Diagnosis of MS

Recommendation 1: Use of the 2017 McDonald criteria ^{Reference Thompson, Banwell and Barkhof2}is recommended for the diagnosis of RMS and PPMS. McDonald criteria should only be applied to patients presenting clinically with events that are considered highly suspicious for CNS demyelination, after exclusion of reasonable alternative diagnoses.

A rapid and accurate diagnosis is essential to enable earlier initiation of treatment, which has been shown to be associated with better outcomes in patients with their first attack of MS, or “clinically isolated syndrome” (CIS), and RMS.^{Reference Kappos, Freedman and Polman4,Reference Freedman, Comi and De Stefano5} Use of the 2017 McDonald criteria enables more first-attack patients to be diagnosed with RMS at baseline with greater sensitivity but with lower specificity.^{Reference van der Vuurst de Vries, Mescheriakova and Wong6} A major concern of the International Panel (IP) developing the McDonald criteria was misdiagnosis of MS, most notably in patients with nonspecific neurological signs and atypical findings on magnetic resonance imaging (MRI).^{Reference Thompson, Banwell and Barkhof2,Reference Calabrese, Gasperini and Tortorella7} For that reason, the IP recommended the use of cerebrospinal fluid (CSF) analysis to help eliminate other conditions that may mimic MS if there are atypical findings or diagnostic uncertainty. The classical finding of CSF-specific oligoclonal banding (OCB), which demonstrates the existence of an inflammatory process within the CNS, is now recognized as being the result of long-term intrathecal stimulation of immunoglobulin (Ig) production and can thus substitute for other requirements in the diagnostic criteria for “dissemination in time”.

Accordingly, the CMSWG recommends that, first and foremost, the McDonald criteria only be applied to patients presenting clinically with events that are considered highly suspicious for CNS demyelination, and that MRI or CSF findings should always be interpreted by clinicians with expertise in MS, after exclusion of reasonable alternative diagnoses. An MRI should be obtained promptly, ideally within 1 week of the initial presentation.^{Reference Traboulsee, Létourneau-Guillon and Freedman8} Use of a gadolinium (Gd) contrast agent with MRI is recommended in patients presenting with their first clinical attack. This can facilitate an earlier diagnosis of MS by demonstrating new (Gd-enhancing) and older lesions, thus fulfilling the requirements for demonstrating “dissemination in time”, and can help to rule out other non-MS conditions. Cortical lesions can be used to show “dissemination in space” but are difficult to identify with conventional MRI sequences used in clinical care.

It should be noted that newer MRI techniques (e.g., susceptibility-weighted imaging), including the “central vein sign”^{Reference Sati, Oh and Constable9}) are emerging that may further improve the specificity of current criteria by enabling the differentiation of white matter lesions that are more likely to be MS-type plaques.

The Magnetic Resonance Imaging in Multiple Sclerosis research network has proposed including paraclinical evidence of optic nerve lesions (MRI, visual evoked potentials, or optical coherence tomography [OCT]) to fulfill criteria for dissemination in space.^{Reference Filippi, Preziosa and Meani10} Although not currently recommended,^{Reference Thompson, Banwell and Barkhof2} identifying asymptomatic optic nerve involvement in patients with optic neuritis may be relevant as supportive evidence in selected cases. Bilateral optic neuritis and poor recovery from attacks would be more suggestive of a neuromyelitis optica spectrum disorder or myelin oligodendrocyte glycoprotein (MOG) antibody-related disease.

CSF studies are useful to identify atypical findings (e.g., significantly elevated protein concentration, pleocytosis with >50 cells/µl, or the presence of neutrophils, eosinophils, and atypical cells) that would suggest an alternative diagnosis.^{Reference Stangel, Fredrikson, Meinl, Petzold, Stüve and Tumani11} At present, agarose gel electrophoresis with isoelectric focusing and immunoblotting or immunofixation for immunoglobulin-G (IgG) is the most sensitive and accepted method of OCB testing.^{Reference Thompson, Banwell and Barkhof2} The CMSWG recommends that CSF studies be performed only by highly qualified laboratories. Routine testing for aquaporin-4 IgG (AQP4-IgG) or MOG antibodies is not recommended in adult patients with typical MS findings.^{Reference Jarius, Paul and Aktas12}

At present, the radiologically isolated syndrome (RIS), or the incidental finding of MS-like lesions in the absence of clinical signs or symptoms of MS, is not considered an MS phenotype and treatment is generally not indicated. However, it should be noted that an estimated 50% of individuals with RIS will subsequently develop MS, including PPMS.^{Reference Lebrun-Frenay, Kantarci and Siva13} Predictors of a future clinical event include spinal cord lesions, OCB in the CSF, and demographic factors (male sex, age < 37 years);^{Reference Lebrun-Frenay, Kantarci and Siva13–Reference Makhani, Lebrun and Siva15} MRI lesions demonstrating the “central vein sign” may also have prognostic value.^{Reference Suthiphosuwan, Sati and Guenette16}

The McDonald criteria can also be used to diagnose POMS. Pediatric MS will be addressed in a separate section below.

Treatment Initiation – Relapsing MS

Recommendation 2: All RMS patients should be encouraged to start treatment with a DMT soon after diagnosis to reduce their risk of disability worsening and to improve long-term outcomes.

The principal objective of treatment is to delay or prevent disability accrual by reducing the frequency of relapses and MRI lesions. Selected RIS cases at high risk of a clinical event may be considered for therapy;^{Reference Tornatore, Phillips, Khan, Miller and Hughes17,Reference Alshamrani, Alnajashi and Freedman18} this recommendation is controversial and ongoing studies will clarify this issue. With respect to CIS, injectable^{Reference Jacobs, Beck and Simon19–Reference Comi, De Stefano and Freedman23} and oral^{Reference Miller, Wolinsky and Kappos24,Reference Leist, Comi and Cree25} DMTs have been shown to slow the development of RMS by reducing the chances of having relapses, MRI lesions, or disease progression, an effect that appears to be sustained during long-term follow-up. While new diagnostic criteria now categorize many CIS patients as having MS, treatment benefits have been demonstrated even in contemporary CIS cohorts (i.e., not fulfilling 2017 McDonald criteria at their first attack),^{Reference Freedman, Leist and Comi26} and some of these patients can be offered therapy. The impact of early treatment on longer-term disability outcomes is less certain.^{Reference Kinkel, Dontchev and Kollman27–Reference Miller, Vermersch and Kappos29}

All DMTs used for CIS, as well as other DMTs approved as initial therapies, have demonstrated efficacy in the relapsing phase of MS to reduce relapses and MRI lesion development and, in some cases, to slow disease progression, as measured by the Expanded Disability Status Scale (EDSS).^{30–Reference Hauser, Bar-Or and Comi37} Treatment within the first 2 years after diagnosis has been shown to produce sustained benefits compared to delayed treatment.^{Reference Chalmer, Baggesen and Nørgaard38–Reference Iaffaldano40} A database analysis by the MSBase Study Group reported a significant reduction in the risk of developing SPMS when an injectable DMT was started within 5 years of disease onset.^{Reference Brown, Coles and Horakova39} The Big MS Data Network, which pools data from MSBase and several European patient registries, found that the optimal time to start DMTs to prevent accumulation of long-term disability was within the first 6 months after disease onset.^{Reference Iaffaldano40} The caveat is that these analyses of large, uncontrolled patient populations do not constitute high-quality evidence.^{Reference Gliklich, Dreyer and Leavy41}

Although the primary evidence for all currently available MS treatments is as first-line therapy, in Canada, the DMTs approved for use as starting treatment (base therapy) are five injectable agents (glatiramer acetate, interferon-β-1a [three formulations], and interferon-β-1b) and two oral agents (teriflunomide and dimethyl fumarate). One MAb (ocrelizumab) has recently been approved in Canada for initial therapy in patients with more aggressive presentations.

Few studies have directly compared injectable and oral DMTs.^{Reference Mikol, Barkhof and Chang42–Reference Vermersch, Czlonkowska and Grimaldi44} Although a recent network meta-analysis suggested that pegylated interferon-β-1a and dimethyl fumarate have superior efficacy to other base therapies,^{Reference Li, Hu, Zhang and Li45} there are insufficient data to demonstrate that one base injectable or oral DMT is superior to another. As a result, the choice of treatment will need to be individualized according to disease activity, severity, and comorbidities. After apprising the patient of all available treatment options, discussion will be needed to ascertain the patient’s preferences (e.g., side effect profile, oral vs. injectable), risk tolerance, and other factors that may influence treatment selection.

In addition to the base therapies, there are five DMTs available in Canada considered to be higher efficacy: two oral agents (fingolimod and cladribine) and three MAbs (natalizumab, ocrelizumab, and alemtuzumab). All have demonstrated significant efficacy in phase III trials.^{Reference Giovannoni, Comi and Cook35,Reference Hauser, Bar-Or and Comi37,Reference Polman, O’Connor and Havrdova46–Reference Cohen, Coles and Arnold48} Higher-efficacy agents have been commonly studied as initial therapies but are generally reserved for patients with a poor response or tolerability with a base therapy. Escalating to the use of these agents requires assessment and determination of suboptimal response (see below). Some of these agents should be considered as initial or induction therapies for patients presenting with high disease activity, aggressive or rapidly evolving MS at onset. However, the strategy of treatment initiation with a base therapy, with the view to switching within 6–12 months to one of the higher-efficacy DMTs, is the most commonly and conservatively applied one today for most patients.

Recommendation 3: Risk stratification, based on demographic and clinical factors known to be associated with early disease worsening, should be performed for individual patients at first presentation and on an ongoing basis. This will assist clinicians in developing an appropriate treatment plan in consultation with patients and enable prompt optimization of the regimen as required.

Patients at risk of a more aggressive clinical course, worse outcomes, and/or a poorer response to DMTs include males, individuals of non-White ethnicity, and those with high-risk clinical/radiological disease factors (Table 1).^{Reference Damasceno, Von Glehn, Brandão, Damasceno and Cendes49–Reference Fisniku, Brex and Altmann51} There is some evidence to suggest that obesity, smoking, and certain comorbidities (e.g., rheumatoid arthritis, vascular disease, and psychiatric disorders) may be associated with more active disease or worse outcomes,^{Reference Manouchehrinia, Hedström, Alfredsson, Olsson, Hillert and Ramanujam52–Reference McKay, Tremlett and Fisk54} but this requires further study.

Table 1: Demographic and clinical/radiological factors that may be associated with a worse prognosis in MS patients at diagnosis

Evidence of highly active disease (e.g., frequent relapses and new MRI lesions), extensive CNS involvement (multifocal, lesion number and location, and T2 burden of disease), and/or inadequate recovery/repair (residual impairment, higher baseline EDSS score) or cognitive reserve are prognostic of a worse clinical course and poorer long-term outcomes in CIS and RMS.^{Reference Tomassini, Fanelli, Prosperini, Cerqua, Cavalla and Pozzilli55,Reference Spelman, Meyniel and Rojas56} It has been suggested that demographic factors have a lower impact on prognosis than clinical/radiological factors but may modulate the phenotypic expression of disease activity.^{Reference Tintore, Rovira and Río57} For example, one database analysis found that men were more likely to have pyramidal, brain stem, and cerebellar relapses, which were associated with worse outcomes; women more commonly had sensory or visual symptoms, which showed better recovery; and older patients had poorer recovery from relapses.^{Reference Kalincik, Buzzard and Jokubaitis58}

Considerable progress has been made in researching the prognostic value of biomarkers of axonal damage and neurodegeneration, such as neurofilament-light chain in CSF or serum, glial fibrillary acidic protein in CSF, and retinal nerve fiber layer thickness on OCT.^{Reference Novakova, Axelsson and Malmeström59} While the results to date are promising, it is premature to recommend biomarker testing as a guide to clinical decision-making.^{Reference Rotstein and Montalban60,Reference Harris and Sadiq61}

The initial clinical assessment will include a complete patient history, neurological examination and consideration of prognostic factors. An MRI is recommended. Other paraclinical testing may include OCBs in CSF; examination of the visual system (e.g., evoked potentials, OCT) will help to characterize demyelination and may be useful in diagnosis and prognosis.^{Reference Heidari, Radcliff and McLellan62–Reference Kim, Kim, Park and Jeong64} These measures may help to identify patients at higher risk of early worsening who may be candidates for a more aggressive treatment plan – either initiation with a higher-efficacy agent, or closer monitoring and earlier planned escalation. A patient’s risk status may become more apparent in the first few years after diagnosis so vigilance is needed to identify ongoing disease activity that may necessitate a prompt change to a more effective agent.

Recommendation 4. The treatment plan should consider the patient’s general health status including comorbidities. Wellness efforts, such as smoking cessation, weight reduction, and regular physical activity, should be encouraged. Vitamin D supplementation (600–4000 IU/day) may provide some added clinical benefit.

The patient’s general health status is important to consider during treatment planning. Medical and psychiatric comorbidities are highly prevalent in the MS population^{Reference Zhang, Tremlett and Leung65} and may be associated with relapses, worsening disability, and poorer quality of life.^{Reference Kowalec, McKay and Patten66–Reference Conway, Thompson and Cohen69} The presence of comorbid conditions will also be an important consideration during treatment selection and optimization. Clinicians need to work in collaboration with other healthcare providers, including the patient’s family physician, to ensure that other medical conditions are being adequately managed.^{Reference Marrie70}

Patients with MS should be encouraged to adopt a healthier lifestyle as part of the overall disease management strategy. There is some evidence to suggest that smoking cessation, avoidance of obesity, a balanced diet, and regular physical activity may reduce symptoms and improve clinical and radiological outcomes.^{Reference Degelman and Herman71-Reference Esposito, Bonavita, Sparaco, Gallo and Tedeschi73} Vitamin D supplementation has been shown to be beneficial in some but not all studies:^{Reference Løken-Amsrud, Holmøy and Bakke74–Reference Kampman, Steffensen, Mellgren and Jørgensen77} a dose of 600–4000 IU/day is recommended as add-on therapy with a DMT.⁷⁸

Treatment Initiation – Primary Progressive MS (PPMS)

Recommendation 5: Clinicians with experience in treating patients with PMS should offer ocrelizumab to PPMS patients with active disease (relapses and/or MRI activity) provided the benefits outweigh the risks.

The diagnosis of PPMS should be based on the 2017 McDonald criteria of 1 year of disability progression determined prospectively or retrospectively, with two of the following criteria: ≥1 T2 lesions (periventricular, cortical, juxtacortical, and infratentorial); ≥2 T2 lesions in the spinal cord; and presence of CSF-specific OCBs.^{Reference Thompson, Banwell and Barkhof2} MRI lesions may be symptomatic or asymptomatic.^{Reference Thompson, Banwell and Barkhof2} The clinical course should be determined annually using the modifiers “active” with or without progression, and “not active” with or without progression, with activity defined as clinical relapses and/or new or enlarging MRI lesions.^{Reference Lublin3} Some DMTs have demonstrated modest effects on progression, most notably in younger PPMS patients (<51 years) with ongoing overt inflammatory activity.^{Reference Montalban, Hauser and Kappos79,Reference Hawker, O’Connor and Freedman80} It is unclear if these agents influence long-standing progression or modify the pathophysiology of progression unrelated to focal inflammation, which may include progression as a result of normal aging.

At present, ocrelizumab is the only approved DMT that has been shown to be effective in PPMS. The agent should be offered to PPMS patients with active disease (relapses and/or MRI activity) based on the results of a phase III study, which reported a relative 25% reduction in 6-month confirmed disability progression (CDP) versus placebo (i.e.,29.6% vs. 35.7%, respectively).^{Reference Montalban, Hauser and Kappos79} Patients without active inflammatory changes but worsening disability progression may also be candidates for treatment. Early intervention is recommended since it is likely that the benefits of therapy are greatest in the first few years of disease onset and treatment will be less effective later in the disease course. Ocrelizumab is also recommended in PPMS patients with active disease with upper limb impairment.^{Reference Fox, Markowitz and Applebee81} Treatment can be considered regardless of the patient’s age, duration of PPMS, pyramidal functional score, or EDSS score, although younger (<51 years), more recently diagnosed patients with active inflammatory disease are more likely to have a better response.^{Reference Montalban, Hauser and Kappos79} Caution is recommended when considering treatment for PPMS subgroups that are less likely to benefit from treatment, such as older patients, those with long-standing stable disease (not active, without progression) and/or significant neurological deficits, since the limited benefits may not justify the risks associated with treatment.

Rituximab, an anti-CD20 MAb, may be considered as an alternative therapy for PPMS in regions that permit off-label use in MS due to cost or other considerations. This recommendation is based on a post hoc analysis of a phase II/III trial that showed a significant reduction in time to 3-month CDP in the subgroup of patients aged < 51 years and/or with Gd-enhancing lesions;^{Reference Hawker, O’Connor and Freedman80} results should be viewed with caution since the overall trial results were negative. (Treatment initiation in SPMS will be discussed below.)

Evaluating Treatment Response

Treatment optimization is founded on the principles of prompt recognition of an inadequate response to a given DMT in an individual patient, either due to lack of efficacy or poor tolerability, and a switch to a more effective therapy when required. Unfortunately, there is a lack of consensus on how to define an adequate treatment response. Several CSF or serum biomarkers of disease activity and treatment response have been proposed but have not been sufficiently validated for use in clinical practice.

In consequence, clinicians must infer a treatment response according to the level of disease activity, as demonstrated by relapses and/or active MRI lesions, after a treatment has been initiated. The rationale for this approach is the finding that ongoing relapses and active lesions over the short term are predictive of disability worsening in patients treated with interferon-β, teriflunomide, and fingolimod.^{Reference Sormani, Li and Bruzzi82-Reference Boster, Hawker and Ritter85} Attaining no evidence of disease activity (NEDA), defined as no relapses, no EDSS worsening, and no MRI lesion activity, is an ideal goal but is difficult to achieve in practice. Most patients will not achieve NEDA even with a high-efficacy DMT,^{Reference Havrdová, Galetta and Hutchinson86–Reference Coles, Twyman and Arnold90} and the NEDA rate will invariably decline during the course of treatment.^{Reference Rotstein, Healy, Malik, Chitnis and Weiner91} NEDA has been criticized as not reflecting the underlying pathophysiology of MS,^{Reference Hegen, Bsteh and Berger92} and the predictive value of NEDA for long-term disability outcomes has been questioned.^{Reference Goodin, Reder and Traboulsee93,Reference Cree and Gourraud94} Thus, patients and clinicians will need to tolerate some minimal evidence of disease activity (MEDA), a term that has not been adequately defined. In studies to date, minimal evidence of MRI activity (< 3 new T2 or < 2 Gd+ lesions) was not predictive of EDSS worsening over a 6.7-year follow-up.^{Reference Río, Rovira and Tintoré95} However, a retrospective analysis reported that the long-term risk of disability (EDSS ≥ 6) was similar with NEDA and MEDA, when MEDA was defined as no relapses, <3 new T2 lesions, and no Gd+ lesions in the first year of treatment.^{Reference Prosperini, Mancinelli and Haggiag96} Additional studies using different definitions of MEDA are required.

Consequently, there is a need to better define what sort of ongoing disease activity indicative of a suboptimal response is of greater clinical concern. The following summarizes the different domains considered by the CMSWG and recommendations as to when a treatment regimen needs to be optimized.

Relapses

Recommendation 6: The therapeutic response should be evaluated early in RMS patients to determine the benefit of therapy within the first 2 years after DMT initiation. Treatment response should also be continuously evaluated at regular intervals thereafter. Efficacy assessments should be based on at least two time points using clinical and radiological outcomes. It is recommended that treatment be switched in the first 2 years when there is clear evidence of a suboptimal response.

A relapse is defined according to 2017 McDonald criteria: a clinical episode with patient-reported symptoms and objective findings typical of MS reflecting a focal or multifocal inflammatory demyelinating event in the CNS, developing acutely or subacutely, with a duration ≥ 24 hours, with or without recovery, and in the absence of fever or infection.^{Reference Thompson, Banwell and Barkhof2} In unclear cases of new or recurrent neurologic symptoms sustained < 24 hours (e.g., Lhermitte’s symptom, trigeminal neuralgia and cognitive impairment), a relapse may be confirmed by ≥1 new localizing MRI lesions.

A number of analyses have shown that frequent relapses in the first 2 years after diagnosis are prognostic of poorer disability outcomes during long-term follow-up.^{Reference Río, Rovira and Tintoré95–Reference Bermel, You and Foulds98} On-treatment “breakthrough” relapses appear to be more predictive of worse outcomes than relapses in untreated patients.^{Reference Jokubaitis, Spelman and Kalincik99} Even minimal ongoing disease activity in the 1–2 years after treatment initiation is highly predictive of disability worsening.

The clinical assessment should consider relapse severity and recovery, both of which have been associated with subsequent severe events and poorer outcomes in some but not all studies.^{Reference Mowry, Pesic, Grimes, Deen, Bacchetti and Waubant100,Reference Naldi, Collimedaglia and Vecchio101} This will require a clinical evaluation, if possible during an attack as well as 3–6 months post-attack, to ascertain the degree of recovery. It may be useful to assess the impact of relapses on work/school attendance and daily functioning as an indicator of relapse severity. The phenotype of on-treatment relapses should also be evaluated: relapses affecting bowel/bladder, cerebellar, pyramidal, and brain stem function have been reported to have the greatest impact on disability accrual.^{Reference Stewart, Spelman and Havrdova102}

Accordingly, on-treatment relapses may be stratified as being of Major or Minor concern (Table 2). Minor criteria generally co-occur (e.g., one mild relapse with one new lesion and no functional limitation); a change in therapy may be considered if a Minor criterion (e.g., one mild relapse) is associated with a second worrisome sign (e.g., two new lesions or a lesion of significant size). Patients meeting any of the Major criteria should be considered to have a suboptimal response, and an immediate change in treatment is recommended. It is important to note that evaluation of on-treatment relapses should only be performed once the drug has achieved a full clinical effect; the time to clinical effect is typically 2–6 months after drug initiation and will differ depending on the DMT used (Table 3). Relapses that occur before the maximal efficacy of the drug has been reached should be given less weight.

Table 2: Recommended criteria for switching therapies in RRMS. A change in DMT is indicated for patients who meet any of the Major criteria

* >1.5 points if baseline EDSS 0. If baseline EDSS >5.5, any EDSS change would be a Major concern.

** >1 spinal cord lesions may warrant a Major concern.

Table 3: Time to effect of disease-modifying therapies. Treatment response should be evaluated after the full clinical effect has been attained

The same criteria apply for switching therapies in years 2–10 of treatment although the evidence that on-treatment relapses are predictive of disability worsening after >2 years on therapy is less robust. Re-dosing may be warranted in patients who have received a 2-year course of treatment with an immune reconstitution therapy (cladribine and alemtuzumab) followed by a period off treatment. In such cases, a return of relapse activity may be attributable to a wearing off of the drug’s pharmacodynamic effects or an inadequate overall dose.

Treatment Sequencing

Recommendation 11. Most RMS patients can be expected to require more than one DMT during the treatment course to control their disease and limit worsening disability. Escalation to a higher-efficacy therapy is generally recommended for treated patients who meet a Major criterion (Table 2). When sequencing therapies, clinicians should recognize that a given therapy may have an impact on future treatment choices. Prior to initiating treatment, the clinician should develop a plan as to how medications might be sequenced so that safety concerns or other factors will not limit subsequent treatment options or delay the initiation of the next DMT.

After initiating a DMT, there is a need for close monitoring and early detection of breakthrough disease activity with the view to early escalation to a more effective therapy, if required. Clinicians should recognize the presence of negative prognostic factors (Table 1) and be prepared to act early by switching to a more effective DMT in these higher-risk individuals. A new baseline MRI on treatment is recommended (see Recommendation 8). Clinical response should be evaluated at 6–12 months after DMT initiation since ongoing disease activity is associated with poorer outcomes. The association of early breakthrough disease and disability accrual is strongest in the first 2 years on therapy but remains predictive for 5 years after treatment initiation.^{Reference Scalfari, Neuhaus and Degenhardt97,Reference Jokubaitis, Spelman and Kalincik99}

Escalation to a higher-efficacy therapy is generally recommended for treated patients who meet a Major criterion (Table 2) indicative of breakthrough disease activity or severity.^{Reference Chalmer, Kalincik, Laursen, Sorensen and Magyari142} A DMT with a different mode of action may be preferred. A lateral switch from one base therapy (injectable or oral) to another may be considered in patients with poor tolerability/adherence. However, the need to switch provides clinicians with an opportunity to escalate therapy to improve efficacy, which may be preferable, especially in patients with negative prognostic factors.

There are few clinical concerns when switching patients from a base therapy to a higher-efficacy DMT. A washout period, that is, a period off treatment to allow the drug to clear and physiologic parameters to normalize, will generally not be required. Blood test results (e.g., lymphocyte count, hepatic enzymes) should be in the normal range before the next treatment is initiated. When discontinuing teriflunomide, an active elimination protocol is used to wash out the drug. Vigilance for PML is recommended for patients switching from DMTs with a known risk of PML (dimethyl fumarate, fingolimod, natalizumab, and ocrelizumab). A lumbar puncture may be considered to rule out John Cunningham virus (JCV) in CSF, especially if switching from one of these medications to a potent immunosuppressive drug, such as cladribine or alemtuzumab.

There are no phase III studies to date comparing higher-efficacy therapies. Thus, the choice of higher-efficacy agent will depend on the severity of ongoing disease activity, and the relative benefits and risks of the therapy as evaluated by the clinician and patient. Two treatment approaches are available: continuous immunomodulation (natalizumab, fingolimod, and ocrelizumab) and intermittent immunomodulation with immune reconstitution (cladribine and alemtuzumab), with both approaches associated with a somewhat unique risk profile.

Natalizumab, which blocks immune cell trafficking into the CNS, is often employed as a rescue therapy in patients with aggressive MS due to its high efficacy and rapid onset of action. It can generally be used for up to 18 months regardless of JCV antibody status or JCV Ab index. The drug can be maintained thereafter in patients who are JCV Ab-negative, with close monitoring of JCV serostatus every 3–6 months and clinical/MRI vigilance for PML. JCV Ab-positive patients can continue on natalizumab up to 24 months if the JCV Ab index value ≤ 0.9 but caution is advised if treatment is maintained beyond 24 months. If the regimen is continued, it is important to include in the clinical notes that the patient has acknowledged the increasing risk of PML with cumulative drug exposure and has agreed to close clinical/MRI surveillance. JCV Ab+ patients on natalizumab >2 years will generally be switched to another DMT, ideally during a period of stable disease. Extended interval dosing (300 mg q6–8 weeks) with natalizumab has been proposed as a means of possibly reducing PML risk;^{Reference Zhovtis Ryerson, Frohman and Foley143} PML cases have still been reported with extended interval dosing,^{Reference Scarpazza, De Rossi, Tabiadon, Turrini, Gerevini and Capra144} and patients must be fully informed of the risk of PML. All patients will require a screening MRI when discontinuing natalizumab; a lumbar puncture to detect JCV DNA in CSF may be considered. The risk of disease reactivation after natalizumab discontinuation may be mitigated somewhat if treatment is switched during a period of relative disease quiescence or if the transition time is < 1–2 months.^{Reference Prosperini, Kinkel, Miravalle, Iaffaldano and Fantaccini145,Reference Vollmer, Honce and Sillau146} There are limited data that switching from natalizumab to alemtuzumab is more effective than to fingolimod.^{Reference Pfeuffer, Schmidt and Straeten147} However, switching from natalizumab to any DMT with a long duration of action may be considered a high-risk approach since treatment could not be withdrawn in such circumstances if the patient had subclinical PML.

Fingolimod, which sequesters lymphocytes in secondary lymphoid organs, may also be considered when there is a need to switch to a higher-efficacy therapy. The principal safety concerns are the risk of opportunistic infections associated with chronic immunosuppression, and clinical worsening on drug discontinuation reported in some but not all studies.^{Reference Fragoso, Adoni and Gomes148,Reference Vermersch, Radue, Putzki, Ritter, Merschhemke and Freedman149} There are few data on sequencing from fingolimod to other high-efficacy DMTs. There have been case reports of clinical worsening after switching from fingolimod to ocrelizumab, rituximab, or alemtuzumab.^{Reference Schmidt and Schulten150–Reference Bernard-Valnet, Pignolet and Biotti152} Conversely, there are reports that rituximab and alemtuzumab are effective in patients with an inadequate response to fingolimod,^{Reference Huhn, Bayas and Doerck153,Reference Alcalá, Gascón, Pérez-Miralles, Domínguez, Gil-Perotín and Casanova154} although persistent T cell depletion may occur after a fingolimod–alemtuzumab switch.^{Reference Cabrera-Maqueda, Fuentes-Rumí and Carreón-Guarnizo155}

A washout period has traditionally been recommended when switching among second-line agents to allow lymphocyte counts and other indices (e.g., liver enzymes) to return to normal. The caveat is that anti-trafficking drugs, such as fingolimod and natalizumab, are prone to disease “rebound” in the first 3–6 months after cessation, so a washout period <3 months is generally advised. It should be noted that when switching from fingolimod to alemtuzumab, lymphocyte counts should return to normal since alemtuzumab may be less effective if initiated when lymphocytes are still sequestered in secondary lymphoid organs.

A preferred approach when sequencing from a base therapy may be to switch to a cell-depleting agent (cladribine, ocrelizumab, and alemtuzumab). Cladribine is an oral drug that is administered for 8–10 days per year for 2 years (cumulative dose 3.5 mg/kg) and which produces significant suppression of T and B cells. The main safety consideration is moderate-to-severe lymphopenia, which may be minimized if treatment is initiated in patients with a normal lymphocyte count (grade 0 lymphopenia at start, grade 1 prior to Year 2 dosing).¹⁵⁶ There is no reported increase in infections with the exception of herpes zoster.^{Reference Cook, Leist and Comi157} After the 2-year course of treatment, patients with an adequate response to cladribine who subsequently experience breakthrough disease may be re-dosed with cladribine or switched to another DMT.^{Reference Giovannoni, Soelberg Sorensen and Cook158} There are no data on the optimal strategy nor on the safety and efficacy of sequencing cladribine with other agents.

Ocrelizumab is an anti-CD20 MAb that is dosed every 6 months to produce chronic suppression of B cells. Infusion-related reactions are common but generally mild to moderate in severity.^{Reference Mayer, Kappos and Racke159} There is an increased risk of infections (upper respiratory tract, urinary tract, and herpes zoster) but no reported increase in opportunistic infections.^{Reference Hauser, Bar-Or and Comi37} PML has rarely occurred; a small number of cases have been reported after switching from a high-efficacy therapy, and one case has been reported in an older patient who was previously untreated.^{Reference Manners160} There have been case reports of hepatitis B virus reactivation during therapy.^{Reference Ciardi, Iannetta and Zingaropoli161} Treatment for up to 6 years has been reported to be effective.^{Reference Giovannoni, Kappos and Hauser162} An emerging concern is that chronic B cell suppression with ocrelizumab or rituximab has been associated with cases of hypogammaglobulinemia.^{Reference Derfuss, Weber and Hughes163,Reference Makatsori, Kiani-Alikhan and Manson164} There are no published data on the safety or efficacy of sequencing DMTs in patients with an inadequate response to ocrelizumab.

Alemtuzumab is an anti-CD52 MAb administered for 8 treatment days over 2 years, which results in profound T and B cell suppression. T cell depletion is sustained for several years, whereas B cells hyper-repopulate within 6–9 months.^{Reference Baker, Herrod, Alvarez-Gonzalez, Giovannoni and Schmierer165} About 90% of patients experience infusion reactions despite pretreatment with corticosteroids, antipyretics, and antihistamines.^{Reference Cohen, Coles and Arnold48} Thyroid disorders are very common; other secondary autoimmunities are less common. Prolonged T cell suppression is also associated with a risk of infections, including serious opportunistic infections.^{Reference Buonomo, Zappulo, Viceconte, Scotto, Borgia and Gentile166} A further concern is the occurrence of ischemic or hemorrhagic stroke and cervical arterial dissection, which has necessitated a change to the US product label.¹⁶⁷ The effectiveness of a 2-year treatment course has been demonstrated for up to 9 years.^{Reference Montalban, Arnold and Boyko168} Patients who experience a return of disease activity may benefit from a third course of treatment.^{Reference Schippling, Bass and Boster169} There are limited data on switching patients to another DMT. B cell-directed therapy has been proposed for patients with B cell-mediated disease activation or autoimmunity associated with alemtuzumab treatment,^{Reference Hyun, Kim, Kim, Kim and Kim170–Reference Massey, Barnett, Curnow and Sutton172} but additional data are required.

Autologous hematopoietic stem cell transplantation (AHSCT) may be considered relatively early in the treatment course for younger patients (18–31 years^{Reference Tornatore, Phillips, Khan, Miller and Hughes173}) with rapidly evolving MS. Preliminary data suggest that in patients with an inadequate response to a DMT, AHSCT may be more effective than a switch to another DMT,^{Reference Burt, Balabanov and Burman174} although it should be noted that in that study, some higher-efficacy agents (ocrelizumab and alemtuzumab) were not included. AHSCT may also be considered in patients with early aggressive disease with a poor prognosis or worsening disability despite treatment with a higher-efficacy DMT.^{Reference Rush, MacLean and Freedman175}

Treatment of Secondary Progressive MS

Recommendation 13. Ongoing treatment of patients transitioning to SPMS who still have active inflammatory disease is recommended. Use of siponimod, now approved in Canada, may be considered. Consider stopping treatment in patients with SPMS characterized by progression without inflammatory disease activity, with close monitoring to identify breakthrough inflammatory disease activity.

SPMS is defined as progressive accumulation of disability after an initial relapsing course and may be categorized as active with or without progression, not active with progression, and not active without progression (stable disease).^{Reference Lublin3} A careful assessment of relapses is needed since pseudorelapses are very common in PMS.

There are several unknown factors regarding the treatment of SPMS. There are no data on the potential benefits of continuing a higher-efficacy DMT after SPMS onset and it is unclear if the current DMT should be maintained after the transition to SPMS. Clinical trials of higher-efficacy agents (e.g., natalizumab, alemtuzumab, and fingolimod) have demonstrated limited or no benefit in patients with progressive disease.^{Reference Kapoor, Ho and Campbell190–Reference Lublin, Miller and Freedman192}

It is generally advised to continue with the current DMT after the onset of SPMS since many patients will have ongoing inflammatory disease;^{Reference Luchetti, Fransen, van Eden, Ramaglia, Mason and Huitinga193,Reference Frischer, Weigand and Guo194} subclinical disease activity may worsen if treatment is withdrawn. A change in treatment may be warranted in patients with active SPMS who continue to have relapses or new MRI lesions, with the caveat that there is insufficient evidence to identify criteria for a suboptimal response in patients with SPMS. Accordingly, the CMSWG recommends that the current DMT should be maintained or treatment should be escalated, in patients who transition to SPMS who continue to have active disease (relapses, new MRI lesions). Treatment may be maintained but should not be initiated in those with stable (no relapses or disability progression) SPMS.

Siponimod, a selective sphingosine 1-phosphate receptor-1,5 modulator, has been approved in Canada and other countries for active SPMS;¹⁹⁵ approval was based on the results of a phase III trial demonstrating a relative 21% reduction in 3-month CDP versus placebo (i.e.,CDP 26% vs. 32%, respectively).^{Reference Kappos, Bar-Or and Cree196} Use of siponimod, may be considered for the treatment of patients with active SPMS. At present, there are no data on whether patients on another DMT during the transition to SPMS would benefit from a switch to siponimod.

Oral cladribine, a purine analog, has also been approved in some countries (not Canada) for active SPMS,¹⁹⁷ based on preliminary results from randomized trials of injectable formulations.^{Reference Rice, Filippi and Comi198,Reference Beutler, Sipe, Romine, Koziol, McMillan and Zyroff199} At present, oral cladribine is generally not recommended for the treatment of non-active PMS. There are no data on whether cladribine-treated patients who transition to SPMS would benefit from continuing on the regimen or switching to siponimod or another high-efficacy DMT.

Safety and Other Considerations

Recommendation 14. Shared decision-making is important when selecting the optimal treatment for individual patients. The potential benefits of specific DMTs must be weighed against the risk of short- and long-term adverse effects associated with that agent. All patients must be fully informed of the potential risks associated with treatment before a DMT is initiated.

The safety of DMTs derives primarily from data obtained in clinical trials and real-world observations, which provide a clearer picture of potential short-term than of long-term adverse effects. New adverse events do emerge in the post-marketing period, and it is important that clinicians exercise caution with newer agents and report adverse events to regulatory authorities. This is especially important now that many patients will be exposed to more than one DMT during their treatment course, and the risk of cumulative toxicities with sequential therapy is largely unknown. Neurologists will need to become familiar with autoimmune, infectious, and oncologic conditions and be prepared to face still unknown complications.

All patients must be fully informed of potential adverse effects and possible long-term toxicities associated with treatment.^{Reference Ayrignac, Bilodeau and Prat204} Clinicians should document that patients have acknowledged potential risks. When switching to a higher-efficacy DMT, they must agree beforehand to adhere to the pretreatment protocol and safety monitoring requirements for that drug.

Other Issues

Recommendation 15. Female MS patients of childbearing age should use a reliable method of contraception. Discontinuation of DMTs is generally recommended prior to conception.

Clinicians and patients need to develop a pregnancy plan that would enable a period of treatment to stabilize disease while avoiding potentially harmful drug effects on the fetus. A few months of treatment and stabilization of disease in an active patient prior to pregnancy may reduce the risk of postpartum relapse.^{Reference Hughes, Spelman and Gray205} Pregnancy would ideally be scheduled for a period when disease activity has been low for a year.^{Reference Portaccio, Tudisco and Pastò206} For patients with minimal disease activity, glatiramer acetate and interferon-β drugs can be used up until pregnancy with no washout period required.^{Reference Coyle, Oh, Magyari, Oreja-Guevara and Houtchens207} Treatment can be continued through pregnancy and breastfeeding if the benefits outweigh the risks. A washout may not be required with dimethyl fumarate due to the drug’s short half-life. Teriflunomide should be used only in cases where the patient understands and agrees to strict contraception prior to pregnancy and to undergo an active elimination protocol prior to pregnancy; confirmation of drug elimination with a blood test prior to conception is recommended.^{Reference Coyle, Oh, Magyari, Oreja-Guevara and Houtchens207}

For patients with highly active disease who are contemplating pregnancy within 2 years, anti-trafficking drugs (fingolimod and natalizumab) should be avoided due to the risk of worsening MS after drug discontinuation and potential teratogenic effects with fingolimod.²⁰⁸ Use of a long-acting cell-depleting therapy (e.g., cladribine, alemtuzumab, and ocrelizumab) would be preferred; patients should wait for 4 months after the last dose of alemtuzumab or 6 months after the last dose of cladribine or ocrelizumab before trying to conceive.^{Reference Coyle, Oh, Magyari, Oreja-Guevara and Houtchens207} In high-risk patients, use of natalizumab and ocrelizumab can be considered up to conception after extensive discussion with an experienced clinician about the potential benefits and risks.^{Reference Portaccio, Annovazzi and Ghezzi209} There are some data to suggest that these agents are not transported across the placenta until the second trimester. Use of natalizumab (q4–8 weeks) can be considered for the first two trimesters in patients with aggressive MS during pregnancy, but hematologic monitoring of the infant after childbirth will be required.^{Reference Haghikia, Langer-Gould and Rellensmann210} With alemtuzumab, close surveillance of new onset thyroid dysfunction during pregnancy is advised. Cytotoxic agents (e.g., mitoxantrone, cyclophosphamide) should be avoided in women of childbearing age; if disease activity warrants their use, the risk of infertility should be discussed with the patient beforehand.

Relapses during pregnancy should only be treated if they are disabling. The preferred treatment is prednisone, prednisolone, or methylprednisolone for 3–5 days, but these agents should be avoided as much as possible in the first trimester. There is insufficient evidence to support the use of routine steroids or monthly intravenous immunoglobulins (IVIg) during pregnancy. Plasmapheresis can be used in severe, refractory relapses.

Exclusive breastfeeding for 6 months has been reported to reduce the risk of postpartum relapses.^{Reference Hellwig, Haghikia, Rockhoff and Gold211} Clinicians should support exclusive breastfeeding in patients without significant disease activity or fatigue. Breastfeeding should not be discouraged in favor of resuming medication except in cases of highly active disease. Postpartum relapses may be treated with methylprednisolone or IVIg,^{Reference Avila-Ornelas, Avila and Stosic212,Reference Winkelmann, Rommer, Hecker and Zettl213} but resumption of a DMT would be the preferred approach. Glatiramer acetate and interferon-β may be used during breastfeeding; fingolimod, teriflunomide, dimethyl fumarate, cladribine, and cytoxic agents should be avoided.^{Reference Almas, Vance, Baker and Hale214}

Ocrelizumab or natalizumab should be considered for highly active patients or those with a significant postpartum relapse, since these agents have a more rapid onset of action and extremely low transfer to breast milk. Patients who choose not to breastfeed should be started on a DMT as soon as possible after delivery.

Canadian Multiple Sclerosis Working Group Members

Douglas L. Arnold, Montreal Neurological Institute and Hospital, Montreal, Québec; Philippe Beauchemin, CHU de Québec-Université Laval, Québec, Québec City; Virender Bhan, Fraser Health MS Clinic, Burnaby, British Columbia; Jodie M. Burton, University of Calgary, Calgary, Alberta; Virginia Devonshire, University of British Columbia, Vancouver, British Columbia; Pierre Duquette, Centre hospitalier de l’Université de Montréal, Montreal, Québec; François Émond, CHU de Québec – Université Laval, Hôpital de l’Enfant-Jésus, Québec, Québec; Mark S. Freedman, The Ottawa Hospital Research Institute, Ottawa, Ontario; Paul S. Giacomini, Montreal Neurological Institute and Hospital, Montreal, Québec; Marc Girard, Centre hospitalier de l’Université de Montréal, Montreal, Québec; Fabrizio Giuliani, University of Alberta, Edmonton, Alberta; Francois Grand’Maison, Clinique de SP Neuro Rive-Sud, Greenfield Park, Québec; Marika Hohol, St. Michael’s Hospital, Toronto, Ontario; Olinka Hrebicek, Royal Jubilee Hospital, Victoria, British Columbia; Liesly Lee, Sunnybrook Health Sciences Centre, Toronto, Ontario; Michael C. Levin, University of Saskatchewan, Saskatoon, Saskatchewan; James J. Marriott, University of Manitoba, Winnipeg, Manitoba; Suresh Menon, McMaster University, Hamilton, Ontario; Xavier Montalban, St. Michael’s Hospital, Toronto, Ontario; Sarah A. Morrow, London Health Sciences Centre, London, Ontario; Mary Lou Myles, University of Alberta, Edmonton, Alberta; Jiwon Oh, St. Michael’s Hospital, Toronto, Ontario; David Patry, Foothills Medical Centre, Calgary, Alberta; Daniela Pohl, Children’s Hospital of Eastern Ontario, Ottawa, Ontario; Alexandre Prat, Centre hospitalier de l’Université de Montréal, Montreal, Québec; Dalia Rotstein, St. Michael’s Hospital, Toronto, Ontario; Daniel Selchen, St. Michael’s Hospital, Toronto, Ontario; Penelope Smyth, University of Alberta Hospital, Edmonton, Alberta; Sunita Venkateswaran, Children’s Hospital of Eastern Ontario, Ottawa, Ontario; Reza Vosoughi, St. Michael’s Hospital, Toronto, Ontario; and E.Ann Yeh, The Hospital for Sick Children, Toronto, Ontario.

Disclosures

The Canadian Treatment Optimization Recommendations was a project of the Canadian MS Working Group (CMSWG) under the aegis of the Canadian Network of MS Clinics. All of the authors have reviewed the final version of this manuscript and have agreed with the recommendations. CMSWG members received no remuneration for their development of the recommendations or the accompanying manuscript. Participants were reimbursed for costs associated with attending the June 2019 meeting. Funding was provided by the Canadian Network of MS Clinics through unrestricted grants obtained from EMD Serono, Roche, Biogen, Sanofi-Genzyme, Teva, and Pendopharm. Corporate donors had no involvement in CMSWG discussions, in the development of the recommendations or in the review of the manuscript. The CMSWG acknowledges the assistance of Anne St-Michel and Steven Manners of Communications Lansdowne for logistics and editorial development, with funding through grants obtained by the Canadian Network of MS Clinics.

Author Disclosures

Mark S. Freedman has received grants from Sanofi Genzyme, Hoffmann La Roche, and EMD Serono; honoraria from Sanofi Genzyme, Hoffmann La Roche, EMD Serono, Actelion, Janssen/J&J, Alexion, Biogen, Novartis. and Teva Canada Innovation; and participated in speakers’ bureaux for Sanofi Genzyme and EMD Serono.

Virginia Devonshire has received honoraria for attending advisory board meetings for EMD Serono, Roche, Sanofi, and Biogen.

Pierre Duquette has received grants for investigator-initiated trials from Biogen and EMD Serono.

Paul S. Giacomini has received fees for speaking, consulting, and advisory board participation for Novartis, Biogen, EMD Serono, Sanofi Genzyme, Hoffmann La Roche, Teva, Actelion, Alexion, Celgene, and Pendopharm.

Fabrizio Giuliani has received grants from Biogen and Hoffmann La Roche; and honoraria from Novartis, EMD Serono, and Teva.

Michael C. Levin has received honoraria from Biogen, Pendopharm, Hoffmann La Roche, Merck, and Sanofi Genzyme; and non-financial support from Biogen, Pendopharm, and Sanofi Genzyme.

Xavier Montalban has received speaking honoraria and travel expenses from Biogen, Novartis, Sanofi Genzyme, Teva, Hoffmann La Roche, Celgene, Actelion, Excemed, and EMD Serono; has participated in scientific meetings and advisory board meetings for Biogen, Novartis, Sanofi Genzyme, Teva, Hoffmann La Roche, Celgene, Actelion, Excemed, and EMD Serono; and received travel expenses for scientific meeting participation for the MS International Federation and the National MS Society.

Sarah A. Morrow has received grants from the Multiple Sclerosis Society of Canada and CIHR; has acted as site principal investigator for studies with Novartis, Roche, and EMD Serono; and has received research funds for investigator-initiated studies from Hoffmann La Roche, Biogen, Sanofi Genzyme, and EMD Serono.

Jiwon Oh has received grants from Biogen, Hoffmann La Roche, and Sanofi Genzyme; and honoraria from Biogen, Hoffmann La Roche, EMD Serono, Celgene, Novartis, and Sanofi Genzyme.

Dalia Rotstein has received research support from the Consortium of MS Centers, the Multiple Sclerosis Society of Canada, and Hoffmann La Roche; and has served as a speaker or consultant for Alexion, Biogen, EMD Serono, Novartis, Hoffmann La Roche, and Sanofi Aventis.

E. Ann Yeh has received grants from Biogen, the National MS Society, the Consortium of MS Centers, the Multiple Sclerosis Society of Canada, the Ontario Institute for Regenerative Medicine, SCN, the Sick Kids Foundation, CBMH, Teva and the Guthy Jackson Foundation; and honoraria from ACI, the US FDA, and Juno.

Statement of Authorship

MSF designated the subgroups that would develop the preliminary recommendations. The other 10 authors served as team leaders in developing the preliminary recommendations by their subgroups. The 10 subgroups (and team leaders) were Diagnosis (XM); Treatment initiation – Relapsing MS (FG); Treatment initiation – Progressive MS (MCL); Evaluating treatment response – Relapses and progression (DR); Evaluating treatment response – MRI (JO); Evaluating treatment response – Cognition (SAM); Treatment sequencing (PSG); Pediatric MS (EAY); Safety (PD); and Other important issues (VD). MSF led the full Working Group discussion to finalize the consensus recommendations. All of the authors (MSF, XM, FG, MCL, DR, JO, SAM, PSG, EAY, PD, and VD) reviewed all drafts and revisions of the manuscript. All of the authors have reviewed the final version of this manuscript and have agreed with the conclusions.