Study Of Preventing Postoperative Recurrence Of Crohn’s Disease

Crohn’s disease(CD)is an etiology unknown chronic inflammatory disease of the digestive tract,complicated with some systemic manifestations.Etiology of CD maybe results from an interaction of genetic susceptibility,immunological dysregulation of the mucosal immune system,gut microflora and environmental factors.Pathology feature of CD is non-caseating granulomas and transmural inflammation,affecting all the digestive tract from the mouth to the anus.The ileum and ascending colon are the most commonly affected sites,and the disease often recurs after surgical resection of macroscopical lesions.CD patients need repeated surgery for recurrence all the lifetime,with risk for short bowel syndrome,thus surgery of Crohn’s disease should be as conservative as possible.Although postoperative recurrence is very common,the optimal methods of evaluation,prevention and management are still not obvious.75%of patients need intestinal resection during their lifetime,after surgery,recurrence is still very common,70-90%paitents developed endoscopic recurrence 12 months after surgery.Endoscopic recurrence is superior to clinical recurrence;10-year reoperation rate is as high as 30-70%.Except postoperative endoscopic mucosal evaluation,no other method could predict postoperative recurrence effectively.The Crohn’s disease activity index(CDAI)and the Harvey-Bradshaw index are the two common methods to assess the activity and severity of the disease,but often influenced by other non-CD gastrointestinal or extraintestinal disorders.These clinical scores do not include the endoscopic evaluation,thus two endoscopic scores are as follows:the Crohn’s Disease Endoscopic Index of Severity and the Simplified Endoscopic Score-Crohn’s Disease.Predictors of Crohn’s disease postoperative recurrence include smoking(strong level of evidence),penetrating disease(strong level of evidence),duration of disease(strong level of evidence),history of prior resection(strong level of evidence),family history of IBD,anatomical site of disease,type of anastomosis,disease extent,age at disease onset,and perianal lesions.No prophylactic medical treatment is associated with early recurrence.Penetrating disease and continuing smoking are definite risks for postoperative recurrence.Ileocolonoscopy is the only method for evaluating mucosal recurrence.However,surrogate markers such as inflammatory markers,especially fecal lactoferrin and calprotectin levels,are promising.AZA is generally used to reduce immunogenicity and maintain response.AZA can be used in the perioperative period and beyond for maintenance of remission.However,AZA may cause some adverse effects in 28%of the patients.The most serious adverse effect is leucopenia,which can develop suddenly and unpredictably,in between blood tests,although it is rare(around 3%).T2 is a chloroform/methanol extract of Tripterygium wilfordii Hook F(TWHF),the traditional Chinese medicine.It has both immunomodulatory and anti-inflammatory activities.It can be used to maintain the remission of CD.Our previous animal studies have revealed that the major component of T2,triptolide,could prevent the development of chronic colitis in interleukin-10 deficient mice.The phase I clinical trial in our institute also demonstrated that T2,or combined with enteral nutrition,is efficient for induction of remission in patients with active Crohn’s disease.We follow up all the patients as much as possible.They are scheduled to undertake colonoscopy every 6-12 months after surgery;every time they need do blood regular test,C reactive protein,erythrocyte sedimentation rate and biochemistry;current history including adverse events would be recorded;CDAI would be calculated every time.This study is aiming to investigate the influence of of surgical interventions to postoperative recurrence,the outcome of initial percutaneous drainage versus surgical drainage for intra-abdominal abscesses in Crohn’s disease,efficacy and safety of T2 for preventing postoperative recurrence of Crohn’s disease,efficacy and safety study of T2 versus azathioprine for the maintenance of postoperative clinical and endoscopic remission in Crohn’s disease.The whole manuscript is divided into two chapters:Chapter 1 The influences of surgical interventions to postoperative recurrencePart 1 Surgical procedure in active complex Crohn’s disease Objective:To compare the prognosis between staged surgery and one stage surgery inactive complex Crohn’s disease.Methods:Clinical data of 33 patients with active complex CD from February 2006 to September 2010 were analyzed retrospectively.Inclusion criteria:Patients who were diagnosed as CD by pathology or endoscopy with Crohn’s Disease Activity Index(CDAI)>220 and long history of preoperative steroid use(over 6 months),or complicated with severe preoperative malnutrition.The indications for surgery include enterocutaneous or enteroenteric fistula,with/without intra-abdominal abscess,intestinal obstruction,and acute intestinal perforation with intra-abdominal sepsis.The surgical procedures,including staged surgery and one stage definite surgery were chosen by experienced IBD surgeon.All patients quit smoking and received immunosuppressant therapy-TwHF or azathioprine,together with enteral nutrition supplement for preventing postoperative recurrence.All patients were followed after the surgery about CDAI,serum C reactive protein(CRP),erythrocyte sedimentation rate(ESR)and so on,and postoperative complications,clinical and endoscopic recurrence were recorded.Results:Of the 33 patients,14 underwent one stage definite surgery,19 received staged surgery,postoperative complication rate between the two groups were 10/14 vs 5/19(71%vs 26%,P=0.015),the early clinical recurrence rate within postoperative 3 months were 5/14 vs 0/19(36%vs 0%,P=0.008).In regard to cumulative probability of a post-operative course free from clinical or endoscopic recurrence,staged surgery group was superior to one stage definite surgery group(P=0.0003 and 0.0058).Conclusion:The concept of damage control surgery should be performed in the surgical treatment of active complex CD,staged surgery could significantly increase the success rate of surgery,reduce postoperative complications and postoperative early relapse,delay postoperative recurrence.Part 2 The outcome of initial percutaneous drainage versus surgical drainage for intra-abdominal abscesses in Crohn’s diseaseObjective:Percutaneous drainage(PD)of Crohn’s related abscesses is becoming popular with the development of techniques.We retrospectively analyzed the outcome of initial PD versus initial surgical drainage for intra-abdominal abscesses in Crohn’s disease.Methods:Twenty-three patients of Crohn’s disease complicated with intra-abdominal or pelvic abscesses treated in our institution between July 2001 and April 2010 were retrospectively identified from 188 patients with proven Crohn’s disease.Outcome measures included abscess recurrence after different treatments,post-drainage complications,ultimate stoma creation and subsequent surgery for Crohn’s disease.Results:Patients were divided into initial PD group(n=10)and initial surgery group(n=13),post-drainage complications were more common in initial surgery group(2/10 vs 9/13,P=0.036),abscess recurred in three patients(2/10 vs 1/13,NS),subsequent surgery was needed in 10 patients(6/10 vs 4/13,NS).Ultimate stoma creation were significantly more in initial surgery group(1/10 vs 9/13,P=0.01).Conclusions:Initial PD group had lower rate of post-drainage complications and ultimate stoma creation,compared to initial surgery group.Although subsequent surgery may not be avoided after PD,it can provide safe anastomosis for resections.Long-term follow up should be done to assess the outcome of PD.Chapter 2 Medical therapy for preveting postoperative recurrence of Crohn’s diseasePart 1 efficacy and safety of T2 for preventing postoperative recurrence of Crohn’s diseaseObjective:To review the experience of T2,a chloroform/methanol extract of Tri pterygium wilfordii Hook F,the traditional Chinese medicine,on clinical,endosc opic and surgical recurrence after intestinal resection for Crohn’s disease.Methods:Eighty-seven patients diagnosed as Crohn’s disease after intestinal rese ction were reviewed retrospectively,they all received T2(60mg daily per os)tab lets.Patients received clinical assessments every 3 months,endoscopy every year,the blood samples were collected during their visit for determining serum triptol ide concentrations.Results:Only three patients withdrew due to adverse events.Postoperative 1-year clinical and endoscopic recurrence rates for patients with anastomosis were 5/55(9.1%)and 4/44(9.1%)respectively,as to patients with stoma were 7/28(25%)a nd 9/28(32.1%).Surgical recurrence rates were 8/55(14.5%)and 4/28(14.3%)pat ients within postoperative 5 years.Conclusions:T2,60 mg daily per os,was effective and safe in preventing posto perative recurrence of Crohn’s disease.Part 2 An Efficacy and Safety Study of T2 versus Azathioprine for the Maintenance of Postoperative Clinical and Endoscopic Remission in Crohn’s DiseaseObjective:A prospective randomized controlled study to compare the efficacy an d safety of T2 vs.azathioprine for the maintenance of postoperative clinical and endoscopic remission in Crohn’s disease.Methods:Patients with Crohn’s disease who had undertaken intestinal resection a nd anastomosis were randomly assigned into two groups:T2 60mg/day and azath ioprine 2.0mg/kg/day.Patients need check regular blood test,C-reactive protein(CRP),erythrocyte sedimentation rate(ESR)and biochemistry every 13 weeks,a nd do colonoscopy or enteroscopy every 26 weeks,until 52 weeks.Clinical,end oscopic and surgical recurrence rate at 26 and 52 weeks will be compared,as w ell as CRP,ESR and adverse events.Results:In all,85 patients were inrolled,until now,38 patients had followed up for more than 26 weeks and included for analysis.At 26 weeks,clinical recurr ence rates of both groups were 0%,at 52 weeks,2/24 vs 1/14(P=ns).At 26 weeks,endoscopic recurrence rates of both groups were 8/21 vs 2/12(P=ns),at 52 weeks,9/13vs7/11(P=ns).Surgical recurrence rates at 52 weeks were 1/18 vs 0/11(P=ns).The adverse events of both groups were 8/24(33%)vs 3/14(21%),P=ns.Each group had 1 patient withdrawal the drug.Conclusions:T2,60 mg daily per os,was as effective and safe as azathioprine in preventing postoperative clinical and endoscopic recurrence of Crohn’s disease with good tolarence.