Research advances in Coronavirus Disease 2019 and rheumatoid arthritis
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摘要: 类风湿关节炎（RA）是一种慢性炎症性疾病，主要累及滑膜，还可侵蚀骨关节，甚至导致关节功能丧失。新型冠状病毒肺炎（COVID-19）患者可有肌肉骨骼症状，且危重症者病死率高。细胞因子在RA和COVID-19的发病中起重要作用，但其具体机制尚不清楚，研究应用于RA的抗风湿药物或可指导COVID-19的治疗。本文对COVID-19与RA的相关研究进行综述，以期进一步提高对疾病发病机制、临床表现和治疗药物的认识，从而改善患者预后。Abstract: Rheumatoid arthritis(RA) is an autoimmune disease characterized by chronic synovial inflammation,which eventually leads to different degrees of bone and cartilage erosion,even disability of joint.The patients of Coronavirus Disease 2019(COVID-19) can have musculoskeletal symptoms,and the mortality rate of critical patients is high.Cytokines play an important role in the pathogenesis of RA and COVID-19,the exact mechanism of which is unknown,and commonly used drugs of RA may guide the treatment of COVID-19.This article mainly reviewed the correlation between COVID-19 and RA in order to further improve the understanding of thepathogenesis,clinical manifestations,and treatment drugs of the disease and improve patients' outcomes.
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Keywords:
- Coronavirus Disease 2019 /
- rheumatoid arthritis /
- cytokine storm /
- treatment drugs
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输卵管妊娠是临床最常见的异位妊娠，其发生率占异位妊娠的95%~98%[1], 患者的临床表现多为不规则阴道出血、腹痛，可伴贫血、休克症状，如处理不及时，将严重威胁妇女健康。输卵管妊娠一经诊断，多采用手术治疗，随着微创技术的发展，腹腔镜因具有创伤小、恢复快等优点，是治疗输卵管妊娠的首选方式[2]。输卵管妊娠的手术方式有患侧输卵管切除术与保留输卵管妊娠病灶清除术，而患者手术后的生育结局及卵巢功能情况是临床关注的重点，本研究比较了这两种术式的临床应用效果，现报告如下。
1. 资料与方法
1.1 一般资料
选取2015年5月—2017年1月收治的输卵管妊娠患者100例，按照随机分组法分为2组，各50例。观察组患者平均年龄(30.10±5.30)岁，体质量(55.70±5.10) kg, 停经(42.50±5.50) d, 输卵管包块直径(4.11±1.02) cm; 对照组患者平均年龄(28.80±6.20)岁，体质量(52.30±5.60) kg, 停经(43.50±6.00) d, 输卵管包块直径(4.00±0.98) cm。2组一般资料比较，差异无统计学意义(P>0.05), 具有可比性。纳入标准: 有不同程度的阴道不规则出血及腹痛等输卵管妊娠临床表现，B超未见宫内妊娠囊，附件区出现包块，血β-人绒毛膜促性腺激素(β-HCG)水平升高，术中无失血性休克、术后病理确诊，术后有生育要求，未避孕。排除标准: 具有其他影响妊娠的因素; 合并心、肝、肾、肺等功能障碍; 随访失联者; 有随访困难、沟通障碍、不能配合者。
1.2 方法
采用气管插管全身麻醉，取截石位，脐上1 cm切口，形成气腹，置入10 mm Trocar, 压力一般保持12~15 mmHg, 在正麦氏点和反麦氏点穿刺5 mm切口置入Trocar, 应用腹腔镜进行探查，明确病灶。置入腹腔镜器械并探查盆腹腔。初步吸净盆腔内积血，腹腔镜下输卵管抽芯切除术+宫角缝扎: 提起患侧输卵管伞端，自输卵管系膜处轻微电凝后，剪刀沿着输卵管系膜紧贴输卵管管芯剪切到输卵管峡部近子宫端、游离患侧输卵管，在宫角处予以2-0不可吸收线缝扎后在缝扎线外侧剪切输卵管，切除后套袋取出。腹腔镜下输卵管妊娠病灶清除术: 电针在输卵管膨大最明显、最薄处纵形切开管壁长达病灶全程，水压分离妊娠物，钳夹妊娠病灶装袋，并反复冲洗输卵管腔，有明显出血点则小心电凝创面后，予以3-0可吸收线缝合开窗面。
1.3 观察指标
比较2组患者的手术时间、术中出血量、住院时间及术后2、7 d血清β-HCG下降情况，抽取患者术后1、3、6个月后的月经来潮第3天清晨空腹状态下的静脉血，离心后分离血清，使用酶联免疫吸附(ELISA)法检测血清抗缪勒管激素(AMH)、黄体生成素(LH)、卵泡刺激素(FSH)和雌二醇(E2)水平，并随访18个月观察患者的宫内妊娠率及异位妊娠率。
1.4 统计学处理
本研究数据采用SPSS 23.0软件进行统计分析，以(x±s)表示计量资料，以[n(%)]表示计数资料，分别采用χ2检验与t检验, P < 0.05表示差异具有统计学意义。
2. 结果
2.1 治疗情况
观察组的术中出血量显著少于对照组(P < 0.05), 2组的手术时间和住院时间无显著差异(P>0.05), 见表 1。
表 1 2组治疗情况比较(x±s)组别 手术时间/min 出血量/mL 住院时间/d 对照组(n=50) 42.81±12.09 29.96±19.95 3.10±1.00 观察组(n=50) 38.76±12.58 18.74±15.22* 2.94±1.16 与对照组比较, *P < 0.05。 2.2 血清β-HCG下降情况
观察组术后2、7 d的血清β-HCG下降率均显著高于对照组(P < 0.05), 见表 2。
表 2 2组术后血β-HCG下降情况比较(x±s)% 组别 术后2 d 术后7 d 对照组(n=50) 67.10±8.76 83.40±5.41 观察组(n=50) 70.54±6.87* 85.56±5.16* β-HCG: β-人绒毛膜促性腺激素。与对照组比较, *P < 0.05。 2.3 治疗后血清激素水平比较
治疗1、3、6个月后，观察组患者的血清AMH、LH、FSH、E2水平与对照组比较，差异均无统计学意义(P>0.05), 见表 3。
表 3 2组手术治疗后激素水平情况比较(x±s)组别 时点 AMH/(ng/mL) FSH/(IU/L) LH/(IU/L) E2/(IU/L) 对照组(n=50) 治疗1个月后 2.83±0.75 5.39±1.48 4.74±1.27 79.20±21.30 治疗3个月后 2.91±0.75 5.48±1.43 4.78±1.24 80.92±20.94 治疗6个月后 2.91±0.72 5.58±1.37 4.82±1.20 80.40±20.14 观察组(n=50) 治疗1个月后 2.72±0.64 5.72±1.56 4.58±1.24 74.58±16.80 治疗3个月后 2.81±0.65 5.77±1.52 4.61±1.23 76.40±16.53 治疗6个月后 2.79±0.62 5.74±1.50 4.59±1.23 79.10±15.49 AMH: 抗缪勒管激素; LH: 黄体生成素; FSH: 卵泡刺激素; E2: 雌二醇。 2.4 随访妊娠情况
随访18个月显示，腹腔镜下输卵管抽芯切除+宫角缝扎组与腹腔镜下保留输卵管组患者的宫内妊娠率无显著差异(P>0.05), 而2组发生持续性异位妊娠率分别为4.00%、12.00%, 证明保留输卵管患者术后再次受孕时更容易出现宫外孕情况。见表 4。
表 4 2组患者随访妊娠情况对比[n(%)]组别 宫内妊娠 宫外孕 未受孕 对照组(n=50) 30(60.00) 6(12.00) 14(28.00) 观察组(n=50) 29(58.00) 2(4.00)* 19(38.00)* 与对照组比较，*P < 0.05。 3. 讨论
受精卵在输卵管内着床并发育的异位妊娠称为输卵管妊娠，随着孕产妇保健意识的不断加强，异位妊娠的早期诊断率及治疗率明显提高。随着腹腔镜技术的不断发展，除极少部分失血性异位妊娠患者需行开腹手术治疗外，多数患者可选择腹腔镜手术治疗[3]。在治疗输卵管妊娠患者时，临床医生对于保留还是切除输卵管多年来一直存在争议，目前仍是争议的话题。有学者[4]认为，对于双侧输卵管有损伤的患者，保留输卵管可以部分增高宫内妊娠的概率，甚至可作为将来生育的异位妊娠患者的一线治疗方法。本研究显示，输卵管妊娠患者保留患侧输卵管并未增高宫内妊娠率，反而提升异位妊娠的发生率。原因在于手术过程中腹腔镜开窗异位妊娠病灶取出时需切开输卵管并钳夹、电凝输卵管，纤毛受损，输卵管部分缺损或离断，即使缝合患侧输卵管使其外观看似正常，但真正的运输功能已经受到破坏，再次妊娠时有可能在功能残缺的输卵管管道着床。还有可能存在管内残留的滋养叶细胞继续生长，导致持续性异位妊娠，影响了手术成功率[5]。有研究[6]报道输卵管病灶清除术的自然妊娠累积率并不比输卵管切除术高，而术后持续异位妊娠发生率显著高于输卵管切除术(7% vs. 1%), 因而输卵管切除术为异位妊娠首选的手术治疗，这与郑华等[7]的结论一致。本研究结果显示，保留输卵管与切除输卵管的异位妊娠发生率分别为12.00%与4.00%, 证实输卵管切除术患者可显著降低异位妊娠的发生率，而宫内妊娠率与保留输卵管患者无差异。Cheng等[8]也认为，患者对侧输卵管外观正常，行患侧输卵管切除术对日后的宫内妊娠不会造成影响，且能降低持续性异位妊娠的发生率。而从成本效益来说，有研究[9]表明在保留输卵管行妊娠病灶清除术后通过自然受孕持续怀孕的患者平均治疗费用明显高于输卵管切除术患者，而在持续妊娠率方面并没有受益。另外有学者[10-11]认为，输卵管切除术后会潜在影响患者卵巢功能，手术侧卵巢的卵泡数量、活性与健侧相比均有明显降低，对卵巢排卵功能造成影响，降低了再次妊娠概率。
卵巢血供主要来源于卵巢动脉及子宫动脉的卵巢分支，卵巢动脉在进入卵巢前，尚有分支走行于输卵管系膜内供应输卵管，在行输卵管切除术时，输卵管系膜切断或将使输卵管系膜中的卵巢侧支动脉弓血管受到损伤，影响卵巢的血供，不利窦卵泡发育，使卵巢激素分泌受影响，进而导致卵巢功能下降[12]。作者认为，不管何种手术方式，均需要尽可能避免对卵巢血供的影响。评价卵巢功能的主要指标有卵巢性激素FSH、LH、E2、AMH、卵巢体积及窦卵泡数，其中基础FSH水平是临床最常用的评估卵巢储备功能的指标，而AMH在整个月经周期呈相对稳定状态，这意味着AMH可作为一种不依赖于月经周期的反映卵泡质量与数量的优先指标，是评价卵巢储备功能的独立因子[13]。本研究显示, 2组术后激素FSH、LH、E2、AMH水平无显著差异，表明输卵管切除术联合宫角缝扎不会增加对卵巢功能的影响，与相关研究[14]认为在输卵管切除术之前和之后血清AMH水平没有显著差异的观点相符。金白灵等[15]的Meta分析结果显示，单侧输卵管切除术前和术后获卵数差异无统计学意义，推测健侧卵巢可在一定程度上代偿手术卵巢的功能，因而单侧输卵管切除对卵巢的功能影响不大。本研究使用不可吸收线进行宫角缝合，避免电凝损伤，并有效关闭输卵管间质部; 同时有效减少了输卵管残端遗漏管腔，降低了胚胎在此植入造成的异位妊娠的风险。赫英东等[16]研究认为，对于间质部破裂的输卵管妊娠患者，切除输卵管后应进行缝合，减小电凝损伤及后续妊娠子宫破裂的风险。本研究中，保留输卵管组术中出血量多于输卵管切除组，估计与患者血HCG水平有关，血HCG水平越高，滋养细胞组织活性强，越容易侵蚀突破输卵管管腔，造成出血，止血过程中对输卵管破坏作用增大。再者，异位妊娠的部位、包块大小、激素水平、缝合技术与质量、电凝器械的使用以及术者的经验，均会影响术后患者的远期预后情况[17-19]。
综上所述，腹腔镜下输卵管妊娠的治疗可优先选择患侧输卵管抽芯切除术联合宫角缝扎术，与保守手术相比，对宫内妊娠率及卵巢功能无明显影响，且能降低再次异位妊娠的发生风险。
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