Acute severe ulcerative colitis: State of the art treatment
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
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Patients with acute severe ulcerative colitis (ASUC) should be hospitalized.
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Management of ASUC requires close collaboration between surgeon and gastroenterologist.
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Intravenous corticosteroids (60 mg of methylprednisolone daily, or equivalent) remain the cornerstone of medical therapy for ASUC.
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About 30% of patients with ASUC do not respond to intravenous corticosteroids and require a rescue therapy.
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All patients admitted with ASUC should have stool cultures and stool assay for Clostridium difficile
Research agenda
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The criteria for steroid nonresponse and predictors of nonresponse in acute severe ulcerative colitis (ASUC) remain relatively heterogeneous.
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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.
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A molecular-level explanation of resistance to corticosteroids is currently being investigated.
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Further investigation into predictors of response to salvage therapy
Conflict of interest statement
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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.
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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)
- et al.
Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression
Clin Gastroenterol Hepatol: Offic Clin Pract J Am Gastroenterol Assoc
(2007) - et al.
Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study
Gastroenterology
(2005) - et al.
Intravenous cyclosporine versus intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis
Gastroenterology
(2001) - et al.
Prognosis of severe attacks in ulcerative colitis: effect of intensive medical treatment
Dig Liver Dis: Offic J Italian Soc Gastroenterol Italian Assoc Study Liver
(2004) - et al.
Triple immunosuppressive therapy in the treatment of severe ulcerative colitis
Gastroenterol Hepatol
(2004) - et al.
Intravenous cyclosporin in ulcerative colitis: a five-year experience
Am J Gastroenterol
(1999) - et al.
Outcome of a conservative approach in severe ulcerative colitis
Dig Liver Dis: Offic J Italian Soc Gastroenterol Italian Assoc Study Liver
(2004) - et al.
Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial
Lancet
(2012) - et al.
Preliminary report: cyclosporin in treatment of severe active ulcerative colitis
Lancet
(1990) - et al.
Efficacy of intravenous cyclosporin in moderately severe ulcerative colitis refractory to steroids
Gastroenterol Clin Biol
(2005)
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
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
Factors predictive of response to cyclosporin treatment for severe, steroid-resistant ulcerative colitis
Am J Gastroenterol
The use of Cyclosporin A in acute steroid-refractory ulcerative colitis: long term outcomes
J Crohn's & colitis
Cyclosporine treatment of severe ulcerative colitis in children
J Pediatr
Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis
Gastroenterology
Long-term outcome in patients with ulcerative colitis treated with intravenous cyclosporine A is determined by previous exposure to thiopurines
J Crohn's & colitis
Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial
The lancet Gastroenterology & hepatology
Cyclosporine in the treatment of severe attack of ulcerative colitis: a systematic review
Gastroenterol Hepatol
Treatment of acute ulcerative colitis with infliximab, a retrospective study from three Danish hospitals
J Crohn's & colitis
Infliximab three-dose induction regimen in severe corticosteroid-refractory ulcerative colitis: early and late outcome and predictors of colectomy
J Crohn's & colitis
Severe pediatric ulcerative colitis: a prospective multicenter study of outcomes and predictors of response
Gastroenterology
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
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
Outcomes of rescue therapy in acute severe ulcerative colitis: data from the United Kingdom inflammatory bowel disease audit
Aliment Pharmacol Therapeut
Review article: the practical management of acute severe ulcerative colitis
Aliment Pharmacol Therapeut
Review article: acute severe ulcerative colitis - evidence-based consensus statements
Aliment Pharmacol Therapeut
Third european evidence-based consensus on diagnosis and management of ulcerative colitis. Part 2: current management
J Crohn's & colitis
Predicting outcome in severe ulcerative colitis
Gut
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
Cyclosporine in severe ulcerative colitis refractory to steroid therapy
N Engl J Med
Steroid-refractory ulcerative colitis: predictive factors of response to cyclosporine and validation in an independent cohort
Inflamm Bowel Dis
Colectomy rate in steroid-refractory colitis initially responsive to cyclosporin: a long-term retrospective cohort study
BMC Gastroenterol
Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis
Inflamm Bowel Dis
Factors affecting the efficacy of cyclosporin A therapy for refractory ulcerative colitis
J Gastroenterol Hepatol
Prognostic factors for colectomy in refractory ulcerative colitis treated with calcineurin inhibitors
Exp Therapeut Med
The use of ciclosporin in paediatric inflammatory bowel disease: an Italian experience
Aliment Pharmacol Therapeut
Cyclosporine as an alternative to surgery in children with inflammatory bowel disease
J Pediatr Gastroenterol Nutr
Predictive factors of response to cyclosporine in steroid-refractory ulcerative colitis
Am J Gastroenterol
Ciclosporin use in acute ulcerative colitis: a long-term experience
Eur J Gastroenterol Hepatol
Intravenous cyclosporine in attacks of ulcerative colitis: short-term and long-term responses
Dig Dis Sci
Role of cyclosporin in preventing or delaying colectomy in children with severe ulcerative colitis
Langenbeck's Arch Surg
Outcomes of salvage therapy for steroid-refractory acute severe ulcerative colitis: ciclosporin vs. infliximab
Aliment Pharmacol Therapeut
Infliximab or cyclosporine for acute severe ulcerative colitis: a retrospective analysis
J Gastroenterol Hepatol
Cyclosporine is safe and effective in patients with severe ulcerative colitis
J Clin Gastroenterol
Cyclosporine therapy in inflammatory bowel disease: short-term and long-term results
J Clin Gastroenterol
Audit of cyclosporin use in inflammatory bowel disease: limited benefits, numerous side-effects
Eur J Gastroenterol Hepatol
High-dose intravenous cyclosporine in steroid refractory attacks of inflammatory bowel disease
Hepato-Gastroenterology
Treatment of fulminant ulcerative colitis with cyclosporine A
Scand J Gastroenterol
Intravenous cyclosporin as rescue therapy in severe ulcerative colitis: time for a reappraisal?
Eur J Gastroenterol Hepatol
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