Medical Policy: 02.04.43 

Original Effective Date: July 2013 

Reviewed: March 2018 

Revised: March 2018 

 

Benefit Application:

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.

 

Description:

Measurement of Serum Antibodies to Infliximab (Remicade) and Adalimumab (Humira)

Tumor necrosis factor (TNF) inhibitors (e.g. infliximab, adalimumab) are used in the treatment of a number of inflammatory conditions. However, the use of these agents have been associated in some patients with the development of antidrug antibodies (ADA), which may promote adverse effects and diminish drug efficacy. The measurement of serum antibodies to infliximab (Remicade) and adalimumab (Humira) has been proposed to monitor for the formation of anti-drug antibodies (ADA) which may cause some patients to become non-responders.

 

Infliximab (Remicade) is an intravenous tumor necrosis factor (TNF) blocking agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of: moderately to severely active rheumatoid arthritis (RA) in combination with methotrexate; moderately to severely active Crohn's disease (CD); moderately to severely active ulcerative colitis; active ankylosing spondylitis (AS); active psoriatic arthritis (PsA); and chronic severe plaque psoriasis.

 

Adalimumab (Humira) is a subcutaneous tumor necrosis factor (TNF-α) inhibitor that is FDA approved for treatment of: moderately to severely active Crohn’s disease (CD); moderately to severely active ulcerative colitis (UC); moderately to severely active rheumatoid arthritis; moderately to severely active polyarticular juvenile idiopathic arthritis (pJIA); active psoriatic arthritis (PsA); active ankylosing spondylitis (AS); moderate to severe plaque psoriasis; moderate to severe Hidradenitis Suppurativa; and non-infectious intermediate posterior and paneuveitis.

 

Infliximab is a chimeric (mouse/human) anti-tumor necrosis factor (TNF-α) monoclonal antibody. Adalimumab is a fully human monoclonal antibody to TNF-α. Therapy with monoclonal antibodies has revolutionized therapy in patients with inflammatory diseases such as inflammatory bowel disease (Crohn’s disease, 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. It is estimated that 1 out of 3 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 are also associated with injection site reactions (adalimumab) and acute infusion reactions and delayed hypersensitivity reactions (infliximab).

 

Detection of Antidrug Antibodies (ADA)

The detection and quantitative measurement of antidrug antibodies (ADA) is difficult, owing to drug interference and identifying when antibodies 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. One retrospective study in 63 patients demonstrated comparable diagnostic accuracy between 2 different ELISA methods in patients with IBD (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 results.

 

Treatment Options for Secondary Non-response to Anti-TNF Therapy:

A diminished or suboptimal response to infliximab, adalimumab or vedolizumab 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 and affecting a patient’s loss of response. However, currently there are no society guidelines that recommend testing serum levels or levels of antibodies regarding the use of TNF-inhibitor therapy (e.g. infliximab, adalimumab or vedolizumab).

 

The measurement of antibodies to include the measurement of serum drug concentrations to adalimumab, infliximab or vedolizumab include but are not are not limited to the following tests:

  • Prometheus Anser ADA
  • Prometheus Anser IFX
  • Prometheus Anser VDZ

 

Clinical Utility Regarding Measurement of Serum Antibodies to Infliximab (Remicade) and Adalimumab (Humira)

Several algorithms have been developed for management of patients with IBD (inflammatory bowel disease) or RA (rheumatoid arthritis) who have relapsed during TNF-inhibitor therapy. These algorithms are generally based on evidence that has indicated an association between ADA (antidrug antibodies), reduced serum drug levels, and relapse. None of the algorithms has included evidence demonstrating improved health outcomes, such as reduced time to recovery from relapse (response).

 

Afif et al (2010) evaluated the clinical utility of measuring ATI (antibodies to infliximab) and referred to as human anti-chimeric antibodies (HACAs) in the study and infliximab concentrations by retrospectively reviewing patient medical records with inflammatory bowel disease (IBD) (patients with a diagnosis of Crohn’s disease, ulcerative colitis or indeterminate colitis) who had HACA infliximab concentrations measured and whether the result affected clinical management. A record review from 2003 to 2008 identified 155 patients who had received infliximab and underwent testing for HACA and infliximab concentrations, and met the study inclusion criteria. One hundred twelve patients (71.8%) of the initial tests were ordered by a single physician. Forty-seven percent of patients were on concurrent immunosuppressant medication consisting of azathioprine, 6-mercaptopurine, or methotrexate. 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%). HACAs (ATIs –antibodies to infliximab) were identified in 35 patients (23%) and therapeutic infliximab concentrations in 51 patients (33%). Of 177 tests assessed, the results impacted treatment decisions in 73%. In HACA (ATI) positive patients, change to another anti-tumor necrosis factor (TNF) agent was associated with a complete or partial response in 92% of patients, whereas dose escalation occurred in 17%. The authors retrospectively determined clinical response to infliximab.

 

The authors concluded that measurement of HACA (ATI) and infliximab concentration had a clinically useful effect on patient management. The strategy of increasing infliximab dose in patients with HACA (ATI – antibody to infliximab) was ineffective, whereas in patients with sub-therapeutic infliximab concentrations, this strategy may be a good alternative to changing to another anti-TNF agent. A prospective randomized trial should be conducted to confirm these findings.

 

Study limitations included the retrospective design and using ELISA testing for HACA (ATI). Because there was no control group, one cannot determine what changes in management would have been made absent HACA (ATI) measurement. Because clinicians are likely to change management for patients who do not achieve or maintain a clinical response, it is important to understand how these management decisions differ when ATI are measured.

 

In 2014, Steenholdt et al reported results of a non-inferiority trial and cost-effectiveness analysis of 69 patients with CD who relapsed (CDAI ≥220 and/or ≥1 draining perianal fistula) during infliximab therapy. Patients were randomized to infliximab dose intensification (5 mg/kg every 4 weeks) or algorithmic treatment based on serum infliximab level and ATI (antibodies to infliximab): Patients with sub-therapeutic infliximab level (<0.5 μg/mL) had infliximab dose increased if ATI were undetectable or were switched to adalimumab if ATI were detectable; patients 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 patients using RIA (radioimmunoassay) in single-blind fashion (patients unaware but investigators aware of test results). Randomized groups were similar at baseline; overall, 55 (80%) of 69 patients had nonfistulizing disease. Most patients (70%) had therapeutic serum infliximab levels without detectable ATI; revised diagnoses in 6 (24%) of 25 such patients in the algorithm arm included bile acid malabsorption, strictures, and IBS. In both intention-to-treat (ITT) and per-protocol analyses, similar proportions of patients in each randomized group achieved clinical response at week 12, defined as a minimum 70-point reduction from baseline CDAI for patients with nonfistulizing disease and a minimum 50% reduction in active fistulas for patients with fistulizing disease (ITT, 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; p=0.781). Only the ITT analysis fell within the prespecified non-inferiority margin of -25% for the difference between groups.

 

Conclusions on the non-inferiority of an algorithmic approach compared with dose intensification from this trial are limited. The non-inferiority margin was arguably large and was exceeded in the conservative per-protocol analysis. Dropouts were frequent and differential between groups; 17 (51%) of 33 patients in the algorithm group and 28 (78%) of 36 patients in the control group completed the 12-week trial. A large proportion of patients (24%) in the algorithmic arm were potentially misdiagnosed (ie, CD flare was subsequently determined not to be the cause of relapse); the comparable proportion in the control arm was not reported. In most patients (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 patients with inflammatory bowel disease (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 patients, trough adalimumab levels and ADA (antidrug antibodies) 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 across 3 groups: (1) those with a therapeutic adalimumab level (>4.9 μg/mL28), (2) those with a sub-therapeutic adalimumab level and undetectable ATA (antibodies to adalimumab); and (3) those with a sub-therapeutic adalimumab level and detectable ATA. After adalimumab optimization, more group 2 patients achieved clinical remission (16 [67%] of 24 patients) than group 1 (12 [29%] of 41 patients; p<0.01 vs group 2) and group 3 (2 [12%] of 17 patients; p<0.01 vs group 2) patients. Duration of remission was longest in group 2 (mean, 15 months) compared with group 1 (mean, 5 months) and group 3 (mean, 4 months; p<0.01 for both comparisons vs group 2). At 1 year, 13 (52%) of 24 patients in group 2 maintained clinical remission compared with no patients in groups 1 or 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 patients (n=30 CD, n=22 UC) who failed to achieve clinical remission after adalimumab optimization were switched to infliximab. More patients in group 3 achieved clinical remission (12 [80%] of 15 patients) than in group 1 (2 [7%] of 29 patients) or group 2 (2 [25%] of 8 patients; p<0.01 for both comparisons vs group 3). Duration of response after switching to infliximab was longest in group 3 (mean, 14 months) compared with group 1 (mean, 3 months) and group 2 (mean, 5 months; p<0.01 for both comparison vs group 3). At 1 year, 8 (55%) of 15 patients in group 3 maintained clinical remission compared with no patients in groups 1 or 2 (p<0.01 for both comparisons vs group 3). Results were similar using objective measures of clinical remission (calprotectin level, endoscopic Mayo score).

 

These results suggested that patients with inflammatory bowel disease (IBD) who relapse on adalimumab and have sub-therapeutic serum adalimumab levels may benefit from a higher adalimumab dose if ATA (antibodies to adalimumab) are undetectable or from a change to another TNF inhibitor if ATA are detectable. Relapsed patients who have therapeutic serum adalimumab levels may benefit from change to a different drug class. Strengths of the study include its use of subjective and objective measures of remission and blinded serum drug level and ATA monitoring. However, results were influenced by the small sample size, use of ELISA for antibody testing, and lack of ADA (antidrug antibodies) levels for decision making. Subsequent study comparing the management using the algorithm proposed with usual care is needed. Ideally, using more than 1 method of assaying antibodies would further assessment of analytic validity. Finally, the lead author of the study received lecture fees from the ADA (antidrug antibodies) test provider (Theradiag).

 

In 2016, Lombardi et. al. investigated the prevalence of anti-adalimumab antibodies and the association with clinical indexes and tumor necrosis factor (TNF-α) serum levels in psoriatic patients. Patient group I (n=20) receiving biological therapies after switching from adalimumab; patient group II (n=30) ongoing adalimumab therapy; patient group III (n=30) novel adalimumab therapy; patient group IV (n=15) biological therapies other than adalimumab; group V healthy subjects (n=15) never treated with immunosuppressants or biologicals. All groups were tested at enrollment. Group II was also tested at 12 months, and group III at 1, 3 and 6 months. The primary and secondary outcome measures, standard clinical evaluations (Psoriasis Area Severity Index (PASI)), blood samples and two-site ELISA based measurement of serum adalimumab trough levels, anti-adalimumab antibodies and TNF-α. The false positive rate was 23% for anti-adalimumab detection and 22% for anti-adalimumab antibodies in patients naïve to adalimumab. Spurious positivity for anti-adalimumab antibodies (one-time-point positivity in group III during follow-up) accounted for 33% of the total. The prevalence of anti-drug antibodies was highest (87%) in group I patients. No correlations were found between the presence of anti-adalimumab antibodies of adalimumab levels and changes in PASI scores. There was a high variability of results, high prevalence of false-positives and lack of association between anti-adalimumab antibodies and TNF-α level/PSAI score limit the assay’s usefulness. Accurate clinical evaluation is key to early identification of treatment failures.

 

Summary Clinical Utility Regarding Measurement of Serum Antibodies to Infliximab (Remicade) and Adalimumab (Humira)

Convincing evidence for the clinical utility of antidrug antibodies (ADA) testing is currently lacking. The majority of studies are related to inflammatory bowel disease. Uncontrolled retrospective studies in inflammatory bowel disease (IBD) have demonstrated the impact of ADA testing on treatment decisions but cannot demonstrate improved patient 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 et. al.) and lack of clinical assessments to guide treatment decisions (in Steenholdt et. al.). Additionally, determination of 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 to relapsed patients with IBD who have low serum adalimumab levels, but this finding requires confirmation in larger, randomized trials. Lombardi et. al. (2016) investigated the prevalence of anti-adalimumab antibodies and the association with clinical indexes and tumor necrosis factor (TNF-α) serum levels in psoriatic patients. There was a high variability of results, high prevalence of false-positives and lack of association between anti-adalimumab antibodies and TNF-α level/PSAI score limit the assay’s usefulness. Further randomized controlled trials are needed to investigate the efficacy of proposed management algorithms regarding antidrug antibodies (ADA) testing.

 

Summary of Evidence Regarding Measurement of Serum Antibodies to Infliximab (Remicade) and Adalimumab (Humira)

For individuals who have rheumatoid arthritis (RA), psoriatic arthritis (PsA), juvenile idiopathic arthritis (JIA), Crohn's disease (CD), ulcerative colitis (UC), ankylosing spondylitis (AS), or psoriasis (Ps) who receive evaluation for anti-tumor necrosis factor α inhibitor antibodies to infliximab and adalimumab, the evidence includes multiple systemic reviews, a randomized controlled trial (RCT), and other observational studies. 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 antidrug antibodies (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 has described management changes after measuring ADA. A small, randomized controlled trial (RCT) 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 assays, some having significant limitations, have been used in studies; ADA threshold values that are informative for discriminating treatment responses have not been established. In 2017, the American Gastroenterological Association issued a guideline on therapeutic drug monitoring in inflammatory bowel disease that utilizes trough concentrations for therapeutic drug monitoring for anti-tumor necrosis factors. The guideline also states “uniform thresholds for clinically relevant antibody titers are lacking. At this time, it is unclear how antibodies effect 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”. More controlled data is needed to define the best cut-off to define abnormal values of the measured monitor parameters, define optimal thresholds for the different interventions and the subpopulations as to who will benefit the most from this testing. The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Measurement of Serum Antibodies to Vedolizumab (Entyvio)

Vedolizumab (Entyvio) is an intravenous tumor necrosis factor blocking agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of: moderately to severely active ulcerative colitis (UC); and moderately to severely active Crohn’s disease (CD). Vedolizumab is generally given for those patients who have had an inadequate response with, lost response to, or were intolerant to tumor necrosis factor (TNF) blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids. This drug is used for achieving clinical response or remission, or achieving corticosteroid-free remission.

 

Serum concentrations of vedolizumab (VDZ) may vary among equally dosed patients which can affect patient outcomes. Some patients may develop immunogenicity (non-response) to VDZ by producing antibodies to vedolizumab and the presence of persistent anti-vedolizumab antibody has been observed to reduce serum concentrations of vedolizumab. Incorporating therapeutic drug monitoring into clinical practice has been proposed to allow clinicians to optimize treatment by maintaining effective drug concentrations over time and affecting a patient’s loss of response.

 

For individuals who have ulcerative colitis (UC) or Crohn’s disease (CD) receiving vedolizumab, there is an interest in monitoring this therapy not only for the purpose of identifying markers that will serve as end points for successful treatment, but also for timely cessation or switching of therapy in those unlikely to respond. However, based on the peer reviewed medical literature further randomized controlled trials are needed to investigate the efficacy of proposed preventative and management algorithms regarding antidrug antibodies (ADA) testing. Currently there are no society guidelines that include recommendations for ADA testing. More controlled data is needed to define the best cut-off to define abnormal values of the measured monitor parameters, define optimal thresholds for the different interventions and the subpopulations as to who will benefit the most from this testing. The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Practice Guidelines and Position Statements

 

American College of Gastroenterology

Clinical guidelines have not included recommendations for testing for antidrug antibodies (ADA) in patients treated with tumor necrosis factor (TNF) inhibitors.

 

American College of Rheumatology

Clinical guidelines have not included recommendations for testing for antidrug antibodies (ADA) in patients treated with tumor necrosis factor (TNF) inhibitors.

 

American Gastroenterological Association (AGA)

In 2017, the American Gastroenterological Association (AGA) issued a guideline on therapeutic drug monitoring in inflammatory bowel disease. Due to paucity of data at the time of publication, this guideline does not address the role of therapeutic drug monitoring (TDM) in patients treated with vedolizumab or ustekinumab. The guideline included the following recommendations for therapeutic drug monitoring in inflammatory bowel disease:

 

StatementStrength of RecommendationQuality of Evidence
In adults with active IBD treated with anti-TNF agents, the AGA suggests reactive therapeutic drug monitoring to guide treatment changes. Conditional recommendation, very low quality of evidence.
Comment: Of note, there may be a small subset of patients who may still respond by targeting higher target concentrations. Optimal trough concentrations for induction therapy are uncertain.
Conditional recommendation Very low quality
In adult patients with quiescent IBD treated with anti-TNF agents, the AGA makes no recommendation regarding the use of routine proactive therapeutic drug monitoring. No recommendation Knowledge gap
In adult patients with IBD being started on thiopurines, the AGA suggests routine TPMT testing (enzymatic activity or genotype) to guide thiopurine dosing.
Comment:Routine laboratory monitoring, including CBC, should be performed, regardless of TPMT testing results
Conditional recommendation Low quality
In adult patients treated with thiopurines with active IBD or adverse effects thought to be due to thiopurine toxicity, the AGA suggests reactive thiopurine metabolite monitoring to guide treatment changes.
Comment:When measuring thiopurine metabolite monitoring in patients with active IBD-related symptoms, we suggest a target 6-thioguanine (6-TGN) cutoff between 230-450 pmol/8 x 108 RBCs when used as monotherapy; optimal 6-TGN cutoff when thiopurines are used in combination with anti-TNF agents is uncertain
Conditional recommendation Very low quality
In adult patients with quiescent IBD treated with thiopurines, the AGA suggests against routine thiopurine metabolite monitoring Conditional recommendation Very low quality

 

Based on the guideline recommendations the below is the suggested target trough concentrations when applying reactive therapeutic drug monitoring in patients with active inflammatory bowel disease on maintenance therapy with anti-tumor necrosis factors:

 

DrugSuggested Trough Concentration ug/mLComments
Infliximab >5 Six studies (929 patients) provided data on proportion of patients not in remission above predefined infliximab thresholds (1, 3, 5, 7, and 10 mg/mL). Based on these, proportion of patients not in remission decreased from 25% when using an infliximab threshold of ≥1 mg/mL, to 15% with an infliximab trough concentration of ≥ 3 mg/mL, to approximately 4% with an infliximab trough concentration of ≥ 7 mg/mL or ≥ 10 mg/mL
Adalimumab > Four studies provided data on proportion of patients not in remission above adalimumab trough concentration >5.0 ± 1 mg/mL or 7.5 ± 1 mg/mL. On analysis of different thresholds, proportion of patients not in remission progressively decreased from 17% when using an adalimumab threshold ≥5.0 ± 1 mg/mL, to 10% with an adalimumab trough concentration of ≥ 7.5 ± 1 mg/mL.
Certolizumab
Pegol
≥20 One study provided data from an exposure response pooled analysis from 9 trials. On analysis of different thresholds, proportion of patients not in remission progressively decreased from 42% when using a certerolizumab threshold of ≥10 mg/mL to 26% with a certolizumab trough concentration of ≥20 mg/mL
Golimumab Unknown There is a lack of sufficient evidence available to establish a target trough goal

 

Based on this evidence and target trough concentrations, the panel developed an algorithm for how patients and physicians using shared decision making may respond to reactive therapeutic drug monitoring (TDM) testing. Initially, only the trough concentrations should be assessed. If the level is at or above the target trough, then the patient may consider switching to a different drug class, although escalating index therapy may be a reasonable alternative (especially if reactive TDM is performed in asymptomatic patients with ongoing endoscopic activity, or in patients with perianal disease where target trough concentrations may be higher). In the presence of sufficient trough concentrations, results of antibody testing should not guide treatment decisions. If the trough concentration is low (below the suggested threshold, in patients with active IBD) and no anti-drug antibodies are present, then the index drug should be optimized using any of the following techniques: shortening the dosing interval and/or increasing the drug dose, and/or adding an immunomodulatory agent. If there is no detectable drug (zero trough concentration) and high-titer anti-drug antibodies are present, then the patient should consider switching to a different drug within the class or to a different drug class. If there is no detectable drug and low-titer antibodies are present, then one can consider trying to optimize the index drug by shortening the dosing interval and/or increasing the drug dose, and/or adding an immunomodulator agent. Typically, optimizing the drug will be attempted before changing to a different drug within the class or switching to a new drug class, although some might opt to change to a different drug within the class or switch to a new drug class. It should be noted that 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.

 

There are several issues that remain unresolved even after assessing the evidence. The best-available evidence did not address the optimal timing for measuring trough concentrations. In most cases, the panel recommends that a trough level for infliximab or adalimumab be drawn as close to the next dose as possible (ie, within 24 hours). Additionally, while the drug trough concentration is consistent across different commercial assays, assays for anti-drug antibodies are not readily comparable with each other.

 

When anti-drug antibodies are detected, it is unclear what antibody level is clinically meaningful. Low-titer antibodies may be transient and non-neutralizing, such that shortening the drug-dosing interval and/or escalating the dose may optimize the trough concentration in this setting of low-titer antibodies. In contrast, high-titer anti-drug antibodies, especially with undetectable trough concentrations, are generally persistent and neutralizing. In this setting, especially with undetectable drug, there may be very limited benefit to attempting dose escalation of the index agent, and switching to a different drug within the same class may be more effective. Unfortunately, current data do not allow us to identify optimal anti-drug antibody cutoffs for high- vs low-titer antibodies, in the current commercially available assays.

 

Further studies are needed to better define clinically meaningful vs insignificant anti-drug antibodies, based on titers and/or persistence in repeated testing, and at which titers can anti-drug antibodies be suppressed below needing to change drug therapies.

 

National Institute for Health and Care Excellence (NICE)

In 2016, the National Institute for Health and Care Excellence (NICE) issued guidance on therapeutic monitoring of TNF-α inhibitors in Crohn’s disease. NICE recommends the following that laboratories monitoring TNF-α inhibitors in patients with Crohn’s disease who have lost response to the treatment, should work with clinicians to collect data through either a prospective study, a local audit, or a registry.

 

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer LDTs must be licensed by CLIA 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 Inc., a College of American Pathologists-accredited lab under CLIA, offers non-radio-labeled, fluid phase homogenous mobility shift assay (HMSA) tests called Anser™ IFX for infliximab, Anser™ ADA for adalimumab and Anser™ VDZ for vedolizumab. These tests are not based on an enzyme-linked immunosorbent assay (EILSA) and each can measure antidrug antibodies in the presence of detectable drug levels, improving upon a major limitation of the ELISA method. These tests measure serum drug concentrations and antidrug antibodies.

 

Prior Approval:

Not applicable

 

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, including but not limited to Anser IFX is considered investigational.

 

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, including but not limited to Anser ADA is considered investigational.

 

Measurement of antibodies to vedolizumab and measurement of serum vedolizumab levels in an individual receiving treatment with vedolizumab, either alone or as a combination test, including but not limited to  Anser VDZ is considered investigational.

 

Based on the review of the peer reviewed medical literature there is insufficient evidence to determine the role of the measurement of antibodies to infliximab, adalimumab or vedolizumab, whether performed separately or combined with the measurement of serum drug levels. Convincing evidence for the clinical utility of measuring antidrug antibodies (ADA) testing currently is lacking. 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 has described management changes after measuring ADA (antidrug antibodies). Further prospective randomized controlled trials are needed to investigate the efficacy of proposed preventative and management algorithms regarding antidrug antibodies (ADA) testing. In 2017, the American Gastroenterological Association issued a guideline on therapeutic drug monitoring in inflammatory bowel disease that utilizes trough concentrations for therapeutic drug monitoring for anti-tumor necrosis factors. The guideline also states “uniform thresholds for clinically relevant antibody titers are lacking. At this time, it is unclear how antibodies effect 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”. More controlled data is needed to define the best cut-off to define abnormal values of the measured monitor parameters, define optimal thresholds for the different interventions and the subpopulations as to who will benefit the most from this testing. There is insufficient evidence to demonstrate that the use of these tests results in improved net health outcomes.

 

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, Prometheus® Anser®  ADA or Prometheus® Anser® VDZ )

 

Selected References:

  • Dubeau MF, Ghosh S. Optimizing infliximab therapy for inflammatory bowel disease- the tools are getting sharper. Gastroenterol Hepatol. 2012; 8(2):134-6.
  • 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, 2016.
  • 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
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Policy History:

  • March 2018 - Annual Review, Policy Revised
  • July 2017 - Interim Review, Policy Revised
  • March 2017 - Annual Review, Policy Revised
  • March 2016 - Annual Review, Policy Revised
  • April 2015 - Annual Review, Policy Revised
  • May 2014 - Annual Review, Policy Revised
  • July 2013 - New Policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

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