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Multi-Centered Clinical Validation Demonstrating Superior Precision in Lupus Diagnosis: T Cell Autoantibodies and TC4d Outperform Conventional Lupus Erythematosus Biomarkers
Positive AVISE
Lupus Test Results:
The study clearly establishes a link between the superiority of the AVISE test and the benefit to patients through early treatment intervention. Delayed diagnosis can lead to increased disease burden and diminished quality of life.
Diagnosis
6X greater odds
AVISE Lupus [+]1 vs traditional ANA [+]2 establishing SLE diagnosis following AVISE
Treatment Initiation
3X greater odds
AVISE Lupus [+]1 vs traditional ANA [+]2 initiating SLE treatment following AVISE
Negative AVISE
Lupus Test Results:
The study demonstrated that a negative AVISE test is more conclusive than the standard of care, as it is reflected by the lower number of repeat testing and fewer follow-up visits. Convincingly ruling out lupus is often a critical step for achieving diagnostic clarity for the patient and reducing costs on the system.
Repeat Testing
3.5X less frequent
AVISE Lupus vs. traditional ANA tested patients in a mean 285 days of follow up for AVISE and 305 days of follow-up for tANA
Repeat Testing
3.5X less frequent
AVISE Lupus vs. traditional ANA tested patients in a mean 285 days of follow up for AVISE and 305 days of follow-up for tANA
Laboratory Cost
2X lower
AVISE Lupus [-] vs traditional ANA [-] in first six-month follow-up period
Follow-up Visits
1 fewer visits
AVISE Lupus [-] vs traditional ANA [-] in first sixth-month follow-up period
References:
1. AVISE Lupus + = Tier 1 and Tier 2 Positive.
2. tANA + = ANA (IFA) 1:160 ≥ and/or one or more of the following
positive: anti-dsDNA, anti-smith.
Summary
T Cell autoantibodies, TIgG and TIgM, as well as the T Cell-bound complement protein fragment C4d (TC4d) are novel diagnostic biomarkers that have demonstrated high specificity and sensitivity for systemic lupus erythematosus (SLE). This study aimed to characterize the clinical performance of the emergent T Cell biomarkers in a multi-center clinical validation cohort.
Using electronic health record (EHR) data from 01/2016 to 12/2020, linked with HealthCore and Medicare medical and pharmacy claims and cost data, two cohorts were established: the AVISE cohort and the tANA cohort. AVISE and tANA test results were classified as positive, negative, or indeterminate and 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 AVISE and tANA cohorts.
The significantly greater likelihood of SLE diagnosis and SLE medication initiation in AVISE positive vs. tANA positive patients demonstrates superior clinical actionability, potentially shortening the time to diagnosis. AVISE negative patients experienced a greater decrease in outpatient lab testing post-test relative to tANA negative patients, supporting the superior negative predictive value of AVISE vs. tANA.
The main cohort included 21,827 AVISE testing episodes and the tANA arm included 22,778. A total of 2,437 (11.2%) patients tested positive by AVISE compared to 5,364 (23.6%) of tANA positive patients. Among patients with no baseline prescription for SLE medication(s), AVISE positive patients were more likely to initiate SLE medications compared to tANA positive patients (43% vs. 32%, OR = 1.57, 95% CI 1.41-1.76). The treatment effect was larger in patients new to the practice within the preceding year, 55% vs. 33% (adjusted OR = 2.77, 95% CI 2.31-3.32). AVISE positive patients were over five-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), and similar in the 5 new patient cohort 30% vs. 6% (OR = 6.34, 95% CI 5.12-7.86). Linked Columbus-Medicare data revealed a greater decrease in post-test vs. pre-test mean annualized outpatient lab testing in AVISE negative (-$985, p < 0.0001) vs. tANA negative (-$356, p<0.0001) patients.
Methods
A cohort of 400 adult patients enrolled across 3 academic and 2 community-based autoimmune rheumatic centers were tested for TC4d, TIgG, TIgM and an extensive autoantibody profile. The cohort was comprised of 105 SLE patients, 173 patients with autoimmune rheumatic diseases (ARD), 83 apparently healthy volunteers (AHV) and 39 other non-autoimmune disease controls (OD). Diagnostic specificity was assessed against the ARD, AHV and OD groups, individually. Semi-quantitative flow cytometry analysis included TIgG and TIgM autoantibodies, cell-bound complement activation products (CB-CAPs), TC4d, erythrocyte-bound C4d (EC4d) and B lymphocyte-bound C4d (BC4d). Conventional autoantibodies and soluble complement proteins, C3 and C4, were assessed by ELISA and immunoturbidimetry, respectively.
Conclusions
The novel SLE biomarkers TC4d, TIgG and TIgM consistently outperformed conventional markers across multiple cohorts. Their integration enhanced diagnostic sensitivity, especially in SLE-specific autoantibody negative patients with normal complement levels. When coupled with conventional biomarkers, these novel tests may enable earlier and more accurate SLE detection, leading to more timely diagnosis and treatment.
Results
In a ROC analysis distinguishing ANA-positive SLE (N = 91) from ARD, TIgG, BC4d and TC4d demonstrated AUC values of 0.81, 0.80 and 0.79, respectively. They outperformed anti-dsDNA (0.72), C3 (0.69), TIgM (0.67), C4 (0.66) and anti-Smith (0.61). A similar ranking of discriminatory power was observed in a ROC analysis distinguishing ANA-positive SLE vs. OD as well as ANA-positive SLE vs. AHV. At 95% diagnostic specificity for SLE vs. AHV, the sensitivity (95% CI) of TC4d, TIgG and TIgM for SLE was 58.1%, 31.4% and 29.5%, respectively. The T Cell SLE biomarkers uniquely identified 19% (20/105) of SLE patients who were otherwise negative (serologically inactive) for conventional SLE autoantibodies and had normal serum complement levels. Among the serologically inactive SLE subset, the T Cell SLE biomarkers collectively identified 53% of subjects.
References:
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Front. Immunol., 25 Feb 2025, Sec. T Cell biology, Volume 16 - 2025, https://doi.org/10.3389/fimmu.2025.1518208