Effects of Thiopurine Withdrawal on Vedolizumab-Treated Patients With Ulcerative Colitis: A Randomized Controlled Trial.

BACKGROUND & AIMS: The impact of thiopurine de-escalation while on vedolizumab versus continuing thiopurine therapy in ulcerative colitis (UC) is unclear. We aimed to determine the effect of thiopurine withdrawal for patients with UC in remission on vedolizumab. METHODS: This multicenter randomized controlled trial recruited UC patients on vedolizumab 300 mg intravenously every 8 weeks and a thiopurine. Patients in steroid-free clinical remission for ≥6 months and endoscopic remission/improvement (Mayo endoscopic subscore ≤1) were randomized 2:1 to withdraw or continue thiopurine. Primary outcome was comparing week 48 vedolizumab trough concentrations. Secondary outcomes were clinical relapse (partial Mayo score ≥3 and fecal calprotectin >150 µg/g or increase in Mayo endoscopic subscore ≥1 from baseline), fecal calprotectin remission (<150 µg/g), C-reactive protein remission (<5 mg/L), centrally read endoscopic remission (Mayo endoscopic subscore = 0), histologic remission (Nancy index = 0), histo-endoscopic remission, and adverse events. RESULTS: In total, 62 patients were randomized to continue (n = 20) or withdraw (n = 42) thiopurine. At week 48, vedolizumab trough concentrations were not significantly different between continue and withdrawal groups (14.7 µg/mL, interquartile rate [IQR], 12.3-18.5 µg/mL versus 15.9 µg/mL, IQR, 10.1-22.7 µg/mL, respectively, P = 0.36). The continue group had significantly higher fecal calprotectin remission (95.0%, 19/20 versus 71.4%, 30/42; P = .03), histologic remission (80.0%, 16/20 versus 48.6%, 18/37; P = .02), and histo-endoscopic remission (75.0%, 15/20 versus 32.4%, 12/37; P = .002) than the withdrawal group. Histologic activity (hazard ratio [HR], 15.5; 95% confidence interval [CI], 1.6-146.5; P = .02) and prior anti-tumor necrosis factor exposure (HR, 6.5; 95% CI, 1.3-33.8; P = .03) predicted clinical relapse after thiopurine withdrawal. CONCLUSIONS: Thiopurine withdrawal did not affect vedolizumab trough concentrations. However, it may increase fecal calprotectin, histologic, and histo-endoscopic activity. Histologic activity and prior anti-tumor necrosis factor exposure may predict disease relapse on thiopurine withdrawal for patients using vedolizumab for UC. Australian and New Zealand Trial Registry, number ACTRN12618000812291.

Adalimumab Drug Levels at Secondary Loss of Response Do Not Predict Response to Dose-intensification in Crohn's Disease: A Retrospective, International Multicenter Study.

BACKGROUND: The exposure-response relationship is less established for adalimumab (ADA) compared with infliximab in inflammatory bowel disease (IBD). Evidence supporting therapeutic drug monitoring post dose-intensification of ADA is limited. We aimed to explore the association between ADA drug levels and Crohn's disease (CD) activity at loss of response, and at 6 and 12 months post dose-intensification. METHODS: We performed a retrospective study of adult patients with CD receiving dose-intensified weekly ADA following secondary loss of response at 3 tertiary centers across 5 years. ADA trough levels were analyzed using a drug-sensitive enzyme-linked immunosorbent assay at loss of response, and 6 and 12 months after dose-intensification. Rates of clinical remission, objective remission (C-reactive protein <5 mg/L, fecal calprotectin <150 µg/g, or absence of inflammation at endoscopy or imaging), and ADA failure were investigated. RESULTS: A total of 131 CD patients were included, with a median disease duration of 9 (interquartile range, 4-17) years. 51% were biologic exposed prior to ADA and 50% received concomitant immunomodulators. Baseline drug levels measured at secondary loss of response did not discriminate between subsequent responders and non-responders at either 6 or 12 months post dose-intensification. However, both higher drug levels at 6 and 12 months and a higher increment from baseline were associated with improved outcomes. On receiver-operating characteristic analyses, post-escalation ADA drug levels >10.7 µg/mL (area under the receiver-operating characteristic curve [AUROC], 0.66; P = .013) and >10.9 µg/mL (AUROC, 0.67; P = .032) were associated with objective remission at 6 and 12 months, respectively. CONCLUSIONS: Drug levels following dose-intensification rather than at the time of secondary loss of response were associated with subsequent CD remission.

Literature supporting therapeutic drug monitoring at secondary loss of response and post dose-intensification of adalimumab is limited. Adalimumab drug levels following dose-intensification rather than at the time of secondary loss of response are associated with subsequent Crohn's disease remission.

Pharmacist-Driven Therapeutic Infliximab Monitoring at the Point of Care Using Rapidly Assessed Drug Levels in Patients with Inflammatory Bowel Disease.

BACKGROUND: 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. METHODS: 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 mcg/mL. Disease activity was assessed both clinically and biochemically. RESULTS: The rapid assay and ELISA detected similar infliximab levels, and the strategy added approximately 30 minutes to the duration of infusion events. Only 20% of 48 patients (77% with Crohn disease) had baseline trough infliximab concentrations within the therapeutic range. This value increased 3-fold after 24 and 48 weeks of interventions. One in 2 patients had baseline supratherapeutic levels, and most were brought into the therapeutic range without a discernible impact on disease activity by 1 dose adjustment, but 2 or 3 adjustments were generally needed for 29% of patients with subtherapeutic levels. Overall, drug costs were reduced by 4%. CONCLUSIONS: Immediate dose adjustment after 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 affecting disease activity, offsetting (at least partly) costs associated with dose escalation.

Therapeutic Drug Monitoring of Subcutaneous Infliximab in Inflammatory Bowel Disease-Understanding Pharmacokinetics and Exposure Response Relationships in a New Era of Subcutaneous Biologics.

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.

De-escalation from Dose-Intensified Anti-TNF Therapy Is Successful in the Majority of IBD Patients at 12 Months.

BACKGROUND: 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. AIMS: To evaluate rates of successful de-escalation at 12 months and to determine factors that may predict success. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

SARS-CoV-2 vaccination in patients with inflammatory bowel disease.

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.

A Single Educational Intervention Improves Pregnancy-Related Knowledge and Emotional Health Among Women With IBD Who Are Pregnant or Wish to Conceive.

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.

Comparison of SB2-Infliximab With Originator-Infliximab in the Measurement of Serum Concentrations: A Short Communication.

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 used 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 when measured by commonly used commercial assays. METHODS: Sera from 2 healthy controls, 2 patients with ulcerative colitis (1 with quiescent disease and 1 with active disease), and 2 patients with Crohn disease (1 with quiescent disease and 1 with active disease) were spiked with SB2-infliximab or originator-infliximab at 0-20 mcg/mL. Concentrations were measured using 3 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 mcg/mL, with the mean difference between the molecules being at worst 0.04 mcg/mL (95% confidence intervals, -0.011 to 0.093). CONCLUSIONS: The originator and SB-2 biosimilar-infliximab behaved similarly in several currently used assays in 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.

Thiopurines and their optimization during infliximab induction and maintenance: A retrospective study in Crohn's disease.

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.

Effects of fiber intake on intestinal pH, transit, and predicted oral mesalamine delivery in patients with ulcerative colitis.

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 < 0.01). Colonic transit in the UC cohort varied widely after a low-fiber intake but tended to normalize after the high fermentable fiber intake. Hypothetical coating dissolution profiles were heterogeneous in UC patients, with a multi-matrix delayed release system having the highest likelihood of patients (20-40%) with incomplete dissolution, and predominant small intestinal dissolution predicted for Eudragit L (94% patients) and S (44-69%). CONCLUSIONS: Patients with quiescent UC have abnormalities in intestinal pH and transit in response to acute changes in fermentable fiber intake. These have potentially detrimental effects on predicted luminal release patterns of pH-dependent 5-aminosalicylic acid release systems.

Infliximab, adalimumab and vedolizumab concentrations across pregnancy and vedolizumab concentrations in infants following intrauterine exposure.

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.

Practical management of inflammatory bowel disease patients during the COVID-19 pandemic: expert commentary from the Gastroenterological Society of Australia Inflammatory Bowel Disease faculty.

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 is 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 patients in the context of the COVID-19 pandemic in the Australasian setting.

A virtual clinic increases anti-TNF dose intensification success via a treat-to-target approach compared with standard outpatient care in Crohn's disease.

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 < 0.002). Rates of appropriate dose intensification (82.6% vs 40.0%, P < 0.001), biomarker remission (faecal calprotectin P = 0.002), tight-disease monitoring (84.1% vs 28.8%, P < 0.001) and treatment de-escalation (21.3% vs 10.0%, P = 0.027) also favoured the virtual clinic cohort. CONCLUSION: This study favoured a virtual clinic-led model-of-care over standard outpatient care in facilitating treatment success as part of an effective treat-to-target approach in Crohn's disease. A virtual clinic model-of-care also improved treatment outcomes and quality of use of intensified anti-TNF therapy through processes that promoted appropriate dose intensification and tight-disease monitoring, while encouraging more frequent dose de-escalation.

Review article: determination of the therapeutic range for therapeutic drug monitoring of adalimumab and infliximab in patients with inflammatory bowel disease.

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.

Therapeutic Drug Monitoring of Biologics During Induction to Prevent Primary Non-Response.

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.

Comparison of Adalimumab Serum Drug Levels When Delivered by Pen Versus Syringe in Patients With Inflammatory Bowel Disease. An International, Multicentre Cohort Analysis.

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.