CIS

A high dose cholecalciferol, a form of vitamin D, significantly reduced the risk of further disease activity in people with clinically isolated syndrome (CIS), published findings from a Phase 3 trial show. Vitamin D was similarly effective for reducing disease activity among a subgroup of participants who would…

A new machine learning model is able to predict the risk of converting from clinically isolated syndrome, or a first event of multiple sclerosis (MS)-like symptoms, to clinically definite disease, a study found. “Our study developed a machine-learning model that not only provides a numerical estimate of the…

High blood levels of the nerve damage biomarker neurofilament light chain (NfL) significantly increased the risk of people with clinically isolated syndrome (CIS) converting to definite multiple sclerosis (MS), according to an analysis of clinical trial data. CIS patients with higher NfL levels also made the transition earlier…

Within the first 12 years after the onset of symptoms, about one-fourth of people with clinically isolated syndrome — or a first episode of multiple sclerosis (MS) symptoms — showed a worsening of disability independent of relapses, a study reports. This type of disease progression, called progression independent…

In the years after a diagnosis of clinically isolated syndrome (CIS) — a first episode of neurological symptoms suggestive of multiple sclerosis (MS) — the odds of maintaining employment progressively decrease, according to a recent study. The risk of decreasing or losing employment was particularly high among individuals…

Iron rim lesions, or specific regions of chronic inflammation seen on MRI scans of the brain, are associated with greater disability and poorer outcomes in multiple sclerosis (MS), a study indicates. These findings “could support the use of iron rim lesions as an imaging biomarker for disease severity and…

A novel algorithm that combines genetic, environmental, and clinical data could be useful for predicting whether people with a first onset of multiple sclerosis (MS)-like disease — known as clinically isolated syndrome (CIS) — will experience relapses or a worsening of their disease over time. The…

The use of oral contraceptives does not increase the risk of a second attack of symptoms or the progression of disability in women with clinically isolated syndrome (CIS) or early stage multiple sclerosis, a study demonstrated. Notably, the researchers also “did not find a protective effect on disability…

Editor’s note: The Multiple Sclerosis News Today team is providing in-depth coverage of the virtual 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Oct. 13–15. Go here to see the latest stories from the conference. Lesions…

Editor’s note: The Multiple Sclerosis News Today team is providing in-depth coverage of the virtual 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Oct. 13–15. Go here to see the latest stories from the…

Studied for the first time, Aubagio (teriflunomide) slowed the loss of cortical grey matter and whole-brain volume in people with clinically isolated syndrome (CIS) during two years of therapy, a study found. The treatment was especially effective in those without brain lesions before treatment.

Older age at disease-modifying therapy (DMT) discontinuation is the main predictive factor of sustained “no evidence of disease activity” (NEDA) in people starting DMT immediately after being diagnosed with clinically isolated syndrome (CIS), according to a study in Austria. In particular, patients discontinuing DMT at age 45 or…

After a pregnancy or childbirth, most women who went on to develop clinically isolated syndrome (CIS) did so about three years later than those who were never pregnant, a large and multicenter study reported. Multiple pregnancies or births, however, were not seen to further affect CIS onset. More research is…

The U.S. Food and Drug Administration (FDA) has approved Novartis‘ Kesimpta (ofatumumab) as a self-administered treatment for adults with relapsing forms of multiple sclerosis (MS), meaning those with clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and active secondary progressive MS (SPMS). According to Novartis,…

Australian scientists have discovered subsets of immune cells that differ between people who have multiple sclerosis (MS) and those who don’t. Because the prevalence of these cells correlates with autoimmune attacks, they represent potential targets for MS therapies. The study, “IgG3 + B…

Supporting evidence that infection with Epstein-Barr virus (EBV) could be one of the root causes of multiple sclerosis (MS), a recent study found all of its 901 early disease patients carry antibodies against this virus, meaning that all are or have been exposed to it. The study, “…

The U.S. Food and Drug Administration (FDA) has approved Zeposia (ozanimod) oral capsules to treat adults with relapsing forms of multiple sclerosis (MS), including relapsing-remitting MS (RRMS),  active secondary progressive MS (SPMS), and clinically isolated syndrome (CIS). Due to the COVID-19 pandemic, however, when it will arrive in clinics…

A blood-cleansing process known as immunoadsorption appears to be superior to plasma exchange in treating relapses that don’t respond to conventional steroid therapy in people with multiple sclerosis (MS) or clinically isolated syndrome (CIS), a study reports. These findings were reported in “Safety and efficacy of immunoadsorption…

A large retrospective study suggests that a magnetic resonance imaging (MRI) marker — called “brain atrophied T2 lesion volume” — could help predict the timing of multiple sclerosis (MS) progression. According to the study, this marker was the only MRI parameter capable of predicting disease progression, compared with other…

A 30-year study of outcomes in multiple sclerosis (MS) patients reports that radiological findings in the first year of disease onset, and the amount of disability evident at five years, helps to predict both the likelihood of a person advancing to secondary progressive MS (SPMS) and long-term survival. The study,…

The volume of atrophied (shrunken) regions in the brain, as visible through magnetic resonance imaging (MRI) scans, can predict disease progression in people with multiple sclerosis (MS), new research reveals. The finding was published in the journal Radiology in an article titled, “Atrophied Brain T2 Lesion Volume…

  Detecting changes to the brain’s central vein using common magnetic resonance imaging (MRI) scans is a useful and accurate strategy to enhance diagnosis of multiple sclerosis (MS), a new study shows. Analysis of more than 4,000 brain lesions, obtained from contrast-enhanced MRI scans collected from eight neuroimaging European…

Imaging techniques that measure damage to the brain, in addition to those that detect lesions, may be useful in predicting likely disease progression in people with clinically isolated syndrome (CIS), a study found. The study, “Early imaging predictors of longer term multiple sclerosis risk and severity…

Routine screening through magnetic resonance imaging (MRI) of people with multiple sclerosis (MS) can predict long-term disease progression — leading to more certainty and informing better treatment choices, a 15-year study reported. The study, titled “Early imaging predictors of long-term…

The percentage of Taiwanese who develop multiple sclerosis (MS) after an episode of clinically isolated syndrome (CIS) is lower than that reported for other ethnicities, and those who do progress are likely to have a milder disease course, a study found, supporting how factors like geography and genetics…

A woman’s age at her first menstruation, or becoming pregnant and breastfeeding does not substantially influence the long-term risk of multiple sclerosis (MS) or the risk of increased disability, a study of a large number of patients with clinically isolated syndrome…

When the U.S. Food and Drug Administration approved the disease-modifying therapy Mayzent for relapsing types of multiple sclerosis, it specified in its label that the treatment was for people with clinically isolated syndrome, relapsing-remitting MS, and — importantly — secondary progressive MS provided they have "active" disease. The approval is good news, an MS researcher and physician said to Multiple Sclerosis News Today in an interview, but "surprising" in that the FDA's decision was largely based on a trial that didn't involve CIS patients and wasn't focused on responses among particular types of SPMS. “It's the first time that I've seen in the MS field that regulators made an approval designation — active secondary progressive MS — based on an underpowered subgroup analysis,” said Robert Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic. Novartis' medication, as a first oral therapy approved in the U.S. for a form of SPMS, is a big step forward in MS treatment, he said. But details of the FDA's decision caught him off guard. Fox served on the steering committee for the EXPAND Phase 3 clinical trial , on which the FDA decision was largely based. His clinic was also one of the sites treating and evaluating patients in this pivotal study. Results of the EXPAND trial showed that Mayzent could reduce the risk of disability progression at three months (the trial’s primary endpoint, or goal) by 21% in treated SPMS patients, compared to those given a placebo. Among those with active SPMS (meaning with relapses), a 33% reduction was observed. The treatment, an S1P modulator that works in part to keep lymphocytes from entering the brain to trigger inflammation, also decreased the annualized relapse rate by 55% and improved cognitive processing speed in all treated patients.  “What was found, and I think quite clearly found in a large-size study, was that siponimod in patients with secondary progressive MS clearly slowed the progression of clinical disability over the course of the trial,” Fox said. “It's a statistical concept — obviously patients either progress or they don't progress — but on an overall basis there was a 21% slowing in the rate of progression of clinical disability.” The FDA’s decision is particularly important for SPMS patients. While Ocrevus (ocrelizumab) also treats all relapsing MS forms and people with primary progressive disease (PPMS), it's an intravenous therapy given every six months. Mavenclad (cladribine), approved for relapsing patients in the U.S. just days after Mayzent, is another oral and active disease therapy. To Fox, Mayzent seemed to reach beyond only those secondary progressive patients with clinically active disease. “Really, this is the only drug that's been found to be effective in secondary progressive MS," he said. “To that degree, it stands alone.” That's why two points in the FDA's decision surprised him. The first is the label's specific mention of clinically isolated syndrome. CIS is defined as the first clinical presentation of this disease — a neurological episode that lasts at least 24 hours, and is characterized by inflammatory demyelination (the loss of myelin, the protective coat surrounding neurons).   For clinicians like Fox, CIS is a first manifestation of MS — a kind of "mono sclerosis." Since there’s only one documented attack, it can’t yet be considered multiple sclerosis, “as the multiple hasn't happened,” Fox said, but many "in the field consider CIS to be … an early stage of MS." “If the patient has a whole bunch of lesions on their brain [as seen on an MRI scan] and they had a single clinical event, ah, probably, they have MS,” he said. Regulatory bodies like the FDA, however, have historically considered CIS to be its own separate entity. That makes this decision doubly surprising, according to Fox, since the EXPAND trial only enrolled patients with SPMS, not CIS.   “It's the first time I've seen them approve for CIS specifically when there wasn't a trial in CIS,” Fox said. “I agree with it — I don't have a problem with it — it just surprised me that the regulators were so progressive in their appreciation of MS.” The second — and far more unsettling — surprise was the FDA’s decision to only approve Mayzent for “active” SPMS patients, instead of all SPMS patients. This decision didn’t come out of nowhere, he noted, but it remains puzzling in the context of the EXPAND trial.  In compiling trial results, investigators did a subgroup analysis — as they often do, almost as an aside for research reasons — and found more favorable responses to Mayzent treatment in patients with active inflammation before the trial's start, those it determined to be with "active" disease.   “There was a third of patients who had a relapse in the two years prior to enrollment, and those patients actually had a 30% slowing in disability progression, compared to the 21% overall,” Fox said. This certainly does suggest that Mayzent can be more effective in people with active disease — but there's a catch. The trial itself was not designed to make such a distinction. It enrolled SPMS patients regardless of activity, and its priority goal was changes in disease progression across all who were treated with Mayzent or given a placebo.   “What's important is that the trial was powered for the overall outcome. It was not powered for subgroup analysis,” Fox said, considering this a crucial point.  In clinical studies, being “powered” refers to the enrolling of whatever specific number of participants a study needs to ensure its results will reach statistical significance. More people are redundant and, as such, an unnecessary cost; fewer could mean that trial's conclusions cannot be supported by rigorous scientific measures.  In other words, Fox said, the only conclusions that can be drawn from the EXPAND study reliably — with rigor — are based on data drawn from all its SPMS patients, not a subgroup with active disease. This trial “followed over 1,600 patients for the clinical disability. These are purposely powered so that you're not following twice as many people as you need to … you're powered for that primary outcome,” he said. “So, how could they [the FDA] look at a subgroup analysis and make an approval decision based on a subgroup analysis that was underpowered?” The neurologist gave as examples other subgroup differences found in trial analyses that didn't affect regulatory approval — but to his mind, equally could have. One was an analysis finding female SPMS patients responded to the therapy better than males, showing lesser disease progression. "So why didn't they just approve it for the females and not the males?" Fox asked. But, when asked, Fox did not think the label to necessarily be an error. "My point is the absurdity of it," he said. "How could they make the regulatory approval based on a subgroup analysis that wasn't powered for conclusions?" He was also particularly troubled because the FDA “didn't define what ‘active’ means — is it just a relapse, or is it MRI disease activity?"  For many clinicians, “active” SPMS refers to ongoing inflammation that can be observed on MRI (magnetic resonance imaging) scans. In EXPAND, however, the active subgroup was defined as patients with clinical relapses within two years of being enrolled in the trial. Fox worries about this apparent lack of a regulatory definition of "active" SPMS, since “obviously, the insurance companies are going to seize upon that, and they're going to look for every way they can to avoid covering it for patients.” Mayzent, Fox agreed, is likely to be expensive. The therapy is reported to carry a U.S. list price of $88,500 a year. “I always have a concern about the cost of these drugs. They're all fearfully expensive,” he said, noting he treats SPMS patients. His focus now is on working to ensure that possible regulatory and financial hurdles won’t pose too much of an obstacle for patients, especially those with SPMS. “I don't know what the insurance companies are going to do with this, but I'm hoping that it is available for my patients, and I say that as their clinician,” Fox concluded.

Smoking and low levels of vitamin D can worsen prognosis for people with clinically isolated syndrome (CIS), researchers who developed a model for predicting long-term disability progression report. Their study, “Predicting the course of CIS patients adding…

Lesions in the infratentorial region of the brain at the onset of clinically isolated syndrome (CIS) and lesions in white matter one year after CIS onset are associated with worse disability 30 years later, a study reports. The study, “Early MRI predictors of long-term multiple sclerosis outcomes:…

Poor sleep quality is very common among patients with relapsing-remitting multiple sclerosis (RRMS) or clinically isolated syndrome (CIS), and is associated with a lower quality of life, and greater fatigue, depression and anxiety, according to a real-world study in patients treated with Betaferon (interferon beta-1b). The study, “…