Infliximab | place in therapy review endoscopic healing. Ambulatory patients with moderate disease who continue to have symptoms of left-sided disease despite an adequate course of oral mesalamine may benefit from rectal mesalamine and/or rectally administered topical steroids to alleviate their urgency and rectal blood loss. Rectal mesalamine at a once-daily dose of 1 to 4 g is superior to rectal steroids for treating distal disease and should always be considered as the first option (Marshall & Irvine 1997). Rectal mesalamine therapy also results in a more rapid and better disease control in patients with extensive disease (Marteau et al. 2005). Immunosuppressives The purine analogs azathioprine and 6-mercaptopurine have a steroid-sparing effect in patients with UC responding to corticosteroids but are not a treatment option for patients failing these agents since they require 2 to 4 months of therapy at adequate doses to produce a clinical effect. The folate antagonist methotrexate has not proven to be efficacious in a randomized trial to treat patients with moderately active steroid-refractory UC. Recently, evidence from an uncontrolled open-label trial has suggested a role for oral methotrexate in the treatment of moderate UC (Cummings et al. 2005), but patients should know that a 6- to 8-week lag phase is to be expected before this treatment is efficacious. Oral cyclosporine at a starting dose of 5 mg/kg with subsequent adjustment of trough levels to therapeutic ranges has been proposed to treat patients with refractory UC based on results in open-label studies (Actis et al. 1999; Navazo et al. 2001). The other calcineurin inhibitor used in solid organ transplantation, tacrolimus, given at an initial dose of 0.1 mg/kg has also been reported in open-label trials to be efficacious in this setting (Fellermann et al. 2002; Baumgart et al. 2006), given for a median of 2 years in one of the patient cohorts (Baumgart et al. 2006). Recently, a placebo-controlled Japanese study confirmed the efficacy of high-dose tacrolimus in active colitis, with controlled dosing to give a trough level of 10–15 ng/mL (Ogata et al. 2006). However, both cyclosporine and tacrolimus are considered nephrotoxic when used long term at these dose levels and attempts to interrupt treatment after a period of 3 months is usually made. Given the current evidence and the lack of long- term safety data, oral tacrolimus and cyclosporine should be regarded as “bridge” therapy, since azathioprine typically has a delayed onset of action and an induction agent is needed to cover the first 3 to 6 months. Fulminant colitis Only 15–20% of patients with UC will ever experience an attack of fulminant colitis requiring in-hospital management (Edwards & Truelove 1963). Patients with pancolitis appear to be predisposed to severe flares. Fulminant UC is a serious, potentially life- threatening condition and hospitalization should be considered in all patients with severe attacks. Even if patients have been treated with oral corticosteroids for the ongoing flare, intravenous corticosteroids at a dose equivalent to prednisolone 60 mg should be considered. Pioneering studies by Truelove et al. have shown 154 that by applying this strategy, 64% of patients will enter clinical remission and only 23% require total proctocolectomy (Truelove et al. 1978). Regardless of the treatment strategy these patients require intensive attention by a surgical-medical team experienced in dealing with severe colitis. When patients fail 3 to 5 days of intravenous corticosteroids at adequate doses, and continue to report frequent bloody diarrhea with fever or high C-reactive protein levels, they should be considered for total proctocolectomy or rescue medical treatment (Travis et al. 1996). Complications such as toxic megacolon or uncontrolled bleeding should favor surgical intervention. Intravenous cyclosporine has been shown to be an effective rescue therapy for severe UC attacks in three controlled trials (Lichtiger et al. 1994; D’Haens et al. 2001; Van Assche et al. 2003). In the trial by Lichtiger et al., nine out of 11 patients treated with intravenous cyclosporine 4 mg/kg avoided colectomy, versus none of the nine placebo-treated patients. Data from one single- center controlled trial in 73 patients indicate that intravenous cyclosporine 2 mg/kg per day as initial treatment may prove effective for severe attacks of UC, although not all of these patients were failing intravenous corticosteroids. When results from controlled and uncontrolled trials are pooled, 76–85% of patients will respond to intravenous cyclosporine and avoid colectomy in the short term, with a median time to response of 4 to 5 days (Van Assche et al. 2003). In responding patients, initiation of oral cyclosporine therapy at 5–8 mg/kg divided into two daily doses should be considered along with gradual steroid tapering and initiation of azathioprine or 6-mercaptopurine. However cyclosporine use in UC has been associated with mortality, mostly as a result of opportunistic infections (Arts et al. 2004). Following initial response to cyclosporine for fulminant UC, about 50% of patients avoid colectomy at 3 years (Cohen et al. 1999; Arts et al. 2004; Campbell et al. 2005; Moskovitz et al. 2006). Lower colectomy-free rates have been recently reported with follow-up extending to 7 years (Moskovitz et al. 2006). The patient population already failing adequate courses of azathioprine or 6-mercaptopurine is most prone to colectomy following initial response to cyclosporine (Moskovitz et al. 2006). However, cyclosporine is only administered in 3-month courses to patients with IBD. This probably explains why patients failing azathioprine are more prone to early colectomy after initial response to cyclosporine since no adequate exit strategy can be provided. Oral cyclosporine and tacrolimus can be considered to treat severe attacks of UC, but only retrospective uncontrolled data are available for UC and the one controlled trial with oral tacrolimus included ambulatory, less severe patients (Baumgart et al. 2006; Ogata et al. 2006). 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, and the short-term complications and long-term outcomes of pouch surgery early in the course of a severe flare of UC. The important need for colectomy (at least 50% after 5 to 7 years) despite initial successful medical management and the considerable toxicity of cyclosporine therapy, emphasizes the active and early role of the surgical team in the management of patients with UC. Early © 2007 Core Medical Publishing Limited