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The value of ustekinumab (UST) therapeutic drug monitoring (TDM) in clinical practice remains unclear. This study examined the impact of UST TDM on clinical decision making in patients with Crohn’s disease (CD). A total of 110 consecutive UST-treated CD patients were enrolled in this multicenter, single-arm cross-sectional study. During a single study visit, clinical decisions, disease characteristics, and serum and fecal samples were obtained. The primary outcome was congruency of the actual and two hypothetical clinical decisions based on provision of UST TDM (with and without fecal calprotectin [FCP]) to participating clinicians. Decisions were compared against those of a review panel. A sub-study retrospectively measured the associations of clinical outcomes at the next follow-up visit with serum UST concentration [UST]. No differences in the pattern of decisions by clinicians were observed before and after provision of UST TDM (P = 1.0) or UST TDM + FCP (P = 0.86). However, 39% (TDM) and 50% (TDM + FCP) of hypothetical decisions differed from the initial decisions. The review panel’s decisions differed with the addition of TDM + FCP (P = 0.0006), but not TDM alone (P = 0.16). The sub-study (n = 53) failed to detect an association between therapeutic serum [UST] at the initial study visit and clinical outcomes at the next visit. In consecutive CD patients treated with UST, the addition of TDM into routine clinical practice did not significantly impact clinical decisions and there was no association between short-term clinical outcomes and serum [UST]. Further studies are warranted before clinicians routinely implement UST TDM into clinical practice.

Adalimumab and golimumab are subcutaneously administered anti-tumor necrosis factor α (TNFα) biologics used in the treatment of ulcerative colitis (UC). To date, no studies have directly compared treatment patterns and healthcare resource utilization (HRU) among patients with UC receiving these therapies in a real-world setting. The objective of this study was to compare these outcomes among patients with UC treated with either adalimumab or golimumab using a US claims database. Patients with UC treated with golimumab or adalimumab were identified using the US Optum Clinformatics® Data Mart database. Outcomes of interest included treatment patterns (discontinuations, dose optimizations, persistence, and concomitant medication use) and HRU (outpatient office visits, emergency room [ER] visits, and inpatient stays). Propensity score matching (PSM) was used to account for differences in confounding variables between groups. Overall, 990 patients were identified (golimumab: n = 277; adalimumab: n = 713). After PSM, 246 patients were included in each group. There were no significant differences between the adalimumab and golimumab groups over the full follow-up period in terms of treatment discontinuations (53.7% vs. 51.2%; P = 0.5881), dose optimizations (35.4% vs. 39.4%; P = 0.3515), or persistence (338.2 vs. 361.2 days; P = 0.4194). During the year after initiating therapy, there were no significant differences in concomitant immunosuppressant (21.9% vs. 21.7%; P = 0.9686) or corticosteroid use (74.7% vs. 78.8%; P = 0.3573) or in HRU outcomes including outpatient office visits (93.3% vs. 94.0%; P = 0.7660), ER visits (15.2% vs. 10.9%; P = 0.2238), and inpatient stays (15.2% vs. 13.6%; P = 0.6680). In this nationwide PSM cohort study of patients with UC receiving golimumab or adalimumab, no significant differences were observed between groups for treatment patterns or HRU outcomes. High rates of concomitant corticosteroid use, treatment discontinuations, and HRU while on therapy highlight key unmet needs in the treatment of UC.

Background The efficacy of golimumab to induce and maintain remission in biologic-naïve patients with ulcerative colitis (UC) is established from placebo-controlled trials. However, golimumab’s real-world effectiveness, important to physicians and payers, remains unexplored. Aim The goal of this study was to describe real-world use and rate of persistence among UC patients with golimumab therapy and to assess factors that predict discontinuation during golimumab maintenance treatment. Methods A retrospective study of UC patients receiving golimumab maintenance therapy (August 2012–August 2015) was conducted on dosing data from a national case management program. Treatment persistence, defined as time from index prescription to the last dose (gap in dose >60 days), was assessed using Kaplan-Meier survival analysis. Predictors of treatment persistence were explored with Cox proportional hazards regression. Results One hundred thirty-six patients (50.7% male) with a mean (SD) age of 44.4 (15.6) years were included. At golimumab initiation, 72.1% were naïve to anti-TNFs; 77.2% received 200 mg, while 4.4% and 18.4% received 50 mg and 100 mg, respectively, every 4 weeks (induction therapy). The median time to discontinuation was 530 days, with a cumulative probability of 63% to remain on therapy at one year. Age, gender, golimumab induction, golimumab maintenance dose and prior anti-TNF exposure were not significantly associated with treatment persistence. Dose adjustment occurred in 7.4% of patients during maintenance treatment. Conclusions Overall, the persistence rate of golimumab observed in the current real-world study is similar to that described in previous single-centre UC cohorts and consistent with that seen in controlled clinical trials.

Background Therapeutic drug monitoring is an important adjunct in optimising IBD management in patients treated with anti-TNF therapies. However, it remains unclear whether these principles apply to non-anti-TNF biologic therapies, such as the anti-IL12/23 agent, ustekinumab (UST). A follow-up analysis of the ‘mUST-DECIDE’ study explores the correlation between UST drug level and clinical outcomes. Methods 111 consecutive UST-treated adult CD patients across 11 sites in Canada from April 2017 to January 2018 were evaluated. Clinical decisions were recorded for all subjects at the single study visit and blood was drawn for TDM (Sanquin, radioimmunoassay). A retrospective chart review was completed in patients who had a follow-up visit ≥ 30 days after the baseline visit. Improved disease control (primary outcome) was defined as a composite assessment outcome meeting ≥ 1 disease control criterion (symptomatic, endoscopic/imaging, biochemical) without any of the non-response criteria (inadequate or loss of response, worsening of any disease control criteria, initiation of any CD-related medications and adverse events). Serum [UST] were categorised as therapeutic, subtherapeutic or uninterpretable based on their position in a 2 compartment PK model [subjects on Q8W dosing were assessed as per the log-linear model which projected a therapeutic level of ≥4.5 µg/ml at 4 weeks and ≥1.0 µg/ml at 8 weeks]. Results 53 patients had a clinical follow-up visit and an interpretable serum [UST]. Patients had refractory disease (89% anti-TNF-exposed, median 16.4 years since diagnosis), but clinically well (66% had baseline HBI Conclusion The sub-study did not detect any association between routine serum [UST] and short-term clinical outcomes at the next patient visit. These data broadly suggests that the routine measurement of serum UST in CD patients does not aid in disease management, though further studies across different clinical scenarios (e.g. loss of response) are warranted.

James C Gregor,1 Martin Williamson,2 Dorota Dajnowiec,2 Bernie Sattin,2 Erik Sabot,3 Baljinder Salh4 1Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada; 2Janssen Inc., Toronto, ON, Canada; 3OptumInsight, Boston, MA, USA; 4Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada Background: Given the large armamentarium of therapies for inflammatory bowel disease (IBD), physicians cannot fully describe all treatments to patients and, therefore, make assumptions regarding treatment attributes communicated to patients. This study aimed to assess out-of-pocket willingness-to-pay that IBD patients allocate to treatment attributes.Methods: Adult patients receiving therapy for IBD were invited to access a cross-sectional web-based discrete-choice experiment (May 22–August 31, 2015) that presented paired medication scenarios with varying efficacy, safety, and administration parameters. Preference weights and willingness-to-pay for each attribute level were assessed by a hierarchical Bayes method including a multinomial logit model.Results: A total of 586 IBD patients were included, 404 (68.9%) with Crohn’s disease and 182 (31.1%) with ulcerative colitis. Genders were evenly distributed; the majority of patients (70.1%) were 50 years or younger and had postsecondary education (75.4%), while the median health status was 7 (Likert scale: 1 [poor] – 10 [perfect]). Regarding relative preference-weight estimates, for the average respondent, reducing pain during administration, mucosal healing, and symptom relief were the highest-ranking attributes. Conversely, infusion reactions and risk of hospitalization or surgery were the lowest-ranking attributes. In multivariate analysis, patient sociodemographics did not affect the rank order of attributes although small differences were observed between asymptomatic and symptomatic patients in the previous year.Conclusion: This study has important implications related to understanding patient preferences and designing patient-centered strategies. IBD patients prioritize treatments with low administration pain. Additionally, these results concur with treatment guidelines emphasizing patients’ preference for mucosal healing and symptom control. Keywords: inflammatory bowel disease, patient preference, willingness-to-pay, discrete choice

BACKGROUND: Tolerance to therapy is critical for pts to receive the maximal treatment benefit. In Phase 3 clinical trials for ustekinumab (UST) for moderate to severe Crohn’s disease (CD), UNITI-1 enrolled anti-TNF failures and UNITI-2 enrolled conventional therapy failures. In UNITI-1, 36.4% had previous intolerance (infusion-related reactions [IRR], delayed hypersensitivity reactions, or injection site reactions [ISR]) that led to discontinuation of the anti-TNF. UNITI-2 enrolled pts that were not intolerant to anti-TNFs, but some were intolerant to immunomodulators (39%) or corticosteroids (15%). AIMS: Here we assess tolerability as measured by IRR, delayed hypersensitivity, or ISR to UST in the Phase 3 CD trials. METHODS: All enrolled pts in UNITI-1 and UNITI-2 were given an intravenous (IV) induction infusion of UST 130mg, UST ~6 mg/kg, or placebo (PBO). The IM-UNITI maintenance study began 8 weeks after IV induction; UST IV responders were randomized to UST 90mg SC Q8W, UST 90mg SC Q12W, or PBO. Non-randomized patients, included non-responders to placebo who received 130mg IV UST, then continued to UST 90mg SC Q12W maintenance therapy; non-responders to IV UST who received UST 90 mg SC, then continued UST 90 mg SC Q8W in maintenance; and IV placebo responders who received placebo SC in maintenance. RESULTS: Overall, IRR were infrequent: 4.0 % and 1.9 % of all pts in UNITI 1 & 2, respectively, experienced infusion reactions to the single IV dose. There were no differences in IRR between PBO & UST, or between UST doses (UNITI 1 IRRs in 2.0%, PBO and 4.5% UST 130mg and 3.6%, UST ~6 mg/kg; UNITI 2 IRRs in 2.9%, PBO and 2.4% UST 130mg and 1.4%, UST ~6 mg/kg). During IM-UNITI, in non-randomized pts who were non-responders to placebo induction and received a 130mg IV injection, IRR to PBO and UST were similar and infrequent (2.5% and 1.8%, respectively). There were no anaphylactic or delayed hypersensitivity reactions to any IV dose. After SC administration, ISRs were infrequent and not different across groups. In the combined (randomized and non- randomized) population, ISRs were 1.7 % with PBO, and 3.0% with UST. No serious ISRs were reported. The most common ISR was erythema, reported in 1.1 % of PBO, and 1.7% of UST. There were no anaphylactic or delayed hypersensitivity reactions to any SC dose. Amongst randomized pts, ISRs were infrequent and consistent between groups. ISRs occurred in 3/418 (0.7 %) of all UST 90mg Q12W injections and in 12/599 (2.0 %) of all UST 90mg Q8W injections. One pt in the entire phase 3 program discontinued therapy due to ISR. CONCLUSIONS: In a broad population of pts with Crohn’s disease, many of whom were intolerant to previous therapies, UST had a tolerable profile. Rates of IRR and ISR were minimal, and were not different between groups, nor populations. FUNDING AGENCIES: Janssen Research & Development, LLC funded this study

RecA fibrils in physiological conditions have been successfully imaged using Tapping Mode atomic force microscopy. This represents the first time images of recA have been obtained without drying, freezing and/or exposure to high vacuum conditions. While previously observed structures - the monomer, the hexamer, the short rod - were seen, a new type of fibril was also observed. This protofibril is narrower in diameter than the standard fibril, and occurs in three distinct morphologies: aperiodic, 100-nm periodic, and 150-nm periodic. In addition, much longer rods were observed, and appear curved and even circular.

The formation of the RecA/DNA nucleofilament on nicked circular double stranded (ds) DNA in the presence of ATPgammaS was studied using the atomic force microscope (AFM) at nanometer resolution. The AFM allowed simultaneous observation of both dsDNA substrate and RecA protein-coated sections such that they are highly distinguishable. Using a time series of images, the complex formation was monitored. AFM imaging provided direct evidence that assembly of the nucleofilaments occurs via a nucleation and growth mechanism. The nucleation step is much slower than the growth phase, as demonstrated by the predominance of naked dsDNA at early and middle time points, followed by the rapid appearance of partially then fully formed complexes. Observation of the formation of nucleation sites without accompanying growth on unnicked dsDNA enabled an estimate of the nucleation rate, of 5 x 10(-5) RecA min(-1) bp(-1). The published model for the analysis of RecA assembly on dsDNA deduces a single kinetic parameter that prevents the separate determination of nucleation rate and growth rate. By directly measuring the nucleation rate with the AFM, this model is employed to determine a growth rate of 202 min(-1). These AFM results provide the first direct evidence of previous results on complex formation obtained only by indirect means.

SummaryBackground Tumour necrosis factor (TNF)-antagonists have an established role in the treatment of inflammatory bowel diseases (IBDs), however, subtherapeutic drug levels and the formation of anti-drug antibodies (ADAs) may decrease their efficacy. Aim The evidence supporting the use of therapeutic drug monitoring (TDM) based clinical algorithms for infliximab (IFX) and their role in clinical practice will be discussed. Methods The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies-to-infliximab. Results Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long-term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence-based manner and are probably not cost-effective. Multiple TDM-based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy. Conclusions Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post-hoc analyses of randomised controlled trials.

The design and implementation of a hot stage for control of the sample temperature in atomic force microscope (AFM) imaging in fluid is described. This heater design is optimally suited for AFM studies that are biological in nature, where the sample needs to be held near physiological conditions. The ease of assembly, simplicity of design, and low cost makes it suitable for implementation in any laboratory for both research or teaching purposes. The small size and self-contained nature of the device allows it to be incorporated into any AFM system. We demonstrate the ability of the heater to function reliably at elevated temperatures where clear, high resolution images of plasmid DNA under water can be routinely obtained.

All structured biological macromolecules must overcome the thermodynamic folding problem to populate a unique functional state among a vast ensemble of unfolded and alternate conformations. The exploration of cooperativity in protein folding has helped reveal and distinguish the underlying mechanistic solutions to this folding problem. Analogous dissections of RNA tertiary stability remain elusive, however, despite the central biological importance of folded RNA molecules and the potential to reveal fundamental properties of structured macromolecules via comparisons of protein and RNA folding. We report a direct quantitative measure of tertiary contact cooperativity in a folded RNA. We precisely measured the stability of an independently folding P4-P6 domain from the Tetrahymena thermophila group I intron by single molecule fluorescence resonance energy transfer (smFRET). Using wild-type and mutant RNAs, we found that cooperativity between the two tertiary contacts enhances P4-P6 stability by 3.2 +/- 0.2 kcal/mol.