|MP 2.04.84||Measurement of Serum Antibodies to Infliximab and Adalimumab|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/10:2014
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Infliximab and adalimumab in autoimmune disease
Infliximab is a chimeric (mouse/human) anti-TNF-α monoclonal antibody. Adalimumab is a fully human monoclonal antibody to TNF-α. Therapy with monoclonal antibodies has revolutionized therapy in patients with immune diseases such as inflammatory bowel disease (IBD; CD, UC), RA 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 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 reason for therapeutic failures
remains a matter of debate. One proposed factor associated with loss of response is the production of antidrug antibodies, which accelerate clearance of the drug.(1) Antidrug antibodies also have been associated with acute infusion reactions (both drugs) and with delayed hypersensitivity reactions (infliximab). As a fully human antibody, adalimumab is considered less immunogenic than chimeric antibodies, such as infliximab.
Detection of antidrug antibodies
The detection and quantitative measurement of antidrug antibodies has been fraught with difficulty. 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, limiting clinical utility. Other techniques available for measuring antibodies include the radioimmunoassay (RIA) method, and more recently, the homogenous mobility shift assay (HMSA) using high-performance liquid chromatography.
Disadvantages of the RIA method are associated with the complexity of the test and prolonged incubation time, and safety concerns related to the handling of radioactive material. The HMSA has the advantage of being able to measure 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, i.e., double antigen ELISA and antihuman lambda chain ELISA. (2) 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 anti-TNF therapy
A diminished or suboptimal response to infliximab or adalimumab can be managed in several ways: shortening the interval between doses, increasing the dose, switching to a different anti-TNF agent (in patients who continue to have loss of response after receiving the increased dose), or switching to a non-anti-TNF agent.
Prometheus® Laboratories Inc. offers nonradiolabeled, fluid-phase HMSA tests called Anser™IFX for infliximab and Anser™ADA for adalimumab. Neither test is ELISA based, and each can measure antidrug antibodies in the presence of detectable drug levels, improving upon a major limitation of the ELISA method. Both tests measure serum drug concentrations and antidrug antibodies.
These tests were developed and their performance characteristics determined by Prometheus Laboratories Inc. Neither has been cleared or approved by the U.S. Food and Drug Administration.
Prometheus Laboratories Inc. is a CAP-accredited Clinical Laboratory Improvement Amendment (CLIA) laboratory.
Measurement of 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.
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.
According to materials from Prometheus on Anser™IFX and Anser™ADA, these tests will be reported using one unit of CPT code 84999 (unlisted chemistry procedure).
BlueCard/National Account Issues
Measurement of antibodies to infliximab or to adalimumab may be performed in specific reference laboratories, i.e., Prometheus® Inc.
This policy was created in 2012 and has been updated annually with searches of the MEDLINE database, most recently through September 10, 2014. Literature that describes the analytic validity, clinical validity, and clinical utility of measuring serum antidrug antibodies was sought. Most studies of antibodies to infliximab or to adalimumab report on both serum drug levels, as well as levels of antidrug antibodies, and correlate these levels to response rates of disease. Serum drug levels and disease response will not be addressed in this policy and therefore the data reported on antidrug antibodies will be highlighted from the aforementioned studies.
Most of the data on the use of measurements of antidrug antibodies are from patients with inflammatory bowel disease (IBD), with limited literature for other diseases such as rheumatoid arthritis (RA).
Analytic and clinical validation
Measurement 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. (3) 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, defined to have an upper negative limit of approximately 97.5%. Using receiver operating characteristic analysis, a cut point of 1.19 μg/mL was calculated for ATI; the false positive rate with this cut point was 3%. For serum infliximab levels, a cut point of 0.98 μg/mL was calculated; the false positive rate with this cut point was 5%.
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.
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.(5) Samples were analyzed by 3 binding assays-radioimmunoassay (RIA), ELISA, and HMSAand 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.
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. (6) 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 comparison between studies (few with clinical relevance) impossible. 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.
Lee et al (2012) conducted a meta-analysis of patients with 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.(7) Databases were searched through October 2011, and 18 studies involving 326 patients were included. Studies included 9 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 to 2.67). Immunosuppressants resulted in a 50% reduction in the risk of developing ATI (p<0.001). Patients with ATI were less likely to be in clinical
remission, but this was not statistically significant (RR=0.90; 95% CI, 0.79 to 1.02; p=0.10). The metaanalysis 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.
Nanda et el (2013) conducted a meta-analysis of studies that reported on clinical outcomes according to the presence or absence of ATI in patients with inflammatory bowel disease (IBD). (8) Databases were searched to February 2012 or later, and 11 studies involving 707 patients were included. Six of these studies (2 RCTs, 1 prospective cohort study, and 3 retrospective cohort studies) were included in the meta-analysis by Lee, described above. All included studies had high risk of bias in at least one quality domain (study eligibility criteria, measurement of exposure and outcome, control for confounders, and completeness of follow-up). The outcome of interest was loss of response to infliximab, defined as “relapse of clinical symptoms in patients who were in clinical remission from, or had responded to, infliximab.” Measures of loss of response varied across studies and included clinician assessment, standardized scales (Crohn’s Disease Activity Index [CDAI], Harvey Bradshaw Index, Simple Clinical Colitis Activity Index), and requirement for surgery or presence of non-healing fistula.
Patients with ATIs had a 3-fold greater risk of loss of response than those without ATIs (pooled risk ratio [RR]: 3.2 [95% CI: 2.0–5.0]). This result was driven primarily by 532 patients with Crohn’s disease (pooled RR: 3.2 [95% CI: 1.9–5.5]); pooled results for 86 patients with ulcerative colitis were not statistically significant (pooled RR: 2.2 [95% CI: 0.5–9.0]). (Eighty-nine patients with unspecified IBD also were included in the meta-analysis.) In addition to potential bias in included studies and heterogeneity in outcome assessment, the meta-analysis is limited by heterogeneity in the method of ATI detection (double-antigen ELISA, antihuman lambda chain ELISA, and fluid-phase RIA). Study investigators state, “The true incidence of ATI in IBD patients treated with infliximab remains unknown due to the different administration schedules, timing of ATI measurements, methods used in ATI detection, and the presence of serum infliximab.” Finally, a funnel plot suggested the presence of publication bias.
A2012 “ambispective” analysis enrolled 94 patients (some analyzed retrospectively, some enrolled prospectively) who were treated with infliximab at a single institution for spondyloarthritis (50 ankylosing spondylitis, 12 undifferentiated spondyloarthritis, 22 psoriatic arthritis, and 10 IBD-associated spondyloarthritis). (7) Disease activity was measured every 6 months using the Ankylosing Spondylitis Disease Activity Score (ASDAS), and patients were monitored for ATI development (by bridging ELISA) and infusion reactions. During a mean duration of follow-up of 7 years, 25.5% of patients developed ATI. At 6 months, 1 year, and >4 years, ASDAS scores were higher (indicating more severe disease) in patients with ATI than in patients without ATI. Of 11 patients who developed infusion reactions, ATI were present in 8 (73%). Mean ATI titers were higher in patients who had infusion reactions than in those who did not (p=0.028). ATIs developed more commonly in patients who did not receive concomitant methotrexate (34.5% vs. 11.1%, p=0.011). A limitation of the study is that serum samples were not collected from all patients at each of the 3 time points studied (6 months, 1 year and >4 years); serum samples were obtained from 56 patients immediately after beginning treatment, from 9 patients during the first year of treatment, and from 29 patients after the first year of treatment.
Measurement of antibodies to adalimumab
Wang et al (2013) developed and validated a non-radiolabeled HMSA to measure antibodies-to-adalimumab (ATA) and adalimumab levels in serum samples.(10) 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 et al (2011) 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.(11) All 3 patients had ATA detected using radioimmunoassay (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 follow-up, 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. (12) 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. (13) 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 (2012) 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. (14) 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.
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 (8) identified publication bias.
Several authors have published algorithms for management of patients with IBD(15-17) or RA18 who relapse during TNF-inhibitor therapy. These algorithms are generally based on evidence, including that reviewed earlier, that indicate an association between antidrug antibodies, reduced serum drug levels, and relapse. None include evidence demonstrating improved health outcomes, such as reduced time to recovery from relapse (response), using algorithmic rather than dose-escalation approaches.
Antibodies to infliximab
Inflammatory bowel disease (IBD)
Afif et al (2010) evaluated the clinical utility of measuring ATI (referred to as human antichimeric antibodies [HACA] in the study) and infliximab concentrations by retrospectively reviewing the medical records of patients with IBD who had had ATI and infliximab concentrations measured. The study sought to determine whether these results affected clinical management. (19) 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. (19) Limitations to the study included its retrospective design and that the testing for antibodies to infliximab was performed using the enzyme-linked immunosorbent assay (ELISA) method. 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. (20) 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 µg/mL 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<0.001). 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 (21) 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).
In 2014, Steenholdt et al published a randomized noninferiority trial and cost-effectiveness analysis of 69 patients with CD who relapsed (CDAI ≥220 and/or ≥1 draining perianal fistula) during infliximab therapy.(5) 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 (<0.5 µg/mL(20) ) 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 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(22) included bile acid malabsorption, strictures, and IBS. In both intention-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 (intention-to-treat: 58% in the algorithm group vs 53% in the control group; x²test, p=0.810; per-protocol: 47% in the algorithm group vs 53% in the control group;x² test, p=0.781). However, only the intention-to-treat analysis fell within the prespecified noninferiority 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 noninferiority 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. Cutoff values for therapeutic infliximab levels and ATI were derived from a single retrospective study.(20) Dropouts 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).
Finckh et al (2010) 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). (23) 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 et al (2006) 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. (24) 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.
Antibodies to adalimumab
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.(25) 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 antiadalimumab antibody testing and were switched to infliximab. Clinical and endoscopic responses after adalimumab optimization and after infliximab therapy for 6 months were compared among 3 groups: (1)
those with therapeutic adalimumab level (>4.9 µg/mL(26) ), (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; x² test, 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  months) compared with group 1 (mean [SD], 5  months) and group 3 (mean [SD], 4  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 g/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  months) compared with group 1 (mean [SD], 3  months) and group 2 (mean [SD], 5  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.
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 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(19) ) and use of clinical assessments to guide treatment decisions (in Steenholdt(20) ). Additionally, determination of a clinically relevant threshold for ATI level is complicated by the use of various assay methods. 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.
Ongoing and Unpublished Clinical Trials
An online search of 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).\
Primary Completion Dateb
A Randomized, Multi-Center Biomarker Trial to Predict Therapeutic Responses of Patients With Rheumatoid Arthritis to a Specific Biologic Mode of Action
Effect of the Combination of Methotrexate and Adalimumab on Reduction of Immunization in Ankylosing Spondylitis (COMARIS)
Comparative Analysis of Two Therapeutic Strategies in Patients With Spondyloarthritis Treated With Anti-TNF Biologics (STRADA)
TNF: tumor necrosis factor.
Summary of Evidence
Antibodies-to-infliximab (ATI) or to adalimumab (ATA) are present in a substantial number of patients treated with infliximab or adalimumab, respectively, and there may be a correlation between the level of these antibodies and clinical response. However, the clinical utility of measuring antidrug antibody concentrations has not been established, as it is unknown 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 with those made in the absence of ATI measurement. One RCT that compared ATI-informed management of relapse with standard dose escalation did not demonstrate benefit with the ATI approach. Additionally, technical factors related to different assay methods are unresolved, and ATI or ATA threshold values that are informative for discriminating treatment response have not been definitively established.
Therefore, the measurement of antibodies to infliximab in a patient receiving treatment with infliximab is considered investigational, and the measurement of antibodies to adalimumab in a patient receiving treatment with adalimumab is considered investigational.
Practice Guidelines and Position Statements
Current clinical guidelines from the American College of Gastroenterology27,28 and the National Institute for Health and Care Excellence29,30 do not include recommendations for antidrug antibody testing for patients treated with tumor necrosis factor inhibitors.
U.S. Preventive Services Task Force Recommendations
Measurement of serum antibodies to infliximab or adalimumab is not a preventive service.
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
- Ordas I, Mould DR, Feagan BG et al. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther 2012; 91(4):635-46.
- Kopylov U, Mazor Y, Yavzori M et al. Clinical utility of antihuman lambda chain-based enzyme-linked immunosorbent assay (ELISA) versus double antigen ELISA for the detection of anti-infliximab antibodies. Inflamm Bowel Dis 2012; 18(9):1628-33.
- Wang SL, Ohrmund L, Hauenstein S et al. Development and validation of a homogeneous mobility shift assay for the measurement of infliximab and antibodies-to-infliximab levels in patient serum. J Immunol Methods 2012; 382(1-2):177-88.
- Steenholdt C, Bendtzen K, Brynskov J, et al. Clinical implications of measuring drug and anti-drug antibodies by different assays when optimizing infliximab treatment failure in Crohn's disease: post hoc analysis of a randomized controlled trial. Am J Gastroenterol. Jul 2014;109(7):1055-1064. PMID 24796769
- Steenholdt C, Brynskov J, Thomsen OO, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn's disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut. Jun 2014;63(6):919-927. PMID 23878167
- Cassinotti A, Travis S. Incidence and clinical significance of immunogenicity to infliximab in Crohn's disease: a critical systematic review. Inflamm Bowel Dis. Aug 2009;15(8):1264-1275. PMID 19235918
- Lee LY, Sanderson JD, Irving PM. Anti-infliximab antibodies in inflammatory bowel disease: prevalence, infusion reactions, immunosuppression and response, a meta-analysis. Eur J Gastroenterol Hepatol. May 27 2012;24(9):1078-1085. PMID 22647738
- Nanda KS, Cheifetz AS, Moss AC. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis. Am J Gastroenterol. Jan 2013;108(1):40-47; quiz 48. PMID 23147525
- Plasencia C, Pascual-Salcedo D, Nuno L, et al. Influence of immunogenicity on the efficacy of longterm treatment of spondyloarthritis with infliximab. Ann Rheum Dis. Dec 2012;71(12):1955-1960. PMID 22563028
- Wang SL, Hauenstein S, Ohrmund L, et al. Monitoring of adalimumab and antibodies-to-adalimumab levels in patient serum by the homogeneous mobility shift assay. J Pharm Biomed Anal. May 5 2013;78-79:39-44. PMID 23454676
- Korswagen LA, Bartelds GM, Krieckaert CL, et al. Venous and arterial thromboembolic events in adalimumabtreated patients with antiadalimumab antibodies: a case series and cohort study. Arthritis Rheum. Apr 2011;63(4):877-883. PMID 21452312
- Masson PL. Thromboembolic events and anti-tumor necrosis factor therapies. Int Immunopharmacol. Dec 2012;14(4):444-445. PMID 22954485
- Bartelds GM, Krieckaert CM, Nurmohamed MT, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305(14):1460-1468. PMID
- Garces S, Demengeot J, Benito-Garcia E. The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis. Ann Rheum Dis. Dec 6 2012. PMID 23223420
- Eser A, Primas C, Reinisch W. Drug monitoring of biologics in inflammatory bowel disease. Curr Opin Gastroenterol. Jul 2013;29(4):391-396. PMID 23703367
- Khanna R, Sattin BD, Afif W, et al. Review article: a clinician's guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease. Aliment Pharmacol Ther. Sep 2013;38(5):447-459. PMID 23848220
- Lichtenstein GR. Comprehensive review: antitumor necrosis factor agents in inflammatory bowel disease and factors implicated in treatment response. Therap Adv Gastroenterol. Jul 2013;6(4):269-293. PMID 23814608
- Garces S, Antunes M, Benito-Garcia E, et al. A preliminary algorithm introducing immunogenicity assessment in the management of patients with RA receiving tumour necrosis factor inhibitor therapies. Ann Rheum Dis. Jun 2014;73(6):1138-1143. PMID 23666932
- Afif W, Loftus EV, Jr., Faubion WA, et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol. May 2010;105(5):1133-1139. PMID 20145610
- Steenholdt C, Bendtzen K, Brynskov J, et al. Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn's disease. Scand J Gastroenterol. Mar 2011;46(3):310-318. PMID 21087119
- Dubeau MF, Ghosh S. Optimizing infliximab therapy for inflammatory bowel disease- the tools are getting sharper. Gastroenterol Hepatol (N Y). Feb 2012;8(2):134-136. PMID 22485083
- Tan M. Importance of defining loss of response before therapeutic drug monitoring. Gut. Jul 16 2014. PMID 25031226
- Finckh A, Dudler J, Wermelinger F, et al. Influence of anti-infliximab antibodies and residual infliximab concentrations on the occurrence of acquired drug resistance to infliximab in rheumatoid arthritis patients. Joint Bone Spine. Jul 2010;77(4):313-318. PMID 20471890
- Bendtzen K, Geborek P, Svenson M, et al. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Arthritis Rheum. Dec 2006;54(12):3782-3789. PMID 17133559
- Roblin X, Rinaudo M, Del Tedesco E, et al. Development of an algorithm incorporating pharmacokinetics of adalimumab in inflammatory bowel diseases. Am J Gastroenterol. Aug 2014;109(8):1250-1256. PMID 24913041
- Roblin X, Marotte H, Rinaudo M, et al. Association between pharmacokinetics of adalimumab and mucosal healing in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. Jan 2014;12(1):80-84 e82. PMID 23891927
- Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. Mar 2010;105(3):501-523; quiz 524. PMID 20068560
- Lichtenstein GR, Hanauer SB, Sandborn WJ. Management of Crohn's disease in adults. Am J Gastroenterol. Feb 2009;104(2):465-483; quiz 464, 484. PMID 19174807
- National Institute for Health and Care Excellence. Infliximab (review) and adalimumab for the treatment of Crohn's disease. NICE technology appraisals [TA187], May 2010. http://www.nice.org.uk/Guidance/TA187. Accessed September 17, 2014.
- National Institute for Health and Care Excellence. Crohn's disease: management in adults, children and young people. NICE guidelines [CG152], October 2012. http://www.nice.org.uk/guidance/CG152. Accessed September 17, 2014.
|CPT||No specific code (see policy guidelines)|
|ICD-9-CM Diagnosis||Investigational for all relevent diagnoses|
|ICD-10-CM (effective 10/1/15)||Investigational for all relevent diagnoses|
|ICD-10-PCS (effectve 10/1/15)||Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.|
Serum infliximab and antichimeric antibodies
Serum infliximab and antibodies to infliximab
Serum adalimumab and antibodies to adalimumab
|08/09/12||Add to Medicine -Pathology/Laboratory section||Measurement of antibodies to infliximab, either alone or as a combination test which includes the measurement of serum infliximab levels, is considered investigational.|
|9/12/13||Replace policy||Policy reviewed with literature search through July 2013; references 2, 6-12 added. Title changed to add “…and Adalimumab.” “Measurement of antibodies to adalimumab in a patient receiving adalimumab, either alone or as a combination test which includes the measurement of serum adalimumab levels” added to the policy statement; considered investigational.|
|10/09/14||Replace policy||Policy updated with literature review through September 10, 2014. References 4-5, 15-18, 22, and 25-30 added. No change to policy statements.|