Adult patients with autoinflammation of unknown origin partially phenocopy the immune presentation of Still’s disease

Autoinflammation of unknown origin remains amongst the most enigmatic of systemic autoinflammatory disorders (SAID), with systemic autoinflammatory symptoms in the absence of a molecular or clinical diagnosis with a recognized SAID. Here, we aim to understand the immunological process behind patients with autoinflammation of unknown origin. We collect samples from 36 patients manifesting recent disease activity across 30 European medical centers, and employ deep immunophenotyping and plasma proteomics to compare to 58 healthy controls and an additional demographically similar cohort comprising 92 SAID patients. Machine-learning approaches identify key immunological changes, including the upregulation of CD38 and HLA across T cell subsets and the upregulation of acute-phase plasma proteins in autoinflammation of unknown origin patients. The immunological traits of these previously poorly characterised patients partially phenocopy Still's disease presentation. Thus, this study identifies potential biomarkers and disease mediators in autoinflammation of unknown origin.