Historical note and terminology

Until 1993, no disease-modifying therapy existed that was proven to decrease CNS damage in multiple sclerosis. CNS damage is recognized to be immune-mediated. All the current multiple sclerosis disease-modifying therapies directly impact the immune system. In fact, there are now over 25 products (including generics) that have been approved by the United States Food and Drug Administration to treat multiple sclerosis. The disease-modifying therapies are outlined in Table 1. The one exception not included on this list is mitoxantrone, an anthracenedione chemotherapy agent given at 12 mg/m2 intravenous every 3 months, to a lifetime limit of 140 mg/m2. This disease-modifying therapy is virtually never used for multiple sclerosis anymore. This is due to its associated cardiomyopathy and treatment-related leukemia risks, as well as the availability of numerous safer options. The multiple sclerosis disease-modifying therapies cover 10 distinct mechanisms of action (12; 19).

Table 1. Multiple Sclerosis Disease Modifying Therapies

Multiple sclerosis is recognized as a spectrum disorder (Table 2). It is unknown if anyone can develop multiple sclerosis, or if it is limited to a genetically vulnerable subpopulation. Multiple sclerosis can exist for years before it is ever symptomatic, and it may remain asymptomatic. Autopsy studies suggest up to 25% of multiple sclerosis is clinically silent. Radiologically isolated syndrome refers to the incidental finding of abnormal CNS MRI consistent with multiple sclerosis in an individual with no history or examination to suggest multiple sclerosis or another explanatory disorder (03). New diagnostic criteria were proposed recently (16). Radiologically isolated syndrome is not yet recognized as a multiple sclerosis phenotype. When probed carefully, cognitive deficits and olfactory dysfunction have been reported. Male sex, younger age, and spinal cord lesions increase the likelihood of presenting with multiple sclerosis over the next five years (34%). By 10 years, 51% of patients with radiologically isolated syndrome present with either relapsing or primary progressive multiple sclerosis. In this 10-year study, younger age, positive CSF oligoclonal bands, and infratentorial and spinal cord lesions predicted more rapid conversion (15). Two small therapeutic trials have been conducted in RIS (17; 21). ARISE randomized N=87 subjects to oral dimethyl fumarate (N=44) or placebo (N=43). Over 96 weeks CIS occurred in 7% versus 33%, an 80% risk reduction, and N=59 (68%) completed the study. In the TERIS trial, N=89 were randomized to oral teriflunomide (N=44) or placebo (N=45). There were 28 clinical events (N=24 CIS, N=4 progression). There were eight events in the teriflunomide arm versus 20 in the placebo arm. There was a 72% decrease in adjusted relative risk with DMT. N=71 (79%) completed the study. Prodromal multiple sclerosis is a more recently recognized disease stage; it appears to occur 5 to 10 years before symptomatic neurologic presentation, with nonspecific abnormalities, such as fatigue, bladder, and infectious issues (31). This stage was discovered using studies pairing information from extensive administrative databases with multiple sclerosis-specific databases. A study from Bavaria argued that these prodromal events might actually represent unrecognized multiple sclerosis neurologic issues (10).

Table 2. Multiple Sclerosis Spectrum and Clinical Phenotypes

There are four multiple sclerosis clinical phenotypes: clinically isolated syndrome, relapsing multiple sclerosis, primary progressive multiple sclerosis, and secondary progressive multiple sclerosis (18). Relapsing multiple sclerosis presents with a first attack (clinically isolated syndrome). This accounts for 85% to 90% of multiple sclerosis presentations. Clinically isolated syndrome examples are optic neuritis, incomplete transverse myelitis, and isolated brainstem or cerebellar syndrome. Perhaps 60% to 70% of instances of clinically isolated syndrome are found to be relapsing multiple sclerosis. They are labeled “clinically isolated syndrome-high risk” if MRI is abnormal consistent with multiple sclerosis, and this would be sufficient to offer multiple sclerosis therapy provided other diseases were ruled out or remained less likely than multiple sclerosis.

Primary progressive multiple sclerosis shows slow worsening from onset, most often as a progressive myelopathy with gradual deterioration in leg strength and walking ability. This phenotype accounts for 10% to 15% of multiple sclerosis presentations and is the only form with an equal sex ratio. The final phenotype, secondary progressive multiple sclerosis, is a relapsing patient who transitions to gradual worsening. This is typically around midlife (ages 45 to 55 years). Clinical manifestation of progressive multiple sclerosis is connected to age, suggesting a critical barrier of CNS reserve has been exceeded. It also assures inevitable disability.

Two disease activity measures have been defined (18). Both require a specified timeframe, typically the last year. Active multiple sclerosis applies to all phenotypes. This measure is met by having a relapse or a new or enlarging T2 or contrast MRI lesion. If these have not occurred, the individual is considered not active. Active disease is a marker for relapsing disease. The second measure, progressing or not progressing, refers only to the two progressive phenotypes. Deterioration on the neurologic examination over the last year would be progressing, whereas an unchanged examination would be not progressing. Progressive disease is a marker for smoldering inflammation/neurodegeneration.

Clinical aspects

Description

Any individual with clinically isolated syndrome who qualifies as high risk for multiple sclerosis and does not have a more likely alternative diagnosis should be offered a disease-modifying therapy. Most patients with clinically isolated syndrome-high risk present between the ages of 15 and 50 years. They should have at least two lesions on brain MRI. A single brain lesion is problematic and should be supported with other abnormalities. A thorough diagnostic workup typically includes selected blood work, cervical and thoracic MRIs (which should visualize the conus), CSF evaluation, and optical coherence tomography looking for occult optic nerve damage. Standardized MRI protocols have been recommended (32). One or more convincing additional abnormalities should tip the decision in favor of a multiple sclerosis diagnosis and therapy. The clinical syndrome should be highly suggestive (optic neuritis, incomplete transverse myelitis, brainstem or cerebellar syndrome, hemispheral syndrome, paroxysmal attacks), should last 24 hours or longer, and should occur without fever or infection (to exclude a pseudorelapse) or encephalopathy. The clinically isolated syndrome can be monofocal or multifocal (dependent on a single symptomatic area, or more than one symptomatic area).

All newly diagnosed relapsing patients should be offered disease-modifying therapy. All patients with primary progressive multiple sclerosis should be aware of the approved disease-modifying therapy (ocrelizumab), and there should be a discussion about whether to treat. Factors such as age, comorbidities, ability to ambulate, tempo of progression, and presence of focal inflammatory components would all be considerations.

Therapy has not typically been offered for radiologically isolated syndrome. Instead, most patients are closely followed with serial brain MRI and clinical follow-up to document any ongoing, CNS-damaging process. Some practitioners will treat if there are spinal cord lesions or enhancing lesions because of increased risk of subsequent clinical expression. The positive results from both ARISE and TERIS may change this approach. There is also a single dose BCG vaccine versus placebo study, estimated to enter N=100 radiologically isolated syndrome (NCT03888924).

Patients with active secondary progressive multiple sclerosis should be offered disease-modifying therapy. Patients with secondary progressive multiple sclerosis who are above age 60 and remote from a clinical relapse or new macroscopic MRI lesions (T2 or contrast) may be considered for disease-modifying therapies with positive phase III progressive trials (the humanized anti-CD20 monoclonal or siponimod), but benefits cannot be considered as certain. Risks, including sequelae of immunosenescence, and the fact that disease-modifying therapy efficacy likely diminishes with age, must be considered.

Therapeutic principles are emerging to help guide best use of disease-modifying therapies in multiple sclerosis (22) (Table 3).

Table 3. Multiple Sclerosis Therapeutic Principles

Treating early and at a younger age is desirable. Pediatric multiple sclerosis (onset before age 18 years) is unusual and occurs in 2% to 5% of cases. It is overwhelmingly relapsing multiple sclerosis. The CNS is still developing, and the relapse/macroscopic lesion rate is typically highest. There are limited formal trials in pediatric multiple sclerosis, but PARADIGMS compared oral fingolimod (0.5 mg by mouth daily; 0.25 mg for those 40 kg or less) to intramuscular interferon beta-1a 30 mcg weekly (05). Fingolimod was significantly better at suppressing multiple sclerosis disease activity (relapse rate, new enlarging T2 lesions), and in a post hoc analysis, delayed time to 3-month confirmed disability worsening. However, it is clear that any disease-modifying therapy that works in adults will work in pediatric multiple sclerosis. The optimal disease-modifying therapy should be chosen for pediatric multiple sclerosis. It may be crucial to minimize damage during this developing period of the CNS, in particular, to protect cognition (20).

Shared decision-making means not only educating and informing the individual with multiple sclerosis but also determining their goals, preferences, and concerns. The healthcare provider can make their best recommendations after fully understanding the individual’s concerns and expectations (23).

Treat to target is helpful for an understanding of the expected post-treatment course and determination of what might be unacceptable. The most acceptable target is typically low disease activity (for example, an occasional single lesion on surveillance brain MRI), although this should trigger a sooner subsequent MRI (for example, 6 months later). A stricter target might be no evidence of disease activity (NEDA). This means (typically over at least the past year) no relapse, no confirmed worsening on the neurologic examination, and no new or enlarging T2 or new contrast lesion on MRI (30). The longer NEDA is maintained, the greater its significance. Of course, this does not look at microscopic damage. That would be better conveyed by examining annual brain volume loss. A NEDA-4 measure has been proposed, which adds a requirement for 0.4% or lower brain volume loss a year, considered normal range (11). However, the individual reliability of a single brain volume measure has been questioned, and this is not used in current clinical practice.

There should be a review of prior vaccinations and a discussion about vaccines that should be given prior to starting a disease-modifying therapy.

The American Academy of Neurology (AAN) 2018 Practice Guidelines indicate disease-modifying therapy selection is so important that it should be the basis of a separate visit (22). Drug, disease, and patient factors are all taken into account, along with practical factors, such as affordability and reimbursement and access to third-party payers and availability (Table 3). When there is concern about more severe disease and poor prognostic profile, disease-modifying therapy effectiveness becomes crucial. Therefore, it is important to be aware of disease prognostic factors (Table 4).

Table 4. Multiple Sclerosis Disease Prognosis Factors

Injectable disease-modifying therapies

Interferon betas. Interferon betas, injectable disease-modifying therapy agents, are among the earliest approved disease-modifying therapies for relapsing forms of multiple sclerosis. They date back to the 1990s. They are immunomodulatory and not immunosuppressive. Originally proposed for multiple sclerosis because of their antiviral action, it is likely that there are immunomodulatory properties of this cytokine that benefit multiple sclerosis. They induce an anti-inflammatory and regulatory response, downregulate MCH class II and costimulatory and adhesion molecules, modulate the cytokine network, decrease blood-brain barrier permeability, and may stimulate nerve growth factor release (04).

The safety and efficacy are well established for relapsing forms of multiple sclerosis. Efficacy is moderate. Monitoring involves CBC (plus differential), hepatic panel, and thyroid-stimulating hormone done initially two to three times annually, then less frequently. Injection site reactions (generally with subcutaneous injections) and flu-like symptoms occur in 30% to 40%. Dose escalation, premedication (acetaminophen, ibuprofen, corticosteroids), and continued use can treat the flu-like reactions. Neutralizing antibodies have never been definitively shown to impair efficacy. A rare late adverse event is thrombotic microangiopathy, with hemolytic uremic syndrome.

As a class, there have been thousands of human pregnancy exposures to interferon beta without clear teratogenicity. No pregnancy washout is needed, and interferon betas can be used during pregnancy, although they rarely are. They are also considered safe to use while breastfeeding.

Use of interferon beta as initial therapy is falling, most likely due to their moderate efficacy and the needle route of administration.

Glatiramer acetate. Glatiramer acetate is the second class of injectables that also date back to the 1990s. It consists of random polymers of four amino acids (glutamic acid, lysine, alanine, tyrosine). It is a biophysical analog of myelin basic protein. Glatiramer acetate is immunomodulatory but not immunosuppressive. It is the only disease-modifying therapy that requires no blood study monitoring. Glatiramer acetate induces T helper 2 suppressor cells, manipulates the cytokine network, induces release of neurotrophic factors, targets antigen-presenting cells, and binds to the major histocompatibility complex (MHC).

The two significant adverse events are injection-site reactions (including lipoatrophy, with loss of the subcutaneous fat layer to produce cosmetic dimpling) and the systemic reaction or immediate postinjection reaction. This is a benign but frightening adverse event, immediately following injection, characterized by chest pain, flushing, difficulty breathing, palpitations, and anxiety. It clears spontaneously, typically after some minutes.

Glatiramer acetate has had over 7,000 human pregnancy exposures without any evidence of harm. It does not require a washout and can be used during pregnancy and while breastfeeding.

Use of glatiramer acetate is falling, but it endures because of its allure as the “safest” disease-modifying therapy with no monitoring requirements and basically no pregnancy concerns.

Oral disease-modifying therapies

S1P-R modulators. Fingolimod was the first approved oral disease-modifying therapy. It has been followed by three second-generation S1P-R modulators that are not a prodrug like fingolimod, are more selective (fingolimod affects S1P-R 1, 3, 4, 5; ozanimod and siponimod affect S1P-R 1 and 5; ponesimod affects S1P-R 1), and are dose-escalated over the first 1 to 2 weeks, which avoids requirements for first-dose monitoring in the vast majority of patients (25). Siponimod completed a successful phase III trial in secondary progressive multiple sclerosis but did not get the expected approval (13). Rather, it was approved for relapsing forms of multiple sclerosis to include clinically isolated syndrome, relapsing multiple sclerosis, and active secondary progressive multiple sclerosis. Ozanimod completed two successful phase III trials in relapsing multiple sclerosis, compared to intramuscular interferon beta-1a (06; 07). Ponesimod is the most recently approved disease-modifying therapy. In its phase III trial, it was superior to teriflunomide on relapse and MRI outcomes (14). On a patient-reported outcome looking at fatigue, ponesimod kept fatigue stable versus worsening in the teriflunomide arm. However, this secondary outcome was not included in the label; additional studies are needed to confirm.

The S1P-R modulators are not cytolytic but interfere with cell trafficking. They are immunosuppressive, and at least 61 cases of progressive multifocal leukoencephalopathy (PML) have been attributed to fingolimod. The S1P-R modulators act by binding to the S1P-R 1 and CCR7+ central memory and naïve T cells in particular and blocking lymphocyte egress from lymph nodes into blood. There is a 70% to 80% decrease in circulatory blood lymphocytes. A minority of patients who come off fingolimod may experience rebound activity once it is fully out of the system. This takes 6 to 8 weeks.

S1P-R modulators on first exposure can cause bradycardia and, rarely, heart block. They can cause modest erosion of pulmonary function tests. They can cause macular edema and vision loss; those with diabetes, uveitis, or cataract surgery are at increased risk. S1P-R modulators have been associated with hypertension, rare skin malignancies (some clinicians require annual skin checks), and, occasionally, significant cryptococcal and herpes virus infections.

Therefore, individuals with multiple sclerosis who have comorbidly significant cardiac and pulmonary conditions or diabetes are not optimal candidates.

Prescreening for S1P-R modulators involves CBC with differential, hepatic panel, varicella-zoster virus antibodies, EKG, cardiac evaluation for certain pre-existing conditions, and baseline OCT to rule out macular edema. OCT is repeated after 3 to 4 months of therapy. Vaccinations should be reviewed, because fingolimod interferes with both the cellular and humoral vaccine response. Medications are reviewed that may have additive immunosuppressive effects or QT interval bradycardia impact. First-dose monitoring is required for fingolimod over six hours. An EKG is done at beginning and end, with hourly vital signs.

With regard to the second-generation S1P-R modulators, siponimod requires genotyping. CYP2C9*1/*3 cannot be treated; CYP2C9*1/*3 and *2/*3 are treated with 1 mg daily as the maximum dose. There are three cases of progressive multifocal leukoencephalopathy. With regard to ozanimod, it is contraindicated with severe untreated sleep apnea and in those on a monoamine oxidase inhibitor. The label cautions about interactions with tyramine and a number of specific drug classes (in addition to immunosuppressives and cardiac drugs, they include adrenergic and serotonergic drugs, combination beta blocker and calcium channel blockers, CYP2C8 inhibitors and inducers). The active agents for ozanimod are largely two metabolites that have a longer T 1/2 than the parent compound for fingolimod. There has been one case of progressive multifocal leukoencephalopathy. With regard to ponesimod, it is dose-escalated over two weeks. There are no cases of progressive multifocal leukoencephalopathy thus far.

Teriflunomide. Teriflunomide selectively inhibits dihydroorotate dehydrogenase, a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway. The salvage pathway is untouched. De novo pyrimidine synthesis is required for rapidly dividing lymphocytes, which are pathogenic in multiple sclerosis. Teriflunomide is cytostatic rather than cytocidal. To date, it has not been associated with a documented case of progressive multifocal leukoencephalopathy and has been considered as immunomodulatory with little to no immunosuppressive activity.

Teriflunomide is given at 14 mg by mouth daily. The United States is the only country where a 7 mg form was also approved; this dose is not as efficacious as the 14 mg dose and is typically used when tolerability is a key issue.

Teriflunomide is the active ingredient of leflunomide, an oral rheumatoid arthritis drug available since 1998. A black box warning on liver toxicity was applied to teriflunomide based on rheumatoid arthritis data. The second black box warning involved teratogenicity in animal models.

Teriflunomide is a moderate efficacy disease-modifying therapy that is well tolerated. It was able to achieve a significant disability, relapse, and MRI effect over placebo in two phase III relapsing multiple sclerosis trials. In active comparator trials, it was equivalent to subcutaneous interferon beta-1a but inferior to ofatumumab, ponesimod, and ublituximab on the primary outcome.

Prescreening for teriflunomide includes CBC with differential, hepatic panel, tuberculosis blood test, and pregnancy test (if appropriate). According to the FDA label, ALT should be checked monthly for six months. Blood work can then be done twice a year. Teriflunomide, because of enterohepatic recycling, can persist in the body up to two years. Blood levels can be measured (< 0.2 ng/ml is negative) and can be washed out by using cholestyramine or charcoal protocols over 11 days.

Other adverse events are temporary hair thinning in the first six months, hypertension, gastrointestinal issues, and, very rarely, peripheral neuropathy.

Fumarates. The fumarates include dimethyl fumarate, at least a dozen generics, diroximel fumarate, and monomethyl fumarate. The active metabolite is monomethyl fumarate. Dimethyl fumarate and diroximel fumarate are prodrugs that are converted in the gastrointestinal tract (by esterases in the duodenum) to monomethyl fumarate.

Monomethyl fumarate activates the Nrf2 pathway, which is involved in response to oxidative stress. This impacts energy metabolism in effector T cells and inhibits aerobic glycolysis. The half-life is very short (about 1 hour), emphasizing the critical importance of taking this oral medication twice a day. Major adverse events are gastrointestinal (abdominal pain, diarrhea, nausea, vomiting) in the first few weeks and flushing (highest during the first month).

A slow-dose escalation upgrade when initiating therapy, and symptomatic therapy, helps mitigate gastrointestinal side effects. The diroximel fumarate and monomethyl fumarate products have much less in the way of gastrointestinal side effects than does dimethyl fumarate.

A minority of individuals develop lymphopenia (09). This may be more so for CD8+ T cells, especially memory versus naïve cells, than CD4+ T cells. All 12 documented progressive multifocal leukoencephalopathy cases with dimethyl fumarate have occurred in the setting of lymphopenia. Mean lymphocyte counts decrease by 30% in the first year and then stabilize. Six percent of patients experience counts less than 0.5 x 109/L. The drug label suggests interrupting treatment if lymphocyte counts persist at less than 500 for more than six months. Lymphocyte recovery may be delayed.

Cladribine. Cladribine is a cytotoxic oral purine analog that produces sustained lymphopenia. It is considered a long-lasting induction (durable, immune reconstitution) agent. Short-term treatment has a longer-lasting impact. There is intracellular accumulation of the metabolite 2-chlorodeoxyadenosine, which is triphosphorylated and incorporated into mitochondrial and nuclear DNA to produce lymphocyte apoptosis. The impact on T cells is more prolonged than on B cells. Cladribine is given at 3.5 mg/kg over five days in two successive months in years 1 and 2. These are two annual courses, each consisting of two cycles. No further treatment is given in years 3 and 4. It was approved for relapsing forms of multiple sclerosis but recommended for those who had tried at least one other disease-modifying therapy. It produces prolonged lymphopenia, with increased risk for infection, including varicella zoster.

Prior to starting therapy, routine cancer screening guidelines should be followed. Pregnancy should be excluded. CBC with differential, hepatic panel, varicella-zoster virus antibodies, human immunodeficiency virus (HIV), tuberculosis, and hepatitis B and C screening should be completed. Varicella-zoster virus vaccination should be carried out in antibody-negative individuals, and any recommended vaccinations should be given prior to initiating therapy. During therapy, CBC with differential, including lymphocyte count, is monitored. Anti-herpes prophylaxis is given for lymphocyte counts less than 200.

Monoclonal antibodies

Natalizumab. Natalizumab is a humanized monoclonal antibody against the adhesion molecule alpha4 integrin. It is binding and not cytolytic. It interferes with cell trafficking and blocks lymphocyte penetration into the CNS. Stopping natalizumab carries a risk of rebound in a minority of individuals. Because it washes out by 3 months, a new disease-modifying therapy is typically started one month after discontinuation, so it has 3 months to become active. The fixed dosing is 300 mg intravenous every four weeks. However, use of extended dosing is increasing. Natalizumab is a unique immunosuppressive disease-modifying therapy in that it carries real risk for progressive multifocal leukoencephalopathy. To date, at least 892 cases have occurred in multiple sclerosis subjects. Extended dosing (6 weeks is the best studied, but eight weeks has also been used) seems to maintain efficacy but lowers the risk of progressive multifocal leukoencephalopathy. The NOVA trial comparing 4 week versus 6 week dosing reported no differences in 1 or 2 degree clinical outcomes or exploratory outcomes. On a quality of life outcome, the 6-week group showed a higher proportion who worsened (26). Natalizumab has excellent efficacy and tolerability.

Progressive multifocal leukoencephalopathy is the major concern, with three principle risk factors. The major one is JC virus antibody positivity, especially with higher JC virus antibody index (which correlates with titer). Virtually all progressive multifocal leukoencephalopathy cases are JC virus antibody positive. The second risk factor is time on treatment. Very few cases occur in the first year, whereas cases go up particularly after two years on treatment. The third risk factor is prior immunosuppressive therapy. This appears to permanently increase risk of progressive multifocal leukoencephalopathy. It also voids any predictive value to the quantitative antibody index.

Natalizumab also has a modest risk for significant herpes infections. When discontinuing natalizumab, it is very common to do a baseline brain MRI to exclude any suspicious lesion for progressive multifocal leukoencephalopathy. CSF would be obtained if any suspicious lesion was seen. The new disease-modifying therapy is typically started by 1 month to avoid rebound (this leaves 2 months for the new disease-modifying therapy to take effect). If there is suspicion of progressive multifocal leukoencephalopathy while on treatment, natalizumab should be discontinued. Brain MRI with and without contrast is obtained, along with CSF looking for JC virus positive PCR. Plasma exchange or immunoadsorption has been instituted to remove the monoclonal, but it is not clear whether it benefits all subjects (08). If immune reconstitution inflammatory syndrome (IRIS) occurs, it is treated with corticosteroids. Immune reconstitution inflammatory syndrome contributes to morbidity and mortality. Novel therapeutic approaches to progressive multifocal leukoencephalopathy are being evaluated (08).

Alemtuzumab. This humanized monoclonal antibody is directed against CD52, a cell surface glycoprotein present on greater than 95% of T cells, B cells, monocytes, and eosinophils. Its function is unknown. Alemtuzumab is cytolytic, with rapid cell depletion of CD4+ and CD8+ T cells in particular. B cells and monocytes come back by six months. Reconstituted lymphocytes appear to have regulatory properties (increase in regulatory T cells and memory T cells). Alemtuzumab is an induction, long-lasting agent. It is given at 12 mg intravenous daily for five days in year 1 and daily for 3 days in year 2. Perhaps 50% of patients may go 10 years not requiring additional treatment, or a 3-day course can be repeated or a new disease-modifying therapy started.

Alemtuzumab infusion can cause a cytokine storm and pseudorelapse; therefore, patients are typically premedicated with corticosteroids. Alemtuzumab can cause immune-mediated thyroid disease (40%), thrombocytopenia (2%), glomerular nephropathies (0.3%), and cytopenias (0.1% to 0.2%). This requires monthly blood and urine monitoring for 48 months after the last dose. There are black box warnings on autoimmunity, infusion reactions, strokes, and malignancies. Rare strokes have been reported within 3 days of administration. There are concerns about thyroid cancer, lymphoproliferative disorders, and melanoma. Annual skin examinations are recommended. There is prophylactic antiherpes therapy for at least two months post-therapy and until the CD4+ T cell count rises above 200 cells per mcl. Dietary listeria risks are also avoided around the infusion time. For all these reasons, the label recommends at least two other disease-modifying therapies be tried before going to alemtuzumab. Pretesting involves completion of any important vaccinations (including varicella-zoster virus if no immunity); CBC plus differential, creatinine, thyroid-stimulating hormone, urinalysis with cell count, tuberculosis and hepatitis, and appropriate additional infection screening; skin examination, and HPV testing for women.

Anti-CD20 monoclonals. There are three FDA-approved anti-CD20s for multiple sclerosis. The humanized anti-CD20 ocrelizumab, given intravenously at 600 mg every six months, is approved for relapsing forms of multiple sclerosis and primary progressive multiple sclerosis (the only such disease-modifying therapy). The human anti-CD20 ofatumumab, given subcutaneously at 20 mg monthly (after three weekly loading doses), is approved for relapsing forms of multiple sclerosis. A third chimeric glycoengineered anti-CD20 (ublituximab), given intravenously at 450 mg every six months (after a day 1 150 mg infusion, and day 15 450 mg infusion), was approved on December 28, 2022 for relapsing forms of multiple sclerosis. It is infused over one hour. The supportive positive phase 3 relapsing trials (ULTIMATE I, II) were published in 2022 (29). Rituximab, a chimeric anti-CD20, is used to treat non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, and several other disorders. It is given intravenously every six months or so. It has been used off-label in multiple sclerosis at much less cost.

CD20 is expressed on B cells, from the pre-B cell stage to mature B cells, and some plasmablasts. The anti-CD20s are cytolytic and deplete B cells chiefly via antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis mechanisms. The CD20 epitope target influences the kill mechanism. Ocrelizumab has significant overlap (90% or greater) with the rituximab target, whereas the ofatumumab and ublituximab targets are unique.

The anti-CD20s showed excellent efficacy for relapsing multiple sclerosis. Ocrelizumab was studied against subcutaneous interferon beta-1a 44 mcg three times weekly, and ofatumumab and ublituximab were studied against oral teriflunomide. The anti-CD20s showed significantly better relapse, disability, and MRI suppression. The phase III ocrelizumab data for primary progressive multiple sclerosis versus placebo are less impressive. Progression confirmed over 12 weeks was significantly less, but still occurred. Only patients younger than 56 years of age were entered, and they had to have abnormal CSF as an inflammatory marker. In a post hoc analysis, women with primary progressive multiple sclerosis did not show any benefit on progression. This sex-based difference has not yet been answered in subsequent trials but appears not to hold up in real world data.

Ofatumumab has more enhanced CDC, whereas ocrelizumab shows enhanced ADCC. Ublituximab was glycoengineered to markedly enhance ADCC. The major difference for ofatumumab is the ability to treat at home with a simple injection that does not need pretreatment, perhaps because of a smaller but more frequent dose. Other benefits are only theoretic at this point. Ofatumumab binds to CD20 more tightly, with a slower dissociation rate and better kill rate. It may hit B cells in lymph nodes somewhat better, and it may not take as long to wear off. The anti-CD20s are the only monoclonal disease-modifying therapies without a required monitoring program.

Prescreening requires ruling out hepatitis B infection. It is typical to rule out hepatitis C and tuberculosis and to check CBC plus differential, hepatic panel, IgG to varicella-zoster virus, and quantitative immunoglobulins (IgG, IgM, IgA). Vaccinations should be carefully reviewed because live or attenuated vaccines are not recommended on therapy. There is routine premedication before the intravenous dose, and that first dose is given at 50% separated by two weeks.

Accelerated ocrelizumab dosing (over 2 hours) is available if the first few doses go well. A minority of individuals on long-term anti-CD20 therapy may become IgG-deficient. This may make them vulnerable to infections. Quantitative immunoglobulins are routinely monitored. The best course of action in the setting of chronic hypogammaglobulinemia is not clear. Obviously, secondary infections would be of concern. The disease-modifying therapy could be switched, or the patient could receive prophylactic monthly IVIG.

To date, concerns about malignancies and breast cancer, raised after the initial ocrelizumab trials, have not panned out in postmarketing surveillance. Immune-mediated colitis, as well as neutropenia, are rare complications of anti-CD20 therapy.

Additional treatment considerations

Relapse therapy. Standard therapy for multiple sclerosis relapse is a short course of high-dose corticosteroids. This is typically 1 gram of methylprednisolone given intravenously daily for 3 to 7 days (depending on the severity of the relapse). Patients are counseled that steroids will not affect the degree of recovery but can speed up the timeframe of recovery. There is never a guarantee that steroids will work, but they have diffuse anti-edema and anti-inflammatory actions that are probably most meaningful when used early. There is no rationale for an oral taper, and that is rarely used now. Because of excellent bioavailability, high-dose steroids can be given intravenously or orally; the key feature is the high dose.

Acthar gel is available as an alternate intramuscular or subcutaneous delivery versus corticosteroids, but this agent is extremely expensive, and no clear superiority to steroids has ever been demonstrated. Plasma exchange is reserved for severe multiple sclerosis relapses not responsive to steroids. Typically a five- to seven-session exchange is used.

Intravenous immune globulin (IVIG) has limited data to suggest benefit in multiple sclerosis but is an alternative agent. It would be most logical to try after plasma exchange or as an alternative in patients ineligible for plasma exchange.

Symptom management. A number of symptoms can occur during the course of multiple sclerosis, with tremendous impact on quality of life (Table 5). Symptoms are important to recognize and treat. The approach should be multipronged (Table 6).

Table 5. Symptoms That Occur in Multiple Sclerosis and Require Treatment

Table 6. Approach to Multiple Sclerosis Symptom Management

Enhancing CNS reserve. There is increasing evidence that positive lifestyle choices and pursuing a wellness program can promote brain health, result in positive CNS changes, and help the individual with multiple sclerosis to age better (Table 7). This should be discussed at the time of diagnosis and monitored on an ongoing basis.

Table 7. Important Lifestyle and Behavioral Choices to Promote Health

A second factor involves comorbid conditions, which need to be identified early and should be optimally managed to avoid additional CNS damage.

COVID-19 pandemic considerations

Multiple sclerosis itself does not appear to increase the risk for COVID-19 infection or for more severe infection. However, there are identifiable subset groups of concern. Older individuals with multiple sclerosis, males, those with ambulatory disability or with progressive multiple sclerosis, those with comorbid conditions (diabetes, cancer, cerebrovascular disease, chronic renal disease, COPD, heart disease, obesity, pregnancy, smoking), and Black and Latino people, are at increased risk. COVID-19 infection has not been associated with an increase in relapses.

Some studies report that anti-CD20 therapy is associated with increased risk for infection and potentially more severe illness (02; 24; 28). Recent corticosteroid or methylprednisolone use is associated with worse outcome (01; 27). There is concern that certain disease-modifying therapies interfere with COVID-19 vaccine response. The two classes in particular are the anti-CD20s and the S1P-R modulators. In an analysis of N=125 Israeli patients with multiple sclerosis who received the Pfizer vaccine, fingolimod in particular, and anti-CD20 to a lesser extent, reduced the positivity rate to the spike protein in individuals with multiple sclerosis (01). They did not test for neutralizing antibodies or for the cellular vaccine response. Further studies supported that anti-CD20 interferes with the humoral vaccine response, and fingolimod interferes with both the humoral and cellular immune response. The impact of disease-modifying therapy on multiple sclerosis COVID-19 vaccine response is a focus of ongoing studies and will need to be clarified in the future.