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Cell-Bound Complement Activation Products in Systemic Lupus Erythematosus: Comparison with Anti-dsDNA and Standard Complement Measurements
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
In this multi-centered, cross sectional clinical validity study, the performance characteristics of cell-bound complement activation products (CB-CAPs) and AVISE Lupus were compared to anti-dsDNA and complement C3 and C4 in SLE. The results demonstrated that AVISE Lupus testing, with CB-CAPs outperformed traditional SLE (systemic lupus erythematosus) biomarkers across the spectrum of disease activity.
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
The study enrolled 794 subjects and included 304 SLE patients and a control group. The control group was composed of 285 people with other rheumatic diseases, and 205 healthy individuals. Anti-dsDNA and other autoantibodies were measured using solid-phase immunoassays, while levels of EC4d and BC4d were quantified using flow cytometry. Complement proteins were identified using immunoturbidimetry. Disease activity in SLE was evaluated using a non-serological Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) Modification. A two-tiered methodology combining CB-CAPs with autoantibodies to cellular and citrullinated antigens was also developed. Statistical analyses used area under receiver operating characteristic curves and calculations of area under the curve (AUC), sensitivity and specificity.
Conclusions
CB-CAPs have higher sensitivity than standard complement and anti-dsDNA measurements, and may help with the differential diagnosis of SLE in combination with other autoantibodies.
Results
AUC for EC4d (0.82±0.02) and BC4d (0.84±0.02) were higher than those yielded by C3 (0.73±0.02) and C4 (0.72±0.02) (p<0.01). AUC for CB-CAPs was also higher than the AUC yielded by anti-dsDNA (0.79±0.02), but significance was only achieved for BC4d (p<0.01). The combination of CB-CAPs in multivariate testing methodology with anti-dsDNA, and autoantibodies to cellular and citrullinated antigens yielded 80% sensitivity for SLE and specificity ranging from 70% (Sjogren's disease) to 92% (rheumatoid arthritis) (98% vs. normal). A higher proportion of patients with SLE with higher levels of disease activity tested positive for elevated CB-CAPs, reduced complement and anti-dsDNA (p<0.03).
References:
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Lupus Sci. Med, 2014 Oct 1;1(1):e000056. doi: 10.1136/lupus-2014-000056. eCollection 2014