Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Measurement of Serum Antibodies to and Measurement of Serum Levels of Infliximab and Adalimumab

Policy #:06.02.39b

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin 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 Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract.

The intent of this policy is to communicate that measurements of serum antibodies to and serum levels of infliximab and adalimumab are considered experimental/investigational.

For information on policies related to this topic, refer to the Cross References section in this policy.

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) are considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

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) are considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.
Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, measurement of antibodies to infliximab in an individual receiving treatment with infliximab, either alone or as a combination test that includes the measurement of serum infliximab levels, is not eligible for payment under the medical benefits of the Company’s products because the service is considered experimental/investigational and, therefore, not covered.

Services that are experimental/investigational are a benefit contract exclusion for all products of the Company. Therefore, they are not eligible for reimbursement consideration.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Anser™IFX and Anser™ADA are laboratory procedures developed by Prometheus Laboratories Inc. and are not regulated by the US Food and Drug Administration (FDA).

Clinical Laboratory Improvement Amendments (CLIA) laboratory establishes quality standards for all laboratory testing. Prometheus Laboratories Inc. is a CAP-accredited (CLIA) laboratory.

Description

BACKGROUND OF INFLIXIMAB AND ADALIMUMAB IN AUTOIMMUNE DISEASES

Infliximab is a chimeric (mouse/human) anti-tumor necrosis factor α (TNF-α) monoclonal antibody. Adalimumab is a fully human monoclonal antibody to TNF-α. Therapy with monoclonal antibodies has revolutionized therapy in individuals with inflammatory diseases such as inflammatory bowel disease (IBD; Crohn disease, ulcerative colitis), rheumatoid arthritis, and psoriasis. These agents are generally given to individuals who fail conventional medical therapy, and they are typically highly effective for induction and maintenance of clinical remission. However, not all individuals respond, and a high proportion of individuals lose response over time. An estimated one-third of individuals do not respond to induction therapy (primary nonresponse), and among initial responders, response wanes over time in approximately 20% to 60% of individuals (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 are also associated with injection site reactions (adalimumab) and acute infusion reactions and delayed hypersensitivity reactions (infliximab). As a fully human antibody, adalimumab is considered less immunogenic than chimeric antibodies, such as infliximab.

DETECTION OF ANTIDRUG ANTIBODIES (ADA)

The detection and quantitative measurement of 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 the 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 the 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 ADA when infliximab is present in the serum. Studies evaluating the validation of results among different assays are lacking, making interstudy comparisons difficult. One retrospective study in 63 individuals demonstrated comparable diagnostic accuracy between 2 different ELISA methods in individuals with IBD (i.e., double antigen ELISA and antihuman lambda chain-based ELISA) (Kopylov et al 2012). This study did not include an objective clinical and endoscopic scoring system for validation of results.

ANSER™IFX AND ANSER™ADA

Prometheus® Laboratories Inc. offers nonradiolabeled, fluid-phase homogenous mobility shift assay (HMSA) tests called Anser™ IFX for infliximab and Anser™ ADA for adalimumab. Neither test is ELISA 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. Other proprietary commercial and/or academic labs may offer similar testing.

These tests were developed and their performance characteristics determined by Prometheus Laboratories Inc. Although the US Food and Drug Administration (FDA) has not been involved in the regulation of laboratory procedures historically, recently, the FDA is reported to be involved in the evaluation of certain lab tests. Anser™IFX and Anser™ADA have not been cleared or approved by the U.S. Food and Drug Administration.

TREATMENT OPTIONS FOR INDIVIDUALS WITH SECONDARY LOSS RESPONSE TO ANTI-TNF THERAPY

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 individuals who continue to have loss of response after receiving the increased dose), or switching to a nonanti-TNF agent.

ANALYTIC AND CLINICAL VALIDATION OF ANSER™IFX AND ANSER™ADA

Analytic validity of antibodies-to-infliximab (ATI) testing by HMSA was demonstrated using ELISA as a standard comparator. Test performance characteristics were considered robust. However, a subsequent comparative study identified substantial variability across ATI assay methods using a functional cell-based assay as standard. The pharmacokinetic properties of adalimumab (long half-life relative to dosing interval) prevented use of ELISA as a standard comparator in tests of analytic validity of Antibodies-to-adalimumab (ATA). Test performance characteristics were determined by comparison to a standard curve generated by serial dilutions of pooled rabbit antisera. Lack of comparison to an alternative method of antibody detection raises uncertainty about the analytic validity of the ATA test. The commercial Prometheus® HMSA assays do not suffer from many of the technical performance limitations of older assays; however, the HMSA assays do not distinguish neutralizing and non-neutralizing antibodies.

A large body of evidence has evaluated the clinical validity of ADA testing. ADA has been associated with secondary nonresponse in RA, SpA, but not clearly in IBD. The presence of ADA has been consistently associated with an increased risk of infusion-site reaction related to infliximab and injection site reactions related to adalimumab. A concomitantly administered immunosuppressant agent reduces the risk of developing ADA.

CLINICAL UTILITY OF ANSER™IFX AND ANSER™ADA

Several authors have published algorithms for management of individuals with IBD or RA who relapse during TNF-inhibitor therapy. These algorithms are generally based on evidence, including that reviewed earlier, which indicate an association between antidrug antibodies, reduced serum drug levels, and relapse. None include evidence demonstrating improved health outcomes, such as reduced time to recovery from relapse (response), using algorithmic rather than dose-escalation approaches.

Afif et al (2010) evaluated the clinical utility of measuring ATI (referred to as human antichimeric
antibodies [HACA] in the study) and infliximab concentrations by retrospectively reviewing the medical records of individuals with IBD who had had ATI and infliximab concentrations measured. The study sought to determine whether these results affected clinical management. Medical record review from 2003 to 2008 identified 155 individuals who had had ATI and infliximab concentrations measured and who met the study inclusion criteria. A single physician ordered Seventy-two percent of the initial tests. The authors retrospectively determined clinical response to infliximab. Forty-seven percent of individuals were on concurrent immunosuppressive medication. The main indications for testing were loss of response to infliximab (49%), partial response after initiation of infliximab (22%), and possible autoimmune/delayed hypersensitivity reaction (10%). ATI were identified in 35 individuals (23%) and therapeutic infliximab concentrations in 51 individuals (33%). Of 177 tests assessed, the results impacted treatment decisions in 73%. In ATI-positive individuals, change to another anti-TNF agent was associated with a complete or partial response in 92% of individuals, whereas dose escalation had a response of 17%.

The authors concluded that measurement of ATI and infliximab concentration impacted management and was clinically useful. Increasing the infliximab dose in individuals with ATI was ineffective, whereas in individuals with subtherapeutic infliximab concentrations, this strategy was considered a good alternative to changing to another anti-TNF agent. Limitations to the study included its retrospective design and that the testing for antibodies to infliximab was performed using the enzyme-linked immunosorbent assay (ELISA) method. Because there was no control group in this study, it is not possible to determine what changes in management would have been made in the absence of ATI measurement. Clinicians are likely to make some changes in management for individuals who do not achieve or maintain a clinical response, and it is important to understand how these management decisions differ when ATI are measured.

In 2014, Steenholdt et al reported results of a noninferiority trial and cost-effectiveness analysis of 69 individuals with CD who relapsed (CDAI ≥220 and/or ≥1 draining perianal fistula) during infliximab therapy. Individuals were randomized to infliximab dose intensification (5 mg/kg every 4 weeks) or algorithmic treatment based on serum infliximab level and ATI: individuals with subtherapeutic infliximab level (<0.5 μg/mL24) had infliximab dose increased if ATI were undetectable or were switched to adalimumab if ATI were detectable; individuals with therapeutic infliximab level underwent repeat testing of infliximab and ATI levels if ATI were detectable or diagnostic reassessment if ATI were undetectable. Serum infliximab and ATI levels were measured in all individuals by RIA in single-blind fashion (individuals unaware but investigators aware of test results). Randomized groups were similar at baseline; overall, 55 (80%) of 69 individuals had nonfistulizing disease. Most individuals (70%) had therapeutic serum infliximab levels without detectable ATI; revised diagnoses in 6 (24%) of 25 such individuals in the algorithm arm25 included bile acid malabsorption, strictures, and IBS. In both intention-to-treat and per-protocol analyses, similar proportions of individuals in each randomized group achieved clinical response at week 12, defined as a minimum 70-point reduction from baseline CDAI for individuals with nonfistulizing disease and a minimum 50% reduction in active fistulas for individuals with fistulizing disease (intention-to-treat: 58% in the algorithm group vs 53% in the control group; p=0.810; per-protocol: 47% in the algorithm group vs 53% in the control group; Pearson's chi-squared test, p=0.781). Only the intention-to-treat analysis fell within the prespecified noninferiority margin of -25% for the difference between groups.

Conclusions concerning noninferiority of an algorithmic approach compared with dose intensification from this trial are limited. The noninferiority margin was arguably large and was exceeded in the conservative per-protocol analysis. Dropouts were frequent and differential between groups; 17 (51%) of 33 individuals in the algorithm group and 28 (78%) of 36 individuals in the control group completed the 12-week trial. A large proportion of individuals (24%) in the algorithmic arm were potentially misdiagnosed (i.e., CD flare was subsequently determined not to be the cause of relapse); the comparable proportion in the control arm was not reported. In most individuals (80% who had nonfistulizing disease), only a subjective measure of treatment response was used (minimum 70-point reduction from baseline CDAI).

Roblin et al (2014) conducted a single-center, prospective observational study of 82 individuals with IBD (n=45 CD, n=27 UC) with clinical relapse (CDAI >220 or Mayo Clinic >5) during treatment with adalimumab 40 mg every 2 weeks. For all individuals, trough adalimumab levels and ADA were measured in a blinded fashion using ELISA, and adalimumab dose was optimized to 40 mg weekly. Those who did not achieve clinical remission (CDAI <150 or Mayo score <2) within 4 months underwent repeat trough adalimumab and anti-adalimumab antibody testing and were switched to infliximab. Clinical and endoscopic responses after adalimumab optimization and after infliximab therapy for 6 months were compared among 3 groups: (1) those with therapeutic adalimumab level (>4.9 μg/mL27), (2) those with subtherapeutic adalimumab level and undetectable ATA; and (3) those with subtherapeutic adalimumab level and detectable ATA. After adalimumab optimization, more group 2 individuals achieved clinical remission (16 [67%] of 24 individuals) compared with group 1 (12 [29%] of 41 individuals; p<0.01 vs group 2) and group 3 (2 [12%] of 17 individuals; p<0.01 vs group 2). Duration of remission was longest in group 2 (mean [SD], 15 [5] months) compared with group 1 (mean [SD], 5 [2] months) and group 3 (mean [SD], 4 [3] months; log-rank test, p<0.01 for both comparisons vs group 2). At 1 year, 13 (52%) of 24 individuals in group 2 maintained clinical remission compared with no individuals in group 1 or group 3 (p<0.01 for both comparisons vs group 2). Results were similar when remission was defined using calprotectin levels (<250 μg/g stool) or endoscopic Mayo score (<2).

Fifty-two individuals (n=30 CD, n=22 UC) who failed to achieve clinical remission after adalimumab optimization were switched to infliximab. More individuals in group 3 achieved clinical remission (12 [80%] of 15 individuals) compared with group 1 (2 [7%] of 29 individuals) and group 2 (2 [25%] of 8 individuals; p<0.01 for both comparisons vs group 3). Duration of response after switch to infliximab was longest in group 3 (mean [SD], 14 [7] months) compared with group 1 (mean [SD], 3 [2] months) and group 2 (mean [SD], 5 [3] months; log-rank test, p<0.01 for both comparison vs group 3). At 1 year, 8 (55%) of 15 individuals in group 3 maintained clinical remission compared with no individuals in group 1 or group 2 (p<0.01 for both comparisons with group 3). Results were similar using objective measures of clinical remission (calprotectin level and endoscopic Mayo score).

These results suggest that individuals with IBD who relapse on adalimumab and have subtherapeutic serum adalimumab levels may benefit from increased adalimumab dose if ATA are undetectable or change to another TNF-inhibitor if ATA are detectable. Relapsed individuals who have therapeutic serum adalimumab levels may benefit from change to a different drug class. Strengths of the study are use of both subjective and objective measures of remission and blinded serum drug level and ATA monitoring. However, results are limited owing to the small sample size, use of ELISA for antibody testing, and lack of ADA levels for decision making. Subsequent study comparing the management using the algorithm proposed with usual care is needed. Ideally, more than one method of antibody assay would be used to further assess analytic validity. Finally, the first author of the paper received lecture fees from the ADA test provider (Theradiag).

Convincing evidence for the clinical utility of ADA testing currently is lacking. Uncontrolled retrospective studies in IBD demonstrate impacts of ADA testing on treatment decisions but cannot demonstrate improved individual outcomes compared with a no-testing strategy. Additional limitations of these studies include lack of clinical follow-up after treatment decisions were made (in Afif) and use of clinical assessments to guide treatment decisions (in Steenholdt). Additionally, determination of a clinically relevant threshold for ADA level is complicated by the use of various assay methods. A small, nonrandomized prospective study suggested that ADA levels may be informative in relapsed individuals with IBD who have low serum adalimumab levels, but this finding requires confirmation in larger, randomized trials. Methodological flaws, including relapse misclassification, limit conclusions from the RCT in individuals with relapsed IBD. Direct or indirect evidence for clinical utility in RA or SpA was not identified. Finally, although ADA are associated with increased risk of infliximab infusion and adalimumab injection site reactions, whether testing for ADA can reduce that risk is unclear. For example, Lichtenstein et al (2013) conducted a systematic review of infliximab-related infusion reactions and concluded “…there is a paucity of systematic and controlled data on the risk, prevention, and management of infusion reactions to infliximab.” They added that “[m]ore randomised controlled trials are needed in order to investigate the efficacy of the proposed preventive and management algorithms.”

PRACTICE GUIDELINES AND POSITION STATEMENTS

Current clinical guidelines from the American College of Gastroenterology, the American College of Rheumatology, and the European League Against Rheumatism (EULAR) do not include recommendations for testing for ADA in individuals treated with tumor necrosis factor inhibitors. An important question included in the EULAR research recommendations was: “Is measurement of serum drug and/or drug antibody levels useful in clinical practice?” The National Institute for Health and Care Excellence has not formally released draft guidance regarding ADA, but a press release indicates an “in research only” recommendation.

SUMMARY

Infliximab (Remicade®; Janssen Biotech) is an intravenous tumor necrosis factor α (TNF-α) blocking agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis (RA), Crohn disease (CD), ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and ulcerative colitis. Adalimumab (Humira®; AbbVie) is a subcutaneous TNF-α inhibitor that is FDA-approved for treatment of these indications (CD and ulcerative colitis [UC] in adults only) and juvenile idiopathic arthritis. Following primary response to infliximab and adalimumab, some individuals become nonresponders (secondary nonresponse). The development of antidrug antibodies (ADA) is considered to be a cause of secondary nonresponse.

The evidence for measuring anti-TNF-α inhibitor antibodies in individuals who have rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis; inflammatory bowel diseases (Crohn disease, ulcerative colitis); ankylosing spondylitis; or plaque psoriasis includes multiple systematic 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 individuals 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 individuals with CD 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 limitations—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.
References


Afif W, Loftus EV, Jr., Faubion WA, et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in individuals with inflammatory bowel disease. Am J Gastroenterol. 2010;105(5):1133-1139.

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 individuals. Biomed Res Int. 2015;2015:604872.

Bendtzen K. Personalized medicine: theranostics (therapeutics diagnostics) essential for rational use of tumor necrosis factor-alpha antagonists. Discov Med. 2013;15(83):201-211.

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. 2011;13(5):395-401.

Eser A, Primas C, Reinisch W. Drug monitoring of biologics in inflammatory bowel disease. Curr Opin Gastroenterol. 2013;29(4):391-396.

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. 2014;20(10):1714-1721.

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. 2013;72(12):1947-1955.

Garces S, Antunes M, Benito-Garcia E, et al. A preliminary algorithm introducing immunogenicity assessment in the management of individuals with RA receiving tumour necrosis factor inhibitor therapies. Ann Rheum Dis. 2014;73(6):1138-1143.

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. 2015;67(8):2011-2019.

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. 2013;38(5):447-459.

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. 2012;18(9):1628-1633.

Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105(3):501-523; quiz 524.

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. 2012;24(9):1078-1085.

Lichtenstein GR. Comprehensive review: antitumor necrosis factor agents in inflammatory bowel disease and factors implicated in treatment response. Therap Adv Gastroenterol. 2013;6(4):269-293.

Lichtenstein GR, Hanauer SB, Sandborn WJ. Management of Crohn's disease in adults. Am J Gastroenterol. 2009;104(2):465-483; quiz 464, 484.

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. 2015;14(9):812-829.

Nanda KS, Cheifetz AS, Moss AC. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in individuals with inflammatory bowel disease (IBD): a meta-analysis. Am J Gastroenterol. 2013;108(1):40-47; quiz 48.

NICE. 2015; https://www.nice.org.uk/news/press-and-media/nice-says-more-research-needed-on-tests-to-helpguide-treatment-of-digestive-disorder.
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Roblin X, Marotte H, Rinaudo M, et al. Association between pharmacokinetics of adalimumab and mucosal healing in individuals with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2014;12(1):80-84 e82.

Roblin X, Rinaudo M, Del Tedesco E, et al. Development of an algorithm incorporating pharmacokinetics of adalimumab in inflammatory bowel diseases. Am J Gastroenterol. 2014;109(8):1250-1256.

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). 2012;64(5):625-639.

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. 2014;73(3):492-509.

Steenholdt C, Brynskov J, Thomsen OO, et al. Individualised therapy is more cost-effective than dose intensification in individuals with Crohn's disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut. Jun 2014;63(6):919-927.

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.2011;46(3):310-318.

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. 2014;109(7):1055-1064.

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Vande Casteele N, Gils A, Singh S, et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol. 2013;108(6):962-971.

Wang SL, Hauenstein S, Ohrmund L, et al. Monitoring of adalimumab and antibodies-to-adalimumab levels in individual serum by the homogeneous mobility shift assay. J Pharm Biomed Anal. 2013;78-79:39-44.

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 individual serum. J Immunol Methods. 2012;382(1-2):177-188. PMID 22691619

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Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

THE FOLLOWING CODE IS USED TO REPRESENT PROMETHEUS® ANSER™ IFX TESTING OR PROMETHEUS® ANSER™ ADA TESTING:


84999



Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

This service is considered experimental/investigational for all diagnoses.


HCPCS Level II Code Number(s)

N/A


Revenue Code Number(s)

N/A

Coding and Billing Requirements


Cross References


Policy History

06.02.39b
11/21/2018This policy has been reissued in accordance with the Company's annual review process.
11/22/2017This policy has been reissued in accordance with the Company's annual review process.


Effective 10/05/2017 this policy has been updated to the new policy template format.


Version Effective Date: 06/20/2016
Version Issued Date: 06/20/2016
Version Reissued Date: 11/26/2018

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