Medical Policy: 02.04.43
Original Effective Date: July 2013
Reviewed: April 2015
Revised: April 2015
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.
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 immune 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 remains a matter of debate. One proposed factor associated with loss of response is the production of antidrug antibodies, which accelerates clearance of the drug, leading to sub-therapeutic drug concentrations and, ultimately, to treatment failure. However, other patient related factors, such as sex and/or body size, disease severity, including TNF burden and serum albumin concentration among others, also may influence the pharmacokinetics of these agents. The current practice management for 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.
Detection of Antidrug Antibodies
The detection and quantitative measurement of antidrug antibodies has been fraught with difficulty. First generation assays (i.e. enzyme-linked immunosorbent assays (ELISA) can only measure antidrug antibodies in the absence of detectable drug levels due to interference of the drug with the assay, limiting clinical utility. 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.
It is also difficult to interpret drug levels in the absence of antibody levels, and to interpret antibody levels in the absence of serum drug levels. Measuring one without the other may result in an incorrect interpretation of a clinical situation.
Antibodies to infliximab (ATI) or to adalimumab (ATA) are present in a substantial number of patients treated with infliximab or adalimumab, respectively, and there may be a correlation between the level of these antibodies and clinical response. However, the clinical utility of measuring antidrug antibody concentrations has not been established, as it is not known how patient management would change based on test results. Limited, evidence describes changes in the management after measurement of ATI, but does not compare these management changes to those made in the absence of ATI measurement. In addition, there are technical factors relating to the use of different assay methods across studies, it has not yet been established whether the use of threshold levels aids in the discrimination of treatment response, nor has the optimal timing of when to measure antibody levels been established.
Therefore, the measurement of antibodies to infliximab in a patient receiving treatment with infliximab is considered investigational, and the measurement of adalimumab in a patient receiving treatment with adalimumab is considered investigational.
Practice Guidelines and Position Statements
Current clinical guidelines from the American College of Gastroenterology and the National Institute for Health and Care Excellence do not include recommendations for antidrug antibody testing for patients treated with tumor necrosis factor inhibitors.
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.
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 infliximab 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. There is insufficient evidence to demonstrate the use of these tests results in improved health outcomes compared to usual clinical management.
Procedure Codes and Billing Guidelines:
- To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
- 84999 Unlisted laboratory code (when specified as Prometheus ® Anser™ IFX testing OR Prometheus® Anser™ ADA Testing)
Wellmark's policy is based on:
- National Institute for Health and Clinical Excellence (NICE). Crohn's disease: management in adults, children and young people. National Institute for Health and Clinical Excellence (NICE); 2012 Oct. 34 p. (NICE clinical guideline; no. 152).
- Dubeau MF, Ghosh S. Optimizing infliximab therapy for inflammatory bowel disease- the tools are getting sharper. Gastroenterol Hepatol. 2012; 8(2):134-6.
- Cassinotti A, Travis S. Incidence and clinical significance of immunogenicity to infliximab in Crohn's disease: a critical systematic review. Inflamm Bowel Dis. 2009; 15(8):1264-75.
- Blue Cross and Blue Shield Medical Policy Reference Manual. 2013:5. Accessed 5/20/13.
- Yanai H, Hanauer SB. Assessing response and loss of response to biological therapies in IBD. Am J Gastroenterol 2011; 106:685-698
- Valor L,de la TorreI. Understanding the Immunology Concept.Clinical Rheumatology. 2013;9:1-4
- Prometheus Therapeutics & Diagnostics Anser IFX and Anser ADA. www.answerifx.com
- Medscape. Therapeutic Drug Monitoring for Anti-TNF Therapy in Inflammatory Bowel Disease. Released 2/7/2013. www.medscape.org/viewarticle/778647
- Intrid Ordas, et al. Therapeutic Drug Monitoring or Tumor Necrosis Factor Antagonist in Inflammatory Bowel Disease. Clinical Grastroenterology and Hepatology 2012;10:1079-1087
- Gastroenterology & Hepatology August 2013, Volume 9, Issue 8, Supplment 4. Special Meeting Edition, Clinical Research Highlights in IBD: Diagnosis and Anti-Tumor Necrosis Factor Monitoring, Digestive Disease Week 2013.
- American College of Gastroenterology, Management of Crohn’s Disease in Adults, 2008.
- American College of Gastroenterology, Ulcerative Colitis Practice Guidelines in Adults, March 2010.
- Roblin X, Rinaudo M, Del Tedesco E, et al. Development of an Algorithm Incorporating Pharmacokinetics of Adalimumab in Inflammatory Bowel Disease. Am J Gastroenterology. Aug 2014;109(8):1250-1256
- Roblin X, Marotte H, et. al. Association Between Pharmacokinetics of Adalimumab and Mucosal Healing in Patients with Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2014 Jan 12(1):80-84
- Steenholdt C, Brynskoy J, et. al. Individualized Therapy is More Cost Effective Than Dose Intensification in Patients with Crohn’s Disease Who Lose Response to Anti-TNF Treatment: A Randomized Controlled Trial. Gut 2014 June;63(6):919-27
- Steenholdt C, Bendtzen K, 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 Gastroenterology 2014 Jul:109(7):1055-64
- National Institute of Health (NIH), Frank I. Scott, M.D., M.S.C.E and Gary R. Lichtenstein, M.D., Therapeutic Drug Monitoring of Anti-TNF Therapy in Inflammatory Bowel Disease. Curr Treat Options Gastroenterol. 2014 March; 12(1): 59-75
Date Reason Action
July 2013 New Policy New Policy
May 2014 Annual review Policy revised
April 2015 Annual review Policy revised
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of technology assessment of new and emerging treatments, devices,
drugs, etc. They are developed to
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*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.