Abstract
Background
The profound molecular heterogeneity of SLE remains a fundamental barrier to therapeutic progress.
Methods
We integrated clinical and multi-omic profiling, including transcriptomics, autoantigen microarrays, proteomics, and flow cytometry, across three randomised trials (BEAT-Lupus, CALIBRATE, ACCESS) and two observational cohorts to identify distinct lupus endotypes.
Findings
Using multivariate distance-based matching of autoantibody profiles to integrate molecular heterogeneity, we identified anti-RNP/anti-Sm co-positivity (RNP+Sm+) as a distinct myeloid-dominant inflammatory endotype.
Enriched in patients of Black ancestry (approx. 50%), RNP+Sm+ SLE is characterised by expanded intermediate monocytes showing enhanced TLR4-driven inflammation during flares, elevated pro-inflammatory cytokines (TNF-alpha, IL-6, IL-12, IFN-gamma, CCL2), IFNA10-biased interferon signalling, and systemic metabolic activation. IgG autoantibody profiling confirmed epitope spreading to spliceosomes and novel autoreactivity against circadian-metabolic regulators (SIRT1, NCOA1, SREBF1).
Clinically, this endotype manifests as high-grade disease activity (2.5-fold flare risk), nephritis, vasculitis, and enteritis. Hyperferritinaemia correlates with flares exclusively in RNP+Sm+ SLE (r=0.81), reflecting underlying macrophage activation. RNP+Sm+ patients exhibit profound therapeutic resistance: 44% failed first-line immunosuppression (rising to 61% in Black patients), while also showing substantially reduced efficacy (60% lower response) with second-line B-cell-depleting therapies (rituximab, obinutuzumab). Resistance to rituximab therapy was driven by rapid B-cell repopulation, rising BAFF levels, and sustained cytokines despite peripheral depletion. Consequently, they remain heavily steroid-dependent and accrued greater organ damage.
Conclusion
The RNP+Sm+ signature defines a high-risk, refractory, myeloid-driven lupus endotype characterised by activity linked hyperferritinemia that likely requires therapies directed at the underlying interferon and myeloid-centred pathways.
Funding
BEAT-Lupus: Arthritis UK and GSK. ACCESS and CALIBRATE: National Institute of Allergy and Infectious Diseases of the NIH.
Context and Significance
Systemic lupus erythematosus (SLE) is immunologically heterogeneous, yet conventional classifications fail to predict therapeutic outcomes. While autoantibodies are central to diagnosis, whether specific combinations define mechanistically distinct subsets remains unresolved. Here, we demonstrate that anti-RNP/anti-Sm co-positivity (RNP⁺Sm⁺) identifies a clinically aggressive, myeloid-dominant endotype disproportionately affecting Black patients. Multi-omics 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 profound first-line therapeutic resistance. Subsequently, this endotype shows poor response to B-cell-depleting therapies, necessitating prolonged glucocorticoid dependence and accelerated organ damage. Establishing RNP⁺Sm⁺ as a lupus endotype and ferritin as a companion disease activity biomarker enables precision stratification and highlights an underserved, high-risk population requiring urgent development of alternative strategies like myeloid-targeted and interferon-directed therapies.
Highlights
Anti-RNP/Sm co-positivity defines a high-risk, flare-prone, myeloid-dominant SLE endotype
RNP⁺Sm⁺ patients, especially Black patients, show profound refractoriness to first-line and B-cell depletion therapies
Expanded intermediate monocytes with TLR4 upregulation and IFNA10-biased interferon signalling
Hyperferritinaemia correlates with disease activity exclusively in RNP⁺Sm⁺ patients
Full Text Availability
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