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A Reassuring Rejoinder Against Malignant Influences of Topical Calcineurin Use in Children

A Reassuring Rejoinder Against Malignant Influences of Topical Calcineurin Use in Children The topical calcineurin inhibitors tacrolimus and pimecrolimus are useful and effective anti-inflammatory immunomodulator adjuncts in managing atopic dermatitis (AD). Unfortunately, because of the increased risk of lymphoma in transplant recipients receiving systemic tacrolimus and because of malignant neoplasms in animal studies with pimecrolimus, their use as topical agents has raised concerns.1 Yet the topical use of these drugs in humans since the mid-1990s has not appeared to cause any clear immunosuppressive propensity toward malignancy. Topical tacrolimus ointment, 0.03% and 0.1%, became available in late 2000 as short-term therapy for moderate to severe AD in adults and children whose condition had not responded adequately to topical corticosteroid therapy. Pimecrolimus cream, 1%, was approved by the Food and Drug Administration (FDA) in December 2001 for treatment of mild to moderate AD in adults and in children older than 2 years. Both were categorized as second-line agents for intermittent, noncontinuous therapy, and these limitations were cited in an American Academy of Dermatology Consensus Conference in 2003.2 However, the effectiveness and apparent safety after use of these drugs in several thousand children sparked great optimism and even direct-to-consumer advertising in the United States. In response, the Pediatric Advisory Committee of the FDA in early 2005 issued a recommendation for a “black box” warning in the package inserts of the topical calcineurin inhibitors, noting off-label use in younger children and postmarketing reports of malignant neoplasms in adults and children and in a study that showed occurrence of lymphoma in monkeys receiving 30-fold oral dosing of pimecrolimus.3,4 The black box warning stated the following3(p1233): “Long-term Safety of Topical Calcineurin Inhibitors Has Not Been Established” “Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors…” This warning impeded therapy and negatively affected several realms of AD management: The caregivers—pediatricians, family physicians, and nurse practitioners—who provide the front line of therapy for children were discouraged from using this important new therapeutic alternative. Most returned to use of topical corticosteroids and resumed their overly cautious prescribing of inadequate potencies, leaving many children to continue in pruritic distress. Pharmacists also interfered with adequate therapy, warning patients against topical corticosteroid use but also frightening them with the specter of calcineurin-induced cancer. The third rung in this downward course of eczema care has been the “blogosphere” crying out against “steroid addiction”5 and often suggesting care limited to alternative medicine.6 The study by Margolis and colleagues7 in this issue of JAMA Dermatology will hopefully help to improve the management of AD, countering the concerns raised by FDA warnings. This Pediatric Eczema Elective Registry (PEER) postmarketing study was established in 2004 to provide a 10-year assessment of cancer in children treated with pimecrolimus. They report 5 malignant neoplasms among 7457 children (26 792 person-years), which, when compared with the standardized rates in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program, indicates that cancer is an unlikely risk from use of pimecrolimus cream. Atopic dermatitis is a common disease, affecting from 6% to 20% of children,8,9 and imposes a heavy burden on medical care.10 Progress in therapy of AD has been slow for many decades, in large part because of concerns about adverse effects of new drugs in the predominantly young population affected. The hesitancy of the FDA is naturally transmitted to pharmaceutical developers, who see potential obstacles to approval and unrestricted use in the largest segment of the patient population with AD. Concern about possibly important immunosuppressive effects from use of topical calcineurin inhibitors in children has slowed progress for another decade. Although the study has so far evaluated risk in only approximately 27 000 of the total projected 40 000 person-years, it is reassuring that the occurrence of lymphoma and/or leukemia is no more frequent than in the general population. In addition, the skin application sites do not appear to be at higher risk for melanoma or keratinocytic neoplasms, although risk of the latter is presumed to be low in children. The positive and optimistic report of pimecrolimus postmarketing surveillance by Margolis et al7 should help reduce the physician and pharmacist concerns that have restricted the use of these effective topical alternatives to corticosteroids. The interim results should help bring relief to a larger segment of the many young individuals with AD. Back to top Article Information Corresponding Author: Jon M. Hanifin, MD, Department of Dermatology, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR 97239-4501 (hanifinj@ohsu.edu). Published Online: February 18, 2015. doi:10.1001/jamadermatol.2014.4306. Conflict of Interest Disclosures: None reported. References 1. Ring J, Möhrenschlager M, Henkel V. The US FDA ‘black box’ warning for topical calcineurin inhibitors: an ongoing controversy. Drug Saf. 2008;31(3):185-198.PubMedGoogle ScholarCrossref 2. Eichenfield LF, Hanifin JM, Luger TA, Stevens SR, Pride HB. Consensus conference on pediatric atopic dermatitis. J Am Acad Dermatol. 2003;49(6):1088-1095.PubMedGoogle ScholarCrossref 3. Stern RS. Topical calcineurin inhibitors labeling: putting the "box" in perspective. Arch Dermatol. 2006;142(9):1233-1235.Google Scholar 4. Food and Drug Administration. Pediatrics Advisory Committee Sixth Meeting. Rockville, MD: Food and Drug Administration; February 15, 2005. http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4089T2.pdf. Accessed January 20, 2015. 5. Rapaport MJ, Lebwohl M. Corticosteroid addiction and withdrawal in the atopic: the red burning skin syndrome. Clin Dermatol. 2003;21(3):201-214.PubMedGoogle ScholarCrossref 6. Hajar T, Leshem YA, Hanifin JM, et al. A systematic review of topical steroid withdrawal (“steroid addiction”) in patients with atopic dermatitis and other dermatoses [published online ahead of print January 12, 2015]. J Am Acad Dermatol. doi:10.1016/j.jaad.2014.11.024.Google Scholar 7. Margolis DJ, Abuabara K, Hoffstad OJ, Wan J, Raimondo D, Bilker WB. Association between malignancy and topical use of pimecrolimus [published online February 18, 2015]. JAMA Dermatol. doi:10.1001/jamadermatol.2014.4305.Google Scholar 8. Hanifin JM, Reed ML; Eczema Prevalence and Impact Working Group. A population-based survey of eczema prevalence in the United States. Dermatitis. 2007;18(2):82-91.PubMedGoogle ScholarCrossref 9. Silverberg JI, Hanifin J, Simpson EL. Climatic factors are associated with childhood eczema prevalence in the United States. J Invest Dermatol. 2013;133(7):1752-1759.PubMedGoogle ScholarCrossref 10. Hay RJ, Johns NE, Williams HC, et al. The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions. J Invest Dermatol. 2014;134(6):1527-1534.PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Dermatology American Medical Association

A Reassuring Rejoinder Against Malignant Influences of Topical Calcineurin Use in Children

JAMA Dermatology , Volume 151 (6) – Jun 1, 2015

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Publisher
American Medical Association
Copyright
Copyright © 2015 American Medical Association. All Rights Reserved.
ISSN
2168-6068
eISSN
2168-6084
DOI
10.1001/jamadermatol.2014.4306
pmid
25692944
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Abstract

The topical calcineurin inhibitors tacrolimus and pimecrolimus are useful and effective anti-inflammatory immunomodulator adjuncts in managing atopic dermatitis (AD). Unfortunately, because of the increased risk of lymphoma in transplant recipients receiving systemic tacrolimus and because of malignant neoplasms in animal studies with pimecrolimus, their use as topical agents has raised concerns.1 Yet the topical use of these drugs in humans since the mid-1990s has not appeared to cause any clear immunosuppressive propensity toward malignancy. Topical tacrolimus ointment, 0.03% and 0.1%, became available in late 2000 as short-term therapy for moderate to severe AD in adults and children whose condition had not responded adequately to topical corticosteroid therapy. Pimecrolimus cream, 1%, was approved by the Food and Drug Administration (FDA) in December 2001 for treatment of mild to moderate AD in adults and in children older than 2 years. Both were categorized as second-line agents for intermittent, noncontinuous therapy, and these limitations were cited in an American Academy of Dermatology Consensus Conference in 2003.2 However, the effectiveness and apparent safety after use of these drugs in several thousand children sparked great optimism and even direct-to-consumer advertising in the United States. In response, the Pediatric Advisory Committee of the FDA in early 2005 issued a recommendation for a “black box” warning in the package inserts of the topical calcineurin inhibitors, noting off-label use in younger children and postmarketing reports of malignant neoplasms in adults and children and in a study that showed occurrence of lymphoma in monkeys receiving 30-fold oral dosing of pimecrolimus.3,4 The black box warning stated the following3(p1233): “Long-term Safety of Topical Calcineurin Inhibitors Has Not Been Established” “Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors…” This warning impeded therapy and negatively affected several realms of AD management: The caregivers—pediatricians, family physicians, and nurse practitioners—who provide the front line of therapy for children were discouraged from using this important new therapeutic alternative. Most returned to use of topical corticosteroids and resumed their overly cautious prescribing of inadequate potencies, leaving many children to continue in pruritic distress. Pharmacists also interfered with adequate therapy, warning patients against topical corticosteroid use but also frightening them with the specter of calcineurin-induced cancer. The third rung in this downward course of eczema care has been the “blogosphere” crying out against “steroid addiction”5 and often suggesting care limited to alternative medicine.6 The study by Margolis and colleagues7 in this issue of JAMA Dermatology will hopefully help to improve the management of AD, countering the concerns raised by FDA warnings. This Pediatric Eczema Elective Registry (PEER) postmarketing study was established in 2004 to provide a 10-year assessment of cancer in children treated with pimecrolimus. They report 5 malignant neoplasms among 7457 children (26 792 person-years), which, when compared with the standardized rates in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program, indicates that cancer is an unlikely risk from use of pimecrolimus cream. Atopic dermatitis is a common disease, affecting from 6% to 20% of children,8,9 and imposes a heavy burden on medical care.10 Progress in therapy of AD has been slow for many decades, in large part because of concerns about adverse effects of new drugs in the predominantly young population affected. The hesitancy of the FDA is naturally transmitted to pharmaceutical developers, who see potential obstacles to approval and unrestricted use in the largest segment of the patient population with AD. Concern about possibly important immunosuppressive effects from use of topical calcineurin inhibitors in children has slowed progress for another decade. Although the study has so far evaluated risk in only approximately 27 000 of the total projected 40 000 person-years, it is reassuring that the occurrence of lymphoma and/or leukemia is no more frequent than in the general population. In addition, the skin application sites do not appear to be at higher risk for melanoma or keratinocytic neoplasms, although risk of the latter is presumed to be low in children. The positive and optimistic report of pimecrolimus postmarketing surveillance by Margolis et al7 should help reduce the physician and pharmacist concerns that have restricted the use of these effective topical alternatives to corticosteroids. The interim results should help bring relief to a larger segment of the many young individuals with AD. Back to top Article Information Corresponding Author: Jon M. Hanifin, MD, Department of Dermatology, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR 97239-4501 (hanifinj@ohsu.edu). Published Online: February 18, 2015. doi:10.1001/jamadermatol.2014.4306. Conflict of Interest Disclosures: None reported. References 1. Ring J, Möhrenschlager M, Henkel V. The US FDA ‘black box’ warning for topical calcineurin inhibitors: an ongoing controversy. Drug Saf. 2008;31(3):185-198.PubMedGoogle ScholarCrossref 2. Eichenfield LF, Hanifin JM, Luger TA, Stevens SR, Pride HB. Consensus conference on pediatric atopic dermatitis. J Am Acad Dermatol. 2003;49(6):1088-1095.PubMedGoogle ScholarCrossref 3. Stern RS. Topical calcineurin inhibitors labeling: putting the "box" in perspective. Arch Dermatol. 2006;142(9):1233-1235.Google Scholar 4. Food and Drug Administration. Pediatrics Advisory Committee Sixth Meeting. Rockville, MD: Food and Drug Administration; February 15, 2005. http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4089T2.pdf. Accessed January 20, 2015. 5. Rapaport MJ, Lebwohl M. Corticosteroid addiction and withdrawal in the atopic: the red burning skin syndrome. Clin Dermatol. 2003;21(3):201-214.PubMedGoogle ScholarCrossref 6. Hajar T, Leshem YA, Hanifin JM, et al. A systematic review of topical steroid withdrawal (“steroid addiction”) in patients with atopic dermatitis and other dermatoses [published online ahead of print January 12, 2015]. J Am Acad Dermatol. doi:10.1016/j.jaad.2014.11.024.Google Scholar 7. Margolis DJ, Abuabara K, Hoffstad OJ, Wan J, Raimondo D, Bilker WB. Association between malignancy and topical use of pimecrolimus [published online February 18, 2015]. JAMA Dermatol. doi:10.1001/jamadermatol.2014.4305.Google Scholar 8. Hanifin JM, Reed ML; Eczema Prevalence and Impact Working Group. A population-based survey of eczema prevalence in the United States. Dermatitis. 2007;18(2):82-91.PubMedGoogle ScholarCrossref 9. Silverberg JI, Hanifin J, Simpson EL. Climatic factors are associated with childhood eczema prevalence in the United States. J Invest Dermatol. 2013;133(7):1752-1759.PubMedGoogle ScholarCrossref 10. Hay RJ, Johns NE, Williams HC, et al. The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions. J Invest Dermatol. 2014;134(6):1527-1534.PubMedGoogle ScholarCrossref

Journal

JAMA DermatologyAmerican Medical Association

Published: Jun 1, 2015

References