Version May 2024
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. This topic will discuss reasons for switching or stopping DMT, including ineffectiveness or intolerance, a heightened risk of progressive multifocal leukoencephalopathy, and pregnancy planning.
The initial treatment of relapsing-remitting multiple sclerosis (RRMS) with disease-modifying therapies (DMTs) is reviewed separately. (See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)
Other aspects of MS are discussed elsewhere:
● 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
INEFFECTIVENESS OR INTOLERANCE OF DMT — The response to disease-modifying therapy (DMT) should 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 magnetic resonance imaging (MRI), and the onset or progression of sustained disability. (See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults", section on 'Monitoring response to therapy'.)
Breakthrough or refractory disease — Some patients with relapsing-remitting multiple sclerosis (RRMS) have disease activity that is refractory to initial DMT. Although refractory disease is hard to define, the frequency and severity of clinical relapses and MRI lesion activity on therapy are the crucial factors.
When to consider switching DMT — A single relapse of mild severity or a single new MRI lesion within six months of starting DMT is concerning but is usually insufficient to demand a change in therapy. However, any serious MS relapse, multiple relapses regardless of severity, or a pronounced increase in MRI activity with multiple new T2 lesions, particularly after more than six months on therapy, should prompt a review of treatment options with a predisposition to change the DMT [1,2].
Guidelines from the American Academy of Neurology (AAN) suggest switching to another DMT for people with MS who are adherent to DMT therapy long enough for the treatment to take full effect when they experience one or more relapses, two or more unequivocally new MRI-detected lesions, or increased disability on examination over a one-year period [3]. However, none of the available DMTs are definitively proven to reduce disability progression for patients who appear to have secondary progressive MS. This factor must be considered when deciding whether to switch to another DMT.
When to reconsider the diagnosis — Apparent inflammatory breakthrough (eg, a clinical relapse, or new or expanding lesions on MRI) occurring despite treatment with higher-efficacy DMTs should inspire reconsideration of diagnosis of MS.
●Were the "relapses" true relapses, or pseudorelapses? In the absence of a new demyelinating event, previous clinical deficits may temporarily worsen in the setting of any elevated physiologic temperature (including fever, physical activity, high environmental temperature) or metabolic upset, and may last for hours to a day or more. Such worsening, termed "pseudorelapses," is thought to reflect conduction block in previously demyelinated axons.
●Is a different diagnosis more appropriate (eg, neuromyelitis optica spectrum disorder [NMOSD] or myelin oligodendrocyte glycoprotein antibody-associated disease [MOGAD]), thus explaining the breakthrough? (see "Evaluation and diagnosis of multiple sclerosis in adults", section on 'Differential diagnosis')
MS disease activity scoring systems — Some experts use scoring systems or formal definitions of MS disease activity to aid in decisions about the effectiveness of DMT. Examples include the Rio score, the modified Rio score, and the treatment goal of no evidence of disease activity (NEDA) [4].
●The Rio score, evaluated at one year, assigns one point each for more than two active T2 lesions on MRI, one or more relapses in the first year, and an increase in Expanded Disability Status Scale (EDSS) score of one or more points sustained over at least six months and confirmed at the end of follow-up [5]. Tested in 222 patients with RRMS who were treated with interferon beta DMT, Rio scores ≥2 predicted poor outcome at three years, while scores ≤1 predicted better outcomes.
●The modified Rio score, evaluated at one year, assigns one point for more than five new T2 lesions on MRI, one point for one relapse, and another point for two or more relapses [6]. Evaluated at one year in patients with RRMS who were treated with interferon beta drugs, a modified Rio score ≥2 predicted a three-year disability progression of 65 percent, a score of 1 predicted a three-year disability progression of 33 percent, and a score of 0 predicted three-year disability progression of 24 percent. For patients considered at medium risk, the development of one or more relapse or two or more new T2 lesions on brain MRI within six months of the initial evaluation is associated with high risk of disability progression [2].
●NEDA, usually assessed at one or two years of follow-up, requires no clinical relapses, no sustained disability progression lasting at least three months, and no enhancing lesions and no new or enlarging T2 lesions on brain MRI [7,8].
Intolerance — Patients may not tolerate DMT because of adverse effects. Interferon beta formulations in particular are often poorly tolerated because of the high frequency of injection site reactions and flu-like symptoms (eg, fevers, chills, fatigue, myalgia) [9]. The most common adverse effects are discussed separately for the individual DMTs. (See "Overview of disease-modifying therapies for multiple sclerosis".)
Switching to a different DMT — There is no standard protocol for changing DMT in patients with drug intolerance, relapses, or clinically silent MRI lesions. The overall goal is to balance the risks posed by the medications to the risks posed by the disease, though prognosticating long-term outcomes in MS is difficult. Consideration of the contribution of medication adherence and other factors to inadequate treatment response is also important. The best options for switching DMTs depend in part upon the initial treatment choice. (See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)
The available evidence, though not definitive, suggests that the infusion DMTs (natalizumab, ocrelizumab, and alemtuzumab), injectable ofatumumab, and oral cladribine have the highest efficacy (although some consider cladribine as intermediate in efficacy); oral fingolimod and oral dimethyl fumarate have an intermediate efficacy; and oral teriflunomide and the older injection DMTs (interferons and glatiramer) have the lowest efficacy. These differences in efficacy can guide decisions about switching DMT in patients with breakthrough or refractory disease. Patients with breakthrough or refractory disease initially treated with a lower-efficacy DMT may benefit from switching to higher-efficacy DMT, while patients initially treated with a high-efficacy DMT may be switched to a different high-efficacy DMT. (See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults", section on 'Comparative efficacy'.)
In all cases, the patient, clinician, and care team should jointly consider the decision to switch DMT as part of shared decision-making, incorporating the patient's values and preferences, and evaluating the benefits, risks, and burdens of the available DMTs. (See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults", section on 'Shared decision-making'.)
While there is no clear consensus, some experts advise a washout period between medications when switching from one DMT to another in order to avoid excessive immunosuppression and its associated increased risk of infection [9]. This concern must be weighed against the risks of recurrent or rebound disease during the planned washout.
●Initial treatment with interferons, glatiramer, or teriflunomide – The interferon beta (IFNB) drugs, glatiramer acetate, and oral teriflunomide are generally considered to be among the low-efficacy DMTs for treating relapsing forms of MS. For patients initially treated with these drugs who have an inadequate response, escalation can be achieved by switching to high-efficacy infusion DMT using natalizumab or ocrelizumab, or by switching to intermediate-efficacy oral DMT using a fumarate (dimethyl fumarate or bioequivalent) or a sphingosine 1-phosphate receptor modulator (eg, fingolimod, siponimod, ozanimod). Switching to the opposite class of injectable treatments or from an interferon or glatiramer to oral teriflunomide offers no clear therapeutic advantage in terms of effectiveness, but this strategy may be helpful if intolerance of the initial therapy is the reason for switching.
●Initial treatment with natalizumab – For patients initially treated with natalizumab who have a breakthrough disease or who seroconvert to positive anti-JCV antibody status, it is reasonable to switch to a different high-efficacy DMT, such as ocrelizumab [10]. Alemtuzumab is another option but is generally reserved in the United States for patients with highly active RRMS who have had an inadequate response to two or more DMTs.
Switching to oral DMT is also an option favored by some experts, but other experts prefer to avoid switching from natalizumab to less effective oral therapy (eg, dimethyl fumarate, fingolimod, siponimod, ozanimod, and teriflunomide) due to concerns about the risk of a rebound of MS activity. Less commonly, some experts use monthly intravenous glucocorticoid bolus, typically 1000 mg of methylprednisolone, to potentially reduce the risk of rebound for patients who are stopping natalizumab and starting a less effective DMT. Prolonged natalizumab washout also appears to be associated with increased risk of rebound.
For patients treated with natalizumab, particularly those who are seropositive for the JCV antibody, it is important to determine whether new or worsening neurologic symptoms or MRI changes are caused by MS or by progressive multifocal leukoencephalopathy (PML). (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Surveillance for PML'.)
Decisions about treatment options for patients who develop JCV antibodies while on natalizumab are discussed below. (See 'JCV antibody status' below.)
●Initial treatment with ocrelizumab, ofatumumab, rituximab, or ublituximab – Patients with an inadequate response to these DMTs may be switched to a different highly effective DMT (eg, from ocrelizumab or rituximab to natalizumab). Other options (oral or older injectable DMTs) may be less effective. Optimizing the timing of switching from an anti-CD20 DMT to another DMT can be challenging since the medication effects of anti-CD20 therapies last for many months, making it hard to know when to begin the next medication. Specific infectious risks in transitioning from anti-CD20 therapy to another MS therapy, and the optimal way to mitigate them, are also less clear.
Since anti-CD20 DMTs may lower JCV antibody titers [11,12], some experts check JCV antibody titer before starting an anti-CD20 DMT; this information could be helpful if there is a subsequent reason to consider switching from the anti-CD20 DMT to natalizumab.
●Initial treatment with oral fumarates or sphingosine 1-phosphate receptor modulators – For patients initially treated with oral fumarates (dimethyl fumarate or congeners) or sphingosine 1-phosphate receptor modulators (fingolimod, siponimod, ozanimod, and ponesimod) who have an inadequate response, the main options are switching to highly effective infusion therapy such as natalizumab or ocrelizumab or switching to a different agent of similar efficacy. Switching to lower efficacy IFNB, glatiramer, or teriflunomide may risk a rebound of MS activity, particularly after stopping sphingosine 1-phosphate receptor modulators.
●Patients with poor response to two or more DMTs – Because of its safety profile, alemtuzumab is usually reserved for patients with highly active RRMS who have had an inadequate response to two or more first-line DMTs in the United States. Other options for patients who are poor responders to all first-line DMTs have limited evidence of efficacy but are sometimes used in this setting; these include intravenous methylprednisolone 1000 mg every 30 days (monthly), intravenous immune globulin, or intravenous pulse cyclophosphamide with pulse methylprednisolone. (See "Overview of disease-modifying therapies for multiple sclerosis", section on 'Cyclophosphamide' and "Overview of disease-modifying therapies for multiple sclerosis", section on 'Glucocorticoids' and "Overview of disease-modifying therapies for multiple sclerosis", section on 'Intravenous immune globulin'.)
Autologous hematopoietic stem cell transplantation is being evaluated at a few centers for refractory RRMS [13]. (See "Overview of disease-modifying therapies for multiple sclerosis", section on 'Stem cell transplantation'.)
Risk of rebound of MS activity — Discontinuation of certain DMTs has been associated with a rebound of MS activity, characterized by marked clinical deterioration in the either the rate or severity of relapses and/or new disease activity on MRI that is increased compared with pretreatment disease activity. Most cases of rebound have followed discontinuation of fingolimod [14] and natalizumab [15,16], while rare reports have implicated dimethyl fumarate [17] and teriflunomide [18].
Our experts generally advise minimizing delays between natalizumab or S1P modulators and the next DMT and tend to switch to anti-CD20 DMT in this context to avoid rebound (unless there are contraindications), although this has not been studied in the context of a randomized trial. Clear discussions with the patient of risks and benefits is warranted.
Some experts employ a monthly intravenous glucocorticoid bolus, typically 1000 mg of methylprednisolone, to potentially reduce the risk of rebound for patients who are stopping natalizumab or fingolimod. However, this is not a proven strategy, nor is it clear how long this strategy should be used.
RISK OF PML — Progressive multifocal leukoencephalopathy (PML) is rare, life-threatening neurologic disease of the central nervous system that is caused by the polyomavirus JC (JCV). PML has developed primarily in patients treated with natalizumab, but rare cases have been reported in patients treated with several other disease-modifying therapies (DMTs).
Natalizumab-associated PML — The risk of natalizumab-associated PML is increased in patients who are seropositive for anti-JCV antibodies, have prior immunosuppressant treatment, and/or are exposed to natalizumab for more than 24 months (figure 1). Surveillance for PML includes routine testing for JCV antibody status, clinical vigilance and neurologic follow-up, and magnetic resonance imaging (MRI) monitoring. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Surveillance for PML'.)
Treatment modifications to reduce the risk of PML with natalizumab treatment include extended interval dosing (eg, to every six weeks) or discontinuing natalizumab and switching to a different DMT, as discussed in the sections that follow. Extended interval dosing is reviewed separately. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Extended interval dosing'.)
When there is suspicion for PML, natalizumab should be discontinued. The management of natalizumab-related PML is discussed elsewhere. (See "Progressive multifocal leukoencephalopathy (PML): Treatment and prognosis", section on 'Natalizumab-associated PML'.)
JCV antibody status — We suggest testing for anti-JCV antibodies at baseline and every six months while on natalizumab therapy (table 1). While the risk of PML is extremely low in the first year on therapy, even for patients who are JCV seropositive, it is cumulative with ongoing exposure, so discontinuation earlier rather than later after determination of JCV antibody positivity probably reduces the risk of PML most effectively. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Surveillance for PML'.)
Discontinuation and switching — When natalizumab is discontinued because of an increased or unacceptable risk of PML, we suggest starting another DMT as soon as possible to reduce the risk of a severe rebound of MS disease activity. Some experts switch to a different high-efficacy DMT, such as B-cell depleting agents ocrelizumab or rituximab while others may switch to drugs of intermediate efficacy, such as dimethyl fumarate.
Careful planning is needed for a switch to another DMT. As mentioned, discontinuation of natalizumab can be associated with a severe rebound of MS disease activity, sometimes leading to permanent accrual of disability or to a severe reaction similar to the immune reconstitution inflammatory syndrome [19-22]. Thus, it is usually advisable to not have an extended planned "washout" period but, rather, to begin the next therapy immediately. In a randomized controlled trial of patients changing therapy from natalizumab to fingolimod, a shorter natalizumab washout period was associated with fewer MS relapses and new MRI lesions [23].
In our experience, transitioning to B-cell depleting DMTs in this context has not been associated with major breakthrough disease. However, we perform a careful evaluation for the possibility of subclinical PML prior to initiating a switch, particularly if switching another high-efficacy DMT with sustained effects on the immune system. In our practice, history, examination, and repeat brain MRI are required at a minimum; although no evidence basis exists to guide clinicians, we often discuss the pros and cons of lumbar puncture at this time to obtain JCV polymerase chain reaction (PCR) status. Further study is needed to optimize the period of transitioning off natalizumab.
Other DMTs associated with PML risk — There is a very low risk of PML associated with the use of sphingosine 1-phosphate receptor modulators (see "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'S1PR modulators') or fumarates (see "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Fumarates') to treat MS.
PREGNANCY — Guidance regarding the use of DMT during pregnancy, including the risk of continuing or discontinuing DMT, is reviewed elsewhere. (See "Multiple sclerosis: Pregnancy planning", section on 'Preconception planning and care'.)
Considerations regarding DMT use during breastfeeding are also reviewed separately. (See "Multiple sclerosis: Pregnancy and postpartum care", section on 'Breastfeeding and MS'.)
REASONS FOR STOPPING DMT — While there is no consensus, some experts believe it is reasonable to discuss discontinuation of disease-modifying therapy (DMT) for older patients with a remote MS diagnosis, particularly those who have had stable disease with no new relapses or magnetic resonance imaging (MRI) changes for a prolonged period [9,24]. Older patients (eg, older than 55 or 70 years in different studies) with relapsing-remitting multiple sclerosis (RRMS) are less likely to benefit from DMT than younger patients [25,26].
Other reasons for DMT discontinuation include intolerance, progression of MS, or lack of response to DMT [9]. Stopping DMT as part of pregnancy planning is common. (See 'Pregnancy' above.)
There are few data to inform decisions about stopping DMT. The multicenter DISCOMS trial, enrolled patients (age 55 years) with various types of MS on DMT with no relapse for five years and no new lesion on MRI for three years before study entry [27]. Patients were randomly assigned in a 1:1 ratio to continue or discontinue DMT. At two years, an MS relapse or a new or expanding T2 brain MRI lesion occurred in fewer patients in the continue group compared with the discontinue group (6/128 [4.7 percent] versus 16/131 [12.2 percent], risk difference 7.5 percent, 95% CI 0.6-15.0 percent). The difference favoring the continue group was primarily due to MRI activity, as the groups had similar rates of MS relapse (0.8 versus 2.3 percent) and confirmed disability progression (11.1 versus 12.3 percent). The results are not definitive due to trial limitations including the small number of outcome events, the relatively short-term (two-year) follow-up, and the high proportion of participants using older injectable DMTs.
The approach to DMT for patients who reach the stage of secondary progressive MS is reviewed elsewhere. (See "Treatment of secondary progressive multiple sclerosis in adults".)
COVID-19 PANDEMIC — Available data are limited but suggest that disease-modifying therapies (DMTs) for MS do not greatly increase the risk of developing symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or affect the severity of coronavirus disease 2019 (COVID-19) in patients who develop symptomatic disease. However, there are concerns about DMTs (eg, alemtuzumab, ocrelizumab, rituximab, cladribine, and others) that cause lymphocyte or B cell depletion, which may increase the risk of developing severe COVID-19. Patients on B cell depleting regimens (anti-CD20) may not develop a robust antibody response. Since the antibody response is not as robust, patients may be more susceptible to getting COVID, but a robust T-cell response is key to preventing serious disease [28]. These issues are reviewed separately. (See "Overview of disease-modifying therapies for multiple sclerosis", section on 'COVID-19 and DMTs'.)
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".)
SUMMARY AND RECOMMENDATIONS
●Some patients with relapsing-remitting multiple sclerosis (RRMS) have disease activity that is refractory to initial disease-modifying therapy (DMT). Any serious relapse, multiple relapses regardless of severity, or a pronounced increase in magnetic resonance imaging (MRI) activity with multiple contrast-enhancing lesions, particularly after more than a few months on therapy, should prompt a review of treatment options with a predisposition to change the DMT. Patient intolerance of adverse effects may also prompt a change in DMT. (See 'Breakthrough or refractory disease' above and 'Intolerance' above.)
●There is no standard protocol for changing DMT in patients with drug intolerance, relapses or clinically silent MRI lesions. Patients with breakthrough or refractory disease initially treated with less effective DMTs may benefit from switching to more effective DMTs, while patients initially treated with a highly effective DMT may be switched to a different highly effective DMT. (See 'Switching to a different DMT' above.)
●Discontinuation of certain DMTs, particularly fingolimod and natalizumab has been associated with a rebound of multiple sclerosis (MS) activity, characterized by marked clinical deterioration in the either the rate or severity of relapses and/or new disease activity on MRI. (See 'Risk of rebound of MS activity' above.)
●Progressive multifocal leukoencephalopathy (PML) is rare, life-threatening neurologic disease of the central nervous system that is caused by the polyomavirus JC (JCV). PML has developed primarily in patients treated with natalizumab, but rare cases have been reported in patients treated with several other DMTs. (See 'Risk of PML' above.)
●The risk of natalizumab-associated PML is increased in patients who are seropositive for anti-JCV antibodies, have prior immunosuppressant treatment, and/or are exposed to natalizumab for longer periods of time (table 2). Modifications to reduce the risk of PML with natalizumab treatment include extended interval dosing or, alternatively, discontinuing natalizumab and switching to a different DMT. We suggest testing for anti-JCV antibodies at baseline every six months while on natalizumab therapy. (See 'Natalizumab-associated PML' above and "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Surveillance for PML'.)
●For women who desire to become pregnant, the risk of possible adverse effects of DMTs on the fetus must be weighed against DMT discontinuation and increased risk of maternal disease relapses. Guidance regarding pregnancy planning for women with MS and the use of DMTs during pregnancy, the postpartum period, and breastfeeding is reviewed separately. (See "Multiple sclerosis: Pregnancy planning" and "Multiple sclerosis: Pregnancy and postpartum care".)
●It is reasonable to discuss DMT discontinuation for older patients with a remote MS diagnosis, particularly those who have had stable disease with no new relapses or MRI changes for a prolonged period. (See 'Reasons for stopping DMT' above.)
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