Proactive TDM Research Articles

The role of proactive therapeutic drug monitoring in guiding infliximab therapeutic optimization in pediatric patients with Crohn's disease: A retrospective study

AbstractTherapeutic drug monitoring (TDM) plays an important role in guiding treatment plan adjustments and clinical outcomes in Crohn's disease. To evaluate the role of TDM‐guided optimization of infliximab dosage in patients with pediatric Crohn's disease. Medical records of patients with pediatric Crohn's disease who were treated with infliximab and had proactive TDM from June 2020 to June 2022 at the Children's Hospital of Chongqing Medical University were included. Baseline influencing factors for infliximab trough concentration (TC) and clinical outcomes before and after the treatment change were analyzed to assess the value of adjusting treatment in the patients. Forty‐six patients (male‐to‐female ratio = 1.55:1, age <18 years) were included. Univariate and multivariate analyses showed that hormone exposure (odds ratio: 0.042, 95% confidence interval: 0.002–0.924, p = 0.044), perianal lesions (5.813, 0.984–34.349, p = 0.052), simplified endoscopic score for Crohn's disease (1.656, 1.065–2.577, p = 0.025), and total protein (TP) (0.851, 0.749–0.967, p = 0.014) were correlated with infliximab TC. Shortening the treatment interval increased the infliximab TC (pre vs. post = 1.69 ± 0.8 vs. 12.03 ± 6.64, p = 0.001, n = 12) after 93.9 ± 37.47 days, decreased the pediatric Crohn's disease activity index and simplified endoscopic score for Crohn's disease, and increased the biochemical remission, clinical remission, endoscopic remission, and endoscopic response rates; however, there was no statistical significance. Hormone exposure, perianal lesions, simplified endoscopic score for Crohn's disease, and TP levels before the first infliximab use affected the infliximab TC. Shortening the treatment interval can improve infliximab TC levels and clinical outcomes.

Impact of HLA-DQA1*05 Genotype in Immunogenicity and Failure to Treatment with Tumour Necrosis Factor-alpha Antagonists in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

HLA-DQA1*05 carriage has been associated with an increased risk of immunogenicity in patients with immune-mediated inflammatory diseases treated with tumour necrosis factor-alpha [TNF-a] antagonists. Results have shown an inconsistent association with a loss of response [LOR] in patients with inflammatory bowel disease [IBD], which could be modified when using proactive optimisation and association with immunomodulatory drugs. To define the association of HLA-DQA1*05 on anti-drug antibody development and loss of response [LOR] to anti-TNF-a in IBD. We searched MEDLINE, EMBASE, and SCOPUS, for the period up to August 2023, to identify studies reporting the risk of immunogenicity and/or LOR in IBD patients with HLA-DQA1*05 genotype. A total of 24 studies comprising 12 papers, 11 abstracts and one research letter, with a total of 5727 IBD patients, were included. In a meta-analysis of 10 studies [2984 patients; 41.9% with HLA-DQA1*05 genotype], HLA-DQA1*05 carriers had higher risk of immunogenicity compared with non-carriers (risk ratio, 1.54; 95% confidence interval [CI], 1.23 - 1.94; I2 = 62%) [low certainty evidence]. Lack of therapeutic drug monitoring [TDM] increased immunogenicity in the presence of risk human leukocyte antigen [HLA] [risk ratio 1.97; 95% CI, 1.35 - 2.88; I2 = 66%], whereas proactive TDM revoked this association [very low certainty of evidence]. A meta-analysis of six studies [765 patients] found that risk for secondary LOR was higher among HLA-DQA1*05 carriers [hazard ratio 2.21; 95% CI, 1.69 - 2.88; I2 = 0%] [very low certainty evidence], although definition and time to assessment varied widely among studies. HLA-DQA1*05 carriage may be associated with an increased risk of immunogenicity and secondary LOR in IBD patients treated with TNF-a antagonists.

Evaluation of Proactive Therapeutic Drug Monitoring Application in Infliximab Users in Ulcerative Colitis

Abstract Objective To evaluate the application of proactive pro-drug therapy (TDM) at week six in users of infliximab therapy in ulcerative colitis patients and to analyze the need for further disease optimization. Method This is a retrospective analysis that will be carried out simultaneously at the Hospital de Clínicas de Passo Fundo and at the Endoclin Diagnostic Center in the city of Passo Fundo, with secondary data collection between January 2020 and May 2022. The sample included patients from both sexes, regardless of age, who are being followed up in the services mentioned above, by signing the informed Free and Clarified Consent Term. Results 63.2% of patients required optimization of their treatment based on the serum level assessment at week six. Conclusion Proactive TDM performed at week six benefits patients in order to complete indications for treatment to avoid lack of drug response and complications from the disease.

P713 Proactive therapeutic infliximab monitoring during induction phase in inflammatory bowel disease

Abstract Background Therapeutic drug monitoring (TDM) of infliximab (IFX) in patients with Crohn’s disease (CD) and ulcerative colitis (UC) is increasingly used in clinical routine, although proactive TDM is still controversial. Nevertheless, disease activity and drug clearance are higher at the induction phase leading to an increased risk of inadequate drug exposure and treatment failure. The aim of the study was to evaluate the efficacy of the implementation of an early proactive TDM strategy, comparing clinical remission (CR) and biochemical remission (BR) at week 14 and 52, and endoscopic improvement (EI) between two groups. Methods Retrospective cohort study conducted in an Inflammatory Bowel Disease (IBD) unit of a tertiary care hospital. Biologic-naïve patients diagnosed of CD or UC who initiated IFX from 2019 to 2021 (p-TDM group) and from 2016 to 2019 (no-TDM group) were included. In the p-TDM group, proactive IFX trough levels and antidrug antibodies were measured since week 2 and dose adjustment since week 6 was performed using a previously validated population pharmacokinetic model (Fasanmade et al. Clinical Therapeutics 2011). In the no-TDM group, dose escalation was performed considering symptoms, blood, or stool results. CR was defined as Harvey-Bradshaw Index <5 in CD and partial Mayo clinic score <3 in UC. BR was stablished as fecal calprotectin (FCP) <150 mcg/g or c-reactive protein <0.5 mg/dL. EI was defined as lack of ulcerations in CD and Mayo endoscopic score 0-1 in UC. A combined variable to evaluate objective remission (OR) at week 52 was defined as: FCP <150 mcg/g or EI in UC, and EI or radiologic improvement (MRI) in CD. Moreover, surgery, hospitalization and treatment discontinuation rates were compared between both groups. Results 30 patients were included in each group: 13 UC, 16 CD and 1 IBD unclassified. There were no statistical differences in baseline characteristic between groups (table 1). Outcomes at week 14 and 52 are shown in table 2. At week 14, CR rate was significantly higher in p-TDM than in no-TDM (86.7% vs 56.7%, p=0.01). Although BR rate at week 14 was numerically higher in p-TDM, it did not achieve statistical significance (61.1% in p-TDM vs 50.0% in no-TDM, p=0.59). However, limitations in blood and stool collection were considerable at this timepoint. During first year, hospitalizations tend to be fewer in p-TDM group. There were no statistically differences in CR and BR or in EI between groups at week 52. Although OR rate was higher in p-TDM than in no-TDM, it did not reach statistical significance (60.9% vs 33.3%, p=0.06). Conclusion Proactive TDM during induction phase, especially in naïve patients, could be a useful tool to obtain optimal IFX trough levels and to classify correctly primary failure.

P528 Effectiveness, Safety and Incremental Costs of Proactive Therapeutic Drug Monitoring of Infliximab in a Prospective Cohort of Inflammatory Bowel Disease Patients

Abstract Background The use of infliximab (IFX) is limited by low treatment persistence. Proactive therapeutic drug monitoring (pTDM) has been shown to increase the treatment persistence in inflammatory bowel disease (IBD) patients but the real-life data evaluating effectiveness, safety and costs of this approach are scarce. Therefore, the aim of this study was to assess survival on treatment, safety and costs of pTDM of IFX in the treatment of IBD. Methods IBD patients who started IFX in a referral centre using pTDM between January 2018 and March 2021 were included. The main outcomes were treatment persistence, adverse events and incremental costs of pTDM. IFX trough levels were assessed in the week 14 and subsequently every six months by commercially available ELISA kit (Ridascreen R-Biopharm) and with the cut-off level of 3μg/ml . Costs related to the measurements of levels and the costs of intensified treatment were calculated. The costs of pTDM were compared with costs of a modelled cohort using reactive TDM (rTDM) based on the data from the same cohort. The model used arbitrarily determined intensification regimen to 5mg/kg of IFX every 4 weeks in case of pharmacokinetically determined clinical or endoscopic loss of response. The calculation was performed for the first year of treatment. Results Overall, 99 patients with IBD were included (58 men – 59%; mean age 39,96 years, minimum-maximum, 20-73 years; 64% patients with Crohn′s disease; mean disease duration 103 months, minimum – maximum, 8-402 months). The treatment was intensified in 57 patients (58%). Overall treatment survival using pTDM was 87% at 6 months, 77% at one year, 66% at two years and 60% at both, the third and fourth year of treatment. There were no differences between patients on conventional regimen vs. intensified regimen with regards to adverse events. The costs related to pTDM in this cohort of 99 patients were € 90 306,56 while the costs of the modelled cohort using rTDM were € 24 846,30. The overall incremental costs were thus € 65 460,26 with mean costs per patient for the first year of treatment of € 661,21. Conclusion Proactive TDM of IFX results in a steady 60% treatment persistence beyond the second year of treatment with no impact on the safety. In the context of this solid treatment persistence, the incremental costs related to proactive TDM seem negligible when considering the costs of alternative biologicals used in case of loss of response to IFX.

Impact of proactive of infliximab monitoring using the Bayesian approach in the maintenance phase in patients with inflammatory bowel disease

Background and objectivesThere is increasing evidence that proactive monitoring is useful in improving the control of inflammatory bowel disease, although it remains controversial. The aim of this study was to evaluate the efficacy of proactive TDM based on the Bayesian approach to optimise the IFX dose compared with the standard of care dosing in patients with IBD. MethodsRetrospective observational cohort of inflammatory bowel disease patients>18 years. Patients were classified into two groups according to the strategy used to optimise the dose of IFX: a standard therapy group (ST-group) with clinically based dose adjustment and therapeutic drug monitoring group (TDM-group), with estimation of pharmacokinetic parameters calculated by Bayesian prediction. ResultsA total of 153 patients were included. Of these, 75 were in the TDM-group. Clinical response at week 52 was evaluated in 114 patients. The proportion of patients who achieved clinical remission was higher in the TDM than in the ST-group (80.7% vs 61.4%, respectively, p=0.023). A total of 28 patients (24.6%) met the parameters for the composite variable ‘poor clinical outcome’ at week 52. The proportion of patients who reached this outcome was lower in the TDM-group than in the ST-group (12.3% vs 36.8%, respectively, p=0.002). ConclusionsProactive therapeutic drug monitoring using Bayesian approach is associated with higher secondary response and fewer long-term complications.

P395 Proactive Therapeutic Drug Monitoring May Reduce the Need for Combination Therapy in Inflammatory Bowel Disease Patients Treated with Infliximab

Abstract Background Combination therapy with an immunomodulator [IM] is recommended by ECCO guidelines for patients with moderate-to-severe inflammatory bowel disease (IBD) treated with infliximab [IFX]. Combination therapy reduce anti-drug antibody (ATI) formation. Maintenance of adequate trough IFX levels is also known to reduce ATI formation. Methods We hypothesised that the use of proactive TDM in patients receiving IFX monotherapy would result in equivalent therapy outcomes compared with patients receiving IFX in combination with an immunomodulator. A pilot study using proactive TDM was undertaken at our unit with IFX and ATI levels, assessed at trough, in all IBD patients receiving IFX. We retrospectively evaluated the outcome of proactive IFX TDM on IFX therapy outcome. Baseline demographics, IFX dosing schedules and use of concomitant immunomodulators were documented. The study primary endpoint was time to infliximab discontinuation in IFX monotherapy and combination therapy groups. Results 109 IBD patients receiving IFX with proactive TDM assessment were included. Median age, 36 years, 46% were female and, 36% UC., 37% and, 67% of patients were receiving IFX combination and monotherapy respectively. There was no significant difference in mean time to drug discontinuation between IFX combination and monotherapy groups, 2.33 [95% CI, 2.2–2.5] versus, 2.32 [95% CI, 2.0 –, 2.6] years respectively, p = 0.63. ATI concentrations [median] did not differ significantly between IFX combination and monotherapy groups, 2.9 AU/mL versus, 11.6 AU/mL, p = 0.54. In a multivariate analysis disease activity [p=0.005], low IFX levels [p=0.01] and elevated ATIs [p=0.001] were all independently associated with IFX discontinuation. There was no association between the use of IFX combination therapy and rates of IFX discontinuation, p=0.42. Conclusion Infliximab persistence, which is a proxy for successful therapy outcome, was similar in IFX monotherapy and combination therapy groups when proactive TDM was utilised. In the absence of concomitant immunomodulatory therapy, proactive TDM may improve IFX monotherapy outcomes, by maintaining higher IFX concentrations.

P467 Therapeutic drug monitoring of biologics in Inflammatory Bowel Disease: Nordic survey on implementation and barriers in clinical practice

Abstract Background Therapeutic drug monitoring (TDM) is a useful tool to optimise biologic treatments of patients with inflammatory bowel disease (IBD). Albeit broadly recommended by gastrointestinal societies, it is, however, currently unknown how TDM has been adopted and is being used in everyday clinical practice. The aim of the study was to investigate how TDM has been taken up by physicians including barriers for implementation. Methods A web-based survey on TDM was distributed to all gastroenterology consultants in the Nordic countries via national gastroenterology- and IBD societies. Results Out of 377 physicians responding, 297 handled IBD patients on biologic therapies and were thus eligible for inclusion (NO 118 (40%), DK 86 (29%), SE 50 (17%), FI 33 (11%), IS 10 (3%)). The vast majority were consultant gastroenterologists (n=252, 85%), 152 (51%) were employed at university hospitals, 136 (46%) at community hospitals, and 9 (3%) in private practice. Overall, 257 (87%) used TDM during biologic therapies; 231 (90%) used reactive TDM and 163 (63%) proactive TDM. Common indications were to improve efficacy (70%), aid treatment decisions (62%), improve safety (36%), and improve cost-effectiveness (32%). Notably, Danish physicians used TDM to a significantly lesser extent than all others (58% vs 98%; odds ratio (OR) 0.03 [95%CI 0.01- 0.09], p<0.001); in particular outside the capital region (OR 0.15 [0.05–0.46], p=0.001). Reactive TDM was applied both at primary (74%) and secondary treatment failure (99%) and predominantly for TNF-inhibitors (90–98%) (vedolizumab 63%, ustekinumab 46%). Proactive TDM was used by 80% during maintenance therapy and 56% during induction, and mostly for TNF-inhibitors (79–97%) (vedolizumab 70%, ustekinumab 54%). Proactive TDM was more commonly used in NO, SE, and FI (p<0.001), and by physicians managing >10 IBD patients per week (OR 2.71 [1.34–5.48], p=0.005), but was not associated with employment at university hospital, size of hospital catchment area, or seniority. Main barriers to the use of TDM were lack of guidelines (51%), long response time from the laboratory (49%), lack of knowledge regarding how to use and interpret test results (42%), costs (38%), and currently available evidence (31%). Among physicians using TDM, only 66% reported awareness of TDM guidelines or recommendations. Conclusion TDM, and in particular reactive TDM of TNF-inhibitors, has been broadly adopted into clinical practice in the Nordic countries to improve efficacy and assist treatment decisions. Across the Nordic countries, IBD physicians call for improved test response times and, notably, TDM guidelines detailing indications for TDM and interpretation of test results.

P478 The role of proactive measurement of adalimumab trough levels and antibodies to adalimumab in Greek patients with Inflammatory Bowel Disease

Abstract Background Therapeutic drug monitoring (TDM) of adalimumab trough levels (ADA-TLs) and antibodies to adalimumab (ADA-Abs) in patients with inflammatory bowel disease (IBD) is usually performed in a reactive setting when the disease flares. There is not enough evidence in favor of proactive TDM in these patients. Methods We aimed to evaluate the role of proactive measurement of ADA-TLs and ADA-Abs in IBD patients under treatment with adalimumab. Consecutive IBD patients on maintenance treatment with ADA, were included. ADA-TLs and Abs were measured using ELISA (Immunoguide, Aybayteche, Turkey) on serum samples drawn before ADA administration. At the same time serum biomarkers [Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), white blood cells (WBC), hemoglobin (Hgb), platelets (PLT)] as well as home-based fecal calprotectin (FC) ±3 months from blood sampling were assessed. After the measurements patients were followed and treatment changes made were recorded. Results A total of 52 patients receiving ADA maintenance therapy [48 CD, 4 UC, 31 males, mean age (±SD) 42.1±12.6 years, 8 on combination therapy with immunomodulators (IMMs), 23 under intensified dose (either 40mg/w or 80mg/2w)] were included. Median (IQR) time since ADA initiation was 31 (17.5–38.5) months and median value (IQR) of serum ADA-TLs was 8.24 μg/ml (3.32–10.02). Five out 52 (9.6%) were positive for ATIs (>3 AU/ml). Patients with positive Abs had median (IQR) ADA-TLs 0.41 μg/ml (0.10–0.71) statistically lower compared to those with negative Abs [8.86μg/ml (5.6–10.0) (p=0.0004)]. The correlations of ADA-TLs with disease characteristics, treatment and biomarkers in IBD patients are presented in Table 1. Elevated CRP was negatively associated with ADA-TLs. No other significant correlations were observed except a trend towards significance for body mass index (BMI) and ADA treatment duration (both p=0.09). After a median (IQR) follow up of 15 (11.5–16) months treatment optimization became necessary in 4 patients (8%) [adalimumab dose intensification in 2, change to a clinical trial medication in 1 and 1 underwent surgery] who initially had significantly lower ADA-TLs than the rest patients [median (IQR) ADA-TLs 0.51μg/ml (0.26-5.09-10.04) vs 8.62 (4.48–10.04); p=0.0362]. Conclusion Proactive measurement of ADA-TLs and Abs in patients under maintenance treatment with adalimumab may be worth using along with other parameters in the management of IBD patients. Additional long term research in larger populations focused on the optimal use of proactive TDM is needed.

P505 Early therapeutic drug monitoring after induction therapy with infliximab: correlation with intestinal ultrasound

Abstract Background Therapeutic drug monitoring (TDM) in patients receiving infliximab (IFX) has a role in assessing treatment and managing outcomes. Infliximab trough levels (ITL) have been suggested as useful markers for treatment optimization in Crohn’s disease (CD).Our goals were: to assess the relationship between ITL and transmural inflammation as assessed by intestinal ultrasound(IUS), following induction therapy with IFX; to assess which clinical, laboratorial or IUS parameters better predicted adequate levels by the end of induction therapy. Methods Prospective multicentric cohort study including patients with active CD starting IFX therapy. Clinical disease activity assessed using the Harvey-Bradshaw index (HBI), C-reactive protein (CRP), fecal calprotectin (FC) were measured at week 0 and after induction therapy (week 14). IUS was performed at week 0 and 14, bowel wall thickness (BWT) from the worst segment was selected for analysis. Ileocolonoscopy was performed at W0 and SES-CD was registered. ITL were measured at W14. Results We included 36 patients with CD (61% male; median age 30 years (range 16–73)). According to Montreal classification, most patients were A2 (69%), had ileocolonic disease (L3 56%) and an inflammatory phenotype (B1 58%).Perianal disease was present in 42%. Combination therapy was used in 61%. After induction therapy, 81% were in clinical remission (HBI <5) and 43% had laboratorial remission (normal CRP and FC). IUS response (decrease >25% in BWT) was observed in 24% of patients and remission (BWT normalization) in 11%. Median ITL were 4.3 (IQR 2.3–8.1) and 64% had ITL >3 ug/ml. There was a good negative correlation between ITL and SES-CD (r=-0.492, p=0.003). Adequate ITL were associated with lower HBI (1.5 vs 4.5, p=0.052), laboratory remission (61% vs 15%, p=0.014), lower BWT (4 vs 5.5 mm, p=0.009) and sonographic response (39% vs 0%, p=0.014) at W14. At the end of induction, we found a fair to good correlation between ITL and HBI (r=-0.430, p=0.009),CRP (r=-0,510, p=0.001), FC (r=-0.590, p=0.001) and BWT (R=-0.506, p=0.002). Receiver operating characteristic (ROC) curve analysis showed that FC at W14 had the largest area under the curve (AUC) in predicting adequate ITL (0.813 vs 0.716 vs 0.739 vs 0.772, p<0.05). Conclusion Patients with higher disease burden measured by ileocolonoscopy at baseline had lower ITL after induction. Adequate ITL were associated with laboratorial remission and sonographic response at the end of induction, with a good correlation with clinical, laboratorial and sonographic parameters. These findings suggest that adequate IFX levels after induction are associated with a better control of inflammation in IBD, so early proactive TDM during induction may be helpful in treatment management.

Therapeutic drug monitoring of anti-tumour necrosis factor-α agents in inflammatory bowel disease: Limits and improvements.

Since the publication of the American Gastroenterological Association's recommendations in 2017, there have been no significant changes in the biological monitoring recommendations in inflammatory bowel disease. Possible limitations are the lack of evidence to recommend proactive therapeutic drug monitoring (pTDM) over reactive TDM (rTDM), and the limited information about individualized dosing methods. This article aims to review the TDM strategy updates and the use of individualized dosing methods. For the analysis of the TDM strategies and individualized dosing method, a search was carried out in PubMed and Cochrane Central. In the TDM case, since August 2017. A total of 263 publications were found, but only 7 related to proactive TDM. Five of these publications directly compared pTDM vs rTDM and 2 were randomized clinical trials. Six studies found benefits of pTDM and 1 found no differences. Regarding the individualized dosing method, 229 distinct results were found. Population pharmacokinetics was the most widely used method to develop individual dosage models and to analyse the influence of factors on drug concentrations (albumin concentration, weight, presence of anti-drug antibodies etc). We have found no major changes in TDM strategies. There is a growing trend towards the use of pTDM because it has shown a longer duration of treatment response, lower rates of discontinuation and relapses. However, the available evidence is limited and of low quality. Despite the common use of population pharmacokinetic methods to analyse pharmacokinetic factors, they are not commonly used for personalized dosing.

Therapeutic Drug Monitoring of Tumor Necrosis Factor Antagonists in Crohn Disease: A Theoretical Construct to Apply Pharmacokinetics and Guidelines to Clinical Practice.

Therapeutic drug monitoring (TDM) is the measurement of drug and antidrug antibody concentrations in individuals to guide treatment decisions. In patients with Crohn disease (CD), TDM, used either reactively or proactively, is emerging as a valuable tool for optimization of tumor necrosis factor (TNF) antagonist therapy. Reactive TDM is carried out in response to treatment failure, whereas proactive TDM involves the periodic monitoring of patients responding to TNF antagonist therapy to allow treatment optimization. In patients with CD, most of the available data for TDM relate to the first-to-market TNF antagonist infliximab and, to a lesser extent, to adalimumab and certolizumab pegol. Several gastroenterology associations, including the American Gastroenterology Association, have endorsed the use of reactive TDM in patients with active CD. However, fewer recommendations currently exist for the use of proactive TDM, although several new prospective randomized controlled trials evaluating proactive TDM strategies have been published. In this review, the current evidence for reactive and proactive TDM is discussed, and a proactive treatment algorithm for certolizumab pegol based on previously published threshold concentrations is proposed.

Proactive TDM for Crohn's Disease Patients in Clinical Remission Under Anti-TNF Treatment: Current State of Evidence.

Proactive TDM for Crohn's Disease Patients in Clinical Remission Under Anti-TNF Treatment: Current State of Evidence.

Is it Time to be Active with Proactive TDM?

Is it Time to be Active with Proactive TDM?

Is Therapeutic Drug Monitoring for Anti-tumour Necrosis Factor Agents in Adults With Inflammatory Bowel Disease Ready for Standard of Care? A Systematic Review and Meta-analysis.

Using therapeutic drug monitoring [TDM] in adult patients with inflammatory bowel disease [IBD] remains controversial. We conducted a systematic review and meta-analysis to answer four clinical PICO [Population, Intervention, Comparator, Outcome] questions. We searched MEDLINE, Embase, Web of Science, and Cochrane Central from inception to June 30, 2019. Remission was defined by the manuscripts' definitions of clinical remission. Data were analysed using RevMan 5.3. Quality of evidence was assessed with GRADE methodology. We identified and screened 3365 abstracts and 11 articles. PICO 1 Reactive vs No TDM: six studies pooled showed 57.1% [257/450] failed to achieve remission following reactive TDM vs 44.7% [268/600] in the no TDM group (risk ratio [RR]: 1.14; 95% confidence interval [CI] 0.88-1.47). PICO 2 Proactive vs no TDM: five studies pooled showed 19.5% [75/384] failed to maintain remission in the proactive TDM group vs 33.4% [248/742] in the no TDM group [RR: 0.60; 95% CI 0.35-1.04]. PICO 3 Proactive vs Reactive TDM: two retrospective studies pooled showed 14.2% [26/183] failure to maintain remission in the proactive TDM group and 64.7% [119/184] in the reactive TDM group [RR: 0.22; 95% CI 0.15-0.32]. PICO 4 TDM [proactive/reactive] vs No TDM: we pooled 10 studies showing 39.7% [332/837] failed to achieve remission in the TDM [proactive/reactive] cohort vs 40.3% [428/1063] in the no TDM cohort [RR: 0.94; 95% CI 0.77-1.14]. Overall, the quality of evidence in each PICO was very low when using GRADE. This meta-analysis shows that data supporting use of TDM in adults are limited and of very low quality. Further well-designed randomized controlled trials are needed to determine the place of TDM in clinical practice.

P384 Lower infliximab trough levels are associated with higher bowel wall thickness in Crohn’s disease

Abstract Background Therapeutic drug monitoring (TDM) is currently used to optimise anti-TNFα therapy in Crohn’s disease, as higher infliximab trough levels (ITL) are associated with better rates of clinical remission and mucosal healing. Transmural healing is emerging as a potential target in Crohn′s disease, but whether there is any relation with ITL remains unclear. Here, we investigated the relation between ITL with bowel wall thickness (BWT) in patients with CD in maintenance therapy with IFX. Methods A retrospective cohort study of CD patients treated with IFX in mono or combination therapy. Patients were included if they had an available ITL during maintenance therapy and available entero-magnetic resonance or computerised tomography performed ±4 months. Transmural inflammation was defined as BWT ≥ 4 mm. Median BWT was measured in the most affected segment. An ROC curve was plotted to determine the best cut-off point of ITL to predict transmural inflammation. Mann–Whitney U-test, logistic regression and Spearman correlation were performed to assess the ITL relation with BWT. Results Twenty-nine patients were included (males 55.2%; mean age 39.6 ± 18 years; combo therapy 48.2%). According to the Montreal Classification, most patients were A2 (75.2%), with ileal (L1: 34.5%) or ileocolic disease (L3: 51.7%), and behaviour was: B1 41.4%, B2 24.1%, and B3 34.5%, with concomitant perianal disease in 37.9%. 82.2% were in clinical remission. The median IFX TL was 3.2 μg/ml (IQR 1.15–5.15) and median bowel wall thickness was 7 mm (IQR 4–9). 75.9% of patients had BWT > 4 mm. A BWT > 4 mm was associated with lower clinical remission rates (75% vs. 100%, p = 0.27) and higher C-reactive protein (0.31 vs. 0.14, p = 0.09), albeit not significantly. The area under the curve of ITL for bowel wall thickness was 0.70 (best cut-off value 1.8). Having ITL < 1.8 μg/ml was associated with higher median BWT (8.7 vs. 5.9 mm, p = 0.02) and was a predictive factor for transmural inflammation (OR 1.57, 95% CI [1.08–2.30], p = 0.02). BWT showed a fair correlation with ITL (r = −0.43, p = 0.02). Conclusion In our cohort of CD patients treated with infliximab (mono or combo therapy), lower infliximab trough levels were associated with higher bowel wall thickness, reflecting worse transmural inflammation. Proactive TDM could offer a possibility to improve BWT and reduce transmural inflammation.

Proactive Therapeutic Drug Monitoring of Adalimumab Is Associated With Better Long-term Outcomes Compared With Standard of Care in Patients With Inflammatory Bowel Disease.

Therapeutic drug monitoring [TDM] has proven to be effective for optimising anti-tumour necrosis factor [TNF] therapy in inflammatory bowel disease [IBD]. Nevertheless, the majority of data refer to infliximab and reactive testing or association studies. We aimed to compare the long-term outcome of patients with IBD who received at least one proactive TDM of adalimumab, with standard of care, defined as empirical dose escalation and/or reactive TDM. This was a multicentre retrospective cohort study. Patients on maintenance adalimumab therapy from June 2006 to December 2015 were eligible. We analysed time to treatment failure from start of adalimumab until the end of follow-up [July 2016]. Treatment failure was defined as drug discontinuation for secondary loss of response or serious adverse event or need for IBD-related surgery. Serum adalimumab concentrations and antibodies to adalimumab were measured using the Prometheus homogeneous mobility shift assay. A total of 382 patients with IBD [Crohn's disease, n = 311, 81%] were included and received either at least one proactive TDM [n = 53] or standard of care [empirical dose escalation, n = 279; reactive TDM, n = 50]. Patients were followed for a median of 3.1 years [interquartile range, 1.4-4.8 years]. Multiple Cox regression analyses showed that at least one proactive TDM was independently associated with a reduced risk for treatment failure (hazard ratio [HR]: 0.4; 95% confidence interval [CI]: 0.2-0.9; p = 0.022). This multicentre, retrospective cohort study reflecting real-life clinical practice provides the first evidence that proactive TDM of adalimumab may be associated with a lower risk of treatment failure compared with standard of care in patients with IBD.

Clinical Outcomes With Therapeutic Drug Monitoring in Inflammatory Bowel Disease: A Systematic Review With Meta-Analysis.

We undertook a systematic review and meta-analysis examining the effectiveness of therapeutic drug monitoring [TDM] to improve clinical outcomes in inflammatory bowel disease patients treated with anti-tumour necrosis factor alpha [anti-TNF] drugs. We searched MEDLINE, Epub Ahead of Print, EMBASE and Cochrane up to October 2017 for randomized trials [RCTs] and cohort studies comparing proactive or reactive TDM to each other or empiric care. Outcomes included clinical remission [primary], clinical relapse, endoscopic remission, anti-TNF response durability, cost and adverse events [secondary]. Pooled odds ratios and mean differences were calculated. The search identified nine studies [three RCTs, six observational], focused on infliximab maintenance therapy in adults. Neither proactive nor reactive TDM was associated with superior clinical remission rates compared to empiric dose optimization. However, evidence of a cost benefit, particularly for reactive TDM vs empiric care, was identified. In several studies, TDM, particularly proactive TDM, was associated with favourable outcomes related to durability of anti-TNF response, such as lower drug discontinuation rates compared to empiric care and reactive TDM, and lower relapse rates compared to empiric care. No consistent benefit was found for endoscopic or surgical outcomes. The existing limited evidence does not support an association between any TDM strategy and superior clinical remission rates but does support a cost savings benefit [particularly for reactive TDM] and suggests a potential benefit for anti-TNF durability [particularly proactive TDM]. Additional, longer-term studies are needed, particularly to further investigate proactive TDM, and to generate data on other anti-TNF agents, the induction period and paediatric populations.

Proactively Optimized Infliximab Monotherapy Is as Effective as Combination Therapy in IBD.

Infliximab (IFX) discontinuation is not uncommon during the first year of treatment due to inadequate drug concentrations and anti-IFX antibodies (ATI). Both combination therapy and proactive therapeutic drug monitoring (pTDM) are used to decrease ATI and increase IFX durability. We proposed that monotherapy (Mono) is as effective as combination therapy (Combo) if the first maintenance infusion is dosed based on week 10 pTDM. In a retrospective cohort of 83 patients with inflammatory bowel disease (IBD), we examined the frequency of IFX discontinuation, ATI, infusion reactions, and IFX concentrations during the first year of treatment in patients receiving week 10 pTDM-guided IFX monotherapy (Mono pTDM; n = 16) compared with patients on mono (n = 32) or combination therapy (n = 35) in whom TDM was introduced at or after week 14, per standard of care (SOC). The frequency of IFX discontinuation was lower with Mono pTDM compared with Mono SOC (P = 0.04) but did not differ with Combo SOC (P = 1). At first TDM, no patient in the pTDM strategy had ATI, vs 41% in Mono SOC (P = 0.002) and 6% in Combo SOC (P = 1). Of the 13 subjects with ATI in Mono SOC, 7 (47%) had ATI already at week 14. IFX trough concentrations with Mono pTDM were higher during maintenance compared with Mono SOC (9.5 vs 6.4 µg/mL, P = 0.04) but not Combo SOC. Infliximab durability did not differ between patients on IFX monotherapy dosed based on p-TDM and patients receiving combination therapy. In the absence of concomitant immunosuppression, proactive TDM may improve IFX durability by maintaining higher IFX concentrations entering into maintenance. Further studies are needed to confirm our findings.