Maria Kłopocka

Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial

BACKGROUND Filgotinib (GLPG0634, GS-6034) is a once-daily, orally administered, Janus kinase 1 (JAK1)-selective inhibitor. The FITZROY study examined the efficacy and safety of filgotinib for the treatment of moderate-to-severe Crohns disease. METHODS We did a randomised, double-blind, placebo-controlled phase 2 study, which recruited patients from 52 centres in nine European countries. We enrolled eligible patients aged 18-75 years with a documented history of ileal, colonic, or ileocolonic Crohns disease for 3 months or more before screening, as assessed by colonoscopy and supported by histology, and a Crohns Disease Activity Index (CDAI) score during screening between 220 and 450 inclusive. Patients were randomly assigned (3:1) to receive filgotinib 200 mg once a day or placebo for 10 weeks. Patients were stratified according to previous anti-tumour necrosis factor alpha exposure, C-reactive protein concentration at screening (≤10 mg/L or >10 mg/L), and oral corticosteroid use at baseline, using an interactive web-based response system. The primary endpoint was clinical remission, defined as CDAI less than 150 at week 10. After week 10, patients were assigned based on responder status to filgotinib 100 mg once a day, filgotinib 200 mg once a day, or placebo for an observational period lasting a further 10 weeks. The filgotinib and placebo treatment groups were compared using ANCOVA models and logistic regression models containing baseline values and randomisation stratification factors as fixed effects. Analyses were done on the intention-to-treat non-responder imputation set. The trial was registered at ClinicalTrials.gov, number NCT02048618. FINDINGS Between Feb 3, 2014, and July 10, 2015, we enrolled 174 patients with active Crohns disease confirmed by centrally read endoscopy (130 in the filgotinib 200 mg group and 44 in the placebo group). In the intention-to-treat population, 60 (47%) of 128 patients treated with filgotinib 200 mg achieved clinical remission at week 10 versus ten (23%) of 44 patients treated with placebo (difference 24 percentage points [95% CI 9-39], p=0·0077). In a pooled analysis of all periods of filgotinib and placebo exposure over 20 weeks, serious treatment-emergent adverse effects were reported in 14 (9%) of 152 patients treated with filgotinib and three (4%) of 67 patients treated with placebo. INTERPRETATION Filgotinib induced clinical remission in significantly more patients with active Crohns disease compared with placebo, and had an acceptable safety profile. FUNDING Galapagos.

Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial

BACKGROUND PF-00547659 is a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) to selectively reduce lymphocyte homing to the intestinal tract. We aimed to assess the efficacy and safety of PF-00547659 in patients with moderate to severe ulcerative colitis. METHODS This phase 2, randomised, double-blind, placebo-controlled clinical trial recruited patients aged 18-65 years from 105 centres in 21 countries, with a history (≥3 months) of active ulcerative colitis extending more than 15 cm beyond the anal verge (with a total Mayo score ≥6 and a Mayo endoscopic subscore ≥2) who had failed or were intolerant to at least one conventional therapy. Patients were stratified by previous anti-TNFα treatment, and randomly assigned by a computer-generated randomisation schedule to receive a subcutaneous injection of 7·5 mg, 22·5 mg, 75 mg, or 225 mg PF-00547659 or placebo at baseline, then every 4 weeks. Patients, investigators, and sponsors were blinded to the treatment. The primary endpoint was the proportion of patients achieving remission (total Mayo score ≤2 with no individual subscore >1 and rectal bleeding subscore ≤1) at week 12. The efficacy analysis included all patients who received at least one dose of the randomised treatment; the safety analysis was done according to treatment received. All p values were one-sided and multiplicity-adjusted. This study is registered with ClinicalTrials.gov, number NCT01620255. FINDINGS Between Nov 2, 2012, and Feb 4, 2016, we screened 587 patients; 357 were eligible and randomly assigned to receive placebo (n=73) or PF-00547659 at doses of 7·5 mg (n=71), 22·5 mg (n=72), 75 mg (n=71), or 225 mg (n=70). Remission rates at week 12 were significantly greater in three of four active-treatment groups than in the placebo group (2·7% [two of 73]): 7·5 mg (11·3% [eight of 71]), 22·5 mg (16·7% [12 of 72]), 75 mg (15·5% [11 of 71]), and 225 mg (5·7% [four of 70]). These rates corresponded to a stratum-adjusted (anti-TNFα-naive and anti-TNFα-experienced) risk difference versus placebo of 8·0% for 7·5 mg (90% CI 1·9 to 14, p=0·0425), 12·8% for 22·5 mg (5·6 to 19·9, p=0·0099), 11·8% for 75 mg (4·8 to 18·8, p=0·0119), and 2·6% for 225 mg (-1·2 to 6·4, p=0·1803). Four of 73 (5·5%) patients had a serious adverse event in the placebo group, ten of 71 (14·1%) in the 7·5 mg group, one of 70 (1·4%) in the 22·5 mg group, three of 73 (4·1%) in the 75 mg group, and three of 70 (4·3%) in the 225 mg group. No safety signal was observed for the study drug. INTERPRETATION PF-00547659 was safe and well tolerated in this patient population, and better than placebo for induction of remission in patients with moderate to severe ulcerative colitis. The greatest clinical effects were observed with the 22·5 mg and 75 mg doses. FUNDING Pfizer.

Brain-gut axis in the pathogenesis of Helicobacter pylori infection.

Helicobacter pylori (H. pylori) infection is the main pathogenic factor for upper digestive tract organic diseases. In addition to direct cytotoxic and proinflammatory effects, H. pylori infection may also induce abnormalities indirectly by affecting the brain-gut axis, similar to other microorganisms present in the alimentary tract. The brain-gut axis integrates the central, peripheral, enteric and autonomic nervous systems, as well as the endocrine and immunological systems, with gastrointestinal functions and environmental stimuli, including gastric and intestinal microbiota. The bidirectional relationship between H. pylori infection and the brain-gut axis influences both the contagion process and the hosts neuroendocrine-immunological reaction to it, resulting in alterations in cognitive functions, food intake and appetite, immunological response, and modification of symptom sensitivity thresholds. Furthermore, disturbances in the upper and lower digestive tract permeability, motility and secretion can occur, mainly as a form of irritable bowel syndrome. Many of these abnormalities disappear following H. pylori eradication. H. pylori may have direct neurotoxic effects that lead to alteration of the brain-gut axis through the activation of neurogenic inflammatory processes, or by microelement deficiency secondary to functional and morphological changes in the digestive tract. In digestive tissue, H. pylori can alter signaling in the brain-gut axis by mast cells, the main brain-gut axis effector, as H. pylori infection is associated with decreased mast cell infiltration in the digestive tract. Nevertheless, unequivocal data concerning the direct and immediate effect of H. pylori infection on the brain-gut axis are still lacking. Therefore, further studies evaluating the clinical importance of these host-bacteria interactions will improve our understanding of H. pylori infection pathophysiology and suggest new therapeutic approaches.

Contrast-enhanced Ultrasound for Detection of Crohn’s Disease Activity: Systematic Review and Meta-analysis

BACKGROUND AND AIMS Reports on imaging of active Crohns disease (aCD) using contrast-enhanced ultrasound (CEUS) are encouraging. However, the statistical power of most published papers is limited due to the small size of the patient groups included. This study was performed to verify the diagnostic value of CEUS in detecting aCD. METHODS A systematic literature search was performed by two independent reviewers for articles on the test characteristics of CEUS for the identification of aCD. The quality of the analysed studies was evaluated using a quality assessment tool for diagnostic accuracy studies (QUADAS-2). Pooling was performed using a diagnostic random-effect model and bivariate analysis. RESULTS Eight articles were included in the final analysis, with a total of 332 patients. There was no significant publication bias. Significant heterogeneity was found regarding CEUS methodology and sonographic definitions of aCD. In a bivariate analysis, pooled sensitivity was 0.94 (95% CI 0.87-0.97) and pooled specificity was 0.79 (95% CI 0.67-0.88). Spearman correlation statistics presented no significant diagnostic threshold effect (r = 0.12, p > 0.9). Subgroup analysis showed that relative intestine wall enhancement had the highest diagnostic value (area under the curve 94%), while the presence of enhancement and analysis of the slope were less useful (area under the curve 91 and 90%, respectively). CONCLUSIONS CEUS presents good sensitivity and moderate specificity in the detection of the aCD. Large-scale randomized trials with quantitative evaluation of CEUS images are necessary to promote this technique in clinical practice.

Autonomic nervous function in Helicobacter pylori-infected patients with atypical chest pain studied by analysis of heart rate variability.

Objectives Cardiovascular autonomic neurous system (ANS) activity estimated by analysis of heart rate variability (HRV) was compared in Helicobacter pylori-positive and H. pylori-negative male patients suffering from atypical chest pain to verify the hypothesis that autonomic neural system might be the way linking chronic H. pylori infection with gastrointestinal tract disorders. Methods We have analysed data obtained from 101 male patients examined in our clinic due to atypical chest pain, without evidence of serious cardiovascular, respiratory and digestive tract or metabolic diseases. In each patient, besides interview and physical examination, were performed: gastroscopy with mucosa biopsy (for urease test and histology), oesophageal pH-metry and manometry, ultrasound abdomen examination, chest X-ray, exercise test on running track, 24-h ECG Holter monitoring with time-domain and frequency-domain HRV analysis, and echocardiography. Results In comparison with H. pylori-negative, in all H. pylori-infected patients (n = 63) a significantly greater low frequency power, an index of sympathetic activity, and higher values of vagal tone parameters [pNN50, percentage of differences between RR intervals that are greater than 50 ms; high-frequency power in HRV analysis (HF)] were observed. The relationship between H. pylori infection and the HF value was confirmed in multi-factorial analysis. The aforementioned ANS activity differences were accompanied by: significantly fewer gastro-oesophageal acid reflux episodes, lower gastric acidity and more effective and complete oesophageal peristalsis in H. pylori-positive patients. Conclusions H. pylori infection may affect ANS activity and via this way also contribute to gastro-oesophageal and cardiovascular pathology.

Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population.

Most inflammatory bowel diseases (IBDs) are classic complex disorders represented by common alleles. Here we aimed to define the genetic architecture of pediatric and adult-onset IBDs for the Polish population. A total of 1495 patients were recruited, including 761 patients with Crohn’s disease (CD; 424 pediatric), 734 patients with ulcerative colitis (UC; 390 pediatric), and 934 healthy controls. Allelotyping employed a pooled-DNA genome-wide association study (GWAS) and was validated by individual genotyping. Whole exome sequencing (WES) was performed on 44 IBD patients diagnosed before 6 years of age, 45 patients diagnosed after 40 years of age, and 18 healthy controls. Altogether, out of 88 selected SNPs, 31 SNPs were replicated for association with IBD. A novel BRD2 (rs1049526) association reached significance of P = 5.2 × 10−11 and odds ratio (OR) = 2.43. Twenty SNPs were shared between pediatric and adult patients; 1 and 7 were unique to adult-onset and pediatric-onset IBD, respectively. WES identified numerous rare and potentially deleterious variants in IBD-associated or innate immunity-associated genes. Deleterious alleles in both groups were over-represented among rare variants in affected children. Our GWAS revealed differences in the polygenic architecture of pediatric- and adult-onset IBD. A significant accumulation of rare and deleterious variants in affected children suggests a contribution by yet unexplained genetic components.

Clinical significance of Helicobacter pylori infection in patients with acute coronary syndromes: an overview of current evidence.

Although Helicobacter pylori (Hp) primarily colonizes gastric mucosa, it can occasionally inhabit in atherosclerotic plaques. Both forms of Hp infection may be involved in the pathogenesis of atherosclerosis via activation of a systemic or local inflammatory host reaction and induction of plaque progression and/or instability, possibly leading to coronary syndromes. The association between Hp infection and cardiovascular endpoint prevalence remains uncertain; however, it has been reported in many epidemiological investigations and may be reasonably explained by pathophysiological mechanisms. Besides the inflammatory pathway, Hp infection may trigger acute coronary syndromes by enhanced platelet reactivity and increased risk of gastrointestinal bleeding (type 2 myocardial infarction). The former seems to be predominantly related to the stimulatory effect of Hp infection on von Willebrand factor-binding and P-selectin activation, and the latter results from cytotoxic bacteria properties and aggravation of digestive tract injury related to aspirin or dual antiplatelet therapy. Despite these premises, the role of Hp infection in cardiovascular syndromes should still be recognized as controversial and requiring randomized, controlled trials to evaluate the outcome of Hp eradication in both cardiac and gastroenterological endpoints. Such need is also justified by potential bias of previous studies resulting from (1) using different diagnostic methods for identification of Hp infection, since only a small number of studies required confirmation of active Hp infection; and from (2) common lack of adjustment for important confounders such as socioeconomic status, smoking and effectiveness of eradication therapy, as well as the genetic characteristics of both the host and the bacterium.

Improvement in health-related quality of life after therapy with omeprazole in patients with coronary artery disease and recurrent angina-like chest pain. A double-blind, placebo-controlled trial of the SF-36 survey

BackgroundMany patients with coronary artery disease (CAD) have overlapping gastroenterological causes of recurrent chest pain, mainly due to gastroesophageal reflux (GER) and aspirin-induced gastrointestinal tract damage. These symptoms can be alleviated by proton pump inhibitors (PPIs). The study addressed whether omeprazole treatment also affects general health-related quality of life (HRQL) in patients with CAD.Study48 patients with more than 50% narrowing of the coronary arteries on angiography without clinically overt gastrointestinal symptoms were studied. In a double-blind, placebo-controlled, cross-over study design, patients were randomized to take omeprazole 20 mg bid or a placebo for two weeks, and then crossed over to the other study arm. The SF-36 questionnaire was completed before treatment and again after two weeks of therapy.ResultsPatients treated with omeprazole in comparison to the subjects taking the placebo had significantly greater values for the SF-36 survey (which relates to both physical and mental health), as well as for bodily pain, general health perception, and physical health. In comparison to the baseline values, therapy with omeprazole led to a significant increase in the three summarized health components: total SF-36; physical and mental health; and in the following detailed health concept scores: physical functioning, limitations due to physical health problems, bodily pain and emotional well-being.ConclusionsA double dose of omeprazole improved the general HRQL in patients with CAD without severe gastrointestinal symptoms more effectively than the placebo.

Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohn's disease: report of the OPERA study.

Objective This phase II, randomised, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of PF-00547659, a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule (MAdCAM) to selectively reduce lymphocyte homing to the intestinal tract, in patients with moderate-to-severe Crohn’s disease (CD). Design Eligible adults were aged 18–75 years, with active moderate-to-severe CD (Crohn’s Disease Activity Index (CDAI) 220–450), a history of failure or intolerance to antitumour necrosis factor and/or immunosuppressive agents, high-sensitivity C reactive protein >3.0 mg/L and ulcers on colonoscopy. Patients were randomised to PF-00547659 22.5 mg, 75 mg or 225 mg or placebo. The primary endpoint was CDAI 70-point decrease from baseline (CDAI-70) at week 8 or 12. Results In all, 265 patients were eligible for study entry. Although CDAI-70 response was not significantly different with placebo versus PF-00547659 treatment at weeks 8 or 12, remission rate was greater in patients with higher baseline C reactive protein (>5 mg/L vs >18.8 mg/L, respectively). Soluble MAdCAM decreased significantly from baseline to week 2 in a dose-related manner and remained low during the study in PF-00547659-treated patients. Circulating β7+ CD4+ central memory T-lymphocytes increased at weeks 8 and 12 with PF-00547659 treatment. No safety signal was seen. Conclusions Clinical endpoint differences between PF-00547659 and placebo did not reach statistical significance in patients with moderate-to-severe CD. PF-00547659 was pharmacologically active, as shown by a sustained dose-related decrease in soluble MAdCAM and a dose-related increase in circulating β7+ central memory T cells. Trial registration number NCT01276509; Results.

Working Group Guidelines on the nursing roles in caring for patients with Crohn's disease and ulcerative colitis in Poland

Inflammatory bowel disease (IBD), including Crohns disease and ulcerative colitis, present a major challenge for present-day gastroenterology due to their increasing incidence, chronic nature, risk of permanent worsening of quality of life of patients, and the costs of conservative and invasive treatment. Basic and advanced nursing care are important parts of the multidisciplinary care for patients. The developed guidelines on the nursing care, which are compliant with the European guidelines published by Nurses-European Crohns & Colitis Organisation (N-ECCO), were adjusted to the current situation in Poland. Significant issues that are important for nursing teams have been identified, with particular emphasis on the specificity of working in centres specialising in the care of IBD patients. The Working Group paid attention to the conditions that should be satisfied in order to optimise the nursing care for IBD patients, and the necessity to develop professional and scientific cooperation with European centres within European Crohns & Colitis Organisation (ECCO) and N-ECCO.