Inflammatory biomarkers in complex regional pain syndrome: A systematic review and meta-analysis

Complex regional pain syndrome (CRPS) is a chronic condition characterized by autonomic and inflammatory symptoms and signs. The underlying mechanisms of CRPS remain unclear, and no definitive diagnostic biomarker has been identified. A previous meta-analysis from 2013 identified an inflammatory profile associated with CRPS, but it had methodological limitations. To address these gaps, we conducted a systematic review and meta-analysis to update and investigate the levels of inflammatory biomarkers in CRPS. We searched Embase, Scopus, and PubMed for studies published between 2003 and October 2025 that investigated inflammatory biomarkers in CRPS patients diagnosed according to the Budapest criteria compared to healthy controls (PROSPERO: CRD42023477197). Quality and risk of bias of included studies were assessed by the Newcastle-Ottawa Scale (NOS). Publication bias was evaluated using Egger's and Begg's tests and the Trim and Fill method. Our analysis included 12 studies (438 CRPS patients and 443 healthy controls). Compared with controls, CRPS patients exhibited increased levels of pro-inflammatory cytokines (TNF-α and IL-8), biomarkers receptors (sIL-2Rα, sTNFRII, and sVEGRF3). Only one study reported increased levels of CD14⁺CD16⁺ cells accompanied by decreased levels of the anti-inflammatory cytokine IL-37 in CRPS patients. Additionally, inflammatory biomarker levels were higher in plasma samples and when measured using multiplex assay. This study reinforces the hypothesis of a distinct systemic inflammatory profile in the chronic phase of CRPS and supports the relevance of inflammatory mediators as potential biomarkers for disease characterization and future therapeutic targets. PERSPECTIVES: This study reinforces the role of inflammatory biomarkers in patients with CRPS, in addition to supporting a characteristic profile of CRPS patients. It also suggests that these biomarkers may be part of a broader panel and highlights plasma and multiplex assays as suitable approaches for exploring mechanistic pathways.