Marastoni Damiano, Colato Elisa, Foschi Matteo, Tamanti Agnese, Ziccardi Stefano, Eccher Chiara, Crescenzo Francesco, Bajrami Albulena, Schiavi Gian Marco, Camera Valentina, Anni Daniela, Virla Federica, Guandalini Maddalena, Turano Ermanna, Pizzini Francesca Benedetta, Montemezzi Stefania, Bonetti Bruno, Howell Owain, Magliozzi Roberta, Nicholas Richard S, Scalfari Antonio, Granziera Cristina, Kappos Ludwig, Calabrese Massimiliano
Neurology B, Department of Neurosciences, University of Verona, Italy.
MS Centre, Department of Anatomy and Neuroscience, Amsterdam UMC, location VUmc, the Netherlands.
Neurol Neuroimmunol Neuroinflamm. 2025 Jul;12(4):e200399. doi: 10.1212/NXI.0000000000200399. Epub 2025 May 1.
The objective of this study was to determine, at the time of diagnosis, a CSF and MRI profile of intrathecal compartmentalized inflammation predictive of progression independent of relapse activity (PIRA) in early relapsing-remitting multiple sclerosis (RRMS).
This five-year prospective study included 80 treatment-naïve patients with RRMS enrolled at time of diagnosis. All patients underwent a lumbar puncture, regular neurologic evaluations including an Expanded Disability Status Scale (EDSS) assessment every 6 months, and an annual 3T brain MRI. PIRA was defined as having a confirmed disability progression independent of relapse activity. CSF levels of 68 inflammatory molecules were evaluated in combination with white matter and cortical lesion number (CLn) and volume, and regional gray matter thickness and volume.
During the follow-up, 23 patients with RRMS (28.8%) experienced PIRA. At diagnosis, participants with PIRA were older (44.0 ± 10.7 vs 37.4 ± 12.4, = 0.017) and with more disability (median EDSS score [interquartile range] of 3 [range 2-4] for PIRA vs 1.5 [range 1-2] for no PIRA group, < 0.001). Random forest selected LIGHT, CXCL13, sTNFR1, sTNFR2, CCL7, MIF, sIL6Rbeta, IL35, CCL2, and IFNβ as the CSF markers best associated with PIRA. sTNFR1 (hazard ratio [HR] 10.11 [2.61-39.10], = 0.001), sTNFR2 (HR 5.05 [1.63-15.64], = 0.005), and LIGHT (HR 1.79 [1.11-2.88], = 0.018) were predictors of PIRA at regression analysis. Baseline thalamus volume (HR 0.98 [0.97-0.99], = 0.005), middle frontal gyrus thickness (HR 0.05 [0.01-0.72], = 0.028), and CLn (HR 1.15 [1.05-1.25], = 0.003) were MRI predictors of PIRA.
A specific intrathecal inflammatory profile associated with TNF superfamily markers, CLn, and atrophy of several cortical and deep gray matter regions, assessed at time of diagnosis, is predictive of PIRA in early MS.
本研究的目的是在早期复发缓解型多发性硬化症（RRMS）诊断时，确定脑脊液（CSF）和磁共振成像（MRI）特征，以预测鞘内局限性炎症独立于复发活动（PIRA）的进展情况。
这项为期五年的前瞻性研究纳入了80例诊断时未接受过治疗的RRMS患者。所有患者均接受了腰椎穿刺、定期神经学评估，包括每6个月进行一次扩展残疾状态量表（EDSS）评估，以及每年一次的3T脑部MRI检查。PIRA定义为具有独立于复发活动的确诊残疾进展。评估了68种炎症分子的脑脊液水平，并结合白质和皮质病变数量（CLn）及体积，以及区域灰质厚度和体积。
在随访期间，23例RRMS患者（28.8%）出现了PIRA。诊断时，发生PIRA的参与者年龄较大（44.0±10.7岁对37.4±12.4岁，P = 0.017），残疾程度更高（PIRA组的EDSS评分中位数[四分位间距]为3[范围2 - 4]，无PIRA组为1.5[范围1 - 2]，P < 0.001）。随机森林分析选择LIGHT、CXCL13、sTNFR1、sTNFR2、CCL7、MIF、sIL6Rβ、IL35、CCL2和IFNβ作为与PIRA最相关的脑脊液标志物。在回归分析中，sTNFR1（风险比[HR] 10.11[2.61 - 39.10]，P = 0.001）、sTNFR2（HR 5.05[1.63 - 15.64]，P = 0.005）和LIGHT（HR 1.79[1.11 - 2.88]，P = 0.018）是PIRA的预测指标。基线丘脑体积（HR 0.98[0.97 - 0.99]，P = 0.005）、额中回厚度（HR 0.05[0.01 - 0.72]，P = 0.028）和CLn（HR 1.15[1.05 - 1.25]，P = 0.003）是PIRA的MRI预测指标。
在诊断时评估的与TNF超家族标志物、CLn以及几个皮质和深部灰质区域萎缩相关的特定鞘内炎症特征，可预测早期MS中的PIRA。
