Systemic absorption with complications during topical tacrolimus treatment for orofacial Crohn disease.

Abstract

Tacrolimus (Prograf®, Fujisawa, Japan) is an established oral immunosuppressive treatment used to prevent allograft rejection in solid organ transplantation. Topical tacrolimus has been shown in randomized, controlled trials to be effective in treatment of atopic dermatitis (1). More recently, it also has been described as a useful adjunct for treatment of orofacial or perineal Crohn disease that is unresponsive to more conventional therapy (2). To date, there have been no reports of significant systemic absorption resulting in complications during dermatologic or gastroenterologic practice when using standard dosing regimens. Significant absorption is thought not to occur in practice with levels less than 1 μg/L, although theoretically it can happen at concentrations of 0.5 μg/L (4). We report the first case of significant systemic absorption resulting in complications during topical Tacrolimus therapy. CASE REPORT A 15-year-old girl with long-term Crohn disease (orofacial and ileocolonic) presented with a disease relapse lasting 6 months. The disease especially affected the orofacial region. At the time, her Crohn disease had been treated with budesonide for 6 months, and treatment with azathioprine had been commenced 3 months previously for steroid dependency. She also was receiving treatment with ranitidine, fluoxetine, and an oral iron preparation. She had obsessive-compulsive disorder, which was diagnosed 4 years previously. The maximum dose of budesonide and azathioprine did not attain remission of her disease activity in the perioral region. She was unable to attend school or perform her normal social activities because of teasing and bullying because of her facial appearance. After discussion with the patient and her family and considering her poor quality of life, topical Tacrolimus was prescribed. A preparation was made containing a mixture of Orabase and Tacrolimus with a concentration of 0.05%. The solution was applied liberally twice daily to the affected area around the mouth in a maximum area of 1–2 cm2. This regimen was successful in achieving almost complete resolution of disease activity on the affected site within 3–4 weeks. Five weeks after starting treatment shingles developed on the right thoracolumbar region of her back. A random tacrolimus concentration was checked at this point and was found to be 9 μg/L. A white blood cell count measured at the same time was 4 × 109/L with a neutrophil count of 2.1 × 109/L. She was admitted to the hospital and received a 1-week course of intravenous aciclovir because she was considered to be at a significant risk of disseminated varicella infection. She had a medical history of varicella but not of zoster. She responded well to aciclovir and had no complications. Her dosage of topical Tacrolimus was reduced to a once-a-day application, without change to the strength of the dose. Her dosages of azathioprine and budesonide were not altered. This regimen was not discontinued because sudden withdrawal has been shown to result in rapid relapse (2). She remained clinically well after discharge from the hospital, and the orofacial Crohn disease remained quiescent for the following 18 months. Attempts at dose reduction have failed. Tacrolimus concentrations have been checked regularly, showing a range between undetectable and 2 μg/L. Topical Tacrolimus is a useful treatment for recalcitrant orofacial Crohn disease. However, we report for the first time significant systemic absorption resulting in complications. Although budesonide and azathioprine were prescribed concurrently, and both medications theoretically could be responsible for the development of shingles, we believe that tacrolimus was the most likely cause because it was the newest medication prescribed (within 5 weeks of occurrence of the complication) and because systemic concentrations were reached. Importantly, there was no change in the differential white cell count. The dosage used for this patient was similar to that described in dermatologic practice and in other patients with Crohn disease (2,3). It may be that higher systemic absorption can occur when applied in the perioral region. Particular care must be taken when administering the ointment close to mucosal surfaces. Further studies of weaker solutions and once-daily application in this context are needed. We conclude that all patients undergoing this therapy should undergo regular therapeutic drug monitoring by measurement of serum tacrolimus concentrations on a weekly basis for the first month of treatment and then fortnightly and monthly thereafter or at any time when complications occur. Based on our experience and that represented in previously published materials, topical tacrolimus is a useful treatment for oral Crohn disease (2). However, it should be reserved for patients who are unresponsive to more conventional treatment with steroids and immunosuppressants and in whom the oral disease has a significant effect on quality of life.