Methotrexate treatment of Arthritis caused by Chikungunya virus (MARCH): A randomized controlled trial of methotrexate versus placebo in the treatment of chronic arthritis after chikungunya infection

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。目前还没有标准的循证医学 治疗CHIKV慢性关节炎。法国指南建议在治疗中使用甲氨蝶呤 然而，目前还没有关于甲氨蝶呤的随机安慰剂对照试验， 支持这一建议。我们的长期目标是指导CHIKV关节炎的循证治疗。 本提案的主要目标是确定6个月的疗效和组织病理学影响， 在哥伦比亚的一项研究中，甲氨蝶呤（n=100）与安慰剂（n=50）治疗慢性CHIKV关节炎的滑膜炎。 随机对照试验。我们的中心假设是，甲氨蝶呤将显着减少慢性 与安慰剂相比，CHIKV关节炎疾病严重程度并抑制白细胞积聚和炎性 滑膜组织中的细胞因子表达。该假设将在2个特定目标中进行评价。在目标1中，我们 确定口服甲氨蝶呤治疗与安慰剂治疗慢性CHIKV关节炎6个月的疗效。 在目标2中，我们将通过获得滑膜活检来确定甲氨蝶呤对滑膜炎症的影响 治疗前和治疗期间的样本。理由：这项工作将确定联合国的作用和机制， 甲氨蝶呤治疗慢性CHIKV关节炎，目的是将该领域推向 循证标准治疗。这项工作可能产生的更广泛影响是， 慢性病毒性关节炎的病理机制和可能的治疗选择。

ABSTRACT Chikungunya virus (CHIKV) is an alphavirus spread by mosquitos that causes persistent arthritis in approximately 25% of people two years after initial infection. There is currently no standard evidence-based treatment for CHIKV chronic arthritis. The French guidelines suggest the use of methotrexate in the treatment of chronic CHIKV arthritis however there are no randomized placebo-controlled trials of methotrexate to support this recommendation. Our long-term goal is to guide the evidence-based treatment of CHIKV arthritis. The main goal of this proposal is to determine the efficacy and histopathologic effects of 6 months of methotrexate (n=100) versus placebo (n=50) on synovitis in chronic CHIKV arthritis in Colombia in a randomized controlled trial. Our central hypothesis is that methotrexate will significantly decrease chronic CHIKV arthritis disease severity compared to placebo and suppress leukocyte accumulation and inflammatory cytokine expression in synovial tissue. This hypothesis will be evaluated in 2 specific aims. In Aim 1, we will determine the efficacy of oral methotrexate treatment versus placebo for 6 months in chronic CHIKV arthritis. In Aim 2, we will determine the effect of methotrexate on synovial inflammation by obtaining synovial biopsy samples before and during treatment. Rationale: This work will define the role and mechanism of methotrexate in the treatment of chronic CHIKV arthritis with the goal of advancing the field towards an evidence-based standard treatment. The potential broader impact of this work is the potential identification of the pathologic mechanism of chronic viral arthritis and a possible therapeutic option.