# TIMP‐2 as a Potential Indicator of Persistent Arthralgia in Chikungunya: Evidence From a Brazilian Cohort Study

## TL;DR

This study found that TIMP-2 levels and early musculoskeletal symptoms may predict long-term joint pain in people infected with Chikungunya virus.

## Contribution

TIMP-2 is identified as a novel potential biomarker for persistent arthralgia in Chikungunya patients.

## Key findings

- Lower MMP-2 levels were associated with recovery from Chikungunya-related joint pain.
- TIMP-2 levels varied significantly across clinical outcomes, suggesting a role in disease progression.
- Swollen joints, skin rash, and elevated TIMP-2 levels predicted persistent arthralgia in the chronic phase.

## Abstract

Chikungunya virus (CHIKV) infection can trigger a sustained inflammatory response, often leading to chronic musculoskeletal pain. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) may contribute to the persistence of arthralgia through their involvement in joint tissue remodeling and degradation. This study aimed to evaluate the potential of MMPs and TIMPs as plasma biomarkers of persistent arthralgia in individuals diagnosed with Chikungunya Fever (CHIKF). A prospective cohort study was conducted using plasma samples from 133 CHIKF‐positive individuals recruited during the acute or post‐acute phases. Sociodemographic and clinical data were collected at outpatient visits. At 90 days post‐symptom onset, participants were assessed for persistent arthralgia using a self‐reported Visual Analog Scale (VAS) for joint pain and categorized into two groups: Recovered (VAS 0–3, n = 71) or Persistent Arthralgia (VAS 4–10, n = 62). Plasma levels of MMP‐2, MMP‐9, and TIMP‐2 were quantified using multiplex bead‐based ELISA (LegendPlex), while MMP‐1, MMP‐3, MMP‐14/MT1‐MMP, and TIMP‐1 were measured via sandwich ELISA. Plasma samples from 51 CHIKV‐negative individuals were used as controls. Statistical analyzes were performed using GraphPad Prism v9.0, IBM SPSS Statistics and Stata. Among post‐acute participants, lower MMP‐2 levels were significantly associated with recovery compared to those with persistent arthralgia and to controls. TIMP‐2 levels varied significantly across clinical outcomes, supporting its involvement in CHIKV‐induced pathology. Multivariate analysis identified swollen joints, skin rash, and elevated TIMP‐2 levels during the post‐acute phase as independent predictors of persistent arthralgia in the chronic phase. No significant differences were observed for MMP‐1, MMP‐3, MMP‐9, MMP‐14, or TIMP‐1. These findings suggest a potential role for TIMP‐2 and musculoskeletal manifestations as early indicators of chronic joint symptoms following CHIKV infection. Further studies are needed to validate these biomarkers and better understand the mechanisms underlying chronic Chikungunya‐related arthralgia across diverse populations.