Advanced treatment or early and efficient treatment, how to choose the initial treatment plan for multiple sclerosis?

*For medical professional reading reference Is this question bothering you too? Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, which occurs in young and middle-aged people aged 20 to 40.
As of now, there are more than 2.
5 million MS patients worldwide
.

Although MS remains an incurable disease, early initiation of disease-modifying therapy (DMT) can reduce the frequency of relapses, delay disease progression, reduce brain volume loss, and improve patient outcomes [1]
.

At present, there are more than 20 DMT drugs on the market [2], of which 5 are listed in China
.

With the increase in the types of therapeutic drugs, there is still controversy on the choice of MS treatment strategies.
Some people think that high-efficiency treatment should be given at an early stage or even first; Advanced treatment strategies [3-7]
.

 Figure 1: Advanced treatment and early high-efficiency treatment strategies Are early high-efficiency strategies worth spreading? Don't worry, let the bullet fly for a while.
The early and efficient treatment strategy originated from the "inverted pyramid therapy" proposed by Professor Giovannoni in 2018 [6], which refers to the treatment of no evidence of disease activity (NEDA) or even NEDA 4/5.
The goal is to initiate high-efficiency DMT therapy initially for all confirmed MS patients without de-escalation during the treatment process, which is usually suitable for MS patients with high disease activity [4,7,8]
.

 The original intention of the early and high-efficiency treatment strategy is to help patients achieve NEDA, including no recurrence, no disability progression, no MRI-accessible new active lesions, and no brain atrophy [9]
.

However, since the concept of early high-efficiency treatment was proposed, studies published in recent years to evaluate its efficacy have not used all NEDA indicators as research endpoints, but only evaluated its effect on delaying disability progression, which is contrary to the original intention of the strategy.
of [10,11]
.

 In addition, there is a lack of uniform definitions for highly effective DMT drugs in different studies [10-12]
.

At present, some studies have pointed out that the annual recurrence rate (ARR) is reduced by more than 50%, which is a high-efficiency drug [13]
.

At present, the most recognized high-efficiency drugs are all monoclonal antibody DMT drugs.
As macromolecular biological agents, monoclonal antibodies cannot pass through the blood-brain barrier and can only play a role in the periphery [14]
.

It is worth mentioning that the gold standard for evaluating drug efficacy is randomized controlled clinical trials (RCTs), however, the above studies evaluating the efficacy of early-stage high-efficiency treatment strategies are mostly based on observational real-world studies
.

In the clinic, a variety of factors can affect the results of observational cohort studies, resulting in data from real-world studies that are inevitably less complete and potentially less accurate than data from RCT studies, so more research data is still needed for validation.
[15,16]
.

 The advanced treatment strategy has been proven for a long time, and it is suitable for a wider population.
Advanced treatment is the standard treatment method in current clinical practice and is suitable for most patients with relapsing-remitting (RRMS) [17].
For DMT drugs, first-line DMT drugs with moderate efficacy but good safety are selected, including β-interferon, glatiramer acetate, teriflunomide, etc.
After that, with the gradual progress of the patient's disease, when the first-line DMT drugs are less effective Best time to replace with second-line DMT drugs with stronger efficacy but poorer safety[3]
.

 Teriflunomide is a first-line treatment drug unanimously recommended by domestic and foreign guidelines, and it is also the first oral DMT drug on the market in China
.

Several studies have evaluated the efficacy and safety of teriflunomide
.

The 9-year TEMSO extension study showed that ARR continued to decrease during long-term treatment with teriflunomide, and up to ≥55% of patients did not experience relapse during the extension period
.

In addition, in the core and extension phases, half of the patients did not have any disability progression, ≥80% of the patients had no T1 gadolinium-enhancing lesions during the study period, the total lesion volume remained relatively stable through 252 weeks, and there were no new or expected lesions throughout the follow-up period In addition to the adverse events [18], this fully illustrates the advantages of advanced treatment
.

 Figure 2: Data from a long-term follow-up study of teriflunomide "According to local conditions" is a classic Chinese saying, and it is also crucial to deeply verify the efficacy and safety of the therapeutic drug in the Chinese population
.

Breast cancer resistance protein (BCRP; ABCG2) is adenosine triphosphate (ATP)-binding efflux transporter, and the ABCG2 c.
421C>A polymorphism is associated with decreased expression of ABCG2 protein
.

ABCG2 c.
421C>A can significantly affect the pharmacokinetics of teriflunomide, the active metabolite of leflunomide
.

Subjects carrying the c.
421C>A genotype had higher plasma concentrations of teriflunomide, and the pharmacokinetic parameters Cmax and AUC were higher than non-carriers
.

The mutation rate of this gene is about 29%-36% in Asian population, but only about 9%-11% in Caucasian population [19]
.

The ABCG2 genotype may be a key factor affecting the interindividual variability of teriflunomide concentrations in Chinese subjects
.

The TOWER China subgroup data published in November 2018 when teriflunomide was launched in China showed that teriflunomide can reduce ARR by 71.
2%, which is far better than the 36.
3% of TOWER's global population [20,21]
.

 Figure 3: Teriflunomide TOWER subgroup Chinese population data In addition, a teriflunomide China real-world data presented at the 2021 International Conference of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) showed that teriflunomide treatment Significantly reduced ARR in MS patients by 78%; in addition, up to 75% of patients treated with teriflunomide remained relapse-free during the study period; up to 82% of patients did not experience disability progression
.

In terms of safety, up to 66.
4% of patients did not experience any adverse events, and no serious adverse events were reported [22]
.

 It can be seen that the advantage of advanced treatment is that it can enable patients to achieve satisfactory disease control while receiving relatively safe drugs, which can well balance the efficacy and safety, and can also significantly improve the long-term prognosis of patients [6] ]
.

 Advanced or early and efficient? The choice of treatment strategy from the pathogenesis of MS Most MS patients show relapsing-remitting state in the early stage of the disease
.

In the later stages of RRMS, the patient's disability continues to accumulate
.

Inflammatory disease activity, as reflected by relapse frequency or new foci as reflected by MRI activity, attenuates over time, suggesting a shift in disease mechanism from adaptive to innate immunity [23-25]
.

 Early understanding of the pathogenesis of MS only saw T and B cells interacting in the periphery
.

As the core cells of MS immunopathophysiology and autoimmune regulation of the central nervous system (CNS), the imbalance between pro-inflammatory effector T cells Th1, Th17 and regulatory T cells leads to the acute attack of MS
.

At the same time, B cells can act as antigen-presenting cells to activate T cells, inducing T cells to express a variety of membrane molecules and cytokines; on the other hand, activated T cells and their secreted cytokines provide B cells with a second signal of activation and induce quiescence.
Phase B cells enter the cell proliferation cycle, produce antibodies, and differentiate into plasma cells or memory B cells
.

In addition, pro-inflammatory effector B cells or anti-inflammatory regulatory B cells activate or downregulate the pro-inflammatory response of T cells and myeloid cells [26]
.

The bidirectional interaction between T cells and B cells is the basis of the acute exacerbation of MS
.

This allows the treatment of MS to target peripheral and focal inflammation, targeting short-term therapeutic goals, reducing recurrence rates and reducing MRI activity [27,28]
.

 In recent years, with the in-depth understanding of the pathogenesis of MS, the two pathways of demyelination, smoldering lesions, and neurodegenerative diseases in the CNS have been gradually recognized by clinicians
.

In the immune-dependent pathway, the activation of immune resident cells in the CNS such as microglia and astrocytes; in the immune-independent pathway, the damage of mitochondria and the release of iron ions synergistically lead to axonal damage and neurodegeneration
.

These pathogenic mechanisms within the CNS have enabled clinicians to have a further in-depth understanding of chronic smoldering inflammation, compartmentalized CNS immune responses, and involvement of the innate immune system, and have also enabled clinicians to realize that the treatment of MS should not be limited to short-term The reduction of recurrence and MRI activity should focus on the long-term treatment goals, namely delaying disability progression and loss of brain volume [27-30]
.

 In the head-to-head study of CD20 monoclonal antibody ofatumumab and teriflunomide, although there was a significant difference between the groups in the primary end point of ARR, there was no difference between the two groups in the delay of brain volume loss.
showed a significant difference, and teriflunomide had a tendency to be numerically superior to ofatumumab [31]
.

Utuximab, which is also a CD20 monoclonal antibody, has recently published data from a head-to-head phase III study with teriflunomide.
Although the primary endpoint ARR reached a significant difference between groups, no significant difference was found in confirmed disability progression.
[32]
.

This may indicate that the first-line DMT drug teriflunomide is not inferior to the long-term treatment goal of MS in slowing disability progression and brain volume loss
.

 MS is a chronic disease requiring life-long treatment, and the long-term safety of drugs is also an important factor that clinicians and patients need to consider when choosing DMT drugs
.

Since teriflunomide was approved in the United States in 2012, the clinical practice for many years has fully verified the safety of teriflunomide
.

Expert Comments In recent years, with the increase in the types of DMT drugs, the clinical strategies for MS treatment are gradually divided into two types: early and high-efficiency treatment and advanced treatment.
However, the choice of the two is still inconclusive
.

The early and high-efficiency strategies were proposed relatively late, and the existing studies evaluating their efficacy have many shortcomings; and with the deepening of the understanding of the disease mechanism of MS, the treatment goals of MS are no longer limited to short-term reduction of recurrence and MRI activity.
Rather, the focus should be on slowing disability progression and brain atrophy in the long term
.

Advanced treatment is a classic treatment strategy for MS, which has been proven in clinical practice for a long time.
Teriflunomide is a representative drug for advanced treatment strategies.
Long-term follow-up studies and clinical practice experience show that teriflunomide has excellent curative effect.
It can effectively delay disability progression and reduce brain atrophy in MS patients with good safety, and the benefits are more significant in the Chinese population
.

In general, when clinicians choose treatment strategies in practice, they need to comprehensively weigh the risks and benefits of treatment options; at the same time, it should be noted that MS patients in Asia have different clinical characteristics from patients in North America and Europe.
In the management of Chinese MS patients, the individual characteristics of Chinese patients should also be taken into consideration, and the treatment path with "Chinese characteristics" should be adopted
.

 At present, two randomized controlled studies (TREAT-MS, DELIVER-MS) directly comparing advanced and early efficient treatment strategies are underway, and it is expected that the research data will be released as soon as possible to better guide clinical decision-making
.

Expert Profile Quan Chao • Chief Physician and Master Supervisor of Neurology Department of Huashan Hospital Affiliated to Fudan University • Member of Neuroimmunology Group of Neurology Branch of Chinese Medical Association • Young Member of Neurology Branch of Shanghai Medical Association • Member of Neuroimmunology Genetics and Biochemistry Group of Neurology Branch of Shanghai Medical Association • ICC-Member of International Clinical Consortium for NMO• Member of NMO Treatment Choice Consensus Board• Editor of Neuroimmunology Reports• Chair National Natural Science Foundation of China • Focuses on clinical and scientific research on central nervous system demyelinating diseases, including "neuromyelitis optica" and "multiple sclerosis"
.

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.

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