Treatment Options

Disease-Modifying Therapies

The main goal of the treatment of multiple sclerosis (MS) is to decrease relapse frequency and slow the progression of disability. Before the introduction of modern Disease-Modifying Therapy (DMT), MS was treated by broad-spectrum immunosuppressive medications, including azathioprine, methotrexate, mycophenolate mofetil, intravenous (IV) immunoglobulin and corticosteroids. However, the efficacy of these agents was investigated only in small and underpowered studies, and they are rarely prescribed today. The era of true DMTs began with the approval of interferon β in 1993. The efficacy of interferon β is the result of its broad immunomodulatory effects, which inhibit production of a broad spectrum of pro-inflammatory T-cell cytokines. In the three decades since the approval of interferon β, many other DMTs with distinct mechanisms of action have been developed and entered into clinical use (see Figure 3-1). Nevertheless, all DMTs prevent or limit lymphocyte-mediated neuroinflammation that characterizes MS lesions.

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Cladribine, a nucleotide (deoxyadenosine) analogue, inhibits deoxyribonucleic acid (DNA) synthesis in proliferating lymphocytes, causing DNA damage and depleting their number by apoptosis and autophagy. Teriflunomide is a selective inhibitor of dihydroorotate dehydrogenase (DHODH), an enzyme required for pyrimidine synthesis in mitochondria. The inhibition of DHODH impairs DNA synthesis and blocks lymphocyte proliferation; however, unlike cladribine, teriflunomide is not a nucleotide analog, does not intercalate into DNA and does not decrease the viability of non-proliferating cells. Like interferons, glatiramer acetate and fumarates have immunomodulatory effects, effecting a change in the lymphocyte population and a shift from a Th1 pro-inflammatory response to a Th2 anti-inflammatory response. However, their mechanisms of action at the molecular level are unknown. Sphingosine 1-phosphate (S1P) receptor modulators (fingolimod, siponimod, ozanimod and ponesimod) bind to one or more subtypes of S1P receptors, a class of cell-surface receptors that is expressed in multiple tissues and organ systems, including the immune system. Although the exact mechanism for their efficacy in MS is unknown, S1P receptors are believed to act through inhibiting the ability of lymphocytes to leave the lymph nodes, reducing lymphocyte numbers in peripheral blood and therefore in the central nervous system (CNS). Five monoclonal antibodies have received Food and Drug Administration (FDA) approval for use in MS. The first, natalizumab (approved in 2004), binds the leukocyte-expressed VLA-4 antigen (the α4β1 integrin, which is required for efficient cell migration); this inhibits the migration of lymphocytes into the CNS. The other four act by depleting lymphocyte numbers: alemtuzumab depletes both T and B cells by binding an antigen common to both cell types (CD52), while ocrelizumab, ofatumumab and ublituximab deplete B cells by targeting a B cell-specific antigen (CD20). Mitoxantrone, a type II topoisomerase inhibitor, also inhibits lymphocyte proliferation, but is uncommonly used today since most other DMTs have a better safety profile.

There are 19 individual DMT agents approved for use in the United States; these agents, their mechanisms of action, key efficacy data, and main adverse events (AEs), are shown in Table 3-4. In the table, the agents are organized into three categories based on the mode of administration: injection-based, including subcutaneous (SC) and intramuscular (IM); oral; and intravenous (IV). The primary endpoint in the efficacy trials was annualized relapse rate (ARR), which is the average number of relapses for a group of patients in a trial. The other measure of efficacy shown in Table 3-4 is confirmed disability worsening (CDW), which measures the increase in the EDSS score or another measure of disability, which may have varied in individual trials.

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Most DMTs are approved for the treatment of Relapsing-Remitting MS (RRMS) or active Secondary Progressive MS (SPMS), since these forms of MS are thought to be driven by peripheral immune activation. Ocrelizumab is, to date, the only DMT to be approved for Primary Progressive MS (PPMS), based on data that showed a 24% risk reduction in 12-week CDW (defined as a ≥ 1.0-point increase from baseline in the EDSS score, or ≥0.5-point increase if the baseline EDSS score was >5.5, sustained for 12 or more weeks) in patients with PPMS treated with ocrelizumab compared to those who received the placebo.

Overall, DMTs have a good safety profile, however more efficacious therapies tend to also have more serious adverse effects associated with them. Infections, particularly urinary tract infections, upper respiratory tract infections and pneumonias, are AEs shared between all DMTs because of their immune-suppressive effects. Infusion reactions (headache, nausea, urticaria, pruritus and flushing) may occur with DMTs that are administered by IV infusion. For an overview of the major AEs for each agent, consult Table 3-4; for more detailed information, consult the drug label. Some DMTs, notably natalizumab and alemtuzumab, are part of the FDA-mandated Risk Evaluation and Mitigation Strategy (REMS) drug safety program; alemtuzumab for its association with autoimmune conditions, infusion reactions, stoke and malignancies and natalizumab for its association with progressive multifocal leukoencephalopathy (PML). Periodic safety monitoring is required for these and certain other DMTs, including:

• Interferon β (complete blood count [CBC] with differential and liver function every 3-6 months)
• S1P modulators (ocular examination whenever a change in vision is noted, CBC with differential every 3-6 months, periodic liver enzyme testing for fingolimod and if clinically indicated for other S1P modulators)
• Fumarates (CBC with differential and liver function testing every 3-6 months)
• Teriflunomide (CBC with differential every 3-6 months, liver function every month for first 6 months then every 3-6 months)
• Cladribine (age-appropriate cancer screenings, CBC with differential 2 and 6 months after starting each course; if lymphocyte count <200/μL, monitor monthly until month 6)
• Natalizumab (John Cunningham virus [JCV] serology every 3-6 months, brain MRI every 6-12 months for JCV-seronegative patients)
• Alemtuzumab (CBC with differential, creatinine, thyrotropin, ALT, AST, hepatitis panel, varicella-zoster virus antibodies, tuberculosis testing, urinalysis)
• Ocrelizumab, ofatumumab and ublituximab (CBC with differential every 6 months, liver function panel, serum immunoglobulins, HIV serology, hepatitis B and C serology, tuberculosis testing every year)

With so many approved DMTs, physicians have a plethora of options to choose from for the treatment of RRMS and active Secondary Progressive MS (SPMS). Ultimately the choice should be tailored to the individual patient’s needs and preferences. However, two general treatment approaches are typically employed: the escalation approach and the induction approach. In the escalation approach, treatment starts with a DMT that has comparatively low efficacy but a better safety profile; the rationale is to spare the patient from unnecessary AEs if the disease is not highly active. The patient is maintained on this treatment until there is evidence of increased disease activity, at which point a more potent DMT is prescribed. The induction approach, by contrast, starts the patient immediately on a high potency DMT; the rationale being that aggressively suppressing relapses early in the disease course may slow the accrual of irreversible neuronal damage. There is no data at present to unambiguously support either of these two strategies over the other, neither in general nor in specific populations. The treatment options, organized by potency, are shown in Table 3-5.

Whatever approach is chosen initially, in certain circumstances it becomes desirable or necessary to switch from one DMT to another. This includes new or increased inflammatory activity on MRI, emergence of treatment-associated AEs, or poor adherence to the prescribed DMT. The response to treatment should be monitored regularly, with an initial assessment 3-6 months after starting a DMT and then annually thereafter (unless a more frequent monitoring schedule is clinically indicated). Signs indicative of relapse, functional decline, or increased lesion activity justify switching from a low- or moderate-efficacy DMT to a high-efficacy drug (a so-called “vertical switch”). The emergence of serious AEs, reduced drug tolerability, or injection fatigue could require a switch to another DMT from the same efficacy category (a “horizontal switch”).

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Treatment Options: Acute Relapses

While DMTs are used for long-term management and to limit the frequency of acute relapses, when a relapse does occur the first-line treatment is a short course of IV or oral corticosteroids (e.g., 3-5 days of 1g methylprednisolone by infusion or 3-5 days of 500-1250 mg prednisone by mouth). Corticosteroids are preferred in this context because of their rapid onset of action, flexible administration options (IV and oral) and their compatibility with DMTs (which should continue to be used during a relapse). Although acute MS relapses are rare during pregnancy, they can be managed with the standard steroid regimen; however, since there is some data to suggest an increased risk of orofacial cleft and miscarriage, steroids should be limited to relapses that markedly decrease the pregnant patient’s quality of life. The drawbacks of corticosteroid use are the associated AEs, which most frequently include insomnia, mood disturbances and gastrointestinal distress, and may rarely include serious AEs such as psychiatric symptoms, cardiac arrhythmias, hepatotoxicity, osteoporosis and vascular necrosis of the hip. However, the intended time course of corticosteroid use for acute relapse management typically precludes the emergence of serious AEs, which are rare with short-term use. Co-administration with non-steroidal anti-inflammatory drugs greatly increases the risk of peptic ulcers and should be avoided.

For patients who have contraindications to or cannot tolerate corticosteroids, or for those (approximately 5-20%) who fail to respond to corticosteroids, a second-line option for the treatment of acute relapse is plasma exchange. Therapeutic plasma exchange involves the separation of cellular components from plasma, and their re-infusion in albumin; this removes up to 90% of antibodies and immune complexes, thus reducing inflammation. Response rates for plasma exchange have been reported at 40-90%.

Symptomatic Treatments

Common symptoms of MS, including spasticity, neuropathic pain, fatigue and cognitive issues, can be managed with specific, symptom-targeted strategies spanning lifestyle optimization, non-pharmacologic interventions and pharmacologic treatments. Many lifestyle interventions are associated with improvements in all MS-associated symptoms. These include regular exercise, including aerobic, resistance, flexibility and neuromotor exercises; exercises should be more frequent and intensive in patients with an EDSS score of 4.5 and lower, but with modifications can and should be performed in patients with higher EDSS scores. Non-ambulatory patients can replace aerobic exercise with breathing exercises. All patients with MS also benefit from a healthier diet, with an increase in fruits and vegetables and a reduction in processed foods and refined sugars; dietary modifications appear to be particularly effective for reducing fatigue. Patients with MS may also benefit from a referral to a physiotherapist and/or a registered dietitian to improve their symptoms.

For spasticity (a symptom with a prevalence as high as 80% in MS), pharmacologic options that may be useful include baclofen, tizanidine and gabapentin. For neuropathic pain, pharmacological options include gabapentin, pregabalin, duloxetine and lamotrigine; complementary approaches such as acupuncture may help some patients. Pharmacologic options commonly used for fatigue management include amantadine, modafinil and stimulants such as Adderall, however a trial examining these drugs as compared to placebo, showed no significant advantage of these medications compared to placebo. For cognitive impairment (which affect up to 65% of patients with MS), specific management strategies include neuropsychological testing and cognitive therapy; emerging evidence suggests that dalfampridine (at the same dose for walking speed improvement) may improve cognitive symptoms, but there is no approved pharmacologic therapy for cognitive deficiency in MS.

The ideal model of MS care includes a multidisciplinary approach; in addition to the medical team (neurologists, physiatrists, nurses, other specialists), this may include physical therapists, occupational therapists and (neuro)psychologists. Physical therapy is particularly important, helping preserve physical functioning. Regular exercise and rehabilitation programs have been shown to improve aerobic capacity, muscular strength, walking mobility and quality of life (QoL) while reducing fatigue and depression. While high-quality evidence on the efficacy of occupational therapy in MS is lacking, it may be of benefit to patients with MS whose symptoms prevent them from carrying out essential daily tasks, including not only productive work but also self-care and leisure activities. Finally, psychosocial support is essential to manage the cognitive and emotional challenges associated with MS. Neuropsychology specialists, including psychiatrists, clinical psychologists, speech therapists and cognitive rehabilitators, are a critical part of a multidisciplinary MS team.

Treatment in Special Populations

Although estimates vary, in 2-10% of patients with MS the first attack occurs before the age of 18; this is termed pediatric-onset MS (POMS). Since this is a rare occurrence in an already rare disease, extra care must be taken in the diagnostic process to exclude similar disorders, including anti-aquaporin-4-associated neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody spectrum disorder (MOGSD). Once confirmed, treatment should begin promptly. However, while physicians have a choice of numerous DMTs for the treatment of adult patents, the armamentarium of DMTs for POMS is limited; fingolimod is the only drug with FDA approval for use in pediatric patients (10 years of age and older). Nevertheless, many DMTs are used in children off-label. Initially, most neurologists favored agents on the lower end of the potency spectrum (interferon β, glatiramer acetate and fumarates); however, the paradigm is now shifting and physicians increasingly favor higher potency drugs, including natalizumab and B cell depleting mAbs.

The treatment of MS presents a distinct set of challenges in older adults, who often have a higher comorbidity burden, a weakening immune system, often advanced neurodegeneration, limited neuroregenerative potential and a different risk/benefit profile for DMTs. Furthermore, older adults are underrepresented in most MS clinical trials, many of which excluded patients above 50 years of age. The choice of DMT is impacted by the potential affects of aging on the pharmacokinetics and pharmacodynamics of each drug, the potential for drug-drug interactions with other medications the patient may be taking, and any age-dependent effects on the risk-benefit profile (eg, the risk of natalizumab-related PML increases with age). This must be decided on an individual basis for each patient, and ideally together with them. Ocrelizumab, the only DMT approved for PPMS, is an important option for many older patients with advanced disease; however, the risks of significant immunosuppression in this population need to be kept in mind when using potent medications like ocrelizumab. Another consideration is whether and when to discontinue treatment with DMTs, as sometimes the risk of continued treatment may exceed the benefits derived from any DMT.

The impact and management of comorbidities in the context of MS affects almost all patients with the disease. Since patients with comorbidities are typically excluded from clinical trials, good quality evidence is often lacking to guide decisions. A high comorbidity burden is associated with a lower likelihood of initiating an injectable DMT, and comorbidities related to mental health are associated with earlier discontinuation of DMTs. There is also data to suggest that comorbidities are linked to earlier switching from one DMT to another, due to safety or tolerability issues. The presence of MS also impacts the treatment of comorbidities; there is evidence to suggest that people with MS are more likely to undergo cardiac catheterization or die after a myocardial infarction, and have greater mortality from breast and colorectal cancer, compared to patients without MS.

Personalizing Treatment Plans

Given the heterogeneity of MS symptoms and impact, the ideal approach to MS care should be individualized to the patient, and address both medical and psychosocial needs. This includes many of the elements discussed earlier in this section, including the choice and timing of therapy, treatment of comorbidities, and addressing the needs common to the specific population the patient belongs to. However, it also means incorporating shared decision-making (SDM) in the care plan and honoring the patient’s own goals and preferences. Empowering the patient starts with simply explaining to them that they have a choice in their treatment, and that the physician is there to help them make the best choice. Each treatment option should be presented, with a frank and open discussion of the associated advantages and drawbacks. In this step, it is important to remember that more information is not necessarily better, since providing too much too quickly may overwhelm the patient and preclude his or her further engagement with the SDM process. A reasonably informed but engaged patient can weigh the options with their physician, voice their preferences and incorporate them into the treatment plan. Many patients with MS are anxious about the uncertainty of their trajectory; the development of more accurate, noninvasive disease progression biomarkers holds great promise for the advancement of personalized MS care.

Emerging Therapies and Clinical Trials

The field of MS therapeutics is rapidly evolving, with many investigational agents and approaches currently under development. One stream of research is looking for additional DMTs with a broadly anti-inflammatory or immunosuppressive mechanism of action. The most promising new class of such drugs are the Bruton Tyrosine Kinase (BTK) inhibitors; these agents target an essential enzyme in the activation pathways of microglia, macrophages and B lymphocytes. Inhibition of BTK reduces inflammation but does not deplete the target cells, raising the possibility that BTK inhibitors may work synergistically with other DMTs. Several BTK inhibitors are currently in clinical trials, including tolebrutinib, fenebrutinib, and remibrutinib. Neuroprotective agents (i.e., those that reduce the rate of brain tissue loss without necessarily affecting inflammation) under investigation include α-lipoic acid, ibudilast and simvastatin.

Another research avenue is focused on identifying therapies with the potential to promote remyelination. While remyelination (i.e., the formation of new myelin) occurs physiologically in patients with RRMS, restoring neurological function after demyelinating injury, its capacity declines in progressive MS. The decline is believed to occur because of age-dependent depletion of OPCs, the progenitor cells of myelinating oligodendrocytes, and/or the diminished capacity of OPCs to differentiate into oligodendrocytes. Of the three initially promising remyelinating agents (high-dose biotin, opicinumab and clemastine), only the antihistamine clemastine is still under investigation.

Autologous hematopoietic stem cell transplantation (AHSCT) is another option for the treatment of MS, with documented efficacy in ~4,000 cases over the past two decades. It is an intensive procedure that “resets” the immune system by re-introducing autologous, non-autoreactive lymphocytes after a chemical ablation of the immune system. The optimal candidates for AHSCT are patients with RRMS who are young, ambulatory and show high disease activity. Such patients tolerate the procedure better than older patients, and the treatment itself is more efficacious for active inflammatory disease. However, there is a need for rigorous patient selection and close follow-up, as AHSCT involves significant risk, including treatment-related mortality (estimated at about 0.2% in the most recent data) and the development of secondary autoimmune disease.