CurrentCentenePolicy N/A

Genetic Testing for Immune Autoimmune Rheumatoid Disorders (PDF)

Defines medical necessity criteria for specific genetic and biomarker tests for immune, autoimmune, and rheumatoid disorders (including periodic fever multigene panels, RA biomarker panels, RA TNFi algorithmic tests, HLA-B27 typing, and other gene-based diagnostic testing) and identifies investigational uses.

Policy Summary

PayerCentene

PolicyGenetic Testing for Immune Autoimmune Rheumatoid Disorders (PDF)

Policy CodePolicy N/A

Change TypeRevisions (coverage and criteria updates)

Effective Date

Next Review Date

Key ActionDocument recurrent fever episodes and exclusion of common causes; follow plan-specific prior authorization procedures and document required clinical and therapeutic history for PrismRA (0456U).

SourceLink

POLICY UPDATE CHANGES

Rheumatoid Arthritis TNFi Treatment Response Algorithmic Tests: Coverage status changed from non-covered to covered based on LCD guidelines; PLA code 0456U added to Policy Reference Table.

Rheumatoid Arthritis Biomarker Activity Panels: streamlined background/rationale and references updated; MBDA (81490) remains considered investigational.

HLA Typing for Axial Spondyloarthritis: Removed requirement that HLA-B27 results be required to establish diagnosis and reworded criteria for clarity; added/clarified gene lists for other disorders.

3Fever episodes threshold

81404,81479,81490,0456U,81374Key CPT/PLA codes referenced

11/2024

Date of last revision

Coverage Summary

This policy addresses genetic and biomarker testing for immune, autoimmune, and rheumatoid disorders, defining medical necessity criteria for specific tests (e.g., multigene panels for periodic fever syndromes, algorithmic RA predictive tests, MBDA panels, and HLA-B27 typing) and identifying investigational uses. Last review: 11/2024.

Covered when criteria met: Periodic fever multigene panels (CPT 81404, 81479) are medically necessary for recurrent unexplained fevers meeting the policy threshold; PrismRA algorithmic test (PLA 0456U) is covered for adults with moderately-to-severely active RA who meet the specified prior-therapy and response/intolerance criteria. Considered investigational: MBDA panels (CPT 81490) for guiding RA treatment and any other uses not meeting stated criteria.

Other covered testing includes HLA-B27 typing (CPT 81374) for patients with clinical or radiographic features of axial spondyloarthritis and targeted genetic testing to establish or confirm diagnoses for specified primary immunodeficiency and related disorders when clinical features are present.

Quick Facts / Thresholds

Recurrent Fever EpisodesThree or more episodes of unexplained fever in a six-month period, occurring at least seven days apart

Unexplained fever (FUO) definitionTemperature >38.3 C (100.9 F) lasting more than three weeks with no obvious source despite appropriate investigation

Date of last revision11/2024

Medical Necessity Criteria (detailed trees)

Periodic Fever Syndromes Multigene Panel - Medically Necessary

Genetic testing for periodic fever syndromes via multigene panel (81404, 81479) is medically necessary when ALL of the following are met:

ALL of the following

The member/enrollee has three or more episodes of unexplained fever in a six-month period, occurring at least seven days apart
Policy references Soon and Laxer (2017) definition
Common causes of fever have been ruled out, including viral or bacterial infection
Document later lists that infections, immunodeficiency, malignancy, inflammatory bowel disease, and adverse drug reactions should be ruled out before considering autoinflammatory diseases

Periodic Fever Syndromes Multigene Panel - Investigational

Genetic testing for periodic fever syndromes (81404, 81479) is considered investigational when the medically necessary criteria above are NOT met (i.e., for all other indications).

Coding

Periodic Fever Syndromes Multigene Panel - Common CPT codes (examples)CPTCovered

81404	Molecular pathology multigene panel, specified
81479	Unlisted molecular pathology procedure
81406	Add-on codes referenced in document (listed in text)
81407	Add-on codes referenced in document (listed in text)
81408	Add-on codes referenced in document (listed in text)

Rheumatoid Arthritis Biomarker Activity PanelsCPTNot Covered

81490

Multianalyte algorithmic assay with algorithmic report (e.g., Vectra)

Rheumatoid Arthritis TNFi Treatment Response Algorithmic TestsCPT|PLACovered

0456U

PrismRA algorithmic test (PLA code)

HLA Typing for Axial SpondyloarthritisCPTCovered

81374

HLA-B27 DNA typing

Other Covered Immune/Autoimmune/Rheumatoid - example CPT codesCPTCovered

81400	Molecular pathology procedure, target-specific sequencing (example listed)
81401	Molecular pathology procedure (example listed)
81402	Molecular pathology procedure (example listed)
81403	Molecular pathology procedure (example listed)
81404	Molecular pathology multigene panel (also listed above)
81405	Molecular pathology procedure (example listed)
81406	Molecular pathology procedure (add-on example listed)
81407	Molecular pathology procedure (add-on example listed)

Provider Actions & Billing Impact

Prior Authorization

Prior authorization likely required per Health Plan

Prior authorization likely required per Health Plan. As this is a Centene clinical policy, tests governed by this policy (including multigene panels, algorithmic tests, and HLA typing) are subject to the Health Plan's medical necessity review and prior authorization processes. Providers should follow plan-specific prior authorization procedures when submitting claims for these tests.

Follow the Health Plan's prior authorization process for genetic and biomarker testing governed by this policy
Submit documentation supporting medical necessity per the policy criteria when requesting prior authorization

Documentation Required

Document recurrent fever episodes and exclusion of common causes

Document recurrent fever episodes and exclusion of common causes. For coverage of periodic fever multigene panels (e.g., CPT 81404, 81479), providers must document at least three episodes of unexplained fever within a six-month period occurring at least seven days apart and show that common causes have been ruled out (for example viral or bacterial infection, immunodeficiency, malignancy, inflammatory bowel disease, and adverse drug reactions). Reference Soon & Laxer (2017) for the ≥3 episodes/6-months and exclusion recommendations.

Background and Evidence

Rationale: Genetic testing helps distinguish primary (inherited) from secondary immunodeficiency and can establish or confirm diagnoses that guide management for rare, genetically associated immune disorders. The policy notes that primary disorders are often genetic and may present at birth or in adulthood, whereas secondary disorders arise from drugs or comorbid conditions.

For periodic/recurrent fever syndromes, genetic multigene panels are indicated after common causes (infections, immunodeficiency, malignancy, inflammatory bowel disease, drug reactions) are excluded and when the criterion of three or more unexplained fever episodes in six months, ≥7 days apart is met (Soon & Laxer 2017).

Regarding rheumatoid arthritis, multibiomarker disease activity (MBDA) tests are defined as serum biomarker scores but the ACR and the policy conclude there is insufficient evidence to support MBDA use to guide RA treatment decisions (MBDA/CPT 81490 considered investigational). By contrast, algorithmic molecular tests to predict TNFi response (e.g., PrismRA) follow CMS LCD L39424 coverage-aligned criteria for adults with moderately-to-severely active RA and prior csDMARD failure/intolerance.

Citation	Key point
Soon & Laxer 2017	Defines recurrent/periodic fever as ≥3 episodes in 6 months occurring ≥7 days apart and recommends ruling out infections, immunodeficiency, malignancy, IBD, and adverse drug reactions before considering autoinflammatory diseases.
CMS LCD L39424	Provides coverage criteria for molecular biomarker testing to guide targeted therapy selection in RA: adult with moderately to severely active RA; failure/contraindication/intolerance to at least one csDMARD; either has not initiated b/tDMARD or has initiated and is being considered for an alternate class after failure.
ACR 2019	Lists MBDA (Vectra) among RA disease activity measures but states evidence is insufficient to support MBDA use to aid RA treatment decisions per the policy.

Definitions

Multibiomarker disease activity (MBDA) testsA validated approach that uses serum biomarkers to objectively measure rheumatoid arthritis disease activity

Unexplained feverA fever of unknown origin (FUO): temperature >38.3 C (100.9 F) that lasts for more than three weeks with no obvious source despite appropriate investigation

Medicare Determinations

Name	Number	Type	Effective Date
MolDX: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis	L39424	LCD

Revision History

11/24material_revisionLatest

Rheumatoid Arthritis TNFi Treatment Response Algorithmic Tests: Coverage status changed from non-covered to covered based on LCD guidelines; PLA code 0456U added to Policy Reference Table.

11/24revisedLatest

Rheumatoid Arthritis Biomarker Activity Panels: Streamlined background/rationale and references updated; MBDA (81490) remains considered investigational.

11/24material_revision

Policy Summary

PayerCentene

PolicyGenetic Testing for Immune Autoimmune Rheumatoid Disorders (PDF)

Policy CodePolicy N/A

Change TypeRevisions (coverage and criteria updates)

Effective Date

Next Review Date

SourceLink

On This Page

Indication other than the criteria-defined recurrent unexplained fevers

Investigational for all other indications

Rheumatoid Arthritis Biomarker Activity Panels

Coverage stance for MBDA panels (81490):

Use of multibiomarker disease activity (MBDA) scores for rheumatoid arthritis (81490) is considered investigational

Rheumatoid Arthritis TNFi Treatment Response Algorithmic Tests (PrismRA)

Genetic algorithmic test (PrismRA, 0456U) coverage criteria — considered medically necessary when ALL of the following are met:

ALL of the following

The member/enrollee is age 18 or older
The member/enrollee has a diagnosis of moderately to severely active rheumatoid arthritis (RA)
The member/enrollee previously received first-line therapy for RA with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD)
The member/enrollee is unresponsive/refractory or intolerant to the csDMARD therapy despite a therapeutic dose
ONE of
- The member/enrollee has not yet initiated a biologic or targeted synthetic therapy (b/tDMARD) for RA (i.e., TNFi)
- The member/enrollee has initiated a biologic or targeted synthetic therapy (b/tDMARD) for RA (i.e., TNFi) and is unresponsive/refractory or intolerant to a therapeutic dose and consideration is for an alternate class
The member/enrollee has not had previous testing using molecular biomarkers for predictive therapy selection for rheumatoid arthritis

PrismRA - Investigational

PrismRA (0456U) is considered investigational for all other indications not covered by the above criteria.

Any indication not meeting the specified coverage criteria for PrismRA

HLA-B27 Typing for Axial Spondyloarthritis (81374)

HLA-B27 typing is medically necessary when the following are met:

The member/enrollee has clinical or radiographic features of axial spondyloarthritis

Clinical/radiographic features per ASAS criteria and supporting references (e.g., radiograph or MRI findings plus SpA features or HLA-B27 plus SpA features)

HLA-B27 Typing - Investigational

HLA-B27 typing (81374) is investigational for all other indications.

Any use not meeting the clinical or radiographic features criterion

Other Covered Immune, Autoimmune, and Rheumatoid Disorders - Diagnostic Genetic Testing

Genetic testing to establish or confirm diagnosis to guide management is medically necessary when the member/enrollee demonstrates clinical features consistent with the disorder. The list is not comprehensive.

Agammaglobulinemia: X-linked and autosomal recessive (BTK)

Autoimmune Lymphoproliferative Syndrome (ALPS) (FAS)

Chronic Granulomatous Disease (CGD) (CYBA, CYBC1, NCF1, NCF2, NCF4, CYBB)

Complement Deficiencies

Congenital Neutropenia Syndromes (e.g., ELANE-related neutropenia) (ELANE, HAX1)

Familial Hemophagocytic Lymphohistiocytosis (HLH) (PRF1, STX11, STXBP2, UNC13D)

Hyper IgE Syndrome (HIES) (STAT3)

Hyper IgM Syndromes (CD40LG)

Leukocyte Adhesion Deficiency (LAD) (CD18, Kindlin-3, ITGB2)

NEMO Deficiency Syndrome (NEMO / IKKG)

Severe Combined Immune Deficiency (SCID) and Combined Immune Deficiency (IL2RG)

WHIM Syndrome (CXCR4)

Wiskott-Aldrich Syndrome (WAS)

Other Genetic Testing Not Specified

Genetic testing to establish or confirm diagnosis of other immune, autoimmune, or rheumatoid disorders not specifically discussed will be evaluated per the General Approach to Genetic and Molecular Testing policy.

Uses not specifically addressed in this policy are reviewed under the General Approach to Genetic and Molecular Testing policy

Three or more unexplained fever episodes within a six-month period, occurring at least seven days apart
Documentation that infections, immunodeficiency, malignancy, inflammatory bowel disease (IBD), and adverse drug reactions have been ruled out
Reference supporting definition and recommendations: Soon & Laxer (2017)

Documentation Required

Document prior therapeutic history for PrismRA (0456U)

Document prior therapeutic history for PrismRA (PLA code 0456U). To meet coverage for PrismRA (0456U), providers must document that the patient is age 18 or older, has a diagnosis of moderately to severely active rheumatoid arthritis, previously received first-line csDMARD therapy with inadequate response or intolerance despite adequate dosing, and their biologic/targeted therapy status (either has not initiated a b/tDMARD such as a TNFi, or has initiated and is unresponsive/refractory or intolerant and consideration is for an alternate class). Also document that no prior molecular biomarker testing for predictive therapy selection for RA has been performed.

Age ≥ 18 years
Confirmed diagnosis of moderately to severely active rheumatoid arthritis
Prior adequate csDMARD therapy with inadequate response or intolerance despite therapeutic dosing
Biologic/targeted therapy (b/tDMARD) status: either not yet initiated OR initiated and failed/intolerant (considering alternate class)
No prior molecular biomarker testing for predictive therapy selection for rheumatoid arthritis

Denial Risk

Investigational use denial risk

Investigational use denial risk. Use of multibiomarker disease activity panels (MBDA) such as Vectra (CPT 81490) is considered investigational; claims for MBDA panels and other tests or uses designated investigational are at risk for denial when submitted for investigational indications. Avoid submitting claims for investigational indications or ensure supporting documentation demonstrates the indication meets medically necessary criteria in this policy.

Affected code: 81490 (MBDA / multianalyte algorithmic assays)
Do not submit claims for investigational indications without documentation demonstrating the indication meets policy medical necessity criteria

HLA Typing for Axial Spondyloarthritis: Removed requirement that HLA-B27 results be required to establish diagnosis and reworded criteria for clarity; added/clarified gene lists for other disorders.

04/24revised

Minor rewording for clarity throughout; moved known familial variant criteria to the General Approach policy and clarified condition names.

10/23revised

Semi-annual review: updated title to reflect V1.2024/V2.2024, updated coding and reference table entries (added multiple CPT codes to Other Covered Immune list).

03/23revised

Policy developed and approved; semi-annual review updates including title/versioning and background/rationale updates.