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Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults

Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults
Literature review current through: Sep 2023.
This topic last updated: Aug 15, 2023.

INTRODUCTION — Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system that is a leading cause of disability in young adults.

The initial treatment of relapsing-remitting multiple sclerosis (RRMS) with disease-modifying therapies (DMTs) is reviewed here. Switching DMT because of ineffectiveness, intolerance, or other reasons is reviewed separately. (See "Indications for switching or stopping disease-modifying therapy for multiple sclerosis".)

The treatment of progressive forms of MS is also reviewed separately. (See "Treatment of secondary progressive multiple sclerosis in adults" and "Treatment of primary progressive multiple sclerosis in adults".)

Other aspects of MS are discussed elsewhere:

Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects

Pathogenesis and epidemiology of multiple sclerosis

Clinical presentation, course, and prognosis of multiple sclerosis in adults

Evaluation and diagnosis of multiple sclerosis in adults

Manifestations of multiple sclerosis in adults

Symptom management of multiple sclerosis in adults

Evaluation and diagnosis of multiple sclerosis in adults

PATTERN AND COURSE OF MS — MS is categorized into several clinical subtypes, as reviewed here briefly and discussed in detail separately. (See "Clinical presentation, course, and prognosis of multiple sclerosis in adults", section on 'Disease onset and pattern'.)

A clinically isolated syndrome (CIS) is the first clinical episode that is consistent with a demyelinating etiology and is suggestive of MS. (See "Clinical presentation, course, and prognosis of multiple sclerosis in adults", section on 'Clinically isolated syndrome'.)

A radiologically isolated syndrome (RIS) is defined by incidental brain or spinal cord magnetic resonance imaging (MRI) findings that are highly suggestive of MS, based upon location and morphology within the central nervous system, in an asymptomatic patient lacking any history, symptoms, or signs of MS. (See "Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis", section on 'Radiologically isolated syndrome'.)

Relapsing-remitting multiple sclerosis (RRMS) is characterized by clearly defined relapses with either full recovery, or with sequelae and residual deficit upon recovery. There is no or minimal disease progression during the periods between disease relapses, though individual relapses themselves may result in severe residual disability. (See "Clinical presentation, course, and prognosis of multiple sclerosis in adults", section on 'Relapsing-remitting MS'.)

Secondary progressive multiple sclerosis (SPMS) begins as relapsing-remitting disease, but over time the disease enters a stage of steady deterioration in function, with or without superimposed attacks, hence the designation of "secondary." Secondary progressive disease is the single largest category of MS. Typically, when the secondary progressive stage is reached, the relapse rate is also reduced. This type of MS, which ultimately develops in up to 90 percent of untreated patients with RRMS after 25 years, causes the greatest amount of neurologic disability attributable to MS. (See "Clinical presentation, course, and prognosis of multiple sclerosis in adults", section on 'Secondary progressive MS'.)

SPMS can be further characterized at different points in time as either active (with relapses and/or evidence of new MRI activity) or not active, as well as with progression (evidence of disease worsening on an objective measure of change over time, with or without relapses) or without progression. Disease-modifying therapy (DMT) is available for active secondary progressive MS. (See "Treatment of secondary progressive multiple sclerosis in adults".)

Primary progressive multiple sclerosis (PPMS) represents approximately 10 percent of MS cases and is characterized by disease progression from onset, although occasional plateaus, temporary minor improvements, and acute relapses may occur. (See "Clinical presentation, course, and prognosis of multiple sclerosis in adults", section on 'Primary progressive MS'.)

PPMS can also be characterized at different points in time as either active (with a relapse and/or evidence of MRI activity) or not active, as well as with or without progression. DMT for primary progressive MS is reviewed separately. (See "Treatment of primary progressive multiple sclerosis in adults".)

DMT INDICATIONS, TIMING, AND GOALS

Who should be treated? — Everyone with a diagnosis of clinically definite relapsing-remitting multiple sclerosis (RRMS) should be offered disease-modifying therapy (DMT) [1-3]. DMTs are described briefly here and reviewed in detail separately. There is considerable evidence that earlier treatment is associated with a better long-term outcome [4-9]. (See "Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects".)

DMTs have also shown benefit for selected patients with a clinically isolated syndrome (CIS), secondary progressive multiple sclerosis (SPMS), or primary progressive multiple sclerosis (PPMS), as follows:

Patients with a CIS or RIS suggestive of MS who do not completely meet McDonald criteria for MS but have additional clinically silent lesions in the brain or spinal cord detected by magnetic resonance imaging (MRI) (see "Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis")

Patients who reach the stage of SPMS and have active disease, as determined by ongoing clinical relapses and/or new MS lesions on MRI (see "Treatment of secondary progressive multiple sclerosis in adults")

Patients with PPMS who are younger (eg, age ≤55 years) or have active disease on MRI (see "Treatment of primary progressive multiple sclerosis in adults")

Importance of early treatment — We start DMT as soon as possible for all patients with RRMS. Accumulating data from observational studies suggest that the use of DMT is associated with a lower long-term risk of MS disease progression [4-10], which may be enabled more with the early use of the high-efficacy monoclonal antibody DMTs (eg, natalizumab and alemtuzumab) [11,12]. As an example, an observational cohort study analyzed data for over 1500 propensity-matched patients with RRMS and a minimum follow-up period of four years who were untreated or treated with interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab [6]. Initial treatment with each of these DMTs was associated with a lower risk of conversion to secondary progressive MS compared with no DMT treatment; the risk was lower for early initial DMT (within five years of disease onset) compared with later treatment. Furthermore, the associated risk of conversion was lower for initial treatment with fingolimod, alemtuzumab, or natalizumab compared with initial treatment with glatiramer acetate or interferon beta (hazard ratio 0.66, 95% CI 0.44-0.99, five-year absolute risk 7 percent [16 of 235] versus 12 percent [46 of 380]. One limitation to this study is that relatively few patients contributed to each of the individual comparisons, and patients using various treatment strategies often came from different time periods and countries. Another is that techniques such as propensity scores cannot fully account for unmeasured confounders.

Treatment goals — The primary treatment goals of DMT are preventing MS relapses (attacks), reducing the accumulation of neurologic impairment and disability over time, and reducing brain inflammation and injury [13]. Accumulating data suggest that DMTs reduce disability progression in adult and pediatric patients with RRMS, at least in the short term (eg, two to three years) [14-16].

However, it is not yet established whether these medications reduce long-term disability, and whether they do so differentially. In an effort to address the long-term effect on DMTs on disability, an analysis of observational data from the MSBase registry compared worsening and improvement of disability and the incidence of relapses during periods of DMT treatment versus no treatment [17]. For 1085 patients with RRMS and 15 or more years of follow-up, 1061 of whom used injectable therapies, treated patients were less likely to experience relapses (hazard ratio [HR] 0.59, 95% CI 0.50-0.70) and worsening of disability (HR 0.81, 95% CI 0.67-0.99). The novel methodology used for the study considered every three-month epoch as on-treatment or off-treatment. However, this may be difficult to apply to people with MS, since immune-modulating medications may take longer than three months to gain effectiveness when started, and similarly may take longer than three months to lose effectiveness when stopped. Further studies are needed to confirm whether DMTs lower the risk of long-term disability.

CATEGORIES OF DMT — A number of immunomodulatory agents have important beneficial effects for patients with RRMS, mainly a decreased relapse rate and a slower accumulation of brain lesions on MRI. These DMTs for MS can be grouped by method of administration into infusion, oral, and injectable drugs.

Monoclonal antibodies — Monoclonal antibodies for MS include natalizumab, ocrelizumab, rituximab, ofatumumab, ublituximab, and alemtuzumab. These DMTs may be preferred for patients with more active disease and for those who place a high value on efficacy and are risk-tolerant. However, serious safety issues, including infections, are possible adverse effects of several of these medications. (See "Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects", section on 'Monoclonal antibodies'.)

Oral therapies — Oral therapies for MS include the fumarates (dimethyl fumarate, diroximel fumarate, monomethyl fumarate), sphingosine 1-phosphate receptor (S1PR) modulators (fingolimod, siponimod, ozanimod, ponesimod), teriflunomide, and cladribine. These oral DMTs may be preferred for patients who value a self-administered oral medication over medications requiring injections and infusions. (See "Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects", section on 'Oral therapies'.)

Platform injection therapies — Older injectable (intramuscular and subcutaneous) forms of DMT for MS include recombinant human interferon beta-1b, recombinant human interferon beta-1a, and glatiramer acetate. The interferons and glatiramer acetate were the first DMTs approved for MS and are sometimes called the "platform" therapies for this reason. These older DMTs may be preferred for patients who value safety and are less concerned about convenience or achieving the highest effectiveness. (See "Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects", section on 'Oral therapies'.)

Comparative efficacy — The available evidence, based upon a limited number of randomized controlled trials, indirect cross-trial comparisons, observational studies, and clinical experience, suggests that the monoclonal antibodies (natalizumab, ocrelizumab, ofatumumab, and alemtuzumab), and (possibly) cladribine have the highest efficacy; S1PR modulators (eg, fingolimod) and fumarates (eg, dimethyl fumarate) have an intermediate efficacy; and teriflunomide and the older platform DMTs (interferons and glatiramer) have the lowest efficacy [18-30]. However, it is uncertain how closely DMT efficacy inferred from clinical studies correlates with effectiveness in the "real world," where the populations and related treatment decisions differ from the scenarios in trials.

Clinicians should tell patients that the relative additional benefit of highly effective DMTs comes from comparisons of their average ability to reduce relapses and new MS lesions on MRI in large groups. However, the average benefit of a DMT may not apply to an individual patient; that person may be much more likely, or much less likely, to respond to a given agent. None of the DMTs constitute a cure; they are only partially effective for reducing the relapse rate, and whether all or any reduce long-term disability progression is still under active investigation.

FACTORS INFLUENCING THE CHOICE OF DMT — A number of issues may help to guide DMT options for individual patients [13].

Assessment for risk of MS worsening — The risk of future disease activity (ie, a relapse or new T2 or enhancing lesions on brain MRI within the next two years) in patients with RRMS can help guide the choice of DMT. Clinicians should assess patients with RRMS at presentation and periodically thereafter for features associated with a poor prognosis and higher risk of future relapse and severe disability [3]. These include the following [3,13,31-38]:

Demographic:

Onset of MS after age 30, even though the risk of relapse paradoxically decreases with age

Motor or cerebellar onset

Male sex

Americans of Black, Asian, or Hispanic ethnicity

Former or current smoking

Comorbid cardiovascular disease

Obesity

Sedentary lifestyle

Clinical:

Poor relapse recovery

Frequent early attacks

Presence of oligoclonal bands in the cerebrospinal fluid

Radiologic:

High burden of disease by T2 lesion volume on MRI

Ongoing disease activity by enhancing or new T2 lesions on MRI

Spinal cord lesion(s)

Presence of brain atrophy

Of these, the most important factors predicting a worse clinical course and poor long-term outcome are the presence of highly active disease (eg, frequent relapses and new MRI lesions), extensive radiologic involvement of MS lesions (eg, multifocal lesions, high lesion number; and high T2 burden of disease), spinal cord involvement, and/or poor relapse recovery [3]. Patients with these characteristics may be good candidates for starting treatment with highly effective DMT. (See 'Starting with high efficacy therapy' below.)

However, prognostic studies are often limited because few have examined all factors concomitantly in representative populations (eg, Black patients have often been underrepresented in these cohorts, which tend to enroll predominantly White patients from Europe).

Shared decision-making — Shared decision-making incorporates the patient's values and preferences into medical decisions and puts the patient at the center of care.

Patient values and preferences include individual patient views about drug efficacy, safety, tolerability (with a goal of minimizing risks and side effects), and convenience; willingness to perform injections, readiness to start DMT, urgency to start DMT, and likelihood of adherence.

The patient, clinician, and care team should jointly consider the decision to start a DMT and select the best option, evaluating the evidence, benefits, risks, and burdens of the available DMTs [13,39]. Important aspects include patient education about the natural history of MS, the patient's prognostic factors, the DMT categories and differentiating factors, the treatment goals, and the expected treatment outcomes. Decision aids (eg, text, audio-visual material, interactive media) about MS and the role of DMT may also be helpful.

This process takes time. Experts generally advise that providing a second, close follow-up appointment after the appointment at which the diagnosis is confirmed and the DMT options are presented. This allows newly diagnosed patients the opportunity to review the diagnosis and consider therapies and questions they have about them before committing to a specific therapy. Laboratory testing ordered at the first visit helps inform the relative safety of some DMTs, and the test results can be incorporated into the discussion at the follow-up appointment.

Shared decision making has been associated in some studies with improvements in disease knowledge, satisfaction with care, treatment adherence, health outcomes, and health-related quality of life [13,39-41].

Women of childbearing potential — Women with MS are typically at childbearing potential for most of the relapsing-remitting phase of the disease. Women of childbearing potential may wish to avoid starting DMTs that are confirmed or possible teratogens (eg, teriflunomide, cladribine, fingolimod, siponimod, ozanimod), or that may be associated with greater risk of rebound on discontinuation (natalizumab, fingolimod, and, presumably, siponimod and ozanimod) if they are planning pregnancy soon or are unwilling to use highly effective contraceptive strategies. Other DMTs have uncertain risks during pregnancy and breastfeeding. These issues are discussed separately. (See "Multiple sclerosis: Pregnancy planning" and "Multiple sclerosis: Pregnancy and postpartum care".)

Drug availability — The availability of some DMTs may be limited due to geographic distribution, national regulations, cost and financial limitations, and insurance restrictions.

SELECTING INITIAL DMT — There is no uniform method for selecting initial disease-modifying therapy (DMT) for patients with relapsing-remitting multiple sclerosis (RRMS). Two broad treatment paradigms are advocated by different experts: starting with highly effective therapy or starting with low-risk therapy. In addition, some experts and patients prefer to start with oral therapy, which is (on average) intermediate for efficacy and risk.

Starting with high efficacy therapy — An approach favored by some experts is to start most patient with RRMS using one of the high efficacy DMTs, such as natalizumab, ocrelizumab, and ofatumumab. The main advantage of this approach is the relatively high efficacy of these DMTs, given natural history data for MS, which suggest that relapses and new magnetic resonance imaging (MRI) changes are most frequent at the onset of MS [42], a time when patients are youngest and when DMTs may be most effective and tolerable [21]. The main disadvantage of this approach is the risk of severe adverse events with these therapies; this includes the risk of serious infections (eg, the risk of progressive multifocal leukoencephalopathy [PML] with natalizumab, the potential risk of developing severe coronavirus disease 2019 [COVID-19] (see 'COVID-19 pandemic' below), and the potential impact on COVID-19 vaccine effectiveness) and the risk of breakthrough disease associated with natalizumab withdrawal. The burden and inconvenience of periodic infusions or injections is another disadvantage of some of these DMTs.

Because of their safety profile, some high-efficacy DMTs (eg, alemtuzumab, cladribine) are usually reserved for patients who do not tolerate or have an inadequate response to other drugs for MS.

Starting with low-risk therapy — Another approach favored by some experts is to start treatment using older injectable DMTs (beta interferons and glatiramer acetate) for patients with RRMS, particularly for those with a minimal disease burden or who are risk averse. Escalation to intermediate efficacy oral DMT or high efficacy infusion DMT is then implemented only for patients who develop new MS attacks or evidence of new lesions on brain MRI [21]. The main advantage of this approach is that the older injectable DMTs have long-term evidence of safety; serious adverse events are rare. The main disadvantages are the relatively modest efficacy of the older injectable DMTs (see 'Comparative efficacy' above) and the burden and inconvenience of administration by injection. Some authors point out that most patients who start with platform DMTs will eventually switch (for various reasons) to more effective DMTs; additionally, starting patents on less effective DMTs may risk greater disability over time [21,43].

Our approach — For patients with RRMS, we recommend DMT and typically start with one of the agents listed below:

Higher effectiveness DMTs

Intravenous natalizumab

Intravenous ocrelizumab

Subcutaneous ofatumumab

Intermediate effectiveness DMTs

Oral fumarates (dimethyl fumarate, diroximel fumarate, or monomethyl fumarate)

Oral sphingosine 1-phosphate receptor (S1PR) modulators (fingolimod, siponimod, ozanimod, or ponesimod)

Lower effectiveness DMTs

Oral teriflunomide

Intramuscular recombinant human interferon beta-1a

Subcutaneous recombinant human interferon beta-1a

Subcutaneous pegylated recombinant human interferon beta-1a

Subcutaneous recombinant human interferon beta-1b

Subcutaneous glatiramer acetate

In choosing among these and other available DMTs, clinicians should incorporate individual patient prognostic factors, values and preferences, and drug-related factors (adverse effect profile, cost, availability, and burden of administration), using a shared decision-making process (see 'Shared decision-making' above) to optimize choices for individual patients. Ideally, the goal is to try to match the patient's disease severity with the most appropriate DMT; a patient with severe disease with ongoing risk of activity should often be on a more efficacious DMT, while a patient with mild disease should often be on a safe and tolerable DMT. Most of the medications are relatively easy to discontinue if patients are unable to tolerate them or there is breakthrough disease, lowering the pressure to "get it right" the first time.

The following are reasonable options for choosing initial DMT (algorithm 1):

For patients with highly active disease and for patients who place a high value on efficacy and are relatively risk-tolerant, start with highly effective therapy using intravenous natalizumab or anti-CD20 therapy. With natalizumab therapy, the risk of progressive multifocal leukoencephalopathy increases with the duration of treatment, particularly for those who demonstrate JC virus seropositivity. Alemtuzumab is also highly effective but is usually reserved for patients who have had an inadequate response to one or more DMTs for RRMS because of its safety profile. Oral cladribine is often considered high efficacy but is typically reserved for patients who have had breakthrough disease while on another DMT or are intolerant of other DMTs for MS.

For patients with less active disease and for patients who value convenience using a self-administered oral medication compared with medications requiring injections or infusions, start with an oral DMT such as a fumarate or an S1PR modulator. However, serious safety issues (including infections) are possible adverse effects of these medications; clinicians must monitor laboratory tests and other factors related to the adverse effects of these agents, particularly if severe lymphopenia occurs. Of the oral therapies, many patients choose fumarates due to their seemingly better safety profile compared with the S1PR modulators, but practices vary widely [44-46]. The potential teratogenicity of teriflunomide and cladribine limit their use for a disease where a substantial portion of patients are of childbearing potential.

For patients who place the highest value on safety and are willing to accept lower effectiveness, start with one of the beta interferons or glatiramer.

IMPLEMENTATION

Baseline assessments — Most DMTs require baseline and periodic monitoring of clinical parameters (eg, blood pressure) and laboratory tests such a complete blood cell count with lymphocytes, liver function testing, and urinalysis [3,13]. Additional testing is required for certain DMTs, such as screening for the JC virus in patients on natalizumab or for hepatitis B prior to anti-CD20 therapy. Some experts advise a pregnancy test for women of childbearing potential before starting DMT and prior to some infusions. (See "Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects".)

Immunizations — Before starting DMT, immunization status should be reviewed and updated according to local and national recommendations [3,13]. Patients should also be screened for immunity to varicella zoster virus and hepatitis A, B, and C, and vaccinated against these viruses as indicated or available. Some DMTs (eg, ocrelizumab) require that patients receive the last dose of all necessary vaccinations (including, potentially those against severe acute respiratory syndrome coronavirus 2 [SARS CoV-2]) at least four weeks before starting treatment for live or live-attenuated vaccines, and at least two weeks before starting treatment for non-live vaccines. Extending this principle to all anti-B cell therapies (rituximab, ofatumumab, bioequivalents) is prudent, considering the anti-CD20 therapies attenuate vaccine responsiveness. However, it is not always feasible or safe to wait; some multi-part vaccines (eg, hepatitis B) could delay treatment start by months, which is unacceptable for patients with ongoing risk of disease activity.

COVID-19 pandemic — We advise coronavirus disease 2019 (COVID-19) vaccination as soon as practical for all patients with MS, in accordance with local availability and allocation priorities. (See "COVID-19: Vaccines".)

Guidance on the use of DMTs in patients with MS during the COVID-19 pandemic is provided separately. (See "Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects", section on 'COVID-19 pandemic and DMTs'.)

The management of COVID-19 is discussed in several UpToDate topic reviews. (See "COVID-19: Management in nursing homes" and "COVID-19: Management in hospitalized adults" and "COVID-19: Management of adults with acute illness in the outpatient setting".)

Monitoring response to therapy — The response to disease-modifying therapy (DMT) can be monitored by clinical follow-up with careful attention to possible manifestations of MS disease activity including acute attacks (relapses), development of new MS lesions (particularly more than one) on brain magnetic resonance imaging (MRI), and possibly the onset or progression of sustained disability (the latter needs confirmation) [1,2]. Since DMTs are only partially effective, many MS experts recommend more aggressive treatment when new lesions develop on MRI when the patient is on a specific treatment for six months or more, which is thought to be enough time for DMT to take effect, even when the patient appears to be doing well clinically. (See "Indications for switching or stopping disease-modifying therapy for multiple sclerosis", section on 'Breakthrough or refractory disease'.)

Periodic MRI – We supplement the clinical information with periodic neuroimaging (eg, MRI) studies to monitor the development of new asymptomatic MS lesions. MRI imaging also serves to screen asymptomatic patients for lesions suggestive of serious complications (eg, infectious, inflammatory, cerebrovascular) of DMTs [47].

In agreement with a consensus guideline, we obtain a brain MRI before starting or switching DMT, another approximately three to six months later, and annually thereafter [48]. More frequent neuroimaging may be desirable for some patients, but is impractical due to financial constraints. Note that the value of screening MRIs likely declines over time in patients on higher-efficacy therapy, and there is debate in the field as to whether even annual imaging is needed in people on these medications. Less frequent imaging may be reasonable for individuals with years of clinically and radiologically stable disease.

Use of gadolinium contrast – Guidelines recommend limiting the use of MRI with gadolinium contrast to selected clinical scenarios [48]:

When detection or confirmation of recent (ie, within one year) clinical disease activity will influence treatment decisions, such as starting or escalating therapy

When a recent comparable MRI scan is not available

When assessment of new MRI disease activity is difficult due to a high baseline T2 lesion burden

Repeated contrast-enhanced MRI studies can lead to gadolinium accumulation in brain tissues [49-53]. Although there are no documented adverse effects of such accumulation, it is prudent to carefully reflect on whether gadolinium is needed with each MRI.

EDSS – In addition to MRI, some experts assess patients with the Expanded Disability Status Scale (EDSS) (table 1) every three months, but it is uncertain if change in EDSS alone is an indication to switch therapy in the absence of clinical relapse or MRI evidence of MS disease activity.

Symptom management – A range of symptomatic problems can occur in patients with MS. Cognitive dysfunction, depression, fatigue, and mood swings are increasingly common with disease progression. Paroxysmal symptoms, spasticity, tremor, seizures, sphincter dysfunction, and sexual dysfunction may also complicate disease progression. The management of these issues is discussed in detail separately. (See "Symptom management of multiple sclerosis in adults".)

Acute attacks – Acute attacks (relapses) of MS are typically treated with glucocorticoids, which accelerate recovery. Indications for treatment of a relapse include functionally disabling symptoms with objective evidence of neurologic impairment. This is reviewed in detail separately. (See "Treatment of acute exacerbations of multiple sclerosis in adults".)

Duration of treatment — Most disease-modifying therapies (DMTs) are continued indefinitely in clinically stable patients with relapsing-remitting multiple sclerosis (RRMS) unless side effects are intolerable or safety concerns arise [1,2]. However, it may be reasonable to discuss stopping DMT for older patients who have had no new relapses or magnetic resonance imaging (MRI) changes for a prolonged period. This issue is reviewed in detail elsewhere. (See "Indications for switching or stopping disease-modifying therapy for multiple sclerosis", section on 'Reasons for stopping DMT'.)

For women who desire to become pregnant (or theoretically for men who are using teriflunomide), the risk of possible adverse effects of DMTs on the fetus must be weighed against DMT discontinuation and increased risk of maternal disease relapses. Rebound of MS activity may occur after discontinuing certain DMTs, particularly natalizumab, fingolimod, and, in some case reports, teriflunomide and dimethyl fumarate. These factors must be considered when counseling a woman who wishes to conceive, ideally in consultation with an MS specialist and maternal-fetal medicine specialist. (See "Indications for switching or stopping disease-modifying therapy for multiple sclerosis", section on 'Pregnancy'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple sclerosis and related disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Multiple sclerosis in adults (The Basics)")

SUMMARY AND RECOMMENDATIONS

Types of disease-modifying therapy (DMT) – A number of immunomodulatory agents have important beneficial effects for patients with relapsing-remitting multiple sclerosis (RRMS), mainly a decreased relapse rate and a slower accumulation of brain lesions on magnetic resonance imaging (MRI). These disease-modifying therapies (DMTs) for multiple sclerosis (MS) are available as monoclonal antibodies, oral therapies, and older (platform) injectable drugs. (See 'Categories of DMT' above.)

Comparative efficacy of DMTs – The available evidence suggests that several monoclonal antibodies (natalizumab, ocrelizumab, ofatumumab, ublituximab, and alemtuzumab) and an oral DMT (cladribine) have the highest efficacy, while oral sphingosine 1-phosphate receptor (S1PR) modulators (eg, fingolimod) and oral fumarates (eg, dimethyl fumarate) have an intermediate efficacy, and oral teriflunomide and the older injection DMTs (interferons and glatiramer) have the lowest efficacy. It is less certain how these efficacy differences translate in the "real world," where the populations and related treatment decisions differ from the scenarios in trials. (See 'Comparative efficacy' above.)

Assessing the risk of MS worsening – Clinicians should assess patients with RRMS at presentation and periodically thereafter for features associated with a poor prognosis and higher risk of future relapse and severe disability. The most important factors predicting a worse clinical course and poor long-term outcome are the presence of highly active disease (eg, frequent relapses and new MRI lesions), extensive radiologic involvement of MS lesions (eg, multifocal lesions, high lesion number; and high T2 burden of disease), and/or poor relapse recovery. (See 'Assessment for risk of MS worsening' above.)

Patient- and drug-specific factors influencing DMT choice – Several issues may narrow DMT options, including patient values and preferences and drug-specific factors. Women of childbearing potential may wish to avoid some or all DMTs with the potential for fetal harm. (See 'Factors influencing the choice of DMT' above and "Multiple sclerosis: Pregnancy planning" and "Multiple sclerosis: Pregnancy and postpartum care".)

Shared decision-making – Using shared decision making, the patient, clinician, and care team should jointly consider the decision to start a DMT and select the best option, evaluating the evidence of benefits, risks, and burdens of the available DMTs. (See 'Shared decision-making' above.)

Treatment paradigms – There is no uniform method for selecting initial DMT for patients with RRMS. Two broad treatment paradigms are advocated by different experts: starting with highly effective therapy or starting with low-risk therapy. In addition, some experts and patients prefer to start with oral therapy, which is intermediate for efficacy and risk. (See 'Selecting initial DMT' above.)

Our approach – For patients with RRMS, we recommend DMT (Grade 1A). We typically start with one of the agents listed below (see 'Our approach' above):

Higher effectiveness DMTs for initial treatment

-Intravenous natalizumab

-Intravenous ocrelizumab

-Subcutaneous ofatumumab

Intermediate effectiveness DMTs for initial treatment

-Fumarates: oral dimethyl fumarate, diroximel fumarate, or monomethyl fumarate

-S1PR modulators: oral fingolimod, siponimod, ozanimod, or ponesimod

Lower effectiveness DMTs for initial treatment

-Oral teriflunomide

-Intramuscular recombinant human interferon beta-1a

-Subcutaneous recombinant human interferon beta-1a

-Subcutaneous pegylated recombinant human interferon beta-1a

-Subcutaneous recombinant human interferon beta-1b

-Subcutaneous glatiramer acetate

Choosing among the DMT effectiveness categories – In choosing among these and other available DMTs, clinicians should incorporate individual patient prognostic factors, values and preferences, and drug-related factors (adverse effect profile, cost, availability, and burden of administration), using a shared decision making (see 'Shared decision-making' above) to optimize choices for individual patients (algorithm 1). The following options are reasonable guides to selecting therapy (see 'Our approach' above):

-For patients with highly active disease, and for patients who place a high value on efficacy and are relatively risk-tolerant, start with highly effective therapy using intravenous natalizumab or ocrelizumab.

-For patients with less active disease and for patients who value convenience using a self-administered medication compared with medications requiring injections or infusions, start with an oral fumarate or S1PR modulator.

-For patients who place the highest value on safety and have less active disease, start with one of the beta interferons or glatiramer.

Monitoring response to therapy – The response to DMT can be monitored by clinical follow-up with careful attention to possible manifestations of MS disease activity including acute attacks (relapses), new or contrast-enhancing lesions on MRI, and, possibly, the onset or progression of sustained disability. (See 'Monitoring response to therapy' above.)

  1. Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 2018; 90:777.
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Topic 1687 Version 113.0

References

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