This document addresses the measurement of serum concentrations of tumor necrosis factor (TNF) antagonist drugs and antibodies to TNF antagonist drugs in individuals with various conditions. Such testing has been proposed as a way to detect individuals with poor or lack of response to treatment with TNF antagonist drugs with the goal of altering treatment to optimize outcomes.
Note: For more information regarding Tumor Necrosis Factor Antagonists, please see:
Investigational and Not Medically Necessary:
The measurement of serum concentrations of tumor necrosis factor antagonist drugs or antibodies to tumor necrosis factor antagonist drugs is considered investigational and not medically necessary under all circumstances.
A number of published studies have suggested that the development of antibodies against certain anti-tumor necrosis factor alpha (TNF-α) drugs may be associated with impairment of treatment efficacy and hypersensitivity reactions. This has been investigated in several clinical studies involving individuals with various conditions, especially those undergoing treatment with infliximab and adalimumab for inflammatory bowel disease (IBD) and rheumatoid arthritis.
In a prospective observational study involving 125 subjects, Unger and others (2014) investigated the natural history of antibodies to infliximab (ATI). They reported that, when followed prospectively, most subjects who developed ATI did so within the first year of therapy. It was also reported that some subjects developed transient ATI, which is apparently of little clinical significance, and can appear haphazardly at any time during treatment. Finally, they observed that the onset of clinical loss of response may lag behind the appearance of anti-infliximab antibodies.
A meta-analysis published by Garcês in 2013 investigating the detection of antibodies to infliximab (ATI), adalimumab (ATA), and etanercept (Enbrel® ) included 17 trials involving 865 subjects. Results of this meta-analysis suggested that antibodies against infliximab or adalimumab reduced drug response rate by 68%, and that this effect could be attenuated by methotrexate or azathioprine/mercaptopurine. However, they did not address whether or not altering the therapeutic regimen according to serum drug and ATA data impacted clinical outcomes.
A meta-analysis of 68 studies involving 14,651 subjects with rheumatoid arthritis, spondyloarthritis, and IBD examined the immunogenicity of adalimumab, infliximab, etanercept, golimumab, and certolizumab (Thomas 2015). Antidrug antibodies were detected in 25.3% of subjects receiving infliximab, 14.1% receiving adalimumab, 6.9% receiving certolizumab, 3.8% receiving golimumab, and 1.2% receiving etanercept. Overall, the presence of antidrug antibodies reduced the odds of a clinical response by 67%. For subjects receiving infliximab, the presence of antidrug antibodies decreased the odds of a response by 58%. The same results were reported for those receiving golimumab. For subjects receiving adalimumab, the odds of a clinical response in those with antidrug antibodies was decreased by 87%. By indication, the presence of antidrug antibodies deceased response by 27% in subjects with rheumatoid arthritis and by 18% in those with spondyloarthritis. No effect was reported for subjects with IBD. An analysis of adverse events indicated that the presence of antidrug antibodies resulted in an increased risk of infusion and injection site reactions (odds ratio [OR]=3.25). The authors concluded that the presence of antidrug antibodies was significantly associated with reduced clinical response and increased infusion and injection site reactions.
Measurement of ATI and Infliximab Drug Serum Concentration
The use of serum ATI and infliximab concentrations in the monitoring and management of individuals being treated with infliximab has been proposed and discussed in the medical literature. Finckh and colleagues tested whether the presence of ATI and residual circulating infliximab levels prior to subsequent infusion were associated with acquired infliximab resistance in rheumatoid arthritis (RA) (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. A total of 64 subjects with RA on longstanding infliximab therapy were included; 24 had an acquired therapeutic resistance to infliximab, and 40 had continuous good response to infliximab. The two groups had similar disease characteristics; however, subjects 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 (OR, 0.4; 95% confidence interval [CI], 0.1-1.5), while the presence of ATI 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, 42% of subjects with acquired infliximab resistance had either low infliximab or high ATI levels. The authors concluded that their results suggested that the assessment of ATI and residual infliximab levels is of limited value for individual subjects with RA in routine clinical care.
Pascual-Salcedo (2011) investigated the long-term impact of the presence of ATI on the efficacy of infliximab treatment. This case series study involved 85 subjects with RA who were evaluated at 6 months, 12 months, and greater than 4 years. The report indicates that ATI were detected in 28 (32.9%) subjects and were present in all subjects who were found to be non-responders using the European League Against Rheumatism (EULAR) assessment tool. Throughout the study, ATI levels were higher in EULAR criteria non-responders vs. subjects reported to be good and moderate EULAR responders (p=0.05 at 6 months, p=0.02 at 1 year, p=0.003 at > 4 years). Nine (10.5%) subjects with high ATI levels developed infusion-related reactions. In 44 (51.7%) subjects, an acquired resistance to infliximab was observed and required either an increased dosage or a reduced time interval between infusions to achieve a clinical improvement. The authors reported that median survival time on treatment was shorter for subjects with detectable ATI (4.15 vs. 8.89 years; p=0.0006). The concurrent use of methotrexate was not associated with a lower incidence of subjects with ATI, but those receiving concurrent therapy were reported to have lower levels of ATI (p=0.073) and longer on-treatment survival (p=0.015). Infusion-related reactions were recorded in 9 subjects who had detectable ATI concentrations vs. no infusion reactions in subjects with no ATI (p=0.041). Discontinuation of infliximab treatment was reported in 45 (53.5%) subjects. A significantly higher proportion of those with ATI stopped therapy vs. those with no ATI (82.1% vs. 29.3%; p<0.001). The authors concluded that the presence of ATI was associated with loss of clinical response as well as an increase in infusion reactions and discontinuation of treatment.
In a retrospective case series study by Vande Casteele (2013), 1232 samples from 90 subjects with IBD were evaluated for the presence of ATI with a homogeneous mobility shift assay (HMSA). Subjects were stratified by whether or not they had previously detectable ATI. It was reported that in 15 (28%) of the 53 subjects with previously detectable ATI, the ATI disappeared over time. Discontinuation of therapy occurred in 26 (68%) of the 38 subjects with sustained ATI vs. 2 (13%) discontinuations in the 15 subjects with transient ATI (relative risk [RR]=5.1; p=0.0005). The authors reported that an infliximab trough level at week 14 that was < 2.2 μg/ml was predictive of discontinuation of therapy due to persistent loss of response or hypersensitivity reactions with 74% specificity and 82% sensitivity (likelihood ratio 3.1; p=0.0026).
In 2015, Vande Casteele and colleagues published the results of two studies investigating the role of serum ATI and infliximab concentrations in subjects receiving treatment for gastrointestinal (GI) conditions. The first study was a randomized controlled trial (RCT) involving 263 adults, 178 with Crohn's disease and 85 with ulcerative colitis, with stable responses to maintenance infliximab therapy (Vande Casteele, 2015a). The authors altered infliximab dose based on an algorithm intended to achieve trough concentration of 3-7 μg/mL. Once stable trough concentrations were achieved, subjects were randomly assigned on a 1:1 basis to undergo further dosing based on either clinical features (n=123) or on trough infliximab concentrations (n=128). Subjects were followed for 12 months. The results indicated that of the 76 subjects with initial trough concentrations < 3 μg/mL, 69 (91%) achieved trough concentrations of 3-7 μg/mL after dose escalation. This resulted in a higher proportion of remission in subjects with Crohn's disease than before dose escalation (88% vs 65%; p=0.020) and a decrease in the median concentration of C-reactive protein (3.2 vs 4.3 mg/L; p<0.001). Similar changes were not reported in subjects with ulcerative colitis. Of 72 subjects with trough concentrations > 7 μg/mL, 67 (93%) achieved trough concentrations of 3-7 μg/mL after dose reduction. Remission was achieved in 66% of subjects whose dosing was based on clinical features alone (controls) vs. 69% of subjects whose dosing was based on trough concentrations (p=0.686). However, disease relapsed was reported in 21 subjects who received clinical features-based dosing (17%) vs. 9 subjects who received concentration-based dosing (7%) (p=0.018). The authors concluded that after dose optimization, continued concentration-based dosing was not superior to clinically based dosing for achieving remission after 1 year. However, fewer relapses were reported during the course of treatment.
The other study was an observational study involving 1487 trough serum samples from 483 subjects with Crohn's disease who had previously participated in other studies conducted by the investigators (Vande Casteele, 2015b). The authors attempted to identify the concentrations of infliximab and ATI that were most discriminant for disease remission, defined as C-reactive protein concentration of ≤ 5 mg/L. The results indicated infliximab concentrations were detectable in 77.1% of subjects and undetectable in 22.9%. ATI positivity was noted in 9.5% of subjects with detectable infliximab concentrations and 71.8% in those with undetectable infliximab concentrations. The authors concluded that infliximab concentrations of > 2.79 μg/mL (area under the curve [AUC]=0.681) and ATI concentrations of < 3.15 U/mL (AUC=0.632) were associated with remission of Crohn's disease. They also noted that their multivariable analysis showed that concentrations of both infliximab trough (OR=1.8, p<0.001) and ATI (OR=0.57, p=0.002) were independent predictors of remission. Their conclusions were that, "The development of ATI increases the probability of active disease even at low concentrations and in the presence of a therapeutic concentration of drug during infliximab maintenance therapy."
Steenholdt and colleagues attempted to establish clinically relevant threshold levels of infliximab and/or ATI (2011). A total of 106 subjects with IBD (85 with Crohn's disease and 21 with ulcerative colitis) were identified over the course of a 10-year period (2001 to 2010). All subjects were receiving infliximab treatment for IBD, as well as concurrent medications to prevent acute infusion reactions and to limit the development of ATI. Subjects who received infliximab maintenance therapy were classified as having one of two responses: (1) maintenance of response (subjects had a good clinical response to infliximab induction therapy and continued this response over the course of maintenance treatment) or (2) loss of response (subjects 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.
For subjects with Crohn's disease, 69% maintained their response to infliximab, and the remaining 31% had loss of response. Baseline characteristics of the two groups were well-balanced, and there were no significant differences in the total number of infliximab infusions administered to the two groups. Infliximab trough levels were significantly increased among subjects with Crohn's disease who maintained response to therapy compared to subjects who lost response (p<0.0001). Using data from these subjects, 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 subjects with a loss of response to infliximab maintenance therapy. Trough levels of ATI were significantly higher in subjects with Crohn's disease who had lost response to infliximab maintenance therapy compared to subjects who had maintained response (p<0.0001). 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 subjects with Crohn's disease who had lost response to infliximab maintenance therapy. Similar determinations of infliximab and anti-infliximab antibody trough levels were made in the subjects with ulcerative colitis, although this group of subjects was much smaller. Limitations to this study included its retrospective design and small sample size. Also, this study did not examine the changes in management made as a result of testing for ATI.
Afif and colleagues describe a case series study in which the clinical utility of ATI and infliximab serum concentration testing were assessed retrospectively (2010). The study included 155 subjects with Crohn's disease, ulcerative colitis, or indeterminate colitis treated with infliximab. Testing was conducted randomly at the time of treatment and at the discretion of the treating physician based upon loss of response to infliximab (49%), partial response to infliximab (22%), or possible autoimmune/delayed hypersensitivity response (10%). A total of 112 (71.8%) tests were requested by a single physician. Records for all subjects who had undergone testing between January 2003 and August 2008 were retrospectively reviewed by the authors. Those missing post-testing follow-up or receiving infliximab as part of a clinical trial were excluded. The purpose of the study was to determine when the results of testing changed treatment or helped avoid inappropriate clinical management. Prior to infliximab and ATI testing, complete response to infliximab treatment was reported in 65% (100/155) of subjects, partial response was reported in 29% (45/155) of subjects, and no response was reported in 6% (10/155) of subjects. After ATI and infliximab serum concentration testing, the authors noted that concurrent immunosuppressive therapy was significantly associated with negative ATI status (p<0.032) as well as therapeutic infliximab concentrations (p<0.001). Out of 110 subjects with loss of response or partial response, 17% (n=19) had detectable ATI and 45% (n=50) had non-therapeutic infliximab concentrations. Out of 16 subjects tested for autoimmune/delayed hypersensitivity reactions, 6 had detectable ATI. It was determined by the authors that ATI and infliximab test results impacted treatment decisions in 73% of the 177 tests assessed for the 155 cases (22 subjects had repeat testing and treatment adjustment). As a result of testing, 35 subjects were found to have positive ATI concentrations. Twelve of these subjects were switched to another anti-TNF drug resulting in complete or partial clinical response in 11 subjects (92%). In 6 subjects, infliximab dosage was increased, resulting in response in only 1 (17%) and none achieved therapeutic infliximab concentrations with dose escalation. Out of the 155 subjects, 63 had sub-therapeutic concentrations of infliximab. A total of 29 of these subjects underwent dose escalation with complete or partial response in 25 (86%). Another 6 were changed to another anti-TNF drug with response in 2 (33%). The results of this study are promising, and suggest that ATI and infliximab testing may have a significant impact on treatment plans. Whether or not these decisions result in long-term outcome benefits over conventional management is not yet known. Also, it should be clarified that while testing done in this study was noted as being done at Prometheus Laboratories, it is unclear if the test described in the study is the same PROMETHEUS® Anser™ IFX test currently being commercially offered by Prometheus Laboratories.
A meta-analysis by Lee and colleagues (2012) was conducted in subjects with IBD receiving infliximab to determine: (a) the prevalence of ATI, (b) the effect of ATI on the prevalence of infusion reactions, and (c) the effect of ATI on disease remission rates. Databases were searched through October 2011 and 18 studies involving 3326 subjects were included. Studies included nine RCTs, five cohort studies and four 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 subjects with ATI (RR=2.07; 95% CI, 1.61-2.67). Immunosuppressants resulted in a 50% reduction in the risk of developing ATI (p<0.00001). Subjects 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 subjects who test positive for ATI are at an increased risk of infusion reactions, but have similar rates of remission compared with subjects who test negative for ATI.
Another meta-analysis conducted by Nanda and colleagues (2013) investigated the association between ATI and loss of clinical response in relation to infliximab levels in individuals with IBD. The authors included 13 studies that met inclusion criteria, which encompassed data from 1378 subjects. All of the included studies had a high risk of bias in at least one quality domain. The pooled risk ratio of loss of clinical response to infliximab in subjects with IBD who had ATI vs. those without ATI was 3.2 (p<0.0001). This estimate was mostly based on data from subjects with Crohn's disease (n=494, p<0.0001). Data limited to subjects with ulcerative colitis (n=86) with ATI exhibited a non-significant RR of loss of response of 2.2 (p=0.3). There was significant heterogeneity between studies, both in methods of ATI detection and clinical outcomes reported. A funnel plot suggested a risk of publication bias in the included studies (studies with larger size and more events produced RRs closer to 1, i.e. no effect).
Maneiro (2013) published a meta-analysis investigating the association of immune response to anti-TNF monoclonal antibody drugs and response to treatment in subjects with immune-mediated inflammatory diseases including IBD and spondyloarthropathies. The study included 60 studies with a significant heterogeneity in study design, and methods used to determine antibody status and assess clinical response. The authors reported that in individuals with RA receiving either infliximab or adalimumab, a significantly improved response was seen in subjects without antibodies (OR=0.03 for seropositive subjects). However, no analysis is provided for subjects who received infliximab only. For subjects with spondyloarthropathies, two studies involving the use of infliximab were included. It was reported that seronegative subjects had improved results on the Assessment in Ankylosing Spondylitis International Working Group (ASAS) tool than did seropositive subjects (OR=0.28). With regard to subjects with IBD, significantly improved clinical responses were reported for antibody-negative subjects (OR=0.53). Remission in IBD subjects was reported to have occurred only in one of the two studies evaluating infliximab, with an OR of 0.027 for antibody-negative subjects.
At this time, only one study has been published in the peer-reviewed literature investigating the impact of ATI on treatment in subjects with non-GI conditions. Plasencia (2013) conducted a case series study that involved 94 subjects undergoing treatment with infliximab for spondyloarthritis (n=50), undifferentiated spondyloarthritis (n=12), psoriatic arthritis (n=22) and spondyloarthritis associated with IBD (n=10). ATI were detected in 24 (25.5%) subjects. Subjects with detectable ATI had higher scores on the Ankylosing Spondylitis Disease Activity Score tool vs. those without ATI (p=0.038 at 6 months; p=0.042 at 1 year; and p=0.024 at > 4 years). Eleven subjects (12%) developed infusion-related reactions. Of these 11, 8 subjects (73%) had detectable ATI. Additionally, the 11 subjects with infusion-related reactions had higher ATI titres (median 12,931 AU/ml, vs. median 2454 AU/ml; p=0.028) and shorter treatment survival (4.25 years vs. 8.19 years, p<0.001). ATI development occurred more frequently in the subjects not receiving methotrexate (20/58 [34.5%] vs. 4/36 [11.1%], p=0.011). A total of 27 (28.7%) subjects interrupted their infliximab treatment, mostly due to an insufficient response or the infusion-related reactions. A larger fraction of subjects with ATI discontinued their infliximab treatment (18/24 [75%] vs. 9/70 [12.8%]; p<0.001). The median infliximab survival time was 4.25 years (95% CI, 3.06-5.43) in the subjects with ATI versus 8.19 years (95% CI, 7.54-8.85) without ATI (p<0.001). The subjects with ATI who did not discontinue the biological treatment had significantly lower antibody levels than those who discontinued treatment (p=0.005). The authors concluded "ATI development is associated with a poor clinical response, the discontinuation of treatment and an increased incidence of adverse effects. Long-term follow-up demonstrates that ATI may form at any time, resulting in secondary inefficacy."
Measurement of Antibodies-to-adalimumab (ATA) and Adalimumab Serum Concentration
Published evidence describing the use of serum ATA and adalimumab drug concentrations is limited. The first study reported involved 121 subjects with RA receiving treatment with adalimumab followed for 28 weeks (Bartelds, 2007). ATA were detected in 21 subjects (17%), EULAR non-responders had ATA significantly more often than good EULAR responders (34% vs. 5%; p=0.032). Subjects with ATA showed less improvement in disease activity than subjects without antibodies (p=0.001). The presence of ATA during follow-up was associated with lower serum adalimumab concentrations at 28 weeks (p<0.001). Good EULAR responders had higher serum adalimumab concentrations than moderate responders (p=0.021) and non-responders (p=0.001). Concurrent methotrexate use was lower in the group with anti-adalimumab antibodies (52%) than in the group without antibodies (84%) (p=0.003). The authors concluded that serum antibodies against adalimumab were associated with lower serum adalimumab concentrations and non-response to adalimumab treatment.
Bartelds (2010) reported a case series study involving 235 subjects with RA treated with adalimumab and focused on the impact of ATA and ATI in 52 subjects (22%) who had been previously treated with infliximab ('switchers'). The remainder of the cohort (n=183, 78%) were anti-TNF naïve. At 28 weeks, the decrease in Disease Activity Scale-28 (DAS-28) for the entire cohort was 1.6 ± 1.5. ATA were detected in 46 subjects (20%). Change in DAS-28 scores was 1.8 ± 1.4 in ATA-negative subjects and 0.6 ± 1.3 in ATA-positive subjects (p<0.0001). Thirty-three of the 52 switchers (63%) had ATI detected. Subjects with ATI more often developed ATA than anti-TNF naïve subjects (11 [33%] vs. 32 [18%]; p=0.039). Change in DAS-28 was greater for anti-TNF naive subjects (1.7 ± 1.5) than for switchers without ATI (p=0.009). However, change in DAS-28 for switchers with anti-infliximab was 1.2 ± 1.3 and did not differ significantly from anti-TNF naïve subjects (p=0.262). The authors concluded that response to adalimumab was limited in switchers without anti-infliximab antibodies. This raises the question whether a second anti-TNF treatment should be offered to subjects with RA for whom an initial treatment with an anti-TNF blocker fails, in the absence of anti-biological antibodies.
In 2015, Mazor and others reported the results of a study involving 71 subjects with Crohn's disease undergoing adalimumab therapy. The authors reported a negative correlation between adalimumab drug concentrations and ATA levels (Spearman's r=-0.411, p<0.001) and a positive correlation between adalimumab drug concentrations and remission (Area Under the Curve [AUC] 74.8%, p<0.001). They also reported that the presence of ATA was not correlated with remission (p=0.06). However, ATA levels of over 3 μg/mL-equivalent were highly predictive of disease activity.
Studies Addressing Multiple Drugs
Several studies have been published that address the measurement of blood concentration and antibody titers of multiple drugs, including infliximab, adalimumab and etanercept.
Jani (2015) reported the results of a prospective nonrandomized study involving 331 subjects receiving either adalimumab (n=160) or etanercept (n=171) that investigated the impact of antidrug antibodies on long-term treatment response. At 12 months, 24.8% of subjects receiving adalimumab were found to have ATA. At the same time point, none of the subjects receiving etanercept developed antibodies. In subjects with ATA, drug concentrations were found to be significantly decreased and negatively correlated (Spearman r=-0.51, p<0.0001). In univariate analysis, adalimumab concentration and ATA status were significantly associated with change in the DAS-28 tool at 12 months (regression coefficient 0.078, p<0.0001; and regression coefficient -0.76, p<0.001, respectively). These factors remained significant in the multivariate analysis. The detection of low adalimumab concentrations at 3 months was associated with an AUC of 0.66. Detection of ATA at 3 months was associated with an AUC of 0.63. The presence of both low adalimumab and ATA was associated with an AUC of 0.71. The authors concluded that low adalimumab concentrations and the presence of ATA at 3 months were significant predictors of no response at 12 months according to EULAR criteria.
A retrospective study involving 247 pediatric and adult subjects with IBD and suspected loss-of-response to anti-TNF agents was published by Yanai (2015). Ulcerative colitis was noted in 42 subjects. Overall, 330 loss-of-response events were reported, 188 to infliximab and 142 to adalimumab. The threshold for lack of efficacy of increased dose or switch to another anti-TNF drug was reported as trough concentrations of adalimumab > 4.5 mcg/mL and infliximab > 3.8 mcg/mL, with specificity of 90%. The investigators set these measures as adequate trough concentrations for each drug, respectively. Adequate trough concentrations identified subjects who responded to expectant management or out-of-class interventions with more than 75% specificity. ATA concentrations of > 4 μg/mL-equivalent or ATI > 9 μg/mL-equivalent identified subjects who did not respond to an increased drug dosage with 90% specificity. Subjects with high titers of ATA had longer durations of response when anti-TNF agents were switched than when dosage was increased (p=0.03). Dosage increases were more effective for subjects with no or low titers of anti-drug antibodies (ADA) (p=0.02). An analysis of confirmed inflammatory loss-of-response events (n=244) produced similar results, with subjects with adequate trough levels having longer duration of response when switched to a different class of agent than when anti-TNF was optimized by either a dosage increase or by a switch within the anti-TNF class (p=0.002). They concluded that trough levels of drug or ADAs may be useful in guiding therapeutic decisions for more than two-thirds of individuals with IBD with either clinically suspected or definite inflammatory loss of response to therapy.
Ungar (2016) reported the results of another retrospective study involving 145 subjects with IBD (111 with Crohn's disease and 34 with ulcerative colitis) treated with infliximab (n=78) or adalimumab (n=67). Concomitant immunomodulator therapy was noted in 47% of subjects in the infliximab group, with an association with significantly higher drug concentrations (3.7 μg/mL vs. 2.2 μg/mL, p=0.018). Of the adalimumab group subjects, 3% were also treated with immunomodulators, but with no significant impact on drug concentrations (4.2 μg/mL vs. 3.35 μg/mL, p=0.37). Mucosal healing data was collected via colonoscopy and compared with serum levels of ADAs, clinical scores, and levels of C-reactive protein. The authors reported that median serum concentrations of infliximab and adalimumab were significantly higher in subjects with mucosal healing than those with active disease (for infliximab, 4.3 vs 1.7 μg/mL, p=0.0002; for adalimumab, 6.2 vs 3.1 μg/mL, p=0.01). Concentrations of infliximab above 5 μg/mL (AUC=0.75; p<0.0001) and levels of adalimumab above 7.1 μg/mL (AUC=0.7; p=0.004) identified subjects with mucosal healing with 85% specificity. Increasing levels of infliximab > 8 μg/mL and adalimumab > 12 μg/mL failed to produce further significant improvements in mucosal healing. In subjects with measurable levels of infliximab > 3 μg/mL, the presence of ATI was associated with a lower rate of mucosal healing compared to those with no ATI (16% vs 50%, respectively; p=0.003). No such association was found with regard to adalimumab and ATIs (18.5% vs. 37%, p=0.13). This may have been due to small subject numbers (n=5 with ATIs and n=13 without, respectively). The authors concluded that there was a significant association between serum levels of anti-TNF agents and level of mucosal healing. They proposed that serum levels of 6-10 μg/mL for infliximab and 8-12 μg/mL for adalimumab are required to achieve mucosal healing in 80%-90% of individuals with IBD, and that this could be considered as a "therapeutic window."
The available studies to date have not demonstrated in randomized comparative trials the presence of a clinical utility benefit to therapeutic regimens guided by serum TNF drug or antibody concentration data when compared to standard treatment regimens. Such evidence is necessary to properly and adequately judge clinical response, adverse reactions, and need for a change in therapy. Further study is warranted.
The measurement of serum concentrations of infliximab and adalimumab, and antibodies-to-infliximab and antibodies-to-adalimumab have been proposed as a way to detect individuals with poor or lack of response to treatment, with the goal of altering treatment to optimize outcomes.
One commercial test available to test for infliximab and ATI concentrations in blood samples is the PROMETHEUS Anser IFX test (Prometheus Laboratories Inc., San Diego, CA). This is a non-radiolabeled HMSA proposed for the measurement of serum concentrations of infliximab and ATI in individuals with inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease. Prometheus Laboratories states that markedly different serum concentrations of infliximab have been reported in people receiving similar doses. They contend that this variation may result in varying clinical outcomes. The results of this test are aimed at identifying individuals who may benefit from adjusted doses of infliximab or a different drug.
Prometheus Laboratories markets the PROMETHEUS® Anser ADA™ test, which is similar to their infliximab test but for adalimumab and antibodies for adalimumab.
Several other laboratory companies market enzyme-linked immunosorbent assay (ELISA) test kits to measure antibodies-to-infliximab and antibodies-to-adalimumab, including but not limited to, Sanquin Blood Supply, Eagle Biosciences, and RayBiotech. Such tests have different sensitivity and specificity than the HMSA-based tests.
Antibodies-to-adalimumab (ATA): Substances manufactured by the body to act against the presence of adalimumab. ATAs have been proposed to decrease the efficacy of adalimumab therapy.
Adalimumab: A biologic disease-modifying antirheumatic drug (DMARD) belonging to a class of drugs referred to as tumor necrosis factor (TNF) antagonists (inhibitors). These types of drugs target specific pathways of the immune system and either enhance or inhibit immune response. Adalimumab is also known by the brand name Humira® .
Antibodies-to-infliximab (ATI): Substances manufactured by the body to act against the presence of infliximab. ATI have been proposed to decrease the efficacy of infliximab therapy.
Infliximab: A biologic disease-modifying antirheumatic drug (DMARD) belonging to a class of drugs referred to as tumor necrosis factor (TNF) antagonists (inhibitors). These types of drugs target specific pathways of the immune system and either enhance or inhibit immune response. Infliximab is also known by the brand name Remicade® .
The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
When services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.
|80299||Quantitation of therapeutic drug, not elsewhere specified [when specified as measurement of serum concentrations of tumor necrosis factor (TNF) antagonist drugs, with associated chemiluminescent assay (82397)]|
|84999||Unlisted chemistry procedure [when specified as measurement of serum concentrations of TNF antagonist drugs and antibodies to TNF antagonist drugs (for example, the PROMETHEUS Anser IFX test or PROMETHEUSAnser ADA test)]|
|Note: When CPT code 86352 Cellular function assay involving stimulation (eg, mitogen or antigen) and detection of biomarker (eg, ATP) is used to describe measurement of serum concentrations of TNF antagonist drugs and antibodies to TNF antagonist drugs, the service is considered investigational and not medically necessary.|
Peer Reviewed Publications:
PROMETHEUS Anser ADA test
PROMETHEUS Anser IFX test
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|Reviewed||02/02/2017||Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Rationale and References sections.|
|Reviewed||02/04/2016||MPTAC review. Updated Rationale, Background, and Coding sections. Removed ICD-9 codes from Coding section.|
|Reviewed||02/05/2015||MPTAC review. Updated Rationale, Background, and Definitions sections.|
|Revised||02/13/2014||MPTAC review. Updated document title. Expanded scope of investigational and not medically necessary position statement to include measurement of serum drug concentrations and anti-drug antibodies in individuals receiving treatment with any TNF drug. Updated Rationale, Background, Definitions, and Coding sections.|
|New||08/08/2013||MPTAC review. Initial document development.|