REVIEW ARTICLE

Surgical Management of Ulcerative Colitis in the Era of Biologicals Bikash Devaraj, MD and Andreas M. Kaiser, MD

Purpose: Proctocolectomy has been a curative option for patients with severe ulcerative colitis. In recent years, there has been a growing use of medical salvage therapy in the management of patients with moderate to severe ulcerative colitis. We aimed at reviewing the role of surgical management in a time of intensified medical management on the basis of published trial data. The aim was to determine the efficacy of aggressive medical versus surgical management in achieving multifaceted treatment goals. Methods: A comprehensive search of Pubmed, Medline, the Cochrane database was performed. Abstracts were evaluated for relevance. Selected articles were then reviewed in detail, including references. Recommendations were then drafted based on evidence and conclusions in the selected articles.

Results: The majority of patients with UC will not need surgery. However, steroid-refractoriness and steroid-dependence signal a subset of patients with more challenging disease. Biological therapy has been shown to achieve short-term improvement and temporarily reduce the need for a colectomy. However, there is a substantial financial and medical price to pay because a high fraction of these salvaged patients will still need a curative colectomy but may be exposed to the negative impact of prolonged immunosuppression, chronic illness, and a higher probability to require 3 rather than 2 operations. Proctocolectomy with ileo-anal pouch anastomosis—performed in 1, 2, or 3 steps depending on the patient’s condition—remains the surgical procedure of choice. Even though it has its share of possible complications, it has been associated with excellent long-term outcomes and high levels of satisfaction, such that in the majority of patients they become indistinguishable from unaffected normal individuals. Conclusions: The current data demonstrate that use of medical salvage therapy in the treatment of UC will likely continue to grow and evolve. Consensus is being developed to better define and predict failure of medical therapy and clarify the role of the different treatment modalities. For many patients, sacrificing the nonresponsive diseased colon is an underused or unnecessarily delayed chance to normalize their health and life. Biologicals in many instances may have to be considered the bridge to that end. (Inflamm Bowel Dis 2015;21:208–220) Key Words: ulcerative colitis, inflammatory bowel disease, colectomy, proctocolectomy, biological treatment, steroid-refractoriness, steroid-dependence, salvage treatment

U

lcerative colitis (UC) is a complex chronic disease associated with acute and chronic mucosal inflammation limited to the colon and rectum. It is characterized by intermittent exacerbations. Typical symptoms experienced by patients in an acute flare include bloody diarrhea, crampy abdominal pain, intolerance of oral intake, urgency, and tenesmus; a number of extraintestinal manifestations can be seen in some patients. The pathogenesis remains poorly understood; however, one of the more plausible models hypothesizes that an exaggerated autoimmune response is triggered by microbial/viral antigens (e.g., comensal intestinal flora) in genetically susceptible individuals and induces a chronic destructive inflammatory process.1 The incidence of UC in Western countries is in the range of 5 to 20 Received for publication June 14, 2014; Accepted July 8, 2014. From the Department of Colorectal Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California. The authors have no conflicts of interest to disclose. Reprints: Andreas M. Kaiser, MD, Department of Colorectal Surgery, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 7418, Los Angeles, CA 90033 (e-mail: [email protected]). Copyright © 2014 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000178 Published online 16 September 2014.

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new cases per 100,000 per year with a bimodal peak age of onset with the predominant one between 15 and 35 years of age.2–6 The prevalence ranges from 150 to 300 cases per 100,000 per year with substantial geographical variation.5,7 In contrast to Crohn’s disease, for which nicotine has invariably been seen associated with a negative impact, UC may be favorably affected by the use of nicotine8; the significance of this observation remains unclear.9 The rectum is universally affected by the disease, but the degree of proximal extension of the confluent and circumferential inflammation varies. Based on the extent of involvement, the Montreal classification (in addition to a severity score of S0–S3) categorizes the disease as proctitis (E1), left-sided colitis (E2, distal to the splenic flexure), and extensive colitis (E3, proximal to splenic flexure), the latter of which includes the 20% of patients with pancolitis.10,11 An estimated 10% to 20% of patients with pancolitis also demonstrate backwash ileitis, that is, an inflammation of the adjacent last segment of the ileum. Its significance has been debated with regards to an increased risk for development of pouchitis after restorative proctocolectomy.12–14 Historically, approximately 25% to 45% of the patients with UC required at some point an operative treatment.15,16 Proctocolectomy as a definitive cure for UC has undoubtedly and particularly since the introduction of a restorative ileo-anal pouch evolved as Inflamm Bowel Dis
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one of the most successful treatments modern medicine has to offer for any condition.17,18 In the overwhelming majority of patients, it results in a complete elimination of the disease. Although the function thereafter is not and cannot be expected to be exactly normal, the resolution of consuming symptoms and cessation of chronic medical care (e.g., hospitalizations, recurrent transfusions) and of immunosuppressive therapy, combined with the substantial reduction of the risk of primary malignancy arising from to the chronic inflammatory and regenerative process or of secondary treatmentinduced neoplasms, are the corner stones for the frequently dramatic improvement in quality of life (QOL).17,18 In the past few decades, substantial progress has revolutionized both the medical and the surgical treatment approaches for UC. Following the success of biologicals in the treatment of Crohn’s disease, the advent of biological therapy as a mainstay in the treatment for steroid-refractory UC has arguably been one of the biggest strides forward in the medical management and understanding of UC. In 2005, the Food and Drug Administration extended approval for the use of infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor alpha, as rescue therapy to patients with refractory UC; broadened indications and other anti–tumor necrosis factor (anti-TNF) antibodies followed, such as adalimumab, certolizumab pegol, golimumab. Although the intervention with biologicals as such seems rather simple and highly targeted, the biological ramifications of such a bold blockade within an extremely sophisticated immune system are far from being understood. Hence, the adoption of biologicals into the treatment algorithm of UC medical management has not been without its own share of complications, both in the long run (opportunistic infections, lymphoma, neurodemyelination) and in the acute setting in regards to the risk of increasing morbidity for surgery.19 Other classes of biologicals with new target mechanisms (e.g., integrin receptor antagonists) have already come out or are being developed. A recent randomized controlled trial has touted the efficacy of yet another biological drug, vedolizumab, in the medical treatment of patients with UC that were refractory to infliximab therapy or in whom infliximab was contraindicated.20,21 On the other end of the treatment spectrum, the surgical management of UC has also advanced: restorative proctocolectomy with ileal pouch anal anastomosis (IPAA) has not only become the gold standard surgical procedure with excellent longterm data over nearly 40 years published for thousands of patients worldwide, but the approach has evolved too with standardization of the technique, introduction of new and minimally invasive technology, and adaption of protocols for enhanced recovery after surgery. In experienced centers, pouch failure rates are as low as 5% to 10%.17 Introduction of laparoscopic techniques to this highly complex pan-abdominal and pelvic surgery have resulted in increased patient satisfaction and improved cosmesis as well as a potentially decreased negative long-term impact in regards to formation of adhesions, hernias, or fecundity.22 Moreover, functional outcomes, QOL, and patient satisfaction after proctocolectomy and IPAA remain high in long-term follow-up.17,23,24 As our experience and surgical/technical skills have increased over time, the area of concern when counseling patients with UC has shifted

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to reducing the incidence of short- and long-term pouch failure. In this context, there has been ample speculation about whether the use of biologicals would truly reduce the need for surgery or only delay the inevitable whereby increasing the risk of postoperative complications.25–27 Our contribution therefore aims at reviewing the current treatment regimens, both medical and surgical, in the management of patients with UC, particularly at the intersection of the 2 modalities. The various surgical modules are highlighted to define their role in the modern treatment guideline algorithms.

CLINICAL COURSE AND DISEASE SPECTRUM OF UC The course of UC is characterized by frequent exacerbations and remissions.1,5 Subjective symptoms and general physical findings vary considerably and are generally unspecific. As neither the clinical nor the pathological picture are absolutely indicative of the disease and may evolve over time, other differential diagnoses, such as Crohn’s disease, indeterminate colitis, ischemic colitis, diverticulitis, or infectious colitis, should be contemplated when establishing the diagnosis or in the event of unexpected disease behavior.28,29 In particular, Clostridium difficile or cytomegaly virus are frequently superimposed onto existing UC,30–32 a phenomenon that should be interpreted less as “another treatable condition” than as a surrogate marker of poorly controlled UC.29,33–35 A number of surrogate markers (e.g., C-reactive protein, fecal calprotectin) and severity scales have been used to monitor disease activity and treatment response.36–38 However, colonoscopy with visual assessment of the mucosal integrity (e.g., Mayo score39,40) and serial biopsies remain the diagnostic and surveillance procedures of choice to define the evolution of the disease and the treatment effectiveness toward the goal of mucosal healing.41 Imaging techniques, such as MRI enterography and possibly even PET scans, have a role for differentiating between UC and Crohn’s disease but remain controversial in assessing the disease activity.42,43 Apart from the impact the colonic and extracolonic manifestations on the QOL, the true risks of the disease originate from its potential for short- and long-term morbidity and mortality related to colorectal and systemic complications.16,44 In acute terms, these include the development of life-threatening episodes (fulminant colitis, toxic megacolon, bleeding, and perforation), hypercoagulability with thromboembolism, or toxic multiple organ dysfunction. In the longer run, growth retardation in children, cancer development, and medication-induced side effects (steroids, pancreatitis, opportunistic infections, and extracolonic tumors) become more relevant and adversely impact survival.19 UC is an established risk factor for developing colorectal cancer.45 The true incidence of colitis-associated tumors (colorectal cancer, lymphoma) varies considerably between population-based studies and studies carried out at tertiary referral centers. Whether as a result of better surveillance or better epidemiological data, the risk overall might not be as high as historically reported because there may have been a steady decline over the past 6 decades.46 www.ibdjournal.org |

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TREATMENT GOALS

MEDICAL MANAGEMENT OF UC

After establishing or confirming the diagnosis of UC, a synopsis of issues and comprehensive treatment plan should be worked out with the individual patient.5,47 Goals, benchmarks, and a timeframe for follow-up and subsequent decisions should be outlined and routinely defined during each encounter, but particularly whenever a new treatment or change of management are to be contemplated (Table 1). Interdisciplinary discussion is generally advised before escalation of any treatment to realign the various treatment modalities. It is relevant to note that “reduction of colectomy rates” is only one among multiple other treatment goals and should not receive the highest priority. Preservation of a healed colon is unquestionably desirable, but perseverance on this as the only benchmark even for a treatment-refractory, severely diseased colon unfairly neglects the other goals and may harm the patient on other levels.

Medical management for UC consists of supportive measures and at controlling the patients’ symptoms by resolving or suppressing the underlying inflammatory autoimmune process. The selection of a particular regimen largely depends on the extent and severity of the disease and the response to previous treatments. Classical medications include systemic or topical steroids (prednisone, budesonide), derivatives of 5-aminosalicylic acid (5-ASA, sulfasalazine, mesalamine), or immunosuppressants (azathioprine, 6-mercaptopurine, methotrexate, cyclosporine A).5,33–35,48 Reported efficacy in inducing clinical remission vary considerably (see summary in Table 2). Oral 5-ASA or mesalamine enemas alone may be sufficient in treating mild UC mainly limited to the rectum or left side of the colon (E1, E2). Enteral budesonide may play a role for intermediate severity disease.54 However, for insufficient response or more severe UC, first-line administration of systemic prednisone (in addition to oral 5-ASA) is needed with an initial boost and subsequent taper. Intravenous (IV) corticosteroids have been considered the main reason for the decrease over several decades in morbidity and mortality of patients with severe UC5,48; steroids are able to induce and maintain remission in 70% to 80% of the patients.55 Nonetheless, up to 30% of such patients are either steroid-refractory or become steroiddependent, that is, have a response but are unable to taper off the medication without flare of the disease.56 Immune modulators, such as azathioprine and 6-mercaptopurine, have shown success in inducing and maintaining steroid-free remission53; however, it may take weeks to months before establishing an effect, and in 21.5%, the drug has to be discontinued for adverse effects. Salvage or rescue treatment is a term used for patients with severe UC who are refractory to baseline drug combinations. Immune modulators such as cyclosporine A have been used for that purpose with moderate immediate (80%) but lack of lasting effectiveness in 50% of patients.57 These patients who need to have the treatment escalated—either with surgery or more recently with introduction of biologicals—are sought to be identified on prognostic parameters, whereby particularly failure to respond to IV steroid treatment seems to be an indicator for necessary salvage therapy. Several composite indices have been proposed but not necessarily validated for the same purpose. Travis et al58 developed the Oxford Index from a prospective study, suggesting with a positive predictive value of 85% that individuals with .8 bowel movements per day OR 3 to 8 bowel movements per day AND a C-reactive protein .45 mg/dL despite 3 days of IV corticosteroid administration should have salvage therapy commenced. Yet, another index developed by Ho et al59 added the presence of colonic dilatation and hypoalbuminemia to stool frequency as factors predictive of steroid therapy failure. With conventional treatment failing, biological therapy has opened a completely new platform of nonsurgical salvage therapy for patients with UC unresponsive to IV steroids. A number of

TABLE 1. Global Treatment Goals for Patients Suffering from UC General Subjective well-being (health status) and QOL Functional status (at home/at work) Avoidance of disability Colonic symptoms Induction of remission Maintenance of remission Maintenance of steroid-free remission Avoidance of acute life-threatening complications Avoid masking of colonic perforation Objective parameters Mucosal healing Normalization of activity parameters (C-reactive protein, calprotectin) Systemic symptoms Minimizing opportunistic infections Recover from malnutrition Normalize growth Reduction of extraintestinal symptoms (arthritis, DVT/PE, etc) Health maintenance Reduction of hospitalizations Reduction of transfusion requirement Optimization of direct and indirect cost/benefit/risk Avoidance of secondary morbidity Osteoporosis, adrenal insufficiency, cataract Tumors Opportunistic infections Surgical Avoidance of colectomy? Avoidance of postsurgical complications (leak, pelvic sepsis) Avoidance of ostomy DVT/PE, deep vein thrombosis/pulmonary embolism.

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TABLE 2. Efficacy of Medication Regimens in for Induction of Remission in UC Author Group

Year

Follow-up (yr)

N

Medication

Remission (%)

Campbell et al49 Rutgeerts et al50 Lawson et al51 cochrane review Feagan and McDonald52 cochrane review Timmer et al53 cochrane review Feagan et al21

2005 2005 2006 2012 2012 2013

7 1 1 1 1–2 1

76 365 786 7700 286 374

CSA Infliximab Infliximab 5-ASA Azathioprine, 6-MP Vedolizumab

10–35 69 69 25–60 45–60 48a

a Patients refractory to treatment with 5-ASA, azathioprine, 6-MP, steroids, or infliximab. 6-MP, 6-mercaptopurine.

prospective trials were carried out over time to investigate the effectiveness of various antibodies. The Active Ulcerative Colitis (ACT) trials 1 and 2 became the benchmarks for usage of infliximab (an anti–tumor necrosis factor chimeric antibody) in patients with moderate-to-severe steroid-refractory UC, whereby ACT 2 also required previous failure of 5-ASA therapy.50 In each trial with approximately 364 nonhospitalized patients with moderate-to-severe UC, patients were randomized to receive either infliximab (5 or 10 mg/kg) or placebo for 46 weeks (ACT 1) or 22 weeks (ACT 2). In ACT 1, clinically significant response rates were noted by week 8 in 69% versus 61% versus 37% for 5 mg/kg, 10 mg/kg, or placebo, respectively.50 Similar results were noted in ACT 2 with 64%, 69%, and 29% response rates for the respective groups.50 Furthermore, in both trials, remission rates were significantly higher in the treatment arms with 27% (ACT 1) and 38% (ACT 2) compared with 15% and 6% in the respective placebo groups. In follow-up reports to the ACT 1 and 2 trials, the colectomy rates at 54 weeks were decreased with 10% compared with 17% in patients treated with infliximab versus placebo, respectively; in addition, 3-year efficacy data in ACT 1 and 2 patients suggested that maintenance treatment with infliximab was well tolerated.60 A Cochrane database review of 7 randomized controlled trials that also included hospitalized patients concluded that in patients with moderate-to-severe steroid refractory UC, infliximab was 3 times more effective in inducing remission than placebo (risk ratio, 3.22; 95% confidence interval [CI], 2.18–4.76); in addition, infliximab was also twice as effective in inducing clinical response (risk ratio, 1.99; 95% CI, 1.65–2.41) and endoscopic remission (risk ratio, 1.88; 95% CI, 1.54–2.28) at week 8.51 Of the 4 approved anti– TNF-a antibodies, infliximab seemed to have the highest efficacy.20 Drugs against other biological targets showed discordant results. Natalizumab, a humanized monoclonal antibody against a4 integrin chains, was approved for use in induction and maintenance therapy for moderate-to-severe Crohn’s disease.61 However, the broader targeting of integrin a4 chains was associated with increased systemic immunological adverse effects; in particular, in the central nervous system, natalizumab was linked with the development of progressive multifocal leukoencephalopathy

associated with a subclinical reactivation of JC virus.62 More recently, vedolizumab—a new humanized monoclonal antibody specifically targeting gut integrin a4b7—revealed promising results in patients with severe UC refractory to conventional treatments and to infliximab.21 The increased precision of vedolizumab in specifically targeting gastrointestinal tract integrins is expected to cause less systemic and neurological side effects. The GEMINI-1 study group randomized 2 cohorts of 374 and 521 steroid- and infliximab-refractory patients, respectively, to receive either 2 doses of vedolizumab (300 mg) or placebo at weeks 0 and 2. Response rates at 6 weeks were defined as reduction of at least 3 points in the Mayo clinic score (0–12), a decrease in rectal bleeding subscore, and at least 30% reduction from baseline Mayo clinical score. At week 6, vedolizumab achieved a 47.1% response rate compared with 25.5% in the placebo group (P , 0.0001; 95% CI, 11.6–31.7). In addition, vedolizumab’s potential role in maintenance therapy was explored by randomizing patients with response to vedolizumab to receive either placebo or vedolizumab at either 4- or 8-week intervals. At 52 weeks of follow-up, vedolizumab maintenance therapy achieved clinical remission in 42% and 45% (for 8- versus 4-wk interval, respectively) compared with 16% in the placebo group (P , 0.0001; 95% CI, 18–40.4).21 This preliminary study demonstrated significant efficacy in inhibiting the adhesion and thus trafficking of inflammatory cells to the gut, offering a new strategy concept for the understanding and treatment of inflammatory bowel disease based on reinforcement of the intestinal barrier function rather than unselective immunosuppression. More studies to confirm the long-term efficacy of vedolizumab will be needed and are undoubtedly underway.

THE SURGEONS’ INTERPRETATION OF TRIAL DATA The current trend is clear: medical treatment of patients with moderate-to-severe UC with biologicals has evolved to playing a bigger role in both induction and maintenance therapy with the goal to reduce the rate of colectomy.20 With seemingly the latter often being reported as the last resort and the only negative endpoint (as implemented in the term “failure”), almost www.ibdjournal.org |

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any added treatment would be justifiable.63 However, it is important to be aware of substantial limitations of the studies including landmark trials in regards to the level of remission, length of follow-up, long-term colectomy rates, and adverse events including morbidity and mortality.

1. Follow-up: In most reported trials, follow-up was long enough to qualify for a good study design but was far from sufficient to determine the long-term impact and durability of the tested interventions. For example, ACT 1 and 2 had follow-up periods of 54 and 30 weeks only: even though the reported response rates were significantly higher in the treatment arms for that limited period,50 the rates as such were far from stellar (when compared with 40 years of follow-up after surgery).17 Furthermore, the study data reflect primary nonresponse rates, but underestimate the incidence of secondary nonresponders over time. The long-term extensions of ACT 1 and 2 only encompassed 229 of the original 484 infliximab-treated patients (47.3%), of which 30.6% discontinued the treatment.60 Hence, only 32.9% of the patients formed the basis for the authors’ statement that maintenance treatment was effective.60 2. Colectomy rates: Reported short-term colectomy rates were limited for the (short) follow-up periods and hence generally underestimated the true fraction of patients who ultimately either require or choose surgery. The rates of colectomy under biological treatment ranged between 10% and 34% in randomized trials (Table 3) and up to 80% in open-label studies,71 and hence were not significantly different from historical data on colectomy rates in nonresponders to steroid. Even large-scale epidemiological outcome studies were not able to demonstrate a decline in needed colectomies since implementation of biological treatment.69,72 3. Nonresponders: As the majority of studies focused on “success,” the primary and secondary nonresponders remained generally not well characterized. Most data only indirectly

TABLE 3. Colectomy Rates with Infliximab Treatment in Severe UC Author Group

Year

Follow-up Period

N

Colectomy Rates (%)

Aratari et al64 Ferrante et al65 Sandborn et al66 Teisner et al67 Halpin et al68 Moore et al69 Monterubbianesi et al70

2008 2008 2009 2010 2013 2014 2014

60 33 12 24 13 108 12

52 121 360 52 44 2537 113

20 17 10a 27 34 10 26

a

Moderate-to-severe UC cases.

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suggest an overall deterioration of those patients who might have ended up being in substantially worse condition after an exposure to biologicals than before.73–75 In practical terms, this translates into a higher cumulative risk of adverse events, a higher probability that the inevitable surgery will have to be split into a 3-stage approach rather than the electively most common 2-stage approach, and a higher morbidity and mortality.73–75 4. Adverse events: A recent systematic review on biological agents summarized 8 randomized controlled trials and suggested similar incidence of overall adverse events (81.4% versus 69.8%), severe adverse events (10.7 versus 12.3%), treatment-terminating adverse events (8.3 versus 6.4%), and serious infectious complications (1.7 versus 1.9%) from pooled data in treatment versus placebo arms, respectively.20 Although the authors’ conclusion predictably suggested that there was increased efficacy with biologicals but no difference in adverse events, the comparison falls short of a reality check. The combination of protracted illness, possible malnutrition, and escalating multidrug immunosuppression regimens has been associated with substantially increased risks and odds ratios for opportunistic infections and otherwise rare tumors, such a fatal hepatosplenic T-cell lymphoma or Kaposi’s sarcoma.19,76

INDICATIONS FOR SURGICAL MANAGEMENT OF UC There is general consensus that surgery is not typically needed for the majority of patients, particularly those with mild and limited disease.28,77 Based on the disease behavior and treatment response, there are 4 categories of indications for the surgical intervention (Table 4).77 The first category of life-threatening complications seems rather straightforward as surgery invariably should be the mainstay of treatment because the outcome of medical management beyond supportive measures for toxic megacolon, perforation, or uncontrolled bleeding (rare) invariably is either dismal or nonlasting.5,35,78 Larger audits confirm that morbidity and mortality of emergency surgeries are substantially higher than those of elective procedures, which suggests that the decision for surgery is often delayed for too long, hence putting the patient in jeopardy.73–75 The second category relates to the known risk of UC to develop colorectal cancer. Routine surveillance with systematic biopsies is recommended to start no later than 7 to 8 years after onset of the disease to monitor for possible dysplasia as a cancer precursor. However, detection of malignancy in UC is challenging because cancers may be multifocal and present as flat plaque-like lesions (rather than a mass) that can be endoscopically indistinguishable from the adjacent nondysplastic mucosa. Furthermore, 18% to 20% of patients are found to develop cancer before 8 years, and 2% of patients develop a cancer despite surveillance.79 There is little debate about the need for a colectomy when a single or multifocal locoregional

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TABLE 4. Four Categories of Indications for the Surgical Intervention in Patients with UC Category Life-threatening complications

Cancer-related

Insufficient treatment response

Treatment side effects

(Procto-)Colectomy Indicated

Surgery Indication to be Individualized

Toxic megacolon Colonic perforation (spontaneous, instrumentation-induced) Uncontrolled/persistent massive hemorrhage Proven localized cancer High-grade dysplasia RLD, non–adenoma-like (former DALM) Low-grade dysplasia in flat mucosa or multifocal Colonic “stricture” Treatment-induced secondary tumors Treatment refractoriness: lack of mucosal healing, persistent symptoms, frequent recurrences/ flare-ups/hospitalizations despite optimal medical therapy Chronic corticosteroid dependence Activity-linked extracolonic manifestations Unacceptable life style (mismatch of symptoms and expectations) Growth retardation (children) Side effects/intolerance/complications from medications: cataract, cushing, osteoporosis, hypertension, hyperglycemia, pancreatitis, neurological, skin, extraintestinal malignancy)

— — — Metastatic nonobstructive/nonperforated cancer Low grade dysplasia due to inflammation (regenerative atypia) RLD, adenoma-like (“polyp” in noninflamed colon) — — — Noncompliance with medication regimen

Anticipated lack of access to long-term high-intensity medical treatment (e.g., travel) — — — —

DALM, dysplasia associated lesion or mass; RLD, raised lesion with dysplasia.

colorectal cancer, high-grade dysplasia, or multifocal lowgrade dysplasia are found and confirmed by an expert pathologist.80 In contrast, the impact of non–adenoma-like low-grade dysplasia remains controversial. If low-grade dysplasia is distinct from regenerative atypia or detected in flat mucosa, it warrants if not immediately a colectomy at least a careful monitoring. Benign strictures are rare (#10%) in patients with chronic UC,81,82 and the presence of a stricture should be considered malignant until proven otherwise. A colectomy is strongly advised even if biopsies are unrevealing or show “only” dysplasia. So far the largest category of patients who should consider a colectomy are the ones who have an insufficient response to medical management, are steroid dependent, or develop relevant side effects from medical management. Even though there are a few objective parameters of response, the definition of what exactly “insufficient response” entails for the patient is rather subjective. As long as there is no immediate danger, the decision when expectations are not met should be left to the well-informed patient. The thrive for a balanced view makes it advisable to consult a specialist surgeon before escalation of treatment is considered. Most importantly, a patient’s decision toward surgery should not be interpreted as a defeat of

the gastroenterologist in a tug of war but as a very reasonable step toward elimination of the chronic illness.

SURGICAL TREATMENT OF UC The following 3 goals should be achieved with surgical treatment in patients with UC:

• Cure the patient from the disease and/or from toxic effects of the medications • Perform a reconstruction with low morbidity but high life-style quality • Minimize morbidity or mortality of any procedure. Surgical management for UC can be understood as a combination of different modules (Fig. 1).77 The first goal is to achieve (near) complete elimination of the disease preferably in 1 but under urgent circumstances in 2 steps; the second goal is to establish the individual route of waste elimination. The 2 goals are not necessarily linked to each other but depend on the specific circumstances and patient condition.

Surgical Goal 1: Elimination of the Disease Historically, segmental resections were attempted for limited disease not involving the whole colon. The results were invariably www.ibdjournal.org |

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FIGURE 1. Surgical modules for treatment of UC. Adapted with permission from Kaiser AM, Beart RW Jr. Surgical management of ulcerative colitis. Swiss Med Wkly. 2001;131:323–337.77

poor, as the previously uninvolved segments would commonly develop inflammation and recurrent symptoms with vengeance. Likewise, Turnball blowholes are of historical rather than practical interest and were largely abandoned because leaving the severely diseased even though vented megacolon in the patient would much less likely lead to a rapid turnaround of a life-threatening condition. With very few exceptions, the following 2 surgical options have their place in the surgical management of UC:

the rare cuff or pouch cancers.83,84 Surveillance and routine biopsy of the rectal cuff can be easily performed in the office setting. Mucosectomy of the remaining rectal cuff is usually reserved for special situations such as the presence of dysplasia or treatmentrefractory symptoms from the rectal remnant (“cuffitis”). In case a permanent ileostomy is planned (primarily or secondarily), the proctocolectomy should include de-epithelialization of the whole anal canal to avoid a mucus-draining “wet anus.”

Proctocolectomy

Total Abdominal Colectomy

Proctocolectomy has become the gold standard because removal of the entire colon and rectum eliminates the diseasebearing bowel and effectively achieves cure in the majority of patients with UC.28 When IPAA is planned, a small rectal cuff of 1 to 2 cm is left behind to enable a double-stapling anastomosis and decrease the risk of a compromised anal sphincter mechanism. A meta-analysis of routine mucosectomy versus double-stapled IPAA found the former to be associated with an increased risk of stricture and functional disturbances, including increased nighttime seepage and decreased resting and squeeze pressures.83 Furthermore, there was no statistically significant advantage for the mucosectomy patients in regards to controlling residual disease or preventing

This procedure involves removing the entire colon to the point of the confluence of the teniae. Given the high success rates with proctocolectomy, a rectum-sparing resection under elective circumstances seems counterintuitive and has largely been abandoned. However, total abdominal colectomy with end ileostomy is the surgical approach of choice for all urgent or emergency situations where the goal is to eliminate the majority of diseased colon as fast as possible without distorting the anatomical planes or losing the pelvic spaces. The more delicate portions of pelvic dissection and pouch creation and anastomosis are left for a time when the patient has recovered from the disease and the immunosuppression. As the endoscopic appearance of the rectal

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remnant likely will change postoperatively, it is crucial to document its condition at the time of the abdominal colectomy.85

Surgery for Cancer The surgical treatment for localized cancers in the colon remains the same as for the underlying colitis,86,87 but depending on the pathological tumor stage, adjuvant chemotherapy may have to be added. If there is a known rectal cancer, the management should always be shifted to neoadjuvant chemoradiation for 2 reasons: (1) the growth pattern of cancer in UC if often very different from sporadic cancer such that pretreatment staging efforts become unreliable and (2) postoperative radiation should always be dissuaded in the presence of a pelvic pouch because it will invariably damage the pouch and result in a poor functional outcome. Sphincter preservation follows the same principles as in non–IBD-related rectal cancer, but for midlevel and distal rectal cancer, a mucosectomy should be considered. In patients with metastatic disease but no evidence of obstruction or perforation, the primary treatment should rely on systemic chemotherapy. Under favorable circumstances, if the metastatic disease is limited and/or the response to the systemic therapy is excellent, a resection of the primary and metastatic tumor can be considered at a later stage.

Surgical Goal 2: Intestinal Rearrangement After the resection is completed, the decision on the selection of the most appropriate type of intestinal rearrangement depends on a number of patient and disease-related factors, including urgency of the operation, patient condition, completeness of the resection, underlying sphincter function, body habitus, personal preference, and personality. The 4 possible options are outlined (Fig. 1).

Continuity Restoration: IPAA For restoration of intestinal continuity, an ileo-anal pouch is created to serve as a new storage area with a high-volume/low pressure profile. The ileal J-pouch has become the most common pouch configuration secondary to its simplicity in creation and overall good functional outcome. A 12- to 15-cm-long pouch is created by folding the terminal ileum and fusing the 2 antimesenteric limbs into one space. The tip of that pouch may either be stapled or hand sewn down to the rectal cuff as previously described.85 If the pelvic floor is difficult to reach with a standard approach, the small bowel mesentery may have to be lengthened by means of a number of surgical maneuvers. Alternatively, an S-pouch (or rarely a straight ileo-anal anastomosis) may be used, but their functional results are problematic. The S-pouch is at risk for functional outlet obstruction if the efferent limb is too long, whereas a straight ileo-anal anastomosis results in high frequency and suboptimal continence rates. If despite all tricks and maneuvers reach remains impossible, an anastomosis may have to be foregone for the time being: the diverted pouch should be left in the pelvis without anastomosis to prevent loss of the pelvic space and potentially allowing an anastomosis in a second attempt at

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a later time. If problems with reach are even anticipated because of patient factors including obesity, a total colectomy with end ileostomy would seem a prudent temporary choice. A diverting loop ileostomy at the time of pouch creation likely does not reduce the incidence of a leak but reduces the septic sequelae should an anastomotic leak occur; but even without a complication an ileostomy may be advantageous because it allows for a smoother functional transition if use of the pouch is delayed until it has nicely healed and the bowel tissue elasticity returned to normal.85 One-stage procedures without diverting ostomy should only offered to carefully selected individuals who are nutritionally optimized and are at least 6 months out from receiving any immunosuppressants if everything during the surgery is perfect.88 Criteria to take down the temporary ileostomy include a minimum interval of 6 to 12 weeks after the primary surgery, normalized general health and nutritional status, clinical and radiographic evidence of proper pouch healing, and completed weaning from steroids.

Continuity Restoration: Ileorectal Anastomosis Under elective conditions, some authors advocated preservation of the rectum in selected young patients to avoid the negative impact of a pelvic dissection.89 However, the arguments in favor of a proctocolectomy are a lot stronger. It makes little sense to leave either active disease or a burned-out “rigid-pipe” rectum behind: the probability of a worse functional result, recurrent symptoms, the need for continued surveillance, and for a future abdominal operation are simply too high. As previously described, this procedure has largely been abandoned in favor of a restorative proctocolectomy.

Permanent Ostomy: End Ileostomy (Brooke) A well-formed end-ileostomy remains a generally very predictable solution, the primary creation of a Brooke ileostomy is rare and chosen in a minority of patients who (1) do not qualify for a restorative procedure or (2) for unspecified personal reasons prefer a stoma. A bit more common is the creation of an end ileostomy in the first phase (emergency/urgent total colectomy) of a 3-stage approach or the secondary creation of a Brooke ileostomy in patients who have failed an IPAA. The advantages of a well-formed end ileostomy in a well-chosen location are not negligible; its disadvantages, however, include the need for an external appliance, which has to be emptied several times per day, and the psychological and social implications of having a permanent ileostomy.90 In addition, stoma complications and device-related problems are not uncommon, such as hernia, prolapse, retraction, leakage, and skin irritations. The latter can be the result of suboptimal location, suboptimal appliances or handling, mismatch between appliance and body configuration, or secondary to allergic reactions.91

Permanent Ostomy: Continent Ileostomy (Kock pouch, Barnett Continent Ileal Reservoir, T-pouch) The concept of a continent ileostomy was first described in 1969 by Kock,92 who had developed a high volume/low pressure www.ibdjournal.org |

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reservoir with an intussuscepted nipple valve. The principal design should allow fecal material to accumulate in a pouch whereby the valve mechanism prevents spillage of the waste to the outside. Several times per day, at the patient’s convenience, the pouch is emptied by inserting a tube through the skin-level stoma into the reservoir. An external ileostomy nipple and an appliance are therefore not needed and the opening is covered with a flat dressing. Functioning Kock pouches have achieved high levels of acceptance,93,94 but the procedure was also associated with frequent complications with up to 15% to 40% of the patients requiring surgical pouch revisions.95,96 In the ensuing years, the pouch not only lost market shares to the evolving IPAA but also remained a surgical rescue for patients who failed an IPAA or were not candidates for it. The pouch and valve constructions were subject to many modifications (e.g., Barnett continent ileal reservoir),97 which primarily attempted to overcome the fundamental flaws associated with the intussuscepted valve mechanism. The most common type of valve dysfunction was secondary to desintussusception (valve slippage), which led to leakage and difficulties in intubating the pouch.98 The development of the T-pouch relied on a different valve design without the intussusception, hence reducing the risk of valve disintegration and failure so often seen in the Kock pouches.99 A recent 10-year review of 40 patients who underwent T-pouch creation demonstrated that the T-pouch procedure can be accomplished safely and dramatically improved functional outcomes, in particular, with fecal control and decreased social restrictions.96 Contraindications include Crohn’s disease, morbid obesity, short-bowel syndrome, and excessive adhesions.

LONG-TERM OUTCOME AND COMPLICATIONS OF IPAA The mortality of elective surgery for UC over the years has dropped to less than 1%, and a good functional outcome is expected in .90% of all patients (Table 5).17,28 In the largest case series to date, the Cleveland clinic recently reported their outcomes in a 25-year follow-up on 3707 patients who had undergone IPAA surgery.17 A perioperative mortality rate of ,0.1% was reported. With regard to early complications (within 30 d after surgery), wound infection was the most common at 7.4% followed by pelvic sepsis and anastomotic leak with 6.4% and 4.8%, respectively. In contrast, the most common late complication was pouchitis affecting 34% patients, half of whom (16%) would develop chronic pouchitis defined as having at least 3 attacks of pouchitis in 1 year. Patients with inflammatory bowel disease were statistically more likely to develop pouchitis or late anastomotic stricture when compared with patients with familial adenomatous polyposis (P ¼ 0.011). Not surprisingly, patients with Crohn’s disease had a more than double the rate of longterm pouch failure compared with UC or patients with familial adenomatous polyposis (13.3% versus 5.1% or 4.8%, respectively). The majority of IPAA patients retained full continence of stool and gas (80%) at 10 years. Furthermore, 75% of IPAA patients maintained overnight incontinence. Using Cleveland global QOL scores, the authors reported 9/10 QOL and quality of health at 10 years after IPAA surgery. Happiness scores were also high at 10/10 ten years after IPAA surgery, confirming previous reports that patients who have undergone IPAA surgery are overall happy with their surgery and experience a better QOL

TABLE 5. Long-term IPAA Functional Outcomes

University of Minneapolis Mt Sinai, New York University of Toronto, Canada Mayo clinic Lahey clinic Auckland University of Utah Helsinki University, Finland St. Mark’s Hospital, United Kingdom University of Chicago Mayo clinic Sydney, Australia Cedars-Sinai, Los Angeles University of Heidelberg Hyogo College of Medicine, Japan Cleveland clinic, Ohio Total and weighted averages

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Author Group

Year

N

Pouch Failure (%)

Pelvic Sepsis (%)

Pouchitis (%)

Gemlo et al100 Bauer et al101 MacRae et al102 Meagher et al103 Breen et al104 Neilly et al105 Dayton et al106 Lepisto et al107 Tulchinsky et al108 Michelassi et al109 Hahnloser et al110 Rickard et al111 Murrell et al112 Leowardi et al113 Ikeuchi et al88 Fazio et al17 —

1992 1997 1997 1998 1998 1999 2002 2002 2003 2003 2007 2007 2009 2010 2010 2013 —

253 392 551 1310 628 201 510 486 634 391 1885 516 334 294 1000 3707 13,092

9.9 3.1 10.5 10.2 2.5 9.4 2.4 5.3 9.7 — 7.9 — — 12.6 7.5 5.0 6.8

5.1 10.2 11.8 5.6 6.5 5.3 — — 5.0 6.4 — — — — — 3.3 5.2

31 — — 48 — 44 32 36 — — — 21 27 — — 34 35.4

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than before their surgery.17,114 In studies with more than 200 patients since the 1980’s, cumulative weighted pouch loss was 6.8%, pelvic sepsis 5.2%, and incidence of pouchitis 35.4% (Table 5). The majority of patients typically report an average of 5 to 7 bowel movements per day and 1 at night. Supportive management is important and includes the administration of bulking fibers and antidiarrheal medications as well as topical application of zinc oxide–based barrier ointments to protect the perianal skin from maceration by intestinal contents.

COST ANALYSIS SURGERY VERSUS MEDICAL TREATMENT In an era of exploding healthcare cost, when financial constraints become increasingly relevant in guiding therapeutic decisions, one should examine the cost of surgical treatment compared woith medical therapy primarily with a focus on biological therapy given their increasing widespread use in patients with UC. Depending on the medication examined (infliximab versus adalimumab), the annual cost per remission with these medications accumulates up to $150,000 versus $330,000.115 Analysis of cost-effectiveness comparing colectomy and infliximab treatment in patients with UC demonstrated lower cost ($270,000 versus $306,000) and greater quality-adjusted life years (QALY; 18.3 versus 16.6) for colectomy compared with infliximab therapy when drawn out over a 70-year time span, even though infliximab in short-term analysis (#2 yr) demonstrated lower cost.116 However, in another analysis over a 1-year period, infliximab treatment resulted in an incremental costeffectiveness ratio of £18,388 per QALY gained compared with £13,200 per QALY for surgical treatment,117 whereby the authors still claim that infliximab treatment was “cost-effective” given that it was below a “willingness to pay level” of $100,000/ QALY. A model simulating 2 cohorts of patients with UC (medical versus surgical) and following them out for 80 years found the cost to be lower in the surgical than the medical cohort ($147,763 versus $236,370 respectively) while QALY gained was at 20.7 in both groups.118 Although analysis of financial data is always very difficult, it seems evident that treatment with biologicals is very expensive and accumulates cost by nature of the need for repeated treatment. Combined with a lack of efficacy over varying periods and a later need for surgical intervention,72 a comparison of pure medical cost versus surgical cost may not be appropriate because the medical arm at a high frequency will require and accumulate both medical and surgical costs.

EFFECT OF BIOLOGICAL THERAPY ON SURGICAL MORBIDITY Emergency surgery has always been associated with higher morbidity and mortality, a fact that has been reconfirmed on multiple occasions.119 Presence of complications in conjunction with malnutrition and immunosuppression create a high-risk triad. High-dose steroids have been of particular concern in regards to

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increasing the incidence of anastomotic leaks.120 Other authors reported patients eventually subjected to urgent surgeries being sicker and hence at a higher risk for complications.73–75,121 A major question has therefore been whether biologicals themselves would contribute to a worse outcome. The retrospective data in the literature are at variance—with some studies suggesting a higher incidence of complications,27,122,123 while others have not been able to confirm that.124–127 One might therefore speculate that infliximab—depending on the circumstances—is one of the confounding factors itself: for example, if the infliximab administration worsens the patient’s overall condition, its impact would be negative; vice versa, if the infliximab ameliorated a very bad disease and patient condition toward surgery, the overall morbidity would be expected to improve.

CONCLUSIONS Treatment of UC will continue to evolve particularly with respect to biological therapy. A paradigm shift in targeting the immune cell trafficking through the intestinal barrier holds promise in the medical therapy of patients with UC refractory to conventional and anti-TNF biological therapy. Proctocolectomy with IPAA remains the gold standard of the surgical treatment for UC and over several decades has shown an excellent benefit/risk profile, functional outcome, and a significantly improved QOL. Deconditioning of patient with unreasonably long escalations of ineffective medications adds to the morbidity of surgical intervention and exposes the patient to 3 rather than 2 operations. Given the higher cost of biologicals and persistent need for colectomy, patients should be offered an unbiased discussion of surgery versus rescue medical management once the first-line treatment fails.

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33. Van Assche G, Dignass A, Bokemeyer B, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 3: special situations. J Crohns Colitis. 2013;7:1–33. 34. Dignass A, Eliakim R, Magro F, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis. J Crohns Colitis. 2012;6:965–990. 35. Dignass A, Lindsay JO, Sturm A, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. J Crohns Colitis. 2012;6:991–1030. 36. De Vos M, Louis EJ, Jahnsen J, et al. Consecutive fecal calprotectin measurements to predict relapse in patients with ulcerative colitis receiving infliximab maintenance therapy. Inflamm Bowel Dis. 2013;19:2111–2117. 37. Yoon JY, Park SJ, Hong SP, et al. Correlations of C-reactive protein levels and erythrocyte sedimentation rates with endoscopic activity indices in patients with ulcerative colitis. Dig Dis Sci. 2014;59:829–837. 38. Sehgal R, Koltun WA. Scoring systems in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol. 2010;4:513–521. 39. Bewtra M, Brensinger CM, Tomov VT, et al. An optimized patientreported ulcerative colitis disease activity measure derived from the Mayo score and the simple clinical colitis activity index. Inflamm Bowel Dis. 2014;20:1070–1078. 40. Colombel JF, Loftus EV Jr, Tremaine WJ, et al. The safety profile of infliximab in patients with Crohn’s disease: the Mayo clinic experience in 500 patients. Gastroenterology. 2004;126:19–31. 41. Bouguen G, Levesque BG, Pola S, et al. Feasibility of endoscopic assessment and treating to target to achieve mucosal healing in ulcerative colitis. Inflamm Bowel Dis. 2014;20:231–239. 42. Deepak P, Bruining DH. Radiographical evaluation of ulcerative colitis. Gastroenterol Rep (Oxf). 2014;2:169–177. 43. Parbo P, Stribolt K, Rittig CS, et al. Active ulcerative colitis diagnosed by (18)F-FDG PET/CT in an anti-TNF alpha treated patient with no visible luminal lesions on colonoscopy. Int J Colorectal Dis. 2014;29:643–644. 44. Ventham NT, Kennedy NA, Duffy A, et al. Comparison of mortality following hospitalisation for ulcerative colitis in Scotland between 19982000 and 2007-2009. Aliment Pharmacol Ther. 2014;39:1387–1397. 45. Ekbom A, Helmick C, Zack M, et al. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med. 1990;323:1228–1233. 46. Castano-Milla C, Chaparro M, Gisbert JP. Systematic review with metaanalysis: the declining risk of colorectal cancer in ulcerative colitis. Aliment Pharmacol Ther. 2014;39:645–659. 47. Bitton A, Buie D, Enns R, et al. Treatment of hospitalized adult patients with severe ulcerative colitis: Toronto consensus statements. Am J Gastroenterol. 2012;107:179–194; author reply 195. 48. Burger D, Travis S. Conventional medical management of inflammatory bowel disease. Gastroenterology. 2011;140:1827 e2–1837 e2. 49. Campbell S, Travis S, Jewell D. Ciclosporin use in acute ulcerative colitis: a long-term experience. Eur J Gastroenterol Hepatol. 2005;17:79–84. 50. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353: 2462–2476. 51. Lawson MM, Thomas AG, Akobeng AK. Tumour necrosis factor alpha blocking agents for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2006:CD005112. 52. Feagan BG, MacDonald JK. Once daily oral mesalamine compared to conventional dosing for induction and maintenance of remission in ulcerative colitis: a systematic review and meta-analysis. Inflamm Bowel Dis. 2012;18:1785–1794. 53. Timmer A, McDonald JW, Tsoulis DJ, et al. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2012;9:CD000478. 54. Danese S, Siegel CA, Peyrin-Biroulet L. Review article: integrating budesonide-MMX into treatment algorithms for mild-to-moderate ulcerative colitis. Aliment Pharmacol Ther. 2014;39:1095–1103. 55. Sachar DB. Maintenance therapy in ulcerative colitis and Crohn’s disease. J Clin Gastroenterol. 1995;20:117–122. 56. Kaur M, Targan SR. Ulcerative colitis: steroid-refractory ulcerative colitisciclosporin or infliximab? Nat Rev Gastroenterol Hepatol. 2013;10:8–9. 57. Garcia-Lopez S, Gomollon-Garcia F, Perez-Gisbert J. Cyclosporine in the treatment of severe attack of ulcerative colitis: a systematic review. Gastroenterol Hepatol. 2005;28:607–614.

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