Información del artículo
Abstract
In this review the controversy regarding the association between topical pimecrolimus and tacrolimus and the development of tumors is unfolded. After reviewing the literature we conclude that, currently, there is no scientific evidence of an increased incidence of skin cancer, lymphomas or systemic immunosuppression in those patients that use or have used topical calcineurin inhibitors. Published studies lack adequate number of patients and/or the follow-up time is short enough to conclude that topical use of calcineurin inhibitors might be associated with the reported cases of skin cancer and lymphoma. Nevertheless the possibility of long term cutaneous and/or systemic side effects cannot be excluded.
Key words:
pimecrolimus
tacrolimus
nonmelanoma skin cancer
melanoma
lymphoma
posttransplant lymphoproliferative disease
experimental studies
Resumen
En esta revisión se expone la controversia que existe acerca de la relación que hay entre el pimecrolimus y tacrolimus tópicos y la aparición de tumores. Después de revisar la literatura médica se concluye que actualmente no existe evidencia científica de un incremento de cáncer de piel ni de linfomas ni del desarrollo de una inmunosupresión sistémica en aquellos pacientes que han utilizado o están utilizando los inhibidores tópicos de la calcineurina. Los estudios publicados carecen de suficiente número de pacientes y/o el periodo de seguimiento es corto como para concluir que el uso tópico de los inhibidores de la calcineurina puede asociarse a los casos notificados de cáncer de piel y linfoma. Sin embargo, no se puede excluir la posibilidad de que aparezcan efectos secundarios cutáneos y/o sistémicos a largo plazo.
Palabras clave:
pimecrolimus
tacrolimus
cáncer de piel no melanoma
melanoma
linfoma
enfermedad linfoproliferativa postrasplante
estudios experimentales
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References
[1.]
E. Fonseca.
Inhibidores tópicos de la calcineurina.
Piel, 19 (2004), pp. 4-7
[2.]
U.S. Food and Drugs Administration. Anonymous: new warnings for two eczema drugs. Available from: http://www.fda.gov/fdac/departs/2006/206_upd.html. Accessed March 11, 2007.
[3.]
European Medicines Agency Cautious use of protopic/protopy and elidel. Available from: http://www.emea.europa.eu/pdfs/general/direct/pr/9888206en.pdf Accessed March 11, 2007.
[4.]
E. Baselga.
Tratamiento de la dermatitis atópica en la infancia.
Actas Dermosifiliogr, 94 (2003), pp. 345-355
[5.]
Agencia Española del Medicamentos y Productos sanitarios Elidel (pimecrolimus) y Protopic (tacrolimus) y riesgos de tumores, 4 de abril del 2005. Available from: http://www.agemed.es/actividad/alertas/docs/NI_2005-7.pdf Accessed March 11, 2007.
[6.]
J.C. Becker, R. Houben, C.S. Vetter, E.B. Brocker.
The carcinogenic potential of tacrolimus ointment beyond immune suppression: a hypothesis creating case report.
BMC Cancer, 11 (2006), pp. 7
[7.]
D.B. Yarosh, A.V. Pena, S.L. Nay, M.T. Canning, D.A. Brown.
Calcineurin inhibitors decrease DNA repair and apoptosis in human keratinocytes following ultraviolet B irradiation.
J Invest Dermatol, 125 (2005), pp. 1020-1025
[8.]
Food and Drug Administration. Novartis Elidel (pimecrolimus) cream 1% briefing document, (6/2006). Available from: www.fda.gov/cder/foi/label/2006/021302s011lbl.pdf Accessed March 11, 2007.
[9.]
Food and Drug Administration Astellas Pharma (tacrolimus) ointment 0,03% and 0,1% briefing document, (6/2006). Available from: http://www.fda.gov/cder/foi/label/2006/050777s012lbl.pdf Accessed March 11, 2007.
[10.]
J. Callen, S. Chamlin, L.F. Eichenfield, C. Ellis, M. Girardi, M. Goldfarb, et al.
A systematic review of the safety of topical therapies for atopic dermatitis.
Br J Dermatol, 156 (2007), pp. 203-221
[11.]
L. Doelker, C. Tran, A. Gkomouzas, D. Grand, O. Sorg, J.H. Saurat, et al.
Production and clearance of cyclobutane dipyrimidine dimers in UV-irradiated skin pretreated with 1% pimecrolimus or 0.1% triamcinolone acetonide creams in normal and atopic patients.
Exp Dermatol, 15 (2006), pp. 342-346
[12.]
T. Hultsch, A. Kapp, J. Spergel.
Immunomodulation and safety of topical calcineurin inhibitors for the treatment of atopic dermatitis.
Dermatology, 211 (2005), pp. 174-187
[13.]
M. Grassberger, T. Baumruker, A. Enz, P. Hiestand, T. Hultsch, F. Kalthoff, et al.
A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases: in vitro pharmacology.
Br J Dermatol, 141 (1999), pp. 264-273
[14.]
S. Jonas, N. Rayes, U. Neumann, R. Neuhaus, W.O. Bechstein, O. Guckelberger, et al.
De novo malignancies after liver transplantation using tacrolimus-based protocols or cyclosporine-based quadruple immunosuppression with an interleukin-2 receptor antibody or antithymocyte globulin.
Cancer, 80 (1997), pp. 1141-1150
[15.]
D. Ellis, R. Jaffe, M. Green, J.J. Janosky, S. Lombardozzi-Lane, R. Shapiro, et al.
Epstein-Barr virus-related disorders in children undergoing renal transplantation with tacrolimusbased immunosuppression.
Transplantation, 68 (1999), pp. 997-1003
[16.]
C.C. Otley, M.R. Pittelkow.
Skin cancer in liver transplant recipients.
Liver Transpl, 6 (2000), pp. 253-262
[17.]
K.A. Papp, K. Breuer, M. Meurer, J.P. Ortonne, P.C. Potter, Y. de Prost, et al.
Long-term treatment of atopic dermatitis with pimecrolimus cream 1% in infants does not interfere with the development of protective antibodies after vaccination.
J Am Acad Dermatol, 52 (2005), pp. 247-253
[18.]
E.R. Stiehm, R.L. Roberts, M.S. Kaplan, J. Corren, E. Jaracz, M.J. Rico.
Pneumococcal seroconversion after vaccination for children with atopic dermatitis treated with tacrolimus ointment.
J Am Acad Dermatol, 53 (2005), pp. S206-S213
[19.]
U. Wahn, J.D. Bos, M. Goodfield, R. Caputo, K. Papp, A. Manjra, et al.
Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children.
Pediatrics, 110 (2002), pp. e2
[20.]
A.R. Ellingsen, F.B. Sorensen, J.O. Larsen, M.S. Deleuran, K. Thestrup-Pedersen.
Stereological quantification of lymphocytes in skin biopsies from atopic dermatitis patients.
Acta Derm Venereol, 81 (2001), pp. 258-262
[21.]
J.M. Hanifin, A.S. Paller, L. Eichenfield, R.A. Clark, N. Korman, G. Weinstein, et al.
US Tacrolimus Ointment Study Group Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis.
J Am Acad Dermatol, 53 (2005), pp. S186-S194
[22.]
S. Reitamo, J.P. Ortonne, C. Sand, F. Cambazard, T. Bieber, R. Folster-Holst, European Tacrolimus Ointment Study Group, et al.
A multicentre, randomized, double-blind, controlled study of long-term treatment with 0.1% tacrolimus ointment in adults with moderate to severe atopic dermatitis.
Br J Dermatol, 152 (2005), pp. 1282-1289
[23.]
C. Paul, M. Cork, A.B. Rossi, K.A. Papp, N. Barbier, Y. de Prost.
Safety and tolerability of 1% pimecrolimus cream among infants: experience with 1133 patients treated for up to 2 years.
Pediatrics, 117 (2006), pp. e118-e128
[24.]
J.Y. Koo, A.B. Fleischer Jr, W. Abramovits, D.M. Pariser, C.O. McCall, T.D. Horn, et al.
Tacrolimus ointment is safe and effective in the treatment of atopic dermatitis: results in 8000 patients.
J Am Acad Dermatol, 53 (2005), pp. S195-S205
[25.]
E.J. Van Leent, M.E. Ebelin, P. Burtin, B. Dorobek, P.I. Spuls, J.D. Bos.
Low systemic exposure after repeated topical application of Pimecrolimus (Elidel), SD Z ASM 981) in patients with atopic dermatitis.
Dermatology, 204 (2002), pp. 63-68
[26.]
B.R. Allen, M. Lakhanpaul, A. Morris, S. Lateo, T. Davies, G. Scott, et al.
Systemic exposure, tolerability, and efficacy of pimecrolimus cream 1% in atopic dermatitis patients.
Arch Dis Child, 88 (2003), pp. 969-973
[27.]
J. Harper, A. Green, G. Scott, E. Gruendl, B. Dorobek, M. Cardno, et al.
First experience of topical SDZ ASM 981 in children with atopic dermatitis.
Br J Dermatol, 144 (2001), pp. 781-787
[28.]
L. Fonacier, J. Spergel, E.N. Charlesworth, D. Weldon, V. Beltrani, J. Bernhisel-Broadbent, et al.
American College of Allergy, Asthma and Immunology; American Academy of Allergy, Asthma and Immunology. Report of the Topical Calcineurin Inhibitor Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology.
J Allergy Clin Immunol, 115 (2005), pp. 1249-1253
[29.]
J. Harper, C. Smith, A. Rubins, A. Green, K. Jackson, S. Zigure, et al.
A multicenter study of the pharmacokinetics of tacrolimus ointment after first and repeated application to children with atopic dermatitis.
J Invest Dermatol, 124 (2005), pp. 695-699
[30.]
A. Allen, E. Siegfried, R. Silverman, M.L. Williams, P.M. Elias, S.K. Szabo, et al.
Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome.
Arch Dermatol, 137 (2001), pp. 747-750
[31.]
D. Thaci, K. Steinmeyer, M.E. Ebelin, G. Scott, R. Kaufmann.
Occlusive treatment of chronic hand dermatitis with pimecrolimus cream 1% results in low systemic exposure, is well tolerated, safe, and effective. An open study.
Dermatology, 207 (2003), pp. 37-42
[32.]
J.M. Spergel, D.Y. Leung.
Safety of topical calcineurin inhibitors in atopic dermatitis: evaluation of the evidence.
Curr Allergy Asthma Rep, 6 (2006), pp. 270-274
[33.]
A.D. Ormerod.
Topical tacrolimus and pimecrolimus and the risk of cancer: how much cause for concern?.
Br J Dermatol, 153 (2005), pp. 701-705
[34.]
F.M. Arellano, C.E. Wentworth, A. Arana, C. Fernández.
Paul CF Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis.
J Invest Dermatol, 127 (2007), pp. 808-816
[35.]
T.G. Berger, M. Duvic, A.S. Van Voorhees, M.J. VanBeek, I.J. Frieden.
American Academy of Dermatology Association Task Force. The use of topical calcineurin inhibitors in dermatology: safety concerns. Report of the American Academy of Dermatology Association Task Force.
J Am Acad Dermatol, 54 (2006), pp. 818-823
[36.]
T. Langeland, V. Engh.
Topical use of tacrolimus and squamous cell carcinoma on the penis.
Br J Dermatol, 152 (2005), pp. 183-185
[37.]
A.A. Qureshi, M.A. Fischer.
Topical calcineurin inhibitors for atopic dermatitis: balancing clinical benefit and possible risks.
Arch Dermatol, 142 (2006), pp. 633-637
[38.]
Food and Drug Administration. Alerts for healthcare professionals tacrolimus (marketed as Protopic), March 2005. Available from: http://www.fda.gov/cder/drug/infoSheets/HCP/ProtopicHCP.htm. Accessed March 11, 2007.
[39.]
M. Naylor, C. Elmets, E. Jaracz, J.M. Rico.
Non-melanoma skin cancer in patients with atopic dermatitis treated with topical tacrolimus.
Dermatolog Treat, 16 (2005), pp. 149-153
[40.]
Food and Drug Administration. Alerts for healthcare professionals pimecrolimus (marketed as Elidel), March 2005. Available from: http://www.fda.gov/cder/drug/infoSheets/HCP/elidelHCP.htm. Accessed March 11, 2007.
[41.]
J. Ring, J. Barker, H. Behrendt, L. Braathen, U. Darsow, L. Dubertret, et al.
Review of the potential photococarcinogenicity of topical calcineurin inhibitors: position statement of the European Dermatology Forum.
J Eur Acad Dermatol Venereol, 19 (2005), pp. 663-671
[42.]
H. Jiang, S. Yamamoto, K. Nishikawa, R. Kato.
Anti-tumorpromoting action of FK506, a potent immunosuppressive agent.
Carcinogenesis, 14 (1993), pp. 67-71
[43.]
Y. Niwa, T. Terashima, H. Sumi.
Topical application of the immunosuppressant tacrolimus accelerates carcinogenesis in mouse skin.
Br J Dermatol, 149 (2004), pp. 960-967
[44.]
J. Lubbe, O. Sorg.
Tacrolimus ointment and skin carcinogenesis in the DMBA/TPA model in mice.
Br J Dermatol, 151 (2004), pp. 1275-1276
[45.]
C. Tran, J. Lubbe, O. Sorg, L. Doelker, P. Carraux, C. Antille, et al.
Topical calcineurin inhibitors decrease the production of UVB-induced thymine dimers from hairless mouse epidermis.
Dermatology, 211 (2005), pp. 341-347
[46.]
Asociación Española de Pediatría. Sobre la seguridad de pimecrolimus y tacrolimus, 7 de Junio del 2005. Available from: http://www.aeped.es/comunicado/index.htm. Accessed March 11, 2007.
[47.]
European Academy of Dermatology and Venereology. New recommendations of FDA and EMEA regarding labels of topical calcineurin inhibitors. Available from: http://www.eadv.org/article.asp?AID = 421&keyword = tacrolimus. Accessed March 11, 2007.
[48.]
American Academy of Dermatology. AAD information on Elidel and Protopic. Available from: http://www.aad.org/professionals/AdvocacyGovRelSkin/tci_information.htm. Accessed March 11, 2007.
Copyright © 2007. Academia Española de Dermatología y Venereología and Elsevier España, S.L.
