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Background The optimal use of infliximab depends on the measurement of trough levels with subsequent appropriate dose adjustment. With the introduction of biosimilars, it is important to demonstrate that the biosimilar behaves similarly in the assay utilized as the originator-infliximab, for which the assays were developed. In this study, the authors aimed to compare the concentrations of SB2-infliximab (Renflexis®) with that of originator-infliximab (Remicade®) when added to serum from healthy subjects and those with inflammatory bowel disease (IBD) when measured by commonly employed commercial assays. Methods Sera from two healthy controls, two patients with ulcerative colitis (one with quiescent disease, one with active disease), and two patients with Crohn's disease (one with quiescent disease, one with active disease) were spiked with SB2-infliximab or originator-infliximab at 0-20 μg/mL. Concentrations were measured using three commonly used assay kits (Lisa-Tracker®, Shikari Q-Inflix®, Promonitor IFX®) and one rapid test (Quantum Blue®). The results were compared using Bland-Altman techniques. Results Close agreement was observed between measured concentrations for all assays, irrespective of the origin of the serum. Limits of agreement varied between at worst -0.302 and 0.465 μg/mL, with the mean difference between the molecules being at worst 0.04 μg/mL (95% confidence intervals -0.011, 0.093). Conclusions The originator and SB-2 biosimilar-infliximab behaved similarly in several currently utilized assays in terms of their concentrations in biological fluids. Clinicians can be confident that therapeutic drug monitoring using platforms designed and developed for the originator-infliximab can be applied to SB-2-infliximab.

CT-P13 is the first subcutaneous infliximab molecule approved for the management of inflammatory bowel disease (IBD). Compared to intravenous therapy, SC infliximab offers a range of practical, micro- and macroeconomic advantages. Data from the rheumatological literature suggest that subcutaneous CT-P13 may lead to superior disease outcomes in comparison to intravenous infliximab. Existing studies in IBD have focussed on pharmacokinetic comparisons and are inadequately powered to evaluate efficacy and safety differences between the two modes of administration. However, emerging clinical trial and real-world data support comparable clinical, biochemical, endoscopic and safety outcomes between subcutaneous and intravenous infliximab in both luminal Crohn’s disease and ulcerative colitis. Across the available data, subcutaneous CT-P13 provides relative pharmacokinetic stability and higher trough drug levels when compared to intravenous administration. The clinical impact of this observation on immunogenicity and treatment persistence is yet to be determined. Trough levels between the two methods of administration should not be compared in isolation as any subcutaneous advantage must be considered in the context of comparable total drug exposure and the theoretical disadvantage of lower peak concentrations compared to intravenous therapy. Furthermore, target drug levels for subcutaneous CT-P13 associated with remission are not known. In this review, we present the available literature surrounding the pharmacokinetics of subcutaneous CT-P13 in the context of therapeutic drug monitoring and highlight the potential significance of these observations on the clinical management of patients with IBD.

Therapeutic monitoring of infliximab is limited by the time lag between drug-level measurement and dose adjustment, along with the cost of dose escalation. Strategies for dose reduction in stable patients on maintenance infliximab at supratherapeutic levels are uncertain. This study determined the feasibility of a pharmacist-driven strategy for immediate dose adjustment using a sliding scale at the point of care in stable patients with inflammatory bowel disease on maintenance therapy.Adult patients with stable disease undergoing maintenance therapy with infliximab infusions, 5 mg/kg every 8 weeks, were prospectively studied. Trough drug levels were assessed by a rapid assay (and later by ELISA) at all infusions for up to 12 months with immediate but quantitatively small dose adjustment according to a sliding scale targeting a therapeutic range of 3-7 µg/mL. Disease activity was assessed both clinically and biochemically.The rapid assay and ELISA detected similar infliximab levels, and the strategy added approximately 30 min to the duration of infusion events. Only 20% of 48 patients (77% with Crohn's disease) had baseline trough infliximab concentrations within the therapeutic range. This value increased threefold after 24 and 48 weeks of interventions. One in two patients had baseline supratherapeutic levels and most were brought into the therapeutic range without discernible impact on disease activity by one dose adjustment, but two or three adjustments were generally needed for 29% of patients with sub-therapeutic levels. Overall, drug costs were reduced by 4%.Immediate dose adjustment following infliximab rapid assay performed by a pharmacist using a sliding scale is a feasible strategy. Supratherapeutic infliximab levels can be safely and quickly brought into the therapeutic range using small dose adjustments without impacting disease activity, offsetting (at least partly) costs associated with dose escalation.

Data on outcomes following de-escalation of intensified anti-TNF therapy in inflammatory bowel disease (IBD) are limited and concerns about relapse limit willingness to de-escalate. To evaluate rates of successful de-escalation at 12 months and to determine factors that may predict success. Single-centre experience of IBD patients that were de-escalated following deep remission on dose-intensified infliximab (IFX) or adalimumab (ADA) for secondary loss of response. Patients were classified as ‘successes’ if remaining on reduced anti-TNF or ‘failures’ if requiring re-escalation, steroids, surgery or enrolment into a clinical trial at 12 months. Patient demographics, disease characteristics, biomarkers (faecal calprotectin, C-reactive protein, albumin) and anti-TNF drug levels were collected 6-monthly. Of 25 patients (20 CD, 5 UC), 16 (64%) were successes 12 months post-de-escalation. Median time to failure was 6 months. Six of the nine failures required anti-TNF re-escalation and three entered a clinical trial. Re-escalation recaptured response in all six patients. There was no significant difference in baseline biomarker activity between the two groups. There was no difference in infliximab levels between successes and failures at the time of de-escalation (5.5 vs. 5.3, p = 0.63) as well as 6 months (3.1 vs. 4.6, p = 0.95) and 12 months (3.2 vs. 4.5, p = 0.58) post-de-escalation. Nearly two-thirds of patients remained on reduced anti-TNF dosing 12 months after de-escalation. All patients who failed de-escalation were recaptured after dose re-escalation. De-escalation with close monitoring may be considered in patients on intensified anti-TNF therapy in sustained remission.

Background There is considerable interest in improving the education and care of women with inflammatory bowel disease (IBD) to improve pregnancy outcomes. Despite increased awareness, not all women with IBD have access to pregnancy-related education and the quality of counseling is variable. We aimed to assess the effectiveness of a simple educational intervention for improving pregnancy-related knowledge and to evaluate the effect of education on patient outcomes including anxiety, depression, and quality of life in women with IBD. Methods This prospective study of women with IBD who were pregnant or planning a pregnancy evaluated the effectiveness of a single gastroenterologist-led educational intervention in improving pregnancy-related knowledge, measured using the Crohn’s and Colitis Pregnancy Knowledge score 1 month postintervention. Secondary outcomes included the effect on anxiety and depression, quality of life, medication adherence, and patient satisfaction. Results One hundred women with IBD were recruited. Fifty percent were pregnant at the time of the intervention. Baseline knowledge scores were similar independent of the patients’ pregnancy status or whether they had previously received counseling from their gastroenterologist. Median Crohn’s and Colitis Pregnancy Knowledge scores postintervention (n = 82) were higher than preintervention scores (14/17 vs 10/17; P < 0.001). In addition, 32% of patients had poor knowledge at baseline (score ≤7/17), compared to only 5% after the intervention (P < 0.001). There was a significant improvement in total anxiety and depression and quality of life scores postintervention. Medication adherence and patient satisfaction were excellent. Conclusions Uptake of this gastroenterologist-led educational intervention has the potential to improve pregnancy knowledge, promote medication adherence, and enhance quality of life for women with IBD globally.

BACKGROUND AND AIM Limited data are available on the effects of fermentable fiber in altering intestinal pH and transit to predict efficacy-based delivery profiles of pH-dependent mesalamine coatings in ulcerative colitis (UC). This study aimed to examine regional pH and transit after acute changes in fermentable fiber intake in quiescent UC patients and their effects on drug release systems. METHODS In a randomized, double-blind study, 18 patients with quiescent UC and 10 healthy controls were supplied meals high (13 g) or low (≤ 2 g) in fermentable fiber and subsequently ingested a wireless pH-motility capsule. After a ≥ 3-day washout, they crossed over to the other diet. Measurements of intestinal pH and transit were used to predict drug release for the various pH-dependent coatings. RESULTS Increasing fermentable fiber intake lowered overall (median 6.2 [6.1-6.7] vs low: 6.9 [range or interquartile range: 6.4-7.4]; P = 0.01) and distal pH (7.8 [7.3-8.1] vs 8.2 [8.0-8.5]; P = 0.04) in controls. In UC patients, only cecal pH was decreased (high: 5.1 [4.8-5.5] vs low: 5.5 [5.3-5.7]; P

The COVID‐19 pandemic, caused by the novel coronavirus SARS‐CoV‐2, has emerged as a public health emergency and challenged healthcare systems globally. In a minority of patients, SARS‐CoV‐2 manifests with a severe acute respiratory illness and currently there are insufficient data regarding the virulence of COVID‐19 in inflammatory bowel disease patients taking immunosuppressive therapy. This review aims to summarise the current literature and provide guidance on the management of inflammatory bowel disease (IBD) patients in the context of the COVID‐19 pandemic in the Australasian setting.

BACKGROUND Virtual clinics represent a novel model of care in inflammatory bowel disease. Their effectiveness in promoting high quality use of biologic therapy and facilitating a treat-to-target approach is unknown. AIM To evaluate clinical and process-driven outcomes in a virtual clinic compared to standard outpatient care amongst patients receiving intensified anti-TNF therapy for secondary loss of response. METHODS We performed a retrospective multi-centre, parallel, observational cohort study of Crohn's disease patients receiving intensified anti-TNF therapy for secondary loss of response. Objective assessments of disease activity and anti-TNF trough levels at secondary loss of response and during subsequent 6-month semesters, were compared longitudinally between virtual clinic and standard outpatient care cohorts. The primary endpoint was treatment success, with appropriateness of dose intensification, tight disease monitoring and treatment de-escalation representing secondary outcomes. RESULTS Of 149 patients with similar baseline characteristics, 69 were managed via a virtual clinic and 80 via standard outpatient care. There were higher rates of treatment success in the virtual clinic cohort (60.9 vs 35.0%, P

Background Adalimumab is administered via a pre-filled syringe or spring-loaded pen. In a previous study in Crohn’s disease, higher drug levels were observed in syringe users. The aim of this study was to evaluate the impact of delivery device on adalimumab drug levels in patients with Crohn’s disease. Methods Consecutive Crohn’s disease patients treated with maintenance adalimumab [40 mg fortnightly] were recruited from five centres. The first recorded drug level with matched clinical and biochemical markers of disease activity was compared between pen and syringe users. Results Of 218 patients, 64% used pen, with a median faecal calprotectin 110 μg/g and serum C-reactive protein 4 mg/L. In comparison to pen, syringe users had higher albumin [39 vs 42 g/L; p = 0.016], lower Harvey-Bradshaw Index [2 vs 1; p = 0.017], and higher rates of concomitant immunomodulation [54% vs 71%; p = 0.014]. Drug levels were equivalent between pen and syringe users [median 5.3 vs 5.2 μg/ml; p = 0.584], even after controlling for disease activity and immunomodulation. Syringe users at Alfred Health had higher drug levels than pen [6.1 vs 4.5 μg/ml; p = 0.039]; a greater proportion achieved therapeutic levels [75% vs 44%; p = 0.045]. A higher proportion of pen users from Saint-Étienne had therapeutic levels [79% vs 42%; p = 0.027], yet no significant difference in drug levels [7.9 vs 4.5 μg/ml; p = 0.119]. Conclusions Delivery device does not appear to significantly affect adalimumab drug levels. Given differences between study sites, studies evaluating administration education and technique are warranted.

Background The current COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2), has drastically impacted societies worldwide. Vaccination against SARS-CoV-2 is expected to play a key role in the management of this pandemic. Inflammatory conditions such as inflammatory bowel disease (IBD) often require chronic immunosuppression, which can influence vaccination decisions. Aim This review article aims to describe the most commonly available SARS-CoV-2 vaccination vectors globally, assess the potential benefits and concerns of vaccination in the setting of immunosuppression and provide medical practitioners with guidance regarding SARS-CoV-2 vaccination in patients with IBD. Methods All published Phase 1/2 and/or Phase 3 and 4 studies of SARS-CoV-2 vaccinations were reviewed. IBD international society position papers, safety registry data and media releases from pharmaceutical companies as well as administrative and medicines regulatory bodies were included. General vaccine evidence and recommendations in immunosuppressed patients were reviewed for context. Society position papers regarding special populations, including immunosuppressed, pregnant and breast-feeding individuals were also evaluated. Literature was critically analysed and summarised. Results Vaccination against SARS-CoV-2 is supported in all adult, non-pregnant individuals with IBD without contraindication. There is the potential that vaccine efficacy may be reduced in those who are immunosuppressed; however, medical therapies should not be withheld in order to undertake vaccination. SARS-CoV-2 vaccines are safe, but data specific to immunosuppressed patients remain limited. Conclusions SARS-CoV-2 vaccination is essential from both an individual patient and community perspective and should be encouraged in patients with IBD. Recommendations must be continually updated as real-world and trial-based evidence emerges.

Background: The impact of pregnancy on levels of biologic agents in patients with IBD is undefined and time to elimination in vedolizumab-exposed infants is unknown. Aims: To determine the effect of pregnancy on infliximab, adalimumab and vedolizumab levels and to study infant vedolizumab clearance. Methods: In a prospective observational study, maternal drug levels were measured pre-conception, in each trimester, at delivery and postpartum. The association between drug levels and gestation in weeks was assessed using generalised estimating equation modelling. Infant vedolizumab levels were performed at birth (cord blood), 6 weeks and 3 months or until undetectable. Results: We included 50 IBD patients (23 on infliximab, 15 on adalimumab and 12 on vedolizumab) with at least two intrapartum observations, plus 5 patients on vedolizumab with only mother and baby samples at delivery. Modelling showed no change in adalimumab levels, an increase in infliximab levels of 0.16 (95% CI 0.08-0.24) µg/L/week (P < 0.001) and a decrease of 0.18 (95% CI: −0.33 to −0.02) µg/L/week (P = 0.03) for vedolizumab. In 17 mother-baby pairs, median infant vedolizumab levels at birth were lower than maternal levels (P < 0.05) with an infant:maternal ratio of 0.7 (IQR 0.5-0.9). Vedolizumab was undetectable between 15 and 16 weeks of age in all 12 infants completing follow-up testing. Conclusions: During pregnancy, adalimumab levels remain stable, while infliximab levels increase and vedolizumab levels decrease. However, the increments were small suggesting that intrapartum therapeutic drug monitoring and dose adjustment are not indicated. Unlike infliximab and adalimumab, infant vedolizumab levels are lower in cord blood than in mothers and appear to clear rapidly.

Data on outcomes following de-escalation of intensified anti-TNF therapy in inflammatory bowel disease (IBD) are limited and concerns about relapse limit willingness to de-escalate.To evaluate rates of successful de-escalation at 12 months and to determine factors that may predict success.Single-centre experience of IBD patients that were de-escalated following deep remission on dose-intensified infliximab (IFX) or adalimumab (ADA) for secondary loss of response. Patients were classified as 'successes' if remaining on reduced anti-TNF or 'failures' if requiring re-escalation, steroids, surgery or enrolment into a clinical trial at 12 months. Patient demographics, disease characteristics, biomarkers (faecal calprotectin, C-reactive protein, albumin) and anti-TNF drug levels were collected 6-monthly.Of 25 patients (20 CD, 5 UC), 16 (64%) were successes 12 months post-de-escalation. Median time to failure was 6 months. Six of the nine failures required anti-TNF re-escalation and three entered a clinical trial. Re-escalation recaptured response in all six patients. There was no significant difference in baseline biomarker activity between the two groups. There was no difference in infliximab levels between successes and failures at the time of de-escalation (5.5 vs. 5.3, p = 0.63) as well as 6 months (3.1 vs. 4.6, p = 0.95) and 12 months (3.2 vs. 4.5, p = 0.58) post-de-escalation.Nearly two-thirds of patients remained on reduced anti-TNF dosing 12 months after de-escalation. All patients who failed de-escalation were recaptured after dose re-escalation. De-escalation with close monitoring may be considered in patients on intensified anti-TNF therapy in sustained remission.

Background and aim Combining therapy with a thiopurine is favored when commencing infliximab in Crohn's disease; however, the optimal 6-thioguanine nucleotide (TGN) level and how long to continue thiopurines after induction are uncertain. We aimed to compare outcomes after induction and during maintenance in combination therapy versus infliximab monotherapy in Crohn's and to examine whether TGN levels were associated with outcomes. Methods Crohn's patients induced with infliximab with or without concomitant thiopurines were retrospectively identified. Response to induction and clinical outcomes in subsequent 6-month maintenance semesters were analyzed. A TGN level ≥235 pmol/8 × 108 red blood cells was considered therapeutic. Results In 89 patients, response to induction was higher in combination therapy than monotherapy (74 vs 47%, P = 0.04). This benefit was only seen in patients with a therapeutic TGN (odds ratio 3.72, confidence interval 1.07-13.0, P = 0.04). Combination therapy during induction yielded a three times longer time to subsequent need for treatment escalation or treatment failure compared with monotherapy (29 vs 9 months, P = 0.01), with both therapeutic and subtherapeutic TGNs independent predictors on multivariate analysis. Among 370 semesters, there was no difference in outcomes between combination therapy and monotherapy (P = 0.42), nor when combination semesters were stratified by therapeutic versus subtherapeutic TGN (P = 0.56). In semester 1 only, a significantly higher remission rate was observed with therapeutic compared with subtherapeutic TGN (76% vs 33%, P = 0.02). Conclusions Combination therapy dosed with an optimized thiopurine was superior to infliximab monotherapy for induction of response, durability of response, and clinical outcomes in the first 6 months following induction. Thereafter, combination therapy yielded no clinical advantage, supporting consideration of thiopurine withdrawal on a case-by-case basis.

BACKGROUND The benefit of concomitant immunomodulation with adalimumab (ADA) in Crohn's disease is poorly understood. We aimed to compare ADA monotherapy with combination therapy with thiopurines, stratified by thioguanine nucleotides (TGNs). METHODS Retrospective observational study of ADA induction and maintenance. Thiopurines were classified according to TGNs (>235 pmol/8 × 10 red blood cell therapeutic). RESULTS At induction, response was more frequent in combination than ADA monotherapy (83% versus 61%, P = 0.02) and with therapeutic compared with subtherapeutic TGNs (87% versus 70% P = 0.011). Among 280 maintenance semesters in 91 patients, remission was higher with combination than monotherapy (81% versus 60%, P < 0.0001) and therapeutic versus subtherapeutic TGNs (85% versus 58%, P = 0.004). Therapeutic TGN (odds ratio [OR] 4.32, 95% CI, 1.41-13.29, P = 0.01) and albumin (OR 1.09, 95% CI, 1.01-1.18, P = 0.03) were predictors of response to induction. Therapeutic TGN (OR 3.71, 95% CI, 1.87-7.34, P < 0.0001) and ileal disease (OR 0.21, 95% CI, 0.08-0.57, P = 0.002) were predictors of remission semesters. Concomitant immunomodulation at induction was associated with longer time to failure (69 versus 36 months, P = 0.009). Therapeutic TGN at induction (P = 0.03) and male sex (P = 0.026) were associated with time to failure. CONCLUSIONS Combination therapy was superior to ADA monotherapy for induction and during maintenance. This benefit was increased further when thiopurines resulted in therapeutic TGNs. Early use of adequately dosed thiopurines (≥3 months before starting ADA) was associated with improved clinical outcomes.

SummaryBackground Whether therapeutic drug monitoring for adalimumab needs to be performed at trough has not been defined. Aim To determine intra-patient adalimumab drug-level variation and to identify modulating patient and disease factors. Methods In this prospective observational study, adult patients with Crohn's disease established on maintenance adalimumab had drug levels measured repeatedly according to pre-defined schedules (visit 1: day 4–6, visit 2: day 7–9, trough: day 13–14) across two consecutive fortnightly cycles. Disease activity was assessed using Harvey–Bradshaw Index, C-reactive protein and faecal calprotectin. For this analysis, trough levels ≥4.9 μg/mL were considered therapeutic. Results Nineteen patients underwent 111 evaluations. Mean intra-patient drug levels from paired visits between cycles did not differ (visit1 cycle1: 4.81, cycle2: 5.21 μg/mL, P = 0.24, visit2 cycle1: 4.86, cycle2: 4.82, P = 0.91 and trough cycle1: 3.95, cycle2: 3.95, P = 0.99), irrespective of disease activity. Drug levels were stable over the first 9 days (visit 1–2), but declined to trough by a mean 1.06 and 0.89 μg/mL between visit 1 or 2, respectively (P < 0.001). Models using nontemporal factors (smoking, syringe delivery device) and levels at earlier visits accounted for 66–80% of the variance in trough levels. On receiver-operating curve analysis, thresholds identified in the first 9 days that predicted a therapeutic trough level were similar to the trough threshold itself, with high sensitivity but modest specificity. Conclusion While therapeutic drug monitoring should be performed at trough, a drug level ≥4.9 μg/mL obtained during the first 9 days predicts a therapeutic trough drug level with reasonable confidence.

Background Evidence supporting therapeutic drug monitoring with adalimumab (ADA) in Crohn’s disease (CD) is not as strong as for infliximab. Data examining whether changes in ADA drug exposure after dose intensification are associated with outcomes are lacking. We aimed to explore associations between ADA drug level exposure at loss of response and then at 6 and 12 months and compare these to short term clinical outcomes. Methods Retrospective study of adult CD patients who underwent ADA intensification to weekly dosing for secondary loss of response at three tertiary centres between 2013 and 2018. We compared trough ADA drug levels using a drug sensitive ELISA at loss of response and at 6 and 12 months after intensification with paired rates of clinical remission (Harvey Bradshaw Index Results In total, 133 CD patients were included; median disease duration 8 years (IQR 4–17), 51% were biologic-exposed and 49% received concomitant immunomodulation. Rates of clinical remission, objective remission and ADA failure were 73.0%, 37.4% and 25.0% at 6 months and 65.8%, 34.0% and 42.8% at 12 months, respectively. Drug levels measured at secondary loss of response did not discriminate between subsequent responders and non-responders; however increases in drug levels at 6 and 12 months were associated with improved outcomes at these time points (Figure 1). ROC analysis demonstrated that ADA drug levels 6 months after intensification > 8.9, 9.6 and 8.9 µg/ml were associated with clinical remission, objective remission and ADA non-failure respectively. Similar results were demonstrated with ADA drug levels at 12 months after dose intensification (Figure 1). Conclusion ADA drug levels at loss of response are not associated with subsequent 6 or 12 month outcomes. However, measurement of subsequent ADA drug levels at 6 and 12 months post escalation demonstrates that higher levels (with a target threshold between 7.7–10.9μg/ml) were associated with favourable outcomes. This study suggests that performing TDM subsequent to dose escalation of ADA has a role in predicting outcomes. Further, prospective studies dosing to target ADA drug levels are therefore needed.

Background Differentiating between infectious gastroenteritis and a flare of inflammatory bowel disease (IBD) can be difficult. Small studies have shown that thrombocytosis may not occur in infectious gastroenteritis. We aimed to determine whether thrombocytosis is a reliable biomarker in distinguishing between these two diagnoses in patients presenting with diarrhoea. Methods A retrospective cohort study was conducted at a tertiary referral IBD centre. From January 2000 and December 2018, patients admitted with acute diarrhoea were included. Inclusion criteria were infective gastroenteritis, IBD flare or both. IBD diagnosis was confirmed by standard clinical, radiological and histopathological criteria. Clinical and biochemical parameters were collected. Results There were 351 infectious and 506 IBD flare cases. Among these 216 (42.8%) had Crohn’s disease, 276 (54.7%) ulcerative colitis, and 13(2.6%) had IBD-unclassified. Table 1 summarises the main results. Those with acute IBD flare had a longer duration of diarrhoea, bloody diarrhoea, lower albumin and anaemia (p < 0.05 for all comparisons). Patients with infectious diarrhoea were more likely to be older, female, have vomiting and fever and leucocytosis (p < 0.05 for all comparisons). Median platelet count was higher in patients with IBD flares, 334 vs. 220 (p < 0.001) and persisted on multivariate analysis (p < 0.001, OR1.45). On multivariate analysis, other significant associations for IBD flare were age (OR.85, p < 0.001) female sex (OR.23, p < 0.110), blood in faeces (OR 5.98, p < 0.001) vomiting (OR .17, p < 0.001) and albumin (OR.83, p = 0.02). A sub-analysis compared patients with known IBD and infectious gastroenteritis with an identified pathogen (n = 47), with those with an IBD flare alone showed no significant difference in platelet count between groups (419 vs. 465, respectively, p = 0.17). Conclusion Our study shows significant differences between clinical and biological markers in patients with acute IBD flares compared with those with infectious gastroenteritis. In particular, thrombocytosis occurs in IBD flares but not in infectious gastroenteritis. This biomarker can be used to differentiate between these diagnoses and guide management.

Biologic therapies have revolutionized the management of inflammatory bowel disease [IBD], but primary and secondary non-responses occur in a significant proportion of patients. Therapeutic drug monitoring [TDM] now has an established role in the treatment algorithm for managing secondary loss of response to anti-tumour necrosis factor [anti-TNF] agents during maintenance therapy. Data to support the use of TDM in the management of secondary loss of response to vedolizumab and ustekinumab are emerging. The potential to prevent primary non-response to biologic agents during induction is of equal, and potentially greater, clinical importance. Again, most data supporting the use of ‘proactive' TDM during induction pertains to the use of anti-TNF agents, but signals of efficacy for the use of TDM during induction with other biologic classes are now appearing. This review aims to summarize data on the use of TDM during induction to prevent pharmacokinetic primary non-response to all three classes of biologic therapy currently available for the treatment of IBD.

Background Clinical application of therapeutic drug monitoring (TDM) to optimise anti-TNF therapies in patients with IBD depends upon target ranges. Aims To review methodology used to determine therapeutic ranges and critically compare and contrast its application to infliximab and adalimumab. Methods A systematic review was performed, and relevant literature was summarised and critically examined. Results Upper limits of the therapeutic range are determined by toxicity, a plateau response and cost. Lower limits are determined by optimal concentration on the target of action in vitro and/or in vivo, or by correlation of drug levels with clinical efficacy using area-under-receiver-operator-curve (AUROC) analysis. In 43 studies, there were huge variations in time at which infliximab and adalimumab levels were measured, the end-points used (clinical remission to mucosal healing), the clinical setting (active disease vs maintenance phase) and the reason for TDM (proactive vs reactive). In the maintenance phase for infliximab, lower trough limits 2.8-5.7 µg/mL are reported depending upon end-points used, with consistent AUROC 0.68-0.77. Adalimumab TDM targets are even less consistent with a lower limit 5.9-11.8 µg/mL (AUROC 0.66-0.83) in some studies, but no cut-off can be identified that is significantly associated with outcome in others, related to inherent pharmacokinetic and pharmacodynamic differences, and heterogeneity of study design. Conclusions Evidence for exposure-response relationship is stronger for infliximab than adalimumab. Due to heterogeneity in settings for drug level measurements, therapeutic ranges vary. These factors need to be taken into account when interpreting the evidence and extending this to therapeutic strategies for IBD patients.

Background Virtual clinics (VC) represent a novel model-of-care which promote quality use of biologics and facilitate a treat-to-target (T2T) approach. We aimed to evaluate the clinical and process-driven outcomes of intensified anti-TNF therapy for secondary loss of response (SLoR) in a VC compared with standard outpatient care (SoC). Methods A retrospective multicenter, parallel observational cohort study of patients with Crohn’s disease (CD) who underwent anti-TNF dose intensification to address SLoR with up to 2-years of follow-up was undertaken. Objective assessments of disease activity and anti-TNF trough levels at SLoR then during subsequent 6-month semesters were compared longitudinally between VC and SoC groups. ‘Anti-TNF escalation success’ was the primary endpoint, defined as achieved when two consecutive 6-month semesters of objective assessment demonstrated inactive disease. Dose intensification was defined as ‘appropriate’ if there was both objective evidence of disease activity, plus anti-TNF trough levels at or below the lower limit of the therapeutic range prior to intensification. ‘Treatment escalation failure’ was defined by the occurrence of one or more of biologic switching, discontinuation or further intensification; recommencement of corticosteroids, or IBD-related surgery. Results 149 patients (69 VC vs. 80 SoC) underwent infliximab (n = 94) or adalimumab (n = 55) dose intensification with similar baseline patient, disease and treatment characteristics between cohorts. The median duration of follow-up post dose-intensification was 1.9 and 1.5 years for the SoC and VC cohorts respectively (p = 0.37). There were higher rates of appropriate dose intensification (82.6 vs. 40.0%, p < 0.01) across the VC cohort. Higher proportions of anti-TNF escalation success (60.9 v 35.0%, p < 0.01), biomarker remission (i.e., C-Reactive Protein ( Conclusion This study favoured a VC-led model of care over standard outpatient-based IBD care in facilitating an effective T2T approach to CD management. A VC model of care improved quality use of intensified anti-TNF therapy through processes that promoted appropriate dose intensification and encouraged more frequent anti-TNF dose de-escalation. Moreover, tight semester-based monitoring using a T2T-based strategy facilitated by the VC was associated with improved treatment outcomes.

The introduction of vedolizumab, a lymphocyte adhesion inhibitor, has expanded the relatively limited therapeutic armamentarium available for Crohn’s disease and ulcerative colitis. Despite its effectiveness, both primary nonresponse and secondary loss of response to vedolizumab do occur, as is observed with the use of anti-tumour necrosis factor (TNF) therapy. Further, in a proportion, onset of efficacy may be relatively slow. A large body of data support an exposure–response relationship with anti-TNF drug levels, which has led to therapeutic drug monitoring becoming incorporated into everyday clinical management. The influence of patient and disease factors on the pharmacokinetics of anti-TNF levels, including immunogenicity, has also been examined. The role of therapeutic drug monitoring with vedolizumab is less clear. This review summarizes the available evidence on the pharmacokinetics and pharmacodynamics of vedolizumab in inflammatory bowel disease and how drug levels, immunogenicity and other factors influence clinical outcomes. Vedolizumab clearance is increased with very high body weight and hypoalbuminaemia, but is not influenced by the addition of an immunomodulator. Immunogenicity is uncommon. α4β7 receptor saturation occurs at low serum vedolizumab drug levels, and measuring it alone is insufficient to predict clinical outcomes. Using quartile analysis of vedolizumab drug levels, there appears to be a modest exposure–response relationship during induction. Drug levels at week 6 of approximately >20 μg/ml have been shown to be associated with improved clinical outcomes, including subsequent mucosal healing rates during maintenance and avoiding the need to dose escalate due to lack of response. There are currently insufficient data to support the routine use of therapeutic drug monitoring during maintenance therapy. Further studies to elucidate the role of therapeutic drug monitoring of vedolizumab are needed.

The management of inflammatory bowel disease (IBD) has advanced significantly in recent years, with increasing availability of biologic agents, the use of measurable objective biomarkers of inflammation (e.g., fecal calprotectin) and increasing use of therapeutic drug monitoring (TDM) to optimize individual therapies. IBD management has evolved towards a treat-to-target approach, of which TDM is an increasingly essential part. However, the clinical utilization of TDM varies globally and between institutions, and the ideal best practice use of TDM remains unclear. The recently published American Gastroenterology Association (AGA) TDM guideline attempted to address these issues for clinicians. It consisted of five recommendations on the use of TDM in IBD (1). Two of these recommendations considered anti-tumor necrosis factor (TNF)-α agents, with the remaining three relevant to thiopurines. Recommendations were not made on TDM of newer biologics agents such as vedolizumab and ustekinumab, due to the current paucity of data. The article was accompanied by a detailed technical review (2), a decision support tool (3), and a patient guide (4). The recommendations were developed by the AGA guideline panel, using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. A literature review was performed in March 2016, and the panel met in February 2017 before finalizing the guideline.

SummaryBackground Therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients receiving anti-tumour necrosis factor (TNF) agents can help optimise outcomes. Consensus statements based on current evidence will help the development of treatment guidelines. Aim To develop evidence-based consensus statements for TDM-guided anti-TNF therapy in IBD. Methods A committee of 25 Australian and international experts was assembled. The initial draft statements were produced following a systematic literature search. A modified Delphi technique was used with 3 iterations. Statements were modified according to anonymous voting and feedback at each iteration. Statements with 80% agreement without or with minor reservation were accepted. Results 22/24 statements met criteria for consensus. For anti-TNF agents, TDM should be performed upon treatment failure, following successful induction, when contemplating a drug holiday and periodically in clinical remission only when results would change management. To achieve clinical remission in luminal IBD, infliximab and adalimumab trough concentrations in the range of 3-8 and 5-12 μg/mL, respectively, were deemed appropriate. The range may differ for different disease phenotypes or treatment endpoints—such as fistulising disease or to achieve mucosal healing. In treatment failure, TDM may identify mechanisms to guide subsequent decision-making. In stable clinical response, TDM-guided dosing may avoid future relapse. Data indicate drug-tolerant anti-drug antibody assays do not offer an advantage over drug-sensitive assays. Further data are required prior to recommending TDM for non-anti-TNF biological agents. Conclusion Consensus statements support the role of TDM in optimising anti-TNF agents to treat IBD, especially in situations of treatment failure.

Conventional thiopurines are effective for the maintenance of remission of Crohn's disease and ulcerative colitis, however, up to half of patients are intolerant or unresponsive to these medications. Thioguanine is an alternative thiopurine that has shown efficacy in inflammatory bowel disease, and is particularly useful to circumvent certain side effects associated with conventional thiopurines, for example, pancreatitis. Its association with nodular regenerative hyperplasia of the liver has hindered its widespread use. Areas covered: We aim to outline the rational use of thioguanine, including safety monitoring, with particular regard to hepatotoxicity. A literature search was performed: PubMed was searched for full papers and abstracts published in English since January 2000 using the following terms, alone and in combination: 'azathioprine', 'thiopurine', 'Crohn's disease', 'inflammatory bowel disease', 'nodular regenerative hyperplasia', 'mercaptopurine', 'thioguanine', 'ulcerative colitis'. Further relevant papers were identified from the reference lists of selected papers. Expert commentary: Despite optimisation strategies such as metabolite measurements and the use of allopurinol, a significant proportion of patients will remain intolerant to thiopurines, especially those with allergic reactions, including pancreatitis. For this subgroup of patients we suggest that low dose thioguanine is an alternative to other therapies that are either parenteral or expensive.

Thioguanine (TG) is efficacious in inflammatory bowel disease (IBD), but its toxicity, particularly nodular regenerative hyperplasia (NRH) of the liver, has limited its use. We assessed the long-term clinical outcomes and safety of TG in patients whom were intolerant or refractory to conventional immunomodulators.This is a retrospective, single-centre study of IBD patients treated with TG from 2001-2013. Response was defined as clinical remission (Harvey-Bradshaw Index 5 for Crohn's disease (CD), Simple Clinical Colitis Activity Index 4 for ulcerative colitis (UC)) without corticosteroids or, if receiving anti-tumour-necrosis-factor (anti-TNF) therapy, absence of dose escalation. We recorded TG failure, withdrawal and adverse events. Patients were monitored with biochemistry, liver biopsy and/or magnetic resonance imaging (MRI).54 patients (47 CD and 7 UC) whom received TG (mean dose: 27 mg/d (range: 20-40 mg/d)) as monotherapy (TG was efficacious and well tolerated in one out of two patients who had previously failed conventional immunomodulators. NRH did not occur.

Background: Nosocomial diarrhoea is common and its investigation carries a significant healthcare cost. This study aimed to determine the utility of faecal lactoferrin (FL), a readily measurable marker of intestinal inflammation, in hospitalized patients with diarrhoea. Methods: FL was quantified in consecutive faecal samples submitted to a hospital pathology laboratory. Patient data were extracted from hospital records. Receiver–operator curve (ROC) analysis was performed in a subset of patients where a decision about low or high likelihood of inflammation could be confidently made. Multivariate analyses were performed to identify associations with an elevated FL. Cost analyses were also performed. Results: A total of 511 faecal samples from 433 patients (48% male, median age 67 years) was studied. Median FL concentration was 3.4 µg/mL (range 0–288). ROC analysis indicated an optimal cut-off value of 1.25 µg/mL (sensitivity 92%, specificity 97%, negative predictive value 97%) compared with the manufacturer's cut-off of 7.25 µg/mL (60%, 66% and 85% respectively). Multivariate analysis at the lower cut-off minimized potentially confounding variables. Proton pump inhibitor use independently increased (OR 2.3, 95% CI 1.5–3.8) and current smoking reduced (0.61, 0.38–0.99) the likelihood of an elevated FL. Only one out of 32 bacteriological positive samples would have been missed if FL was instituted as a screening test prior to microbiological assessment, which could have reduced laboratory-related costs by up to 56%. Conclusion: In hospitalized patients, a normal FL effectively excludes inflammatory diarrhoea and is proposed as a screening test prior to microbiological assessment of faeces. Prospective evaluation of this approach is warranted.

In the last 15 years the management of inflammatory bowel disease has evolved greatly, largely through the increased use of immunomodulators and, especially, anti-tumor necrosis factor (anti-TNF) biologic agents. Within this time period, confidence in the use of anti-TNFs has increased, whilst, especially in recent years, the efficacy and safety of thiopurines has been questioned. Yet despite recent concerns regarding the risk: benefit profile of thiopurines, combination therapy with an immunomodulator and an anti-TNF has emerged as the recommended treatment strategy for the majority of patients with moderate-severe disease, especially those who are recently diagnosed. Concurrently, therapeutic drug monitoring has emerged as a means of optimizing the dosage of both immunomodulators and anti-TNFs. However the recommended therapeutic target levels for both drug classes were largely derived from studies of monotherapy with either agent, or studies underpowered to analyze outcomes in combination therapy patients. It has been assumed that these target levels are applicable to patients on combination therapy also, however there are few data to support this. Similarly, the timing and duration of treatment with immunomodulators when used in combination therapy remains unknown. Recent attention, including post hoc analyses of the pivotal registration trials, has focused on the optimization of anti-TNF agents, when used as either monotherapy or combination therapy. This review will instead focus on how best to optimize immunomodulators when used in combination therapy, including an evaluation of recent data addressing unanswered questions regarding the optimal timing, dosage and duration of immunomodulator therapy in combination therapy patients.

Crohn's disease (CD) is a risk factor for vitamin B12 deficiency due to frequent involvement of the terminal ileum. Conventional screening for B12 deficiency with serum B12 is relatively insensitive and measures total B12 concentration, of which a minority is present in a biologically active form. Holotranscobalamin (holoTC) combined with methylmalonic acid (MMA) is believed to be more accurate in identifying impaired B12 status. We evaluated the prevalence and risk factors for B12 deficiency using holoTC supported by MMA among patients with CD.We performed a single-center service evaluation of 381 patients with CD who underwent B12 assessment (holoTC/MMA) and compared them with 141 patients with ulcerative colitis. Eighty-nine patients with CD underwent paired serum B12 and holoTC. Among patients with CD, risk factors including terminal ileal resection length, ileal inflammation on endoscopy, and disease characteristics on magnetic resonance imaging were recorded.Prevalence of B12 deficiency among patients with CD was 33% compared with 16% in ulcerative colitis (P0.0001). In 89 patients who underwent paired tests, conventional testing identified B12 deficiency in 5% of patients with CD, which increased to 32% using holoTC/MMA. Independent risk factors for B12 deficiency were ileal resection length ≤20 cm (odds ratio: 3.0, 95% confidence interval, 1.5-6.0, P = 0.002) and20 cm (odds ratio: 6.7, 95% confidence interval, 3.0-14.7, P0.0001) and ileal inflammation (odds ratio: 3.9, 95% confidence interval, 2.2-6.9, P0.0001). On magnetic resonance imaging, active terminal ileal inflammation (P = 0.02) and an increased disease burden (≥1 skip lesion, P = 0.01 and prestenotic dilatation3 cm, P = 0.01) were associated with B12 deficiency.Vitamin B12 deficiency is common in patients with CD. holoTC supported by MMA identifies patients with B12 deficiency considered replete on conventional testing.

Introduction The use of therapeutic drug monitoring (TDM) for anti-TNF drugs has become increasingly widespread over recent years. It is now used in many centres to guide clinical decisions regarding dose optimisation, the use of concomitant immunomodulators as well as switching or withdrawal of treatment. 1 TDM usually includes the measurement of serum trough levels of infliximab (IFX) or adalimumab (ADA) as well as anti-drug antibodies (ADAb). There are two different approaches to measuring ADAb; some techniques measure total ADAb (drug-ADAb complexes as well as free ADAb), whilst other measure only free ADAb. However, the clinical relevance of the differing data generated by these techniques is not yet fully understood. Methods A prospective evaluation of trough drug levels and ADAb was performed using our standard ELISA assay (LISA TRACKER, Theradiag) in 145 IBD patients on anti-TNF agents between January and May 2014. This technique measures only free ADAb. The samples were also anaylsed using an ELISA assay that measures total ADAb (IDKmonitor, Immundiagnostik). Long term outcomes were evaluated for 21 (17 IFX, 4 ADA) patients with Crohn’s disease (CD) who were found to have negative free ADAb but positive total ADAb. Outcome assessments were made by review of a prospectively maintained database, with a mean follow-up period of 22 months. Clinical outcome measures included; the need to escalate/switch/withdraw biologic treatment, infusion/injection-site reactions, documented clinical flare (HBI > 5) and need for steroid treatment. Biochemical outcome measures included; CRP > 5 mg/L and faecal calprotectin >150 ug/g. The subsequent development of positive free ADAb and subtherapeutic/undetectable drug levels were also collected as outcome measures. Results Anti-drug antibody (ADAb) detection: Of the 21 CD patients with positive total ADAb and negative free ADAb at the time of initial sampling, 3 (14%) went on to subsequently develop positive free ADAb during the follow-up period. Sixteen patients (75%) were taking concomitant immunomodulators, including all 3 patients who subsequently developed free ADAb. The mean IFX trough level in patients who went on to develop free ADAb was 1.05 ug/ml, compared to 4.04 ug/ml in those who did not. Outcomes: All 3 (100%) of the patients who developed positive free ADAb subsequently went on to have subtherapeutic or undetectable drug levels and required a switch in anti-TNF therapy. Two of the 3 (67%) had a flare in disease activity with an elevated faecal calprotectin. Two (67%) also developed significant infusion reactions. Of the remaining 18 patients who did not subsequently developed free ADAb, only one patient (6%) required a switch in anti-TNF, 4 (22%) developed clinical flares and 3 (17%) required steroid treatment. None of the 18 patients who remained free ADAb negative had undetectable drug levels during the follow-up period. Conclusion Long-term outcomes were not shown to be adversely affected by the presence of total ADAb, in the absence of free ADAb and adequate drug levels. However, patients who subsequently developed free ADAb and subtherapeutic or undetectable drug levels had unfavourable long-term outcomes. The presence of total ADAb does not appear to accurately predict the development of free ADAb. This data supports the use of ELISA techniques which measure free ADAb as well as drug levels. Our study and other similar work, 2 suggests that quantification of drug-ADAb complexes (total ADAb) appears to be less relevant to long-term clinical outcomes and therefore, less informative to clinical decision making. References 1 Ben-Horin S, Chowers Y. Tailoring anti-TNF therapy in IBD: drug levels and disease activity. Nature Reviews Gastroenterology & Hepatology 2014; 11 :243–255. 2 van schouwenburg, et al. Long-term measurement of anti-adalimumab using pH-shift-anti-idiotype antigen binding tests shows predictive value and transient antibody formation. Ann Rheum Dis . 2013; 72 :1680–6. Disclosure of Interest None Declared