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February 18, 2019 News by Jonathan Grinstein

Protein That Turns Certain T-cells into Inflammatory Agents Identified in Early Study

A protein called Satb1 appears to be the "on switch" that turns a type of T-cell called Th17 from its typical protective role into one that is disease-causing, and key in the development of multiple sclerosis (MS) and other inflammatory autoimmune disorders, a study reports. These findings suggest that Satb1 may be a therapeutic target for autoimmune diseases like MS. The research article, “Satb1 regulates the effector program of encephalitogenic tissue Th17 cells in chronic inflammation,” was published in the journal Nature Communications. Immune cells called T-helper 17 (Th17) cells play a range of roles in immunity, including protecting against infecting pathogens — bacteria, viruses, and other microorganisms that can cause disease. But Th17 cells are also players in the development of such autoimmune diseases as MS, psoriasis, inflammatory bowel disease, and rheumatoid arthritis. This is because Th17 cells can be stimulated to become T-cells that engage in pathogenic, or disease-causing, immune programs. How Th17 cells switch from their typical and helpful immunity role to that of a pathogenic actor has not been resolved, although it is thought critical to treating inflammatory autoimmune diseases. An international team led by researchers at Osaka University and Kyoto University, in Japan, tried to identify the mechanism behind the disease-causing program of Th17 cells. To do so, they built upon previous findings showing that a protein regulator called Satb1 is important in the development of Th17 cell subsets. "We have known for some time that Satb1 is indispensable for the development of T-cells in the thymus. However, how it is involved in the regulation of pathogenic processes of Th17 cells in inflamed tissues had not been examined," Keiko Yasuda, MD, the study's lead author, said in a press release. Researchers used a standard mouse model of MS, called experimental autoimmune encephalomyelitis (EAE) mice. These animals had genetically-modified Th17 cells that lacked Satb1. Researchers tested how Th17 cells lacking Satb1 acted when subject to inflammatory conditions, and how they were stimulated to activate a "pathogenic effector program." Interestingly, these modified mice were resistant to the development of EAE, or MS-like, disease. Researchers saw fewer Th17 cells infiltrating the animals' spinal cord. Also, Th17 cells lacking Satb1 showed poorer production of key pathogenic signaling molecules in autoimmunity, notably one called granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is known to cause localized tissue inflammation in MS and other inflammatory autoimmune diseases. Researchers went on to show that Satb1 can act as a switch between benign and pathogenic Th17 cells, depending on their exposure to healthy or inflammatory conditions. They found molecules that boost the pathogenicity of Th17 cells, such as Bhlhe40, and molecules that promote normal immune function, such as PD-1.  Of note, PD-1 is shut down when Th17 cells engage in their pathogenic effector program. These results showed Satb1 to be a key regulator of Th17 cell pathogenicity in these MS mice. Halting Th17 cells from making Satb1 may offer a way of treatting various autoimmune diseases. “Together, our findings, in addition to providing novel insights into the molecular mechanisms underlying the pathogenic program of tissue Th17 cells in mice, may help design novel immunotherapeutic approaches such as small molecule modifiers of Satb1 for the treatment of autoimmune diseases,” the researchers wrote. Future studies are needed to confirm these results in people. A previous study in people also suggested a link between Satb1 and the pathogenic function of Th17 cells in the central nervous system of MS patients. Overall, "our results suggest that manipulating Satb1 gene expression in Th17 cells could form the basis of novel treatments for various autoimmune diseases caused by Th17 cells. If we can prevent the pathogenic processes of Th17 cells, we may be able to alleviate or even eliminate disease symptoms," concluded Shimon Sakaguchi, PhD, one of the study's senior authors.

February 15, 2019 News by Larry Luxner

Newly Published NMSS Study Confirms Nearly 1 Million Americans Have MS

It’s finally official: Around 900,000 Americans and quite possibly more than that have multiple sclerosis (MS) — easily double the long-accepted figure of 400,000. Since MS News Today first reported on this finding in November 2017, the National Multiple Sclerosis Society (NMSS) study, which reached that conclusion, has…

February 14, 2019 News by Santiago Gisler

Continuous Use of Gilenya for Up to 3 Years Can Lead to 50% Drop in Annual Relapse Rates, Real-world Study Says

Multiple sclerosis patients who began treatment with Gilenya and stayed with it continuously showed a more than 50 percent reduction in annual relapse rates, a real-world study following these people for up to three years found. Gilenya, marketed by Novartis, is an oral disease-modifying treatment for relapsing-remitting multiple sclerosis , approved in 2010. It acts by binding and modulating receptors — called sphingosine-1-phosphate receptor — on lymphocytes (adaptive immune cells). By binding to these receptors, Gilenya prevents lymphocytes from leaving the lymph nodes and reaching the brain and spinal cord, and so lower lymphocyte-induced inflammation and damage. Although several clinical trials have reported reduced annualized relapse rates (ARRs) upon treatment with Gilenya, few long-term real-life studies have examined the relapse rate reductions over a long term. A team, led by Novartis researchers and a scientist at Central Texas Neurology Consultants, collected MS patient data from the MarketScan database, a U.S. claims database including medical and pharmacy claims (bills submitted to health insurance providers), between 2009 and 2016. Among 9,312 MS patients in the database with at least one filled Gilenya prescription, 1,599 adults (mean age, 46) met the study's inclusion criteria, including having at least one inpatient or two outpatient claims, and a total of four years of continuous health plan enrollment. Among these 1,599 patients, all used Gilenya for one year (cohort 1), 1,158 (72.4%) took Gilenya continuously up to the start of year two (cohort 2), and 937 (58.6%) used the therapy up to the start of year three (cohort 3). Baseline analysis — measures taken at the study's start — showed that the most common MS-linked symptoms were disorders of the optic nerve and visual pathways (reported in 22-24%), followed by fatigue/malaise (20-21%). Hypertension (20-21%) and depression (15-16%) were the most common physical and mental comorbidities, respectively. The mean annualized relapse rates (AARs) at baseline in these three groups of patients — cohorts 1 to 3 — ranged between 0.48 and 0.51. A consistent reduction in ARRs was seen in all three groups: cohort 1 had a 0.25 ARR at the close of the first year, for a 51% reduction from the baseline rate; cohort 2 a 0.22 ARR at the start of year two, for a  54% lowering in relapse rates from baseline; and cohort 3 had 0.23 ARR at the third year, amounting to a 53% reduction. As expected, when researchers calculated ARRs among patients with continuous Gilenya use over these three years, they found a greater reduction in annual relapse rates. Mean ARRs in continuous-use patients were 0.19 (a 61% reduction) during the first year, 0.18 (a 62% reduction) during the second year, and 0.18 (a 61% reduction) at the start of the third year. “This retrospective claims database study found that patients with MS who received fingolimod [Gilenya] therapy experienced a durable and sustained reduction in relapse rates over a 3-year period,” the researchers wrote, with findings representing “a durable reduction in relapse rates by [more than] 50%.” Reasons that some patients discontinued treatment were not a focus of this study, they added.

February 12, 2019 News by Jonathan Grinstein

MMP-9 Protein a Possible Marker of PML in Tysabri-treated RRMS Patients, Study Suggests

A protein called MMP-9 could be a predictive marker of progressive multifocal leukoencephalopathy development in patients with relapsing-remitting multiple sclerosis (RRMS) who are being treated with Tysabri (natalizumab), a study suggests. The study, “Dynamic changes of MMP-9 plasma levels correlate with JCV reactivation and immune activation in natalizumab-treated multiple sclerosis patients,” was published in the journal Nature Scientific Reports. Brain inflammation in multiple sclerosis patients occurs when immune cells breach the blood-brain barrier. This layer of cells protect the brain and its supporting fluids, such as cerebral spinal fluid (CSF), from dangerous agents circulating in blood. How easily immune cells can break through the blood-brain barrier depends on its porousness. For instance, it is known that decreasing the activity of matrix metalloproteinases (MMP) increases the protective layer’s permeability. Matrix metalloproteinases are a family of proteins responsible for the degradation of collagen and other proteins in the extracellular matrix, which provides structural and biochemical support to surrounding cells. One metalloproteinase, called MMP-9, has been extensively studied in multiple sclerosis. MMP-9 levels are elevated in the CSF of multiple sclerosis patients and considered a potential biomarker of disease activity and possible therapeutic target. Tysabri (marketed by Biogen) is one of the most effective treatments for RRMS currently available. It works by blocking the entry of immune cells into the brain. Tysabri is known to decrease MMP-9 levels in the CSF and serum in RRMS patients. However, Tysabri has been associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML). This rare and often fatal viral disease, caused by the John Cunningham virus (JCV), is characterized by progressive damage and/or inflammation at multiple sites in the brain. The reduced migration of immune cells across the blood-brain barrier induced by Tysabri is thought to be the cause of this increased PML risk. Whether MMP-9 is involved in this process has not been studied. To look at this, a team led by researchers from Sapienza University and Aldo Moro University in Italy investigated MMP plasma levels following Tysabri treatment in the context of JCV. The team specifically looked at how levels of MMP-9 were linked to disease-related processes. Samples from 34 RRMS patients being treated with Tysabri (intravenous dose of 300 mg every four weeks) were analyzed. As expected, results showed that MMP-9 plasma levels stabilized within one year of Tysabri treatment (up to 12 Tysabri infusions), although they began to steadily rise afterward (between 12 and 24 infusions). These increased MMP-9 plasma levels were not associated with clinical relapses in RRMS patients. "MMP-9 levels increased in plasma accordingly with [Tysabri] infusion number," the researchers wrote. In comparing JCV-positive and JCV-negative samples, the researchers observed an increase in MMP-9 plasma levels in JCV-positive samples. This result suggested that JCV circulation in peripheral blood could be implicated in the increase of MMP-9 levels. Interestingly, increased MMP-9 plasma levels were found to be correlated with immune cell activation. "Our findings suggest a potential pathogenic role of MMP-9 in the development of progressive multifocal leukoencephalopathy during [Tysabri] treatment, and its possible use as a marker of JCV reactivation,” the researchers wrote. Future studies are nonetheless needed to confirm these findings in larger groups of RRMS patients.

February 12, 2019 News by Alice Melão, MSc

Direct Nerve Stimulation Using MyoRegulator System Seen to Reduce Spasticity in Mice with Spinal Injury

Treatment with PathMaker Neurosystems’ anodal trans‐spinal direct current stimulation (tsDCS), a non-invasive direct nerve stimulation tool called MyoRegulator, was found to effectively ease spasticity in mice with spinal cord injury, a study reports. A link between the ability to control muscle contraction and the levels of a specific neuronal…

February 8, 2019 News by Jose Marques Lopes, PhD

Medicare Rules, Higher Cost-sharing Load Increase Out-of-pocket Spending for MS Therapies, Study Reports

Restrictive access policies by Medicare and a rising cost-sharing burden lead to an increased price of disease-modifying therapies for multiple sclerosis patients, according to new research. The findings also revealed that Medicare beneficiaries without a low-income subsidy may spend on average $6,894 for their MS treatments in 2019, with generic versions of Copaxone representing the highest burden. Approximately 25-30% of patients with MS are covered by Medicare through disability. In 2013, MS Medicare beneficiaries with MS and without low-income subsidies averaged $4,389 a year in out-of-pocket expenses, second only to hepatitis. Despite a greater number and diversity of DMTs for MS treatment, their price has increased substantially over the past two decades. In fact, expenses related to DMTs for MS are among the highest by class in the Medicare market. “It’s a dysfunctional market that lacks the typical incentives for most other consumer prices,” Daniel Hartung, the study’s lead author, said in an Oregon Health & Science University (OHSU) press release written by Erik Robinson. “Aside from the public optics, there are few incentives for companies not to raise prices. Most intermediaries in the drug distribution channel, including drug companies, benefit from higher prices,” Hartung said. These high prices may lead to reduced access, as insurance companies can restrict coverage or manage use through prior authorization or step-therapy policies, and high deductibles or cost-sharing components in health plans that increase the financial burden for patients. Now, a team at OHSU and the Oregon State University College of Pharmacy used prescription drug plan formulary files to analyze changes in coverage policies from 2007 to 2016, and to estimate out-of-pocket spending for DMTs for MS within Medicare Part D program, through which outpatient prescriptions are financed. Eleven DMTs available during the study period were analyzed. Tysabri and Lemtrada were not part of the analysis because they are delivered via intravenous infusion in the clinic setting, and are typically covered through Medicare Part B. Results revealed that the price for Betaseron , Copaxone 20 mg , Rebif, and Avonex — the four therapies available in 2007 — quadrupled over the 10-year study period. Except for Copaxone 40 mg and its 20 mg generic formulation (Glatopa, by Sandoz), prices for the other DMTs introduced after 2007 increased by 9–13% per year. These include Novartis’ Extavia (interferon beta-1b) and Gilenya (fingolimod), Biogen’s Plegridy (peginterferon beta-1a) and Tecfidera (dimethyl fumarate), and Sanofi Genzyme’s Aubagio (teriflunomide). In 2007, 99-100% of plans covered the four available medications, with the exceptions being Rebif (88%). These percentages fell to 54-89% in 2016. Coverage of the other DMTs varied between 21% (Extavia) to 92% for Copaxone 40 mg. In turn, coverage for the three oral options — Gilenya, Aubagio and Tecfidera — generally increased or was maintained over time, ranging from 46% for Aubagio to 83% for Gilenya. The use of prior authorization increased from 61-66% in 2007, to 84-90% in 2016. Also, the share of plans with at least one DMT available without limitations declined from 39% to 17%. The average projected out-of-pocket spending for 2019 across DMTs was $6,894. The highest projected out-of-pocket expenses ($8,219) are associated with generic glatiramer acetate, both Glatopa and Mylan’s 20 mg/mL and 40 mg/mL generic formulations, approved by the U.S. Food and Drug Administration in 2017. This is more than with any of Copaxone’s formulations. According to the team, this is the result of a higher coinsurance payment (37% vs. 25%) expected for generic medications compared to brand-name options, as well as the fact that manufacturers of generics do not provide discounts toward a beneficiary’s total out-of-pocket spending, unlike what is mandated by the Affordable Care Act for brand-name therapies. “This is a pernicious effect of the release of a generic and an unfortunate effect of Medicare rules,” Dennis Bourdette, MD, one of the study’s co-authors, said. A proposal by U.S. President Donald Trump's administration addresses this by eliminating manufacturer discounts from the calculation to determine a patient’s total out-of-pocket spending. Such strategy would reduce the disparity between brand-name and generic therapies, the researchers said. “In this study we found that Medicare beneficiaries with MS who require a [DMT] face considerable policy-related access restrictions and high out-of-pocket spending,” the researchers wrote. “There is an urgent need for policies that slow the growth of drug prices, improve access, and shield patients from excessively high out-of-pocket spending,” they concluded.

February 5, 2019 News by Patricia Inacio, PhD

Genetic Variants in Inflammasome Genes Influence MS Severity, Progression, Study Suggests

Genetic variants that enhance the activity of the NLRP3 inflammasome or the interleukin-1 beta cytokine are linked to higher severity and progression of multiple sclerosis, a study suggests. Previous studies with mouse models of MS have shown that a complex of innate immune system receptors and sensors, known as the inflammasome, is likely a player promoting the immune system’s attack on the central nervous system in MS and, consequently, the loss of myelin. Follow-up studies showed that people carrying mutations that enhance the function of the NLRP3 inflammasome — one of the three components of the inflammasome complex — had a worse prognosis, once again supporting the role of the inflammasome in MS. Once activated, the inflammasome triggers an enzyme called caspase-1 that promotes the production of two very powerful proinflammatory cytokines called interleukin (IL)-1 beta and IL-18. To further evaluate the role of the inflammasome in MS, a team led by researchers at the Universidade de Sao Paulo in Brazil analyzed the genetic sequence of five inflammasome genes — NLRP1, NLRP3, NLRC4, IL-1 beta, and IL-18 — in blood samples retrieved from 264 patients diagnosed with MS or other demyelinating diseases. They also analyzed 233 healthy individuals used as controls. The team specifically looked at eight variations in certain nucleotides (the building blocks of DNA), called single nucleotide polymorphisms (SNPs). Previous studies reported a link between SNPs in inflammasome-related genes and certain forms of MS. Results showed that SNPs associated with low serum levels of IL-18 were significantly less frequent in MS patients than in controls. In contrast, variants that enhance the function of NLRP3 and IL-1 beta were associated with severity and progression of MS, as measured by the Expanded Disability Status Scale. These results suggest that the "activation of NLRP3 inflammasome could represent a risk factor for MS clinical presentation,” the researchers wrote. A particular variant in the NLRC4 gene was less frequent in patients whose disease progressed rapidly compared with those who had a slower disease, an intriguing observation, according to researchers, suggestive of a “protection effect of this variant against a bad prognosis.” Carriers of this variant also responded better to treatment with interferon-beta. Regarding MS type, the genetic variant that promotes the function of the IL-1 beta gene was significantly more frequent in progressive forms of MS than in relapsing-remitting MS, strengthening once again the negative effects of IL-1 beta in the disease. An analysis of inflammasome activity in blood monocytes, a group of immune cells, showed that the inflammasome is permanently activated in MS compared with healthy controls. "This study emphasizes that a constitutive activation of NLRP3 inflammasome, principally through IL-1 beta production, represents a risk factor for both the development of MS and the progression to severe forms of the disease. On the other hand, low IL-18 production and/or NLRC4 activation were beneficial for MS patients,” the team concluded.

February 1, 2019 News by Alice Melão, MSc

Study Shows Benefits of Low Temperature Exercise for MS Patients

Reducing body temperature during physical exercise can help rewire the brain and improve motor control in patients with multiple sclerosis (MS), a new research study at Canada’s Memorial University shows. Physical exercise can have several benefits for patients with MS, including improved strength and reduced symptoms of fatigue and…

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