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SummaryBackgroundInfliximab and adalimumab have established roles in inflammatory bowel disease (IBD) therapy. UK regulators mandate reassessment after 12 months' anti‐TNF therapy for IBD, with consideration of treatment withdrawal. There is a need for more data to establish the relapse rates following treatment cessation.AimTo establish outcomes following anti‐TNF withdrawal for sustained remission using new data from a large UK cohort, and assimilation of all available literature for systematic review and meta‐analysis.MethodsA retrospective observational study was performed on 166 patients with IBD (146 with Crohn's disease (CD) and 20 with ulcerative colitis [UC) and IBD unclassified (IBDU)] withdrawn from anti‐TNF for sustained remission. Meta‐analysis was undertaken of all published studies incorporating 11 further cohorts totalling 746 patients (624 CD, 122 UC).ResultsRelapse rates in the UK cohort were 36% by 1 year and 56% by 2 years for CD, and 42% by 1 year and 47% by 2 years for UC/IBDU. Increased relapse risk in CD was associated with age at diagnosis [hazard ratio (HR) 2.78 for age <22 years], white cell count (HR 3.22 for >5.25 × 109/L) and faecal calprotectin (HR 2.95 for >50 μg/g) at drug withdrawal. Neither continued immunomodulators nor endoscopic remission were predictors. In the meta‐analysis, estimated 1‐year relapse rates were 39% and 35% for CD and UC/IBDU respectively. Retreatment with anti‐TNF was successful in 88% for CD and 76% UC/IBDU.ConclusionsAssimilation of all available data reveals remarkable homogeneity. Approximately one‐third of patients with IBD flare within 12 months of withdrawal of anti‐TNF therapy for sustained remission.

Summary Background Ustekinumab is effective in Crohn's disease. However, a substantial proportion of patients will not respond or lose response to ustekinumab. The current evidence to support the effectiveness of dose‐optimisation for ustekinumab nonresponse is limited. Aim To assess the effectiveness of dose escalation of ustekinumab. Methods This was a multicentre retrospective cohort study. We included active Crohn's disease patients who received a standard‐dose intravenous induction and at least one subcutaneous ustekinumab 90 mg dose. All enrolled patients received dose escalation by either shortening the interval between the doses to every 4 or 6 weeks, intravenous reinduction or a combination of strategies. The primary outcome of the study was clinical response at week 16 after dose escalation. Results A total of 142 patients (22 centres/14 countries) were included. The patients were dose‐escalated after a median treatment duration of 30 weeks. At week 16 from escalation, 73/142 (51.4%) responded to treatment, including 55/142 (38.7%) in clinical remission. Corticosteroid‐free remission was achieved in 6/34 (17.6%) patients on corticosteroids at the time of escalation; 118/142 (83%) continued treatment beyond week 16. Follow‐up data beyond week 16 were available for 74/118 (62.7%) patients. On the last follow‐up, 51/98 (52%) patients with available data responded to treatment, including 41/98 (42%) in clinical remission. Conclusions Intensification of ustekinumab maintenance dosage was effective in over 50% of the patients. This strategy should be considered in patients who are nonresponsive to every 8 weeks ustekinumab maintenance dosing.

BackgroundThiopurines (azathioprine and mercaptopurine) remain integral to most medical strategies for maintaining remission in Crohn's disease (CD) and ulcerative colitis (UC). Indefinite use of these drugs is tempered by long-term risks. While clinical relapse is noted frequently following drug withdrawal, there are few published data on predictive factors.AimTo investigate the success of planned thiopurine withdrawal in patients in sustained clinical remission to identify rates and predictors of relapse.MethodsThis was a multicentre retrospective cohort study from 11 centres across the UK. Patients included had a definitive diagnosis of IBD, continuous thiopurine use ≥3 years and withdrawal when in sustained clinical remission. All patients had a minimum of 12 months follow-up post drug withdrawal. Primary and secondary end points were relapse at 12 and 24 months respectively.Results237 patients were included in the study (129 CD; 108 UC). Median duration of thiopurine use prior to withdrawal was 6.0 years (interquartile range 4.4–8.4). At follow-up, moderate/severe relapse was observed in 23% CD and 12% UC patients at 12 months, 39% CD and 26% UC at 24 months. Relapse rate at 12 months was significantly higher in CD than UC (P = 0.035).Elevated CRP at withdrawal was associated with higher relapse rates at 12 months for CD (P = 0.005), while an elevated white cell count was predictive at 12 months for UC (P = 0.007).ConclusionThiopurine withdrawal in the context of sustained remission is associated with a 1-year moderate-to-severe relapse rate of 23% in Crohn's disease and 12% in ulcerative colitis.

Background Intestinal macrophages are key immune cells in the maintenance of intestinal immune homeostasis and have a role in the pathogenesis of inflammatory bowel disease (IBD). However, the mechanisms by which macrophages exert a pathological influence in both ulcerative colitis (UC) and Crohn disease (CD) are not yet well understood. Methods We purified intestinal macrophages from gastrointestinal mucosal biopsies (patients with UC, patients with CD, and healthy donors) and analyzed their transcriptome by RNA sequencing and bioinformatics, confirming results with quantitative polymerase chain reaction and immunohistochemistry. Results Compared with those of healthy donors, intestinal macrophages in patients with UC and with CD showed cellular reprograming of 1287 and 840 dysregulated genes, respectively (false discovery rate ≤ 0.1). The UC and CD intestinal macrophages showed an activated M1 inflammatory phenotype and the downregulation of genes engaged in drug/xenobiotic metabolism. Only macrophages from CD showed, concomitant to an M1 phenotype, a significant enrichment in the expression of M2 and fibrotic and granuloma-related genes. For the first time, we showed (and validated by quantitative polymerase chain reaction and immunohistochemistry) that intestinal macrophages in patients with IBD present both M1 and M2 features, as recently described for tumor-associated macrophages, that affect key pathways for IBD pathology, represented by key markers such as MMP12 (fibrosis), CXCL9 (T-cell attraction), and CD40 (T-cell activation). Conclusions Our data support the therapeutic targeting of macrophages to maintain remission in IBD but also indicate that a shift toward an M2 program—as proposed by some reports—may not limit the recruitment and activation of T cells because M2 features do not preclude M1 activation in patients with UC or CD and could exacerbate M2-related CD-specific features such as fibrosis and the formation of granulomas.

ObjectiveTo understand the effectiveness of ustekinumab in treating Crohn’s disease (CD) in a UK real-world setting.DesignRetrospective cohort study using prospectively maintained clinical records.SettingSingle UK inflammatory bowel disease centre.PatientsAdult patients with an established diagnosis of CD prescribed ustekinumab outside of clinical trials at University Hospital Southampton (UHS).InterventionsUstekinumab, a monoclonal antibody to the shared p40 subunit of interleukin (IL) 12 and IL-23 as part of routine clinical care.Main outcome measuresEffectiveness as measured by an improvement in physician’s global assessment, drug persistence and improvement in biomarkers (C-reactive protein (CRP), albumin and calprotectin).Results84 patients were included, 72 had a postinduction review and 49 had 1-year data. At postinduction clinical review, clinical response occurred in 53% of patients and clinical remission occurred in 8%. For patients on ustekinumab at 1 year, clinical response occurred in 71% and remission in 14%. Adverse events included four patients with infections requiring admission, one drug-related rash, five CD surgeries and two CD exacerbations.ConclusionsUstekinumab was well tolerated in a complex UK CD population and demonstrated benefit to patients in terms of clinical response and improvement of biomarkers and with some patients attaining clinical remission. No unexpected safety signals were seen.

The public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden, to Department of Defense, Washington Headquarters Services, Directorate for Information AFRL-PR-WP-TP-2006-240 SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSORING/MONITORING AGENCY ACRONYM(S) AFRL-PR-WP ABSTRACTAn analytical and experimental study was conducted for the application of spray cooling in a micro gravity and high-g environment. Experiments were carried out aboard the NASA KC-135 reduced gravity aircraft, which provided both the microgravity and high-g environments. In reduced gravity, surface tension flow was observed around the spray nozzle, due to unconstrained liquid in the test chamber and flow reversal at the heat source. A transient analytical model was developed to predict the temperature and the spray heat transfer coefficient within the heated region. Comparison of the experimental transient temperature variation with analytical results showed good agreement for low heat input values. The transient analysis also verified that thermal equilibrium within the heated region could be reached during the 20-25s reduced gravity portion of the flight profile. ABSTRACT An analytical and experimental study was conducted for the application of spray cooling in a microgravity and high-g environment. Experiments were carried out aboard the NASA KC-135 reduced gravity aircraft, which provided both the microgravity and high-g environments. In reduced gravity, surface tension flow was observed around the spray nozzle, due to unconstrained liquid in the test chamber and flow reversal at the heat source. A transient analytical model was developed to predict the temperature and the spray heat transfer coefficient within the heated region. SUBJECT TERMS