Combination therapy with oral tacrolimus (FK506) and azathioprine or 6-mercaptopurine for treatment-refractory Crohn's disease perianal fistulae

Abstract

Summary:Our aim was to report the clinical experience with combination treatment using tacrolimus and either azathioprine (AZA) or 6-mercaptopurine (6MP) in patients with Crohn's disease (CD) perianal fistulae. The medical records of all patients with Crohn's disease perianal fistulae seen at the Mayo Clinic from 1996-1998 who were treated with tacrolimus were reviewed. Clinical response was classified as: complete response, partial response, and nonresponse. Eleven patients were treated with oral tacrolimus for a mean duration of 22 weeks. The initial oral dose of tacrolimus ranged from 0.15 to 0.31 mg/kg/day. Azathioprine or 6MP was continued in combination with tacrolimus in seven patients and initiated simultaneously with tacrolimus in four patients. All patients improved clinically, seven had a complete response, and four had a partial response. The mean time to initial improvement was 2.4 weeks, and the mean time to complete response was 12.2 weeks. The most frequent adverse events were nausea, paresthesias, nephrotoxicity, and tremor. Patients with nephrotoxicity had a significantly higher mean initial tacrolimus dose (0.3 1 mg/kg/day) compared with patients who did not have nephrotoxicity (0.25 mgkg/day) (p = 0.035); however, there was not a statistically significant association between the starting dose or mean blood level and clinical response. Combination therapy with oral tacrolimus and AZA or 6MP may be effective treatment for CD perianal fistulae. Higher initial tacrolimus doses increase the risk of nephrotoxicity without improving clinical response.

Medium-term results of oral tacrolimus treatment in refractory inflammatory bowel disease

“…Lowry et al 24 observed a benefit of a combination therapy with tacrolimus and purine analogs in perianal fistulizing CD. Sixty-four percent of their patients had complete fistula closure within 3 months, while the remaining patients experienced a partial response.…”

Topical tacrolimus in the treatment of perianal Crohnʼs disease

“…29,30 Case reports and uncontrolled trials [31][32][33] have suggested benefit of oral and intravenous tacrolimus in IBD, as well as in inflammatory skin conditions such as pyoderma gangrenosum. 34 -36 Fistulizing disease has also been reported to respond favorably to systemic tacrolimus in case reports 37,38 and in retrospective 39 and uncontrolled prospective trials. 33 A recent placebo-controlled trial showed more than 50% reduction in fistula drainage in 43% of tacrolimus-treated patients, compared with 8% for placebo-treated patients, but the trial did not demonstrate an effect on remission.…”

Review article: practical management of inflammatory bowel disease patients taking immunomodulators

“…127 Given its efficacy in transplant rejection and reliable oral absorption, clinical trials in Crohn's disease and UC have been performed. There has been one placebo-controlled trial showing efficacy of tacrolimus improving perianal fistulas in patients with Crohn's disease, 128 and small open-label experiences showing benefit in active lumenal 129,130 and fistulizing…”