Blood Levels of Tumor Necrosis Factor Alpha and Its Type 2 Receptor Are Elevated in Patients with Boston Type I Keratoprosthesis

<b>Purpose</b>: Boston keratoprosthesis (KPro) patients are prone to glaucoma even with well-controlled intraocular pressure (IOP). Recent experimental data have shown that soluble tumor necrosis factor alpha (TNF-<i>α</i>) after ocular injury may contribute to progressive retinal damage and subsequent glaucoma. This study evaluates the blood plasma levels of soluble TNF-<i>α</i>, TNF receptors 1 (TNFR1) and 2 (TNFR2), and leptin in patients with Boston type I KPro. <b>Methods</b>: Venous blood samples were collected from KPro patients with glaucoma (KPro G, <i>n</i> = 19), KPro patients without glaucoma (KPro NoG, <i>n</i> = 12), primary angle closure glaucoma without KPro (PACG, <i>n</i> = 13), and narrow angles without glaucoma or KPro (NA, <i>n</i> = 21). TNF-<i>α</i>, TNFR1, TNFR2, and leptin levels were quantified using the enzyme-linked immunosorbent assay. Erythrocyte sedimentation rate (ESR) was assessed using the Westergren test. Patients with underlying autoimmune conditions or diabetes were excluded from the study. <b>Results</b>: All groups had similar age, body mass index (BMI), IOP, and ESR (<i>p</i> ≥ 0.11). The mean time from KPro surgery to blood draw was 5.3 ± 3.7 years. Compared to NA patients (0.72 ± 0.3 pg/ml), KPro G and KPro NoG patients had higher blood plasma levels of TNF-<i>α</i> (1.18 ± 0.58 pg/ml, <i>p</i> = 0.006; 1.16 ± 0.50 pg/ml, <i>p</i> = 0.04, respectively). Similarly, KPro G patients had higher blood plasma levels of TNFR2 (2768 ± 1368 pg/ml) than NA patients (2020 ± 435 pg/ml, <i>p</i> = 0.048). In multivariate analysis, KPro status remained positively associated with TNF-<i>α</i> levels (<i>β</i> = 0.36; 95% confidence intervals [CI]: 0.14–0.58; <i>p</i> = 0.002) and TNFR2 levels (<i>β</i> = 458.3; 95% CI: 32.8–883.7; <i>p</i> = 0.035) after adjusting for age, gender, BMI, glaucoma status, and ESR. TNFR1 and leptin levels were not significantly different in the study groups. <b>Conclusions</b>: We detected elevated serum levels of TNF-<i>α</i> and TNFR2 in KPro patients. Longitudinal studies are needed to establish TNF-<i>α</i> and TNFR2 as serum biomarkers related to KPro surgery. <b>Abbreviations</b>: BCVA: best corrected visual acuity; BMI: body mass index; CDR: cup-to-disc ratio; EDTA: ethylenediaminetetraacetic acid; ELISA: enzyme-linked immunosorbent assay; ESR: erythrocyte sedimentation rate; HVF: Humphrey visual field; IOP: intraocular pressure; KPro G: keratoprosthesis with glaucoma; KPro NoG: keratoprosthesis without glaucoma; KPro: keratoprosthesis; MD: mean deviation; NA: narrow angle; non-KPro: without keratoprosthesis; PACG: primary angle closure glaucoma; RNFL: retinal nerve fiber layer; TNF-α: tumor necrosis factor alpha; TNFR1: tumor necrosis factor receptor 1; TNFR2: tumor necrosis factor receptor 2

**研究目的**：即便眼内压（intraocular pressure, IOP）控制良好，波士顿I型角膜假体（Boston type I KPro）患者仍易罹患青光眼。近期实验数据表明，眼部损伤后产生的可溶性肿瘤坏死因子α（soluble tumor necrosis factor alpha, TNF-α）可能参与进展性视网膜损伤及后续青光眼的发生。本研究旨在检测波士顿I型角膜假体患者的血浆可溶性TNF-α、肿瘤坏死因子受体1（TNF receptors 1, TNFR1）、肿瘤坏死因子受体2（TNF receptors 2, TNFR2）及瘦素（leptin）水平。

**研究方法**：本研究纳入的受试者包括合并青光眼的KPro患者（KPro G，n=19）、未合并青光眼的KPro患者（KPro NoG，n=12）、无KPro的原发性闭角型青光眼（primary angle closure glaucoma, PACG，n=13），以及无青光眼或KPro的窄房角受试者（narrow angles, NA，n=21）。采用酶联免疫吸附试验（enzyme-linked immunosorbent assay, ELISA）定量检测血浆TNF-α、TNFR1、TNFR2及瘦素水平；采用魏氏法（Westergren test）检测红细胞沉降率（erythrocyte sedimentation rate, ESR）。本研究排除合并自身免疫性疾病或糖尿病的受试者。

**研究结果**：四组受试者的年龄、体质量指数（body mass index, BMI）、眼内压及红细胞沉降率均无显著差异（p≥0.11）。从KPro手术至采血的平均时间为5.3±3.7年。与窄房角组受试者（0.72±0.3 pg/ml）相比，KPro G组与KPro NoG组患者的血浆TNF-α水平均显著升高（分别为1.18±0.58 pg/ml，p=0.006；1.16±0.50 pg/ml，p=0.04）。同样，KPro G组患者的血浆TNFR2水平（2768±1368 pg/ml）显著高于窄房角组（2020±435 pg/ml，p=0.048）。多变量回归分析显示，在校正年龄、性别、BMI、青光眼状态及红细胞沉降率后，KPro状态仍与TNF-α水平（β=0.36；95%置信区间[CI]：0.14~0.58；p=0.002）及TNFR2水平（β=458.3；95%置信区间[CI]：32.8~883.7；p=0.035）呈正相关。各组间TNFR1与瘦素水平无显著差异。

**研究结论**：本研究发现KPro患者的血清TNF-α与TNFR2水平升高。未来需开展纵向研究，以明确TNF-α与TNFR2作为与KPro手术相关的血清生物标志物的可行性。

**缩写表**：BCVA：最佳矫正视力（best corrected visual acuity）；BMI：体质量指数（body mass index）；CDR：杯盘比（cup-to-disc ratio）；EDTA：乙二胺四乙酸（ethylenediaminetetraacetic acid）；ELISA：酶联免疫吸附试验（enzyme-linked immunosorbent assay）；ESR：红细胞沉降率（erythrocyte sedimentation rate）；HVF：汉弗莱视野（Humphrey visual field）；IOP：眼内压（intraocular pressure）；KPro G：合并青光眼的角膜假体患者（keratoprosthesis with glaucoma）；KPro NoG：未合并青光眼的角膜假体患者（keratoprosthesis without glaucoma）；KPro：角膜假体（keratoprosthesis）；MD：平均偏差（mean deviation）；NA：窄房角（narrow angle）；non-KPro：无角膜假体；PACG：原发性闭角型青光眼（primary angle closure glaucoma）；RNFL：视网膜神经纤维层（retinal nerve fiber layer）；TNF-α：肿瘤坏死因子α（tumor necrosis factor alpha）；TNFR1：肿瘤坏死因子受体1（tumor necrosis factor receptor 1）；TNFR2：肿瘤坏死因子受体2（tumor necrosis factor receptor 2）