Fagligt Selskab for Gastroenterologiske sygeplejerkser Mikroskopisk colitis Fagligt Selskab for Gastroenterologiske sygeplejerkser Landskursus, Kolding 16. November 2012 Ole Bonderup, Medicinsk afdeling, Regionshospitalet Silkeborg

Mikroskopisk colitis

Ole Bonderup, Medicinsk afd. Regionshospitalet Silkeborg Mikroskopisk colitis Collagenous Colitis (Lindström, 1976) Lymphocytic Colitis (Read et al.1980) (Lazenby et al., 1989) Microscopic Colitis Ole Bonderup, Medicinsk afd. Regionshospitalet Silkeborg

Mikroskopisk colitis

Mikroskopisk colitis

Mucosal tears in collagenous colitis Allende DS et al. Am J Gastroenterol 2008

Mikroskopisk colitis It´s best to know what you are looking for before you look for it Normal colon mucosa Lymphocytic colitis Collagenous colitis

Mikroskopisk colitis MC versus non MC Interobserver agreement 91% (kappa = 0.90) Intraobserver agreement 95% (kappa = 0.89). Tre patologer vurderer 20 lymfocytære, 20 collagene 30 normale I vort eget studie god correlation melllem to vurderinger af inflammation og tykkelse af collagent lag. Limsui D, et al Inflamm Bowel Dis. 2009

Epidemiologi If we now turn to the background for our studies we could ask: What is the natural history of cc. What will happen if no treatment is instituted. We have to realise that there are no prospective studies of the long term course of cc. Therefore we have only, some indications of the natural history. However this picture could indicate the answer.

Mikroskopisk colitis - epidemiologi CC LC Sweden 1984-93 9.0/1 --- Spain 1993–97 4.8/1 2.7/1 Sweden 1993-98 7.5/1 2.1/1 US 1994-01 6.7/1 1.6/1 Iceland 7.9/1 5.0/1 Female/male ratio

Incidence of collagenous colitis. Annual incidence per 100.000 inhabitants Örebro, Sweden 1984-88 1989-93 1993-95 1996-98 Olmsted County, 1985-89 1990-93 1994-97 1997-2001

Incidence of lymphocytic colitis Annual incidence per 100.000 inhabitants Örebro, Sweden 1993-95 1996-98 1999-04 Olmsted County, 1985-89 1990-93 1994-97 1998-01

Symptomer If we now turn to the background for our studies we could ask: What is the natural history of cc. What will happen if no treatment is instituted. We have to realise that there are no prospective studies of the long term course of cc. Therefore we have only, some indications of the natural history. However this picture could indicate the answer.

Mikroskopisk colitis F Baert et al, Gut 1999

Mikroskopisk colitis Hovedsymptomet ved mikroskopisk colitis er et svært diaré-problem. Hyppigt et meget langvarigt diaré-problem Afføringen beskrives som vandtynd op til 10 -15 gange i døgnet. Der er ofte pludselig indsættende og uimodståelig afføringstrang.

Mikroskopisk colitis Der er sædvanligvis ingen ”advarsels-symptomer” Ingen blod i afføringen Intet større vægttab Ingen væsentlige smerter Er dette tilfældet skal andre sygdomme overvejes

Mikroskopisk colitis - symptomer Svære afføringsgener Diaré Natlig afføring Imperiøs afføring Incontinens Lette almensymptomer Vægttab Mavesmerter Meteorisme Ole Bonderup, Regionshospitalet Silkeborg

Livskvalitet If we now turn to the background for our studies we could ask: What is the natural history of cc. What will happen if no treatment is instituted. We have to realise that there are no prospective studies of the long term course of cc. Therefore we have only, some indications of the natural history. However this picture could indicate the answer.

Mikroskopisk colitis - livskvalitet Hjertesorg er svær at bære Mavekneb det er dog værre Piet Hein

Mikroskopisk colitis - livskvalitet Kronisk diaré = Dårlig livskvalitet

Mikroskopisk colitis – livskvalitet Quality of life (SF-36) in patients with collagenous and lymphocytic colitis. CC. N=38 LC. N=13 Controls Physical funct. 56.2 74.4 85.7 Role limitation – physical 35.2 83.7 Bodily pain 46.7 58.3 79.1 General health 45.4 68.1 Role limit – emotional 41.6 52.5 63.3 Vitality 79.2 88.8 Mental health 55.5 83.3 90.3 Social functioning 56.0 74.3 73.9 Miehlke et al. Ole Bonderup, Medicinsk afd.Regionshospitalet Silkeborg

Mikroskopisk colitis– livskvalitet H. Hjortswang, 2005

Etiologi If we now turn to the background for our studies we could ask: What is the natural history of cc. What will happen if no treatment is instituted. We have to realise that there are no prospective studies of the long term course of cc. Therefore we have only, some indications of the natural history. However this picture could indicate the answer.

Kollagen colitis - etiologi Importance of intraluminal agencies ?

Food Drugs Bile acids ? Bacte- ria

Behandling If we now turn to the background for our studies we could ask: What is the natural history of cc. What will happen if no treatment is instituted. We have to realise that there are no prospective studies of the long term course of cc. Therefore we have only, some indications of the natural history. However this picture could indicate the answer.

Mikroskopisk colitis Ubehandlet har sygdommen ofte et langvarigt kronisk forløb. Almentilstanden er relativ upåvirket, men sygdommen påvirker i svær grad livskvaliteten.

Collagenous colitis - background Retrospective evaluation of treatment in collagenous colitis. No. of pts. Effect No effect Adv. effect Sulphasalazine 108 37 26 45 Mesalazine 16 8 8 0 Olsalazine 15 4 6 5 Prednisolone 39 32 6 1 Budesonide 2 2 0 0 Metronidazole 44 24 16 4 Erythromycin 15 10 4 1 Penicillin 8 8 0 0 Cholestyramin 44 26 17 1 Loperamide 69 49 18 2 What have been the previous treatment options for these patients? This is a retrospective analysis of treatment provided for 163 patients with cc. Some patients were treated on the basis of the experience from chronic inflammatory bowel diseases, some patients were treated with antibiotics and some with simple anti-diarrhoeals. However, none of the treatment options seemed fully effective. Bohr et al. Gut, 1996

Kollagen colitis Dobbelt-blind undersøgelse Budesonide treatment of collagenous colitis Long-term budesonide treatment of collagenous colitis

Budesonide Chemical structure of budesonide This is the chemical formula for budesonide. Budesonide is a modified glucocorticosteroid. The effect of budesonide is - similar to other glucocorticosteroids - mediated by a binding to intracytoplasmatic steroid receptors. The activation of the steroid receptors primarily results in a well known potent antiinflammatory response. Chemical structure of budesonide

Ole Bonderup, Medicinsk afd. Regionshospitalet Silkeborg Kollagen kolitis Budesonide Steroid med lokal virkning Frigøres i terminale ileum Høj affinitet for steroid receptore High first-pass metabolisme i leveren Ole Bonderup, Medicinsk afd. Regionshospitalet Silkeborg

Double-blind treatmente phase Double-blind follow-up (off treatment) Kollagen colitis Budesonide treatment of collagenous colitis. Study design of the 8 week randomised, double-blind, placebo-controlled trial. Budesonide n = 10 R Placebo n = 10 Double-blind treatmente phase Double-blind follow-up (off treatment) 8 weeks 8 weeks R, randomisation

Budesonide treatment of collagenous colitis. Results of the 8 week randomised, double-blind, placebo-controlled trial. Clinical effect + effect - effect Budesonide (n=10) 10 Placebo (n=10) 2 8 P<0.001

Ole Bonderup, Medicinsk afd. Regionshospitalet Silkeborg Kollagen colitis Budesonide Ole Bonderup, Medicinsk afd. Regionshospitalet Silkeborg

Ole Bonderup, Medicinsk afd. Regionshospitalet Silkeborg Kollagen colitis Kaplan-Meier curve of the risk of relapse after 8 weeks budesonide treatment . Ole Bonderup, Medicinsk afd. Regionshospitalet Silkeborg

Ole Bonderup, Medicinsk afd. Regionshospitalet Silkeborg Kollagen colitis Long-term budesonide treatment of collagenous colitis. Study design of the 54 week randomised, double-blind, placebo-controlled trial. Ole Bonderup, Medicinsk afd. Regionshospitalet Silkeborg

Kollagen colitis Double-blind maintenance phase Double-blind follow-up (off treatment) 6 30 54 weeks Budesonide 6 mg once daily 4/17 (23.5%) 17 13/17 (76.5%)*** Placebo 17 2/17 (12%) 2/17 (12%) ***p<0.001 versus placebo (Fisher’s exact test)

Ole Bonderup, Medicinsk afd. Regionshospitalet Silkeborg Kollagen colitis Ole Bonderup, Medicinsk afd. Regionshospitalet Silkeborg

Kollagen colitis

Budesonide 10% 100% Pharmacokinetic of budesonide This figure illustrates the pharmacokinetic properties of budesonide. After oral ingestion budesonide – protected in capsules - is transported through the stomach and the proximal part of the small intestine. In the terminal ileum the capsule is released and the drug is almost completely absorbed in the terminal ileum and ascending colon. However, after absorption about 90% of budesonide is metabolised in the liver and only about 10% is released to the systemic circulation. These pharmacokinetic properties favour the balance between the desired clinical effect and the risk of side effects. Pharmacokinetic of budesonide

Ækvieffektive forhold budesonid versus prednisolon Budesonid (Entocort) Prednisolon Klinisk effekt ved aktiv Crohn’s sygdom . . . . 9 mg p.o. 40 mg p.o. Påvirkning af binyrebarkfunktionen . . . . . 9 mg p.o. 6 mg p.o.

Kollagen colitis - behandling NSAID NSAID seponeres. Kost Nedsætte kaffe forbrug Anti-diaré behandling. HUSK Imodium Questran Ole Bonderup, Medicinsk afd. M1, Regionshospitalet Silkeborg

Kollagen colitis -behandling Budesonide First-line behandling i 8-12 uger 9 mg 1x dgl i 2 - 4 uger 6 mg 1x dgl i 2 - 4 uger 3 mg 1x dgl i 4 - 8 uger Ved recidiv behandling i 24 uger Omkring 30% har behov for langtidsbehandling Ole Bonderup, Medicinsk afd. Regionshospitalet Silkeborg

EMCC Consensus Treatment of Microscopic Colitis MC established Drug-induced colitis ?Consider drug withdrawel* asymptomtatic  no Tx Dietary recommendations* quit smoking mild symptoms moderate/severe symptoms* i.e. antidiarrheals +/- cholestyramine* Budesonid 9 mg/ for 6-8 weeks failure failure relapse mild/moderate symptoms Alternative drugs Aminosalicylates +/- Cholestyramin Bismuth Probiotics Retreatment with Budesonide*(intermittend, continous) + Calcium/Vitamin D severe symptoms Immunomodulators i.e. AZT, MTX failure relapse, intolerance failure Surgery