Medical Policy: 02.04.43
Original Effective Date: July 2013
Reviewed: March 2017
Revised: July 2017
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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.
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 rheumatoid arthritis (RA), Crohn's disease (CD) (adult and pediatric), ankylosing spondylitis (AS), psoriatic arthritis (PsA), psoriasis (Ps), and ulcerative colitis (UC). Adalimumab (Humira) is a subcutaneous tumor necrosis factor (TNF-α) inhibitor that is FDA approved for treatment of Crohn’s disease (CD) (adult and pediatric), ulcerative colitis (UC), rheumatoid arthritis, psoriatic arthritis (PsA), ankylosing spondylitis (AS), psoriasis (Ps) and juvenile idiopathic arthritis (JIA). Following primary response to infliximab and adalimumab, some patients become secondary nonresponders. The development of antidrug antibodies (ADA) is considered to be a cause of this secondary nonresponse.
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. 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 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).
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.
The measurement of antibodies to include the measurement of serum drug concentrations to adalimumab, infliximab or vedolizumab include but are not limited to the following tests:
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).
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 has included 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 (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).
Convincing evidence for the clinical utility of antidrug antibodies (ADA) testing is currently lacking. 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) and lack of clinical assessments to guide treatment decisions (in Steenholdt). 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. Further randomized controlled trials are needed to investigate the efficacy of proposed preventative and management algorithms regarding antidrug antibodies (ADA) testing. The evidence is insufficient to determine the effects of the technology on net health outcomes.
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 single 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. Currently there are no society guidelines that include recommendations for this 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.
Vedolizumab (Entyvio) is an intravenous tumor necrosis factor blocking agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of ulcerative colitis (UC) and 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.
Clinical guidelines have not included recommendations for testing for antidrug antibodies (ADA) in patients treated with tumor necrosis factor (TNF) inhibitors.
Clinical guidelines have not included recommendations for testing for antidrug antibodies (ADA) in patients treated with tumor necrosis factor (TNF) inhibitors.
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.
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.
Measurement of antibodies to infliximab in a patient receiving treatment with infliximab, either alone or as a combination test whih includes the measurement of serum infliximab (i.e. Anser IFX) is considered investigational.
Measurement of antibodies to adalimumab in a patient receiving treatment with adalimumab, either alone or as a combination test which includes the measurement of serum adalimumab levels (i.e. Anser ADA) is considered investigational.
Measurement of antibodies to vedolizumab in a patient receiving treatment with vedolizumab, either alone or as a combination test which includes the measurement of serum vedolizumab levels (i.e. Anser VDZ) is considered investigational.
There is insufficient evidence in the published medical literature 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. 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. There is insufficient evidence to demonstrate that the use of these tests results in improved net health outcomes and therefore, is considered investigational.
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