Successful Topical Tacrolimus (FK506) Therapy in a Child With Pyoderma Gangrenosum

Abstract

The inflammatory skin disease pyoderma gangrenosum is characterized by destructive ulceration, typically occurring on the calves and thighs and less commonly on the buttocks and face. Lesions vary in size and may be multiple, often rapidly ulcerating to form deep painful wounds. Ulcers characteristically have ragged purple edges that overhang. In many patients a concomitant condition can be identified such as inflammatory bowel disease, rheumatoid arthritis, chronic autoimmune hepatitis, and various hematologic and solid tumours (1,2). Treatment of these ulcers in the past has been disappointing. The large lesions usually run a chronic course and heal very slowly, with traditional dressings often in combination with systemic steroids or immunosuppressants. Since 1998, a small number of case have been reported of adults with pyoderma gangrenosum whose lesions heal with the use of topical tacrolimus (FK506) (2–4). We report, to the best of our knowledge, the first successful treatment of a child with pyoderma gangrenosum using topical tacrolimus. CASE REPORT A 14-year old boy with an 11-year history of ulcerative colitis was admitted with an acute exacerbation of colitis, arthralgia, weight loss, and an evolving 3-cm ulcerated area on the right calf, consistent with a diagnosis of pyoderma gangrenosum. He was initially treated with intravenous hydrocortisone (100 mg every 8 hours) and topical silver sulfadiazine with 0.2% chlorhexidine cream to his ulcer. His colitis rapidly resolved, and after 2 days therapy was changed to oral prednisolone (40 mg/day). Despite daily dressings, the ulcer continued to increase in size, achieving a maximum diameter of 5 cm at 3 days (Fig. 1). At this stage, treatment with topical tacrolimus (0.3% ointment in paraffin) was begun as a twice-daily application. Twenty-four hours after the first application, the ulcer improved dramatically. At 96 hours, the topical tacrolimus was discontinued because the ulcer was obviously healing well and serum concentrations of tacrolimus showed significant absorption at 3.1 μg/L. Treatment continued with twice daily dressings of paraffin tulle (with 0.5% chlorhexidine acetate) and decreasing doses of oral steroids. On review at 3 weeks, the ulcer had almost healed (Fig. 2), and it had totally healed by 5 weeks.FIG. 1.: Five-centimeter ulcer on calf before starting treatment with topical tacrolimus.FIG. 2.: Three weeks after beginning topical tacrolimus therapy, the ulcer has almost healed.DISCUSSION Historically, therapies for pyoderma gangrenosum have had unsatisfactory results. However, some limited success has been achieved with systemic steroids and the immunosuppressant agents cyclosporine and tacrolimus (3). Other therapies that show some potential include intralesional injections of steroids and cyclosporine. Most authors agree that optimal ulcer care is vital for healing and the prevention of secondary infection (1). Severe side effects have limited the use of systemic steroids and immunosuppressants. Consequently, topical preparations of tacrolimus have been investigated as a possible alternative with some reports of success. Three published reports of a total of 4 patients with pyoderma gangrenosum in whom conventional treatment had failed comment on the efficacy of topical tacrolimus. Reich et al. (2) described two patients. The first was a 48-year-old man with recurrent pyoderma gangrenosum who had previously been slow to heal. Monotherapy of 0.1% tacrolimus ointment applied twice daily caused resolution in 3 weeks. The second patient, a 27-year-old woman with ulcerative colitis had multiple areas of pyoderma gangrenosum. One ulcer was treated with 0.1% tacrolimus ointment, whereas the others were treated with hydrocolloid dressings only. The additional use of tacrolimus ointment produced a more rapid resolution of the ulcer. Concurrent medication included cyclosporine, 5-aminosalicylic acid, and budesonide. Schuppe et al. (3) described a 32-year-old woman with a 10-cm lesion on her right calf. This was initially treated with oral prednisolone, but showed no signs of healing until daily application of topical tacrolimus (0.5%) was begun. The ulcer resolved completely after 12 weeks of treatment. Jolles et al. (4) reported successfully treating a 30-year-old woman who had a 2-year history of severe pyoderma gangrenosum with a combination of oral tacrolimus and topical tacrolimus (0.1%). Healing occurred after 3 months of treatment. These case reports document no side effects from the topical tacrolimus other than minor local irritation. However, Schuppe et al. (3) and Reich et al. (2) reported a lack of significant systemic absorption of the drug. Tacrolimus is produced from the fungus Streptomycetes tsukubaensis and has a stronger immunosuppressive effect than cyclosporine, being 10 to 100 times more potent. Most intensely studied in the prevention of allograft rejection, tacrolimus exerts its immunosuppressive effect by complexing with an intracellular FK-binding protein that inhibits calcineurin. Calcineurin is essential for the transcription of interleukin 2 (IL-2), and tacrolimus inhibits IL-2 production. The absence of IL-2 prevents activation and proliferation of T lymphocytes (5,6). Adverse effects of systemic tacrolimus therapy are similar to those of cyclosporine and include headache, diarrhea, hypertension, and nephrotoxicity (5,7). Topical administration theoretically minimizes the incidence of such adverse effects while delivering therapeutic concentrations of the drug to the affected skin. Although topical cyclosporine is largely ineffective, topical tacrolimus has shown promising results in a number of dermatologic conditions (6). Topical tacrolimus is increasingly used to treat dermatologic diseases such as atopic dermatitis, lichen planus, and psoriasis (6). In general, very few reports document significant systemic absorption of topically applied tacrolimus in any of the patients described. Most investigation in this area concerns the treatment of atopic dermatitis, and studies have shown that some systemic absorption occurs in most patients, but this is significant in only a minority (7–11). In a study that evaluated treatment of lichen planus, only one patient of six had detectable serum concentrations of tacrolimus, with concentrations measuring between 9 μg/L and 15 μg/L on three separate occasions (12). Recent case reports have also described the use of topical tacrolimus to treat oral and perineal Crohn disease. Seven of eight patients responded well to the treatment, and all patients had undetectable blood concentrations of tacrolimus (13). On reviewing the literature, and our own patient's significant systemic absorption after only 4 days of treatment (a level considered therapeutic for liver transplantation), we recommend that all patients who receive topical tacrolimus should have serum concentrations measured at regular intervals. We used a 0.3% concentration of tacrolimus. A lesser concentration may have been sufficient with less systemic absorption. In the patient presented in this report, topical tacrolimus was used early in the acute phase of the disease. A rapid response was seen and total reepithelialization occurred by 5 weeks. We suggest that topical tacrolimus may work best if used in the early acute phase of the disease, rather than using it only in chronic disease when other treatments have failed. In summary, this case report supports the use of topical tacrolimus to treat pyoderma gangrenosum and is the first to report success in a child. Because of the small number of case reports to date, further studies are necessary to evaluate the efficacy of topical tacrolimus in pyoderma gangrenosum. However, it is clear that if topical tacrolimus is used, serum concentrations must be measured.