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. 2018 Mar 13:10:299-310.
doi: 10.2147/CLEP.S146442. eCollection 2018.

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)

Jordi Castellsague  1 , Josephina G Kuiper  2 , Anton Pottegård  3 , Ingegärd Anveden Berglind  4 , Daniel Dedman  5 , Lia Gutierrez  1 , Brian Calingaert  6 , Myrthe Pp van Herk-Sukel  2 , Jesper Hallas  3 , Anders Sundström  4 , Arlene M Gallagher  5 , James A Kaye  7 , Carolina Pardo  8 , Kenneth J Rothman  7 , Susana Perez-Gutthann  1
Affiliations

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)

Jordi Castellsague et al. Clin Epidemiol. .

Abstract

Background: There is a concern that topical tacrolimus and pimecrolimus, indicated for second-line treatment of atopic dermatitis, may increase the risk of lymphoma and skin cancer, particularly in children.

Objective: The aim of this study was to compare incidence rates (IRs) of lymphoma and skin cancer between new users of topical tacrolimus or pimecrolimus and users of moderate- to high-potency topical corticosteroids (TCSs) and untreated subjects.

Methods: This is a multicenter cohort study with frequency matching by strata of propensity scores in population databases in the Netherlands, Denmark, Sweden, and the UK. IR ratios (IRRs) were estimated using Mantel-Haenszel methods for stratified analysis.

Results: We included 19,948 children and 66,127 adults initiating tacrolimus, 23,840 children and 37,417 adults initiating pimecrolimus, 584,121 users of TCSs, and 257,074 untreated subjects. IRs of lymphoma per 100,000 person-years were 10.4 events in children and 41.0 events in adults using tacrolimus and 3.0 events in children and 27.0 events in adults using pimecrolimus. The IRR (95% confidence interval [CI]) for lymphoma, tacrolimus versus TCSs, was 3.74 (1.00-14.06) in children and 1.27 (0.94-1.71) in adults. By lymphoma type, the highest IRR was 3.17 (0.58-17.23) for Hodgkin lymphoma in children and 1.76 (95% CI, 0.81-3.79) for cutaneous T-cell lymphoma (CTCL) in adults. For pimecrolimus versus TCSs, the highest IRR was 1.31 (95% CI, 0.33-5.14) for CTCL in adults. Compared with untreated subjects, adults using TCSs had a higher incidence of CTCL (IRR, 10.66; 95% CI, 2.60-43.75). Smaller associations were found between tacrolimus and pimecrolimus use and the risk of malignant melanoma or nonmelanoma skin cancer.

Conclusion: Use of topical tacrolimus and pimecrolimus was associated with an increased risk of lymphoma. The low IRs imply that even if the increased risk is causal, it represents a small excess risk for individual patients. Residual confounding by severity of atopic dermatitis, increased monitoring of severe patients, and reverse causation could have affected the results.

Keywords: cutaneous T-cell lymphoma; database study; malignant melanoma skin cancer; topical calcineurin inhibitors.

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Conflict of interest statement

Disclosure At the time of the study, JC, LG, BC, KJR, JAK, and SP-G were full-time employees of RTI Health Solutions, an independent nonprofit research organization that does work for government agencies and pharmaceutical companies. As employees of RTI Health Solutions, SP-G, KJR, and JAK also participate in scientific advisory boards (for studies and medications) that are funded by pharmaceutical companies. JGK and MPPvH-S are employees of the PHARMO Institute for Drug Outcomes Research. This independent research institute performs financially supported studies for government and related health care authorities and several pharmaceutical companies. JH and AP are employees of the University of Southern Denmark, Clinical Pharmacology and Pharmacy. They have participated in studies funded by pharmaceutical companies (Alcon, Almirall, Astellas, Astra-Zeneca, Boehringer-Ingelheim, Pfizer, Menarini, Servier, and Takeda), with money paid to their employer. DD and AMG are employees of the Clinical Practice Research Datalink (CPRD), which provides contract research services for government and related health care authorities and pharmaceutical companies. IAB and AS were full-time employees of the Centre for Pharmacoepidemiology at the Karolinska Institutet during the conduct of the study. They have both taken part in studies undertaken at the Centre, financed by pharmaceutical companies, but have never received compensation personally from any company. CP is an employee of Astellas Pharma Europe. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Study cohorts. Note: “Corticosteroids” refer to moderate- to high-potency topical corticosteroids.
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