Dpartement de Pharmacologie, Univ. de Bordeaux, France.
Drug Saf. 2011 Jul 1;34(7):577-85. doi: 10.2165/11590200-000000000-00000.
Anti-tumour necrosis factor (TNF) agents, through their intense immunoregulatory effect, have been suspected to increase the risk of malignant lymphoma. However, the classical epidemiological approaches conducted over about the last 10 years have not totally succeeded in addressing the question of a causal or artifactual association. Therefore, the analysis of a substantial set of case reports, although usually considered as poorly generalizable to the general population, could be particularly informative. Two main sources of case reports in postmarketing settings are available; publications in medical journals and reports to pharmacovigilance systems.
The aim of the study was to compare the characteristics of case reports from both these sources in order to understand whether they provided the same information for the investigation of the causal link between lymphoma and anti-TNF agents.
All case reports of malignant lymphoma in patients treated with an anti-TNF agent published in MEDLINE and all reports to the French pharmacovigilance system up to 1 February 2010 were identified. Cases of malignant lymphoma identified in postmarketing surveillance from both sources were compared regarding the following variables: age, sex, anti-TNF agent involved, indication for use, type of lymphoma, prior or concomitant immunosuppressive drugs and time to onset of lymphoma.
A total of 81 published case reports and 61 cases reported to the French pharmacovigilance system were compared. In published reports, patients were younger (p = 0.03) and more frequently receiving a first anti-TNF treatment (p = 0.03), particularly infliximab (p = 0.03). Conversely, in the pharmacovigilance system reports, a succession of different anti-TNFs (p = 0.03) and adalimumab (p < 0.0001) were more frequently reported. Lymphomas in patients treated with anti-TNF agents for Crohn's disease were more prevalent in published cases than in pharmacovigilance reports (p < 0.0001), and in particular involved hepatosplenic T-cell lymphoma. Conversely, rheumatoid arthritis was the main indication for anti-TNF agents in pharmacovigilance reports (p = 0.01). Time to onset was markedly shorter in published cases (median 12 months) than in pharmacovigilance reports (median 30 months; p = 0.0001).
Characteristics of published cases and those reported to the French pharmacovigilance system differed markedly for all characteristics tested, except sex and the use of prior or concomitant immunosuppressive drugs. Published case reports favoured convincing arguments for drug causation whereas cases reported to the pharmacovigilance system were more disparate but could describe more accurately the reality of lymphoma occurrence in this particular population. These results argue for the use of the pharmacovigilance reports when case reports are used to investigate the causal link between lymphoma and anti-TNF agents at the population level. Data from cases notified to the French pharmacovigilance system did not indicate an increased risk of lymphoma during the early phase of anti-TNF treatment. To confirm this hypothesis, a study combining pharmacovigilance reports from several countries, or, if feasible, a cohort study both with a large sample size and a long duration of follow-up would be required.
抗肿瘤坏死因子（TNF）药物通过其强烈的免疫调节作用，被怀疑会增加恶性淋巴瘤的风险。然而，过去约 10 年进行的经典流行病学方法并未完全成功地解决因果关系或人为关联的问题。因此，对大量病例报告的分析，尽管通常认为不太适用于一般人群，但可能具有特别的信息价值。在上市后环境中有两种主要的病例报告来源；医学期刊上的出版物和药物警戒系统的报告。
本研究旨在比较这两种来源的病例报告的特征，以了解它们是否为调查抗 TNF 药物与淋巴瘤之间的因果关系提供了相同的信息。
在 MEDLINE 中检索到所有接受抗 TNF 药物治疗的恶性淋巴瘤患者的病例报告，并检索到截至 2010 年 2 月 1 日的法国药物警戒系统的所有报告。比较来自这两个来源的上市后监测中的恶性淋巴瘤病例的以下变量：年龄、性别、涉及的抗 TNF 药物、使用指征、淋巴瘤类型、先前或同时使用的免疫抑制剂以及淋巴瘤发病时间。
共比较了 81 篇发表的病例报告和 61 例向法国药物警戒系统报告的病例。在发表的报告中，患者更年轻（p=0.03），且更常接受首次抗 TNF 治疗（p=0.03），特别是英夫利昔单抗（p=0.03）。相反，在药物警戒系统报告中，更常报告连续使用不同的抗 TNF 药物（p=0.03）和阿达木单抗（p<0.0001）。在接受抗 TNF 药物治疗克罗恩病的患者中，发表的病例中更常报告淋巴瘤（p<0.0001），特别是肝脾 T 细胞淋巴瘤。相反，类风湿关节炎是药物警戒报告中抗 TNF 药物的主要适应证（p=0.01）。发病时间在发表的病例中明显短于药物警戒报告（中位数 12 个月）（中位数 30 个月；p=0.0001）。
所有测试的特征除了性别和使用先前或同时使用的免疫抑制剂外，发表的病例和向法国药物警戒系统报告的病例的特征明显不同。发表的病例报告支持药物因果关系的有力证据，而向药物警戒系统报告的病例则更加分散，但可以更准确地描述该特定人群中淋巴瘤发生的实际情况。这些结果表明，在人群水平上调查淋巴瘤与抗 TNF 药物之间的因果关系时，应同时使用药物警戒报告和病例报告。向法国药物警戒系统报告的病例数据并未表明在抗 TNF 治疗早期增加淋巴瘤的风险。为了证实这一假设，需要结合来自多个国家的药物警戒报告进行研究，或者如果可行的话，进行一项具有较大样本量和较长随访时间的队列研究。
