Exagenica (United Kingdom)

BackgroundSystemic Lupus Erythematosus (SLE) is a complex clinical disease that often takes years and repeated testing to adequately diagnose. Standard biomarkers have low specificity (ANA) or low sensitivity (anti-dsDNA, anti-Smith). The advent of a multianalyte assay panel (MAP) incorporating innovative cell-bound complement activation markers warrants comparison of its clinical utility to conventional autoantibodies for the diagnosis and treatment of SLE.ObjectiveThis study compares the likelihood of SLE diagnosis, SLE treatment initiation, and the downstream impact on healthcare utilization on over 40,000 patients tested with either MAP (AVISE Lupus) versus standard of care lab testing with traditional anti-nuclear antibody (ANA) testing strategy cohort (tANA).MethodsUsing electronic health record (EHR) data from the Illumination Health registry (an integrated EHR record database encompassing records from over 300 US rheumatologists), an observational retrospective cohort study was performed. Health records from 01/2016 to 12/2020 and administrative claims with cost data for a subset of patients linkable to the HealthCore Integrated Research Database (HIRD) and Medicare data were analyzed. Two cohorts were established: MAP testing strategy and the tANA approach. Each test result was classified as positive, negative, or indeterminate and outcomes were stratified based on test results. Multivariable logistic regression was used to estimate odds ratios (OR) comparing the likelihood of SLE medication initiation and SLE diagnosis between the MAP and tANA cohorts. Test impact on SLE diagnosis, treatment initiation, patterns of repeat testing, and downstream healthcare utilization were analyzed.Results21,827 MAP testing episodes and 22,778 tANA testing episodes were included in the main cohort. Findings include: 2,437 (11.2%) patients tested positive by MAP compared to 5,364 (23.6%) of tANA(+) patients. MAP(+) patients were over 5-fold more likely to be diagnosed with SLE as compared to the tANA patients, 31% vs. 8% (OR = 5.11, 95% CI 4.43-5.89). Similarly, the new patient cohort was 6-fold more likely to achieve an SLE diagnosis when MAP is used, 30% vs. 6% (OR = 6.34, 95% CI 5.12- 7.86).Among patients with no baseline prescription for SLE medication(s), MAP(+) patients were more likely to initiate SLE medications compared to tANA(+) (43% vs. 32%, OR = 1.57, 95% CI 1.41-1.76). In patients new to the practice within the preceding year, the treatment effect was even larger 55% vs. 33% (adjusted OR = 2.77, 95% CI 2.31-3.32).Repeated testing was 3.5 times higher in tANA tested patients than in those tested with MAP.Linked EHR-Medicare data revealed a greater decrease in post-test vs. pre-test mean annualized outpatient lab testing in MAP(-) (-$985, p < 0.0001) vs. tANA(-) (-$356, p<0.0001) patients. A similar analysis of outpatient lab testing in EHR-HealthCore linked data revealed similar numerical trends but did not reach significance (p > 0.05).ConclusionsThe significantly greater likelihood of SLE diagnosis and SLE medication initiation in MAP(+) vs. tANA(+) patients is consistent with improved clinical actionability, potentially shortening time to diagnosis. MAP(-) patients experienced a greater decrease in outpatient lab testing post-test relative to tANA(-) patients, supporting the improved negative predictive value of MAP vs. tANA, and MAP patients were tested 3.5 fewer times than tANA patients, reducing valuable health-care dollars.

BackgroundClassification criteria for antiphospholipid syndrome (APS) require that antiphospholipid antibody (aPL) positivity is confirmed after at least 12 weeks. We tested the hypothesis that aPL at high titers remain positive while low titers fluctuate over time. As both platelet-bound C4d (PC4d) and aPL are associated with thrombosis in systemic lupus erythematosus (SLE), we also evaluated whether PC4d can aid in APS diagnosis.MethodsData from serum or plasma sent to Exagen’s laboratory for routine aPL testing were analyzed. Anti-cardiolipin (aCL) and anti-beta2 glycoprotein-1 antibodies (aB2GP1) were measured by chemiluminescence or ELiA fluorescence enzyme immunoassay; anti-phosphatidylserine/prothrombin complex antibodies (aPS/PT) by ELISA; PC4d by flow cytometry. Statistical analysis included descriptive statistics, logistic regression, and Pearson correlation.ResultsMore than 80% of positive samples with aCL and aB2GP1 at high titers - but not low titers - were positive at a retest. Non-criteria aPL (aPS/PT) followed a similar trend. aCL and aB2GP1 measured with two different technologies were highly correlated. PC4d and IgG of the three aPL were at best moderately correlated even when only positive aPL samples were analyzed (coefficient: 0.1917 to 0.2649).ConclusionsHigh titers aPL are often persistently positive, allowing an earlier diagnosis and risk assessment at the time of the initial screening. Conversely, a retest may be necessary for low titers. The high correlation between two methodologies suggests that these findings are independent of assay platform. The low to moderate correlation between PC4d and aPL might suggest a possible additive value to evaluate association with thrombosis in autoimmune diseases.

ObjectivesTo evaluate the association between lupus severity and cell-bound complement activation products (CB-CAPs) or low complement proteins C3 and C4.MethodsAll subjects (n=495) fulfilled the American College of Rheumatology (ACR) classification criteria for SLE. Abnormal CB-CAPs (erythrocyte-bound C4d or B-lymphocyte-bound C4d levels >99th percentile of healthy) and complement proteins C3 and C4 were determined using flow cytometry and turbidimetry, respectively. Lupus severity was estimated using the Lupus Severity Index (LSI). Statistical analysis consisted of multivariable linear regression and groups comparisons.ResultsAbnormal CB-CAPs were more prevalent than low complement values irrespective of LSI levels (62% vs 38%, respectively, p<0.0001). LSI was low (median 5.44, IQR: 4.77–6.93) in patients with no complement abnormality, intermediate in patients with abnormal CB-CAPs (median 6.09, IQR: 5.31–8.20) and high in the group presenting with both abnormal CB-CAPs and low C3 and/or C4 (median 7.85, IQR: 5.51–8.37). Odds of immunosuppressant use was higher in subjects with LSI ≥5.95 compared with subjects with LSI <5.95 (1.60 vs 0.53, p<0.0001 for both). Multivariable regression analysis revealed that higher LSI scores associated with abnormal CB-CAPs—but not low C3/C4—after adjusting for younger age, race and longer disease duration (p=0.0001), which were also independent predictors of disease severity (global R2=0.145).ConclusionAbnormalities in complement activation as measured by CB-CAPs are associated with increased LSI.