CurrentBlue Cross Blue Shield - NebraskaPolicy M.83

MA Specialty Testing: Immunology and Rheumatology (Preauthorization Required)

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Governs preauthorization and medical necessity criteria for genetic, algorithmic, and biomarker tests used to evaluate autoimmune, immune deficiency, and rheumatologic conditions for Blue Cross Blue Shield - Nebraska members.

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CurrentBlue Cross Blue Shield - NebraskaPolicy M.83

MA Specialty Testing: Immunology and Rheumatology (Preauthorization Required)

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Policy Summary

PayerBlue Cross Blue Shield - Nebraska

PolicyMA Specialty Testing: Immunology and Rheumatology (Preauthorization Required)

Policy CodePolicy M.83

Change TypeNo material change

Effective DateMay 1, 2026

Next Review DateJan 1, 2027

Key ActionObtain preauthorization for specialty immunology and rheumatology tests; follow CMS NCD/LCD guidance when applicable.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

requiredPrior authorization

1-timePrismRA frequency

insufficientSLE algorithmic tests

multipleTest groups listed

appliesNCD/LCD precedence

Coverage Criteria for Immunology and Rheumatology Tests

HLA-DQ Genotyping Analysis

HLA-DQA1 and HLA-DQB1 genotyping analysis to rule out celiac disease may be considered reasonable and necessary when ALL of the following are met:

HLA-DQ genotyping for celiac rule-out: A. The member is being evaluated for celiac disease AND B. The member meets at least one of: 1) had an inconclusive serology (antibody) result OR 2) had an inconclusive histology (biopsy) result OR 3) started a gluten free diet before evaluation for celiac disease AND C. HLA-DQA1 and HLA-DQB1 genotyping analysis has not been previously performed.

If these conditions are not met, test is considered not reasonable and necessary.

Periodic Fever Syndrome Multigene Panel

Genetic testing for periodic fever syndromes via multigene panel may be considered reasonable and necessary when ALL of the following are met:

Periodic fever panel: A. The member has three or more episodes of unexplained fever in a six-month period, occurring at least seven days apart, AND B. Common causes of fever have been ruled out, including viral or bacterial infection.three or more episodes in six months

If criteria are not met, testing is not reasonable and necessary.

Evidence-Based Rheumatoid Arthritis Algorithmic Tests (PrismRA)

Rheumatoid arthritis algorithmic test (PrismRA) may be considered reasonable and necessary a maximum of one time for therapeutic selection when ALL of the following are met:

PrismRA for TNFi therapy selection: A. Member age >=18 AND B. Diagnosis of moderately to severely active RA AND C. Previously received first-line csDMARD therapy AND D. Unresponsive/refractory or intolerant to the therapy despite a therapeutic dose AND E. Either 1) has not yet initiated a biologic/targeted synthetic therapy OR 2) has initiated a biologic/targeted synthetic therapy and is unresponsive/refractory or intolerant to a therapeutic dose.one-time maximum

PrismRA is limited to selection of TNF inhibitors per criteria; other uses are considered not reasonable and necessary. CMS MolDX LCD L39424 eligibility elements apply for biomarker-guided targeted therapy selection.

Not Reasonable and Necessary Algorithmic Tests

Certain algorithmic tests are considered not reasonable and necessary:

Not covered algorithmic tests: Rheumatoid arthritis algorithmic tests with insufficient evidence of clinical validity (e.g., Vectra) and systemic lupus erythematosus diagnostic and prognostic algorithmic tests (e.g., AVISE-Lupus, SLE-key® Rule Out, aiSLE DX®) are considered not reasonable and necessary for all indications.

Requests for these tests should be denied.

Other Covered Immune, Autoimmune, and Rheumatoid Disorders

Genetic or targeted biomarker testing to establish or confirm select rare immune, autoimmune, or rheumatic disorders may be considered reasonable and necessary when ALL of the following are met:

Other covered immune/genetic disorders: The member demonstrates clinical features consistent with the specific disorder listed (examples include BTK for X-linked agammaglobulinemia; FAS for ALPS; CYBA/CYBB/NCF genes for CGD; PRF1/STX11/STXBP2/UNC13D for familial HLH; STAT3 for HIES; CD40LG for Hyper IgM; IL2RG for SCID; WAS for Wiskott-Aldrich; CXCR4 for WHIM; CD18/Kindlin-3/ITGB2 for LAD; NEMO/IKKG for NEMO deficiency).

Clinical features and resources such as GeneReviews/OMIM may be referenced to support testing.

HLA-DQ genotyping for celiac disease

Covered when used in select clinical scenarios per guideline guidance

HLA-DQ genotyping indications: Genetic testing for CD-compatible HLA haplotype may be used when there is serology-histology discrepancy or when the individual has already started a gluten-free diet before evaluation; a negative result effectively rules out celiac disease.

ACG and AGA guidance support limited/second-line use.

ANA and ANA subserology testing

Covered when testing aligns with clinical suspicion and guideline recommendations

ANA initial testing: ANA testing is indicated as an initial screen when there is a high clinical suspicion of connective tissue disease (e.g., SLE, dermatomyositis, Sjögren, mixed/connective tissue disorders).

ACR/EULAR define positive ANA as required entry for SLE classification; avoid testing in low pre-test probability settings.

ANA subserology testing: Autoantibody subserologies (e.g., anti-dsDNA, anti-Smith, Sjögren antibodies, anti-CCP, RF) should be ordered based on specific clinical findings and generally only following a positive ANA when further evaluation is indicated; routine or serial ANA testing without specific clinical indication is discouraged.

Choosing Wisely and specialty guidance recommend against indiscriminate testing due to false positives and limited utility.

RA molecular biomarker testing for targeted therapy selection

Coverage aligned with CMS MolDX LCD L39424 requirements

Eligibility for RA biomarker testing: All CMS LCD conditions must be met, including age >=18, confirmed moderate-to-severe RA, failure/intolerance/contraindication to first-line therapy at adequate dosing, and consideration of b/tDMARD initiation or change due to treatment failure or intolerance.

Reference CMS LCD L39424; prior therapeutic trial and failure/intolerance of first-line RA therapy is required.

SLE diagnostic and prognostic algorithmic tests

Not covered due to insufficient evidence

Algorithmic SLE tests: Tests such as AVISE-Lupus, SLE-key® Rule Out, aiSLE DX® Flare Risk Index, or aiSLE DX® are not supported for coverage because published evidence is insufficient to demonstrate improved health outcomes; conflicts of interest in available studies further limit reliability.

Concert Evidence Review concluded insufficient evidence; these tests are excluded from coverage.

The policy identifies specific molecular, genetic, and algorithmic tests that are not reasonable and necessary when used outside the indications described. Examples include HLA-DQA1/DQB1 genotyping when used for indications other than to help rule out celiac disease, multigene periodic fever panels when clinical criteria are not met, and algorithmic rheumatoid arthritis or systemic lupus erythematosus panels lacking evidence of clinical validity. Requests for tests defined as not reasonable and necessary will be denied if documentation does not demonstrate the required clinical criteria are met.

Use of covered tests is limited to the clinical scenarios and thresholds specified elsewhere in the policy; testing performed outside those specified criteria is considered not reasonable and necessary and therefore not medically necessary.

Systemic lupus erythematosus diagnostic and prognostic algorithmic tests (for example, AVISE‑Lupus, SLE‑key® Rule Out, aiSLE DX® and similar PLA/algorithmic assays) are explicitly not covered for all indications due to insufficient evidence demonstrating improved health outcomes and concerns about conflicts of interest in available clinical utility studies.

Requests for coverage of these SLE algorithmic diagnostic or prognostic tests should be denied; alternative evaluation should follow standard clinical assessment and guideline‑recommended testing.

These medical policies are developed to guide benefit administration and reflect evidence‑based coverage determinations; however, they do not constitute authorization, certification, or a contract for benefits. Benefits for a particular service are determined by the member’s applicable benefit contract and plan terms.

Preauthorization is required for specialty immunology and rheumatology testing described in this policy; meeting policy medical necessity criteria does not by itself guarantee coverage where contractual exclusions or plan limits apply.

Use of tests listed in this policy outside the specific clinical criteria identified (for example, HLA‑DQ genotyping when criteria for celiac disease rule‑out are not met; periodic fever multigene panels when fever episode thresholds are not satisfied; or algorithmic RA/SLE panels for unsupported indications) is considered not reasonable and necessary and therefore not medically necessary.

Providers should document clinical evidence meeting the stated criteria before ordering these specialty tests to avoid denials related to out‑of‑criteria use.

Antinuclear antibody (ANA) testing and extensive autoantibody panels should not be performed indiscriminately. ANA testing is intended as an initial screen when there is a high clinical suspicion for a connective tissue disease; routine or serial ANA measurements without specific clinical indication are discouraged.

Performing ANA or broad autoantibody panels in patients with low pre‑test probability (for example, nonspecific symptoms such as isolated fatigue, myalgia, or fibromyalgia) can lead to false positives and unnecessary downstream testing and may be considered not medically necessary.

Procedure and PLA Codes

Celiac HLA-DQ Genotyping reference codesmixed

81375	HLA-DQ genotyping (listed in reference table)
81376	HLA-DQ genotyping (listed in reference table)
81377	HLA-DQ genotyping (listed in reference table)
81382	HLA-DQ genotyping (listed in reference table)
81383	HLA-DQ genotyping (listed in reference table)
K90.0	Celiac disease diagnosis code (listed in reference table)
R10.0-R10.13	Abdominal pain codes (listed in reference table)
R10.3-R10.829	Abdominal pain codes (listed in reference table)
R10.84-R10.9	Abdominal pain codes (listed in reference table)

Periodic fever multigene panel reference codesmixed

81404	Multigene panel (listed for periodic fever syndromes and other panels)
81479	Miscellaneous molecular pathology (listed for periodic fever syndromes)
M04.1	Diagnosis code referenced in periodic fever panel row
R50.9	Fever, unspecified
A68.9	Diagnosis code referenced in periodic fever panel row

Rheumatoid arthritis and SLE algorithmic test codesmixed

81599	Unlisted molecular pathology (PrismRA referenced)
81490	Protein-based multiplex assay (Vectra referenced)
0062U	SLE-key Rule Out (listed)
0312U	Avise Lupus (listed)
0446U	aiSLE DX Disease Activity Index (listed)
0447U	aiSLE DX Flare Risk Index (listed)

Other covered immune/autoiummune/rheumatoid disorder molecular codesCPT

81400	Tiered molecular pathology code listed under other covered immune disorders
81401	Tiered molecular pathology code listed under other covered immune disorders
81402	Tiered molecular pathology code listed under other covered immune disorders
81403	Tiered molecular pathology code listed under other covered immune disorders
81404	Tiered molecular pathology code listed under other covered immune disorders
81405	Tiered molecular pathology code listed under other covered immune disorders
81406	Tiered molecular pathology code listed under other covered immune disorders
81407	Tiered molecular pathology code listed under other covered immune disorders
81408	Tiered molecular pathology code listed under other covered immune disorders

Quick Code Search / Procedure entry guidanceneutral

No codes listed

CPT-PLA — PLA examples including autoimmune PLA codesmixed

0062U	Autoimmune (systemic lupus erythematosus), IgG and IgM analysis of 80 biomarkers, algorithm reported with a risk score
0312U	Autoimmune diseases (eg, SLE), analysis of 8 IgG autoantibodies and 2 cell-bound complement activation products with algorithmic SLE-likelihood assessment

HLA Class II typingCPT

81375	HLA II LOW RESOLUTION HLA-DRB1/3/4/5 AND -DQB1
81376	HLA CLASS II TYPING LOW RESOLUTION ONE LOCUS EA
81377	HLA II LOW RESOLUTION ONE ANTIGEN EQUIVALENT EA
81382	HLA CLASS II TYPING HIGH RESOLUTION ONE LOCUS EA
81383	HLA II HIGH RESOLUTION 1 ALLELE/ALLELE GROUP

Molecular pathology procedure levelsCPT

81400	MOLECULAR PATHOLOGY PROCEDURE LEVEL 1
81401	MOLECULAR PATHOLOGY PROCEDURE LEVEL 2
81402	MOLECULAR PATHOLOGY PROCEDURE LEVEL 3
81403	MOLECULAR PATHOLOGY PROCEDURE LEVEL 4
81404	MOLECULAR PATHOLOGY PROCEDURE LEVEL 5
81405	MOLECULAR PATHOLOGY PROCEDURE LEVEL 6
81406	MOLECULAR PATHOLOGY PROCEDURE LEVEL 7
81407	MOLECULAR PATHOLOGY PROCEDURE LEVEL 8

Molecular pathology levels — single-level CPTCPT

81407

MOLECULAR PATHOLOGY PROCEDURE LEVEL 8

Molecular pathology levels — additional single-level CPTCPT

81408

MOLECULAR PATHOLOGY PROCEDURE LEVEL 9

Unlisted and specialized assay CPTsCPT

81479	UNLISTED MOLELCULAR PATHOLOGY PROCEDURE
81490	AUTOIMMUNE RHEUMATOID ARTHRTS ANALYS 12 BIOMRKRS
81599	UNLISTED MULTIANALYTE ASSAY ALGORITHMIC ANALYSIS

Periodic fever episode count

Required episode frequencyThree or more episodes of unexplained fever within a six‑month period, occurring at least seven days apart

Prior Authorization, Documentation, and Operational Notes

Prior Authorization

Obtain prior authorization for specialty immunology/rheumatology tests

Preauthorization is required for MA specialty immunology and rheumatology testing; when a Medicare NCD/LCD exists it takes precedence and must be met first.

Prior Authorization

Ensure RA biomarker requests meet CMS LCD eligibility

Requests for molecular biomarker testing to guide targeted therapy selection in rheumatoid arthritis must meet all CMS LCD L39424 eligibility elements (e.g., adult ≥18, confirmed moderate-to-severe RA, and prior adequate first-line therapy failure/intolerance).

Prior Authorization

Submit prior auth for listed PLA/CPT codes

Preauthorization is required for the specialty tests listed in this policy; enter the procedure code from the policy (PLA/CPT) when requesting prior authorization.

Background and Scope

This policy covers specialty testing used to diagnose or exclude celiac disease (HLA‑DQA1/DQB1 genotyping), evaluate hereditary periodic fever syndromes (multigene panels), consider evidence‑based algorithmic testing to guide rheumatoid arthritis therapy selection (PrismRA), and assess or confirm select rare immune, autoimmune, and rheumatic genetic disorders. Each covered test group is associated with defined clinical criteria and, where applicable, usage limits (for example, PrismRA: one‑time maximum for TNF inhibitor selection).

Tests and algorithmic panels for systemic lupus erythematosus are reviewed separately and are currently not supported for coverage due to insufficient evidence; other covered tests require documentation that meets the policy’s specified clinical thresholds and guideline‑aligned indications.

Definitions

Unexplained fever (FUO) — Definition and clinical context

Definition (FUO)Fever of unknown origin: temperature > 38.3 C (100.9 F) lasting more than three weeks with no obvious source despite appropriate investigation

Signs or symptoms of autoimmune/systemic rheumatic disease and myositis — Multisystem manifestations summary

Multisystem manifestationsMay include musculoskeletal (joint pain/swelling, morning stiffness, muscle weakness), cardiopulmonary (pericarditis, interstitial lung disease, pulmonary hypertension), hematologic (leukopenia, thrombocytopenia, hemolysis), dermatologic (alopecia, oral ulcers, malar or discoid rash), neuropsychiatric (delirium, psychosis, seizures), and renal dysfunction (proteinuria, nephritis)

Myositis overlap featuresMuscle weakness, elevated muscle enzymes (CK), interstitial lung disease, inflammatory arthritis, characteristic skin findings (heliotrope rash, mechanic’s hands), nailfold capillary changes, Raynaud phenomenon

Unexplained fever (fever of unknown origin, FUO) — Temperature and duration threshold

Policy Summary

PayerBlue Cross Blue Shield - Nebraska

PolicyMA Specialty Testing: Immunology and Rheumatology (Preauthorization Required)

Policy CodePolicy M.83

Change TypeNo material change

Effective DateMay 1, 2026

Next Review DateJan 1, 2027

Key ActionObtain preauthorization for specialty immunology and rheumatology tests; follow CMS NCD/LCD guidance when applicable.

SourceLink

On This Page

Prior Authorization

Include molecular pathology CPTs on prior authorization

Preauthorization is required for the molecular pathology procedures enumerated in the policy (including CPTs such as 81407, 81408, 81479, and 81490); include these CPTs on authorization requests.

Include CPTs 81407, 81408, 81479, 81490 (and 81599 where applicable) on the prior authorization request.

Step Therapy

Limit PrismRA to one-time TNFi therapy selection

PrismRA may be authorized a maximum of one time to guide selection of a TNF inhibitor after the member has failed or is intolerant to first-line csDMARD therapy and other criteria are met.

Limit authorization to one-time use for TNFi therapeutic selection per policy criteria.

Step Therapy

Document prior csDMARD trial and failure/intolerance for RA testing

Before ordering RA biomarker testing, document prior therapeutic trial and failure or intolerance of first-line conventional synthetic DMARD therapy at adequate dosing as required by CMS LCD guidance.

Provide documentation of first-line csDMARD trial, dosing, and reason for discontinuation (failure, intolerance, or contraindication).

Note

Provider action placeholder

This policy inventory placeholder is retained for completeness; follow applicable prior authorization and documentation rules in the policy when submitting requests.

Note

Provider action placeholder

This policy inventory placeholder is retained for completeness; ensure required code/diagnosis pairing and documentation per policy when requesting tests.

Documentation Required

Attach clinical documentation supporting medical necessity

Clinical documentation submitted with the authorization request must support the specific medical necessity criteria for the test (e.g., inconclusive serology or biopsy or prior gluten-free diet for HLA‑DQ genotyping; three or more unexplained fevers in six months for periodic fever panels; prior csDMARD failure and RA severity for PrismRA).

Documentation Required

Reference guideline-directed indications in justification

Justification should reference guideline-directed indications where applicable (e.g., ACG/AGA for HLA‑DQ genotyping in celiac disease, ACR/EULAR/AAFP guidance for ANA and subserology testing).

Billing Rule

Enter procedure + diagnosis (≥3 characters) in Quick Code Search

When using the Quick Code Search, enter both a procedure and a diagnosis; type at least the first three characters of each code to add the code pair.

Enter a procedure code first, then a diagnosis code, then click 'Add Code Pair'.
Provide at least the first 3 characters of each code for search entry.

Documentation Required

Align submission documentation with policy committee requirements

Medical policy documentation is used to administer plan benefits; documentation submitted for authorization should align with the policy committee requirements and clinical literature cited in the policy.

Denial Risk

Expect denial when test is outside policy-defined indications

Requests for tests that the policy defines as not reasonable and necessary (for all indications) will be denied — examples include HLA‑DQA1/DQB1 genotyping outside listed celiac rule-out indications, periodic fever panels when criteria are unmet, and SLE algorithmic or certain RA algorithmic tests with insufficient evidence.

If the specific coverage criteria are not met, do not expect authorization—these requests are denial triggers.

Denial Risk

Do not order SLE algorithmic panels for coverage

Systemic lupus erythematosus algorithmic panels (e.g., AVISE‑Lupus, SLE‑key® Rule Out, aiSLE DX®) are not supported for health plan coverage due to insufficient evidence and will be denied.

Billing Rule

Enter complete procedure + diagnosis code pair for automated approval

Failure to enter the required procedure/diagnosis code pair (or leaving the pair incomplete) may prevent automated approval via Quick Code Search and could result in denied or held requests.

Denial Risk

Obtain preauthorization to avoid claim denial

Lack of required preauthorization for specialty immunology and rheumatology tests under this policy may result in claim denial; obtain prior authorization before performing listed specialty tests.

Temperature threshold> 38.3 C (100.9 F)

Duration thresholdLasting more than three weeks with no obvious source despite appropriate investigation

Differential categoriesInfections, malignancies, autoimmune conditions, and miscellaneous (classic, nosocomial, immune deficient, HIV‑related subgroups)

Signs or symptoms of autoimmune/systemic rheumatic disease — Examples of syndromic presentations

Syndromic presentationsMay represent SLE, systemic sclerosis, dermatomyositis/polymyositis, Sjögren syndrome, rheumatoid arthritis, or mixed/undifferentiated connective tissue disease

Common signsPolyarthritis/synovitis, morning stiffness, muscle weakness, interstitial lung disease, rashes, oral ulcers

Signs or symptoms of myositis — Clinical features and laboratory findings

Clinical featuresMuscle weakness, inflammatory arthritis, characteristic dermatologic eruptions (eg, heliotrope rash, mechanic’s hands), nailfold capillary abnormalities, Raynaud phenomenon

Laboratory findingsElevated muscle enzymes, especially creatine kinase (CK)

Synovitis — Definition and presenting features

DefinitionInflammation of the synovial membrane (joint lining)

Presenting featuresJoint pain, stiffness, swelling, erythema, and/or warmth

0062U — PLA code description for autoimmune SLE algorithmic assay

0062U descriptionAutoimmune (systemic lupus erythematosus), IgG and IgM analysis of 80 biomarkers, utilizing serum, algorithm reported with a risk score

Intended use noteAlgorithmic assay reports an overall risk score based on analysis of multiple biomarkers

0312U — PLA code description for autoimmune algorithmic assay

0312U descriptionAutoimmune diseases (eg, systemic lupus erythematosus), analysis of 8 IgG autoantibodies and 2 cell‑bound complement activation products; individual components reported along with an algorithmic SLE‑likelihood assessment

Assay modalitiesUses ELISA, flow cytometry, and indirect immunofluorescence on serum, plasma, and whole blood

CPT 81490 description — RA multibiomarker CPT description as listed

81490 descriptionAutoimmune (rheumatoid arthritis), analysis of 12 biomarkers using immunoassays, utilizing serum; prognostic algorithm reported as a disease activity score

Context of useListed as the CPT for RA multibiomarker/prognostic algorithmic assays (eg, Vectra) in the policy coding section