张莉芸医生的科普号

译者：段姣妞校正：郭乾育审核：许珂Abstract：OBJECTIVE:Cardiovasculardisease (CVD) is the leading cause of mortality inpatientswithrheumatoid arthritis(RA).Hydroxychloroquine(HCQ) has been shown to improve survival rates in other inflammatory diseases. We aimed to assess the available literature on thecardiovascularimpact of HCQ inpatientswith RA.METHODS:We systematically searched for studies evaluating the effects of HCQ oncardiovascularoutcomes of known risk factors for CVD inpatientswith RA. Databases searched were MEDLINE (via PubMed), EMBase, Cochrane Library and the American College of Rheumatology and European League Against Rheumatism annual meetings. A meta-analysis was performed with a random-effects model, estimating mean differences (MDs), HRs and 95% CIs. Data were extracted by one investigator and independently checked by another.RESULTS:The literature search revealed 185 articles and abstracts of interest; further examination resulted in 16 studies fulfilling the criteria. The MDs between HCQ users and non-users in levels of total, low-density and high-density cholesterol and triglycerides were -9.8 (95% CI -14.0 to -5.6), -10.6 (95% CI -14.2 to -7.0), +4.1 (95% CI 2.2 to 6.0) and -19.2 (95% CI -27.2 to -11.1), respectively. Diabetes incidence was lower for HCQ ever users than never users (HR 0.59 (95% CI 0.49 to 0.70)). HCQ seemed to decrease insulin resistance and incidence of CVD, but data were too few for meta-analysis.CONCLUSION:Besides its limited efficacy for disease activity and progression, HCQ may benefit themetabolicprofile and to a lesser extentcardiovascularevents inpatientswith RA, which suggests its usefulness combined with other conventional synthetic disease-modifying antirheumatic drugs.摘要目的：心血管疾病（CVD）是类风湿关节炎（RA）患者的主要死因。已证实羟氯喹（HCQ）可改善其他炎性疾病的生存率。我们旨在评估目前可获得的有关HCQ对RA患者心血管作用的文献。方法：我们系统性检索了评估HCQ对已知CVD危险因素的RA患者心血管结局作用的研究。检索的数据库是MEDLINE（经Pubmed），EMBase，Cochrane图书馆，ACR及EULAR会议。对随机效应模型、估算平均差（MDs）、HRs和95%CIs进行meta分析。由一名审查者提取数据，另一名审查者单独检查。结果：共检索到185篇文献及感兴趣的摘要，在符合纳入标准的16项研究中进一步考察结果。HCQ使用者和未使用者之间总胆固醇、低密度和高密度胆固醇和甘油三酯水平的MD分别是-9.8 (95% CI -14.0 to -5.6), -10.6 (95% CI -14.2 to -7.0), +4.1 (95% CI 2.2 to 6.0) and -19.2 (95% CI -27.2 to -11.1)。曾经使用HCQ者糖尿病发生率较未使用者低(HR，0.59 (95% CI 0.49 to 0.70))。HCQ可能会降低胰岛素抵抗及CVD发生率，但数据太少无法进行meta分析。结论：研究显示，除对疾病活动性及进展的有限疗效外，HCQ可能对RA患者代谢水平及较小程度的心血管事件有益，这表明其联合其他常规抗风湿药物在改善疾病中的有效性。引自：Rempenault C, Combe B, et al. Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and meta-analysis.Ann Rheum Dis.2018 Jan;77(1):98-103.

翻译：和平校对：郭乾育审核：许珂AbstractOBJECTIVE:To determine the role of CCL21 and its receptor CCR7 in the pathogenesis ofrheumatoid arthritis(RA).METHODS:Histologic studies were performed to compare the expression of CCR7 and CCL21 in RA synovial tissue. Next, the role of CCL21 and/or CCR7 in angiogenesis was examined using in vitro chemotaxis, tube formation, and in vivo Matrigel plug assays. Finally, the mechanism by which CCL21 mediates angiogenesis was determined by Western blot analysis and endothelial cell chemotaxis and tube formation assays.RESULTS:CCL21, but not CCL19, at concentrations present in the RA joint, induced human microvascular endothelial cell (HMVEC) migration that was mediated through CCR7 ligation. Suppression of the phosphatidylinositol 3-kinase pathway markedly reduced CCL21-induced HMVEC chemotaxis and tube formation; however, suppression of the ERK and JNK pathways had no effect on these processes. Neutralization of either CCL21 in RA synovial fluid or CCR7 in HMVECs significantly reduced the induction of HMVEC migration and/or tube formation by RA synovial fluid. We further demonstrated that CCL21 is angiogenic, by showing its ability to promote blood vessel growth in Matrigel plugs in vivo at concentrations that are present in RA joints.CONCLUSION:Angiogenesis is dependent on endothelial cell activation, migration, and proliferation, and inhibition of angiogenesis may provide a novel therapeutic approach in RA. This study identified a novel function of CCL21 as a mediator of RA angiogenesis, supporting CCL21/CCR7 as a therapeutic target in RA.摘要：目的：明确CCL21及其受体CCR7在类风湿关节炎（RA）发病机制中的作用。方法：采用组织学研究比较RA滑膜组织中CCR7及CCL21表达差异。此外，通过体内及体外实评估CCL21和/或CCR7血管生成作用，体外实验检测其趋化作用及血管形成，体内实验选用基质凝胶塞试验。最后，通过Western blot法、内皮细胞趋化性及血管形成分析法评估CCL21介导血管生成的机制。结果：在RA关节所含浓度下，CCL21可通过与CCR7结合诱导人微血管内皮细胞（HMVEC）迁移。抑制磷脂酰肌醇-3激酶通路可显著降低CCL21诱导的HMVEC趋化性及血管形成。但抑制ERK和JNK通路则无上诉过程。中和RA滑液中CCL21或HMVEC的CCR7均可显著抑制HMVEC迁移和/或血管生成。体内基质凝胶塞试验中，在RA关节所含浓度下，CCL21是促血管生成因子，具有促进血管生长的作用。结论：血管生成依赖于内皮细胞的活化、迁移及增殖，抑制血管生成可能是RA治疗的一种新的手段。本实验发现CCL2对RA血管生成具有调控作用，表明CCL21/CCR7可作为RA的治疗靶点。引自：Pickens SR,Chamberlain ND,Volin MV,et al.Role of the CCL21 and CCR7 pathways inrheumatoid arthritisangiogenesis.ArthritisRheum.2012 Aug;64(8):2471-81. doi: 10.1002/art.34452.

译者：付毛毛校对：刘素苗审核：许珂To investigate the association between primary Sjgren'ssyndrome(pSS) and coronary heart disease (CHD), and the influence of medications for pSS patients on risk of CHD. The authors identified 4175 patients with a new diagnosis of pSS between 2002 and 2013 from the National Health Insurance Research database. The control-to-case ratio was 4:1. The risk and cumulative incidences of CHD were calculated. The adjusted hazard ratio (HR) of CHD for pSS patients was 1.17 (1.03-1.34) after adjusting for age, sex, comorbidities, and medications. The cumulative incidence for CHD in the pSS group was significantly higher than that in the control group (log-rank p<0.0001). The risk of CHD in pSS patients was increased with age by 4% per year, and 45- to 59-year-olds were at the highest risk (HR=1.464, 1.195-1.794). The application of corticosteroids (HR=1.45, 1.07-1.97) as well as NSAIDS (HR=1.31, 1.05-1.65) both increased the risk of CHD among pSS patients. pSS is associated with an increased risk of subsequent CHD in Taiwan. Primary Sjgren'ssyndromemight be an independent risk factor for CHD. Use of corticosteroids and NSAIDS in the treatment of pSS patients increased the risk of developing CHD.探讨原发性干燥综合征（pSS）与冠心病（CHD）之间的关系，以及pSS患者用药后对冠心病风险的影响。作者从国家健康保险研究数据库中确定了4175名在2002年至2013年之间新诊断为pSS的患者。病例对照比值比为4：1。计算冠心病的风险和累积发生率。调整年龄，性别，并发症和药物后，冠心病患者调整后的危险比（HR）为1.17（1.03-1.34）。pSS组冠心病的累积发病率显着高于对照组（log-rank p<0.0001）。pSS患者中随年龄的增加，冠心病的风险每年增加4％，45至59岁的患者风险最高（HR = 1.464,1.195-1.794）。皮质类固醇（HR = 1.45,1.07-1.97）以及非甾体抗炎药（NSAIDS）（HR = 1.31,1.05-1.65）的应用均增加了pSS患者发生CHD的风险。 在台湾，pSS与继发CHD的风险增加有关。原发性干燥综合征可能是冠心病的独立危险因素。使用皮质类固醇和NSAIDS治疗pSS患者增加了CHD发生的风险。引自：Wu XF, Huang JY, Chiou JY.Increased risk of coronary heart disease among patients with primary Sjgren's syndrome: a nationwide population-based cohort study.Sci Rep. 2018 Feb 2;8(1):2209.

(l)很多慢性炎性风湿性疾病（包括弥漫性结缔组织病）病因不明，但普遍认为感染仍可能是重要的发病因素。感染可直接引起组织（关节）炎症，可引起机体对病原体或其持续产生的抗原发生免疫反应，多由免疫复合物介导引起骨关节肌肉炎症，可使机体对病原体的特异免疫反应与自身抗原起交叉反应，还可发生器官特异性免疫反应并与自身抗原起交叉免疫反应。(2)很多风湿性疾病特别是结缔组织病都发生于有一定的遗传背景的人群中。首先，遗传与患者的易感性和疾病表达密切相关，对临床病情及预后有一定意义，还可对研究发病机制提供线索。(3)很多风湿性疾病尤其是结缔组织病皆是异质性(heterogenous)疾病，换言之都存在不同的亚型。因为引起发病的病因不同，患者的遗传素质不同，所以很可能发病机制也不全相同，从而临床表现的病程、轻重、类型甚或治疗反应也不尽相同。异质性疾病提示临床医师处理这些疾病，无论在诊断、治疗上都不该是千篇一律的。风湿病学的研究方向应是区分不同亚型。(4)很多风湿性疾病都是侵犯多器官、多系统的，结缔组织病更是如此，表现上往往有重叠，往往缺乏单一能与其他疾病区分的特征。因此，风湿病学工作者应具备广泛的内科学，如肾脏病、呼吸系统疾病等基础知识，以避开风湿性疾病分类标准的局限性。

风湿性疾病（rheumatic diseases）是泛指影响骨、关节及其周围软组织，如肌肉、滑囊、肌键，筋膜、神经等的一组疾病，其病因可以是感染性、免疫性、代谢性、内分泌性、退行性、地理环境性、遗传性、肿瘤性等。风湿性疾病可以是周身性或系统性的（几乎所有结缔组织病），也可以是局限性的（如肩周炎或某一滑囊炎）；可以是器质性的，也可以是精神性的或功能性的。

译者：卫春 修改：梁美娥 审核：许珂Abstract：Background：Treatment with disease-modifying anti-rheumatic drugs (DMARDs) has raised concerns about the risk of malignancies in rheumatoid arthritis (RA) patients. However, the association between biologic DMARDs (bDMARDs) and malignancy in previous reports remains controversial. Therefore we aimed to estimate the incidence of malignancy in early RA patients and to evaluate the relative risk of malignancy with use of bDMARDs.Methods：A retrospective cohort of incident RA patients was established using the Korean National Claims Database. Among a total of 14,081 RA patients identified, 1684 patients with a history of malignancy were excluded. We calculated the incidence rate of overall and individual malignancies. The standardized incidence ratio (SIR) of malignancies in bDMARD users was compared to that in nonusers. Multivariable logistic regression analysis was used to evaluate the impact of bDMARDs on the development of malignancies in early RA patients.Results：A total of 12,397 early RA patients without a history of malignancy were enrolled. During 41,599 person-years (PY) of follow-up, 725 malignancies developed in 561 patients (174.3/10,000 PY) and 21 hematologic malignancies developed (5.0/10,000 PY). Patients treated with bDMARDs had a significantly lower incidence of overall malignancy compared to those not treated with bDMARDs (SIR 0.45 (95% CI 0.28–0.70)). However, this relationship was not significant with regard to hematologic malignancies (SIR 2.65 (95% CI 0.55–7.76)). On multivariable analysis, bDMARD use was a protective factor against the development of overall malignancy (odds ratio 0.42 (95% CI 0.25–0.73)). However, bDMARD use had no significant protective effect against the development of hematologic malignancies (odds ratio 1.69 (95% CI 0.38–7.59)).Conclusions：In early RA patients, bDMARD use decreases the overall risk of developing malignancies; however, it does not affect the risk of developing hematologic malignancies.摘要：背景：先前有报道显示，抗风湿药物（DMARDs）治疗会增加类风湿关节炎（RA）患者患肿瘤的风险。然而，DMARDs药物协会和先前报道的恶性肿瘤风险研究仍然是有争议的。因此，本研究目的是评估早期RA患者恶性肿瘤发病率和评价使用bDMARDs药物发生恶性肿瘤的相对风险。方法：使用韩国国家数据库建立了类风湿关节炎患者的回顾性队列研究。总共14081例RA患者，有1684例患有恶性肿瘤病史的RA患者被排除在外。统计使用bDMARDs药物的患者相比未使用者总体和个体恶性肿瘤标准化发病率（SIR）。多变量logistic回归分析来评估bDMARDs药物对早期RA患者恶性肿瘤发生发展的影响。结果：总共纳入12397名无恶性肿瘤病史的早期RA患者。在共41599人-年（PY）的随访，561例725恶性肿瘤（174.3/10000 PY）和21（5.0/10000 Py）血液系统恶性肿瘤的发展。使用bDMARDs药物治疗的患者相比没有接受bDMARDs药物患者，有显着降低总体恶性肿瘤的发病率（SIR 0.45（95% CI 0.28–0.70））。然而，在恶性血液病方面并不显著（SIR 2.65（95% CI 0.55 - 7.76））。在多变量分析中，使用bDMARDs药物是对整体恶性肿瘤发展的保护性因素（比值比为0.42（95% CI 0.25–0.73））。然而，对血液系统恶性肿瘤的发展无明显保护作用（比值比为1.69（95% CI 0.38–7.59））。结论：在早期RA患者，使用bDMARDs药物降低总体恶性肿瘤发生的风险；然而，它并不影响血液系统恶性肿瘤的发展风险。摘自：Soo-Kyung Cho, Jiyoung Lee, Minkyung Han, et al. The risk of malignancy and its incidence in early rheumatoid arthritis patients treated with biologic DMARDs[J]. Arthritis Res Ther. 2017; 19: 277. doi: 10.1186/s13075-017-1482-y.

急性风湿性心肌炎最早的临床表现是二尖瓣和主动脉瓣的杂间，此杂音由瓣膜返流造成，可单独或同时出现，二尖瓣区的杂音最多见。病变轻微的局限性心肌炎，可能无明显的临床症状。弥漫性心肌炎可有心包炎和充血性心力衰竭的临床症状，如心前区不适或疼痛，心悸，呼吸困难以及水肿等。

风湿性疾病很多以疼痛〔关节、肌肉、软组织、神经等的疼痛）为主要症状。但也不是所有风湿性疾病都疼痛。风湿性疾病中，各种原因所致的关节炎占重要组成部分;但风湿性疾病不只限于关节炎。

弥漫性结缔组织病简称结缔组织病（connective tissue disease,CTD），曾称胶原病。是风湿性疾病中的一大类，它除有风湿病的慢性病程、肌肉关节病变外，尚有以下特点：（1）属自身免疫病，CTD属非器官特异性自身免疫病，自身免疫性是CTD的发病基础。自身免疫性是指淋巴细胞丧失了对自身组织（抗原）的耐受性，以至于淋巴细胞对自身组织出现免疫反应并导致组织损伤。引起自身免疫性反应的可能因素如下：①病原体：如沙门菌、志贺菌、耶尔森菌、EB病毒、腺病毒等。②遗传基础：如强直性脊柱炎、系统性红斑狼疮、类风湿关节炎等均有不同程度的遗传倾向性。③隐藏的细胞表位被暴露而成为新的自身抗原。④性激素。⑤其他：如超抗原等。（2）以血管和结缔组织慢性炎症的病理改变为基础。（3）病变累及多个系统，包括肌肉、骨骼系统。（4）异质性，即同一疾病，在不同患者的临床表现和预后差异甚大。（5）对糖皮质激素的治疗有一定反应。（6）疾病多为慢性病程，逐渐累及多个器官和系统，只有早期诊断，合理治疗才能使患者得到良好的预后。

（1）弥漫性结缔组织病：类风湿关节炎、系统性红斑狼疮、系统性硬化症、多发性肌炎和皮肌炎、血管炎、干燥综合症、重叠综合征等。（2）脊柱关节病：强直性脊柱炎、Reiter综合征、银屑病关节炎、未分化脊柱关节病等。（3）退行性变：原发性或继发性骨关节炎等。（4）和感染有关的风湿病：化脓性关节炎、反应性关节炎、风湿热等。（5）与代谢和内分泌有关的风湿病：痛风、淀粉样病变、肢端肥大症、免疫缺陷病。（6）肿瘤相关的风湿病：多发性骨髓瘤，滑膜肉瘤等。（7）神经血管疾病：神经性关节病、压迫性神经病变（周围神经受压、神经根受压等）、雷诺病等。（8）骨与软骨病变：骨质疏松、骨软化、肥大性骨关节病、弥漫性原发性骨肥厚、骨炎等。（9）非关节性风湿病：关节周围病变、椎间盘病变、特发性腰痛、肌腱炎、其他痛综合征（如精神性风湿病）等。（10）其他有关节症状的疾病：周期性风湿病、间歇性关节积液、药物相关的风湿综合征、慢性活动性肝炎等。