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Medicare Administrative Contractors (MACs)
Applicable States/Territories

Rheumatoid Arthritis: Biologic Markers and Pharmacologic Assessment

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• LCD Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis L39481 | J5, J8 - Wisconsin Physicians Service Insurance Corporation IA, IN, KS, MI, MO, NE
• LCD Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis L39427_ | J15-CGS Administrators, LLC KY, OH
• LCD Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis L39467_ | JE- Noridian Healthcare Solutions, LLC CA, HI, NV, American Samoa, Guam, Northern Mariana Islands
• LCD Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis L39469 | JF - Noridian Healthcare Solutions, LLC AK, AZ, ID, MT, ND, OR. SD. UT, WA, WY
• LCD Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis L39424 | JJ, JM - Palmetto GBA AL, GA, NC, SC, TN, VA, WV
• LCD Molecular Pathology Procedures L34519 | JN - First Coast FL, Puerto Rico,

Description

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that causes deterioration of the joints, inflammation, loss of mobility, pain and stiffness. RA affects multiple joints, most commonly the hands, wrists and other joints such as the elbows, feet, hips, knees, neck and shoulders.

Common laboratory tests used to diagnose and monitor treatment for RA include, but may not be limited to, anti-citrullinated peptide antibodies (anti- CCP or ACPA), C reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF) and serum IgM rheumatoid factor.

Testing has been developed or is in development to assist in diagnosing and guiding treatment decisions in RA which include, but may not be limited to, presence of autoantibodies to carbamylated proteins (eg, Avise Anti-CarP) and panel testing for RA (eg, RheumAssure) that evaluates many common tests (eg, RF, CCP and 14-3-3 eta) associated with RA simultaneously and have been proposed to aid in the diagnosis of RA.

Methotrexate (MTX), a disease modifying antirheumatic drug (DMARD), is known as the gold standard therapy for long term management in the treatment of RA alone or in combination with other medications (eg, hydroxychloroquine sulfate [Plaquenil]). Drug level testing (eg, Avise HCQ and Avise MTX) has been purported to determine how an individual metabolizes the drug and to guide dosing. Tumor necrosis factor (TNF-alpha) inhibitors, such as adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi and Simponi Aria) and infliximab (Remicade), are pharmacotherapeutic agents used for the treatment of many inflammatory conditions, including RA. Lab testing has been developed to try to identify the serum drug concentration and development of antibodies to tumor necrosis factor-alpha inhibitor (TNFi).

Rheumatoid Arthritis: Biologic Markers and Pharmacologic Assessment Page: 3 of 9

The test must be ordered by a physician who is treating the beneficiary and the results will be used in the management of a beneficiary’s specific medical problem. For jurisdictions with no Medicare guidance for a particular test, Humana will utilize the MolDX program and Technical Assessments for molecular assays as the standard to evaluate clinical utility, analytical and clinical validity in conjunction with adhering to Medicare’s reasonable and necessary requirement.

In interpreting or supplementing the criteria above and in order to determine medical necessity consistently, Humana may consider the following criteria:

• Molecular Biomarker Testing to guide targeted therapy selection in RA will be considered medically reasonable and necessary when the following requirements are met:
  • Individual is at least 18 years of age with a confirmed diagnosis of moderately to severely active RA; AND
  • Individual has a history of failure, contraindication, or intolerance to at least one first-line therapy for the treatment of RA (eg, conventional synthetic DMARDs [csDMARDs]) despite adequate dosing; AND
  • Individual has not initiated a biologic or targeted synthetic therapy (b/tDMARD) for RA (eg, TNFi, Janus Kinase [JAK] inhibitor) OR has initiated b/tDMARD therapy and is being considered for an alternate class of targeted therapies as a result of failure, contraindication, or intolerance to the initial targeted therapy despite adequate dosing; AND
  • The test predicts response and/or non-response to at least one class of targeted or biologic therapies for RA according to multiple validated response/remission criteria:
    • Accuracy that exceeds that which can be obtained from the combination of existing clinical and other data; AND
    • Demonstrated reproducibility across clinical study cohorts; AND
  • Testing using molecular biomarkers has not been previously performed for predictive therapy selection in RA; AND
  • If the test relies on an algorithm, the algorithm must be validated in a cohort that is not a development cohort for the algorithm; AND
  • The lab providing the test is responsible for clearly indicating to treating physicians the population and indication(s) for test use; AND
  • If applicable, performance characteristics are equivalent or superior to the average performance of other similar tests (for the same intended use) evaluated by this contractor upon successful completion of a technical assessment

Since the clinical utility of predictive testing is largely dependent upon consensus-based management recommendations, this policy is subject to change pending changes in the literature and in consensus guidelines. **New tests that become available with significantly improved performance may render older tests no longer compliant with this policy.

The use of the criteria in this Medicare Advantage Medical Coverage Policy provides clinical benefits highly likely to outweigh any clinical harms. Services that do not meet the criteria above are not medically necessary and thus do not provide a clinical benefit. Medically unnecessary services carry risks of adverse outcomes and may interfere with the pursuit of other treatments which have demonstrated efficacy.

Coverage Limitations

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US Government Publishing Office.

Electronic Code of Federal Regulations: Part 411

42 CFR § 411.15 - Particular Services Excluded from Coverage

The following tests may not be considered a benefit (statutory exclusion)16:

• Tests considered screening in the absence of clinical signs and symptoms of disease that are not specifically identified by the law; OR
• Tests that confirm a diagnosis or known information; OR
• Tests to determine risk for developing a disease or condition; OR
• Tests performed to measure the quality of a process; OR
• Tests without diagnosis specific indications; OR
• Tests identified as investigational by available literature and/or the literature supplied by the developer and are not a part of a clinical trial

These treatments and services fall within the Medicare program's statutory exclusion that prohibits payment for items and services that have not been demonstrated to be reasonable and necessary for the diagnosis and treatment of illness or injury (§1862(a)(1) of the Act). Other services/items fall within the Medicare program's statutory exclusion at 1862(a)(12), which prohibits payment.

The following services/items will not be considered medically reasonable and necessary:

• Genetic tests that have not demonstrated clinical utility, analytical and clinical validity via the MolDX Program; OR
• 14-3-3 eta protein; OR
• HLA typing in RA (81376); OR
• Levels of antibodies to adalimumab or infliximab (eg, Anser ADA and Anser IFX); OR
• Levels of hydroxychloroquine (eg, Avise HCQ); OR
• Levels of methotrexate polyglutamates (eg, Avise MTX); OR
• Panels for RA unless ALL components in the panel are relevant to the personal history of the individual being tested8 eg, RheumAssure; OR
• Presence of autoantibodies to carbamylated proteins (eg, Avise Anti-CarP)

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A review of the current medical literature shows that the evidence is insufficient to determine that this service is standard medical treatment for these indications. There remains an absence of randomized blinded clinical studies examining benefit and long-term clinical outcomes establishing the value of this service in clinical management for these indications.

Summary of Evidence

14-3-3 eta protein Serum 14-3-3 eta may be helpful diagnostically in RA as some data suggest that it may have similar sensitivity and specificity to RF and ACPA in distinguishing patients with RA from osteoarthritis, other autoimmune disorders, and healthy controls. However, in a cohort of patients with arthralgia, preselected for ACPA and/or RF positivity, the added predictive value of 14-3-3 eta could not be established.17

HLA typing in RA Evidence indicates genetic markers are not useful for diagnosis or screening of RA. Although certain HLA alleles are strongly associated with severe RA, these alleles are common in the normal carriage population.

Knowledge of a patient's HLA status and other genetic markers may be useful with further developments in diagnosis and screening, in estimating prognosis, and in predicting the response to specific therapies, but a role for HLA testing in RA outside the research setting has not been established.

Levels of antibodies to adalimumab, infliximab or drug concentration of hydroxychloroquine, methotrexate polyglutamates in the treatment of RA Limited evidence suggests in selected patients suspected of inadequate adherence to therapy, it is reasonable to perform measurement of MTX polyglutamates in those patients in whom this information would change the treatment strategy. No additional recommendations from professional organizations or the US Food & Drug Administration (FDA) prescribing information.

Autoantibodies to carbamylated proteins (eg, Avise Anti-CarP) The identification of both ACPAs and anti-carbamylated protein antibodies (anti-CarP Abs) has greatly facilitated approaches toward RA, especially in the fields of early diagnosis and prognosis prediction of the disease. Although these antibodies share many common features and can function synergistically to promote disease progression, they differ mechanistically and have unique clinical relevance. The current evidence suggests a synergic effect of RF and ACPA in predicting the development of RA and an erosive phenotype, controversies exist regarding the additive value of anti-CarP Abs.