Author Archives: Jonathan Grinstein

Cleveland Clinic Nevada Joins DELIVER-MS Trial Assessing RRMS Treatments

The Cleveland Clinic Nevada is recruiting participants for DELIVER-MS, a clinical trial comparing two common treatment approaches for relapsing-remitting multiple sclerosis (RRMS). Results from the DELIVER-MS trial, titled “Determining the Effectiveness of Early Intensive Versus Escalation Approaches for the Treatment of Relapsing-Remitting Multiple Sclerosis” (…

Non-contrast MRI Effective in Monitoring Progression of MS, Study Shows

The evaluation of disease progression in multiple sclerosis (MS) patients through magnetic resonance imaging (MRI) can be performed without the use of a contrast agent, new research has shown. These findings suggest that routine use of contrast-enhanced MRI is unnecessary for most follow-ups with MS patients, reducing both imaging time and cost without missing new or enlarged lesions. The research article, “Accuracy of Unenhanced MRI in the Detection of New Brain Lesions in Multiple Sclerosis,” was published in the journal Radiology. MRI with the administration of a contrast agent is generally considered a requirement for follow-up scans in MS patients. Typically, the contrast agent used is gadolinium — a heavy metal that enhances the MRI result,  helping provide diagnostic data. However, the use of gadolinium contributes to longer MRI scan times and increased costs. Also, there is some evidence that not all gadolinium leaves the body after administration, though its long-term health impact is unclear. Now, MRI with higher magnetic field strengths — such as 3 Tesla MRI (Tesla is the unit for magnetic field strength) — have become widely available, especially for brain imaging. Also, recently introduced three-dimensional MRI outperforms conventional two-dimensional MRI in visualizing lesions. Improvements in MRI technology, as well as scanning methods, have also improved the sensitivity in detecting new or enlarged lesions in MS at follow-ups. Researchers from the Technical University of Munich, Germany, tested whether using contrast material influences the detection of new or enlarged MS lesions, critical for the assessment of interval disease progression — defined as at least one new or enlarged lesion on follow-up MRI scans. "These factors warrant evaluation of strategies for reducing or omitting contrast agent, especially in MS patients who often accumulate a high number of MRI scans over their lifetimes," Benedikt Wiestler, MD, the study's senior author, said in a press release. The retrospective study looked at 507 follow-up MRI scans, acquired from 359 MS patients, to assess new or enlarged lesions. Participants had an average age of 38.2 years. Of the 507 scans, 264 showed disease progression in the form of 1,992 new or enlarged lesions. "In over 500 follow-up scans, we missed only four of 1,992 new or enlarged lesions," Wiestler said. "Importantly, we did not miss disease activity in the non-enhanced scans in a single follow-up scan." The researchers then tested whether two different imaging methods (image subtraction methods) picked up on MS lesions specific to contrast or non-contrast enhanced MRI. With either method, contrast-enhanced MRI did not reveal interval disease progression that was missed in readouts of the non-enhanced scans. “In conclusion, our data support the view that modern three-dimensional sequences at 3.0 Tesla in combination with image subtraction are ready to supersede routine use of contrast material in most instances of follow-up investigations of patients with MS, reducing both imaging time and cost without missing new or enlarged lesions,” the researchers said. It is important to note that, though non-enhanced MRI appears adequate to reliably assess interval disease progression, contrast enhancement with gadolinium reveals information on lesion age. This data can help identify active demyelination of nerve fibers, and obtain an accurate differential diagnosis that cannot be determined in non-enhanced MRI scans. Nevertheless, the study showed that the combination of three-dimensional MRI and subtraction image methods can improve the sensitivity for detecting new MS lesions. "Several vendors have made tools for generating subtraction images commercially available," Wiestler said. "Implementing such tools into the routine clinical workflow will help to make the use of contrast agent dispensable in routine follow-up imaging of MS patients."

#ACTRIMS2019 – Botox Earns High Marks from Patients, Physicians as Treatment for Spasticity, ASPIRE Follow-up Finds

Patients with a range of diseases and disorders, including multiple sclerosis (MS), report high satisfaction with botulinum toxin — also known as Botox  — as a treatment for spasticity, results from the ASPIRE clinical trial show. The data were presented last week by Daniel S. Bandari, MD, from the MS Center of California & Research Group at the Hoag Neurosciences Institute, at the 4th Annual Americas Committee for Treatment and Research in Multiple Sclerosis Forum in Dallas, Texas. His poster was titled “Individualized OnabotulinumtoxinA Treatment for Spasticity in Multiple Sclerosis Resulted in High Patient and Clinician Satisfaction: The Aspire Study.” Botox is approved by the U.S. Food and Drug Administration (FDA) to treat muscle spasms, spasticity, and bladder symptoms in patients with a spectrum of diseases, including MS. It is estimated that six to nine of every 10 MS patients experience spasticity at some point. In collaboration with developer Allergan, an international team of researchers examined real-world data on the effectiveness of Botox to treat spasticity in a study called ASPIRE (NCT01930786). Researchers also assessed both patient and clinician satisfaction with the treatment. The ASPIRE trial is a prospective, international, multicenter, observational study in centers across North America, Europe, and Asia, that examined 730 adult patients (average age 53.6 years) with spasticity symptoms. In this patient group, the most common diseases were stroke (56%), followed by MS (16%). Of the initial patients, 397 (54%) completed a two-year follow-up period. Researchers observed a wide range of injections in upper and lower limbs. Anatomical location and electromyogram (EMG) localization were the most frequently used injection guiding methods in upper and lower limbs, respectively. In MS patients, the most common treated upper limb spasticity presentation was flexed elbow; the most common lower limb presentation treated was equinovarus foot (in which one or both feet are rotated inward and downward). Overall, clinicians and patients were satisfied with the effectiveness of Botox in easing spasticity symptoms. "The majority of patients and clinicians were satisfied that onabotulinumtoxinA treatment improved the patient’s ability to participate in therapy/exercise" Bandari said, specifying 72% of the patients and 91% of the clinicians. Furthermore, Bandari added, "the majority of patients and clinicians also indicated that they would continue to use onabotulinumtoxinA treatment for spasticity" after the study's end, specifically 92% of the patients and 98% of clinicians. Regarding safety, 261 of the initial 730 patients (35.8%), reported 831 adverse side effects. Of these, 23 were considered treatment-related. The most common treatment-related side effect was muscular weakness. Overall, the team concluded that the results "add to the body of evidence on the safety and effectiveness of onabotulinumtoxinA for the treatment of spasticity." Bandari also emphasized that "ASPIRE provides valuable, real-world data ... which may help guide clinical strategies." It also "captured the individualized nature of onabotulinumtoxinA utilization for spasticity in MS patients, while consistently demonstrating high satisfaction among patients and clinicians.”

Vitamin B12, Folic Acid Supplements Yield Multiple Benefits for MS Patients

Vitamins B12 and B9 (folic acid) supplements can lower levels of homocysteine (a common amino acid), improve anemia status, and boost self-reported physical health in patients with multiple sclerosis, according to new research. The study suggests a potential role for these two vitamins in improving the quality of life of MS patients. Despite treatment, MS patients often experience symptoms that interfere with their daily lives. Many patients have turned to dietary supplements with the hope they would reduce the severity of their symptoms. There is substantial literature suggesting the benefits of various supplements for MS, including vitamin B12 and folic acid. Homocysteine, of which high levels are associated with heart disease and detrimental effects in the nervous system, can be more prevalent in MS patients compared to healthy individuals. That suggests homocysteine is "one of the causative factors in the pathogenesis [development] of MS," researchers wrote. Lack of vitamin B12 — naturally found in meat, fish, poultry, eggs, and dairy products — can lead to a disruption in myelination, the process of forming a protective myelin coat around nerve cells. The loss of myelin is a hallmark of MS. A lack of folic acid, together with too little vitamin B12, has been linked to neurological symptom onset in MS patients. Meanwhile, vitamin B12 and folic acid supplements have shown promising results among these patients. In addition, MS patients are known to have an increased risk for the development of megaloblastic anemia — a condition in which the bone marrow produces unusually large, immature red blood cells referred to as megaloblasts. The most common causes of megaloblastic anemia are a deficiency of either vitamin B12 or folic acid. Based on these observations, researchers from Urmia University of Medical Sciences and Kermanshah University of Medical Sciences, in Iran, studied the effects of vitamin B12 and folic acid supplements in  relapsing-remitting multiple sclerosis (RRMS) patients. The team looked specifically at serum homocysteine levels, anemia status, and quality of life. This double-blinded clinical trial (IRCT2015100313678N7) enrolled 50 RRMS patients (age 20-40 years), who were divided into two groups: the vitamin group, which received three doses of 1 mg vitamin B12 injection (spaced a month apart) plus 5 mg folic acid tablets daily; and the placebo group, which received neutral saline injections. All participants completed two quality-of-life questionnaires, one geared toward physical health and the other toward mental health, at the start and end of the study. Blood samples were collected from all participants, and blood pressure readings were taken. Results showed a drop in average homocysteine blood serum levels in the vitamin group, which may be indicative of an improvement in nervous system health. Researchers also observed a decrease in mean corpuscular volume (MCV) in the vitamin group, which is indicative of improved anemia status. At the end of the study the vitamin group showed improvements in both physical and mental fields in the quality-of-life questionnaires. However, RRMS patients in the control group (without vitamin supplements) also had an increase in the quality-of-life questionnaire for mental health, obscuring any conclusions on the effect of vitamin supplements in MS patients’ mental health. “Results of the present study have shown that homocysteine levels, anemia status, and eventually the quality of life of patients with MS can be significantly improved by administration of 1 mg of vitamin B12 monthly and adding rich-food sources of folic acid on their diet,” the researchers wrote. The team nonetheless emphasizes that "further studies in the field of MS dietary patterns must be conducted."

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.

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.

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