Current Treatment Options in Gastroenterology DOI 10.1007/s11938-014-0036-5

Inflammatory Bowel Disease (G Lichtenstein, Section Editor)

Management of Severe Ulcerative Colitis Neeraj Narula, MD, FRCPC Bindia Jharap, MD Jean-Frederic Colombel, MD* Address * Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1069, New York, NY 10029, USA Email: [email protected]

* Springer Science+Business Media, LLC 2015

This article is part of the Topical Collection on Inflammatory Bowel Disease Keywords Ulcerative colitis I Severe I Colectomy I Infliximab I Cyclosporine I Remicade

Opinion statement Acute severe steroid-refractory ulcerative colitis (ASUC) provides challenges for physicians and surgeons who manage these patients. When a patient is diagnosed with ASUC, they should be admitted for inpatient management including intravenous corticosteroids, venous thromboembolism prophylaxis, oral or enteral feeding if tolerated, and exclusion of infection including Clostridium difficile. Failure to improve by day 3 of corticosteroids requires escalation to medical rescue therapies such as infliximab or cyclosporine, or surgical management with colectomy. This chapter will review management of ASUC with a focus on the medical rescue options available.

Introduction Ulcerative colitis (UC) is a chronic inflammatory disease of the colon, characterized by mucosal ulceration and can manifest with diarrhea, hematochezia, and weight loss. About 25 % of patients will experience a severe attack requiring hospitalization [1]. Severe UC is defined as passage of six or more bloody bowel movements per day, combined with at least one of anemia (hemoglobin G10.5 g/dl), fever (937.8 °C), tachycardia (heart rate9 90 bpm), or elevated erythrocyte sedimentation rate (930 mm/h) [2]. An attack of UC is often unpredictable

and can present in patients with long-standing limited disease. In patients hospitalized for severe UC, prognosis was initially quite poor, but intensive treatment with intravenous corticosteroids has helped decrease mortality rates to 1 % since the 1970s [3]. Medical rescue therapies or surgery are necessary for those who fail to respond to intravenous steroids. This review will provide detailed guidance with a series of evidence-based recommendations on the treatment of hospitalized severe UC patients.

Inflammatory Bowel Disease (G Lichtenstein, Section Editor)

Initial management of acute severe ulcerative colitis Recommendation: Patients with severe ulcerative colitis should be admitted to hospital for intensive treatment. Recommendation: Surgeons should be consulted at the time of admission to introduce the possibility of colectomy. Colectomy is appropriate for early management in certain patients, including intestinal perforation, exsanguinating hemorrhage, and toxic megacolon. Initial assessment should include determining the presence of any surgical emergency.

Rule out infectious causes

Recommendation: All patients admitted with ASUC should have stool cultures and stool PCR assay for Clostridium difficile performed at the time of admission. Recommendation: Unless demonstrating signs of systemic toxicity or high index of suspicion for C. difficile infection, empiric antibiotics are not recommended. Recommendation: Patients should have flexible sigmoidoscopy performed within 24 h of admission to assess severity of disease and rule out CMV infection.

C. Difficile infection (CDI) can present with toxic megacolon or fulminant colitis and may mimic or present superimposed on a flare of ulcerative colitis. In addition to risk factors of hospitalization, antibiotic use, immunosuppression, and the presence of other comorbidities, the presence of UC itself may be a risk factor [4]. The proportion of UC patients whose hospitalization is complicated with CDI has risen substantially, increasing from 24 per 1,000 in 1998 to 39 per 1,000 in 2005 (pG0.05) [5]. Patients with concurrent CDI have higher mortality (OR 4.7, 95 % CI 2.9 – 7.9), longer hospitalization (OR 3.0, 95 % CI 2.3 – 3.7) [5], and higher colectomy rates (OR 10.0, 95 % CI 2.7 – 36.3) [6] than those with IBD alone. There is a paucity of evidence examining the role of empiric therapy against CDI in those presenting with acute severe UC while awaiting results of testing, but this has been conditionally recommended by the ACG CDI task force with low-quality supporting evidence [7]. For those who do have CDI, there is a high failure rate of up to 50 % using metronidazole as a first-line agent, so oral vancomycin is a preferred treatment agent for C. difficile in UC patients [8]. There are no data to support use of fecal microbiota transplantation for C. difficile infection in severe UC patients. Initiation of corticosteroids while awaiting results of infectious workup is reasonable, but escalation of corticosteroids or commencement of rescue salvage therapies should be avoided until culture results are confirmed negative. If stool cultures are positive, it has been suggested by some investigators to avoid increase in corticosteroids or rescue salvage therapies for at least 72 h after initiation of treatment with antibiotics [7].

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Early flexible sigmoidoscopy by an experienced endoscopist should also be performed to assess severity of disease and obtain biopsies to exclude the presence of cytomegalovirus (CMV) infection. The exact role of CMV infection in UC is unclear, but is associated with steroid refractory UC and a worsened disease course [9]. The prevalence of CMV infection in patients with active UC is estimated at 4.6 – 22 % depending on the population studied and the methods of detection [10]. Use of immunohistochemistry or molecular techniques such as quantitative PCR are recommended given higher sensitivity and diagnostic accuracy [11]. In some presentations, it may be a mere bystander and treatment with antivirals does not appear to impact the course of disease. Case series of patients receiving antivirals suggest achievement of clinical remission in 67 – 100 % of cases [12–15]. Patients with severe UC that are found to have CMV detected on histopathology should be treated with ganciclovir, with the caveat that some patients will still not respond to treatment and may require colectomy or medical rescue therapies.

Use of corticosteroids

Recommendation: Patients should be initiated on intravenous corticosteroids at admission, using up to 60 mg of methylprednisolone daily (or equivalent of an alternative). Recommendation: Patients who respond to intravenous corticosteroids should be transitioned to oral steroids after 3 – 5 days with a plan for a non-steroid based maintenance therapy.

Intravenous corticosteroids (ICS) are a first-line medical therapy for patients presenting with acute severe UC. The introduction of intravenous steroids as initial treatment has led to substantial reductions in mortality of ulcerative colitis [16]. The first trial establishing the benefit of ICS found a clinical response rate of 73 % in 49 patients who were treated with 60 mg of IV methylprednisolone in an open-label fashion [2]. Since then, several steroid formulations have been tried with benefit in severe UC. A systematic review suggested no difference between various steroid formulations [3]. A metaregression analysis did not find any correlation between increased corticosteroid dosing and reduction in colectomy rate, and concluded doses beyond 60 mg per day of methylprednisolone or equivalent should not be used [3]. Another study examined 60 mg/day of methylprednisolone administered in an intravenous bolus (bid) regimen or continuous infusion (at similar doses), and found similar rates of clinical remission and colectomy at 1 year [17]. There are no prospective comparative clinical trials comparing methods of steroid delivery. The preference for intravenous delivery compared to oral is largely based on historical cohorts and pharmacologic data. Pharmacokinetic data suggest that patients with active severe UC achieve significantly higher maximum plasma steroid concentrations after intravenous dosing compared to oral [18]. Further, in severe UC patients who fail oral steroids, treatment with ICS has been found to

Inflammatory Bowel Disease (G Lichtenstein, Section Editor) induce remission in 53 – 57 % of patients [19, 20]. Thus, in the ASUC setting, maximizing chance for response requires use of ICS initially.

Venous thromboembolism prophylaxis

Recommendation: All patients admitted with ASUC should have venous thromboembolism prophylaxis initiated, preferably with heparin or low-molecular weight heparin (LMWH).

Patients with UC are at increased risk of venous thromboembolic (VTE) events inherent to their illness, and these risks increase with greater disease extent and severity of disease. A meta-analysis estimated the relative risk for VTE among UC patients as 2.57 (95 % CI 2.02 – 3.28) [21], and risk increases substantially during a hospitalized flare (sixfold that during a non-hospitalized flare) [22•]. There does not appear to be an increased risk of bleeding complications in those who receive VTE prophylaxis, even in those patients with rectal bleeding at admission [23]. As a result, pharmacologic VTE prophylaxis is routinely recommended for hospitalized IBD patients, as per the ACCP recommendation for acutely ill hospitalized medical patients at increased risk of thrombosis [24]. Only in the setting of severe bleeding should this be substituted with mechanical prophylaxis such as intermittent pneumatic compression.

The role of nutrition Recommendation: Patients should be offered oral diet at admission, or enteral nutrition if oral feeding is not tolerated.

Oral or enteral feeding is preferred for patients admitted with ASUC. The use of complete bowel rest, in the form of total parenteral nutrition (TPN) is not recommended, and has been evaluated in three small randomized trials. Two small randomized trials each randomized 27 patients with moderate to severe UC to TPN or an oral diet, and did not find any difference between the groups with regards to steroid reduction, colectomy-free discharge, or mortality [25, 26]. Another small trial suggested increased complications in those randomized to TPN compared to total enteral nutrition, with significantly more adverse events and postoperative complications in those receiving TPN [27]. Bowel rest may lead to poorer outcomes due to starvation of colonic enterocytes of short-chain fatty acids which are vital for tissue repair and metabolism [28]. TPN may have a role in those patients unable to tolerate oral feeds or who are to undergo colectomy, although a recent retrospective series found increased post-operative

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complications due to line infections in UC patients receiving pre-operative TPN [29]. Early involvement of nutritional expertise is recommended as poorer outcomes tend to occur in patients with evidence of severe malnutrition [30].

Anticipate future options

Recommendation: Assess for risk of tuberculosis and hepatitis B in anticipation of potential start of infliximab. Patients not receiving thiopurines at the time of their admission should also have TPMT enzyme activity assay performed where possible.

The presence of untreated latent tuberculosis and hepatitis B infection are both considered contraindications to anti-TNFα therapies. To avoid subsequent delays, testing should be performed early to determine whether any contraindications exist that would preclude use of infliximab in the event of corticosteroid failure. Testing for tuberculosis should be performed with a tuberculin skin test or interferon-γ release assay and chest X-ray. Testing for hepatitis B can be done with hepatitis B surface antigen, hepatitis B core antibody, and surface antibody to screen for immunity. As thiopurines may be used for future maintenance therapy, or possibly as combination induction therapy with infliximab in patients who fail corticosteroids, thiopurine methyltransferase (TPMT) enzyme testing can be performed if available to determine which patients are at increased risk of bone marrow suppression. Consideration can be given to avoiding thiopurines in young male EBV-seronegative patients given the risk of early post-mononucleosis lymphomas [31]. Serologic testing for EBV is not currently recommended for IBD patients.

Predicting response and prognosis

Recommendation: During the first 3 days of hospitalization, there are some who advocate that patients should have daily CRP levels and abdominal X-rays for early identification of patients failing therapy and likely to require surgery or medical rescue therapy. Tools such as the ‘Oxford Index’ can be applied at day 3 to determine likelihood of failure with corticosteroids. Recommendation: It is the authors’ recommendation that patients should be reassessed at least twice daily with objective measurement of symptoms using a tool such as the Lichtiger score to monitor for patient deterioration and guide treatment decisions.

Prediction of patients likely to fail ICS should be performed in order to introduce rescue therapies or surgery early and minimize adverse outcomes. Performing early flexible sigmoidoscopy can determine the presence of extensive deep colonic ulcerations which has been shown to predict the need for colectomy (Fig. 1) [32, 33]. There are several scoring tools that examine over 20

Inflammatory Bowel Disease (G Lichtenstein, Section Editor)

Fig. 1. Endoscopic evidence of deep colonic ulceration in severe UC (Photograph courtesy of Dr. Benjamin E. Cohen, Mount Sinai Hospital).

different variables attempting to best predict prognosis [34]. Two of the better validated tools for this include that by Travis et al. and Ho et al. [35, 36]. The Travis et al. prediction model (the ‘Oxford Index’) suggests after 3 days of intravenous steroids, patients with greater than eight bowel movements or a Creactive protein (CRP)945 with a stool frequency between three and eight bowel movements will require colectomy in about 85 % of cases [35]. This index was developed prior to the era of biologic therapy, thus its applicability in the era of biologics in predicting colectomy is not certain. The Ho et al. model identifies mean stool frequency, colonic dilatation within the first 3 days, and hypoalbuminemia as poor predictors and a numerical risk score of 4 or more based on these variables had a sensitivity of 85 % and specificity of 75 % for prediction of non-response [36]. A recent retrospective study compared both of these tools using data from the UK IBD audit and found they were equally able to identify patients at high risk of failing medical therapy and requiring secondline therapy or colectomy [37]. The best model for children is likely that published by Turner et al., where they found the Pediatric Ulcerative Colitis Activity Index (PUCAI) at days 3 and 5 to best predict response compared to other measures. A PUCAI greater than 45 at day 3 had a negative predictive value of 94 % for patients likely to fail ICS [38]. A PUCAI greater than 65 at day 5 had a positive predictive value of 100 % for need of rescue therapy [38]. The response to corticosteroid therapy should be decided early in the course of treatment. Use of an objective scoring tool such as the Modified Truelove Witts Severity Index (also known as the Lichtiger score) should be used to follow patient response to treatment. Although largely validated as a tool for assessment of response to medical rescue therapies such as cyclosporine or infliximab, it can also be used to follow patients receiving ICS [39, 40•]. Scores of greater than 10 are consistent with severe UC, and response is defined as a

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fewer than 10 points with a decrease of at least 3 points compared to the baseline score. A decision to proceed with alternative salvage therapies or surgery should be made promptly as it has been demonstrated that increased post-operative complications tend to correlate with longer time from admission to colectomy [41]. Given the ability of prediction models to predict poor prognosis by day 3 of admission, it is recommended to make a decision on escalation to second-line medical therapies or surgery at this time.

Medical rescue therapies

Recommendation: For patients deemed to have failed corticosteroids, either infliximab or cyclosporine are reasonable options to use as medical rescue therapy. Recommendation: Patients receiving rescue therapies should have response assessed 5 – 7 days after initiation by objective measures such as the Lichtiger score. Responders should have corticosteroids transitioned to oral and weaned down over a period of several weeks to several months.

The goals of medical rescue therapy are to help induce remission and avoid colectomy in patients who do not have response to ICS. Rescue therapy may also play a role by providing sufficient symptomatic improvement that allows weaning off corticosteroids and improvement in nutritional status. If colectomy is determined to be still necessary due to refractory symptoms, it can take place in an elective setting, where post-operative morbidity and mortality are significantly improved compared to urgent colectomy [42].

Cyclosporine

Recommendation: If cyclosporine is initiated for medical rescue therapy, it should be dosed at 2 mg/kg/day via continuous intravenous infusion with target blood concentrations of 150 – 250 ng/mL.

Cyclosporine, a calcineurin inhibitor, was the first therapy used in severe UC refractory to corticosteroids. This was largely based on a landmark small randomized trial where nine of 11 patients who received 4 mg/kg/day of intravenous cyclosporine responded to treatment within 7 days, compared to none of nine patients given placebo [39]. Further, five patients in the placebo arm were subsequently crossed over and given cyclosporine, with all of them demonstrating treatment response. A subsequent randomized controlled trial of 73 steroid-refractory UC patients found similar efficacy of 4 mg/kg/day and 2 mg/kg/day of intravenous cyclosporine, with a trend towards reduced

Inflammatory Bowel Disease (G Lichtenstein, Section Editor) hypertension in the lower dose group [43]. In patients who respond to cyclosporine, patients can be transitioned to oral cyclosporine at 5 mg/kg/ day. A thiopurine can be started concurrently with the goal to discontinue cyclosporine by 3 – 6 months. These studies support initiation of cyclosporine for patients with steroid refractory severe UC. The initial response rates reported in clinical trials is 64 – 86 %, but long-term outcomes do not appear as promising [39, 43, 44]. Several centers have reported observational follow up of patients who responded to cyclosporine and colectomy rates at up to 7 years range from 38 – 88 % [45– 47]. Colectomy rates are lower in those maintained on thiopurines compared to no maintenance strategy [48, 49]. Further, cyclosporine is associated with several complications including hypertension, opportunistic infection, nephrotoxicity, seizures, paresthesias, hypokalemia, hypocalcemia, hypomagnesemia, and gingival hyperplasia. Its use is complicated by need for drug level monitoring and the need for caution when prescribing other drugs given metabolism through the cytochrome P450 enzyme system. Patients with hypocholesterolemia (totalG120 mg/dl) or hypomagnesemia (G1.5 mg/dl) have higher risk of seizures [50]. Lower doses of intravenous cyclosporine should be used in this population with daily monitoring of cholesterol, electrolytes, and drug levels. Tacrolimus is another calcineurin inhibitor that has been studied in severe steroid-refractory UC. It has very reliable oral absorption and a lower reported incidence of some side effects like hirsuitism [51]. Controlled trials from Japan of oral tacrolimus in steroid-refractory or -dependent UC targeting trough levels of 10 – 15 ng/mL have shown 2-week response rates of 50 – 68 % [52, 53]. Concerns exist, however, of whether the patients enrolled in these trials were as severe as those enrolled in Western studies of cyclosporine, based on the low colectomy rates observed during the open-label extension phases of both trials and the lower threshold of disease activity that triggers admission to hospital in Japan [54]. Some recent observational data has suggested tacrolimus is an option for maintenance therapy and can help achieve mucosal healing [55, 56]. These studies are limited, however, by their small numbers and retrospective nature, and questions still persist regarding the need for concomitant thiopurine therapy, duration and follow-up of maintenance treatment, and its efficacy in avoiding colectomy long-term.

Infliximab

Recommendation: If infliximab is initiated for medical rescue therapy, it should be dosed at 5 mg/kg initially. Response should be assessed by days 5 – 7 after start of infliximab. Recommendation: Concurrent use of thiopurines is recommended with infliximab to improve efficacy and time of response. Recommendation: Patients who respond to infliximab should receive a full induction regimen of three doses, and be maintained afterwards on maintenance infliximab with a thiopurine if initiated.

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Infliximab (IFX) is a TNFα antagonist which has proven effective in moderate-to-severe UC [57]. Its efficacy in severe steroid-refractory UC is not as clear, however. An initial pilot study of patients with severe UC found four of eight patients (50 %) who received IFX (a single dose at 5 mg/kg, 10 mg/kg, or 20 mg/kg) had treatment response compared to none of three patients who received placebo [58]. A subsequent randomized trial, however, administered IFX at 5 mg/kg at weeks 0 and 2 and did not find a significant difference in week 6 remission between the IFX and placebo group (9/23 vs. 6/20 respectively, p=0.76) [59]. A larger trial administered a single dose of IFX at 4 – 5 mg/kg or placebo in steroid-refractory severe or moderately severe UC and found significantly lower rates of colectomy in the IFX group at 3 months after randomization (7/24 vs. 14/21 respectively, p=0.017) [60]. A subsequent follow-up study confirmed that the colectomy rate after 3 years remained lower in those who received the initial single dose of IFX (12/24 vs. 16/21, p=0.012) [61]. Achievement of mucosal healing was predictive of lower risk of colectomy, and none of the eight patients in endoscopic remission at 3 months required colectomy during the follow-up [61]. Recent literature has suggested that severe UC patients may require larger IFX doses during induction. Higher levels of fecal IFX have been demonstrated in nonresponders to IFX compared to those who improve with IFX, suggesting some patients with severe disease may lose the drug in their stool leading to insufficient response [62]. An accelerated dosing regimen of IFX in hospitalized severe UC patients with three doses given within a median of 24 days was compared retrospectively with standard IFX dosing (0, 2, and 6 weeks), and 3-month colectomy rates were found to be significantly lower in the accelerated dosing group (1/15 vs. 14/35, p=.039) [63•]. A large prospective study is ongoing looking at the role of early infliximab levels for guidance of management and the utility of doses of 10 mg/kg in this setting (Clinicaltrials.gov: NCT01971814). Concurrent initiation of thiopurines with IFX may be reasonable, given the combination of IFX with thiopurines leads to higher rates of corticosteroid-free remission and mucosal healing long term in moderate to severe UC patients compared to either as monotherapy (as demonstrated in UC-SUCCESS), although this has not been studied specifically in acute severe steroid-refractory patients [64].

Comparison of infliximab and cyclosporine Two large clinical trials have examined the efficacy of IFX and cyclosporine in patients with severe steroid-refractory UC. The first study conducted by the GETAID group randomized 111 steroid-refractory patients to either 2 mg/kg/ day of intravenous cyclosporine followed by transition to oral cyclosporine, or IFX 5 mg/kg infusion at weeks 0, 2, and 6. Responders in both groups were transitioned to azathioprine at 2.5 mg/kg/day. At the end of the study, cyclosporine was not found to be superior to IFX with treatment failure rates of 60 % and 54 % respectively (p=0.49) [40•]. Rates of colectomy at 98 days were also similar between the two groups. There, however, were a few limitations of this study, including insufficient power to detect a less than 30 % difference between the two interventions and lack of long-term outcomes beyond 98 days.

Inflammatory Bowel Disease (G Lichtenstein, Section Editor) Recently, the results of the UK-CONSTRUCT study were presented. This mixed-methods study randomized 270 steroid-refractory patients to 2 mg/kg/ day of intravenous cyclosporine or IFX 5 mg/kg infusions at weeks 0, 2, and 6. Responders in the cyclosporine group were continued on oral cyclosporine with some responders transitioned to azathioprine. IFX responders may have been continued on maintenance IFX at the discretion of the treating gastroenterologist. At the end of the study, no significant differences were seen in qualityadjusted survival, colectomy rates, mortality, and serious adverse reactions between the two treatment groups [65]. A meta-analysis comparing IFX and cyclosporine in ASUC reported better treatment response and lower risk of colectomy at 12 months with IFX, with comparable short-term adverse events, but this was largely based on observational data due to a paucity of randomized controlled trials in this field [66]. Either IFX or cyclosporine are reasonable first-line options to use in the management of steroid-refractory ASUC, although many clinicians prefer to use IFX given its ease of use, tolerability, ability to use for maintenance therapy, and since drug level monitoring is not necessary as it is for calcineurin inhibitors. Pneumocystis Jiroveci prophylaxis with trimethoprim-sulfamethoxazole is recommended for patients receiving triple therapy including either a calcineurin inhibitor or TNFα antagonist [67]. There is no consensus on if prophylaxis is required for patients on dual or mono therapy.

Sequential rescue therapy

Recommendation: Sequential rescue therapy should not be routinely used, but can be considered in selected patients at centres experienced with use of calcineurin inhibitors.

Third-line salvage therapy, after failure of intravenous steroids and a rescue agent, is generally not recommended as it is felt that its risks may exceed its benefits [68]. This is largely based on initial reports of unacceptably high rates of serious infection and death following sequential therapy with cyclosporine and IFX [69, 70]. Recently, several other centers have reported their experiences with sequential rescue therapy of IFX and cyclosporine or vice versa with results suggesting a treatment response rate of 66 – 72 % and a remission rate of 44 – 48 % [71–73]. There were minimal serious adverse infections reported and one mortality from this sequence; however, the patient who died had extenuating circumstances and remained on corticosteroids for over 3 months prior to sequential therapy. After his eventual colectomy, he incurred nosocomial pneumonia and died 2 days post-operatively [73]. This suggests that sequential therapy may be a reasonable option in patients failing an initial rescue therapy, with the caveat that there may be an increased risk of complications including mortality. Sequential rescue therapy has not been prospectively compared with colectomy for failed initial medical rescue therapy. Management with sequential therapies should only be performed at centers experienced with the use of

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calcineurin inhibitors and can be considered on a case-by-case basis with patient education of the risks and benefits of such a strategy.

Recently approved therapies There have been some new drugs investigated and approved in the United States for use in ulcerative colitis within the past year, including golimumab and vedolizumab. Golimumab is a subcutaneous anti-TNFα agent which was demonstrated in the PURSUIT-SC study to be effective by week 6 in improving clinical response, remission, and mucosal healing in patients with moderate to severely active ulcerative colitis [74]. Vedolizumab is a humanized monoclonal antibody that antagonizes α4β7 integrin, which is expressed on certain white blood cells implicated in the pathogenesis of IBD. The binding of α4β7 integrin prevents adhesion of these white blood cells to intestinal mucosal addressin cell adhesion molecule 1 (MAdCAM-1), an adhesion molecule expressed mainly on blood vessels and lymph nodes within the gastrointestinal tract. The GEMINI-1 study demonstrated that intravenous vedolizumab is highly effective at induction of clinical response, remission, and mucosal healing after 6 weeks of therapy [75]. The safety profile of both of these medications is excellent, especially for vedolizumab, which seems not to be associated with adverse events outside the gastrointestinal tract such as infection or neoplasia. Neither of these drugs, however, has been studied in the hospitalized steroid-refractory UC population, and both of the above studies excluded patients who required higher doses of corticosteroids or were considered at risk of colectomy [75, 76]. The time required to respond to induction dosing compared to IFX or cyclosporine suggests that neither vedolizumab nor golimumab should be used in ASUC patients until further research has explored their potential in this setting.

Surgical management of severe UC

Recommendation: In patients who do not respond to corticosteroids, colectomy should be offered as an alternative to medical rescue therapy. Colectomy should again be offered to patients failing medical rescue therapies.

Colectomy is another option for patients with acute severe UC (Fig. 2). The optimal timing and positioning of colectomy relative to medical management is challenging, with gastroenterologists and surgeons offering different opinions [77–79]. A common theme, however, is that surgery should be considered early in the course as a useful alternative, rather than only as an option for failed medical management. There are certain cases where colectomy may be necessary early in management of the acute severe UC patient, including intestinal perforation, exsanguinating hemorrhage, and toxic megacolon. Without the presence of any of these complicating factors, a trial of medical management with ICS is

Inflammatory Bowel Disease (G Lichtenstein, Section Editor)

Fig. 2. Surgical specimen from patient with severe UC (Photograph courtesy of Dr. Noam Harpaz, Mount Sinai Hospital).

reasonable. Decision to proceed to alternative salvage therapies or surgery should be made promptly as post-operative complications tend to increase with longer time from admission to colectomy [41]. After 3 days of hospitalization, a decision should be made regarding the response to steroids and whether it is necessary to escalate to medical rescue therapies or surgery depending on patient preferences. If there is no improvement within 7 days after salvage therapy is initiated, then urgent colectomy is recommended as per recommendations from the European Crohn’s and Colitis Organization and the American College of Gastroenterology [68, 80]. If possible, colectomy should be performed in a high-volume centre as improved clinical outcomes and lower risk of mortality has been demonstrated for UC patients [81]. Proctocolectomy with ileal pouch-anal anastomosis (IPAA) is a commonly performed operation for UC and can be performed in one or multiple stages. However, in the urgent setting, colectomy with ileostomy is preferred and a completion proctectomy with pouch can be done at a later date after the patient has improved physically and nutritionally. Urgent colectomy is associated with high mortality and morbidity. A recent meta-analysis concluded the risk of post-operative mortality after emergent surgery in UC is 5.7 % (95 % CI 4.0 – 8.1 %) [82]. The overall morbidity post-colectomy is 50.8 % (95 % CI 45.9 – 55.7), predominantly composed of infectious complications such as septicemia (18 %), pneumonia (11.2 %), abscess (8.6 %), and wound infections (12.7 %) [42]. Outcomes of elective colectomy are significantly better with improved morbidity and mortality rates compared to urgent colectomy [42, 82].

Risk of post-operative complications in patients on rescue therapies Concerns have been raised regarding patient outcomes after colectomy in patients who were on pre-operative rescue therapies such as IFX or cyclosporine.

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Fig. 3. Approach to treatment of hospitalized ASUC. UC – ulcerative colitis; IFX – infliximab; CsA – cyclosporine; 6MP – 6-mercaptopurine; VTE- venous thromboembolism; IV- intravenous.

Idenfy and admit paent with severe UC

Any indicaon for surgery? (i.e. perforaon, toxic megacolon, lifethreatening hemorrhage)

No: Yes: Refer for colectomy.

Rule out infecons, offer VTE prophylaxis & oral feeds. Treat with IV corcosteroids X 72 hours.

Non-response: Consider medical rescue therapy or surgery.

Response: Switch to oral steroids and taper. Discuss maintenance strategy.

Surgery: Refer for colectomy.

Medical Rescue Therapy: IFX or IV CsA. Assess response aer 7 days .

Response:

Non-response

If IFX, complete IFX inducon followed by IFX maintenance. If CsA, swith to oral CsA and bridge to azathioprine/6MP.

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Surgery: Refer for colectomy.

Sequenal rescue therapy: Proceed with cauon in specialized centres only.

Inflammatory Bowel Disease (G Lichtenstein, Section Editor) Retrospective studies have suggested post-operative outcomes in patients who receive cyclosporine and corticosteroids are no different than those who receive steroids alone [83, 84]. Although initially some reports had suggested an increased risk of post-operative complications in UC patients receiving IFX [85, 86], subsequent meta-analyses have not confirmed this risk [87, 88]. The risk of post-operative complications may, however, be related to higher doses and duration of corticosteroid use pre-operatively [89].

Conclusions The management of acute severe UC can prove to be challenging. Figure 3 is a practical algorithm that can help guide clinicians through the management of acute severe UC. Early initiation of treatment is essential, but early evaluation of treatment response is just as important. The decision of medical rescue therapies versus surgery can be difficult for patients and clinicians. Surgery can be valuable and a life-saving option for some patients with UC. Some patients, however, can be managed well with medical rescue therapies, which may prevent or postpone the need for surgery. Response to medical rescue therapies should be determined within 7 days of initiation, as prolonged medical treatment and hospitalization is associated with poorer patient outcomes. Both medical and surgical therapies have their risks and benefits and individualizing treatment for each patient is essential. Collaborative care with a gastroenterologist, a surgeon, and other allied health professionals, including but not limited to a nutritionist and stoma nurse, is recommended to help patients make decisions regarding their care and maximize the chance of successful outcomes.

Compliance with Ethics Guidelines Conflict of Interest Neeraj Narula declares that he has no conflict of interest. Bindia Jharap declares that she has no conflict of interest. Jean-Frederic Colombel has served as consultant, advisory board member or speaker for Abbvie, Amgen, Bristol Meyers Squibb, Celltrion, Ferring, Genentech, Giuliani SPA, Given Imaging, Janssen, Merck & Co., Millenium Pharmaceuticals Inc., Nutrition Science Partners Ltd., Pfizer Inc. Prometheus Laboratories, Receptos, Sanofi, Schering Plough Corporation, Takeda, Teva Pharmaceuticals, UCB Pharma, Vertex, Dr. August Wolff GmbH & Co. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance 1. 2. 3.

4. 5.

6.

7. 8.

9.

10.

11.

12.

13.

14.

Dinesen L, Walsh A, Protic M, et al. The pattern and outcome of acute severe colitis. J Crohn’s Colitis. 2010;4:431–7. Truelove S, Jewell D. Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet. 1974;1:1067–70. Turner D, Walsh C, Steinhart A, et al. Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a metaregression. Clin Gastroenterol Hepatol. 2007;5:103–10. Ananthakrishnan A, Issa M, Binion D. Clostridum difficile and inflammatory bowel disease. Med Clin N Am. 2010;94:135–53. Ananthakrishnan A, McGinley E, Binion D. Excess hospitalization burden associated with clostridium difficile in patients with inflammatory bowel disease. Gut. 2008;57:205–10. Navaneethan U, Mukewar S, Venkatesh P, et al. Clostridium difficile infection is associated with worse long term outcome in patients with ulcerative colitis. J Crohn’s Colitis. 2012;6:330–6. Surawicz C, Brandt L, Binion D, et al. Guidelines for diagnosis, treatment, and prevention of clostridium difficile infections. Am J Gastroenterol. 2013;108:478–98. Issa M, Vijayapal A, Graham M, et al. Impact of clostridium difficile on inflammatory bowel disease. Clin Gastroenterol Hepatol. 2007;5:345–51. Ayre K, Warren B, Jeffery K, et al. The role of CMV in steroid-resistant ulcerative colitis: a systematic review. J Crohn’s Colitis. 2009;3:141–8. Kandiel A, Lashner B. Cytomegalovirus colitis complicating inflammatory bowel disease. Am J Gastroenterol. 2006;101:2857–65. Kim J, Simpson N, Klipfel N, et al. Cytomegalovirus infection in patients with active inflammatory bowel disease. Dig Dis Sci. 2010;55:1059–65. Papadakis K, Tung J, Binder S, et al. Outcome of cytomegalovirus infections in patients with inflammatory bowel disease. Am J Gastroenterol. 2001;96:2137–42. Cottone M, Pietrosi G, Martorana G, et al. Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn’s colitis. Am J Gastroenterol. 2001;96:773–5. Criscuoli V, Casa A, Orlando A, et al. Severe acute colitis associated with CMV: a prevalence study. Dig Liver Dis. 2004;36:818–20.

15.

Vega R, Bertran X, Menacho M, et al. Cytomegalovirus infection in patients with inflammatory bowel disease. Am J Gastroenterol. 1999;94:1053–6. 16. Sonnenberg A. Time trends of mortality from crohn’s disease and ulcerative colitis. Int J Epidemiol. 2007;36:890–9. 17. Bossa F, Fiorella S, Caruso N, et al. Continuous infusion vs. bolus administration of steroids in severe attacks of ulcerative colitis: a randomized, double-blind trial. Am J Gastroenterol. 2007;102:601–8. 18. Berghouse L, Elliott P, Lennard-Jones J, et al. Plasma prednisolone levels during intravenous therapy in acute colitis. Gut. 1982;23:980–3. 19. Daperno M, Sostegni R, Scaglione N, et al. Outcome of a conservative approach in severe ulcerative colitis. Dig Liver Dis. 2004;36:21–8. 20. Meyers S, Sachar D, Golberg J, et al. Corticotropin versus hydrocortisone in the intravenous treatment of ulcerative colitis. Gastroenterology. 1983;85:351–7. 21. Yuhara H, Steinmaus C, Corley D, et al. Meta-analysis: the risk of venous thromboembolism in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2013;37:953–62. 22.• Grainge M, West J, Card T. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet. 2010;375:657– 63. This article highlights the very high risk of VTE in IBD patients experiencing a flare. 23. Ra G, Thanabalan R, Ratneswaran S, et al. Predictors and safety of venous thromboembolism prophylaxis among hospitalized inflammatory bowel disease patients. J Crohn’s Colitis. 2013;7:e479–85. 24. Kahn S, Lim W, Dunn A, et al. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis: 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141(Suppl):e195S–226. 25. Dickinson R, Ashton M, Axon A, et al. Controlled trial of intravenous hyperalimentation and total bowel rest as an adjunct to the routine therapy of acute colitis. Gastroenterology. 1980;79:1199–204. 26. McIntyre P, Powell-Tuck J, Wood S, et al. Controlled trial of bowel rest in the treatment of severe acute colitis. Gut. 1986;27:481–5. 27. Gonzalez-Huix F, Fernandez-Banares F, Esteve-Comas M, et al. Enteral versus parenteral nutrition as adjunct

Inflammatory Bowel Disease (G Lichtenstein, Section Editor) therapy in acute ulcerative colitis. Am J Gastroenterol. 1993;88:227–32. 28. Roediger W. The starved colon - diminished mucosal nutrition, diminished absorption, and colitis. Dis Colon Rectum. 1990;33:858–62. 29. Salinas H, Dursun A, Konstantinidis I, et al. Does preoperative total parenteral nutrition in patients with ulcerative colitis produce better outcomes? Int J Color Dis. 2012;27:1479–83. 30. Detsky A, Baker J, O’Rourke K, et al. Predicting nutrition-associated complications for patients undergoing gastrointestional surgery. J Parenter Enter Nutr. 1987;11:440–6. 31. Beaugerie L. Lymphoma: the bete noire of the longterm use of thiopurines in adult and elderly patients with inflammatory bowel disease. Gastroenterology. 2013;145:927–30. 32. Carbonnel F, Lavergne A, Lemann M, et al. Colonoscopy of acute colitis. A safe and reliable tool for assessment of severity. Dig Dis Sci. 1994;39:1550–7. 33. Cacheux W, Seksik P, Lemann M, et al. Predictive factors of response to cyclosporine in steroid-refractory ulcerative colitis. Am J Gastroenterol. 2008;103:637–42. 34. Travis S, Satsangi J, Lemann M. Predicting the need for colectomy in severe ulcerative colitis: a critical appraisal of clinical parameters and currently available biomarkers. Gut. 2011;60:3–9. 35. Travis S, Farrant J, Ricketts C, et al. Predicting outcome in severe ulcerative colitis. Gut. 1996;38:905–10. 36. Ho G, Mowat C, Goddard C, et al. Predicting the outcome of severe ulcerative colitis: development of a novel risk score to aid early selection of patients for second-line medical therapy or surgery. Aliment Pharmacol Ther. 2004;19:1079–87. 37. Churchhouse A, Lynch R, Protheroe A, et al. Predicting outcome in acute ulcerative colitis: comparison of the travis and ho scores using UK IBD audit data. Gut. 2014;63 Suppl 1:A1. 38. Turner D, Mack D, Leleiko N, et al. Severe pediatric ulcerative colitis: a prospective multicenter study of outcomes and predictors of response. Gastroenterology. 2010;138:2282–91. 39. Lichtiger S, Present D, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med. 1994;330:1841–5. 40.• Laharie D, Bourreille A, Branche J, et al. Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial. Lancet. 2012;380:1909–15. Landmark randomized controlled trial comparing infliximab and cyclosporine in steroid refractory severe UC. 41. de Silva S, Ma C, Proulx M, et al. Postoperative complications and mortality following colectomy for ulcerative colitis. Clin Gastroenterol Hepatol. 2011;9:972–80.

42.

43.

44.

45.

46.

47.

48.

49.

50. 51. 52.

53.

54. 55.

56.

Teeuwen P, Stommel M, Bremers A, et al. Colectomy in patients with acute colitis: a systematic review. J Gastrointest Surg. 2009;13:676–86. Van Assche G, D’Haens G, Noman M, et al. Randomized, double-blind comparison of 4 vs 2 mg/kg intravenous cyclosporine in severe ulcerative colitis. Gastroenterology. 2003;125:1025–31. D’Haens G, Lemmens L, Geboes K, et al. Intravenous cyclosporine vs. intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis. Gastroenterology. 2001;120:1323–9. Cohen R, Brodsky A, Hanauer S. A comparison of the quality of life in patients with severe ulcerative colitis after total colectomy versus medical treatment with intravenous cyclosporin. Inflamm Bowel Dis. 1999;5:1–10. Campbell S, Travis S, Jewell D. Ciclosporin use in acute ulcerative colitis: a long-term experience. Eur J Gastroenterol Hepatol. 2005;17:79–84. Moskovitz D, Van Assche G, Maenhout B, et al. Incidence of colectomy during long-term followup after cyclosporine-induced remission of severe ulcerative colitis. Clin Gastroenterol Hepatol. 2006;4:760–5. Canas-Ventura A, Marquez L, Ricart E, et al. Risk of colectomy in patients with ulcerative colitis under thiopurine treatment. J Crohns Colitis. 2014. Sharkey L, Bredin F, Nightingale A, et al. The use of cyclosporine A in acute steroid refractory ulcerative colitis: long term outcomes. J Crohn’s Colitis. 2011;5:91–4. Loftus C, Loftus Jr E, Sandborn W. Cyclosporin for refractory ulcerative colitis. Gut. 2003;52:172–3. Bousvaros A. "Tac"kling a difficult problem - using tacrolimus to maintain remission in ulcerative colitis. J Clin Gastroenterol. 2011;45:479–80. Ogata H, Matsui T, Nakamura M, et al. A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut. 2006;55:1255–62. Ogata H, Kato J, Hirai F, et al. Double-blind, placebocontrolled trial of oral tacrolimus (FK506) in the management of hospitalized patients with steroidrefractory ulcerative colitis. Inflamm Bowel Dis. 2012;18:803–8. Annunziata M, Hanauer S. Calcineurin inhibition in severe ulcerative colitis: lost in translation? Inflamm Bowel Dis. 2012;18:809–10. Landy J, Wahed M, Peake S, et al. Oral tacrolimus as maintenance therapy for refractory ulcerative colitis an analysis of outcomes in two London tertiary centres. J Crohn’s Colitis. 2013;7:e516–21. Miyoshi J, Matsuoka K, Inoue N, et al. Mucosal healing with oral tacrolimus is associated with favorable medium- and long-term prognosis in steroidrefractory/dependent ulcerative colitis patients. J Crohn’s Colitis. 2013;7:e609–14.

Management of Severe Ulcerative Colitis 57.

Rutgeerts P, Sandborn W, Feagan B, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–76. 58. Sands B, Tremaine W, Sandborn W, et al. Infliximab in the treatment of severe, steroid-refractory ulcerative colitis: a pilot study. Inflamm Bowel Dis. 2001;7:83–8. 59. Probert C, Hearing S, Schreiber S, et al. Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: a randomised controlled trial. Gut. 2003;52:998–1002. 60. Jarnerot G, Hertervig E, Friis-Liby I, et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology. 2005;128:1805–11. 61. Gustavsson A, Jarnerot G, Hertervig E, et al. Clinical trial: colectomy after rescue therapy in ulcerative colitis - 3-year follow-up of the Swedish-Danish controlled study. Aliment Pharmacol Ther. 2010;32:984–9. 62. Brandse J, Wildenberg M, de Bruyn J, et al. Fecal loss of infliximab as a cause of lack of response in severe inflammatory bowel disease. Gastroenterology. 2013;144(5 Suppl 1):S36. 63.• Gibson D, Heetun Z, Redmond C, et al. An accelerated infliximab induction regimen reduces the need for early colectomy in patients with acute severe ulcerative colitis. Clin Gastroenterol Hepatol. 2014. Interesting retrospective study reporting improved patient outcomes with accelerated infliximab dosing regimen. 64. Panaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014;146:392–400. 65. Williams J, Fasihul Alam M, Alrubaiy L, et al. Comparative clinical effectiveness of infliximab and ciclosporin for acute severe ulcerative colitis: early results from the CONSTRUCT trial. Presented at UEGW, Vienna, Austria. October 20, 2014. 66. Narula N, Marshall J, Colombel J, et al. Infliximab or cyclosporine as rescue therapy in patients with severe ulcerative colitis refractory to steroids: a systematic review and meta-analysis. Am J Gastroenterol. 2014;109(Supplement 2s):S524. 67. Rahier J, Ben-Horin S, Chowers Y, et al. European evidence-based consensus on the prevention, diagnosis, and management of opportunistic infections in inflammatory bowel disease. J Crohn’s Colitis. 2009;3:47–91. 68. Dignass A, Lindsay J, Sturm A, et al. Second european evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. J Crohn’s Colitis. 2012;6:991– 1030. 69. Maser E, Deconda D, Lichtiger S, et al. Cyclosporine and infliximab as rescue therapy for each other in patients with steroid-refractory ulcerative colitis. Clin Gastroenterol Hepatol. 2008;6:1112–6. 70. Leblanc S, Allez M, Seksik P, et al. Successive treatment with cyclosporine and infliximab in

71.

72.

73.

74.

75. 76.

77. 78. 79. 80.

81.

82.

83.

84.

Narula et al.

steroid-refractory ulcerative colitis. Am J Gastroenterol. 2011;106:771–7. Protic M, Seibold F, Schoepfer A, et al. The effectiveness and safety of rescue treatments in 108 patients with steroid-refractory ulcerative colitis with sequential rescue therapies in a subgroup of patients. J Crohns Colitis. 2014. Ordas I, Domenech E, Garcia-Sanchez V, et al. Toxicity and mortality related to the use of ciclosporin in steroid refractory ulcerative colitis: a multicentric nationwide study (ENEIDA). Gastroenterology. 2013;144(5 Suppl 1):S407. Chaparro M, Burgueno P, Iglesias E, et al. Infliximab salvage therapy after failure of ciclosporin in corticosteroid-refractory ulcerative colitis: a multicentre study. Aliment Pharmacol Ther. 2012;35:275–83. Sandborn W, Feagan B, Marano C, et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146:85–95. Feagan B, Rutgeerts P, Sands B, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369:699–710. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369(8):711–21. Becker J, Stucchi A. Treatment of choice for acute severe steroid-refractory ulcerative colitis is colectomy. Inflamm Bowel Dis. 2009;15:146–9. Halfvarson J, Jarnerot G. Treatment of choice for acute severe steroid-refractory ulcerative colitis is remicade. Inflamm Bowel Dis. 2009;15:143–5. Lichtiger S. Treatment of choice for acute severe steroidrefractory ulcerative colitis is cyclosporine. Inflamm Bowel Dis. 2009;15:141–2. Bitton A, Buie D, Enns R, et al. Treatment of hospitalized adult patients with severe ulcerative colitis: Toronto consensus statements. Am J Gastroenterol. 2012;107:179–94. Kaplan G, McCarthy E, Ayanian J, et al. Impact of hospital volume on postoperative morbidity and mortality following a colectomy for ulcerative colitis. Gastroenterology. 2008;134:680–7. Singh S, Al-Darmaki A, Frolkis A, et al. Postoperative mortality for the inflammatory bowel diseases: A systematic review and meta-analysis of population-based studies. Gastroenterology. 2014;146(5 Suppl. 1). Powar M, Martin P, Croft A, et al. Surgical outcomes in steroid refractory acute severe ulcerative colitis: the impact of rescue therapy. Color Dis. 2013;15:374–9. Hyde G, Jewell D, Kettlewell M, et al. Cyclosporin for severe ulcerative colitis does not increase the rate of perioperative complications. Dis Colon Rectum. 2001;44:1436–40.

Inflammatory Bowel Disease (G Lichtenstein, Section Editor) 85.

86.

87.

Mor I, Vogel J, da Luz Moreira A, et al. Infliximab in ulcerative colitis is associated with an increased risk of postoperative complications after restorative proctocolectomy. Dis Colon Rectum. 2008;51:1202–7. Selvasekar C, Cima R, Larson D, et al. Effect of infliximab on short-term complications in patients undergoing operation for chronic ulcerative colitis. J Am Coll Surg. 2007;204:956–62. Narula N, Charleton D, Marshall J. Meta-analysis: peri-operative anti-TNFα treatment and postoperative complications in patients with

88.

89.

inflammatory bowel disease. Aliment Pharmacol Ther. 2013;37:1057–64. Yang Z, Wu Q, Wang F, et al. Meta-analysis: effect of preoperative infliximab use on early postoperative complications in patients with ulcerative colitis undergoing abdominal surgery. Aliment Pharmacol Ther. 2012;36:922–8. Ferrante M, D’Hoore A, Vermeire S, et al. Corticosteroids but not infliximab increased short-term postoperative infectious complications in patients with ulcerative colitis. Inflamm Bowel Dis. 2009;15:1062–70.