Emergence of severe spondyloarthropathy-related entheseal pathology following successful vedolizumab therapy for inflammatory bowel disease.

OBJECTIVES: Vedolizumab (VDZ) blocks α4ß7 integrin and is licenced for the treatment of IBD. It has been associated with mild SpA-related features, including sacroiliitis and synovitis. Herein we report a series of cases demonstrating the emergence of severe SpA-associated enthesitis/osteitis following successful IBD therapy with VDZ. METHODS: We evaluated 11 VDZ-treated patients with IBD across seven centres who developed severe active SpA and/or enthesopathy, with the aim of characterizing the VDZ-associated SpA or entheseal flares. Imaging features demonstrating particularly severe disease were recorded. RESULTS: De novo SpA developed in 9 of 11 patients and flare of known SpA in 2 patients, with 4 patients requiring hospitalization due to disease severity. Available data showed that one of seven cases were HLA-B27 positive. The median time from VDZ initiation to flare was 12 weeks, with IBD well controlled in 7 of 10 patients (no data for 1 patient) at flare. Severe SpA enthesitis/osteitis was evident on MRI or US, including acute sacroiliitis (n = 5), extensive vertebral osteitis (n = 1), peri-facetal oedema (n = 1) and isolated peripheral enthesitis (n = 3). Due to arthritis severity, VDZ was discontinued in 9 of 11 patients and a change in therapy, including alternative anti-TNF, was initiated. CONCLUSION: Severe SpA, predominantly HLA-B27 negative, with osteitis/enthesitis may occur under successful VDZ treatment for IBD, including in subjects with prior anti-TNF therapy for intestinal disease.

Longitudinal impact of IBS-type symptoms on disease activity, healthcare utilization, psychological health, and quality of life in inflammatory bowel disease.

OBJECTIVES: The impact of irritable bowel syndrome (IBS)-type symptoms on the natural history of inflammatory bowel disease (IBD) is uncertain. We aimed to address this in a longitudinal study of secondary care patients. METHODS: Longitudinal disease activity was defined by disease flare, escalation of medical therapy, hospitalization, or intestinal resection. The number of investigations performed and clinics attended determined healthcare utilization. Psychological well-being and quality of life were assessed using validated questionnaires. These outcomes were compared over a minimum period of 2 years between patients reporting IBS-type symptoms and patients with quiescent disease, occult inflammation, and active disease at baseline. RESULTS: In 360 IBD patients, there were no differences in longitudinal disease activity between patients with IBS-type symptoms and patients with quiescent disease or occult inflammation. Disease flare and escalation of medical therapy was more common in patients with active disease than in patients with IBS-type symptoms (hazard ratio (HR) = 3.16; 95% confidence interval (CI) 1.93-5.19 and HR = 3.24; 95% CI 1.98-5.31, respectively). A greater number of investigations were performed in patients with IBS-type symptoms than quiescent disease (P = 0.008), but not compared with patients with occult inflammation or active disease. Anxiety, depression, and somatization scores at follow up were higher, and quality-of-life scores lower, in patients with IBS-type symptoms when compared with patients with quiescent disease, but were similar to patients with active disease. CONCLUSIONS: IBS-type symptoms in IBD were associated with increased healthcare utilization, psychological comorbidity, reduced quality of life, but not adverse disease activity outcomes during extended follow-up.

METRIC (MREnterography or ulTRasound in Crohn's disease): a study protocol for a multicentre, non-randomised, single-arm, prospective comparison study of magnetic resonance enterography and small bowel ultrasound compared to a reference standard in those aged 16 and over.

BACKGROUND: Crohn's disease (CD) is a lifelong, relapsing and remitting inflammatory condition of the intestine. Medical imaging is crucial for diagnosis, phenotyping, activity assessment and detecting complications. Diverse small bowel imaging tests are available but a standard algorithm for deployment is lacking. Many hospitals employ tests that impart ionising radiation, of particular concern to this young patient population. Magnetic resonance enterography (MRE) and small bowel ultrasound (USS) are attractive options, as they do not use ionising radiation. However, their comparative diagnostic accuracy has not been compared in large head to head trials. METRIC aims to compare the diagnostic efficacy, therapeutic impact and cost effectiveness of MRE and USS in newly diagnosed and relapsing CD. METHODS: METRIC (ISRCTN03982913) is a multicentre, non-randomised, single-arm, prospective comparison study. Two patient cohorts will be recruited; those newly diagnosed with CD, and those with suspected relapse. Both will undergo MRE and USS in addition to other imaging tests performed as part of clinical care. Strict blinding protocols will be enforced for those interpreting MRE and USS. The Harvey Bradshaw index, C-reactive protein and faecal calprotectin will be collected at recruitment and 3 months, and patient experience will be assessed via questionnaires. A multidisciplinary consensus panel will assess all available clinical and imaging data up to 6 months after recruitment of each patient and will define the standard of reference for the presence, localisation and activity of disease against which the diagnostic accuracy of MRE and USS will be judged. Diagnostic impact of MRE and USS will be evaluated and cost effectiveness will be assessed. The primary outcome measure is the difference in per patient sensitivity between MRE and USS for the correct identification and localisation of small bowel CD. DISCUSSION: The trial is open at 5 centres with 46 patients recruited. We highlight the importance of stringent blinding protocols in order to delineate the true diagnostic accuracy of both imaging tests and discuss the difficulties of diagnostic accuracy studies in the absence of a single standard of reference, describing our approach utilising a consensus panel whilst minimising incorporation bias. TRIAL REGISTRATION: METRIC - ISRCTN03982913 - 05.11.13.

Genetic variation among populations of, and evidence of deep divergence within, the Rio Grande Chirping Frog, Eleutherodactylus campi (Anura: Eleutherodactylidae).

Herein we report the first molecular assessment of intra-species genetic variation and interrelationships within the Rio Grande Chirping frog, Eleutherodactylus campi. We analyzed 548 base pairs of 16S rRNA gene for 71 ingroup individuals belonging to the genus Eleutherodactylus (including 42 E. campi sampled from 15 localities in the United States and Mexico) and four outgroup samples. By unveiling two highly divergent and geographically structured clades within E. campi this study provides a novel phylogenetic placement of E. campi populations north and south of the Rio Grande Valley as sister groups to each other. The observed level of genetic divergence between these two clades (5.8%) is, on average, comparable to or greater than the levels of divergence found between several currently valid amphibian species pairs. Estimates of Time to Most Common Ancestor (TMRCA) indicate that the phylogeographic split between the two E. campi clades may have occurred 7.6 MYA (i.e., late Miocene), consistent with the geologic history of southwestern North America. The study also confirms that south Texas served as the source population for populations of E. campi in its introduced range (i.e., Alabama, Louisiana, and Texas). Overall, this molecular study indicates that E. campi consists of two deeply divergent lineages corresponding to its populations north and south of Rio Grande Valley. These results suggest that the recovered lineages may represent independent species and thereby highlight the need for further research to clarify their status.

METRIC-EF: magnetic resonance enterography to predict disabling disease in newly diagnosed Crohn's disease-protocol for a multicentre, non-randomised, single-arm, prospective study.

INTRODUCTION: Crohn's disease (CD) is characterised by discontinuous, relapsing enteric inflammation. Instituting advanced therapies at an early stage to suppress inflammation aims to prevent future complications such as stricturing or penetrating disease, and subsequent surgical resection. Therapeutics are effective but associated with certain side-effects and relatively expensive. There is therefore an urgent need for robust methods to predict which newly diagnosed patients will develop disabling disease, to identify patients who are most likely to benefit from early, advanced therapies. We aim to determine if magnetic resonance enterography (MRE) features at diagnosis improve prediction of disabling CD within 5 years of diagnosis. METHODS AND ANALYSIS: We describe the protocol for a multicentre, non-randomised, single-arm, prospective study of adult patients with newly diagnosed CD. We will use patients already recruited to the METRIC study and extend their clinical follow-up, as well as a separate group of newly diagnosed patients who were not part of the METRIC trial (MRE within 3 months of diagnosis), to ensure an adequate sample size. Follow-up will extend for at least 4 years. The primary outcome is to evaluate the comparative predictive ability of prognostic models incorporating MRE severity scores (Magnetic resonance Enterography Global Score (MEGS), simplified MAgnetic Resonance Index of Activity (sMaRIA) and Lémann Index) versus models using standard characteristics alone to predict disabling CD (modified Beaugerie definition) within 5 years of new diagnosis. ETHICS AND DISSEMINATION: This study protocol achieved National Health Service Research Ethics Committee (NHS REC), London-Hampstead Research Ethics Committee approval (IRAS 217422). Our findings will be disseminated via conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN76899103.

Ipilimumab-induced colitis: experience from a tertiary referral center.

BACKGROUND: Ipilimumab is an anticytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody used for the treatment of malignant melanoma. It can cause immune-mediated inflammatory adverse events, including diarrhoea and even intestinal perforation or death in clinical trials but there is a dearth of data on postmarketing outcomes. METHODS: A total of 546 patients attending for treatment of metastatic melanoma between 1 January 2009 and 31 August 2015 were identified by interrogation of the oncology database. A total of 83 of these patients received ipilimumab. Clinical information was extracted from chart reviews, endoscopy and radiology reports, and prescription data. RESULTS: A total of 83 patients received ipilimumab. Only 19.3% (n = 16) of patients developed a diarrhoeal illness not attributable to other causes. The median grade of diarrhoea among included patients was 2 (range 1-4). In two cases, diarrhoea settled spontaneously without any specific treatment. A total of 87.5% of patients received antidiarrhoeal agents such as loperamide or codeine. These resolved symptoms in all patients with grade 1 diarrhoea. For other treatment, 50% patients received systemic glucocorticosteroids and 31.3% required infliximab. Infliximab resolved symptoms in 100% of cases compared with 50% for systemic glucocorticosteroids. CONCLUSIONS: The rate of diarrhoea related to ipilimumab in real-world practice is substantial, but below the range observed in data from RCTs. Grade 1 colitis can usually be managed symptomatically, without recourse to stopping ipilimumab. When diarrhoea was grade 2 or above, results from glucocorticosteroids use proved disappointing; but infliximab has been shown to work well. Further research is required into the earlier use of infliximab as an effective treatment for ipilimumab-induced diarrhoea.

Relationship of Body Mass Index to Clinical Outcomes after Infliximab Therapy in Patients with Crohn's Disease.

BACKGROUND & AIMS: There are conflicting data for the role of obesity in Crohn's disease (CD) and the effect on long-term clinical outcomes is poorly studied. Some evidence suggests obesity is associated with diminished responsiveness to biological agents, especially anti-tumour necrosis factor antibodies. METHODS: We aimed to examine the influence of body mass index (BMI) on the response to infliximab in CD in a retrospective analysis. The outcomes of interest within 12 months were: (1) Composite loss of response (CD-related flare or surgery; LOR); (2) any CD-related surgery (CDRS); and (3) CD-related intestinal resectional surgery (CDRIS). RESULTS: A total of 388 patients were included. The mean BMI was 24.2kg/m(2) [± standard deviation (SD) 5.1]. Of the 388 patients, 137 (35.4%) were overweight (BMI: 25-29.9kg/m(2)) or obese (BMI: ≥30kg/m(2))-160 (41.6%) patients had LOR during the 12 months follow-up; 121 (31.4%) required CDRS, and 109 (28.2%) required CDRIS. Multivariate analysis showed that increasing BMI (per unit, kg/m(2) increase) reduced the risk of LOR [odds ratio (OR): 0.98], CDRS (OR: 0.95), and CDRIS (OR: 0.95). Rates for all outcomes were higher, but not significantly so, in the extreme categories (underweight and obese) and lower in the underweight categories compared with normal BMI. Exclusion of the obese category of patients strengthened this relationship. CONCLUSIONS: Body mass index at first infusion of infliximab has a non-linear relationship with outcomes at 12 months. The worst outcomes are at the extremes of weight (underweight and obese categories). Increasing BMI is associated with a modest reduction in risk of LOR, CDRS, and CDRIS within 12 months, increasing with the exclusion of the obese category.

Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease. METHODS: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15). FINDINGS: Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27-1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28-0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04-0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42-1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group. INTERPRETATION: Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence. FUNDING: Medical Research Council.

Differential expression of the mammalian homologue of fasciclin II during olfactory development in vivo and in vitro.

Developing olfactory sensory neurons are guided to the glomeruli of the olfactory bulb by an increasingly stringent process that is influenced by expression of odorant receptors, cell adhesion molecules (CAMs), and other kinds of signaling cascades. A fundamental feature of the projection is the connecting of broad zones in the epithelium to broad zones in the bulb, also termed rhinotopy. One molecule that parallels and may aid neurons in establishing rhinotopy is the mammalian homologue of fasciclin II (OCAM/mamFas II; also known as RNCAM and NCAM-2), an immunoglobulin superfamily CAM that is differentially expressed in the developing and mature olfactory epithelium (OE): Axons elaborated by ventral and lateral epithelium express the protein at high levels, whereas dorsomedial axons express little or no OCAM/mamFas II. Our investigation has demonstrated that OCAM/mamFas II is detectable early in the development of the rat OE. mRNA is evident on RT-PCR and in situ hybridization by E12.5, and protein is apparent by immunohistochemistry by E13.5. By using a tissue culture system that separates ventral septal epithelium (OCAM/mamFas II-positive) from dorsal (OCAM/mamFas II-negative), we find that explants maintain protein expression levels in vitro that are characteristic of the phenotype at the original location in vivo. At least some neurons are born in culture, suggesting that any cues that direct differential expression are also maintained in vitro. Finally, high OCAM/mamFas II expression correlates with increased growth and fasciculation of olfactory axons in vitro. These data and the similarity between OCAM/mamFas II, on the one hand, and fasciclin II and NCAM, on the other, suggest that OCAM/mamFas II might play a role in growth and fasciculation of primary olfactory axons during development of the projection.

Efficacy, tolerability, and predictors of response to infliximab therapy for Crohn's disease: a large single centre experience.

BACKGROUND: Infliximab is licenced for use in Crohn's disease (CD). Trial data demonstrate that infliximab is effective for inducing remission of active CD, healing fistulising CD, and preventing relapse once in remission. However, long-term data regarding efficacy, safety, and predictors of response are still emerging. AIM: To examine these issues in a large cohort of patients who received infliximab for CD. METHODS: A retrospective analysis of prospectively collected data was performed for 210 patients receiving infliximab for luminal or fistulising CD. Response to infliximab induction therapy, and sustained clinical benefit, were assessed by a decrease in Harvey-Bradshaw Index (HBI) of ≥ 2 points. Remission was defined as an HBI ≤ 4. Physician's global assessment was used where HBI could not be obtained. Demographic and disease factors that may predict response to therapy were analysed by Kaplan-Meier plots and univariate and multivariate analyses. RESULTS: Overall, 173 (82.4%) patients responded to infliximab induction, with 114 (65.9%) achieving sustained clinical benefit. Almost 40% of the study cohort had an HBI ≤ 4, indicating remission, at last point of follow-up (median 24 months). Concomitant immunosuppression predicted sustained clinical benefit in the first 6 months of therapy (P=0.03). An inflammatory disease phenotype (P=0.04 univariate analysis, P=0.03 Kaplan Meier analysis) and male gender (P=0.03) also predicted sustained clinical benefit. Episodic therapy was associated with an increased likelihood of secondary non-response. Adverse events, including malignancies, were few. CONCLUSION: In this single centre study, infliximab was efficacious and well-tolerated in CD.

Survey on the use of adalimumab as maintenance therapy in Crohn's disease in England and Ireland.

INTRODUCTION: Adalimumab is effective in inducing and maintaining response/remission in patients with Crohn's disease either naive to biological therapies or after secondary failure of infliximab. AIM: To present the first 'real-life' survey data from England and Ireland on the use of adalimumab. METHOD: A retrospective audit conducted through a web-based questionnaire in England/Ireland. RESULTS: We analysed data on 61 patients (35 female, 26 male) with a median age of 33 years (range 17-71 years) and an average follow-up of 8 months. The maximal maintenance dose was 40 mg every other week in 84% of patients, 40 mg weekly in 13% and 80 mg weekly in 3%. Maintenance adalimumab achieved remission in 57% of patients. The ongoing response rate was 83.6%. An additional 8% had a secondary loss of response after an average of 8.4 months (range 2-17). Adverse effects were observed in 23% of patients: of which there was local pain in 29%, infection in 36%, headaches in 14%, leucopenia (on azathioprine) in 7%, a painful rash in 7% and serum-sickness-type reaction in 7%. Adverse events led to discontinuation in two patients. CONCLUSION: This English/Irish audit shows an acceptable response/remission and safety profile of adalimumab in the treatment of Crohn's disease. In contrast to earlier data from Scotland, dose escalation was only observed in 16% of patients. The majority of responders were steroid-free at follow-up.

The role of aquaporins in excretion in insects.

One of the aspects of insect osmoregulation that has most intrigued researchers is the ability of a simple tubular epithelium, such as the Malpighian tubule, to create both hypo- and hyperosmotic urine. Indeed, Ramsay's initial observation that isolated tubules could secrete a hypoosmotic urine led him to attribute the phenomenon to the active transport of water. In the ensuing decades several models for solute recycling have been proposed, but only in the last 15 years has it become clear that tubule water permeability is due to the presence of aquaporins (AQPs), the ubiquitous water transport proteins. There are 13 known human AQPs, and they are tissue and even membrane specific. It is now clear that the number and type of AQPs within a membrane are the major determinants of its water transport capacity. There are many gene homologs for the AQPs, so proof of function requires expression of the protein in a defined system. Within the insects, only seven AQPs have been functionally expressed and, of these, four directly or indirectly function in excretion. In this paper we review the basic structure and general function of AQPs and then examine the source, localization and functional attributes of those isolated from insects.