Latest Review Date: June 2024

Category: Laboratory

POLICY:

Serum biomarker panel testing with proprietary algorithms and/or index scores for the diagnosis of systemic lupus erythematosus and other connective tissue diseases is considered investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease (CTD) that can be difficult to diagnose because individuals 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 individuals 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. Laboratory-developed, diagnostic panel tests with proprietary algorithms and/or index scores for the diagnosis of SLE and other autoimmune CTDs are commercially available.

Systemic Lupus Erythematosus

Systemic lupus erythematous (SLE) is an autoimmune connective tissue disease (CTD). It is 1 of several types of lupus, the others being cutaneous and drug-induced. About 90% of lupus patients are women between the ages of 15 and 44 years. Systemic lupus erythematous 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 increase mortality, most commonly from cardiovascular disease due to accelerated atherosclerosis. Systemic lupus erythematous 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.1, The morbidity associated with SLE is substantial. Symptoms such as joint and muscle pain can impact quality of life and functional status. Systemic lupus erythematous also increases patients' risk of infection, cancer, avascular necrosis (bone death), and pregnancy complications (eg, preeclampsia, preterm birth). The course of the disease is variable, and patients generally experience flares of mild-to-severe illness and remission.

Other Connective Tissue Diseases

Several other CTDs may require a differential diagnosis from SLE (e.g., rheumatoid arthritis, thyroid disease, Sjögren syndrome, antiphospholipid syndrome, and polymyositis).

Rheumatoid arthritis (RA) is a chronic inflammatory peripheral polyarthritis. Rheumatoid arthritis can lead to deformity through stretching of tendons and ligaments and destruction of joints through erosion of cartilage and bone. RA can also affect the skin, eyes, lungs, heart, and blood vessels.

Graves’ disease is an autoimmune disorder that leads to over activity of the thyroid gland. The disease arises from thyroid stimulating hormone-receptor antibodies. It is the most common cause of hyperthyroidism. Blood tests may show raised thyroid-stimulating immunoglobulin (TSI) antibodies.

Hashimoto disease, also known as chronic lymphocytic thyroiditis, is an autoimmune disorder and is the most common cause of hypothyroidism second to iodine insufficiency. It is characterized by an underactive thyroid gland and gradual thyroid failure. Diagnosis is confirmed with blood tests for thyroid stimulating hormone (T4) and antithyroid antibodies.

Sjögren syndrome is an autoimmune disorder characterized by dryness of the eyes and mouth due to diminished lacrimal and salivary gland function. Affected individuals may also have symptoms of fatigue, myalgia, and cognitive dysfunction which may be difficult to distinguish clinically from fibromyalgia or medication side effects. Typical antibodies include anti-nuclear antibody (ANA), anti-SSA and anti-SSB or rheumatoid factor.

Antiphospholipid syndrome is a systemic autoimmune disorder characterized by venous or arterial thrombosis and/or pregnancy morbidity. Antiphospholipid antibodies are directed against phospholipid-binding proteins.

Polymyositis and dermatomyositis are inflammatory myopathies characterized by muscle weakness and inflammation. Dermatomyositis may also have skin manifestations.

KEY POINTS:

This evidence review has been regularly updated with searches of the PubMed database. The most recent literature review was updated through April 18, 2024.

Summary of Evidence

For individuals with signs and/or symptoms of systemic lupus erythematosus (SLE) who receive serum biomarker panel testing, the evidence includes several diagnostic accuracy studies and 1 prospective evaluation of clinical utility that compared the impact of the test results on physicians' evaluation of individuals with a clinical suspicion for SLE. Relevant outcomes are test accuracy, symptoms, and quality of life. Observational studies have been primarily retrospective in design, not performed in the intended-use population and lacking concurrent, appropriate comparator. Additionally, a randomized controlled trial (RCT) evaluated the influence of test results from Avise and standard diagnosis laboratory testing on rheumatologists’ change in physician global assessment for the likelihood of SLE, which is not a health outcome. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with signs and/or symptoms of connective tissue diseases (CTDs) (besides SLE) who receive serum biomarker panel testing, more studies are needed. Relevant outcomes are test accuracy, symptoms, and quality of life. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

No guidelines or statements were identified.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Avise SLE, systemic lupus erythematosus, SLE, serum biomarker panel test, SLE-Key, Exagen, CTDs, connective tissue disorders

APPROVED BY GOVERNING BODIES:

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 (LDTs) must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply. Refer to member’s benefit plan.

CURRENT CODING:

CPT Codes:

There are no specific CPT codes for this type of testing. It might be reported using a single CPT code or combination of the CPT codes below.

REFERENCES:

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. Jul 2021; 8(1).
2. American College of Rheumatology (ACR). 1997 Update of the 1982 American College of Rheumatology Revised Criteria for Classification of Systemic Lupus Erythematosus. n.d.; www.rheumatology.org/Portals/0/Files/1997%20Update%20of%201982%20Revised.pdf.
3. Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. Arthritis Rheumatol. Sep 2019; 71(9): 1400-1412.
4. Food and Drug Administration. Guidance for Industry: Systemic Lupus Erythematosus - Developing Medical Products for Treatment. June 2010. www.fda.gov/media/71150/download.
5. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press
6. J C-V, Chitkara P, Christianakis S, et al. Finding the best approach to autoimmune connective tissue disease diagnosis (Paid supplement supported by Exagen Diagnostics). Rheumatology News. 2014; August: 1-8.
7. Kalunian KC, Chatham WW, Massarotti EM, et al. Measurement of cell-bound complement activation products enhances diagnostic performance in systemic lupus erythematosus. Arthritis Rheum. Dec 2012; 64(12):4040-4047.
8. Kasitanon N, Magder LS, Petri M. Predictors of survival in systemic lupus erythematosus. Medicine (Baltimore). May 2006; 85(3):147-156.
9. Liang E, Taylor M, McMahon M. Utility of the AVISE Connective Tissue Disease test in predicting lupus diagnosis and progression. Lupus Sci Med. 2020; 7(1): e000345.
10. Mossell J, Goldman JA, Barken D, et al. The Avise Lupus test and cell-bound complement activation products aid the diagnosis of systemic lupus erythematosus. Open Rheumatol J. 2016; 10:71-80.
11. 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. Sep 2022; 28(9): 1021-1032.
12. Petri M, Orbai AM, Alarcon GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. Aug 2012; 64(8):2677-2686.
13. 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.
14. 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. Feb 2021; 3(2): 116-123.
15. Ramsey-Goldman R, Alexander RV, Massarotti EM, et al. Complement Activation in Patients With Probable Systemic Lupus Erythematosus and Ability to Predict Progression to American College of Rheumatology-Classified Systemic Lupus Erythematosus. Jan 2020; 72(1): 78-88.
16. Romero-Diaz J, Isenberg D, Ramsey-Goldman R. 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. 
17. Vitali C, Bencivelli W, Isenberg DA, et al. 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.
18. 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.
19. Wallace DJ, Silverman SL, Conklin J, et al. Systemic lupus erythematosus and primary fibromyalgia can be distinguished by testing for cell-bound complement activation products. Lupus Sci Med. 2016; 3(1): e000127.

POLICY HISTORY:

Medical Policy Panel, August 2014

Medical Policy Group, September 2014 (1): New policy

Medical Policy Administration Committee, October 2014

Available for comment September 23 through November 6, 2014

Medical Policy Panel, August 2015

Medical Policy Group, August 2015 (3): Updates to Description, Key Points, Coding & References; no change in policy statement

Medical Policy Panel, June 2016

Medical Policy Group, June 2016 (3): 2016 Updates to Key Points; no change in policy statement.

Medical Policy Panel, July 2017

Medical Policy Group, July 2017 (3): 2017 Updates to Title, Description, Key Points, Approved by Governing Bodies & References; the phrase “and other connective tissue diseases” added to policy statement to clarify any connective tissue disorder included in investigational status

Medical Policy Panel, June 2018

Medical Policy Group, June 2018 (7): Updates to Key Points and References. Coding Section- added CPT 88188 and 88189. No change in Policy Statement.

Medical Policy Group, September 2018: Quarterly coding update. Added new CPT code 0062U and new key word SLE-key.

Medical Policy Panel, June 2019

Medical Policy Group, June 2019 (9): 2019 Updates to Description and Key Points. Added CPT code 0039U. Added key words: Exagen, CTDs, connective tissue disorders. No change to policy statement.

Medical Policy Panel, June 2020

Medical Policy Group, July 2020 (9): 2020 Updates to Description, Key Points, and References. No change to policy statement.

Medical Policy Panel, June 2021

Medical Policy Group, June 2021 (9): 2021 Updates to Description, Key Points, and References. Policy statement updated to remove “not medically necessary,” no change to policy intent.

Medical Policy Group, March 2022 (9): Quarterly coding update. Added new CPT code 0312U to current coding section.

Medical Policy Panel, June 2022

Medical Policy Group, June 2022 (9): 2022 Updates to Description, Key Points, References. No change to policy statement.

Medical Policy Group, December 2022 (9): Updated current coding section by adding the following verbiage: "There are no specific CPT codes for this type of testing. It might be reported using a single CPT code or combination of the CPT codes below." No change to policy intent.

Medical Policy Panel, June 2023

Medical Policy Group, June 2023 (5): Updates to Description, Key Points, Benefit Application, and References. No change to Policy Statement.

Medical Policy Panel, June 2024

Medical Policy Group, June 2024 (5): Updates to Description, and Key Points. No change to Policy Statement.  

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.