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Neurotoxicity in the setting of pediatric atopic dermatitis treated with modified cyclosporine and itraconazole
J AM ACAD DERMATOL VOLUME 69, NUMBER 4
Letters e177
Fig 1. Primary cutaneous follicular lymphoma. A, Papules located on the scalp in 2007. B, In 2012, the patient was free of lesions at all previously affected sites, including the back, after each course of acitretin.
Funding sources: None. Conflicts of interest: None declared. Correspondence to: Laurent Machet, MD, PhD, Service de Dermatologie, CHU de Tours, F-37044 Tours cedex 01, France E-mail: [email protected] REFERENCES 1. Morales AV, Advani R, Horwitz SM, Riaz N, Reddy S, Hoppe RT, et al. Indolent primary cutaneous B-cell lymphoma: experience using systemic rituximab. J Am Acad Dermatol 2008;59:953-7. 2. Senff NJ, Noordijk EM, Kim YH, Bagot M, Berti E, Cerroni L, et al. Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas. Blood 2008;112:1600-9. 3. Cheeley J, Sahn RE, Delong LK, Parker SR. Acitretin for the treatment of cutaneous T-cell lymphoma. J Am Acad Dermatol 2013;68:247-54. 4. Knol AC, Qu ereux G, Brocard A, Ballanger F, Khammari A, Nguyen JM, et al. About the cutaneous targets of bexarotene in CTCL patients. Exp Dermatol 2010;19:e299-301. 5. Barna G, Sebestyen A, Weischede S, Petak I, Mihalik R, Formelli F, et al. Different ways to induce apoptosis by fenretinide and all-trans-retinoic acid in human B lymphoma cells. Anticancer Res 2005;25:4179-85. http://dx.doi.org/10.1016/j.jaad.2013.04.006
Neurotoxicity in the setting of pediatric atopic dermatitis treated with modified cyclosporine and itraconazole To the Editor: A 14-year-old boy with recalcitrant atopic dermatitis was prescribed modified cyclosporine at 5 mg/kg/d (100 mg by mouth twice
daily) with minimal clinical improvement. He had persistently subtherapeutic cyclosporine trough levels, and particularly severe involvement of the head and neck. Treatment with itraconazole at 100 mg by mouth daily was initiated, both for possible Malassezia overgrowth and to concurrently increase cyclosporine levels via the cyclosporineitraconazole CYP3A4 interaction. The cyclosporine trough levels increased and his dermatitis rapidly improved. Six months after originally starting cyclosporine therapy and 2 months after adding itraconazole, he developed increasing anxiety, and difficulties with memory, learning, sports, and performance of simple daily tasks such as tying his shoes. Standardized scores on the Illinois Standard Achievement Test from 7th grade to the 8th grade dropped from the 70th to the 13th percentile. Cyclosporine trough levels remained within the desired range and his dermatitis in excellent control. Electroencephalography and comprehensive neurologic evaluation produced unrevealing findings. Neuropsychiatric testing demonstrated a spatial intelligence quotient defect with disabilities in written expression. Because of the possible relationship of his symptoms to administration of cyclosporine or the cyclosporine-itraconazole combination, both medications were discontinued. Within weeks, the cognitive issues markedly improved. Subsequent neuropsychiatric testing produced entirely normal results, and he regained his original academic performance. He was able to perform tasks as before, and was selected as a freshman for the junior varsity lacrosse team.
e178 Letters
Although not previously described with administration for atopic dermatitis, cyclosporine neurotoxicity is reported in 10% to 28% of patients with transplantation. It commonly manifests as posterior reversible encephalopathy syndrome, which is characterized by hypertension, headache, vomiting, confusion, seizures, visual abnormalities, and occasionally motor abnormalities.1 Our patient demonstrated cognitive decline in the absence of hypertension or the localizing neurologic signs of posterior reversible encephalopathy syndrome. Isolated neuropsychiatric side effects associated with cyclosporine use in the transplantation population include confusion (29%), disorientation (6%), and irritability (2%), along with anxiety, amnesia, decreased responsiveness, and altered mental function.1-3 Calcineurin inhibition is thought to alter sympathetic outflow and vasodilation causing ischemia and generation of reactive oxidative species.4 Neurotoxicity has been reported when blood levels are therapeutic, as in our patient, and even subtherapeutic.1,2 The untoward cognitive effects experienced in this boy were temporally related to the concurrent administration of cyclosporine and itraconazole. Although neurotoxicity is described with itraconazole alone and reports of cyclosporine neurotoxicity in patients with transplantation do not examine concurrent azole administration, azole medications have been shown to potentiate the neurotoxicity of vinca alkaloids, presumably through their shared metabolism by cytochrome P450.5 The occurrence of cyclosporine-induced neurotoxicity in an otherwise healthy boy with atopic dermatitis further implicates cyclosporine as causative of neurotoxicity in patients with transplantation. Although cyclosporine levels were maintained in the therapeutic range, the coadministration of itraconazole and cyclosporine could have contributed to the observed toxicity. Neuropsychiatric adverse effects should be recognized as a potential risk of cyclosporine, or the combination of subtherapeutic cyclosporine doses and itraconazole, in the treatment of immunemediated skin disorders. Stephanie L. Bayers, BSBA, Lisa Arkin, MD, Benjamin Bohaty, MD, and Amy S. Paller, MS, MD Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois Funding sources: None. Conflicts of interest: None declared.
J AM ACAD DERMATOL
OCTOBER 2013
Correspondence to: Amy S. Paller, MS, MD, Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N St Clair St, Suite 1600, Chicago, IL 60611-2941 E-mail: [email protected] REFERENCES 1. Iyer RS, Chaturvedi A, Pruthi S, Khanna PC, Ishak GE. Medication neurotoxicity in children. Pediatr Radiol 2011;41:1455-64. 2. Gijtenbeek JM, van den Bent MJ, Vecht CJ. Cyclosporine neurotoxicity: a review. J Neurol 1999;246:339-46. 3. Wijdicks EF. Neurotoxicity of immunosuppressive drugs. Liver Transpl 2001;7:937-42. 4. Dohgu S, Sumi N, Nishioku T, Takata F, Watanabe T, Naito M, et al. Cyclosporin A induces hyperpermeability of the blood-brain barrier by inhibiting autocrine adrenomedullinmediated up-regulation of endothelial barrier function. Eur J Pharmacol 2010;644:5-9. 5. Moriyama B, Henning SA, Leung J, Falade-Nwulia O, Jarosinski P, Penzak SR, et al. Adverse interactions between antifungal azoles and vincristine: review and analysis of cases. Mycoses 2012;55:290-7.
http://dx.doi.org/10.1016/j.jaad.2013.03.041
Eruptive squamous cell carcinoma in a patient receiving abatacept for rheumatoid arthritis To the Editor: Squamous cell carcinomas (SCCs) are common cutaneous malignancies, often arising from precursor lesions known as actinic keratoses (AKs), and most develop in the setting of chronic exposure to ultraviolet radiation. Rheumatoid arthritis (RA) is an independent risk factor for nonmelanoma skin cancer (NMSC),1 a risk heightened by the use of immunosuppressive medications.2 We present a case of eruptive SCC and AKs in a patient with RA, after initiation of abatacept. A 45-year-old woman with a history of AKs and RA was referred to the dermatology department for multiple erythematous, hyperkeratotic papules and plaques on her face, chest, arms, forearms, and legs, predominantly in a sun-exposed distribution. She had previously been treated with hydroxychloroquine, methotrexate, etanercept, and adalimumab, and in the previous year with leflunomide, prednisone (5-10 mg daily), and infliximab, but never cyclophosphamide or cyclosporine. She had been started on abatacept (500 mg intravenously every 4 weeks) 3 months before presentation. Biopsy specimens obtained at the initial visit revealed 1 SCC in situ and 1 hypertrophic AK. Over the next 3 years, she was treated with surgical excision, topical 5-fluorouracil, and liquid nitrogen cryotherapy for 6 additional SCCs and [100 new AKs, at a rate of approximately 2 SCCs
Letters e177
Fig 1. Primary cutaneous follicular lymphoma. A, Papules located on the scalp in 2007. B, In 2012, the patient was free of lesions at all previously affected sites, including the back, after each course of acitretin.
Funding sources: None. Conflicts of interest: None declared. Correspondence to: Laurent Machet, MD, PhD, Service de Dermatologie, CHU de Tours, F-37044 Tours cedex 01, France E-mail: [email protected] REFERENCES 1. Morales AV, Advani R, Horwitz SM, Riaz N, Reddy S, Hoppe RT, et al. Indolent primary cutaneous B-cell lymphoma: experience using systemic rituximab. J Am Acad Dermatol 2008;59:953-7. 2. Senff NJ, Noordijk EM, Kim YH, Bagot M, Berti E, Cerroni L, et al. Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas. Blood 2008;112:1600-9. 3. Cheeley J, Sahn RE, Delong LK, Parker SR. Acitretin for the treatment of cutaneous T-cell lymphoma. J Am Acad Dermatol 2013;68:247-54. 4. Knol AC, Qu ereux G, Brocard A, Ballanger F, Khammari A, Nguyen JM, et al. About the cutaneous targets of bexarotene in CTCL patients. Exp Dermatol 2010;19:e299-301. 5. Barna G, Sebestyen A, Weischede S, Petak I, Mihalik R, Formelli F, et al. Different ways to induce apoptosis by fenretinide and all-trans-retinoic acid in human B lymphoma cells. Anticancer Res 2005;25:4179-85. http://dx.doi.org/10.1016/j.jaad.2013.04.006
Neurotoxicity in the setting of pediatric atopic dermatitis treated with modified cyclosporine and itraconazole To the Editor: A 14-year-old boy with recalcitrant atopic dermatitis was prescribed modified cyclosporine at 5 mg/kg/d (100 mg by mouth twice
daily) with minimal clinical improvement. He had persistently subtherapeutic cyclosporine trough levels, and particularly severe involvement of the head and neck. Treatment with itraconazole at 100 mg by mouth daily was initiated, both for possible Malassezia overgrowth and to concurrently increase cyclosporine levels via the cyclosporineitraconazole CYP3A4 interaction. The cyclosporine trough levels increased and his dermatitis rapidly improved. Six months after originally starting cyclosporine therapy and 2 months after adding itraconazole, he developed increasing anxiety, and difficulties with memory, learning, sports, and performance of simple daily tasks such as tying his shoes. Standardized scores on the Illinois Standard Achievement Test from 7th grade to the 8th grade dropped from the 70th to the 13th percentile. Cyclosporine trough levels remained within the desired range and his dermatitis in excellent control. Electroencephalography and comprehensive neurologic evaluation produced unrevealing findings. Neuropsychiatric testing demonstrated a spatial intelligence quotient defect with disabilities in written expression. Because of the possible relationship of his symptoms to administration of cyclosporine or the cyclosporine-itraconazole combination, both medications were discontinued. Within weeks, the cognitive issues markedly improved. Subsequent neuropsychiatric testing produced entirely normal results, and he regained his original academic performance. He was able to perform tasks as before, and was selected as a freshman for the junior varsity lacrosse team.
e178 Letters
Although not previously described with administration for atopic dermatitis, cyclosporine neurotoxicity is reported in 10% to 28% of patients with transplantation. It commonly manifests as posterior reversible encephalopathy syndrome, which is characterized by hypertension, headache, vomiting, confusion, seizures, visual abnormalities, and occasionally motor abnormalities.1 Our patient demonstrated cognitive decline in the absence of hypertension or the localizing neurologic signs of posterior reversible encephalopathy syndrome. Isolated neuropsychiatric side effects associated with cyclosporine use in the transplantation population include confusion (29%), disorientation (6%), and irritability (2%), along with anxiety, amnesia, decreased responsiveness, and altered mental function.1-3 Calcineurin inhibition is thought to alter sympathetic outflow and vasodilation causing ischemia and generation of reactive oxidative species.4 Neurotoxicity has been reported when blood levels are therapeutic, as in our patient, and even subtherapeutic.1,2 The untoward cognitive effects experienced in this boy were temporally related to the concurrent administration of cyclosporine and itraconazole. Although neurotoxicity is described with itraconazole alone and reports of cyclosporine neurotoxicity in patients with transplantation do not examine concurrent azole administration, azole medications have been shown to potentiate the neurotoxicity of vinca alkaloids, presumably through their shared metabolism by cytochrome P450.5 The occurrence of cyclosporine-induced neurotoxicity in an otherwise healthy boy with atopic dermatitis further implicates cyclosporine as causative of neurotoxicity in patients with transplantation. Although cyclosporine levels were maintained in the therapeutic range, the coadministration of itraconazole and cyclosporine could have contributed to the observed toxicity. Neuropsychiatric adverse effects should be recognized as a potential risk of cyclosporine, or the combination of subtherapeutic cyclosporine doses and itraconazole, in the treatment of immunemediated skin disorders. Stephanie L. Bayers, BSBA, Lisa Arkin, MD, Benjamin Bohaty, MD, and Amy S. Paller, MS, MD Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois Funding sources: None. Conflicts of interest: None declared.
J AM ACAD DERMATOL
OCTOBER 2013
Correspondence to: Amy S. Paller, MS, MD, Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N St Clair St, Suite 1600, Chicago, IL 60611-2941 E-mail: [email protected] REFERENCES 1. Iyer RS, Chaturvedi A, Pruthi S, Khanna PC, Ishak GE. Medication neurotoxicity in children. Pediatr Radiol 2011;41:1455-64. 2. Gijtenbeek JM, van den Bent MJ, Vecht CJ. Cyclosporine neurotoxicity: a review. J Neurol 1999;246:339-46. 3. Wijdicks EF. Neurotoxicity of immunosuppressive drugs. Liver Transpl 2001;7:937-42. 4. Dohgu S, Sumi N, Nishioku T, Takata F, Watanabe T, Naito M, et al. Cyclosporin A induces hyperpermeability of the blood-brain barrier by inhibiting autocrine adrenomedullinmediated up-regulation of endothelial barrier function. Eur J Pharmacol 2010;644:5-9. 5. Moriyama B, Henning SA, Leung J, Falade-Nwulia O, Jarosinski P, Penzak SR, et al. Adverse interactions between antifungal azoles and vincristine: review and analysis of cases. Mycoses 2012;55:290-7.
http://dx.doi.org/10.1016/j.jaad.2013.03.041
Eruptive squamous cell carcinoma in a patient receiving abatacept for rheumatoid arthritis To the Editor: Squamous cell carcinomas (SCCs) are common cutaneous malignancies, often arising from precursor lesions known as actinic keratoses (AKs), and most develop in the setting of chronic exposure to ultraviolet radiation. Rheumatoid arthritis (RA) is an independent risk factor for nonmelanoma skin cancer (NMSC),1 a risk heightened by the use of immunosuppressive medications.2 We present a case of eruptive SCC and AKs in a patient with RA, after initiation of abatacept. A 45-year-old woman with a history of AKs and RA was referred to the dermatology department for multiple erythematous, hyperkeratotic papules and plaques on her face, chest, arms, forearms, and legs, predominantly in a sun-exposed distribution. She had previously been treated with hydroxychloroquine, methotrexate, etanercept, and adalimumab, and in the previous year with leflunomide, prednisone (5-10 mg daily), and infliximab, but never cyclophosphamide or cyclosporine. She had been started on abatacept (500 mg intravenously every 4 weeks) 3 months before presentation. Biopsy specimens obtained at the initial visit revealed 1 SCC in situ and 1 hypertrophic AK. Over the next 3 years, she was treated with surgical excision, topical 5-fluorouracil, and liquid nitrogen cryotherapy for 6 additional SCCs and [100 new AKs, at a rate of approximately 2 SCCs