702 Form

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Medical Policy Serum Biomarker Panel Testing for Systemic Lupus Erythematosus and Other Connective Tissue Diseases
Table of Contents • Policy: Commercial • Coding Information
• Information Pertaining to All Policies
• Policy: Medicare • Description
• References
• Authorization Information • Policy History

Policy Number: 702 BCBSA Reference Number: 2.04.123 (For Plan internal use only) NCD/LCD: NA

Related Policies
Multibiomarker Disease Activity Blood Test for Rheumatoid Arthritis, #677 Policy Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity
Medicare HMO BlueSM and Medicare PPO BlueSM Members

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. Prior Authorization Information Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.

Outpatient Commercial Managed Care (HMO and POS) This is not a covered service. Commercial PPO and Indemnity This is not a covered service. Medicare HMO BlueSM This is not a covered service. Medicare PPO BlueSM This is not a covered service. CPT Codes / HCPCS Codes / ICD Codes Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

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Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

The following codes are included below for informational purposes only; this is not an all-inclusive list. The following CPT code is considered investigational for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue:

CPT Codes CPT codes: Code Description 0062U Autoimmune (systemic lupus erythematosus), IgG and IgM analysis of 80 biomarkers, utilizing serum, algorithm reported with a risk score 0312U Autoimmune 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

Description Connective Tissue Diseases Systemic Lupus Erythematosus Systemic lupus erythematous (SLE) is an autoimmune connective tissue disease (CTD). It is one 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 (eg, rheumatoid arthritis, thyroid disease, Sjögren syndrome, antiphospholipid syndrome, and polymyositis). Rheumatoid arthritis 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. Rheumatoid arthritis can also affect the skin, eyes, lungs, heart, and blood vessels. Graves disease is an autoimmune disorder that leads to overactivity 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 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.

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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 antinuclear antibody (ANA), anti-Sjögren-syndrome- related antigen, anti-Sjögren syndrome type B, 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. Summary
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. 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. Policy History Date Action 8/2025 Annual policy review. Policy updated with literature review through April 23, 2025; no references added. Policy statement unchanged. 8/2024 Annual policy review. Description summary and references updated. Policy statements unchanged. 8/2023 Annual policy review. Description summary and references updated. Policy statements unchanged. 8/2022 Annual policy review. Description summary and references updated. Policy statements unchanged. 4/2022 Clarified coding information. 8/2020 Annual policy review. Description, summary and references updated. Policy statements unchanged. 8/2019 Annual policy review. Description, summary and references updated. Policy statements unchanged. 11/2018 Annual policy review. Description and summary clarified.

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10/2018 Annual policy review. Clinical criteria in Table 1 for synovitis clarified under the description section. Summary and references updated. Clarified coding information 7/2018 Annual policy review. New references added. Summary clarified. 9/2017 Annual policy review. The phrase “and other connective tissue diseases” added to policy statement and title.
11/2015 Annual policy review. New references added. 1/2015 Annual policy review. New medical policy describing investigational indications.
Effective 1/1/2015. Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines

References

1. Kasitanon N, Magder LS, Petri M. Predictors of survival in systemic lupus erythematosus. Medicine (Baltimore). May 2006; 85(3): 147-156. PMID 16721257
2. 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.
3. American College of Rheumatology (ACR). 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 26, 2024.
4. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. Sep 1997; 40(9): 1725. PMID 9324032
5. 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. PMID 31385462
6. Guidelines for referral and management of systemic lupus erythematosus in adults. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Arthritis Rheum. Sep 1999; 42(9): 1785-96. PMID 10513791
7. 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. Aug 2012; 64(8): 2677-86. PMID 22553077
8. Suresh E. Systemic lupus erythematosus: diagnosis for the non-specialist. Br J Hosp Med (Lond). Oct 2007; 68(10): 538-41. PMID 17974296
9. Food and Drug Administration. Guidance for Industry: Systemic Lupus Erythematosus - Developing Medical Products for Treatment. June 2010. https://www.fda.gov/media/71150/download. Accessed April 26, 2024.
10. McElhone K, Abbott J, Shelmerdine J, et al. 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
11. 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(0 11): S37-46. PMID 22588757

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12. Isenberg DA, Rahman A, Allen E, et al. 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
13. Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. Feb 2002; 29(2): 288-91. PMID 11838846
14. Bae SC, Koh HK, Chang DK, et al. 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
15. 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. 1992; 10(5): 541-7. PMID 1458710
16. Gladman D, Ginzler E, Goldsmith C, et al. 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
17. 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): 4040-7. PMID 22932861
18. Liu CC, Kao AH, Hawkins DM, et al. Lymphocyte-bound complement activation products as biomarkers for diagnosis of systemic lupus erythematosus. Clin Transl Sci. Aug 2009; 2(4): 300-8. PMID 20161444
19. Navratil JS, Manzi S, Kao AH, et al. Platelet C4d is highly specific for systemic lupus erythematosus. Arthritis Rheum. Feb 2006; 54(2): 670-4. PMID 16447243
20. 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. PMID 25396070
21. 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. PMID 26870391
22. 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. PMID 27867431
23. 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. PMID 32231785
24. 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. PMID 35775579
25. 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. Arthritis Rheumatol. Jan 2020; 72(1): 78-
26. PMID 31469249
27. 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. PMID 33538130
28. 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. PMID 31592328