Safety Monitoring of Disease-Modifying Therapies in Multiple Sclerosis

Over the past decade, several new therapies for the treatment of multiple sclerosis (MS) have been developed. Most are used in individuals with relapsing forms of MS, because these therapies mainly target the inflammatory aspects of the disease (eg, relapses, new or enhancing lesions). With this expanding arsenal of disease-modifying therapies (DMTs), an adequate understanding of safety profiles and unique considerations of these therapies becomes imperative. DMT classes differ based on the mechanism of action, resulting in different side effects and monitoring requirements. DMT selection requires consideration of factors beyond MS disease activity, including individual factors such as childbearing potential and underlying cardiac or autoimmune conditions. Furthermore, individual preference, which influences DMT adherence, is key in therapy selection. Taking all this into consideration, guidance in DMT selection and appropriate safety monitoring are important roles of the clinician caring for people with MS. In this article, we provide an overview of the currently available DMTs, highlighting important safety considerations and routine monitoring requirements. These suggestions and monitoring requirements are derived from different resources, including clinical trial data and real-world experience.

Modulation of Immune Cell Function or Pathways

Beta-Interferons

Beta-interferons (IFNΒ) were the first class of DMTs developed for MS. Despite being extensively researched, their mechanism of action is not fully understood. Their effects stem from activation of the interferon receptor on leukocytes, resulting in increased anti-inflammatory and decreased proinflammatory cytokines.¹

Laboratory tests are recommended at baseline and periodically for people taking IFNΒ because of the effects IFNΒ can have on immune cells and organs. Baseline complete blood count (CBC) with differential, liver function tests (LFT), and thyroid-stimulating hormone levels are recommended before starting IFNΒ, with periodic monitoring thereafter. The frequency of laboratory monitoring is variable in clinical practice.² One approach is to check CBC and LFT at 1, 3, and 6 months, followed by every 6 months thereafter, while monitoring thyroid-stimulating hormone levels every 6 to 12 months. However, the frequency of testing may vary based on treatment duration and if laboratory abnormalities develop (eg, leukopenia or transaminitis).

Mild cytopenia is common with IFNΒ treatment.³ More severe grade 3 to 4 cytopenia (ie, total white blood cells <2, neutrophils <1, lymphocytes <0.5, platelets <50 x 10⁹/L) occurs in 2% to 4% of individuals.^3,4 No increase in opportunistic infections or reduction in vaccination response is seen with IFNΒ therapy.^3,4 Mild elevations in LFT are common; increases 2.5 to 5 times the upper limit of normal (eg, alanine transaminase >36 IU/L and aspartate transaminase >30 IU/L, but this varies between laboratories) are relatively rare and may require dose reduction/witholding of medication with consideration of potential unmasking of autoimmune hepatitis.^5-7

Very common side effects include injection site reactions (ISRs) and flu-like symptoms, which are typically mild and self-limited, and respond to over-the-counter analgesics.⁸ In rare cases, ISRs can lead to cellulitis, isolated skin necrosis, or Nicolau syndrome, a complication caused by microembolization and localized vasospasm of terminal vasculature.⁹ Hence, it is important to educate individuals on the range of possible ISRs and proper injection techniques.

Even though IFNΒ treatment is typically withheld during pregnancy, maternal–fetal exposure is not associated with adverse outcomes.^10-12 Breastfeeding may also be considered during IFNΒ treatment.¹¹

Glatiramer Acetate

Glatiramer acetate (GA) is an injectable synthetic copolymer that mimics myelin basic protein (MBP) and may impair MBP binding to class II major histocompatibility complex, resulting in a shift to a more anti-inflammatory cytokine profile.¹ This alteration of immune processes has demonstrated no increase in the risk of infections and requires no specific laboratory monitoring.¹³

Mild ISRs are common with GA as is lipoatrophy at injection sites, which can be minimized by rotating injection sites. Less commonly, an immediate postinjection reaction consisting of flushing, dyspnea, and palpitations can occur idiosyncratically in 15% of individuals but is not life-threatening and does not necessarily indicate drug allergy.¹⁴ Rarely, severe ISRs (eg, skin necrosis, Nicolau syndrome) can occur, and should be monitored for by individuals and clinicians.¹⁵

GA is safe in pregnancy (although it is typically stopped at pregnancy detection) and may be continued during breastfeeding.^11-13,16

Fumarates (Dimethyl and Diroximel)

Dimethyl fumarate (DMF) (Tecfidera; Biogen, Cambridge, MA), monomethyl fumarate (Bafiertam; Banner Life Sciences, High Point, NC), and diroximel fumarate (Vumerity; Biogen, Cambridge, MA) derive immunomodulatory effects through the active metabolite monomethyl fumarate, which activates nuclear factor erythroid 2-related factor 2 (Nrf2), promoting a shift to anti-inflammatory cytokine profiles and enhancing cellular responses to oxidative stress.¹⁷ The active metabolite monomethyl fumarate also exists as a DMT. Before treatment initiation, CBC with differential and LFT should be obtained, and these should be repeated every 3 to 6 months. The frequency of these laboratory studies may vary in practice based on the clinical scenario.

People with MS taking DMF may experience a 30% reduction in absolute lymphocyte count (ALC) within the first year of therapy.¹⁸ However, most plateau with counts above 0.9 x 10⁹/L, and only 2.2% have an ALC less than 0.5 x 10⁹/L sustained for more than 6 months.¹⁸ Progressive multifocal leukoencephalopathy (PML) is rare with DMF and is usually seen in the context of prolonged lymphopenia.¹⁹ More frequent CBC with differential monitoring is recommended if ALC drops below 0.8 x 10⁹/L because of risk for PML. People with ALC below 0.5 x 10⁹/L are at greater risk of prolonged lymphopenia, so holding or discontinuing the fumarate should be considered.¹⁸ In the setting of lymphopenia, one approach is to monitor CBC with differential monthly for trend or improvement. If ALC remains below 0.5 x 0.9/L for 3 to 6 months, a transition to another DMT should be considered, as clinically appropriate. Vaccination response appears to be maintained even in the setting of mild fumarate-associated lymphopenia.^20,21

Gastrointestinal symptoms and skin flushing are common adverse effects, occurring in up to 40% of individuals, but symptoms often improve after a few weeks.² Mild gastrointestinal symptoms and flushing may be mitigated by taking fumarate tablets with food. Some people may require symptomatic interventions for their gastrointestinal symptoms (eg, antidiarrheal agents); others may need aspirin premedication for severe flushing.

Because of insufficient safety data, fumarates are not recommended during pregnancy or breastfeeding.^10-12,16

Key Takeaways

• IFNΒ treatment requires regular laboratory monitoring of CBC with differential and LFT as well as vigilance for ISRs.
• GA has few major safety concerns, has no monitoring requirements, and is safe in pregnancy and breastfeeding.
• Fumarates are commonly associated with gastrointestinal side effects and skin flushing, and, more rarely, lymphopenia, which requires regular monitoring.

Reduction of Cell Proliferation

Reduction of cell proliferation is another mechanism of action of DMT.

Teriflunomide

Teriflunomide (Aubagio; Sanofi, Bridgewater, NJ), an oral medication, is the most commonly used agent to reduce cell proliferation. Teriflunomide inhibits dihydroorotate dehydrogenase (DHODH), resulting in impaired pyrimidine synthesis needed for B-cell and T-cell proliferation.^22,23

Based on current guidelines and clinical experience, baseline tuberculosis screening, CBC with differential, and LFT are required before treatment initiation, followed by monthly LFT for the first 6 months of treatment (because of risk for liver toxicity).^23,24 Clinicians should be mindful of possible hematologic side effects and obtain CBC with differential for further evaluation as indicated, although current clinical practice usually relies upon regular CBC with differential every 6 months.

Common side effects include headache, mild transaminitis, diarrhea, and transient alopecia; less common side effects include hypertension and increased nasopharyngeal infections.^23,24 Rarely, peripheral neuropathy can occur with teriflunomide and should be evaluated with basic neuropathy laboratory studies and electrophysiologic testing.²³

Mitoxantrone

Mitoxantrone reduces cell proliferation through inhibition of topoisomerase, leading to impaired DNA repair.²⁴ It is administered as an infusion every 3 months and has a lifetime dose limit because of its potential side effects. Mitoxantrone requires baseline and postinfusion CBC with differential, LFT, and assessment of left ventricular ejection fraction for safety monitoring.²⁴ Because of its cardiac side effect profile and emerging cases of acute myeloid leukemia, it is rarely used in North America, especially considering the availability of other DMTs.

Because of their inherent mechanisms of action, teriflunomide and mitoxantrone are known teratogens and are contraindicated in pregnancy as well as breastfeeding.^11,12,16,23 If pregnancy occurs during treatment with teriflunomide, the medication should be discontinued promptly and an accelerated washout protocol consisting of cholestyramine or activated charcoal may be used.^11,16,23 Furthermore, teriflunomide is detected in semen, so men on teriflunomide should be counseled on family planning and transition to another DMT before conception.^16,23

Key Takeaways

• Teriflunomide commonly causes transient hair thinning and headache; rarely, peripheral neuropathy may occur.
• There is concern that teriflunomide is teratogenic, so counseling on family planning should be provided to both men and women with MS.
• Mitoxantrone has a notable cardiac side effect profile and left ventricular ejection fraction should be monitored closely.

Cell Trafficking

Sphingosine-1-phosphate receptors (S1PRs) are found throughout the body and are involved in many different functions. There are five known S1PRs, with most of the therapeutic benefit in MS deriving from action on S1PR1.

S1PR Modulators

S1PR modulators bind to S1PRs on lymphocytes, causing their sequestration in secondary lymphoid tissues and reduction of lymphocyte trafficking into the central nervous system.^22,25 Fingolimod (Gilenya; Novartis, East Hanover, NJ), the first S1PR modulator approved for MS, acts on 4 different S1PRs (S1PR1, S1PR3, S1PR4, and S1PR5).²⁵ Second-generation S1PR modulators are more selective and were developed to reduce potential side effects; Siponimod (Mayzent; Novartis, East Hanover, NJ) and ozanimod (Zeposia; Bristol Myers Squibb, New York, NY) act primarily on S1PR1 and SIPR5, whereas ponesimod (Ponvory; Janssen/Johnson & Johnson, Beerse, Belgium) acts primarily on S1PR1.

Baseline CBC with differential, electrocardiogram, renal function panel, LFT, varicella-zoster virus immunoglobulin G, ophthalmologic examination (or equivalent optical coherence tomography), and dermatologic examination are required before treatment initiation.²² Ophthalmologic examination should be repeated at 3 to 4 months after treatment commencement.²⁵ For siponimod, CYP2C9 genotype must be obtained, because certain polymorphisms of this gene lead to decreased metabolism of siponimod and potential for increased side effects.²⁶

Because of their potential cardiovascular effects, S1PR modulators are contraindicated in people with a history of major cardiovascular events (eg, unstable angina, myocardial infarction, heart failure with recent decompensation or hospitalization) or cerebrovascular events (eg, transient ischemic attack or stroke).²⁵ Some forms of heart block or heart rhythm abnormalities, including complete heart block or prolonged QT interval (≥500 ms), or use of certain antiarrhythmics, also represent contraindications to fingolimod use.²⁵ Fingolimod requires regular cardiac monitoring, for a minimum of 6 hours during first dose administration, consisting of at least heart rate and blood pressure measurements; duration and extent of first dose monitoring may be extended based on individual factors.²⁵

Common side effects include bradycardia, infections (including herpes zoster), and transaminitis.²⁵ Risk of opportunistic infections (eg, PML and cryptococcal meningitis)with fingolimod treatment and possibly other S1PR modulators appears to increase with age and duration of treatment. There is also an increased risk of macular edema (with the highest risk in people with diabetes), hypertension, melanoma, basal cell carcinoma, and possibly lymphoma.²⁵ Use of fingolimod and other S1PR modulators is associated with less robust vaccination response.^22,25,27,28

Fingolimod and other S1PR modulators are not recommended in pregnancy and should be discontinued upon pregnancy detection, and breastfeeding is not recommended during SIPR modulator treatment.^11,12,16,25

Natalizumab

Natalizumab (Tysabri; Biogen, Cambridge, MA) is an infusion-based monoclonal antibody that binds to alpha-4 integrin receptors, which ultimately inhibits leukocyte migration across the blood–brain barrier.^2,29 It is administered as an infusion therapy every 4 weeks but dosing intervals and laboratory assessment intervals may be altered in clinical practice as indicated.

Baseline CBC with differential, LFT, John Cunningham virus (JCV) antibodies, and human immunodeficiency virus (HIV) assessment are required; CBC with differential, LFTs, and JCV antibodies should be repeated at a minimum every 6 months, and HIV testing should be repeated only as clinically indicated.²⁹ Baseline brain MRI is also recommended and in clinical practice is usually repeated on a yearly basis.²⁹ It is not recommended to initiate or continue natalizumab in people with high-titer positive JCV antibodies because of the risk of PML. In people who have low-titer positive JCV antibodies, JCV antibody testing should be repeated every 3 months to reassess titers and plan to continue natalizumab therapy. Testing for antinatalizumab antibodies should be considered if severe infusion-related reactions occur or breakthrough MS activity is noted.

Common infections, such as urinary or respiratory tract infections, may occur and can prevent long-term use. The most concerning rare potential side effect is PML.²⁹ Risk factors for PML development include serum JCV antibody positivity, previous immunosuppressant use, and longer duration of natalizumab treatment.^29-32 Individuals without serum JCV antibodies, with no previous immunosuppression, and with less than 2 years of natalizumab treatment have a 1/10,000 risk of PML; the risk rises to about 1/100 in those with all 3 risk factors.^31,32 Recent data suggest that extended-interval dosing (6 vs 4 weeks) may mitigate PML risk.³⁰ There is increased risk of rebound disease activity after 8 weeks; thus, it is not recommended to extend intervals beyond this point. Data on vaccination response during natalizumab treatment are mixed and indicate a normal to reduced response.^33,34

Cell-trafficking therapies are unique with their propensity for rebound activity after cessation of therapy. In attempts to prevent severe rebound activity after cessation of an S1PR modulator or natalizumab, clinicians will start the subsequent DMT shortly after stopping the cell-trafficking therapy.

Natalizumab may be continued during pregnancy, and because of the risk of rebound, some experts recommend continuing until 30 to 34 weeks of pregnancy with extended-interval dosing (6 to 8 weeks).^11,12,16,29 However, continuation of natalizumab into the third trimester of pregnancy should be done with caution because of the risk for anemia, thrombocytopenia, and/or other hematologic abnormalities in the neonate.^12,35 Natalizumab is expressed in breastmilk in low concentrations, and breastfeeding while on treatment should be based on a discussion of risks vs benefits between the clinician and the individual.^11,16

Key Takeaways

• S1PR modulators can be associated with bradycardia and other manageable side effects but require close monitoring for infections as time goes on.
• S1PR modulators are contraindicated in people with a history of stroke or most major cardiovascular events.
• Natalizumab requires close monitoring for PML, with routine assessment of JCV antibody status.
• Both S1PR modulator and natalizumab discontinuation may be associated with disease rebound activity, but this can be mitigated by starting the next treatment shortly after stopping these medications.

Targeted Cell Lysis or Depletion

Several DMT use mechanisms of targeted cell depletion, which has durable effects on the adaptive immune system (B and T cells).

Cladribine

Cladribine (Mavenclad; Merck, Darmstadt, Germany) is an oral medication that acts as a purine analogue disrupting cell proliferation and inducing cell death.³⁶ This process affects lymphocytes selectively based on enzyme concentrations that promote cladribine activation and prevent its degradation within the cells, causing cell death.^22,24 Because of its profound effects on lymphocytes and other cells, clabridine is given for 2 years total, divided into 2 to 4 cycles per year with no further therapy given thereafter.

Preinitiation CBC with differential, lymphocyte count, and LFT are recommended, as well as regular monitoring at intervals of 2 months and 6 months after each scheduled treatment cycle in year 1 and year 2.^22,36 Other baseline laboratory studies include hepatitis B and C screening as well as tuberculosis and HIV assessment.³⁶ Year 2 of therapy can be postponed up to 6 months if ALC remains below 0.8 x 10⁹/L and should be deferred completely if ALC does not normalize (usually greater than 1 x 10⁹/L).²² Side effects include headache, nasopharyngeal infections, hepatic injury, and lymphopenia.³⁶ Cladribine was previously associated with increased risk of malignancy and is contraindicated in people with current malignancy.³⁶

Cladribine is contraindicated during pregnancy and attempts to conceive should be delayed to at least 6 months after the last dose, although safety analysis has suggested that the risk of congenital malformation and spontaneous abortion are no different than the general population.^11,36,37 Breastfeeding is not recommended during treatment with cladribine until 10 days after the last dose.^11,36

Alemtuzumab

Alemtuzumab (Lemtrada; Sanofi, Bridgewater, NJ) is a humanized anti-CD52 monoclonal antibody that depletes both mature B and T cells as well as other immune cells.³⁸ It is a yearly infusion therapy given for 2 consecutive years.^22,38 Monitoring consists of monthly CBC with differential among other laboratory studies during the treatment period (ie, 48 months) and for 48 months after the last dose.^22,24,38,39 Recommended safety monitoring, including CBC with differential, serum creatinine (or renal function panel), and urinalysis, is required to assess for alemtuzumab-related secondary autoimmunity, such as thyroid disorders, immune thrombocytopenic purpura, glomerulonephritis, and other hematologic abnormalities.^38,39 Other safety considerations include infusion-associated reactions, ranging from rash to cardiac arrhythmias and vascular events.³⁸ Alemtuzumab is contraindicated in pregnancy and attempts to conceive should be delayed until at least 4 months after the last dose.^{11,12,16,38,39} Breastfeeding should be based on a consideration of risks vs benefits because of expression of alemtuzumab in breast milk.^11,38

Anti-CD20 Agents

Anti-CD20 agents are some of the most widely used DMTs. They act by targeting the anti-CD20 protein on B cells, leading to cell lysis and depletion, through slightly different mechanisms,⁴⁰ discussion of which is beyond the scope of this review article.³⁶ Ocrelizumab (Ocrevus; Genentech, South San Francisco, CA), the first MS-specific agent within this class, is a humanized monoclonal antibody administered as an infusion therapy approximately once every 6 months, although extended-interval dosing (eg, 9 or 12 months) has been used in clinical practice without any notable increase in MS activity.^40-42 Ublituximab (Briumvi; TG Therapeutics, Morrisville, NC) is a similar agent with a chimerized monoclonal anti-CD20 antibody provided as an infusion therapy every 6 months, but at a faster rate than ocrelizumab.⁴⁰ Ofatumumab (Kesimpta; Novartis, East Hanover, NJ) is a fully human anti-CD20 antibody administered as a monthly subcutaneous injection.⁴⁰

Safety monitoring consists of baseline CBC with differential, LFT, and immunoglobulin levels, along with hepatitis and tuberculosis screening because of risk for infection reactivation.⁴¹ Pre-initiation VZV titers are also obtained in clinical practice due to risk for infection reactivation. After initiation of treatment, CBC with differential and immunoglobulins should be monitored every 6 to 12 months.^40,41 Some clinicians periodically assess lymphocyte subset counts to confirm B-cell depletion, usually through CD19 counts.²²

Potential side effects of this DMT class include infusion or injection-related reactions, hypogammaglobulinemia leading to increased infection risk (eg, nasopharyngeal, urinary tract), decreased vaccination responses, and, rarely, PML.^40,41 Of note, ofatumumab treatment may have maintained vaccination response and immunoglobulin levels, as opposed to other anti-CD20 therapies.⁴⁰ Ocrelizumab has also been associated with immune colitis (manifesting with persistent diarrhea) and a questionable increased risk of breast cancer.⁴¹

Pregnancy and breastfeeding data are limited for these agents, but current recommendations include avoiding active DMT use during pregnancy and delaying pregnancy for 3 to 6 months after the last infusion.^11,12,41 Breastfeeding may be safe because of limited bioavailability of agents in breast milk.¹¹

Key Takeaways

• The majority of cell-depleting DMTs have a durable treatment effect that requires infrequent administration.
• Anti-CD20 therapies require baseline CBC with differential and LFT as well as other indicated laboratory studies and routine monitoring every 6 to 12 months.
• Infusion anti-CD20 therapies and other infrequently administered therapies may be used in pregnancy planning because of prolonged intervals between dosing.
• The full safety profile of newer and more potent immune therapies continues to evolve.

Conclusion

A growing selection of DMT has paved the way for more tailored MS care while introducing some changes to clinical practice. Side effects are often associated with DMT mechanisms of action and may be influenced by duration of time on a certain medication along with preexisting comorbidities. Recommended safety monitoring is imperative during the use of these agents and requires detailed tracking and follow-up by a clinician familiar with the expanding armamentarium of MS DMTs.