Adalimumab Levels Research Articles

Comparing Point-of-Care Technology to ELISA Testing for Infliximab and Adalimumab Levels in Adult Inflammatory Bowel Disease Patients: A Prospective Pilot Study.

Introduction: Therapeutic drug monitoring (TDM) has proven to be a valuable strategy for optimizing biologic therapies, among which are anti-tumor necrosis factor (anti-TNF) treatments in inflammatory bowel disease (IBD). In particular, reactive TDM has been shown to manage treatment failures more cost-effectively than empirical dose adjustments for anti-TNF drugs. However, several challenges currently impede the widespread adoption of TDM in clinical practice, particularly addressing the delay between sample collection and result availability. To overcome this limitation, the use of point-of-care technology tests (POCTs) is a potential solution. Point-of-care technology tests are medical diagnostic tests performed at the site of patient care to provide immediate results, allowing for quicker decision-making and treatment. The current standard of care (SOC) for drug level measurement relies on the enzyme-linked immunosorbent assay (ELISA), a method that is time-consuming and requires specialized personnel. This study aims to evaluate a novel, user-friendly, and efficient POCT method (ProciseDx Inc.) and compare its performance with the SOC ELISA in assessing infliximab and adalimumab levels in blood samples from IBD patients. Methods: In this prospective, single-center study, we collected blood samples from IBD patients, both CD and UC, receiving infliximab (87 IBD patients; 50% UC and 50% CD) or adalimumab (60 patients; 14% UC and 48% CD) and we analyzed the blood's drugs levels using both the ProciseDx Analyzer POC and the SOC ELISA. We examined the correlation between the two methods using statistical analyses, including the Deming regression test. Additionally, we assessed the ease of use, turnaround time, and overall practicality of the POCT in a clinical setting. Results: The ProciseDx test demonstrated a strong correlation with the SOC ELISA for measuring both infliximab and adalimumab levels. In particular, the overall correlation between the ProciseDx POCT and the ELISA assessments showed an r coefficient of 0.83 with an R squared value of 0.691 (95% CI 0.717-0.902) for IFX measurements, and an r coefficient of 0.85 with an R squared value of 0.739 (95% CI 0.720-0.930). Conclusions: the ProciseDx POC test offers significantly faster turnaround times and is more straightforward to use, making it a viable alternative for routine clinical monitoring. Despite its promising potential, further refinement and validation of the ProciseDx test are necessary to ensure its effectiveness across diverse patient populations and clinical settings. Future research should focus on optimizing the POC tests' performance and evaluating its long-term impact on IBD management.

No Correlation between Anti-drug Antibodies and Therapeutic Response in Tunisian Patients with Chronic Inflammatory Diseases Treated by TNF Blockers.

Tumor necrosis factor alpha (TNF alpha) blockers such as infliximab (IFX) and adalimumab (ADA) had significantly changed the course of inflammatory diseases such as rheumatoid arthritis (RA), spondyloarthritis (SpA) and Crohn's disease (CD). However, about 30% of patients do not respond to these treatments. This lack of response may be due to the formation of antibodies against these drugs (anti-drug antibodies: ADAbs). The aim of this study was to determine the prevalence of ADAbs against IFX and ADA, and the trough serum concentration of IFX and ADA in RA, SpA or CD patients and to assess their impact on the therapeutic response. A cross sectional, multi-centric study was conducted, including patients with RA, SpA or CD treated with IFX or ADA as a first biotherapy for at least 6 months. ADAbs and trough levels were measured by an Enzyme Linked Immunosorbent assay (ELISA). 197 patients were included (57 RA, 73 SpA and 67 CD). ADAbs were positive in 40% of cases for IFX and 25% for ADA. They were positive in 40% of SpA, 35% of RA, and 21% of CD. The presence of ADAbs was inversely correlated to the trough levels of IFX and ADA during RA (p = 0.01 and p < 0.0001), SpA (p < 0.01 and p < 0.0001) and CD (p = 0.001 and p = 0.04). For all pathologies, the presence of ADAbs was not correlated with disease activity. Concomitant methotrexate significantly reduced immunogenicity. In our study, the presence of ADAb and low trough levels seem to not affect the therapeutic response in patients on TNF alpha antagonists. Other tracks more than immunogenicity should be investigated to explain the loss of response to these biotherapies.

Ultrasound transmural healing correlates with higher adalimumab drug concentration in Crohn's disease only in the short-term.

Anti-TNF drugs have revolutionized the treatment of Crohn's disease (CD) and have set new therapeutic targets. A direct correlation between anti-TNF trough levels and endoscopic healing in IBD patients has been established, but the association between drug levels and transmural healing assessed by ultrasound is not yet clearly defined. To evaluate the correlation between the serum concentration of adalimumab (ADA) and sonographic transmural healing in CD patients at different times during the follow-up of patients. In this retrospective, cross-sectional study all patients with CD who were undergoing treatment with ADA in our center were included. Intestinal ultrasound (IUS) was performed before the initiation of the drug and for response monitoring. ADA serum-through levels were compared between patients with and without transmural healing at different periods of time. 92 patients were included, all patients showed signs of inflammatory activity in the baseline IUS. In the IUS monitoring of the response to ADA, 34 (34.8%) patients presented transmural healing. Among patients in the first year of treatment, those with sonographic healing showed higher median levels than patients without transmural healing (12.0 µg/mL vs. 9.3 µg/mL, respectively; p= 0.007). There was no correlation found between adalimumab levels and sonographic healing in patients undergoing treatment for over a year. Higher adalimumab through levels were corelated with transmural healing with ultrasound during the first year of treatment. This correlation was not found after one year of treatment.

P098 Anti-adalimumab antibodies are associated with active Juvenile Idiopathic Arthritis

Abstract Background/Aims Biologics have been used widely in the UK to treat Juvenile Idiopathic Arthritis (JIA) for over two decades. As this population has aged and switched biologics, there has been a growth in the cohort of patients who have switched through a greater number of biologics, consequently having fewer therapeutic options available. Our group has recently published data suggesting adalimumab has a greater drug survival compared to etanercept and infliximab. As part of our further investigation, we examined the relationship between adalimumab antibodies (AAA) and drug levels, stratified by disease activity (remission vs. active disease). Methods We conducted a retrospective observational study among patients with JIA and measured adalimumab drug levels and AAAs. The key metrics measured were AAAs (AU/L) and adalimumab drug levels (mg/mL). Disease remission was determined using standard Wallace criteria.The differences between the active and remission groups were examined with the Mann-Whitney U test. Results Among our cohort of 293 JIA patients receiving adalimumab, 179 had recorded adalimumab levels and AAAs. In 146 of these patients, we were able to measure disease activity, which was stratified into two distinct categories: Remission (N = 96) and Active (N = 50) according to Wallace criteria. Within our cohort of patients, there was a significant difference in both adalimumab drug levels, (P = 0.004) and AAAs (P = 0.00009) among those with active disease when compared to those in remission. Specifically, those with active disease exhibited a higher geometric mean AAA of 156.89 AU/L [95% CIs (95% confidence intervals) 129.65-189.85] when compared to those in remission with a mean of 65.25 AU/L (95% CI 41.10-103.58). The median AAA levels in those with active disease was 91 AU/L (IQR 0-200), compared with 0 (IQR 0-12.5) among those in remission. With respect to adalimumab drug levels, the geometric mean in patients with active disease was 7.27 mg/mL (95% CI 5.15-10.26) compared with 8.55 mg/mL (95% CI 7.26, 10.07) for patients in remission. The median drug level in the active group was 2.3 mg/ml (IQR 0-11.9) when compared with 9.4 mg/ml (IQR 3.8-13.1) in the remission group. Conclusion Various studies have demonstrated that the presence of AAAs is associated with secondary failure in JIA and other rheumatic diseases. However, the precise relationship between AAAs, adalimumab drug concentration and disease activity are yet to be elucidated, thus their regular monitoring is not currently part of guidelines or routine clinical practice.To our knowledge this is the largest single-centered cross-sectional study investigating the relationship of AAAs and remission state in JIA.Our study demonstrates that not only are higher AAAs associated with lower drug concentration, but that this is further associated with active disease. Disclosure M.W. Carrim: None. D. Sen: None. M. Shipa: None. C. Fisher: None. T. AlSulaim: None. A. Bouraoui: None. M. Leandro: None. C. Ciurtin: None. J. Glanville: None.

Adalimumab Dose Reduction and Withdrawal in Stable Non-Infectious Pediatric Uveitis: An Open-Label, Prospective, Pilot Study

ABSTRACT Purposes This study investigated the feasibility of adalimumab (ADA) dose reduction and withdrawal strategy in children with stable pediatric non-infectious uveitis (PNIU). Methods This open-label prospective pilot trial recruited 18 stable PNIU patients (33 eyes) between two and eighteen years old who were treated with standard doses of ADA (20/40 mg every 2 weeks) plus oral methotrexate. The interval of ADA injection was extended to 4 weeks and followed up for 24 weeks. If the uveitis remained stable, ADA was discontinued and followed up for another 24 weeks. ADA was considered successfully stopped if no relapse occurred during this period. The relapse-free survival rate, best corrected visual acuity (BVCA), anterior chamber cell (ACC), vitritis, macular thickness (MT), and serum ADA levels were evaluated. Approval Number: 2021KYPJ201. ClinicalTrials.gov identifier: NCT05155592. Results The relapse-free survival rate was 22.2% (4/18) at 48 weeks. 33.3% (6/18) of patients relapsed when ADA was given every 4 weeks, while 44.5% of patients (8/18) relapsed after ADA was stopped. The four patients successfully withdrawn from ADA were all diagnosed with BD. No statistically significant differences (p > 0.05) were observed in BCVA and MT between baseline and final follow-up. The proportion of ACC and vitritis exhibited an upward trend (p < 0.05) during follow-up. Serum ADA gradually decreased to zero during follow-up in both non-recurrence and recurrence groups. Conclusions In PNIU children who reached remission for 6 months, ADA dose reduction and withdrawal were associated with a high risk of inflammation recurrence. Timely adjustment of ADA to the last effective dosage frequency can regain control of the inflammation. Detection of ADA serum levels in patients with recurrence may help find the appropriate interval of ADA use.

Observational Study to Compare Biological Drug Concentration Quantification Techniques and Immunogenicity in Patients with Immune-Mediated Diseases.

Measuring biological drugs' trough concentrations and the concentrations of anti-drug antibodies is a valuable practice for treatment optimization. ELISA techniques are the gold standard for biological drug concentration quantification, but new techniques such as chemiluminescence immunoassays present some advantages. The aim of this unicentric prospective observational study is to compare the infliximab, adalimumab, vedolizumab and ustekinumab trough levels and anti-adalimumab and anti-infliximab antibodies concentrations obtained when using a chemiluminescent instrument (i-TRACK®, Theradiag, Croissy-Beaubourg, France) and an ELISA instrument (TRITURUS®, Griffols, Barcelona, Spain). Linear regression, Pearson or Spearman tests, Bland-Altman plots and the Cohen kappa test were applied for every sample. The correlation was excellent for both assays in the measurement of all drug concentrations. In general, values were lower when measured using i-TRACK than when using TRITURUS, especially when the values were high. Both techniques proved valuable in clinical practice for monitoring adalimumab and infliximab drug concentration. However, the results were modest for ustekinumab and vedolizumab, so caution is recommended and further research is needed. The limited number of anti-drug antibody-positive samples precluded a comparison between the techniques.

P337 Proactive therapeutic drug monitoring of Adalimumab, but not HLADQ*A1 determination, predicts inflammatory bowel disease outcome and persistence of treatment

Abstract Background Anti-TNF drugs have proven effective in managing Inflammatory Bowel Disease (IBD), but a significant percentage of patients exhibit primary or secondary non-response. Therapeutic drug monitoring (TDM) is a valuable tool for optimizing patient management. HLA-DQA1*05 gene has been investigated as a potential marker for immunogenicity and loss of response to anti-TNF therapy.This prospective, multicentric study aimed to assess the clinical impact of determining Adalimumab (ADA) levels and anti-adalimumab antibodies (Abs) in IBD patients and the influence of the HLA-DQA1*05 allele on the response and maintenance of ADA treatment over a 24-month follow-up. Methods Patients initiating ADA treatment between October 2020 and October 2022 were enrolled. Demographic data and IBD characteristics were recorded. Clinical Activity Index, C reactive protein (CRP), faecal calprotectin (FC), endoscopy or radiological activity, Global Physician Assesment (GPA) and PRO (by IBDQ-9) were prospectively collected at baseline and at the same time that ADA levels: week 4, 10, 30 and 12 months. HLA-DQA1*05 was genotyped at baseline. Pearson coefficient was utilized to assess correlations between ADA levels and disease activity. Results We included 170 (age 42±17 years, 54% female) IBD patients (74% Crohn`s Disease, 24% Ulcerative Colitis and 2% Indeterminate colitis) who started ADA (85% naïve to anti-TNF). At baseline, 80% had an active disease (GPA=1); CRP and FC were 10.72 ±17.85 mg/L and 568 ±775 µg/g; PRO at baseline was 63±8.6. HLA was determined in 167 patients, of whom 71 (42%) were HLA-DQA1*05 positives. Median follow up was 17 months. No correlation between HLA and drug levels or Abs was founded. ADA levels at the end of induction was correlated with ADA levels during follow up. ADA serum concentration &amp;gt;7 µg/mL at weeks 4 and 10 correlated with improved clinical response at corresponding time points (p&amp;lt;0.001). Patients with ADA levels &amp;gt;7 µg/mL at week 10 demonstrated better disease control at 12 months. 41 patients stopped ADA. It was associated with active disease, low ADA levels, and adverse clinical and laboratory markers. HLA-DQA1*05 positivity did not correlate with adverse reactions or Abs during the observational period. A significative improvement in PROs in patients who started treatment with ADAL (62.73 at baseline and 69.42 at week 30) (p&amp;lt;0.001) was observed. Conclusion Early Drug level monitoring of Adalimumab may improve the management of IBD patients. PCR, CF and GPA at week 10 may predict treatment failure. ADA levels &amp;gt;7 µg/mL is associated with a better clinical response in short and long-term, independent of HLADQA1*05.

P851 Therapeutic drug monitoring of infliximab and adalimumab versus clinical control during maintenance therapy in patients with Inflammatory Bowel Disease

Abstract Background Although it is known that the levels of infliximab or adalimumab are correlated with clinical response, there is controversy about the best strategy to follow in patients with Inflammatory Bowel Disease (IBD) in remission and undergoing maintenance treatment. Methods We conducted a randomized, prospective, single-blinded, and multicentre trial in patients with Crohn’s Disease (CD) or Ulcerative Colitis (UC) who have remained in clinical remission for at least 12 weeks and are receiving adalimumab (ADA) or infliximab (IFX) as maintenance treatment. Patients were assigned to two groups. In the first group, patient management was done considering therapeutic drug monitoring (TDM). In the second, according to usual clinical practice (CP). The optimal serum range was within 3-7µg/ml and 5-8µg/ml for IFX and ADA respectively, based on the use of Promonitor-IFX, and Promonitor-ADL kits. The primary endpoint was to maintain patients in clinical remission (target &amp;gt;16% between both groups at 12 months) and diminish the frequency of flare-ups. Results In total, 209 patients were randomized, 29 UC (27.6%), 76 CD (72.4%) as the clinical practice group, and 24 UC (23.1%), 80 CD (76.9%) as the drug monitoring therapeutic group. Infliximab was administered in 105 patients and adalimumab in 104. Remission at the end of the study was achieved in 98.1% of the proactive dosing group and 90.5% of the clinical practice group (p=0.02), with a difference between both groups of 7.6%. The number of flare-ups was 1.3/10 patient-years in the TDM group and 2.4/10 patient-years in the CP group. The IRR of flare-up throughout the study was 0.71 (95% CI 0.32 – 1.55). In the group with IFX: IRR = 0.56 (95% CI 0.08 – 3.81) and with ADA: 0.78 (95% CI 0.29-2.16). The changes made in the drug dose are shown in Table 1. Conclusion Differences were found in favour of the TDM group, with increasing remission rates (7.6%) and half number of flare-ups. However, the pre-established effectiveness remission target (16%) was not met. In the subgroup of patients with Infliximab, management through TDM seems to have an advantage over usual clinical control.

P493 Do antiTNF or Ustekinumab trough levels correlate with joint extraintestinal manifestations activity in Inflammatory bowel disease patients?

Abstract Background Inflammatory spondyloarthritis(SpA) are the most common extraintestinal manifestations (EIM) associated to inflammatory bowel disease (IBD), with a prevalence of 20-50% for axial SpA(axSpA) and 5-20% for peripheral(pSpA). AntiTNF is the optimal therapy in axSpA intolerant or refractory to NSAIDs, also effective in pSpA. An optimal trough level has not been yet established in this clinical setting. Aim, to evaluate the correlation between antiTNF and UST trough levels and joint EIM activity in IBD patients. Methods Prospective, multicenter,cohort study. IBD patients diagnosed with articular EIM under antiTNF or Ustekinumab(UST) for at least 6 months were included. Blood samples were obtained just before administering the drug(trough levels), and a simultaneous evaluation by a rheumatologist and a gastroenterologist, was performed. Definitions: inactive AxSp=ASDAS-CRP&amp;lt;1.3 and BASDAI&amp;lt;2, inactive pSp=arthritis, enthesitis and dactylitis=0, active AxSp=ASDAS-CRP &amp;gt;2.1 and BASDAI&amp;gt;4, active pSp= artritis, entesitis o dactilitis &amp;gt; 0. Aim, to evaluate the correlation between antiTNF and UST trough levels and joint EIM activity in IBD patients. Results A total of 135 patients were included: mean age 51 ± 15, 59 (43.7%)women), 80% CD. 60(44.4%) patients presented axSpA, 50(37%) pSpA and 25(18.5%) mixed. 12(8.9%) had active IBD. Table 1 summarizes the patients' main demographic and clinical characteristics distributed by SpA activity. Fifty-three(39%) were on infliximab (IFX), 61(45.2%), on adalimumab (ADA) and 22 (16.3%) on UST treatment. NSAIDs treatment(12.7% vs 3.1%, p&amp;lt;0.05), higher fecal calprotectin(FC)(486 ± 709 vs 228.2 ± 297, p&amp;lt;0.05), and the prior use of biologics(33.8% vs 17.6%, p&amp;lt;0.05) were more frequent among active vs inactive SpA patients. No differences between IFX(7.05 ± 4.16 vs 5.79± 4.05, p=ns), ADA(7.98 ± 4.20 vs 9.51 ± 6.15 p=ns) and UST levels(3.39 ± 3.47 vs 3.08 ±2.69, p=ns), were found between active and inactive SpA patients, even when were distributed by type of SpA(axSpA/mixed and pSpA). Body mass index(b:-0,29, p=0.01)FC(b:-0,28, p=0.01), and intensified therapy(b:-0,28, p=0.01) were associated to higher IFX levels in the whole SpA cohort. Patients with axSpA or mixed were articular active more frequently than pSpA patients(82% vs 18%, p &amp;lt;0.05). IBD activity was correlated to articular activity only among pSpA patients(2% active IBD in inactive pSpA vs 20% active IBD in active pSpA patients, p=0.03). Conclusion AntiTNF and UST trough levels are not correlated to joint activity in patients with IBD and SpA. In our study more than 80% of patients with active SpA were inactive regarding IBD. Only pSpA patients presented correlation between IBD and articular activities.

P553 The safety and efficacy of adalimumab 80mg weekly as maintenance therapy in pediatric Crohn’s Disease

Abstract Background Intensification of adalimumab (ADL) dosing to weekly 40 mg injections, in response to low drug levels, has been shown to provide beneficial outcomes in pediatric patients with Crohn’s disease (CD). Our study aimed to evaluate the safety and efficacy of weekly 80 mg ADL administration in children with CD. Methods In this retrospective cohort study conducted across five Israeli centers, we reviewed the medical records of pediatric CD patients who received a high dose of ADL 80 mg weekly injections between 2016 and 2023. Collected data included demographic characteristics, disease features, laboratory studies, and treatment outcomes. Results Thirty-two children with CD were included: mean age 15.8 (±1.7) years at intensification, 21 male (66%), 18 (56%) with L3 phenotype. The median time to ADL 80 mg intensification from ADL induction was 48.4 weeks (IQR 23.1-122.5). The mean weighted Pediatric Crohn's Disease Activity Index (wPCDAI) was 28.5 (±16.9) at the time of intensification and the median calprotectin and C-reactive protein levels were 937 μg/g (IQR 540-1410) and 1.3 mg/dL (IQR 0.6-5.2), respectively. Clinically active disease was the main reason for ADL intensification (30, 94%). Baseline ADL levels were available in 30 patients (94%) with a median of 3.8 μg/mL (IQR 2.4-7.2). Among these, 23 children (77%) failed to achieve a target of ≥ 7.5 μg/mL. The median follow-up duration from the intensification dose was 91.2 weeks (IQR 53.6-149.1). Corticosteroids were required in 5/32 (15.6%) children, with a median time of 32.3 weeks (IQR 10.7-51.3) from intensification. There was no statistically significant difference in steroid utilization rates between children who achieved a target baseline drug level of ≥ 7.5 μg/mL and those who did not (p=0.934). Thirteen individuals (41%) discontinued ADL treatment, within a median of 24.7 weeks (IQR 11.7-57.1) from intensification. CD-related exacerbation, hospitalization, and surgery rates were 9 (28%), 4 (13%), and 2 (6%), respectively. No statistically significant differences were found in exacerbation (p=0.406), hospitalization (p=0.322), or surgery rates (p=0.427) between children who achieved a baseline ADL trough concentration level of ≥ 7.5 μg/mL and those who did not. Overall, ADL intensification was safe, but 3 (9%) patients developed new-onset psoriasis. Conclusion Our findings support the safety and efficacy of administering ADL at a weekly dosage of 80 mg as maintenance therapy in pediatric patients with moderate to severe CD.

Development and validation of a novel therapeutic drug monitoring-based nomogram for prediction of primary endoscopic response to anti-TNF therapy in active Crohn's disease.

Anti-tumor necrosis factor (TNF) monoclonal antibodies, especially infliximab (IFX) and adalimumab (ADA), are considered the first-line treatment for active Crohn's disease (CD). However, the predictive role of therapeutic drug monitoring (TDM) of serum anti-TNF in monitoring the treatment of inflammatory bowel disease (IBD) remains controversial. To explore the correlation between serum anti-TNF levels and early endoscopic response in active CD using a TDM-based nomogram. Cross-sectional study. The simplified endoscopic activity score for CD (SES-CD), Crohn's disease activity index (CDAI), laboratory parameters, and the serum trough levels of IFX and ADA were assessed. The trough levels of IFX or ADA were significantly higher in patients with endoscopic response compared to non-responders in the development cohort (p < 0.001). The IFX and ADA levels showed a weak but significantly negative correlation with SES-CD (p < 0.001), CDAI (p < 0.001), and C-reactive protein (CRP) (p < 0.001) at week 14 post-IFX therapy in the development cohort. Furthermore, the receiver operating characteristic curve revealed that an optimal level of IFX (4.80 μg/mL) and ADA (8.80 μg/mL) exhibited the best performance in predicting endoscopic response. Concomitantly, we developed a novel nomogram prediction model based on the results of multivariate logistic regression analysis, which consisted of CRP, albumin (Alb), and anti-TNF trough levels at week 14. The nomogram showed significant discrimination and calibration for both IFX and ADA in the development cohort and performed well in the external validation cohort. This study demonstrates a robust association between serum concentrations of IFX, ADA, Alb, and CRP and primary endoscopic response in active CD patients. Importantly, the TDM- and laboratory marker-based nomogram may be used to evaluate the primary endoscopic response to anti-TNF therapy, especially for optimizing treatment strategies and switching therapy in CD patients.

Psoriatic arthritis: the role of self-reported non-adherence, non-trough drug levels, immunogenicity and conventional synthetic DMARD co-therapy in adalimumab and etanercept response.

The aim of this study was to assess the relationship between self-reported non-adherence, non-trough drug levels, immunogenicity and conventional synthetic DMARD (csDMARD) co-therapy in TNF inhibitor (TNF-i) drug response in PsA. Serum samples and adherence questionnaires were collected at baseline, 3, 6 and 12 months for PsA patients prescribed TNF-i. Non-trough adalimumab (ADL) and etanercept (ETN) drug levels were measured at 3 and 6 months using commercially available ELISAs. Clinical response was assessed using PsA response criteria (PsARC) and change in 28-joint DAS (ΔDAS28) between baseline and 3, 6 and 12 months. In 244 PsA patients (52.5% ADL and 47.5% ETN), self-reported non-adherence was associated with PsARC non-response over 12 months using generalized estimating equation (GEE) modelling (P = 0.037). However, there was no significant difference between non-trough ADL or ETN drug levels based on self-reported non-adherence. Higher ETN levels at 3 months were associated with PsARC response at 3 (P = 0.015), 6 (P = 0.037) and 12 months (P = 0.015) and over 12 months using GEE modelling (P = 0.026). Increased ADL drug levels at 3 months were associated with greater ΔDAS28 at 3 months (P = 0.019). ADL anti-drug antibody-positive status was significantly associated with lower 3- and 6-month ADL levels (P < 0.001) and ΔDAS28 and PsARC response at 3, 6 and 12 months. Meanwhile, MTX co-therapy was associated with a reduction in immunogenicity at 3 and 6 months (P = 0.008 and P = 0.024). Although both were associated with reduced response, the objectively measured non-trough drug levels showed more significant associations with drug response than self-reported non-adherence measures.

Non-trough serum drug levels of adalimumab and etanercept are associated with response in patients with psoriatic arthritis

Abstract Objectives Up to 40% of PsA patients experience first-line tumour necrosis factor inhibitors (TNF-i) failure. Lower serum drug levels (SDL) have been associated with lower response in autoimmune conditions. This study aimed to: (i) establish the relationship between adalimumab (ADL) and etanercept (ETN) SDL and 3-month response; and (ii) identify optimal non-trough SDL thresholds in PsA. Methods PsA patients commencing ADL or ETN were recruited to the UK observational study OUTPASS. Patients were seen pre-TNF-i and at 3 months when response was measured, and non-trough serum samples collected. Response was defined according to the PsARC or EULAR criteria. Descriptive statistics and concentration-effect curves established differences in SDL based on response. Receiver operating characteristic curves and regression identified optimal SDL thresholds. Results PsA ETN (n = 97) PsARC and EULAR good responders had significantly higher 3-month SDL compared to non-responders (P = 0.006 and P = 0.020, respectively). Non-trough 3-month ETN SDL discriminated PsARC responders from non-responders (AUC = 0.70), with a threshold of 1.8 µg/ml being 63% specific and 69% sensitive. EULAR good and non-/moderate responders were discriminated with an AUC of 0.65 with a threshold of 2.0 µg/ml being 57% specific and 69% sensitive. ADL prescribed (n = 104) EULAR good responders had significantly higher 3-month SDL (P = 0.049). Non-trough 3-month ADL SDL discriminated EULAR good and non-/moderate responders (AUC = 0.63) with a threshold of 3.6 µg/ml being 48% specific and 81% sensitive. Conclusion Higher 3-month SDL were detected in responders. Interventions to optimise SDL may improve treatment response earlier. This study suggests 3-month SDL thresholds which may be useful in clinical practice to optimize treatment response.

What Should We Know about Drug Levels and Therapeutic Drug Monitoring during Pregnancy and Breastfeeding in Inflammatory Bowel Disease under Biologic Therapy?

Data on the real long-term influences of in utero drug exposure in pregnant women on childhood development are scarce and remain not well determined and depend on the duration of in utero drug exposure and maternal drug levels. Therapeutic drug monitoring (TDM) during pregnancy may help limit fetal drug exposure while maintaining an effective dose for the treatment of the underlying inflammatory bowel disease (IBD) in women. Most antibody therapies used in patients with IBD are IgG molecules which are actively transported across the placenta, especially during the third trimester of the pregnancy. Here, we propose an up-to-date clinical review to summarize the available findings of serum drug levels in maternal blood during pregnancy, in the cord blood, infants at delivery and in breast milk of patients with IBD treated with biologics. Conversely, in comparison to adalimumab (ADA) levels, which are relatively stable during pregnancy, infliximab (IFX) drug clearance decreased significantly during the last two trimesters of the pregnancy, leading to increasing drug concentrations in the blood of the pregnant women. As most guidelines recommend using live vaccines in infants at the age of one or earlier in case of negative serum drug levels in newborns, statistical models could help clinicians in making a decision to adjust the last dose of the biologic during pregnancy and to determine the optimal date to vaccinate. Altogether, data from the literature offers strong reassurance in terms of safety for anti-TNFα therapies during pregnancy not only for IBD patients who intend to conceive, but also for pregnant women and for the physicians taking care of these patients. ADA and IFX levels in breast milk are detectable, but at very low levels, and therefore, it is recommended to pursue breast feeding under anti-TNFα therapy. Our knowledge on ustekinumab or vedolizumab levels in pregnant women remains unclear and scarce. These drugs are currently not recommended for patients with IBD in clinical practice. Therefore, TDM and proactive dose adjustment are not necessary during pregnancy since its impact on making a clinical decision have not yet been clearly demonstrated in routine practice. Overall, drug concentrations in the cord blood, an infant at birth and postpartum serum concentrations in infants, due to active placental drug transfer, may have a greater impact than the limited drug transfer in breast milk during lactation on the risk of infection and developmental outcomes. Ustekinumab and vedolizumab exposure during pregnancy and lactation are both considered low risk by the recent ECCO guidelines despite the limited data that are currently available.

Enhancing Therapeutic Drug Monitoring in Inflammatory Bowel Disease: A Comparative Analysis of Rapid Point-of-Care Infliximab, Adalimumab and Anti-Drug Antibodies' Determination against ELISA.

The introduction of point-of-care (POC) assays into clinical practice in patients with inflammatory disease enables on-demand therapeutic decision making. The aim of this study was to compare the POC test Quantum blue (Bühlmann Laboratories) for infliximab (IFX), adalimumab (ADL), and its anti-drug antibodies with the traditional ELISA assay (Promonitor). A total of 200 serum samples were analyzed. Samples were classified into the following three different groups; sub-therapeutic range (IFX < 3 μg/mL and ADL < 5 μg/mL); therapeutic range (IFX: 3-7 μg/mL and ADL: 5-12 μg/mL) and supra-therapeutic range (IFX levels > 7 μg/mL and ADL levels > 12 μg/mL). Significant higher values were measured using the POC test (p < 0.001) for IFX results but no differences in ADL trough levels were observed (p = 0.3101). Spearman's correlation indicated a good correlation between the two assays (rs = 0.88 for ADL and rs = 0.93 for IFX), and McNemar's test revealed significant differences (p = 0.016) when classifying IFX samples between therapeutic and supra-therapeutic ranges but no significant differences were found among the other ranges for either IFX or ADL. These results show that we should be cautious when using these rapid measurement methods, and new targets should probably be defined for IFX when using this new analytical method.

Serum levels of infliximab and adalimumab are associated with deep remission in inflammatory bowel disease

ObjectiveDeep remission defined by clinical-biomarker remission and mucosal healing has emerged as a new therapeutic target in inflammatory bowel disease. The aim of this study was to define an optimal cut-off concentration for infliximab and adalimumab during maintenance therapy associated with deep remission. The secondary objective, was to evaluate the influence of variables on anti tumor necrosis factor-alpha concentrations and deep remission. MethodRetrospective study including 120 and 122 patients inflammatory bowel disease diagnosed who received maintenance therapy with infliximab and adalimumab. Biomarker remission was considered by C-reactive protein < 5 mg/L and fecal calprotectin < 100 µg/g. Crohn's disease clinical remission was defined by a Harvey Bradshaw score < 5 and mucosal healing by a simple endoscopic score for Crohn's disease< 3. In ulcerative colitis, it was defined as a Mayo total score < 3 and Mayo endoscopic subscore < 2. Receiver operating characteristic test was performed to determine drug concentration thresholds associated with deep remission. Anti tumor necrosis factor-alpha concentrations were classified into quartiles. X2 and Kruskal-Wallis test were used to compare discrete and continuous variables between quartile groups. Multivariate logistic regression was performed to identify patient characteristics and serological facto C-reactive protein rs associated with deep remission. ResultsAnti tumor necrosis factor-alpha concentrations were higher in patients with deep remission, in infliximab (4.4, interquartile range: 3.3-6.5 vs 2.3, interquartile range: 1.1-4.2 µg/mL, P < 0.005) and adalimumab (6.3, interquartile range: 4.2-8.2 vs 3.9, interquartile range: 2.4-5.5 µg/mL, P < 0.005). A Receiver operating characteristic test identified a concentration threshold of 3.1 µg/mL in infliximab (area under the Receiver operating characteristic test curve, 0.72) and 6.3 µg/mL in adalimumab (area under receiver operating characteristic test curve, 0.75) associated with deep remission. Factors associated with the highest quartiles of serum infliximab concentration were: elevated body mass index, absence of previous inflammatory bowel disease-surgery, C-reactive protein < 5 mg/L, and fecal calprotectin < 100 µg/g. In adalimumab, higher quartiles were related to concomitant immunosuppressants, low body mass index, absence of previous inflammatory bowel disease-surgery, and C-reactive protein < 5 mg/L and fecal calprotectin < 100 µg/g. Multivariate regression identified fecal calprotectin < 100 µg/g, C-reactive protein < 5 mg/L, infliximab > 3.1 µg/mL and adalimumab concentrations > 6.3 µg/mL as factors significantly associated with deep remission. ConclusionsTrough infliximab and adalimumab concentrations, C-reactive protein < 5 mg/L and fecal calprotectin < 100 µg/g are associated with deep remission during maintenance therapy. Cutoff point of 3.1 and 6.3 g/mL for infliximab and adalimumab respectively, were identified as deep remission predictors.

High BMI is associated with lower TNF-α inhibitor serum trough levels and higher disease activity in patients with axial spondyloarthritis

BackgroundTNF-α inhibitor (TNFi) serum trough levels have previously been found to be related to disease activity in axial spondyloarthritis (axSpA). However, most research regarding serum trough levels has been conducted in patients who only recently started TNFi therapy. Therefore, our objective was to explore TNFi serum trough level measurements in relation to disease activity and BMI in the total axSpA population in daily clinical practice, also including patients on long-term TNFi therapy.MethodsConsecutive patients from the Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort were approached for a TNFi serum trough level measurement during their regular outpatient visit at the UMCG. Spearman’s correlation coefficient was used to analyse the relation of serum trough levels with disease activity and BMI. Logistic regression was performed to analyse the relation between therapeutic drug levels and disease activity, corrected for potential confounders, including BMI.ResultsThirty-four patients on adalimumab and 21 patients on etanercept were included. Mean age was 45 ± 12 years, 47% were male, median BMI was 26.4 (IQR 23.9–32.5) and median treatment duration was 41 months (range 2–126). According to definitions of Sanquin, 47% of patients had therapeutic serum trough levels. No significant correlations were found between TNFi levels and disease activity (ASDAS-CRP: adalimumab: ρ = -0.16, p = 0.39; etanercept: ρ = -0.29, p = 0.20). TNFi levels were moderately correlated with BMI (adalimumab: ρ = -0.48, p = 0.004; etanercept: ρ = -0.50, p = 0.021). Patients with active disease (ASDAS ≥ 2.1) showed higher BMI than patients with inactive disease (median 29.7 vs. 24.6, p = 0.015). In multivariable regression analyses, BMI was identified as the only confounder for the relationship between therapeutic drug levels and ASDAS.ConclusionIn this cross-sectional, observational study of axSpA patients mainly on long-term treatment with TNFi, higher BMI was significantly associated with lower adalimumab and etanercept serum trough levels and higher disease activity.

Adalimumab serum levels and anti-drug antibodies: associations to treatment response and drug survival in inflammatory joint diseases.

To explore associations between serum adalimumab level, treatment response and drug survival in order to identify optimal drug levels for therapeutic drug monitoring of adalimumab. Also, to assess the occurrence and risk factors of anti-drug antibody (ADAb) formation. Non-trough adalimumab and ADAb levels were measured by automated fluorescence assays in serum collected after 3 months of adalimumab treatment in patients with RA, PsA or axial SpA (axSpA) included in the observational NOR-DMARD study. Treatment response was evaluated after 3 months and drug survival was evaluated during long-term follow-up. In 340 patients (97 RA, 69 PsA, 174 axSpA), the median adalimumab level was 7.3 mg/l (interquartile range 4.0-10.3). A total of 33 (10%) patients developed ADAbs. Findings were comparable across diagnoses. In RA and PsA, adalimumab levels ≥6.0 mg/l were associated with treatment response [odds ratio (OR) 2.2 (95% CI 1.0, 4.4)] and improved drug survival [hazard ratio 0.49 (95% CI 0.27, 0.80)]. In axSpA, a therapeutic level could not be identified, but higher adalimumab levels were associated with response. Factors associated with ADAb formation were previous bDMARD use, no methotrexate comedication and the use of adalimumab originator compared with GP2017. Higher adalimumab levels were associated with a better response and improved drug survival for all diagnoses, with a suggested lower threshold of 6.0 mg/l for RA/PsA. This finding, the large variability in drug levels among patients receiving standard adalimumab dose and the high proportion of patients developing ADAbs encourages further investigations into the potential role of therapeutic drug monitoring of adalimumab.

P084 The relationship between self-reported adherence, drug levels and tumour necrosis factor inhibitor response in psoriatic arthritis

Abstract Background/Aims It is not currently possible to accurately predict tumour necrosis factor inhibitor (TNF-i) response in psoriatic arthritis (PsA). In rheumatoid arthritis, suboptimal adherence to TNF-i and reduced drug levels have been associated with decreased response. Suboptimal treatment adherence (16%-81%) has been reported in PsA although little is known about the impact on TNF-i response. Self-reported adherence may be biased, but direct drug measurements offer an objective adherence evaluation. The objective of this study is to assess the relationship between self-reported adherence, drug levels, and drug response to TNF-i in PsA. Methods Blood samples and adherence questionnaires were collected at 3, 6 and 12 months for PsA patients prescribed biologic or targeted synthetic anti-rheumatic drugs in a UK multi-centre observational study (OUTPASS). Self-reported adherence was measured using two previously validated questionnaires (MARS5 and Treatment). Adherence was classified as self-reporting never missing or delaying a dose, unless medically advised. Adalimumab (ADA) and etanercept (ETN) drug levels were measured at 3 and 6 months using commercially available ELISAs. Clinical response was assessed using PsARC and ΔDAS28 between baseline and 3, 6 and 12 months. Univariate regression and general estimating equations were used to assess associations across timepoints. Results In the OUTPASS cohort (46% ADA, 40% ETN), 42% of patients self-reported non-adherence within the first 12 months of treatment. Patients with self-reported non-adherence at 6 months using the MARS5 questionnaire were significantly less likely to achieve a PsARC response at 6 months [odds ratio (OR)=0.40, P = 0.047] in univariate regression. Non-adherence, reported using the Treatment questionnaire, was associated with decreased PsARC response over 12 months [OR = 0.52, P = 0.031]. There was no association (P &amp;gt; 0.05) between whether a patient returned a self-reported adherence questionnaire and response. Drug levels at 3 months (n = 70 (ADA), 73 (ETN)) were associated with drug levels at 6 months (n = 61 (ADA), 67 (ETN)) for both ADA [β = 0.47, P = 0.001] and ETN [β = 0.41, P = 0.018] paired samples. Higher 3-month ADA levels were associated with increased ΔDAS28 response at 3 months [β = 0.11, P = 0.036] and PsARC response at 12 months [OR = 1.39, P = 0.028]. Higher 3-month ETN levels were associated with increased PsARC response at 3 months [OR = 1.50, P = 0.026]. Increased ADA levels were associated with improved ΔDAS28 over 12 months [β = 0.07, P = 0.001] and higher ETN levels associated with enhanced PsARC response [OR = 1.17, P = 0.022] over 12 months. Levels of neither drug were associated (P &amp;gt; 0.05) with any self-reported adherence measures at any time point. Conclusion There was no association between self-reported adherence and TNF-i drug levels in ADA or ETN-treated PsA patients. Objectively measured adherence via drug level measurements were more strongly associated with drug response than self-reported measures, particularly using ΔDAS28 as the measure of response. Disclosure P.D.K. Curry: None. A.P. Morris: None. M. Jani: None. H. Chinoy: Grants/research support; HC received grant support from Eli Lilly and UCB. A. Barton: Grants/research support; AB has received fees/grant awards from Galapagos, Scipher Medicine, Roche-Chugai, Pfizer and BMS. J. Bluett: Grants/research support; JB has received a research grant award from Pfizer. Other; JB has received travel/conference fees from UCB, Pfizer and Eli Lilly.

P437 Early therapeutic drug monitoring of Adalimumab, but not HLADQ*A1 determination, predicts inflammatory bowel disease outcome

Abstract Background Anti-TNF drugs are effective treatments for the management of Inflammatory Bowel Disease (IBD), yet treatment failure is common. Monitoring drug levels and their antibodies (ATIs) can be useful to optimize the management of patients. In addition, the HLA-DQA1*05 gene has been recently related as a possible marker of immunogenicity and loss of response to anti-TNF therapy.The aim of this study was to evaluate the clinical impact of determining adalimumab (ADA) levels and anti-adalimumab ATIs in patients with IBD, and the influence of the HLA-DQA1*05 allele on the response and maintenance of adalimumab treatment in this population. Methods This observational, multicentric and prospective study enrolled patients who started treatment with ADA from October 2020 to October 2022. Demographic data and IBD characteristics were recorded. Clinical Activity Index (Harvey Index and Parcial Mayo Score) and C reactive protein(CRP), faecal calprotectin (FC), endoscopy or radiological activity, Global Physician Assesment (GPA) and PRO (by IBDQ-9) were prospectively collected at baseline and at the same time that ADA levels: week 4, 10, 30 and 12 months. HLA-DQA1*05 was genotyped at baseline. Pearson coefficient was used to assess the correlation between ADA levels and activity disease at different points Results We included 131 (age 42±17 years, 56% female) IBD patients (78% Crohn`s Disease, 21% Ulcerative Colitis and 1% Indeterminate colitis) who started treatment with ADA (80% were naïve to anti-TNF and 57% started ADA combined with immunomodulator treatment). At baseline, 81% had an active disease (Global Physician Assesment=1), 49% had CRP &amp;gt;5 mg/L and 77% had FC &amp;gt; 150 mg/kg. PRO at baseline was 63±9.1. HLA was determined in 99 patients, of whom 42 (42%) were HLA-DQA1*05 positives. We found a positive correlation between PRO score and Hb levels and albumin, meanwhile a negative correlation with FC and CRP at week 0. No correlation with ADA levels or ATIs was established. Patients HLA-DQA1*05 positive had not more adverse reaction or ATIs during the observational period. Patients with ADA serum concentration &amp;gt;7µg/mL at week 4 had CRP &amp;lt;5mg/dL at week 4 (p=0.04) and at week 10 (p=0.01). Patients with ADA serum concentration &amp;gt;7µg/mL at week 10 had more stable disease (PGA =0) and CRP &amp;lt;5mg/L, FC &amp;lt;150 mg/kg at week 10 (p&amp;lt;0.05), CRP &amp;lt;5mg/L at week 30 (p&amp;lt;0.05) and FC &amp;lt;150 mg/kg at 12 months. Conclusion Early Drug level monitoring of Adalimumab (after induction) may improve the management of IBD patients. Our study shows that ADA levels &amp;gt;7 µg/mL is associated with a better clinical response in short and long-term, independent of HLADQA1*05.