Erica Slaughter

By applying a validated algorithm to multiple sets of administrative health data (AHC), researchers have shown that there has been a steady rise in the prevalence of 

 in the US over the past 5 years to nearly 1 million people.

This number is nearly double that of previously reported estimates from prior studies, which had estimated that this population in the US numbered approximately 

403,630 individual cases (95% CI 387,445-419,833)

. Establishing an accurate estimate of MS prevalence in the US is essential for evaluating changes in disease frequency in relation to changing population demographics.

“We must understand the reasons behind the growing MS prevalence estimates in the US,” Mitchell Wallin, MD, MPH, Director for The Multiple Sclerosis Centers of Excellence (MSCoE) East at the US Department of Veterans Affairs (VA), told 

®. “For example, how are the demographic changes in the US influencing the incidence and mortality experience of MS?”

Wallin said more neurologists and health care providers experienced in MS will be needed to care for the rising rate of older patients with MS.

“Using large population-based MS cohorts and datasets that are well characterized is critical to a better understanding of the disease,” he said.

In a new study, researchers describe how this novel algorithm-based approach responds to the need for estimating the true prevalence of MS in the US, using analyses of AHCs from government and private health claims databases as the most reliable and cost-effective method. Previously, the primary method used to estimate national MS prevalence has been probability health surveys that relied on patient or family member reports of physician-diagnosed MS.

The data are less reliable due to the risk of the inclusion of false-positive MS cases or provisional cases that would not meet formal case definition criteria, and insufficient numbers of people with MS to enable precise estimation of MS prevalence, much less prevalence within demographic or regional subgroups. What’s more, the national survey no longer includes questions about MS.

While AHC databases present a tremendous resource for analyzing neurologic disease incidence using the international disease coding (ICD) system, there are potential limitations when used for epidemiological purposes. The algorithm developed is optimal in terms of sensitivity, specificity, and simplicity, requiring ≥3 MS-related hospitalizations, outpatient visits, or prescription release encounters for an MS disease-modifying therapy within a 1-year period that was approved by the US Food and Drug Administration (FDA) for MS by 2010. Depending on the dataset, the sensitivity of the MS algorithm was 86% to 92% and the specificity was 66% to 83%, when tested among individuals with at least 1 MS claim.

“The planned US Neurological Disease Surveillance System, if properly launched and funded, could be very helpful in this regard and should be supported,” continued Wallin. “Additionally, we must understand how the aging process itself impacts with morbidity and mortality of MS.”

Though the MS Prevalence Workgroup intends to analyze how race impacts MS prevalence to the extent possible in national healthcare datasets, more work must be done to confirm new variables, because of known risk factors for MS onset and progression, Wallin concluded.

The prevalence of MS in the United States

Articles

A new report shows that multiple sclerosis diagnoses have steadily risen in older patients in the past 5 years, bucking previous patient rate estimates.

Multiple Sclerosis Prevalence Nears 1 Million US Patients

Biochemical differences in cerebrospinal fluid (CSF) metabolites may distinguish between patients with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS), according to a study. The findings show that pyrimidine metabolism not associated with aging in particular may serve as a biomarker to characterize SPMS pathogenesis and indicate potential markers of disease progression.

Participants with RRMS (n= 30), SPMS (n= 16), and controls with non-inflammatory neurological diseases (n= 10) were subjected to clinical examination with expanded disability status scale (EDSS) scoring, a lumbar puncture, and MRI imaging with contrast agent at baseline. From patients’ CSF, metabolite identification was performed using 8 tandem mass spectrometry analyses on pooled samples stratified from the separate groups.

Investigators found that multiple pathways, including tryptophan, phenylalanine, and pyrimidine metabolism, were altered in patients with SPMS when comparing to patients with RRMS and to controls.

Tryptophan metabolism achieved the highest impact in the comparison between SPMS and controls and the second highest in the comparison with RRMS patients. Thymine, methionine, uridine, deoxyuridine, and glutamine are associated with disability, disease activity, and brain atrophy.

Known to be the medium of communication between the immune system and the CNS, it stands to reason that these metabolites play a central role in the disease course. Increased levels of kynurenic acid (KYNA) have previously been found to be elevated in all patients with MS; in this study, investigators found that KYNA levels were more elevated in patients with SPMS compared to patients with RRMS.

 to underlie impairment in memory and cognition and be associated with other neurodegenerative disorders. Levels of the serotonin derivative N-acetylserotonin were significantly increased in patients with SPMS compared to patients with RRMS and controls. Serotonin, which has been shown to regulate macrophages, T cells, and dendritic cells, 

 to be a connection between MS pathology and an unbalanced microbiota through modulation of the serotonergic system (SS).

Potentially confounding these findings are gender and treatment status that may alter metabolite expressions. Investigators also observed that the limited sample size of patients may have decreased the statistical power and confidence in the findings. That said, it being held in a single center provides them the advantage of avoiding inter-center variabilities.

“Facing this limitation, a pathway analysis was advantageous as it couples statistical testing to molecular functioning and investigates the metabolites in groups rather than independently,” they noted.

Other potential underlying confounders that may affect relationships between metabolite levels and radiological or clinical outcome measures were not investigated. These findings must be confirmed by replication in another cohort.

“These findings support the importance of pyrimidine metabolism in MS and in particular in the SPMS stage of the disease, and suggest them as potential markers of disease progression,” the investigators concluded. “These findings are of importance for the characterization of the molecular pathogenesis of SPMS and support the hypothesis that the CSF metabolome may be used to explore changes that occur in the transition between the RRMS and SPMS pathologies.”

Biochemical Differences in Cerebrospinal Fluid between Secondary Progressive and Relapsing&#8315;Remitting Multiple Sclerosis

The known medium of communication between the immune system and central nervous system, metabolites could believably play a role in the multiple sclerosis disease course.


Cerebrospinal Fluid Metabolite Change Marks RRMS Patient Conversion to SPMS

A recently published study shows that modulation of the integrated stress response (ISR) may be an effective neuroprotective therapy for 

 patients with Sephin1 treatment. Sephin1 was shown to protect oligodendrocytes, axons, and myelin, which is correlated with a prolonged ISR, as well as reduced central nervous system (CNS) inflammation, in MS mouse models with chronic experimental autoimmune encephalomyelitis (EAE).

The pathological hallmarks of MS are the destruction of oligodendrocytes, the myelin-producing cells of the CNS, with resultant demyelination and axonal degeneration. The ISR, a cellular protective response that is activated by a variety of cytotoxic insults, has been shown to be triggered in oligodendrocytes by CNS inflammation.

The findings, from investigators at the University of Chicago, further demonstrate that Sephin1 treatment of chronic EAE mice significantly delays disease onset and reduces the number of inflammatory CD3+ T cells and inflammatory cytokine production within the CNS, without affecting the peripheral immune response. The team hypothesized that Sephin1 could lead to better clinical outcomes in MS patients as a safe, neuroprotective drug.

When used in combination with interferon beta-1a (IFN-b), the decrease in clinical disease development in chronic EAE mice was even more pronounced, and may produce better therapeutic outcomes than with either Sephin1 or IFN-b alone. Investigators found that onset of disease was significantly delayed with combination therapy compared to IFN-b treatment alone, which did not affect the onset of disease.

Combination treatment also seemed to affect disease course, as chronic EAE mice treated with both Sephin1 and IFN-b reached the peak of disease much later than those treated with IFN-b alone. Brian Popko, PhD, Jack Miller Professor of Neurological Disorders, and Director, The University of Chicago Center for Peripheral Neuropathy, speculated to 

that Sephin1’s benefits would be complementary to current immunomodulatory therapies, as it acts on the distinct ISR pathway, and with oligodendrocyte protection.

“This is supported by the studies presented in our manuscript that showed that Sephin1 and interferon beta provided additive therapeutic benefit to a mouse model inflammatory demyelination,” Popko explained.

Similar in mechanism of action to Sephin1, Guanabenz was investigated in a clinical trial for its safety and tolerability in patients with MS (NCT02423083). The trial has since been terminated due to side effects. The anti-hypertensive drug had previously been shown to successfully delay disease onset and attenuate clinical symptoms in chronic EAE mice. Guanabenz, an alpha-2 adrenergic receptor agonist, is characterized by its lowering of blood pressure, Popko said, as well as its propensity to create drowsiness, lethargy, and additional adverse effects in patients.

“Sephin1 does not display these adrenergic effects, such that it should be much more tolerable,” he said. “Nevertheless, it will, of course, need to go through safety testing before being introduced to MS patients.”

Popko and colleagues are presently investigating the potential of Sephin1 to provide protection to remyelinating oligodendrocytes against inflammation in EAE mice.

“We are hopeful that Sephin1, which prolongs the integrated stress response, will provide protection to remyelinating oligodendrocytes in the presence of an inflammatory environment,” Popko said. “We are testing this in mouse models of demyelination that display an inflammatory environment during CNS remyelination.”

Sephin1, which prolongs the integrated stress response, is a promising therapeutic for multiple sclerosis

Such results should be available to the team by this summer.

Early findings indicate that Sephin1 could lead to better clinical outcomes in MS patients as a safe, neuroprotective drug.

Sephin1 May Provide Neuroprotective Benefits for Multiple Sclerosis

A phase 3 multi-center, randomized, double-blind, parallel group, active-controlled superiority study assessing oral ponesimod versus teriflunomide (Aubagio) in relapsing 

 (OPTIMUM) is nearing its estimated primary completion date of April 17, 2019.

The 1100-patient study, which kicked off in June 2015, is a comparison of the efficacy and safety of once-daily 20 mg ponesimod and 14 mg teriflunomide. The primary outcome measure is annualized relapse rate (ARR) with secondary outcome measures of time to 12-week confirmed disability accumulation (CDA), percent change in brain volume (PCBV), time to first confirmed relapse, cumulative number of combined unique active lesions (CUAL), and change from baseline to week 108 in fatigue-related symptoms.

Ponesimod is an orally active, selective sphingosine-1-phosphate receptor 1 (S1P

) immunomodulator which prevents lymphocytes from leaving lymph nodes, thus rapidly reducing circulating blood lymphocyte counts and preventing infiltration of lymphocytes into target tissues. 

In a double-blind, placebo-controlled, dose-finding phase 2b study evaluating ponesimod

, study author Tomas Olsson, MD, PhD, and colleagues found that ponesimod 10, 20, or 40 mg was well-tolerated and significantly reduced the number of new T1 Gd+ lesions at weeks 12-24 of the 24-week trial.

 revealed that ponesimod has a favorable safety profile that allows for maximizing its ability to inhibit circulating lymphocytes in a given dosing regimen. It can be sustained with continued dosing, and with its short half-life, is rapidly eliminated upon discontinuation.

"Our clinical development program for ponesimod in multiple sclerosis was already innovative when we decided to move into phase 3,” Guy Braunstein, MD and Head of Global Clinical Development at Actelion Ltd., said in a statement. “OPTIMUM is the first study in MS to target superiority over a commercialized oral therapy. It also includes a number of patient-oriented outcome assessments."

Actelion is also sponsoring a second phase 3 trial with ponesimod, the multicenter, randomized, double-blind, parallel-group, add-on, superiority study (POINT). An ongoing trial with an estimated completion date of March 2020, POINT compares the efficacy, safety, and tolerability of therapy with 20 mg ponesimod vs placebo, in an estimated enrollment of 600 subjects with active RMS who are treated with twice-daily dimethyl fumarate (Tecfidera).

"I have always believed that combination therapy is the future for the treatment of relapsing multiple sclerosis,” Jean-Paul Clozel, MD and Chief Executive Officer of Actelion, said in a statement. “The properties of ponesimod, supported by our preclinical knowledge and clinical results, all point towards ponesimod being ideally suited for use in combination.”

The primary outcome measure of POINT is the confirmed relapses per subject-year as compared to placebo. Secondary outcome measures include CDA, time to first confirmed relapse, CUALs per post-baseline scan, longitudinal change over time in fatigue-related symptoms as measured by the symptoms domain of the FSIQ-RMS, and longitudinal percent change from baseline over time in brain volume. Treatment adverse events (AE) and serious AEs will also be recorded.

“With POINT, the first trial in active RMS adding one oral drug to another, we will assess the clinical utility of combination therapy with ponesimod, to offer patients better control of their disease,” said Braunstein.

Details and updates to the trial, “Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis (OPTIMUM),” can be found 

The 1100-patient study is comparing once-daily ponesimod and teriflunomide for patients with the relapsing form of the disease.