The George Institute for Global Health, New Delhi, India.
Department of Medicine, McMaster University, Hamilton, ON, Canada.
Lancet Child Adolesc Health. 2023 Jan;7(1):13-25. doi: 10.1016/S2352-4642(22)00283-8. Epub 2022 Nov 10.
Atopic dermatitis is a prevalent condition in children and can be effectively managed with medications such as topical calcineurin inhibitors (pimecrolimus or tacrolimus). A key unresolved safety concern is whether use of topical calcineurin inhibitors is associated with cancer. We systematically reviewed the risk of cancer in patients with atopic dermatitis exposed to topical calcineurin inhibitors.
As part of the 2022 American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters atopic dermatitis guidelines, we searched MEDLINE, Embase, the Latin American and Caribbean Health Sciences Literature database, the Índice Bibliográfico Espanhol de Ciências da Saúde database, the Global Resource of Eczema Trials database, WHO's International Clinical Trials Registry Platform, the US Food and Drug Administration database, the European Medicines Agency database, company registers, and relevant citations from inception to June 6, 2022. We included randomised controlled trials and comparative and non-comparative non-randomised studies in any language addressing cancer risk in patients with atopic dermatitis using topical calcineurin inhibitors. We excluded split-body studies and studies with less than 3 weeks of follow-up. Paired reviewers independently screened records, extracted data, and assessed risk of bias in duplicate. We used Bayesian models to estimate the probability for cancer due to topical calcineurin inhibitor exposure and the GRADE approach to determine the certainty of the evidence. Patients, advocacy groups, and care providers set a priori thresholds of important effects. This study is registered with Open Science Framework, https://osf.io/v4bfc.
We identified and analysed 110 unique studies (52 randomised controlled trials and 69 non-randomised studies [11 were non-randomised study extensions of randomised controlled trials]) including 3·4 million patients followed up for a mean of 11 months (range 0·7-120). The absolute risk of any cancer with topical calcineurin inhibitor exposure was not different from controls (absolute risk 4·70 per 1000 with topical calcineurin inhibitors vs 4·56 per 1000 without; odds ratio 1·03 [95% credible interval 0·94-1·11]; moderate certainty). For all age groups and using data from observational studies and randomised controlled trials, the use of pimecrolimus (OR 1·05 [95% credible interval 0·94-1·15]) or tacrolimus (0·99 [0·89-1·09]) is likely to have had little to no association with cancer compared with no topical calcineurin inhibitor exposure. For pimecrolimus versus tacrolimus, the finding was similar (0·95 [95% credible interval 0·83-1·07]). Findings were similar in infants, children, and adults, and robust to trial sequential, subgroup, and sensitivity analyses.
Among individuals with atopic dermatitis, moderate-certainty evidence shows that topical calcineurin inhibitors do not increase the risk of cancer. These findings support the safe use of topical calcineurin inhibitors in the optimal treatment of patients with atopic dermatitis.
American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology via the Joint Task Force on Practice Parameters.
特应性皮炎是儿童中常见的疾病，可以通过使用局部钙调神经磷酸酶抑制剂（吡美莫司或他克莫司）等药物进行有效治疗。一个尚未解决的关键安全问题是使用局部钙调神经磷酸酶抑制剂是否与癌症有关。我们系统地回顾了特应性皮炎患者使用局部钙调神经磷酸酶抑制剂与癌症风险的关系。
作为 2022 年美国过敏、哮喘和免疫学学会与美国过敏、哮喘和免疫学学会联合实践参数特应性皮炎指南的一部分，我们在 MEDLINE、Embase、拉丁美洲和加勒比健康科学文献数据库、Índice Bibliográfico Espanhol de Ciências da Saúde 数据库、全球湿疹试验资源数据库、世界卫生组织国际临床试验注册平台、美国食品和药物管理局数据库、欧洲药品管理局数据库、公司登记处以及 2022 年 6 月 6 日之前的相关引文进行了搜索。我们纳入了在特应性皮炎患者中使用局部钙调神经磷酸酶抑制剂的随机对照试验和比较及非随机非对照研究，无论语言如何，都评估了癌症风险。我们排除了分体研究和随访时间少于 3 周的研究。配对审查员独立筛选记录、提取数据，并重复评估偏倚风险。我们使用贝叶斯模型来估计因局部钙调神经磷酸酶抑制剂暴露而导致癌症的概率，并使用 GRADE 方法来确定证据的确定性。患者、倡导团体和护理提供者预先设定了重要效果的阈值。本研究在 Open Science Framework 上注册，网址为 https://osf.io/v4bfc。
我们共确定并分析了 110 项独特的研究（52 项随机对照试验和 69 项非随机对照研究[11 项是非随机对照试验的扩展），包括 340 万名患者，平均随访 11 个月（范围为 0.7-120 个月）。与对照组相比，局部钙调神经磷酸酶抑制剂暴露后任何癌症的绝对风险并无差异（局部钙调神经磷酸酶抑制剂组的绝对风险为每 1000 人 4.70 例，而无局部钙调神经磷酸酶抑制剂组为每 1000 人 4.56 例；比值比 1.03[95%可信区间 0.94-1.11]；中等确定性）。在所有年龄组中，并且使用来自观察性研究和随机对照试验的数据，与无局部钙调神经磷酸酶抑制剂暴露相比，使用吡美莫司（比值比 1.05[95%可信区间 0.94-1.15]）或他克莫司（0.99[0.89-1.09]）可能与癌症的发生几乎没有关联。对于吡美莫司与他克莫司，这一发现也相似（0.95[95%可信区间 0.83-1.07]）。在婴儿、儿童和成人中，研究结果相似，并且对试验序贯、亚组和敏感性分析具有稳健性。
在特应性皮炎患者中，中等确定性证据表明局部钙调神经磷酸酶抑制剂不会增加癌症风险。这些发现支持在治疗特应性皮炎患者的最佳治疗中安全使用局部钙调神经磷酸酶抑制剂。
美国过敏、哮喘和免疫学学会与美国过敏、哮喘和免疫学学会通过联合实践参数工作组提供。
