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Native American (NA) populations have higher rates of rheumatic disease and present with overlapping disease symptoms and nontraditional serologic features, thus presenting an urgent need for better biomarkers in NA diagnostics. This study used a machine learning approach to identify immune signatures that more effectively stratify NA patients with rheumatic disease.Adult NA patients with autoantibody-positive (AAB+) rheumatoid arthritis (RA; n = 28), autoantibody negative (AAB-) RA (n = 18), systemic autoimmune rheumatic disease (n = 28), arthralgia/osteoarthritis (n = 28), or polyarthritis/undifferentiated connective tissue disease (n = 28), and control patients (n = 28) provided serum samples for cytokine, chemokine, and AAB assessment. Random forest clustering and soluble mediator groups were used to identify patients and control patients with similar biologic signatures. The American College of Rheumatology criteria specific for systemic disease and RA identified differences in disease manifestations across clusters.Serum soluble mediators were not homogenous between different NA rheumatic disease diagnostic groups, reflecting the heterogeneity of autoimmune diseases. Clustering by serum biomarkers created 5 analogous immune phenotypes. Soluble mediators and pathways associated with chronic inflammation and involvement of the innate, B cell, T follicular helper cell, and interferon-associated pathways, along with regulatory signatures, distinguished the 5 immune signatures among patients. Select clinical features were associated with individual immune profiles. Patients with low inflammatory and higher regulatory signatures were more likely to have few clinical manifestations, whereas those with T cell pathway involvement had more arthritis.Serum protein signatures distinguished NA patients with rheumatic disease into distinct immune subsets. Following these immune profiles over time may assist with earlier diagnoses and help guide more personalized treatment approaches.

Objective Many Native American (NA) patients with systemic lupus erythematosus (SLE) do not exhibit the classical SLE autoantibody profiles of European American (EA) and African American (AA) patients with SLE. The poorer SLE disease outcomes noted in NA patients highlights a need for more equitable diagnostic and prognostic tools for NA patients with SLE. The objective was to identify informative autoantibody profiles for NA, AA, and EA patients with SLE using an expanded set of autoantigens. Methods Sera from 49 NA, 49 AA, and 49 EA age-, sex-, and antinuclear autoantibody titer-matched patients with SLE who met the American College of Rheumatology classification criteria and 10 ethnicity-, sex-, and age-matched controls were tested for autoantibody reactivity by autoantigen microarrays. Autoantibodies that were significantly elevated in patients with SLE compared with ethnicity-specific controls were selected for hierarchical clustering. Differences in clinical criteria between patient clusters were determined by Fisher's exact test and corrected for multiple comparisons. Results NA, AA, and EA patients with SLE each had a cluster distinguished by higher levels of anti-Ro52 and another cluster distinguished by nucleic acid-specific autoantibodies. Additional clusters were distinguished in NA patients by elevated extracellular matrix autoantibodies and were distinguished in AA patients by elevated Sm/RNP autoantibody and elevated nucleolin/histone autoantibody. Two EA patient clusters with similar nucleic acid- and Ro52-specific autoantibodies were distinguished by either high or low histone 2A reactivity. Renal manifestations trended higher in the NA Ro52 cluster and were significantly enriched in the AA nucleolin/histone cluster. The AA nucleolin/histone cluster and EA H2A cluster had higher disease activity. Conclusion Expanded autoantibody profiles can identify informative subsets of patients with SLE.

Background Autoantibodies (AAbs) are a hallmark of systemic lupus erythematosus (SLE). Common SLE AAbs show differences in specificities, levels and associations with clinical characteristics of disease which may be influenced by ethnicity.(1-2) NA SLE patients do not always exhibit classical AAb profiles.(2) Understanding how AAb profiles associate with clinical disease, including in NA patients, is important to better inform disease management. Objectives To identify patient subsets enriched for renal disease by clustering NA, AA and EA SLE patients into more homogeneous disease subsets based on expanded AAb profiles. Methods Serum samples from 49 NA, 49 AA, and 49 EA age, sex and ANA titer-matched SLE patients who met ACR classification and 10 sex and age matched controls from each ethnicity were tested for AAb reactivity by autoantigen microarray. Normalized fluorescence intensity (NFI) for AAb binding was determined for each individual for all autoantigens. Ratios of NFIs to total IgG were calculated and converted to Z-scores. Kruskal-Wallis analysis of Z-score transformed AAb ratios were used to identify AAbs that differed significantly between patients and controls for each ethnicity; these AAbs were used for hierarchal clustering of SLE subjects within each ethnicity. The enrichment of SLE clinical criteria within each cluster was determined by Fisher’s exact test. Results AAbs to nucleic acids and Ro52 were present in SLE patients of all three ethnicities. On average, NA SLE patients, but not EA or AA SLE patients, had lower levels of AAbs against extracellular matrix (ECM) antigens compared to controls. AA and EA, but not NA, SLE patients had significantly higher levels of AAbs to Sm, RNP and histones compared to matched controls. In each ethnicity four clusters of SLE subjects were identified by ethnicity-specific AAbs. All three groups had a cluster of subjects enriched in nucleic acid-specific AAbs and a cluster of subjects enriched in Ro52 AAbs. The NA group also had two clusters enriched in ECM AAbs. The AA group had an Sm/RNP AAb enriched cluster and a nucleolin/histone AAb enriched cluster. Two additional EA SLE clusters had similar levels of nucleic acid-specific AAbs and Ro52 AAbs, but were distinguished by significant differences in histone 2A (H2A) AAb levels. Renal manifestations were significantly enriched in the NA Ro52 cluster and the AA nucleolin/histone cluster compared to other SLE patient clusters of the same ethnicity. Conclusion Expanded AAb profiles can be used to identify SLE subsets that are more likely to have renal manifestations of disease. References [1] Sanchez E, et al. Impact of genetic ancestry and sociodemographic status on the clinical expression of systemic lupus erythematosus in American Indian-European populations. Arthritis Rheum. 2012;64(11):3687-94. [2] Kheir JM, et al. Unique clinical characteristics, autoantibodies and medication use in Native American patients with systemic lupus erythematosus. Lupus Sci. & Med. 2018;5:e000247. Acknowledgement This research supported by the National Institute of Allergy and Infectious Disease (U19AI082714), National Institute of Arthritis, Musculoskeletal and Skin Diseases (P30AR053483, P30AR073750), and National Institute of General Medical Sciences (U54GM104938) of the US NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the United States government. Disclosure of Interests None declared

Objective: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with varied morbidity and mortality. We assessed clinical presentations, autoantibody specificities and therapeutic interventions in Native American (NA) patients with SLE. Methods: Patients with SLE meeting 1997 American College of Rheumatology classification criteria (n=3148) were enrolled between 1992 and 2010 in the multiethnic, cross-sectional Lupus Family Registry and Repository. Clinical, demographic and therapeutic information were extracted from medical records using a standardised form and formalised training. Autoantibodies were assessed by indirect immunofluorescence (antinuclear antibodies (ANA) and antidouble-stranded DNA), precipitin (ENA) and ELISA (IgG and IgM anticardiolipins). Results: NA patients met SLE classification at a younger age (29.89±12.3 years) than European Americans (EA; 32.02±12.87, P=0.0157) and a similar age to African-Americans (AAs) and Hispanics (HIS). More NA patients had concurrent rheumatic diseases or symptoms, such as Raynaud's phenomenon, interstitial lung disease, Sjögren's syndrome and systemic sclerosis. Compared with EAs, NAs were more likely to have high-titre ANA (≥1:3240; P