Cyclosporine and skin cancer: An international dermatologic perspective over 25 years of experience. A comprehensive review and pursuit to define safe use of cyclosporine in dermatology

SIERRADERM, Center for Dermatology, Grass Valley, CA, USA.
Journal of Dermatological Treatment (Impact Factor: 1.67). 09/2011; 23(4):290-304. DOI: 10.3109/09546634.2011.590792
Source: PubMed


Cyclosporine A (CsA), a powerful immunosuppressant drug effective in treating a variety of dermatologic diseases, is often avoided due to potential adverse side effects such as skin cancer. CsA-induced skin cancers are well documented in organ transplant literature. This association is less clear when dermatologic guidelines are followed (e.g., low dose, healthy patients, time-limited use, no other immunosuppressive agents, etc.). Marcil and Stern estimated increased risk of squamous cell carcinoma (SCC) after CsA treatment equivalent to 200 PUVA treatments while the original data collected by Sandoz Ltd. reported a significantly less skin malignancies at doses of 5 mg/kg/day or less. Reviewing 60 studies and over 1700 patients in 25 years of existing US and international multicenter studies revealed 63 patients (less than 1%) with skin cancer. No skin cancers were reported with 6 months continuous use or up to 2 years of intermittent therapy. PUVA phototherapy overwhelmingly preceded CsA use in reported cases. Overall, 14 case reports were found suggesting CsA-induced skin cancers with the majority either having violated accepted dermatologic safety guidelines or enrolling patients with significant pre-existing carcinogenic risk factors. When reviewing over 25 years of dermatologic experience worldwide, it is not clearly substantiated that skin cancer risk is necessarily increased in patients using CsA.

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    • "The concurrent administration of CsA and UVB has not been studied extensively and, even if contraindicated, has successfully been used in sporadic cases for a short period of time [54]. While a recent systematic review with over 25 years of dermatologic experience worldwide does not clearly substantiate that skin cancer risk is necessarily increased in patients using CsA for cutaneous diseases, unlike organ transplant recipients [55], it is well established that there is an increased risk of nonmelanoma skin cancers with association of PUVA therapy and CsA [56]. In a comparative, open-label study, narrow-band- (NB-) UVB phototherapy alone was compared with sequential CsA-NB-UVB in two groups of 30 patients with plaque psoriasis (PASI > 15). "
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    ABSTRACT: Cyclosporine A (CsA) is one of the most effective systemic drugs available for the treatment of psoriasis, as evidenced by the results of several randomized studies and by a prolonged experience in dermatological setting. In clinical practice, CsA is usually used for the induction of psoriasis remission at a daily dose included in the range of 2.5-5 mg/kg and with intermittent short-term regimens, lasting on average 3-6 months. The magnitude and rapidity of response are dose dependent, as well as the risk of development of adverse events. Therefore, the dose should be tailored to patient's needs and general characteristics and adjusted during the treatment course according to both the efficacy and tolerability. Some studies support the feasibility of pulse administration of CsA for a few days per week for both the induction and the maintenance of response in psoriasis patients. This paper will review the data on CsA regimens for plaque-type psoriasis and will focus the attention on dose, treatment duration, novel schedules, and role in combination therapies, including the association with biologicals.
    The Scientific World Journal 07/2013; 2013(11):805705. DOI:10.1155/2013/805705 · 1.73 Impact Factor
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    • "One example is CsA, a NFAT signal pathway inhibitor and immunosuppressive drug, which is traditionally associated with an increased risk of neoplasia. However, recent studies provide evidence that CsA (at doses up to 50 mg/kg) does not facilitate tumor progression but partially inhibits tumor growth [36], [37], and the suggestion that CsA could be used in anti-tumor therapy has been emerging. In this study, we showed that in GBM cells, CsA effectively inhibits cell invasion, but has no effect on cell proliferation. "
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    ABSTRACT: Members of the nuclear factor of activated T cells (NFAT) family have been identified as regulators of oncogenic transformation in several human malignancies. A prominent member of this family, NFAT1, is associated with tumor cell survival, apoptosis, migration and invasion. Here, we investigated the role of NFAT1 in glioma cells. In 111 clinical samples, microarray analysis demonstrated that NFAT1 was over-expressed in glioblastoma multiforme (GBM), compared with low-grade gliomas, a result confirmed by RT-PCR in 24 clinical samples and in the U87 and U251 cell lines. Immunohistochemistry and immunofluorescence stain indicated that over-expressed NFAT1 was mainly located in the nucleus, where it acted as a transcription factor. After treatment with the NFAT antagonist cyclosporin A (CsA) and FK506, levels of NFAT1 in the nuclei of U87 GBM cells were dramatically reduced. The invasive potential of U87 cells was reduced by the same treatment, as well as by inhibition of NFAT1 expression using small hairpin RNA. Proliferation of U87 cells was unaffected by CsA, FK506 and NFAT1 shRNA transfection. Clustering analysis and Pearson correlation analysis of microarray data showed that the expression of NFAT1 correlated with the expression of the invasion-related genes cyclooxygenase-2 (COX-2), matrix metalloproteinase-7 (MMP-7) and MMP-9, a result confirmed by in vitro analysis. These findings demonstrate that NFAT1 contributes to the invasive potential but not the proliferation of GBM cells, and suggest that CsA may find application as an adjuvant in combined treatment strategies for GBM.
    PLoS ONE 06/2013; 8(6):e66008. DOI:10.1371/journal.pone.0066008 · 3.23 Impact Factor
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    ABSTRACT: BACKGROUND: There is no known association between the development of keratoacanthomas and prurigo nodules. OBJECTIVE: We report a case series of 7 patients with a long-standing history of actinic damage, pruritus, and prurigo nodularis who developed widespread keratoacanthomas within the same affected area. METHODS: This was a retrospective case series assessing the clinical characteristics of patients with multiple keratoacanthomas arising in association with prurigo nodules. RESULTS: All 7 patients were elderly Caucasian women (mean age 79 ± 3.7 years) with actinically damaged skin and a long-standing history of widespread pruritus and prurigo nodules. All patients had histologically confirmed keratoacanthomas, or squamous cell carcinomas with the clinical appearance of a keratoacanthoma, that developed within the field of prurigo nodules. All 7 patients had a clinical response to acitretin with a decrease in the number of lesions. Four patients had an associated eczematous dermatitis and were also treated with cyclosporine with improvement in pruritus and prurigo nodules and no increase in keratoacanthomas. LIMITATIONS: The retrospective design and small number of patients are limitations to this study. CONCLUSION: Our case series represents a distinct subset of elderly individuals with extensive actinic damage who we believe are predisposed to developing both prurigo nodules and keratoacanthomas.
    Journal of the American Academy of Dermatology 05/2013; 69(3). DOI:10.1016/j.jaad.2013.03.035 · 4.45 Impact Factor
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