El Jurdi Najla, Hamilton Betty K, Pidala Joseph A, Onstad Lynn, Mun Christine, Jain Sandeep, Lee Stephanie J
Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
Blood & Marrow Transplant Program, Cleveland Clinic, Cleveland, Ohio.
Transplant Cell Ther. 2025 Apr;31(4):226.e1-226.e9. doi: 10.1016/j.jtct.2025.02.004. Epub 2025 Feb 7.
Ocular graft-versus-host disease (oGVHD) is one of the most common initial manifestations of chronic GVHD (cGVHD) leading to significant morbidity and reduced quality of life. Early detection of oGVHD using susceptibility/risk biomarkers is urgently needed to enable preemptive therapy.
In this subset analysis of patients enrolled on the CATCH Study (NCT04188912), we tested whether changes in tear film cytokines or ocular symptoms, as assessed by the Lee symptom scale (LSS) eye subscale, can predict oGVHD onset.
LSS eye subscores, Inflammadry (MMP9) and conjunctival washing samples were collected before hematopoietic cell transplantation (HCT) and every 2 months (mos) until 12 mos. A custom-designed 13-plex human cytokine magnetic bead panel was used to measure: IL-10, IL-17A, IL-1Ra, IL-1α, ELA2, IL-1β, LIGHT/TNFSF14, NGAL, OSM, IL-8, IP-10, TNF-α, and VEGF-A. Cytokine levels at the pre-HCT visit were compared across the groups using the Kruskal-Wallis test. Fold change (FC) of the cytokines, defined as post-HCT value divided by pre-HCT value, was calculated and FC ≥ 2 was used in further analyses. oGVHD diagnosis was based on the NIH diagnostic criteria and having an eye score ≥1. Cox regression models were used to examine the longitudinal relationships between potential predictors and oGVHD development.
Of the 44 patients included, 18 developed oGVHD, 11 had cGVHD without oGVHD, and 15 did not have any cGVHD. Median age was 64.5 years, median time from HCT to cGVHD was 6.4 mos and to oGVHD was 8.3 mos. There were no significant differences in baseline cytokine levels among groups. None of the tear cytokines or the InflammaDry MMP9 test predicted oGVHD onset. Clinically meaningful change in LSS eye score was associated with subsequent oGVHD development when compared to cGVHD without eye involvement (HR 2.5, 95% CI 1.2-5.1, P = .01); and when compared to controls (HR 3.0, 95% CI 1.4-6.0, P = .004) but the PPV of LSS change ≥15 points was low (27.6%), with a higher NPV (89.4%).
This is the first prospective longitudinal study of tear cytokines and symptoms in a cohort of patients observed closely through HCT for development of cGVHD. We were not able to identify any biological susceptibility/risk markers for oGVHD. Patient-reported symptoms as measured by the LSS are associated with oGVHD development but the low PPV and overlap with diagnostic criteria limit its usefulness as a biomarker to guide preemptive treatment studies.
眼部移植物抗宿主病（oGVHD）是慢性移植物抗宿主病（cGVHD）最常见的初始表现之一，会导致严重的发病率并降低生活质量。迫切需要利用易感性/风险生物标志物早期检测oGVHD，以便进行抢先治疗。
在这项对参与CATCH研究（NCT04188912）的患者进行的亚组分析中，我们测试了泪膜细胞因子的变化或由李氏症状量表（LSS）眼部子量表评估的眼部症状是否能预测oGVHD的发作。
在造血细胞移植（HCT）前以及每2个月（月）直至12个月时收集LSS眼部子评分、Inflammadry（MMP9）和结膜冲洗样本。使用定制设计的13种人细胞因子磁珠板测量：IL-10、IL-17A、IL-1Ra、IL-1α、ELA2、IL-1β、LIGHT/TNFSF14、NGAL、OSM、IL-8、IP-10、TNF-α和VEGF-A。使用Kruskal-Wallis检验比较各组在HCT前访视时的细胞因子水平。计算细胞因子的变化倍数（FC），定义为HCT后值除以HCT前值，FC≥2用于进一步分析。oGVHD诊断基于美国国立卫生研究院（NIH）诊断标准且眼部评分≥1。使用Cox回归模型检查潜在预测因素与oGVHD发生之间的纵向关系。
纳入的44例患者中，18例发生oGVHD，11例患有无oGVHD的cGVHD，15例未患任何cGVHD。中位年龄为64.5岁，从HCT到cGVHD的中位时间为6.4个月，到oGVHD的中位时间为8.3个月。各组之间基线细胞因子水平无显著差异。泪液细胞因子或InflammaDry MMP9检测均未预测oGVHD发作。与无眼部受累的cGVHD相比，LSS眼部评分有临床意义的变化与随后的oGVHD发生相关（风险比[HR] 2.5，95%置信区间[CI] 1.2 - 5.1，P = 0.01）；与对照组相比（HR 3.0，95% CI 1.4 - 6.0，P = 0.004），但LSS变化≥15分的阳性预测值（PPV）较低（27.6%），阴性预测值（NPV）较高（89.4%）。
这是第一项对通过HCT密切观察cGVHD发生情况的患者队列中的泪液细胞因子和症状进行的前瞻性纵向研究。我们未能识别出任何oGVHD的生物学易感性/风险标志物。通过LSS测量的患者报告症状与oGVHD发生相关，但低PPV以及与诊断标准的重叠限制了其作为指导抢先治疗研究的生物标志物的实用性。
