Evidence of central neuroimmune alterations in fibromyalgia: a systematic review of case-control studies

• Evidence suggests central neuroimmune alterations in fibromyalgia • Findings point to possible glial and neurometabolic alterations in key regions. • Several studies report associations with pain, affective, and cognitive symptoms. • Neuroimmune mechanisms may interact with stress-related processes in fibromyalgia. • Current evidence remains heterogeneous and requires further validation. Fibromyalgia (FM) is a chronic disorder characterized by widespread pain, fatigue, and cognitive or affective symptoms. Despite its high prevalence among middle-aged women and substantial clinical impact, the central mechanisms underlying FM remain poorly understood. Evidence points to a multicausal origin, potentially involving the immune system. Although peripheral immune dysregulation has been consistently reported, no systematic review has yet evaluated central neuroimmune changes and their clinical relevance. A systematic review was conducted in accordance with PRISMA 2020 guidelines and registered in PROSPERO (CRD420251036797). Searches were performed in PubMed, Web of Science, and Scopus for records published up to January 5, 2025. 18 studies reporting central immune alterations in FM patients were included. 9 employed neuroimaging techniques, 6 analyzed cerebrospinal fluid, 2 investigated differential gene expression, and one used a translational cellular approach. Although high heterogeneity across studies and methodologies, findings suggested convergent patterns of glial and neurometabolic abnormalities in cortical and subcortical brain regions, alongside alterations in immune-related proteins and markers of disrupted neuroimmune signaling. Consistent with previous reports of peripheral findings, the available evidence suggests that FM may involve central neuroimmune alterations encompassing both pro-inflammatory and regulatory mechanisms across genetic, molecular, and cellular levels. Alterations in brain regions converge on key networks implicated in pain processing, emotional regulation, cognition, and behavior. These findings support a neuroimmune framework for FM and highlight the potential role of neuroimmune processes in its pathophysiology.