title: Topical calcineurin inhibitors and lymphoma risk: evidence update with implications for daily practice.
abstract: Topical calcineurin inhibitors (TCIs), commercially available since 2000-2001, are the first and only topical medications approved for chronic treatment of atopic dermatitis (AD) in pediatric patients and remain a welcomed alternative to topical corticosteroids. In January 2006, the US Food and Drug Administration (FDA) issued a boxed warning requirement based on a theoretical risk of malignancy (including lymphoma) with TCI use. However, in the years since, analyses of epidemiologic and clinical data have failed to demonstrate a causal relationship between TCI use and malignancy or lymphoma risk, especially for pimecrolimus cream. In fact, the observed number of malignancies and lymphomas observed both in post-marketing surveillance and reported to the FDA using its adverse events reporting system is much lower among TCI-exposed patients than the expected number for the general population. Furthermore, among children enrolled in post-marketing pediatric registry studies for both tacrolimus and pimecrolimus followed for up to 5.5 years [10,724 patient-years (PY)] or 6.5 years (16,219 PY), respectively, the observed number of malignancies and lymphomas is very low and similar to the number expected for a sample of similar size in the general population. In addition to reporting these comparative malignancy and lymphoma data, this article provides a historical overview of the boxed warning requirement and critically evaluates the preclinical, clinical, and epidemiological evidence that has thus far failed to substantiate a relationship between TCI use and malignancy. The authors also provide practical clinical advice for optimizing AD management and patient care in the context of the boxed warning.
authors.affiliation: Saint Louis University and Cardinal Glennon Children's Hospital, 1465 S Grand Ave., St. Louis, MO 63104, USA. esiegfri@slu.edu
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Siegfried
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Jaworski
authors.forename: Adelaide A
authors.initials: AA
authors.lastname: Hebert
mesh_terms: D000329:Advertising; D000818:Animals; D065095:Calcineurin Inhibitors; D003876:Dermatitis, Atopic / Q000188:drug therapy; D004348:Drug Labeling; D019317:Evidence-Based Medicine; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D008223:Lymphoma / Q000139:chemically induced*; D012307:Risk Factors; D016559:Tacrolimus / Q000009:adverse effects* / Q000031:analogs & derivatives*; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; C117268:pimecrolimus; D016559:Tacrolimus