Quebec's Multi-Party Observatory on Zoonoses and Adaptation to Climate Change.

Climate change has been linked with the establishment and geographical expansion of zoonotic diseases, an example of which is the well-documented increase in human cases of Lyme disease in Quebec, Canada. As temperatures continue to increase in Quebec, it is anticipated that several zoonotic diseases will be affected. In response to the growing zoonotic issues facing public health authorities, Quebec's Multi-Party Observatory on Zoonoses and Adaptation to Climate Change (Observatoire multipartite québécois sur les zoonoses et l'adaptation aux changements climatiques) (the Observatory) was founded in 2015 as part of the Quebec government's Climate Change Action Plan (Plan d'action 2013-2020 sur les changements climatiques). The Observatory was designed to bring together agencies involved in formulating public policy and experts from the disciplines of human health, animal health and environmental sciences, in a manner similar to the innovative "One World, One Health" approach. The Observatory provides a platform for knowledge sharing and consensus building among representatives of public policy decision makers and scientists. Its main objectives are to anticipate and prioritize potential issues associated with zoonotic diseases in Quebec, in order to support applicable risk management and climate change adaptation. This article describes what the Observatory is, what it does and outlines its plans for the future.

Impact of indoor air quality on respiratory health: results of a local survey on housing environment.

OBJECTIVES: The 'Mon habitat: plus qu'un simple toit' (MHPQST) survey was designed to identify public health risks and priorities for local decision makers in relation to housing. The aims of the present study were to describe the exposure of households to indoor air contaminants and to verify the relationship between these contaminants and respiratory symptoms/diseases. STUDY DESIGN: This is a cross-sectional study. METHODS: MHPQST was conducted in Baie-Saint-Paul, a French Canadian municipality (7000 inhabitants) using a protocol adapted from the 'Large Analysis and Review of European Housing and Health Status' study performed in Europe in 2002-2003. Households were selected from two sectors (less favorable and more favorable). Data collection was achieved using three tools (two questionnaires and one inspection grid). Indoor air variables were analyzed in relation to respiratory symptoms/diseases using logistic regression models adjusted for age, gender, income, smoking status, and proximity. RESULTS: A total of 161 dwellings (294 inhabitants) participated in the survey. Presence of mold on walls, ceilings, or floors was detected by the investigators in 21% of the dwellings. Nearly half of the households were in contact with a pet at home and 12% with environmental tobacco smoke. Exposure to these three determinants was significantly associated with certain respiratory symptoms/diseases. CONCLUSION: Molds, pets at home, and environmental tobacco smoke are environmental determinants that were associated with respiratory health in the present survey. These results enabled sensitizing local stakeholders regarding the importance of indoor air quality for the respiratory health of their population.

The development of a magnetic resonance imaging index for fistulising Crohn's disease.

BACKGROUND: Magnetic resonance imaging (MRI) is the gold standard for assessment of perianal fistulising Crohn's disease (CD). The Van Assche index is the most commonly used MRI fistula index. AIMS: To assess the reliability of the Van Assche index, and to modify the instrument to improve reliability and create a novel index for fistulising CD. METHODS: A consensus process developed scoring conventions for existing Van Assche index component items and new items. Four experienced radiologists evaluated 50 MRI images in random order on three occasions. Reliability was assessed by estimates of intraclass correlation coefficients (ICCs). Common sources of disagreement were identified and recommendations made to minimise disagreement. A mixed effects model used a 100 mm visual anologue scale (VAS) for global severity as outcome and component items as predictors to create a modified Van Assche index. RESULTS: Intraclass correlation coefficients (95% confidence intervals) for intra-rater reliability of the original and modified Van Assche indices and the VAS were 0.86 (0.81-0.90), 0.90 (0.86-0.93) and 0.86 (0.82-0.89). Corresponding ICCs for inter-rater reliability were 0.66 (0.52-0.76), 0.67 (0.55-0.75) and 0.58 (0.47-0.66). Sources of disagreement included number, location, and extension of fistula tracts, and rectal wall involvement. A modified Van Assche index (range 0-24) was created that included seven component items. CONCLUSIONS: Although "almost perfect" intra-rater reliability was observed for the assessment of MRI images for fistulising CD using the Van Assche index, inter-rater reliability was considerably lower. Our modification of this index should result in a more optimal instrument.

Systematic review with meta-analysis: placebo rates in induction and maintenance trials of Crohn's disease.

BACKGROUND: Minimising placebo response is essential for drug development. AIM: To conduct a meta-analysis to determine placebo response and remission rates in trials and identify the factors affecting these rates. METHODS: MEDLINE, EMBASE and CENTRAL were searched from inception to April 2014 for placebo-controlled trials of pharmacological interventions for Crohn's disease. Placebo response and remission rates for induction and maintenance trials were pooled by random-effects and mixed-effects meta-regression models to evaluate effects of study-level characteristics on these rates. RESULTS: In 100 studies containing 67 induction and 40 maintenance phases and 7638 participants, pooled placebo remission and response rates for induction trials were 18% [95% confidence interval (CI) 16-21%] and 28% (95% CI 24-32%), respectively. Corresponding values for maintenance trials were 32% (95% CI 25-39%) and 26% (95% CI 19-35%), respectively. For remission, trials enrolling patients with more severe disease activity, longer disease duration and more study centres were associated with lower placebo rates, whereas more study visits and longer study duration was associated with higher placebo rates. For response, findings were opposite such that trials enrolling patients with less severe disease activity and longer study duration were associated with lower placebo rates. Placebo rates varied by drug class and route of administration, with the highest placebo response rates observed for biologics. CONCLUSIONS: Placebo rates vary according to whether trials are designed for induction or maintenance and the factors influencing them differ for the endpoints of remission and response. These findings have important implications for clinical trial design in Crohn's disease.

Review article: dose optimisation of infliximab for acute severe ulcerative colitis.

BACKGROUND: Although optimal medical management of acute severe ulcerative colitis (UC) is ill-defined, infliximab has become a standard of care. Accumulating evidence suggests an increased rate of infliximab clearance in patients with acute severe UC and a reduced colectomy rate with an intensified infliximab induction regimen. AIM: To assess the strength of the current evidence for the relationship between infliximab pharmacokinetics, dosing strategies and disease behaviour in patients with acute severe UC. METHODS: We systematically searched MEDLINE and conference proceedings from 2000 to 2016 for relevant articles describing the pharmacokinetics of infliximab in acute severe UC and/or infliximab dose intensification strategies in acute severe UC. Eligible articles described randomised controlled trials, and cohort, cross-sectional, and case-controlled studies. RESULTS: Of 400 citations identified, 76 studies were eligible. Increased infliximab clearance occurs in patients with acute severe UC, and is driven by the total inflammatory burden and leakage of drug into the colonic lumen. Several cohort studies suggest that infliximab dose intensification is beneficial to at least 50% of acute severe UC patients and the results of case-controlled studies indicate that an intensified infliximab dosing regimen with 1-2 additional infusions in the first 3 weeks of treatment could reduce the early (3-month) colectomy rate by up to 80%, although these data require prospective validation. CONCLUSIONS: Uncontrolled studies suggest a benefit for infliximab dose optimisation in patients with acute severe UC. A randomised controlled trial in acute severe UC patients comparing a personalised infliximab dose-optimisation strategy with conventional dosing is a research priority.

Randomised clinical trial: a phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis.

BACKGROUND: Matrix metalloproteinase-9 is a proteolytic enzyme whose expression is increased in ulcerative colitis. AIM: To evaluate the safety and efficacy of GS-5745, a fully humanised anti-matrix metalloproteinase-9 monoclonal antibody, in moderately-to-severely active ulcerative colitis. METHODS: We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS-5745 or placebo. Multiple-dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS-5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS-5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS-5745. Exploratory analyses in the multiple-dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS-5745 were explored using histological and molecular approaches. RESULTS: Twenty-three of the 42 patients (55%) receiving multiple doses of GS-5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS-5745 showed target-mediated drug disposition, approximately dose-proportional increases in maximum plasma concentration and more than dose-proportional increases in the area under the plasma drug concentration-time curve. Clinical response occurred in 18/42 patients (43%) receiving GS-5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS-5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS-5745 had reductions in matrix metalloproteinase-9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation. CONCLUSION: This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS-5745 in the treatment of ulcerative colitis.

IOIBD technical review on endoscopic indices for Crohn's disease clinical trials.

BACKGROUND: Crohn's disease (CD) is a chronic disabling and progressive IBD. Only strategies looking beyond symptoms and based on tight monitoring of objective signs of inflammation such as mucosal lesions may have the potential for disease modification. Endoscopic evaluation is currently the gold standard to assess mucosal lesions and has become a major therapeutic endpoint in clinical trials. Several endoscopic indices have been proposed to evaluate disease activity; unvalidated and arbitrary definitions have been used in clinical trials for defining endoscopic response and endoscopic remission in CD. METHODS: In these recommendations from the International Organization for the Study of Inflammatory Bowel Disease, we first reviewed all technical aspects of available endoscopic scoring systems in the literature. Second, in order to achieve consensus on endoscopic definitions of remission and response in trials, a two-round vote based on a Delphi method was performed among 14 specialists in the field of IBDs. RESULTS: At the end of the voting process, the investigators ranked first a >50% decrease in Simple Endoscopic Score for Crohn's Disease (SES-CD) or Crohn's Disease Endoscopic Index of Severity for the definition of endoscopic response, and an SES-CD 0-2 for the definition of endoscopic remission in CD. All experts agreed on a Rutgeerts' score i0-i1 for the definition of endoscopic remission after surgery.

Development of interim patient-reported outcome measures for the assessment of ulcerative colitis disease activity in clinical trials.

BACKGROUND: Patient-reported outcomes (PROs) have an increasingly important role in the evaluation of new therapies for inflammatory bowel disease. The US Food and Drug Administration has issued formal guidance to describe the role of PRO instruments in evaluation of claims for product labelling. However, no validated PRO exists for ulcerative colitis. AIM: To investigate whether the PROs from the Mayo Clinic Score (MCS) for UC can be modified, to develop an interim PRO for use in clinical trials, alone or in combination with endoscopy. METHODS: Data from an induction trial of a mesalazine (mesalamine) formulation were used to compare effect sizes between mesalazine and placebo for PRO items (stool frequency and rectal bleeding) alone and in combination with endoscopy. The operating properties of the PRO were validated using data from a phase 2 trial of MLN02, a humanised antibody to the α4ß7 integrin in patients with UC. RESULTS: A two-item PRO (PRO2) consisting of rectal bleeding = 0 and stool frequency ≤1 or ≤2, combined with an endoscopy subscore ≤1 yielded statistically significant differences between active drug and placebo. This combination yielded the most similar effect sizes and placebo rates for remission, compared to the primary trials. Use of PRO items alone yielded high placebo remission rates in both data sets, although rates were lower when the items were combined and remission defined as PRO2 = 0. CONCLUSION: Patient-reported outcomes items derived from the Mayo Clinic Score combined with endoscopy as a co-primary endpoint may be an appropriate interim outcome measure for ulcerative colitis trials.

Review article: pharmacological aspects of anti-TNF biosimilars in inflammatory bowel diseases.

BACKGROUND: Anti-tumour necrosis factor (anti-TNF) monoclonal antibodies have shown efficacy in inflammatory bowel diseases (IBD). As these therapies lose patent protection, biosimilar versions of the originator products are being developed, such as the infliximab biosimilar CT-P13; however, some uncertainty exists regarding their pharmacology in IBD. AIM: To review the literature on anti-TNF biosimilars focusing on pharmacokinetics, pharmacodynamic properties and comparative effectiveness, related to their use in IBD. METHODS: A PubMed literature search was performed using the following terms individually or in combination: 'biosimilars,' 'CT-P13,' 'Crohn's disease,' 'inflammatory bowel disease,' 'ulcerative colitis,' 'anti-TNFα therapy,' 'infliximab,' 'adalimumab,' 'pharmacokinetics,' 'immunogenicity.' RESULTS: Bioequivalence of CT-P13 and infliximab was shown in ankylosing spondylitis (AS) and therapeutic equivalence in rheumatoid arthritis (RA). Preliminary results of CT-P13 in IBD come from small post-marketing registries and case series with a relatively short-term follow-up period and suggest comparable efficacy and safety to infliximab. Inter- and intra-individual differences in exposure and response are well known for the original molecules but dosing regimens and concomitant medications are different for RA compared to IBD, limiting the ability to translate some of the pharmacology data in RA to IBD. Uncertainty exists about cross-reactivity of anti-drug antibodies and whether similar exposure-response relationships will be observed for biosimilars and efficacy thresholds for therapeutic drug monitoring can be used interchangeably. CONCLUSIONS: It is likely that biosimilars will be widely used for the treatment of IBD due to their cost savings and comparable efficacy. Nevertheless, robust post-marketing studies and pharmacovigilance are warranted in the coming years.

A retrospective analysis: the development of patient reported outcome measures for the assessment of Crohn's disease activity.

BACKGROUND: The Crohn's Disease Activity Index (CDAI) is a measure of disease activity based on symptoms, signs and a laboratory test. The US Food and Drug Administration has indicated that patient reported outcomes (PROs) should be the primary outcome in randomised controlled trials for Crohn's disease (CD). AIM: As no validated PRO exists for CD, to investigate whether CDAI diary card items could be modified for this purpose. METHODS: Data from a trial of rifaximin-extended intestinal release were used to identify cut-points for stool frequency, pain and general well-being using receiver operating characteristic curves with CDAI <150 as criterion. The operating properties of 2- and 3-item PRO were evaluated using data from a trial of methotrexate in CD. Regression analysis determined PRO2 and PRO3 scores that correspond to CDAI-defined thresholds of 150, 220 and 450 and changes of 50, 70 and 100 points. RESULTS: Optimum cut-points for CDAI remission were mean daily stool frequency ≤1.5, abdominal pain ≤1, and general well-being score of ≤1 (areas under the ROC curve 0.79, 0.91 and 0.89, respectively). The effect estimates were similar using 2- and 3-item PROs or CDAI. PRO2 and PRO3 values corresponding to CDAI scores of 150, 220 and 450 points were 8, 14, 34 and 13, 22, 53. The corresponding values for CDAI changes of 50, 70 and 100, were 2, 5, 8 and 5, 9, 14. Responsiveness to change was similar for both PROs. CONCLUSION: Patient reported outcomes derived from CDAI diary items may be appropriate for use in clinical trials for CD.

Validated gene expression biomarker analysis for biopsy-based clinical trials in ulcerative colitis.

BACKGROUND: Accurate and reproducible measurement of expression of pro-inflammatory cytokines in colonic biopsies from patients with ulcerative colitis (UC) is essential for proof-of-concept and mechanism-of-action studies. Few studies have rigorously established the number of biopsies required for accurate and reproducible biomarker measurements. AIM: To validate methods for measuring changes in gene expression in colonic biopsy samples. METHODS: Twelve colonic biopsies were obtained from each of six healthy controls, six patients with inactive UC and seven patients with active UC. Mayo endoscopic scores were used as a clinical reference standard. Quantitative PCR was used to assess mRNA expression of eight known inflammatory genes. The power to detect a reduction in gene expression in active vs. inactive UC was calculated using a linear mixed effect model. RESULTS: mRNA analysis of colonic biopsies is a sensitive and feasible approach for measuring inflammatory gene expression in colonic biopsies. Inflammatory biomarkers correlate with Mayo endoscopic subscores for each colonic region. For most genes, three rectal biopsies from two to four patients are required to detect changes in gene expression corresponding to active vs. inactive UC to achieve a power of 80% with an alpha of 0.05. CONCLUSION: Our data suggest that systematic measurement of inflammatory biomarkers at the mRNA level can be a valuable tool for hypothesis testing, and assessment of clinical activity and response to therapy in ulcerative colitis.

A prospective cohort study to determine the relationship between serum infliximab concentration and efficacy in patients with luminal Crohn's disease.

BACKGROUND: Patients with Crohn's disease (CD) may experience disease relapse on maintenance infliximab. Anti-drug antibodies likely contribute to loss of response, and serum infliximab levels likely correlate with efficacy. AIM: To prospectively evaluate the relationship between trough serum infliximab concentration and disease activity. METHODS: Adult patients (N = 327) with a diagnosis of CD who had received at least five consecutive infliximab infusions and who planned to receive at least two additional infusions were enrolled. The Crohn's Disease Activity Index (CDAI), serum infliximab, C-reactive protein (CRP) and antibodies-to-infliximab (ATI) were assessed at baseline, week 4 and week 8. Receiver operating characteristic (ROC) analysis examined the relationship between infliximab concentrations and disease activity. RESULTS: The mean CDAI score, which decreased 1.05 points between infusions, did not correlate with the mean change in trough infliximab concentration (+0.39 µg/mL; r = 0.099, P = 0.083), but was associated with the mean change in CRP concentration (r = 0.19, P < 0.001). Trough infliximab concentrations below 2.8-4.6 µg/mL best predicted a ≥ 70 point increase in the CDAI between infusions, and those below 2.7-2.8 µg/mL best predicted CRP >5 mg/mL at the second infusion. ATI at either visit decreased the proportion of patients with therapeutic infliximab trough levels compared with patients who were ATI negative (17.5% vs. 77.3% at visit 1 and 13.8% vs. 75.6% at visit 3; P < 0.001 for both comparisons). CONCLUSIONS: This prospective study confirms the relationship between trough infliximab concentrations, inflammation and antibodies-to-infliximab. Infliximab trough concentrations below 3 µg/mL may increase the likelihood of symptoms and inflammation (ClinicalTrials.gov identifier: NCT00676988).

Seroprevalence of seven zoonotic infections in Nunavik, Quebec (Canada).

In Nunavik, common practices and food habits such as consumption of raw meat and untreated water place the Inuit at risk for contracting zoonotic diseases. The aim of this study was to determine the seroprevalence of seven zoonotic infections among the permanent residents of Nunavik. The study was conducted in the fall 2004 as part of the Nunavik Health Survey. Blood samples from adults aged 18-74 years (n = 917) were collected and analysed for the presence of antibodies against Trichinella spp., Toxocara canis, Echinococcus granulosus, Brucella spp., Coxiella burnetii, Leptospira spp. and Francisella tularensis. Information on sociodemographic characteristics, traditional activities, drinking water supply and nutrition was gathered using english/inuktitut bilingual questionnaires. The chi-squared test was used to evaluate associations between seropositivity and other measured variables. Statistically significant variables were included in a multivariate logistic regression model to control for confounding factors. Estimated seroprevalences were 8.3% for E. granulosus, 3.9% for T. canis, 5.9% for Leptospira spp. and 18.9% for F. tularensis. Seroprevalence was ≤ 1% for Trichinella spiralis, Brucella spp. and C. burnetii. For most infections, seropositivity tended to increase with age. In multivariate analyses, seroprevalence was positively (i.e. directly) associated with age and residence in the Ungava coast area for F. tularensis; age and residence in the Hudson coast area for T. canis; female gender, lower level of schooling and frequent cleaning of water reservoirs for E. granulosus. No risk factor for Leptospira spp. infection was identified. No associations were detected with regards to food habits or environmental exposures. A small but significant portion of the Nunavik population has serologic evidence of exposure to at least one of the pathogenic microorganisms investigated. Further studies are needed to better understand the mechanisms for transmission of zoonotic infections and their potential reservoirs in Nunavik.

Spatio-temporal variations and age effect on Toxoplasma gondii seroprevalence in seals from the Canadian Arctic.

Toxoplasmosis is a significant public health threat for Inuit in the Canadian Arctic. This study aimed to investigate arctic seals as a possible food-borne source of infection. Blood samples collected from 828 seals in 7 Canadian Arctic communities from 1999 to 2006 were tested for Toxoplasma gondii antibodies using a direct agglutination test. Polymerase chain reaction (PCR) was used to detect T. gondii DNA in tissues of a subsample of seals. Associations between seal age, sex, species, diet, community and year of capture, and serological test results were investigated by logistic regression. Overall seroprevalence was 10·4% (86/828). All tissues tested were negative by PCR. In ringed seals, seroprevalence was significantly higher in juveniles than in adults (odds ratio=2·44). Overall, seroprevalence varied amongst communities (P=0·0119) and by capture year (P=0·0001). Our study supports the hypothesis that consumption of raw seal meat is a significant source of infection for Inuit. This work raises many questions about the mechanism of transfer of this terrestrial parasite to the marine environment, the preponderance of infection in younger animals and the natural course of infection in seals. Further studies to address these questions are essential to fully understand the health risks for Inuit communities.

Assessment of real-time PCR for quantification of Legionella spp. in spa water.

AIMS: Legionella bacteria ubiquitously colonize natural freshwater and are responsible for legionellosis in humans. Several cases of legionellosis have been associated in particular with the use of whirlpool spas. The objective of this study was to verify whether real-time PCR is applicable for the quantification of Legionella spp. in spa water. METHODS AND RESULTS: The study compared concentrations obtained by real-time PCR vs that obtained by conventional culture for 101 spa water samples. For the culture method, Legionella spp. were detected and quantified in 14 of 101 samples with measured concentrations ranging from 250 to 3.5 × 10(5) CFU l(-1). With the real-time PCR method, Legionella spp. were detected and quantified in 42 of 101 samples with concentrations ranging from 1000 to 6.1 × 10(7) GU l(-1). Results revealed a significant but weak correlation (r(2) = 0.1867) between the two methods. The positive predictive value (35%) of the PCR method compared to conventional culture herein was low. In contrast, the negative predictive value was excellent, reaching 93%. CONCLUSIONS: Real-time PCR could be used as a screening tool to rapidly ascertain the absence of Legionella spp. in spa water. However, a positive result involves the need to resort to conventional culture. SIGNIFICANCE AND IMPACT OF THE STUDY: Data of this study highlighted the pros and cons of quantification of Legionella spp. in spa water with real-time PCR using a commercial quantitative PCR kit in a routine laboratory, when compared to conventional culture.