Low Infliximab Research Articles

Reactive Immunomodulator Addition to Infliximab Monotherapy Restores Clinical Response in Inflammatory Bowel Disease: A Meta-Analysis.

Patients with inflammatory bowel disease (IBD) receiving infliximab (IFX) commonly experience immunogenic loss of response (LOR) by formation of anti-drug antibodies (ADAs). An immunomodulator (IMM) used in combination with initial IFX induction is known to reduce ADA development and improve clinical outcomes. We aimed to assess the impact of reactively adding an IMM to patients on IFX monotherapy. We conducted a retrospective cohort study and systematic review with meta-analysis of patients with IBD demonstrating immunologic LOR, with or without clinical LOR, that had an IMM (azathioprine, 6-mercaptopurine, or methotrexate) reactively added (reactive combination therapy; rCT) to combat elevated ADAs and raise IFX level. Data were extracted for pooled effect size estimation using random-effects models, and ADA and IFX trough levels were compared pre- and post-IMM initiation. We identified 6 patients who received rCT due to rising ADA titers and low IFX levels. Median ADA titer decreased from 506ng/mL (interquartile range (IQR) [416-750]) to 76.5ng/mL (IQR [25.8-232]), an 85% decrease (p = 0.031). Median IFX trough increased from 0.4µg/mL (IQR [0.4-0.48]) to 8.25µg/mL (IQR [3.7-9.6]), a 20.6-fold increase (p = 0.038). Meta-analysis pooled effect size of 7 studies with 89 patients showed an 87% ADA titer reduction [95% confidence interval (CI) = 72-94%], 6.7-fold increased IFX trough (95% CI = 2.4-18.7), and 76% clinical remission rescue rate (95% CI = 59-93%). These results suggest rCT is a valid rescue strategy in patients with immunogenic LOR to IFX to reduce ADA titers, restore therapeutic IFX levels, and recapture clinical remission of IBD.

Biomarkers predicting the effect of anti-TNF treatment in paediatric and adult inflammatory bowel disease.

Paediatric and adult inflammatory bowel disease (pIBD, aIBD) patients may lose response to anti-tumour necrosis factor (TNF) treatment within the first year. Adult-extrapolated weight-based dosing is incorrect in children, due to age-related pharmacokinetic differences. We investigated biomarkers for initial and maintenance of response to infliximab (IFX) or adalimumab (ADA), comparing pIBD and aIBD patients. In this prospective, observational study, pIBD (n = 24) and aIBD (n = 21) patients were included when initiating anti-TNF. Escalation from standard dosing and continued anti-TNF at 12 and 18 months were assessed. Biomarkers included clinical laboratory parameters, faecal calprotectin (FCP) and IFX trough levels (TLs). Plasma proteomics was performed in pIBD. During our study, treatment escalation (in clinical loss of response) occurred more common in pIBD versus aIBD (p = 0.02). We established that IFX therapy escalation in pIBD patients was not due to low infliximab levels. We identified 9 pro-inflammatory proteins that were elevated in patients losing response. Anti-TNF exposure-response relationship may be different in pIBD versus aIBD. No biomarkers for maintained response were identified, but 9 inflammatory proteins were of interest as potential predictors for loss of response in pIBD.

P684 Using a pharmacokinetic simulation model to determine the optimal infliximab intensification strategy to address loss of response in inflammatory bowel disease

Abstract Background The optimal dose intensification strategy to address loss of response associated with low infliximab levels remains uncertain. Favorable associations between higher infliximab levels and objective endpoints imply that post-intensification trough and treatment targets may have utility. This simulation study aimed to identify intensification strategies capable of achieving post-intensification trough thresholds associated with aspirational treatment targets in Crohn’s disease (CD) and ulcerative colitis (UC). Methods A previously published infliximab pharmacokinetic model, applied to 200 simulated patients, identified those with subtherapeutic(<3.00mg/L) trough levels after 30-weeks of standard dosing, and subsequently applied ten dose intensification strategies (Figure 1) over a further 32 weeks. The proportion of simulations achieving infliximab trough thresholds associated with endoscopic remission (CD >9.7mg/L; UC >7.5mg/L) was the primary outcome, with clinical improvement (CD >7.0mg/L; UC >3.7mg/L) and perianal fistula healing (CD >10.1mg/L) representing secondary outcomes. Outcomes were stratified by intensity of dose intensification, with five deemed intensive (>10mg/kg 8-weekly). The impact of pre-intensification antibodies to infliximab (ATI) on post-intensification trough levels was also evaluated. Results The median pre-intensification infliximab trough level was 0.91mg/L (IQR 1.31). Intensive intensification strategies were more likely to achieve infliximab trough concentrations associated with endoscopic remission (UC: 34.76 v 10.56%, CD: 25.80 v 4.92%), clinical improvement (UC: 61.40 v 34.52%, CD: 39.58 v 12.12%) and perianal fistula healing (24.70 v 4.50%, all p<0.01) than standard intensification strategies (Figure 2). When controlling for cumulative (mg/kg) infliximab dose over 32 weeks, strategies that concurrently dose increased and interval shortened achieved the highest trough levels (all p<0.01). Patients simulated to have ATI prior to dose intensification had lower median infliximab trough levels at weeks 30/32 (3.38 mg/L, IQR 5.52 mg/L) compared to those without ATI (3.89 mg/L IQR 6.14 mg/L) across all dose intensification strategies (p=0.015). Conclusion This simulation-based analysis highlights the potential of using post-intensification trough level targets to guide dosing strategy and intensity. Combined high-dose, interval-shortened strategies appear to achieve higher infliximab levels, which may be important in the pursuit of stringent endpoints such as endoscopic remission and fistula healing. These findings require validation across real-world cohorts.

Serum Concentrations of Infliximab and IL-6 for Predicting One-Year Discontinuation of Infliximab Treatment Owing to Secondary Non-response in Patients with Rheumatoid Arthritis.

Secondary non-response to infliximab (IFX) occurs in some patients with rheumatoid arthritis (RA). Although therapeutic drug monitoring (TDM) is a useful tool to optimize IFX therapy, it is unclear whether it can help to identify the risk of secondary non-response. This study aimed to explore the utility of serum levels of IFX or other biomarkers to predict IFX discontinuation owing to secondary non-response. A single-center, retrospective study was conducted using the Kyoto University Rheumatoid Arthritis Management Alliance cohort database between 2011 and 2020. Serum IFX levels were measured using liquid chromatography-tandem mass spectrometry. An electrochemiluminescence assay was used to quantify serum levels of tumor necrosis factor-α and interleukin-6 and detect anti-drug antibodies. Eighty-four out of 310 patients were eligible for this study. The cutoff levels of biomarkers were determined by receiver operating characteristic analysis. IFX persistence was similar between groups stratified using IFX levels, tumor necrosis factor-α levels, interleukin-6 levels, and anti-drug antibodies positivity. The group with lower IFX and higher interleukin-6 levels had the worst therapy persistence (p = 0.017) and the most frequent disease worsening (90.0%, p < 0.001). Evaluating both interleukin-6 and IFX levels, not just IFX alone, enabled us to identify patients at risk of discontinuing IFX treatment. These findings support the utility of measuring IFX and interleukin-6 levels for successful maintenance therapy for RA.

P531 A model-based tool for guiding infliximab induction dosing to maximise long-term deep remission in children with inflammatory bowel diseases

Abstract Background Adequate infliximab (IFX) concentrations during induction treatment are predictive for deep remission (corticosteroid-free clinical and endoscopic remission) at six months in children with Crohn’s disease (CD) and ulcerative colitis (UC).1 Under standard IFX induction dosing, children often have low IFX trough concentrations.2 Model-informed precision dosing (MIPD) is advocated as a promising IFX dosing strategy. We aimed to develop and validate an MIPD framework for guiding paediatric IFX induction treatment. Methods Data from 31 children (4-18 years, 15-76 kg, 20:11 CD:UC) receiving standard IFX induction dosing (5 mg/kg at week [w]0, w2, and w6) were repurposed.1 Eight paediatric population pharmacokinetic models were evaluated (six 2-compartment models and two 1-compartment models). Modelling and simulation were used to identify exposure targets, an optimal sampling strategy, and to develop a multi-model prediction algorithm for implementation into an MIPD software tool.3 A role for IFX clearance monitoring was evaluated. Results A total of 251 IFX concentrations were available (6-10 samples per patient). One patient had undetectable IFX concentrations at w6 and w12 but had no measurable antibodies to IFX (ATI). At six months after start of the IFX treatment, 58% (18/31) of patients achieved deep remission. The measured IFX concentration at w12 was the best predictor and classifier for deep remission. A 7.5 mg/L IFX concentration target at w12 was associated with a 64% probability of deep remission at six months (Figure 1). With standard dosing, less than 80% of simulated children &amp;lt;40 kg attained this target (Figure 2). Immunomodulator combo-therapy only subtly improved probability of target attainment. Presence of ATI lowered the target attainment considerably. The w12 target was most accurately and precisely achieved by implementing MIPD at w6 using the w6 IFX concentration. The multi-model algorithm outperformed single models when optimising the w6 dose based on combined w2 and w4 concentrations. MIPD using only the w2 concentration resulted in biased and imprecise predictions. The predictive performance of the MIPD multi-model algorithm was robust to misspecification of ATI status. IFX clearances at w6 and w12 were predictive for deep remission (P=0.02) (Figure 3). An IFX module was added to the TDMx software tool to facilitate MIPD and clearance monitoring (https://tdmx.shinyapps.io/Infliximab_paediatric/). Conclusion A freely available, interactive, multi-model MIPD software tool is provided to facilitate IFX induction dosing and improve deep remission rates in children with CD and UC. 1van Hoeve et al. J Pediatr 2022. 2van Rheenen et al. J Crohns Colitis 2020. 3Kantasiripitak et al. CPT:PSP 2022.

A Model-Based Tool for Guiding Infliximab Induction Dosing to Maximize Long-term Deep Remission in Children with Inflammatory Bowel Diseases.

Adequate infliximab concentrations during induction treatment are predictive for deep remission [corticosteroid-free clinical and endoscopic remission] at 6 months in children with inflammatory bowel diseases [IBD]. Under standard infliximab induction dosing, children often have low infliximab trough concentrations. Model-informed precision dosing [MIPD; i.e. model-based therapeutic drug monitoring] is advocated as a promising infliximab dosing strategy. We aimed to develop and validate an MIPD framework for guiding paediatric infliximab induction treatment. Data from 31 children with IBD [4-18 years] receiving standard infliximab induction dosing (5 mg/kg at week [w]0, w2 and w6) were repurposed. Eight paediatric population pharmacokinetic models were evaluated. Modelling and simulation were used to identify exposure targets, identify an optimal sampling strategy, and develop a multi-model prediction algorithm for implementation into an MIPD software tool. A role for infliximab clearance monitoring was evaluated. A 7.5 mg/L infliximab concentration target at w12 was associated with 64% probability of deep remission at 6 months. With standard dosing, less than 80% of simulated children <40 kg attained this target. The w12 target was most accurately and precisely achieved by implementing MIPD at w6 using the w6 infliximab concentration [rapid assay required]. The multi-model algorithm outperformed single models when optimizing the w6 dose based on both w2 and w4 concentrations. MIPD using only the w2 concentration resulted in biased and imprecise predictions. Infliximab clearances at w6 and w12 were predictive for deep remission. A freely available, multi-model MIPD tool facilitates infliximab induction dosing and improves deep remission rates in children with IBD.

P543 Point-of-care testing in therapeutic drug monitoring of infliximab

Abstract Background Within the past 20 years infliximab (IFX), a monoclonal antibody targeting tumor necrosis factor-alpha, has become an established therapy for inducing and maintaining remission in inflammatory bowel disease (IBD). IFX therapeutic drug monitoring (TDM) using the point-of-care (POC) methods showed to be able to produce results fast enough to allow IFX dose adjustments before drug infusion. This study aimed to compare IFX quantification using two POC tests, Procise IFX (Procise Dx) and Quantum Blue Infliximab assay (Bühlmann Laboratories AG). Methods Serum samples from 22 IBD patients (M=64%) on IFX maintenance therapy were collected immediately before drug infusion. Capillary blood was also collected from 6 IBD patients by finger prick using whole blood pipettes (Procise Dx). Crohn’s disease (CD) was diagnosed in 12 patients and ulcerative colitis (UC) in 10 patients. For method comparison, a Passing Bablok regression was used and for qualitative comparison weighted kappa statistic was obtained after stratification of results by therapeutic range (&amp;lt;3 mg/l, ≥3 to 7 mg/L, and ≥7 mg/L). Results Both methods measured lower IFX concentrations in CD patients (4,95 (0,65 – 5,80) mg/L) than in UC patients (8,50 (4,80 – 12,20) mg/L). In two patients with confirmed IFX antibodies, both methods showed immeasurably low IFX concentrations. Passing Bablok regression analysis of IFX concentration in serum sample has showed a proportional deviation between two POC methods (y=0.416 (-0.654 to 1.279) + 0.753 (0.648 to 0.923)x). A good comparison has been observed for capillary blood measured using Procise IFX test and serum samples measured using Quantum Blue Infliximab assay (y=-2.732 (-4.315 to 1,867) + 1.263 (0.278 to 1.566)x), although IFX concentration was lower in capillary blood. Classification of results according to therapeutic interval showed good agreement for serum samples and serum and whole capillary blood measurements (κ=0.79 (0.59–0.999 and κ=0.80 (0.45–1.00), respectively). Conclusion Because of proportional differences, two POC tests can’t be used interchangeably for longitudinal TDM of IFX in IBD patients. There is a need for caution in the interpretation of IFX in whole blood, due to its possibly lower concentration.

Potential application of measuring serum infliximab levels in rheumatoid arthritis management: A retrospective study based on KURAMA cohort data.

Infliximab (IFX) therapy has considerably improved the treatment of rheumatoid arthritis (RA). However, some patients still do not respond adequately to IFX therapy, or the efficacy of the treatment diminishes over time. Although previous studies have reported a relationship between serum IFX levels and therapeutic efficacy, the potential applications of IFX therapeutic drug monitoring (TDM) in clinical practice remain unclear. The purpose of this study was to investigate the potential applications of IFX TDM by analyzing a Japanese cohort database. Data were collected retrospectively from the Kyoto University Rheumatoid Arthritis Management Alliance cohort between January 1, 2011, and December 31, 2018. Serum IFX levels were measured using a liquid chromatography-tandem mass spectrometer. Out of the 311 RA patients that used IFX, 41 were eligible for the analysis. Serum IFX levels were significantly higher in responders than in non-responders. An optimal cut-off value was determined to be 0.32 μg/mL based on a receiver operating characteristic curve. At the IFX measurement point, a better therapeutic response was observed in the high IFX group (n = 32) than in the low IFX group (n = 9). Conversely, at the maximum effect point, when DAS28-ESR was the lowest between IFX introduction and measurement points, there were no differences in responder proportions between the low and high IFX groups. IFX primary ineffectiveness could be avoided with appropriate dose escalation without blood concentration measurement in clinical practice. In conclusion, IFX TDM could facilitate the identification of secondary non-responders and in turn, proper IFX use.

P304 Rational infliximab induction dosing to achieve long-term deep remission in children with Inflammatory Bowel Diseases

Abstract Background Adequate infliximab (IFX) trough concentrations (TCs) during induction treatment are predictive for long-term clinical and endoscopic remission in paediatric patients with inflammatory bowel diseases (IBD). However, under the approved weight-based dosing (5 mg/kg), children often have low IFX TCs, since the relationship between bodyweight and the IFX pharmacokinetic (PK) parameters is nonlinear. Therefore, there is a need to optimise paediatric dosing to engage optimal IFX TCs during induction treatment. Methods Fifty-two paediatric patients with IBD (34 Crohn’s disease (CD), 18 ulcerative colitis (UC)) contributed IFX samples (246 intermediate and 150 trough samples) during either induction treatment (n=32) or maintenance treatment (n=20). A population PK (popPK) model was developed to describe the relationship between IFX dose and exposure. The previously published IFX popPK model based on data of 112 children with CD in the Phase 3 REACH trial was used as a frequentist prior to inform parameter estimation using NONMEM. Our popPK model was used to simulate IFX TCs during induction treatment under different induction dosing regimens (5 mg/kg, 7.5 mg/kg, and 10 mg/kg IFX at weeks 0, 2, and 6). Probabilities of TC target attainment (PTA) were compared. The TC target, associated with a 75% probability of achieving deep remission (DR) at six months after initiating IFX treatment, was identified using a logistic regression model and a ROC analysis. DR was defined as combined endoscopic remission (Simple Endoscopic Score for CD &amp;lt;3 or Mayo endoscopic sub-score 0) and corticosteroid-free clinical remission (Paediatric CD or UC Activity Index &amp;lt;10). Results The median boyweight was 44 kg (range 15-92 kg). A 2-compartment popPK model with first-order elimination described IFX concentrations well (Table 1). The IFX clearance by weight increased with decreasing bodyweight, decreasing serum albumin and absence of immunomodulator combo-therapy. Also, the IFX volume of distribution in the central and peripheral compartment by weight increased with decreasing bodyweight. A total of 18/32 (56%) patients in the induction treatment achieved DR at six months. An IFX TC of 23.0 mg/L at week 6 was identified as the TC target (100% sen, 33% spe, 100% npv, and 50% ppv). Children with a bodyweight less than 30 kg could only reach a 50% PTA when receiving 10 mg/kg IFX combo-therapy during induction (Figure 1). While children with a bodyweight above 30 kg had more than 50% PTA when receiving either 10 mg/kg IFX monotherapy or 7.5 mg/kg IFX combo-therapy (Table 2). Conclusion IFX doses higher than 5 mg/kg are needed during induction in children with IBD to facilitate the attainment of the TC target, thereby increasing the chance of long-term DR.

P408 Anti-Drug Antibodies Detected in the Presence of Adequate Infliximab Drug Levels In IBD Patients in Clinical Remission have Limited Clinical Significance

Abstract Background Immunogenicity, with the development of antibodies-to-infliximab (ATI) increases drug clearance and can lead to loss of infliximab (IFX) response in inflammatory bowel disease(IBD). Reporting of ATI is variable between commercial assays with some assays having high sensitivity for low-titre antibodies. Uniform thresholds for clinically relevant antibody titres are lacking. It is unclear how ATI affect treatment outcome when adequate trough IFX concentrations are present and ATI are detected. Methods We aimed to assess the impact of ATI detected in the presence of adequate IFX levels on the outcome of IFX therapy in IBD patients in clinical remission. A proactive therapeutic drug monitoring(TDM) strategy was utilized in our unit with IFX and ATI levels, assessed at trough, in all IBD patients receiving IFX. Baseline demographics were collected. Patients were grouped based on disease activity. An adequate trough IFX level was a concentration &amp;gt; 3 µg/mL, with low levels defined as &amp;lt; 3 µg/mL. ATI positivity was defined as a concentration &amp;gt; 10 AU/mL. Receiver operating characteristic analysis was performed to evaluate the classifying performance of ATI concentration for low IFX levels. Survival analysis was performed to determine IFX persistence in patients with adequate IFX levels and positive ATI. Follow up TDM assessments, where available, were documented to determine changes in ATI concentration over time in patients with adequate IFX levels. Results 108 patients were included. Median age 36years. 46% were female. 36% had ulcerative colitis, 60% Crohn’s disease. 35% were receiving concomitant immunomodulators. 56% of patients were in remission at the time of TDM assessment. 44%, 30% and 26% of patients had IFX levels &amp;lt; 3 µg/mL, 3 – 7 µg/mL and &amp;gt; 7 µg/mL. Median [range] ATI concentration was 11 AU/mL [0 – 800]. ATI positivity occurred in 25%, 19% and 8% of IFX groups with levels &amp;lt; 3 µg/mL, 3 – 7 µg/mL and &amp;gt; 7 µg/mL. There was a weak inverse correlation between trough ATI and IFX concentration (p=0.01)(Figure 1). ATI concentration performed poorly as a classifier of low IFX levels (AUC 0.568)(p=0.39). 83%(15/18) of IBD patients in remission with adequate IFX levels and positive ATI remained on IFX for the duration of follow up with a mean cumulative time on IFX of 111.2 weeks (95% CI 105.1 – 117.3)(Figure 2). In this group, there was no significant change in ATI titre comparing index with follow up TDM assessments (p=0.14)(Figure 3). Conclusion ATI positivity in the presence of adequate IFX levels is common with proactive TDM. For patients in clinical remission ATI positivity in the presence of adequate IFX levels has limited clinical significance. Care should be taken to avoid unnecessary therapy alterations in this patient subgroup.

Factors associated with reduced infliximab exposure in the treatment of pediatric autoimmune disorders: a cross-sectional prospective convenience sampling study

BackgroundInadequate systemic exposure to infliximab (IFX) is associated with treatment failure. This work evaluated factors associated with reduced IFX exposure in children with autoimmune disorders requiring IFX therapy.MethodsIn this single-center cross-sectional prospective study IFX trough concentrations and anti-drug antibodies (ADAs) were measured in serum from children diagnosed with inflammatory bowel disease (IBD) (n = 73), juvenile idiopathic arthritis (JIA) (n = 16), or uveitis (n = 8) receiving maintenance IFX infusions at an outpatient infusion clinic in a tertiary academic pediatric hospital. IFX concentrations in combination with population pharmacokinetic modeling were used to estimate IFX clearance. Patient demographic and clinical data were collected by chart review and evaluated for their relationship with IFX clearance.ResultsIFX trough concentrations ranged from 0 to > 40 μg/mL and were 3-fold lower in children with IBD compared to children with JIA (p = 0.0002) or uveitis (p = 0.001). Children with IBD were found to receive lower IFX doses with longer dosing intervals, resulting in dose intensities (mg/kg/day) that were 2-fold lower compared to children with JIA (p = 0.0002) or uveitis (p = 0.02). Use of population pharmacokinetic analysis to normalize for variation in dosing practices demonstrated that increased IFX clearance was associated with ADA positivity (p = 0.004), male gender (p = 0.02), elevated erythrocyte sedimentation rate (ESR) (p = 0.02), elevated c-reactive protein (CRP) (p = 0.001), reduced serum albumin concentrations (p = 0.0005), and increased disease activity in JIA (p = 0.009) and IBD (p ≤ 0.08). No significant relationship between diagnosis and underlying differences in IFX clearance was observed. Multivariable analysis by covariate population pharmacokinetic modeling confirmed increased IFX clearance to be associated with anti-IFX antibody positivity, increased ESR, and reduced serum albumin concentrations.ConclusionsEnhanced IFX clearance is associated with immunogenicity and inflammatory burden across autoimmune disorders. Higher systemic IFX exposures observed in children with rheumatologic disorders are driven primarily by provider drug dose and interval selection, rather than differences in IFX pharmacokinetics across diagnoses. Despite maintenance IFX dosing at or above the standard recommended range for IBD (i.e., 5 mg/kg every 8 weeks), the dosing intensity used in the treatment of IBD is notably lower than dosing intensities used to treat JIA and uveitis, and may place some children with IBD at risk for suboptimal maintenance IFX exposures necessary for treatment response.

Impact of infliximab therapeutic drug level monitoring on outcomes of patients with inflammatory bowel disease: A real-world experience from a Middle Eastern cohort

Background and study aimTherapeutic drug monitoring (TDM) through measurement of infliximab (IFX) trough levels and antibodies to infliximab (ATI) is performed to guide IFX intensification strategies and improve its efficacy. We conducted this study to explore the relationship between clinical and endoscopic/radiological remission and IFX and ATI levels in patients with inflammatory bowel disease (IBD) treated with IFX and to evaluate the appropriateness of treatment decision post TDM. Patients and methodsThis was a cross-sectional study of a cohort of adult patients with IBD. Serum IFX trough concentrations and ATI were measured. ResultsA total of 129 patients [104] with ulcerative colitis (UC) and 25 with Crohn’s disease (CD)] were included in this study, of whom 61.2% were men. The mean disease duration was 6.7 years, and 72% of patients with UC had extensive colitis. The mean serum IFX trough level was 4.1 µg/mL; the IFX trough levels were subtherapeutic in 75 patients (58%), therapeutic in 37 patients (29%), and supratherapeutic in 17 patients (13%). Positivity to ATI was found in 16 patients (12.4%). Only 43 patients (33.3%) underwent an appropriate change in therapy after TDM, patients with penetrating CD disease had low IFX levels and higher C-reactive protein levels at 12 months before TDM. ConclusionsPatients with IBD with therapeutic IFX levels tend to have increased endoscopic/radiological remission rates. However, an appropriate change in management based on TDM was absent in the majority of patients, potentially reflecting the need to have a dashboard to support and guide clinicians in decision-making.

Особенности ответа на инфликсимаб пациентов с воспалительными заболеваниями кишечника и анкилозирующим спондилитом

Aim: to compare the efficacy of infliximab in inflammatory bowel disease (IBD) and ankylosing spondylitis (AS) and its relationship with drug concentration and the level of antibodies against this medication. Patients and Methods: this prospective observational study included 34 patients with AS, Crohn’s disease, and ulcerative colitis who received infliximab for 7.5 [5; 21.5] months. Treatment efficacy was assessed in all patients by a single measurement of trough concentration of infliximab and serum antibodies (Abs) against this medication. Results: infliximab was reported to be clinically effective in 63.6% of patients with IBD and 83.3% of patients with AS. Abs against infliximab were identified in 22.7% of patients with IBD and 25% of patients with AS. Low infliximab concentration was detected in 31% of patients Пациенwith IBD and 50% of patients with AS. Meanwhile, no significant differences between the groups were reported. Among patients with antiinfliximab Abs, a good treatment effect was observed in two patients (25%) who received therapy for &gt; 16 months. In patients with AS, infliximab inefficacy and infusion reactions were accounted for by the generation of Abs (66.7%) or low infliximab concentration (100%). Among patients with IBD, Abs and low infliximab concentration were identified only in 25% patients in whom infliximab was ineffective. In contrast to AS, certain factors affecting drug efficacy (i.e., hormone dependence and body mass index), its concentration (i.e., extraintestinal manifestation), and Ab levels (i.e., disease duration and body mass index) were identified in IBD. Conclusions: features identified that represent various mechanisms of immune escape and immunogenicity in inflammatory immunemediated disorders should be considered when extrapolating the data between disorders and developing management strategy for inadequate treatment response to infliximab. KEYWORDS: infliximab, ankylosing spondylitis, inflammatory bowel disease, trough concentration, antibodies against infliximab. FOR CITATION: Nuriakhmetova T.Yu., Valeeva I.Kh., Shevnina Ya.O. et al. Specificity of treatment response to infliximab in patients with inflammatory bowel disease and ankylosing spondylitis. Russian Medical Inquiry. 2021;5(2):64–70. DOI: 10.32364/2587-6821- 2021-5-2-64-70.

Early Inflammatory Markers are Associated With Inadequate Post-Induction Infliximab Trough in Pediatric Crohn's Disease.

In pediatric Crohn's disease, infliximab trough concentrations after standard weight-based induction therapy are commonly below 7 μg/mL. Clinical treatment outcomes are associated with post-induction infliximab trough concentration. Markers of inflammation are associated with low infliximab concentrations during maintenance dosing. We sought to determine if early markers of disease activity are associated with inadequate post-induction infliximab trough concentrations in pediatric Crohn's disease. We performed a retrospective single-center case-control study of pediatric Crohn's disease patients to assess the association between baseline and week-2 biomarkers (albumin, C-reactive protein, and erythrocyte sedimentation rate) and inadequate post-induction infliximab trough concentration (<7 μg/mL) in patients treated with standard 5 mg/kg dosing. Baseline and week-2 biomarker values were coded as dichotomous variables at clinically useful thresholds. Univariable logistic regression was used to calculate odds ratios of developing an inadequate infliximab trough concentration for each threshold, as well as thresholds in combination. Fifty-five patients were evaluated. Early biomarker thresholds significantly associated with inadequate post-induction infliximab trough concentrations included baseline C-reactive protein >1 mg/dL (odds ratio [OR] 4.58; 95% confidence interval [CI] 1.24--17.01), both baseline C-reactive protein >0.5 mg/dL and albumin <3.5 g/dL (OR 8.31; 95% CI 1.99--34.63), and week-2 C-reactive protein >0.5 mg/dL or albumin <3.5 mg/dL or erythrocyte sedimentation rate >25 mm/hour (OR 11.08; 95% CI 2.14--57.22). Routine baseline and week-2 markers of disease activity at clinically useful thresholds were associated with inadequate post-induction infliximab trough concentration in pediatric Crohn's disease patients receiving standard weight-based induction dosing.

S2857 Intestinal Behcet’s Disease Involving Terminal Ileum

INTRODUCTION: Behcet’s Disease (BD) is a rare, chronic, inflammatory vasculitis that affects several organ systems. Gastrointestinal involvement occurs in 3 to 25% of patients, with prevalence of 1–2/1,000,000 in the United States. We present a case of a patient with BD developing abdominal pain, diarrhea, and weight loss. CASE DESCRIPTION/METHODS: 57-year-old man with known oral and genital BD presented with fever, 1-week 15lb weight loss, abdominal pain and non-bloody diarrhea. He had been on infliximab, colchicine and prednisone. Laboratory studies exhibited iron deficiency anemia and leukopenia. Abdominal CT showed wall thickening of terminal ileum with fat stranding consistent with terminal ileitis. Tuberculosis, Cytomegalovirus and Histoplasma on serum were negative. Colorectal surgery was consulted, and in light of refractory ileitis patient underwent laparoscopic right hemicolectomy with ileocolic anastomosis. Histopathology demonstrated acute ischemic necrosis with ileal ulceration. After surgery, he was continued on low dose prednisone and infliximab infusions with resolution of intestinal symptoms. DISCUSSION: Intestinal BD presents with abdominal pain, anorexia, vomiting, diarrhea, dyspepsia, and bloody/non-bloody stools. Mucosal ulcerations are thought to be the underlying factor behind the symptoms, likely secondary to a combination of vein and venule vasculitis and large vessel involvement leading to ischemia and subsequent infarction. Diagnosis can be challenging given clinical similarities with Inflammatory Bowel Disease (IBD), however findings of vasculitis on biopsy favors intestinal BD over IBD. Imaging modalities are useful in its diagnosis including barium swallow, CT, and MRI which demonstrate colonic wall thickening. Endoscopy often reveals large deep punched out ulcers with discrete margins usually in the ileocecal region. Treatment is similar to IBD, including medical and surgical modalities. First line agents are sulfasalazine, mesalamine and corticosteroids. Second line are infliximab and adalimumab. Colectomy is indicated if medical therapy fails or with presence of bowel perforation, fistulae or GI bleeding. After surgery, recurrence is seen up to 40–80% of cases, with 80% requiring re-operation. Keep in mind that patients with history of BD can develop colitis.Image 1.: Pre-operative CT showing the coronal sequence of images. Notice the circumferentially thickened, irregular terminal ileum in the right lower quadrant. There is secondary luminal narrowing and adjacent fat stranding compatible with transmural involvement.Image 2.: Pre-operative CT as above. Image series.

Therapeutic thresholds and mechanisms for primary non-response to infliximab in inflammatory bowel disease

Background Primary non-response to infliximab (IFX) inherits a poor prognosis in inflammatory bowel disease (IBD). We explored underlying mechanisms and therapeutic thresholds in an effort to provide basis for optimizing therapy. Methods A prospectively followed cohort of 166 IBD patients having received standard IFX induction therapy (5 mg/kg at weeks 2, 6, and 14) had trough IFX and anti-IFX antibodies (Abs) retrospectively assessed at weeks 2 (n = 148) and 6 (n = 108). Circulating TNFα was measured in matched primary non-responders (n = 29) and responders (n = 21) at baseline and weeks 6 and 14. Clinical outcome at week 14 was supported by disease activity scores in half of patients. Results In all, 18 patients (11%) had primary non-response. Infliximab was consistently lower throughout the induction phase in non-responders as compared to responders (Week 2: IFX median 18.9 μg/mL vs. 23.3, p < .05. Week 6: 8.4 vs. 17.0, p < .05). Optimal IFX thresholds associated with response was 22.9 μg/mL at week 2 (sensitivity 51%, specificity 80%, AUCROC 0.67, p < .05) and 11.8 at week 6 (72%, 77%, 0.71, p < .05). Anti-IFX Abs occurred in 28% of primary non-responders and associated with low IFX and treatment failure (OR 13.7 [2.8–67.5], p < .01). Markers of disease activity (disease activity scores, albumin, CRP) also associated with low IFX. Circulating TNFα was higher throughout induction in non-responders with ulcerative colitis but not Crohn’s disease. Conclusion IBD patients with primary IFX failure generally have lower IFX trough than responders during early induction phase. Pharmacokinetic failure seems common in ulcerative colits, whereas pharmacodynamic failure appears common in Crohn’s disease.

P362 Prospective study of phArmaCokinetics of InFliximab during induction in patients with Crohn’s disease and ulcerative colitis (PACIFIC)

Abstract Background Loss of response (LOR) to infliximab (IFX) remains a challenge in routine management of IBD patients. We evaluated IFX high-resolution pharmacokinetics (PK) during induction with intermediate and peak PK levels. Methods This is a prospective, multicentre (n = 9), interventional study approved by EC (P2017/484). Fourteen blood samples were collected per patient from baseline to week 30. All patients were IFX naïve with active disease according to clinical, biological and endoscopy criteria. The primary outcome evaluated the inter-individual variability of IFX PK during induction and correlation with remission at week 30. In addition to trough levels (TLs), intermediate (ILs) and peak levels (PLs) were also measured and defined as drug level between two infusions and drug level early on after infusion (+2h), respectively. Remission was defined as having a Harvey Bradshaw Index (HBI) ≤ 4 and C-Reactive Protein (CRP) ≤5 for Crohn’s disease (CD), and as a clinical Mayo score ≤2 and faecal calprotectin &amp;lt;250 µg/g for ulcerative colitis (UC). IFX samples were measured by ELISA (Apdia) while a drug-tolerant affinity capture elution anti-infliximab assay was used to measure anti-infliximab antibodies (ATI) at weeks 6, 22 and 30. Results Demographic and baseline data of the study population are presented in Table 1. Among the 62 patients enrolled, 33.9% of patients (n = 21/62) were in remission at week 30. Eight patients dropped out due to disease worsening. Median TLs at week 6 were higher among patients in clinical remission at week 30 (p = 0.02) confirming previous observations. However, ILs at day 3 as well as PLs after the third infusion were also significantly higher in patients in clinical remission at week 30 (Figure 1a–c). ATI were detected as soon as week 6. At week 2, infliximab levels were significantly lower among patients in which ATI developed at a later time point (p = 0.006) and this observation was confirmed when measuring ILs at day 17 (p = 0.002), TLs at week 6 (p = 0.002) and ILs at week 10 (p = 0.001). Conclusion This multicentre prospective study demonstrates that intermediate levels as early as day 3 predict remission at week 30 in IBD patients. Low IFX levels during induction were correlated to future ATI development. PK modelling may allow to better select patients early on for sustained remission with infliximab.

Short‐term results of clinical monitoring of biosimilar infliximab in non‐infectious uveitis

AbstractPurposeTo observe the efficacy, safety and immunogenicity of biosimilar infliximab (CT‐P13) in patients with refractory non‐infectious uveitis (NIU).MethodsRetrospective observational study. Indication for treatment was active uveitis unresponsive to classical immunosuppressants. Clinical data were retrospectively analyzed at baseline and 3 months of treatment. The main outcome measures were uveitis activity, adverse effects and serum biosimilar infliximab trough concentrations as well as anti‐infliximab antibodies (ATI).ResultsNine patients received biosimilar IFX after failing classical immunosuppressive treatment. Mean age was 53 years. The most common diagnosis was Birdshot (n = 4), followed by sarcoidosis (n =3 ), Behcet (n = 1), and Sympathetic Ophthalmia (n = 1). The duration of treatment ranged from 18 to 192 weeks. Five patients without active disease and one patient with activity had IFX levels &gt;9 μg/mL. Two patients with active disease and 1 patient in remission had undetectable levels of IFX. Two patients with undetectable levels of IFX had positive anti‐infliximab antibodies (ATI) levels; both patients showed activity. The other patient with undetectable levels of IFX had no ATI and was in remission. None of the patients with IFX levels &gt;9 μg/mL had positive ATI levels. One patient dropped out of treatment due to infusion‐related skin eruptions.ConclusionBiosimilars are pharmacologically highly similar to an approved biological pharmaceutical ‘reference’ product, but are not exact copies. Even if limited to a small group, this study provides evidence that low biosimilar IFX trough levels associate with increased antibodies in most, but not in all cases.The clinical use of measuring biosimilar infliximab (IFX) trough levels and antibodies against IFX (ATIs) remains unclear.

Practice pattern variability in the management of acute severe colitis: a UK provider survey

IntroductionLack of comparative trial data on dosing regimens of infliximab in patients with acute severe ulcerative colitis (ASUC) failing intravenous corticosteroids has resulted in variability of rescue regimes in ASUC...

P058 Serum infliximab and corresponding anti-infliximab antibody: Analysis of over 30,000 patient results using lab developed chemiluminescent immunoassays

BACKGROUND: Assays to measure TNF inhibitors and anti-drug antibodies (ADAb) in patient serum are being utilized to manage failure to respond and loss of response. These monitoring assays may also be used to proactively titrate doses and dosing intervals (1). Here, 37,165 infliximab (IFX) patient results over 4 years were analyzed. METHODS: Measurements of drug and ADAb levels were performed by lab developed chemiluminescent immunoassays (2). The lower limits of quantitation are 0.4 μg/mL for IFX and 22 ng/mL for its ADAb. Drug assays measure free (ADAb-unbound) drug while ADAb assays detect total antibodies (including IgM and IgG subtypes) and are drug- tolerant to the presence of up to &gt;50 μg/mL of drug. Clinical histories and blood collection timing are unknown. RESULTS: Of 37,165 measured IFX samples, 55% (20,359) were ADAb-free and 45% (16,806) had measurable anti-infliximab antibodies, ranging in concentration from 22 to 3.5 million ng/mL. In the absence of ADAb, IFX concentrations were from 0.4 to &gt;50 μg/mL, with the majority (&gt;60%) between 3.0 to 20 μg/mL. In the presence of ADAb, an inverse relationship between IFX concentrations and anti-IFX antibodies was demonstrated. As a baseline reference, an ADAb-free mean drug level from 16,463 samples with IFX between 0.4 and 30 μg/mL was found to be 10.0 μg/mL. Mean IFX concentrations decreased in samples with increasing ADAb. Low ADAb (&lt;200 ng/mL) appears to have minimal impact on mean drug levels while high ADAb (&gt;1,000 ng/mL) is invariably associated with severely diminished IFX (10% or less than the mean). CONCLUSION(S): Upon analysis of 37,165 infliximab patient samples, 45% exhibited anti-infliximab antibodies. Though collection timing and clinical histories are not known, we found that of all ADAb- free samples, about one third (36%) were within the target range of 3–10 μg/mL for infliximab and 36% of samples were subtherapeutic at &lt;3.0 μg/mL. High titer ADAb are almost invariably associated with very low or absent IFX levels. In contrast, low titer antibodies have little or no impact on drug levels. Our findings are consistent with American Gastroenterological Association Critical Care Pathways for Crohn's Disease and Ulcerative Colitis where low and high antibody scenarios are managed very differently (increase drug dose/consider immunomodulatory vs switch within class). It may be possible to treat away low titer ADAb by increasing drug or adding an immunomodulator (3). Therefore, drug-tolerant anti-drug antibody assays that have been designed both (1) to detect low level ADAb and (2) to distinguish low to intermediate to high titers with high resolution (from 22 to 2,000+ ng/mL) may be most helpful in preventing, managing and treating immunogenicity.