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.
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 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.
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)
- 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.
- Medscape. Therapeutic Drug Monitoring for Anti-TNF Therapy in Inflammatory Bowel Disease. Released 2/7/2013.
- 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
- Bendtzen K. Personalized medicine: theranostics (therapeutics diagnostics) essential for rational use of tumor necrosis factor-alpha antagonists. Discov Med. Apr 2013;15(83):201-211. PMID 23636137
- Kopylov U, Mazor Y, Yavzori M, et al. Clinical utility of antihuman lambda chain-based enzyme-linked immunosorbent assay (ELISA) versus double antigen ELISA for the detection of anti-infliximab antibodies. Inflamm Bowel Dis. Sep 2012;18(9):1628-1633. PMID 22038899
- 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. Aug 31 2012;382(1-2):177-188. PMID 22691619
- 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. J Pharm Biomed Anal. May 5 2013;78-79:39-44. PMID 23454676
- Meroni PL, Valentini G, Ayala F, et al. New strategies to address the pharmacodynamics and pharmacokinetics of tumor necrosis factor (TNF) inhibitors: A systematic analysis. Autoimmun Rev. Sep 2015;14(9):812-829. PMID 25985765
- Garces S, Demengeot J, Benito-Garcia E. The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis. Ann Rheum Dis. Dec 2013;72(12):1947-1955. PMID 23223420
- Lee LY, Sanderson JD, Irving PM. Anti-infliximab antibodies in inflammatory bowel disease: prevalence, infusion reactions, immunosuppression and response, a meta-analysis. Eur J Gastroenterol Hepatol. May 27 2012;24(9):1078-1085. PMID 22647738
- Nanda KS, Cheifetz AS, Moss AC. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis. Am J Gastroenterol. Jan 2013;108(1):40-47; quiz 48. PMID 23147525
- Thomas SS, Borazan N, Barroso N, et al. Comparative Immunogenicity of TNF Inhibitors: Impact on Clinical Efficacy and Tolerability in the Management of Autoimmune Diseases. A Systematic Review and Meta-Analysis. BioDrugs. Aug 2015;29(4):241-258. PMID 26280210
- Arstikyte I, Kapleryte G, Butrimiene I, et al. Influence of Immunogenicity on the Efficacy of Long-Term Treatment with TNF alpha Blockers in Rheumatoid Arthritis and Spondyloarthritis Patients. Biomed Res Int. 2015;2015:604872. PMID 26064930
- Frederiksen MT, Ainsworth MA, Brynskov J, et al. Antibodies against infliximab are associated with de novo development of antibodies to adalimumab and therapeutic failure in infliximab-to-adalimumab switchers with IBD. Inflamm Bowel Dis. Oct 2014;20(10):1714-1721. PMID 25069030
- Jani M, Chinoy H, Warren RB, et al. Clinical utility of random anti-tumor necrosis factor drug-level testing and measurement of antidrug antibodies on the long-term treatment response in rheumatoid arthritis. Arthritis Rheumatol. May 2015;67(8):2011-2019. PMID 26109489
- Castillo-Gallego C, Aydin SZ, Marzo-Ortega H. Clinical utility of the new ASAS criteria for spondyloarthritis and the disease activity score. Curr Rheumatol Rep. Oct 2011;13(5):395-401. PMID 21748416
- Vande Casteele N, Gils A, Singh S, et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol. Jun 2013;108(6):962-971. PMID 23419382
- Eser A, Primas C, Reinisch W. Drug monitoring of biologics in inflammatory bowel disease. Curr Opin Gastroenterol. Jul 2013;29(4):391-396. PMID 23703367
- Khanna R, Sattin BD, Afif W, et al. Review article: a clinician's guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease. Aliment Pharmacol Ther. Sep 2013;38(5):447-459. PMID 23848220
- Lichtenstein GR. Comprehensive review: antitumor necrosis factor agents in inflammatory bowel disease and factors implicated in treatment response. Therap Adv Gastroenterol. Jul 2013;6(4):269-293. PMID 23814608
- Garces S, Antunes M, Benito-Garcia E, et al. A preliminary algorithm introducing immunogenicity assessment in the management of patients with RA receiving tumour necrosis factor inhibitor therapies. Ann Rheum Dis. Jun 2014;73(6):1138-1143. PMID 23666932
- Afif W, Loftus EV, Jr., Faubion WA, et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol. May 2010;105(5):1133-1139. PMID 20145610
- Steenholdt C, Bendtzen K, Brynskov J, et al. Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn's disease. Scand J Gastroenterol. Mar 2011;46(3):310-318. PMID 2108711925.
- Tan M. Importance of defining loss of response before therapeutic drug monitoring. Gut. Jul 16 2014. PMID 25031226
- Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. Mar 2010;105(3):501-523; quiz 524. PMID 20068560
- Lichtenstein GR, Hanauer SB, Sandborn WJ. Management of Crohn's disease in adults. Am J Gastroenterol. Feb 2009;104(2):465-483; quiz 464, 484. PMID 19174807
- 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):625-639. PMID 22473917
- 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. PMID 24161836
- NICEExternal Site
March 2016 - Annual Review, Policy Revised
April 2015 - Annual Review, Policy Revised
May 2014 - Annual Review, Policy Revised
July 2013 - New Policy
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