Neurology B, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
Neurology Unit, Department of Neuroscience, Multiple Sclerosis Center, S. Maria delle Croci Hospital, AUSL, Romagna, Ravenna, Italy.
Front Immunol. 2024 Feb 9;15:1343892. doi: 10.3389/fimmu.2024.1343892. eCollection 2024.
Cladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug initiation. Biomarkers that can predict early disease activity are needed.
To estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine.
Forty-two RRMS patients (30F/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The 'no evidence of disease activity' (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs.
Three patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91).
CSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug's effect on chronic macrophage and microglia activation deserves further evaluation.
克拉屈滨已被引入作为治疗复发缓解型多发性硬化症（RRMS）的高效药物。初始队列研究表明，在药物起始后的第一年存在早期疾病活动。需要能够预测早期疾病活动的生物标志物。
评估克拉屈滨治疗起始后脑脊液（CSF）标志物与临床和影像学反应的相关性。
本研究纳入了 42 例 RRMS 患者（30 例女性/12 例男性），进行了一项前瞻性纵向研究。所有患者在治疗起始时进行了 CSF 检查，进行临床随访，包括扩展残疾状况量表（EDSS）评估，并在 6、12 和 24 个月时进行了 3T MRI 扫描，包括评估白质（WM）和皮质病变（CL）。采用免疫分析多重技术评估 67 种炎症标志物的 CSF 水平。在 2 年后评估“无疾病活动”（NEDA-3）状态，并定义为无复发、EDSS 无残疾恶化和无 MRI 活动，包括 CL。
在随访过程中，有 3 例患者失访。随访结束时，19 例（48%）患者仍处于无疾病活动状态。IFNγ、几丁质酶 3 样蛋白 1、IL32、骨桥蛋白、IL12(p40)、IL34、IL28A、sTNFR2、IL20 和 CCL2 与疾病活动的相关性最佳。当将年龄、性别和基线 EDSS 纳入包括这些因素的多变量回归模型时，几丁质酶 3 样蛋白 1（p = 0.049）在疾病活动患者中显著增加。最后，将几丁质酶 3 样蛋白 1 加入 EDSS、性别、年龄、既往复发、WM 病变数量、CL、钆增强病变和脊髓病变数量的模型中进行 ROC 分析，提供了 0.76（95%CI 0.60-0.91）的 AUC。
CSF 几丁质酶 3 样蛋白 1 可能为预测克拉屈滨治疗起始后最初几年疾病活动提供预后信息。该药对慢性巨噬细胞和小胶质细胞激活的影响值得进一步评估。
