A safety assessment of topical calcineurin inhibitors in the treatment of atopic dermatitis

Department of Dermatology, The Mount Sinai School of Medicine, New York, NY, USA.
MedGenMed: Medscape general medicine 02/2006; 8(4):8.
Source: PubMed


Atopic dermatitis (AD) is a common childhood disease that can disrupt the lives of patients and their families and, in turn, affect their quality of life. The goal of treatment is the long-term control of AD by minimizing the frequency and severity of flares. Topical corticosteroids of various potencies have been the mainstay of pharmacologic treatment of AD flares. In the past few years, the introduction of topical calcineurin inhibitors (TCIs) has provided physicians with an effective, well-tolerated alternative to topical corticosteroids. In January 2006, a boxed warning and a patient medication guide were added to TCI product labels in the United States after the US Food and Drug Administration raised concerns about their safety. These concerns were based on rare cases of skin malignancy and lymphoma, and a theoretical risk stemming from the systemic use of calcineurin inhibitors in animal studies and transplant patients. However, the boxed warning states that no causal link has been established between TCI use and malignancy. Pharmacokinetic studies have also shown that treatment with TCIs leads to only minimal systemic absorption. In addition, controlled, blinded studies have found no evidence of systemic immunosuppression and no causal relationship between the use of TCIs and the occurrence of lymphoma or other malignancies. Overall, TCIs have been shown to be an effective and valuable treatment option for AD.

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    • "The FDA’s decision prompted criticism by various experts [29–32] and medical associations, including the American College of Allergy Asthma and Immunology (ACAAI) and the American Academy of Allergy, Asthma, and Immunology (AAAAI) [33], and the American Academy of Dermatology (AAD) [34]. The critics asserted that the benefit-risk ratio had not been assessed appropriately, especially in light of the impact of AD on patients and the risk of significant adverse effects with topical corticosteroids [30–32]. "
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    ABSTRACT: Atopic dermatitis (AD) is an inflammatory skin disease commonly affecting children and managed by pediatricians, primary care physicians, allergists, and dermatologists alike. For many years, the only available topical pharmacological treatment was topical corticosteroids. This changed in 2000-2001, when topical formulations of two calcineurin inhibitors (tacrolimus and pimecrolimus) were approved for short-term or chronic intermittent treatment of AD in patients ≥2 years of age, in whom other treatments have been ineffective or contraindicated. These topical calcineurin inhibitors (TCIs) quickly became a popular treatment option due at least in part to concerns over adverse events associated with prolonged topical corticosteroid use, especially in children. However, based on theoretical concerns about a possible risk of lymphoma associated with TCI use, a Boxed Warning was placed on both products in 2006. Since then, despite an extensive body of evidence, no causal relationship has been demonstrated between TCI use and an increased risk of lymphoma; however, the US FDA has concluded that a link cannot be ruled out. In fact, based on post-marketing surveillance of spontaneous, literature, and solicited reports, we report here that the lymphoma incidence in the topical pimecrolimus-exposed population is up to approximately 54-fold less than that seen in the general US population. This review summarizes the mechanism of action of TCIs, the factors that prompted the Boxed Warning, and recent TCI safety and efficacy data. Based on these data, both topical corticosteroids and TCIs should have defined roles in AD management, with TCIs favored for sensitive skin areas (e.g., face) and instances where topical corticosteroids have proven ineffective, thereby minimizing the risk of adverse effects with both drug classes.
    Paediatric Drugs 04/2013; 15(4). DOI:10.1007/s40272-013-0013-9 · 1.98 Impact Factor
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    • "These concerns were related to the immunosuppression and increased incidence of lymphoproliferative disease associated with systemically-administered calcineurin inhibitors in transplant patients, and to studies in animal models involving high doses of orally-administered drug. Although rare cases of lymphoma and skin malignancies have been reported in post-marketing surveillance studies, no causal relationship has been established between these cases and the use of TCIs, and the reported lymphoma cases were no greater than the expected rate in the general population (Lebwohl and Gower 2006; Munzenberger and Montejo 2007). Numerous pharmacokinetic studies have shown that the administration of topical pimecrolimus or tacrolimus results in negligible amounts of drug absorption into the systemic circulation (Munzenberger and Montejo 2007). "
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    ABSTRACT: Atopic dermatitis is a chronic, inflammatory skin condition that affects 10% to 20% of children and 1% to 3% of adults in the US. Symptoms often result in sleeplessness, psychological stress, poor self-esteem, anxiety, and poor school or work performance. The cost of atopic dermatitis is estimated to be US$0.9 to 3.8 billion every year. Topical steroids are first-line treatment for atopic dermatitis, and recent advances in vehicle technologies have resulted in improved patient tolerability and compliance. Topical calcineurin inhibitors are also safe and effective topical treatments for atopic dermatitis, and provide an additional therapeutic option for patients with this disease. Systemic immunomodulators are used in the treatment of severe refractory disease. Cyclosporine, methotrexate, azathioprine, mycophenolate mofetil, and interferon gamma have been used in the management of severe atopic dermatitis. This review highlights the current and emerging trends in the treatment of atopic dermatitis.
    Patient Preference and Adherence 02/2008; 2:387-92. · 1.68 Impact Factor
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    ABSTRACT: Atopic dermatitis (AD) is a common, chronic, inflammatory skin disease that can significantly reduce the quality of life of not only patients but also entire families. This review will focus on the currently available non-pharmacologic and pharmacologic treatments for the control and management of AD. A review of English-language articles from January 1953 to May 2006 was performed within the MEDLINE database. Search terms included, but were not limited to, atopic dermatitis, topical corticosteroids, and topical calcineurin inhibitors. Studies evaluating the diagnosis, physical and psychological burden, and underlying pathophysiology of AD were included. Particular focus was placed on literature presenting key safety and efficacy data from clinical trials involving AD treatment. Although good skin care and trigger avoidance are fundamental to AD management, most patients also require pharmacologic intervention. Topical therapies comprise the foundation of AD treatment. In particular, topical corticosteroids have been a mainstay in AD treatment for several decades and the newer topical calcineurin inhibitors have become a valuable addition to the therapeutic armamentarium. TCIs are a safe and effective AD treatment; they limit the number of disease flares, extend the time between flares, and provide a steroid-sparing option that may be of particular benefit in the pediatric population. The use of more potent therapies, such as systemic (oral/injected) agents or phototherapy, is typically limited to the treatment of severe, refractory disease. Additionally, owing to the increased risk for bacterial, viral, and fungal infections in patients with AD, topical or systemic antimicrobials are an important component of treatment. Case reports and small-scale studies were typically not included in this analysis and owing to the limited number of trials evaluating TCSs, consensus statements and comprehensive review articles were used to obtain information pertaining to the use of this treatment in AD. AD is a common, chronic disease requiring a long-term management strategy that incorporates preventive measures and a multipronged treatment approach.
    Current Medical Research and Opinion 01/2008; 23(12):3091-103. DOI:10.1185/030079907X242593 · 2.65 Impact Factor
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