Abstract
目的
探讨系统性红斑狼疮(systemic lupus erythematosus, SLE)合并视网膜病变的临床及免疫学特点。
方法
选择2009年1月至2022年7月于北京大学人民医院住院的无高血压无糖尿病的SLE合并视网膜病变患者50例(眼病组)，按性别、年龄匹配病程中无视物模糊症状及眼底检查没有视网膜病变的SLE患者50例(非眼病组)，对两组患者的临床表现、实验室检查及淋巴细胞亚群进行分析。
结果
眼病组患者最常见的眼底表现为棉絮斑(33/50，66.0%)，其次是视网膜出血(31/50，62.0%)。视网膜病变可发生在SLE病程的任何阶段，中位时间为1年(病程范围为20 d至30年)。眼病组出现狼疮性肾炎比例(72.0% vs. 46.0%, P=0.008)和浆膜炎比例(58.0% vs. 28.0%, P=0.002)显著高于非眼病组。眼病组同时出现神经精神性狼疮(neuropsychiatric systemic lupus erythematosus, NPSLE)比例较非眼病组升高，但差异无统计学意义。与非眼病组相比，眼病组中抗心磷脂抗体阳性比例(30.0% vs. 12.0%, P=0.027)、系统性红斑狼疮疾病活动指数评分(中位数22.0 vs. 10.5, P < 0.001)、红细胞沉降率(P < 0.001)，C反应蛋白水平(P=0.019)和24 h尿蛋白定量(P=0.026)均显著升高，血红蛋白水平明显减低[(91.64±25.18) g/L vs. (113.96±18.57) g/L, P < 0.001]。与非眼病组相比，SLE视网膜病变患者外周血CD19+B细胞比例显著升高(P=0.010)，CD4+T细胞比例明显减低(P=0.025)，自然杀伤(natural killer，NK)细胞比例减低(P=0.051)。
结论
SLE视网膜病变提示更高的SLE疾病活动性，更易合并肾脏系统、血液系统等损害，建议对所有SLE患者尽早进行眼底筛查。SLE视网膜病变患者可能存在更显著的B细胞异常增殖，应给予积极治疗以防止其他重要脏器受累。
Keywords: 系统性红斑狼疮, 视网膜病变, 临床特点, 淋巴细胞亚群
Abstract
Objective
To investigate the clinical and immunological characteristics of systemic lupus erythematosus (SLE) with retinopathy.
Methods
Fifty SLE patients with retinopathy without hypertension and diabetes (retinopathy group) who were hospitalized in the Peking University People's Hospital from January 2009 to July 2022 were screened. Fifty SLE patients without blurred vision during the course of the SLE and without retinopathy in the fundus examinations (non-retinopathy group) matched for sex and age were selected. Their clinical manifestations, laboratory tests and lymphocyte subsets were statistically analyzed.
Results
The most common fundus ocular change of the SLE patients with retinopathy was cotton-wool spots (33/50, 66.0%), followed by intraretinal hemorrhage (31/50, 62.0%). Retinopathy could occur at any stage of SLE duration, with a median of 1 year (20 days to 30 years). The proportion of lupus nephritis (72.0% vs. 46.0%, P=0.008) and serositis (58.0% vs. 28.0%, P=0.002) in the retinopathy group were significantly higher than those in the non-retinopathy group. The proportion of neuropsychiatric systemic lupus erythematosus (NPSLE) in the retinopathy group was higher, but there was no significant difference between the two groups. Compared with the non-retinopathy group, the proportion of positive anti-cardiolipin antibody (30.0% vs. 12.0%, P=0.027), the SLEDAI score (median 22.0 vs. 10.5, P < 0.001), erythrocyte sedimentation rate (P < 0.001), C-reactive protein (P=0.019) and twenty-four hours urine total protein level (P=0.026) in the retinopathy group were significantly higher, and the hemoglobin level was significantly lower [(91.64±25.18) g/L vs. (113.96±18.57) g/L, P < 0.001]. The proportion of CD19+ B cells in peripheral blood of the patients with SLE retinopathy was significantly increased (P=0.010), the proportion of CD4+ T cells was significantly decreased (P=0.025) and the proportion of natural killer (NK) cells was lower (P=0.051) when compared with the non-retinopathy group.
Conclusion
Retinopathy in SLE suggests a higher activity of SLE disease with more frequent hematologic and retinal involvement. It is recommended to perform fundus examination as soon as a patient is diagnosed with SLE. SLE patients with retinopathy may have stronger abnormal proliferation of B cells, and aggressive treatment should be applied to prevent other important organs involvement.
Keywords: Systemic lupus erythematosus, Retinopathy, Clinical characteristics, Lymphocyte subsets
系统性红斑狼疮(systemic lupus erythematosus, SLE)是最常见的自身免疫性疾病之一，以体内存在多种自身抗体及多器官系统损害为主要特征[1]。SLE发病机制尚不明确，越来越多证据表明SLE患者体内存在B细胞耐受异常和异常增殖活化[2]。约1/3的SLE患者患有眼部病变，包括干燥性角结膜炎、角膜炎、视网膜病变等[3]，有研究表明3%的控制良好的SLE患者和29%的活动性SLE患者患有视网膜病变[4-5]，SLE视网膜病变可引起视力下降甚至致盲，严重影响患者生活质量。本研究旨在通过病例回顾的方法探讨SLE患者合并视网膜病变的临床表现、免疫学指标及免疫细胞亚群特点，期望能帮助临床医生早期识别及诊治这部分患者，改善其预后。
1. 资料与方法
1.1. 患者一般资料
选择2009年1月至2022年7月于北京大学人民医院住院的无高血压无糖尿病的SLE视网膜病变患者50例(眼病组)，其中包括女性44例，男性6例，平均年龄(32.0±12.0)岁，病程20 d至30年，中位病程为1年。按1 ∶1比例、性别、年龄(±5岁)匹配病程中无视物模糊症状及眼底检查未见视网膜病变的SLE患者50例(非眼病组)。两组患者均符合美国风湿病学会(American College of Rheumatology, ACR)1997年修订的SLE分类标准[6]，所有患者均在眼科接受散瞳后眼底检查、眼科医师会诊，根据眼底表现选择完善眼底荧光素血管造影(fundus fluorescein angiography, FFA) 和光学相干断层扫描(optical coherence tomography, OCT)检查。排除合并糖尿病、高血压、动脉硬化患者及羟氯喹等药物引起的视网膜病变患者。收集两组患者临床资料包括临床表现(包括狼疮性肾炎、神经精神性狼疮、肺部病变、血液系统受累等)、实验室检查(包括红细胞沉降率、C反应蛋白、血红蛋白、尿白细胞、尿红细胞、24 h尿蛋白、补体C3、补体C4、抗ds-DNA抗体等)及淋巴细胞亚群分析结果[包括CD3+T细胞、CD4+T细胞、CD8+T细胞、CD19+B细胞及自然杀伤(natural killer，NK)细胞]，采用系统性红斑狼疮疾病活动指数(systemic lupus erythematosus disease activity index, SLEDAI)评估疾病活动性[7]。
1.2. 统计学分析
应用SPSS 20.0及GraphPad Prism软件，计数资料以百分数表示并使用卡方检验或Fisher’s精确检验进行比较，计量资料使用独立t检验或Mann-Whitney U检验进行比较，符合正态分布的数据以均数±标准差表示，并使用t检验进行分析，非正态分布数据以M(P25, P75)表示，使用Mann-Whitney U检验分析，P < 0.05认为差异有统计学意义。
2. 结果
2.1. SLE视网膜病变患者的眼底表现
在50例SLE合并视网膜病变患者中，最常见的眼底病变表现为软性渗出(棉絮斑)(33/50，66.0%)，其次为视网膜出血(31/50，62.0%，图 1)，以及硬渗出物(9/50，18.0%)、黄斑水肿(9/50，18.0%)、视网膜血管阻塞(4/50，8.0%)、视乳头水肿(2/50，4.0%)，63.0%患者表现出两种或两种以上的眼底病变。
图 1.
眼底检查显示的狼疮性视网膜病变
Lupus retinopathy shown by fundus examinations
A, cotton-wool spots; B, hemorrhages; C, cutton-wool spots and hemorrhages; D, vaso-occlusion.
2.2. SLE视网膜病变患者临床特点和免疫学特点
眼病组患者中72%合并狼疮性肾炎，58%患有浆膜炎，20%患有神经精神性狼疮(表 1)。眼病组患者合并狼疮性肾炎、浆膜炎比例均较非眼病组显著升高(P=0.008, P=0.002)，眼病组患者中神经精神性狼疮(neuropsychiatric systemic lupus erythematosus, NPSLE)比例升高，但两组之间差异无统计学意义(表 1)。与非眼病组相比较，眼病组患者红细胞沉降率、C反应蛋白、24 h尿蛋白定量水平、抗心磷脂抗体阳性比例均显著升高(P < 0.001, P=0.019, P=0.026, P=0.027);眼病组患者中血红蛋白水平显著降低[(91.64±25.18) g/L vs. (113.96±18.57) g/L, P < 0.001]，C3、C4水平也显著降低(P=0.006, P=0.018, 表 2); 抗双链DNA抗体(double stranded deoxyribonucleic acid, dsDNA) 滴度及抗核小体抗体(anti-nucleosome antibodies, AnuA) 滴度较非眼病组升高，但差异没有统计学意义(表 2); SLEDAI评分显著高于非眼病组[22.00(16.75~29.00)vs. 10.50(6.00~15.25), P < 0.001, 表 1]。SLE视网膜病变患者外周血CD19+ B细胞比例显著升高[(28.50±15.37)% vs. (16.49±9.89)%, P=0.010]，CD4+T细胞比例减低(P=0.025)，NK细胞比例减低，但两组间差异无统计学意义(P=0.051，表 3，图 2)。眼病组与非眼病组间在发热、皮疹、黏膜溃疡、脱发、关节炎、血管炎、肌炎、白细胞减少、血小板减少、抗核抗体、抗dsDNA抗体、抗Sm抗体、抗核糖核蛋白(ribonucleoprotein, RNP)抗体、抗SSA抗体、抗SSB抗体、AnuA、抗人球蛋白试验(Coombs test)阳性比例，以及血白蛋白、免疫球蛋白IgA、IgG、IgM水平等方面差异均无统计学意义(表 1、2)。
表 1.
两组患者的临床特点比较
Clinical characteristics between the two groups
| Variable | Retinopathy group (n=50) | Non-retinopathy group (n=50) | χ2/U | P |
| SLEDAI, systemic lupus erythematosus disease activity index; NPSLE, neuropsychiatric systemic lupus erythematosus. *P < 0.05. # P < 0.001. a, Fisher’s exact test. | ||||
| SLEDAI, M (P25, P75) | 22.00 (16.75, 29.00) | 10.50 (6.0, 15.25) | 223.5 | < 0.001# |
| Fever, n (%) | 13 (26.0) | 12 (24.0) | 0.053 | 0.817 |
| Rash, n (%) | 16 (32.0) | 17 (34.0) | 0.045 | 0.832 |
| Hair loss, n (%) | 8 (16.0) | 6 (12.0) | 0.332 | 0.564 |
| Mucosal ulcer, n (%) | 7 (14.0) | 6 (12.0) | 0.088 | 0.766 |
| Arthritis, n (%) | 9 (18.0) | 10 (20.0) | 0.065 | 0.799 |
| Vasculitis, n (%) | 4 (8.0) | 5 (10.0) | 0.000 | 1.000a |
| Myositis, n (%) | 4 (8.0) | 2 (4.0) | 0.177 | 0.678a |
| NPSLE, n (%) | 10 (20.0) | 4 (8.0) | 2.076 | 0.148a |
| Thrombocytopenia, n (%) | 21 (42.0) | 12 (24.0) | 3.664 | 0.056 |
| Leukopenia, n (%) | 12 (24.0) | 11 (22.0) | 0.056 | 0.812 |
| Cylindruria, n (%) | 9 (18.0) | 2 (4.0) | 3.677 | 0.051a |
| Hematuria, n (%) | 25 (50.0) | 12 (24.0) | 7.250 | 0.007* |
| Proteinuria, n (%) | 30 (60.0) | 20 (40.0) | 4.000 | 0.046* |
| Pyuria, n (%) | 23 (46.0) | 7 (14.0) | 12.190 | < 0.001# |
| Lupus nephritis, n (%) | 36 (72.0) | 23 (46.0) | 6.986 | 0.008* |
| Serositis, n (%) | 29 (58.0) | 14 (28.0) | 9.180 | 0.002* |
表 2.
两组患者的实验室检查差异
Laboratory differences between the two groups
| Variable | Retinopathy group (n=50) | Non-retinopathy group (n=50) | t/U | P |
| Hb, hemoglobin; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; Alb, albumin; 24h-UTP, twenty-four hours urine total protein; ANA, antinuclear antibody; dsDNA, double stranded deoxyribonucleic acid; Sm, Smith; RNP, ribonucleoprotein; SSA, Sjögren’s syndrome related antigen A; SSB, Sjögren’s syndrome related antigen B; AnuA, Anti-nucleosome antibodies; ACLA, anticardiolipin antibody; β2 GP 1, β2 glycoprotein 1 antibody; LAC, lupus anticoagulant; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM immunoglobulin M; C3, complement 3; C4, complement 4. *P < 0.05. # P < 0.001. a, Fisher’s exact test. | ||||
| Hb/(g/L), x±s | 91.64±25.18 | 113.96±18.57 | 4.838 | < 0.001# |
| ESR/(mm/h), M (P25, P75) | 42.00 (24.00, 64.50) | 18.50 (7.00, 34.25) | 583.5 | < 0.001# |
| CRP/(mg/L), M (P25, P75) | 2.91 (1.61, 6.76) | 1.41 (0.56, 6.89) | 654.0 | 0.019* |
| Alb/(g/L), x±s | 30.78±6.70 | 33.05±7.61 | 1.517 | 0.133 |
| 24 h-UTP/(g/d), M (P25, P75) | 0.64 (0.22, 1.87) | 0.19 (0.10, 1.44) | 700.0 | 0.026* |
| ANA (+), n (%) | 46 (92.0) | 45 (90.0) | 0.000 | 1.000a |
| Anti-dsDNA (+), n (%) | 31 (62.0) | 30 (60.0) | 0.042 | 0.838 |
| Anti-dsDNA/(IU/mL), M (P25, P75) | 113.30 (29.80, 200.00) | 49.60 (19.68, 200.00) | 735.0 | 0.146 |
| Anti-Sm antibody (+), n (%) | 10 (20.0) | 9 (18.0) | 0.065 | 0.799 |
| Anti-RNP antibody (+), n (%) | 19 (38.0) | 20 (40.0) | 0.042 | 0.838 |
| Anti-SSA antibody (+), n (%) | 21 (42.0) | 27 (54.0) | 1.442 | 0.230 |
| Anti-SSB antibody (+), n (%) | 6 (12.0) | 5 (10.0) | 0.102 | 0.749 |
| AnuA (+), n (%) | 29(58.0) | 24 (48.0) | 1.004 | 0.316 |
| AnuA/(RU/mL), M (P25, P75) | 44.68 (8.23, 151.43) | 22.63 (9.40, 186.42) | 881.0 | 0.736 |
| ACLA (+), n (%) | 15 (30.0) | 6 (12.0) | 4.882 | 0.027* |
| ACLA/(U/mL), M (P25, P75) | 4.60 (2.00, 11.40) | 3.50 (2.15, 7.28) | 878.5 | 0.364 |
| Anti-β2 GP 1 (+), n (%) | 15 (30.0) | 10 (20.0) | 1.477 | 0.224 |
| Anti-β2 GP 1/(RU/mL), M (P25, P75) | 6.72 (2.08, 37.14) | 7.47 (2.83, 14.61) | 931.5 | 0.773 |
| LAC (+), n (%) | 9 (18.0) | 3 (6.0) | 2.367 | 0.121a |
| LAC/s, M (P25, P75) | 1.02 (0.95, 1.37) | 0.99 (0.93, 1.13) | 693.0 | 0.251 |
| Coombs test (+), n (%) | 29 (58.0) | 20 (40.0) | 7.241 | 0.072 |
| IgA (g/L), x±s | 2.42±1.28 | 2.88±1.28 | 1.671 | 0.098 |
| IgG/(g/L), M (P25, P75) | 13.50 (10.25, 20.30) | 13.90 (8.80, 19.00) | 921.5 | 0.463 |
| IgM/(g/L), M (P25, P75) | 1.09 (0.56, 1.66) | 0.90 (0.47, 1.36) | 798.5 | 0.213 |
| C3/(g/L), M (P25, P75) | 0.41 (0.253, 0.627) | 0.59 (0.385, 0.712) | 704.5 | 0.006* |
| C4/(g/L), M (P25, P75) | 0.05 (0.025, 0.130) | 0.12 (0.046, 0.157) | 755.5 | 0.018* |
表 3.
两组患者外周血淋巴细胞亚群差异
Laboratory differences in SLE patients with retinopathy and without retinopathy
| Variable | Retinopathy group | Non-retinopathy group | t/U | P |
| NK cell, natural killer cell. *P < 0.05. # P < 0.001. | ||||
| CD3+ T cells/%, x±s | 62.86±13.95 | 68.95±12.88 | 1.241 | 0.228 |
| CD4+ T cells/%, x±s | 26.28±6.48 | 33.46±11.03 | 2.357 | 0.025* |
| CD8+ T cells/%, x±s | 36.47±11.47 | 35.49±10.84 | -0.244 | 0.809 |
| CD19+ B cells/%, x±s | 28.50±15.37 | 16.49±9.89 | -2.738 | 0.010* |
| NK cells (%), M (P25, P75) | 3.65 (1.53, 7.13) | 5.10 (4.25, 7.25) | 74.000 | 0.051 |
图 2.
两组患者外周血CD4+T细胞、CD8+T细胞、CD19+B细胞和NK细胞水平
The levels of CD4+T cells, CD8+T cells, CD19+B cells and NK cells in the peripheral blood of two groups
A, the proportion of CD4+ T cells in the retinopathy group was significantly decreased (P=0.025); B, there was no significant difference in the proportion of CD8+T cells between the two groups; C, the proportion of CD19+ B cells was significantly increased in the retinopathy group (P=0.010); D, the proportion of NK cells was decreased in the retinopathy group, but there was no significant difference between the two groups (P=0.051). NK, natural killer cell; RG, retinopathy group; NRG, non-retinopathy group; ns, not significant. *P < 0.05.
3. 讨论
本研究SLE视网膜病变患者病程范围为20 d至30年，提示视网膜病变可发生在SLE病程的任何阶段。既往的研究发现[8-9]，SLE视网膜病变患者中狼疮性肾炎与NPSLE比例显著升高，视网膜病变提示SLE有更高的疾病活动性。本研究显示SLE视网膜病变患者疾病活动度显著升高(中位SLEDAI为22)，肾受累比例更高，与上述文献一致。虽然本研究SLE视网膜病变患者中NPSLE比例较非眼病组升高，但差异无统计学意义，可能与入组患者例数较少有关。
SLE视网膜病变的发病机制尚不清楚，目前认为可能由免疫复合物沉积介导的血管炎和视网膜血管血栓栓塞引起[10]，视网膜病变的组织病理学提示视网膜血管壁可见免疫复合物及补体沉积[11]。本研究发现SLE视网膜病变患者中最常见的眼底表现为棉絮斑，在另一项研究中有类似的发现，以棉絮斑为表现的轻度视网膜病变更为常见[12]，通常对视力影响较小；而视网膜血管血栓栓塞发生率虽然较低，但可引起严重视力下降[13]，在本研究中占8.0%。糖皮质激素治疗SLE后出现的视网膜并发症主要表现为中心性浆液性脉络膜视网膜病变，该病是一种以局限性黄斑部浆液性视网膜剥离，伴一个或多个视网膜色素上皮层特发性渗漏为特征的眼底病[14]，本研究治疗均用到剂量不等的糖皮质激素，未见上述视网膜病变发生。抗磷脂抗体是血栓形成的危险因素[15]，多项研究表示抗磷脂抗体的存在与视网膜血管疾病的患病率增加有关[16-17]。本研究显示SLE视网膜病变患者的抗心磷脂抗体阳性比例更高，其中4名SLE视网膜血管阻塞患者均为抗磷脂抗体阳性。
已有研究表明B细胞在SLE发病机制中发挥重要作用，表现为B细胞对自身抗原的耐受性丧失，自身反应性B细胞异常激活，产生大量自身抗体[18]。Wei等[19]的研究显示活动性SLE患者中过渡性B细胞、转换记忆B细胞、浆细胞的数量增加，与疾病活动性相关。本研究显示SLE视网膜病变患者中CD19+B细胞比例明显升高，提示SLE视网膜病变患者体内可能存在更显著的B细胞异常增殖，产生大量自身抗体，提示更高的疾病活动性。目前，已有多个案例报告利妥昔单抗诱导的B细胞耗竭疗法成功用于多例难治性SLE视网膜病变患者[20-22]。本研究发现眼病组患者CD4+T细胞比例较无视网膜病变患者显著下降，提示SLE视网膜病变患者体内同时存在明显的T细胞亚群异常。另外，本研究还显示眼病组NK细胞比例比非眼病组降低，虽差异无统计学意义，但可能提示眼病组NK细胞亚群异常，Liu等[23]研究提示SLE患者外周血NK细胞比例显著低于健康对照组，并且其NK细胞亚群及表型异常，部分反映了疾病活动性。本研究提示SLE视网膜病变患者外周血T淋巴细胞亚群存在明显异常，B细胞比例明显增高，可为临床SLE合并视网膜病变患者的治疗提供一定参考依据。遗憾的是本研究为回顾性研究，纳入的样本数量较少，可能使研究结果存在偏移，同时无法对B细胞亚群、T细胞、NK细胞亚群及功能进行更详细的研究，希望未来的研究能联合多中心、扩大样本量，以减少选择偏倚，同时可对SLE视网膜病变患者的淋巴细胞亚群功能、疾病治疗转归、生物标志物等进一步详细研究，为SLE视网膜病变诊治提供参考。
综上所述，视网膜病变可发生于SLE任何阶段，提示更高的疾病活动度。SLE合并视网膜病变患者体内CD19+B细胞明显增高，且更易合并其他重要器官系统(如肾、血液系统等)损害，提示预后不良，建议尽早对所有SLE患者进行眼底筛查，对于合并视网膜病变的SLE患者应给予积极治疗。
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