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

> **NIH NIH U01** · GEORGE WASHINGTON UNIVERSITY · 2023 · $259,670

## Abstract

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.

## Key facts

- **NIH application ID:** 10861515
- **Project number:** 3U01AR079717-02S1
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Aileen Chang
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $259,670
- **Award type:** 3
- **Project period:** 2022-09-22 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10861515

## Citation

> US National Institutes of Health, RePORTER application 10861515, Cutting Edge Pain Research in the Methotrexate treatment of Arthritis caused by Chikungunya virus (MARCH) Trial (3U01AR079717-02S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10861515. Licensed CC0.

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