disease progression

Treating primary progressive multiple sclerosis patients with Ocrevus (ocrelizumab) led to a three-fold increase in the proportion of those showing no evidence of disease progression and no signs of inflammatory disease activity over more than two years of treatment, results of a Phase 3 trial show, and support new measures that might better capture disability in PPMS patients. The research, “Evaluation of No Evidence of Progression or Active Disease (NEPAD) in Patients With Primary Progressive Multiple Sclerosis in the ORATORIO Trial,” was published in the journal Annals of Neurology. Measuring disease progression in clinical trials and clinical practice requires reliable and comprehensible measures. Although widely used, the Expanded Disability Status Scale (EDSS, range 0-10) cannot fully capture changes in walking speed and hand or arm function, which are key determinants of overall disability in progressive forms of MS. No evidence of progression (NEP) is a newer measure that reflects the absence of disability progression, including upper limb function and walking speed. Maintaining NEP status means stable disease with no worsening in EDSS, in walking ability (assessed by the Timed 25-Foot Walk (T25FW) test, or the time it takes to walk 25 feet as quickly and safely as possible), and in upper limb function (assessed by the 9-Hole Peg Test (9HPT), a test of arm and hand dexterity). Patients with PPMS have less frequent signs of disease activity, which include relapses and brain lesions (assessed though magnetic resonance imaging or MRI). So scientists proposed a new measure — called “no evidence of progression or active disease” (NEPAD) — to evaluate both NEP and clinical and MRI measures of active disease. The researchers believe that NEPAD may represent a more sensitive and comprehensive measure of disease control in PPMS patients. The randomized, double-blind ORATORIO Phase 3 trial (NCT01194570) analyzed the efficacy and safety of Ocrevus — developed by Genentech, part of the Roche group — in 732 PPMS patients (age range 18–55). Results showed that Ocrevus treatment delayed the relative risk of disability progression by 25% compared to placebo, while also reducing the volume of chronic brain lesions and total brain volume loss. As a result, Ocrevus became the first therapy approved by the U.S. Food and Drug Administration and the European Commission for both PPMS and relapsing MS. Now, researchers assessed Ocrevus’ effect in PPMS patients included in the Roche-funded ORATORIO study using as trial goals changes in NEP and NEPAD. These people received either 600 mg of Ocrevus or placebo by intravenous (IV) infusion every six months for a minimum of 120 weeks (about 2.3 years). The trial’s main goal was time to onset of clinical disability progression (CDP) sustained for at least 12 weeks. CDP was defined as a 1.0 point or greater increase in EDSS score from a baseline (study start) score of 5.5 or less, or a 0.5-point increase from a baseline score greater than 5.5. NEP status, analyzed in 230 placebo- and 461 Ocrevus-treated patients, was defined as no evidence of CDP for 12 weeks, no 20% or more change in hand/arm function as measured by the 9HPT for 12 weeks, and no 20% or more change in walking ability as measured by the T25FW test for 12 weeks. "The 20% cut-off for progression on the T25FW test and the 9HPT has previously been shown to be a clinically meaningful magnitude of disease progression," the study noted. In turn, NEPAD — assessed in 234 placebo- and 465 Ocrevus-treated patients — included NEP, no brain MRI-measured disease activity, and no relapses. Relapses were defined as new or worsening neurological symptoms attributable to MS lasting longer than 24 hours and preceded by neurological stability for a minimum of 30 days. Brain MRI scans were conducted at baseline, and weeks 24, 48, and 120; new or enlarging T2 lesions and/or T1 enhancing lesions were considered evidence of MRI disease activity (T1 MRI imaging offers information about current disease activity by highlighting areas of active inflammation, while a T2 MRI image provides information about disease burden or lesion load). Overall, the majority of the PPMS patients analyzed experienced clinical disease progression or evidence of disease activity. From baseline to week 120, Ocrevus-treated patients who achieved NEP (42.7% of 461 people) or NEPAD (29.9% of 465)  — no disease activity or progression — were found to have lower T2 brain lesion volume and a lower EDSS score (lesser disability) compared to those with evidence of MS progression. They also had a slightly superior performance on the 9HPT and the T25FW test. Patients who reached NEPAD also showed fewer T1 lesions than patients with progressing or active disease. Compared to placebo treatment, the proportion of Ocrevus-treated PPMS patients maintaining NEP or NEPAD from baseline to week 120 was higher — for NEP, 42.7% versus 29.1% in the placebo group; for NEPAD, 29.9% versus 9.4% in the placebo group. These results showed that Ocrevus treatment increased the proportion of PPMS patients with NEPAD throughout the 120 weeks of the study by three-fold. “In conclusion, ocrelizumab (Ocrevus) increased the proportion of patients with PPMS with no evidence of progression and no clinical and subclinical disease activity compared with placebo,” the team wrote. “As such, NEPAD may represent a meaningful and comprehensive disease outcome in patients with PPMS.” However, data from ORATORIO's open-label extension and real-world data are needed to "determine whether NEPAD maintained throughout 120 weeks will translate into sustained NEPAD and enhanced protection against accrual of disability in patients with PPMS over the long term," the researchers concluded. Of note, five of the study’s 11 authors are employees and/or shareholders of Roche or Genentech.

Multiple sclerosis (MS) that appears to be "genuinely benign" 15 years after diagnosis is evident in a small number of patients, a large population-based study from the U.K. reports. But, its researchers note, the term “benign” is often not clinically accurate as used, because it is based largely on perceptions of disease impact. The study “How common is truly benign MS in a UK population?” was published in the Journal of Neurology, Neurosurgery & Psychiatry. The concept of benign MS is controversial, especially among clinicians. Still, long-term epidemiological studies have consistently identified a small fraction of patients whose MS progresses very slowly over a long span of years. Determining the prevalence of this type of MS in the population has been difficult, as estimates can vary significantly depending of the definition of “benign” that is adopted. Researchers sought to determine an accurate estimate of benign MS in the U.K. population, using a rigorous and comprehensive clinical definition of a truly benign disease. This definition included minimal physical disability (EDSS score of less than 3), and no significant fatigue, mood disturbance, cognitive impairment or interrupted employment in the absence of treatment with disease-modifying therapies over 15 years or more years after symptom onset. They screened an U.K. population-based registry containing data on 3,062 MS patients to identify those with "unlimited walking ability" 15 or more years after diagnosis. A representative sample of 60 patients  from this pool was analyzed (45 women and 15 men, mean age of 57); they had a mean disease duration of 28 years. Nine out of these 60 (15%; 8 women and one men) fulfilled the study’s criteria for truly benign disease. These nine people had a mean age of 27 at symptom onset, a median EDSS disability score of 1.5 (minimal signs of disability), and a mean disease duration of 31 years. "Those nine individuals with truly benign MS all remained in a relapsing–remitting state," the study noted. "However, only two out of nine showed disease arrest within the first decade; the remainder all continued to experience relapses well into their second or third decade of MS," but the rates of such relapses were low. MS in the remaining patients was not classified as benign, mostly due to evidence of cognitive difficulties (57%), and the disease's impact on employment status (52%) with many taking early retirement. Based on these results, a population frequency for "benign MS" under the definitions used was estimated at 2.9%. But the researchers noted that a large proportion of patients (65%; 39 patients out of 60) reported their disease as benign, according to a lay definition. Their self-reported status poorly agreed with the clinical assessments done throughout the study. "There is no accepted definition to offer patients when exploring whether they feel their MS is benign; the definition we chose incorporates the fundamental principles of low impact on a person, absence of complications and a favourable outcome and is in line with definitions provided by third-party support groups," the researchers wrote. Many  considering themselves with benign disease did so based on their "perception" of their disease, the team added, and one that "appeared to be driven as much by mood, fatigue and bladder function as by physical ability."  “In conclusion, after detailed clinical assessment, a small minority of people with MS appear genuinely unaffected by symptoms after 15 years,” the researchers added. They also called attention to the fact that EDSS-based definitions of benign MS and the inconsistency between patient and clinician perception of benign MS compromise the use of the term ‘benign’ in clinical practice. They also emphasize that studying individuals with benign MS “has the potential to uncover clues to mechanisms underlying favorable outcomes in MS, provide insights into new therapeutic targets and have implications for patient counselling, individual patient management and the construct of clinical trials.”

A meta-analysis of 13 case-control studies shows that the levels of the protein neurofilament light chain (NFL) are significantly higher in both the cerebrospinal fluid and blood of multiple sclerosis (MS) patients, compared to healthy controls. This finding adds to previous evidence supporting the usefulness of NFL as a…

Cerebrospinal fluid of progressive multiple sclerosis (MS) patients may carry lower levels of cell-free mitochondrial DNA, according to a team of researchers who say this may be a sign of neurodegeneration among these patients. The study “Cell-free mitochondrial DNA in progressive multiple sclerosis” was published in the journal Mitochondrion.

As a 61-year-old woman diagnosed in 2010 with primary progressive multiple sclerosis (PPMS), I was overjoyed when the U.S. Food and Drug Administration (FDA) approved the therapy Ocrevus (ocrelizumab) in March 2017. Because Ocrevus is the first treatment approved to possibly slow the progression of PPMS, the FDA’s green…

Long-term treatment with disease-modifying therapies (DMTs) appears to lessen the risk of disease worsening in relapsing-remitting multiple sclerosis (RRMS) patients, an 18-year follow-up study suggests. But these therapies were not seen to benefit those who had progressed to secondary progressive multiple sclerosis (SPMS). The study, “Onset of secondary…

Researchers have created a detailed map of the mouse nervous system, including the location of the many diverse cell types in the brain, in the largest study yet of the makeup of the mammalian nervous system.  The new map could provide new clues about the origin of neurological…

Hair Loss Seen in RRMS Patients Using Aubagio Often Temporary and Mild, Study Says I read a lot of questions on multiple sclerosis (MS) social media groups from people who are worried about hair loss caused by their disease-modifying therapy (DMT). Aubagio (teriflunomide) is one DMT with…

The number, location, and size of lesions can help predict the risk of progression from clinically isolated syndrome (CIS) to multiple sclerosis (MS) within one year, a new study shows. The study, “MRI in predicting conversion to multiple sclerosis within 1 year,” was published in the journal…

Quanterix’s ultra-sensitive Simoa assay has the potential to open new uses for the brain biomarker known as neurofilament light chain, including the possibility to detect early evidence of neurological diseases like multiple sclerosis (MS), Parkinson’s, and Alzheimer’s, and ably evaluate efforts to treat and prevent them, the company…

Removing a specific microRNA molecule — miR-150 – eased disease severity, inflammation, and loss of myelin in a mouse model of multiple sclerosis (MS), researchers report. Their study, “Silencing miR-150 Ameliorates Experimental Autoimmune Encephalomyelitis,” was published in the journal Frontiers in Neuroscience. Micro RNAs (miRNAs) are…

Cerebrospinal fluid levels of neurofilament light chain, a protein associated with nerve cell damage, can predict disease progression in people with clinical isolated syndrome (CIS) and relapsing-remitting multiple sclerosis (RRMS), a Swedish study found. Higher levels…

Brain Iron Levels Correlate with MS Progression, Disability Risk, Study Shows Currently, doctors measure shrinkage in the brain as a way to predict physical and cognitive decline in people with multiple sclerosis (MS). But it takes a long time to see this brain atrophy on a standard…

Evaluating the local differences in iron accumulation in the deep gray matter of the brain using a special magnetic resonance imaging (MRI) technique, may help identify multiple sclerosis (MS) patients at greater risk for disease progression and disability, a study reports. The study “Brain Iron by Using Quantitative MRI…

Cladridine may be effective in preventing disability progression and reducing damage to nerve cells in people with progressive forms of multiple sclerosis (MS), researchers suggest based on a case study of two such patients given the injectable treatment. MS is characterized by progressive degeneration of cells in the central nervous system, mostly…

Brain volume loss takes place at a faster rate in the first five years of multiple sclerosis than later in disease course, researchers report in a study that calls for scientists to “reconsider” — for this and related reasons — proposals to use volume loss as a measure of treatment efficacy…

An MRI technique known as magnetization transfer ratio (MTR) correlated closely with the progression of slowly evolving lesions (SELs) — a specific type of multiple sclerosis lesion — in patients with secondary progressive MS (SPMS). According to the researchers, monitoring changes in SELs — which indicate demyelination and loss of nerve fibers —…

Atrophy seen in areas of the spinal cord is a better predictor of physical disability in secondary progressive multiple sclerosis (SPMS) patients than loss of brain volume, a new study reports. The research was presented at the 4th Congress of the European Academy of Neurology (EAN), recently held in Lisbon,…

Grey matter atrophy — its loss —  follows a sequential pattern that expands to involve more regions of the brain over time in all multiple sclerosis (MS) patients, regardless of their disease type, a new study reports. Atrophy progression is also similar between relapsing-remitting multiple sclerosis (RRMS) and primary-progressive multiple sclerosis (PPMS)…

When a progressively debilitating disease like multiple sclerosis (MS) causes a patient to feel physically “wiped out” after a simple daily activity, such as a shower, it is of utmost importance for these individuals and the people in their support system to understand how they can maintain independence for…

Magnetic resonance imaging (MRI) used to assess inflammation in multiple sclerosis (MS) patients should include scans of the spinal cord and not be restricted to the brain, because brain scans alone risk underestimating disease progression, a study suggests. These results were shared in the presentation, “Measuring disease activity in…

Measuring the response of the pupil to light stimulating the eye is a non-invasive and easy way to assess multiple sclerosis (MS) severity and progression, researchers report. A clinical study found that poor, or dysfunctional, pupil response was associated with longer disease duration and greater disease severity in relapsing-remitting multiple…

Levels of neurofilament light chain are a reliable predictor of disease worsening and progression in relapsing-remitting MS (RRMS) patients, a new study shows. Moreover, treatment with Gilenya (fingolimod), marketed by Novartis, can reduce the levels of NfL for up to 10 years. These findings were shared recently in the presentation “…

Researchers have unveiled a new cell death mechanism called pyroptosis — also known as “fiery death” — as a main factor driving neurodegeneration and loss of myelin in people with multiple sclerosis (MS). An inhibitor of pyroptosis, currently undergoing testing in human clinical trials for epilepsy, decreased central nervous system inflammation…

Young adults at age 20 who are obese and smoke are not only at a higher risk of developing relapsing multiple sclerosis — those who become MS patients after age 20 are also more likely to advance to secondary progressive MS more quickly, researchers in Sweden report. But the link…

Atrophy (shrinkage) of brain lesions correlates with physical disability in patients with multiple sclerosis (MS), new research reports. The study, “Atrophied Brain Lesion Volume: A New Imaging Biomarker in Multiple Sclerosis,” was published in the Journal of Neuroimaging. Magnetic resonance imaging (MRI) scans are used routinely on MS patients…

Age at disease onset, number of early relapses, and the extent of brain damage at baseline can help identify those who are at high risk of progression from relapsing-remitting multiple sclerosis into the secondary progressive phase of the disease, a new study shows. The study with that finding, “…

A potential biomarker — the ratio of antibody proteins in cerebrospinal fluid at the time of diagnosis — was seen to predict which  multiple sclerosis patients will progress into full-blow disability some five years after being diagnosed in a new study. If confirmed in larger clinical studies, this biomarker could to…

A new American Academy of Neurology (AAN) guideline recommends that multiple sclerosis (MS) patients in general be counseled to start treatment with disease-modifying therapies (DMTs) as early as possible. Considerations on switching and stopping treatments are also presented in the guideline. The report, “Practice guideline recommendations…

Novartis’ investigational oral treatment siponimod (BAF312) reduces the risk of disability progression in patients with secondary progressive multiple sclerosis (SPMS), a new analysis of Phase 3 trial results show. Using what the company describes as more accurate methods to assess siponimod effect’s on progression risk, necessary because the…