side effects are mainly due to sulfapyridine

Sulfasalazine pharmacologySulfasalazine pharmacology

Sulfasalazine

Sulfapyridine

5-ASA

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

=

=

Ulcerative proctocolitisUlcerative proctocolitis The mild or moderately active form The mild or moderately active form The maintenance of remissionThe maintenance of remission

Crohn’s diseaseCrohn’s disease The mild or moderately active form The mild or moderately active form The maintenance of remissionThe maintenance of remission The prevention of postoperative relapsesThe prevention of postoperative relapses

The indications of sulfasalazine treatment

The indications of sulfasalazine treatment

Sulfasalazine toxicity

Sulfasalazine toxicity

Frequent side effects: dyspepsia, nausea, loss Frequent side effects: dyspepsia, nausea, loss of appetite, headacheof appetite, headache

Allergic reactions: rushes, fever, arthralgyAllergic reactions: rushes, fever, arthralgy Haematologic changes: Haematologic changes:

mild: haemolysis, neutropenie, folic acid def.mild: haemolysis, neutropenie, folic acid def. sever: haemolysis, agranulocytosissever: haemolysis, agranulocytosis

Sever toxic reactions: pulmonary, liver, Sever toxic reactions: pulmonary, liver, pancreas, skin, neurologicpancreas, skin, neurologic

Sulfasalazine analogsSulfasalazine analogs

=Sulfapyridine 5-ASA

==

Oral preparatesOral preparates Rectal Rectal preparatespreparates

Sustained release

Olsalazine

5-ASA

4-ASA

mesalamine

balsalazine

Carrier molecule

OlsalazineOlsalazine

= N N

Bacterial splitingBacterial spliting

5-ASA 5-ASA+

SteroidsSteroids Systemic actingSystemic acting

oral preparates, oral preparates, suppositoria,suppositoria, enemasenemas (the most frequently used is metilprednisolone)(the most frequently used is metilprednisolone)

(not used for long lasting therapy – side effects)(not used for long lasting therapy – side effects) Locally acting (fast metabilising)Locally acting (fast metabilising)

oral, oral, enemasenemas (budenoside (budenoside

is the most frequently used - relatively safe)is the most frequently used - relatively safe)

Locally acting corticosteroidsLocally acting corticosteroids

IndicationsIndications Proctitis and left-sided Proctitis and left-sided

colitiscolitis PreparationsPreparations

Systemic Systemic actingacting

WeekWeek systemic effects systemic effects ((partly partly absorabsorbingbing))

No systemic effect No systemic effect („first pass”metabolism in („first pass”metabolism in

the liver)the liver)

hydrocortisonhydrocortison prednisolon metasulfo-benzoateprednisolon metasulfo-benzoate

budesonidebudesonide

Systemic acting corticosteroidsSystemic acting corticosteroids

OralOral IndicationsIndications

PreparationsPreparations

ParenteralParenteral

Moderately severe and severe Moderately severe and severe ulceratve colitis and Crohn’s diseseulceratve colitis and Crohn’s disese

prednisoloneprednisolone methylprednisolonemethylprednisolone Other corticosteroidesOther corticosteroides

Severe or toxic ulcerative colitis or Severe or toxic ulcerative colitis or Crohn’s diseaseCrohn’s disease

Immun-modulantsImmun-modulants

AZA/6MP - Imuran AZA/6MP - Imuran

MethotrexatMethotrexat

Cyclosporin-ACyclosporin-A

AntibioticsAntibiotics

MetronidazolMetronidazol CiprofloxacinCiprofloxacin

The „biologic” treatmentThe „biologic” treatment

The „biologic treatment” are targetted on a The „biologic treatment” are targetted on a specific site of the inflammatory cascade specific site of the inflammatory cascade (cytokin or kemokin effector molecules).(cytokin or kemokin effector molecules).

They influence the activation of the immune They influence the activation of the immune system.system.

The theoretical possibilities of the biological treatment

The theoretical possibilities of the biological treatment

Nativ biological preparations ( vaccines or Nativ biological preparations ( vaccines or other preparates containing living, killed or other preparates containing living, killed or attenuated mikroorganisms) attenuated mikroorganisms)

Recombinant peptides, proteins (growth Recombinant peptides, proteins (growth hormon, erythropoetin etc)hormon, erythropoetin etc)

AntibodiesAntibodies Nuclein acidsNuclein acids Cell or gen therapyCell or gen therapy

Possible „biological” therapiesPossible „biological” therapies

Rekombinant cytokinesRekombinant cytokines Rekombinant immunoadhaesinesRekombinant immunoadhaesines Oligopeptid receptor agonists, Oligopeptid receptor agonists,

antagonistsantagonists Antisense oligonucleotidsAntisense oligonucleotids Chimera- or human monoklonal Chimera- or human monoklonal

antibodiesantibodies

Biotechnological moleculesBiotechnological molecules

EffectEffect Ind.Ind. FaseFase

Lymphocyte diff: Lymphocyte diff:

TH1/TH2TH1/TH2

anti-IFanti-IF antibody antibody

IL-10IL-10

CDCD

CDCD

CUCU

II.II.

III.(-)III.(-)

II. (-)II. (-)

Lymphocyte functionLymphocyte function

anti-sense ICAM-1 (Isis 2302)anti-sense ICAM-1 (Isis 2302)

CDCD

CUCU

III.(-)III.(-)

II.II.

TNF-mediated inflammationTNF-mediated inflammation

InfliximabInfliximab

CDP571CDP571

TNF rec. fusions protein (etanercept)TNF rec. fusions protein (etanercept)

p55 TNF binding protein (onercept)p55 TNF binding protein (onercept)

ThalidomidThalidomid

CD,CU CD,CU CD,CUCD,CU

CDCD

CDCD

CDCD

IV, IIIIV, III

III,II.III,II.

II. (-)II. (-)

II.II.

II.a.II.a.

IF, EGF, Il-11, anti-CD40 ligand antibodyIF, EGF, Il-11, anti-CD40 ligand antibody CD,CUCD,CU II.II.

The role of pro-inflammatoric cytokines in Crohn’s disease

The inflammation and injury ov mucosa

The inflammation and injury ov mucosa

Plasma cellPlasma cell

Plasma cellPlasma cell

IL-6IL-6

B sejtB sejt

Inflammatory cell adhaesionInflammatory cell adhaesion

AntigenAntigen

Antigen presenting cellAntigen presenting cell

T cell activation

T cell activation

TNFTNF

GM-CSFGM-CSFIL-1IL-1

IL-8IL-8 Humoral immune response

Humoral immune response

Leukotriens, superoxidoks, nitrit oxid and prostaglandins

Leukotriens, superoxidoks, nitrit oxid and prostaglandins

Infliximab – mode of action

Chimera és „human” antibodiesChimera és „human” antibodies

TNF-17 kD proinflammatoric cytokin

TNF-17 kD proinflammatoric cytokin

Produced: by monocyte, makrophag, Th1 CD4+, NK-cells, Produced: by monocyte, makrophag, Th1 CD4+, NK-cells, mastocytesmastocytes

Effects:Effects: InfluencesInfluences

the proliferácionthe proliferácion the differenciationthe differenciation the functionthe function

Of nearly each cell Of nearly each cell Acute phase reaction (inflammation)Acute phase reaction (inflammation) Cytotoxicity, apoptosisCytotoxicity, apoptosis Enhancement of IL-1, IL-6 productionEnhancement of IL-1, IL-6 production Systemic reactionSystemic reaction TumorTumor

Possibilities for decreasing the effect of TNF-

Possibilities for decreasing the effect of TNF-

To block the production of TNFTo block the production of TNF PentoxiphyllinPentoxiphyllin ThalidomideThalidomide GSC, cyclosporinGSC, cyclosporin

TNF monoclonal antibodiesTNF monoclonal antibodies InfliximabInfliximab CDP571CDP571

TNF neutralizing proteinTNF neutralizing protein

Infliximab-RemicadeInfliximab-Remicade Chimera monoclonalis IgG1 TNF-Chimera monoclonalis IgG1 TNF- antibody antibody Effect:Effect:

Blocks the solubl TNF-Blocks the solubl TNF- Binds the transmembran TNF- Binds the transmembran TNF- Has an effect on the cytolysisHas an effect on the cytolysis It has antigen propertiesIt has antigen properties

Indication:Indication: Fistulazing CDFistulazing CD Activ, refracter CDActiv, refracter CDSide effectss: Side effectss: upper respir. Inflamm.upper respir. Inflamm.

late hypersensitivitylate hypersensitivitymyalgy, arthalgy, fever, oedemamyalgy, arthalgy, fever, oedema

Iv. steroidIv. steroid oral 5-ASAoral 5-ASA AZA/6MPAZA/6MP AntibioticsAntibiotics TNF- α antibodyTNF- α antibody Complication - surgeryComplication - surgery

The treatment strategy of sever Crohn’s disease

The treatment strategy of sever Crohn’s disease