Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2012054
Category:	Laboratory
Initiated:	August 2012
Last Review:	June 2023

Measurement of Serum Antibodies to Infliximab, Adalimumab, Vedolizumab, and Ustekinumab

Description:

Biologic agents used to treat autoimmune diseases include infliximab, adalimumab, vedolizumab, and ustekinumab. Infliximab (Remicade) is an intravenous tumor necrosis factor (TNF) alpha blocking agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and ulcerative colitis. Adalimumab (Humira) is a subcutaneous TNF alpha inhibitor that is FDA-approved for treatment of Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and psoriatic arthritis in adults only and those with juvenile idiopathic arthritis, hidradenitis suppurativa, and uveitis. Vedolizumab (Entyvio) is an intravenous integrin receptor antagonist that is FDA approved for treatment of ulcerative colitis and Crohn’s disease in adults. Ustekinumab (Stelara) is an intravenous and subcutaneously administered human interleukin (IL)-12 and IL-23 antagonist that is FDA approved for the treatment of psoriatic psoriasis, Crohn disease, and ulcerative colitis in adults, and plaque psoriasis in children and adults. Following the primary response to these medications, some patients become secondary nonresponders. The development of antidrug antibodies is considered a cause of this secondary nonresponse.

Biologic agents (e.g., infliximab, adalimumab, vedolizumab, or ustekinumab) are used to treat multiple inflammatory diseases including rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis; inflammatory bowel disease (e.g., Crohn disease, ulcerative colitis), ankylosing spondylitis, and plaque 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 a 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) (Bendtzen, 2013). ADA are also associated with injection site reactions and acute infusion reactions and delayed hypersensitivity reactions.

Detection of antidrug antibodies

The detection and quantitative measurement of ADA is difficult. First-generation assays, (i.e., enzyme-linked immunosorbent assays [ELISA]) can only measure antidrug antibodies in the absence of detectable drug levels due to interference of the drug with the assay. 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, along with safety concerns related to the handling of radioactive material. The homogenous mobility shift assay 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 interstudy comparisons difficult. One retrospective study in 63 patients demonstrated comparable diagnostic accuracy between 2 different ELISA methods in patients with inflammatory bowel disease (i.e., double antigen ELISA and antihuman lambda chain ELISA) (Kopylov, 2012). This study did not include an objective, clinical and endoscopic scoring system for validation of results.

Treatment options for patients with secondary loss of response to infliximabanti-TNF therapy

A diminished or suboptimal response to infliximab, adalimumab, vedolizumab, or ustekinumab can be managed in several ways: shortening the interval between doses, increasing the dose, switching to a different biologic agent (in patients who continue to have a loss of response after receiving the increased dose), or switching to a non-biologic agent.

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 Act (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, a College of American Pathologists‒accredited lab under the CLIA, offers 4 non-radio-labeled, fluid-phase homogenous mobility shift assay tests: Anser IFX (for infliximab), Anser ADA (for adalimumab), Anser VDZ (for vedolizumab), and Anser UST (for ustekinumab). The tests measure both serum drug concentrations and ADA. They are not based on an ELISA test and can measure ADA in the presence of detectable drug levels, improving on a major limitation of the ELISA method.

Coding

According to materials from Prometheus on Anser™IFX , Anser™ADA, Prometheus Anser™ VDZ and Prometheus Anser™ UST, these tests will be reported using CPT code 84999 (unlisted chemistry procedure).

Policy/
Coverage:

Effective June 2018

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Measurement of serum antibodies to infliximab

Measurement of serum antibodies to infliximab in a patient receiving treatment with infliximab, either alone or as a combination test which includes the measurement of serum infliximab levels, does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, measurement of serum antibodies to infliximab in a patient receiving treatment with infliximab, either alone or as a combination test which includes the measurement of serum infliximab levels, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Measurement of serum antibodies to adalimumab

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 does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, 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, is considered investigational.

Measurement of serum antibodies to vedolizumab

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, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, 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, is considered investigational.

Measurement of serum antibodies to ustekinumab

Measurement of antibodies to ustekinumab in a patient receiving treatment with ustekinumab, either alone or as a combination test which includes the measurement of serum ustekinumab levels, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, measurement of antibodies to ustekinumab in a patient receiving treatment with ustekinumab, either alone or as a combination test which includes the measurement of serum ustekinumab levels, is considered investigational.

Effective Prior to June 2018

Measurement of serum antibodies to infliximab

Measurement of serum antibodies to adalimumab

Effective prior to September 2013

Rationale:

This policy was created in 2012 and is based on a search of the MEDLINE database through July 2012. Literature that describes the analytic validity, clinical validity, and clinical utility of measuring serum antibodies to infliximab was sought. Most studies of antibodies to infliximab report on both serum infliximab levels, as well as levels of antibodies to infliximab, and correlate these levels to response rates of disease. Serum infliximab levels and disease response will not be addressed in this policy and therefore the data reported on antibodies to infliximab will be highlighted from the aforementioned studies.

Most of the data on the use of measurements of antibodies to infliximab are from patients with inflammatory bowel disease, with limited literature for other diseases such as rheumatoid arthritis.

Analytic and clinical validation of measurements of antibodies to infliximab

Wang and colleagues developed and validated a non-radiolabeled homogeneous mobility shift assay (HMSA) to measure the antibodies-to-infliximab (ATI) and infliximab levels in serum samples (Wang, 2012). Full method validation was performed on both the ATI- and infliximab-HMSA, and the clinical sample test results were compared with those obtained from a bridging ELISA method to evaluate the difference in performance between the 2 assays. Intra- and inter-assay precision rates (as indicated by the coefficient of variation [CV]) for the ATI- and infliximab-HMSA were <4% and <15%, respectively, and <6% and <15%, respectively, considered to be robust.

Sera from 100 healthy subjects (obtained from blood bank donors) were tested to determine the cut points of the assay. The false positive rate with this cut point was 3%.

One hundred serum samples that previously had tested positive with ELISA were reanalyzed by the new method. There was a high correlation between the 2 methods for ATI levels (p<0.001). The new method identified 5 false-positive samples from the bridging ELISA method, thought to be due to a higher rate of nonspecific binding in the ELISA method.

A systematic review of the literature up to October 2008 by Cassinotti and Travis was undertaken to determine whether ATI have any clinical importance for infliximab efficacy or safety (Cassinotti, 2008). The authors offered the following findings from their review: that the biological and clinical mechanisms of ATI development are poorly understood, that the incidence of ATI in vivo depends on multiple analytical and clinical factors (both patient- and treatment-related), that the presence of ATI is weakly and variably associated with clinical response and infusion reactions (but not with reactions relevant to clinical decision making), and that enormous variation in the methods of reporting ATI and immunogenicity of infliximab make almost any interpretation possible from different studies (few with clinical relevance). Conclusions of the systematic review were that there was no clear evidence that ATI have an impact on efficacy or safety, nor is there a need to measure or prevent them in clinical practice.

A meta-analysis by Lee and colleagues was conducted in patients with inflammatory bowel disease (IBD) receiving infliximab to determine: the prevalence of ATI, the effect of ATI on the prevalence of infusion reactions, and the effect of ATI on disease remission rates (Lee, 2012). Databases were searched through October 2011, and 18 studies involving 3,326 patients were included. Studies included 9 randomized controlled trials (RCTs), 5 cohort studies and 4 retrospective cohort studies. The prevalence of ATI was 45.8% when episodic infusions of infliximab were given and 12.4% when maintenance infliximab was given. The rates of infusion reactions were significantly higher in patients with ATI (relative risk [RR]: 2.07; 95% confidence interval [CI]: 1.61–2.67). Immunosuppressants resulted in a 50% reduction in the risk of developing ATI (P<0.00001). Patients with ATI were less likely to be in clinical remission, but this was not statistically significant (RR: 0.90; 95% CI: 0.79-1.02; p=0.10). The meta-analysis concluded that patients who test positive for ATIs are at an increased risk of infusion reactions, but have similar rates of remission compared with patients who test negative for ATIs.

Clinical utility of antibodies to infliximab

Inflammatory bowel disease

Afif and colleagues evaluated the clinical utility of measuring ATI (referred to as HACA in the study) and infliximab concentrations by retrospectively reviewing the medical records of patients with inflammatory bowel disease (IBD) who had had ATI and infliximab concentrations measured. The study sought to determine whether these results affected clinical management (Afif, 2010). Medical record review from 2003 to 2008 identified 155 patients who had had ATI and infliximab concentrations measured and who met the study inclusion criteria. Seventy-two percent of the initial tests were ordered by a single physician. Clinical response to infliximab was retrospectively determined by the authors. Forty-seven percent of patients 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 patients (23%) and therapeutic infliximab concentrations in 51 patients (33%). Of 177 tests assessed, the results impacted treatment decisions in 73%. In ATI-positive patients, change to another anti-TNF agent was associated with a complete or partial response in 92% of patients, 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 patients with ATI was ineffective, whereas in patients with subtherapeutic infliximab concentrations, this strategy was considered a good alternative to changing to another anti-TNF agent (Afif, 2010). Limitations to the study included its retrospective design and that the testing for antibodies to infliximab was performed using the enzyme-linked immunoabsorbant assays (ELISA) method. Since 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 patients who do not achieve or maintain a clinical response, and it is important to understand how these management decisions differ when ATI are measured.

Steenholdt and colleagues attempted to establish clinically relevant threshold levels of infliximab and/or ATI (Steenholdt, 2011). A total of 106 patients with IBD (85 with Crohn’s disease [CD] and 21 with ulcerative colitis [UC]) were identified over the course of 10 years (2001 to 2010). All patients were receiving infliximab treatment for IBD, as well as concurrent medications to prevent acute infusion reactions and to limit the development of ATI. Patients who received infliximab maintenance therapy were classified as having 1 of 2 responses: maintenance of response (patients had a good clinical response to infliximab induction therapy and continued this response over the course of maintenance treatment) or loss of response (patients who initially experienced a good clinical response to infliximab induction therapy but subsequently lost this response during maintenance treatment, resulting in discontinuation of therapy).

The classification of infliximab response was based on clinical assessment; investigators were blinded to the results of the serum trough level analyses. Trough levels of infliximab and/or ATI were measured as the serum concentration immediately prior to an infusion of infliximab, using a radioimmunoassay. Of the CD patients, 69% maintained their response to infliximab, and the remaining 31% had loss of response. Baseline characteristics of the 2 groups were well-balanced, and there were no significant differences in the total number of infliximab infusions administered to the 2 groups. Infliximab trough levels were significantly increased among CD patients who maintained response to therapy compared to patients who lost response (p<0.0001). Using data from these patients, the authors assigned a cutoff value of 0.5 μg/mL as clinically relevant for infliximab trough concentrations. Trough concentrations less than 0.5 were associated with a sensitivity of 86% (95% CI: 64-97) and a specificity of 85% (95% CI: 72-94) for identifying patients with a loss of response to infliximab maintenance therapy. Trough levels of ATI were significantly higher in CD patients who had lost response to infliximab maintenance therapy compared to patients who had maintained response; p<.0001). Using these data, the authors defined a cutoff value of 10 U/mL as clinically relevant for ATI concentrations. ATI trough levels of 10 U/mL or higher were associated with a sensitivity of 81% (95% CI 61-93) and a specificity of 90% (95% CI 79-96) for the identification of CD patients who had lost response to infliximab maintenance therapy. Similar determinations of infliximab and anti-infliximab antibody trough levels were made in the UC patients, although this group of patients was much smaller.

Limitations to this study included that it was retrospective and small, there was a lack of definitive criteria for response to infliximab maintenance therapy, and maintenance or loss of response was determined by chart review. Also, this study did not examine the changes in management made as a result of testing for ATI.

A commentary on the Steenholdt study (Steenholdt, 2011) noted the limitations of the study and highlighted that the decision to continue or discontinue infliximab was based on clinical assessment by the gastroenterologist and not on infliximab trough level or ATI status, and that infliximab serum levels were measured as trough levels just prior to infliximab infusions but not at any other point in time. The commentary also stated that prospective studies should be required to base decision analyses on these cutoff levels and to see whether they support treatment algorithms to either increase infliximab dosage (low infliximab trough levels, no ATI), change to another anti-TNF monoclonal antibody (high ATI levels), or switch to another class of TNF inhibitors (adequate infliximab trough levels, no ATI).

Rheumatoid arthritis

Finckh and colleagues tested whether the presence of ATI and residual circulating infliximab levels prior to another infusion were associated with acquired infliximab resistance in rheumatoid arthritis (RA) (Finckh, 2010). A multivariate logistic regression was used to analyze the relationship between ATI, residual infliximab concentrations, and acquired infliximab resistance in a nested cohort within a Swiss RA registry. Sixty-four RA patients on longstanding infliximab therapy were included; 24 had an acquired therapeutic resistance to infliximab, and 40 had continuous good response to infliximab. The 2 groups had similar disease characteristics, however, patients with acquired infliximab resistance required significantly higher dosages of infliximab and shorter infusion intervals than long-term good responders. The presence of residual infliximab tended to be associated with a decreased risk of acquired therapeutic resistance (odds ratio [OR] 0.4, 95% CI: 0.1-1.5), while the presence of ATIs tended to be associated with an increased risk of acquired therapeutic resistance (OR: 1.8, 95% CI: 0.4 - 9.0). The presence of either high ATI levels or low residual infliximab concentrations was strongly associated with acquired therapeutic resistance to infliximab (OR: 5.9, 95% CI: 1.3 - 26.6). However, just 42% of patients with acquired infliximab resistance had either low infliximab or high ATI levels. The authors concluded that their results suggested that the assessment of ATIs and residual infliximab levels is of limited value for individual patients in routine clinical care.

Bendtzen and colleagues conducted a study to investigate whether serologic monitoring of infliximab bioavailability and immunogenicity in individual patients with RA would be useful to optimize treatment regimens to improve efficacy and tolerability (Bendtzen, 2006). Measurement of levels of anti-infliximab antibodies was by radioimmunoassay. Sera from 106 randomly selected RA patients were tested within 6 months of therapy initiation, and associations between findings of serum assays and disease activity, infusion reactions, and treatment failure occurring within 18 months were assessed. The trough serum infliximab levels after the first 2 intravenous infusions varied considerably between patients. At this stage, only 13% of the patients were anti-infliximab antibody positive. With subsequent infusions, the frequency of antibody positivity rose to 30% and 44% (at 3 months and 6 months, respectively), accompanied by diminished trough levels of infliximab. Low infliximab levels at 1.5 months predicted antibody development and later treatment failure. There were highly significant correlations between high levels of antibodies and later dose increases, side effects, and cessation of therapy. Cotreatment with methotrexate resulted in slightly reduced antibody levels after 6 months; other disease-modifying antirheumatic drugs and prednisolone had no effect. The authors concluded that the development of anti-infliximab antibodies, heralded by low pre-infusion serum infliximab levels, was associated with increased risk of infusion reaction and treatment failure and that early monitoring may help optimize dosing regimens for individual patients, diminish side effects, and prevent prolonged use of inadequate infliximab therapy.

Summary

Antibodies to infliximab (ATI) are present in a substantial number of patients treated with infliximab, and there may be a correlation between the level of these antibodies and clinical response. However, the clinical utility of measuring anti-infliximab antibody concentrations has not been established, as it is not known how patient management would change based on test results. Limited evidence describes changes in management after measurement of ATI, but does not compare these management changes to those made in the absence of ATI measurement. In addition, there are technical factors relating to the use of different assay methods across studies, it has not yet been established whether the use of threshold levels aids in the discrimination of response to infliximab, nor has the optimal timing of when to measure antibody levels been established.

2013 Update

This policy is updated with a literature search of the MEDLINE database through August 2013. Information has been added to the policy on the measurement of antibodies to adalimumab. The following is a summary of the key identified literature.

Analytic and Clinical Validity:

Measurement of antibodies to adalimumab

Wang and colleagues developed and validated a non-radiolabeled HMSA to measure antibodies-to-adalimumab (ATA) and adalimumab levels in serum samples (Wang, 2013). Analytic validation of performance characteristics (calibration standards, assay limits, intra- and inter-assay precision, linearity of dilution, and substance interference) was performed for both the ATA- and adalimumab-HMSA. Because the elimination half-life of adalimumab (10-20 days) overlaps the dosing interval (every 2 weeks), ATA-positive sera to provide calibration standards were difficult to collect from human patients. (The drug-free interval for antibody formation is small.) Therefore, antisera from rabbits immunized with adalimumab were pooled to form calibration standards. Serial dilutions of these ATA calibration standards then generated a standard curve against which test samples were compared. Over 29 experimental runs, intra-assay precision and accuracy for the adalimumab-HMSA (as indicated by the coefficient of variation [CV]) was <20% and <3%, respectively; inter-assay (run-to-run, analyst-to-analyst and instrument-to-instrument) precision and accuracy were <12% and <22%, respectively. For the ATA-HMSA, CVs for intra-assay precision and accuracy were <3% and <13%, respectively; CVs for inter-assay precision and accuracy were <9% and <18%, respectively. ELISA could not be used as a standard comparator due to competition from circulating drug.

Sera from 100 healthy subjects (obtained from blood bank donors) were tested to determine the cut points of the assay, defined as the threshold above which samples were deemed to be positive with an upper negative limit of approximately 99%. The calculated cut point for serum adalimumab levels was 0.68 μg/mL, which yielded a false positive rate of 3%. For ATA, the calculated cut point was 0.55 U/mL, which yielded a false positive rate of 1%.

Analysis of 100 serum samples from patients who were losing response to adalimumab showed that 44% were above the cut point for ATA, and 26% were below the cut point for serum adalimumab level. In samples below the adalimumab cut point (0.68 μg/mL), 68% were ATA positive; in samples with adalimumab levels >20 μg/mL, 18% were ATA positive.

Korswagen and colleagues reported on 3 patients (2 with rheumatoid arthritis and 1 with psoriatic arthritis) who developed severe venous and arterial thromboembolic events during treatment with adalimumab (Korswagen, 2011). All 3 patients had ATA detected using RIA. The authors conducted a retrospective search for thromboembolic events among 272 consecutive patients with rheumatoid arthritis treated with adalimumab at a single institution in The Netherlands. Arterial thromboembolic events were defined as myocardial infarction, cerebrovascular accident, transient ischemic attack, peripheral arterial thrombosis, and small-vessel occlusion. Venous thromboembolic events were defined as deep vein thrombosis with or without pulmonary embolism, superficial vein thrombosis, and thrombosis at unusual sites. Serum samples were collected at baseline and just before adalimumab injection at 1, 3, and 6 months after baseline and every 6 months thereafter. Eight thromboembolic events were found, 4 of which occurred in patients with ATA. Incidence rates were 26.9/1,000 person-years for patients with ATA and 8.4/1,000 person-years for patients without ATA. Unadjusted hazard ratio (HR) was 3.8 (95% CI: 0.9–15.3), p=0.064; adjusted (for duration of followup, age, body mass index, erythrocyte sedimentation rate, and previous thromboembolic events) HR was 7.6 (95% CI: 1.3–45.1), p=0.025. Because the incidence of thromboembolic events before adalimumab treatment (7.4/1,000 person-years) was close to that observed in ATA-negative adalimumab-treated patients, the authors suggest that the observed result was not due to systemic inflammation associated with rheumatoid arthritis. A subsequent report suggested that thromboembolic events associated with anti-TNF therapy is more likely due to TNF inhibition and the predisposition of some patients to lupus-like reactions, including antiphospholipid syndrome. (10) All 3 patients described by Korswagen had antibodies to double-stranded DNA (dsDNA), phospholipids, and/or β2-glycoprotein.

This same cohort was assessed for development of ATA and the clinical relevance of ATA during 3 years of follow-up (Bartelds, 2011). After 3 years of adalimumab treatment, ATA were detected by RIA in 28% of patients (n=76). ATA titers correlated with adalimumab serum levels (measured by ELISA). In comparison with ATA-negative patients (n=196), ATA-positive patients were more likely to discontinue participation in the study due to treatment failure (38% vs. 14%, HR 3.0 [95% CI: 1.6-5.5], p<0.001). ATA-negative patients were more likely than ATA-positive patients to:

Have sustained minimal disease activity score in 28 joints (DAS28 <3.2; 48% vs. 13%; HR 3.6 [95% CI: 1.8-7.2; p<0.001).
Achieve sustained remission (DAS28 <2.6; 34% vs. 4%; HR 7.1 [95% CI: 2.1-23.4], p<0.001).

Measurement of antibodies to infliximab or adalimumab

Garces et al. conducted a meta-analysis of studies of infliximab and adalimumab used to treat rheumatoid arthritis, ankylosing spondylitis, spondyloarthritis, psoriasis, Crohn’s disease, and ulcerative colitis (Garces, 2012). Databases were searched to August 2012, and 12 prospective cohort studies involving 860 patients (540 with rheumatoid arthritis, 132 with spondyloarthritis, 130 with IBD, and 58 with psoriasis) were included. The outcome of interest was drug response, assessed by using standard assessment scales for rheumatologic diseases (e.g., European League Against Rheumatism [EULAR] criteria for rheumatoid arthritis; Assessment in Ankylosing Spondylitis 20% response criteria or Anklylosing Spondylitis Disease Activity Score for spondyloarthritis; Psoriasis Area and Severity Index for psoriasis) and clinician assessment for IBD. Overall, detectable anti-drug antibodies were associated with a 68% reduction in drug response (pooled risk ratio [RR] 0.32 [95% CI: 0.22–0.48]). Significant heterogeneity was introduced by varying use of immunosuppressant co-therapy (e.g., methotrexate) across studies. To assess anti-drug antibodies, most studies used RIA, which is less susceptible than ELISA to drug interference and may be more accurate.

Conclusions: Analytic validity of ATI testing was demonstrated using ELISA as a standard comparator. Test performance characteristics were considered robust. 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 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. Evidence for the clinical validity of ATI and ATA measurements suggests clinical correlations with infusion reactions and response to treatment. However, this evidence is mixed and limited in some cases by flawed study designs. Heterogeneity in patient populations, use of concomitant immunosuppressants, methods and timing of antibody measurements, and outcome measures limits cross-study comparisons .One study (6) identified publication bias.

Antibodies to adalimumab

Studies of the clinical utility of ATA measurement have not been published. Information about the Anser™ADA test is provided by Prometheus on its website. Several posters presented at the Annual Digestive Disease Week conference in May 2013 that address the clinical validity of the test are cited (Afif, 2010) and the use of clinical assessments to guide treatment decisions (Steenholdt, 2011). Finally, determination of a clinically relevant threshold for ATI level is complicated by the use of varyious assay methods.

Conclusions: Evidence for the clinical utility of ATI and ATA testing currently is lacking. Uncontrolled retrospective studies in IBD demonstrate impacts of ATI testing on treatment decisions but cannot demonstrate improved patients outcomes compared to a no-testing strategy. Additional limitations of these studies include lack of clinical follow-up after treatment decisions were made and the use of clinical assessments to guide treatment decisions (Steenholdt, 2011). Finally, determination of a clinically relevant threshold for ATI level is complicated by the use of varyious assay methods.

Summary

Therefore, the measurement of antibodies to infliximab in a patient receiving treatment with infliximab does not meet primary coverage criteria and is considered investigational, and the measurement of antibodies to adalimumab in a patient receiving treatment with adalimumab does not meet primary coverage criteria and is considered investigational

Practice Guidelines and Position Statements

Current clinical guidelines from the American College of Gastroenterology and the National Institute for Health and Care Excellence (NICE) do not recommend antidrug antibody testing for patients treated with TNF inhibitors.

Ongoing Clinical Trials

A search of the online ClinicalTrials.gov database in August 2013 identified one relevant randomized controlled trial that is currently in progress, NCT00851565. The study is entitled, “Use of Combined Measurements of Serum Infliximab and Anti-infliximab Antibodies in the Treatment of Patients with Crohn’s Disease Failing Infliximab Therapy.” Adults with Crohn’s disease who relapsed after a previous good response to infliximab are eligible. Target enrollment is 120 patients. In the intervention group, management of loss of response to infliximab will be guided by serum infliximab and ATI levels according to a prespecified algorithm. In the control group, loss of response will be managed according to current standards of care (i.e., to increase infliximab dose) without knowledge of serum infliximab or ATI levels. Primary outcome measures are the proportion of patients with response at week 12, defined by reduction in CDAI for patients with luminal disease or by reduction in draining fistulas in patients with fistulizing disease (non-inferiority endpoint), and expenses related to Crohn’s disease (superiority endpoint). The primary completion date (final data collection) was February 2012, and the study completion date is February 2014.

2014 Update

A literature search conducted through September 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

In 2014, Steenholdt et al published a post hoc comparison of different ATI assays.4 Blood samples were collected from 66 (96%) of 69 patients enrolled in a randomized controlled trial (RCT) (discussed next) that assessed algorithmic treatment for Crohn disease (CD) relapse during infliximab therapy (Steenholdt, 2014). Samples were analyzed by 3 binding assays– radioimmunoassay (RIA), ELISA, and HMSA – and by a reporter gene assay, a functional cell-based technique. ATI were detected in 18 patients (27%) by radioimmunoassay, 6 patients (9%) by ELISA, and 22 patients (33%) by HMSA. The reporter gene assay reported anti-infliximab activity, most likely due to ATI, in 7 patients (11%). As observed by the authors, this suggests that ATI detected by RIA and HMSA are not necessarily functionally active. Five patients (8%) were ATI-positive and 43 patients (65%) were ATI-negative by all 4 assays. Correlations were statistically significant (p<0.001) in all pairwise comparisons (Pearson r, 0.77-0.96). However, statistical agreement between assays could not be estimated accurately (eg, using the intraclass correlation coefficient) because different assays reported values on different arbitrary scales. Regardless of assay used, most patients (74%-88%) had therapeutic serum infliximab levels and undetectable ATI, suggesting nonpharmacologic reasons for relapse or for symptoms mimicking relapse.

Several authors have published algorithms for management of patients with IBD Eser, 2013; Khanna, 2013; Lichtenstein, 2013) or RA (Garces, 2014) who relapse during TNF-inhibitor therapy. These algorithms are generally based on evidence, including that reviewed earlier, that indicate an association between anti-drug 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.

In 2014, Steenholdt et al published a randomized 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 (Steenholdt, 2014). Patients were randomized to infliximab dose intensification (5 mg/kg every 4 weeks) or algorithmic treatment based on serum infliximab level and ATI: Patients with subtherapeutic infliximab level (<0.5mcg/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 by RIA 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 non-fistulizing disease. Most patients (70%) had therapeutic serum infliximab levels without detectable ATI; revised diagnoses in 6 (24%) of 25 such patients in the algorithm arm22 included bile acid malabsorption, strictures, and IBS. In both intent-to-treat 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 (intent to treat: 58% in the algorithm group vs 53% in the control group; chi-square, p=0.810; per-protocol: 47% in the algorithm group vs 53% in the control group; chi-square, p=0.781). However, only the intent-to-treat analysis fell within the prespecified non-inferiority margin of –25% for the difference between groups.

Conclusions that can be drawn from this study are limited; ie, an algorithmic approach to management of patients who relapse during infliximab therapy may or may not be noninferior (equivalent) to dose intensification. Study flaws include that the reported power calculation indicated that the study was underpowered to detect a difference between treatment groups. A large non-inferiority margin that permitted 50% fewer patients to respond to algorithm-based treatment compared with control (dose intensification) has uncertain clinical value. Investigators were unblinded to serum infliximab and ATI levels. Cut-off values for therapeutic infliximab levels and ATI were derived from a single retrospective study (Steenholdt, 2011). Drop-outs were large 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 algorithm arm were 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).

In 2014, Roblin et al published a single-center, prospective observational study of 82 patients who had IBD (n=45CD, n=27 UC) with clinical relapse (CDAI >220 or Mayo Clinic >5) during treatment with adalimumab 40 mg every 2 weeks (Roblin, 2014a). Patients with fistulizing CD were apparently not enrolled. For all patients, trough adalimumab levels and antibodies to adalimumab 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 mcg/mL) (Roblin, 2014b), (2) those with subtherapeutic adalimumab level and undetectable ATA; and (3) those with subtherapeutic adalimumab level and detectable ATA. After adalimumab optimization, more patients in group 2 achieved clinical remission (16 [67%] of 24 patients) compared with group 1 (12 [29%] of 41 patients; chi-square, p<0.01 vs group 2) and group 3 (2 [12%] of 17 patients; Fisher’s exact test, 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 patients in group 2 maintained clinical remission compared with no patients in group 1 or group 3 (Fisher’s exact test, p<0.01 for both comparisons vs group 2). Results were similar when remission was defined using calprotectin levels (<250 mcg/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) compared with group 1 (2 [7%] of 29 patients) and group 2 (2 [25%] of 8 patients; Fisher’s exact test, 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 patients in group 3 maintained clinical remission compared with no patients in group 1 or group 2 (Fisher’s exact test, 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 patients 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 patients 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 preliminary due to the small sample size, use of ELISA for antibody testing, and lack of randomization; a comparison of patient characteristics across the 3 groups was not provided, and potential confounders are unknown. Replication in a larger study with randomization to treatment based on clinical response or treatment based on serum drug level and ATA monitoring is required. Ideally, more than one method of antibody assay would be used to further assess analytic validity.

A small, nonrandomized prospective study suggested that ATA levels may be informative in relapsed patients with IBD who have low serum adalimumab levels, but this finding requires confirmation in larger, randomized trials. Conclusions that can be drawn from 1 RCT in patients with relapsed IBD are limited by substantial methodologic flaws, including incorrect diagnosis of relapse in most patients.

A search of online site ClinicalTrials.gov identified 3 active Phase 4 RCTs that are assessing anti-TNF inhibitor antibodies in rheumatic conditions (see Table 1). A trial in patients with RA compares clinical response and antibody formation with various biologic agents (NCT01638715); a trial in patients with ankylosing spondylitis assesses reduction in ATA with addition of methotrexate (COMARIS; NCT01895764); and a trial in patients with spondyloarthritis compares a dose intensification strategy with a strategy guided by TNF-inhibitor drug level and antibody formation using clinical outcomes (STRADA; NCT01971918).

Active Trials of Anti-TNF Antibodies Listed at ClinicalTrials.gov

Rheumatoid Arthritis (NCT01638715) A Randomized, Multi-Center Biomarker Trial to Predict Therapeutic Responses of Patients With Rheumatoid Arthritis to a Specific Biologic Mode of Action with an enrollment of 200 participants and primary completion date of June 2015.

Spondylarthropathies (NCT01895764) Effect of the Combination of Methotrexate and Adalimumab on Reduction of Immunization in Ankylosing Spondylitis (COMARIS) with an enrollment of 110 subjects and primary completion date of March 2016.

Spondylarthropathies (NCT01971918) Comparative Analysis of Two Therapeutic Strategies in Patients With Spondyloarthritis Treated With Anti-TNF Biologics (STRADA) with an enrollment of 104 subjects and primary completion date of November 2016.

2016 Update

A literature search conducted through September 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

Measurement of Antibodies to Adalimumab

Wang and colleagues (2013) developed and validated a non-radiolabeled HMSA to measure antibodies-to-adalimumab (ATA) and adalimumab levels in serum samples (Wang, 2013). Analytic validation of performance characteristics (calibration standards, assay limits, intra- and inter-assay precision, linearity of dilution, substance interference) was performed for both the ATA- and adalimumab-HMSA. Because the elimination half-life of adalimumab (10-20 days) overlaps the dosing interval (every 2 weeks), ATA- positive sera to provide calibration standards were difficult to collect from patients. (The drug-free interval for antibody formation is short.) Therefore, antisera from rabbits immunized with adalimumab were pooled to form calibration standards. Serial dilutions of these ATA calibration standards then generated a standard curve against which test samples were compared. Over 29 experimental runs, intra-assay precision and accuracy for the adalimumab-HMSA (as indicated by the CV) were less than 20% and 3%, respectively; inter-assay (run-to-run, analyst-to-analyst, and instrument-to-instrument) precision and accuracy were less than 12% and less than 22%, respectively. For the ATA-HMSA, CVs for intra-assay precision and accuracy were less than 3% and 13%, respectively; CVs for inter-assay precision and accuracy were less than 9% and less than 18%, respectively. ELISA could not be used as a standard comparator due to competition from circulating drug.

Following evaluation of analytic validity of the a non-radiolabeled HMSA assay, Wang et al (2013) tested sera from 100 healthy subjects (obtained from blood bank donors) to determine the cut points of the assay, defined as the threshold above which samples were deemed to be positive with an upper limit of approximately 99%. The calculated cut point for serum adalimumab levels was 0.68 μg/mL, which yielded a false-positive rate of 3%. For ATA, the calculated cut point was 0.55 U/mL, which yielded a false-positive rate of 1%. Analysis of 100 serum samples from patients who were losing response to adalimumab showed that 44% were above the cut point for ATA, and 26% were below the cut point for serum adalimumab level. In samples below the adalimumab cut point (0.68 μg/mL), 68% were ATA positive; in samples with adalimumab levels greater than 20 μg/mL, 19% were ATA-positive.

Section Summary: Analytic Validity

Analytic validity of ATI testing by homogeneous mobility shift assay 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 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 (Meroni, 2015).

Clinical Validity

There is a substantial body of evidence examining associations of ADA with nonresponse and injection or infusion site reactions; numerous systematic reviews and meta-analyses have been published. Accordingly, the review of evidence concerning clinical validity focuses on the most current systematic reviews and studies published subsequent to the search dates of those reviews (White, 2008) as well as relevant studies not included in identified reviews, for example those focusing on adverse reactions and ADA.

Systematic Reviews and Meta-Analyses

Five reviews published from 2012 through 2015 were identified (Garces, 2013; Lee, 2012; Meroni, 2015; Nanda, 2013; Thomas, 2015). The number of included studies ranged from 11 (Nanda, 2013) to 68 (Thomas, 2015), varying according to review objectives and conditions of interest. Although not detailed here, there was considerable overlap in included studies across reviews

A systematic review and meta-analysis by Thomas and colleagues (Thomas, 2015) included 68 studies (14,651 patients) in patients with RA (n=8766), SpA (n=1534), and IBD (n=4351) and examined the immunogenicity of infliximab (39 comparisons), adalimumab (15), etanercept (5), golimumab (14), and certolizumab (8). The review identified studies published through December 2013 and included 38 RCTs and 30 observational studies (study quality rated as good [n=32], moderate [n=26], or poor [n=10]). The pooled prevalence of ADA varied with disease and drug (Table 1, highest with infliximab 25.3%). Duration of exposure (reported in 60 studies) was examined for its potential effect on the development of ADA and most studies employed ELISA assays. The presence of ADA was associated with lower odds of response across most drugs and diseases (see Table 2). An exception was in studies of IBD (similar to that reported by Lee et al). The use of immunosuppressive agents substantially decreased the risk of ADA (odds ratio [OR], 0.26; 95% CI, 0.21 to 0.32). Finally, infusion reactions and injection site reactions were more common (Table 3) when ADA were detectable (OR=3.25; 95% CI, 2.35 to 4.51). Evaluation of potential publication bias, or overall assessment (eg GRADE or similar) for the body of evidence was not reported. Additionally, no measures of heterogeneity were reported.

The systematic review by Meroni and colleagues (Meroni, 2015) searched Pubmed through March 2013 and included 57 studies of infliximab (n=34), adalimumab (n=18), and etanercept (n=5). Studies included primarily patients with IBD and RA, but also SpA and psoriasis. Most studies were prospective cohort designs (n=42) and a formal assessment of study quality (bias) was not reported. The authors noted considerable variability in the time from drug administration to ADA and drug bioavailability testing across studies. Varied antibody testing assay methods were used including solid-phases RIA, traditional ELISA, fluid-phase RIA, and bridging ELISA; cutoffs for positive test results were also inconsistently reported. The ranges of patients with detectable ADA varied substantially but were consistent with other reviews. Qualitatively, the presence of ATI was associated with lower infliximab levels and lower risk of disease control or remission. The presence of ATI also increased the risk of infusion reactions. When ascertained, the time to development of ATI varied from as little as 16 weeks to over a year. The time to ATA positivity varied e.g., 50% of patients with detectable ATA at 28 weeks to a median time of 1 year. Finally, for both infliximab or adalimumab immunosuppression was associated with less ADA positivity. The authors concluded that "the lack of homogeneity in study design and methodologies used in the studies analyzed limited the opportunity to establish the time-course and clinical consequences of anti-drug antibody development...." Although qualitative, the authors included many studies, and provided a detailed review of each study not reported by the other meta-analyses. The author’s conclusions are consistent with the meta-analyses but with emphasis on important aspects of heterogeneity across studies.

Studies of Clinical Validity Published Subsequent to Searches of Systematic Reviews

Three recent publications not included in a systematic review were identified (Arstikyte, 2015; Frederiksen, 2014; Jani, 2015). Results were consistent with conclusions of the systematic reviews.

Arstikyte and colleagues (Arstikyte, 2015) prospectively evaluated the association of ADA with adverse events, clinical response, and drug levels in 143 symptomatic patients (62 with RA, 81 with SpA; mean age 45 years [SD=13]) treated with TNF blockers in Lithuania. All patients receiving adalimumab or infliximab were tested and 1 of 3 patients given etanercept (because more commonly used). A response in RA patients was defined was either good, moderate, or low according to EULAR criteria (van Gestel, 1996); and SpA disease activity considered inactive, moderate, high, or very high according to established criteria (Castillo-Gallego, 2011) with inactive and moderately active disease defined as response. At least 3 months after therapy initiation, a single serum sample was obtained prior to dosing between January 2012 and December 2013; disease activity and other patient characteristics (eg, symptom duration, health status) were assessed concurrently. Serum adalimumab, infliximab, and etanercept levels were obtained; ADA was assayed using a bridging ELISA. Of 57 patients receiving infliximab, 14 (24.6%) had detectable antibodies with 13 of the 14 undetectable infliximab trough levels. Disease activity at baseline was unassociated with the development of ADA in either disease. In patients achieving response infliximab and adalimumab trough levels were higher, but not significantly (p=0.09 and p=0.14 respectively). Adalimumab concentrations were, however, higher in nonresponders (p<0.001). Antibodies to infliximab were associated with infusion reactions but with little certainty (OR=5.9; 95% CI, 1.0 to 33.3) as was stopping infliximab treatment or changing agent. Study strengths include its prospective design, standardized assessments, and responder definition. Limitations involve the small number of nonresponders and no indication whether any eligible participants declined enrollment. Finally, the associations reported are consistent with other reports and ADA results were not apparently used in decision-making.

Frederiksen and colleagues (Frederiksen, 2014) conducted a single-center retrospective cohort study of IBD patients treated with infliximab (n=187) or adalimumab (n=57) in Denmark. ADA were assayed using fluid-phase RIA 49% of infliximab-treated patients developed antibodies compared with 21% of those treated with adalimumab. Development of antibodies to adalimumab was associated with secondary nonresponse PPV 0.91 (95% CI, 0.59 to 1.0), sensitivity 0.50 (95% CI, 0.27 to 0.73), NPV 0.74 (95% CI, 0.57 to 0.87), specificity 0.97 (95% CI, 0.82 to 1.0) (with values varying according to adalimumab trough levels). The authors also reported that patients switching to adalimumab from infliximab who had antibodies were more likely to develop antibodies to adalimumab. The findings are consistent with other studies and evaluation of ADI using RIA (strength of the study). However, conclusions are limited by the retrospective nature and sample size.

Jani and colleagues (Jani, 2015) measured ADA by RIA together with drug levels in 331 RA patients treated with adalimumab (n=160) and etanercept (n=171) between November 2008 and March 2013. Patients were participants in the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate conducted in 60 UK centers across the UK. Disease activity was assessed using the Disease Activity Score in 28 joints (DAS28) score. A response was evaluated using EULAR response criteria or changed DAS28 score. Following 12 months of adalimumab therapy, ADA were detectable in 24.8% of patients (almost all were detectable by 6 months) and were associated with lower drug levels. Both routine (non-trough) drug levels and antibodies to adalimumab were associated with DAS28 at 12 months. In predicting EULAR nonresponse, the AUC for adalimumab concentration less than 5 mg/mL at 3 months was 0.66 (95% CI, 0.55 to 0.77) and for presence of ADA 0.68 (95% CI, 0.54 to 0.81). None of the etanercept patients developed detectable ADA. Although derived from a well-established observational study designed to examine predictors (genetic and other) of treatment response, ADA levels were not used to inform treatment decisions. These results corroborate other study findings.

While many studies have evaluated clinical validity using single ADA measurements, at least one study assessed their persistence over time. Casteele and colleagues (Casteele, 2013) analyzed infliximab trough and ATI levels using an HMSA assay with banked serum obtained from 90 IBD patients treated between May 1999 and August 2011. ATI levels had been previously assayed using an ELISA-based test. A total of 1232 samples were evaluated (mean 14 per patient). Treatment decisions were made solely on clinical evaluation and CRP levels. ATI were detected in 53 of 90 (59%) of patients but subsequently were non-detectable in 15 of the 53 (28%). Persistent ATIs were associated with discontinuation of infliximab (RR=5.1; 95% CI, 1.4 to 19.0), but the wide confidence interval reflects considerable uncertainty. Although transience of ATI in IBD has not been carefully scrutinized, if replicated, these results suggest interpreting a single ATI result cautiously.

Summary of Evidence

The evidence for measuring anti-TNF- a inhibitor antibodies in patients who have rheumatoid arthritis, Crohn disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, or juvenile idiopathic arthritis 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 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 results inform management changes leading to improved outcomes compared with management directed by symptoms, clinical assessment, and standard laboratory evaluation. Limited evidence describes management changes after measuring ADA. A small, randomized controlled trial in patients with CD comparing ATI-informed management of relapse with standard dose escalation did not demonstrate improved outcomes with the ATI approach. Additionally, many different assays—some having significant limitations—have been utilized in studies; ADA threshold values that are informative for discriminating treatment response have not been established. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

Current clinical guidelines from the American College of Gastroenterology the American College of Rheumatology and EULAR (Smolen, 2014) do not include recommendations for antidrug antibody testing for patients 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 (NICE, 2015).

2019 Update

Annual policy review completed with a literature search using the MEDLINE database through May 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Practice Guidelines and Position Statements

American College of Gastroenterology Institute

The American College of Gastroenterology Institute (2017) published guidelines on therapeutic drug monitoring in inflammatory bowel disease (Feuerstein, 2017). The guidelines note that “When anti-drug antibodies are detected, it is unclear what antibody level is clinically meaningful…. 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 oncentrations and low or high anti-drug antibodies, the evidence to clarify optimal management is lacking.”

2020 Update

A literature search was conducted through May 2020. There was no new information identified that would prompt a change in the coverage statement.

2021 Update

Annual policy review completed with a literature search using the MEDLINE database through May 2021. No new literature was identified that would prompt a change in the coverage statement.

2022 Update

Annual policy review completed with a literature search using the MEDLINE database through May 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Syversen et al reported on results of a randomized, parallel-group, open-label trial of 411 adults with RA, spondyloarthritis, psoriatic arthritis, ulcerative colitis, CD, or psoriasis who received either proactive therapeutic drug monitoring of infliximab therapy based on serum infliximab level and ADA, or standard therapy without serum infliximab level or ADA (Syversen, 2021). Serum trough infliximab levels and ADA were measured at each infusion in the therapeutic drug monitoring group. The infliximab dose or interval could be adjusted based on the therapeutic range during induction and during treatment. If ADA was greater than 50 mcg/L at any point, therapy with infliximab was switched to a different agent.

There was no difference between the therapeutic drug monitoring group and standard therapy group in clinical remission at week 30 (50.5% vs 53% of patients, respectively; p=.78) (Svversen, 2021). During infliximab treatment, 36 (18%) patients in the therapeutic drug monitoring group and 34 (17%) in the standard therapy group developed ADAs ≥15 mcg/L. Antidrug antibodies ≥50 mcg/L (the threshold for discontinuation) occurred in 20 (10%) of patients in the therapeutic drug monitoring group and 30 (15%) in the standard therapy group. The remission rate in patients who developed ADAs was 56% in the therapeutic drug monitoring group and 35% in the standard therapy groups. The trial was limited by the small sample size of subjects who developed ADAs.

In 2019, the American College of Gastroenterology published a guideline on ulcerative colitis (UC) (Rubin, 2019). The guideline stated: "In patients with moderately to severely active UC who are responders to anti-TNF therapy and now losing response, we suggest measuring serum drug levels and antibodies (if there is not a therapeutic level) to assess the reason for loss of response (conditional recommendation, very low quality of evidence)."

In 2018, the American College of Gastroenterology published a guideline on Crohn disease (CD) (Lichtenstein, 2018). Although acknowledging that a detailed review of therapeutic drug monitoring was beyond the scope of the guideline, it stated: "If active CD is documented, then assessment of biologic drug levels and antidrug antibodies (therapeutic drug monitoring) should be considered."

In 2019, the National Institute for Health and Care Excellence issued guidance on therapeutic monitoring of tumor necrosis factor α inhibitors in the treatment of patients with rheumatoid arthritis (NICE, 2019). The Institute stated: "Enzyme-linked immunosorbent assay (ELISA) tests for therapeutic monitoring of tumour necrosis factor (TNF)-alpha inhibitors (drug serum levels and antidrug antibodies) show promise but there is currently insufficient evidence to recommend their routine adoption in rheumatoid arthritis." It also recommended that "laboratories currently using ELISA tests for therapeutic monitoring of TNF-alpha inhibitors in rheumatoid arthritis should do so as part of research and further data collection."

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through May 2023. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

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