近日，欧洲药品管理局（EMA）发布公告，称已经完成了接种人乳头瘤病毒（HPV）疫苗的年轻女性中两种综合征，即复杂性区域疼痛综合征（CRPS）和体位性心动过速综合征（POTS）报告的证据审查。接种此疫苗旨在预防女性罹患宫颈癌以及其他HPV相关癌症和癌前疾病。与初始推荐一致，EMA证实了这些证据不支持HPV疫苗与CRPS或POTS的发生之间存在因果关系。因此，没有理由变更疫苗的使用方式或修改当前的产品信息。
HPV疫苗以商品名Gardasil/Silgard、Gardasil 9和Cervarix在欧盟上市，这些疫苗在获批后已被多个国家纳入国家免疫规划项目中。估计全球有超过6300万女性接种了Gardasil/Silgard，超过1900万女性接种了Cervarix。
CRPS是一种累及肢体的慢性疼痛综合征，POTS是一种在坐位或站位时心率异常加快，同时伴有头晕、晕厥和无力以及头痛、周身疼痛、恶心和疲乏等症状的综合征，某些患者的症状可严重影响生活质量。CRPS和POTS的症状可与其他疾病重叠，使得对一般人群和疫苗接种个体诊断较为困难。然而，现有的估计值提示，在一般人群中，每年每100万名10岁~19岁的女孩和年轻女性中约有150名会发生CRPS，每年每100万名女孩和年轻女性中至少有150名可能发生POTS。即使考虑到可能的漏报，该审查也未发现在接种疫苗的女孩中上述综合征的总发生率与该年龄组中预期的发生率存在差异的证据。
EMA的审查纳入了已发表的研究、临床试验数据、患者和医疗保健专业人士报告的疑似不良反应以及成员国提供的数据。管理局的药物警戒风险评估委员会（PRAC）负责初步审查。在作出结论的过程中，还咨询了该领域顶级专家组的意见，并考虑接收若干患者组的详细信息，同时该信息强调了这些综合征可能对患者和家庭的影响。PRAC的审查结果连同患者组的更多陈述被提交至管理局的人用药品委员会（CHMP）。CHMP一致认为现有证据不支持CRPS和POTS由HPV疫苗所致。因此，不建议对这些疫苗的许可或产品信息作出任何变更。
该审查认为，目前全球有超过8000万女孩和妇女接种了这些疫苗，在某些欧洲国家推荐的年龄组中90%接种了这些疫苗。使用这些疫苗预期可预防许多宫颈癌（子宫颈癌症，在欧洲每年导致超过20000例死亡）以及HPV所致的各种其他癌症和疾病。因此，HPV疫苗的获益仍大于已知的副作用。与所有的药品一样，EMA将继续密切监测这些疫苗的安全性，并将在发现任何未来的副作用的新证据时予以考虑。
目前， CHMP的意见将提交至欧洲委员会作出法律约束决定。稍后将在EMA的网站上发布包含支持管理局审查证据的评估报告。（EMA网站）
HPV vaccines: EMA confirms evidence does not support that they cause CRPS or POTS
Reports after HPV vaccination consistent with what would be expected in this age group
EMA has now completed its review of the evidence surrounding reports of two syndromes, complex regional pain syndrome (CRPS) and postural orthostatic tachycardia syndrome (POTS) in young women given human papillomavirus (HPV) vaccines. These vaccines are given to protect them from cervical cancer and other HPV-related cancers and pre-cancerous conditions. In line with its initial recommendations, EMA confirms that the evidence does not support a causal link between the vaccines (Cervarix, Gardasil/Silgard and Gardasil 9) and development of CRPS or POTS. Therefore there is no reason to change the way the vaccines are used or amend the current product information.
CRPS is a chronic pain syndrome affecting a limb, while POTS is a condition where the heart rate increases abnormally on sitting or standing up, together with symptoms such as dizziness, fainting and weakness, as well as headache, aches and pains, nausea and fatigue. In some patients they can severely affect the quality of life. The syndromes are recognised to occur in the general population, including adolescents, regardless of vaccination.
Symptoms of CRPS and POTS may overlap with other conditions, making diagnosis difficult in both the general population and vaccinated individuals. However, available estimates suggest that in the general population around 150 girls and young women per million aged 10 to 19 years may develop CRPS each year, and at least 150 girls and young women per million may develop POTS each year. The review found no evidence that the overall occurrence of these syndromes in vaccinated girls were different from expected occurrence in these age groups, even taking into account possible underreporting. The review noted that some symptoms of CRPS and POTS may overlap with chronic fatigue syndrome (CFS, also known as myalgic encephalomyelitis or ME). Many of the reports considered in the review have features of CFS and some patients had diagnoses of both POTS and CFS. Results of a large published study that showed no link between HPV vaccine and CFS were therefore particularly relevant.
The Agency’s review included published research, data from clinical trials and reports of suspected side effects from patients and healthcare professionals, as well as data supplied by Member States. The Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) was responsible for the initial review. In reaching its recommendations, it also consulted a group of leading experts in the field, and took into account detailed information received from a number of patient groups that also highlighted the impact these syndromes can have on patients and families.
The findings of the PRAC were passed to the Agency’s Committee for Medicinal Products for Human Use (CHMP), along with further representations from patient groups. The CHMP concurred that the available evidence does not support that CRPS and POTS are caused by HPV vaccines. It therefore did not recommend any changes to the terms of licensing or the product information for these medicines.
The review recognised that more than 80 million girls and women worldwide have now received these vaccines, and in some European countries they have been given to 90% of the age group recommended for vaccination. Use of these vaccines is expected to prevent many cases of cervical cancer (cancer of the neck of the womb, which is responsible for over 20,000 deaths in Europe each year) and various other cancers and conditions caused by HPV. The benefits of HPV vaccines therefore continue to outweigh the known side effects. The safety of these vaccines, as with all medicines, will continue to be carefully monitored and will take into account any future new evidence of side effects that becomes available.
The CHMP’s position will now be passed to the European Commission for a legally binding decision. The assessment report containing the evidence supporting the Agency’s review will be published shortly on EMA’s website.
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