# Multiple Sclerosis & Pharmacotherapeutic Treatment: A Pedagogic Tutorial for Healthcare Providers

Charlotte Silvestre, Julien Antih, Baptiste Perrier, Lucas Fabrega, Florence Bichon, Patrick Poucheret

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## ► To cite this version:

Charlotte Silvestre, Julien Antih, Baptiste Perrier, Lucas Fabrega, Florence Bichon, et al. Multiple Sclerosis & Pharmacotherapeutic Treatment: A Pedagogic Tutorial for Healthcare Providers. Multiple Sclerosis Journal, 2025, 3 (3), pp.32. 10.3390/sclerosis3030032. [https://doi.org/10.3390/sclerosis3030032](https://doi.org/10.3390/sclerosis3030032)

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Review

# Multiple Sclerosis & Pharmacotherapeutic Treatment: A Pedagogic Tutorial for Healthcare Providers

Charlotte Silvestre<sup>1,2 ID</sup>, Julien Antih<sup>1,2 ID</sup>, Baptiste Perrier<sup>2</sup>, Lucas Fabrega<sup>2</sup>, Florence Bichon<sup>1,2</sup>
and Patrick Poucheret<sup>1,2,* ID</sup>

## Abstract

**Background:** Multiple sclerosis is a multifactorial neurodegenerative disease characterized by autoimmune and inflammatory processes. Despite advancements in disease-modifying therapies, multiple sclerosis remains challenging due to its complex pathophysiology and variable clinical presentation. Current therapies focus on managing inflammation and promoting immunosuppression but do not achieve complete symptom regression or enhance remyelination. Emerging therapies, such as Peroxisome Proliferator-Activated Receptor gamma (PPARγ) agonists and Bruton tyrosine kinase (BTK) inhibitors, show promise in modulating inflammation and targeting immune cells. Innovative approaches like human fetal neural precursor cells (hfPNCs) and mesenchymal stem cell transplantation are being explored to reduce neural inflammation and improve neuroprotection. Early diagnosis and intervention are crucial for managing multiple sclerosis effectively and preventing progression to severe forms and permanent disability. Therapeutic education for individuals with multiple sclerosis and their caregivers is essential, emphasizing the need for clear, reliable information to support disease management and improve quality of life. **Objectives:** This review provides an up-to-date overview of multiple sclerosis pathophysiology, current treatments, and emerging therapies, aiming to enhance the knowledge base of healthcare professionals and researchers, facilitating informed decision-making and contributing to ongoing research efforts.

**Keywords:** multiple sclerosis; pharmacotherapeutic; healthcare providers

## 1. Multiple Sclerosis

### 1.1. Definition

Multiple sclerosis is an inflammatory and autoimmune neurodegenerative disease that leads to demyelination. Multiple sclerosis can present in two forms: a relapsing–remitting course or a primary progressive course. The relapsing–remitting form can evolve into a secondary progressive form.

### 1.2. Epidemiology

Multiple sclerosis affects approximately 2.8 million people worldwide, according to the World Health Organization (WHO) and the Multiple Sclerosis International Federation [1].

<figure><img src="image_4.png" /></figure>

check for
updates

Academic Editor: Georges E. R. Grau

Received: 4 August 2025

Revised: 14 September 2025

Accepted: 18 September 2025

Published: 19 September 2025

**Citation:** Silvestre, C.; Antih, J.; Perrier, B.; Fabrega, L.; Bichon, F.; Poucheret, P. Multiple Sclerosis & Pharmacotherapeutic Treatment: A Pedagogic Tutorial for Healthcare Providers. *Sclerosis* **2025**, *3*, 32.
https://doi.org/10.3390/sclerosis3030032

**Copyright:** © 2025 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license
(https://creativecommons.org/licenses/by/4.0/).

<footnote n="1">1 Qualisud, Univ Montpellier, Avignon Université, CIRAD, Institut Agro, IRD, Université de La Réunion, 34093 Montpellier, France; charlotte.silvestre@umontpellier.fr (C.S.); florence.bichon@umontpellier.fr (F.B.)</footnote>

<footnote n="2">2 ISM (Institut Santé et Médicaments)/HDI (Health and Drugs Institute) Project for Health Care Professionals and Students Education, Laboratoire de Pharmacologie et de Physiopathologie, Université de Montpellier, 34093 Montpellier, France; baptistepe07200@gmail.com (B.P.); lucas.fabrega.mtp@outlook.com (L.F.)</footnote>

<footnote>* Correspondence: patrick.poucheret@umontpellier.fr</footnote>
As an autoimmune disease, multiple sclerosis predominantly affects females, with a female-to-male ratio of 2:1. In some countries, such as those in Northern Europe, this ratio can rise to 4:1 [1,2]. On average, individuals with multiple sclerosis are diagnosed at the age of 32 [1].

### 1.3. Pathophysiology

In the pathophysiology of multiple sclerosis, B and T cells disrupt the myelin, the protective sheath surrounding neuronal axons (Figure 1). These immune attacks create demyelination patches that disrupt nerve transmission. Around these patches, inflammatory involvement promotes the destruction of myelin and myelin-producing cells (oligodendrocytes). Additionally, axonal degeneration significantly contributes to permanent neuronal damage. Remyelination can occur, temporarily reducing symptoms and their severity. Therefore, symptoms vary depending on the regions of the brain or spinal cord affected by demyelination and inflammation [3,4].

<figure><img src="image_5.png" /><figcaption>**Figure 1.** Pathophysiological Mechanisms of Immune-Mediated Demyelination in Multiple Sclerosis. Scheme generated with Copilot.</figcaption></figure>

### 1.4. Symptoms and Severity

People with multiple sclerosis exhibit a significant variability of symptoms, which can evolve depending on the form of the disease.

Symptoms of multiple sclerosis encompass a wide range of issues, including motor disorders such as decreased muscle strength and paresis, vestibular disorders leading to disturbed walking due to vertigo, and sensory disorders like paresthesia and abnormal sensations of cold or heat. Visual problems can range from blurred vision to blindness. Genital-sphincter disorders may include incontinence, erectile dysfunction in men, and pain in women. Neurocognitive disorders are also common, featuring depressive syndromes and concentration and memory problems. If central lesions are present, intellectual capacity may be impaired.

Individuals with relapsing–remitting multiple sclerosis may experience symptoms that partially or completely regress due to the intermittent nature of the disease. However, the frequency of relapsing phase does not predict the severity of disability [4,5]. Individuals with progressive forms of multiple sclerosis (either primary or secondary) do not experience symptom regression due to the continuous progression of the disease. This dichotomy in the evolution of multiple sclerosis is encapsulated by the concept of Progression Independent of Relapse Activity (PIRA) [2,6]. This phenomenon aligns with the concept of
silent progression, where individuals with a relapsing–remitting form may experience a
progression of symptoms and disabilities even during remission phases [2,7,8].

1.5. *Diagnosis*

Diagnosis is based on clinical symptoms and imaging through magnetic resonance imaging (MRI), which allows visualization of lesions caused by demyelination. To diagnose multiple sclerosis, the updated 2017 McDonald criteria are employed [9]. The updated criteria now include cerebrospinal fluid analysis and the investigation of neurofilaments, which are indicative of demyelination and inflammation [9–12]. These criteria rely on the number of clinical attacks, the number of lesions objectively and clinically demonstrated, and potential evidence of spatial and/or temporal dissemination. If an individual has experienced at least two clinical attacks and has two objective clinical proofs or one proof with a history of lesions, an MRI is not necessary for the diagnosis of multiple sclerosis. However, in the case of a first clinical attack, an MRI exam is required regardless of the number of objective clinical lesions to confirm spatial or temporal dissemination [9].

1.6. Associated Factors

There are several factors associated with multiple sclerosis. Like other autoimmune diseases, there is a genetic predisposition and a link to tobacco exposure. Smoking is associated with disease progression and the transition from a relapsing–remitting form to secondary progressive multiple sclerosis. Therefore, smoking cessation is crucial to prevent this evolution [13,14]. Latent infection with the Epstein–Barr virus (EBV) is also associated with multiple sclerosis [15]. Reduced sunlight exposure and consequently lower levels of vitamin D increase the risk of developing multiple sclerosis, which explains the higher prevalence in less sunny countries [2,16]. Jacobs et al. reanalyzed various studies from consortiums using Mendelian randomization. Their findings indicate that both childhood and adult body mass index (BMI) are risk factors for developing multiple sclerosis [16].

**2. Therapeutic Strategies**

Therapeutic strategies for multiple sclerosis vary depending on the disease form. During relapses, intravenous administration of methylprednisolone, a corticosteroid, is employed. To promote remission, disease-modifying therapies involving immunomodulators or immunosuppressants are prescribed. Adherence to these therapies is crucial for optimal management of multiple sclerosis. It is closely associated with improved disease outcomes and a reduced relapse rate [17]. Figure 2 illustrates the therapeutic strategies employed in the management of multiple sclerosis, categorized by disease stage. Section 3 provides detailed information on each medication, including its mechanism of action, administration protocol, and associated adverse effects.

Symptomatic treatment can be prescribed to improve the quality of life for people
living with multiple sclerosis. To counteract spasticity, muscle relaxation can be induced by
baclofen, a gamma-aminobutyric acid (GABA) analog that binds to GABA-B receptors, or by
dantrolene, a medication that promotes the sequestration of calcium ions in the sarcoplasmic
reticulum, leading to muscle relaxation. Fampridine, a potassium channel inhibitor, may
enhance nerve transmission and improve walking. Other types of medications can be used,
such as antidepressants or anxiolytics to combat depression and anxiety, phosphodiesterase
type V inhibitors to address erectile dysfunction, and botulinum toxin injections into the
detrusor muscle of the bladder to manage urinary incontinence.

The heterogeneity of symptoms and medications, coupled with the progression of
multiple sclerosis, poses challenges for healthcare professionals. This review aims to facili-
tate the understanding of pharmacotherapeutic treatments for multiple sclerosis among healthcare providers.

<figure><img src="image_6.png" /><figcaption>**Figure 2.** Flow diagram of multiple sclerosis therapeutic strategies.</figcaption></figure>

**3. Management of Pharmacotherapeutics in Multiple Sclerosis for Healthcare Providers**

Medication for multiple sclerosis may vary according to the disease's progression. Corticosteroids are exclusively used for relapse management. Disease-modifying therapies are based on immunomodulators and immunosuppressants.

3.1. *Relapse Management*

Relapse management in multiple sclerosis is exclusively conducted with intravenous administration of methylprednisolone (Table 1). The use of corticosteroids for relapse prevention has not demonstrated efficacy. Chronic treatment is maintained but may be adjusted in cases of frequent relapses. The initial effects of methylprednisolone typically manifest eight to ten days after the commencement of corticosteroid therapy.

Methylprednisolone is administered intravenously over a period of three to five days. The primary adverse effects include immunosuppression, necessitating caution in cases of infection. Metabolic disorders such as salt and water retention, hyperglycemia, muscle loss, and bone disorders are also reported. Additionally, gastric ulcers may occur.
<table><caption>**Table 1.** Management of multiple sclerosis relapse.</caption><thead><tr><th>Medication</th><th>Administration</th><th>Main Adverse Effects</th><th>Precaution of Use</th></tr></thead><tbody><tr><td rowspan="7">Methylprednisolone</td><td>Intravenous</td><td>Immunosuppression</td><td>Infections</td></tr><tr><td rowspan="6">1g/day, 3–5 days</td><td>Salt and water retention</td><td></td></tr><tr><td>Hyperglycemia</td><td></td></tr><tr><td>Gastric ulcer</td><td></td></tr><tr><td>Bone disorder</td><td></td></tr><tr><td>Muscle loss</td><td></td></tr></tbody></table>

## 3.2. Immunomodulators

Immunomodulators include interferon β-1a and 1b, peg-interferon β-1a and glatiramer acetate (Table 2). These medications modulate immune system activity and inflammation. Interferon β is known to regulate the inflammatory response. The mechanism of action of glatiramer acetate is not fully understood, but this medication promotes anti-inflammatory cytokine production, thereby regulating the inflammatory status. Glatiramer acetate primarily targets innate immune cells, such as monocytes and dendritic cells, which in turn modulate the adaptive immune response [18–20].

<table><caption>**Table 2.** Immunomodulators used as multiple sclerosis disease-modifying therapy.</caption><thead><tr><th></th><th>Medication</th><th>Administration</th><th>Main Adverse Effects</th><th>Precaution of Use</th></tr></thead><tbody><tr><td rowspan="6">RR & SP forms</td><td>Interferon β-1b</td><td></td><td></td><td></td></tr><tr><td>Betaferon</td><td>Subcutaneous<br>Every other day</td><td></td><td></td></tr><tr><td>Interferon β-1a</td><td></td><td></td><td></td></tr><tr><td>Avonex</td><td>Intramuscular<br>1/week</td><td>Injection-site reaction<br>Flu-like syndrome</td><td></td></tr><tr><td>Rebif</td><td>Subcutaneous<br>3/week</td><td>Tachycardia<br>Dyspnea<br>Flushing</td><td>Infection</td></tr><tr><td>Peg-interferon<br>β-1a</td><td></td><td>Convulsion<br>Depression</td><td>Severe depression</td></tr><tr><td rowspan="2">RR form</td><td>Plegridy</td><td>Intramuscular or<br>subcutaneous<br>Every two weeks</td><td>Leucopenia</td><td></td></tr><tr><td>Glatiramer acetate</td><td></td><td></td><td></td></tr><tr><td></td><td>Copaxone<br>& generic<br>equivalent<br>medications</td><td>Subcutaneous<br>20 mg: every day<br>40 mg: 3/weeks</td><td></td><td></td></tr></tbody></table>

RR: relapsing–remitting disease; SP: secondary progressive disease.

Interferon β-1a medications and glatiramer acetate are exclusively indicated for the relapsing–remitting form of multiple sclerosis. In contrast, interferon β-1b (Betaferon) can be used for forms of the disease that present with relapses, including both relapsing–remitting and secondary progressive multiple sclerosis [21,22]. Interferon β-1a is available in two forms: as a standalone (Avonex, Rebif) and as a pegylated form (Plegridy). The advantage of the pegylated form is its administration schedule. Plegridy is administered every two weeks, whereas the standalone forms require more frequent dosing—once a week for Avonex and three times a week for Rebif [23].

Injection-site reactions and flu-like symptoms are the most common adverse effects. To mitigate these, it is recommended to rotate the injection site and take an antipyretic such as acetaminophen prior to administration. Tachycardia, dyspnea, flushing, and convulsions may occur during immunomodulator therapy. Leucopenia can also develop, though it is less severe compared to immunosuppressive medications. It is crucial to ensure the
absence of any current infections before administering either therapy. Depression can also occur during treatment, which is why these therapies are contraindicated in cases of severe depressive syndrome.

### 3.3. Immunosuppressants

As described in the Section 1.3, the immune system plays a significant role in multiple sclerosis through demyelination caused by B and T cells and the resulting inflammatory environment. This involvement explains why immunosuppressants act through various pathways to promote lymphocyte redistribution, inhibit lymphocyte proliferation, and prevent their transmigration into the central nervous system. Table 3 outlines the mechanisms of action of immunosuppressants used as disease-modifying therapies in multiple sclerosis.

<table><caption>**Table 3.** Mechanism of action of immunosuppressive medications.</caption><thead><tr><th>Medication</th><th>Mechanism of Action</th></tr></thead><tbody><tr><td>Fingolimod<br>Siponimod<br>Ozanimod<br>Ponesimod</td><td>Modulation of lymphocyte S1P receptors<br>↓<br>Prevent lymphocyte depletion<br>Favor lymphocyte redistribution</td></tr><tr><td>Dimethyl fumarate<br>Diroximel fumarate<br>Monomethyl fumarate</td><td>Would activate the nrf2 transcription factor, promoting the expression of antioxidant genes</td></tr><tr><td>Teriflunomide</td><td>Inhibition of dihydroorotate (mitochondrial enzyme involved in pyrimidine synthesis)<br>↓<br>Reduction of lymphocyte proliferation</td></tr><tr><td>Cladribine</td><td>Deoxyadenosine analog<br>↓<br>Increase the expression of deoxycytidine kinase<br>↓<br>Promote apoptosis of lymphocyte</td></tr><tr><td>Ofatumumab<br>Ocrelizumab<br>Ublituximab</td><td>Monoclonal antibody against CD20<br>↓<br>Favor B lymphocyte depletion</td></tr><tr><td>Natalizumab</td><td>Monoclonal antibody against ITG4<br>↓<br>Prevent lymphocyte transmigration into CNS</td></tr><tr><td>Mitoxantrone</td><td>DNA intercalator, topoisomerase II inhibitor<br>↓<br>Suppression of lymphocyte proliferation</td></tr></tbody></table>

CNS: central nervous system.

The "mod" family, including fingolimod, siponimod, ozanimod and ponesimod, modulates lymphocyte activity through the S1P receptor family [24–30]. Fumarate compounds such as dimethyl fumarate, diroximel fumarate, and monomethyl fumarate activate the Nrf2 transcription factor, promoting the expression of antioxidant genes and the production of antioxidant proteins [31]. Teriflunomide inhibits the mitochondrial dihydroorotate dehydrogenase enzyme involved in pyrimidine synthesis, thereby reducing lymphocyte proliferation [32–34]. Cladribine, a deoxyadenosine analog, induces lymphocyte apoptosis [35]. Ofatumumab, ocrelizumab, and ublituximab are monoclonal antibodies against CD20, respectively human, humanized, and chimeric. Natalizumab, a humanized monoclonal antibody against ITG4, an integrin present at the blood-brain barrier, prevents
lymphocyte transmigration into the central nervous system by blocking this protein [36]. Mitoxantrone, a DNA intercalator and potent topoisomerase II inhibitor, leads to myelosuppression, including lymphocyte suppression [37].

The administration schedule is detailed in Table 4. Briefly, compounds from the “mod” family, fumarate compounds, teriflunomide, and cladribine can be administered orally, whereas the other medications are injectable.

<table><caption>**Table 4.** Immunosuppressants used as multiple sclerosis disease-modifying therapy.</caption><thead><tr><th></th><th>Medication</th><th>Administration</th><th>Main Adverse Effects</th><th>Contraindications</th></tr></thead><tbody><tr><td rowspan="5">Oral administration</td><td>Fingolimod (Gilenya)</td><td>0.5 mg/day</td><td rowspan="5">Depending on route administration: gastrointestinal disorders or injection-site reaction<br>Leucopenia and neutropenia leading to increased risk of infections<br>Cardiotoxicity (hypertension, conduction disorders)<br>Liver toxicity<br>Flu-like syndrome<br>Asthenia<br>Arthralgia<br>Macular oedema<br>Flushing<br>Risk of progressive multifocal leukoencephalopathy</td><td>Infections<br>Immunodeficiency syndrome<br>Evolving cancer<br>Severe liver failure<br>Cardiac history within the last 6 months (MI, stroke)<br>Severe arrhythmia<br>Pregnancy and women of childbearing age not using effective contraception<br>Live vaccines<br>Arrhythmogenic medications<br>Progressive multifocal leukoencephalopathy</td></tr><tr><td>Siponimod (Mayzent)</td><td>1 or 2 mg/day</td></tr><tr><td>Ozanimod (Zeposia)</td><td>0.92 mg/day</td></tr><tr><td>Ponesimod (Ponvory)</td><td>20 mg/day</td></tr><tr><td>Dimethyl fumarate (Tecfidera)</td><td>240 mg twice a day</td></tr><tr><td>Diroximel fumarate (Vumerity)</td><td>462 mg twice a day</td><td></td><td></td></tr><tr><td>Monomethyl fumarate (Bafiertam)</td><td>95 mg twice a day</td><td></td><td></td></tr><tr><td>Teriflunomide (Aubagio)</td><td>14 mg/day</td><td></td><td></td></tr><tr><td>Cladribine (Mavenclad)</td><td>4 doses of 40–100 mg (BMI dependent) at weeks: 1–3–46–48</td><td></td><td></td></tr><tr><td rowspan="5">Parenteral administration</td><td>Ofatumumab (Kesimpta)</td><td>Subcutaneous 20 mg/month</td><td></td><td></td></tr><tr><td>Ocrelizumab (Ocrevus)</td><td>Intravenous 600 mg every six months</td><td></td><td></td></tr><tr><td>Ublituximab (Briumvi)</td><td>450 mg every six months</td><td></td><td></td></tr><tr><td>Natalizumab (Tysabri)</td><td>Subcutaneous or intravenous</td><td></td><td></td></tr><tr><td>Mitoxantrone * (Novantrone)</td><td>Intravenous 12 mg/m² every three months</td><td></td><td></td></tr></tbody></table>

Some adverse effects are dependent on the route of administration. Oral medications may cause digestive issues, while parenteral medications can lead to injection-site reactions. The primary adverse effects of immunosuppressants include leucopenia and neutropenia, which significantly increase the risk of infections [38]. Therefore, current infections must be closely monitored, and immunodeficiency syndromes or advanced cancer are contraindications. These medications can also impact the heart and liver, leading to contraindications in cases of recent severe cardiovascular incidents and liver failure. More general adverse effects include asthenia, arthralgia, and flushing. Macular edema is another potential adverse effect. The use of natalizumab carries a higher risk of developing progressive multifocal leukoencephalopathy, a severe adverse effect and contraindication for individuals with a history of this condition.

Alemtuzumab is a human monoclonal antibody targeting CD52, a molecule expressed on B and T cells. This therapy has been associated with serious adverse effects in people living with multiple sclerosis, including severe cardiovascular events such as cerebrovascular accidents, severe immunodeficiency, and secondary autoimmune diseases (e.g., autoimmune thyroid disease, immune thrombocytopenic purpura) [39,40]. These significant risks have led to the restriction of its use.

### 3.4. Switching Disease-Modifying Therapies

Switching disease-modifying therapies is recommended in cases of significant adverse effects or reduced efficacy, either clinically (e.g., relapses) or radiologically. The transition may require a washout period depending on the specific medication. Shipley et al. compiled data on recommended washout durations for various treatments [41]. Interferon, glatiramer acetate, and teriflunomide do not require a washout period. In contrast, a short

<footnote>* Mitoxantrone is a DNA intercalator also used on oncology. Its adverse effects are those of immunosuppressants but can also lead to nausea, hair loss and infertility.</footnote>
washout period (0–4 weeks) is advised for natalizumab, Nrf2 activators, and S1P modulators; a moderate period (approximately 3 months) for ocrelizumab; and up to 12 months for cladribine.

**4. Future Treatments**

Scientific research is continuously evolving, future therapies aim to improve the quality of life for individuals with multiple sclerosis through the practice of physical activity and traditional medicine, optimizing the use of existing treatments, and developing new treatments.

Sokratous et al. conducted a study on a small cohort of five individuals with relapsing-remitting multiple sclerosis to investigate the impact of bilateral upper limb movements over a twelve-week period on corticospinal plasticity. The participants exhibited a bilateral reduction in motor threshold, indicating a decreased threshold required to elicit a motor response. Additionally, these individuals showed improvements in various clinical outcomes, including central motor conduction time [42]. The impact of progressive aerobic exercise on walking, asthenia, cardiovascular function, and quality of life was tested in a randomized controlled trial involving 86 individuals with multiple sclerosis. The findings suggest that aerobic exercise has a positive effect primarily on asthenia [43]. The quality of life improvements for individuals with multiple sclerosis may be further enhanced through music-cued gait training, particularly in terms of walking and reducing asthenia [44].

Asthenia is a significantly affected symptom in multiple sclerosis. Lavender, commonly used in Persian traditional medicine for neurological diseases, has been evaluated through capsule administration against a placebo over a 60-day period in individuals with multiple sclerosis. The mean multiple sclerosis fatigue index markedly decreased in participants supplemented with lavender capsules, from 40.56 at baseline to 7.04 after 60 days, while it remained relatively unchanged in the control group (41.43 at baseline vs. 38.17 after 60 days) [45].

MS14® is a natural-based product composed of *Penaeus latisculatus* (90%), *Apium graveolense* L. (5%), and *Hypericum perforatum* L. (5%). It exhibits anti-inflammatory properties and may prevent neurodegeneration. These properties have been evaluated in individuals with multiple sclerosis. Participants supplemented with MS14® experienced improvements in general symptoms such as asthenia and walking compared to the control group [46,47].

Saffron exhibits antioxidant and anti-inflammatory properties that may be used in the care of multiple sclerosis. Kouchaki et al. evaluated the effects of crocin supplementation, a bioactive compound found in saffron, on inflammatory biomarkers, anxiety, and depression scores in individuals with multiple sclerosis [48]. Comparing eight weeks of crocin supplementation to a placebo against baseline parameters, they observed a reduction in high-sensitivity CRP and an improvement in anxiety. Other parameters were not affected by the supplementation.

These natural approaches help alleviate some symptoms of multiple sclerosis but do not specifically target the pathophysiological pathways involved in the disease. This is why Hartung et al. investigated the tolerability and safety of administering the same dose of ocrelizumab, a known monoclonal antibody already approved as a disease-modifying therapy, over different durations (3.5 h vs. 2 h). The shorter administration time was well tolerated by people with multiple sclerosis, with most patients switching from the conventional administration time to the shorter duration [49].

New treatment targets for multiple sclerosis also include the Peroxisome Proliferator-Activated Receptor gamma (PPARγ) [50–52]. PPARγ is a nuclear transcription factor that modulates inflammation and promotes M2-polarized macrophages. It also downregulates the production of proinflammatory cytokines. Activation of PPARγ through specific ago-
nists may be beneficial in the management of inflammation of multiple sclerosis. The use of PPARγ agonists to manage neuronal inflammation could be relevant in other neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and HIV-associated neurological disorder (HAND). Pioglitazone, a PPARγ agonist, was tested against placebo in a small cohort (n = 22) of individuals with multiple sclerosis. After one year of this adjunctive treatment, pioglitazone appeared to reduce the occurrence of lesions in the white matter [53].

Another target in the pathophysiology of multiple sclerosis is Bruton tyrosine kinase (BTK) [54,55]. Indeed, BTK may contribute to neuroinflammation by activating microglia and enhancing cortical demyelination, thereby promoting chronic lesion development. Inhibiting this protein may lead to immunosuppression and reduce inflammation by targeting immune cells such as B cells and microglial cells involved in multiple sclerosis. Evobrutinib, an oral BTK inhibitor, was evaluated in a clinical trial involving 267 individuals with multiple sclerosis, divided into five groups: one receiving placebo, one treated with dimethyl fumarate as the reference therapy, and three receiving evobrutinib (25 mg once daily, 75 mg once daily, or 75 mg twice daily). The group treated with 75 mg once daily showed the most promising results, with a significant reduction in MRI-detected lesions. However, evobrutinib treatment did not lead to a reduction in relapse rates or disability progression. These inhibitors are currently in phase 3 clinical trials following promising results in phases 1 and 2 [56–58].

To manage progressive forms of multiple sclerosis, human fetal neural precursor cells (hfPNCs) were transplanted intrathecally into the cerebrospinal fluid. Twenty-four weeks after administration, participants receiving the higher dose of hfPNCs exhibited increased levels of cerebrospinal anti-inflammatory cytokines and neuroprotective compounds [59]. Intrathecal mesenchymal stem cell transplantation has also been tested in individuals with progressive multiple sclerosis to reduce neural inflammation by secreting anti-inflammatory cytokines and to improve neural transmission through their differentiation into oligodendrocytes or the secretion of growth factors. Six months after transplantation, neuronal inflammatory markers were decreased. These two trials are promising for improving biomarkers and potentially long-term symptoms of progressive multiple sclerosis [60].

**5. Therapeutic Education of the Patient**

Therapeutic education for individuals with multiple sclerosis is crucial for helping them understand and adapt to their disease, thereby improving their ability to manage their lives and maintain their quality of life. Therapeutic education programs aim to empower individuals to become autonomous and effective in responding to symptoms, as well as to support their mental and emotional well-being. These programs can be delivered through individual or group sessions, and a personal booklet can be used for follow-up. Patt et al. evaluated a novel inpatient energy management training program incorporating high-intensity interval training in individuals with multiple sclerosis (NCT04356248). The program demonstrated superior outcomes in health-related quality of life compared to the conventional progressive muscle relaxation program. Furthermore, participants experienced an improvement in mental well-being during the trial period [61,62].

Caregivers, who play a vital role in the management of multiple sclerosis, must be included in therapeutic programs to learn about the disease and to preserve their own physical, mental, and emotional health. Telehealth interventions have been explored to support individuals living with multiple sclerosis and their primary caregivers in developing resilience skills. In one program (NCT03555253), caregivers received guidance from a "resilience coach" on disease-related symptoms—particularly fatigue and mood—alongside training in communication strategies to reduce isolation and promote self-care. This ap-
proach appears promising, given the critical role caregivers play in disease progression. The authors recommend increasing joint sessions involving both the person with multiple sclerosis and their caregiver, as well as individual sessions between the caregiver and the coach [63]. People with multiple sclerosis are often motivated to assist newly diagnosed individuals and contribute to research, but they require clear, reliable, and comprehensive information about the disease, treatment options, and strategies for maintaining their quality of life [64]. Additionally, ongoing support and resources should be provided to ensure they can effectively manage their condition over time.

**6. Conclusions**

Multiple sclerosis is a multifactorial neurodegenerative disease characterized by autoimmune and inflammatory pathophysiology. Disease-modifying therapies have been developed to manage inflammation or promote immunosuppression through targeted lymphoproliferation pathways. However, none of these treatments allow for complete regression of symptoms or enhance remyelination. Few future therapeutics are currently being developed or appear effective against multiple sclerosis. Early diagnosis, targeted therapeutic interventions and therapeutic educational programs can help mitigate the impact of the disease and improve long-term outcomes for patients.

**Author Contributions:** Conceptualization, C.S. and P.P.; validation, P.P.; writing—original draft preparation, C.S.; writing—review and editing, J.A., B.P., L.F., F.B., and P.P.; supervision, P.P. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Acknowledgments:** We would like to thank the students and health care providers for their support in developing our didactic and pedagogy research project ISM (Institut Santé et Médicaments)/HDI (Health and Drugs Institute) for Health Care Professional and Student Education.

**Conflicts of Interest:** The authors declare no conflicts of interest.

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