The aim: studying MS from all angles

MS is one of the most common conditions affecting the central nervous system (brain and spinal cord). More than 2.8 million people around the world are currently living with the disease. [1]

In MS, the body’s immune system mistakenly attacks a protective layer called the myelin sheath that surrounds the nerve fibers of the central nervous system (CNS). This process, called ‘demyelination’, interferes with the transmission of electrical messages between the brain and other parts of the body – leading to a range of symptoms including problems with vision, movement, sensation, or balance. [2] Other symptoms, such as fatigue and changes in thinking and memory, are often more hidden but can also have negative effects on a person’s social well-being and quality of life. [2]

MS is two to three times more common in women than in men. [1] Historically, most people are diagnosed with the condition between 20 and 40 years of age, but the progress, severity, and specific symptoms of the condition are different for everyone. Recent/accumulating evidence suggests that the clinical course of MS may be more of a continuum with a more nuanced and concurrent contribution of progression present from the beginning of all categories of MS. [3] Most people are diagnosed with relapsing-remitting MS, which is where they experience attacks (or relapses) of symptoms, which then fade or disappear (go into remission).[4] This activity is often followed years or even decades later by a steady worsening of symptoms and disability (secondary progressive MS). [4] But around 10 to 15% of people with MS will experience steadily worsening symptoms and disability from the start (primary progressive MS). [4]

“It can be difficult for patients to get a diagnosis at first, as there is currently no single definitive test to confirm MS and the symptoms may differ between individuals,” says Danielle Harlow, our Senior Medical Director, Global Medical Affairs, Neurology and Immunology. “This challenge may lead to delays in starting treatment, however the data are now overwhelming that earlier diagnosis and treatment can help improve long-term outcomes for patients.”

To treat their disease and manage symptoms, MS patients will usually receive a combination of medications along with physical therapies, alongside lifestyle adaptations and support.

A variety of MS medications are available, which fall broadly into three categories: 1) those that treat an active relapse, such as steroids that can help improve symptoms by reducing inflammation at the affected site; 2) those that aim to prevent acute relapses and slow the progression of the disease (called disease-modifying therapies or DMTs); or 3) those that can help ease specific symptoms of MS, such as treatments for pain, tremors, or muscle spasticity. [2]

DMTs are sometimes called ‘immunotherapies’ because they work by dampening the activity of the immune system to reduce the frequency and severity of attacks on the CNS and slow the progression of disability. [5] DMTs can also prevent new areas of damage or scarring in the brain or spinal cord that can be seen on a magnetic resonance imaging (MRI) scan – known as MRI lesions. [6]

“DMTs are intended to alter the trajectory of the disease and reduce nervous system damage,” says Harlow. “In recent years as our understanding of the biology of MS has evolved, these treatments have become increasingly more targeted in how they prevent immune cells from attacking the brain and spinal cord.”

But while MS patients have several treatment options, many will continue to progress even on medications – suggesting new therapeutic approaches are still urgently needed.

Scientists are making great strides in understanding why the immune system malfunctions in MS, leading it to incorrectly recognize and attack myelin and cause neuronal damage.

Our immune system protects us from harm caused by pathogens, such as bacteria and viruses. The immune response is split into two arms: innate immunity, which we are born with – and adaptive immunity, which is acquired following exposure to a pathogen. The innate immune response is the body’s first line of defense – providing non-specific physical, chemical, and cellular defenses to fight infection. In contrast, the adaptive immune response uses certain types of immune cells – called B cells and T cells – to mount a slower, more sophisticated attack against a foreign invader. [7]

B cells and T cells are now well recognized as key contributors to the development of MS by causing acute inflammation in the CNS. [8] Many current DMTs work by preventing these adaptive immune cells from attacking and damaging nerves. [8] But more recently, it has come to light that innate immune cells within the CNS – called microglia – may also play a critical role in nerve damage in MS, even from the earliest stages of the disease. [9],[10]

“The importance of microglia may have been underappreciated until now,” says Harlow. “But we’re now realizing that these cells are ‘smoldering’ within the CNS – driving ongoing neuroinflammation and neurodegeneration that contribute to ongoing disability accumulation.”

Even on treatment, some MS patients continue to progress in the absence of relapses and the appearance of new MRI lesions, suggesting new therapeutic approaches that can target both the acute inflammation that leads to MRI lesions and relapses as well as the ongoing ‘smoldering’ inflammation underlying neurodegeneration and disability progression are needed. [10],[11]

The improved understanding of the biology of MS is revealing new avenues for developing more effective treatments that can slow down or even stop disease progression.

“It’s thought that the majority of disability accumulation that’s independent of relapse is likely due to ongoing central inflammation,” says Harlow. “But we’re currently limited in our ability to target that pathology with existing treatments.”

One new pathway that is being studied in the context of central inflammation and MS is Bruton’s tyrosine kinase (BTK), an enzyme that is crucial for the normal function of many of the immune cells – both in the innate and adaptive arms of the immune system – and thought to be involved in driving nerve damage in MS. [12] Understanding BTK's activity could identify more effective ways to reduce both inflammation caused by the entry of peripheral B and T cells into the CNS and inflammation driven by activation of microglia within the CNS and therefore synergistically prevent progressive nerve damage in MS patients.

Several BTK inhibitors are currently in development as potential treatments for patients with MS. [12] The clinical significance of inhibiting BTK in MS is unknown and currently under investigation.

We have spent more than 20 years researching and developing ways to improve the lives of people with MS. With increasing evidence indicating that neurodegeneration begins very early in MS and is driven by inflammation caused by both adaptive and innate immune cells in the CNS, researchers are striving to develop new drugs targeting cells in both the innate and adaptive arms of the immune system – to help improve outcomes for MS patients.

“I think the rate of understanding of the disease and new treatments in the pipeline just keeps accelerating,” says Harlow. “I’m really excited about the future,” she continues. 

US-NONNI-01339 March 2023

^{[1] https://www.msif.org/about-ms/what-is-ms/
[2] https://doi.org/10.1038/s41572-018-0041-4 (Filippi, M. et al. Nat Rev Dis Primers 2018;4:43)
[3] https://doi.org/10.1016/S1474-4422(22)00289-7
[4] https://www.msif.org/about-ms/types-of-ms/
[5] https://www.frontiersin.org/articles/10.3389/fneur.2022.824926/full Yang JH, Rempe T, Whitmire N, Dunn-Pirio A, Graves SJ. Therapeutic Advances in Multiple Sclerosis. Front Neurol . 2022 Jun 3;13:824926. doi: 10.3389/fneur.2022.824926. eCollection 2022
[6] https://doi.org/10.1093/brain/awz144 (Filippi, M. et al. Brain 2019;142(7):1858–1875)
[7] https://journals.lww.com/cjasn/Fulltext/2015/07000/A_Brief_Journey_through_the_Immune_System.21.aspx Yatim KM, Lakkis FG. A brief journey through the immune system. Clin J Am Soc Nephrol . 2015 Jul 7;10(7):1274-81. doi: 10.2215/CJN.10031014. Epub 2015 Apr 6.
[8] https://doi.org/10.1016/j.neuron.2018.01.021 (Baecher-Allan, C. et al. Neuron 2018;97(4):742–768)
[9] https://doi.org/10.1038/nrneurol.2016.110 (Mishra, M. and Yong, V. Nat Rev Neurol 2016;12:539–551)
[10] https://doi.org/10.1177/17562864211066751 (Giovannoni, G. et al. Ther Adv Neurol Disord 2022;15:17562864211066751)
[11] https://jamanetwork.com/journals/jamaneurology/fullarticle/2799601?utm_campaign=articlePDF&utm_medium=articlePDFlink&utm_source=articlePDF&utm_content=jamaneurol.2022.4655
[12] https://www.nature.com/articles/s41587-020-00790-7}