Identifying novel biomarkers for systemic lupus erythematosus associated with macrophage activation syndrome

Macrophage activation syndrome (MAS) represents a subtype of hemophagocytic lymphohistiocytosis (HLH) associated with autoimmune diseases. Systemic lupus erythematosus (SLE) is one of the most common autoimmune diseases that induce MAS. The overlapping systemic symptoms of SLE and clinical manifestations of HLH pose challenges in clinical diagnosis, contributing to significant rates of underdiagnosis and misdiagnosis, warranting further investigation. Identifying early diagnostic biomarkers with high sensitivity and specificity for MAS in SLE holds significant clinical importance.

Active SLE (SLEDAI 2k score≥5) patients were recruited from January 2022 to January 2024, from Peking University People's Hospital. MAS was diagnosed according to HLH-2004 criteria or HScore≥ 169. RNA sequencing was utilized to conduct a preliminary examination of the differences in mRNA expression profiles among peripheral blood mononuclear cells (PBMC) derived from healthy controls (HC), patients with moderately active SLE, and those with SLE-MAS. Subsequently, key differentially expressed mRNA candidates were selected to verify their accuracy in predicting MAS within the active SLE population by stratifying SLE patients into groups with or without MAS through using Real-time PCR method. Meanwhile, clinical baseline data were collected for further analysis.

Overall, 50 active SLE patients were enrolled eventually, 28 % developed MAS. In this study, RNA-seq of PBMCs from active SLE patients revealed KLRG1, KLRC3, and ULK2 as key mRNA predictors of SLE-MAS. Clinically, SLE-MAS patients showed higher rates of fever, cytopenia, lymphadenopathy, acute liver injury, and thrombotic microangiopathy, and with obvious abnormal HLH-related laboratory tests in comparison with active SLE group. Among the three transcripts, KLRG1 achieved the best performance (AUC 0.927, sensitivity 88.9 %, specificity 92.9 %), KLRC3 and ULK2 all have to been shown good identification ability, with an AUC of 0.885 and 0.843 respectively, all outperforming traditional diagnostic indicators including Fer, FIB, and TG.

KLRG1, KLRC3, and ULK2 are potential biomarkers for predicting MAS in SLE patients. Among them, KLRG1 has the highest sensitivity (0.889) and specificity (0.929) for predicting SLE induced MAS, which is considered the optimal biomarker for diagnosing MAS in SLE. These findings position KLRG1 as a minimally invasive, early-warning biomarker that could promptly predict MAS and might guide timely MAS-directed therapy in SLE.