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Azathioprine as a postoperative prophylaxis reduces symptoms in aggressive Crohn's disease
Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
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2006 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, Vol. 41, no 10, 1190-1195 p.Article in journal (Refereed) Published
Abstract [en]

Objective. Recurrence of Crohn's disease (CD) after surgery is common. Azathioprine/6-mercaptopurine (Aza/6-MP) is effective in controlling medically induced remission but, so far, has only been sparsely investigated after surgically induced remission. This study comprises a subset of CD patients considered to have an aggressive disease course and chosen for treatment with Aza postoperatively. Material and methods. In 1989-2000, a total of 100 patients with CD were given Aza/6-MP as a postoperative prophylaxis. Fourteen Aza/6-MP-intolerant patients were compared with 28 Aza-tolerant patients, matched for gender, age, and duration of disease. Patients were prospectively registered for symptoms using a modified Crohn's disease activity index (CDAI) and perceived health was assessed on a visual analogue scale (VAS). The primary outcome variable was the modified CDAI postoperatively integrated over time, other variables were time to first relapse (modified CDAI ≥ 150), time to first repeated surgery, number of courses of steroids, and repeated surgery per year of follow-up. Patients were followed for a median of 84.7months (23.2-140). Results. The modified CDAI integrated over time was 93 for Aza-treated patients compared with 184 for controls (p = 0.01) and time to first relapse was 53 and 24 months, respectively (p < 0.05). Aza-treated patients needed fewer courses of corticosteroids (p = 0.05) compared with controls. Perceived health did not differ between the groups, nor did need of repeated surgery. Time to first repeat operation was 53 and 37 months, respectively. Conclusions. In CD patients considered to have an aggressive disease course, Aza reduced symptoms after surgery and prolonged the time to symptomatic relapse. The findings support a role for Aza as a postoperative maintenance treatment in CD. © 2006 Taylor & Francis.

Place, publisher, year, edition, pages
2006. Vol. 41, no 10, 1190-1195 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-35679DOI: 10.1080/00365520600587378Local ID: 28126OAI: diva2:256527
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2011-01-11
In thesis
1. Surgery and immuno modulation in Crohn’s disease
Open this publication in new window or tab >>Surgery and immuno modulation in Crohn’s disease
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Crohn’s disease is a chronic inflammatory bowel disease with unknown origin. This study investigates the combined use of surgery and immuno modulation in Crohn’s disease. The outcome of medication and surgery in 371 operations on 237 patients between 1989 and 2006 were evaluated. Moreover the effects of prednisolone, azathioprine and infliximab on the healing of colo-colonic anastomosis in 84 mice with or without colitis were evaluated.

The use of thiopurines after abdominal surgery in selected cases of severe Crohn’s disease was found to prolong the time to clinical relapse of the disease from 24 to 53 months. Patients on postoperative maintenance therapy with azathioprine had a decreased symptomatic load over time and needed fewer steroid courses.

The use of thiopurines was found to be a risk factor of anastomotic complications in abdominal surgery for Crohn’s disease together with pre-operative intra-abdominal sepsis and colo-colonic anastomosis. The risk for anastomotic complications increased from 4 % in those without any of these risk factors to 13 % in those with any one and 24 % if two or three risk factors were present.

In patients with two or more of these, or previously established, risk factors prior to surgery one should consider refraining from anastomosis or doing a proximal diverting stoma. Another possibility is to use a split stoma in which both ends of a future delayed anastomosis are brought out in the same ostomy hole of the abdominal wall. This method was found to significantly decrease the number of risk factors prior to the actual anastomosis as well as decreasing the risk of anastomotic complications, without increasing the number of operations or the time spent in hospital.

In the animal model all three medications had an ameliorating effect on the colitis compared with placebo. Only prednisolone was found to interfere with the healing of the colo-colonic anastomoses with significantly decreased bursting pressure compared with placebo as well as azathioprine and infliximab.

The association between azathioprine therapy and anastomotic complications may be due to a subgroup of patients with a more severe form of the disease who have an increased risk of such complications and also are more prone to receive intense pharmacological therapy.

Abstract [sv]

Crohns sjukdom är en kronisk inflammatorisk tarmsjukdom av oklar orsak. Huvudsyftet med denna avhandling var att undersöka den kombinerade behandlingen med kirurgi och immunhämmare vid Crohns sjukdom.

Utfallet av medicinsk och kirurgisk behandling vid 371 operationer på 237 patienter mellan 1989 och 2006 utvärderades. Därutöver studerades effekterna av kortison, immunhämmare och behandling med inflammationsdämpande antikroppar på läkning av tjocktarms-skarv på 84 möss med eller utan inflammation i tarmen.

Vid utvalda fall med svårare form av Crohns sjukdom visade sig förebyggande behandling med immunhämmare efter kirurgi förlänga tiden till återfall av symptom från 24 till 53 månader. Patienter med immunhämmare som underhållsbehandling hade också minskade symptom under uppföljningstiden med ett minskat behov av kortison.

Immunhämmande behandling inför kirurgi visade sig, liksom pågående infektion i bukhålan och sydd skarv på tjocktarmen, vara en riskfaktor för att drabbas av komplikationer vid bukkirurgi på grund av Crohns sjukdom. Risken för infektionskomplikationer i bukhålan ökade från 4 % hos dem utan någon av dessa riskfaktorer till 13 % hos dem med någon och 24 % hos dem med två eller tre riskfaktorer inför operationen. Hos patienter med två eller fler kända riskfaktorer bör man överväga att avstå från att sy en skarv på tarmen vid kirurgi eller möjligen skydda skarven med en avlastande stomi. Ett alternativ till detta är att anlägga en delad stomi där bägge ändarna av den framtida skarven tas ut genom en och samma stomiöppning i bukväggen. Denna metod med en fördröjd skarv på tarmen visade sig minska antalet kirurgiska riskfaktorer inför själva skarvningen och dessutom minska risken för tidiga infektiösa komplikationer i bukhålan, utan att vare sig öka antalet kirurgiska ingrepp eller förlänga vårdtiden på sjukhus.

I en djurmodell visade sig alla tre läkemedlen ha en lindrande effekt på tarminflammation jämfört med placebo. Endast kortison visade sig påverka läkningen negativt med en sänkning av bristningstrycket i den sydda skarven på tjocktarmen, jämfört med placebo såväl som med immunhämmare och antikropps-behandling. Kopplingen mellan immunhämmare och komplikationer efter sydda skarvar på tarmen behöver alltså inte vara en direkt läkemedelseffekt. Orsaken kan istället vara att en undergrupp av Crohnpatienter har en svårare sjukdomsform som ger både ökad komplikationsrisk och större behov av intensiv medicinsk behandling.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 95 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1150
Crohn’s disease, surgery, immuno modulation, complications, stoma, anastomosis, DSS, bursting pressure
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-54816 (URN)978-91-7393-542-5 (ISBN)
Public defence
2009-10-23, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Available from: 2010-04-14 Created: 2010-04-14 Last updated: 2010-09-17Bibliographically approved

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Myrelid, PärAndersson, PeterAlmer, SvenBodemar, GöranOlaison, Gunnar
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Faculty of Health SciencesDivision of surgeryDepartment of Surgery in ÖstergötlandGastroenterology and HepatologyDepartment of Endocrinology and Gastroenterology UHL
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Scandinavian Journal of Gastroenterology
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