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病毒，可导致慢性关节炎。 大约25%的人在初次感染后两年。疼痛是CHIKV的主要症状 关节炎目前没有针对CHIKV慢性关节炎的标准循证治疗。 我们U 01的主要目标是确定6个月甲氨蝶呤治疗与 安慰剂对哥伦比亚慢性CHIKV关节炎的临床表现和滑膜机制的影响， III期随机对照试验，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的具体目标，以量化临床疼痛， 这项试验将积累丰富的临床和组学数据，沿着基于组织的分析， 与基孔肯雅病毒性关节炎和甲氨蝶呤的独特疼痛状态相关的途径和基因 在代表性不足的拉丁裔人口中的治疗。 我们对NOSI应用的中心假设是，伤害性疼痛、神经性疼痛和伤害性疼痛起作用， 通过涉及炎性细胞因子（IL-1和IL-6）的机制在CHIKV关节炎发病率中起重要作用， 促炎性神经肽（降钙素基因相关肽（CGRP）和P物质（SP））， 神经营养因子神经生长因子（NGF）和涉及炎症的基因途径，GABA能， 肾上腺素能、肾上腺素能和下丘脑-垂体-肾上腺系统。这一假设将在 扩大我们的两个具体目标。 在母目标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关节炎在扩展目标1.1中，我们建议通过以下措施来增强我们的成果衡量标准： 另外的功能性疼痛指标表征了 拉丁美洲慢性基孔肯雅关节炎队列研究，包括健康的社会决定因素评估 作为疼痛严重程度和对治疗反应的调节剂。 在母目标2中，我们将通过获得滑膜组织， 治疗前和治疗期间的活检样本。在扩展目标2.1中，我们建议确定 甲氨蝶呤对组织损伤和疼痛机制之间双向相互作用的影响 采用免疫测定和免疫组织化学染色法检测外周血和滑膜组织中CGRP、SP 和NGF、细胞因子谱分析以及单细胞RNAseq转录组学和ATACseq染色质状态分析， 确定它们是否与临床疼痛状态相关，并定义与缓解相关的标记物 疼痛状态。 影响：这项工作将定义CHIKV关节炎中不同的疼痛表型和预测生物标志物， CHIKV关节炎疼痛的机制和甲氨蝶呤在治疗CHIKV关节炎疼痛中的效用。