Treatment of severe steroid refractory ulcerative colitisThe care for a patient with ulcerative colitis UC remains challenging despite the fact that morbidity and mortality rates have been considerably reduced during the last 30 years. The traditional management with intravenous corticosteroids was definitiln by the introduction of steroid refractory ulcerative colitis definition and infliximab. In this review, we focus on the treatment of patients with moderate to severe UC. The steroid refractory ulcerative colitis definition recommendations difference in strength and bulking based on current literature, published guidelines and reviews, and were discussed at a consensus meeting of Swiss experts in the field. Comprehensive treatment algorithms were developed, aimed for daily clinical practice.
Treatment of severe steroid refractory ulcerative colitis
Although systemic steroids are highly efficacious in ulcerative colitis UC , failure to respond to steroids still poses an important challenge to the surgeon and physician alike. If patients fail 3 to 5 d of intravenous corticosteroids and optimal supportive care, they should be considered for any of three options: The choice between these three options is a medical-surgical decision based on clinical signs, radiological and endoscopic findings and blood analysis CRP, serum albumin. The data on infliximab as a medical rescue in fulminant colitis are more limited although the efficacy of this anti tumor necrosis factor TNF monoclonal antibody has been demonstrated in a controlled trial.
Controlled data on the comparative efficacy of cyclosporine and infliximab are not available at this moment. Both drugs are immunosuppressants and are used in combination with steroids and azathioprine, which infers a risk of serious, even fatal, opportunistic infections. Therefore, patients not responding to these agents within d should be considered for colectomy and responders should be closely monitored for infections.
Some patients with ulcerative colitis UC remain symptomatic despite optimal doses of oral 5-aminosalicylic acid 5-ASA drugs, topical therapy with either 5-ASA or steroids, and systemic corticosteroids.
This can occur regardless of the extent of colonic involvement. However, steroids are highly efficacious in UC. In patients with early relapse after an initial successful course of systemic steroids, subsequent courses of steroids are probably less efficacious, but this has never been studied in a controlled trial. The distinction can be important since treatment options in the two settings may differ.
In patients who have initially responded, the dose of oral steroids can be temporarily increased to the dose level that controlled symptoms before, whereas patients never responding need alternative options on the short term. The approach to treatment should be based on the severity of the disease flare. Moderately ill patients can usually be managed in an outpatient setting with the approaches summarized below. Disease flares are considered to be moderate or moderate-to-severe when symptoms impair with activities of daily life, but are not necessitating immediate hospitalization.
Fulminant UC necessitates IV therapy in hospital as described below and regardless of previous oral steroid use[ 3 ]. Only 15 to 20 percent of patients with UC will ever experience an attack of fulminant colitis[ 4 ]. Patients entering hospital with fulminant colitis should be evaluated for other causes of severe colitis. We always perform an un-prepped sigmoidoscopy to assess disease severity, to obtain mucosal biopsies, and to provide a baseline assessment.
Total colonoscopy and ileoscopy should not be attempted as it carries the risk of inducing toxic megacolon. As a rule sigmoidoscopy in fulminant colitis should be performed by an experienced endoscopist with minimal inflation and at the first sign of discomfort from the patient no further proximal progression should be attempted.
Infectious colitis should be excluded with stool culture for bacterial pathogens, C. The likelihood of infectious colitis is geographically determined but should be considered in all patients. Although the precise role of active cyto-megalo virus CMV replication in fulminant colitis is still debated, the presence of CMV inclusions in a colonic biopsy should be ruled out. In the recent patient history foreign travel and non steroidal anti inflammatory drugs NSAID use should be recorded.
Clinically disease severity should be assessed using the criteria in the Lichtiger score including stool frequency, nocturnal diarrhea and fecal incontinence, rectal bleeding, abdominal cramping and tenderness and general well being.
Others signs of fulminant colitis include fever, lethargy and dehydration. Blood analysis should include: A plain abdominal X-ray should be obtained initially and at regular intervals during the hospitalization. We generally treat those patients with IV prednisolone 60 mg daily or equivalent as a continuous infusion regardless of prior oral corticosteroid therapy.
Pioneering studies by Truelove et al[ 1 ] have shown that applying this strategy 64 percent of patients will enter clinical remission and only 23 percent require rescue total procto-colectomy. Supportive therapy for this condition includes relative bowel rest and parenteral nutrition if needed. The value of antibiotics as a prophylactic or adjuvant therapy in the setting of fulminant colitis has not been established. However, patients with high fever, signs of peritonitis or high CRP levels should receive broad spectrum antibiotics e.
Even so, initiation of antibiotics should never postpone the decision for procto-colectomy. If patients fail to respond to three to five days of IV steroids, they should be considered for intensified medical therapy described below or colectomy[ 3 , 4 ]. Daily clinical follow up of these patients by both an expert surgeon and physician is required from that stage on and colectomy should be considered if the clinical condition of a patient worsens.
Addition of rectal hydrocortisone drips or mesalamine enemas can be considered at this stage particularly in patients with symptoms secondary to left sided colitis. When patients fail three to five days of IV cortico-steroids at adequate doses and continue to report frequent bloody diarrhea with fever or high CRP levels, they should be considered for surgical colectomy or rescue medical treatment[ 3 , 4 ].
Complications such as toxic megacolon or uncontrolled bleeding should favor the decision towards surgical intervention. Intravenous cyclosporine has been shown to be an effective rescue therapy for severe UC attacks in two controlled trials[ 6 , 7 ]. When results from controlled and non-controlled trials are pooled 76 to 85 percent of patients will respond to IV cyclosporine and avoid colectomy short term.
Before the initiation of IV cyclosporine hypomagnesemia and hypocholesterolemia should be corrected to decrease the risk neurologic toxicity. Therapeutic ranges for cyclosporine blood levels may vary based on the assay used. While patients are on a triple immunosuppressive regimen prophylaxis against Pneumocystis carinii pneumonia should be given and alertness for opportunistic infections in general should be high.
Cyclosporine use in UC has been associated with mortality and most of the fatalities were due to opportunistic infections[ 9 ]. Other complications of cyclosporine therapy include nephrotoxicity, tremor and convulsions, hypertension, gingival hyperplasia and hypertrichosis.
Rare cases of anaphylaxis are contributed to the solvent in Sandimmun, the commercially available formulation of cyclosporine, and occurrence of anaphylaxis allows treatment with oral cyclosporine.
Following initial response to cyclosporine for fulminant UC about 50 percent of patients avoid colectomy at three years[ 9 - 12 ]. Lower colectomy free rates have been recently reported with follow up extending to seven years[ 11 ]. The patient population already failing adequate courses of azathioprine or 6-MP is most prone to colectomy following initial response to cyclosporine[ 10 , 11 ]. Tacrolimus an oral cyclosporine can be considered to treat severe attacks of ulcerative colitis but only retrospective uncontrolled data are available[ 13 - 15 ].
The efficacy of infliximab in the setting of severe UC not responding to therapy with intravenous steroids has been demonstrated recently in a small placebo controlled trial. Open label experience in patients with severe UC attacks has been inconsistent[ 17 , 18 ]. In a recent publication from the colorectal surgery group at the Mayo Clinic, Rochester, MN, an increased risk of infectious postoperative complications was found in a group of infliximab treated patients as compared to controls[ 19 ].
It should be noted however, that disease severity, use of immunosuppressives and IV steroids was higher in the infliximab group. Other retrospective cohorts and the controlled Scandinavian trial have not confirmed this increased complication risk.
However, preliminary results from a cohort of patients treated at the Mount Sinai hospital in New York suggest that patients receiving infliximab followed by cyclosporine or vice versa have a substantial risk of serious adverse events including mortality[ 20 ]. Data on long term avoidance of colectomy with infliximab are as of yet not available, but there is no indication that infliximab would increase surgical complications. Surgical proctocolectomy with ileo-anal pouch anastomosis is a valid option for patients with moderate to severe UC failing medical therapy.
Patients should be counseled about the option of surgery, short term complication and long term outcomes of pouch surgery, early in the course of a severe flare of UC. Also from the first day of hospitalization the surgical team should be involved in the management of the patient with fulminant UC.
Patients with severe attacks of UC should be hospitalized and closely monitored. Cyclosporine is most useful as a bridge to the effect of azathioprine or 6-MP and should be considered particularly in this setting. Long term colectomy free survival rates after initial response to cyclosporine are far from optimal and we have no long term data with infliximab yet.
However, in patients with a dramatic response to any of the two immune therapies a delayed elective colectomy later in the disease course may be a noble goal per se. In patients failing IV steroids, he risk of, even fatal, serious infections with cyclosporine is clearly increased and also patients responding to infliximab should be closely monitored for opportunistic infections.
Proposed treatment algorithm for the management of severe steroid refractory ulcerative colitis. National Center for Biotechnology Information , U. Journal List World J Gastroenterol v. Published online Sep This article has been cited by other articles in PMC.
Abstract Although systemic steroids are highly efficacious in ulcerative colitis UC , failure to respond to steroids still poses an important challenge to the surgeon and physician alike. Open in a separate window.
Cortisone in ulcerative colitis. Final report on a therapeutic trial. Out-patient treatment of ulcerative colitis. Comparison between three doses of oral prednisone. Further experience in the treatment of severe attacks of ulcerative colitis.
Predicting outcome in severe ulcerative colitis. The course and prognosis of ulcerative colitis. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med. Intravenous cyclosporine versus intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis.
Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis. Intravenous cyclosporin in ulcerative colitis: Incidence of colectomy during long-term follow-up after cyclosporine-induced remission of severe ulcerative colitis.
Ciclosporin use in acute ulcerative colitis: Eur J Gastroenterol Hepatol. Low-dose oral microemulsion ciclosporin for severe, refractory ulcerative colitis. Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease--a long-term follow-up. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: Infliximab for patients with refractory ulcerative colitis.
Infliximab for hospitalized patients with severe ulcerative colitis. Cyclosporine CsA and infliximab Infl as acute salvage therapies for each other in severe steroid refractory ulcerative colitis UC Gastroenterology. Effect of infliximab on short-term complications in patients undergoing operation for chronic ulcerative colitis.
J Am Coll Surg. Support Center Support Center.