Skip to main content
SpringerLink
Log in

Association Between the Use of Topical Calcineurin Inhibitors and the Risk of Cancer Among Patients with Atopic Dermatitis: A Nationwide, Population-Based, Retrospective Cohort Study

  • Original Research Article
  • Published:
American Journal of Clinical Dermatology Aims and scope Submit manuscript

Abstract

Importance

The cancer risks associated with treatment with topical calcineurin inhibitors (TCIs) in patients with atopic dermatitis (AD) remain controversial, and limited evidence exists regarding the cancer risks among patients with AD treated with TCIs in Asian populations.

Objectives

This study identified the association between TCI use and the risks of developing all cancers, lymphoma, skin cancers, and other cancers.

Design

This study was a nationwide, population-based, retrospective cohort study.

Setting

Taiwan’s National Health Insurance Research Database.

Participants

Patients diagnosed at least twice with ICD-9 code 691 or at least one time with ICD-9 codes 691 or 692.9 within 1 year between 1 January 2003 and 31 December 2010 were included and followed until 31 December 2018. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using the Cox proportional hazard ratio model.

Exposures

Patients using tacrolimus or pimecrolimus were identified in the National Health Insurance Research Database and compared with patients using topical corticosteroids (TCSs).

Main Outcomes and Measures

The main outcomes were hazard ratios (HRs) of cancer diagnoses and associated outcomes obtained from the Taiwan Cancer Registry database.

Results

After propensity score (PS) matching, the final cohort included 195,925 patients with AD, including 39,185 who were initial TCI users and 156,740 who were TCS users. Propensity score matching was performed according to age, sex, index year, and Charlson Comorbidity Index using a ratio of 1:4. Except for leukemia, HR and 95% CI showed no significant associations between TCI use and the risk of developing all cancer, lymphoma, skin cancers, and other cancers. Sensitivity analysis showed that the lag time HRs for every cancer subtype continued to show no significant association between TCI use and cancer risk, except for leukemia.

Conclusions and Relevance

Our study found no evidence to support an association between TCI use and the risks of almost all cancers compared with TCS use in patients with AD, but physicians should be aware of potentially higher risks of leukemia with TCI use. This study represents the first population-based study focused on the cancer risk of TCI use among patients with AD in an Asian population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Wasserbauer N, Ballow M. Atopic dermatitis. Am J Med. 2009;122(2):121–5.

    Article  PubMed  Google Scholar 

  2. Asher MI, Montefort S, Björkstén B, Lai CKW, Strachan DP, Weiland SK, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006;368(9537):733–43.

    Article  PubMed  Google Scholar 

  3. Beasley R. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet (London, England). 1998;351(9111):1225–32.

  4. Cho YT, Hsieh WT, Chan TC, Tang CH, Chu CY. Prevalence of baseline comorbidities in patients with atopic dermatitis: a population-based cohort study in Taiwan. JAAD Int. 2020;1(1):50–8.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Cai SC, Li W, Tian EA, Allen JC, Tey HL. Topical calcineurin inhibitors in eczema and cancer association: a cohort study. J Dermatolog Treat. 2016;27(6):531–7.

    Article  CAS  PubMed  Google Scholar 

  6. Asgari MM, Tsai A-L, Avalos L, Sokil M, Quesenberry CP. Association between topical calcineurin inhibitor use and keratinocyte carcinoma risk among adults with atopic dermatitis. JAMA Dermatol. 2020;156(10):1066–73.

    Article  PubMed  Google Scholar 

  7. 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):594–9.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Paller AS, Folster-Holst R, Chen SC, Diepgen TL, Elmets C, Margolis DJ, et al. No evidence of increased cancer incidence in children using topical tacrolimus for atopic dermatitis. J Am Acad Dermatol. 2020;83(2):375–81.

    Article  CAS  PubMed  Google Scholar 

  9. 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):1956–63.

  10. Schneeweiss S, Doherty M, Zhu S, Funch D, Schlienger RG, Fernandez-Vidaurre C, et al. Topical treatments with pimecrolimus, tacrolimus and medium- to high-potency corticosteroids, and risk of lymphoma. Dermatology. 2009;219(1):7–21.

    Article  CAS  PubMed  Google Scholar 

  11. Arellano FM, Wentworth CE, Arana A, Fernández C, Paul CF. Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis. J Invest Dermatol. 2007;127(4):808–16.

    Article  CAS  PubMed  Google Scholar 

  12. Arellano FM, Arana A, Wentworth CE, Fernández-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):1111–6 (116.e1-13).

    Article  CAS  PubMed  Google Scholar 

  13. Margolis DJ, Hoffstad O, Bilker W. Lack of association between exposure to topical calcineurin inhibitors and skin cancer in adults. Dermatology. 2007;214(4):289–95.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Chiang CJ, You SL, Chen CJ, Yang YW, Lo WC, Lai MS. Quality assessment and improvement of nationwide cancer registration system in Taiwan: a review. Jpn J Clin Oncol. 2015;45(3):291–6.

    Article  PubMed  Google Scholar 

  16. Polesie S, Gillstedt M, Schmidt SAJ, Egeberg A, Pottegård A, Kristensen K. Use of methotrexate and risk of skin cancer: a nationwide case-control study. Br J Cancer. 2023;128(7):1311–9.

  17. Chou YJ, Wu CY, Pan TY, Wu CY, Chang YT. Risk of malignancy in patients with psoriasis receiving systemic medications: a nested case-control study. Dermatol Ther. 2022;35(11): e15804.

    Article  PubMed  Google Scholar 

  18. Jiyad Z, Olsen CM, Burke MT, Isbel NM, Green AC. Azathioprine and risk of skin cancer in organ transplant recipients: systematic review and meta-analysis. Am J Transplant. 2016;16(12):3490–503.

    Article  CAS  PubMed  Google Scholar 

  19. van der Linden MW, Penning-van Beest FJ, Nijsten T, Herings RM. Topical corticosteroids and the risk of diabetes mellitus: a nested case-control study in the Netherlands. Drug Saf. 2009;32(6):527–37.

    Article  PubMed  Google Scholar 

  20. Dekker FW, de Mutsert R, van Dijk PC, Zoccali C, Jager KJ. Survival analysis: time-dependent effects and time-varying risk factors. Kidney Int. 2008;74(8):994–7.

    Article  PubMed  Google Scholar 

  21. 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.

    Article  PubMed  Google Scholar 

  22. Chien LN, Tzeng HE, Liu HY, Chou WC, Tien HF, Hou HA. Epidemiology and survival outcomes of acute myeloid leukemia patients in Taiwan: A national population-based analysis from 2001 to 2015. J Formos Med Assoc. 2023;122(6):505–13.

  23. Kalthoff FS, Winiski A, Fichtinger P, Schwendinger B, Wang S, Weishaeupl C, Stuetz A. Differential inhibition of primary versus preactivated T cells by pimecrolimus but not by tacrolimus in vitro. Int Arch Allergy Immunol. 2007;142(3):255–64.

  24. Niwa Y, Terashima T, Sumi H. Topical application of the immunosuppressant tacrolimus accelerates carcinogenesis in mouse skin. Br J Dermatol. 2003;149(5):960–7.

    Article  CAS  PubMed  Google Scholar 

  25. Wu PC, Huang IH, Liu CW, Huang YC. Topical calcineurin inhibitors and risk of lymphoma: a systematic review and meta-analysis. J Dtsch Dermatol Ges. 2021;19(9):1265–9.

    PubMed  Google Scholar 

  26. Arana A, Wentworth CE, Fernandez-Vidaurre C, Schlienger RG, Conde E, Arellano FM. Incidence of cancer in the general population and in patients with or without atopic dermatitis in the U.K. Br J Dermatol. 2010;163(5):1036–43.

    Article  CAS  PubMed  Google Scholar 

  27. Undre NA, Moloney FJ, Ahmadi S, Stevenson P, Murphy GM. Skin and systemic pharmacokinetics of tacrolimus following topical application of tacrolimus ointment in adults with moderate to severe atopic dermatitis. Br J Dermatol. 2009;160(3):665–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Health Care Administration, Taipei Medical University, Taipei, Taiwan

    Hao-Hsin Huang & Dereck Shen

  2. Department of Pharmacy, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Hao-Hsin Huang

  3. Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, 15F, No. 7, Chung-Shan South Road, Taipei, Taiwan

    Tom C. Chan, Yung-Tsu Cho & Chia-Yu Chu

  4. School of Health Care Administration, College of Management, Taipei Medical University, 172-1 Keelung Road, Section 2, Taipei, 106, Taiwan

    Chao-Hsiun Tang

Authors
  1. Hao-Hsin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dereck Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tom C. Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yung-Tsu Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chao-Hsiun Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chia-Yu Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Chao-Hsiun Tang or Chia-Yu Chu.

Ethics declarations

Author contributions

Data collection and analysis: Hao-Hsin Huang and Dereck Shen; data analysis, critical revision and editing: Tom C. Chan, Yung-Tsu Cho, Chao-Hsiun Tang, Chia-Yu Chu; study conception and design: Hao-Hsin Huang, Tom C. Chan, Yung-Tsu Cho, Chao-Hsiun Tang, Chia-Yu Chu. All authors read and approved the final manuscript.

Funding

None.

Patient consent to participate/publish

Not applicable.

Code availability

Available from the author on request.

IRB Approval

The study was approved by the Taipei Medical University Research Ethics Committee (N202010057).

Conflicts of Interest

Chia-Yu Chu has received honoraria as a consultant and speaker for Viatris. The other authors have no conflicts of interest to declare.

Data Availability Statement

The datasets analyzed during the current study are not publicly available because of legal restrictions by the government of Taiwan in relation to the Personal Information Protection Act, but are available from the corresponding author on reasonable request.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 248 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huang, HH., Shen, D., Chan, T.C. et al. Association Between the Use of Topical Calcineurin Inhibitors and the Risk of Cancer Among Patients with Atopic Dermatitis: A Nationwide, Population-Based, Retrospective Cohort Study. Am J Clin Dermatol 24, 799–808 (2023). https://doi.org/10.1007/s40257-023-00787-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40257-023-00787-3

Search

Navigation