How early is early enough to start treatment for multiple sclerosis (MS)?
With the high-efficacy therapies available, early treatments are crucial. During our recent webinar, Professor Eva Havrdová, Head of the MS Center at the Charles University in Prague, shed light on how accumulating knowledge can reshape the approach to MS treatment. Professor Claudio Gasperini, from University “Sapienza” and director of the Department of Neuroscience at the Camillo-Forlanini Hospital in Rome, facilitated the discussion.
Individuals with radiologically isolated syndrome (RIS) may have symptoms like fatigue, pain, headache, anxiety, low mood, infections [1]. The clinically isolated syndrome (CIS) comes after. The prodromal stage may last 5-10 years. During this period, we can observe that the levels of neurofilament light chains (NfL) increase, the titers of Epstein-Barr Virus (EBV) antibodies are high, and the levels of Vitamin D are low. This stage precedes the appearance of neurological signs. New criteria for a diagnosis of RIS include 1-2 brain lesions in addition to risk factors, spinal cord lesions and gadolinium enhancing lesions [2]. In the future, NfL levels and central vein sign (CVS) will provide us stronger indications as to whether this condition will develop into MS. Treating RIS can delay the first clinical manifestations of MS [3, 4].
Professor Havrdová presented cases of individuals with MS followed by her team. DP, a young lady, presented with symptoms resembling an epileptic seizure and some brain lesions detected with magnetic resonance imaging (MRI). When 10 new lesions appeared with no symptoms, RIS was diagnosed and it was decided to treat her with fingolimod. She has been on fingolimod for 4 years and is now doing quite well, ranking among the best pupils in her class.
Sometimes the prodromal stage can last long enough to destroy the central nervous system (CNS). A young lady showed triparesis within 2-3 weeks: inability to walk, disability of the right hand, and some brainstem problems. Her brain was full of lesions, and she also had spinal cord lesions. In 2019, she started interferon. After six months, since she developed new lesions, she switched to anti-CD20, and now she is stable. Professor Havrdová concluded: “We cannot wait too long; if we are sure, we have to treat. We have several options to preserve the brain tissue of our patients.”
Early actors in MS
Microglia are already known to play a role in MS. We all have activated microglia in our brain. However, microglial activation in people with CIS is higher compared to healthy individuals, especially in presence of brain lesions [5]. We still have not developed drugs that target the microglia. Activated microglia produce several factors, like tumour necrosis factor alpha (TNF- α), interleukin-1A (IL-1A) and complement molecules (Cq1). These factors can then trigger a neurotoxic response in astrocytes. Astrocytes are glial cells which normally support the brain function, by providing nutrients to neurons. However, in response to the factors produced by activated microglia, they can become neurotoxic. Additionally, an accumulation of mature B lymphocytes and plasma cells are already observed in the cerebrospinal fluid (CSF) of individuals with CIS and it correlates with acute brain inflammation [6]. “We know that there is a lot of inflammation even before we see the patient having neurological problems,” Professor Havrdová said.
In 2019, the definition of `silent progression` was proposed to describe the long-term worsening independent from relapses and associated with accelerated brain atrophy [7]: individuals in early stages of MS and with low scores at EDSS may already develop some progression. Progression is not very well evaluated with EDSS. Professor Havrdová points out, “If you really want to evaluate progression, you need to ask the patients. The patient always knows that he or she is progressing, that something takes more time, they are not able to run and so on. When you ask the patient, you can discover progression, which is now called PIRA (progression independent of relapse activity)”.
It is nowadays clear that neurodegenerative processes and inflammation are both present from the beginning of the disease. This is called smouldering MS. Axons are destroyed already in acute lesions, and extensive cortical demyelination and expanding lesions contribute to damage the CNS tissue and it translates into clinical consequences.
Hit early, hit hard
Starting high-efficacy therapies (HET) or escalation therapies within 2 years of the onset of the disease can lead to a better prognosis for individuals with MS compared to starting these therapies with a delay of 5 years [8]. Professor Havrdová added that the HET should be started as soon as possible when specific prognostic markers are observed. These prognostic markers include gadolinium enhancing lesions, brainstem or spinal cord lesions, motor, or cerebellar symptoms (signs of bad prognosis), incomplete recovery from the attacks (which means that the brain has not enough resources), high lesion load, high levels of NfL. In these circumstances, the person with MS must be informed about the possible trajectory of the disease, about the risks and benefit of the treatment, and about the risks of not being treated. A HET may be started when there is no diagnostic doubt and when these prognostic markers are present. The decisions should be shared with the informed person – considering individual plans and lifestyle. The person has also to be informed that a close monitoring will be necessary to detect both PIRA and relapses and ensure safety.
Don’t let the patient lose time and brain tissue
Using platform therapies for too long, beyond the scope of planning pregnancy and breastfeeding, is equivalent to not treating the individual. Healthy lifestyle may also substantially influence the course of MS. People with MS should be solicited to actively work for themselves: contacting the physician when new symptoms occur, engaging in physical exercise and watching their weight, taking care of their psychological well-being (with psychotherapy and cognitive training), stopping smoking, restricting alcohol, and treating comorbidities.
Professor Havrdová concluded that MS starts much earlier than we thought. Any early treatment is not early enough, all prognostic markers must be considered to save the brain tissue and the quality of life of people with MS.
Personalised approach for high-efficacy therapies
In the second part of the webinar, Professor Joep Killestein, director of MS Center in Amsterdam, delved into the topic of personalised approach for high-efficacy therapies in MS. The treatment can be personalised by changing the dose of the drug and the interval between the doses. A less frequent dosing can be more convenient for individuals with MS, reduce side effects and complications. For instance, the risk of developing progressive multifocal leukoencephalopathy (PML) associated with natalizumab can be lowered with a longer interval dosing [10]. Moreover, extended dosing can reduce the costs and promote a more sustainable healthcare. However, an extended interval dosing can increase the resurgence of symptoms when the cycle is over – the wearing-off effect [11].
Professor Killestein discussed the current dosing intervals for natalizumab, which are determined based on serum concentration after 4 weeks. The median concentration of natalizumab after 4 weeks is about 25-36 μg/mL. However, concentrations can vary substantially among individuals with MS, ranging from 0.1 to 110 μg/mL [12]. The primary mechanism of action of natalizumab involves the inhibition of the a4-integrin receptor [13]. Therefore, measuring the a4-integrin receptor occupancy (RO) can help monitor the therapeutic activity of natalizumab [13]. The disease activity can be controlled using a personalised approach to extended interval dosing [14]. The ideal treatment interval likely lies within the range of 6 to 12 weeks, though a small proportion of individuals may still achieve sufficient MS disease management beyond 12 weeks [14]. Professor Killestein paid special attention to subcutaneously administered natalizumab. Indeed, a decrease in concentration of natalizumab levels in the blood was observed in people with MS who switched from intravenous to subcutaneous administration of natalizumab [15].
Personalised approaches to anti-CD20 therapies were also discussed. Extended interval dosing of ocrelizumab was not associated with increased repopulation of effector B cells [16]. Another study showed that higher exposure to ocrelizumab is associated with a lower number of patients showing disease progression [17]. In conclusion, Professor Killestein pointed out that biological effects of monoclonal antibodies can vary among patients. Additionally, many initiatives that aim at optimising treatment regimes are currently underway. He suggested that personalised dosing has more advantages than disadvantages.
Written by Stefania de Vito, PhD
References
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