{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:22:52Z","timestamp":1785435772573,"version":"3.56.0"},"posted":{"date-parts":[[2026,2,14]]},"group-title":"Immunology","reference-count":93,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T00:00:00Z","timestamp":1771027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/03phf2w66","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The profound molecular heterogeneity of SLE remains a fundamental barrier to therapeutic progress.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Findings<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                  <jats:p>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).<\/jats:p>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Funding<\/jats:title>\n                  <jats:p>BEAT-Lupus: Arthritis UK and GSK. ACCESS and CALIBRATE: National Institute of Allergy and Infectious Diseases of the NIH.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Context and Significance<\/jats:title>\n                  <jats:p>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\u207aSm\u207a) 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\u207aSm\u207a 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\u207aSm\u207a 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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Anti-RNP\/Sm co-positivity defines a high-risk, flare-prone, myeloid-dominant SLE endotype<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>RNP\u207aSm\u207a patients, especially Black patients, show profound refractoriness to first-line and B-cell depletion therapies<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Expanded intermediate monocytes with TLR4 upregulation and IFNA10-biased interferon signalling<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Hyperferritinaemia correlates with disease activity exclusively in RNP\u207aSm\u207a patients<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.02.12.705402","type":"posted-content","created":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T12:00:21Z","timestamp":1771070421000},"source":"Crossref","is-referenced-by-count":0,"title":["Elevated ferritin as a companion biomarker of myeloid-driven inflammation in RNP\/Sm co-positive, treatment-resistant SLE endotype"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2087-9437","authenticated-orcid":false,"given":"Muhammad RA","family":"Shipa","sequence":"first","affiliation":[{"name":"Department of Ageing, Rheumatology and Regenerative Medicine, University College London, UK"},{"name":"Department of Rheumatology, University College London hospital, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Beesley","sequence":"additional","affiliation":[{"name":"Department of Ageing, Rheumatology and Regenerative Medicine, University College London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"McClusky","sequence":"additional","affiliation":[{"name":"Department of Ageing, Rheumatology and Regenerative Medicine, University College London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Guichard","sequence":"additional","affiliation":[{"name":"Department of Ageing, Rheumatology and Regenerative Medicine, University College London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon A.","family":"Chung","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University of California, San Francisco, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura A.","family":"Cooney","sequence":"additional","affiliation":[{"name":"Immune Tolerance Network, University of Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek","family":"Gilroy","sequence":"additional","affiliation":[{"name":"Department of Ageing, Rheumatology and Regenerative Medicine, University College London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R","family":"Ehrenstein","sequence":"additional","affiliation":[{"name":"Department of Ageing, Rheumatology and Regenerative Medicine, University College London, UK"},{"name":"Department of Rheumatology, University College London hospital, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"1","key":"2026021704500648000_2026.02.12.705402v1.1","first-page":"367","article-title":"All-cause and cause-specific mortality in systemic lupus erythematosus: a population-based study. 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