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The mainstay of therapy for acute severe ulcerative colitis (UC) is corticosteroids, but about one-third of patients with acute severe UC fail to respond to steroids and ultimately require colectomy. Current medical options for steroid-refractory UC patients are intravenous cyclosporine, infliximab, or tacrolimus. While cyclosporine and infliximab have been studied more extensively and their efficacy as rescue therapy has been confirmed, data from randomized trials and clinical experience regarding tacrolimus in severe UC patients remain limited.

The first randomized, controlled trial of tacrolimus in steroid-refractory UC was reported by Ogata et al in 2006.1 Two tacrolimus arms with low (5–10 ng/mL) and high trough levels (10–15 ng/mL) were compared with a placebo group. At the end of 2 weeks treatment, clinical response was observed in 68% and 38% of the patients of the high and low trough groups, respectively, and in 10% of the placebo group. Patients in the high target serum concentration group were significantly more likely than patients receiving placebo to experience a clinical response (P < 0.001). Limitations of the Ogata et al 2006 study were the small number of patients enrolled in each arm, about 20, which may have been insufficient to detect a true difference in remission rate among groups, and the possibility that patients enrolled in this study may not have had severe disease.

In this issue of Inflammatory Bowel Disease, Ogata et al2 report a phase III double-blind, placebo-controlled trial of tacrolimus in hospitalized patients with steroid-refractory or -dependent UC. Sixty-two active UC patients were randomized to receive “high” doses of oral tacrolimus or placebo with oral dosing adjusted to trough levels of 10–15 ng/mL by an external board to secure blinding. The primary endpoint was “clinical response” after 2 weeks treatment, based on a disease activity index (DAI) score, consisting of clinical and endoscopic findings (range 0–12). Secondary endpoints were clinical remission (DAI score ≤2) and mucosal healings (mucosal appearance subscore ≤1). Clinical response, defined as a decrease in DAI score >4 from baseline and improvements in all categories was achieved in 50% and 13.3% (P = 0.003) in the tacrolimus and placebo groups, respectively. Clinical remission and mucosal healing was achieved in 9.4% and 43.8% in the tacrolimus group and in 0.0% and 13.3% in the placebo group (P = 0.238; P = 0.012), respectively. An additional 12-week, open-label extension of tacrolimus was evaluated in 21 patients. Clinical remission was observed in an additional three patients after 12 weeks treatment. No patients required colectomy during the 12 weeks open-label extension study. Adverse events were mild and no statistically significant difference in incidence was observed between the tacrolimus group and placebo group.

Despite addressing some of the limitations of the previous Ogata et al 2006 trial, several issues remain. In particular, there is limited information regarding demographic and clinic findings (proportion of patients with steroid-refractory or -dependent disease, concomitant immunosuppressant treatments) and there was no stratification for disease severity in responders vs. nonresponders. Similar to the previous 2006 study, none of the patients enrolled in the present study required colectomy during the 12-week open-label extension phase. These data are in contrast with the colectomy rate observed in previous, short-term, cyclosporine and tacrolimus series ranging from 10%–50%. It may be that the disease activity, in this Japanese population, was not as “severe” as patients enrolled into Western studies of cyclosporine. A DAI score ≥6 with a mucosal appearance subscore ≥2 was the inclusion criteria in the present study and a mean total score of about 9.5 in each group of patients was observed. These data suggest that many of the UC patients in the present study had more “moderate,” rather than “severe” disease activity. Moreover, the definition of steroid-resistant disease provided by Ogata et al fails to clarify if responses to steroids were partial or complete and another consideration is the policy to admit patients to the hospital in Japan for medical and nutritional therapies for less severe disease activity than may trigger hospitalizations in the U.S.

Conversely, compared to patients treated with cyclosporine for severe UC, the side effect profile and tolerability were similar to the previous Ogata et al 2006 trial, despite the high trough levels. However, follow-up was short; in comparison, Yamamoto et al3 recently evaluated the adverse events related to long-term, maintenance administration of tacrolimus therapy where tremor was reported in ≈25% of patients, impaired renal function in 18.5%, and infections in 15%.

Therefore, on the basis of the present study, should tacrolimus be used as an alternative to cyclosporine as rescue therapy in steroid-refractory UC? No head-to-head comparison between cyclosporine and tacrolimus in acute severe UC has been published. The only evaluation, in terms of effectiveness and safety with cyclosporine vs. tacrolimus, comes from trials in liver, kidney, and bone marrow transplant patients. In these patient populations, tacrolimus appeared superior to cyclosporine in improving graft survival and in preventing acute rejection after transplantation.4–6 The efficacy of cyclosporine in active severe UC was initially demonstrated in a randomized, placebo-controlled trial in 1994 by Lichtiger et al.7 In that study, 82% of patients “responded” to intravenous cyclosporine (4 mg/kg), whereas there were no responders in the placebo group after an average follow-up period of 7 days (in contrast to 14 days in the oral tacrolimus study). A subsequent trial, comparing intravenous cyclosporine (4 mg/kg) with methylprednisolone in moderate-severe UC, demonstrated similar efficacy in the short term and a more profound effect in the long term.8 Moreover, cyclosporine was more effective than steroids in patients with severe mucosal damage.9

One of the major limits pertaining to the use of cyclosporine has been the potential for serious side effects in the population of patients with severe, steroid-refractory UC. As both efficacy and toxicity of cyclosporine are related to trough blood levels that varied, markedly, both inter- and intraindividually, intravenous cyclosporine administration requires drug blood level monitoring. Although the oral microemulsion form of cyclosporine appears to be effective for UC, only limited data supporting its use for active steroid-refractory disease are available.10 Unlike cyclosporine, tacrolimus absorption, through the intestinal epithelium, does not depend on mucosal integrity, such that dosing is more predictable, even in the presence of bowel inflammation. On the other hand, in severe UC patients upper gastrointestinal tract symptoms, such as nausea and vomiting, are common and oral intake could be compromised. These patients may benefit from intravenous cyclosporine or infliximab rather than tacrolimus.

In a different population of outpatients with moderate/severe UC, the efficacy of infliximab has been demonstrated in two large randomized controlled trials.11 Although response rates were satisfactory, with almost 70% responding and remission rates ranging from 30%–40% in the short term, long-term exposure was characterized by loss of response and sustained, steroid-free, remission was maintained in only ≈20% of patients at 1 year. Jarnerot et al12 investigated the efficacy of infliximab for “moderate-severe” hospitalized UC patients. Forty-five patients were randomized to receive either a single infusion of infliximab or placebo. At 3 months, 7/24 (29%) patients on infliximab and 14/21 (67%) patients on placebo underwent a colectomy (P = 0.017). Infliximab appeared to be more effective in moderate/severe disease than in patients with fulminant colitis. Most recently, a French collaborative study compared cyclosporine to infliximab in a head-to-head trial for hospitalized patients with “severe” UC.13 Approximately 85% of patients in both groups responded to rescue therapy with improvement in both cohorts by 7 days.

Despite the descriptions of “disease severity” in the aforementioned trials, there remains considerable heterogeneity among the patient populations. Already, differences in steroid-refractory vs. steroid-dependency have been alluded to in the Ogata et al trials. Furthermore, different definitions, indices, and endpoints of clinical severity, clinical improvement, clinical remission, and mucosal healing along with concomitant medications and outpatient vs. inpatient treatment require cautious scrutiny when attempting to compare patient populations enrolled in UC trials.14

In general, most patients should be treated aggressively for moderate/severe UC prior to the need for hospitalization. Infliximab has been demonstrated to be effective in this refractory population. The potential for oral administration of tacrolimus compared to induction regimen of intravenous cyclosporine may provide an alternative approach to patients with moderate/severe, steroid-refractory UC prior to the need for hospitalization. One would predict that most steroid-dependent UC patients (already in clinical response/remission/mucosal healing) would be currently treated with a thiopurine or anti-TNF agent.

Once hospitalized, the response to intravenous steroids should be assessed within 3–5 days.15 In the absence of response, therapeutic options, including colectomy, should be discussed with patients. Rescue therapy with intravenous cyclosporine, infliximab, or tacrolimus may be appropriate. While the effect of infliximab and cyclosporine in severe, acute UC patients appears comparable, the positioning of tacrolimus remains less clear. At present, without randomized controlled trials to establish whether tacrolimus has an advantage over infliximab, or if outpatients who fail to respond to tacrolimus or infliximab can be safely and effectively “switched” to the alternate therapy, and in the absence of any predictor of response to individual therapies the choice between the different rescue therapies reflects physician experience as well as patient preference and compliance.

REFERENCES

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  2. REFERENCES
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