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Keywords:

  • Aphthous ulceration;
  • immunosuppressive therapy;
  • Rapamycin;
  • renal transplant;
  • side effect;
  • sirolimus;
  • skin

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

Aphthous ulceration is a common side effect of sirolimus. These lesions of the oral mucous membranes are often painful and debilitating, leading to either dose reduction or discontinuation of sirolimus in a significant number of patients. We report that the direct application of clobetasol, a high potency topical steroid, led to prompt resolution of the aphthous ulcers that developed in our renal transplant patients on sir-olimus-based immunosuppression.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

Sirolimus (Rapamycin, Rapamune®; Wyeth, Madison, NJ), a macrolide antibiotic originally isolated from the actinomycete bacteria Streptomyces hygroscopicus, is a novel immunosuppressant that has been approved for the prevention of acute rejection in renal transplantation (1). Similar to the calcineurin inhibitor tacrolimus (Prograf, Astellus, Japan), sirolimus also binds to FKBP12 immunophilin, but in contrast does not block the calcineurin enzyme pathway. After combining with FKBP12, sirolimus binds to the target of Rapamycin (TOR) protein, leading to the inhibition of cytokine-driven cellular proliferation. One potential advantage of sirolimus is that this drug alone is not known to be nephrotoxic and may potentially prolong renal allograft survival when used in lieu of calcineurin inhibitors (2).

Although sirolimus may not directly injure the kidney, sirolimus has a number of clinically significant side effects including bone marrow suppression, impaired wound healing, hyperlipidemia and interstitial pneumonitis (2–6). In addition, several dermatologic manifestations have been attributed to sirolimus such as acne, edema, vasculitis and aphthous ulceration (7–10). Aphthous ulcers have been observed in several clinical trials with an occurrence rate of up to 60% (7,8,10). This side effect has led to either dose reduction or discontinuation of sirolimus in a significant number of patients.

Antiviral agents and topical anesthetics have been used alone or in combination in an attempt to treat sirolimus derived aphthous ulcers, but have been largely ineffective (9). Our own experience with using systemic or topical antivirals and ‘Miracle Mouthwash’, a combination of lidocaine, diphenhydramine and an antacid, was largely ineffective in altering the overall duration and severity of these lesions, which persist on average between 10–14 days in our patients before subsiding. Clobetasol, a high potency topical steroid, has been demonstrated to effectively and safely treat aphthous ulcers that form in patients with primary dermatological disorders such as lichen planus and pemphigus (11,12). The aim of this study was to evaluate whether clobetasol would be effective in the treatment of the aphthous ulcers that developed in our renal transplant patients taking sirolimus.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

We identified eight renal transplant patients who developed superficial oral lesions after they were prescribed sirolimus as part of their immunosuppressive regimen. These patients were prescribed clobetasol 0.05% cream to be applied topically twice daily directly to the aphthous ulcer. In addition, two patients with 24-h trough serum concentrations of sirolimus (>11 ng/mL) had dose reductions to achieve a target level of 8–10 ng/mL. The following information was obtained from medical records and personal communication at follow-up clinic visits with the patients: age at transplantation, gender, race, date of transplantation, cause of end-stage renal disease (ESRD), trough sirolimus levels, date of initiation of sirolimus therapy, date of diagnosis and location of the aphthous ulceration and time to resolution of the aphthous ulcers.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

The clinical description of the renal transplant patients in this study are summarized in Table 1. Three patients were female and five were male. The median and mean patient ages were 41 and 40 years, respectively (range 19–57 years). The cause of ESRD was diabetes in 6 patients and IgA nephropathy and a nonspecific glomerulonephritis, respectively, in the other two patients. Two patients (patients C and F) were started on sirolimus de novo at time of the transplantation, while the other six were switched to sirolimus from either tacrolimus or cyclosporine.

Table 1.  Basic and clinical characteristics of eight patients who developed aphthous ulceration while on sirolimus
Age of patient at time of renal transplantation, race, gender and transplant typeCause of renal failureLength of time on sirolimus therapy prior to ulcer developmentSirolimus trough level at time of aphthous ulcers diagnosis (ng/mL)Location(s) of aphthous ulcersNumber of days to resolution of aphthous ulcers
A 19-year-old white male cadaveric donorIgA nephropathy1 month20.1Oropharnyx3
B 34-year-old white female living donorDiabetes2 weeks4.2Tongue and lip4
C 43-year-old white male living donorDiabetes6 months8.0Buccal mucosa and lips3
D 44-year-old white female cadaveric donorDiabetes9 months10.3Tongue5
E 29-year-old white female living donorDiabetes3 weeks2.0Tongue and oropharnyx3–7
F 52-year-old white female cadaveric donorGlomerulonephritis6 months4.8Tongue and buccal mucsa4
G 39-year-old white male living donorDiabetes20 months11.7Oropharnyx and bucal mucosa3
H 57-year-old white male living donorDiabetes2 weeks5.1Tongue and periodontal mucosa3–4

Aphthous ulcers were found at various locations including the tongue, lips, buccal mucosa, periodontal mucosa and posterior oropharynx with the majority of patients having multiple lesions. The aphthous ulcers in all eight patients were symptomatic, leading to considerable local discomfort and a self-reported decrease in oral intake. At the time of ulcer diagnosis, the median and mean sirolimus trough levels were 6.6 and 8.3 ng/mL, respectively (range 2.0–20.1 ng/mL). All eight patients were on the tablet formulation of sirolimus and in addition to sirolimus were on a maintenance immunosuppression regimen consisting of prednisone 5–10 mg/day and mycophenolate mofetil 500–1000 mg twice daily. No patients were on calcineurin inhibitors at the time of diagnosis of aphthous ulcers.

Clobetasol therapy led to immediate improvement of symptoms in all eight patients, with complete resolution of their oral lesions within 3 to 7 days. Three patients had recurrent aphthous ulcerations after weeks or months of remission which would resolve with additional courses of clobetasol. Treatment with clobetasol was well tolerated and did not lead to the development of any obvious adverse symptoms in our renal transplant patients. No patient discontinued sirolimus during the study with an average follow-up period of 12 months (range 3–24 months).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

Renal transplantation has become the preferred form of renal replacement therapy for patients with ESRD. One-year renal allograft survival has dramatically improved with the introduction of calcineurin inhibitors (CNI) (13). These agents are now routinely used as a component of the immunosuppressive regimen for the majority of patients transplanted in the United States (14). Long-term graft survival (>5 years) has not matched these improvements possibly secondary to adverse effects of CNI which include nephrotoxicity, hypertension, hyperlipidemia and posttransplant diabetes (15). Sirolimus, a target of Rapamycin (TOR) inhibitor, is a relatively new maintenance immunosuppression agent that has been used successfully in combination with and without CNI in kidney transplant recipients (1,2). Indeed sirolimus has been shown to improve long-term allograft outcomes when calcineurin inhibitors were withdrawn possible due to a proposed absence of nephrotoxicity (16).

Unfortunately sirolimus therapy has been associated with several adverse effects of which one of the more commonly reported is aphthous ulcers, with a prevalence rate of up to 60% in two separate studies (8,10). In the study by van Gelder et al., 9 of 15 stable renal transplant patients converted to sirolimus with mycophenolate mofetil developed oral ulceration while none of the 18 patients who remained on tacrolimus with mycophenolate mofetil developed these lesions (8). Superficial oral lesions were also observed in earlier phase II and phase III studies with sirolimus in renal transplant patients, and were initially attributed to herpes simplex virus (HSV) infections (7,17). Whether HSV is the primary cause of oral ulcerations in patients on sirolimus is uncertain and has become a topic of debate, especially since antiviral therapy has not been demonstrated to be effective in healing these lesions (9). Based upon our own experiences with sirolimus, we do not believe HSV infection is a likely cause of these lesions, as the biopsies we performed on our initial patients on sirolimus who developed aphthous ulcers were without evidence of viral cytopathic changes and did not benefit from empiric acyclovir treatment.

At our own transplant center we estimate approximately 10–15% of our renal transplant patients on sirolimus have developed aphtous ulceration, similar to the rates reported in the multicenter phase III study (7). Prior to using sirolimus, the incidence of aphthous ulcers in our renal transplant patients was extremely rare, occurring primarily in patients being treated with high-dose corticosteroids and antithymocyte antibodies for acute rejections. These aphthous ulcers we believe were likely from HSV reactivation as they were associated with peri-oral vesicular lesions and would respond to acyclovir therapy.

Aphthous ulcerations may also be related to the level of sirolimus exposure since these lesions were more prevalent in the higher dose sirolimus arm in the worldwide phase III study (7). Reducing the dose of sirolimus or switching from a liquid formulation to a tablet form has been reported to lead to improvement of oral ulcers, but neither intervention has been shown to be consistently effective (8,18).

Corticosteroids are commonly used to treat recurrent aphthous ulcerations in primary dermatologic lesions, either given systemically or applied topically directly to the lesions (19,20). A benefit of corticosteroids in the treatment of aphthous ulceration that developed secondary to sirolimus therapy has not been previously demonstrated. All the patients in our study were on low-dose oral prednisone between 5 and 10 mg daily. We did not attempt to increase the daily steroid dose to avoid potentially increasing the risk of developing serious long-term side effects of steroids such as weight gain, diabetes and osteoporosis.

Clobetasol, a high potency topical steroid, has been utilized in patients with aphthous ulceration in lichen planus and pemphigus with good response rates (11,12). Several different preparations, including an ointment, analgesic based, adhesive denture paste and an aqueous solution have been studied. Side effects were rarely reported in these studies but included moon faces, hirsuitism and thrush which developed after several weeks of continuous treatment.

In our patients, we prescribed clobetasol in a cream formulation as this was readily available and easily applicable. We discovered that our renal transplant patients on sirolimus who developed aphthous ulceration had immediate improvement in their symptoms with twice daily application of clobetasol 0.05% cream directly applied to the lesions, with complete resolution of their oral lesions within 3–7 days. The use of other clobetasol preparations such as liquid formulations might prove useful in patients with difficult to reach pharyngeal lesions.

Limitations to our study include the small sample size as well as the absence of a formal control population. The physicians and patients were not blinded to the treatment received. In addition, we did not biopsy the ulcers to definitively eliminate a malignant or infectious etiology of the lesions.

In conclusion, we report that aphthous ulceration that developed in our renal transplant patients on sirolimus had an earlier resolution with clobetasol therapy versus our historical experience. Importantly, these patients were maintained in a therapeutic trough range therefore not increasing the risk for acute rejection that empiric dose reduction would create.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References
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