Medical Policy: 02.04.43
Original Effective Date: July 2013
Reviewed: March 2016
Revised: March 2016
Benefit determinations are based on the applicable contract language in effect at the time the
services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary
based on contract, and individual member benefits must be verified. Wellmark determines medical
necessity only if the benefit exists and no contract exclusions are applicable. This medical
policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document
was developed. Since that time, new technology may have emerged or new medical literature may
have been published. This Medical Policy will be reviewed regularly and be updated as scientific
and medical literature becomes available.
Infliximab (Remicade® Janssen Biotech) is an intravenous tumor necrosis factor (TNF) alpha blocking agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis (RA), Crohn's disease (CD), ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and ulcerative colitis (UC). Adalimumab (Humira® AbbVie) is a subcutaneous tumor necrosis factor (TNF) alpha inhibitor that is FDA approved for treatment of Crohn’s disease (CD) and ulcerative colitis (UC) in adults only and juvenile idiopathic arthritis. Following primary response to infliximab and adalimumab, some patients become non-responders (secondary nonresponse). The development of antidrug antibodies (ADA) is considered to be a cause of secondary nonresponse.
Infliximab is a chimeric (mouse/human) anti-tumor necrosis factor (TNF)-alpha monoclonal antibody. Adalimumab is a fully human monoclonal antibody to TNF-alpha. Therapy with monoclonal antibodies has revolutionized therapy in patients with inflammatory disease such as inflammatory bowel disease (Crohn’s disease and ulcerative colitis), rheumatoid arthritis and psoriasis. These agents are generally given to patients who fail conventional medical therapy, and they are typically highly effective for induction and maintenance of clinical remission. However, not all patients respond, and high proportion of patients lose response over time. An estimated one-third of patients do not respond to induction therapy (primary nonresponse), and among initial responders, response wanes over time in approximately 20% to 60% of patients (secondary nonresponse).
The reason 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 are also associated with injection site reactions (adalimumab) and acute infusion reactions and delayed hypersensitivity reactions (infliximab).
Treatment options for patients with secondary loss of response to anti-TNF therapy include the following: a diminished or suboptimal response to infliximab or adalimumab can be managed in several ways: shortening the interval between doses, increasing the dose, switching to a different anti-TNF agent (in patients who continue to have loss of response after receiving the increased dose) or switching to a non-anti-TNF agent. Incorporating therapeutic drug monitoring into clinical practice has been proposed to allow clinicians to optimize treatment by maintaining effective drug concentrations over time. However, currently there are no society guidelines that recommend testing serum levels or levels of antibodies regarding the use of TNF-alpha inhibitors.
The detection and quantitative measurement of antidrug antibodies (ADA) has been fraught with difficulty, owing to drug interference and identifying when antibodies likely have a neutralizing effect. First generation assays (i.e. enzyme-linked immunosorbent assays (ELISA)) can measure only ADA in the absence of detectable drug levels, due to interference of the drug with the assay. Other techniques available for measuring antibodies include radioimmunoassay (RIA) method, and more recently, the homogenous mobility shift assay (HMSA) using high performance liquid chromatography.
Disadvantages of the RIA method are associated with complexity of the test and prolonged incubation time, and safety concerns related to the handling of radioactive material. The HMSA has the advantage of being able to measure antidrug antibodies when infliximab is present in the serum. Studies evaluating the validation of the results between different assays are lacking, making inter-study comparisons difficult.
The evidence for measuring anti-TNF-a inhibitor antibodies in patients who have rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis; inflammatory bowel diseases (Crohn disease, ulcerative colitis); ankylosing spondylitis; or plaque psoriasis includes multiple systemic reviews, a single randomized controlled trial, and other observational studies. Relevant outcomes are test accuracy and validity, change in disease status, health status measures, quality of life, and treatment-related morbidity. Antibodies-to-infliximab (ATI) or to adalimumab (ATA) develop in a substantial proportion of treated patients and are believed to neutralize or enhance clearance of the drugs. Considerable evidence demonstrates an association between ADA and secondary nonresponse as well as injection site and infusion reactions. The clinical usefulness of measuring ADA 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 describes management changes after measuring ADA. A small, randomized controlled trial in patients with Crohn’s disease comparing ATI-informed management of relapse with standard dose escalation did not demonstrate improved outcomes with the ATI-informed approach. Additionally, many different assays – some having significant limitation – have been used in studies; ADA 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
Current guidelines do not include recommendations for testing for ADA in patients treated with tumor necrosis factor inhibitors.
American College of Rheumatology
Current guidelines do not include recommendations for testing for ADA in patients treated with tumor necrosis factor inhibitors.
National Institute for Health and Care Excellence (NICE)
NICE has not formally released a draft guidance regarding ADA, but a press release issued September 2015 regarding new tests to help guide treatment for people with Crohn’s disease, the tests measuring the levels of drugs called TNF-alpha inhibitors and the levels of antibodies against TNF-alpha inhibitors, states that further research is needed before they can be recommended for routine use.
The draft guidance also recommends that in people with Crohn’s disease whose disease responds to treatment with TNF inhibitor, the tests should only be used in research for monitoring levels of TNF inhibitors and antibodies to TNF inhibitors.
Regulatory Status
Prometheus ® Laboratories Inc. offers nonradiolabled, fluid phase HMSA tests called Anser ™ IFX for infliximab and Anser ™ ADA for adlimumab. Neither test is EILSA based,and each can measure antidrug antibodies in the presence of detectable drug levels, improving upon a major limitation of the ELISA method. Both tests measure serum drug concentrations and antidrug antibodies.
These tests (Anser IFX Assay, Anser ADA Assay) were developed and its performance characteristics determined by Prometheus Laboratories Inc. Neither has been cleared or approved by the U.S. Food and Drug Administration.
Prometheus Laboratories Inc. is a CAP accredited Clinical Laboratory Improvement Amendment laboratory.
Not applicable
The measurement of antibodies to infliximab and measurement of serum infliximab levels in an individual receiving treatment with infliximab, either alone or as a combination test (i.e. Anser IFX) is considered investigational.
The measurement of antibodies to adalimumab and measurement of serum adalimumab levels in an individual receiving treatment with adalimumab, either alone or as a combination test (i.e. Anser ADA) is considered investigational.
There is insufficient evidence in the published medical literature to determine the role of the measurement of antibodies to infliximab or adalimumab, whether performed separately or combined with testing blood levels. Currently there are no society guidelines that include recommendations for this testing and there is insufficient evidence to demonstrate that the use of these tests results in improved health outcomes compared to usual clinical management. Therefore, this testing is considered investigational.
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*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.