Serum Adalimumab Concentrations Research Articles

Antibiotics influence the risk of anti-drug antibody formation during anti-TNF therapy in Chinese inflammatory bowel disease patients.

Aims: The formation of anti-drug antibodies (ADAs) during anti-tumor necrosis factor (anti-TNF) therapy is reported to lead to reducing serum drug levels, which may bring about a loss of response to treatment. Previous research has suggested an association between specific antibiotic classes and ADA formation during anti-TNF therapy. However, there are few studies specifically examining this association in Chinese inflammatory bowel disease (IBD) patients. Therefore, our study aimed to evaluate the possible effect of antibiotic use on ADA formation to anti-TNF therapy in Chinese patients with IBD. Methods: A total of 166 patients with IBD, including 149 with Crohn's disease (CD) and 17 with ulcerative colitis (UC), were included in this retrospective analysis. These patients were initially treated with anti-TNF therapy (infliximab or adalimumab) after January 2018 and reviewed with available ADA levels before October 2023. After univariable analysis of all the variables, a multivariate Cox proportional hazards model was used to assess the association between antibiotic use and ADA development. Results: Among 166 IBD patients treated with infliximab (108/166, 65.1%) or adalimumab (58/166, 34.9%), 31 patients (18.7%) were measured as positive ADA levels. Cox proportional hazard model demonstrated an increased risk of ADA formation in IBD patients who used β-lactam-β-lactamase inhibitor combinations (BL-BLIs) (HR = 5.143, 95%CI 1.136-23.270, p = 0.033), or nitroimidazoles (HR = 4.635, 95%CI 1.641-13.089, p = 0.004) during 12months before the ADA test. On the contrary, a reduced risk was noted in patients treated with fluoroquinolones (HR = 0.258, 95% CI 0.072-0.924, p = 0.037). Moreover, the median serum infliximab or adalimumab concentration in patients with positive ADA levels was significantly lower than that in patients with negative ADA levels (infliximab: 0.30 vs. 1.85μg/mL, p < 0.0001; adalimumab: 0.45 vs. 7.55μg/mL, p = 0.0121). Conclusion: ADA development is associated with various antibiotic classes. BL-BLIs and nitroimidazoles might increase the risk of ADA formation during anti-TNF therapy in Chinese IBD patients, while the treatment with fluoroquinolones could probably reduce such risk. There were certain limitations in the retrospective analysis of the study, therefore, the results are just for reference, and other studies are needed to further confirm our findings.

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.

P611 Relation between AntiTNF levels during the induction and clinical and radiological outcomes in perianal Crohn´s disease

Abstract Background Perianal Crohn's disease(PCD) significantly impacts quality of life with poor long-term prognosis. Anti-tumor necrosis factor(anti-TNF) therapy improves fistula closure rates. However, achieving permanent closure remains challenging. Our aim is to evaluate the relation between antiTNF(infliximab (IFX) and adalimumab(ADA) serum concentrations at induction(w2 and 6), and clinical and radiological outcomes at w24 and w52 Methods We conducted a single tertiary center, retrospective, cohort study including patients with an established diagnosis of PCD treated with antiTNF because of perianal activity. Variables related to their PCD(phenotype, location, fistulas type) were collected. Regarding treatment, we collected serum levels at week 2,6,24 and 52, concomitant treatment and setons presence. We defined clinical response as the absence of drainage on physical examination and clinical remission as the absence of external fistula openings. Radiological response was defined as the absence of T2 hypersignal, gadolinium enhancement, abscess and proctitis in pelvic MRI Results 65 patients were included, baseline characteristics are in Table1. None of the demographic characteristics collected were statistically significant related to clinical or radiological response although non smokers(p=0.01), ileal(p=0.02) and non-stricturing disease(p=0.01) had statistically significant higher drug levels. Taking into account the clinical response at w52, IFX mean levels at w2 were 25.8µg/mL(SD 4.1) in non responders and 30.9µg/mL(SD 14) in responders(p=0.39). At w6 they were 17.2µg/mL(SD 12.2) and 19.4µg/mL(SD 13.8) respectively(p=0.7). ADA mean levels at w2 were 13.3µg/mL(SD 7.7) in non responders and 14µg/mL(SD 6.3) in responders(p=0.87). At w6 they were 10.1µg/mL(SD 3.3) and 12µg/mL(SD 6.1) respectively(p= 0.59). For radiological response at w52 IFX mean levels at w2 were 27µg/mL(SD 15.3) in non responders and 32.7µg/mL(SD 14.5) in responders(p=0.45). At w6 the mean levels were 15.9µg/mL(SD 6.7) and 23.7µg/mL(SD 14.8) respectively(p=0.27). In ADA group the mean levels at w2 were 14.8µg/mL(SD 7.6) in responders and only one patient did not respond. At w6 ADA mean levels were 12.3µg/mL(SD 5.9) in non responders and 12.7µg/mL(SD 6.2) in responders(p=0.94). Early response at w24 was related with a long-term response at w52, 89.9% of the patients who responded at w52, had already responded at w24. Conclusion In our study we observed that almost 90% of the patients who had an early response also responded at w52, so trying to achieve an early response should be an aim in clinical practice. Despite the limited number of patients, our study shows a trend in the relationship between higher antiTNF levels and clinical and radiological response rates

Defining a therapeutic range for adalimumab serum concentrations in the management of pediatric noninfectious uveitis, a step towards personalized treatment

Background Adalimumab is currently considered the most efficacious anti-TNFα agent for childhood noninfectious uveitis (NIU). The objective of this study was to define a therapeutic range for adalimumab trough levels in the treatment of childhood NIU.MethodsA retrospective, observational, pilot study of 36 children with NIU aged < 18 years, treated with adalimumab. Serum adalimumab through levels and adalimumab anti-drug antibodies (ADA) were analysed at least 24 weeks after start adalimumab.ResultsAdalimumab trough levels were significantly higher in complete responders 11.8 μg/mL (range 6.9–33.0) compared to partial or non-responders 9,2 μg/mL (range 0–13.6) (p = 0,004). Receiver–operator characteristics analyses with an area under the curve of 0,749 (95% CI, 0,561–0,937) defined 9.6 µg/mL as the lower margin for the therapeutic range. This cut-off corresponds with a sensitivity of 88% and a specificity of 56% (positive predictive value, 85%; negative predictive value, 62.5%). A concentration effect curve defined 13 µg/mL as the upper margin. Approximately one-third (30.5%) of patients had an adalimumab trough concentration exceeding 13 µg/mL. Free ADA were observed in 2 patients (5.5%).ConclusionsA therapeutic range of adalimumab trough levels of 9.6 to 13 µg/mL, which corresponds with an optimal clinical effect, was identified. Therapeutic drug monitoring may guide the optimisation of treatment efficacy in children with NIU in the treat-to-target era.

Quantifying the Effect of Methotrexate on Adalimumab Response in Psoriasis by Pharmacokinetic–Pharmacodynamic Modeling

Previously, we showed that the combination of methotrexate and adalimumab treatment leads to less antidrug antibody development. In this study, we quantify the pharmacokinetics/pharmacodynamics (PK/PD) of adalimumab and evaluate the influence of methotrexate cotreatment. A population PK-PD model was developed using prospective data from 59 patients with psoriasis (baseline PASI= 12.6) receiving adalimumab over 49 weeks. Typical PK and PD parameters and their corresponding interpatient variability were estimated. We performed a covariate analysis to assess whether interpatient variability could be explained by addition of methotrexate and other covariates. In total, 330 PASIs, 252 adalimumab serum concentrations, and 247 antidrug antibody titers were available. Presence of antidrug antibodies (adalimumab group= 46.7%, adalimumab+ methotrexate group= 38.7%; P= .031) was correlated with increased adalimumab apparent clearance (P < .001). In the PD model, the use of concomitant methotrexate was borderline to significantly correlated with a decreased half-maximal inhibitory concentration (adalimumab concentration for which clinical response score is reduced by half; P < .10). On the basis of our PK-PD model, concomitant use of methotrexate indirectly increases adalimumab concentration, partially through less antidrug antibodies formation, which may result in better efficacy.

Retrospective Assessment of an Adalimumab Model-Informed Precision Dosing Support Tool for Use in Pediatric Inflammatory Bowel Disease.

Therapeutic drug monitoring in pediatric inflammatory bowel disease (IBD) has been used to achieve and maintain remission. Few guidelines exist to aid clinicians in the adjustment of anti-tumor necrosis factor therapies. The objective was to assess the agreement between real-world postinduction and posteriori analysis of retrospective data, using 2 novel pharmacokinetic (PK) models for adalimumab. A retrospective chart review was conducted in pediatric IBD patients treated with adalimumab. A Bayesian clinical decision support tool (InsightRX) was used. Postinduction serum concentration measurements of adalimumab were performed by drug-tolerant, homogenous shift mobility assay. Predicted serum adalimumab concentrations from both models were compared to the actual serum concentrations through a Bland-Altman analysis. Paired sample t test was used for equivalence. A total of 47 patients were included. Forty-one patients (87%) had Crohn disease, and 30 (64%) were male. Most were induced with 160 mg of adalimumab and maintained on 40 mg biweekly. No significant difference resulted between the de Klaver average prediction and mean population concentration (p = 0.294). Significant difference was observed between Ternant and mean population serum adalimumab concentration (p < 0.001). The Bland-Altman plot for the de Klaver method showed no proportional bias. Additionally, 49% of patients required a dose adjustment during maintenance therapy. The de Klaver model was able to provide less bias than the Ternant model and may aid in predicting serum adalimumab concentrations. Approximately half of the patients required dose adjustment during maintenance therapy to obtain a therapeutic drug concentration or achieve clinical remission.

Higher Adalimumab Trough Levels Are Associated with Histologic Remission and Mucosal Healing in Inflammatory Bowel Disease.

(1) Many patients with inflammatory bowel disease (IBD) in endoscopic remission have persistent histologic activity, which is associated with worse outcomes. There are limited data on the association between adalimumab drug concentrations and histologic outcomes using validated histologic indices. We aimed to assess the relationship between adalimumab concentrations and the Robarts Histopathology Index (RHI). (2) Patients from a tertiary IBD center from 2013 to 2020 with serum adalimumab (ADA) trough concentrations measured during maintenance therapy (≥14 weeks) and a colonoscopy or flexible sigmoidoscopy with biopsies performed within 90 days of drug level were included. Blinded histologic scoring using the RHI was performed. Primary analysis assessed the relationship between adalimumab drug concentrations and histologic remission using receiver operating characteristic curve analysis. (3) In 36 patients (26 Crohn's Disease, 9 ulcerative colitis, 1 indeterminate), median adalimumab concentrations were higher (17.3 ug/mL, 12.2-24.0) in patients with histologic remission compared to those without (10.3 ug/mL, 6.8-13.9, p = 0.008). The optimal ADA concentration identified using the Youden threshold was ≥16.3 ug/mL (sensitivity 70%, specificity 90%). Patients with ADA ≥ 16.3 ug/mL had higher histologic remission rates (78%) compared to lower ADA concentrations (14%, p= 0.002), as well as higher mucosal healing rates (86%) compared to lower levels (12%, p = 0.001). Symptoms correlated weakly and non-significantly with both histologic (RHI) scores (r = 0.25, p = 0.2) and adalimumab concentrations (r = 0.05, p = 0.8). (4) The current study demonstrated that higher serum adalimumab concentrations (≥16.3 ug/mL) are needed for histologic remission and mucosal healing assessed using the RHI.

Early At-Home Measurement of Adalimumab Concentrations to Guide Anti-TNF Precision Dosing: A Pilot Study.

Underdosing of adalimumab can result in non-response and poor disease control in patients with rheumatic disease or inflammatory bowel disease. In this pilot study we aimed to predict adalimumab concentrations with population pharmacokinetic model-based Bayesian forecasting early in therapy. Adalimumab pharmacokinetic models were identified with a literature search. A fit-for-purpose evaluation of the model was performed for rheumatologic and inflammatory bowel disease (IBD) patients with adalimumab peak (first dose) and trough samples (first and seventh dose) obtained by a volumetric absorptive microsampling technique. Steady state adalimumab concentrations were predicted after the first adalimumab administration. Predictive performance was calculated with mean prediction error (MPE) and normalised root mean square error (RMSE). Thirty-six patients (22 rheumatologic and 14 IBD) were analysed in our study. After stratification for absence of anti-adalimumab antibodies, the calculated MPE was -2.6% and normalised RMSE 24.0%. Concordance between predicted and measured adalimumab serum concentrations falling within or outside the therapeutic window was 75%. Three patients (8.3%) developed detectable concentrations of anti-adalimumab antibodies. This prospective study demonstrates that adalimumab concentrations at steady state can be predicted from early samples during the induction phase. The trial was registered in the Netherlands Trial Register with trial registry number NTR 7692 ( www.trialregister.nl ).

Validation Study of Novel Point-of-Care Tests for Infliximab, Adalimumab and C-Reactive Protein in Capillary Blood and Calprotectin in Faeces in an Ambulatory Inflammatory Bowel Disease Care Setting.

Background and aims: Point-of-care tests (POCT) allow instant measurement of inflammatory markers and drug concentrations. Here, we studied agreement between a novel POCT device and reference methods of measuring infliximab (IFX) and adalimumab (ADL) serum concentrations and C-reactive protein (CRP) and faecal calprotectin (FCP) concentrations of patients with inflammatory bowel disease (IBD). Methods: In this single-centre validation study, IBD patients were recruited in which IFX, ADL, CRP and/or FCP tests were required. IFX, ADL and CRP POCT were performed on capillary whole blood (CWB), obtained via finger prick. Additionally, IFX POCT was performed on serum samples. FCP POCT was performed on stool samples. Agreement between POCT and reference methods was tested using Passing-Bablok regression, intra-class correlation coefficients (ICC) and Bland-Altman plots. Results: In total, 285 patients participated. Passing-Bablok regression identified differences between the reference method and IFX CWB POCT (intercept = 1.56), IFX serum POCT (intercept = 0.71, slope = 1.10) and ADL CWB POCT (intercept = 1.44). There were also differences in the Passing-Bablok regressions of CRP (intercept = 0.81, slope = 0.78) and FCP (intercept = 51 and slope = 0.46). Bland-Altman plots demonstrated that IFX and ADL concentrations were slightly higher with the POCT and CRP and FCP were slightly lower with POCT. The ICC demonstrated almost perfect agreement with IFX CWB POCT (ICC = 0.85), IFX serum POCT (ICC = 0.96), ADL CWB POCT (ICC = 0.82) and CRP CWB POCT (ICC = 0.91) and moderate agreement with FCP POCT (ICC = 0.55). Conclusions: IFX and ADL results were slightly higher with this novel rapid and user-friendly POCT, whereas CRP and FCP results were slightly lower compared to the reference methods.

Real-World Implementation and Outcomes of Adalimumab Therapeutic Drug Monitoring in Psoriasis: A National Specialized Center Experience

Serum adalimumab concentration is a biomarker of treatment response but therapeutic drug monitoring (TDM) is yet to be implemented in routine psoriasis care. We incorporated adalimumab TDM in a national specialised psoriasis service and evaluated it using the RE-AIM implementation science framework. We undertook pre-implementation planning (validating local assays) and implementation interventions targeted to patients (pragmatic sampling at routine reviews), clinicians (introduction of TDM protocol) and healthcare systems (adalimumab TDM as a key performance indicator). Over 5-months, 170 of 229 (74%) individuals treated with adalimumab received TDM. Clinical improvement following TDM-guided dose escalation occurred in 13 of 15 (87%) non-responders with serum drug concentrations <8.3μg/ml (median PASI reduction 3.2 [IQR 2.2-8.2] after 23.4 weeks), and in all non-responders who had TDM-guided switch in biologic due to supratherapeutic drug concentrations (>8.3μg/mL; n=2) or positive anti-drug antibody (n=2) (PASI reduction 7.8 [7.5-12.9] after 20.0 weeks). Proactive TDM led to dose reduction in 5 individuals with clear skin and sub- or supra-therapeutic drug concentrations; 4 (80%) sustained clear skin after 50 [42-52] weeks. Adalimumab TDM based on pragmatic serum sampling is clinically viable and may lead to patient benefit. Context-specific implementation interventions and systematic implementation assessment may bridge the biomarker research-to-practice gap.

Adalimumab Serum Concentrations, Clinical and Endoscopic Disease Activity in Crohn’s Disease: A Cross-Sectional Multicentric Latin American Study

Despite some variability in ideal serum Adalimumab (ADA) concentrations, there is increasing evidence that higher concentrations of anti-TNF-α agents can be associated with sustained efficacy, and low or undetectable levels may lead to loss of response. This study aims to correlate serum ADA concentrations with clinical and endoscopic activity in patients with Crohn's disease (CD). A cross-sectional and multicentric study was performed with patients with CD, who used ADA for at least 24 weeks. Patients were allocated into groups according to the presence of clinical or endoscopic disease activity. Serum ADA concentrations were measured and compared between groups. Overall, 89 patients were included. A total of 27 patients had clinically active CD and 62 were in clinical remission. Forty patients had endoscopic disease activity and 49 were in endoscopic remission. The mean serum ADA concentration was 10.2 μg/mL in patients with clinically active CD and 14.3 μg/mL in patients in clinical remission (p = 0.395). The mean serum ADA concentration in patients with endoscopic activity was 11.3 μg/mL as compared to 14.5 μg/mL in those with endoscopic remission (p = 0.566). There was no difference between serum ADA concentrations regarding clinical or endoscopic activity in CD, as compared to patients in remission.

A personalised taper-to-target strategy with adalimumab in Crohn's disease

In The Lancet Gastroenterology & Hepatology, Reinier C A van Linschoten and colleagues report the results of the LADI trial. 1 van Linschoten RCA Jansen FM Pauwels RWM et al. Increased versus conventional adalimumab dose interval for patients with Crohn's disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trial. Lancet Gastroenterol Hepatol. 2023; (published online Jan 31.)https://doi.org/10.1016/S2468-1253(22)00434-4 Google Scholar This trial is an excellent opportunity to explore adalimumab exposure–response relationships in patients with Crohn's disease. Surprisingly, no population pharmacokinetic–pharmacodynamic model of adalimumab in patients with Crohn's disease has been published since the approval of the type II variation by the European Medicines Agency in 2007. However, a pharmacokinetic–pharmacodynamic model was developed by marketing authorisation holder AbbVie, describing the temporal relation between adalimumab dose, adalimumab serum concentrations, and the Crohn's Disease Activity Index (CDAI). 2 European Medicines AgencyScientific discussion Humira—emea/h/c/481-482/ii/33. https://www.ema.europa.eu/en/documents/scientific-discussion-variation/humira-h-c-481-ii-33-epar-scientific-discussion-variation_en.pdfDate: 2007 Date accessed: January 15, 2023 Google Scholar Unfortunately, the model code was not shared, preventing model-informed design of the LADI trial through simulating dose-tapering scenarios and their effect on disease severity. 3 Bauer RJ Hooker AC Mentre F Tutorial for $DESIGN in NONMEM: clinical trial evaluation and optimization. CPT Pharmacometrics Syst Pharmacol. 2021; 10: 1452-1465 Crossref PubMed Scopus (0) Google Scholar Increased versus conventional adalimumab dose interval for patients with Crohn's disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trialThe individual benefit of increasing adalimumab dose intervals versus the risk of disease recurrence is a trade-off that should take patient preferences regarding medication and the risk of a flare into account. Full-Text PDF

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.

Relationship between clinical remission of perianal fistulas in Crohn's disease and serum adalimumab concentrations: A multi-center cross-sectional study.

BACKGROUNDCrohn’s disease (CD) is complicated by perianal fistulas in approximately 20% of patients. Achieving permanent fistula closure remains a challenge for physicians. An association between serum anti-tumor necrosis factor-α concentrations and clinical outcomes in patients with CD has been demonstrated; however, little information is available on serum adalimumab (ADA) concentrations and remission of perianal fistulas in such patients.AIMTo study the relationship between serum ADA concentrations and clinical remission of CD-associated perianal fistulas.METHODSThis cross-sectional study of patients with CD-associated perianal fistulas treated with ADA was performed at four French hospitals between December 2013 and March 2018. At the time of each serum ADA concentration measurement, we collected information about the patients and their fistulas. The primary study endpoint was clinical remission of fistulas defined as the absence of drainage (in accordance with Present’s criteria), with a PDAI ≤ 4, absence of a seton and assessment of the overall evaluation as favorable by the proctologist at the relevant center. We also assessed fistula healing [defined as being in clinical and radiological (magnetic resonance imaging, MRI) remission] and adverse events.RESULTSThe study cohort comprised 34 patients who underwent 56 evaluations (patients had between one and four evaluations). Fifteen patients had clinical remissions (44%), four of whom had healed fistulas on MRI. Serum ADA concentrations were significantly higher at evaluations in which clinical remission was identified than at evaluations in which it was not [14 (10-16) vs 10 (2-15) μg/mL, P = 0.01]. Serum ADA concentrations were comparable at the times of evaluation of patients with and without healed fistulas [11 (7-14) vs 10 (4-16) μg/mL, P = 0.69]. The adverse event rate did not differ between different serum ADA concentrations.CONCLUSIONWe found a significant association between high serum ADA concentrations and clinical remission of CD-associated perianal fistulas.

Higher vs Standard Adalimumab Induction Dosing Regimens and Two Maintenance Strategies: Randomized SERENE CD Trial Results

Dose-optimization strategies for biologic therapies in Crohn's disease (CD) are not well established. The SERENE CD (Study of a Novel Approach to Induction and Maintenance Dosing With Adalimumab in Patients With Moderate to Severe Crohn's Disease) trial evaluated higher vs standard adalimumab induction dosing and clinically adjusted (CA) vs therapeutic drug monitoring (TDM) maintenance strategies in patients with moderately to severely active CD. In this phase 3, randomized, double-blind, multicenter trial, eligible adults (Crohn's Disease Activity Index score of 220-450, endoscopic evidence of mucosal inflammation, and previous failure of standard therapies) were randomized to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3; n= 308) or standard induction regimen (adalimumab 160 mg at week 0 and 80 mg at week 2; n= 206) followed by 40 mg every other week from week 4 onward. Co-primary end points included clinical remission at week 4 and endoscopic response at week 12. At week 12, patients were re-randomized to maintenance therapy optimized by Crohn's Disease Activity Index and C-reactive protein (CA; n= 92) or serum adalimumab concentrations and/or clinical criteria (TDM; n= 92); exploratory end points were evaluated at week56. Similar proportions of patients receiving higher induction regimen and standard induction regimen achieved clinical remission at week 4 (44% in both; P= .939) and endoscopic response at week 12 (43% vs 39%, respectively, P= .462). Week 56 efficacy was similar between CA and TDM. Safetyprofiles were comparable between dosing regimens. Higher induction regimen was not superior to standard induction regimen, and CA and TDM maintenance strategies were similarly efficacious. Adalimumab therapy was well tolerated, and no new safety concerns were identified. (ClinicalTrials.gov, Number: NCT02065570).

Monitorización farmacocinética de adalimumab como marcador precoz de fallo secundario en los pacientes con psoriasis en placa moderada-grave

Objectiveto analyze the relationship between infra-therapeutic serum concentrations (SC) of adalimumab (ADA) and secondary failure to treatment in patients with moderate-severe plaque psoriasis. Patients and methodretrospective observational study. Inclusion criteria: adult patients diagnosed with moderate–severe plaque psoriasis under treatment with ADA in whom a pharmacokinetic monitoring had been performed. Variables: demographic, related to the pathology (psoriasis area severity index (PASI) ≥ 5 non-responder), related to treatment (time under treatment and dosage schedule) and related to monitoring (ADA SC (μg/ml) and anti-adalimumab antibodies (AAA; UA/ml)).The association between the results of the pharmacokinetic monitoring and the effectiveness of treatment was evaluated through the relationship between the infra-therapeutic SC (< 3.5 μg/ml) and the appearance of secondary failure, as well as the time elapsed. Results25 patients (7 women) were included, with 49 (95%CI 44,54) years, being 36% (9/25) non-responders. The patients were treated with ADA during 3.6 (95%CI 26, 4.7) years, 32% (8/25) with the dosage schedule reflected in the summary of product characteristics, 40% (10/25) with optimizations and 28% (7 / 25) with intensification. 34 monitoring of ADA Sc were performed (1.4 monitoring/patient), with a median of 3.8 (IQR 9.2) μg/ml; and 12 AAA monitoring (1.1 monitoring/patient), 6 of them being positive. In 57% (4/7) of patients with infra-therapeutic ADA SC, secondary treatment failures were evidenced 3.4 (IQR 1.5) months after the pharmacokinetic monitoring was performed. ConclusionsADA pharmacokinetic monitoring is a tool to support clinical decisions that allows knowing and predicting the clinical response in patients with moderate-severe plaque psoriasis.

Adalimumab Concentration Changes After Dose Escalation in Inflammatory Bowel Disease.

Dose escalation of adalimumab (ADA) for loss or response in inflammatory bowel disease (IBD) is a common practice. Recent data suggest improved outcomes with an ADA concentration of 12 mcg/mL, but limited data are available on the ability to achieve a target concentration. The aim of this study was to determine the expected change in serum ADA concentration after a dose escalation performed every 7 days in patients with IBD. A retrospective cohort of patients with IBD receiving ADA was divided into every fourteen-day dosing, every 7-day dosing, and dose escalation (ie, q14 to q7 day dosing). The primary outcome was the change in ADA concentration. Multiple logistic regression was performed to identify predictors of achieving a target ADA concentration of ≥12 mcg/mL. Overall, 380 patients were identified, of whom 200 underwent dose escalation, 100 remained on q14 days dosing, and 80 were maintained on q7 day dosing. After dose escalation, the mean ADA concentration increased by 5.5 mcg/mL (P < 0.0001). After dose escalation, a significant proportion of patients achieved an ADA concentration ≥12 mcg/mL (P = 0.0019), as well as clinical remission (P = 0.0053). Based on multiple logistic regression, age of <46 years [odds ratio (OR): 2.4; 95% confidence interval (CI): 1.3, 4.6; P < 0.01], body mass index of <29 (OR: 0.21; 95% CI: 0.1, 0.5; P < 0.0001), and initial ADA concentration of ≥3.0 mcg/mL were found to be associated with a target ADA concentration ≥12 mcg/mL (OR: 4.76; 95% CI: 2.3, 9.7; P < 0.0001). The average expected increase in serum ADA concentration after dose escalation from q14 to q7 days was 5.5 mcg/mL. The initial ADA concentration, age, and body mass index may influence the ability to achieve a target ADA concentration after dose escalation.

Using adalimumab serum concentration to choose a subsequent biological DMARD in rheumatoid arthritis patients failing adalimumab treatment (ADDORA-switch): study protocol for a fully blinded randomised superiority test-treatment trial

BackgroundA substantial proportion of rheumatoid arthritis (RA) patients discontinues treatment with tumour necrosis factor inhibitors (TNFi) due to inefficacy or intolerance. After the failure of treatment with a TNFi, treatment can be switched to another TNFi or a bDMARD with a different mode of action (non-TNFi). Measurement of serum drug concentrations and/or anti-drug antibodies (therapeutic drug monitoring (TDM)) may help to inform the choice for the next step. However, the clinical utility of TDM to guide switching has not been investigated in a randomised test-treatment study.MethodsADDORA-switch is a 24-week, multi-centre, triple-blinded, superiority test-treatment randomised controlled trial. A total of 84 RA patients failing adalimumab treatment (treatment failure defined as DAS28-CRP > 2.9) will be randomised in a 1:1 ratio to a switching strategy to either TNFi or non-TNFi based on adalimumab serum trough level (intervention group) or random allocation (control group). The primary outcome is the between-group difference in mean time-weighted DAS28 over 24 weeks.DiscussionThe trial design differs in many aspects from previously published and ongoing TDM studies and is considered the first blinded test-treatment trial using TDM in RA. Several choices in the design of this trial are described, and overarching principles regarding test-treatment trials and clinical utility of TDM are discussed in further detail.Trial registrationDutch Trial Register NL8210. Registered on 3 December 2019 (CMO NL69841.091.19).

Efficacy and safety of switching from reference adalimumab to CT-P17 (100 mg/ml): 52-week randomized, double-blind study in rheumatoid arthritis.

ObjectiveTo compare the safety and efficacy of switching from reference adalimumab to adalimumab biosimilar CT-P17 with continuing reference adalimumab/CT-P17 in active RA.MethodsThis double-blind, phase III study randomized (1:1) subjects with active RA to receive 40 mg (100 mg/ml) CT-P17 or European Union-sourced reference adalimumab subcutaneously every 2 weeks (Q2W) until week (W) 24 [treatment period (TP) 1]. Thereafter, subjects receiving reference adalimumab were randomized (1:1) to continue reference adalimumab or switch to CT-P17 from W26 (both Q2W until W48; TP2). Subjects receiving CT-P17 in TP1 continued CT-P17. W0–W24 results were previously reported; we present W26–W52 findings. End points were efficacy (including joint damage progression), pharmacokinetics, safety and immunogenicity.ResultsOf 607 subjects who initiated TP2 treatment, 303 continued CT-P17, 153 continued reference adalimumab and 151 switched to CT-P17. Efficacy improvements up to W24 were maintained during TP2; efficacy was comparable among groups. At W52, 20% improvement in ACR response rates were 80.5% (continued CT-P17), 77.8% (continued reference adalimumab) and 82.2% (switched to CT-P17). Joint damage progression was minimal. Mean trough serum adalimumab concentrations were similar among groups. CT-P17 and reference adalimumab safety profiles were numerically similar and switching did not affect immunogenicity. At W52, 28.4% (continued CT-P17), 27.0% (continued reference adalimumab) and 28.3% (switched to CT-P17) of subjects were anti-drug antibody-positive. ConclusionEfficacy, pharmacokinetics, safety and immunogenicity of CT-P17 and reference adalimumab were comparable after 1 year of treatment, including after switching from reference adalimumab to CT-P17.Trial registrationClinicalTrials.gov, http://clinicaltrials.gov, NCT03789292.

P544 Point-of-care finger prick test for C-reactive protein, infliximab and adalimumab serum concentrations

Abstract Background Point-of-Care tests (POCTs) allow instant measurement of inflammatory markers and/or drug concentrations. However, currently available POCTs for infliximab (IFX) and adalimumab (ADL) serum concentrations are time consuming. Recently, a new POCT device (ProciseDx, San Diego, CA, USA) was developed which conveniently measures C-reactive protein (CRP), IFX and ADL capillary concentrations within minutes. We aimed to validate this device by comparing POCT results with conventional laboratory tests for serum CRP, IFX and ADL in patients with inflammatory bowel disease (IBD). Methods IBD patients requiring routine measurement of serum CRP, IFX or ADL were invited to participate. Along with serum collection, 20μl of capillary blood was obtained via finger prick and dispensed in a cartridge with a buffer, and placed in the POCT device providing results within two to four minutes. Forty patients were needed to validate the CRP POCT, as this assay was already previously validated in a different population. For the IFX and ADL assays, 120 patients using IFX or ADL were required to validate the POCT. Agreement between the laboratory serum assay and POCT was visualized on a scatter diagram and a Bland-Altman plot. Deming regression was calculated to demonstrate agreement. In addition, Pearson’s correlation coefficient was calculated. Results Until now, 41 patients have been enrolled for the CRP assay, 120 patients for the IFX and 46 patients for the ADL assay. Two ADL patients were sampled twice (n=48). Significant correlations were found for CRP, IFX and ADL (r=0.98, r=0.88 and r=0.86 respectively, Fig. 1). Deming regression analysis of the CRP assay resulted in a slope of 0.71 (95% CI 0.49 to 0.93) and 1.5 (95% CI -0.44 to 3.50) for the intercept. For the IFX assay, the slope was 1.1 (95% CI 0.83 to 1.3) and the intercept was 1.4 (95% CI -0.47 to 3.4). For the ADL assay, the slope was 0.97 (95% CI 0.64 to 1.3) and the intercept was 2.3 (95% CI -0.64 to 5.2). Conclusion A novel POCT using a finger prick approach provides a rapid, user friendly and reliable measurement of CRP, IFX and ADL concentrations within minutes. The capillary CRP was slightly lower than the venous serum CRP, which was consistently observed and considered clinically irrelevant in this cohort.