Azathioprine Linked With Impaired Intestinal Epithelial Postoperative Regeneration in Crohn's Disease

What is known?

* the impact of AZA, immunomodulatory drug widely used in active CD, on the intestinal wall differs from those of steroids, what is reflected in the significant difference in the postoperative anastomotic leaks rate
* AZA inhibits intestinal epithelial cell growth by inducing the apoptosis and inhibiting proliferation of intestinal epithelial cells in in vitro studies What is new?
* The effect of AZA on cellular damage was assessed in humans' study
* AZA increases cell apoptosis in the intestinal epithelium of active CD patients, much stronger than steroids
* AZA actively promotes the DNA damage repair in the intestinal epithelium; the steroid effect, even when combined with AZA, is not so pronounced
* The intensity of proliferative processes, in contrast to steroids, is significantly inhibited in response to AZA
* The disintegration of the mucosa layer in response to AZA is observed
* The difference in the mechanisms of action of AZA and steroids on the intestinal mucosa may be directly related to the reported difference in the risk of septic postoperative complications, but this requires further research

Although conservative treatment of Crohn's disease (CD) is constantly improving some patients still require surgery. Optimal perioperative management includes pharmacological modifications to reduce complications risk. Unfavorable effect of steroids and from recently also biologics on intraabdominal and wound septic complications is known, but until now azathioprine (AZA) is considered to be safe.

The aim of our study was to assess the impact of AZA on intestinal epithelial cells damage as well as restoration and regeneration in patients with active CD as a surrogate marker of healing. We assessed intestinal specimens taken from macroscopically healthy surgical margins of all consecutive CD patients operated due to active isolated ileocecal disease during the study period (2014-2016) in tertiary referral center. We immunohistochemically tested expression of Ki-67, caspase-3 and p-53 as a markers of cell proliferation, apoptosis and DNA damage respectively. Quantitative evaluation of cellular expression of determined proteins was assessed using a confocal microscope. We also performed immunofluorescent tests for cellular integrity using ZO-1 and E-cadherin proteins expression. Additionally we assessed 30 days clinical outcomes.

Eligibility Criteria:
Inclusion Criteria:

* diagnosed with histopathologically confirmed CD at least six months earlier, operated due to active disease characterised by clinical, endoscopical, and radiological findings
* ileocecal involvement
* No other CD manifestations
* Signed informed consent

Exclusion Criteria:

* Previous bowel surgery for CD
* Presence of severe, progressive, uncontrolled cardiological, pulmonary, nephrology, contagious or psychiatric illness whose course could affect the patient's risk of perioperative complications
* Significant disease symptoms so far undiagnosed
* Present or suspected malignancy or previous oncological treatment in the last five years
* Cardiac stimulator or cardioverter-defibrillator
* Pregnancy
* Severe non-abdominal surgery or severe trauma in the last year