Activity

To examine incidence of treatment changes due to abnormal blood-test results and, to explore rates of treatment changes due to liver, kidney and haematological blood-test abnormalities in autoimmune rheumatic diseases (AIRD) treated with low-dose methotrexate or leflunomide.

Data for people with AIRDs prescribed methotrexate or leflunomide were extracted from the Clinical Practice Research Datalink. Participants were followed-up from first prescription of methotrexate or leflunomide in primary-care. Primary outcome of interest was drug discontinuation, defined as a prescription gap of ≥ 90 days following an abnormal (or severely abnormal) blood-test result. Dose reduction was examined between consecutive prescriptions. Incidence rates per 1,000 person-years were calculated.

15,670 and 2,689 participants contributing 46,571 and 4,558 person-years follow-up were included in methotrexate and leflunomide cohorts respectively. The incidence of methotrexate and leflunomide discontinuation with abnormal (severdiscontinuations for severely abnormal results were uncommon.The development and progression of cardiovascular disease (CVD) can mainly be attributed to the narrowing of blood vessels caused by atherosclerosis and thrombosis, which induces organ damage that will result in end-organ dysfunction characterized by events such as myocardial infarction or stroke. It is also essential to consider other contributory factors to CVD, including cardiac remodelling caused by cardiomyopathies and co-morbidities with other diseases such as chronic kidney disease. Besides, there is a growing amount of evidence linking the gut microbiota to CVD through several metabolic pathways. Hence, it is of utmost importance to decipher the underlying molecular mechanisms associated with these disease states to elucidate the development and progression of CVD. A wide array of systems biology approaches incorporating multi-omics data have emerged as an invaluable tool in establishing alterations in specific cell types and identifying modifications in signalling events that promote disease development. Here, we review recent studies that apply multi-omics approaches to further understand the underlying causes of CVD and provide possible treatment strategies by identifying novel drug targets and biomarkers. We also discuss very recent advances in gut microbiota research with an emphasis on how diet and microbial composition can impact the development of CVD. Finally, we present various biological network analyses and other independent studies that have been employed for providing mechanistic explanation and developing treatment strategies for end-stage CVD, namely myocardial infarction and stroke.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A (GLA/AGAL) resulting in lysosomal accumulation of globotriaosylceramide (Gb3). Patients with amenable GLA mutations can be treated with migalastat, an oral pharmacologic chaperone increasing endogenous AGAL activity. In this prospective observational multicenter study safety as well as cardiovascular, renal, and patient-reported outcomes and disease biomarkers were assessed after 12 and 24 months of migalastat treatment under “real world” conditions.

54 patients (26 females) (33 of these [61.1%] pre-treated with enzyme replacement therapy) with amenable mutations were analyzed. Treatment was generally safe and well tolerated. 153 events per 1,000 patient-years were detected. Overall left ventricular mass index decreased after 24 months (all -7.5 ± 17.4 g/m2, p = 0.0118; females -4.6 ± 9.1 g/m2, p = 0.0554; males -9.9 ± 22.2 g/m2, p = 0.0699). After 24 months, females and males presented with a moderate yearly loss of eGFR (-2.6 and -4.4 ml/min/1.73 m2 per year; p = 0.0317 and p = 0.0028, respectively). FD-specific manifestations/symptoms remained stable (all p > 0.05). 76.9% of females and 50% of males suffered from pain, which has not improved under treatment. FD-specific disease scores (DS3 and MSSI) remained stable during treatment. AGAL activities and plasma lyso-Gb3 values remained stable, although some male patients presented with increasing lyso-Gb3 levels over time.

Treatment with migalastat was generally safe and resulted in most patients in an amelioration of left ventricular mass. However, due to the heterogeneity of FD phenotypes, it is advisable that the treating physician monitors the clinical response regularly.

Treatment with migalastat was generally safe and resulted in most patients in an amelioration of left ventricular mass. However, due to the heterogeneity of FD phenotypes, it is advisable that the treating physician monitors the clinical response regularly.

The occurrence of immune-related myositis (irM) is increasing, yet there are no therapeutic guidelines. We sought to analyze the current therapeutic strategies of irM and evaluate the outcomes of immune checkpoint inhibitors (ICI) rechallenge.

We conducted a nationwide retrospective study between April 2018 and March 2020 including irM without myocardial involvement. Depending on the presence of cutaneous signs or unusual histopathological features, patients were classified into two groups typical or atypical irM. Therapeutic strategies were analyzed in both groups. The modalities and outcomes of ICI rechallenge were reviewed.

Among the 20 patients, 16 presented typical irM. Regardless of severity, most typical irM were treated with steroid monotherapy (n = 14/16) and all had a complete response within ≤ 3 weeks. The efficacy of oral steroids for non-severe typical irM (n = 10) was the same with low-dose (≤ 0.5 mg/kg/day) or high-dose (1 mg/kg/day). Severe typical irM were successfully treated with intrare in favor of a safe reintroduction of ICI following symptom resolution and CK normalization in moderate and severe forms of irM.Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer’s disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal aging, we tested the hypothesis that higher segregation of the brain’s connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer’s disease. Using resting-state functional MRI, we assessed both resting-state-fMRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation First, we included 108 individuals with autosomal dominantly inherited Alzheimer’s disease and 71 non-carrier controls. Second, we included 156 amyloid-PET positive subjects across the spectrum of sporadic Alzheimer’s disease as well as 184 amyloid-negative controls. see more In the autosomal dominant Alzheimer’s disease sample, disease severity was assessed by estimated years from symptom onset.