Abstract
原发性干燥综合征(primary Sjögren’s syndrome, pSS)的中枢神经系统受累少见, 常表现为脑白质病变、视神经脊髓炎谱系疾病(neuromyelitis optica spectrum disorder, NMOSD)或横贯性脊髓炎。NMOSD是一类免疫介导的中枢神经系统炎性脱髓鞘病变, 发病特点为高复发、高致残。pSS合并NMOSD患者病情更严重、预后更差。本研究报道1例pSS合并NMOSD妊娠期危重症的病例, 患者为有pSS病史的30岁孕妇, 被诊断为NMOSD, 在妊娠期接受甲泼尼龙琥珀酸钠、丙种球蛋白和硫酸羟氯喹片联合治疗, 治疗后患者出现口干、吞咽困难、腰背以下部位麻木感基本消失。患者于院外未规律服药, 右下肢出现无力、不能活动, 左下肢活动尚可, 偶伴麻木感。后急诊入院, 紧急行剖宫产分娩一健康男婴后, 患者病情加重, 高热伴双下肢瘫痪无力, 无法自主大小便。患者再次接受甲泼尼龙琥珀酸钠、丙种球蛋白治疗, 但症状改善不佳。首次给予利妥昔单抗输注后患者出现尿路感染, 予控制感染后继续规律输注利妥昔单抗, 后期患者行走略跛, 能够控制排尿和排便, 可正常工作。该病例表明, pSS合并NMOSD的妊娠期患者可考虑给予甲泼尼龙琥珀酸钠、丙种球蛋白和硫酸羟氯喹片联合治疗。利妥昔单抗可以明显改善NMSOD患者产后瘫痪、二便失禁等症状, 但同时可能有感染的风险。
Keywords: 妊娠, 视神经脊髓炎, 干燥综合征, 危重病, 利妥昔单抗
Abstract
Central nervous system involvement in primary Sjögren's syndrome (pSS) is less common and usually presents as white matter lesions, neuromyelitis optica spectrum disorder (NMOSD), or transverse myelitis. NMOSD is an immune-mediated inflammatory demyelinating disease of the central nervous system with a high rate of relapse and significant disability. Studies have shown that patients with pSS combined with NMOSD have more severe symptoms and poorer prognosis. Here, we present a case of critical illness in pregnancy-associated NMOSD combined with Sjögren's syndrome. The patient was a 30-year-old pregnant woman with a history of Sjögren's syndrome who was diagnosed with NMOSD. She received combination therapy with steroids, intravenous immunoglobulin (IVIG), and hydroxychloroquine during pregnancy, resulting in partial resolution of numbness below the waist. However, due to irregular medication adherence outside the hospital setting, she developed weakness in her right lower limb accompanied by inability to move it, while her left lower limb still had some mobility but occasional numbness along with urinary and fecal incontinence. Ten days later, she was admitted to the emergency department where an emergency cesarean section was performed to deliver a healthy baby boy. However, her condition worsened postpartum as she developed high fever accompanied by bilateral lower limb paralysis and weakness along with loss of voluntary control over urination and defecation. The patient underwent ano-ther course of treatment consisting of steroids and IVIG; however there was limited improvement in symptoms observed after this intervention. Following administration of rituximab for the first time, the patient developed urinary tract infection which was successfully managed before continuing regular infusions. In later stages the patient could walk slightly with a limp and regained control over urination and defecation, allowing her to resume normal activities. This case suggests that combination therapy with steroids, IVIG, and hydroxychloroquine should be considered for the patients with pregnancy-associated NMOSD combined with Sjögren's syndrome. Rituximab can significantly improve symptoms such as postpartum paralysis in patients with NMOSD, however, there may be a risk of infection associated with its use.
Keywords: Pregnancy, Neuromyelitis optica, Sjögren's syndrome, Critical illness, Rituximab
原发性干燥综合征(primary Sjögren’s syndrome, pSS)是一种多系统受累的自身免疫性疾病，pSS患者中枢神经系统受累占13% [ 1 ] 。pSS常合并视神经损害，其中抗血清水通道蛋白4 (autoantibo-dies against aquaporin-4, AQP4)抗体在发病机制中起重要作用。视神经脊髓炎谱系疾病(neuromyelitis optica spectrum disorder, NMOSD)是由AQP4-IgG介导、补体和细胞因子参与的中枢神经系统自身免疫性疾病，女性患病高于男性，首次发病多见于青壮年。NMOSD与妊娠相互影响，NMOSD可以影响妊娠计划、生育能力，对妊娠结局的影响不一致，更倾向良性结局 [ 2 - 4 ] 。妊娠可引起免疫系统和性激素水平变化，造成疾病复发和进展 [ 5 ] 。合理的免疫抑制治疗可以有效避免妊娠相关的疾病活动。新型单克隆抗体类生物制剂在妊娠期NMOSD患者中的有效性和安全性尚缺乏临床证据 [ 6 ] 。
本研究报道1例妊娠期pSS合并NMOSD的危重患者，通过分析该患者的临床病程表现和治疗，以期为此类罕见患者的诊治提供资料和借鉴。
1. 病例资料
1.1. 患者一般情况
患者，女，30岁，2022年5月9日因“口干1年，季肋部束带感8天”就诊。患者1年前经常饮水润口，进食固体食物需以水送下，未系统诊治，症状持续不缓解。8天前患者受凉后出现腰背以下部位麻木不适，伴肋弓处皮肤紧束感，两侧季肋部束带感，无口腔溃疡，无眼干，无夜尿增多，无脱发、皮疹、手足遇冷变色、肌肉关节疼痛、肌无力等症状，发病以来，饮食正常，睡眠正常，大小便正常。患者既往体健，家族无类似病史。
入院查体：神志清，精神一般，双侧眼球运动、视力和视野检查均正常，心肺听诊无异常，腹部膨隆，腹软，无压痛，偶感宫缩，肝脾肋缘下未触及，第8胸髓以下痛温觉减退，四肢肌力、肌张力均正常，双侧病理征阴性，双下肢无水肿。
常规实验室检查：红细胞沉降率36 mm/h、C反应蛋白(C-reactive protein，CRP)1.0 mg/L、降钙素原(procaicitonin, PCT) 0.05 μg/L，九项呼吸道病原体抗体检查、EB病毒(Epstein-Barr virus，EBV)及巨细胞病毒测定未见明显异常，抗心磷脂抗体、抗β2-糖蛋白抗体均正常。
免疫检查：抗核抗体(antinuclear antibody，ANA)1∶160(颗粒型)，抗干燥综合征抗原A (Sjögren’s syndrome type A, SSA)抗体67.66 U/mL(参考值范围：0~20 U/mL)，抗U1核糖核蛋白抗体(U1 ribonucleoprotein antibody，U1RNP)47.93 U/mL(参考值范围：0~20 U/mL)，抗Ro-52抗体41.49 U/mL(参考值范围：0~20 U/mL)，类风湿因子(rheumatoid factor, RF)阳性，抗水通道蛋白4 (aquaporin-4, AQP4)抗体1∶100，抗髓鞘少突胶质细胞糖蛋白(myelin oligodendrocyte glycoprotein, MOG)抗体阴性，抗胶质纤维酸性蛋白(glial fibrillary acidic protein，GFAP)抗体阴性，IgG 28.70 g/L，IgA 2.12 g/L，IgM 0.96 g/L。
辅助检查：未刺激的全唾液流率≤0.1 mL/min，欧洲抗风湿病联盟干燥综合征疾病活动指数(European League Against Rheumatism Sjögren’s syndrome disease activity index，ESSDAI)评分4分，欧洲抗风湿病联盟干燥综合征患者报告指数(European League Against Rheumatism Sjögren’s syndrome patient reported index, ESSPRI)评分2分。双侧腮腺、颌下腺超声检查：双侧腮腺、颌下腺弥漫性病变(左右侧腮腺、颌下腺评分均为3分)。颈胸MRI检查(2022年5月12日, 图 1 )：延髓、颈4~7平面脊髓内异常信号，胸6、7椎体水平脊髓内可疑病变。心电图检查：窦性心律，部分导联ST段轻度改变。胎儿彩超检查：宫内单胎妊娠，胎儿发育如孕17周 +2 。
颈胸椎磁共振成像
Cervical and thoracic spine magnetic resonance imaging
A1-A2: There is swelling of the medulla oblongata and spinal cord at the C4-7 level, with patchy and nodular abnormal signals observed. On T1-weighted images, there is low signal intensity. On T2-weighted fat-suppressed images, there are high signal intensities with blurred borders. At the level of the T6-7 vertebrae in the thoracic region, there appears to be slightly increased signal intensity on T2-weighted images. B1-B2: There is swelling of the medulla oblongata and spinal cord from the level of C4 to T10 vertebrae. Patchy and nodular abnormal signals are observed within the spinal cord, appearing as low signal intensity on T1-weighted images and high signal intensity on T2-weighted fat-suppressed images with indistinct borders. C1-C2: There is slight swelling of the spinal cord at the levels of C5-6 and T3-9. Linear abnormal signals are observed within the spinal cord, appearing as low signal intensity on T1-weighted images and high signal intensity on T2-weighted fat-suppressed images with indistinct borders. D1-D2: Linear abnormal signals are visible within the spinal cord at the levels of C4-6, appearing as slightly high signal intensity on T2-weighted images and indistinct borders. Similarly, linear abnormal signals are observed within the spinal cord at the levels of T3-9 vertebral bodies, appearing as low signal intensity on T1-weighted images and high signal intensity on T2-weighted fat-suppressed images with indistinct borders.
根据《中国视神经脊髓炎谱系疾病诊断与治疗指南》(2021版)及2016年美国风湿病学会/欧洲抗风湿病联盟(American College of Rheumatology/European League Against Rheumatism，ACR/EULAR) pSS分类标准，患者诊断为：视神经脊髓炎谱系疾病，干燥综合征，孕16周 +1 。
1.2. 治疗过程
患者入院时给予甲泼尼龙40 mg静脉滴注每天1次，硫酸羟氯喹片0.2 g每天2次，人免疫球蛋白20 g/d×5 d，甲钴胺片、维生素B1注射液营养神经、对症治疗。告知患者及其家属，治疗期间随时可能出现病情加重、胎儿停育、流产、视力障碍，严重者可能出现截瘫甚至呼吸肌麻痹，患者仍要求保胎治疗。经治疗17天，患者口干、腰背部截断感等症状明显好转，准予出院。康复期间，嘱患者服用泼尼松32 mg每天1次，硫酸羟氯喹0.2 g每天2次，甲钴胺片0.5 mg每天3次，丙种球蛋白0.4 g/kg静脉滴注每天1次，定期随访。
患者于2022年6月21日门诊查CRP、红细胞沉降率、免疫球蛋白均基本正常，后续患者因院外自行停药，于2022年9月4日再次出现右下肢无力，不能活动，左下肢活动尚可，偶伴麻木感，大小便失禁。患者于2022年9月14日急诊入院，孕34周 +2 ，血白细胞10.98×10 9 /L，中性粒细胞9.47×10 9 /L，血红蛋白90 g/L，血小板计数234×10 9 /L，CRP 4 mg/L，红细胞沉降率38 mm/h，血清钾3.4 mmol/L，免疫球蛋白正常。综合考虑患者情况比较危急，治疗上给予紧急剖宫产术，于2022年9月16日成功分娩一健康男婴。
患者术后当日出现发热，体温最高38.7 ℃，伴双下肢无力，不能坐立、行走，无法自主大小便。查体：神志清，精神差，双肺听诊呼吸音粗，心率98次/min，各瓣膜听诊区未闻及病理性杂音，第4胸髓以下痛温觉消失，双下肢肌力0级，肌张力减弱，双侧病理征阳性，双下肢无水肿。实验室检查：白细胞9.7×10 9 /L，中性粒细胞8.49×10 9 /L，淋巴细胞0.84×10 9 /L，CRP 63.3 mg/L，红细胞沉降率62 mm/h，PCT 0.54 μg/L，血清钾3.27 mmol/L，IgG 24.36 g/L，IgA 2.89 g/L，IgM 1.15 g/L。患者免疫球蛋白偏高，考虑与pSS处于活动期相关。ESSDAI评分7分，ESSPRI评分3分。颈胸MRI检查(2022年9月14日， 图 1 )：延髓、颈4至胸10椎体平面脊髓内异常信号，考虑炎性可能性大，较2022年5月12日MRI对比，颈髓病变范围变小，胸髓病变范围明显扩大。胸部CT检查(2022年9月17日)：两肺渗出性改变，两侧胸膜略厚，肺内微小结节，心包少量积液。患者存在肺部感染、体温反复波动，给予甲泼尼龙40 mg静脉滴注每天1次、头孢他啶2 g静脉滴注每12小时1次抗感染治疗，但体温仍控制不佳。血培养提示大肠杆菌( Escherichia coli )、屎肠球菌( Enterococcus faecium )感染，药敏实验提示哌拉西林/他唑巴坦≤2(敏感)。改用甲泼尼龙琥珀酸钠40 mg每12小时1次联合人免疫球蛋白22.5 g/d、哌拉西林舒巴坦4.5 g静脉滴注每8小时1次抗感染及退热等对症治疗，患者体温恢复正常，CRP、PCT及红细胞沉降率明显降低，免疫球蛋白正常，ESSDAI评分3分，ESSPRI评分2分。胸部CT检查(2022年9月30日)：肺内渗出较前吸收，胸膜增厚较前好转。颈胸MRI检查(2022年10月7日, 图 1 )：颈髓病变无明显变化，胸髓病变范围明显缩小。尽管该患者影像学改善明显，但仍有双下肢瘫痪伴感觉消失，大小便失禁。
因患者治疗效果不理想，考虑加用生物制剂。于2022年10月8日首次输注利妥昔单抗0.5 g，第3天复查白细胞1.21×10 9 /L、中性粒细胞0.09×10 9 /L、淋巴细胞1.01×10 9 /L、血小板计数257×10 9 /L，立即给予人粒细胞刺激因子注射液300 μg皮下注射后患者白细胞及中性粒细胞值恢复正常。后患者出现腹胀不适，夜间无小便，查体腹膨隆，无明显压痛、反跳痛，给予导尿管留置导尿，患者排出小便后腹胀逐渐好转。CRP 15.6 mg/L、红细胞沉降率48 mm/h、PCT 0.28 μg/L，尿液外观混浊，尿白细胞10个/μL，考虑泌尿系感染不除外，应用亚胺培南西司他汀钠0.5 g静脉滴注每6小时1次抗感染治疗。患者炎症指标正常后，分别于2022年11月4日、11月11日、11月19日继续输注利妥昔单抗0.5 g，共输注4次。
1.3. 随访和结局
第4次输注利妥昔单抗后，配合2个月的康复治疗，患者基本恢复行走，大小便正常。查体：四肢肌力、肌张力正常，感觉及共济运动正常，双侧病理征阴性。抗AQP4抗体1 ∶32，较前明显下降，中枢神经脱髓鞘三项抗体检测结果见 图 2 。患者于2023年1月27日查B淋巴细胞绝对数0/μL，血清钾3.98 mmol/L，免疫球蛋白水平正常，ESSDAI评分2分，ESSPRI评分1分。2023年5月18日复查血常规大致正常，B淋巴细胞绝对数15/μL，血清钾3.90 mmol/L，IgG 6.46 g/L，IgA 0.95 g/L，IgM 0.17 g/L。颈胸MRI检查(2023年5月18日， 图 1 )显示颈、胸髓病变范围均较前明显缩小。患者现规律服用小剂量泼尼松片5 mg每天1次联合硫酸羟氯喹0.2 g每天2次治疗。目前患者病情稳定，已恢复正常工作生活。
2022年11月21日患者中枢神经脱髓鞘三项抗体检测(免疫荧光法，CBA ×400)
Antibody detection of central nervous demyelination on November 21, 2022 (immunofluorescence, CBA ×400)
AQP4, autoantibodies against aquaporin-4; MBP, myelin basic protein; MOG, myelinoligodendrocyteglyc-protein; CBA, cell based assay. Serum initial dilution gradient was 1 ∶10 and transfected cells were used.
2. 讨论
目前已有pSS合并NMOSD [ 7 - 10 ] 、NMOSD合并妊娠的相关病例报告 [ 11 - 13 ] ，然而尚未见pSS同时合并NMOSD和妊娠的报道。本文报道的这例pSS合并NMOSD的孕妇，经剖宫产分娩一健康男婴，产后出现严重瘫痪，输注利妥昔单抗恢复良好。
神经系统受累是pSS的常见腺外表现，研究发现，在涎腺和中枢神经系统之间有共同的目标，AQP4(主要在脊髓和视神经表达)和AQP5(主要在涎腺表达)蛋白系列可能存在重叠 [ 14 ] 。现已证实pSS是NMOSD的重要合并症 [ 15 ] 。NMOSD是一种以累及视神经和脊髓为主、急性或亚急性的中枢神经系统炎性脱髓鞘疾病，多见于生育期女性。AQP4的发现揭示了体液免疫是NMOSD的潜在病理生理机制，妊娠期细胞因子表达的变化会影响NMOSD疾病的活动性。
本例患者患有pSS，在治疗过程中及时监控血清免疫球蛋白及钾离子水平是至关重要的。高免疫球蛋白血症是pSS继发多脏器损害的病理基础，pSS患者的血清IgG水平与口腔病变、唾液腺肿大、自身抗体及急性期反应物密切相关 [ 16 ] 。另外，pSS最常累及肾脏，以远端肾小管受累为主，肾小管和涎腺上皮存在交叉抗原性，涎腺上皮的抗体与肾小管抗原结合形成免疫复合物，损害肾小管上皮的质子泵，使肾小管泌氢及泌氨功能发生障碍，导致氢离子在血液中蓄积，大量钾离子自尿中排泄，临床表现为低钾高氯性酸中毒 [ 17 ] 。
NMOSD是一种中枢神经系统的自身免疫性脱髓鞘疾病，可能导致失明和瘫痪。AQP4+NMOSD主要由体液免疫系统介导，促使补体激活并导致灰质和白质内的中枢神经系统脱髓鞘和轴突丢失。有研究发现，妊娠是NMOSD患者复发和残疾的危险因素，妊娠期间孕酮和雌激素水平波动会刺激免疫球蛋白的产生，影响抗体糖基化，促使产生抗体的B细胞形成，导致细胞免疫反应转变为体液免疫，加重NMOSD病程 [ 12 , 18 ] 。Kim等 [ 19 ] 在NMOSD患者中观察到, 发生在NMOSD发病后的妊娠以流产告终者占43%，并且大部分患者选择避免或推迟怀孕。成功怀孕的患者大多数孕前疾病活动度相对较低，而孕前疾病活动度高的患者分娩后复发的风险很高，NMOSD的年化复发率在产后的前3个月显著增加 [ 20 ] 。产后复发风险增加可能是由于怀孕期间免疫耐受性的变化在分娩后逆转 [ 21 ] 。停止免疫抑制或免疫抑制不足可能是产后发作的危险因素，表明这一时期需要临床医生在患者分娩后预先采取措施，通过强化治疗恢复对自身免疫反应的充分抑制 [ 22 ] 。国内研究报道皮质类固醇治疗是妊娠期NMOSD的首选治疗方法，也可以使用其他治疗方法，包括利妥昔单抗、免疫抑制剂、免疫球蛋白。当患者存在长期皮质类固醇治疗禁忌证、或无效、或副作用无法耐受时，建议使用免疫抑制剂或利妥昔单抗治疗 [ 13 , 23 - 25 ] 。目前用于NMOSD患者的部分免疫抑制疗法可能对发育中的胎儿构成重大风险 [ 26 ] ，迄今为止，尚未建立NMOSD孕妇的免疫治疗指南。
B细胞耗竭疗法已被证明对NMOSD的孕前和产后炎症反应及复发活动有效 [ 27 ] 。靶向CD19的B细胞耗竭单克隆抗体伊奈利珠已获得美国食品药品监督管理局(Food and Drug Administration，FDA)批准，其通过胎盘和母乳的转移最小。CD20是一种在B细胞亚群上表达的细胞表面分子，包括前B细胞、未成熟细胞、成熟细胞和记忆B细胞。抗CD20疗法的治疗效果源于外周循环CD20 B细胞的显著消耗。利妥昔单抗已被用于治疗NMOSD多年，通过抗体依赖性细胞毒性、补体依赖的细胞毒性、中性粒细胞和巨噬细胞的吞噬作用、诱导B细胞凋亡等多种机制发挥耗竭B细胞的作用，达到阻断炎症反应、减少细胞因子和自身抗体的目的，从而控制NMOSD发展。利妥昔单抗通过抑制B细胞的病理性功能，可减弱腺体中的B细胞浸润，降低免疫球蛋白水平，从而对pSS起效。鉴于利妥昔单抗的生物学效应显著超出其药代动力学半衰期，对于妊娠相关NMOSD复发风险高的女性而言，其是高效的治疗选择。另外，最近在对19种单克隆抗体的抗CD20疗法的系统评价中，母乳中的药物浓度较低。药物可接受的相对婴儿剂量通常低于10%，在单克隆抗体的系统评价中，368名母乳喂养的婴儿在至少6个月的随访期内没有一个出现发育迟缓 [ 28 ] 。因此，结合本例患者的具体病情，给予患者利妥昔单抗输注，应用后疗效理想。
本例患者首次输注利妥昔单抗后发生白细胞显著减低，出现尿路感染，我们经大量查阅文献发现，利妥昔单抗治疗会增加NMOSD人群感染的风险，尤其会发生在低丙种球蛋白血症的情况下，除了IgG耗竭外，还可能发生IgM和IgA耗竭 [ 29 ] 。与B细胞消耗治疗相关的感染包括上呼吸道感染和鼻咽炎，也有更严重的感染，如疱疹病毒和乙型肝炎病毒再激活。在严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2, SARS-CoV-2)大流行的情况下，这些疗法可能会增加严重新型冠状病毒感染的风险 [ 30 ] ，因此，需要更多的系统评价和病例系列来确定利妥昔单抗的安全性。
综上所述，妊娠期和产后自身免疫性疾病的治疗具有挑战性。皮质类固醇和一些免疫抑制剂的使用可能与早产、低出生体重儿和胎儿宫内生长受限等并发症相关。关于应用利妥昔单抗安全性的数据也非常有限，本例患者给予甲泼尼龙琥珀酸钠、丙种球蛋白和硫酸羟氯喹片治疗，由于患者在院外未按时服药导致病情加重，经紧急剖宫产诞下一健康男婴，之后出现严重瘫痪，大小便失禁，接受第1次利妥昔单抗治疗后出现尿路感染，炎症控制后予规律输注利妥昔单抗恢复良好。本文报道了此例妊娠期NMOSD合并pSS发作的相关治疗，补充了现有的少数关于产后期间给予利妥昔单抗的病例诊疗，证明利妥昔单抗治疗会明显改善患者神经功能，降低致残率，提高日常生活能力，但可能有增加NMOSD患者感染的风险。
Funding Statement
河南省医学科技攻关计划项目[2020-176-01(K)]
Supported by the Henan Medical Science and Technology Research Program Project [2020-176-01(K)]
References
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