Revisiting the safety of topical calcineurin inhibitors in patients with atopic dermatitis

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Topical calcineurin inhibitors (TCI) have emerged from the shadow of topical corticosteroids as another first-line remedies for treating acute flares of atopic dermatitis (AD). The effectiveness of TCI in maintenance therapy is also undeniable. The wider use of TCI increases the relevance of the issue of their safety. The adherence of physicians and their patients to the treatment with TCI is constrained by a controversial FDA black box warning against these drugs based on the theoretical risk of skin tumors, especially lymphoma. This warning, formulated in 2005, has been repeatedly refuted. However, there have been studies that at least partially supported cautious use of TCI. In recent years, the results of large cohort prospective studies clarifying the issue of oncological safety of TCI have been published. The review highlights the results of various studies with optimistic, pessimistic and balanced conclusions regarding the safety of TCI, primarily their effect on tumorigenesis, in order to better inform physicians about the benefit/risk balance when using these drugs in AD patients. The data presented in this review indicate that there is no increased risk of melanoma and other forms of skin cancer in TCI users, but these data do not completely rule out the risk of skin lymphoma. However, the very low level of potential risk to an individual patient gives physicians the right to neglect this risk when choosing TCI as a treatment option for AD.

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Oleg V. Kalyuzhin

I.M. Sechenov First Moscow State Medical University

Author for correspondence.
ORCID iD: 0000-0003-3628-2436

professor of Department of Clinical Immunology and Allergy, I.M. Sechenov First Moscow State Medical University (Sechenov University), MD, PhD, professor

Russian Federation, Moscow


  1. Odhiambo JA, Williams HC, Clayton TO, Robertson CF, Asher MI; ISAAC Phase Three Study Group. Global variations in prevalence of eczema symptoms in children from ISAAC Phase Three. J Allergy Clin Immunol. 2009;124(6):1251–1258.e23. doi: 10.1016/j.jaci.2009.10.009
  2. Mortz CG, Andersen KE, Poulsen LK, Kjaer HF, Broesby-Olsen S, Bindslev-Jensen C. Atopic diseases and type I sensitization from adolescence to adulthood in an unselected population (TOACS) with focus on predictors for allergic rhinitis. Allergy. 2019;74(2):308–317. doi: 10.1111/all.13630
  3. Andersen YM, Egeberg A, Skov L, Thyssen JP. Comorbidities of atopic dermatitis: beyond rhinitis and asthma. Curr Dermatol Rep. 2017;6(1):35–41. doi: 10.1007/s13671-017-0168-7
  4. Ellis CN, Mancini AJ, Paller AS, Simpson EL, Eichenfield LF. Understanding and managing atopic dermatitis in adult patients. Semin Cutan Med Surg. 2012;31(3 Suppl):S18–S22. doi: 10.1016/j.sder.2012.07.006
  5. Wan J, Mitra N, Hoffstad OJ, Yan AC, Margolis DJ. Longitudinal atopic dermatitis control and persistence vary with timing of disease onset in children: a cohort study. J Am Acad Dermatol. 2019;81(6):1292–1299. doi: 10.1016/j.jaad.2019.05.016
  6. Mortz CG, Andersen KE, Dellgren C, Barington T, Bindslev-Jensen C. Atopic dermatitis from adolescence to adulthood in the TOACS cohort: prevalence, persistence and comorbidities. Allergy. 2015;70(7):836–845. doi: 10.1111/all.12619
  7. Kubanov AA, Namazova-Baranova LS, Haitov RM, Il’ina NI, Ambarchyan ET, Arshinskii MI, et al. Clinical guidelines. Atopic dermatitis [Internet]. Moscow; 2020 [cited 2020 Jun 10]. Available from: (In Russ.).
  8. Wollenberg A, Barbarot S, Bieber T, Christen-Zaech S, Deleuran M, Fink-Wagner A, et al. Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part I. J Eur Acad Dermatol Venereol. 2019;33(7):1436. Corrected and republished from: J Eur Acad Dermatol Venereol. 2018;32(5):657–682. doi: 10.1111/jdv.14891
  9. Wollenberg A, Barbarot S, Bieber T, Christen-Zaech S, Deleuran M, Fink-Wagner A, et al. Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part II. J Eur Acad Dermatol Venereol. 2018;32(6):850-878. doi: 10.1111/jdv.14888
  10. Purohit VS, Ports WC, Wang C, Riley S. Systemic tofacitinib concentrations in adult patients with atopic dermatitis treated with 2% tofacitinib ointment and application to pediatric study planning. J Clin Pharmacol. 2019;59(6):811–820. doi: 10.1002/jcph.1360
  11. Yang H, Wang J, Zhang X, Zhang Y, Qin ZL, Wang H, Luo XY. Application of topical phosphodiesterase 4 inhibitors in mild to moderate atopic dermatitis: a systematic review and meta-analysis. JAMA Dermatol. 2019;155(5):585–593. doi: 10.1001/jamadermatol.2019.0008
  12. Rajagopalan M, De A, Godse K, Krupa Shankar DS, Zawar V, Sharma N, et al. Guidelines on management of atopic dermatitis in India: an evidence-based review and an expert consensus. Indian J Dermatol. 2019;64(3):166–181. doi: 10.4103/ijd.IJD_683_18
  13. Reda AM, Elgendi A, Ebraheem AI, Aldraibi MS, Qari MS, Abdulghani MMR, Luger T. A practical algorithm for topical treatment of atopic dermatitis in the Middle East emphasizing the importance of sensitive skin areas. J Dermatolog Treat. 2019;30(4):366–373. doi: 10.1080/09546634.2018.152482
  14. Kalyuzhin OV. Persistiruyushchee subklinicheskoe vospalenie v kozhe kak faktor riska obostrenii atopicheskogo dermatita: ot patofiziologii k lecheniyu. Russian Journal of Allergy. 2017;14(4–5):108–11 (In Russ.). doi: 10.36691/RJA302
  15. Tang TS, Bieber T, Williams HC. Are the concepts of induction of remission and treatment of subclinical inflammation in atopic dermatitis clinically useful? J Allergy Clin Immunol. 2014;133(6):1615–1625.e1. doi: 10.1016/j.jaci.2013.12.1079
  16. Luger TA, Gollnick H. Viewpoint of the German Dermatologic Society (DDG) concerning the decision of the American Food and Drug Administration (FDA) on the use of pimecrolimus cream and tacrolimus ointment in the treatment of atopic dermatitis (neurodermatitis). J Dtsch Dermatol Ges. 2005;3(6):415–416 (In German). doi: 10.1111/j.1610-0387.2005.05038.x
  17. Ormerod AD. Topical tacrolimus and pimecrolimus and the risk of cancer: how much cause for concern? Br J Dermatol. 2005;153(4):701–705. doi: 10.1111/j.1365-2133.2005.06899.x
  18. Ring J, Mohrenschlager M, Henkel V. The US FDA ‘black box’ warning for topical calcineurin inhibitors: an ongoing controversy. Drug Saf. 2008;31(3):185–198. doi: 10.2165/00002018-200831030-00001
  19. [Internet]. FDA Issues Public Health Advisory Informing Health Care Providers of Safety Concerns Associated with the Use of Two Eczema Drugs, Elidel and Protopic [cited 2020 Jun 10]. Available from:
  20. [Internet]. FDA Issues Public Health Advisory Informing Health Care Providers of Safety Concerns Associated with the Use of Two Eczema Drugs, Elidel and Protopic [cited 2020 Jun 10]. Available from:
  21. [Internet]. European Medicines Agency recommends cautious use of Protopic/Protopy and Elidel. London, 27 March 2006. Doc. Ref. EMEA/98882/2006 [cited 2020 Sep 2]. Available from: – Link active 10.06.2020.
  22. Harper J, Smith C, Rubins A, Green A, Jackson K, Zigure S, et al. A multicenter study of the pharmacokinetics of tacrolimus ointment after first and repeated application to children with atopic dermatitis. J Invest Dermatol. 2005;124(4):695–659. doi: 10.1111/j.0022-202X.2005.23644.x
  23. Rubins A, Gutmane R, Valdmane N, Stevenson P, Foster C, Undre N. Pharmacokinetics of 0.1% tacrolimus ointment after first and repeated application to adults with moderate to severe atopic dermatitis. J Invest Dermatol. 2005;125(1):68–71. doi: 10.1111/j.0022-202X.2005.23754.x
  24. Ling M, Gottlieb A, Pariser D, Caro I, Stewart D, Scott G, Abrams K. A randomized study of the safety, absorption and efficacy of pimecrolimus cream 1% applied twice or four times daily in patients with atopic dermatitis. J Dermatolog Treat. 2005;16(3):142–148. doi: 10.1080/09546630510033159
  25. Van Leent EJ, Ebelin ME, Burtin P, Dorobek B, Spuls PI, Bos JD. Low systemic exposure after repeated topical application of Pimecrolimus (Elidel), SD Z ASM 981) in patients with atopic dermatitis. Dermatology. 2002;204(1):63–68. doi: 10.1159/000051813
  26. Draelos Z, Nayak A, Pariser D, Shupack JL, Chon K, Abrams B, Paul CF. Pharmacokinetics of topical calcineurin inhibitors in adult atopic dermatitis: a randomized, investigator-blind comparison. J Am Acad Dermatol. 2005;53(4):602–609. doi: 10.1016/j.jaad.2005.06.013
  27. Euvrard S, Ulrich C, Lefrancois N. Immunosuppressants and skin cancer in transplant patients: focus on rapamycin. Dermatol Surg. 2004;30(4 Pt 2):628–633. doi: 10.1111/j.1524-4725.2004.30148.x
  28. Ellis D, Jaffe R, Green M, Janosky JJ, Lombardozzi-Lane S, Shapiro R, et al. Epstein-Barr virus-related disorders in children undergoing renal transplantation with tacrolimus-based immunosuppression. Transplantation. 1999;68(7):997–1003. doi: 10.1097/00007890-199910150-00017
  29. Niwa Y, Terashima T, Sumi H. Topical application of the immunosuppressant tacrolimus accelerates carcinogenesis in mouse skin. Br J Dermatol. 2003;149(5):960–967. doi: 10.1111/j.1365-2133.2003.05735.x
  30. Niwa Y, Nasr I. Are we starting to induce skin cancer in order to avoid topical steroids? J Eur Acad Dermatol Venereol. 2005;19(3):387–389. doi: 10.1111/j.1468-3083.2004.01123.x
  31. Patel TS, Greer SC, Skinner RB Jr. Cancer concerns with topical immunomodulators in atopic dermatitis: overview of data and recommendations to clinicians. Am J Clin Dermatol. 2007;8(4):189–194. doi: 10.2165/00128071-200708040-00001
  32. Mitamura T, Doi Y, Kawabe M, Lilja H, Motomura M, Oishi Y, et al. Inhibitory potency of tacrolimus ointment on skin tumor induction in a mouse model of an initiation-promotion skin tumor. J Dermatol. 2011;38(6):562–570. doi: 10.1111/j.1346-8138.2010.01046.x
  33. Hui RL, Lide W, Chan J, Schottinger J, Yoshinaga M, Millares M. Association between exposure to topical tacrolimus or pimecrolimus and cancers. Ann Pharmacother. 2009;43(12):1956–1963. doi: 10.1345/aph.1M278
  34. Schneeweiss S, Doherty M, Zhu S, Funch D, Schlienger RG, Fernandez-Vidaurre C, Seeger JD. Topical treatments with pimecrolimus, tacrolimus and medium- to high-potency corticosteroids, and risk of lymphoma. Dermatology. 2009;219(1):7–21. doi: 10.1159/000209289
  35. Margolis DJ, Hoffstad O, Bilker W. Lack of association between exposure to topical calcineurin inhibitors and skin cancer in adults. Dermatology. 2007;214(4):289–295. doi: 10.1159/000100879
  36. Arellano FM, Arana A, Wentworth CE, Fernandez-Vidaurre C, Schlienger RG, Conde E. Lymphoma among patients with atopic dermatitis and/or treated with topical immunosuppressants in the United Kingdom. J Allergy Clin Immunol. 2009;123(5):1111–1116, 116.e1–13. doi: 10.1016/j.jaci.2009.02.028
  37. Siegfried EC, Jaworski JC, Kaiser JD, Hebert AA. Systematic review of published trials: long-term safety of topical corticosteroids and topical calcineurin inhibitors in pediatric patients with atopic dermatitis. BMC Pediatrics. 2016;16:75. doi: 10.1186/s12887-016-0607-9
  38. Siegfried EC, Jaworski JC, Hebert AA. Topical calcineurin inhibitors and lymphoma risk: evidence update with implications for daily practice. J Am Acad Dermatol. 2013;14(3):163–178. doi: 10.1007/s40257-013-0020-1
  39. Legendre L, Barnetche T, Mazereeuw-Hautier J, Meyer N, Murrell D, Paul C. Risk of lymphoma in patients with atopic dermatitis and the role of topical treatment: a systematic review and meta-analysis. J Am Acad Dermatol. 2015;72(6):992–1002. doi: 10.1016/j.jaad.2015.02.1116
  40. Cury Martins J, Martins C, Aoki V, Gois AF, Ishii HA, da Silva EM. Topical tacrolimus for atopic dermatitis. Cochrane Database Syst Rev. 2015;2015(7):CD009864. doi: 10.1002/14651858.CD009864.pub2
  41. Carr WW. Topical calcineurin inhibitors for atopic dermatitis: review and treatment recommendations. Paediatric Drugs. 2013;15(4):303–310. doi: 10.1007/s40272-013-0013-9
  42. Margolis DJ, Abuabara K, Hoffstad OJ, Wan J, Raimondo D, Bilker WB. Association between malignancy and topical use of pimecrolimus. JAMA Dermatol. 2015;151(6):594–599. doi: 10.1001/jamadermatol.2014.4305
  43. Castellsague J, Kuiper JG, Pottegard A, Anveden Berglind I, Dedman D, Gutierrez L, et al. A cohort study on the risk of lymphoma and skin cancer in users of topical tacrolimus, pimecrolimus, and corticosteroids (Joint European Longitudinal Lymphoma and Skin Cancer Evaluation – JOELLE study). Clin Epidemiol. 2018;10:299–310. doi: 10.2147/CLEP.S146442
  44. Mansfield KE, Schmidt SAJ, Darvalics B, Mulick A, Abuabara K, Wong AY, et al. Association between atopic eczema and cancer in England and Denmark. JAMA Dermatol. 2020:e201948. doi: 10.1001/jamadermatol.2020.1948
  45. Muir AB, Whelan KA, Dougherty MK, Aaron B, Navarre B, Aceves SS, et al. The potential for malignancy from atopic disorders and allergic inflammation: a systematic review and meta-analysis. Clin Exp Allergy. 2020;50(2):147–159. doi: 10.1111/cea.13537

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