Coverage Policy Manual
Policy #: 2014018
Category: Laboratory
Initiated: September 2014
Last Review: June 2022
  Biomarker Panel Testing for Systemic Lupus Erythematosus

Description:
SLE is an autoimmune connective tissue disease that affects approximately 1.5 million individuals in the U.S. (Lupus Research Institute, 2014). It is one of several types of lupus, the other 2 being cutaneous and drug-induced lupus. About 90% of lupus patients are women between the ages of 15 and 45 years. SLE causes inflammation and can affect any part of the body, most commonly the skin, heart, joints, lungs blood vessels, liver, kidneys, and nervous system. Although generally not fatal, SLE can lead to increased mortality, most commonly from cardiovascular disease due to accelerated atherosclerosis. SLE can also lead to kidney failure, which may reduce survival. The survival rate in the U.S. is approximately 95% at 5 years and 78% at 20 years. (Kasitanon, 2006). The morbidity associated with SLE is substantial. Symptoms such as joint and muscle pain can impact quality of life and functional status. SLE also increases patients’ risk of infection, cancer, avascular necrosis (bone cancer death), and pregnancy complications (eg, preeclampsia and preterm birth). The course of the disease is variable, and patients generally experience periods of illness (called flares) and periods of remission. Flare severity can range from mild to serious.
 
Treatments for SLE can ameliorate symptoms, reduce disease activity, and slow progression of organ damage, however there is no cure for SLE. Muscle and joint pain, fatigue and rashes are generally initially treated with nonsteroidal anti-inflammatory drugs. Antimalerial drugs such as hydroxychloroquine can relieve some symptoms of SLE including fatigue, rashes, and joint pain. Patients with more serious symptoms, such as heart, lung or kidney involvement, can be treated with corticosteroids or immune suppressants. There are also biologic treatments, such as rituximab, which are U.S. Food and Drug Administration approved for treatment of rheumatoid arthritis and are being evaluated for treatment of SLE.
 
Patients with SLE often present with nonspecific symptoms such as fever, fatigue, joint pain, and rash, which can make the disease difficult to diagnosis. In some patients, the diagnosis can be made with certainty, for example when there are typical symptoms of rash and joint symptoms, and laboratory testing shows a high-titer abnormal antinuclear antibody (ANA) in a pattern that is specific for SLE. However, in many other patients, the symptom patterns are less clear and laboratory testing is equivocal, and as a result, a definitive diagnosis is difficult to make.
 
The diagnosis of SLE has been based on a combination of clinical symptoms and laboratory results. Previously, the American College of Rheumatology (ACR) published 1982 criteria for classifying SLE. In 1997, ACR updated the 1982 criteria for the classification of SLE (ACR, 1982; Hochberg, 1997). In 2019, new classification criteria endorsed by the European League Against Rheumatism (EULAR) and the ACR were developed and validated (Aringer, 2019). The 2019 EULAR/ACR classification criteria requires a positive ANA as an entry criterion. For those with a positive ANA, additive criteria are assessed in 7 clinical and 3 immunological domains. Weighted criteria (ranging from 2 to 10 points) are evaluated within each domain, with only the highest weighted criterion in a specific domain counting towards the total score. The weighted feature allows for criteria that are more tightly associated with SLE to contribute more heavily to the overall score. A classification of SLE requires a total score of 10 points.
 
The EULAR/ACR classification criteria are as follows:
    • Entry criterion: ANA at a titer of 1:80 on HEp-2 cells or an equivalent positive test
    • If entry criterion is present, apply additive criteria (weight):
        • Constitutional: fever (2)
        • Hematologic: leukopenia (2), thrombocytopenia (4), autoimmune hemolysis (4)
        • Neuropsychiatric: delirium (2), psychosis (3), seizure (5)
        • Mucocutaneous: non-scarring alopecia (2), oral ulcers (2), subacute cutaneous or discoid lupus (4), acute cutaneous lupus (6)
        • Serosal: pleural or pericardial effusion (5), acute pericarditis (6)
        • Musculoskeletal: joint involvement (6)
        • Renal: proteinuria >0.5 g/24 h (4), renal biopsy Class II or V lupus nephritis (8), renal biopsy Class III or IV lupus nephritis (10)
        • Antiphospholipid antibodies: anti-cardiolipin antibodies or anti-β2GP1 antibodies or lupus anticoagulant (2)
        • Complement proteins: low C3 or low C4 (3), low C3 and low C4 (4)
        • SLE-specific antibodies: antibodies to double stranded DNA (anti-dsDNA) or antibodies to Smith antigen (anti-sm) (6)
 
The ACR criteria were originally developed for research, but they have been widely adopted into clinical care. If a patient does not fulfill criteria for classification for SLE, lupus can still be diagnosed by clinical judgment; it is recommended that a rheumatologist confirm the diagnosis (ACR Guidelines, 1999). Validation of the 2019 EULAR/ACR criteria reported a sensitivity of 96.1% and a specificity of 93.4% (Aringer, 2019). In comparison, the validation cohort for the ACR 1997 updated criteria reported 82.8% sensitivity and 93.4% specificity. Lastly, it should be noted that the development of the 2019 EULAR/ACR criteria aimed to improve the detection of early or new onset SLE compared to older ACR criteria.
 
Additionally, the Systemic Lupus International Collaborating Clinics (SLICC), an international research group developed revised criteria for diagnosing SLE in 2012 (Petri, 2012). These criteria include more laboratory tests than the 1997 ACR criteria, including elements of the complement system. Patients are classified as having SLE if they satisfy 4 or more of the 18 criteria, including at least 1 clinical criterion and 1 immunologic criterion or they have biopsy-proven nephritis compatible with SLE and with ANA or anti-dsDNA antibodies. In a sample of 690 patients, the SLICC criteria had a sensitivity of 97% and a specificity of 84% for diagnosing SLE, whereas the ACR criteria applied to the same sample had a sensitivity of 83% and a specificity of 96%. It is not clear how well accepted the SLICC recommendations are in the practice setting. The SLICC criteria are as follows:
 
Clinical criteria (in the absence of other known causes):
 
1. Acute cutaneous lupus (including but not limited to lupus malar rash)
2. Chronic cutaneous lupus (including but not limited to discoid rash)
3. Oral ulcers
4. Non-scarring alopecia in the absence of other causes
5. Synovitis involving two or more joints, characterized by swelling or effusion or and thirty minutes or more of morning stiffness.
6. Serositis
7. Renal: excessive protein in the urine, or cellular casts in the urine
8. Neurologic disorder: seizures, psychosis, mononeuritis complex or peripheral or cranial neuropathy
9. seizures
10. Hemolytic anemia
11. Leukopenia or lymphopenia
12. Thrombocytopenia
 
Immunological criteria:
1. ANA above laboratory reference range
2. Anti-dsDNA above laboratory reference range
3. Anti-Sm
4. Antiphospholipid antibody
5. Low complement (low C3, low C4 or low CH150)
6. Direct Coombs tests in the absence of hemolytic anemia
 
To date, the most common laboratory tests performed in the diagnosis of SLE are serum ANA, and if this is positive, tests for anti-dsDNA and anti-Sm. ANA tests are highly sensitive (ie, with a high negative predictive value) but have low specificity and relatively low positive predictive value, particularly when the ANA is positive at a low level. Specificity of testing can be increased by testing for specific antibodies against individual nuclear antigens (extractable nuclear antigens, or ENAs) to examine the “pattern” of ANA positivity. These include antigens against single and double-stranded DNA, histones, Sm, Ro, La, and RNP. The presence of anti-dsDNA or anti-Sm is highly specific for SLE because few patients without SLE test positive; however, neither of these tests have high sensitivity (Suresh, 2007). The presence of other antibody patterns may indicate the likelihood of alternate diagnoses. For example, the presence of Ro and La antibodies suggests Sjogren syndrome, while the presence of antihistone antibodies suggests drug-induced lupus.  
 
Systemic lupus erythematosus is an autoimmune CTD that can be difficult to diagnose because patients often present with diverse, nonspecific symptoms that overlap with other CTDs; to further complicate matters, commonly used laboratory tests are not highly accurate. Moreover, similar symptoms may also present themselves in patients with fibromyalgia. Currently, differential diagnosis depends on a combination of clinical signs and symptoms and individual laboratory tests. More accurate laboratory tests for SLE and other CTDs could facilitate the diagnosis of the disease. Recently, laboratory-developed, diagnostic panel tests with proprietary algorithms and/or index scores for the diagnosis of SLE and other autoimmune CTDs have become commercially available.
 
At least 1 multibiomarker test to aid diagnosis of SLE and other CTDs is commercially available. This panel, Avise CTD (Exagen Diagnostics), contains 22 different tests. It combines 2 smaller panels, a 10-marker panel that includes common SLE tests, as well as cell-bound complement activation products (known as Avise Lupus) and a 12-marker panel that focuses on CTDs other than SLE (known as Avise CTD). Avise CTD includes nuclear antigen antibody markers to help distinguish CTD, a rheumatoid arthritis panel to rule-in or rule-out rheumatoid arthritis, an antiphospholipid syndrome panel to assess risk for thrombosis and cardiovascular events, and a thyroid panel to help rule-in or rule-out Graves disease and Hashimoto's disease.
 
Avise Systemic Lupus Erythematosus Tests:
    • Systemic Lupus Erythematosus Tests
    • 10-marker Avise Lupus test
    • Auto-antibodies: ANA, anti-dsDNA, antimutated citrullinated vimentin, C4d erythrocyte-bound complement fragment, C4d lymphocyte-bound complement, anti-Sm, Jo-1, Sci-70, CENP, SS-B/La
    • Avise CTD test
    • Avise Lupus test plus the following:
    • Auto-antibodies: U1RNP, RNP70, SS-A/Ro
    • Rheumatoid arthritis auto-antibodies: rheumatoid factor IgM, rheumatoid factor IgA, anti-cyclic citrullinated peptide IgG
    • Anti-phospholipid syndrome auto-antibodies: cardiolipin IgM, cardiolipin IgG, β2-glycoprotein 1 IgG, β2-glycoprotein 1 IgM
    • Thyroid auto-antibodies: thyroglobulin IgG, thyroid, thyroid peroxidase
 
The Avise CTD test assesses all 22 markers. Avise CTD uses a 3 step process (J C-V, 2014). The 10-marker panel is done in 2 tiers, and the add-on 12-marker panel is done in a third step to further assist with the differential diagnosis of CTD. In addition, ANA testing is done by enzyme-linked immunosorbent assay and by indirect immunofluorescence. The 2-tiered testing approach to the 10-marker panel is described next.
 
Tier 1: Tests for anti-Sm, EC4d, BC4d, and anti-dsDNA. If any tests are positive, the result is considered suggestive of SLE and no further testing is done. Cutoffs for positivity are greater than 10 U/mL for anti-Sm, greater than 75 U/mL for EC4d, greater than 200 U/mL for BC4d, and greater than 301 U/mL for anti-dsDNA. Positive findings for anti-dsDNA are confirmed with a Crithidia luciliae assay.
 
Tier 2: If the tier 1 tests are negative, an index score is created, consisting of results of tests for ANA, EC4d and BC4d, antimutated citrullinated vimentin, anti-Jo-1, anti-Sci-70, anti-CENP, and anti-Ss-B/La. In other words, there are 6 additional markers and the ratio of EC4d to BC4d, both of which were measured in tier 1.
 
The index score (tier 2), calculated using a proprietary algorithm, rates how suggestive test results are of SLE. Although there is information on cutoffs used to indicate positivity for individual markers, information is not available on how precisely the index score is calculated. The score can range from -5 (highly nonsuggestive of SLE) to 5 (highly suggestive of SLE), and a score of -0.1 to 0.1 is considered indeterminate.
 
Exagen also offers the Avise Lupus Prognostic test, a 10-marker panel that can be ordered with the Avise Lupus and Avise CTD panels. The prognostic test focuses on patients' risk of lupus nephritis, neuropsychiatric SLE, thrombosis, and cardiovascular events. The test includes anti-C1q, anti-ribosomal P, anti-phosphatidylserine/prothrombin immunoglobulin (Ig) M and IgG, anti-cardiolipin IgM, IgG, and IgA and anti-β2-glycoprotein 1 IgM, IgG, and IgA. Four of the 10 markers are included in both panel tests.
 
Additionally, in 2017, Exagen released an advanced blood test that incorporates specialized lupus biomarkers to assist in evaluating SLE disease activity - the AVISE SLE Monitor. The AVISE SLE Monitor test includes EC4d, a patented lupus biomarker that measures complement activation, a novel testing method to better assess changes in anti-dsDNA levels, PC4d (a patented lupus biomarker significantly associated with a history of thrombosis), and the anti-C1q biomarker that assists in evaluating lupus activity and possible kidney damage. C3 and C4 testing is also incorporated in the AVISE SLE Monitor; low levels of these proteins may indicate increased lupus disease activity.
 
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). The Avise® tests (Exagen Diagnostics) are available under the auspices of CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA Clinical for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
 
Coding
There is no specific CPT code for this panel of tests.
 
There are codes that would likely be used for some of the component tests such as:
 
83520: Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified
86038: Antinuclear antibodies (ANA);
86039: Antinuclear antibodies (ANA); titer
86146: Beta 2 Glycoprotein I antibody, each
86147: Cardiolipin (phospholipid) antibody, each Ig class
86200: Cyclic citrullinated peptide (CCP), antibody
86225: Deoxyribonucleic acid (DNA) antibody; native or double stranded
86235: Extractable nuclear antigen, antibody to, any method (eg, nRNP, SS-A, SS-B, Sm, RNP, Sc170, J01), each antibody
86376: Microsomal antibodies (eg, thyroid or thyroid-kidney), each
86800: Thyroglobulin antibody
88184: Flow cytometry, cell surface, cytoplasmic, or nuclear marker, technical component only, first marker
88185: second marker
88187: Flow cytometry, interpretation; 2 to 8 markers
 
Some payers such as Medicare might instruct the use of the unlisted chemistry code for the whole panel:
84999: Unlisted chemistry procedure.
 
Due to the reporting of an index score for the entire panel, the test would more accurately be reported with the unlisted multianalyte assay with algorithmic analysis (MAAA) CPT code – 81599.

Policy/
Coverage:
EFFECTIVE JUNE 2021
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Serum biomarker panel testing with proprietary algorithms and/or index scores (e.g., AVISE SLE, AVISE CTD, AVISE SLE Prognostic) for the diagnosis of systemic lupus erythematosus does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, serum biomarker panel testing with proprietary algorithms and/or index scores (e.g., AVISE SLE, AVISE CTD, AVISE SLE Prognostic) for the diagnosis of systemic lupus erythematosus is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
EFFECTIVE PRIOR TO JUNE 2021
Serum biomarker panel testing with proprietary algorithms and/or index scores (e.g., AVISE SLE, AVISE CTD, AVISE SLE Prognostic) for the diagnosis of systemic lupus erythematosus does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, serum biomarker panel testing with proprietary algorithms and/or index scores for the diagnosis of systemic lupus erythematosus is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 

Rationale:
This policy was created in 2014 with a search of the MEDLINE database through July 2014. Assessment of a diagnostic technology typically focuses on 3 categories of evidence: 1) technical performance (test-retest reliability or interrater reliability); 2) diagnostic accuracy (sensitivity, specificity, and positive and negative predictive value) in relevant populations of patients; and 3) demonstration that the diagnostic information can be used to improve patient outcomes. In addition, subsequent use of a technology outside of the investigational setting may also be evaluated.
 
Technical Accuracy
Some individual biomarkers, eg, ANA and anti-dsDNA, are considered standard of care in the diagnosis of connective tissue diseases, and, presumably, the technical accuracy of these tests has been established. The technical accuracy of tests for novel biomarkers in biomarker panel tests is not known.
 
Diagnostic Accuracy
 
Serum biomarker panel tests
No studies were identified that evaluated the diagnostic accuracy of any commercially available biomarker panel for systemic lupus erythematosus (SLE).
 
One study, published by Kalunian et al in 2012 and supported by Exagen Diagnostics, evaluated the performance of a 7-marker biomarker panel for the diagnosis of SLE; some of these markers are included in a commercially available panel test (Kalunian, 2012). The biomarkers included the auto-antibodies antinuclear antibodies (ANA), anti-dsDNA, and anti-mutated citrullinated vimentin (anti-MCV) measured by enzyme-linked immunosorbent assay (ELISA). In addition, the authors assessed the cell-bound complement activation products, complement receptor 1 levels on erythrocytes and complement C4d levels on erythrocytes (EC4d), platelets (PC4d) and B cells (BC4d), determined by fluorescence-activated cell sorting.
 
The study was cross-sectional and enrolled 593 individuals at 14 sites in the U.S. The sample consisted of 210 patients with SLE (according to the American College of Rheumatology (ACR) classification criteria, updated in 1997), 178 patients with other rheumatic diseases and 205 healthy volunteers. Test results were evaluated by scientists blinded to patient diagnosis.
 
In a multivariate logistic regression, SLE diagnosis was associated with a positive ANA test, a negative anti-MCV test, and elevated values of EC4d and BC4d (area under the curve [AUC]=0.92, p<0.001). The weighted sum of these 4 markers correctly categorized 106 of 148 (71.6%) of SLE patients who were anti-dsDNA negative. (The investigators evaluated the 4-marker index score among individuals who tested negative for anti-dsDNA because of the low sensitivity of this test, 29.5%, and thus high false negative rate). The specificity of the 4-marker index was 98.0% (200 of 204 healthy volunteers with test results were correctly classified). When anti-dsDNA was added to the 4-marker panel, the test had 80% sensitivity for SLE (168 of 210 SLE patients were correctly classified). Moreover, this 5-marker test had 97.6% specificity among healthy individuals (200 of 205 were correctly classified as not having SLE). Moreover, the 5-marker test had 87% specificity in patients with other rheumatic diseases; the most false positives, 9, were in patients with rheumatoid arthritis.
 
Limitations of the study are that it did not include the population of greatest interest to SLE diagnostic testing; that is, individuals with symptoms suggestive of SLE who have not already received a diagnosis. Instead it included individuals either known to have SLE or another rheumatic disease or known to be healthy. Moreover, test accuracy was not compared with concurrent physician diagnosis.
 
It is important to note that the biomarkers in the 5-marker test are part of the 10-marker Avise 2.0 SLE test marketed by Exagen. It is not clear whether the index score reported along with the Avise 2.0 panel is the same or different as the index score reported in the Kalunian et al study.
 
Novel panel components: CB-CAPs
As previously discussed, CB-CAPs are key components of a commercially available biomarker panel test for lupus diagnosis. CB-CAPs include complement C4d levels on erythrocytes, platelets, and B cells. Preliminary investigations of each of these biomarkers have been done by a research team at the University of Pittsburgh.
 
A study on lymphyocyte-bound complement activation products was published by Liu et al in 2009 (Liu, 2009). This was a cross-sectional study including 224 patients with SLE (according to ACR criteria), 179 patients with other autoimmune or inflammatory diseases and 114 healthy controls. Levels of lymphyocyte-bound complement activation products, T-cell bound C4d and C3d (TC4d and TC3d) and B-cell- bound C4d and C3d (BC4d and BC3d) were measured in all participants. The diagnostic accuracy of these markers was accessed using receiver-operating characteristic (ROC) analysis. The AUC was 0.727 for TC4d and 0.770 for BC4d. Based on these estimates, TC4d was estimated to be 56% sensitive and 80% specific for differentiating SLE from other diseases. BC4d had 56% sensitivity and 80% specificity.
 
In addition, the authors compared the CB-CAPs with other, conventionally used, SLE markers. The markers were evaluated as a confirmatory test in patients who tested positive for ANA. This analysis only included the SLE patients, 223 of 224 of whom (99.6%) were positive for ANA. Of the 223 ANA-positive patients, 141 (63%) patients had elevated levels of TC4d and/or BC4d. In contrast, 59 of the 209 ANA-positive patients (28%) tested positive for anti-dsDNA. Moreover, when the more commonly used CAPs, serum C3 and serum C4, were evaluated, 67 of 221 (30%) of ANA-positive patients tested positive for C3 and 82 of 221 patients (37%) tested positive for C4.
 
Previously, a study on platelet C4d was published by Navratil in 2006 (Navratil, 2006). The cross-sectional study included 105 patients with SLE (according to ACR criteria), 115 patients with other autoimmune or inflammatory diseases, and 100 healthy controls. Abnormal levels of platelet C4d were detected in 18% of SLE patients. False negative rate and sensitivity rates were not reported. The authors reported that the marker was 100% specific for a diagnosis of SLE compared with healthy controls and 98% specific compared with patients who had other diseases.
 
Thirdly, Manzi et al reported on the diagnostic accuracy of erythrocyte C4d in 2004 (Manzi, 2004). The cross-sectional study included 100 patients with SLE (according to ACR criteria), 133 patients with other autoimmune or inflammatory diseases and 84 healthy controls. Overall, erythrocyte C4d was 86% sensitive and 71% specific. Moreover, the authors reported that erythrocyte C4d was 72% sensitive and 79% specific for SLE versus other diseases, and 81% sensitive and 91% specific for SLE versus healthy controls.
 
The CB-CAPs lymphocyte-bound BC4d, platelet C4d and erythrocyte C4d are included in the panel test evaluated in the Kalunian et al study discussed earlier (Kalunian, 2012).  As in the Kalunian study, all of the other studies included individuals with known diagnoses; none included patients of greatest interest for diagnostic test—those with symptoms suggestive of disease. Also similar was the lack of a concurrent reference standard in the studies.
 
Effect on Patient Outcomes
No studies were identified that evaluate the impact of serum biomarker panel testing for SLE on patient management decisions or patient outcomes.
 
Summary
Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease that can be difficult to diagnose because patients often present with diverse, nonspecific symptoms, and commonly used laboratory tests are not highly accurate. Currently, the diagnosis of SLE depends on a combination of clinical signs and symptoms and individual laboratory tests. More accurate laboratory tests for SLE could facilitate diagnosis of the disease in many patients. Recently, laboratory-developed, diagnostic panel tests with proprietary algorithms and/or index scores for the diagnosis of SLE have become commercially available.
 
Panel tests for SLE include markers that are standard in the work-up of SLE, but also contain novel markers, most notably cell-bound complement activation products (CB-CAPs). The accuracy of CB-CAPs in establishing a diagnosis of SLE is not known, nor is the use of these novel biomarkers recommended in clinical practice guidelines. In addition to reporting the results of the panel of tests, an index score is reported that rates how suggestive the results of the panel are of a diagnosis of SLE. Information is not available on how this index score is calculated, nor is it known how this score performs in diagnosing SLE compared with currently accepted clinical and laboratory criteria. Finally, the utility of assessing multiple biomarkers simultaneously, rather than the more commonly performed sequential testing, is unknown.
 
Practice Guidelines and Position Statements
In 2014, an international group including participants in the European autoimmunity standardization initiative and the International Union of Immunologic Societies published recommendations on the assessment of autoantibodies to cellular antigens (Agmon-Levin, 2014). The recommendations included the following statements relevant to the diagnosis of SLE:
 
    • The diagnosis of systemic autoimmune rheumatic diseases (SARD) requires a panel of specific laboratory tests (ie, ANA, anti-dsDNA, anti-ENA antibodies)
 
    • The detection of ANA is the first-level test for laboratory diagnosis of SARD.
 
    • If the ANA test is positive, testing for anti-dsDNA antibodies is advised when there is clinical suspicion of SLE
 
    • If the ANA test is positive, testing for anti-ENA antibodies is recommended.
 
2015 Update
A literature search conducted through July 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Putterman and colleagues published data from a large cross-sectional industry-sponsored study evaluating serum biomarkers for the diagnosis of SLE (Putterman, 2014). This study included an analysis of the 10 markers included in the Avise SLE test (plus ANA) using 2-tier testing logic similar to that used in the commercially available panel (see Background section). The study included 2 cohorts (total N=794); 593 participants were enrolled between April to August 2010 and 201 participants enrolled between June 2011 and September 2013. Together, the 2 cohorts consisted of 304 patients who fulfilled the ACR classification criteria for SLE, 161 patients diagnosed with other rheumatic diseases and 205 heathy volunteers. Results of serum testing were available for 764 of 794 (96%) participants.
 
The diagnostic accuracy of the cell-bound complement activation products (CB-CAP) EC4d and BC4d were compared with reduced complement (C3, C4) and anti-dsDNA. The area under the receiver operating curve (ROC) was significantly higher for EC4d (0.82) and BC4d (0.84) than for C3 (0.73) and C4 (0.72), p<0.001. The area under the ROC curve was significantly higher for BC4d than anti-dsDNA (0.79, p=0.009) but there was not a significant difference between EC4d and anti-dsDNA.
 
A total of 140 patients with SLE (46%), 9 patients with other diseases (3%) and 1 healthy volunteer tested positive for at least 1 of the 4 tier 1 markers. Patients testing negative for tier 1 tests underwent tier 2 testing and an index score was calculated. A total of 102 of 164 patients with SLE analyzed in tier 2 (62%) had an index score greater than 0 (ie, suggestive of SLE). Moreover, 245 of 276 patients with other rheumatic diseases had an index score less than 0, ie, not suggestive of SLE. When results of tier 1 and tier 2 testing were combined, the overall sensitivity for SLE was 80% (242/304) and the overall specificity for distinguishing SLE from other diseases was 86% (245/285). The specificity for distinguishing between SLE and health volunteers was 98% (201/205).
 
A limitation of the Putterman et al  and Kalunian et al studies is that study populations included patients with SLE who met ACR classification criteria, but not patients with symptoms suggestive of SLE who failed to meet ACR criteria. It is not known how the diagnostic accuracy of the panel test compares to the ACR classification criteria or to concurrent clinician diagnosis (in the Putterman et al study, the mean time since SLE diagnosis was 11 years). Furthermore, although they are included in the SLICC classification criteria, the complement factors C3 and C4 are not widely used in clinical practice to diagnose lupus and therefore the clinical significance of higher diagnostic accuracy for EC4d and BC4d is unclear.
 
The evidence for the diagnosis of systemic lupus erythematosus (SLE) in patients who have signs and/or symptoms of SLE, using serum biomarker panel testing, consists of several diagnostic accuracy studies. Outcomes of importance are diagnostic accuracy of the test, overall survival, symptoms and disease remission. One study evaluated a panel similar to a commercially available test; it found that the panel test had somewhat higher specificity and lower sensitivity than the most commonly currently used biomarkers. The clinical significance of this degree of difference in diagnostic accuracy is unclear. There is also uncertainly around how the use of a serum biomarker panel test for SLE would change patient management. The evidence is insufficient to determine the effects on health outcomes of the use of serum biomarker panel testing with proprietary algorithms/ and or index scores for the diagnosis of SLE.
 
2016 Update
A literature search conducted through August 2016 did not reveal any new information that would prompt a change in the coverage statement.  
 
2018 Update
A literature search conducted using the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement.
 
An industry-sponsored study analyzed serum biomarkers as well as an algorithm for diagnosing SLE (Wallace, 2016). This study analyzed markers in the Avise Lupus (plus ANA) test using a 2-tier testing logic to evaluate SLE patients who met ACR criteria (n=75) and patients with primary fibromyalgia (n=75). High expression of CB-CAP EC4d or BC4d had 43% sensitivity and 96% specificity for the diagnosis of SLE. Use of a multianalyte assay with the algorithm, including CB-CAP levels, generated indeterminate results in 12 of the 150 subjects enrolled. For the remainder of patients, use of the algorithm to diagnosis SLE was 60% sensitive and 100% specific. Study limitations included selection of patients with well-established diagnosis and long duration of disease.
 
The evidence remains insufficient to determine the effects of the technology on health outcomes.
 
2019 Update
A literature search was conducted through May 2019.  There was no new information identified that would prompt a change in the coverage statement.  
 
2020 Update
A literature search was conducted through May 2020.  There was no new information identified that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Outcomes of interest for SLE include disease activity indices, organ damage, reduction in flares, and reduction in concomitant corticosteroids (Guidance for Industry, 2010). Patient reported outcomes are also encouraged, particularly ones that measure fatigue as most experts agree that it is 1 of the most important symptoms of SLE. However, the U.S. Food and Drug Administration (FDA) has not identified an existing instrument optimal for measuring fatigue in patients with SLE. Both fatigue and pain are the most consequential and frequent symptoms in SLE and these contribute significantly to physical functioning, sleep, and the ability to complete daily tasks, among other quality of life measures (McElhone, 2007). Validated instruments for measuring quality of life in SLE are mainly used in clinical trials. Systemic lupus erythematosus-specific measures include the Lupus-quality-of-life and SLE-specific quality-of-life (SLEQOL) instruments; additionally general quality of life measures are also used to measure health-related quality of life (eg, Short Form 36 [SF-36]). Recommended health outcome measures for disease activity and organ damage per FDA guidance are summarized below (Guidance for Industry, 2010; Romero-Diaz, 2011).
 
Health Outcome Measures Relevant to SLE:
    • The BILAG disease activity index scores disease activity within the last month from A to E. It is described as an ordinal scale index that assesses 9 individual organ systems. Disease activity is scored and converted into 5 levels from A to E. Grade A is very active disease requiring anticoagulation therapy, while Grade E is no current or previous disease activity. Major clinical response as defined by the FDA as BILAG C scores or better at 6 months with no new BILAG A or B scores with maintenance of response between 6 to 12 months. (Isenberg, 2005)
    • The SLEDAI-2K disease activity index measures on a scale from 0 to 105. Disease activity within last 10 days is assessed. A 24-item assessment of 16 clinical symptoms and 8 laboratory results that covers 9 organ systems. Items are weighted giving individual item scores ranging from 1 to 8. Categories of activity range from inactive (score of 0) to very active (score > 12). A score of 6 is considered clinically important and affects the decision to treat (Gladman, 2002).
    • The SLAM-R uses a scale from 0 to 81 to measure disease activity within last month, It evaluates 9 organ systems plus 7 laboratory features. Each organ item is scored 0 to 3 points. Laboratory categories can score a maximum of 21 points. Higher scores indicate higher disease activity. A score of 7 is considered clinically important and affects the decision to treat (Bae, 2001).
    • The ECLAM disease activity index measures disease activity withing the last month on a scale from 0 to 17.5. It is described as a 33-item assessment that is organized into 12 categories, including 10 organ symptoms plus ESR and complement levels. Individual item scores range from 0.5 to 2. Higher scores indicate higher disease activity (Vitali, 1992)
 
Organ damage assessment
    • The SLICC/ACR damage index measures disease damage present 6 months or more after an irreversible event on a scale from 0 to 46. It captures items of permanent change after a diagnosis of SLE that covers specific manifestations in 12 organ systems. The 41-item assessment scores the presence of organ damage from 1 to 3 points. Higher scores indicate higher damage. Organ damage is considered if the score is 1. Cumulative damage is a poor prognostic sign and a predictor of mortality (Gladman, 1996).
 
Liang et al conducted a retrospective single-center study of 117 patients in a rheumatology clinic without a confirmed SLE diagnosis who had received an Avise CTD test as part of their clinical care between April 2014 and November 2016 (Liang, 2020). The study aimed to determine whether the Avise test would aid in assessing the risk of developing SLE in patients who had undifferentiated findings presenting in a real-world setting. At the clinic, patients who had inflammatory arthritis, undifferentiated CTD, or other diagnoses or features suggestive of SLE received Avise testing. In this cohort of patients without a diagnosis of SLE at baseline, the diagnosis at 2 years from baseline changed in 80% (16/20) of patients who had a positive test as opposed to only 28.9% (28/97) who had a non-positive test. Of the 20 patients who had a positive test, 13 (65%) had their diagnosis changed to SLE at 2 years. The Avise test was associated with a specificity of 93%, with a sensitivity of 57%, positive predictive value of 65% and negative predictive value of 90%. The study also observed that patients with a positive Avise test had a significant accrual of clinical features, as defined by SLICC and ACR criteria, as well as organ damage, as defined by the SLICC Damage Index, compared to those without a positive test over the 2 year period. Additionally, there were no significant differences in medication regimens received by positive versus non-positive patients at baseline or at 2 years, except for more frequent use of mycophenolate mofetil in positive patients at year 2. Limitations of the study include its retrospective design and the potential for confirmation bias as treating physicians were aware of the Avise results and were potentially less likely to diagnose SLE in a patient with a negative Avise test. The authors concluded that the Avise CTD may be useful in predicting the development of SLE.
 
Ramsey-Goldman et al evaluated the usefulness of CB-CAPs and a multianalyte assay in patients with suspected SLE to predict progression to SLE as classified by ACR criteria in an industry-sponsored prospective observational study at 7 academic institutions (Ramsey-Goldman, 2020). Patients with probable SLE as suspected by lupus experts who also met 3 ACR criteria (n=92) were enrolled along with patients with established SLE based on ACR and SLICC criteria (n=53). A control group of patients with primary Sjogren's syndrome and other rheumatic diseases (n=101) were also included. The multianalyte panel with algorithm evaluated was the Avise Lupus test. The sensitivity of CB-CAPs and MAP at enrollment was higher compared to anti-dsDNA levels or low complement levels. The MAP was more sensitive and specific than CB-CAPs in patients with probable SLE (40% vs 28% and 96% vs 86%, respectively). The ability of positive CB-CAPs and MAPs to predict fulfillment of the ACR criteria at 9 to 18 months after enrollment was also analyzed. In the subgroup of 20 patients with probable SLE who fulfilled ACR criteria within 18 months, 8 (40%) had a MAP score >0.8 at enrollment. Kaplan-Meier estimates found that a MAP score >0.8 was predictive of progression to classifiable SLE (hazard ratio 3.11, 95% confidence interval 1.26 to 7.69). A limitation of the study was the relatively small population of patients with probable SLE. Ramsey-Goldman et al (2021) continued to follow patients with probable SLE from their original report to better determine whether more patients transitioned to classifiable SLE and whether the MAP score retained its ability to predict this transition (Ramsey-Goldman, 2021). Of the 92 patients with probable SLE, 74 had 1 or 2 follow-up visits 9 to 35 months after enrollment (total follow-up visits: 128). Twenty-eight patients with probable SLE (30.4%) were found to transition to ACR-classifiable SLE. This included 16 individuals in the first year and 12 afterwards. A MAP score >0.8 at enrollment continued to predict a transition to classifiable SLE during follow-up (hazard ratio 2.72; p=.012); individual biomarkers or fulfillment of SLICC criteria did not.
 
Serum biomarker panel tests should be compared with usual clinical diagnosis assessments. Clinical diagnosis for SLE is not standardized, but generally consists of assessments of individual biomarkers in patients with signs and symptoms suspicious of SLE. One randomized controlled trial (RCT) is available directly comparing serum biomarker panel tests to standard diagnosis laboratory testing (Wallace, 2019). The CARE for Lupus Trial was conducted in the United States at 32 sites from July 2017-December 2018. Participants include 145 patients who were referred to a rheumatologist with a clinical suspicion for SLE, including a history of ANA positivity. 72 had the Avise Lupus test and 73 had standard diagnosis laboratory testing.
 
Wallace et al reported quality of life measures with the 5-level EuroQOL-5 Dimension index, however, outcomes were not reported by treatment group (Wallace, 2019).
 
Wallace et al evaluated the clinical utility of the Avise Lupus test for the diagnosis of lupus as compared to standard diagnosis laboratory testing (Wallace, 2019). The primary endpoint of the trial was the change in the physicians' estimate of likelihood of SLE before and after testing (12 weeks after enrollment). Physicians estimated the likelihood on a 5-point Likert scale ranging from 0 (very low) to 4 (very high). At baseline, pretest likelihood was similar between the standard diagnosis laboratory testing group and the Avise Lupus test group and the likelihood of SLE decreased in both groups after testing, but the magnitude of the decrease was greater in the Avise Lupus test group. The change in likelihood of SLE from randomization to post-test was -0.44 ± 0.10 in the Avise Lupus test group versus -0.19 ± 0.07 in the standard diagnosis laboratory testing group (p=.027). The corresponding changes from baseline to end of study at week 12 was -0.31 ± 0.10 versus -0.61 ± 0.10 (p=.025), for each group respectively.
 
There were some study relevance limitations in the comparator (in the standard diagnosis laboratory group, physicians were not directed to order any specific laboratory test – not standard or optimal), the outcomes (formal diagnosis, or fulfillment of classification of SLE not included – key health outcomes not addressed), and follow-up (short follow-up did not allow for confirmation of SLE diagnosis or impact on longer term health outcomes – not sufficient duration for benefit) (Wallace, 2019). Also, there were some study design and conduct limitations: Blinding (no blinding was used in the study [not blinded to treatment assignment] and post-test likelihood of SLE assessed by the treating physician [outcome assessed by treating physician]); Selective Reporting (Between group differences in quality of life measures were not reported [evidence of selective reporting]); Power (Power calculations were not performed [power calculations not reported]); and Statistical (Median differences and 95% confidence intervals between treatment groups for outcomes were not reported [comparative treatment effects not calculated]) (Wallace, 2019).   
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Ramsey-Goldman et al continued to follow patients with probable SLE from their original report to better determine whether more patients transitioned to classifiable SLE and whether the MAP score retained its ability to predict this transition (Ramsey-Goldman, 2021). Of the 92 patients with probable SLE, 74 had 1 or 2 follow-up visits 9 to 35 months after enrollment (total follow-up visits: 128). Twenty-eight patients with probable SLE (30.4%) were found to transition to ACR-classifiable SLE. This included 16 individuals in the first year and 12 afterwards. A MAP score >0.8 at enrollment continued to predict a transition to classifiable SLE during follow-up (hazard ratio 2.72; p=.012); individual biomarkers or fulfillment of SLICC criteria did not.

CPT/HCPCS:
0312UAutoimmune diseases (eg, systemic lupus erythematosus [SLE]), analysis of 8 IgG autoantibodies and 2 cell-bound complement activation products using enzyme-linked immunosorbent immunoassay (ELISA), flow cytometry and indirect immunofluorescence, serum, or plasma and whole blood, individual components reported along with an algorithmic SLE-likelihood assessment
81599Unlisted multianalyte assay with algorithmic analysis
83516Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; qualitative or semiquantitative, multiple step method
83520Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified
84999Unlisted chemistry procedure
86038Antinuclear antibodies (ANA);
86039Antinuclear antibodies (ANA); titer
86146Beta 2 Glycoprotein I antibody, each
86147Cardiolipin (phospholipid) antibody, each Ig class
86200Cyclic citrullinated peptide (CCP), antibody
86225Deoxyribonucleic acid (DNA) antibody; native or double stranded
86235Extractable nuclear antigen, antibody to, any method (eg, nRNP, SS A, SS B, Sm, RNP, Sc170, J01), each antibody
86376Microsomal antibodies (eg, thyroid or liver kidney), each
86800Thyroglobulin antibody
88184Flow cytometry, cell surface, cytoplasmic, or nuclear marker, technical component only; first marker
88185Flow cytometry, cell surface, cytoplasmic, or nuclear marker, technical component only; each additional marker (List separately in addition to code for first marker)
88187Flow cytometry, interpretation; 2 to 8 markers

References: American College of Rheumatology (ACR).(1997) 1997 Update of the 1982 American College of Rheumatology Revised Criteria for Classification of Systemic Lupus Erythematosus. n.d.; https://www.rheumatology.org/Portals/0/Files/1997%20Update%20of%201982%20Revised.pdf. Accessed April 27, 2021.

Aringer M, Costenbader K, Daikh D, et al.(2019) 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. Arthritis Rheumatol. Sep 2019; 71(9): 1400-1412. PMID 31385462

Bae SC, Koh HK, Chang DK, et al.(2001) Reliability and validity of systemic lupus activity measure-revised (SLAM-R) for measuring clinical disease activity in systemic lupus erythematosus. Lupus. 2001; 10(6): 405-9. PMID 11434575

Gladman D, Ginzler E, Goldsmith C, et al.(1996) The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum. Mar 1996; 39(3): 363-9. PMID 8607884

Gladman DD, Ibanez D, Urowitz MB.(2002) Systemic lupus erythematosus disease activity index 2000. J Rheumatol. Feb 2002; 29(2): 288-91. PMID 11838846

Guidance for Industry.(2010) Systemic Lupus Erythematosus - Developing Medical Products for Treatment. Federal Register website. June 2010. https://www.govinfo.gov/content/pkg/FR-2010-06-22/pdf/2010-15080.pdf. Accessed April 27, 2021.

Guidelines for referral and management of systemic lupus erythematosus in adults.(1999) American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Arthritis Rheum. Sep 1999; 42(9): 1785-96. PMID 10513791

Hochberg MC.(1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. Sep 1997; 40(9): 1725. PMID 9324032

Isenberg DA, Rahman A, Allen E, et al.(2005) BILAG 2004. Development and initial validation of an updated version of the British Isles Lupus Assessment Group's disease activity index for patients with systemic lupus erythematosus. Rheumatology (Oxford). Jul 2005; 44(7): 902-6. PMID 15814577

J C-V, Chitkara P, Christianakis S, et al.(2014) Finding the best approach to autoimmune connective tissue disease diagnosis (Paid supplement supported by Exagen Diagnostics). Rheumatology News. 2014;August:1-8.

Liang E, Taylor M, McMahon M.(2020) Utility of the AVISE Connective Tissue Disease test in predicting lupus diagnosis and progression. Lupus Sci Med. 2020; 7(1): e000345. PMID 32231785

McElhone K, Abbott J, Shelmerdine J, et al.(2007) Development and validation of a disease-specific health-related quality of life measure, the LupusQol, for adults with systemic lupus erythematosus. Arthritis Rheum. Aug 15 2007; 57(6): 972-9. PMID 17665467

Petri M, Orbai AM, Alarcon GS, et al.(2012) Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. Aug 2012; 64(8): 2677-86. PMID 22553077

Ramsey-Goldman R, Alexander RV, Conklin J, et al.(2021) 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. Feb 2021; 3(2): 116-123. PMID 33538130

Ramsey-Goldman R, Alexander RV, Conklin J, et al.(2021) 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. Feb 2021; 3(2): 116-123. PMID 33538130

Ramsey-Goldman R, Alexander RV, Massarotti EM, et al.(2020) Complement Activation in Patients With Probable Systemic Lupus Erythematosus and Ability to Predict Progression to American College of Rheumatology-Classified Systemic Lupus Erythematosus. Arthritis Rheumatol. Jan 2020; 72(1): 78-88. PMID 31469249

Romero-Diaz J, Isenberg D, Ramsey-Goldman R.(2011) Measures of adult systemic lupus erythematosus: updated version of British Isles Lupus Assessment Group (BILAG 2004), European Consensus Lupus Activity Measurements (ECLAM), Systemic Lupus Activity Measure, Revised (SLAM-R), Systemic Lupus Activity Questionnaire for Population Studies (SLAQ), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Arthritis Care Res (Hoboken). Nov 2011; 63 Suppl 11: S37-46. PMID 22588757

Vitali C, Bencivelli W, Isenberg DA, et al.(1992) Disease activity in systemic lupus erythematosus: report of the Consensus Study Group of the European Workshop for Rheumatology Research. II. Identification of the variables indicative of disease activity and their use in the development of an activity score. The European Consensus Study Group for Disease Activity in SLE. Clin Exp Rheumatol. Sep-Oct 1992; 10(5): 541-7. PMID 1458710

Wallace DJ, Alexander RV, O'Malley T, et al.(2019) 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. PMID 31592328

Wallace DJ, Silverman SL, Conklin J, et al.(2016) Systemic lupus erythematosus and primary fibromyalgia can be distinguished by testing for cell-bound complement activation products. Lupus Sci Med. 2016;3(1):e000127. PMID 26870391


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2023 American Medical Association.