Mentoring in IBD is an innovative and successful educational program for Canadian gastroenterologists that includes an annual national meeting, regional satellites in both official languages, www.mentoringinibd.com, an educational newsletter series, and regular electronic communications answering key clinical questions with new research. This issue is based on the presentation made by the contributing editors, Drs. Erin Kennedy and A. Hillary Steinhart, at the annual national meeting, Mentoring in IBD XIX: The Master Class, held November 2, 2018 in Toronto, Ontario.
Kate is a 28-year-old woman with a three-year history of Crohn’s disease (CD) with ileal involvement. She had multiple courses of prednisone over the first two years after diagnosis, and azathioprine was started after one year. Six months ago, infliximab was added.
She now presents with increased right lower quadrant pain and 13.5 kg (30 lb.) weight loss. A CT scan showed 30 cm of thickened terminal ileum, with a 5-cm segment of luminal narrowing, prestenotic dilatation and associated phlegmon/abscess.
Surgical rates for CD have decreased over the past 60 years, but the proportion of patients who require surgical intervention over the course of disease is still significant: 16% at one year; 33% at three years; and 46% at 10 years.(1) Increased mortality in CD is primarily due to deaths within 30 days of surgery,(2) and there are other risks involved, including a high risk of recurrence following resection and risk of short bowel with multiple resections.
There are many factors that can influence the risk of surgical complications, including patient age, nutritional status, cardiopulmonary/general medical condition, sepsis, obstruction, medications (including use of steroids, immune suppression, biologics), as well as surgical factors.
Perioperative management should, therefore, attempt to optimize these factors, including: disease staging, control of sepsis, appropriate use of antibiotics, decompression of obstructions, improvement of general medical condition (e.g., treatment of anemia, thromboembolic prophylaxis), optimized medical therapy for CD (e.g., wean steroids, optimized immune suppression and biologic therapy), and nutritional support. When an abscess is present, bowel rest, total parenteral nutrition (TPN), broad-spectrum antibiotics and percutaneous drainage are recommended.(3) The intent of this is to reduce the risk of surgical complications and need for stoma. With respect to nutrition, it has been estimated that up to 75% of CD patients undergoing surgery are malnourished (with varying definitions, including low BMI, >10% unintentional weight loss, anthropometric measurement abnormalities and reduced grip strength).(4) Retrospective studies suggest reduced post-operative complications when pre-operative nutritional support is provided.(5,6) The relative merit of parenteral vs. enteral nutrition has not been studied.
In a broader context, pre-operative optimization has been examined in a retrospective cohort of 78 patients with penetrating ileal CD (37 with abscess) undergoing first ileocecal resection.(7) These patients received nutrition support (n=50), abscess drainage (n=11), broad spectrum antibiotics and weaning of steroids, immunosuppressives and anti-TNF. Among the 78 patients, 58 (74%) had an uncomplicated operative course, 10 (13%) had minor complications and four (5%) had a major complication. Temporary diverting stoma was performed in six patients (8%); these were either due to residual abscess at the time of surgery or to complex ileosigmoid fistula requiring more extensive sigmoid resection.
Another retrospective study of 237 CD patients undergoing surgery at 3 centres did not reveal any significant difference between patients who did and did not receive optimization (nutrition support for ≥1 week and/or optimization of medication) with respect to overall complication, surgical site infections, re-operation, intra-abdominal septic complications or length of stay.(8)
With respect to pre-operative biologic use, a meta-analysis of studies involving pre-operative infliximab showed that there was no difference in major complications, infectious complications, non-infectious complications or surgical complications between those individuals who were on infliximab prior to surgery (n=1407) and those who were not (n=4589).(9) A small meta-analysis of vedolizumab data did not show any significant impact of preoperative vedolizumab (n=140) compared to anti-TNF biologics (n=203) in terms of surgical complications.(10)
Most patients who undergo surgery will experience some form of disease recurrence. A retrospective review of 171 undergoing a primary ileocolic resection for CD showed that the probability of endoscopic recurrence was 29% at one year, 51% at two years and 77% at five years.(11) Clinical recurrence rates were considerably lower: 8%, 13% and 27% at one, two and five years, respectively.(11) Research has shown that the severity of endoscopic lesions is predictive of need for another resection, and that the length of the recurrent segment is correlated with the length of resected segment.(12–14)
Factors affecting risk of recurrence include: smoking, disease type (penetrating or stricturing), family history of IBD, genetics, composition of the microbiome, time from CD diagnosis to resection, number of prior resections, surgical technique and pathologic findings and post-surgical medical prophylaxis.(11,12,15,16) With respect to post-surgical prophylaxis, a meta-analysis of 22 randomized, controlled trials (n=2090) showed that the use of anti-TNFs or thiopurines are associated with large reductions in disease recurrence, while the potential benefit of probiotics, steroids or 5-ASA is less certain (Table 1).(12)
It should be noted that whether or not to employ prophylaxis is not a one-size-fits-all decision; it needs to be made on a patient-by-patient basis. Patient preference may play a role, considering such factors as fear of medication risk, experience with previous medical therapy, concerns about specific classes of therapy, fear of recurrence risk and perception of the required monitoring procedures (e.g., clinical, laboratory, endoscopic, radiologic). The possible impact of disease recurrence also needs to be weighed against the potential impact of therapy; this assessment needs to take into account the patient’s age and comorbidities, as well as the history of response to therapy and the likelihood of recurrence.Current guidelines recognize the importance of prophylaxis for prevention of disease recurrence. The 2017 European Crohn´s and Colitis Organisation (ECCO) guidelines state that “Prophylactic treatment is recommended after ileocolonic intestinal resection in patients with at least one risk factor for recurrence”: and that “the drugs of choice are thiopurines or anti-TNFs.”(16) The American Gastroenterological Association (AGA) has issued similar guidance.(17)
With respect to risk of recurrence, the Rutgeerts score has been developed to stratify patients into four levels of risk for post-surgical recurrences at ileocolic anastomosis and in the neo-terminal ileum using endoscopic findings.(18) For those with no lesions in the distal ileum (Rutgeerts score i0) or with no more than five anastomotic aphthous lesions in the distal ileum (score i1), the five-year rate of clinical recurrence is 6%. Those with more than five aphthous lesions with normal mucosa between the lesions, or skip areas of larger lesions or ulcers up to 1 cm confined to ileocolonic anastomosis (score i2) have a five-year risk of 27%. Those with diffuse aphthous ileitis with diffusely inflamed mucosa between the multiple aphthae (score i3) have a five-year risk of 63%, and those who have diffuse inflammation, with large ulcers and/or nodules/cobble and/or narrowing/stenosis have a five-year clinical recurrence rate of 100%.
A randomized, controlled trial involving 174 CD patients undergoing intestinal resection, with an endoscopically accessible anastomosis, aimed to identify the optimal strategy to prevent postoperative disease recurrence.(19)
All patients received metronidazole 400 mg twice daily for 3 months postoperatively; high-risk patients (one or more of current smoking, perforating disease or previous resection) additionally received a thiopurine from the time of surgery for 18 months until study conclusion (or adalimumab if intolerant of the thiopurine). Patients were randomized to undergo colonoscopy at 6 months (active care) or no colonoscopy (standard care). If there was endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped-up to thiopurine, adalimumab with thiopurine, or weekly adalimumab, depending on their previous therapy. At 18 months, the recurrence rate was significantly lower among patients in the active care arm compared to the standard care arm (49% vs. 67%), with similar patterns among those in the low-risk or high-risk groups at post-surgical baseline.(19)
Based on the current understanding of post-surgical recurrence and the evidence in support of prophylaxis, the author has developed the algorithm shown in Figure 1 to use as a decision-making tool for patients with CD undergoing small bowel resection.
Based on the evidence, Katie was treated with bowel rest and total parenteral nutrition for 6 weeks, followed by ileocolic resection. She received metronidazole 400 mg twice daily for three months postoperatively, and at six months, underwent a follow-up ileocolonoscopy. This revealed recurrence with Rutgeerts i2 score, at which point therapy with infliximab was started.
Mitchell is a 22-year-old male with a 10-year history of CD. He had a laparoscopic ileocecal resection at the age of 14. Three years post-operatively, MRI showed thickening near the anastomosis. Four years post-operatively, a colonoscopy showed an i2 recurrence at the ileal portion of the anastomosis, and you discussed the option of azathioprine with the patient. After this, however, he was lost to follow-up for four years. He returned at age 22, eight years post surgery, presenting with abdominal pain and diarrhea. A colonoscopy showed an i3+ recurrence.
The key considerations for optimal surgical management of ileocolic CD are the timing of the surgery, and the type of anastomosis to be used. More recently, there has been some increasing interest in the extent of mesenteric resection and the patient’s microbiome.
When deciding on whether or not to recommend surgery, one has to weigh the pros and cons of surgery with ileocolic resection against those of medical therapy. The LIR!C study provides some insight into this decision.(20) This was a randomised controlled, open-label trial, in 143 adult patients with non-stricturing, ileocaecal CD who had failed conventional therapy. They were randomized to receive infliximab therapy or laparoscopic ileocaecal resection. The primary outcome was quality of life, measured by the IBDQ, at 12 months, while the key secondary endpoint was endoscopic recurrence at 12 months. In this study, there were no significant differences between groups for either endpoint. This study shows that ileocolic resection for short segment ileocolic CD is an excellent treatment option for short segment terminal ileal CD and should be discussed with patients as early as when initiation of biologic therapy is being considered.
With respect to the surgery itself, there are three main types of anastomosis: side-by-side, end-to-end and the Kono S technique. There have been a number of studies that have compared the side-by-side and end-to-end techniques, and three meta-analyses of these have been published (Table 2).(21–23)
In the most recent analysis by He et al, which included eight randomized controlled trials, the side-to-side technique is preferred, because it is associated with fewer post-operative complications, lower chance of anastomotic leak, and more favorable recurrence and re-operation rates relative to the end-to-end technique.(21) Some other researchers have reported no significant differences in post-operative outcomes between the two techniques,(24) while others have reported lower healthcare utilization rates postoperatively and better quality of life with the end-to-end approach.(25) Prospective, randomized data confirming this association are lacking.
There is less evidence available for the Kono S anastomosis, although the limited data do suggest that it is associated with lower re-operation rates and less risk of stenosis at the anastomosis compared to other methods.(26) Again, however, further evidence is required before this technique can be endorsed over the others.
More recently, it has been hypothesized that the extent of mesenteric resection may play a role in post-operative recurrence, since the mesentery contains pro-inflammatory cells that may promote mucosal ulceration and stricturing, contributing to bowel inflammation and fibrosis from the outside in.
In conventional CD surgery, the mesentery is generally divided relatively distally or close to the bowel wall. A recent study compared the outcomes among 30 consecutive CD patients undergoing ileocolic resection with an extended mesenteric resection to those of 34 patients with similar baseline characteristics who had previously undergone a conventional ileocolic resection (i.e., no extended mesenteric resection in historical controls).(27) In this analysis, the CD re-operation rate was 30% among those with conventional ileocolic resection (9/30) and 2.9% (1/34) among those with extended mesenteric resection. To date, the optimal extent of mesenteric resection to prevent post-operative recurrence has not been adequately studied and should be the focus of future study.
Similarly, the impact of the intestinal microbiome is not yet fully understood. However, it has been demonstrated that bowel surgery leads to changes in the GI microbiome, that post-operative recurrence is associated with elevated levels of Proteus and reduced Faecalibacterium, and that smoking is associated with elevated levels of Proteus.(28) The role of the microbiome and methods of optimizing this environment is also the focus of ongoing research to decrease the risk of post-operative recurrence.
Based on the evidence, Mitchell was offered laparoscopic ileocolic resection; although due to his history of previous surgery, there is an increased risk of requiring conversion to open surgery. Prior to surgery, he was provided nutritional support in an effort to improve his overall well being heading into the procedure. The technique chosen was side-to-side, stapled anastomosis, with mesenteric resection close to the bowel wall. After surgery, he received treatment with azathioprine; antibiotic treatment with metronidazole 400 mg was given twice daily for three months as well. At six months, he underwent a follow-up ileocolonoscopy, which showed i1 Rutgeerts score. The azathioprine was continued as monotherapy, while it was also discussed that the addition of a biologic could be considered if the disease worsened on endoscopic follow-up.
Patrick is a 20-year-old man with a five-year history of ileocolonic CD. He presents with intermittent perianal pain and swelling, with persistent drainage of yellow-brown fluid. He is passing three to four soft stools per day, with no abdominal pain. He is presently on methotrexate maintenance therapy and has previously been treated with prednisone.
The Toronto Consensus group has published a clinical practice guideline for the management of perianal fistulizing CD.(29) This guideline states that surgical intervention should be considered when there is clinical evidence of abscess (e.g., local pain, swelling, fever, inflammatory markers) or when an imaging assessment suggests complicated fistulizing disease (Figure 2).
For those who fit the criteria for surgery, proper evaluation and staging of disease is the critical first step. This includes defining fistula anatomy and/or classification, identifying sepsis/drainable collections, evaluating inflammation in the fistula tracts and the surrounding tissues and assessing associated luminal disease. Endoanal ultrasound is the usual imaging method for perianal fistula, while MRI is another option if available.(30) While MRI is preferred by most patients due to comfort, these modalities have been shown to be similarly accurate for fistula assessment (~90% accuracy), while the combination of two modalities enhances accuracy to 100%.(31) The main goals of the assessment are to assess for undrained collection and for complex, branching fistulas.
The most desirable surgical option for fistulizing CD is seton placement. Diversion and protectomy are less commonly indicated. The goals of seton placement are to keep the fistula tract open with minimal damage to the anal sphincter, to allow drainage, prevent recurrent abscess, reduce chronic inflammation and discomfort and allow the fistula tract to epithelialize (mature). Once the tract has matured, it is unlikely to close. Generally, it takes six to 12 weeks to mature, although shorter tracts generally take less time to mature than longer tracts.
With respect to medical therapy for fistulizing disease, the best evidence has been accumulated with infliximab. The ACCENT II study was a multicenter, double-blind, randomized, placebo-controlled trial, which showed that complete response (i.e., absence of draining fistulas) was significantly more likely among patients treated with infliximab compared to placebo (36% vs. 19%, respectively).(32) Maintenance therapy with infliximab in the same cohort was also associated with a significant reduction in hospitalization over time.(33) Healing of draining fistulas has also been noted with adalimumab. In the CHARM study, patients received open-label adalimumab induction therapy (80 mg at week 0 and 40 mg at week 2), followed by randomization at week 4 to double-blind treatment with placebo, adalimumab 40 mg every other week (eow), or adalimumab 40 mg weekly through week 56.(34) In that study, there was a significant improvement in the proportion of patients with complete fistula closure with adalimumab (30% at 26 weeks and 33% at week 56 for the combined adalimumab group and 13% at each time point for placebo).(34)
With respect to combined medical-surgical approaches, there are limited data available to date. Two retrospective studies have evaluated infliximab combined with surgery.(35,36) One of these involved 23 patients on infliximab. Those who also had seton placement had significantly higher rates of complete closure vs. infliximab alone (100% vs. 83%, P=0.014), a significantly lower recurrence rate (44% vs. 79%, P=0.001) and a significantly longer time to recurrence (135 months vs. 3.6 months, P=0.0001).(35) The other study involved 21 patients treated with infliximab, 10 of whom had seton placement, two who had surgical drainage and one with a diversion.(36) At 9 months, among those with perianal fistula, complete response (complete cessation of fistula drainage with gentle finger compression on two or more consecutive visits) was seen in 67% and partial response (reduction in size, number, drainage, or discomfort associated with the fistula) in 19% of those with seton placement combined with infliximab.(36)
Stem cell therapy has also been investigated for the treatment of fistulizing CD. A recent phase 3, double-blind, multicentre study conducted in Europe and Israel (the ADMIRE study) included 212 patients with CD and treatment-refractory, draining, complex perianal fistulas.(37) The subjects were randomized to a single local injection of stem cells (120 million Cx601 cells) or placebo (control), each in addition to the standard of care. At week 24, a significantly greater proportion of patients treated with the stem cell injection achieved the primary endpoint of combined remission (clinical assessment of closure of all treated external openings that were draining at baseline, and absence of collections >2 cm of the treated perianal fistulas confirmed by masked central MRI) (50% vs. 34%, P=0.024 for the ITT population). At week 52, the difference in combined remission remained statistically significant (56.3% vs. 38.6%, P=0.01).(38)
Patrick’s assessment included a history of intermittent perianal pain, which may suggest the presence of an abscess. He was referred for a surgical consultation, including an examination under anesthesia.
It was found that Patrick required draining of an abscess and seton placement was recommended as the intervention of choice. Furthermore, he was offered maintenance infliximab therapy as a means to reduce the risk of recurrence.
Communication and coordination between gastroenterologists and surgeons are critical in planning surgery for patients with CD.(39) The evidence is clear that medical optimization can reduce post-operative complications and that post-operative prophylaxis can reduce CD recurrence. Among patients with perianal CD, combined surgical and medical management of perianal CD can improve outcomes. A multidisciplinary care conference may help improve this communication and make joint treatment recommendations.
John K. Marshall, MD MSc FRCPC AGAF, Director, Division of Gastroenterology, Professor, Department of Medicine, McMaster University, Hamilton, ON
Erin Kennedy, MD PhD, Associate Professor, Department of Surgery, University of Toronto, Toronto, ON
A. Hillary Steinhart, MD MSc FRCPC, Medical Lead, Centre for Inflammatory Bowel Disease, Mount Sinai Hospital, Professor of Medicine, University of Toronto, Toronto, ON
Alain Bitton, MD FRCPC, McGill University, Montreal, QC
Brian Bressler, MD MS FRCPC, University of British Columbia, Vancouver, BC
Anne M. Griffiths, MC FRCPC, University of Toronto, Toronto, ON
Steven E. Gruchy, MD MSc FRCPC, Dalhousie University, Halifax, NS
Remo Panaccione, MD FRCPC, University of Calgary, Calgary, AB
A. Hillary Steinhart, MD MSc FRCPC, University of Toronto, Toronto, ON
Jennifer Stretton, ACNP MN BScN, St. Joseph’s Healthcare, Hamilton, ON
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