Medical Policy: 02.04.43
Original Effective Date: July 2013
Reviewed: March 2021
Revised: March 2021
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Biologic agents (e.g., infliximab, adalimumab, vedolizumab, or ustekinumab) are used to treat multiple inflammatory conditions, 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 are typically effective for the induction and maintenance of clinical remission. However, not all patients respond, and a high proportion of patients lose response over time. It is estimated that 1 in 3 patients do not respond to induction therapy (primary nonresponse); further, among initial responders (primary response), 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 the development of antidrug antibodies (ADA).
The detection and quantitative measurement of antidrug antibodies (ADA) is difficult owing to drug interference and identifying when antibodies have a neutralizing effect. First generation assays (i.e., enzyme-linked immunosorbent assays (ELISA)) can measure only ADA in the absence of detectable drug levels, due to interference of the drug with the assay. Other techniques available for measuring antibodies include radioimmunoassay (RIA) method, and more recently, the homogenous mobility shift assay (HMSA) using high performance liquid chromatography. Disadvantages of the RIA method are associated with complexity of the test and prolonged incubation time, and safety concerns related to the handling of radioactive material. The HMSA has the advantage of being able to measure antidrug antibodies when infliximab is present in the serum. Studies evaluating the validation of the results between different assays are lacking, making inter-study comparisons difficult. One retrospective study in 63 patients demonstrated comparable diagnostic accuracy between 2 different ELISA methods in patients with IBD (i.e., double-antigen ELISA and antihuman lambda chain-based ELISA). This study did not include an objective clinical and endoscopic scoring system for validation results.
A diminished or suboptimal response to infliximab (Remicade), adalimumab (Humira), vedolizumab (Entyvio) or ustekinumab (Stelara) 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 loss of response after receiving the increased dose) or switching to a nonbiologic agent. Incorporating therapeutic drug monitoring (TMD) into clinical practice has been proposed to allow clinicians to optimize treatment by maintaining effective drug concentrations over time and affecting a patient’s loss of response. However, before TDM can be widely applied in clinical practice, there are several obstacles to their regular use including when to use TDM, how to accurately interpret and apply the results of such testing, and in defining the optimal drug concentration thresholds and ranges to target.
The measurement of antibodies to include the measurement of serum drug concentrations (trough levels) to adalimumab (Humira), infliximab (Remicade), vedolizumab (Entyvio) or ustekinumab (Stelara) include but are not are not limited to the following tests:
The purpose of testing serum antibodies and serum levels (trough levels) to infliximab (Remicade), adalimumab (Humira), vedolizumab (Entyvio), or ustekinumab (Stelara) in patients with arthritis (e.g., rheumatoid, psoriatic, or juvenile idiopathic), inflammatory bowel disease (IBD), ankylosing spondylitis, or plaque psoriasis is to improve health outcomes.
The relevant populations of interest are individuals with arthritis (e.g., rheumatoid, psoriatic, or juvenile idiopathic), IBD, ankylosing spondylitis, or plaque psoriasis.
Patients with these conditions are actively managed by rheumatologists, gastroenterologists, and primary care providers in an outpatient setting.
The test considered is testing for serum antibodies and serum levels (trough levels) to infliximab (Remicade), adalimumab (Humira), vedolizumab (Entyvio), or ustekinumab (Stelara)
The following practice is currently being used to manage arthritis, IBD, ankylosing spondylitis, or plaque psoriasis: standard of care.
The general outcomes of interest are test validity, change in disease status, health status measures, quality of life, and treatment-related morbidity.
Follow-up over months to years is of interest to the relevant outcomes.
Tumor necrosis factor (TNF) inhibitors (e.g. infliximab, adalimumab) are used in the treatment of a number of inflammatory conditions. However, the use of these agents have been associated in some patients with the development of antidrug antibodies (ADA), which may promote adverse effects and diminish drug efficacy. The measurement of serum antibodies to infliximab (Remicade) and adalimumab (Humira) has been proposed to monitor for the formation of antidrug antibodies (ADA) which may cause some patients to become non-responders.
Infliximab (Remicade) is an intravenous tumor necrosis factor (TNF) blocking agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of: moderately to severely active rheumatoid arthritis (RA) in combination with methotrexate; moderately to severely active Crohn's disease (CD); moderately to severely active ulcerative colitis; active ankylosing spondylitis (AS); active psoriatic arthritis (PsA); and chronic severe plaque psoriasis.
Adalimumab (Humira) is a subcutaneous tumor necrosis factor (TNF-α) inhibitor that is FDA approved for treatment of: moderately to severely active Crohn’s disease (CD); moderately to severely active ulcerative colitis (UC); moderately to severely active rheumatoid arthritis; moderately to severely active polyarticular juvenile idiopathic arthritis (pJIA); active psoriatic arthritis (PsA); active ankylosing spondylitis (AS); moderate to severe plaque psoriasis; moderate to severe Hidradenitis Suppurativa; and non-infectious intermediate posterior and paneuveitis Uveitis (UV).
Infliximab is a chimeric (mouse/human) anti-tumor necrosis factor (TNF-α) monoclonal antibody. Adalimumab is a fully human monoclonal antibody to TNF-α. 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 patient’s respond, and high proportion of patients lose response over time. It is estimated that 1 out of 3 patients do not respond to induction therapy (primary nonresponse); further among initial responders, response wanes over time in approximately 20% to 60% of patients (secondary nonresponse). The reasons for therapeutic failures remain a matter of debate but include accelerated drug clearance (pharmacokinetics) and neutralizing agent activity (pharmacodynamics) due to antidrug antibodies (ADA). ADA are also associated with injection site reactions (adalimumab) and acute infusion reactions and delayed hypersensitivity reactions (infliximab).
A test must detect the presence of absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
In 2012, Lee, et.al. conducted a meta-analysis of patients with inflammatory bowel disease receiving infliximab to estimate the prevalence of ATIs (anti-infliximab antibodies), the effect of immunosuppressants on the prevalence of ATI, the effect of ATIs on the prevalence of infusion reactions and the effect of ATIs on the rates of remission. Databases were searched through October 2011, and 18 studies involving 3326 patients were included. The prevalence of ATIs 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 ATIs (relative risk: 2.07; 95% confidence interval, 1.61-2.67). Immunosuppressants resulted in a 50% reduction in the risk of developing ATIs (P<0.00001). The authors concluded, the presence or absence of ATIs did not affect the rates of clinical remission. The prevalence of ATIs depends on the regimen of infliximab administration and the use of immunosuppressants. 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. Further analysis is required to determine whether loss of response is dependent on the titer of ATIs.
Garces et. al. (2013) performed a systematic review and meta-analysis of studies to assess the effect of anti-drug antibodies (ADA) on drug response to infliximab, adalimumab and etanercept, and the effect of immunosuppression on ADA detection, in patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriasis and inflammatory bowel diseases (IBD). Databases were searched through August 2012, and out of 2082 studies the reviewers selected 17 studies (1 RCT; 16 observational studies) involving 865 patients (540 with RA, 132 with SpA, 58 with psoriasis, 130 with IBD). The outcomes of interest was a response, which was assessed using random-effect models, sensitivity analysis, meta-regressions and Egger's test and then calculated. Of 865 patients, ADA against infliximab or adalimumab reduced drug response rate by 68% (RR=0.68, 95% CI=0.12 to 0.36), an effect attenuated by concomitant methotrexate (MTX): <74% MTX+: RR=0.23, 95% CI=0.15 to 0.36; ≥74% MTX+: RR=0.32, 95% CI=0.22 to 0.48. Anti-etanercept antibodies were not detected. Of 936 patients, concomitant MTX or azathioprine/mercaptopurine reduced ADA frequency by 47% (RR=0.53, 95% CI=0.42 to 0.67), particularly when ADA were assessed by RIA (RR=0.36, 95% CI=0.23 to 0.55) compared with ELISA (RR=0.63, 95% CI=0.53 to 0.74). The authors concluded, ADA reduces drug response, an effect that can be attenuated by concomitant immunosuppression, which reduces ADA frequency. Drug immunogenicity should be considered for the management of patients receiving biological therapies.
In 2013, Nanda et. al. conducted a meta-analysis of studies that reported on the impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD). Antibodies to infliximab (ATIs) have been associated with loss of clinical response and lower serum infliximab (IFX) levels in some studies of patients with inflammatory bowel disease (IBD). This has important implications for patient management and development of novel biologic therapies. The objective of this study was to perform a systematic review and meta-analysis of studies that reported clinical outcomes and IFX levels according to patients' ATI status. Thirteen studies met the inclusion criteria, and reported results in 1,378 patients with IBD. All included studies had a high risk of bias in at least one quality domain. The pooled risk ratio (RR) of loss of clinical response to IFX in patients with IBD who had ATIs was 3.2 (95% confidence interval (CI): 2.0-4.9, P<0.0001), when compared with patients without ATIs. This effect estimate was predominantly based on data from patients (N=494) with Crohn's disease (RR: 3.2, 95% CI: 1.9-5.5, P<0.0001). Data only from patients with ulcerative colitis (n=86) exhibited a non-significant RR of loss of response of 2.2 (95% CI: 0.5-9.0, P=0.3) in those with ATIs. Heterogeneity existed between studies, in both methods of ATI detection, and clinical outcomes reported. Three studies (n=243) reported trough serum IFX levels according to ATI status; the standardized mean difference in trough serum IFX levels between groups was -0.8 (95% CI -1.2, -0.4, P<0.0001). A funnel plot suggested the presence of publication bias. The authors concluded, the presence of ATIs is associated with a significantly higher risk of loss of clinical response to IFX and lower serum IFX levels in patients with IBD. Published studies on this topic lack uniform reporting of outcomes. High risk of bias was present in all the included studies.
Meroni et. al. (2015) conducted a systematic analysis to address the pharmacodynamics and pharmacokinetics of tumor necrosis factor (TNF) inhibitors. Databases were searched through March 2013 and studies were stratified by drug, disease area and whether or not concomitant immunosuppressive therapy had been given. All data were tabulated by publication and analyzed descriptively. A total of 57 original research articles were included in the analysis (infliximab n=34; adalimumab n=18; etanercept n=5). There was considerable heterogeneity in study design, methodology for anti-drug antibody detection and drug bioavailability evaluation. Consequently, it was difficult to compare the immunogenic potential of infliximab, adalimumab and etanercept, particularly because different assays with variable sensitivity and specificity were used. The timing of occurrence and the persistence of anti-drug antibodies appeared to be influenced by administration schedules and concomitant immunosuppressive therapy. Monitoring of circulating drug levels and anti-drug antibodies appears to be an emerging and cost-effective strategy for the management of the individual patient. The authors concluded, monitoring drug and anti-drug antibody levels appears to be a putative strategy for optimal and cost-effective intervention. However studies of consistent and homogeneous design, methodology and duration are warranted to assess the true incidence and consequences of immunogenicity.
In 2015, Thomas et. al. examined the immunogenicity of TNF inhibitors (adalimumab, infliximab, etanercept, golimumab, and certolizumab) in rheumatoid arthritis (RA), spondyloarthritis (SpA), and inflammatory bowel disease (IBD), and to examine the potential effect of anti-drug antibodies (ADABs) on the loss of clinical response through a systematic literature review and meta-analysis. Databases were searched through December 2013. A total of 68 studies (14,651 patients) matched the inclusion/exclusion criteria. Patients had RA (n=8766), SpA (n=1534), or IBD (n=4351). Overall, the cumulative incidence of ADABs was 12.7 % [95 % confidence interval (CI) 9.5-16.7]. Of the patients using infliximab, 25.3 % (95 % CI 19.5-32.3) developed ADABs compared with 14.1 % (95 % CI 8.6-22.3) using adalimumab, 6.9 % (95 % CI 3.4-13.5) for certolizumab, 3.8 % (95 % CI 2.1-6.6) for golimumab, and 1.2 % (95 % CI 0.4-3.8) for etanercept. ADABs reduced the odds of clinical response by 67 % overall, although most of the data were derived from articles involving infliximab (nine) and adalimumab (eight). The summary effect for infliximab yielded an estimated odds ratio (OR) (with ADABs versus without) of 0.42 (95 % CI 0.30-0.58); the summary effect for adalimumab yielded an estimated odds ratio (OR) (as above) of 0.13 (95 % CI 0.08-0.22); and the odds ratio (OR) (as above) for golimumab was 0.42 (95 % CI 0.22-0.81). All figures were statistically significant. ADABS decreased response by 27 % in RA and 18 % in SpA, both of which were statistically significant. However, the effect of ADABS on response was not statistically significant for IBD when they only included the studies that reported the duration of exposure in the regression analysis. The use of concomitant immunosuppressives (methotrexate, 6-mercaptopurine, azathioprine, and others) reduced the odds of ADAB formation in all patients by 74 %. The odds ratio (OR) for risk with immunosuppressives versus without was 0.26 (95 % CI 0.21-0.32). The authors concluded, ADABs developed in 13 % of patients. All five TNF inhibitors were associated with ADABs, but to varying degrees depending on the specific TNF inhibitor and the disease. ADABs are associated with reduced clinical response and an increased incidence of infusion reactions and injection site reactions. Concomitant use of immunosuppressives can reduce ADAB formation.
Pecoraro et. al. (2017) conducted a systematic review and meta-analysis evaluating the impact of anti-drug antibodies (ADA) on TNFa threapeutic response in patients affected with autoimmune inflammatory disease. Thirty-four studies enrolling 4273 patients was included. Of these, 794 (18.6%) developed ADA. The analysis showed a significant reduction of response (RR 0.43, 95%CI 0.3-0.63) in patients with ADA respect to patients without, especially in patients treated with Infliximab (RR 0.37) or Adalimumab (RR 0.40). Furthermore, the administration of TNFα inhibitors produced a reaction at the infusion site in 17%, infection in 30% and serious AE in 5% of patients. Although ADA significantly reduced TNFa response, the results should be viewed cautiously due to reported study limitations, including small numbers of studies assessed and considerable heterogeneity. Currently, there are many indications about the use of immunogenicity tests to guide the therapy, but information regarding how to implement it in clinical practice is needed.
In 2019, Papamichael et. al., reviewed current data and provided expert opinion regarding the clinical utility of TDM for biologic therapies in IBD. Biologic Therapies include anti-tumor necrosis factor (anti-TNF) agent’s infliximab and adalimumab. Up to one-third of patients with Crohn’s disease (CD) and ulcerative colitis (UC) show primary non-response (PNR) to biologic therapies, and up to 50% of patients after an initial clinical response stop therapy for either secondary loss of response (SLR) or a serious adverse event.3,4 Both PNR and SLR are due to either pharmacokinetic (PK) or pharmacodynamic (PD) problems. PK issues are associated with inadequate drug exposure, often because of the development of antidrug antibodies (ADA), whereas PD issues are typically related to inflammatory process unrelated to the targeted immunoinflammatory pathway. Therapeutic drug monitoring (TDM), defined as the assessment of drug concentrations and ADA, is an important tool for optimizing biologic therapy. However, there are still some limitations when applying TDM into clinical practice, such as when to use TDM, proper interpretation and application of the results, and the identification of the optimal window/ thresholds to target. These therapeutic windows or thresholds appear to vary on the basis of the outcome of interest and the IBD phenotype. Most of the data on implementation of TDM refer to anti-TNF therapies and the maintenance phase of treatment. Although well-designed large prospective studies are lacking, there are preliminary data mainly from retrospective studies that demonstrate that proactive TDM is associated with better therapeutic outcomes compared with empiric dose optimization and/or reactive TDM. However, before TDM can be widely applied in clinical practice, there are several obstacles to their regular use including when to use TDM, how to accurately interpret and apply the results of such testing, and in defining the optimal drug concentration thresholds and ranges to target. Major limitations of the evidence relate to the lack of large prospective studies and RCTs on TDM of biologic therapy applied on different IBD phenotypes and sparse data on induction therapy and on biologic agents other than infliximab and adalimumab. Moreover, it is unclear whether trough concentrations are the best predictor of initial response to biologics, compared with peak drug concentrations or total drug exposure. Further RCTs to establish the utility of proactive TDM, particularly during the induction phase, should be performed. Additional future directions should include the development of accurate, easily accessible, and affordable rapid assays and dashboards to allow fast dosing adaptation and incorporation of predictive PK models based on patient and disease characteristics.
While many studies have evaluated the clinical validity using single ADA measurements, at least one assessed their persistence over time. Vande Casteele et. al. (2013) investigate the kinetics of ATI (antibodies to infliximab) formation and drug levels in relation to inflammatory markers and the clinical evolution of the patients. IFX trough and ATI levels were measured retrospectively in 1,232 consecutive serum samples of 90 (64 Crohn's disease and 26 ulcerative colitis) patients, 57 with previously detected and 33 without antibodies with a new homogenous mobility shift assay. Testing with new assay confirmed ATI in 53/90 patients (59%) and 37/90 patients (41%) were ATI negative. In 15/53 patients (28%), ATI disappeared over time whereas in 38/53 patients (72%) ATI persisted. The 26/38 (68%) patients with sustained ATI needed to discontinue IFX treatment compared with 2/15 (13%) patients with transient ATI (relative risk 5.1; 95% confidence interval 1.4-19.0; P=0.0005). An IFX trough level at week 14<2.2 μg/ml predicted IFX discontinuation due to persistent loss of response (LOR) or hypersensitivity reactions with 74% specificity and 82% sensitivity (likelihood ratio 3.1; P=0.0026). The authors concluded, ATI may be transient and do not always lead to a worse clinical outcome. Sustained high levels of ATI, however, lead to permanent LOR (loss of response). Patients with low IFX trough levels at week 14 are at risk for ATI formation and IFX discontinuation.
Frederiksen et. al. (2014) conducted a single-center restrospective cohort study of inflammatory bowel (IBD) patients treated with infliximab. A notable proportion of patients with inflammatory bowel disease (IBD) are switched from infliximab (IFX) to adalimumab (ADL). Anti-IFX Abs were evaluated in 187 patients treated with IFX as first line anti-TNF agent. Approximately, half (49%) were positive. Detected anti-IFX Abs had functional capacity as judged by a median IFX concentration below limit of detection (interquartile range, 0.0-0.0 μg/mL) versus 3.8 μg/mL (IQR, 1.3-7.9) in anti-IFX Ab-negative patients, P < 0.0001; but did not cross-react with ADL. Anti-ADL Abs were assessed in 57 ADL-treated patients. Twelve (21%) tested positive. Patients with previous anti-IFX Ab development were significantly more prone to develop anti-ADL Abs (33%) than those without (0%): odds ratio estimated 11, P = 0.04. The anti-ADL Abs were also functional because ADL was undetectable in all anti-ADL Ab-positive patients versus median 8.3 μg/mL (IQR 5.0-11.0) in anti-ADL-negative patients, P < 0.0001. The presence of anti-ADL Abs increased the risk of secondary ADL treatment failure with OR 28 (3-248), P < 0.001. ADL trough levels, irrespectively of anti-ADL Ab status, associated with efficacy of ADL maintenance therapy: AUC(ROC) 0.77 (0.62-0.93), P < 0.01. The authors reported that patients switching from infliximab to adalimumab who had antibodies were more likely to develop ATA. These findings are consistent with other studies and evaluation of ADA using RIA (a strength of this study). Conclusions were limited by the retrospective design and sample size.
In 2015, Jani et. al. investigated whether antidrug antibodies (ADA) and/or drug non-trough levels predict the long-term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody (ADA) and drug levels to optimize future treatment decisions. A total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme-linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non-trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated. Among patients who completed 12 months of follow-up, antidrug antibodies (ADA) were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody (ADA) formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody-positive patients received lower median dosages of methotrexate compared with antidrug antibody-negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m(2) and poor adherence were associated with lower drug levels. Although derived from a well- established observational study to examine predictors (genetic and other) of treatment response, ADA serum levels were not used to inform treatment decisions. Study results corroborated other research findings.
Arstikyte et. al. (2015) analyzed the clinical relevance of the levels of TNFα blockers and anti-drug antibodies (anti-drug Ab) in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) treated with adalimumab (ADA), etanercept (ETA), or infliximab (INF) for a prolonged period of time. Clinical characteristics (disease activity, and adverse events), serum TNFα blockers, and anti-drug Ab levels were evaluated in 62 RA and 81 SpA patients treated with TNFα blockers for a median of 28 months. Anti-ADA Ab were detected in 1 (4.0%) and anti-INF Ab in 14 out of 57 (24.6%) RA and SpA patients. Patient with anti-ADA Ab and 57.1% patients with anti-INF Ab were considered non-responders to treatment. Anti-ETA Ab were not found in any of 61 ETA treated patients. Anti-ADA and anti-INF Ab levels differ between responders and non-responders (P > 0.05). Three (5.3%) patients with high serum anti-INF Ab levels developed infusion related reactions. Patients with anti-INF Ab more often required changing to another biologic drug (OR 11.43 (95% CI 1.08-120.93)) and treatment discontinuation (OR 9.28 (95% CI 1.64-52.52)). Study limitations were the small number of non-responders and lack of specificity on whether any eligible participants declined enrollment.
In 2016, Lombardi et. al. investigated the prevalence of anti-adalimumab antibodies and the association with clinical indexes and tumor necrosis factor (TNF-α) serum levels in psoriatic patients. Patient group I (n=20) receiving biological therapies after switching from adalimumab; patient group II (n=30) ongoing adalimumab therapy; patient group III (n=30) novel adalimumab therapy; patient group IV (n=15) biological therapies other than adalimumab; group V healthy subjects (n=15) never treated with immunosuppressants or biologicals. All groups were tested at enrollment. Group II was also tested at 12 months, and group III at 1, 3 and 6 months. The primary and secondary outcome measures, standard clinical evaluations (Psoriasis Area Severity Index (PASI)), blood samples and two-site ELISA based measurement of serum adalimumab trough levels, anti-adalimumab antibodies and TNF-α. The false positive rate was 23% for anti-adalimumab detection and 22% for anti-adalimumab antibodies in patients naïve to adalimumab. Spurious positivity for anti-adalimumab antibodies (one-time-point positivity in group III during follow-up) accounted for 33% of the total. The prevalence of anti-drug antibodies was highest (87%) in group I patients. No correlations were found between the presence of anti-adalimumab antibodies of adalimumab levels and changes in PASI scores. There was a high variability of results, high prevalence of false-positives and lack of association between anti-adalimumab antibodies and TNF-α level/PSAI score limit the assay’s usefulness. Accurate clinical evaluation is key to early identification of treatment failures.
In 2017, Ara-Martin et. al. examined the relationship between loss of clinical response to anti-tumor necrosis factor (TNF) therapy and the production of anti-drug antibodies (ADAs) and the potential effects of biologic immunogenicity. This observational, non-interventional, cross-sectional study included patients with moderate-to-severe plaque psoriasis and secondary failure of adalimumab, etanercept and infliximab who were seen in the clinical practice setting. Clinical data and blood samples were collected after patient enrollment at the time that next doses of anti-TNF therapy were scheduled. ADA and serum drug concentrations were detected at a central reference laboratory using ELISA. Among 137 enrolled patients, ADA were identified in 31/65 (48%), 0/47 and 8/19 (42%) of patients treated with adalimumab, etanercept and infliximab, respectively. The presence of ADA was associated with a slightly worse clinical response in adalimumab-treated patients (Physician Global Assessment score: 3.7 vs. 3.2, ADA-positive vs. ADA-negative patients [p < .05]; correlation between serum ADA titer and body surface area: r = .292 [p = .019]). Concomitant DMARDs were not associated with anti-TNF immunogenicity in any treatment group. The authors concluded, additional evidence is needed from studies of anti-TNF therapy in psoriasis for clinicians to gain a better understanding of the impact of immunogenicity on clinical response.
Cludts et. al. (2017) conducted a study to develop an antibody assay, applicable for clinical testing, which overcomes the limitation of therapeutic interference and to further determine the relationship between ATA (anti-therapeutic antibodies) development, adalimumab levels and disease activity in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS). Use of an electrochemiluminescence platform permitted development of fit-for-purpose immunoassays. Serum samples from patients, taken prior to and at 12 and 24weeks of treatment, were retrospectively analyzed for levels of adalimumab and ATA. Overall, the antibody prevalence was 43.6% at 12weeks and 41% at 24weeks of treatment. Disruption of immune complexes by acid dissociation, a strategy often adopted for this purpose, only marginally increased the antibody prevalence to 48.7% and 46% at 12 and 24weeks respectively. They found that antibody formation was associated with decreasing levels of circulating adalimumab, but no direct effect on disease activity was evident as assessed using DAS28 for RA patients and BASDAI for PsA and AS patients. Study findings are consistent with others, suggesting that adalimumab can serve as an indicator of ATA; however, limitations included small sample size, retrospective research design and failure to confirm neutralization in all ATA-positive samples.
In 2018, Papamichael et. al. investigated drug retention in inflammatory bowel disease (IBD) patients of whom infliximab was optimized to overcome immunogenicity and variables associated with drug retention. This was a retrospective, multicenter study of consecutive IBD patients with antibodies to infliximab (ATI), based on either proactive or reactive therapeutic drug monitoring, who underwent infliximab optimization (increasing dose, shortening interval, adding an immunomodulator, or combination) to overcome immunogenicity from September 2012 to July 2015; they were followed through December 2015. ATI were analyzed using the drug-tolerant Prometheus homogeneous mobility shift assay. Drug retention was defined as no need for drug discontinuation due to SLR or serious adverse event. The cohort consisted of 22 patients (Crohn's disease, n = 15). At the end of follow-up [median, (IQR): 17.3 (10.5-32.8) months] 77% (15/22) of patients were still on drug. Univariable Cox proportional hazards regression analysis identified first detectable ATI titer as the only variable associated with drug retention (HR: 0.89; 95% CI: 0.82-0.98, p = 0.016). Receiver-operating characteristic analysis identified an ATI titer < 8.8 U/mL associated with drug retention.
In 2019, Papamichael et. al. reported on a multicentre retrospective cohort study. Patients on maintenance adalimumab therapy from June 2006 to December 2015 were eligible. They analyzed time to treatment failure from start of adalimumab until the end of follow-up [July 2016]. Treatment failure was defined as drug discontinuation for secondary loss of response or serious adverse event or need for IBD-related surgery. Serum adalimumab concentrations and antibodies to adalimumab were measured using the Prometheus homogeneous mobility shift assay. A total of 382 patients with IBD [Crohn's disease, n = 311, 81%] were included and received either at least one proactive TDM [n = 53] or standard of care [empirical dose escalation, n = 279; reactive TDM, n = 50]. Patients were followed for a median of 3.1 years [interquartile range, 1.4-4.8 years]. Multiple Cox regression analyses showed that at least one proactive TDM was independently associated with a reduced risk for treatment failure (hazard ratio [HR]: 0.4; 95% confidence interval [CI]: 0.2-0.9; p = 0.022).
A large body of evidence has evaluated the clinical validity of therapeutic drug monitoring (TDM) of biologic agent’s infliximab and adalimumab serum drug levels either alone or in combination with measurements of antibodies in inflammatory conditions such as IBD (inflammatory bowel disease). Preliminary data mainly from retrospective studies may demonstrate that proactive TDM is associated with better therapeutic outcomes compared with empiric dose optimization and/or reactive TDM, however, major limitations of the evidence relate to the lack of large prospective studies and RCTs on TDM of biologic therapy applied on different IBD phenotypes and sparse data on induction therapy and on biologic agents other than infliximab and adalimumab. Moreover, it is unclear whether trough concentrations are the best predictor of initial response to biologics, compared with peak drug concentrations or total drug exposure. Further RCTs to establish the utility of proactive TDM, particularly during the induction phase, should be performed. Additional future directions should include the development of accurate, easily accessible, and affordable rapid assays and dashboards to allow fast dosing adaptation and incorporation of predictive pharmacokinetic (PK) models based on patient and disease characteristic.
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would from randomized controlled trials (RCTs).
Several algorithms have been developed for management of patients with IBD (inflammatory bowel disease) or RA (rheumatoid arthritis) who have relapsed during TNF-inhibitor therapy. These algorithms are generally based on evidence that has indicated an association between ADA (antidrug antibodies), reduced serum drug levels, and relapse. None of the algorithms has included evidence demonstrating improved health outcomes, such as reduced time to recovery from relapse (response).
In 2014, Steenholdt et al reported results of a non-inferiority trial and cost-effectiveness analysis of 69 patients with CD who relapsed (CDAI ≥220 and/or ≥1 draining perianal fistula) during infliximab therapy. Patients were randomized to infliximab dose intensification (5 mg/kg every 4 weeks) or algorithmic treatment based on serum infliximab level and ATI (antibodies to infliximab): Patients with sub-therapeutic infliximab level (<0.5 μg/mL) had infliximab dose increased if ATI were undetectable or were switched to adalimumab if ATI were detectable; patients with therapeutic infliximab level underwent repeat testing of infliximab and ATI levels if ATI were detectable or diagnostic reassessment if ATI were undetectable. Serum infliximab and ATI levels were measured in all patients using RIA (radioimmunoassay) in single-blind fashion (patients unaware but investigators aware of test results). Randomized groups were similar at baseline; overall, 55 (80%) of 69 patients had nonfistulizing disease. Most patients (70%) had therapeutic serum infliximab levels without detectable ATI; revised diagnoses in 6 (24%) of 25 such patients in the algorithm arm included bile acid malabsorption, strictures, and IBS. In both intention-to-treat (ITT) and per-protocol analyses, similar proportions of patients in each randomized group achieved clinical response at week 12, defined as a minimum 70-point reduction from baseline CDAI for patients with nonfistulizing disease and a minimum 50% reduction in active fistulas for patients with fistulizing disease (ITT, 58% in the algorithm group vs 53% in the control group; p=0.810; per-protocol; 47% in the algorithm group vs 53% in the control group; p=0.781). Only the ITT analysis fell within the prespecified non-inferiority margin of -25% for the difference between groups. Conclusions on the non-inferiority of an algorithmic approach compared with dose intensification from this trial are limited. The non-inferiority margin was arguably large and was exceeded in the conservative per-protocol analysis. Dropouts were frequent and differential between groups; 17 (51%) of 33 patients in the algorithm group and 28 (78%) of 36 patients in the control group completed the 12-week trial. A large proportion of patients (24%) in the algorithmic arm were potentially misdiagnosed (ie, CD flare was subsequently determined not to be the cause of relapse); the comparable proportion in the control arm was not reported. In most patients (80% who had nonfistulizing disease), only a subjective measure of treatment response was used (minimum 70-point reduction from baseline CDAI).
Roblin et al (2014) conducted a single-center, prospective observational study of 82 patients with inflammatory bowel disease (IBD) (n=45 CD, n=27 UC) with clinical relapse (CDAI >220 or Mayo Clinic >5) during treatment with adalimumab 40 mg every 2 weeks. For all patients, trough adalimumab levels and ADA (antidrug antibodies) were measured in a blinded fashion using ELISA, and adalimumab dose was optimized to 40 mg weekly. Those who did not achieve clinical remission (CDAI <150 or Mayo score <2) within 4 months underwent repeat trough adalimumab and anti-adalimumab antibody testing and were switched to infliximab. Clinical and endoscopic responses after adalimumab optimization and after infliximab therapy for 6 months were compared across 3 groups: (1) those with a therapeutic adalimumab level (>4.9 μg/mL28), (2) those with a sub-therapeutic adalimumab level and undetectable ATA (antibodies to adalimumab); and (3) those with a sub-therapeutic adalimumab level and detectable ATA. After adalimumab optimization, more group 2 patients achieved clinical remission (16 [67%] of 24 patients) than group 1 (12 [29%] of 41 patients; p<0.01 vs group 2) and group 3 (2 [12%] of 17 patients; p<0.01 vs group 2) patients. Duration of remission was longest in group 2 (mean, 15 months) compared with group 1 (mean, 5 months) and group 3 (mean, 4 months; p<0.01 for both comparisons vs group 2). At 1 year, 13 (52%) of 24 patients in group 2 maintained clinical remission compared with no patients in groups 1 or 3 (p<0.01 for both comparisons vs group 2). Results were similar when remission was defined using calprotectin levels (<250 μg/g stool) or endoscopic Mayo score (<2). Fifty-two patients (n=30 CD, n=22 UC) who failed to achieve clinical remission after adalimumab optimization were switched to infliximab. More patients in group 3 achieved clinical remission (12 [80%] of 15 patients) than in group 1 (2 [7%] of 29 patients) or group 2 (2 [25%] of 8 patients; p<0.01 for both comparisons vs group 3). Duration of response after switching to infliximab was longest in group 3 (mean, 14 months) compared with group 1 (mean, 3 months) and group 2 (mean, 5 months; p<0.01 for both comparison vs group 3). At 1 year, 8 (55%) of 15 patients in group 3 maintained clinical remission compared with no patients in groups 1 or 2 (p<0.01 for both comparisons vs group 3). Results were similar using objective measures of clinical remission (calprotectin level, endoscopic Mayo score). These results suggested that patients with inflammatory bowel disease (IBD) who relapse on adalimumab and have sub-therapeutic serum adalimumab levels may benefit from a higher adalimumab dose if ATA (antibodies to adalimumab) are undetectable or from a change to another TNF inhibitor if ATA are detectable. Relapsed patients who have therapeutic serum adalimumab levels may benefit from change to a different drug class. Strengths of the study include its use of subjective and objective measures of remission and blinded serum drug level and ATA monitoring. However, results were influenced by the small sample size, use of ELISA for antibody testing, and lack of ADA (antidrug antibodies) levels for decision making. Subsequent study comparing the management using the algorithm proposed with usual care is needed. Ideally, using more than 1 method of assaying antibodies would further assessment of analytic validity. Finally, the lead author of the study received lecture fees from the ADA (antidrug antibodies) test provider (Theradiag).
Convincing evidence for the clinical utility of therapeutic drug monitoring (TDM) in biologic agents for the treatment of inflammatory conditions is currently lacking. There are still some limitations when applying TDM into clinical practice, such as when to use TDM, proper interpretation and application of the results, and the identification of the optimal window/thresholds to target. These therapeutic windows or thresholds appear to vary on the basis of the outcome of interest and the IBD phenotype. Most of the data on implementation of TDM refer to anti-TNF therapies and the maintenance phase of treatment. Although well-designed large prospective studies are lacking, there are preliminary data mainly from retrospective studies that demonstrate that proactive TDM is associated with better therapeutic outcomes compared with empiric dose optimization and/or reactive TDM. However, before TDM can be widely applied in clinical practice, there are several obstacles to their regular use including when to use TDM, how to accurately interpret and apply the results of such testing, and in defining the optimal drug concentration thresholds and ranges to target. Major limitations of the evidence relate to the lack of large prospective studies and RCTs on TDM of biologic therapy applied on different IBD phenotypes and sparse data on induction therapy and on biologic agents other than infliximab and adalimumab. Moreover, it is unclear whether trough concentrations are the best predictor of initial response to biologics, compared with peak drug concentrations or total drug exposure. Further RCTs to establish the utility of proactive TDM, particularly during the induction phase, should be performed. Additional future directions should include the development of accurate, easily accessible, and affordable rapid assays and dashboards to allow fast dosing adaptation and incorporation of predictive PK models based on patient and disease characteristics.
Vedolizumab (Entyvio) is an intravenous tumor necrosis factor blocking agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of: moderately to severely active ulcerative colitis (UC); and moderately to severely active Crohn’s disease (CD). Vedolizumab is generally given for those patients who have had an inadequate response with lost response to, or were intolerant to tumor necrosis factor (TNF) blocker or immunomodulator; or had an inadequate response with were intolerant to, or demonstrated dependence on corticosteroids. This drug is used for achieving clinical response or remission or achieving corticosteroid-free remission.
Serum concentrations of vedolizumab (VDZ) may vary among equally dosed patients which can affect patient outcomes. Some patients may develop immunogenicity (non-response) to VDZ by producing antibodies to vedolizumab and the presence of persistent anti-vedolizumab antibody has been observed to reduce serum concentrations of vedolizumab. Incorporating therapeutic drug monitoring into clinical practice has been proposed to allow clinicians to optimize treatment by maintaining effective drug concentrations over time and affecting a patient’s loss of response.
In 2017, Willet et. al. conducted an observational study investigating the association between low trough levels of vedolizumab (Entyvio) during induction therapy for inflammatory bowel disease and need for additional doses within 6 months. The study included 47 patients with Crohn's disease (CD; n = 31) or ulcerative colitis (UC; n = 16) who had not responded to 2 previous treatment regimens with antagonists of tumor necrosis factor and were starting therapy with vedolizumab at 2 hospitals in France, from June 2014 through April 2016. All patients were given a 300-mg infusion of vedolizumab at the start of the study, Week 2, Week 6, and then every 8 weeks; patients were also given corticosteroids during the first 4-6 weeks. Patients not in remission at Week 6 were given additional doses of vedolizumab at Week 10 and then every 4 weeks (extended therapy or optimization). Remission at Week 6 of treatment was defined as CD activity score below 150 points for patients with CD and a partial Mayo Clinic score of < 3 points, without concomitant corticosteroids, for patients with UC. Blood samples were collected each week and serum levels of vedolizumab and antibodies against vedolizumab were measured using an enzyme-linked immunosorbent assay. Median trough levels of vedolizumab and interquartile ranges were compared using the nonparametric Mann-Whitney test. The primary objective was to determine whether trough levels of vedolizumab measured during the first 6 weeks of induction therapy associated with the need for extended treatment within the first 6 months. Based on response to therapy at Week 6, extended treatment was required for 30 of the 47 patients (23 patients with CD and 7 patients with UC). At Week 2, trough levels of vedolizumab for patients selected for extended treatment were 23.0 μg/mL (interquartile range, 14.0-37.0 μg/mL), compared with 42.5 μg/mL in patients who did not receive extended treatment (interquartile range, 33.5-50.7; P = .15). At Week 6, trough levels of vedolizumab <18.5 μg/mL were associated with need for extended therapy (100% positive predictive value, 46.2%; negative predictive value; area under the receiver operating characteristic curve, 0.72) within the first 6 months. Among patients who required extended treatment at Week 10, all of those with trough levels of vedolizumab <19.0 μg/mL at Week 6 had achieved clinical remission 4 weeks later (secondary responders). The authors concluded, patients with CD or UC receiving induction therapy with vedolizumab, low trough levels of vedolizumab at Week 6 (<19.0 μg/mL) are associated with need for additional doses (given at Week 10 and then every 4 weeks). All patients receiving these additional doses achieved a clinical response 4 weeks later. No subjects reported to have developed antibodies to vedolizumab (ATV) during the study.
In 2018, Ward et. al. reported on current data and future direction on therapeutic drug monitoring of vedolizumab (Entyvio) in inflammatory bowel disease. The introduction of vedolizumab (Entyvio), a lymphocyte adhesion inhibitor, has expanded the relatively limited therapeutic armamentarium available for Crohn’s disease and ulcerative colitis. Despite its effectiveness, both primary nonresponse and secondary loss of response to vedolizumab (Entyvio) do occur, as is observed with the use of anti-tumor necrosis factor (TNF) therapy. Further, in a proportion, onset of efficacy may be relatively slow. A large body of data support an exposure–response relationship with anti-TNF drug levels, which has led to therapeutic drug monitoring becoming incorporated into every day clinical management. The influence of patient and disease factors on the pharmacokinetics of anti-TNF levels, including immunogenicity, has also been examined. The role of therapeutic drug monitoring with vedolizumab (Entyvio) is less clear. This review summarizes the available evidence on the pharmacokinetics and pharmacodynamics of vedolizumab in inflammatory bowel disease and how drug levels, immunogenicity and other factors influence clinical outcomes. Vedolizumab (Entyvio) clearance is increased with very high body weight and hypoalbuminaemia but is not influenced by the addition of an immunomodulator. Immunogenicity is uncommon. α4β7 receptor saturation occurs at low serum vedolizumab drug levels, and measuring it alone is insufficient to predict clinical outcomes. Using quartile analysis of vedolizumab drug levels, there appears to be a modest exposure–response relationship during induction. Drug levels at week 6 of approximately >20 μg/ml have been shown to be associated with improved clinical outcomes, including subsequent mucosal healing rates during maintenance and avoiding the need to dose escalate due to lack of response. There are currently insufficient data to support the routine use of therapeutic drug monitoring during maintenance therapy. Further studies to elucidate the role of therapeutic drug monitoring of vedolizumab are needed.
In 2019, Ungaro et. al. examined the association of maintenance vedolizumab concentrations with remission. A cross-sectional multi-center study was performed of inflammatory bowel disease [IBD] patients on maintenance vedolizumab. A homogeneous mobility shift assay [HMSA] was used to determine trough serum concentrations of vedolizumab and anti-drug antibodies [ATVs]. The primary outcome was corticosteroid-free clinical and biochemical remission defined as a composite of clinical remission, normalized C-reactive protein [CRP] and no corticosteroid use in 4 weeks. Secondary outcomes included corticosteroid-free endoscopic and deep remission. Vedolizumab concentrations were compared between patients in remission and with active disease. Logistic regression, adjusting for confounders, assessed the association between concentrations and remission. In total, 258 IBD patients were included [55% CD and 45% UC]. Patients in clinical and biochemical remission had significantly higher vedolizumab concentrations [12.7 µg/mL vs 10.1 µg/mL, p = 0.002]. Concentrations were also higher among patients in endoscopic and deep remission [14.2 µg/mL vs 8.5 µg/mL, p = 0.003 and 14.8 µg/mL vs 10.1 µg/mL, p = 0.01, respectively]. After controlling for potential confounders, IBD patients with vedolizumab concentrations >11.5 µg/mL were nearly 2.4 times more likely to be in corticosteroid-free clinical and biochemical remission. Only 1.6% of patients had ATVs.
In 2019, Papamichael et. al. reviewed the current data and provided expert opinion regarding the clinical utility of therapeutic drug monitoring (TDM) for biologic therapies in inflammatory bowel disease (IBD). The current evidence supporting the role of therapeutic drug monitoring (TDM) regarding vedolizumab derives only from exposure response relationship studies showing that higher vedolizumab concentrations are associated with better therapeutic outcomes. Although there are emerging data that may show an association between drug concentrations and outcomes, they are not sufficient to guide specific induction and maintenance drug concentrations for vedolizumab. Further RCTs to establish the utility of proactive TDM, particularly during the induction phase, should be performed. Additional future directions should include the development of accurate, easily accessible, and affordable rapid assays and dashboards to allow fast dosing adaptation and incorporation of predictive PK models based on patient and disease characteristics.
For individuals who have ulcerative colitis (UC) or Crohn’s disease (CD) receiving vedolizumab (Entyvio), there is an interest in therapeutic drug monitoring (TMD) not only for the purpose of identifying markers that will serve as end points for successful treatment, but also for timely cessation or switching of therapy in those unlikely to respond. Based on the peer reviewed medical literature the available studies to date are insuffecient and have not demonstrated in randomized comparative trials the presence of a clinical utility benefit to therapeutic regimens guided by serum drug levels (trough levels) or measurements of antibodies when compared to standard treatment regimens. Such evidence is necessary to adequately judge clinical response, adverse reactions, and need for a change in therapy. Further randomized controlled trials (RCTs) are needed to investigate the efficacy of the role of therapeutic drug monitoring (TMD) of vedolizumab (Entyvio). More controlled data is needed to define the best cut-off to define abnormal values of the measured monitor parameters, define optimal thresholds for the different interventions and the subpopulations as to who will benefit the most from this testing. The evidence is insufficient to determine the effects of the technology on net health outcomes.
Ustekinumab (Stelara) is a biologic medication approved by the U.S. Food and Drug Administration (FDA) to lower inflammation and help patients with moderate to severe plaque psoriasis, active psoriatic arthritis and moderately to severely active Crohn’s disease. This medication is typically prescribed after non-response to other medications and can be administered subcutaneous or as an IV infusion. Ustekinumab (Stelara) blocks inflammation proteins called IL-12 and IL-23.
Serum concentrations of ustekinumab (Stelara) may vary among equally dosed patients which can affect patient outcomes. Some patients may develop immunogenicity (non-response) by producing antibodies to ustekinumab and the presence of persistent anti- ustekinumab antibody has been observed to reduce serum concentrations of ustekinumab. Incorporating therapeutic drug monitoring into clinical practice has been proposed to allow clinicians to optimize treatment by maintaining effective drug concentrations over time and affecting a patient’s loss of response.
In 2015, Chiu et. al. conducted a prospective observational study on the association between clinical response to ustekinumab and immunogenicity to ustekinumab prior to adalimumab in 76 patients with plaque psoriasis who were treated with ustekinumab for a minimum of 7 months. Blood samples were drawn just prior to scheduled ustekinumab injection during clinic visits. Levels of anti-ustekinumab antibody (AUA) and serum ustekinumab concentration were measured respectively by radioimmunoassays and enzyme-linked immunoassays respectively, and correlated to clinical data and Psoriasis Area and Severity Index (PASI). AUA was detected in 6.5% of patients after a mean of 13 months of treatment. Patients with positive AUA had significantly lower serum ustekinumab concentrations (0.01 versus 0.2 mg/L, p<0.001) and lower PASI50 response than patients without AUA (0% versus 69%, p = 0.004).The percentage of AUA formation was comparable between patients who had failed previous adalimumab with or without anti-adalimumab antibodies (AAA) (14.3% versus 12.5%, p = 1.00). However, a higher proportion of switchers without AAA obtaining PASI50 (71.4% versus 37.5%) and PASI75 response (42.9% versus 12.5%) within 7 months of ustekinumab treatment than with AAA though this difference did not reach statistical significance.
In 2019, Papamichael et. al. reviewed the current data and provided expert opinion regarding the clinical utility of therapeutic drug monitoring (TDM) for biologic therapies in inflammatory bowel disease (IBD). The current evidence supporting the role of TDM regarding ustekinumab (Stelara) is based on 2 exposure-response relationship studies showing that higher ustekinumab concentrations correlate to better therapeutic outcomes At this time, there are still no studies comparing either proactive or reactive TDM with empiric ustekinumab optimization. Although there is emerging data that may show an association between drug concentrations and outcomes, they are not sufficient to guide specific induction and maintenance drug concentrations for ustekinumab (Stelara). Further RCTs to establish the utility of proactive TDM, particularly during the induction phase, should be performed. Additional future directions should include the development of accurate, easily accessible, and affordable rapid assays and dashboards to allow fast dosing adaptation and incorporation of predictive PK models based on patient and disease characteristics.
There is an interest in therapeutic drug monitoring (TMD) not only for the purpose of identifying markers that will serve as end points for successful treatment, but also for timely cessation or switching of therapy in those unlikely to respond. Based on the peer reviewed medical literature the current evidence supporting the role of therapeutic drug monitoring (TDM) regarding ustekinumab (Stelara) is based on 2 exposure-response relationship studies showing that higher ustekinumab concentrations correlate to better therapeutic outcomes. At this time, there are still no studies comparing either proactive or reactive TDM with empiric ustekinumab optimization. Although there is emerging data that may show an association between drug concentrations and outcomes, they are not sufficient to guide specific induction and maintenance drug concentrations for ustekinumab (Stelara). Further RCTs to establish the utility of proactive TDM, particularly during the induction phase, should be performed. Additional future directions should include the development of accurate, easily accessible, and affordable rapid assays and dashboards to allow fast dosing adaptation and incorporation of predictive PK models based on patient and disease characteristics.
The evidence is insufficient to support the use of the therapeutic drug monitoring (TMD) for biologics agents including but not limited to the following assays: Anser ADA (adalimuab [Humira]), Anser IFX (infliximab [Remicade]), Anser UST (ustekimumab [Stelara]) and Anser VDZ (vedolizumab [Entyvio]) in patients with inflammatory conditions to guide treatment optimization. The overall benefit of therapeutic drug monitoring (TMD) using serum drug levels (trough levels), either alone or in combination with measurement of antibodies has not been established. There is absence of clinical utility studies evaluating if therapeutic drug monitoring (TMD) guided dosing adjustments leads to clinically meaningful changes in patient health outcomes, and how those outcomes compare with adjustments based on patient symptoms, clinical assessment, and standard laboratory evaluation. Well-designed studies are needed to expand the existing evidence base to confirm therapeutic drug monitoring (TMD) with biologic agents leads to changes in therapeutic interventions or other changes in disease management that improve patient health outcomes over the long term. Studies should also report how these outcomes compare with adjustments based on patient symptoms, clinical assessment and standard laboratory evaluation. The evidence is insufficient to determine the effects of the technology on net health outcomes.
Clinical guidelines have not included recommendations for testing the measurement of serum drug levels (trough levels) either alone or in combination with measurement of antibodies in patients treated with biologic agents for inflammatory conditions.
Clinical guidelines have not included recommendations for testing the measurement of serum drug levels (trough levels) either alone or in combination with measurement of antibodies in patients treated with biologic agents for inflammatory conditions.
In 2017, the American Gastroenterological Association (AGA) issued a guideline on therapeutic drug monitoring in inflammatory bowel disease. Due to paucity of data at the time of publication, this guideline does not address the role of therapeutic drug monitoring (TDM) in patients treated with vedolizumab or ustekinumab. The guideline includes the following recommendations for therapeutic drug monitoring (TMD) in inflammatory bowel disease:
| Statement | Strength of Recommendation | Quality of Evidence |
|---|---|---|
| In adults with active IBD treated with anti-TNF agents, the AGA suggests reactive therapeutic drug monitoring to guide treatment changes. Conditional recommendation, very low quality of evidence. Comment: Of note, there may be a small subset of patients who may still respond by targeting higher target concentrations. Optimal trough concentrations for induction therapy are uncertain. |
Conditional recommendation | Very low quality |
| In adult patients with quiescent IBD treated with anti-TNF agents, the AGA makes no recommendation regarding the use of routine proactive therapeutic drug monitoring. | No recommendation | Knowledge gap |
| In adult patients with IBD being started on thiopurines, the AGA suggests routine TPMT testing (enzymatic activity or genotype) to guide thiopurine dosing. Comment:Routine laboratory monitoring, including CBC, should be performed, regardless of TPMT testing results |
Conditional recommendation | Low quality |
| In adult patients treated with thiopurines with active IBD or adverse effects thought to be due to thiopurine toxicity, the AGA suggests reactive thiopurine metabolite monitoring to guide treatment changes. Comment:When measuring thiopurine metabolite monitoring in patients with active IBD-related symptoms, we suggest a target 6-thioguanine (6-TGN) cutoff between 230-450 pmol/8 x 108 RBCs when used as monotherapy; optimal 6-TGN cutoff when thiopurines are used in combination with anti-TNF agents is uncertain |
Conditional recommendation | Very low quality |
| In adult patients with quiescent IBD treated with thiopurines, the AGA suggests against routine thiopurine metabolite monitoring | Conditional recommendation | Very low quality |
Based on the guideline recommendations the below is the suggested target trough concentrations when applying reactive therapeutic drug monitoring in patients with active inflammatory bowel disease on maintenance therapy with anti-tumor necrosis factors:
| Drug | Suggested Trough Concentration ug/mL | Comments |
|---|---|---|
| Infliximab | > 5 | Six studies (929 patients) provided data on proportion of patients not in remission above predefined infliximab thresholds (1, 3, 5, 7, and 10 mg/mL). Based on these, proportion of patients not in remission decreased from 25% when using an infliximab threshold of ≥1 mg/mL, to 15% with an infliximab trough concentration of ≥ 3 mg/mL, to approximately 4% with an infliximab trough concentration of ≥ 7 mg/mL or ≥ 10 mg/mL |
| Adalimumab | ≥ 7.5 | Four studies provided data on proportion of patients not in remission above adalimumab trough concentration >5.0 ± 1 mg/mL or 7.5 ± 1 mg/mL. On analysis of different thresholds, proportion of patients not in remission progressively decreased from 17% when using an adalimumab threshold ≥5.0 ± 1 mg/mL, to 10% with an adalimumab trough concentration of ≥ 7.5 ± 1 mg/mL. |
| Certolizumab Pegol |
≥ 20 | One study provided data from an exposure response pooled analysis from 9 trials. On analysis of different thresholds, proportion of patients not in remission progressively decreased from 42% when using a certerolizumab threshold of ≥10 mg/mL to 26% with a certolizumab trough concentration of ≥20 mg/mL |
| Golimumab | Unknown | There is a lack of sufficient evidence available to establish a target trough goal |
Based on this evidence and target trough concentrations, the panel developed an algorithm for how patients and physicians using shared decision making may respond to reactive therapeutic drug monitoring (TDM) testing. Initially, only the trough concentrations should be assessed. If the level is at or above the target trough, then the patient may consider switching to a different drug class, although escalating index therapy may be a reasonable alternative (especially if reactive TDM is performed in asymptomatic patients with ongoing endoscopic activity, or in patients with perianal disease where target trough concentrations may be higher). In the presence of sufficient trough concentrations, results of antibody testing should not guide treatment decisions. If the trough concentration is low (below the suggested threshold, in patients with active IBD) and no anti-drug antibodies are present, then the index drug should be optimized using any of the following techniques: shortening the dosing interval and/or increasing the drug dose, and/or adding an immunomodulatory agent. If there is no detectable drug (zero trough concentration) and high-titer anti-drug antibodies are present, then the patient should consider switching to a different drug within the class or to a different drug class. If there is no detectable drug and low-titer antibodies are present, then one can consider trying to optimize the index drug by shortening the dosing interval and/or increasing the drug dose, and/or adding an immunomodulator agent. Typically, optimizing the drug will be attempted before changing to a different drug within the class or switching to a new drug class, although some might opt to change to a different drug within the class or switch to a new drug class. It should be noted that the reporting of anti-drug antibodies is variable between commercial assays, with some assays being very sensitive for detecting very-low-titer antibodies of limited clinical significance. Uniform thresholds for clinically relevant antibody titers are lacking. At this time, it is unclear how antibodies affect drug efficacy when both active drug and antibodies are detected. In cases of low trough concentrations and low or high anti-drug antibodies, the evidence to clarify optimal management is lacking.
There are several issues that remain unresolved even after assessing the evidence. The best-available evidence did not address the optimal timing for measuring trough concentrations. In most cases, the panel recommends that a trough level for infliximab or adalimumab be drawn as close to the next dose as possible (i.e., within 24 hours). Additionally, while the drug trough concentration is consistent across different commercial assays, assays for anti-drug antibodies are not readily comparable with each other.
When anti-drug antibodies are detected, it is unclear what antibody level is clinically meaningful. Low-titer antibodies may be transient and non-neutralizing, such that shortening the drug-dosing interval and/or escalating the dose may optimize the trough concentration in this setting of low-titer antibodies. In contrast, high-titer anti-drug antibodies, especially with undetectable trough concentrations, are generally persistent and neutralizing. In this setting, especially with undetectable drug, there may be very limited benefit to attempting dose escalation of the index agent and switching to a different drug within the same class may be more effective. Unfortunately, current data do not allow us to identify optimal anti-drug antibody cutoffs for high- vs low-titer antibodies, in the current commercially available assays.
Further studies are needed to better define clinically meaningful versus insignificant anti-drug antibodies, based on titers and/or persistence in repeated testing, and at which titers can anti-drug antibodies be suppressed below needing to change drug therapies.
In 2016, the National Institute for Health and Care Excellence (NICE) issued guidance on therapeutic monitoring of TNF-α inhibitors in Crohn’s disease. NICE recommends the following that laboratories monitoring TNF-α inhibitors in patients with Crohn’s disease who have lost response to the treatment, should work with clinicians to collect data through either a prospective study, a local audit, or a registry.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Prometheus® Laboratories Inc., a College of American Pathologists-accredited lab under CLIA, offers non-radio-labeled, fluid phase homogenous mobility shift assay (HMSA) tests called Anser™ IFX for infliximab, Anser™ ADA for adalimumab, Anser™ VDZ for vedolizumab and Anser™ UST for ustekinumab. These tests are not based on an enzyme-linked immunosorbent assay (EILSA) and each can measure antidrug antibodies in the presence of detectable drug levels, improving upon a major limitation of the ELISA method. These tests measure serum drug concentrations and antidrug antibodies.
Not applicable
In an individual receiving treatment with infliximab (Remicade), the measurement of serum infliximab (Remicade) drug levels (trough levels), either alone or as a combination test with measurement of antibodies to infliximab (Remicade), including but not limited to Prometheus Anser IFX is considered investigational.
In an individual receiving treatment with adalimumab (Humira), the measurement of serum adalimumab (Humira) drug levels (trough levels), either alone or as a combination test with measurement of antibodies to adalimumab (Humira), including but not limited to Prometheus Anser ADA is considered investigational.
In an individual receiving treatment with vedolizumab (Entyvio), the measurement of serum vedolizumab (Entyvio) drug levels (trough levels), either alone or as a combination test with measurement of antibodies to vedolizumab (Entyvio), including but not limited to Prometheus Anser VDZ is considered investigational.
In an individual receiving treatment with ustekinumab (Stelara), yhe measurement of serum ustekinumab (Stelara)drug levels (trough levels), either alone or as a combination test with measurement of antibodies to ustekinumab (Stelara), including but not limited to Prometheus Anser UST is considered investigational.
The evidence is insufficient to support the use of the therapeutic drug monitoring (TMD) for biologics agents including but not limited to the following assays: Anser ADA (adalimuab [Humira]), Anser IFX (infliximab [Remicade]), Anser UST (ustekimumab [Stelara]) and Anser VDZ (vedolizumab [Entyvio]) in patients with inflammatory conditions to guide treatment optimization. The overall benefit of therapeutic drug monitoring (TMD) using serum drug levels (trough levels), either alone or in combination with measurement of antibodies has not been established. There is absence of clinical utility studies evaluating if therapeutic drug monitoring (TMD) guided dosing adjustments leads to clinically meaningful changes in patient health outcomes, and how those outcomes compare with adjustments based on patient symptoms, clinical assessment, and standard laboratory evaluation. Well-designed studies are needed to expand the existing evidence base to confirm therapeutic drug monitoring (TMD) with biologic agents leads to changes in therapeutic interventions or other changes in disease management that improve patient health outcomes over the long term. Studies should also report how these outcomes compare with adjustments based on patient symptoms, clinical assessment and standard laboratory evaluation. The evidence is insufficient to determine the effects of the technology on net health outcomes.
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