Medical Policy

This document addresses multiplex autoantigen microarray testing for the diagnosis and management of systemic lupus erythematosus (SLE), a chronic autoimmune disease. The technology involves simultaneous testing for multiple autoantibodies associated with SLE, and may involve use of a proprietary algorithm to determine a risk score. AVISE^® Lupus test (Exagen Inc., Vista, CA) is available in the United States. Another such test described in the medical literature, the SLE-key^® test (ImmunArray, Richmond, VA,) is not currently available. This document does not address panels of individual tests for evaluating SLE.

Note: For a high-level overview of this document, please see “Summary for Members and Families” below. 

Investigational and Not Medically Necessary:

Multiplex autoantigen microarray testing to screen for, diagnose, or manage systemic lupus erythematous is considered investigational and not medically necessary.

This document describes clinical studies and expert recommendations, and explains why we do not consider multiplex autoantigen microarray testing to be clinically appropriate for the diagnosis and management of systemic lupus erythematosus (SLE, often simply called Lupus). The following summary does not replace the medical necessity criteria or other information in this document. The summary may not contain all of the relevant criteria or information. This summary is not medical advice. Please check with your healthcare provider for any advice about your health.

Key Information

Antibodies are proteins made by the body recognize and respond to substances it identifies as threats, such as germs and viruses. In autoimmune diseases such as lupus, the body may produce antibodies that mistakenly target its own tissues. SLE is a long-term autoimmune disease in which the immune system attacks healthy tissues and can affect the skin, joints, kidneys, heart, lungs, brain, and other organs. Some tests may use a computer-based scoring system to estimate the likelihood that a person has a disease. One such test, the AVISE test, uses a process called multiplex autoantigen microarray testing. The AVISE text uses a blood sample to help diagnose or manage lupus.

What the Studies Show

Multiplex autoantigen microarray tests can detect and measure many antibodies in a single blood sample. Some studies found that using one of these tests, the AVISE Lupus test, changed doctors' confidence in diagnosing lupus and increased the use of lupus medicines after positive test results. One study reported that the test correctly identified many people who had SLE and correctly identified many people who did not have SLE. However, several studies did not compare results with standard lupus testing, making it difficult to know how accurate the test truly is. Other studies looked back at existing records. Studies like these may be less reliable because the information was not collected in a planned way and important information may be missing or incomplete. Studies have also shown that positive test results may be linked to a greater chance of later having a confirmed diagnosis of lupus. However, the available studies did not clearly show that testing improves long-term health outcomes, disease control, or quality of life. The test has not been approved by the United States Food and Drug Administration (FDA) for a specific lupus indication. Better studies are needed to know if multiplex autoantigen microarray testing improves health.

Is this clinically appropriate?

Multiplex autoantigen microarray testing for screening, diagnosing, or managing SLE is not clinically appropriate because it has not been proven to improve health.

(Return to Description/Scope)

Summary

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease diagnosed through a combination of clinical findings and conventional laboratory tests. No single test can definitively diagnose SLE.

Exagen markets a series of laboratory-developed tests, including AVISE Lupus, AVISE^® CTD, AVISE^® SLE Monitor, and AVISE^® SLE Prognostic. These tests combine multiple biomarkers and proprietary algorithms to assist with the diagnosis, monitoring, and risk assessment of individuals with SLE.

Published studies suggest that AVISE testing may influence physician confidence in diagnosing SLE and may affect treatment decisions. However, the available evidence has important limitations. Most studies are retrospective or observational, and several evaluate changes in physician assessment rather than diagnostic accuracy or clinical outcomes. Although some studies report associations between AVISE results and subsequent SLE diagnosis, there is insufficient evidence demonstrating that use of these tests improves diagnostic accuracy beyond established clinical evaluation and standard serologic testing or results in improved health outcomes.

Evidence supporting the monitoring and prognostic applications of AVISE testing is similarly limited. Studies have not established that use of these tests leads to better disease management, reduced complications, or improved long-term outcomes compared with conventional assessment methods. In addition, these laboratory-developed tests have not undergone United States Food and Drug Administration (FDA) review, and major rheumatology organizations, including the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR), do not currently recommend routine use of AVISE testing for the diagnosis, monitoring, or prognostic assessment of SLE. No Centers for Medicare & Medicaid Services (CMS) National Coverage Determinations (NCDs) or Local Coverage Determinations (LCDs) addressing these tests were identified. Overall, the evidence is insufficient to establish the clinical utility of AVISE testing. Additional well-designed, independent studies demonstrating improved diagnostic accuracy, changes in clinical management, and improved patient health outcomes are needed.

Discussion

The diagnosis of SLE is based on a comprehensive clinical evaluation that incorporates medical history, physical examination findings, and conventional laboratory testing. Commonly used laboratory tests include antinuclear antibodies (ANAs), anti-double stranded DNA (anti-dsDNA) antibodies, anti-Smith antibodies, complement levels (C3 and C4), complete blood count, urinalysis, and assessment of kidney function. Classification criteria developed by the ACR and EULAR are frequently used to support diagnostic assessment, although they are not intended to serve as the sole basis for diagnosis. Despite these established approaches, the variable clinical presentation of SLE and the absence of a single definitive diagnostic test have prompted interest in novel biomarker panels intended to improve diagnostic certainty.

The AVISE test panels combine multiple biomarkers, including cell-bound complement activation products and conventional autoantibodies, using proprietary algorithms intended to aid in the diagnosis, monitoring, and prognostic assessment of SLE. A key question about the utility of these tests is not whether they can identify biomarker patterns associated with SLE, but whether their use improves diagnostic accuracy, clinical decision-making, or health outcomes beyond established diagnostic approaches. Therefore, the most relevant evidence evaluates the clinical validity and clinical utility of AVISE testing compared with standard evaluation and laboratory assessment.

Putterman (2014) reported on the diagnostic accuracy of the AVISE Lupus test. The study included 794 individuals; 304 fulfilled ACR classification criteria, 285 were diagnosed with other rheumatic diseases and 205 were healthy volunteers. Blood samples from study participants were analyzed in a central laboratory. When a two-tiered analysis was performed that was similar to the analysis method for the commercially available test (described below in the Background/Overview section), the sensitivity for detecting SLE was 80% and the specificity was 86%.

In 2019, Wallace published findings of a randomized controlled trial (RCT) that included individuals with suspected SLE who were referred to rheumatologists. Other eligibility criteria included having a history of ANA positivity in the past 6 months and clinical assessment within 3 months of study participation. Individuals were randomized to either undergo testing with the AVISE Lupus test or to standard laboratory testing with no specific testing recommendation. All participants had venous blood collected at randomization and sent to Exagen, the manufacturer of the AVISE Lupus test. A total of 145 individuals were randomized, 72 to the AVISE Lupus testing arm and 73 to the standard testing arm. The primary outcome measure was the physician-reported likelihood of SLE using a 5-point Likert scale (0: very low to 4: high). At baseline, this likelihood was 1.46 in the AVISE Lupus arm and 1.42 in the standard testing arm. After reviewing testing results, the physician-reported likelihood of SLE was 1.01 in the AVISE Lupus group and 1.23 in the standard lab testing group; the decrease in the estimate of likelihood was significantly greater in the AVISE Lupus testing group (p=0.027). Findings were similar at the 12-week follow-up; the physician-reported likelihood of SLE was 0.85 in the AVISE Lupus group and 1.11 in the standard testing group (p=0.025). The study did not include a “gold standard” reference test for diagnosing SLE, such as ACR criteria, with which to compare the physician-reported likelihood of SLE. It also did not report health outcomes in the two groups, although it was reported that individuals in the AVISE Lupus group were significantly more likely to initiate prednisone compared with the standard testing group.

Alexander (2021) reported on a retrospective review of medical records of 161 ANA-positive adults who had undergone testing with the AVISE Lupus test. Individuals who had indeterminate or equivocal multianalyte assay panel (MAP) scores were excluded from the review. MAP scores, derived from the AVISE Lupus test algorithm, were scored as negative, tier-2 positive or tier-1 positive. The investigators retroactively estimated the confidence in SLE diagnosis at T0 (when the test was ordered), T1 (when test results were reviewed) and T2 (a later visit that occurred at least 8 months after T1). Confidence was assessed using a 5-point Likert scale (0: very low to 4: high). At T0, physician confidence in an SLE diagnosis was low for 93 cases (58%), moderate for 49 (30%) and high for 19 (12%). At T1, among cases with a negative MAP, physician confidence in SLE diagnosis was very low for 49% of cases and low for 35%. Among cases with a tier-1 positive MAP, confidence was high for 36% and very high for 45%. At T2, for cases with a negative MAP, confidence in SLE diagnosis was very low in 74% and, for cases with a tier-1 positive MAP, confidence was very high for 83%. There were 21 cases (13%) who fulfilled the 1997 ACR criteria for SLE at T0. Hydroxychloroquine was already prescribed to 35 (22%) individuals. After MAP testing, hydroxychloroquine was prescribed more frequently in the groups that tested positive than the group that tested negative. A limitation of this study is that it was retrospective, and physicians were asked to recall their pre-test confidence in SLE diagnosis at the time of record review; this may not accurately reflect their confidence in the SLE diagnosis at T0 or T1. Moreover, although a diagnosis reference standard, in this case the ACR criteria, was reported at T0, but not at T1 or T2, it is not possible from these data to determine the accuracy of SLE diagnosis.

In 2021, Ramsey-Goldman reported on a prospective uncontrolled study in 92 individuals with probable SLE. Eligible individuals were included if they fulfilled ANA criteria and two additional ACR criteria. At each follow-up visit, investigators determined whether participants met criteria for diagnosis of SLE and estimated the date that they met those criteria. Also, at each visit, participants were tested using a multianalyte assay panel (MAP) identical to that in the AVISE Lupus test. A total of 74 of the 92 individuals with probable SLE (80%) had at least 1 follow-up visit within 9 to 35 months after enrollment. There were 28 individuals (30%) diagnosed with SLE per ACR criteria during the study. The authors found that a MAP >0.8 at baseline significantly predicted the transition from probable SLE to SLE. The study did not include a control group or evaluate the impact of testing on disease management.

In 2022, O’Malley published findings of the CAPSTONE study evaluating data from a large patient registry. The investigators compared rates of initiation of SLE medication in 2 groups of individuals; 21,827 individuals tested with the AVISE test and 27,778 individuals treated with standard care that included ANA testing. Mean follow-up after testing was 285 days for the AVISE cohort and 303 days for the ANA testing cohort. A total of 2437 (11.2%) individuals had a positive AVISE test and 5364 (23.5%) had a positive ANA test. Individuals with a positive AVISE test were significantly more likely to initiate SLE medications than those with a positive ANA test (43% vs. 32%, unadjusted odds ratio [OR], 1.57; 95% confidence interval [CI], 1.41 to 1.76). The difference between groups remained statistically significant after multivariate adjustment for potential confounding variables (OR, 2.13; 95% CI, 1.85 to 2.44). Limitations of the analysis include that individuals were not randomized to testing strategy and that the diagnostic accuracy of the AVISE test was not measured directly.

Other Relevant Information

Compared to standard laboratory testing, the AVISE Lupus test has been associated with a greater reduction in physician-reported likelihood of SLE and a higher rate of treatment initiation in individuals with positive results. However, limitations across the body of evidence include lack of gold-standard diagnostic confirmation, absence of randomized comparisons in some studies, retrospective designs, and limited reporting on long-term clinical outcomes. Additionally, the test is not currently FDA approved and is not supported in nationally recognized clinical practice guidelines, highlighting the need for further validation and guidance on its clinical use. No Centers for Medicare & Medicaid Services (CMS) National Coverage Determinations (NCD) or Local Coverage Determinations (LCD) addressing these tests were identified. Current ACR and EULAR recommendations for SLE do not include AVISE Lupus testing.

Published studies suggest the test may aid diagnosis in selected individuals with suspected SLE, but evidence is insufficient for widespread guideline endorsement, and major professional societies have not recommended routine use. The AVISE test may offer incremental diagnostic and prognostic value over traditional serologies, particularly in ANA-positive individuals who lack SLE-specific autoantibodies and in individual with probable/early SLE where complement activation is not yet reflected in serum C3/C4 levels. However, the evidence base is predominantly industry-sponsored, relies on retrospective designs, and the test is not yet endorsed by major rheumatology guidelines.

SLE, is a chronic autoimmune disorder that can affect multiple body systems, particularly the joints, skin, brain, kidneys, lungs and blood vessels. The etiology of SLE is unknown; genetic and epigenetic factors and ethnic origin and environmental factors may all contribute to its development. SLE affects individuals of all ages, but women between the ages of 15 and 44 are at greatest risk of developing the condition. Currently the Centers for Disease Control (CDC) estimates the annual incidence of SLE in the United States to be approximately 5.1 cases per 100,000 persons, corresponding to about 14,000 new cases annually. Incidence is substantially higher among females and certain racial and ethnic minority populations. The CDC currently estimates prevalence in the United States of approximately 204,000 people. This includes about 184,000 females and 20,000 males (CDC, 2024).

SLE can be difficult to diagnose because affected individuals present with a variety of nonspecific symptoms and there are no definitive tests for the disease. Presenting symptoms commonly include fatigue, weight loss, joint pain and fever. SLE can be confused with conditions such as Sjogren syndrome, early rheumatoid arthritis, fibromyalgia, and idiopathic thrombocytopenic purpura. Currently, the diagnosis of SLE is based on a combination of clinical signs and symptoms and immunological laboratory test results. Diagnosis begins by identifying individuals with a high clinical suspicion of the condition. SLE is suspected when there is involvement of at least two organ systems and the presence of characteristic symptoms such as malar rash, discoid rash, unexplained seizures and photosensitivity (Lam, 2016).

SLE is associated with the presence of autoantibodies directed against a range of intracellular autoantigens; collectively these autoantibodies are known as antinuclear antibodies (ANAs). In individuals with suspected SLE, laboratory testing involves a sequence of tests starting with an ANA test. Several methods are available for ANA testing. A 2015 position statement from the ACR stated that the organization supports ANA testing using Human Epithelial type 2 (HEp-2) substrate. Serum ANA testing is highly sensitive, with a positive result in approximately 95% of individuals with SLE (ACR 2015; Lam, 2016). However, ANA tests have a low positive predictive value (PPV) since individuals with positive ANA tests could have other autoimmune diseases and some medications or other diseases such as cancer can lead to a positive ANA test (ACR, 2017; Egner 2000). The ACR updated its position statement in December 2019 and reaffirmed that indirect immunofluorescence assay (IFA) on HEp-2 cells remains the gold standard screening method for ANA testing (ACR, 2019, Mahler 2022). ANA testing by IFA on HEp-2 cells is generally regarded as the reference-standard ANA screening method against which newer multiplex assays, ELISAs, and autoantigen microarrays are often compared (ACR, 2019).

In individuals with clinical suspicion of SLE and a positive ANA test, additional laboratory tests are generally performed including measurement of anti-double-stranded DNA (anti-dsDNA), anti-Smith (Anti-Sm), anti-RNP, anticardiolipin and beta-2 glycoprotein antibodies (Lam, 2016).

In its 2015 (reaffirmed 2019) position statement on the methodology for ANA testing, the ACR stated that it supported use of specific tests in individuals with suspected SLE rather than panels of tests, as follows:

Healthcare providers should avoid ordering panels of ANA subserologies (double stranded DNA, Smith, RNP, SS-A, SS-B Scl-70, centromere) when not appropriately indicated. Instead, ordering healthcare professionals should select specific ANA subserologies based on a patient’s signs and symptoms and when there is a high pretest suspicion for a specific condition.

In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) published criteria for diagnosing SLE that were based on a revision of the ACR criteria. The classification system included 18 items. They comprise criteria similar to the ACR classification system, with the addition of more antiphosolipid antibody testing options and testing for elements of the complement system and the direct Coombs test. A diagnosis of SLE required fulfillment of at least four criteria, including at least one clinical and one immunologic criterion, or the presence of SLE nephritis only in the presence of ANA or anti-dsDNA antibodies. Results of a validation study found a sensitivity of 97% and specificity of 84% for the SLICC criteria in classifying individuals as having or not having SLE. This compared to a sensitivity of 83% and a specificity of 97% for the 1997 ACR criteria (Petri, 2012).

In 2019, the ACR, along with the European League Against Rheumatism (EULAR) published an updated classification system for SLE (Aringer, 2019). The new criteria include 7 clinical domains and 3 immunology domains. The immunology domains include antiphospholipid antibodies, the complement proteins C3 and C4, and the SLE-specific antibodies, anti-dsDNA antibody and the anti-Smith antibody. In a validation study, the authors found a sensitivity of 85% and specificity of 95% for the 1997 ACR criteria, a sensitivity of 97% and specificity of 90% for the 2012 SLICC criteria and a sensitivity of 98% and specificity of 96% for the 2019 ACR criteria. The 2012 SLICC classification criteria have not been formally revised; however, the 2019 EULAR/ACR classification criteria represent the most recent internationally endorsed SLE classification criteria and were developed to improve upon prior ACR and SLICC criteria. The 2019 EULAR/ACR classification criteria and major society guidelines do not reference or recommend the AVISE test, relying instead on traditional ANA, anti-dsDNA, anti-Smith, complement levels, and antiphospholipid antibodies.

The diagnosis of SLE remains complex and no single test or combination of tests are completely accurate. There is a need for additional tests that are simple to use and have high sensitivity and specificity. Emerging technologies for SLE testing include development of improved ANA testing methods, panel testing for multiple serum biomarkers and point of care testing (Olsen, 2017). Another novel approach to SLE testing is multiplexed autoantibody arrays that can detect a large number of autoantibodies. Whereas most laboratory tests are designed to detect 10 to 15 types of ANA-related autoantibodies, multiplexed autoantibody arrays can detect hundreds of types of autoantibodies. Several multiplexed autoantibody arrays, both planar arrays and bead-based arrays, have been studied.

Antibodies: Immune system proteins that recognize and bind to specific targets (antigens) to help the body fight infection or other perceived threats.

Antinuclear Antibodies (ANA): Antibodies to human proteins within the nucleus of a cell.

Autoantibodies: Antibodies to human proteins.

Female: Refers to sex assignment at birth, The gender descriptions used in this document, for example, ‘female’, ‘woman’, and ‘women’, refer to the reproductive capacity of the individual, regardless of gender identity or expression.

Male: Refers to sex assignment at birth. The gender descriptions used in this document, for example, ‘male’, ‘man’, and ‘men’, refer to the reproductive capacity of the individual, regardless of gender identity or expression.

Microarray testing: A microchip-based testing platform that permits the identification and analysis of many pieces of DNA or protein at the same time.

Multiplex: Many elements that are in a complex relationship to one another.

Systemic lupus erythematosus (SLE) (also known simply as lupus): A chronic autoimmune disease that can affect any part of the body.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
For the procedure codes listed below, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Alexander RV, Rey DS, Conklin J, et al. A multianalyte assay panel with cell-bound complement activation products demonstrates clinical utility in systemic lupus erythematosus. Lupus Sci Med. 2021; 8(1):e000528.
2. Egner W. The use of laboratory tests in the diagnosis of SLE. J Clin Pathol. 2000; 53(6):424-432.
3. Lam NC, Ghetu MV, Bieniek ML. Systemic lupus erythematosus: primary care approach to diagnosis and management. Am Fam Physician. 2016; 94(4):284-294.
4. Mahler M, Meroni PL, Bossuyt X, et al. Current concepts and future directions for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. Diagnostics. 2022; 12(3):647.
5. Olsen NJ, Choi MY, Fritzler MJ. Emerging technologies in autoantibody testing for rheumatic diseases. Arthritis Res Ther. 2017; 19(1):172.
6. O'Malley T, Xie F, Su Y, et al. Complement activation products vs standard ANA testing: treatment outcomes, diagnosis, and economic impact (CAPSTONE) in systemic lupus erythematosus. J Manag Care Spec Pharm. 2022; 28(9):1021-1032.
7. Putterman C, Furie R, Ramsey-Goldman R, et al. Cell-bound complement activation products in systemic lupus erythematosus: comparison with anti-double-stranded DNA and standard complement measurements. Lupus Sci Med. 2014; 1(1):e000056.
8. Ramsey-Goldman R, Alexander RV, Conklin J, et al. A multianalyte assay panel with cell-bound complement activation products predicts transition of probable lupus to American College of Rheumatology-Classified lupus. ACR Open Rheumatol. 2021; 3(2):116-123.
9. Wallace DJ, Alexander RV, O'Malley T, et al. Randomised prospective trial to assess the clinical utility of multianalyte assay panel with complement activation products for the diagnosis of SLE. Lupus Sci Med. 2019; 6(1):e000349.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American College of Rheumatology. Antinuclear antibodies (ANA). Last updated February 2025. Available https://rheumatology.org/patients/antinuclear-antibodies-ana. Accessed on August 3, 2026.
2. American College of Rheumatology. 1997 Update of the 1982 American College of Rheumatology revised criteria for classification of systemic lupus erythematosus. Available at: https://www.rheumatology.org/Portals/0/Files/1997%20Update%20of%201982%20Revised.pdf. Accessed on August 3, 2026.
3. Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis. 2019; 78(9):1151-1159.
4. Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012; 64(8):2677-2686.

1. Centers for Disease Control. Lupus Basics. Updated May 2024. Available at: https://www.cdc.gov/lupus/about/?CDC_AAref_Val=https://www.cdc.gov/lupus/facts/detailed.html. Accessed on August 3, 2026.
2. U.S. Dept of Health and Human Services. Office of Women’s Health. Lupus. Updated February 2021. Available at: https://www.womenshealth.gov/lupus. Accessed on August 3, 2026.

AVISE CTD test
AVISE Lupus test
AVISE SLE Monitor test
AVISE SLE Prognostic

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