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Inflammatory Inflammatory bowel diseasesbowel diseases
(IBD)(IBD)
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Inflammatory bowel diseases
Ulcerative colitis
Crohn’s disease
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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
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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
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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.
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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.
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Physical examinationPhysical examination TendernessTenderness Extraintestinal localizationExtraintestinal localization
SkinSkin EyeEye JointsJoints
The diagnosis of the ulcerative colitis II.
The diagnosis of the ulcerative colitis II.
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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.
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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.
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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
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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.
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The differential diagnosis of ulcerative colitisThe differential diagnosis of ulcerative colitis
Irradiation colitisIrradiation colitis Ischaemic colitisIschaemic colitis Infectious colitisInfectious colitis Pseudomembranous Pseudomembranous
colitiscolitis OthersOthers
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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
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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.
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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.
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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.
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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.
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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.
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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
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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.
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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
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The therapy of the inflammatory bowel diseases
The therapy of the inflammatory bowel diseases
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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
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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)
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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)
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A sulfasalazineA sulfasalazine
NN NNazoazo
5-AMINOSALICYL-5-AMINOSALICYL-ACETATACETAT
SULFAPYRIDINSULFAPYRIDIN
The effective partThe effective partThe side effects are mainly due to sulfapyridine
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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.
=
=
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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
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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
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Sulfasalazine analogsSulfasalazine analogs
=Sulfapyridine 5-ASA
==
Oral preparatesOral preparates Rectal Rectal preparatespreparates
Sustained release
Olsalazine
5-ASA
4-ASA
mesalamine
balsalazine
Carrier molecule
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OlsalazineOlsalazine
= N N
Bacterial splitingBacterial spliting
5-ASA 5-ASA+
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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)
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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
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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
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Immun-modulantsImmun-modulants
AZA/6MP - Imuran AZA/6MP - Imuran
MethotrexatMethotrexat
Cyclosporin-ACyclosporin-A
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AntibioticsAntibiotics
MetronidazolMetronidazol CiprofloxacinCiprofloxacin
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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.
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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
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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
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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.
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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
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Infliximab – mode of action
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Chimera és „human” antibodiesChimera és „human” antibodies
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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
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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
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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
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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