It has been known for several years that the diagnosis “multiple sclerosis” conceals a whole range of different illnesses, each requiring customized treatment. Researchers at the University of Basel and the University Hospital of Basel have now described a possible new MS-like disease and explained how to diagnose it.

Multiple sclerosis (MS) is characterized by areas of inflammation in the central nervous system. The immune system attacks the body’s own structures and destroys the covering of nerve cells, known as the myelin sheath. The picture research has painted of the illness is somewhat more complicated, however. It can cause a variety of neurological symptoms, like paresthesia and paralysis of the limbs, which progressively or abruptly worsen. Which parts of the nervous system are affected varies substantially between individuals. A treatment may work for some patients – but make the condition worse in others.

“There’s a huge amount of diversity in how inflammatory autoimmune diseases of the central nervous system like multiple sclerosis present,” explains Professor Anne-Katrin Pröbstel of the University of Basel and University Hospital Basel. Researchers have been gradually discovering the key distinctive features of “atypical” cases of MS for the past ten years. A few of these autoimmune diseases have been given different names to better distinguish them from MS even though they also destroy the myelin sheath. Victims of these diseases often have inflammation in their spinal cords or optic nerves.

In a study of roughly 1,300 patients, Pröbstel’s team has now discovered a biomarker that may make it possible to differentiate another MS-like illness from the others. The researchers have reported their findings in the journal JAMA Neurology.

Antibodies as biomarkers

The team discovered a specific antibody, a type of immunoglobulin A (IgA), in one group of patients. The antibody attacks a component of the myelin sheath called “MOG” (which stands for “myelin oligodendrocyte glycoprotein”). IgA antibodies are typically responsible for protecting mucous membranes.

The precise role of MOG-IgA in this autoimmune disease remains unclear, however. “Victims experience inflammation particularly in their spinal cords and brain stems,” Pröbstel explains. This group of patients was missing other typical biomarkers related to MS or similar diseases.

Next, the researchers want to decipher the role of MOG-IgA and the clinical characteristics arising from it in more detail. “By distinguishing between myelin-destroying autoimmune diseases that were previously all called MS, we’re taking an important step towards a better understanding of the causes of these illnesses and towards individualized treatments,” says the neurologist. Ultimately, the researchers hope to discover what treatments are most effective under what conditions.

A study in mice suggests that inflammation in the brain’s barrier, the meninges, may spill over into grey matter and cause changes that can contribute to progressive multiple sclerosis (MS).  

The research, published today as a Reviewed Preprint in eLife, is described by the editors as an important study that advances our understanding of the mechanisms of brain damage in this autoimmune disease. It involves the use of novel methods to provide what they say is convincing evidence for a gradient of immune genes and inflammatory markers from the meninges to the adjacent brain tissue in mice.

Inflammation within the meninges is found in all types of MS. There is mounting evidence to suggest this inflammation plays a pivotal role in the progression of the disease, including loss of the protective coating on nerves (demyelination), loss of new nerve sprouts (neurites) and decreased volume of grey matter.

“Grey matter injury is linked to disabling MS symptoms like cognitive dysfunction and depression,” explains Sachin Gadani, a neuroimmunology fellow at Johns Hopkins University School of Medicine, Baltimore, US, and a co-first author of the study alongside Saumitra Singh, Postdoctoral Research Fellow at Johns Hopkins University School of Medicine. “Meningeal inflammation appears to be a critical driver of cortical grey matter pathology, but attempts to characterise the mechanism in an unbiased manner have been limited by the absence of spatially resolved data – that is, critical information about the anatomical relationship between meningeal inflammation and the underlying brain tissue. We set out to determine the patterns of gene activity in the meninges and the surrounding grey matter, while preserving the context about the position of those cells in the brain.”

Gadani, Singh and colleagues used an approach called spatial transcriptomics, whereby the pattern of gene activity in a tissue is measured and the information is then pieced back together to show the pattern of gene activity in the original location. They started by measuring gene activity in the inflamed meninges in a mouse model of MS against the meninges in healthy mice, and then compared this to the expression of genes in the surrounding grey matter in both groups of mice.

As the team expected, they found an increased expression (upregulation) of genes related to immune cells and pathways, immune cell infiltration, and the activation of brain-specific immune cells called microglia. To understand more about the proximity of this gene activity to the meningeal region, they analysed patterns of gene activity along a path from the meninges to the thalamus. All the groups of genes declined in activity with increasing distance from the inflamed meningeal region. However, some genes showed a more gradual decline – particularly those involved in immune processes such as antigen processing and presentation. This suggests that some upregulation of pro-inflammatory genes had spilled over from the brain’s meningeal region into the grey matter.

“This is the first time a study has characterised a mouse model of meningeal inflammation and grey matter injury using spatial transcriptomics,” says co-first author Saumitra Singh. “We’ve provided a publicly available dataset from our work that we hope others can use in future research.”

A limitation of this study is that the spatial resolution may not be sufficient to distinguish between the meninges and surrounding grey matter with certainty. Additionally, while the authors used a mouse model that represents many pathological features of MS, it does not fully represent human disease, and the analysis does not consider different timepoints in the development of MS. Despite this, the authors say their findings could pave the way for future studies using human samples.

“Our findings have revealed several candidate pathways in the development of grey matter injury. Future work should focus on spatial transcriptomics in human samples which, thanks to advances in technology, is now becoming more feasible,” concludes senior author Pavan Bhargava, Associate Professor of Neurology at Johns Hopkins University School of Medicine.

The majority of individuals with multiple sclerosis (MS) treat the chronic and progressive neurological disorder with oral medications, likely because of many factors, including convenience, consumer advertising and approval by health insurers, according to Rutgers researchers.

“While two injectable therapies known as platform injectables, were once the mainstay of multiple sclerosis treatment, our study showed oral therapies became the predominate treatment for multiple sclerosis by 2020,” said Mackenzie Henderson, a postdoctoral researcher at the Rutgers Institute for Health, Health Care Policy and Aging Research (IFH) and the lead author of the study. “Our investigation offers an important step in understanding the evolving treatment landscape for MS among U.S. adults and children.”

The study, published in JAMA Neurology, examined a large and diverse sample of commercially insured adults and children in the United States to evaluate trends in uptake of therapies between 2001 and 2020 for patients with MS, a chronic and progressive neurological disorder and the leading cause of nontraumatic disability among young and middle-aged adults.

In 2000, there were two medications approved for MS treatment in the U.S., but over the past 20 years, more than 10 new medications have been approved, according to researchers.

Research on how these approvals have changed clinical practice has been limited. The Rutgers study shows injectable therapies accounted for nearly 100 percent of medications for MS patients in 2001, but by 2020 that decreased to about 25 percent, with oral therapies rising sharply after their introduction in 2010.

Using commercial claims data from more than 100,000 patients with MS between 2001 and 2020, researchers analyzed injectable, infusion and oral treatment trends. They found that oral medications increased sharply in popularity to become the preferable treatment for MS patients over infusion and injectable treatments. Infusion therapies remained low in uptake, accounting for about 8 percent of therapy initiations in 2020, and platform injectable therapy use declined almost 74 percent throughout the study period, according to researchers.

“Despite the availability and efficacy of infusion therapies for multiple sclerosis, we found that their utilization remained relatively low throughout the study period,” said Chintan Dave, a faculty member at the Center for Pharmacoepidemiology and Treatment Science (PETS) at IFH, an assistant professor with Rutgers Ernest Mario School of Pharmacy and a senior author of the study. “This may be due to several factors contributing to this treatment decision by patients and clinicians, including the preference for more convenient oral therapies, the relatively recent introduction of infusion options, and considerations of safety and cost.” 

Researchers said this investigation offers a crucial step in understanding the evolving treatment landscape for MS patients and future research should evaluate the impact of new therapies as they emerge.