Castellsague Jordi, Kuiper Josephina G, Pottegård Anton, Anveden Berglind Ingegärd, Dedman Daniel, Gutierrez Lia, Calingaert Brian, van Herk-Sukel Myrthe Pp, Hallas Jesper, Sundström Anders, Gallagher Arlene M, Kaye James A, Pardo Carolina, Rothman Kenneth J, Perez-Gutthann Susana
Department of Epidemiology, RTI Health Solutions, Barcelona, Spain.
Department Research, PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands.
Clin Epidemiol. 2018 Mar 13;10:299-310. doi: 10.2147/CLEP.S146442. eCollection 2018.
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.
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.
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.
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.
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.
人们担心用于特应性皮炎二线治疗的外用他克莫司和吡美莫司可能会增加淋巴瘤和皮肤癌的风险，尤其是在儿童中。
本研究的目的是比较外用他克莫司或吡美莫司新使用者与中强效外用糖皮质激素（TCS）使用者及未治疗受试者之间淋巴瘤和皮肤癌的发病率（IR）。
这是一项多中心队列研究，在荷兰、丹麦、瑞典和英国的人群数据库中按倾向得分分层进行频率匹配。使用Mantel-Haenszel方法进行分层分析来估计IR比（IRR）。
我们纳入了19948名开始使用他克莫司的儿童和66127名成人、23840名开始使用吡美莫司的儿童和37417名成人、584121名TCS使用者以及257074名未治疗受试者。每100000人年使用他克莫司的儿童淋巴瘤发病率为10.4例，成人发病率为41.0例；使用吡美莫司的儿童发病率为3.0例，成人发病率为27.0例。他克莫司与TCS相比，儿童淋巴瘤的IRR（95%置信区间[CI]）为3.74（1.00 - 14.06），成人IRR为1.27（0.94 - 1.71）。按淋巴瘤类型，儿童霍奇金淋巴瘤的最高IRR为3.17（0.58 - 17.23），成人皮肤T细胞淋巴瘤（CTCL）的IRR为1.76（95% CI，0.81 - 3.79）。吡美莫司与TCS相比，成人CTCL的最高IRR为1.31（95% CI，0.33 - 5.14）。与未治疗受试者相比，使用TCS的成人CTCL发病率更高（IRR，10.66；95% CI，2.60 - 43.75）。在使用他克莫司和吡美莫司与恶性黑色素瘤或非黑色素瘤皮肤癌风险之间发现的关联较小。
外用他克莫司和吡美莫司的使用与淋巴瘤风险增加有关。低发病率表明，即使增加的风险是因果关系，对个体患者来说也只是小的额外风险。特应性皮炎严重程度的残余混杂因素、对重症患者监测的增加以及反向因果关系可能影响了结果。
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