Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus.

BACKGROUND: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. OBJECTIVE: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. METHODS: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. RESULTS: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. CONCLUSIONS: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.

Effects of smoking on clinical treatment outcomes amongst patients with chronic inflammatory diseases initiating biologics: secondary analyses of the prospective BELIEVE cohort study.

The prevalence and disease burden of chronic inflammatory diseases (CIDs) are predicted to rise. Patients are commonly treated with biological agents, but the individual treatment responses vary, warranting further research into optimizing treatment strategies. This study aimed to compare the clinical treatment responses in patients with CIDs initiating biologic therapy based on smoking status, a notorious risk factor in CIDs. In this multicentre cohort study including 233 patients with a diagnosis of Crohn's disease, ulcerative colitis, rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis or psoriasis initiating biologic therapy, we compared treatment response rates after 14 to 16 weeks and secondary outcomes between smokers and non-smokers. We evaluated the contrast between groups using logistic regression models: (i) a "crude" model, only adjusted for the CID type, and (ii) an adjusted model (including sex and age). Among the 205 patients eligible for this study, 53 (26%) were smokers. The treatment response rate among smokers (n = 23 [43%]) was lower compared to the non-smoking CID population (n = 92 [61%]), corresponding to a "crude" OR of 0.51 (95% CI: [0.26;1.01]) while adjusting for sex and age resulted in consistent findings: 0.51 [0.26;1.02]. The contrast was apparently most prominent among the 38 RA patients, with significantly lower treatment response rates for smokers in both the "crude" and adjusted models (adjusted OR 0.13, [0.02;0.81]). Despite a significant risk of residual confounding, patients with CIDs (rheumatoid arthritis in particular) should be informed that smoking probably lowers the odds of responding sufficiently to biological therapy. Registration: Clinical.Trials.gov NCT03173144.

Impact of gluten intake on clinical outcomes in patients with chronic inflammatory diseases initiating biologics: Secondary analysis of the prospective multicentre BELIEVE cohort study.

Chronic inflammatory diseases (CIDs) pose a growing healthcare challenge, with a substantial proportion of patients showing inadequate response to biological treatment. There is renewed interest in dietary changes to optimize treatment regimens, with a growing body of evidence suggesting beneficial effects with adherence to a gluten-free diet. This study compared the likelihood of achieving clinical response to biological treatment after 14-16 weeks in patients with CID with high versus low-to-medium gluten intake. Secondary outcomes of interest included changes in disease activity, health-related quality of life and C-reactive protein. The study was a multicentre prospective cohort of 193 participants with a CID diagnosis (i.e. Crohn's Disease, Ulcerative Colitis, Rheumatoid Arthritis, Axial Spondyloarthritis, Psoriatic Arthritis or Psoriasis) who initiated biological treatment between 2017 and 2020. Participants were stratified based on their habitual gluten intake: the upper 33.3% (high gluten intake) and the remaining 66.6% (low-to-medium gluten intake). The proportion of patients achieving clinical response to biological treatment after 14-16 weeks was compared using logistic regression models. The median gluten intake differed significantly between groups (12.5 g/day vs. 5.9 g/day, standardized mean difference = 1.399). In total, 108 (56%) achieved clinical response to treatment, with no difference between 35 (55%) in the high gluten group and 73 (57%) in the medium-to-low gluten group (OR = 0.96 [0.51-1.79], p = 0.897). No differences were found with secondary outcomes. In conclusion, this study found no association between gluten intake and response to biological treatment in patients with CID.

Microfibrillar-associated protein 4 as a predictive biomarker of treatment response in patients with chronic inflammatory diseases initiating biologics: secondary analyses based on the prospective BELIEVE cohort study.

BACKGROUND: Currently, there are no reliable biomarkers for predicting treatment response in chronic inflammatory diseases (CIDs). OBJECTIVE: To determine whether serum microfibrillar-associated protein 4 (MFAP4) levels can predict the treatment response to biological therapy in patients with CIDs. METHODS: The BELIEVE study was originally designed as a prospective, multi-center cohort study of 233 patients with either rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, Crohn's disease, or ulcerative colitis, initiating treatment with a biologic agent (or switching to another). Clinical assessment and blood sample collection were performed at baseline and 14-16 weeks after treatment initiation. The primary analyses included participants with available blood samples at baseline; missing data were handled as non-responders. The patients were stratified into the upper tertile of serum MFAP4 (High MFAP4) versus a combined category of middle and lower tertiles (Other MFAP4). The primary outcome was the proportion of patients with clinical response to biologic therapy after 14-16 weeks. RESULTS: 211 patients were included in the primary analysis population. The mean age was 43.7 (SD: 14.8) years, and 120 (59%) were female. Positive treatment response was observed in 41 (59%) and 69 (49%) for High MFAP4 and Other MFAP4, respectively. When adjusting for pre-specified variables (CID, age, sex, smoking status, and BMI), the adjusted OR was 2.28 (95% CI: 1.07 to 4.85) for a positive treatment outcome in the High MFAP4 group. CONCLUSION: A high MFAP4 status before initiating biological treatment is associated with a positive clinical response, when adjusting for confounding factors.

The Association between Genetics and Response to Treatment with Biologics in Patients with Psoriasis, Psoriatic Arthritis, Rheumatoid Arthritis, and Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis.

Genetic biomarkers could potentially lower the risk of treatment failure in chronic inflammatory diseases (CID) like psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). We performed a systematic review and meta-analysis assessing the association between single nucleotide polymorphisms (SNPs) and response to biologics. Odds ratio (OR) with 95% confidence interval (CI) meta-analyses were performed. In total, 185 studies examining 62,774 individuals were included. For the diseases combined, the minor allele of MYD88 (rs7744) was associated with good response to TNFi (OR: 1.24 [1.02-1.51], 6 studies, 3158 patients with psoriasis or RA) and the minor alleles of NLRP3 (rs4612666) (OR: 0.71 [0.58-0.87], 5 studies, 3819 patients with RA or IBD), TNF-308 (rs1800629) (OR: 0.71 [0.55-0.92], 25 studies, 4341 patients with psoriasis, RA, or IBD), FCGR3A (rs396991) (OR: 0.77 [0.65-0.93], 18 studies, 2562 patients with psoriasis, PsA, RA, or IBD), and TNF-238 (rs361525) (OR: 0.57 [0.34-0.96]), 7 studies, 818 patients with psoriasis, RA, or IBD) were associated with poor response to TNFi together or infliximab alone. Genetic variants in TNFα, NLRP3, MYD88, and FcRγ genes are associated with response to TNFi across several inflammatory diseases. Most other genetic variants associated with response were observed in a few studies, and further validation is needed.

Fine-mapping inflammatory bowel disease loci to single-variant resolution.

Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

The Danish-American Research Exchange (DARE): a cross-sectional study of a binational research education program.

BACKGROUND: Most medical educational programs emphasize clinical observation or clinical skill acquisition, fewer focus upon research. The Danish-American Research Exchange (DARE) program, sponsored by the Lundbeck Foundation, is unique in that the medical student initiates biomedical research collaboration between Danish and US medical institutions. To achieve this, Danish medical students (DARE students) conduct binational mentored research projects while based in the United States for 10 months. In addition, DARE students are introduced to interdisciplinary thinking about how to develop ultra-low-cost healthcare interventions through the '$10 Challenge'. METHODS: We conducted a cross-sectional study of DARE alumni over five consecutive years (2015-2020, n = 24). Research metrics included completion of a research project, primary authorship, and co-authorship of publications. The number of publications, prior to and after the DARE program were enumerated. For the first four cohorts, graduation from medical school and acceptance or intention to enter a joint MD-PhD program also were assessed. Two focus groups were conducted using constructivist grounded theory. Discussions were transcribed, redacted, and coded using Dedoose software. RESULTS: DARE Medical students were 31.2 years (range 24-35), the majority were women (67%;16/24). The majority (17/24;71%) completed a first author publication in a peer-reviewed journal with a median of 3.9 per DARE alumnus. DARE alumnus reported increased proficiency in biostatistics, epidemiology, coding and public speaking as well as stronger research qualities in creativity, critical thinking, comfort in approaching scientist in both the US and Denmark (p < 0.001 for all). Qualitative key themes included: increased confidence, a deepening of research inquiry and linkage to a research network. CONCLUSIONS: Preliminarily, this study suggests that medical students can initiate binational collaboration in medicine. Benefits include research productivity, intention to pursue academic medical careers, as well as positive impacts on motivation. This medical student-initiated research model lays the groundwork for using this model across other country pairs to promote binational collaboration.

Investigating the Crime Scene-Molecular Signatures in Inflammatory Bowel Disease.

Inflammatory bowel diseases (IBD) are without cure and troublesome to manage because of the considerable diversity between patients and the lack of reliable biomarkers. Several studies have demonstrated that diet, gut microbiota, genetics and other patient factors are essential for disease occurrence and progression. Understanding the link between these factors is crucial for identifying molecular signatures that identify biomarkers to advance the management of IBD. Recent technological breakthroughs and data integration have fuelled the intensity of this research. This research demonstrates that the effect of diet depends on patient factors and gut microbial activity. It also identifies a range of potential biomarkers for IBD management, including mucosa-derived cytokines, gasdermins and neutrophil extracellular traps, all of which need further evaluation before clinical translation. This review provides an update on cutting-edge research in IBD that aims to improve disease management and patient quality of life.

Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10-9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10-4-5.79 × 10-14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10-4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10-4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10-4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3- B cells, CD5+IgD- cells, IgM- cells, IgD-IgM- cells, and CD4-CD8- PBMCs (p = 4.9 × 10-4-8.6 × 10-4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27- cells (p = 9.3 × 10-4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3-, MCP-2-, and IL20-dependent pathways.

Common gene variants within 3'-untranslated regions as modulators of multiple myeloma risk and survival.

We evaluated the association between germline genetic variants located within the 3'-untranlsated region (polymorphic 3'UTR, ie, p3UTR) of candidate genes involved in multiple myeloma (MM). We performed a case-control study within the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 3056 MM patients and 1960 controls recruited from eight countries. We selected p3UTR of six genes known to act in different pathways relevant in MM pathogenesis, namely KRAS (rs12587 and rs7973623), VEGFA (rs10434), SPP1 (rs1126772), IRF4 (rs12211228) and IL10 (rs3024496). We found that IL10-rs3024496 was associated with increased risk of developing MM and with a worse overall survival of MM patients. The variant allele was assayed in a vector expressing eGFP chimerized with the IL10 3'-UTR and it was found functionally active following transfection in human myeloma cells. In this experiment, the A-allele caused a lower expression of the reporter gene and this was also in agreement with the in vivo expression of mRNA measured in whole blood as reported in the GTEx portal. Overall, these data are suggestive of an effect of the IL10-rs3024496 SNP on the regulation of IL10 mRNA expression and it could have clinical implications for better characterization of MM patients in terms of prognosis.

Safety and efficacy of faecal microbiota transplantation for active peripheral psoriatic arthritis: an exploratory randomised placebo-controlled trial.

OBJECTIVES: Although causality remains to be established, targeting dysbiosis of the intestinal microbiota by faecal microbiota transplantation (FMT) has been proposed as a novel treatment for inflammatory diseases. In this exploratory, proof-of-concept study, we evaluated the safety and efficacy of FMT in psoriatic arthritis (PsA). METHODS: In this double-blind, parallel-group, placebo-controlled, superiority trial, we randomly allocated (1:1) adults with active peripheral PsA (≥3 swollen joints) despite ongoing treatment with methotrexate to one gastroscopic-guided FMT or sham transplantation into the duodenum. Safety was monitored throughout the trial. The primary efficacy endpoint was the proportion of participants experiencing treatment failure (ie, needing treatment intensification) through 26 weeks. Key secondary endpoints were change in Health Assessment Questionnaire Disability Index (HAQ-DI) and American College of Rheumatology (ACR20) response at week 26. RESULTS: Of 97 screened, 31 (32%) underwent randomisation (15 allocated to FMT) and 30 (97%) completed the 26-week clinical evaluation. No serious adverse events were observed. Treatment failure occurred more frequently in the FMT group than in the sham group (9 (60%) vs 3 (19%); risk ratio, 3.20; 95% CI 1.06 to 9.62; p=0.018). Improvement in HAQ-DI differed between groups (0.07 vs 0.30) by 0.23 points (95% CI 0.02 to 0.44; p=0.031) in favour of sham. There was no difference in the proportion of ACR20 responders between groups (7 of 15 (47%) vs 8 of 16 (50%)). CONCLUSIONS: In this first preliminary, interventional randomised controlled trial of FMT in immune-mediated arthritis, we did not observe any serious adverse events. Overall, FMT appeared to be inferior to sham in treating active peripheral PsA. TRIAL REGISTRATION NUMBER: NCT03058900.

Are Systemic Corticosteroids Causing Psoriasis Flare-Ups? Questionnaire for Danish Dermatologists, Gastroenterologists and Rheumatologists.

BACKGROUND: Psoriasis flare-ups and the change of morphology from nonpustular to pustular psoriasis following tapering and withdrawal of systemic corticosteroids have been reported. Despite these risks, systemic corticosteroids are still widely prescribed for patients with psoriasis, but the knowledge about psoriasis flare-ups and whether the physicians take precautions during these treatments is limited. METHODS: We conducted a questionnaire study among all dermatologists, gastroenterologists and rheumatologists in Denmark who work at a hospital or in a private practice to investigate the use, opinion and experience with oral, intramuscular and intra-articular corticosteroids in the treatment of patients with psoriasis. RESULTS: We received answers from a total of 248 physicians. Compared with oral and intramuscular corticosteroids, intra-articular corticosteroids were the most reported treatment in patients with psoriasis and only used by the rheumatologists. It was mainly the dermatologists and rheumatologists who had observed psoriasis flare-ups following treatment with oral, intramuscular and intra-articular corticosteroids. Half of the dermatologists (50%) and a fourth of the rheumatologists (29%) had observed at least one psoriasis flare-up following treatment with oral corticosteroids. About 10% of both the dermatologists and the rheumatologists had observed at least one psoriasis flare-up following treatment with intramuscular and/or intra-articular corticosteroids. Overall, 44% of the respondents took precautions, when they treated a patient with psoriasis with oral, intramuscular and intra-articular corticosteroids. CONCLUSION: The results from the questionnaire indicate that systemic corticosteroids for patients with psoriasis can cause flare-ups and should be used with care.

Associations between participation in, intensity of, and time spent on leisure time physical activity and risk of inflammatory bowel disease among older adults (PA-IBD): a prospective cohort study.

BACKGROUND: Inflammatory bowel diseases (IBDs) are diseases of the immune system that share some genetic and lifestyle-related predisposing factors. Increasing incidences have been reported in all age groups. Based on experimental studies suggesting a role of physical activity on intestinal inflammation, this study aimed to investigate the association between leisure time physical activity and the risk of IBD in older adults. METHODS: The study is a prospective cohort study using Danish registry data and questionnaire data from the Danish "Diet, Cancer and Health" cohort. The outcome IBD was defined as having at least two main diagnoses of Crohn's disease or ulcerative colitis registered in the National Patient Registry from the period between December 1993 and May 1997 with an average follow-up of 25 years. Cox proportional hazard models were used to estimate hazard-ratios for IBD onset associated with being physically active and with levels of the metabolic equivalent of task (MET) hours/week of physical activity and hours/week spent on six types of physical activity. All analyses were adjusted for potential confounders. Furthermore, the analyses were stratified according to age-group, occupational physical activity, smoking, BMI and work status to test for effect modification. RESULTS: In total, 54,645 men and women aged between 50 and 64 years were included, and of which there were 529 cases. When comparing physically active with inactive participants measured by MET hours/week there was no statistically significant difference in risk of IBD (0.89 [0.13; 6.27]), regardless of how participation was measured. Results did not indicate any dose-response effect when comparing quartile groups of MET hours/week (HR = 0.97 [0.76; 1.22], HR = 0.82 [0.64; 1.05] and HR = 0.83 [0.65; 1.07] or whether five of the six types of activities were compared with the lowest quartile as reference. For do-it-yourself-work, the third quartile of hours/week was associated with a higher risk of IBD compared to the second quartile of hours/week (HR = 1.44 [1.10; 1.90]. No effect modification was found. CONCLUSIONS: There was no association between physical activity and risk of IBD when comparing physically active with inactive participants. Neither did the results indicate any dose-response effect when comparing quartile groups of MET hours/week with the lowest quartile as reference. Do-it-yourself work, however, appeared to be associated with a higher risk of IBD when comparing the third quartile with the second quartile of hours/week. The study has clinical relevance by its contribution to the explanatory field of the causes of IBD. However, the study has some limitations, and further research is needed to clarify associations between physical activity and risk of IBD.

Intake of dietary fibre, red and processed meat and risk of late-onset Chronic Inflammatory Diseases: A prospective Danish study on the "diet, cancer and health" cohort.

Background: Human and animal studies support the involvement of diet in the development of CID -chronic inflammatory diseases such as inflammatory bowel disease, psoriasis, rheumatoid arthritis, psoriatic arthritis, and multiple sclerosis. Objective: This cohort study aimed to investigate the association between intake of fibre, red and processed meat, and occurrence of late-onset CID (50+ years of age) in the DCH: Danish Diet, Cancer and Health cohort. We hypothesised that risk of late-onset CID would be lower among those with high intake of fibre and/or low intake of meat compared to individuals with low fibre and/or high meat intake. Methods: The DCH recruited 56,468 individuals, aged 50-64 years, between 1993 and 1997. At recruitment, diet intake was registered using food frequency questionnaires as well as lifestyle factors in 56,075 persons. Exposure variables were generated as sex-adjusted tertiles of fibre and meat (g/day). Development of CIDs was identified in national registries. Hazard ratios (HR) of late-onset CIDs (adjusted for age, sex, energy intake, alcohol, smoking, education, comorbidity, and civil status) were estimated for all three exposure variables. Results: During follow-up of 1,123,754 years (median (Interquartile range) = 22.2 (20.1-23.1)), 1,758 (3.1%) participants developed at least one CID. The adjusted HRs for developing CID (low fibre 1.04 [0.89-1.22] and medium fibre 1.04 [0.91-1.18] (high fibre as reference), and medium meat 0.96 [0.86-1.09] and high meat 0.94 [0.82-1.07] (low meat as reference)) or the individual diseases were not statistically significant. Conclusion: This large study did not support that a high intake of fibre and/or a low intake of meat had a high impact on the risk of late-onset CID.

Translational Potential of Metabolomics on Animal Models of Inflammatory Bowel Disease-A Systematic Critical Review.

In the development of inflammatory bowel disease (IBD), the gut microbiota has been established as a key factor. Recently, metabolomics has become important for understanding the functional relevance of gut microbial changes in disease. Animal models for IBD enable the study of factors involved in disease development. However, results from animal studies may not represent the human situation. The aim of this study was to investigate whether results from metabolomics studies on animal models for IBD were similar to those from studies on IBD patients. Medline and Embase were searched for relevant studies up to May 2017. The Covidence systematic review software was used for study screening, and quality assessment was conducted for all included studies. Data showed a convergence of ~17% for metabolites differentiated between IBD and controls in human and animal studies with amino acids being the most differentiated metabolite subclass. The acute dextran sodium sulfate model appeared as a good model for analysis of systemic metabolites in IBD, but analytical platform, age, and biological sample type did not show clear correlations with any significant metabolites. In conclusion, this systematic review highlights the variation in metabolomics results, and emphasizes the importance of expanding the applied detection methods to ensure greater coverage and convergence between the various different patient phenotypes and animal models of inflammatory bowel disease.

Natural disease course of Crohn's disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study.

OBJECTIVE: The Epi-IBD cohort is a prospective population-based inception cohort of unselected patients with inflammatory bowel disease from 29 European centres covering a background population of almost 10 million people. The aim of this study was to assess the 5-year outcome and disease course of patients with Crohn's disease (CD). DESIGN: Patients were followed up prospectively from the time of diagnosis, including collection of their clinical data, demographics, disease activity, medical therapy, surgery, cancers and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis. RESULTS: In total, 488 patients were included in the study. During follow-up, 107 (22%) patients received surgery, while 176 (36%) patients were hospitalised because of CD. A total of 49 (14%) patients diagnosed with non-stricturing, non-penetrating disease progressed to either stricturing and/or penetrating disease. These rates did not differ between patients from Western and Eastern Europe. However, significant geographic differences were noted regarding treatment: more patients in Western Europe received biological therapy (33%) and immunomodulators (66%) than did those in Eastern Europe (14% and 54%, respectively, P<0.01), while more Eastern European patients received 5-aminosalicylates (90% vs 56%, P<0.05). Treatment with immunomodulators reduced the risk of surgery (HR: 0.4, 95% CI 0.2 to 0.6) and hospitalisation (HR: 0.3, 95% CI 0.2 to 0.5). CONCLUSION: Despite patients being treated early and frequently with immunomodulators and biological therapy in Western Europe, 5-year outcomes including surgery and phenotype progression in this cohort were comparable across Western and Eastern Europe. Differences in treatment strategies between Western and Eastern European centres did not affect the disease course. Treatment with immunomodulators reduced the risk of surgery and hospitalisation.

Correction: Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients.

The original version of this Article contained an error in the spelling of the author Ana Rodríguez-Ramos, which was incorrectly given as Ana Rodríguez Ramos. This has now been corrected in both the PDF and HTML versions of the Article.

Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients.

The aim of this case-control study was to evaluate whether 47 single-nucleotide polymorphisms (SNPs) in steroid hormone-related genes are associated with the risk of RA and anti-TNF drug response. We conducted a case-control study in 3 European populations including 2936 RA patients and 2197 healthy controls. Of those, a total of 1985 RA patients were treated with anti-TNF blockers. The association of potentially interesting markers in the discovery population was validated through meta-analysis with data from DREAM and DANBIO registries. Although none of the selected variants had a relevant role in modulating RA risk, the meta-analysis of the linear regression data with those from the DREAM and DANBIO registries showed a significant correlation of the CYP3A4rs11773597 and CYP2C9rs1799853 variants with changes in DAS28 after the administration of anti-TNF drugs (P = 0.00074 and P = 0.006, respectively). An overall haplotype analysis also showed that the ESR2GGG haplotype significantly associated with a reduced chance of having poor response to anti-TNF drugs (P = 0.0009). Finally, a ROC curve analysis confirmed that a model built with eight steroid hormone-related variants significantly improved the ability to predict drug response compared with the reference model including demographic and clinical variables (AUC = 0.633 vs. AUC = 0.556; PLR_test = 1.52 × 10-6). These data together with those reporting that the CYP3A4 and ESR2 SNPs correlate with the expression of TRIM4 and ESR2 mRNAs in PBMCs (ranging from P = 1.98 × 10-6 to P = 2.0 × 10-35), and that the CYP2C9rs1799853 SNP modulates the efficiency of multiple drugs, suggest that steroid hormone-related genes may have a role in determining the response to anti-TNF drugs.KEY POINTS• Polymorphisms within the CYP3A4 and CYP2C9 loci correlate with changes in DAS28 after treatment with anti-TNF drugs.• A haplotype including eQTL SNPs within the ESR2 gene associates with better response to anti-TNF drugs.• A genetic model built with eight steroid hormone-related variants significantly improved the ability to predict drug response.

Risk factors for contagious gastroenteritis in adult patients with diarrhoea in the emergency department - a prospective observational multicentre study.

BACKGROUND: Infectious gastroenteritis is common in the emergency department (ED). Patients infected with either Norovirus or toxigenic Clostridium difficile require special isolation procedures. The aims were to describe the aetiology of infectious gastroenteritis in the ED, evaluate whether current isolation procedures, based on clinical judgement are sufficient, and to identify information that might be used to identify patients requiring isolation. METHODS: Prospective, observational, multicentre study. We collected information on symptoms, vital signs, travel history, the recent use of antibiotics, and infectious contacts and tested faecal samples for Norovirus, C. difficile, and enteropathogenic bacteria. RESULTS: The study enrolled 227 patients, of whom 163 (71%) delivered a faecal sample for Norovirus analysis (13% positive), 171 (74%) for C. difficile (13% positive), and 173 (76%) for enteropathogenic bacteria (16% positive). In total 71% of the patients were isolated using strict precautions, 29% of the isolated patient and 14% of the patients who were not isolated had had a highly contagious GE. Risk factors for Norovirus included frequent vomiting (OR 5.5), recent admission of another patient with Norovirus (OR 2.6), and a short duration of diarrhoea. Risk factors for C. difficile infections included older age (OR 6.0), longer duration of diarrhoea (OR 5.2), mucus in stool (OR 3.5), and previous antibiotic use (OR 23.4). CONCLUSION: Highly contagious GE occurs in » of the GE patients in the EDs, isolation based on clinical judgement is not very efficient. Several risk factors can predict the presence of Norovirus or toxigenic Clostridium difficile. It is uncertain whether this knowledge can improve isolation practices in ED settings. TRIAL REGISTRATION: This study was retrospectively registered in the Clinical Trials Data Base ( NCT02685527 ) and prospectively approved by the Regional Committees on Health Research Ethics for Southern Denmark (project ID S20140200) and Ethics Committee at the Medical Association of Schleswig-Holstein ["Ethikkommission bei der Ärztekammer Schleswig-Holstein", project ID 120/15(I)] and registered with the Danish Data Protection Agency (project ID nr. 2008-58-0035/ 1608).

Disease course of inflammatory bowel disease unclassified in a European population-based inception cohort: An Epi-IBD study.

BACKGROUND AND AIM: A definitive diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) is not always possible, and a proportion of patients will be diagnosed as inflammatory bowel disease unclassified (IBDU). The aim of the study was to investigate the prognosis of patients initially diagnosed with IBDU and the disease course during the following 5 years. METHODS: The Epi-IBD study is a prospective population-based cohort of 1289 IBD patients diagnosed in centers across Europe. Clinical data were captured prospectively throughout the follow-up period. RESULTS: Overall, 476 (37%) patients were initially diagnosed with CD, 701 (54%) with UC, and 112 (9%) with IBDU. During follow-up, 28 (25%) IBDU patients were changed diagnoses to either UC (n = 20, 71%) or CD (n = 8, 29%) after a median of 6 months (interquartile range: 4-12), while 84 (7% of the total cohort) remained IBDU. A total of 17 (15%) IBDU patients were hospitalized for their IBD during follow-up, while 8 (7%) patients underwent surgery. Most surgeries (n = 6, 75%) were performed on patients whose diagnosis was later changed to UC; three of these colectomies led to a definitive diagnosis of UC. Most patients (n = 107, 96%) received 5-aminosalicylic acid, while 11 (10%) patients received biologicals, of whom five remained classified as IBDU. CONCLUSIONS: In a population-based inception cohort, 7% of IBD patients were not given a definitive diagnosis of IBD after 5 years of follow-up. One in four patients with IBDU eventually was classified as CD or UC. Overall, the disease course and medication burden in IBDU patients were mild.