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AVISE ® Interpretation Guide

ed, C dit LIA re -C c e c r A t - i f P i e A Certified d C Laoratory

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Y H S O -D D O - H A , P , C H A O -D -D PH RI , MD-DOH, AVISE Interpretation Guide

Marker (method) Associated Prevalence Interpretation APS AVISE CTDAVISE LUPUSSLE MonitorSLE Prognostic EC4d Systemic 46%-66%1 Cell-Bound Complement Activation Products (CB-CAPs) EC4d & BC4d are (FACS) incorporated in AVISE CTD (and AVISE Lupus) to aid in differential diagnosis X X X Erythematosus (SLE) of SLE compared to other common CTDs and primary Fibromyalgia. AVISE CTD has been validated to offer 80% sensitivity & 86% specificity overal for BC4d SLE. EC4d has been shown to significantly correlate with disease activity.20 (FACS) X X

C3/C4 Systemic Lupus 44%1 Major of the complement process which X (IT) Erythematosus (SLE) play a key role in the inflammatory and immune system. Anti-C1q Anti-C1q 60%18 against the complement C1q are present in 30-60% of (ELISA) (ELISA) SLE patients and correlate with lupus nephritis flares. Occurrence or rise in XX anti-C1q titer may occur before clinical signs of lupus nephritis. Low levels of Anti-C1q have been found in up to 8% of patients with other or otherwise healthy individuals. Anti-dsDNA IgG Systemic Lupus 30-40%3 A positive result helps to rule-in SLE. We perform this test via ELISA as (ELISA and IIF) Erythematosus (SLE) validated, but confirm all positive results (>301 U/mL) via IFA Crithidia to SLE Associated Markers SLE Associated X X ensure the most accurate results possible. One of the ACR Criteria for SLE diagnosis. Anti-dsDNA IgG Systemic Lupus 43% A highly sensitive dsDNA assay with expanded dynamic range. dsDNA by X (CIA) Erythematosus (SLE) CIA has been shown to significantly correlate with disease activty.21 Anti-Nuclear Connective Tissue 97%3 A negative result helps to rule-out SLE. One of the ACR Criteria for SLE Antibodies (ANA) X X Disease diagnosis. (ELISA and IIF) Anti-Ribosomal P Anti-Ribosomal P 30%19 Antibodies against ribosomal proteins (Ribo P) are highly specific for SLE (ELISA) X (ELISA) and can be present in anti-dsDNA or anti-Sm negative patients. Association with neuropsychiatric SLE has also been observed. Anti-Smith IgG Systemic Lupus 5-30%4 Anti-Smith antibodies offer a highly specific, but comparatively insensitive, X X (ELISA) Erythematosus (SLE) clinical marker for SLE. One of the ACR Criteria for SLE diagnosis. Marker (method) Associated Disease Prevalence Interpretation Anti-CENP IgG Scleroderma 20-60%7 Antibodies to centromere (CENP) protein-B are found in 20-60% of patients (ELISA) X X with CREST Syndrome, a limited form of scleroderma with favorable prognosis. Anti-Jo-1 IgG Polymyositis/ 20-30%5 Marker to help with diagnosis of / polymyositis. Found in (ELISA) X X Dermatomyositis about 25% of patients with PM/DM. (PM/DM) Anti-RNP70 Mixed Connective 90%11 Positive RNP70 is associated with Mixed Connective Tissue Disease (MCTD). X (ELISA) Tissue Disease Anti-Scl-70 IgG Scleroderma 28-70%6 Up to 70% of scleroderma patients are positive for Anti-Scl-70. X X (ELISA) Anti-Scl-70 is specific for scleroderma.

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ENA Markers Anti-SS-A/Ro IgG Sjögren’s 60-77% SLE prevalence 40-50%. Sjögren’s Syndrome prevalence 60-77%. Includes (ELISA) X Syndrome & SLE both Ro52 and Ro 60. Found to play a role in neonatal lupus and congenital heart block. Anti-SS-B/La IgG Sjögren’s Syndrome 40-60%8 Serological hallmark of Sjögren’s Syndrome. X X (ELISA) Anti-U1RNP IgG Mixed Connective 95-99%11 In Mixed Connective Tissue Disease (MCTD) presence of U1RNP antibodies (ELISA) X Tissue Disease is required for diagnosis. Not absolute for MCTD, but if present MCTD is highly likely. Anti-Histone Drug-Induced 95%23 Up to 95% of classic drug induced lupus and 50% of SLE patients exhibit Lupus elevated levels of histone . Positivity for anti-histone has also (ELISA) been found in RA, DM, and SS placing added importance on clinical presentation.

1 upus Marker ognostic (method)SE L Associated Disease Prevalence Interpretation AVISE CTDAVI APS SLE Monitor SLE Pr Anti-Cyclic Rheumatoid 70-90%12 Antibodies to Cyclic Citrullinated Peptides(CCP) aid in the diagnosis Citrullinated of (RA). Anti-CCP antibodies are very specific for Peptide IgG X X rheumatoid arthritis and are included in the AVISE Index Calculation to help (ELISA) with differential diagnosis of primary SLE vs. RA. Anti-Mutated Rheumatoid 72%13 MCV can help detect up to 10% of early RA patients who are negative for Citrullinated Arthritis Anti-CCP & RF. A positive result at time of diagnosis predicts more severe X

RA Markers Vimentin (MCV) disease outcomes. Highly elevated levels > 70 may be associated with more IgG (ELISA) sever disease progression. Rheumatoid 70-90%12 Quantitative measurement of IgM & IgA class rheumatoid factor (RF) IgM & IgA X Arthritis antibodies to aid in the diagnosis of rheumatoid arthritis. Presence of IgA (ELISA) RF may be associated with more severe prognosis.

Anti-CarP Rheumatoid 30-49 22 AVISE Anti-CarP is a marker of more severe disease prognosis in RA, (ELISA) Arthritis independent of Anti-CCP or RF status. It is useful in assessing the risk for joint erosions in any RA patient, especially those with seronegative RA.

Associated Disease Prevalence Interpretation β2-Glycoprotein 1 Anti-Phospholipid 45%15 Antibodies to Beta 2 Glycoprotein 1 (β2 GP1) show higher specificity than IgG, IgM & IgA Syndrome (APS) anti-cardiolipin assays. In 3-10% of APS patients, β2 GP1 may be (CIA) X* X X the only positive test. Positive results should be confirmed after 12 weeks. Marker (method) Antibodies to β2-GP1 IgA are less prevalent than IgG or IgM but can occur in isolation. Positive results should be confirmed after 12 weeks. Cardiolipin IgG, Anti-Phospholipid 97%14 Antibodies to cardiolipin are present in SLE patients (30-40%) and APS. IgM & IgA Syndrome (APS) Prevalence of anti-cardiolipin in APS is high but specificity for APS is (CIA) (arterial/venus lower than other anti-phospholipids antibodies. Positive results should be X* X X ) confirmed after 12 weeks. Antibodies to cardiolipin IgA are less prevalent than IgG or IgM but can occur in isolation. Positive results should be

APS Markers confirmed after 12 weeks. Anti- Anti- 38-49%17 Antibodies to the complex phosphatidylserine/prothrombin are a Phosphatidylser- Phosphatidylserine/ distinct marker for APS found to correlate with lupus (LAC) ine/Prothrombin X X Prothrombin (PS/PT) positivity better than other aPL methods regardless of anticoagulant (PS/PT) IgM & IgG IgM & IgG treatment. (ELISA) (ELISA) Marker (method) Associated Disease Prevalence Interpretation Thyroglobulin IgG Hashimoto’s 60-85%16 Anti–thyroglobulin antibodies are found in 60-85% of patients with (ELISA) Thyroiditis Hashimoto’s Thyroiditis and 30-80% of patients with Graves’ disease. X & Graves’ Thyroid Peroxidase Hashimoto’s 71-97%16 Anti–thyroid peroxidase antibodies are found in >90% of patients with IgG Thyroiditis Hashimoto’s Thyroiditis & 71-97% of patients with Graves’ disease. Over (ELISA) X & Graves’ 95% of thyroiditis patients have autoantibodies to Thyroglobulin IgG and/ Thyroid Markers Thyroid or Thyroid peroxidase antibodies.

2 A deeper look at the AVISE® Lupus two tier algorithm

Tier 1 Any of the Following: Anti-Sm > 10 U/mL Negative EC4d > 75 Net MFI Positive BC4d > 200 Net MFI Anti-dsDNA > 301 U/ML

If Tier 1 is Negative move to Tier 2

Tier 2 criteria combines CB-CAPs with additional markers to yield an aggregate index value

Tier 2 ANA

Negative EC4d + BC4d Positive NET MFI Index < - 0.1 Index > 0.1 Anti-CCP Anti-SS-B/La Anti-CENP Anti-Scl-70 Anti-Jo-1

Tier 2 generates an index value based on the following components • ANA component • CB-CAPs component

3 AVISE® CTD and AVISE Lupus result report

The result for the AVISE Lupus algorithm is featured first, plotted along a gradient of increasing likelihood for presence of SLE (See page 6 for likelihood ratios)

Analytes included in Tier 1 and Tier 2 along with respecti ve assessments are reported in two distinct sections

2

4 AVISE® CTD and AVISE Lupus page 2

Details for ANA (HEp-2) are at the top of the page including any observed nuclear and cytoplasmic patterns

Far left column iden es positive(+) and strong positive(++) interpretations for each analyte

Notes:

Notes provid summary statements

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(Note AVISE SLE Prognostic values will be reported separately) 5 Understanding the Utility of the AVISE Lupus Index Value

AVISE Lupus Index Value Test Performance for Diagnosis of SLE

Sensitivity: 80% Positive LR = 5.7 Specificity vs. Negative LR = 0.2 other disease: 86% Diagnosis Odds Ratio (DOR) = 24.6

Likelihood Ratio for SLE by AVISE Lupus Result Values

Figure adapted from Putterman et al. Lupus Science & Medicine. 2014.

Likelihood Ratio Review: A likelihood ratio of 1 is non-informative. The greater the likelihood ratio is above 1 the greater the probability of ruling-in the presence of the target condition (SLE). The lower the likelihood ratio below 1 the lower the probability of ruling-out the presence of the target condition. A given patient's pre-test probability for a condition should always be taken into consideration.

Example1: Positive index value between 1.6 to 2.0 has a likelihood of 8.1. This suggests that a patient with the target condition is 8.1 times more likely to have that corresponding result value compared to a person without the disease.

Example 2: A negative index value between -1.6 to -2.0 has a likelihood ratio of 0.2. This suggests that a person with the target disease is 5 times less likely to have the corresponding result compared to a person without the target condition.

6 Methodology Definitions: *AVISE CTD Includes IgM & IgG isotypes only FACS: Fluorescence-Activated Cell Sorting IFA: Immunofluorescencee ELISA: Enyme-Linked Immunosorbent Assayy CIA: Chemiluminesent Immunoassay Assayy I : Immunoturbidimetry References: 1. Putterman C, et al. Cell-Bound Complement Activation Products in Systemic : Comparison with Anti-Double-Stranded Dna and Standard Complement Measurements. Arthritis & . 2014. 2. Wallace D, et al. Systemic Lupus Erythematosus And Primary Fibromyalgia can be Distinguished by Testing for Cell-Bound Complement Activation Products. Lupus Science & Medicine. 2016. 3. Wichainun R, et al. Sensitivity and Specificity of ANA And Anti-Dsdna In The Diagnosis of Systemic Lupus Erythematosus: A Comparison using Control Sera Obtained from Healthy Individuals and Patients with Multiple Medical Problems. Asian Pac J Allergy Immunol. 2013. 4. Migliorini P, et al. Anti-Sm And Anti-Rnp Antibodies. Clinical Immunology Unit, Department Of Internal Medicine. Autoimmunity. 2005. 5. Zampieri S, et al. Anti-Jo-1 Antibodies. Autoimmunity. 2005. 6. Basu D, Et Al. Anti-Scl-70. Autoimmunity. 2005. 7. Russo K, Et Al. Circulating Anticentromere Cenp-A and Cenp-B Antibodies In Patients with Diffuse and Limited Systemic Sclerosis, Systemic Lupus Erythematosus, and Rheumatoid Arthritis. The Journal Of . 2000. 8. Montecucco C, Et Al. Anti-Ssb/La Antibodies In Sjögren’s Syndrome and Related Autoimmune Diseases. Results of A Quantitative Immunoassay Using a Highly Purified Antigen. Clin Exp Rheumato.1989. 9. Fritzler M, et al. Antinuclear, Anticytoplasmic, and Anti-Sjogren’s Syndrome Antigen A (Ss-A/Ro) Antibodies in Female Blood Donors. Antibodies.1985. 10. Tonello M, et al. Maternal Profiles at Risk for Autoimmune Congenital Heart Block:a Prospective Study In High-Risk Patients. Lupus Science & Medicine. 2016. 11. Hoffman R, et al. Mixed Connective Tissue Disease. Modern Therapeutics In Rheumatic Diseases. 2002. 12. Rantapää-Dahlqvist S, et al. Antibodies Against Cyclic Citrullinated Peptide And Iga Rheumatoid Factor Predict the Development of Rheumatoid Arthritis. Arthritis & Rheumatism. 2003. 13. Lena I, et al. Antibodies Against Mutated Citrullinated Vimentin are a Better Predictor of Disease Activity at 24 Months in Early Rheumatoid Arthritis than Antibodies Against Cyclic Citrullinated Peptides. The Journal of Rheumatology. 2008. 14. Perches P, et al. Evaluation of Antiphospholipid Antibodies Testing for the Diagnosis of Antiphospholipid Syndrome. Revista Brasileira De Reumatologia. 2009. 15. Galli M, et al. Anti–Β2-Glycoprotein I, Antiprothrombin Antibodies, And The Risk Of Thrombosis In The Antiphospholipid Syndrome. Blood. 2003. 16. Engler H, et al. Anti-Thyroid Peroxidase (Anti-Tpo) Antibodies in Thyroid Diseases, Non-Thyroidal Illness And Controls. Clinical Validity of a New Commercial Method for Detection of Anti-TPO (Thyroid Microsomal) Autoantibodies. Clin Chim Acta. 1994. 17. Akhter E, et al. Utility of Antiphosphatidylserine/Prothrombin and Iga Antiphospholipid Assays in Systemic Lupus Erythematosus. J Rheumatol. 2013. 18. Yin Y, et al. Diagnostic Value of Serum Anti-C1q Antibodies in Patients with Lupus Nephritis: A Meta-Analysis. Lupus. 2012. 19. Hanly J, et al. Autoantibodies as Biomarkers for the Prediction of Neuropsychiatric Events In Systemic Lupus Erythematosus. Ann Rheum Dis. 2011. 20. Buyon J, et al. Reduction in erythrocyte-bound complement activation products titers of anti-C1q antibodies association with clinical improvement in systemic lupus erythematosus. Lupus Science of Medicine. 2016. 21. Data on file. Exagen Diagnostics, Inc. 2016. 22. Truchetet ME, et al. Association of the presence of anti–carbamylated protein antibodies in early arthritis with a poorer clinical and radiologic outcome. Arthritis Rheumatology, 2017; 69(12): 2292-2302. 23. Vedove CD, et al. DILE with emphasis on skin manifestations and role of anti-TNF agents. JDDG, 2012 DOI: 10.1111/j.1610-0387.2012.08000. Exagen, AVISE and the Exagen and AVISE logos are registered trademarks of Exagen Diagnostics, Inc. © Copyright 2018 Exagen Diagnostics, Inc. All rights reserved. SA1123 (6/18) www.AviseTest.com | 888.452.1522