Tofacitinib real-world experience in ulcerative colitis in Finland (FinTofUC): a retrospective non-interventional multicenter patient chart data study.

OBJECTIVES: The aim was to define the effectiveness of tofacitinib and to characterize the patient population receiving tofacitinib in a real-world cohort clinical setting for ulcerative colitis (UC) in Finland. METHODS: This is a retrospective non-interventional multicenter patient chart data study conducted in 23 Finnish Inflammatory Bowel Disease (IBD) centers. Baseline demographic and clinical data, clinical remission, steroid-free remission rate and time to tofacitinib discontinuation, colectomy or UC-related hospitalization were studied. RESULTS: The study included 252 UC patients of which 69% were male. Most patients had extensive disease (71%) and were bio-experienced (81%). Tofacitinib demonstrated positive treatment outcomes with clinical response, clinical remission, and steroid-free clinical remission at one year in 33%, 34% and 31% of patients, respectively. Moreover, 64% of patients in pMayo remission at week 16 from the start of tofacitinib were still in remission at one year. Only no or mild disease activity compared to moderate activity at baseline was associated with a higher probability of achieving remission according to pMayo at six months, p = .008. Hospitalizations and/or colectomies during the study period (before treatment discontinuation/end of follow-up) were low (n = 24), with less than 5 colectomies. CONCLUSIONS: In this real-world cohort, including a majority of bio-experienced UC patients, tofacitinib was effective in achieving steroid-free clinical remission in a third of the population at one year. A majority of patients in remission at week 16 were also in remission at one year. Results are in line with earlier published real-world studies. Registration: ClinicalTrials.gov NCT05082428.

Pregnane X receptor gene variant rs7643645 and total mortality in subjects with nonalcoholic fatty liver disease.

Pregnane X receptor (PXR) gene variants rs7643645 and rs2461823 are reported to associate with clinically and histologically more severe liver injury in nonalcoholic fatty liver disease (NAFLD). It is known that the more progressive the NAFLD, the higher the hepatic and extra-hepatic mortality and morbidity. Thus, we investigated the total mortality in Finnish middle-aged ultrasonographically verified NAFLD patients with PXR rs7643645 AA/AG ( n = 217) or GG ( n = 27) variants and rs2461823 CC/CT ( n = 215) or TT ( n = 27) variants. In up to 30 years of follow-up, PXR rs7643645 GG subjects were at an increased risk of total mortality compared with AA/AG subjects, 1.676 (1.014-2.772), P = 0.044. The statistically significant difference prevailed after multiple adjustments for potentially confounding factors, RR, 2.024 (1.191-3.440), P = 0.009. In the subjects without NAFLD ( n = 731), the mortality risk was not associated with rs7643645 variants, 1.051 (0.708-1.560; P = 0.804). There was no difference in the total mortality between the PXR rs2461823 variant subgroups, 1.141 (0.663-1.962; P = 0.634). As the rs7643645 G variant disrupts a putative hepatocyte nuclear factor 4α binding site located in the PXR gene promoter and is associated with lower hepatic expression of PXR and its target genes, our result suggests that genetic disruption of xenobiotic metabolism increases mortality in subjects with NAFLD. Further studies are needed to confirm the results of the present study.

Renal denervation in patients who do not respond to cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) reduces the morbidity and mortality in advanced heart failure (HF) in about two-thirds of the patients. Approximately one-third of the patients do not respond to CRT. The overactivity of sympathetic nervous system is associated with advanced HF and deteriorates the hemodynamic state. We tested the hypothesis that controlling sympathetic overactivity by renal denervation (RDN) could be beneficial in nonresponders for CRT. In our HeartF-RDN study (ClinalTrials.gov. NCT02638324), RDN could not reverse the progression of HF in subjects with New York Heart Association Classification (NYHA) III-IV stage symptoms.

Nonalcoholic fatty liver disease and its prognosis associates with shorter leucocyte telomeres in a 21-year follow-up study.

Leucocyte telomere length (LTL) has been associated with nonalcoholic fatty liver disease (NAFLD), but the evidence is imperfect. Furthermore, liver fibrosis has been shown to correlate with mortality and recent studies have also found associations with LTL and fibrosis suggesting that LTL may have additional prognostic value in liver diseases. Our objective was to study the association of LTL and NAFLD and evaluate the association of LTL in prognosis of NAFLD subjects. Study subjects (n = 847) were middle-aged hypertensive patients. All participants were evaluated for NAFLD and their LTL was measured at baseline. Outcomes were obtained from Finnish Causes-of-Death Register and the Care Register for Health Care in Statistics Finland to the end of 2014. An inverse association with NAFLD prevalence and LTL length was observed (p < .001 for trend). Shortest telomere tertile possessed statistically significantly more NAFLD subjects even with multivariate analysis (shortest vs. middle tertile HR 1.98 p = .006 and shortest vs. longest tertile HR 2.03 p = .007). For the study period, mortality of the study group showed statistically significant relation with telomere length in univariate but not for multivariate analysis. In subgroup analysis, LTL did not associate with prognosis of non-NAFLD subjects. However, LTL was inversely associated with overall mortality in the subjects with NAFLD in both univariate (HR 0.16 p = .007) and multivariate analysis (HR 0.20 p = .045). In middle-aged Caucasian cohort, shorter leucocyte telomeres associated independently with increased prevalence of NAFLD. Shorter LTL was not associated with mortality in non-NAFLD patients whereas it predicted mortality of NAFLD patients independently.

Celiac disease antibody levels reflect duodenal mucosal damage but not clinical symptoms.

OBJECTIVES: This study aimed to investigate, in a real-world population, whether the histological and clinical phenotype differ at baseline and during follow-up in patients with high and low CD (celiac disease) antibody titers. MATERIALS AND METHODS: The study cohort consisted of 96 consecutive patients diagnosed to have CD during the years 2010-2018. The clinical parameters, symptoms and laboratory results were registered and histomorphometry was analyzed from the available duodenal biopsies taken during the primary and follow-up esophageal-gastricduodenoscopies. Patients having immunoglobulin A transglutaminase antibody (tTG-ab) levels above 70 U/mL were classified as high titer patients. RESULTS: Measured by the villous-crypt ratio, the duodenal mucosa was more severely damaged in the high tTG-ab group than in the low tTG-group at baseline (n = 70, 0.61 ± 0.63 vs. 1.02 ± 0.87, p = .003) and during the follow-up when the patients were on gluten-free diet (n = 27, 1.80 ± 0.72 vs. 2.35 ± 0.64, p = .041). Interestingly, the high tTG-ab group members had fewer gastrointestinal symptoms at baseline than those in the low tTG-ab group (43% vs. 68%, p = .013) but lower vitamin D levels (68 ± 34 nmol/L vs. 88 ± 29 nmol/L, p = .034) and more often microcytosis (28% vs. 10%, p = .040). During the follow-up, these differences were no longer detected. CONCLUSIONS: At baseline, CD patients with high tTG-ab have more severe duodenum injury and signs of malabsorption but fewer symptoms. After gluten-free diet has been initiated, the mucosal healing in the high tTG-ab group is prolonged, but symptoms and signs of malabsorption recover equally in both groups.

Metabolic syndrome but not genetic polymorphisms known to induce NAFLD predicts increased total mortality in subjects with NAFLD (OPERA study).

Metabolic syndrome (MetS) and genetic polymorphisms PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 are known inductors of non-alcoholic fatty liver disease (NAFLD). However, knowledge about how these affect the mortality of subjects with NAFLD is scarce. Therefore, we investigated the impact of MetS, PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 on overall and cardiovascular disease (CVD) specific mortality among subjects with or without NAFLD. NAFLD diagnosis was based on liver ultrasound at the baseline. After this and other comprehensive examinations, 958 middle-aged Finns, 249 with NAFLD, were followed for 21 years. The mortality data was gathered from the National Death Registry. After multiple adjustments, the NAFLD individuals with MetS had increased risk of overall mortality as compared to the NAFLD subjects without MetS [2.054 (1.011-4.173, p = .046)]. However, PNPLA3 rs738409 [1.049 (0.650-1.692, p = .844)], TM6SF2 rs58542926 [0.721 (0.369-1.411, p = .340)] or MBOAT7 rs641738 [0.885 (0.543-1.439, p = .621)] did not affect the overall mortality. MetS was also a marker of increased risk of CVD mortality (15% vs. 2%, p = .013) while genetic polymorphisms did not affect CVD mortality. In conclusion, MetS, but not the gene polymorphisms studied, predicts increased overall and CVD-specific mortality among NAFLD subjects.

Antipsychotic drug-induced hypoglycemia and hypothermia.

This case report comprises three cases of antipsychotic drug-induced hypoglycemia and hypothermia. The mechanisms behind these side-effects are not known, but in hypoglycemia we describe signs of inappropriate insulin secretion. We assume that antipsychotic drug-induced hypoglycemia and hypothermia are underdiagnosed. Antipsychotic drugs are, however, widely used and these rare adverse-effects may occur in the clinical practice. It is of utmost importance to measure blood glucose and body temperature of patients taking these drugs who have unspecific symptoms.

Long-term metabolic fate and mortality in obesity without metabolic syndrome.

BACKGROUND: Obesity and metabolic syndrome (MetS) are known to expose to atrial fibrillation (AF), cardiovascular diseases (CVD) and mortality. Metabolically healthy obesity refers to obesity without MetS. This study aimed to investigate how obesity and MetS modify the risk of CVD, AF and mortality in very long-time follow-up. METHODS: Finnish middle-aged subjects (n = 1045) were grouped into four subgroups according to the presence of obesity and MetS. CVD events and AF were followed for 24 years and total mortality for 30 years. Moreover, 600 available patients had a follow-up visit for metabolic examinations after approximately 22 years. RESULTS: One-hundred and sixty-two (30%) subjects without obesity or MetS died during the follow-up. Ninety-two (17%) of the patients in this group had a CVD event and 58 (11%) were diagnosed with AF. As compared to them, obese subjects without MetS had similar metabolic fate and mortality (mortality 26 (38%), p = .143; CVD event 12 (18%), p = .858 and AF 7 (10%), p = .912, respectively), whereas subjects with obesity and MetS had greater mortality (102 (49%), p < .001), more CVD (71 (34%), p < .001) and AF (49 (23%), p < .001). Non-obese individuals with MetS had greater rates of mortality (96 (44%), p < .001) and CVD (80 (37%), p < .001), but not of AF (26 (12%), p = .606). Of the 40 subjects with obesity but without MetS at baseline and available for the follow-up visit, 15 (38%) were metabolically healthy at the follow-up visit. CONCLUSIONS: In the present long-term follow-up study, the presence of MetS, but not obesity only, implies a greater risk of mortality and CVD. The risk of AF is increased only in subjects with both obesity and MetS. However, obesity without MetS tends to progress eventually to obesity with MetS. Key messagesThe presence of metabolic syndrome (MetS), but not obesity only, entails a greater risk of mortality and cardiovascular diseases.The risk of atrial fibrillation is increased only in subjects with both obesity and MetS.Obesity without MetS tends to progress eventually to obesity with MetS.

Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism.

BACKGROUND AND PURPOSE: Many drugs and environmental contaminants induce hypercholesterolemia and promote the risk of atherosclerotic cardiovascular disease. We tested the hypothesis that pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, regulates the level of circulating atherogenic lipids in humans and utilized mouse experiments to identify the mechanisms involved. EXPERIMENTAL APPROACH: We performed serum NMR metabolomics in healthy volunteers administered rifampicin, a prototypical human PXR ligand or placebo in a crossover setting. We used high-fat diet fed wild-type and PXR knockout mice to investigate the mechanisms mediating the PXR-induced alterations in cholesterol homeostasis. KEY RESULTS: Activation of PXR induced cholesterogenesis both in pre-clinical and clinical settings. In human volunteers, rifampicin increased intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and total cholesterol and lathosterol-cholesterol ratio, a marker of cholesterol synthesis, suggesting increased cholesterol synthesis. Experiments in mice indicated that PXR activation causes widespread induction of the cholesterol synthesis genes including the rate-limiting Hmgcr and upregulates the intermediates in the Kandutsch-Russell cholesterol synthesis pathway in the liver. Additionally, PXR activation induced plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of hepatic LDL uptake, in both mice and humans. We propose that these effects were mediated through increased proteolytic activation of sterol regulatory element-binding protein 2 (SREBP2) in response to PXR activation. CONCLUSION AND IMPLICATIONS: PXR activation induces cholesterol synthesis, elevating LDL and total cholesterol in humans. The PXR-SREBP2 pathway is a novel regulator of the cholesterol and PCSK9 synthesis and a molecular mechanism for drug- and chemical-induced hypercholesterolemia.

The association of non-alcoholic fatty liver disease and atrial fibrillation: a review.

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes an enormous burden to human health and health-care systems all over the world. A great proportion of this burden results from increased risk of cardiovascular diseases. Atrial fibrillation (AF) is the most common chronic heart arrhythmia globally and it increases the risk of embolic stroke and heart failure. Recent studies have explored the association between NAFLD and AF with somewhat conflicting results. However, ultrasound-verified prospective studies concur that NAFLD is associated with the incidence of AF. According to epidemiological evidence, the greater the prevalence of NALFD in a population, the stronger the association with AF incidence and prevalence. Specifically, diabetic individuals with NAFLD are at the greatest risk of AF. Additionally, the risk of AF may concentrate most in individuals with advanced NAFLD, particularly those with liver fibrosis. The possible mechanistic factors between NAFLD and AF, particularly obesity and systemic inflammation, are diverse and form a complex interplaying network. However, further studies are needed to elucidate whether NAFLD has a causative role in the development of AF. The purpose of this article is to review and discuss the epidemiologic evidence and possible mechanistic links between these two conditions. KEY MESSAGES Although epidemiologic studies have provided conflicting results on the association of NAFLD and AF, prospective studies with ultrasound-verified NAFLD concur that NAFLD is associated with about 2-fold greater incidence of AF among general population and about 6-fold greater incidence among subjects with type 2 diabetes. The risk of AF among individuals with NAFLD is increased by other cardiovascular risk factors, especially type 2 diabetes and advanced age. The possible mechanistic links between NALFD and AF are diverse, with obesity and systemic inflammation having a significant role, but further studies are needed until NAFLD can be established as a causal factor in the incidence of AF.

Presence of atrial fibrillation is associated with liver stiffness in an elderly Finnish population.

BACKGROUND: Chronic liver injury from different etiologies drives liver fibrosis. However, little is known about the associated factors, systemic factors in particular. Recently, non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation have been shown to be associated with each other. Thereby, we aimed to study the association between atrial fibrillation and liver stiffness. STUDY: Extensive clinical measurements including echocardiography of the heart, transient elastography (TE) of the liver and the presence of atrial fibrillation were determined in elderly Finnish study subjects (n = 76, mean age 73 years) from OPERA (Oulu Project Elucidating the Risk of Atherosclerosis) study cohort. Half of the study subjects had non-alcoholic fatty liver disease, whereas others did not have any known hepatic morbidity. The present study was cross-sectional by nature. RESULTS: The subjects with atrial fibrillation had higher TE values (with atrial fibrillation TE = 9.3kPa, without atrial fibrillation TE = 6.3kPa, p = 0.018). When the cohort was divided to four subgroups (those without NAFLD or atrial fibrillation, with NAFLD but without atrial fibrillation, with both conditions, and with atrial fibrillation but without NAFLD), the TE value was the highest in the subjects with both conditions (5.3kPa, 7.4kPa, 10.8kPa and 7.8kPa, respectively, p = 0.019). Moreover, the higher the TE value, the more prevalent atrial fibrillation was (the atrial fibrillation prevalence by tertiles of TE 27% / 36% / 77%, p = 0.001). Likewise, the greater the TE value, the greater the left atrial diameter, a collateral of atrial fibrillation (left atrial diameters by tertiles of TE 39mm / 45mm / 48mm, p<0.001) was. All these p-values for continuous variables remained statistically significant even after adjustment for common clinically relevant risk factors. CONCLUSIONS: There is an association between atrial fibrillation and liver stiffness. This novel association may have multiple explanations and mechanistic links, which are discussed here and need further studies, prospective studies in particular.

Non-alcoholic fatty liver disease with and without metabolic syndrome: Different long-term outcomes.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) are both shown to increase the risk of cardiovascular diseases and type 2 diabetes. However, there is a great overlap between these two diseases. The present study was aimed to examine the cardiovascular and metabolic prognosis of non-alcoholic fatty liver disease with and without metabolic syndrome. METHODS: Middle-aged subjects (n=958) were divided into four subgroups, those with NAFLD and MetS, those with NAFLD or MetS, and healthy controls. The baseline characteristics of the subgroups were analyzed. The follow-up time for cardiovascular events was about 16years. After approximately 21years the cardiac ultrasound and laboratory parameters were re-analyzed and new type 2 diabetes cases were recorded. RESULTS: Those with both diseases were at the greatest risk for cardiovascular events (p<0.001). Compared to healthy controls, only those with MetS, with or without NAFLD, were at increased risk for the development of type 2 diabetes (p<0.001) and for an increase in left ventricular mass index (p=0.001 and p=0.005, respectively). The cardiovascular and metabolic risk in subjects with NAFLD only was quite similar to that in healthy controls. The I148M variant of the patatin-like phospholipase domain-containing 3 gene (PNPLA3 polymorphism) was most present in those with NAFLD only (p=0.008). CONCLUSIONS: NAFLD with MetS implies a considerable risk for cardiovascular diseases, type 2 diabetes and the increase of left ventricular mass index whereas NAFLD without MetS does not.

Non-Alcoholic Fatty Liver Disease as a Predictor of Atrial Fibrillation in Middle-Aged Population (OPERA Study).

Non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) are widespread diseases and have multiple common risk factors and comorbidities. No studies of association between ultrasonography-diagnosed NAFLD and AF exist in other than diabetic population. The goal of this prospective study was to study the value of NAFLD as a predictor of atrial fibrillation. This study had 958 subjects from the OPERA (Oulu Project Elucidating Risk of Atherosclerosis) cohort, and the mean follow-up time was 16.3 years. NAFLD was diagnosed if the subject had fatty liver in ultrasonography and no excess alcohol intake. AF was followed in the National Registers. In this study 249 subjects (26.0%) had NAFLD and 37 (14.9%) of these had AF whereas only 56 (7.9%) of those without NAFLD experienced AF during the follow-up time (p = 0.001). In the multiple Cox regression analysis including potential confounders (age, sex, study group, diabetes, body mass index (BMI), waist circumference, alcohol consumption, smoking, serum alanine aminotransferase concentration (ALT), systolic blood pressure, quick index, left ventricular mass index, left atrial diameter, coronary artery disease (CAD), atrial natriuretic peptide (ANP) and high sensitive C-reactive protein (hs-CRP)), NAFLD remained as an independent predictor of AF (Adjusted OR, 1.88 (95% Confidence interval (CI) 1.03-3.45)). In conclusion, our data shows that NAFLD is independently associated with the risk of AF.