Silva Francisco, Seo Philip, Schroeder Darrell R, Stone John H, Merkel Peter A, Hoffman Gary S, Spiera Robert, Sebastian Jodi K, Davis John C, St Clair E William, Allen Nancy B, McCune W Joseph, Ytterberg Steven R, Specks Ulrich
Mayo Clinic, Rochester, Minnesota, USA.
Arthritis Rheum. 2011 Aug;63(8):2495-503. doi: 10.1002/art.30394.
An association between therapeutic inhibition of tumor necrosis factor (TNF) and solid malignancies was observed during the Wegener's Granulomatosis Etanercept Trial (WGET), which included 180 patients with granulomatosis with polyangiitis (Wegener's) (GPA). The present study was conducted to determine the malignancy risk beyond the time of exposure to study therapy.
The occurrence and type of solid malignancies were ascertained using a standardized data form. Data collected included vital status, histologic findings, and therapeutic interventions. The Surveillance, Epidemiology, and End-Results database was used to estimate a standardized incidence rate (SIR) for solid malignancies.
Post-trial followup data were available for 153 patients (85% of the original cohort), with a median followup time of 43 months. Fifty percent of these patients had received etanercept. There were no differences in demographic characteristics between the etanercept and placebo groups. Thirteen new solid malignancies were detected, 8 in the etanercept group and 5 in the placebo group. Compared to the general population, the risk of solid malignancies in the etanercept group was increased (SIR 3.92 [95% confidence interval 1.69-7.72]), but was not different from the risk in the placebo group compared to the general population (SIR 2.89 [95% confidence interval 0.94-6.73]). All solid malignancies occurred in patients who had been exposed to cyclophosphamide. The overall duration of disease and a history of malignancy before trial enrollment were associated with the development of malignancy during post-trial followup.
The incidence of solid malignancy remained increased during long-term followup of the WGET cohort. However, this could not be attributed solely to etanercept exposure during the trial. Anti-TNF therapy with etanercept appears to further increase the risk of malignancy observed in patients with GPA treated with cytotoxic agents and should be avoided in these patients.
在韦格纳肉芽肿病依那西普试验（WGET）期间观察到肿瘤坏死因子（TNF）的治疗性抑制与实体恶性肿瘤之间存在关联，该试验纳入了180例肉芽肿性多血管炎（韦格纳氏）（GPA）患者。进行本研究以确定暴露于研究治疗之外的恶性肿瘤风险。
使用标准化数据表格确定实体恶性肿瘤的发生情况和类型。收集的数据包括生命状态、组织学结果和治疗干预措施。利用监测、流行病学和最终结果数据库估计实体恶性肿瘤的标准化发病率（SIR）。
153例患者（占原始队列的85%）有试验后随访数据，中位随访时间为43个月。这些患者中有50%接受了依那西普治疗。依那西普组和安慰剂组在人口统计学特征上没有差异。检测到13例新的实体恶性肿瘤，依那西普组8例，安慰剂组5例。与一般人群相比，依那西普组实体恶性肿瘤的风险增加（SIR 3.92 [95%置信区间1.69 - 7.72]），但与安慰剂组相比，与一般人群的风险没有差异（SIR 2.89 [95%置信区间0.94 - 6.73]）。所有实体恶性肿瘤均发生在曾接受环磷酰胺治疗的患者中。疾病的总病程和试验入组前的恶性肿瘤病史与试验后随访期间恶性肿瘤的发生有关。
WGET队列的长期随访期间实体恶性肿瘤的发病率仍然增加。然而，这不能仅归因于试验期间依那西普的暴露。用依那西普进行抗TNF治疗似乎会进一步增加接受细胞毒性药物治疗的GPA患者中观察到的恶性肿瘤风险，在这些患者中应避免使用。
