Response of Refractory Colitis to Intravenous or Oral Tacrolimus (FK506)

Abstract

Intravenous cyclosporine has proven to be an alternative to emergency colectomy in steroid-refractory ulcerative colitis, whereas the experience with FK506 is limited. In this report we compare intravenous to oral FK506 treatment in 38 patients with refractory ulcerative (n = 33) or indeterminate (n = 5) colitis. FK506 was started intravenously in the first group (n = 18) at a dose of 0.01 to 0.02 mg/kg up to 14 days, followed by 0.1 to 0.2 mg/kg orally, or was started orally at this dose in a second group (n = 20). Additional azathioprine/6-mercaptopurine was given and steroids were tapered in responding patients, followed by a dose reduction of FK506. Clinical disease activity and laboratory parameters were assessed to evaluate efficacy and safety. Primary objectives were the induction of remission (Truelove index of mild) and colectomy-free survival. Treatment lasted for a mean of 7.6 months, and the mean observation period was 16.2 months. Eighteen of 38 patients improved within 14 days, and a complete remission was achieved in 13 patients after 1 month. A colectomy within 1 month was performed in 3 of 38 patients. The overall colectomy rate was 34%. One-half of the patients with a minimum follow-up of 2 years required a colectomy. Intravenous and per oral administration were equally safe and effective. The most frequent adverse events included tremor, hyperglycemia, hypertension, and infection, but none were severe. Renal impairment was rare and subsided upon drug withdrawal. In conclusion. FK506 is effective in the treatment of refractory colitis with per oral dosing being equivalent to intravenous administration.

Effect of oral tacrolimus (FK 506) on steroid‐refractory moderate/severe ulcerative colitis

“…Colectomy could be avoided in 66% of patients after a mean follow up of 16 months, and in 50% of those patients who were observed for longer than 24 months. 8 All patients received long-term treatment with purine analogs. Our response rates are similar to those by Fellermann et al and confirm their retrospective analysis.…”

“…In these studies, however, different criteria for the definition of severe UC were used. 8,15,18 Disease activity was less than severe in part of the population studied, 24 or no definition for severe disease was provided. 2 Several points further indicate the notion that disease activity in our patients was comparable to most of the studies above.…”

“…6,7 Furthermore, tacrolimus is very effective in refractory organ rejection under CyA. 6 Uncontrolled studies have shown that tacrolimus can induce remission in adults 8 and in children 9 with steroid refractory UC as well as in patients with Crohn's colitis and intestinal fistulae. 10,11 Nevertheless, the published experience on the efficacy of tacrolimus in UC is scarce.…”

Efficacy of Tacrolimus for Induction of Remission in Patients With Moderate-to-Severe Ulcerative Colitis: A Systematic Review and Meta-Analysis

“…Figure 1 shows the flow diagram which describes the reasons for citations exclusion. Finally, 22 studies (4)(5)(6)(9)(10)(11)(12)(13)(14)(15)(16)(17)(20)(21)(22)(23)(24)(25)28,30,32,33) that fulfilled eligibility criteria were included. Only two studies were randomized controlled trials (24,25) (Ogata 2006 and Ogata 2012); these were included for meta-analysis.…”

“…It is worth mentioning, according to what is observed from uncontrolled studies, the relatively high proportion of patients who would eventually require colectomy in spite of receiving tacrolimus (4,5,10,13,28,32) (Fellermann 2002, Hogenauer 2003, Baumgart 2006, Benson 2007, Yamamoto 2008, Schmidt 2013. As a consequence, it would seem like tacrolimus could delay the need for colectomy in a selected group of patients -those moderate-to-severe UC patients with prior failure to other therapeutic alternatives.…”