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Measurement of Serum Antibodies to Selected Biologic Agents

Policy Number: MP-510

Latest Review Date: November 2020

Category: Laboratory

Policy Grade: B

POLICY:

Measurement of antibodies to infliximab in a patient receiving treatment with infliximab, either alone or as a combination test which includes the measurement of serum infliximab levels is considered not medically necessary and investigational.

Measurement of antibodies to adalimumab in a patient receiving treatment with adalimumab, either alone or as a combination test which includes the measurement of serum adalimumab levels is considered not medically necessary and investigational.

Measurement of antibodies to vedolizumab in a patient receiving treatment with vedolizumab, either alone or as a combination test which includes the measurement of serum vedolizumab levels is considered not medically necessary and investigational.

Measurement of antidrug antibodies in a patient receiving treatment with a biologic agent, either alone or as a combination test, which includes the measurement of serum TNF blocking agent level, is considered not medically necessary and investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Biologic agents used to treat autoimmune diseases include infliximab, adalimumab, vedolizumab, and ustekinumab. Infliximab (Remicade) is an intravenous tumor necrosis factor α blocking agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and ulcerative colitis. Adalimumab (Humira) is a subcutaneous tumor necrosis factor α inhibitor that is FDA approved for the treatment of Crohn's disease and ulcerative colitis in adults and those with juvenile idiopathic arthritis. Vedolizumab (Entyvio) is an intravenous integrin receptor antagonist that is FDA approved for treatment of ulcerative colitis and Crohn's Disease in adults. Ustekinumab (Stelara) is an intravenous and subcutaneous human interleukin-12 and -23 antagonist that is FDA approved for the treatment of psoriatic psoriasis, Crohn's disease, and ulcerative colitis in adults, and plaque psoriasis in adolescents and adults. Following the primary response to these medications, some patients become secondary nonresponders. The development of antidrug antibodies is considered a cause of this secondary nonresponse.

Infliximab, Adalimumab, Vedolizumab, and Ustekinumab in Autoimmune Diseases

Biologic agents (e.g. infliximab, adalimumab, vedolizumab, or ustekinumab) are used to treat multiple inflammatory conditions, including rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis; inflammatory bowel disease (eg, Crohn disease, ulcerative colitis), ankylosing spondylitis, and plaque psoriasis. These agents are generally given to patients who fail conventional medical therapy, and they are typically highly effective for the induction and maintenance of clinical remission. However, not all patients respond, and a high proportion of patients lose response over time. It is estimated that one in three patients do not respond to induction therapy (primary nonresponse); further, among initial responders, response wanes over time in approximately 20% to 60% of patients (secondary nonresponse). The reasons for therapeutic failures remain a matter of debate but include accelerated drug clearance (pharmacokinetics) and neutralizing agent activity (pharmacodynamics) due to antidrug antibodies (ADA). ADA is also associated with injection-site reactions and acute infusion reactions and delayed hypersensitivity reactions.

Detection of Antidrug Antibodies

The detection and quantitative measurement of ADA is difficult, owing to drug interference and identifying when antibodies likely have a neutralizing effect. First-generation assays (ie, enzyme-linked immunosorbent assays [ELISA]) can measure only ADA in the absence of detectable drug levels, due to the interference of the drug with the assay. Other techniques available for measuring antibodies include the radioimmunoassay method and, more recently, the homogenous mobility shift assay using high-performance liquid chromatography. Disadvantages of the radioimmunoassay method are associated with the complexity of the test and prolonged incubation time, along with safety concerns related to the handling of radioactive material. The homogenous mobility shift assay measures ADA when infliximab is present in serum. Studies evaluating the validation of results among different assays are lacking, making interstudy comparisons difficult. One retrospective study by Kopylov et al (2012), which evaluated 63 patients, demonstrated comparable diagnostic accuracy between 2 different ELISA methods in patients with inflammatory bowel disease(i.e., double-antigen ELISA and antihuman lambda chain-based ELISA). This study did not include an objective clinical and endoscopic scoring system for validation of results.

Treatment Options for Secondary Nonresponse to Biologic Agents

A diminished or suboptimal response to infliximab, adalimumab, vedolizumab, or ustekinumab can be managed in several ways: shortening the interval between doses, increasing the dose, switching to a different anti-TNF biologic agent (in patients who continue to have a loss of response after receiving the increased dose), or switching to a non-biologic agent.

KEY POINTS:

The most recent literature update was performed through October 13, 2020.

Summary of Evidence

For individuals who have rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis; inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis); ankylosing spondylitis; or plaque psoriasis who receive evaluation for serum antibodies to infliximab, adalimumab, vedolizumab, or ustekinumab, the evidence includes multiple systematic reviews, a randomized controlled trial, and observational studies. The relevant outcomes are test validity, change in disease status, health status measures, quality of life, and treatment-related morbidity. Antibodies to biologic agents develop in a substantial proportion of treated patients and are believed to neutralize or enhance clearance of the drugs. Considerable evidence has demonstrated an association between antidrug antibodies and secondary nonresponse as well as injection-site and infusion-site reactions. The clinical usefulness of measuring antidrug antibodies hinges on whether test results inform management changes, thereby leading to improved outcomes, compared with management directed by symptoms, clinical assessment, and standard laboratory evaluation. Limited evidence has described management changes after measuring antidrug antibodies. A small randomized controlled trial in patients with Crohn’s disease comparing antidrug antibody-informed management of relapse with standard dose escalation did not demonstrate improved outcomes with the antidrug antibody-informed approach. Additionally, many assays, some having significant limitations, have been used in studies; antidrug antibody threshold values that are informative for discriminating treatment responses have not been established. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

American College of Gastroenterology Institute

In 2017, the American College of Gastroenterology Institute published guidelines on therapeutic drug monitoring in inflammatory bowel disease. The guidelines note that

“When anti-drug antibodies are detected, it is unclear what antibody level is clinically meaningful…. the reporting of anti-drug antibodies is variable between commercial assays, with some assays being very sensitive for detecting very-low-titer antibodies of limited clinical significance. Uniform thresholds for clinically relevant antibody titers are lacking. At this time, it is unclear how antibodies affect drug efficacy when both active drug and antibodies are detected. In cases of low trough concentrations and low or high anti-drug antibodies, the evidence to clarify optimal management is lacking.”

The guidelines did not address therapeutic drug monitoring in patients treated with vedolizumab or ustekinumab.

National Institute for Health and Care Excellence

In 2016, the National Institute for Health and Care Excellence issued guidance on therapeutic monitoring of tumor necrosis factor α inhibitors in the treatment of patients with Crohn disease. The Institute recommended that laboratories monitoring tumor necrosis factor α inhibitors in patients with Crohn disease who have lost response to the treatment should “work with clinicians to collect data through a prospective study, for local audit, or for submission to an existing registry.”

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Serum infliximab, antichimeric antibodies, antibodies to infliximab, serum adalimumab, antibodies to adalimumab, serum vedolizumab, antibodies to vedolizumab, Anser IFX, Anser ADA, Anser VDZ, Humira, Remicade, Entyvio, Anser UST, serum ustekinumab concentration, Stelara, antibodies to ustekinumab concentration, anti-drug

APPROVED BY GOVERNING BODIES:

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

Prometheus Laboratories, a College of American Pathologists-accredited lab under the Clinical Laboratory Improvement Amendments, offers four non-radio-labeled, fluid-phase homogenous mobility shift assay tests: called Anser IFX (for infliximab), Anser ADA (for adalimumab), Anser VDZ (for vedolizumab), and Anser UST (for ustekinumab). The tests measure both serum drug concentrations and ADA. They are not based on an ELISA test, and can measure ADA in the presence of detectable drug levels, improving on a major limitation of the ELISA method.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP:  Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING:

CPT Codes:

84999

unlisted chemistry procedure (use for PROMETHEUS Anser IFX)

REFERENCES:

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  35. Pecoraro V, De Santis E, Melegari A, et al. The impact of immunogenicity of TNFalpha inhibitors in autoimmune inflammatory disease. A systematic review and meta-analysis. Autoimmun Rev. Jun 2017; 16(6):564-575.
  36. Plasencia C, Pascual-Salcedo D, Nuno L et al. Influence of immunogenicity on the efficacy of longterm treatment of spondyloarthritis with infliximab. Annals of the rheumatic diseases 2012; 71(12):1955-60.
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  41. Sands BE, Feagan BG, Rutgeerts P, et al. Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment had failed. Gastroenterology 2014; 147: 618-627.
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  43. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). May 2012; 64(5):625-39.
  44. Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. Mar 2014; 73(3):492-509.
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  46. Steenholdt C, Bendtzen K, Brynskov J, et al. Clinical implications of measuring drug and anti-drug antibodies by different assays when optimizing infliximab treatment failure in Crohn's disease: post hoc analysis of a randomized controlled trial. Am J Gastroenterol. Jul 2014; 109(7):1055-1064.
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  52. Wang SL, Hauenstein S, Ohrmund L et al. Monitoring of adalimumab and antibodies-to-adalimumab levels in patient serum by the homogeneous mobility shift assay. Journal of pharmaceutical and biomedical analysis 2013; 78-79:39-44.
  53. Wang SL, Ohrmund L, Hauenstein S et al. Development and validation of a homogeneous mobility shift assay for the measurement of infliximab and antibodies-to-infliximab levels in patient serum. J Immunol Methods 2012; 382(1-2):177-88.
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POLICY HISTORY:

Medical Policy Group, August 2012 (1): New policy adopted from MPP update

Medical Policy Administration Committee, October 2012

Available for comment October 24 through December 10, 2012

Medical Policy Panel, September 2013

Medical Policy Group, September 2013 (1): Title changed to add “and Adalimumab;” “Measurement of antibodies to adalimumab in a patient receiving adalimumab, either alone or as a combination test which includes the measurement of serum adalimumab levels” added to the policy statement; considered investigational; update to Key Points and References related to infliximab with no change to policy statement

Medical Policy Administration Committee September 2013

Available for comment September 19 through November 2, 2013

Medical Policy Panel, October 2014

Medical Policy Group, October 2014 (1): No policy change. Update to Key Points and References.

Medical Policy Panel, November 2015

Medical Policy Group, November 2015 (3): 2015 Updates to Description, Key Points, Approved by Governing Bodies & References; no change to policy statement.

Medical Policy Panel, November 2016

Medical Policy Group, November 2016 (3): 2016 Updates to Key Points & References; no change to policy statement.

Medical Policy Panel, November 2017

Medical Policy Group, November 2017 (3): 2017 Updates to Description, Key Points & References; no change to policy statement.

Medical Policy Group, July 2018 (5): 2018 updated policy statement to clarify that Measurement of antibodies to vedolizumab is considered investigational.  This has always been considered investigational; Updated Key Points, Key Words: (serum vedolizumab, antibodies to vedolizumab, Anser VDZ, Entyvio), and References.

Medical Policy Administration Committee July 2018

Available for comment July 11 through August 24, 2018

Medical Policy Panel, November 2019

Medical Policy Group, December 2019 (9): 2019 Updates to Key Points, Description, References. No change to policy statement.

Medical Policy Group, June 2020 (9): Updated title of policy to match association. Changed from "Measurement of Serum Antibodies to Infliximab, Adalimumab, and Vedolizumab" to "Measurement of Serum Antibodies to Selected Biologic Agents". Added key words: Anser UST, serum ustekinumab concentration, Stelara, antibodies to ustekinumab concentration. No change to policy statement or content of policy.

Medical Policy Panel, November 2020

Medical Policy Group, November 2020 (9): 2020 Updates to Key Points, Description, References. Updated code section to include (use for PROMETHEUS Anser IFX) clarification with code 84999. Added statement to policy statement: “Measurement of antidrug antibodies in a patient receiving treatment with a biologic agent, either alone or as a combination test, which includes the measurement of serum TNF blocking agent level, is considered not medically necessary and investigational.” No change to policy statement intent or coverage stance. Added key word: anti-drug


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.