Cg Immune.Auto.Ra.Do 2025.1

Coverage Summary & Scope

Scope: This policy defines medical necessity and investigational determinations for genetic and biomarker tests for immune, autoimmune, and rheumatoid disorders, including periodic fever multigene panels (example CPTs 81404, 81479), multibiomarker disease activity (MBDA) panels for rheumatoid arthritis (example CPT 81490), the PrismRA TNFi treatment response algorithmic test (PLA 0456U), HLA-B27 typing (CPT 81374), and other gene-based tests to establish or confirm specific immune/rheumatic diagnoses. Intended uses addressed include establishing or confirming diagnoses for genetic immune disorders, and predicting treatment response or guiding therapy selection in rheumatoid arthritis.

Background overview: Immunodeficiency disorders may be primary (typically genetic, often presenting at birth though sometimes recognized in adulthood) or secondary (more common, acquired from drugs, cancer, metabolic disease, or infections). Genetic testing is used to establish or confirm diagnoses of primary immune and other rare immune/rheumatic disorders to guide management. In rheumatoid arthritis, molecular biomarker tests have been developed to objectively measure disease activity (MBDA) and to predict response to targeted therapies; the policy addresses MBDA panels (considered investigational) and algorithmic predictive tests such as PrismRA (covered with criteria). Overall coverage stance across the tests is mixed: some gene-based diagnostic tests and PrismRA are covered with criteria, MBDA panels are not covered/investigational, and periodic fever panels and other listed genetic tests are covered when criteria are met.

Surface thresholds and quick facts

Periodic fever episode frequencyThree or more episodes of unexplained fever in a 6-month period, occurring at least 7 days apart

Fever temperature/time definition (FUO)Temperature >38.3 C (100.9 F) lasting more than three weeks with no obvious source despite appropriate investigation

Genes / conditions listed (example)13 specific genes/conditions listed in 'Other Covered' list (e.g., BTK, FAS, CYBA, CYBC1, NCF1, NCF2, NCF4, CYBB, ELANE, HAX1, PRF1, STX11, STXBP2, UNC13D, STAT3, CD40LG, CD18, IL2RG, CXCR4, WAS) — policy lists 13 in stats summary

Discrete coverage categories3 coverage categories highlighted: Periodic Fever Multigene Panels (medically necessary with criteria vs investigational), MBDA panels (investigational), Rheumatoid Arthritis TNFi algorithmic test (PrismRA) — covered with criteria

Representative CPT / PLA codesPeriodic fever panels: example CPT 81404, 81479; MBDA panels: CPT 81490 (investigational); PrismRA PLA code 0456U (now added and covered when criteria met)

Quick stat: new PLA codePLA code 0456U (PrismRA) added to Policy Reference Table and coverage changed to covered with criteria (aligned with CMS LCD)

Medical Necessity Criteria (grouped by test/criteria set)

Periodic Fever Syndromes Multigene Panel — Investigational

Considered investigational when ANY of the following apply:

ANY of the following

For all other indications not meeting the medically necessary criteria

Rheumatoid Arthritis TNFi Treatment Response Algorithmic Tests (PrismRA) — Investigational

Considered investigational when ANY of the following apply:

ANY of the following

For all other indications not meeting the medically necessary criteria

Coding (grouped by coverage status)

Periodic Fever Syndromes Multigene Panel — Example CPT codesCPTCovered

81404	Periodic Fever Syndromes multigene panel (example code listed in policy text)
81479	Unlisted molecular pathology code (example listed)
81406	Referenced in policy header/series (example listed)
81407	Referenced in policy header/series (example listed)
81408	Referenced in policy header/series (example listed)

Rheumatoid Arthritis Biomarker Activity PanelsCPTNot Covered

81490

Multibiomarker disease activity (MBDA) panels (e.g., Vectra) — considered investigational per policy

Rheumatoid Arthritis TNFi Treatment Response Algorithmic TestsCPT

0456U

PrismRA (PLA code) — covered when specified criteria are met (age >=18, moderately to severely active RA, prior csDMARD failure/intolerance, TNFi initiation status, no prior molecular biomarker predictive testing)

HLA Typing for Axial SpondyloarthritisCPT

81374

HLA-B27 typing — covered when clinical or radiographic features of axial spondyloarthritis are present

Other Covered Immune/Autoimmune/Rheumatoid Disorders — Example CPT codesCPTCovered

81400	Example listed in 'Other Covered' category
81401	Example CPT added to Policy Reference Table
81402	Example CPT added to Policy Reference Table
81403	Example CPT added to Policy Reference Table
81404	Also appears in Periodic Fever group (example)
81405	Example CPT added to Policy Reference Table
81406	Example CPT added to Policy Reference Table / referenced in policy
81407	Example CPT added to Policy Reference Table / referenced in policy

Provider Actions & Documentation Requirements

Prior Authorization

Prior authorization likely required per plan policy

Prior authorization may be required by the member's health plan before ordering testing. Follow the health plan's prior authorization procedures and obtain any required approvals prior to testing to avoid claim denials or delays.

Documentation Required

Document recurrent fever episodes and rule-out workup

Document episodes of recurrent/unexplained fever and the diagnostic workup to support medical necessity for periodic fever multigene panels.

Affected CPT codes: 81404, 81479
Required documentation: Three or more episodes of unexplained fever in a 6-month period, occurring at least 7 days apart
Required documentation: Evidence that common causes have been ruled out (e.g., viral or bacterial infection, immunodeficiency, malignancy, inflammatory bowel disease, adverse drug reactions)

Background & Evidence

Primary versus secondary immunodeficiency and role of genetic testing: The policy notes two types of immunodeficiency—primary (rare, usually genetic/hereditary, sometimes presenting in adulthood) and secondary (more common, acquired due to drugs, cancer, diabetes, HIV, etc.). Genetic testing is appropriate to establish or confirm diagnoses of primary immune disorders and other less common immune/rheumatic conditions when clinical features are present, and such testing can guide management.

Molecular biomarkers in rheumatoid arthritis and guideline positions: Multibiomarker disease activity (MBDA) tests are defined as validated serum biomarker approaches to objectively measure RA disease activity; however, the American College of Rheumatology (ACR) 2019 guideline lists the original Vectra DA among disease activity measures but identifies insufficient evidence to support MBDA panels for treatment decisions (no recommendations for or against use to guide therapy). In contrast, the Centers for Medicare & Medicaid Services Local Coverage Determination (MolDX LCD L39424) provides explicit coverage criteria for molecular biomarker testing to guide targeted therapy selection in RA and served as the basis for changing PrismRA (PLA 0456U) coverage status from non-covered to covered with criteria in this policy. These guideline and Medicare positions informed the policy's determinations: MBDA panels (CPT 81490) are considered investigational, while PrismRA is covered when the specified criteria are met.

Citation	Key point
Soon and Laxer 2017	Recurrent/periodic fever syndromes defined as ≥3 episodes in 6 months at least 7 days apart; consider autoinflammatory diseases after ruling out infections, immunodeficiency, malignancy, inflammatory bowel disease, and drug reactions.
ACR 2019	Lists Multibiomarker Disease Activity (MBDA/Vectra) among accepted disease activity measures but notes limited/insufficient evidence to support MBDA panels for guiding treatment decisions.
CMS LCD L39424	Provides coverage criteria for molecular biomarker testing to guide targeted therapy selection in rheumatoid arthritis and served as basis for PrismRA (0456U) coverage change.

Definitions / Quick lookup

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

Medicare Determinations

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

Revision History

11/2024material_changeLatest

Approval Date 11/24: Rheumatoid Arthritis TNFi Treatment Response Algorithmic Tests (PrismRA) coverage status changed from non-covered to covered based on alignment with CMS LCD L39424; PLA code 0456U added to Policy Reference Table.

11/2024material_changeLatest

HLA-B27 criterion removal/clarification: Removed requirement that HLA-B27 results establish a diagnosis of axial spondyloarthritis and reworded criteria for clarity (HLA-B27 testing remains covered with criteria when clinical or radiographic features of axial spondyloarthritis are present).