Acute severe ulcerative colitis: State of the art treatment

https://doi.org/10.1016/j.bpg.2018.05.007Get rights and content

Abstract

Acute severe ulcerative colitis (ASUC) is a potentially life-threatening condition. In the present review, we give a broad overview of the state of the art in the management of this condition. A systematic bibliographic search was performed in PubMed. Patient with ASUC should be hospitalized and managed by a multidisciplinary team (gastroenterologist plus surgeon). Intravenous corticosteroids remain the cornerstone of medical therapy. However, about 30% of patients do not respond. After failing 3–5 days of corticosteroids, patients should be considered for either rescue medical therapy or for colectomy. Cyclosporin and infliximab are similarly effective and safe. Cyclosporin should be mainly used as a “bridge” in thiopurine-naïve patients. More recently, infliximab has become the most widely used salvage therapy. Third-line salvage therapy with either cyclosporin or infliximab is efficacious in some patients but carries a significant risk of complications. Colectomy is appropriate in case of complications or medical rescue therapy failure.

Introduction

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon and rectum that typically presents with rectal bleeding, diarrhea, tenesmus and, sometimes, low abdominal pain. In the majority of patients, the disease is limited to the rectum and/or the left colon and has a mild-moderate course. However, one in five patients will develop at least one severe acute exacerbation during their lifetime, often at the time of disease onset, requiring hospitalization.

Acute severe UC (ASUC) is a potentially life-threatening condition. Prior to the 1950's and the implementation of urgent colectomy and systemic steroids, mortality rates were as high as 70% in patients with ASUC. In recent years, mortality rates have dropped to less than 1% with the combination of medical therapy, rescue therapy, and timely colectomy when indicated [1].

ASUC is generally diagnosed according to Truelove and Witts' criteria, which consists of bloody stool frequency ≥6 per day and at least one of the following: pulse rate >90 bpm, temperature >37.8 °C, hemoglobin <10.5 g/dL and erythrocyte sedimentation rate (ESR) > 30 mm/h. Other indices for defining severity include modified Mayo's classification, which is a combination of clinical and endoscopic findings, and Montreal classification, which is primarily based on Truelove and Witt's criteria. However, Truelove and Witt's criteria are the most widely accepted in clinical practice.

Approximately 60–70% of ASUC will respond adequately to intravenous corticosteroid therapy alone in the short-term [2]. Historically, failure to induce clinical remission with intravenous corticosteroids invariably led to colectomy. The introduction of medical rescue, or salvage, therapies has provided an alternative option to patients previously facing only surgical management [3]. Cyclosporin and infliximab currently represent the mainstays of salvage therapy.

In the present review, we give a broad overview of the state of the art in the management of ASUC.

Section snippets

Search strategy

A systematic bibliographic search was designed to identify studies investigating the management of ASUC. An electronic search was performed in PubMed up to January 2018 using the following algorithm: “acute severe ulcerative colitis” OR “acute severe colitis” OR “refractory ulcerative colitis” OR “steroid-refractory ulcerative colitis” OR “corticosteroid-refractory ulcerative colitis”. In addition, the reference lists from the selected articles were reviewed to identify additional studies of

General management

ASUC is a medical emergency and a potentially life-threatening condition that requires prompt recognition and early initiation of treatment. Any patient meeting the criteria for severe disease should be admitted to hospital for intensive medical therapy [4,5]. Patients with ASUC are best managed by a multidisciplinary team, comprising gastroenterologists, colorectal surgeons, gastroenterology nurses, dietitians, and pharmacists, on a specialized gastrointestinal ward [4]. Sufficient fluid

Historical perspective of the corticosteroid treatment

It is worthy to remember that about 15% of patients with UC suffer in a given moment from a severe attack, a clinical situation which had 30%–50% mortality in the pre-steroid era. In 1954 and 1955 the Oxford Group published in 2 parts a landmark clinical trial in the British Medical Journal. It was a randomized, controlled, and blind study that demonstrated that hydrocortisone was clearly superior to placebo in the treatment of UC attacks. Although ultimately 30%–50% of patients required

Medical rescue therapies

There are a number of options available when considering salvage therapy: cyclosporin and infliximab have been the focus of most active research and currently represent the mainstays of salvage therapy.

Sequential rescue therapy

Second-line rescue therapy, following nonresponse to initial infliximab or cyclosporin, remains controversial. While so-called sequential therapy for refractory flares appears to halt progression to colectomy, such intensive immunosuppression raises safety concerns. In general, it is considered that only a single attempt at rescue therapy with a calcineurin inhibitor or infliximab should be considered before referral for colectomy, because it is felt that the risks may exceed the benefits. This

Surgical treatment

In patients with ASUC, surgery should be performed when indicated (such as in cases of suspected perforation, toxic megacolon or refractory bleeding), when medical rescue therapy is contraindicated, or in cases of failure of medical rescue therapy [4].

Surgery should be considered early in the course as a useful alternative, rather than only as an option for failed medical management. Delaying surgery is associated with increased risk of postoperative complications and, therefore, timing of

Summary

Acute severe ulcerative colitis (ASUC) is a potentially life-threatening condition. In recent years, mortality rates have dropped to less than 1% with the combination of medical therapy, rescue therapy, and timely colectomy when indicated. Patients with ASUC should be admitted to hospital for intensive medical therapy, and are best managed by a multidisciplinary team comprising a gastroenterologist and a surgeon. Stool cultures for enteric pathogens and Clostridium difficile testing are

Practice points

  • Patients with acute severe ulcerative colitis (ASUC) should be hospitalized.

  • Management of ASUC requires close collaboration between surgeon and gastroenterologist.

  • Intravenous corticosteroids (60 mg of methylprednisolone daily, or equivalent) remain the cornerstone of medical therapy for ASUC.

  • About 30% of patients with ASUC do not respond to intravenous corticosteroids and require a rescue therapy.

  • All patients admitted with ASUC should have stool cultures and stool assay for Clostridium difficile

Research agenda

  • The criteria for steroid nonresponse and predictors of nonresponse in acute severe ulcerative colitis (ASUC) remain relatively heterogeneous.

  • In the future, composite scores to evaluate the severity and prognosis of ASUC integrating clinical, biochemical, serological, genetic and other “omic” data will be increasingly investigated.

  • A molecular-level explanation of resistance to corticosteroids is currently being investigated.

  • Further investigation into predictors of response to salvage therapy

Conflict of interest statement

  • Dr. Gisbert has served as a speaker, a consultant and advisory member for or has received research funding from MSD, Abbvie, Hospira, Pfizer, Kern Pharma, Biogen, Takeda, Janssen, Roche, Celgene, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Vifor Pharma.

  • Dr Chaparro has served as a speaker, or has received research or education funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire

References (100)

  • F. Mocciaro et al.

    Cyclosporine or infliximab as rescue therapy in severe refractory ulcerative colitis: early and long-term data from a retrospective observational study

    J Crohn's & colitis

    (2012)
  • D.N. Moskovitz et al.

    Incidence of colectomy during long-term follow-up after cyclosporine-induced remission of severe ulcerative colitis

    Clin Gastroenterol Hepatol: Offic Clin Pract J Am Gastroenterol Assoc

    (2006)
  • F.A. Rowe et al.

    Factors predictive of response to cyclosporin treatment for severe, steroid-resistant ulcerative colitis

    Am J Gastroenterol

    (2000)
  • L. Sharkey et al.

    The use of Cyclosporin A in acute steroid-refractory ulcerative colitis: long term outcomes

    J Crohn's & colitis

    (2011)
  • W.R. Treem et al.

    Cyclosporine treatment of severe ulcerative colitis in children

    J Pediatr

    (1991)
  • G. Van Assche et al.

    Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis

    Gastroenterology

    (2003)
  • A. Walch et al.

    Long-term outcome in patients with ulcerative colitis treated with intravenous cyclosporine A is determined by previous exposure to thiopurines

    J Crohn's & colitis

    (2010)
  • J.G. Williams et al.

    Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial

    The lancet Gastroenterology & hepatology

    (2016)
  • S. Garcia-Lopez et al.

    Cyclosporine in the treatment of severe attack of ulcerative colitis: a systematic review

    Gastroenterol Hepatol

    (2005)
  • C. Mortensen et al.

    Treatment of acute ulcerative colitis with infliximab, a retrospective study from three Danish hospitals

    J Crohn's & colitis

    (2011)
  • R. Monterubbianesi et al.

    Infliximab three-dose induction regimen in severe corticosteroid-refractory ulcerative colitis: early and late outcome and predictors of colectomy

    J Crohn's & colitis

    (2014)
  • D. Turner et al.

    Severe pediatric ulcerative colitis: a prospective multicenter study of outcomes and predictors of response

    Gastroenterology

    (2010)
  • E.A. Maser et al.

    Cyclosporine and infliximab as rescue therapy for each other in patients with steroid-refractory ulcerative colitis

    Clin Gastroenterol Hepatol: Offic Clin Pract J Am Gastroenterol Assoc

    (2008)
  • M. Protic 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 Crohn's & colitis

    (2014)
  • R.W. Lynch et al.

    Outcomes of rescue therapy in acute severe ulcerative colitis: data from the United Kingdom inflammatory bowel disease audit

    Aliment Pharmacol Therapeut

    (2013)
  • D. Seah et al.

    Review article: the practical management of acute severe ulcerative colitis

    Aliment Pharmacol Therapeut

    (2016)
  • J.H. Chen et al.

    Review article: acute severe ulcerative colitis - evidence-based consensus statements

    Aliment Pharmacol Therapeut

    (2016)
  • M. Harbord et al.

    Third european evidence-based consensus on diagnosis and management of ulcerative colitis. Part 2: current management

    J Crohn's & colitis

    (2017)
  • S.P. Travis et al.

    Predicting outcome in severe ulcerative colitis

    Gut

    (1996)
  • G.T. Ho 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 Therapeut

    (2004)
  • S. Lichtiger et al.

    Cyclosporine in severe ulcerative colitis refractory to steroid therapy

    N Engl J Med

    (1994)
  • M. Aceituno et al.

    Steroid-refractory ulcerative colitis: predictive factors of response to cyclosporine and validation in an independent cohort

    Inflamm Bowel Dis

    (2008)
  • G.C. Actis et al.

    Colectomy rate in steroid-refractory colitis initially responsive to cyclosporin: a long-term retrospective cohort study

    BMC Gastroenterol

    (2007)
  • J. Arts et al.

    Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis

    Inflamm Bowel Dis

    (2004)
  • S. Bamba et al.

    Factors affecting the efficacy of cyclosporin A therapy for refractory ulcerative colitis

    J Gastroenterol Hepatol

    (2010)
  • S. Bamba et al.

    Prognostic factors for colectomy in refractory ulcerative colitis treated with calcineurin inhibitors

    Exp Therapeut Med

    (2012)
  • A. Barabino et al.

    The use of ciclosporin in paediatric inflammatory bowel disease: an Italian experience

    Aliment Pharmacol Therapeut

    (2002)
  • K.J. Benkov et al.

    Cyclosporine as an alternative to surgery in children with inflammatory bowel disease

    J Pediatr Gastroenterol Nutr

    (1994)
  • W. Cacheux et al.

    Predictive factors of response to cyclosporine in steroid-refractory ulcerative colitis

    Am J Gastroenterol

    (2008)
  • S. Campbell et al.

    Ciclosporin use in acute ulcerative colitis: a long-term experience

    Eur J Gastroenterol Hepatol

    (2005)
  • F. Carbonnel et al.

    Intravenous cyclosporine in attacks of ulcerative colitis: short-term and long-term responses

    Dig Dis Sci

    (1996)
  • M. Castro et al.

    Role of cyclosporin in preventing or delaying colectomy in children with severe ulcerative colitis

    Langenbeck's Arch Surg

    (2007)
  • A. Croft et al.

    Outcomes of salvage therapy for steroid-refractory acute severe ulcerative colitis: ciclosporin vs. infliximab

    Aliment Pharmacol Therapeut

    (2013)
  • K.E. Dean et al.

    Infliximab or cyclosporine for acute severe ulcerative colitis: a retrospective analysis

    J Gastroenterol Hepatol

    (2012)
  • A.S. Cheifetz et al.

    Cyclosporine is safe and effective in patients with severe ulcerative colitis

    J Clin Gastroenterol

    (2011)
  • S.R. Gurudu et al.

    Cyclosporine therapy in inflammatory bowel disease: short-term and long-term results

    J Clin Gastroenterol

    (1999)
  • N. Haslam et al.

    Audit of cyclosporin use in inflammatory bowel disease: limited benefits, numerous side-effects

    Eur J Gastroenterol Hepatol

    (2000)
  • C. Hermida-Rodriguez et al.

    High-dose intravenous cyclosporine in steroid refractory attacks of inflammatory bowel disease

    Hepato-Gastroenterology

    (1999)
  • O. Holme et al.

    Treatment of fulminant ulcerative colitis with cyclosporine A

    Scand J Gastroenterol

    (2009)
  • G.M. Hyde et al.

    Intravenous cyclosporin as rescue therapy in severe ulcerative colitis: time for a reappraisal?

    Eur J Gastroenterol Hepatol

    (1998)
  • Cited by (26)

    • Egg white peptides ameliorate dextran sulfate sodium-induced acute colitis symptoms by inhibiting the production of pro-inflammatory cytokines and modulation of gut microbiota composition

      2021, Food Chemistry
      Citation Excerpt :

      Ulcerative colitis (UC) is a chronic relapsing inflammatory disease of the colon and rectum (Gisbert & Chaparro, 2018).

    • Abdominal Emergencies in Inflammatory Bowel Disease

      2019, Surgical Clinics of North America
      Citation Excerpt :

      Instead, infliximab has now emerged as the most widely used rescue therapy. One recent literature review demonstrated immediate response rates to infliximab as a rescue therapy agent range between 50% and 83%, with long-term response rates slightly lower at 50% to 63%.14,25 These results are similar to those seen with cyclosporine therapy.

    View all citing articles on Scopus
    View full text