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Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of the colorectum which results from a complex interplay between environmental, genetic and microbial factors. One-fifth of patients with UC will experience an acute flare requiring hospitalization. This is a medical emergency and requires prompt recognition and multidisciplinary management. In patients who fail first-line therapy after approximately 3–5 days of intravenous steroids, medical rescue therapy is indicated with either infliximab (IFX) or cyclosporine (CsA). Optimal dosing strategies for IFX are uncertain, with several retrospective studies suggesting an association between an intensified or accelerated IFX induction regimen and lower colectomy rates, although prospective studies are warranted. In patients not responding to medical rescue therapy, or in those with fulminant colitis, urgent colectomy is indicated. Longer prognosis is suboptimal, with half of patients requiring colectomy within 5 years of presentation with acute severe UC (ASUC).

Keywords

colectomy cyclosporine infliximab ulcerative colitis

Introduction

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is characterized by hematochezia, diarrhea, tenesmus, and during more severe flares, weight loss, fevers and constitutional symptoms.¹ UC is a result of a dysregulated immune response to commensal pathogens in genetically predisposed hosts. It is estimated to account for over $2 billion dollars of direct healthcare expenditure in the United States, with the majority of these costs being driven by hospitalization, biologics and colectomy.^2,3 Disease severity is wide ranging, and 20–30% of UC patients require hospitalization at some point in their disease course for an acute severe flare (ASUC).⁴ Intravenous steroids are the mainstay of therapy, but 30–40% of patients will fail to respond to steroids and require progression to second-line therapy [infliximab (IFX) or cyclosporine (CsA)].^5,6 These second-line therapies are associated with a significant risk for adverse events,^7–9 and colectomy carries a 5% postoperative mortality risk when done emergently in the hospital setting.^10,11 Recent insights in comparative effectiveness, provider practice patterns and biologic pharmacokinetics have allowed for an enhanced insight into how best to optimize the care of these high-risk patients. In this review article we discuss emerging evidence and the implications of these data on the management of ASUC.

Definition and prognosis

ASUC is a medical emergency and requires prompt treatment. Thus, defining the population by criteria is essential. It is most readily diagnosed by the Truelove Witts criteria, which combines frequency of bloody stools (⩾6 per day) with at least one marker of systemic toxicity: pulse rate >90 bpm, temperature >37.8°C, hemoglobin <10.5 g/dl and/or an ESR >30 mm/h.¹² The risk of progression to second-line therapy is directly dependent on the number of variables present on admission, with a 50% risk for colectomy when three or more additional criteria are present.

Another more recently validated risk prediction tool that can be applied on admission is the Ho index, which assigns points based on the presence or absence of three risk factors: mean stool frequency (0–4 points), colonic dilation on imaging (4 points), and hypoalbuminemia (<3 mg/l, 1 point). A risk score of 4 or more predicted a medical failure rate of 85%, and the risk prediction tool had an overall good diagnostic accuracy in the original study (AUC 0.88). The Ho index has recently also been applied after 72 h of intravenous steroids, and in this setting high-risk patients (⩾4 points) require second-line therapy 66% of the time, with 33% requiring colectomy.^13,14 Other composite risk prediction tools are also available, with similar diagnostic accuracy and predictive capacity (Table 1).^13–19

Table 1.

Prognostic scores.^13–19

Index	Variables	Diagnostic accuracy
First 24 h
Truelove Witts	Hematochezia, pulse rate, temperature, Hgb, ESR	50% risk of colectomy when three or more additional criteria
St. Marks	Stool frequency >12	55% risk of colectomy
72–96 h
Seo	Stool frequency, hematochezia, nocturnal bowel movements, abdominal pain, and activity level	Negative predictive value 97%; positive predictive value 52%
Ho	Stool frequency, colonic dilation, hypoalbuminemia	85% sensitivity in original study; validation: 66% require second-line therapy and 33% require colectomy in high-risk group
Oxford	Stool frequency >8/day; or 3–8/day and CRP >45	Positive predictive value 85%
Swedish	CRP and stool frequency	Positive predictive value ~70%
Italian	<40% reduction in stool frequency at day 5

CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

Perhaps the most helpful stratification tool is endoscopy, as it not only stratifies disease activity and prognosis, but also allows providers to rule out concomitant infections and etiologies. Unprepared flexible sigmoidoscopy should ideally be performed within 24 h of presentation; full colonoscopy should be avoided due to the risk of perforation.^4,20 Traditionally patients were classified using the Mayo endoscopic subscore (2–3 being moderate to severe). The greatest risk of colectomy is with the presence of deep colonic ulcerations on endoscopy at the time of admission (Mayo endoscopy subscore of 3).²¹ When these deep ulcers aren’t seen, composite endoscopic instruments can be used to more accurately stratify prognosis. In a retrospective study of 89 patients, patients with a UCEIS score of ⩾5 more often required rescue therapy compared to those with a UCEIS of <4, (50% versus 27%, p = 0.037). Almost all patients with a UCEIS of ⩾7 required medical rescue therapy with IFX or CsA, suggesting this may be a reasonable cut-off for early goal-directed therapy.²²

First-line medical therapy: corticosteroids

Corticosteroids remain the backbone of first-line therapy for ASUC, based upon the landmark trial by Truelove and Witts over 60 years ago.¹² In that seminal study, 213 patients were randomized to receive 100 mg of cortisone or placebo for 6 weeks. Patients receiving steroids had higher rates of clinical remission compared to the placebo group (41% versus 16%, respectively) as well as lower mortality (24% versus 7%, respectively). Furthermore, improvements in sigmoidoscopic appearances were more frequent in the cortisone treated group compared to the placebo group.¹² A meta-analysis of cohort studies and randomized trials published in 2007 examining response to corticosteroids in ASUC reported a pooled response rate to steroids of 67%.²³

Decisions regarding response to steroids need to be made promptly. There is no additional benefit for doses of methylprednisolone above 60 mg and extending treatment beyond 7–10 days appears to confer no additional benefits, and may be associated with increased risk of complications.²³ The simplest index to predict outcome was derived in Oxford from 48 consecutive presentations, demonstrating that a stool frequency of >8 or a C-reactive protein (CRP) of >45 on day 3 of admission predicts an 85% likelihood of requiring colectomy during that admission.¹⁵ The Swedish fulminant colitis index was derived from a retrospective sample of 97 patients using the same covariates as the Oxford index (stool frequency/day + 0.14 × CRP mg/l). This is calculated on day 3 of admission,¹⁶ with subsequent external validation within a clinical trial.¹⁷

Second-line medical therapies

Next, providers will need to consider relative strengths and weakness of therapeutic options and the comparative effectiveness in populations of interest. The two second-line medical therapies used for the management of ASUC when steroids have failed are anti-TNF therapy (IFX) and calcineurin inhibitors (CsA and tacrolimus).

Calcineurin inhibitors

CsA has been shown to be extremely beneficial in the management of ASUC. Original trials have estimated response rates of >80%, with the 2 mg/kg/day dosing being associated with less toxicity and comparable rates of progression to colectomy when compared to the 4 mg/kg/day dose.²⁴ The major drawback to CsA is the potential toxicity, particularly the risk of nephrotoxicity, seizures (often associated with low serum cholesterol), electrolyte abnormalities, hypertension, and serious infections.^25,26 These risks can be mitigated to some extent through drug-level monitoring and infectious prophylaxis, but the drug often remains reserved for patients who have a true contraindication to steroid therapy, and those who are naïve to thiopurine therapy where thiopurines can be used as a long-term bridge upon discharge. Nonetheless, even in the era of IFX, there is still a role for intravenous 2 mg/kg/day dosing, given its rapid onset of action, with subsequent conversion to oral therapy (5 mg/kg) which typically is used for up to 3 months as a bridge to an immunosuppressive agent (azathioprine or mercaptopurine) while steroids are weaned.

Another calcineurin inhibitor, tacrolimus, has been demonstrated to be efficacious in a randomized trial of 63 acute steroid-refractory moderate-to-severe UC patients, with response rates of 50% and mucosal healing rates of 44% after 2 weeks of therapy (p = 0.003 and 0.238 versus placebo respectively).²⁷ Consideration can therefore be given to using CsA with a bridge to tacrolimus upon discharge instead of thiopurine therapy. This feasibility of this was recently demonstrated and allowed for a transition to novel biologic agents not typically considered in the management of ASUC (i.e. vedolizumab, an anti-integrin monoclonal antibody with a delayed onset of action).²⁸

Anti-TNF antibodies

IFX is a monoclonal antibody that is now widely used for the treatment of moderate-to-severe UC. Its use in ASUC has been studied extensively, and it has been demonstrated to be an effective salvage therapy with a significant reduction in risk for colectomy in the short term. In a randomized trial of 45 patients, a single 5 mg/kg dose of IFX in steroid-refractory ASUC led to significantly lower colectomy rates in patients who received IFX compared to placebo (7/24 versus 14/24 respectively, p = 0.017).¹⁷

However, a key unanswered question remains the optimal dosing strategy in ASUC. Prior studies had extrapolated dosing regimens from outpatients with moderate-to-severe disease and followed a standard induction regimen of 5 mg/kg when used in the acute setting for hospitalized ASUC. It is now well documented that ASUC is associated with intestinal protein loss, which leads to hypoalbuminemia and a resultant increased clearance of IFX.^29,30 Furthermore, it was demonstrated that these ASUC patients actually lose IFX in their stool due to high concentrations of mucosal metalloproteinases.^29,30 This enhanced clearance of IFX is associated with worse clinical outcomes and an increased risk of immunogenicity, which predisposes patients to adverse events and intolerance of future infusions or future anti-TNF agents.³¹ In support of this concept, and the potential role of accelerated dosing for ASUC, recent retrospective studies demonstrate an association that patients who received enhanced accelerated dose intensification had much lower rates of colectomy as compared to those who received standard induction dosing.

Gibson and colleagues observed lower colectomy rates in a retrospective analysis of 50 steroid-refractory patients with ASUC, in comparison to historical values (6.7% compared to 40%, p = 0.039) following the introduction of an intensified IFX dosing policy.³² Another multicenter study from Australia retrospectively compared outcome of 9 ASUC patients who had received accelerated IFX dosing (three infusions within a median of 20 days) with 26 patients who had received standard dosing; no difference in colectomy rate was found at 3 months or 12 months.³³ Finally, Govani and colleagues reported 90-day colectomy rates in 17 ASUC patients treated with intensified dosing (one extra IFX infusion at day 3 if the CRP had not dropped below 70 mg/l) compared to that observed in 40 patients receiving the conventional regimen. The accelerated regimen was associated with a lower colectomy rate (47% versus 12.5%, p = 0.01) and no difference in postoperative complications (abscess, urinary or respiratory infections and rectal stump complication).³⁴

These studies highlight the potential importance of accelerated induction IFX, the benefits of which are likely through enhanced pharmacokinetics and drug concentration achievements; however, prospective studies that incorporate pharmacokinetic-based dose optimization are now essential to conduct to validate this point.³⁵

Comparative effectiveness of CsA and IFX

The decision on whether to use CsA or IFX as a rescue agent in steroid-refractory ASUC is a combination of efficacy, safety and patient or provider preference and experience of use.³⁶ Advantages of CsA include the rapid onset of action, shorter half-life (7 h versus 9 days) and ability to transition to other concomitant immunosuppressive agents on discharge (thiopurines or tacrolimus) that can be used with other novel biologic therapies including anti-TNF agents. The advantages of IFX include the ability to monitor drug concentrations with a clear understanding of thresholds to achieve efficacy outcomes and the lack of other side effects seen with CsA that can be difficult to manage (hypertension, electrolyte disturbances, nephrotoxicity and seizures).

In terms of comparative effectiveness, two randomized trials have compared the effectiveness of CsA and IFX as rescue therapies for ASUC. The CySIF trial randomized 115 patients with ASUC who had failed 5 days of steroids and the primary outcome was treatment failure at 7 and 98 days (response, relapse, steroid-free remission, colectomy, death). This study found no significant differences between CsA and IFX with regards to the primary outcome of treatment failure (60% and 54%, p = 0.52), or for individual outcomes at day 7 or 98 specifically.⁶ The CONSTRUCT trial was a much larger, pragmatic (n = 270) trial where the primary outcome was quality-adjusted survival over a 3-year period.^37,38 This trial similarly demonstrated no significant difference between CsA and IFX for the primary endpoint, or the secondary endpoints of colectomy or adverse events. The comparability of these two agents is further supported by a recent meta-analysis of 16 studies reporting on 1473 participants where no definitive differences in efficacy were observed between CsA and IFX.⁵

Another important consideration when choosing salvage therapy for ASUC is the potential impact on future effectiveness of other agents, in particularly the ability to rescue patients who are failing one of these salvage agents. A cohort study from Mt. Sinai in New York suggested that patients receiving sequential therapy (CsA → IFX or IFX → CsA) have an increased risk for adverse events and death³⁹; however, this was not confirmed in other cohort studies and results are conflicting.^40,41 A recent systematic review combined data from 10 studies with 314 participants and quantified the pooled rates with sequential therapy: short-term response rates were 62.4% (95% CI 57–68.7%), colectomy rates 28.3% (95% CI 21.7–34.5%) at 3 months, serious infections in 6.7% (95% CI 3.6–9.8%) and death in 1% (95% CI 0–2.1%). This study also observed that the quality of evidence was low and no definitive decision could be made for whether sequential therapy should be used, and if it is used, what the appropriate sequence of therapies might be.⁴² Current guidelines from the European Crohn’s and Colitis Organization state that third-line therapy (or sequential therapy) can be considered in specialist referral centers in select cases, and no recommendation for or against the use of sequential therapy can be made.^43,44

Taken together, these studies therefore suggest that CsA and IFX are comparable in terms of efficacy and safety profile, and the decision on which agent to use is a combination of preference, provider comfort and experience, and patient-specific factors.⁴⁵

Surgical rescue therapy

The decision to perform colectomy should not be taken lightly in patients with ASUC given the increased risk for mortality when performed emergently, and should therefore be a multidisciplinary decision with colorectal surgeons at high-volume centers as the expertise and volume of the surgeon have been shown to impact surgical outcomes.⁴⁶ Urgent colectomy is most certainly indicated when a complication has occurred (i.e. suspected perforation, toxic megacolon, refractory bleeding), but the most common reason for colectomy in ASUC is failure of medical therapy. Although the goal of medical therapy is to avoid progression to colectomy, providers need to keep in mind that delay in progression to surgery is associated with an increased risk of postoperative complications.⁴⁷ When performing colectomy for ASUC it is advisable to use a three-step approach: sub-total colectomy and ileostomy in the acute setting with the rectum left in-situ, reconstructive surgery 3–6 months later with formation of an ileal pouch and defunctioning loop ileostomy; and finally closure of the ileostomy loop. A specific population of patients where consideration might be given to an alternative approach is female patients of childbearing age. In these patients the formation of a pouch is associated with an increased risk for infertility.⁴⁸ Consideration could therefore be given to sub-total colectomy with delayed pouch formation until they have had an opportunity to build their families.

Known areas of variability in care

Given the variability in outcomes among ASUC patients, differences among patients in risk for failure of therapy and overall comparability of second-line therapies, considerable attention needs to be paid to provider practice patterns and known areas of variability in order to optimize healthcare delivery for these high-risk patients at the population level.

The initial approach to managing ASUC includes: (1) ruling out infectious etiologies as triggers for the flare; (2) avoiding complications of systemic inflammation through thromboprophylaxis for venous thromboembolisms (VTEs); and (3) ensuring adequate nutritional and electrolyte support. The two most notable infections to consider are Clostridium difficile (C. Diff) and Cytomegalovirus (CMV), given the increased risk for colectomy associated with the presence of these. Both of these can be readily excluded through stool PCR testing and flexible sigmoidoscopy with rectal biopsies.^49–51 The benefits of thromboprophylaxis for VTE are largely extrapolated from other colorectal surgery and hospitalized medicine literature, with confirmation of benefit and safety through retrospective IBD studies.^52–55

Despite the demonstrated importance of these factors, considerable variability exists among providers when managing ASUC. A recent retrospective review of the Veterans Healthcare System observed that only 30% of hospitalized colitis patients were placed on VTE prophylaxis, 22% had not been tested for C. Diff and 15% were discharged before meeting criteria for responsiveness to medical therapy.⁵⁶ When looking at practice patterns with regards to the use of medical therapy, a survey of IBD providers revealed that 83% of providers used intravenous corticosteroids as the initial therapy of choice, whereas 17% of providers have begun to directly transition to IFX as first-line treatment for selected ASUC patients. When using IFX, the majority of these providers (65%) would use the standard induction regimen for dosing (5 mg/kg), and only one-third assess for response and perform an accelerated induction of IFX in the hospital. These two studies highlight that although our understanding of disease outcomes and treatment strategies have evolved over the past decade, one area in need of further work is provider education to change practice patterns.

Conclusion

ASUC is a medical emergency requiring prompt recognition and treatment. Risk stratification of those patients at greatest risk for failing standard medical therapy with corticosteroids and requiring progression to second-line therapy is essential. Attention should be paid to excluding treatable complications and triggers such as concomitant infection, and risk factors modified when possible. When using IFX or CsA in ASUC, treatment efficacy is similar and the decision will be made largely on provider comfort and expertise, and patient-specific risks for complications and tolerance. Recent advances in the use of IFX include the use of higher-dose accelerated induction to achieve peak concentrations earlier in the treatment algorithm, and the use of CsA as a bridge to newer biologics once discharged from the hospital. If surgery is to be performed, timing is critical and the decision should be made after close discussion between the patient, gastroenterologist and surgeon.

Footnotes

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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Acute severe ulcerative colitis: latest evidence and therapeutic implications

Abstract

Keywords

Introduction

Definition and prognosis

First-line medical therapy: corticosteroids

Second-line medical therapies

Calcineurin inhibitors

Anti-TNF antibodies

Comparative effectiveness of CsA and IFX

Surgical rescue therapy

Known areas of variability in care

Conclusion

Footnotes

Funding

Conflict of interest statement

References