Skin biomarkers associated with complex regional pain syndrome (CRPS) Type I: a systematic review

Despite increasing research, the pathophysiology of Complex Regional Pain Syndrome (CRPS) remains poorly understood. Due to its easy accessibility, the skin represents an ideal approach to gain a better understanding of the underlying processes. We conducted a systematic review of original studies investigating potential biomarkers cutaneous biomarkers in CRPS. Original articles with a minimum level IV of evidence were screened using the following databases: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and Web of Science Core Collection. Quality assessment was performed using the Methodological Index for Non-Randomized Studies criteria. A total of 11 studies exploring cutaneous biomarkers in 299 CRPS Type I patients were included. The biomarkers identified revealed implications of the following pathophysiological processes: inflammation via interleukins and TNF-a, vascular dysregulation (ET-1/NOx disturbances and hypoxia-high lactate), small fiber neuropathy and hypersensitivity. In terms of skin morphology, evidence suggests: neurite loss, increased expression and disturbed migration of mast cells, as well as an increased expression of α1-adrenoceptors on keratinocytes. The data supporting hypersensitivity had a high risk of bias on quality assessment. The current review has emphasized the current state of knowledge regarding the cutaneous biomarkers in patients suffering from CRPS Type I. Our results serve as a basis for future developments of techniques that would either facilitate diagnosis or may represent therapeutic targets. Trial registration PROSPERO: CRD42020203405. Level of evidence: IV (Systematic Review).