Cutting Edge Pain Research in the Methotrexate treatment of Arthritis caused by Chikungunya virus (MARCH) Trial

甲氨蝶呤治疗基孔肯雅病毒引起的关节炎的前沿疼痛研究（3 月）试验

• 批准号: 10861515
• 负责人: Aileen Chang
• 金额: $ 25.97万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10861515
• 关键词: ATAC-seq; Adrenergic Agents; Alphavirus; Arthritis; Biopsy Specimen; Calcitonin Gene-Related Peptide; Chikungunya virus; Chronic; Clinical; Clinical Trials; Colombia; Culicidae; Data; Evidence based treatment; Genes; Goals; Hypothalamic structure; Immunoassay; Infection; Inflammation; Inflammatory; Interleukin-1; Interleukin-6; Latin American; Latino Population; Methotrexate; Morbidity - disease rate; Nerve Growth Factors; Neuropathy; Neuropeptides; Nociception; Oral; Outcome Measure; Pain; Pain Research; Parents; Pathway interactions; Persons; Phase; Phenotype; Pituitary-Adrenal System; Placebos; Play; Randomized, Controlled Trials; Resolution; Role; Severities; Stains; Substance P; Symptoms; Synovitis; Tissues; Viral Arthritis; Work; arthritic pain; chikungunya; clinical pain; cohort; cytokine; efficacy evaluation; neurotrophic factor; peptide P; peripheral blood; phenotypic biomarker; predictive marker; single-cell RNA sequencing; social health determinants; transcriptomics; treatment response

ABSTRACT Chikungunya virus (CHIKV) is an alphavirus spread by mosquitos that causes persistent arthritis in approximately 25% of people two years after initial infection. Pain is the predominant symptom in CHIKV arthritis. There is currently no standard evidence-based treatment for CHIKV chronic arthritis. The main goal of our U01 is to determine the efficacy of 6 months of methotrexate treatment versus placebo on clinical manifestations and synovial mechanisms in chronic CHIKV arthritis in Colombia in a Phase III randomized controlled trial in order to guide the evidence-based treatment of CHIKV arthritis. Our main goal of this NOSI application is to expand our current specific aims to quantify pain in a clinical trial that will accumulate a rich trove of clinical and omics data along with tissue-based analysis to determine pathways and genes associated with the unique pain state of chikungunya viral arthritis and methotrexate treatment in an underrepresented Latino population. Our central hypothesis of this NOSI application is that nociceptive, neuropathic and nociplastic pain play a significant role in CHIKV arthritis morbidity via mechanisms involving inflammatory cytokines (IL-1 & IL-6), proinflammatory neuropeptides (calcitonin gene-related peptide (CGRP) and substance P (SP)), the neurotrophin nerve growth factor (NGF) and gene pathways involving inflammation, the GABAergic, adrenergic, serotonergic and hypothalamic-pituitary-adrenal systems. This hypothesis will be evaluated in expansion of our 2 specific aims. In the Parent Aim 1, we will determine the efficacy of oral methotrexate treatment versus placebo for 6 months in chronic CHIKV arthritis. In Expanded Aim 1.1, we propose to enhance our outcome measures with additional functional pain metrics that characterize nociceptive, neuropathic and nociplastic pain phenotyping in a Latin American chronic chikungunya arthritis cohort, including assessments of social determinants of health as modifiers of pain severity and response to treatment. In Parent Aim 2, we will determine the effect of methotrexate on synovial inflammation by obtaining synovial biopsy samples before and during treatment. In Expanded Aim 2.1, we propose to determine the effect of methotrexate on the bidirectional interaction between tissue damage and pain mechanisms via analysis of peripheral blood and synovial tissue using immunoassays and immunohistochemical staining for CGRP, SP and NGF, cytokine profiling, and single-cell RNAseq transcriptomic and ATACseq chromatic state analyses to determine if they correlate with the clinical pain state and to define markers that are associated with resolution of pain states. Impact: This work will define the diverse pain phenotypes and predictive biomarkers in CHIKV arthritis, the mechanisms of CHIKV arthritis pain and the utility of methotrexate in the treatment of CHIKV arthritis pain.

摘要 基孔肯雅病毒(CHIKV)是一种由蚊子传播的甲型病毒，可导致持续性关节炎 大约25%的人在初次感染两年后。疼痛是CHIKV的主要症状 关节炎。目前还没有针对CHIKV慢性关节炎的标准循证治疗方法。 我们的U01的主要目标是确定6个月的甲氨蝶呤治疗与 安慰剂对哥伦比亚慢性CHIKV关节炎临床表现和滑膜机制的影响 第三阶段随机对照试验，以指导CHIKV关节炎的循证治疗。 我们这个nosi应用程序的主要目标是扩展我们目前在临床上量化疼痛的具体目标。 该试验将积累丰富的临床和组学数据，以及基于组织的分析，以确定 与基孔肯雅病毒性关节炎和甲氨蝶呤独特疼痛状态相关的途径和基因 在未被充分代表的拉美裔人口中进行治疗。 我们对这一鼻部应用的中心假设是，伤害性、神经病理性和肿瘤性疼痛在 炎性细胞因子(IL-1和IL-6)在CHIKV关节炎发病中的重要作用 促炎神经肽(降钙素基因相关肽(CGRP)和P物质(SP))， 神经营养因子(NGF)和涉及炎症的基因通路，GABA能， 肾上腺素能、5-羟色胺能和下丘脑-垂体-肾上腺系统。这一假设将在#年进行评估。 扩展我们的两个具体目标。 在父母目标1中，我们将确定口服甲氨蝶呤治疗与安慰剂治疗6个月的疗效。 慢性CHIKV关节炎。在扩展的目标1.1中，我们建议通过以下方式增强我们的成果衡量标准 表征伤害性、神经病理性和肿瘤性疼痛表型的其他功能性疼痛指标 拉丁美洲慢性基孔肯雅性关节炎队列，包括对健康的社会决定因素的评估 作为疼痛严重程度和治疗反应的修饰物。 在家长目标2中，我们将通过获取滑膜来确定甲氨蝶呤对滑膜炎症的影响。 治疗前和治疗期间的活组织检查样本。在扩展的目标2.1中，我们建议确定 甲氨蝶呤对组织损伤和疼痛机制双向相互作用的分析 外周血和滑膜组织中CGRP、SP的免疫组织化学检测 以及NGF、细胞因子图谱、单细胞RNAseq转录和ATACseq染色状态分析 确定它们是否与临床疼痛状态相关，并定义与解决相关的标记物 疼痛状态。 影响：这项工作将定义CHIKV关节炎的不同疼痛表型和预测性生物标记物 CHIKV关节炎疼痛的机制及甲氨蝶呤在CHIKV关节炎疼痛治疗中的应用