Loss Of Response Research Articles

Attitudes, perceptions and barriers in implementing therapeutic drug monitoring for anti-TNFs in inflammatory bowel disease: a survey from the Middle East.

A growing body of evidence underscores the beneficial impact of therapeutic drug monitoring (TDM) on the efficacy and cost-effectiveness of anti-tumour necrosis factor (TNF) therapy in patients with inflammatory bowel disease (IBD). We surveyed clinician attitudes, perceptions and barriers related to TDM in IBD in the Middle East. A 15-question survey was distributed through national gastroenterological societies in five Middle Eastern countries (UAE, Saudi Arabia, Kuwait, Lebanon and Egypt). Data on clinician characteristics, demographics, utilization patterns and obstacles related to the adoption of TDM with anti-TNFs were gathered. Logistic regression analysis was used to predict factors influencing the utilization of TDM. Among 211 respondents (82% male), 82% were consultants, 8% were physicians with an interest in gastroenterology (GI), and 6% were GI trainees. Of these, 152 met inclusion criteria, treating >5 IBD patients per month and ⩾1 with an anti-TNF per month. TDM was used in clinical practice by 78% (95% CI: 71-85) of respondents. TDM was utilized following the loss of response (LOR) in 93%, for primary non-response (PNR) in 40% and before restarting anti-TNF therapy after a drug holiday in 33% of respondents, while 34% used TDM proactively. No specific factors were associated with the use of TDM. Barriers to TDM use included cost (85%), time lag to results (71%) and lack of insurance reimbursement (65%). Overall knowledge of TDM (70%), interpretation and actioning of results (76%) or awareness of clinical guidelines (57%) were not perceived as barriers. If barriers were removed, 95% would use TDM more frequently; 93% for LOR, 60% for PNR, 50% when restarting after a drug holiday, and 54% would use TDM proactively. Most gastroenterologists use TDM for LOR, with cost, time lag and insurance reimbursement being significant barriers. Addressing these barriers would increase the judicious use of reactive and proactive TDM to optimize anti-TNF therapy in IBD.

Pediatric IBD Patients Treated With Infliximab and Proactive Drug Monitoring Benefit From Early Concomitant Immunomodulatory Therapy: A Retrospective Analysis of a 10-Year Real-Life Cohort.

Limited approval of second-line treatments in pediatric inflammatory bowel disease (pIBD) necessitates optimized use of infliximab (IFX) with proactive therapeutic drug monitoring (TDM). We investigated whether early combo-therapy with an immunomodulator (IMM) provides additional benefit. In the retrospectively reviewed medical records of all children treated with IFX and proactive TDM between 2013 and 2022, IMMearly (IMM ≤3 months since IFX start) was evaluated against IMMother/no (late/short or no IMM) over follow-up of 3 to 60 months. Kaplan-Meier analysis was used to analyze time to loss of response (LOR) with IFX discontinuation or time to antibodies-to-IFX (ATI) development. Three hundred fifteen patients with pIBD were reviewed; of those, 127 with 2855 visits were included (77 CD, 50 UC/IBD-unclassified). Sixty patients received IMMearly, 20 patients IMMother, and 47 had IFX monotherapy. Median follow-up time was 30 and 26 months for IMMearly and IMMother/no, respectively, with comparable proactive TDM. Infliximab treatment persistence was 68% after 60 months. Loss of response was observed in 7 IMMearly and 15 IMMother/no patients (P = .16). Early combo-therapy significantly delayed LOR with IFX discontinuation (median LOR free interval IMMearly 30 months vs IMMother/no 9 months, P = .01). Patients with IMMother/no were 10-, 3- and 2-times more likely to experience LOR with IFX discontinuation after 1, 3, and 5 years, respectively. There were no significant group differences regarding the presence of any positive (>10 arbitrary units per milliliter [AU/mL]) or high (>100 AU/mL) ATI, median ATI concentrations, and ATI-free interval. Early IMM combo-therapy in proactively monitored patients with pIBD significantly prolonged the median LOR free interval compared with late/short or no IMM treatment.

An Update on Anti-TNF Biosimilar Switching-Real-World Clinical Effectiveness and Safety.

Biological medications for inflammatory bowel disease (IBD) account for a significant burden on provincial budgets. In an effort to curb these rising costs, nationwide switching to biosimilars is expected to be complete in Canada before the end of 2023. Biosimilar products do not require the same rigor for licensing as the originator and therefore there has been appropriate scepticism as to how biosimilars will perform in real-world practice. We have performed a systematic review including real-world observational studies of adult patients with IBD. The primary outcome was clinical effectiveness and/or safety in patients who had switched from originator to biosimilar anti-TNF. Secondary outcomes included loss of response (LOR), treatment persistence or cessation and immunogenicity. We included 43 studies (7,462 patients [70 percent Crohn's disease: 30 percent ulcerative colitis]; 32 infliximab studies, and 11 adalimumab studies). For infliximab, 75 percent patients were in clinical remission at the time of switch and 75 percent maintained clinical remission beyond 12 months, compared to 78 percent of patients who continued originator. For adalimumab, 86 percent patients were in remission at the time of switch with 82 percent maintaining remission at 6 months follow-up. Injection site pain was higher in patients who switched to a citrate containing adalimumab biosimilar, compared with those who continued originator. All other outcomes (LOR, treatment cessation or persistence and serious adverse events) were similar to patients who continued originator (in comparator cohorts or the available literature). Whilst ongoing vigilance is required, these data are reassuring to both patients and clinicians and will significantly help to reduce health-care costs across Canada.

Schnider and Eleveld Models for Propofol Target-Controlled Infusion Anesthesia: A Clinical Comparison.

Various pharmacokinetic/pharmacodynamic (PK/PD) models have been developed to accurately dose propofol administration during total intravenous anesthesia with target-controlled infusion (TIVA-TCI). We aim to clinically compare the performance of the Schnider model and the new and general-purpose Eleveld PK/PD model during TIVA-TCI. We conducted a prospective observational study at a single center, enrolling 78 female patients, including 37 adults (aged < 65 years) and 41 elderly patients (aged ≥ 65 years). These patients underwent breast surgery with propofol-remifentanil TIVA-TCI guided by the bispectral index (BIS) for depth of anesthesia monitoring (target value 40-60) and the surgical plethysmographic index (SPI) for antinociception monitoring (target value 20-50) without neuromuscular blockade. The concentration at the effect site of propofol (CeP) at loss of responsiveness (LoR) during anesthesia maintenance (MA) and at return of responsiveness (RoR), the duration of surgery and anesthesia (min), the time to RoR (min), the propofol total dose (mg), the deepening of anesthesia events (DAEs), burst suppression events (BSEs), light anesthesia events (LAEs) and unwanted spontaneous responsiveness events (USREs) were considered to compare the two PK/PD models. Patients undergoing BIS-SPI-guided TIVA-TCI with the Eleveld PK/PD model showed a lower CeP at LoR (1.7 (1.36-2.25) vs. 3.60 (3.00-4.18) μg/mL, p < 0.001), higher CePMA (2.80 (2.55-3.40) vs. 2.30 (1.80-2.50) μg/mL, p < 0.001) and at RoR (1.48 (1.08-1.80) vs. 0.64 (0.55-0.81) μg/mL, p < 0.001) than with the Schnider PK/PD model. Anesthetic hysteresis was observed only in the Schnider PK/PD model group (p < 0.001). DAEs (69.2% vs. 30.8%, p = 0.001) and BSEs (28.2% vs. 5.1%, p = 0.013) were more frequent with the Eleveld PK/PD model than with the Schnider PK/PD model in the general patient population. DAEs (63.2% vs. 27.3%, p = 0.030) and BSEs (31.6% vs. 4.5%, p = 0.036) were more frequent with the Eleveld PK/PD model than with the Schnider PK/PD model in the elderly. The Schnider and Eleveld PK/PD models impact CePs differently. A greater incidence of DAEs and BSEs in the elderly suggests more attention is necessary in this group of patients undergoing BIS-SPI-guided TIVA-TCI with the Eleveld PK/PD than with the Schnider model.

Sarcopenia assessed by computed tomography or magnetic resonance imaging is associated with the loss of response to biologic therapies in adult patients with Crohn's disease.

Sarcopenia occurs in patients with Crohn's disease (CD). However, the association between sarcopenia and loss of response (LOR) to biologic agents remains unclear. This study explored such an association in CD patients. This retrospective study included 94 CD patients who received biologic therapy. The skeletal muscle cross-sectional area at the third lumbar was assessed by computed tomography or magnetic resonance imaging for sarcopenia evaluation. A LOR was defined by fecal calprotectin (FC) < 250 μg/g or >50% reduction from baseline levels or other factors, such as the used agent being replaced by other biologic agents. The association between sarcopenia and LOR was assessed by logistic regression analysis. LOR was observed in 54 patients (57.4%). The prevalence of sarcopenia in the LOR group was higher than that in response group (70.4% vs. 40.0%, p = 0.003). Sarcopenia (odds ratio [OR] = 3.89, 95% confidence interval [CI]: 1.31-11.54), Montreal L1 type (OR = 0.20, 95% CI: 0.06-0.60), perianal lesions (OR = 4.08, 95% CI: 1.31-12.70), and monocytes percentage (OR = 1.27, 95% CI: 1.02-1.57) at baseline were independent associated factors for LOR. Sarcopenia was also associated with LOR in patients who received infliximab (OR = 3.31, 95% CI: 1.11-9.87). Montreal L1 type, perianal lesions, and monocytes percentage (Model 1), and with additional consideration of sarcopenia (Model 2), were developed to predict LOR. Model 2 showed better performance than Model 1 (area under the curve [AUC] 0.82 vs. 0.75). Sarcopenia was associated with the LOR to biological agents or infliximab in adult patients with CD.

Predictors and optimal management of tumor necrosis factor antagonist nonresponse in inflammatory bowel disease: A literature review.

Tumor necrosis factor-α (TNF-α) antagonists, the first biologics approved for treating patients with inflammatory bowel disease (IBD), are effective for the induction and maintenance of remission and significantly improving prognosis. However, up to one-third of treated patients show primary nonresponse (PNR) to anti-TNF-α therapies, and 23%-50% of IBD patients experience loss of response (LOR) to these biologics during subsequent treatment. There is still no recognized predictor for evaluating the efficacy of anti-TNF drugs. This review summarizes the existing predictors of PNR and LOR to anti-TNF in IBD patients. Most predictors remain controversial, and only previous surgical history, disease manifestations, drug concentrations, antidrug antibodies, serum albumin, some biologic markers, and some genetic markers may be potentially predictive. In addition, we also discuss the next steps of treatment for patients with PNR or LOR to TNF antagonists. Therapeutic drug monitoring plays an important role in treatment selection. Dose escalation, combination therapy, switching to a different anti-TNF drug, or switching to a biologic with a different mechanism of action can be selected based on the concentration of the drug and/or antidrug antibodies.

Separation of responsive and unresponsive patients under clinical conditions: comparison of symbolic transfer entropy and permutation entropy

Electroencephalogram (EEG)-based monitoring during general anesthesia may help prevent harmful effects of high or low doses of general anesthetics. There is currently no convincing evidence in this regard for the proprietary algorithms of commercially available monitors. The purpose of this study was to investigate whether a more mechanism-based parameter of EEG analysis (symbolic transfer entropy, STE) can separate responsive from unresponsive patients better than a strictly probabilistic parameter (permutation entropy, PE) under clinical conditions. In this prospective single-center study, the EEG of 60 surgical ASA I–III patients was recorded perioperatively. During induction of and emergence from anesthesia, patients were asked to squeeze the investigators’ hand every 15s. Time of loss of responsiveness (LoR) during induction and return of responsiveness (RoR) during emergence from anesthesia were registered. PE and STE were calculated at −15s and +30s of LoR and RoR and their ability to separate responsive from unresponsive patients was evaluated using accuracy statistics. 56 patients were included in the final analysis. STE and PE values decreased during anesthesia induction and increased during emergence. Intra-individual consistency was higher during induction than during emergence. Accuracy values during LoR and RoR were 0.71 (0.62–0.79) and 0.60 (0.51–0.69), respectively for STE and 0.74 (0.66–0.82) and 0.62 (0.53–0.71), respectively for PE. For the combination of LoR and RoR, values were 0.65 (0.59–0.71) for STE and 0.68 (0.62–0.74) for PE. The ability to differentiate between the clinical status of (un)responsiveness did not significantly differ between STE and PE at any time. Mechanism-based EEG analysis did not improve differentiation of responsive from unresponsive patients compared to the probabilistic PE.Trial registration: German Clinical Trials Register ID: DRKS00030562, November 4, 2022, retrospectively registered.

Do Vedolizumab trough Levels Predict the Outcome of Subsequent Therapy in Inflammatory Bowel Disease?

Background: Vedolizumab trough serum levels have been associated with clinical and endoscopic response in patients with inflammatory bowel disease (IBD). A recent study demonstrated that higher trough levels before dose escalation are associated with favorable outcomes. Objectives: We aimed to identify whether vedolizumab trough levels predict outcome of subsequent therapy. Methods: This retrospective study included IBD patients consecutively receiving vedolizumab therapy between November 2014 and June 2021. Only patients with a loss of response (LOR) to vedolizumab and available trough drug levels prior to therapy cessation were included. Clinical and endoscopic scores were recorded at 6 and 12 months post switching therapy. Results: Overall, 86 IBD patients (51 Crohn's disease, 35 ulcerative colitis) who discontinued vedolizumab were included; of those, 72 (83.7%) were due to LOR. Upon vedolizumab discontinuation, 66.3% of patients were switched to another biologic therapy. Trough vedolizumab levels at discontinuation due to LOR did not differ between patients with clinical response and LOR regarding subsequent therapy at 6 months [median 33.8 μg/mL (IQR 13.2-51.6) versus 31.7 μg/mL (IQR 9.1-64.8), p = 0.9] and at 12 months [median 29.6 μg/mL (IQR 14.3-51.6) versus 34.1 μg/mL (IQR 12.2-64.7), p = 0.6]. Patients progressing to subsequent surgery had numerically lower vedolizumab trough levels at LOR compared with patients who were treated with an additional medical therapy (median 14.3, IQR 4-28.2 μg/mL versus 33.5, IQR 13-51.6 μg/mL, p = 0.08). Conclusions: Vedolizumab trough levels upon LOR do not predict response to subsequent medical therapy; however, lower drug levels may suggest a more aggressive disease pattern and future need for surgery.

Development of Antibodies to Ustekinumab Is Associated with Loss of Response in Patients with Inflammatory Bowel Disease.

The purpose of this study was to investigate the relationship between anti-drug antibodies detected by a drug-tolerant assay and loss of response (LOR) to therapy in a cohort of patients with IBD being treated with ustekinumab. This retrospective study consecutively enrolled all adult patients with moderate to severe active IBD who had at least 2 years of follow-up after ustekinumab was initiated. LOR was defined as CDAI > 220 or HBI > 4 for Crohn's disease (CD) and partial Mayo subscore > 3 for ulcerative colitis (UC) and with a modification in disease management. Ninety patients were included (78 CD and 12 UC; mean age 37 years). Median levels of anti-ustekinumab antibodies (ATU) were significantly higher in patients with LOR compared to those with ongoing clinical response (15.2 µg/mL-eq CI (7.9-21.5) and 4.7 µg/mL-eq CI (2.1-10.5), respectively; p = 0.04). The area under the ROC curve (AUROC) for ATU in predicting LOR was 0.76. The optimal cut-off point for identifying patients with LOR was 9.5 µg/mL-eq with a sensitivity of 80% and specificity of 85%. Uni- and multivariate analyses showed that serum ATU ≥ 9.5 µg/mL-eq (hazard ratio (HR) 2.54, 95%CI (1.80-5.93)), p = 0.022, prior vedolizumab (HR 2.78, 95%CI (1.09-3.34), p = 0.019) and prior azathioprine (HR 0.54, 95%CI (0.20-0.76), p = 0.014) exposures were the only factors independently associated with LOR to UST. In our real-life cohort, ATU was identified as an independent predictor of LOR to ustekinumab in patients with IBD.

Long-term effectiveness and safety of anti-TNF in pediatric-onset inflammatory bowel diseases: A population-based study

BackgroundAnti-TNF agents are the first biologic treatment option in inflammatory bowel disease (IBD). The long-term effectiveness of this strategy at the population level is poorly known, particularly in pediatric-onset IBD. MethodsAll patients diagnosed with Crohn's disease (CD) or ulcerative colitis (UC) before the age of 17 between 1988 and 2011 in the EPIMAD population-based registry were followed retrospectively until 2013. Among patients treated with anti-TNF, the cumulative probabilities of anti-TNF failure defined by primary failure, loss of response (LOR) or intolerance were evaluated. Factors associated with anti-TNF failure were investigated by a Cox model. ResultsAmong a total of 1,007 patients with CD and 337 patients with UC, respectively 481 (48%) and 81 (24%) were treated with anti-TNF. Median age at anti-TNF initiation was 17.4 years (IQR, 15.1–20.9). Median duration of anti-TNF therapy was 20.4 months (IQR, 6.0–59.9). In CD, the probability of failure of 1st line anti-TNF at 1, 3 and 5 years was respectively 30.7%, 51.3% and 61.9% for infliximab and 25.9%, 49.3% and 57.7% for adalimumab (p = 0.740). In UC, the probability of failure of 1st line anti-TNF therapy was respectively 38.4%, 52.3% and 72.7% for infliximab and 12.5% for these 3 timepoints for adalimumab (p = 0.091). The risk of failure was maximal in the first year of treatment and LOR was the main reason for discontinuation. Female gender was associated with LOR (HR, 1.48; 95%CI 1.02–2.14) and with anti-TNF withdrawal for intolerance in CD (HR, 2.31; 95%CI 1.30–4.11) and disease duration (≥ 2 y vs. < 2 y) was associated with LOR in UC (HR, 0.37; 95%CI 0.15–0.94) in multivariate analysis. Sixty-three (13.5%) patients observed adverse events leading to termination of treatment (p = 0.57). No death, cancer or tuberculosis was observed while the patients were under anti-TNF treatment. ConclusionIn a population-based study of pediatric-onset IBD, about 60% in CD and 70% in UC experienced anti-TNF failure within 5 years. Loss of response account for around two-thirds of failure, both for CD and UC.

HLA-DQA1*05 ASSOCIATES WITH IMMUNOGENICITY AND LOSS OF RESPONSE TO ANTI-TNF THERAPY IN THE IBD POPULATION: A META-ANALYSIS

The human leukocyte antigen (HLA) allele group HLA-DQA1*05 has been associated with the development of antidrug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF)1 in the inflammatory bowel disease (IBD) population, except in the setting of proactive optimization2. We performed a meta-analysis to determine the prevalence of HLADQA1*05 carriage, to define the association of HLA-DQA1*05 on immunogenicity and loss of response (LOR) to anti-TNF, and to explore the impact of therapeutic drug monitoring (TDM) on this association.

Breathe–squeeze: pharmacodynamics of a stimulus-free behavioural paradigm to track conscious states during sedation☆

BackgroundConscious states are typically inferred through responses to auditory tasks and noxious stimulation. We report the use of a stimulus-free behavioural paradigm to track state transitions in responsiveness during dexmedetomidine sedation. We hypothesised that estimated dexmedetomidine effect-site (Ce) concentrations would be higher at loss of responsiveness (LOR) compared with return of responsiveness (ROR), and both would be lower than comparable studies that used stimulus-based assessments. MethodsClosed-Loop Acoustic Stimulation during Sedation with Dexmedetomidine data were analysed for secondary analysis. Fourteen healthy volunteers were asked to perform the breathe–squeeze task of gripping a dynamometer when inspiring and releasing it when expiring. LOR was defined as five inspirations without accompanied squeezes; ROR was defined as the return of five inspirations accompanied by squeezes. Brain states were monitored using 64-channel EEG. Dexmedetomidine was administered as a target-controlled infusion, with Ce estimated from a pharmacokinetic model. ResultsCounter to our hypothesis, mean estimated dexmedetomidine Ce was lower at LOR (0.92 ng ml−1; 95% confidence interval: 0.69–1.15) than at ROR (1.43 ng ml−1; 95% confidence interval: 1.27–1.58) (paired t-test; P=0.002). LOR was characterised by progressively increasing fronto-occipital EEG power in the 0.5–8 Hz band and loss of occipital alpha (8–12 Hz) and global beta (16–30 Hz) power. These EEG changes reverted at ROR. ConclusionsThe breathe–squeeze task can effectively track changes in responsiveness during sedation without external stimuli and might be more sensitive to state changes than stimulus-based tasks. It should be considered when perturbation of brain states is undesirable. Clinical trial registrationNCT04206059.

Development and validation of a clinical radiomics nomogram to predict secondary loss of response to infliximab in Crohn's disease patients

BackgroundInfliximab (IFX) is the first-line treatment for Crohn's disease (CD). However, the secondary loss of response (LOR) is common in IFX therapy. Therefore, non-invasive assessment of LOR in CD patients is the goal pursued by clinicians. MethodsA multicenter study involving 181 CD patients was conducted, with patients being split into a training cohort (n = 102), testing cohort (n = 45), and validation cohort (n = 34). The study evaluated various clinical factors to establish a clinical model, and a radiomics signature was constructed based on reproducible features from computed tomography enterography (CTE). Logistic regression modeling was used to create models based on the radiomics signature and significant clinical factors, with the receiver operating characteristic curve (ROC) used to compare their performance. ResultsThe study found that 64 of the 181 CD patients included experienced secondary LOR. The radiomics signature performed well in predicting secondary LOR, showing good discrimination in the training cohort (AUC [area under the curve], 0.947; 95% confidence interval [CI], 0.910–0.976), the testing cohort (AUC, 0.860; 95% CI, 0.768–0.941), and the validation cohort (AUC, 0.921; 95% CI: 0.831–1.000). Decision curve analysis (DCA) demonstrated the clinical value of the radiomics nomogram. ConclusionsThe CTE-based radiomics model showed good performance in predicting secondary LOR in CD patients. The nomogram can help clinicians choose alternative biologics early for CD patients.

Predictive models assessing the response to ustekinumab highlight the value of therapeutic drug monitoring in Crohn's disease.

Despite the therapeutic efficacy of Ustekinumab (UST) in Crohn's disease (CD), loss of response (LOR) is observed over time. This study aims to evaluate the impact of the UST pharmacokinetics (PK) at induction on clinical and endoscopic outcomes, as well as to find predictive markers of UST response. This retrospective study included 80 CD patients. Pharmacokinetics data (trough levels (TLs)) combined with clinical and biological parameters were fed into tailored logistic regression and tree-based ensemble techniques to predict clinical and endoscopic outcomes at one year of follow-up. TLs at week 16 were significantly lower among patients with moderate to severe endoscopic activity during the follow-up (p=0.04). The best model to predict endoscopic outcome was obtained at week 16 by Random Forest with an area under the receiver operating characteristic curve of 0.92±0.08, sensitivity 91% and specificity 75%, with key inputs such as lymphocyte and monocyte counts at week 8, and UST TLs and CRP at week 16. This real-world study confirms the relationship between early UST TLs and both clinical and endoscopic outcomes. Models were developed for the task of predicting clinical and endoscopic remission in CD patients treated with UST, highlighting the clinical relevance of UST TLs at week 16.

Dose intensification strategy influences infliximab pharmacokinetics but not clinical response after the same number of doses.

The optimal infliximab dose intensification strategy to address secondary loss of response (LOR) remains unclear. This study aimed to compare clinical and pharmacokinetic outcomes following (i) upfront infliximab re-induction with (ii) ongoing 6-weekly dose interval shortening (DIS), after the same number of doses. A prospective parallel cohort study of inflammatory bowel disease patients who required infliximab dose intensification for secondary LOR using (i) re-induction (i.e., repeat 5mg/kg 0, 2, 6-week dosing) followed by 8-weekly maintenance or (ii) 6-weekly 5mg/kg DIS was undertaken. Week 32 clinical response was the primary outcome, with secondary evaluation of infliximab pharmacokinetics and predictors of response. Of 104 patients, 54 underwent re-induction, and 50 underwent 6-weekly DIS; 43 per cohort had clinically active disease, with comparable baseline infliximab levels (2.03 vs 2.02ug/mL, P=0.83). Clinical response was similar across re-induction and DIS cohorts at weeks 12 (69.8 vs 65.1%) and 32 (53.5 vs 62.8%, each P>0.50); however, both strategies demonstrated distinct pharmacokinetic profiles at weeks 6 (18.45 vs 5.36ug/mL, P<0.01), 12 (8.94 vs 5.96ug/mL, P=0.02) and 30 (3.89 vs 6.35ug/mL, P=.0.02). In multivariable analyses, objectively verified active disease at baseline (OR 12.92, 95% CI [1.84-90.84], P=0.01), subtherapeutic week 6 infliximab levels (OR 0.12, 95% CI [0.01, 0.99], P=0.049) and week 12 clinical response (OR 5.44, 95% CI [1.20-19.97], P=0.04) were associated with week 32 response, as were week 2 infliximab levels (OR 1.34, 95% CI [1.02-1.47], P=0.04) following re-induction. Following re-induction, week 2 infliximab levels <15.6ug/mL (AUROC 0.76, 95% CI [0.54-0.99], P<0.05) predicted nonresponse at week 32. Dose intensification strategy impacted immediate and sustained infliximab levels but not clinical response. Upfront intensification was associated with short-term pharmacokinetic advantages, including predictors of response, that diminished with time. Hence, when applying upfront dose intensification, clinicians should consider continuing intensified dosing to sustain early pharmacokinetic advantages based on predictors of (non)response.

P478 Platelet-related indicators for predicting vedolizumab response in patients with Ulcerative Colitis

Abstract Background Ulcerative Colitis (UC) combine both inflammation and coagulation in their pathogenesis and clinical manifestations. Although platelets (PLT) are well known for their role in hemostasis, there are a rising number of studies supporting their considerable role as inflammatory amplifiers in chronic inflammatory conditions. However, whether PLT are related to the efficacy of biologic agents is unknown. This study aimed to investigate whether platelet ratio before and after induction therapy can be predictive biomarkers for the therapeutic outcomes of vedolizumab therapy in UC. Methods Patients with moderate-to-severe UC receiving vedolizumab in our hospital between November 2020 and November 2022 were retrospectively evaluated. Patients with concomitant corticosteroid treatment≥20 mg, immunomodulators, or other conditions that could modify the platelet count were excluded. The primary endpoint was clinical response at the end of the induction period (at 14 weeks). We analyzed the association between platelet count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), C-reactive protein (CRP), fecal calprotectin, and the clinical efficacy of vedolizumab. The above indicators between the response and nonresponse groups were compared via a univariate analysis. The independent risk factors of nonresponse were identified via a multivariate analysis. Results Seventy-one patients with moderate-to-severe active UC started treatment with vedolizumab and 20 patients (28.2%) experienced loss of response (LOR) after induction therapy. The platelet count, albumin, CRP, NLR, PLR, MLR, and Particul Mayo score between the LOR and response groups significantly differed. The Platelet ratio before and after induction therapy cut-off value of 1.077 was predictive of LOR, using receiver operating characteristic analysis (sensitivity:78.0%, specificity:81.8%). A univariate analysis revealed a significant relationship between LOR and the platelet ratio (P＜0.05). Multivariate analysis indicated the platelet ratio as an independent prognostic factor for LOR (OR=11.219, 95% CI:3.316-37.959, P＜0.05). Conclusion Platelet ratio before and after induction therapy is a useful prognostic marker in patients with moderate-to-severe active UC treated with vedolizumab, and may contribute to appropriate use of vedolizumab LOR. A large sample from multiple centers is needed to validate the association between platelet-related measures and the rate of vedolizumab response.

DOP72 HLA-DQA1*05 associates with immunogenicity and loss of response to anti-TNF therapy in the IBD population: A meta-analysis

Abstract Background The human leukocyte antigen (HLA) allele group HLA-DQA1*05 has been associated with the development of antidrug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF)1 in the inflammatory bowel disease (IBD) population, except in the setting of proactive optimization2. We performed a meta-analysis to determine the prevalence of HLADQA1*05 carriage, to define the association of HLA-DQA1*05 on immunogenicity and loss of response (LOR) to anti-TNF, and to explore the impact of therapeutic drug monitoring (TDM) on this association. Methods A systematic search of EMBASE, MEDLINE, Web of Science, and SCOPUS was conducted and identified 49 studies. Fourteen studies were included in the meta-analysis according to our inclusion and exclusion criteria. Two reviewers independently assessed eligibility and extracted data. Data extraction focused on the prevalence of HLADQA1*05 carriage, management style of the subjects (proactive TDM vs not), use of combination therapy with immunomodulators (IMM), and association of the variant with ADA and LOR. To examine the potential mitigating effect of management style, three forest plots were generated for each outcome including: 1. all studies, 2. studies using solely proactive TDM, and 3. studies where TDM was either not defined or not performed. Results The prevalence of HLADQA1*05 carriage was 43.3% across the 14 manuscripts (Table 1). Ten studies used data from adult populations, 2 reported on pediatrics only, and 2 reported on a mix of pediatrics and adults. Nine studies took place in Europe, and 5 occurred in North America. A little over half (57%) were abstracts. All studies included some patients on combination therapy with IMM. Data analysis confirmed that possessing the HLADQA1*05 variant leads to an increased ADA risk (OR 1.63 [95% CI: 1.35 - 1.98]). When focusing on the studies that used proactive optimization of anti-TNF therapy, the variant was no longer a risk factor for developing ADA (OR 0.37 [95% CI: 0.19 - 0.70]). Without proactive optimization, the carriage of HLADQA1*05 appears to consistently be associated with a higher risk of immunogenicity (OR 1.93 [95% CI: 1.58 - 2.36]) (Figure 1). HLADQA1*05 was also found to be a risk factor for LOR (HR 1.84 [95% CI: 1.53 - 2.22]) (Figure 2); insufficient data were available for the studies with proactive TDM on LOR. Conclusion Prevalence of HLADQA1*05 carriage is consistent across studies from both North America and Europe. This variant increases the risk of ADA and LOR to anti-TNF. However, in studies that used solely proactive TDM, variant carriage no longer conferred a risk for ADA. 1. Sazonovs A, et al. Gastro. 2020;158(1):189-199. 2. Spencer EA, et al. Gastro. 2022;162(6):1746-1748.e1743.

P798 Understanding anti-TNF treatment failure: mechanisms and management of loss of response to anti-TNF therapy, three-year data from the PANTS study

Abstract Background PANTS (Personalised Anti-TNF Therapy in Crohn’s disease) is a prospective observational UK-wide study investigating the effectiveness of infliximab (IFX) and adalimumab (ADL) in active luminal Crohn’s disease. Here we report remission rates through three years of follow up; rates of and the factors that predicted loss of response (LOR); and the effect of dose intensification on drug persistence. Methods Remission was defined as CRP of ≤3 mg/L and HBI of ≤4 points (sPCDAI ≤15 in children), without corticosteroid therapy or exit for treatment failure. LOR was defined in patients who initially responded to anti-TNF therapy at week 14 and continued in the PANTS extension, by symptomatic IBD activity that warranted an escalation of corticosteroids, immunomodulatory or anti-TNF therapy, resectional surgery, or exit due to adverse events. The effect of dose intensification at the time of LOR on drug persistence was stratified by optimal anti-TNF drug level (IFX 7, ADL 12) (mg/L) and presence of antibodies (anti-IFX 9, anti-ADL 6) (AU/mL), measured using IDKmonitor® ELISA assays. Results Between March 2013 and July 2016, 1610 patients were included in PANTS: 358/955 (37%) treated with IFX (221/358 [62%] originator and 137/358 [38%] with biosimilar) and 187/655 (29%) treated with ADL, who had not exited for treatment failure at the end of year 1, opted to enrol in the extension. Overall, 41.8%, 39.4%, and 41.3% of IFX- and 38.2%, 39.7%, and 39.2% of ADL-treated patients were in remission at year 1, 2 and 3, respectively. For both drugs, we observed a dose response association between week 14 drug concentration and remission status at the later timepoints (A). 34.3%, 54.0%, and 60.3% of IFX-, and 31.9%, 47.3%, and 69.0% of ADL-treated patients lost response at year 1, 2 and 3, respectively. Multivariable regression analyses showed that low drug concentration was the major independent risk factor associated with LOR for both drugs (B). In patients who developed immunogenicity, factors associated with subsequent drug clearance were lower week 14 drug level (p&amp;lt;0.01), non-immunomodulator use (p=0.04), and obesity (p&amp;lt;0.01), but not carriage of HLA-DQA1*05 (p&amp;lt;0.34). In the setting of LOR (n = 686 episodes), 42% patients had their anti-TNF dose intensified and 29% exited the study without further action (C). Compared to patients who experienced LOR with optimal drug levels, dose intensification was associated with lower rates of drug persistence in patients with immunogenic-pharmacokinetic and non-immunogenic pharmacokinetic treatment failure in patients treated with IFX, but not ADL (D). Conclusion Long term remission was observed in about 40% of patients treated with IFX and ADL. Loss of response and non-remission was predicted by low drug levels.

P436 Efficacy and safety of intravenous ustekinumab re-induction therapy in Crohn’s disease patients with secondary loss of response to ustekinumab maintenance therapy: Week 16 results from the POWER trial

Abstract Background After successful induction, a subset of patients with Crohn’s disease (CD) experience a secondary loss of response (LoR) to ustekinumab (UST) maintenance therapy. Dose intensification may assist in regaining response. The phase 3b randomised, double-blind, multicentre POWER study evaluated efficacy and safety of a single intravenous (IV) re-induction UST dose vs continued UST subcutaneous (SC) treatment in CD patients with LoR to standard UST every 8 weeks (q8w) maintenance therapy. Methods Adults with moderately–severely active CD who initially responded to UST IV induction therapy per label and subsequently experienced LoR were included. LoR for inclusion was defined as CDAI score of ≥220 and ≤450, in addition to elevated CRP (&amp;gt;3mg/L), fCal (&amp;gt;250mg/kg) or endoscopy performed ≤3 months before W0 with evidence of active CD (≥1 ulcerations in the ileum and/or colon). At baseline (W0), randomised patients received either ~6mg/kg IV UST/SC placebo (IV arm), or IV placebo/SC UST 90mg (SC arm), followed by SC UST 90mg dosing in both groups at W8/16. Clinical and biomarker assessments were made at W0/8/16 and optional ileocolonoscopy at W0/16. Primary endpoint: clinical response (CRes; decrease of ≥100 points from W0/CDAI &amp;lt;150) at W16. Additional outcome measures included clinical, biomarker, endoscopic and quality of life endpoints assessed at W8/16. Results The analysis set comprised 215 patients at W0 (IV, n=108; SC, n=107). At W16, 92.6% and 86.0% completed treatment from IV and SC arms, respectively. In both arms (IV, 58.3%; SC, 57.9%) most patients experienced ≥2 biologic failures before initiating UST (Table 1). At W16, 49.1% in the IV arm and 37.4% in the SC arm achieved CRes (p=0.089). Percentages of patients with normalisation of fCal, normalisation of CRP and/or fCal, endoscopic remission and improvement, and improvement in IBDQ score were greater in the IV vs SC arm (Table 2). At W16, similar proportions of patients had ≥1 adverse event (AE) (IV, 60.2%; SC, 61.7%) and serious AEs (IV, 5.6%; SC, 5.6%). The proportions of patients with infections were similar between arms (IV, 23.1%; SC, 21.5%), with only 1 serious infection in each arm. Conclusion POWER is the first randomised, controlled, double-blind trial to assess the efficacy and safety of UST IV re-induction in patients with LoR during UST maintenance therapy. The CDAI-based primary endpoint at W16 was not met. However, patients in this heavily pre-treated population who received IV re-induction showed clinically meaningful improvements at W16 compared with those receiving SC, particularly for objective endpoints, including inflammatory biomarkers and endoscopic outcomes.

P605 Real life efficacy of tofacitinib in different situation in ulcerative colitis: a retrospective worldwide multicentre collaborative study

Abstract Background The orally administered small molecule drug pan-Jak inhibitor tofacitinib (TFB) appears to be effective in the treatment of ulcerative colitis (UC), however, available real world studies are limited by the cohort size. In addition, TFB may also be efficacious in patients with acute severe colitis (ASUC) as a rescue therapy. We aimed to conduct an international cohort study, to investigate the efficacy and safety of TFB in patients with moderate to severe colitis and ASUC. Methods This was a retrospective, international multi-centre, cohort study including 23 tertiary referral centres. UC patients with at least 6 weeks of TFB treatment were included. Physicians categorized the indication as rescue therapy (RT) and chronic activity (CA). Baseline demographic and clinical data, clinical/endoscopic activity indexes, laboratory parameters (including CRP, faecal calprotectin, liver enzymes, lipids, iron homeostasis), adverse events, and hospitalization/colectomy rates were collected at w0, w2-6, w8-14, w22-30 and w48-56 intervals. Steroid-free remission, colectomy rates, primary non-response (PNR) and loss-of response (LOR) rates, and safety was studied. Results A total of 391 UC patients (mean age: 39.2±14.1 years, male/female ratio 208/183; mean follow-up period 33.7±18.1 weeks) were included. 107 patients (27.4%) received TFB as a rescue therapy. Most of the patients received it as a third line treatment (37.4%). Steroid-free remission (SFR) rates were 21.3% (RT: 25.0%, CA: 22.3%) at w14, and 40.1% (RT: 32.5%, CA: 42.2%) at w52. In total, baseline pMayo (OR: 0.856; p=0.007) was negatively associated with w12 SFR, while line of treatment (OR: 0.749; p=0.047) and age (OR: 1.022; p=0.038) influenced the w52 SFR in the CA group. The w12 colectomy rate was 5.1%, and no difference was observed between groups (RT: 8.5%; CA: 3.8%), however, w52 colectomy rate was higher in the RT group (19.2% compared to 5.9%; p&amp;lt;0.001). Line of treatment (OR: 1.66; p=0.036) and age (OR: 0.94; p=0.005) were associated as well with w52 colectomy rate. Mucosal healing (eMayo≤1) rate increased from 3.9% to 43.0% (p&amp;lt;0.001). PNR rate was 22.5% and LOR 54.4%. In total, 67 adverse events (17.1%) were reported, and 17.9% of them were resulted in cessation of the treatment. Thromboembolic event was reported in 1 case, however, this patient had concomitant malignancy. Conclusion TFB is effective in both moderate to severe UC, and in patients with ASUC as a rescue therapy. TFB treatment resulted in high rates of SFR and mucosal healing in short- and long term even after anti-TNF and vedolizumab failure. Higher baseline disease activity and number of previous biological therapies negatively influenced efficacy. Serious adverse events were rare.