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摘要: 青少年局限性硬皮病(juvenile localized scleroderma，JLS)是一种罕见的儿童自身免疫性疾病，早期缺乏特异性症状，易被误诊、漏诊而导致病变加剧，甚至造成机体功能损害和生长障碍等严重后果。为明确JLS病因，指导有效治疗药物的开发和应用，本文综述近年来JLS发病机制相关学说，总结其传统治疗方案和相关新型治疗药物研究进展，以提高临床医生对JLS的认识。Abstract: Juvenile localized scleroderma (JLS) is a rare autoimmune disease in children. The lack of specificity in the early symptoms of JLS makes it easy to be misdiagnosed and missed, which leads to the continuous progression of the lesions, and even causes systemic malfunction and growth disorder. For identifying the etiology of JLS and guiding the development and application of effective therapeutic drugs, we reviewed recent theories about the pathogenesis of JLS and summarized the traditional treatment options and relevant new therapeutic drugs, aiming to further enhance the fundamental understanding of JLS and its therapeutic progress.
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Keywords:
- juvenile localized scleroderma /
- pathogenesis /
- treatment /
- research progress
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高血压是我国患病人数最多的慢性病，也是导致城乡居民心脑血管疾病死亡最重要的危险因素。近年来，随着高血压及相关疾病临床研究证据的不断增加，许多国家和地区相继修订或更新了高血压指南；同时，在中国人群中开展高血压相关临床研究的循证医学证据不断积累，也为我国高血压指南的制订提供了更多循证依据和支持。因此，有必要针对高血压筛查、诊断、评估和治疗领域的关键临床问题，基于当前可获得的最佳循证证据，在充分考虑卫生经济学效益的基础上，开展中国高血压临床实践指南的制订工作。
由中华医学会心血管病学分会、海峡两岸医药卫生交流协会高血压专业委员会、中国康复医学会心血管疾病预防与康复专业委员会联合制定的《中国高血压临床实践指南》(下文简称“指南”)[1]，强调了高血压初始预防和一级预防的理念，将高血压的预防、药物治疗和非药物干预以及长期管理融为一体，是落实“健康中国行动”的重要举措。该指南是我国首部按照国际指南制订标准完成的高血压循证指南，其制订以临床需求和重要问题为导向，旨在解决高血压诊治过程中的关键问题，形成基于高质量临床研究证据且便于临床操作的推荐意见。
1. 强调应重视高血压前期的血压管理，确立了高血压防线前移的理念
新版指南仍将高血压定义为血压水平≥140/90 mm Hg (1 mm Hg=0.133 kPa)，但将血压水平(130~139)/(80~89)mm Hg范围定义为“高血压前期”，其依据是与血压水平低于130/80 mm Hg的人群相比，血压水平处于(130~139)/(80~89)mm Hg的人群其心血管疾病的发生风险明显升高，且大部分人群将在10~15年间进展为真正的高血压[2-5]，重视此类人群的血压和危险因素管理，充分体现了加强初始预防和一级预防的理念，即只有在疾病早期阶段积极干预才能真正降低心血管疾病的发生风险，而非等待血压发展至140/90 mm Hg以上才给予积极干预。
加强高血压前期人群的管理可能增加药物和/或非药物治疗费用，但有望降低因血压升高导致心脑血管并发症的高额治疗费用。最新卫生经济学评价研究也证实，针对血压水平在(130~139)/(80~89)mm Hg且具有较高心血管疾病发生风险的成年人进行降压药物治疗，将获得显著的成本效益，其中青年人群获益最大[6]。
目前我国高血压患者的高血压知晓率和控制率仍不足50%[7-8]，广大居民包括很多医务工作者对于高血压的主观认识和科学认知还有待提高。高血压领域的同道需秉持积极态度，倡导血压控制防线前移，加强社会各群体对早期高血压筛查及管理必要性的认识。
2. 创新性简化心血管疾病危险分层，有助于临床实施和推广
与既往国内外指南不同，新版指南将高血压前期及高血压患者的心血管疾病危险分层大幅简化，仅分为高危和非高危，有助于临床医生对血压升高患者进行快速危险分层，并决定降压治疗策略。既往指南推荐的“低危、中危、高危、极高危”等危险分层标准以及心血管风险评分工具的内容较多，不便于医生记忆和临床应用。新版指南对心血管疾病危险分层的方法和标准进行了简化，可显著提升其临床应用与推广空间。指南将血压≥140/90 mm Hg的患者直接归于高危患者，理由是这部分患者80% 以上伴有2种以上心血管疾病危险因素[9-10]，且可从降压治疗中明确获益。血压水平在(130~139)/(80~89)mm Hg伴靶器官损害的患者，积极降压治疗对于延缓其靶器官损害进展有益；合并≥3个危险因素者，其10年动脉粥样硬化性心血管疾病(atherosclerotic cardiovascular disease，ASCVD) 的发生风险基本≥10%，因此也将其列为高危心血管疾病风险，建议进行药物干预，体现出早防早治的预防理念。指南还首次将心房扩大列入靶器官损害，体现出对高血压-心房颤动事件链的重视。
3. 强调应采取更加积极的态度控制高血压
新版指南对于高血压防控的积极态度主要体现在降压目标值进一步降低。对于大多数高血压患者，推荐将血压降至＜130/80 mm Hg，包括无心血管合并症、合并冠心病、慢性心力衰竭、脑卒中、慢性肾脏病、糖尿病以及年龄＜80岁的老年高血压患者等；起始联合治疗的血压水平也有所降低，推荐血压≥140/90 mm Hg的高血压患者即可起始联合治疗和采用单片复方制剂；同时强调早期达标的重要性，将降压达标时间推荐为4周以内。
4. 充分吸纳高血压诊疗的新技术、新观点、新进展
新版指南积极与国际指南接轨，增加高血压器械干预进展部分，客观分析此类新技术的循证证据，明确适用人群，指明进一步的研究方向；增加单基因遗传性高血压相关内容，体现精准医疗进展。新指南以开放的心态接纳国际医学进步成果，同时也注重中国国情和本土循证证据，增加了北京大学临床研究所武阳丰团队的SSaSS研究成果[11]、中国医学科学院阜外医院蔡军团队的STEP研究成果[12]及中国医科大学附属第一医院孙英贤团队的CRHCP研究成果[13]。
5. 强调继发性高血压筛查的重要性
新版指南强调在新诊断的高血压和难治性高血压群体中开展继发性高血压病因学筛查的重要性，这是高血压防治理念的重大转变，体现了对病因诊断的高度重视。继发性高血压临床多表现为难治性高血压，且病因复杂，涉及多学科多专业，临床医生如不能对继发性高血压充分认识并进行系统筛查，很容易造成误诊和漏诊；而继发性高血压往往伴有严重的靶器官损伤，早期筛查更利于尽早针对病因开展治疗，因此对于新诊断的高血压患者进行继发性高血压筛查具有重要意义。高血压诊治的未来不应仅停留于测量血压、管理血压和控制风险层面，更要重视诱发或导致高血压的原因。强调新诊断的高血压患者应进行继发性高血压筛查，也体现了强化高血压控制的理念，早期控制血压达标，避免治疗走弯路，减少心血管不良事件。
6. 指南严格按照国际标准科学制订
新版指南遵循美国医学研究所最新指南定义[14]和世界卫生组织指南制订手册[15]的制订流程和要求，全文按照国际实践指南报告规范(Reporting Items for Practice Guidelines in Healthcare，RIGHT)[16]撰写。指南制订全程均在方法学专家的指导下完成，在制订之初撰写了详尽的指南计划书并在国际实践指南注册平台(http://www.guidelines-registry.org)进行双语注册；通过制订详细的利益冲突管理办法，要求所有参与制订的成员均填写利益冲突声明表，且指南制订全程未接受任何商业团体的任何形式赞助及支持，保证指南推荐意见的公平、可靠；参与指南制订的成员不仅包括心血管和高血压专科医生，还包括肾脏病科、内分泌科、泌尿外科、血管外科、精神心理科、流行病学、护理学、临床药学、卫生经济学等多学科领域的专家以及患者代表，充分听取各方意见；指南制订过程中采用问卷调查及评分法形成最终纳入指南的44个PICO(Population，Intervention，Comparison，and Outcome)问题，采用推荐意见分级的评估、制订及评价(Grading of Recommendations Assessment，Development and Evaluation，GRADE)分级体系[17]对推荐意见的支持证据体进行评级，对于无证据支持的部分临床问题，则依据专家临床经验，形成基于专家共识的推荐意见，即良好实践主张(good practice statement，GPS)[18]；推荐意见形成后通过2轮德尔菲专家函询法对推荐意见的内容及强度达成共识；在指南制订过程中，由于新的证据不断出现，部分临床问题进行了调整和修改。总之，新版指南是我国高血压领域首部完全按照国际指南制订标准完成的高质量循证指南，其推荐意见均基于目前可获得的高质量证据，并根据临床实际情况给出了推荐意见说明及注意事项。指南的临床问题和推荐意见简洁明了、言简意赅，方便临床医生快速理解并在实际工作中践行。
7. 小结与展望
综上所述，新版指南凝聚了中国高血压及相关领域百余名专家的智慧和汗水，对临床具有重要参考价值和指导意义。需指出的是，高血压领域涵盖的概念和临床问题非常广泛，本指南仅针对最重要的、对临床决策产生重要影响的以及最有争议的问题形成推荐意见，这是循证指南与既往传统指南的区别所在。同时，对于某些临床问题，现有研究证据尚不足以给予有力的支持，新版指南根据目前现有循证证据给出初步推荐意见并提出了未来的研究方向，鼓励积极开展相关研究，以期未来能够更好地指导临床实践。对于高血压这种关注度高、覆盖面广且诊治措施涉及方方面面的疾病而言，形成各方均能够接受且合理的推荐意见实属不易，未来指南制订专家组将根据新的证据持续更新和修订指南。我们坚信新版高血压临床实践指南的发布必将促进我国高血压防治事业的进步，推动“健康中国2030”目标的早日实现。
作者贡献：杨婧懿负责查阅文献资料和撰写论文；徐倩玥参与整理文献和修订论文；余红负责指导和修订论文。利益冲突：所有作者均声明不存在利益冲突 -
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