Perioperative Immune Suppression Management in Patients With Inflammatory Bowel Disease
Samuel Eisenstein, MD
Eisenstein S. Perioperative immune suppression management in patients with inflammatory bowel disease. Consultant. 2016;56(10):884-889.
ABSTRACT: Patients with inflammatory bowel disease (IBD) are at higher risk of septic and thromboembolic complications after surgery. While these patients’ cases are often complicated from a surgical perspective, we now also manage them with a variety of immunosuppressive agents that can increase the risk of postsurgical complications. Whether to withhold or continue these medications in the perioperative period is the subject of ongoing debate in the IBD surgical community. While the evidence to support both approaches is mixed, it does appear that undiverted anastomoses are at an increased risk from perioperative corticosteroids and may present a greater risk for patients receiving biologic therapies for IBD. Regardless, if concern exists that a patient may not have a successful outcome from surgery, it is often prudent to wait 5 half-lives to allow the medication to wash out of the system or to consider judicious diversion at the time of the operation.
KEYWORDS: Inflammatory bowel disease, ulcerative colitis, Crohn disease, immunosuppression, corticosteroids, biologic therapies, surgery, ileal pouch anal anastomosis
It has long been demonstrated that patients with inflammatory bowel disease (IBD) have higher rates of postoperative complications than patients without IBD. A combination of the chronic inflammatory state, poor nutrition, and immunosuppressive medications leaves these patients at higher risk for venous thromboembolism (VTE),1 wound infection,2,3 deep organ space infection,2,3 intestinal fistula,4 and anastomotic leak.2,3
Medical therapy for Crohn disease (CD) and ulcerative colitis (UC) consists of a variety of immunosuppressive agents, including topical and systemic corticosteroids, thiopurines, and biologic agents, the latter of which primarily are monoclonal antibodies and small molecules designed to disrupt the host autoimmune response. While it has long been demonstrated that systemic corticosteroids increase the risk of perioperative complications for all manner of surgeries in all fields of medicine, debate is ongoing about whether other medical therapies, particularly the biologic therapies, increase perioperative complications in patients with IBD.
The debate began after the publication of the 2008 article, “Infliximab in Ulcerative Colitis Is Associated With an Increased Risk of Postoperative Complications After Restorative Proctocolectomy,” by Mor and colleagues at the Cleveland Clinic’s Digestive Disease Institute.5 Infliximab, a monoclonal antibody targeting tumor necrosis factor α (TNF-α) had been used for the treatment of UC since 2000, and the authors reported that the use of infliximab increased the rate of postoperative sepsis, anastomotic leak, and overall complications in patients undergoing ileal pouch anal anastomosis (IPAA) surgery when taking infliximab. Since then, extensive debate has occurred over whether these data are correct and universally applicable, and if so, what should be done about them, not just for infliximab, but for all types of anti–tumor necrosis factor (anti-TNF) therapies including adalimumab, certolizumab, and golimumab.
Beyond just the anti-TNF therapies, new medical treatments for IBD recently have become available, and more will become available in the near future. Now we have anti-integrin medications such as vedolizumab and natalizumab, which target lymphocyte trafficking. Soon we will likely also be using anti-interleukin 12/23 medications such as ustekinumab and Janus kinase (JAK) inhibitors such as tofacitinib, all of which have proven effective in controlling disease progression in subsets of patients with CD and UC. Nevertheless, some of these medications may prove to be double-edged swords for patients with IBD who ultimately fail medical management and require surgery.
When critically evaluating postoperative outcomes in IBD surgery, there is heterogeneity in the literature that must be overcome. While some complications such as infection, VTE, small bowel obstruction, and death are regularly listed, many more are only mentioned sparingly throughout the literature. Furthermore, infectious complications, which are usually listed as superficial (wound), deep (intra-abdominal), and deep organ space (anastomotic leak), may also include other infections such as urinary tract infections and infections with Clostridium difficile. Often, in larger studies, all infectious complications are lumped together into one category. Because of this, it is important to understand how these events are categorized.
This article covers what is known about medical treatments for IBD and how these therapies may impact patients undergoing surgery for their disease in an attempt to optimize their medical treatment before surgery. The primary focus is on infectious complications, given that this is where the true controversy lies. While many questions are still to be answered, with careful timing and medical modification, the likely major risks can be mitigated, and patient outcomes can be optimized.
Surgical treatment for UC is designed to remove the colon and rectum in their entirety and either make an ileostomy or, when feasible, reconstruct the gastrointestinal tract in continuity with the anus, employing an ileal pouch as a neorectum. Surgery is often perfomed in stages so as to minimize the risk of complications, because patients with severe disease are often at high risk for operative complications.
To stage the surgery, the surgeon will often remove the diseased colon first, wean the patient from any immunosuppressive medications, improve their nutrition, and then bring them back for the second stage, where the remaining rectum is removed and the ileal pouch is constructed and anastomosed to the anus (IPAA). This anastomosis is at high risk for leakage, with leak rates as high as 14%,6 and often it is protected with a loop ileostomy, which is closed in a third-stage procedure. Often, if the patient is healthy enough, the first 2 stages of the surgery will be combined in a 2-stage approach; some surgeons even offer patients a single surgery without diversion, although a minority of pouch surgeries are done this way in the United States, because it presents the highest potential for complication in all but the most optimized of patients.
When considering postoperative septic complications, particularly deep space and deep organ space infections in UC, the surgeon can minimize this risk by increasing the number of stages in which the surgery is completed. Historically, factors such a hypoalbuminemia, anemia, corticosteroid usage, and sepsis have all pushed surgeons toward the longer 3-stage approach. Adding these extra procedures, however, increases the risk from exposure to anesthesia, increases the risk of small bowel obstruction,7 and increases cost to the health care system. Patients also express a strong desire to have an ileostomy for as little time as possible and to be done with surgery as quickly as possible. So, ideally, the fewer stages that can be safely employed, the better for the patient and the health care system. By minimizing perioperative risk, the surgeon is often able to offer patients surgery in fewer stages.
There is clear evidence that corticosteroids increase the risk for infectious complications after pouch surgery.8-12 In one large retrospective series from 1996,12 low-dose corticosteroids (< 20 mg/d prednisone) increased the anastomotic leak rate from 3.8% to 20%, and high-dose corticosteroids (> 20 mg/d) increased that leak rate to 50%. Interestingly, there was no increase in early septic complications associated with corticosteroids when the patients were diverted. Numerous other large studies since then support these findings; thus, when a pouch surgeon is considering the approach to each individual patient, corticosteroids factor heavily into whether the patient will have an ileostomy at the time of surgery. Topical corticosteroids such as budesonide generally are not absorbed systemically, and while there are no studies on whether topical corticosteroids contribute to IPAA complications, it is generally felt that at standard dosages (9 mg/d) they do not. However, this may not be true in patients who receive significantly higher doses or patients who have been on the medication for significantly longer than 6 months, where some systemic absorption has been demonstrated.13
Conversely, the thiopurine medications, 6-mercaptopurine and azathioprine, do not appear to increase the rate of perioperative septic complications. While not many studies have been published on these medications in surgery for UC, the largest study,14 from 2002, demonstrated no significant increase in any early or late infectious complications in 151 patients undergoing IPAA. This is fortunate, because there is no defined washout time for these medications, and it can vary based on the individual patient’s thiopurine methyltransferase (TPMT) activity. There is some heterogeneity, based on race, to the functionality of TPMT, but patients fall into 1 of 3 categories: normal metabolizers, intermediate metabolizers, and absent metabolizers. TPMT activity can be tested prior to administration of these medications, which should not be given if TPMT activity is absent.15
The controversy that has been ongoing over the last decade and a half has been whether biologic therapies contribute to postoperative septic complications in patients undergoing IPAA. Since Mor and colleagues5 published their data in 2008 on increased septic complications in infliximab patients undergoing IPAA, there has been a rush to put together ever larger and more definitive series on the subject. Five years after having the 2008 article published, some of the researchers at the Cleveland Clinic’s Digestive Disease Institute went on to look at the outcomes of their patients on infliximab when stratified to subtotal colectomy with subsequent IPAA vs primary total proctocolectomy with IPAA at the same procedure.15 They demonstrated that infliximab significantly increased the risk of 1-year sepsis episodes (hazard ratio, 2.62; P = .027) compared with patients not on these medications. Interestingly, in the patients who initially had been treated with subtotal colectomy, allowed to get off of their medications, and return for their pouch surgery, there was no difference in perioperative pelvic septic complications. Because of these observations, this group has strongly advocated for staging IPAA patients on anti-TNF medications or attempting to get patients off of these medications prior to surgery when feasible. The biggest problem with their data is that it is retrospective and from a single institution.
In fact, numerous other studies have since been published that seem to contradict one another’s findings. Almost 3000 cases were reviewed in 2012 in the largest meta-analysis on the subject,16 and infliximab was shown not to increase total, infectious, or noninfectious complications for patients with UC undergoing surgery. The biggest weakness of this study is that it included a very heterogeneous group of surgeries, including subtotal colectomy without IPAA, which previously has been shown to be associated with a low risk of perioperative complications for patients taking infliximab. A smaller meta-analysis3 from 2015 only included patients undergoing IPAA on infliximab and demonstrated that these patients had an increased risk for any early IPAA complication (odds ratio [OR], 4.27) as well as an increased risk of any complication after ileostomy closure (OR, 2.27). Receiving more than 3 doses of infliximab was associated with complications, while having an infusion less than 12 weeks prior to surgery was not. There was a trend toward an increase in all infectious complications, but interestingly, biologic therapy also seemed protective against wound infection (OR, 0.67). In 2010, Coquet-Reinier and colleagues17 published a case-matched study in an attempt to control for the many variables that can complicate the analysis of these complicated cases and demonstrated no increase in any type of postoperative complication attributable to infliximab.
Because they work through a similar mechanism, expectations for other anti-TNF therapies tend to be extrapolated from or lumped together with the infliximab data. The largest meta-analysis to date,18 from 2013, analyzed almost 4700 patients on any anti-TNF therapy for all patients with IBD. The UC cohort did not have any increase in infectious or noninfectious complications. Likewise, analysis of the Nationwide Danish Cohort from 2003 to 2010 for all patients receiving anti-TNF therapy failed to demonstrate an increase in complications in patients receiving these medications vs patients not on these medications.19 Again, this study included a large number of patients undergoing subtotal colectomy without IPAA, which likely mitigates the risk. In another study from 2015, preoperative anti-TNF levels were compared with surgical outcomes after IPAA for UC, and no significant correlation was demonstrated.20
Based on these data, it appears to be very safe to perform a subtotal colectomy on patients with UC on anti-TNF therapy. Similarly, it may be safe to perform diverted IPAA, although the data on this are mixed. Caution should be exercised when considering an undiverted IPAA for patients on these therapies. Unfortunately, no data have been published on the interactions of some of the newer therapies such as vedolizumab with surgery. Many of these patients have failed numerous other biologic therapies on their way to new and novel treatments and likely have severe UC to begin with. All of this should be considered when planning surgery for patients with UC.
Careful medical management is important in the perioperative period. If it is possible to stop systemic corticosteroid or biologic medications prior to surgery and allow them to wash out, this may allow the patient to undergo a 1- or 2-stage pouch. This is usually not feasible, given that washout times can be quite long for some of these medications (Table); thus, it is important for the surgeon to take the entire condition of the patient into account when staging surgery for UC.
If it is felt that the patient absolutely needs the drug out of their system prior to emergency surgery, plasmapheresis can be employed in certain situations to remove many of these medications. Thiopurines and topical corticosteroids, however, can be continued up to the point of surgery, as can aminosalicylates, which have not been studied in the perioperative setting but are felt to not be systemically absorbed and not increase surgical risk.
Surgery for CD typically presents a much higher risk than does surgery for UC. Surgeons know they will not cure the patient’s disease; therefore, their main goal is to remove or palliate the symptomatic lesion, often a stricture or fistula, while leaving minimally diseased bowel in place. Again, a combination of malnutrition, immune suppression, and chronic disease can lead to numerous postoperative complications, and anastomoses performed to diseased segments of bowel are very prone to leaking or fistulizing. As a result, it can be difficult to tease out whether the increased complication rates for surgery while on biologic therapies for CD are directly attributable to the medications themselves or whether these medications are simply markers of more severe disease. Compounding these issues is the necessity for CD patients to stay on their medical therapy throughout the course of their surgery and recovery to ensure that they do not have a disease flare or develop antibodies to their specific treatment.
This discussion primarily focuses on abdominal surgery in CD, since anorectal procedures in general are fairly low risk, and there does not appear to be an increased risk of complications in these surgeries attributable to medical therapy.
As is the case in UC, corticosteroids have been shown to increase the risk of postoperative complications in CD. In a large 2015 meta-analysis of more than 4000 surgeries,2 corticosteroids at any dose demonstrated an increased OR of 1.99 for intra-abdominal septic complications, including anastomotic leak, abdominal abscess, or enterocutaneous fistula. These findings were confirmed in another study of more than 8000 cases, using the American College of Surgeons National Surgical Quality Improvement Program database, one of the most powerful databases for identifying 30-day surgical outcomes.21
Thiopurines have not been well studied in the surgical setting. One study from 2009 retrospectively analyzed 343 patients in Sweden with CD on thiopurines.22 This study’s results demonstrated an increase in postoperative septic complications for patients on thiopurines from 6% to 16%. In this same cohort, if the thiopurine patients underwent a colo-colonic anastomosis or had a preoperative intra-abdominal abscess, their postoperative septic complication rate increased to 24% from 6%. Unfortunately, a paucity of data exists on this subject, so it is again unclear whether these patients simply have worse disease than their untreated counterparts. Since the washout time is so long and variable for thiopurines, and since they are often used to minimize the host immune response to biologic therapies, it is probably not advisable to wait for thiopurine washout in the perioperative period.
Much as with UC, there is debate as to whether anti-TNF therapy increases the risk of complications in CD. Due to significant heterogeneity between the various studies, it is hard to point to one study that is definitive on the topic. In their 2014 review,23 Spinelli and colleagues identify 13 studies of reasonable quality on the topic, 3 of which point to an increased risk of infectious complications perioperatively. These studies supported an increased risk in overall and general septic complications; however, studies that more closely analyzed individual subtypes of septic complications failed to demonstrate significant increases of one type vs another. Also, when looking at the quality of the studies, some of the larger and better-conducted studies do seem to lean toward an increased risk of complications in patients receiving anti-TNF therapies.
One of the largest meta-analyses looked at more than 4000 patients with CD on anti-TNF therapy in 2013.24 The authors demonstrated that this treatment imparted an increase in all complications (OR, 1.25) as well as any infectious complications (OR, 1.45). One of the biggest drawbacks of this study was a lack of quality assessment. Another drawback from these large studies is the lack of specificity in the type of infectious complication encountered. In a more carefully conducted meta-analysis from 2013, El-Hussuna et al25 looked specifically at anastomotic complications in patients with CD on anti-TNF therapy. They evaluated for heterogeneity within the studies and demonstrated that, in the studies where there was a low bias, there was an increase in anastomotic complications for patients on anti-TNF therapy (risk ratio, 1.63; 95% confidence interval, 1.03-2.60). This effect did not carry across all of the studies where there was an overall high level of bias influencing this difference. Nevertheless, a separate and well-conducted meta-analysis from the same year,26 including almost 1200 patients with CD on infliximab, contradicts these findings, observing no increase in major complications, minor complications, reoperation, or mortality.
As is the case with UC, the literature on CD and biologics either discusses infliximab in isolation or lumps all anti-TNF therapies together. There appears to be no difference between adalimumab, infliximab, and certolizumab in relation to the risk of operative complications, but this is not known definitively. Again, we also do not have any data on the anti-integrin medications or other potential biologic treatments and postoperative outcomes. The initial studies, including the GEMINI trial for vedolizumab,27 rarely mention the cohort that progressed to surgery and do not discuss the outcomes of those surgeries. Even if they did, the small subset of patients in this category would make it difficult to identify statistical significance.
Perioperative medical management of immune suppression remains a topic of much controversy in the surgical community. While all surgeons agree that corticosteroids do contribute significantly to postoperative morbidity, it is not always feasible to get patients off of corticosteroids prior to elective surgery. It is likely just as bad to have a patient who is unable to eat and having 20 bloody bowel movements daily who has lost 30 pounds. The decision tree for these patients is much easier in UC than in CD. In UC, the surgeon can perform a subtotal colectomy and stage the patient’s IPAA to allow for a reasonable time off corticosteroids prior to undertaking a bowel anastomosis.
In CD, this may not be the preferred option. An ileocolic resection or small bowel resection for terminal ileitis is theoretically low risk for anastomotic leakage. In patients on high-dose corticosteroids, it may still be preferable to make an end or diverting loop ileostomy if the patient cannot have his or her corticosteroid dose reduced to a safe level.
However, if the patient can be dropped to a significantly lower corticosteroid dose, this may obviate the need for staging the more low-risk surgeries. Left-sided colonic or ileorectal anastomoses are probably not safe in general on any dose of corticosteroids, however, and it is our practice not to perform these undiverted on patients who are on anything more than the equivalent of 5 mg of prednisone daily.
Thiopurines, on the other hand, appear to be safe in the surgical setting. This is beneficial for several reasons. The first is that they have variable half-lives, and washout times depend on the individual. The second is that thiopurines are being employed synergistically with biologic therapies to minimize the immune response against biologic medications. If a patient can stay on these medications through the perioperative period, it may allow them to have their biologic agent withheld temporarily and restarted postoperatively, with lower risk of loss of efficacy due to antibodies.
Despite more than 15 years of experience, the jury still seems to be out on anti-TNF and other biologic therapies. These medications do appear to increase the risk of postoperative complications in some very specific settings, but it is not clear whether this is an effect specific to the medication or rather just a marker of more severe disease.
It is rare that these medications can be withheld and allowed to wash out prior to surgery; however, if the patient is failing the medication and ultimately requires surgery, there may not be much difference whether or not they are taking it. That being said, washout times can be significant, and patients who are living with severe disease may not feel they can wait it out.
Tofacitinib is a new JAK inhibitor being investigated for use in IBD. It is taken orally 3 times daily, and its half-life and wash out are very short at less than 1 day. If this medication proves to be effective in IBD, its profile would make it an ideal bridging medication for surgery.
In UC, most would advocate for diverting ileoanal anastomoses when performed in the setting of anti-TNF therapy. There does not appear to be an increased risk, however, if no anastomosis is being performed.
CD is a much more difficult situation. If no anastomosis is planned, then the patient likely can continue biologic therapy through the course of surgery. Often, the surgeon will time the operation to coincide with the dosage nadir of the medication. In cases where an anastomosis is planned, much relies on the surgeon’s judgment to determine whether the patient is at high risk for a leak and then to divert these patients. It is our current practice to help mitigate the risk of these medications by withholding a single dose preoperatively and operating on the patient around the time they would have received that dose. The medications can then be started a week or two after surgery if the patient is recovering well. This may help decrease the overall impact of biologic therapies on postoperative outcomes while still allowing patients to resume what may be felt to be an otherwise effective medication that they may require efficacy from for years to come.
More and better studies need to be performed if we are to optimize perioperative outcomes in IBD. Medical therapy for IBD has allowed patients to avoid the surgeon’s knife at much higher rates, but when we are forced to operate on these patients, they are sicker and their immune systems are less effective. As newer medications become available, some may prove better in the surgical setting, and some may prove more dangerous. Large collaborative studies will be necessary for surgical quality control and to streamline perioperative medical optimization. In the meantime, early identification of these concerns, cessation of high-risk medical therapies, and judicious use of diversion by the surgeon can help optimize perioperative outcomes in IBD patients.
Samuel Eisenstein, MD, is an assistant professor of surgery in the Department of Surgery, Section of Colon and Rectal Surgery, at Moores Cancer Center at UC San Diego Health in La Jolla, California.
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