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Surgery and immuno modulation in Crohn’s disease
Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Oncology Centre.
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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1150
Keyword [en]
Crohn’s disease, surgery, immuno modulation, complications, stoma, anastomosis, DSS, bursting pressure
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-54816ISBN: 978-91-7393-542-5 (print)OAI: oai:DiVA.org:liu-54816DiVA: diva2:310533
Public defence
2009-10-23, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2010-04-14 Created: 2010-04-14 Last updated: 2010-09-17Bibliographically approved
List of papers
1. Azathioprine as a postoperative prophylaxis reduces symptoms in aggressive Crohn's disease
Open this publication in new window or tab >>Azathioprine as a postoperative prophylaxis reduces symptoms in aggressive Crohn's disease
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2006 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, 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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-35679 (URN)10.1080/00365520600587378 (DOI)28126 (Local ID)28126 (Archive number)28126 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
2. Thiopurine Therapy Is Associated with Postoperative Intra-Abdominal Septic Complications in Abdominal Surgery for Crohns Disease
Open this publication in new window or tab >>Thiopurine Therapy Is Associated with Postoperative Intra-Abdominal Septic Complications in Abdominal Surgery for Crohns Disease
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2009 (English)In: Diseases of the Colon & Rectum, ISSN 0012-3706, E-ISSN 1530-0358, Vol. 52, no 8, 1387-1394 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Thiopurines are important as maintenance therapy in Crohns disease, but there have been concerns whether thiopurines increase the risk for anastomotic complications. The present study was performed to assess whether thiopurines alone, or together with other possible risk factors, are associated with postoperative intra-abdominal septic complications after abdominal surgery for Crohns disease.

METHODS: Prospectively registered data regarding perioperative factors were collected at a single tertiary referral center from 1989 to 2002. Data from 343 consecutive abdominal operations on patients with Crohns disease were entered into a multivariate analysis to evaluate risk factors for intra-abdominal septic complications. All operations involved either anastomoses, strictureplasties, or both; no operations, however, involved proximal diversion.

RESULTS: Intra-abdominal septic complications occurred in 26 of 343 operations (8%). Thiopurine therapy was associated with an increased risk of intra-abdominal septic complications (16% with therapy; 6% without therapy; P = 0.044). Together with established risk factors such as pre-operative intra-abdominal sepsis (18% with sepsis; 6% without sepsis; P = 0.024) and colocolonic anastomosis (16% with such anastomosis; 6% with other types of anastomosis; P = 0.031), thiopurine therapy was associated with intra-abdominal septic complications in 24% if any 2 or all 3 risk factors were present compared with 13% if any 1 factor was present, and only 4% in patients if none of these factors were present (P andlt; 0.0001).

CONCLUSIONS: Thiopurine therapy is associated with postoperative intra-abdominal septic complications. The risk for intra-abdominal septic complications was related to the number of identified risk factors. This increased risk should be taken into consideration when planning surgery for Crohns disease.

Keyword
Crohns disease, Immunosuppression, Surgery, Postoperative complications, Anastomosis, surgical
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-53691 (URN)10.1007/DCR.0b013e3181a7ba96 (DOI)
Available from: 2010-02-01 Created: 2010-02-01 Last updated: 2017-12-12
3. Split Stoma in Resectional Surgery of High Risk Patients with Ileocolonic Crohn’s Disease
Open this publication in new window or tab >>Split Stoma in Resectional Surgery of High Risk Patients with Ileocolonic Crohn’s Disease
2012 (English)In: Colorectal Disease, ISSN 1462-8910, E-ISSN 1463-1318, Vol. 14, no 2, 188-193 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: Surgery for Crohn’s disease (CD) is at high risk of anastomotic complications, with severe postoperative morbidity and even mortality. This retrospective study of high risk CD patients compared the outcome of primary anastomosis (PA) with that of split stoma (SS) and delayed anastomosis (DA).

Methods: We performed 146 operations for ileocolonic CD from 1995-2006. Patient data were obtained from a prospectively registered data base. Patients with ≥2 preoperative risk factors (n=76) constituted high risk patients. Outcomes following PA or SS with DA were assessed.

Results: The number of risk factors (mean) was 2.4 in the PA group and 3.5 in the SS group at time of resection and 0.2 (p<0.0001) at time of DA after 5.0 (2.3-12.6) months. Anastomotic complications occurred in 19 % (11/57) after PA compared with 0 % (0/19) after DA (p=0.038). The total number of operations and in-hospital time was 1.9 (±1.5) and 20.9 (±35.6) days after PA compared with 2.0 (±0.2) and 17.8 (±10.4) days after DA (p=0.70 and p=0.74).

Conclusions: SS in high risk ileocolonic resections for CD, reduces the number of risk factors at the time of DA and the risk for anastomotic complications, compared to PA, without adding inhospital time or number of operations.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2012
Keyword
Crohn’s Disease; Stoma, Surgical; Surgery; Postoperative Complications; Anastomosis, Surgical
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-54812 (URN)10.1111/j.1463-1318.2011.02578.x (DOI)000298944800019 ()
Available from: 2010-04-14 Created: 2010-04-14 Last updated: 2017-12-12Bibliographically approved
4. Effects of Anti-Inflammatory Therapy on Bursting Pressure of colonic Anastomosis in Dextran Sulfate Sodium Induced Colitis in Mice
Open this publication in new window or tab >>Effects of Anti-Inflammatory Therapy on Bursting Pressure of colonic Anastomosis in Dextran Sulfate Sodium Induced Colitis in Mice
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: The aim of this experimental study was to evaluate the effect of colitis and anti inflammatory therapies, respectively, on the healing of colonic anastomoses in mice.

Methods: Eighty four female C57BL/6 mice where randomized into eight groups; four groups continued receiving plain tap water and four groups receiving dextran sulfate sodium. Intraperitoneal treatment was given for 14 days with placebo, prednisolone (2 mg/kg bodyweight), azathioprine (5 mg/kg bodyweight) or infliximab (5 mg/kg bodyweight) until surgery with transsection of the colon and an end to end colonic anastomosis was performed. All mice were sacrificed on day 2 and bursting pressure measurements were recorded.

Results: In the DSS group the mice receiving placebo (n=4) had a more active inflammation with a bowel weight of 12.8 (10.6-15.0) mg/mm, which differed significantly from all the other therapy arms; prednisolone 8.1 (7.5-9.1) mg/mm (p=0.014), azathioprine 8.2 (7.0-8.5) mg/mm (p=0.0046), infliximab 6.7 (6.4-7.9) mg/mm (p=0.0055). Bursting pressure for the placebo group was 90.0 (71.5-102.8) mmHg and did not differ from the azathioprine or infliximab groups, 84.4 (70.5-112.5) and 92.3 (75.8-122.3) mmHg respectively. In contrast bursting pressure for the prednisolone-treated group was decreased compared to placebo, 55.5 (42.8-73.0) mmHg (p=0.0004), as well as compared with azathioprine (p=0.0004) and infliximab (p=0.0015).

Conclusions: All given therapies had effect on the DSS-induced colitis. A severe decrease in bursting pressure of a colonic anastomosis was seen after preoperative steroids but we found no effect of azathioprine or infliximab. Thus, AZA and IFX may not increase the risk for anastomotic complications per se; the need for these therapies may rather be seen as markers of severe IBD with increased risk of surgical complications.

Keyword
Inflammatory Bowel Disease; Surgery; Postoperative Complications; Anastomosis, Surgical; Colitis, DSS
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-54815 (URN)
Available from: 2010-04-14 Created: 2010-04-14 Last updated: 2010-04-14Bibliographically approved

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