Medication adherence/persistence among patients with active multiple sclerosis in Finland

Objectives To explore adherence, persistence, and treatment patterns in patients with multiple sclerosis (MS) in Finland treated with disease-modifying therapies (DMTs) for active MS in 2005-2018. Materials and Methods The study cohort was identified using the Drug Prescription Register of Social Insurance Institute, Finland. All patients had at least one prescription of glatiramer acetate (GA), beta-interferons, teriflunomide, or delayed-release dimethyl fumarate (DMF). Adherence was calculated using proportion of days covered (PDC) (cutoff >= 0.8). Time to non-persistence was calculated by the number of days on index DMT treatment before the first treatment gap (>= 90 days) or switch and analyzed with time-to-event methodology. Results The cohort included 7474 MS patients (72.2% female; mean age 38.9 years). Treatment switches were steady over 2005-2012, peaked in 2015. PDC means (standard deviations) were GA, 0.87 (0.17); beta-interferons, 0.88 (0.15); DMF, 0.89 (0.14); teriflunomide, 0.93 (0.10). Adherence frequencies were GA, 78.4%; beta-interferons, 81.3%; DMF, 86.9%; teriflunomide, 91.7%. Logistic regression showed that age group, DMT and the starting year, sex, and hospital district independently affected adherence. Patients receiving teriflunomide and DMF, males, and older patients were more likely to persist on treatment. There was no difference in persistence between patients prescribed teriflunomide and DMF, or between GA and beta-interferons. Conclusions Oral DMTs had greater adherence and persistence than injectable DMTs.Peer reviewe

Changes in multiple sclerosis epidemiology in Finland over five decades

Finland is a high-risk region for multiple sclerosis (MS) with several epidemiological studies on the subject published since 1964, but these have not been comprehensively scrutinized. The objective of this study was to review previous studies of Finnish MS epidemiology, introduce new data on MS prevalence in western parts of Finland and do further analyses on data from previous studies. We performed a systematic search on articles regarding MS epidemiology in Finland in PubMed database, and all relevant articles were included in this review. MS prevalences in the western hospital districts of Vaasa, South Ostrobothnia and Pirkanmaa were calculated in 1980-2007 by using previously unpublished data obtained from a retrospective search from hospital administrative registries. To enhance comparability of the epidemiological figures, we calculated age-standardized prevalence of MS from the new data from western hospital districts and previous data from North Ostrobothnia, Southwest Finland and North Karelia. Marked regional differences in MS epidemiology were confirmed with concentration of the disease in the western and south-western parts of the country. The highest regional age-standardized MS prevalence of 288/100 000 was reported in South Ostrobothnia in 2007. A clear and stable increase in MS prevalence was observed through the decades, but the only marked increase in incidence happened in 1990s. Methodological differences hampered direct comparisons of different studies, highlighting the importance of common principles of reporting and standardizing the epidemiological figures. More comprehensive studies on MS epidemiology are still warranted to yield important information concerning the aetiology of the disease

Nerve growth factor signaling through p75 induces apoptosis in Schwann cells via a Bcl-2-independent pathway

Apoptosis is involved in the regulation of Schwann cell numbers during normal development and after axonal damage, but the molecular regulation of Schwann cell death remains unknown. We have used stably transfected rat Schwann cell lines to study the potential roles of nerve growth factor (NGF), the antiapoptotic protein Bcl-2 and the cytokine response modifier A (CrmA) in modulating Schwann cell death in vitro. Bcl-2 inhibited Schwann cell apoptosis induced by survival factor withdrawal, whereas CrmA did not. In contrast, Bcl-2-transfected Schwann cells were susceptible to apoptosis in response to exogenous NGF, whereas CrmA-expressing cell lines were resistant. Demonstration of high levels of the low-affinity neurotrophin receptor p75 but not the high-affinity TrkA receptor on the Bcl-2-transfected cell lines suggested that the NGF-induced killing was mediated by p75. This was confirmed by resistance of Schwann cells isolated from p75 knockout mice to the NGF-induced cell death. Nerve growth factor also promoted the death of wild-type mouse and rat Schwann cells in the absence of survival factor withdrawal. Endogenous Bcl-2 mRNA was expressed by wild-type Schwann cells in all conditions that promoted survival but was downregulated to undetectable levels after survival factor withdrawal. In conclusion, our results demonstrate the existence of two separate pathways that expedite apoptosis in Schwann cells: a Bcl-2-blockable pathway initiated on loss of trophic support, and a Bcl-2-independent, CrmA-blockable pathway mediated via the p75 receptor

Finnish multiple sclerosis patients treated with cladribine tablets : a nationwide registry study

Background: Cladribine tablets for adult patients with highly active relapsing multiple sclerosis (MS) have been available in Finland since 2018. Real-world data from different genetic and geographical backgrounds are needed to complement data from clinical trials.Methods: We investigated the use of cladribine tablets in Finland in a non-interventional cohort study, based on real-world data from the nationwide Finnish MS registry. All eligible patients who had initiated treatment with cladribine tablets in 2018-2020 were included. Descriptive analyses for outcomes were conducted using summary statistics. Time-dependent endpoints were analyzed using cumulated events analysis based on 1-Kaplan-Meier estimates and curves. Subgroups were analyzed separately according to the number of previous disease-modifying therapies (DMTs) and the most common last preceding therapies.Results: Data of 179 patients were analyzed. Median follow-up time was 19.0 months (interquartile range [IQR] 12.0-26.2). Of the 134 patients who were followed for at least 12 months, 112 patients (83.6%) remained relapse-free during follow-up. Mean annualized relapse rate (ARR) was 1.0 (standard deviation [SD] 0.89) at baseline, and 0.1 (SD 0.30) at follow-up. Patients with two or more previous DMTs had shorter time to first relapse (median 2.5 months, IQR 0.6-9.3) when compared to patients with 0-1 previous DMTs (median 11.4 months, IQR 8.7-13.1) (p=0.013). After excluding patients switching from fingolimod (n=33), a statistically significant difference in time to first relapse was no longer observed between the two groups (p=0.252). Adverse events (AEs) were reported in 30 patients (16.8%). The most frequent AE was headache (n=14, 7.8%). One patient (0.6%) died of cardiac arrest. Discontinuation of cladribine tablets was reported in nine patients (5.0%).Conclusion: The mean ARR observed in this cohort was similar to what has been reported in clinical trials. Approximately half of the patients had used two or more previous DMTs before cladribine tablets. These patients had a shorter time to first relapse when compared to patients with 0-1 previous DMTs, mostly driven by early relapses in patients switching from fingolimod.Peer reviewe

Correlation of Circulating Omentin-1 with Bone Mineral Density in Multiple Sclerosis: The Crosstalk between Bone and Adipose Tissue

BACKGROUND: Patients with multiple sclerosis (MS) are at increased risk of osteoporosis and fractures. Adipose tissue-derived adipokines may play important roles in the osteoimmunology of MS. In order to determine whether omentin-1 and vaspin may be related to bone health in MS patients, we compared circulating levels of these recently identified adipokines, between MS patients and healthy controls. METHODS: A total of 35 ambulatory MS patients with relapsing-remitting courses were compared with 38 age- and sex-matched healthy controls. Bone mineral density (BMD) was determined for the lumbar spine (L2-L4) and the proximal femur using dual-energy x-ray absorptiometry. Circulating omentin-1, vaspin, osteocalcin, osteopontin, osteoprotegerin, the receptor activator of nuclear factor-κB ligand, matrix metalloproteinase 9, C-reactive protein and 25-hydroxy vitamin D levels were evaluated by highly specific enzyme-linked immunosorbent assay methods. RESULTS: There was no significant difference between the two groups regarding bone-related cytokines, adipocytokines, and the BMD measurements of patients with MS and the healthy controls. However, in multiple regression analysis, serum omentin-1 levels were positively correlated with BMD at the femoral neck (β = 0.49, p = 0.016), total hip (β = 0.42, p = 0.035), osteopontin (β = 0.42, p = 0.030) and osteocalcin (β = 0.53, p = 0.004) in MS patients. No correlations were found between vaspin, biochemical, and BMD measures in both groups. CONCLUSIONS: Elevated omentin-1 serum levels are correlated with BMD at the femoral neck and the serum levels of osteocalcin and osteopontin in MS patients. Therefore, there is crosstalk between adipose tissue and bone in MS

Early and Late Pathogenic Events of Newborn Mice Encephalitis Experimentally Induced by Itacaiunas and Curionópolis Bracorhabdoviruses Infection

In previous reports we proposed a new genus for Rhabdoviridae and described neurotropic preference and gross neuropathology in newborn albino Swiss mice after Curionopolis and Itacaiunas infections. In the present report a time-course study of experimental encephalitis induced by Itacaiunas and Curionopolis virus was conducted both in vivo and in vitro to investigate cellular targets and the sequence of neuroinvasion. We also investigate, after intranasal inoculation, clinical signs, histopathology and apoptosis in correlation with viral immunolabeling at different time points. Curionopolis and Itacaiunas viral antigens were first detected in the parenchyma of olfactory pathways at 2 and 3 days post-inoculation (dpi) and the first clinical signs were observed at 4 and 8 dpi, respectively. After Curionopolis infection, the mortality rate was 100% between 5 and 6 dpi, and 35% between 8 and 15 dpi after Itacaiunas infection. We identified CNS mice cell types both in vivo and in vitro and the temporal sequence of neuroanatomical olfactory areas infected by Itacaiunas and Curionopolis virus. Distinct virulences were reflected in the neuropathological changes including TUNEL immunolabeling and cytopathic effects, more intense and precocious after intracerebral or in vitro inoculations of Curionopolis than after Itacaiunas virus. In vitro studies revealed neuronal but not astrocyte or microglial cytopathic effects at 2 dpi, with monolayer destruction occurring at 5 and 7 dpi with Curionopolis and Itacaiunas virus, respectively. Ultrastructural changes included virus budding associated with interstitial and perivascular edema, endothelial hypertrophy, a reduced and/or collapsed small vessel luminal area, thickening of the capillary basement membrane, and presence of phagocytosed apoptotic bodies. Glial cells with viral budding similar to oligodendrocytes were infected with Itacaiunas virus but not with Curionopolis virus. Thus, Curionopolis and Itacaiunas viruses share many pathological and clinical features present in other rhabdoviruses but distinct virulence and glial targets in newborn albino Swiss mice brain

NGF Is an Essential Survival Factor for Bronchial Epithelial Cells during Respiratory Syncytial Virus Infection

Background: Overall expression of neurotrophins in the respiratory tract is upregulated in infants infected by the respiratory syncytial virus (RSV), but it is unclear where (structural vs. inflammatory cells, upper vs. lower airways) and why, these changes occur. We analyzed systematically the expression of neurotrophic factors and receptors following RSV infection of human nasal, tracheal, and bronchial epithelial cells, and tested the hypothesis that neurotrophins work as innate survival factors for infected respiratory epithelia. Methodology: Expression of neurotrophic factors (nerve growth factor, NGF; brain-derived neurotrophic factor, BDNF) and receptors (trkA, trkB, p75) was analyzed at the protein level by immunofluorescence and flow cytometry and at the mRNA level by real-time PCR. Targeted siRNA was utilized to blunt NGF expression, and its effect on virus-induced apoptosis/ necrosis was evaluated by flow cytometry following annexin V/7-AAD staining. Principal Findings: RSV infection was more efficient in cells from more distal (bronchial) vs. more proximal origin. In bronchial cells, RSV infection induced transcript and protein overexpression of NGF and its high-affinity receptor trkA, with concomitant downregulation of the low-affinity p75 NTR. In contrast, tracheal cells exhibited an increase in BDNF, trkA and trkB, and nasal cells increased only trkA. RSV-infected bronchial cells transfected with NGF-specific siRNA exhibited decreased trkA and increased p75 NTR expression. Furthermore, the survival of bronchial epithelial cells was dramaticall

Dietary Vitamin D3 Supplements Reduce Demyelination in the Cuprizone Model

Vitamin D is emerging as a probably important environmental risk factor in multiple sclerosis, affecting both susceptibility and disease progression. It is not known to what extent this effect is due to a modulation of peripheral lymphocyte function, or to intrathecal effects of vitamin D. We investigated the effect of dietary vitamin D3 content on de/remyelination in the cuprizone model, which is a well established toxic model of demyelination, with no associated lymphocyte infiltration. The mice received diets either deficient of (<50 IU/kg), or supplemented with low (500 IU/kg), high (6200 IU/kg) or very high (12500 IU/kg) amounts of vit D3. Cuprizone (0.2%) was added to the diet for six weeks, starting two weeks after onset of the experimental diets. Mouse brain tissue was histopathologically evaluated for myelin and oligodendrocyte loss, microglia/macrophage activation, and lymphocyte infiltration after six weeks of cuprizone exposure, and two weeks after discontinuation of cuprizone exposure. High and very high doses of vitamin D3 significantly reduced the extent of white matter demyelination (p = 0.004) and attenuated microglia activation (p = 0.001). No differences in the density of oligodendrocytes were observed between the diet groups. Two weeks after discontinuation of cuprizone exposure, remyelination was only detectable in the white matter of mice receiving diets deficient of or with low vitamin D3 content. In conclusion, high dietary doses of vitamin D3 reduce the extent of demyelination, and attenuate microglia activation and macrophage infiltration in a toxic model of demyelination, independent of lymphocyte infiltration

MiR-126 and miR-126* regulate shear-resistant firm leukocyte adhesion to human brain endothelium

Leukocyte adhesion to brain endothelial cells, the blood-brain barrier main component, is a critical step in the pathogenesis of neuroinflammatory diseases such as multiple sclerosis (MS). Leukocyte adhesion is mediated mainly by selectins, cell adhesion molecules and chemokines induced by pro-inflammatory cytokines such as TNFα and IFNγ, but the regulation of this process is not fully clear. This study investigated the regulation of firm leukocyte adhesion to human brain endothelium by two different brain endothelial microRNAs (miRs), miR-126 and miR-126*, that are downregulated by TNFα and IFNγ in a human brain endothelial cell line, hCMEC/D3. Using a leukocyte adhesion in vitro assay under shear forces mimicking blood flow, we observed that reduction of endothelial miR-126 and miR-126* enhanced firm monocyte and T cell adhesion to hCMEC/D3 cells, whereas their increased expression partially prevented THP1, Jurkat and primary MS patient-derived PBMC firm adhesion. Furthermore, we observed that miR-126* and miR-126 downregulation increased E-selectin and VCAM1, respectively, while miR-126 overexpression reduced VCAM1 and CCL2 expression by hCMEC/D3 cells, suggesting that these miRs regulate leukocyte adhesion by modulating the expression of adhesion-associated endothelial mRNA targets. Hence, human brain endothelial miR-126 and miR-126* could be used as a therapeutic tool to reduce leukocyte adhesion and thus reduce neuroinflammation