Ferritin as a companion biomarker of myeloid-driven inflammation in an RNP/Sm co-positive, treatment-resistant lupus endotype

Systemic lupus erythematosus (SLE) is immunologically heterogeneous, yet current clinical classifications poorly predict therapeutic responses. Although autoantibodies are central to diagnosis, whether specific combinations define mechanistically distinct and therapeutically informative subsets remains unclear. Here, we demonstrate that anti-RNP/anti-Sm co-positivity (RNP⁺Sm⁺) identifies a clinically aggressive, myeloid-dominant endotype disproportionately affecting Black patients where disease activity is marked by hyperferritinemia. Multi-omic integration revealed expansion of intermediate monocytes with enhanced TLR4 expression, IFNA10-biased interferon signalling, and metabolic reprogramming. Clinically, RNP⁺Sm⁺ patients exhibit nephritis, vasculitis, higher flare rates, and resistance to first-line immunosuppression. This endotype shows poor response to conventional immunosuppressants and B-cell-depleting therapies, leading to prolonged glucocorticoid dependence and accelerated organ damage. Establishing RNP⁺Sm⁺ as a serologic classifier together with ferritin as a companion biomarker of disease activity enables both precision stratification and clinical monitoring using routinely available assays. Together, these findings position the RNP⁺Sm⁺ signature as a clinically actionable framework that can support earlier recognition of high‑risk patients and more tailored therapeutic decision-making.Highlights:· Anti-RNP/Sm co-positivity defines a high-risk, flare-prone, myeloid-dominant SLE endotype· RNP⁺Sm⁺ patients, especially Black patients, show marked refractoriness to first-line and B-cell depletion therapies· An increase in TLR4 expressing intermediate monocytes and IFNA10-biased interferon signalling· Hyperferritinaemia correlates with disease activity selectively in RNP⁺Sm⁺ patientsBEAT-lupus (ISRCTN 47873003). CALIBRATE trial (NCT02260934)