Brazilian Consensus for the Treatment of Multiple Sclerosis: Brazilian Academy of Neurology and Brazilian Committee on Treatment and Research in Multiple Sclerosis

ABSTRACT The expanding therapeutic arsenal in multiple sclerosis (MS) has allowed for more effective and personalized treatment, but the choice and management of disease-modifying therapies (DMTs) is becoming increasingly complex. In this context, experts from the Brazilian Committee on Treatment and Research in Multiple Sclerosis and the Neuroimmunology Scientific Department of the Brazilian Academy of Neurology have convened to establish this Brazilian Consensus for the Treatment of MS, based on their understanding that neurologists should be able to prescribe MS DMTs according to what is better for each patient, based on up-to-date evidence and practice. We herein propose practical recommendations for the treatment of MS, with the main focus on the choice and management of DMTs, as well as present a review of the scientific rationale supporting therapeutic strategies in MS.

Multiple sclerosis (MS) is a chronic and disabling disease that mostly affects young patients, resulting in huge consequences for their physical and cognitive domains, and impacting on their quality of life and employability. Its incidence and prevalence is increasing worldwide 1 and still no definite cause is known, the reason why a straight-line delineation of therapeutic recommendation has been hindered and the overall trend has been driven toward a personalized and individualized therapeutic rationale.
Throughout the last decade, the number of disease-modifying therapies (DMTs) approved for the treatment of MS has increased from just a few to more than a dozen. In addition, a number of therapies are often used off-label and several investigational drugs are going through the later stages of development and may soon be approved. While this represents an unprecedented opportunity for personalized therapy in MS, the choice of DMTs is becoming increasingly complex.
Many aspects of the management of MS have not yet been formally assessed by clinical trials. Remarkably, there are few head-to-head comparisons between DMTs, few trials in progressive MS, and no direct comparison between the therapeutic strategies known as escalation (starting with safer but less efficacious drugs, and escalating to more efficacious and often riskier drugs, as needed) and induction (starting with highly efficacious "aggressive" treatments in order to prevent irreversible accumulation of disability, yet with some serious adverse effects) 2 . Nevertheless, these are key aspects and must be addressed by guidelines, even if optimal evidence is not available.
The treatment of MS in Brazil is largely limited by the Ministry of Health Clinical Protocols and Therapeutic Guidelines (Protocolos Clínicos e Diretrizes Terapêuticas) 3 , since most patients get their DMTs from the public health system. The current Clinical Protocols and Therapeutic Guidelines determine a one-size-fits-all strategy, with minimal flexibility to tailor therapy to the needs and preferences of individual patients. Moreover, it delays access to DMTs of higher efficacy and fails to include some of the locallyapproved DMTs.
In this context, experts from the Brazilian Committee on Treatment and Research in Multiple Sclerosis and the Neuroimmunology Scientific Department of the Brazilian Academy of Neurology have convened to establish this Brazilian Consensus for the Treatment of MS, based on an understanding that neurologists should be able to prescribe MS DMTs according to what is better for each patient, and based on up-to-date evidence and practice. Disease-modifying therapies were considered for inclusion in the protocol if at least one phase 3 trial demonstrated their efficacy in MS, plus they were approved by at least one of three regulatory bodies: the Brazilian Health Regulatory Agency (Agência Nacional de Vigilância Sanitária, ANVISA); the United States Food and Drug Administration (FDA); or the European Medicines Agency (EMA). Also considered for inclusion were DMTs for which a positive phase 2 or 3 trial was available, yet without approval for MS by the aforementioned regulatory agencies, but only in the case of them already being available or approved for another indication in Brazil, in order to maximize the utilization of locallyavailable resources. Previous national recommendations published by the Brazilian Committee on Treatment and Research in Multiple Sclerosis 4,5,6,7 and the Brazilian Academy of Neurology 8,9 were taken into account, as were some key international guidelines 10,11,2 .

This guideline represents a consensus of Brazilian experts
On June 23 rd , 2016, the panel-approved protocol was presented at the 17 th Brazilian Committee on Treatment and Research in Multiple Sclerosis Annual Meeting, the largest Brazilian conference on MS, where it was endorsed by the attendees. Subsequent minor changes were made due to new information that became available during manuscript preparation. The completed manuscript was subsequently circulated among all panel members for final approval.

DISEASE-RELATED CONCEPTS
The diagnosis of MS must be made according to the McDonald criteria, revised in 2017 13 . The clinical course must be defined according to the classification of Lublin, modified in 2013, which includes four phenotypes: clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS) 14 . The relapsing-remitting and progressive forms may be further stratified by the presence or absence of disease activity, which can be defined as the occurrence of clinical relapses and/or detection of radiological findings (gadolinium-enhancing lesions and/or new or enlarging T2-weighted lesions) on follow-up magnetic resonance imaging (MRI) 14 .
The progressive phenotypes may be further categorized according to the presence or absence of ongoing progression, which can be assessed by clinical measurements of disability, at least once annually 14 .
In order to guide treatment decisions, some additional stratifications are needed: CIS must be classified according to the risk of evolving to MS, and disease activity, when present, must be classified according to its level, even though universally-accepted criteria are lacking. For the purpose of this protocol, we define high-risk CIS as any case wherein one or more typical T2 lesion(s) on MRI is seen, provided both the clinical presentation and MRI lesion(s) are suggestive of central nervous system (CNS) demyelination and not attributable to other diseases. For such patients, the risk of developing MS ranges from 48% to 81%, depending on the number of lesions 15 .
Therapeutic decisions in MS are often based on the degree of disease activity, which can be rated as low, moderate (or average), and high. The definition of highly active MS is still debatable, but we herein adopt this definition: 1) two or more disabling relapses with incomplete resolution and at least one gadolinium-enhancing lesion or significant increase in T2 lesion load in the previous year in treatment-naive patients and 2) breakthrough disease activity in the previous year, under an adequate course of at least one DMT (in the absence of intolerance or nonadherence), presenting with at least one relapse in the previous year while on therapy and at least nine T2 hyperintense lesions or at least one gadolinium-enhancing lesion 16,17 . For the purpose of this consensus, whenever disease activity is present but does not fulfill the criteria for high activity, it is considered as low or moderate activity.
Aggressive disease can be defined as RRMS with one or more of the following features: 1) Expanded Disability Status Scale score of 4 reached within five years of onset, or early and unexpected acquisition of disability followed by frequent relapses; 2) two or more relapses with incomplete resolution in the past year; 3) two or more MRI studies showing new or enlarging T2 lesions or gadolinium-enhancing lesions despite treatment; 4) no response to therapy with one or more DMTs for up to one year 18,19 .
Nonetheless, the above definitions of high activity and aggressive disease lack the sensitivity to detect many cases with poor prognosis early enough in the disease course. However, there are now known to be several clinical and radiological factors associated with a poorer prognosis (Table 1), which may be present from the onset or become apparent during follow-up and suggest evolution to a more "aggressive" form of the disease 18 . Since there is a clear relationship between the amount of disease activity and final prognosis (presented later in the text), we recommend the parameters of disease activity should always be analyzed alongside the elements concerning prognosis.
The panel understands that these factors (especially if present in association) should prompt the treating neurologist to consider disease activity as high and the prognosis as poor, and to manage DMTs accordingly, even before the patient effectively meets the definition for "aggressive" MS. This approach may allow for the early optimization of DMTs before irreversible accumulation of disability is established.

TREATMENT-RELATED CONCEPTS
This rationale is based on what has been learned over the years from observational studies, controlled clinical trials, pathophysiological concepts and, more recently, real-world registries. In this context, treatment algorithms from many countries 11,20,21,22,23,24,25,26,27,28,29,30,31 have been guided by what have turned out to be very important concepts: 1) early and effective treatment; 2) the existence of a therapeutic window of opportunity; 3) early optimization of treatment during the therapeutic window; 4) the existence of different clinical and radiological phenotypes; and 5) treatment decisions based on different levels of inflammatory activity and/or specific clinical phenotypes, wherever possible, always favoring the best efficacy/risk ratio.
It is widely accepted that the main aspect to be avoided or minimized in MS is the accumulation and progression of disability, with this representing the central goal in planning therapeutic decisions. However, the immediate therapeutic effect of current DMTs is, in fact, centered upon the prevention of clinical and radiologic activity outbreaks, with these being related to focal inflammation. The accumulated disability in MS follows a two-step process. The first phase is very dependent on focal inflammation due to the impairment of adaptive peripheral immunity, predominating in the initial phase of the disease, and leads to the relapsing-remitting phase in which early epitope spreading occurs and underlies the early pathogenic events 32,33,34 . This tends to decline over time as other pathogenic mechanisms, mostly related to innate immunity, lead to the second phase of the disease, which is not as dependent on focal inflammation 35 , but rather on other more spread mechanisms, like CNS-compartmentalized inflammation inside lymphoid follicles within the meninges 36,37 , underlying the progressive phase 38 . The first stage is characterized by the occurrence of clinical relapses and new/enlarging or gadolinium-enhancing lesions on MRI, due to focal demyelinating inflammatory lesions in the early stages of the disease, while the second stage is characterized by the progressive and sustained worsening of functional capacity by mechanisms of axonal degeneration and brain atrophy, which although probably present since the beginning, are more evident in the later stages of the disease or in the so-called secondary progressive phase.
There is much evidence relating the degree of inflammatory activity in the first phase of the disease to the disability grade achieved in the second phase. Large observational cohorts have demonstrated that frequent relapses 39 in the early years of disease 40,41 , as well as short intervals between relapses 40,42,43 , are predictors of reaching greater levels of disability in shorter time periods, while the number of relapses after five years of disease does not substantially influence the time to achieve levels of permanent incapacity or the degree of severity of this phase 40 . In other words, the early course influences long-term evolution. Relapses with residual sequelae also contribute to the long-term accumulation of disability 43,44,45,46,47 . This means that irreversible axonal degeneration occurs very early and is, at least partly, related to inflammation 2,48 . It has also been observed that an older age at disease onset is related to increased risk of a rapid shift to a secondary progressive course 47,49,50,51,52,53 , probably due to the progressive decline with aging of the functional reserves, neuroplasticity and recovery mechanisms, including remyelination. The lesion load on MRI 54,55,56,57,58 , as well as evidence of cerebral atrophy 59,60,61,62,63 , also have direct correlation with long-term disability, meaning that inflammation leads to irreversible nervous damage.
All these data together strongly suggest the existence of a therapeutic window, a time in the early stages of the inflammatory phase of MS during which therapeutic intervention can substantially influence the timing and condition in which the patient will reach the progressive stage. The era of monoclonal antibodies came in to consolidate the existence of a therapeutic window. A retrospective analysis of controlled clinical trials of alemtuzumab revealed that patients treated earlier in the evolution of the disease with a drug considered to have high Severe relapse(s) (i.e., associated with ≥ 1-point change on EDSS, ≥2-point change on any individual functional system, or ≥ 1-point change on any two functional systems during the acute phase; or requiring steroids or other acute-phase treatments; or requiring hospitalization) Multifocal relapse(s), especially if affecting motor, cerebellar, sphincteric, or cognitive functions Disabling relapses (i.e., with partial or incomplete recovery) Frequent relapses in the first 2-5 years after disease onset, or short inter-relapse interval Rapid accumulation of disability related to relapses, e.g., reaching EDSS score ≥3.0 within five years after disease onset

Radiologic features (MRI)
High disease burden at onset (i.e., high T2 lesion volume, ≥ 2 gadolinium-enhancing lesions; T1 lesions suggestive of "black holes"; early signs of brain atrophy; infratentorial and spinal cord lesions) Evidence of disease activity on follow-up (i.e. new/enlarging T2 lesions and/or gadolinium-enhancing lesions) efficacy showed better results for the parameters of sustained long-term disability, when compared to the group receiving treatment later after disease onset 64 . The finding that disease-modifying drugs can delay the conversion from CIS to clinically definite MS 65,66,67,68,69,70 , together with results indicating increased responsiveness to therapies in CIS relative to the relapsing-remitting phase, probably due to the increasing complexity in pathogenic mechanisms as the disease evolves 2,32,71 , also helps to strengthen the concept of a therapeutic window.
The therapeutic window is, therefore, the variable and sometimes short time period in which treatment should be optimized, linking the need for early treatment with that of an effective treatment. Within this context, in addition to the regular monitoring of radiological and clinical disease activity for timely recognition of therapeutic failure, early definition of the clinical phenotype is of extreme importance. Relapses involving the pyramidal, sphincter and cerebellar pathways are known to have a higher correlation with the accumulation of disability, when compared to relapses involving other neurological fields, such as visual and sensory, for instance 43,47,49,52,72,73,74 . Knowing this does not occur randomly, as further relapse phenotypes are predicted by the phenotype of previous relapses 75,76,77 , in the vast majority of cases there are elements that are predictors of prognosis in a patient's clinical presentation ( Table 1). The suggestion of there being a differential impact of phenotypes on long-term disability can justify, wherever possible, an individualized therapeutic management of different and specific phenotypes. Given the different profiles of effectiveness and risk for the various drugs currently available, the choice of treatment should be carefully considered and based on an individual benefit/risk assessment for the patient, where drug efficacy should be appropriate for the severity of phenotype and thereby justify or offset the risks.
Changes in the diagnostic criteria for MS, essentially aimed at accelerating the diagnostic process, progress in neuroimaging techniques in the daily clinical setting, and the approval of high-efficacy drugs, has led to expectations of greater therapy effectiveness, alongside a trend to tolerate less and less disease activity, increasing the possibility of enhancing MS treatment remarkably 78 . The current therapeutic approaches for MS are the so-called escalation or induction strategies 79 .
The rationale for an escalation therapy approach is based on initiating treatment as early as possible using the safest but also less effective DMT, chosen based on the degree of inflammatory activity. This strategy is more often applied to mild or moderate clinical phenotypes, and close monitoring of clinical and MRI activity is advised. Continuing treatment while the disease is stable is recommended, as is promptly switching to a more effective drug when the ongoing treatment becomes ineffective or only partially effective, escalating the efficacy of treatment (but also increasing the risk profile as a consequence) 21,80 .
The rationale for an induction approach arises from the observation that a proportion of MS patients with a more aggressive phenotype require more aggressive treatment from disease onset; very potent drugs are used earlier in this type of approach, with more important safety issues regarding autoimmunity and infectious complications than other drugs. These drugs have mechanisms of action that usually not only provoke long-term immunological remission, but also a re-initiation or "reset" of immunological pathways, or immune reconstitution 81 . This could potentially reduce the epitope spreading, which occurs earlier in the disease course, and the shift in the main site of immune responses from the periphery to the CNS compartment, which seems to occur in later phases of MS 80 .
Evaluation of prognostic factors must be performed every time disease activity is assessed or treatment failure is declared, and treatment decisions regarding drug efficacy or treatment approach must be adjusted accordingly, to follow either a strategy of escalation or induction therapy.

Disease-modifying therapy
The choice of a DMT (and the decision to keep it or change it throughout follow-up) depends on several factors, including phenotype, prognostic factors, activity, progression status, severity, comorbidities, safety profile, tolerability, patient preference, convenience, cost, and availability. To date, there are no established biomarkers to predict the response of individual patients to most DMTs. Table 2 compiles the DMTs included in the protocol and summarizes their posology, clinical efficacy parameters in each phenotype (based on the results of key clinical trials that support their use in MS), and approval status. Figure 1 summarizes the general recommendations of the Brazilian Consensus for the Treatment of MS with regard to when and how to switch DMTs in different contexts, such as lack of efficacy or safety concerns. Figure 2 lists the DMTs that have been included in the Consensus for different MS phenotypes, according to the risk of conversion from CIS to MS, as well as the level of disease activity in RRMS and SPMS.
The first set of DMTs presented for each group in Figure 2 represents the most appropriate initial choices. In the event of intolerance, poor adhesion and/or serious adverse effects, DMTs could be switched within the same groups. On the other hand, in the event of therapeutic failure, patients should be reassessed in relation to phenotype and disease activity, and DMTs should be managed accordingly, which may involve switching to higher efficacy drugs. For example, upon therapeutic failure, a patient with CIS will nearly always have met the criteria for RRMS, and a  ---* Some drugs have been tested in more than one dose or administration scheme; in such cases, only the dose(s) and scheme(s) that have been approved by health authorities or are most commonly used for MS in clinical practice are shown. Some drugs may require dose titration upon start of treatment; we refer the reader to the locally-approved label or to the specific trial publication for detailed prescribing information. ** The effect of each drug on these outcomes is shown for reference purposes only. Significant inter-study variability in terms of eligibility criteria, primary and secondary endpoints, comparator group (placebo or active treatment) and duration of follow-up prevents a direct comparison of treatment effects across different studies. *** Due to recruitment difficulties, these studies were terminated prematurely, which impaired their ability to carry out the planned statistical analysis. However

Choice of DMT
Monitor disease activity (clinically and by MRI) and reassess the phenotype periodically; monitor adherence and tolerance to the DMT; implement safety monitoring as recommended in the product label and current literature If all options within the specifc box are exhausted, consider switch to DMT from the "alternative" box (see figure 2) Switch to DMT from the now-appropriate box (see    patient with low disease activity may have evolved to high disease activity. Conversely, if the management of highly active disease with potent DMTs has achieved a satisfactory response and stability for several years, it would be acceptable (though not mandatory) to consider switching to a lower potency DMT. Finally, if a patient with relapsing MS fails to achieve satisfactory responses (or presents intolerance or safety concerns) with multiple DMTs from the first group, a switch to DMTs of the second (alternative) group shown in Figure 2 should be considered.

CIS
In patients with CIS, the main therapeutic goal is to prevent (or at least delay) the conversion to MS, i.e., the development of further clinical relapses or new MRI lesions that may lead to fulfillment of the McDonald criteria for RRMS. It is likely that all MS DMTs may be effective in doing so; however, in many CIS cases there remains some uncertainty regarding the likelihood of evolving to MS, thus it seems reasonable to start DMTs only in patients with high-risk CIS, as well as to choose safer drugs.
Up to the present time, efficacy in CIS has been demonstrated with the beta interferons, cladribine, glatiramer acetate, and teriflunomide [65][66][67][68][69][70]82 . Since no direct comparison between these is available, any of these drugs are deemed appropriate for the treatment of high-risk CIS.

Relapsing MS
For the purpose of this guideline, we define relapsing MS as any case of RRMS, irrespective of disease activity, as well as SPMS with persistence of superimposed relapses or radiologic signs of activity. This approach reflects the panel's view that, in patients transitioning from the relapsing-remitting form to the secondary progressive form, the presence of relapses may suggest a residual "relapsing" pathophysiological component, potentially treatable with DMTs, which may persist for years. This view is further supported by recent clinical trials including both RRMS and SPMS with relapses, grouped under the term "active relapsing MS" 83 , as well as the recent approval by health authorities of some DMTs for "relapsing forms of MS". The panel recognizes that many of the pivotal trials for DMTs have included only RRMS patients, with the efficacy of such drugs for SPMS being less clear. On the other hand, it also acknowledges that the distinction between RRMS and SPMS in clinical practice is often challenging and may take months or years until the presence of ongoing disease progression (and thus SPMS) is clearly established, particularly if there remain superimposed relapses.
The main goals in patients with relapsing MS are to reduce the annualized relapse rate and appearance of new or enlarging MRI lesions, and consequently the accumulation of disability. Identifying those with high disease activity (or at higher risk of evolving to a more aggressive form of the disease) is of paramount importance to guide the choice of DMT.
If there are no particular concerns regarding high levels of disease activity, it would seem reasonable to start treatment with interferon beta-1a 84,85 , interferon beta-1b 86 , glatiramer acetate 87,88 , pegylated interferon beta-1a 89 , dimethyl fumarate 90,91 , or teriflunomide 92,93 , which usually have a good safety profile and are often more easily available (including in the Brazilian public health system). Overall, these drugs are associated with a moderate reduction in the annualized relapse rate in comparison to placebo (around 30%; except for dimethyl fumarate with an efficacy of around 50%).
For patients meeting the criteria for highly active relapsing MS, or presenting factors associated with poorer prognosis, the treating neurologist should consider drugs of higher potency (associated with a reduction greater than 50% in the annualized relapse rate, usually compared with placebo), whose efficacy has been well established by phase 3 trials. This group comprises alemtuzumab 94,95 , cladribine 96 , fingolimod 97,98 , natalizumab 99 , and ocrelizumab 100 . These drugs are usually associated with more serious safety concerns, including opportunistic infections or secondary autoimmune diseases, to cite a few. Nevertheless, the need to control aggressive (or potentially aggressive) MS before irreversible disability accumulates often justifies the use of such drugs. At the time of the consensus panel meeting, this group of drugs also included daclizumab 101,102 , but it has since been withdrawn from the market (and removed from this guideline) due to recently detected safety issues 103,104 .
A subset of highly active relapsing MS patients may persist with breakthrough disease despite treatment with several drugs from the high potency group, characterizing refractory MS. In such cases, subsequent therapy is largely empiric and may include DMTs like cyclophosphamide 105 , intravenous immunoglobulin 106 , mitoxantrone 107 , rituximab 108 , and autologous hematopoietic stem cell transplantation 109 . These DMTs have had their efficacy suggested by phase 2 trials only (except for mitoxantrone, which was investigated in a phase 3 trial) and are often associated with serious adverse effects, including infertility, neoplasms, or cardiotoxicity). In this group, as an alternative to the aforementioned drugs, experimental DMTs may also be considered, as long as they are offered in a research setting, under appropriate regulatory and ethical approval.

Non-active SPMS
There remains a lack of substantial evidence supporting the benefit of any particular DMT for patients with clearlyestablished SPMS that no longer presents relapses. Not prescribing a DMT is an acceptable choice in this group. If a DMT is considered (e.g., if there is uncertainty regarding the secondary progressive phenotype in a particular case), the off-label nature of this approach should be clearly discussed with the patient. In this context, interferon beta-1b could be preferred, based on one positive phase 3 trial in SPMS 110 . In cases of rapidly-progressive disease, there is some evidence supporting the use of DMTs such as cyclophosphamide, mitoxantrone, and autologous hematopoietic stem cell transplantation, but these would also represent offlabel treatments.
A phase 3 trial of siponimod in patients with SPMS has recently been published, showing modest efficacy in reducing the progression of disability 111 . However, evaluation and approval by health authorities are still pending; therefore, siponimod has not been included in this guideline.

PPMS
The current main therapeutic goal in PPMS is to delay the progression of disability. The only drug approved for this purpose is ocrelizumab, with a modest benefit 112 . Hence, the consensus panel understands that ocrelizumab should be the treatment of choice for patients with PPMS, after consideration of the expected benefits and potential risks on a case-by-case basis.

Special situations
Pediatric MS: To date, the Food and Drug Administration, European Medicines Agency, and Brazilian Health Regulatory Agency have not approved most DMTs for patients younger than 18 years. This reflects the lack of phase 3 randomized clinical trials assessing MS drugs in this age range. Meanwhile, the treatment of pediatric MS remains largely off-label, based on evidence from observational studies. Beta interferons and glatiramer acetate are seemingly safe and effective in this population and should be preferred as first-line therapy, at least until growing evidence and regulatory clearance becomes available for the newer DMTs 113 . Attention should be paid to the specific dose initiation and titration schemes recommended for younger children. Upon therapeutic failure, escalation to drugs other than beta interferons and glatiramer acetate may be considered with caution. Positive results of fingolimod in a phase 3 trial in pediatric MS were recently reported in a conference 114 , but publication of the full study was still pending during the preparation of this guideline and, therefore, the panel could not make a specific recommendation on whether fingolimod should be preferred over other DMTs in this age group.
Pregnancy and breastfeeding: As for pediatric MS, there is only scarce evidence guiding the decision on whether or not to use DMTs (and how to choose them) during pregnancy and breastfeeding. Treating neurologists should discuss this on a case-by-case basis and, when the use of a DMT is judged necessary, glatiramer acetate should usually be preferred over others DMTs.
Radiologically isolated syndrome: At this point, the consensus panel understands there is insufficient evidence to recommend the use of DMTs for patients with radiologically isolated syndrome, i.e., those with the incidental finding of MS-typical lesions on MRI who lack evidence of symptoms or signs compatible with MS.
Tumefactive demyelination syndromes: This is a group of heterogeneous conditions whose relationship to MS is still to be fully elucidated. The consensus panel recommends that only patients fulfilling the diagnostic criteria for MS should be eligible for DMTs. At this point, there is insufficient evidence to guide the choice of specific DMTs. Beta interferons and glatiramer acetate are the most commonly used drugs in most case series, thus could be regarded as preferred 115,116 . On the other hand, there are reports of a controversial association between fingolimod and the occurrence of tumefactive lesions (as well as unfavorable outcomes in this group of patients); thus the panel recommends particular caution when prescribing this drug to patients with tumefactive demyelinating syndromes 116,117 .
Treatment interruption: There is no clear evidence to support a consensus recommendation on whether or when to consider interruption of DMTs in patients with advanced MS or in those with the disputable entity known as "benign MS" 118 . The treating neurologist should discuss this with patients and their family on an individual basis.
For further guidance on the management of special situations, we refer the reader to the recommendations of the Brazilian Academy of Neurology. Figure 3 summarizes the recommendations for the management of relapses. The initial choice is usually intravenous methylprednisolone, 1 g/day, infused over at least 30 minutes, for three to five consecutive days 119 . If intravenous methylprednisolone fails to promote satisfactory recovery, an additional course may be given, with the same or higher dose (1-2 g/day), again for three to five days. High-dose oral methylprednisolone (1 g/day) or dexamethasone (150 mg/day), for three to five consecutive days, may be considered in the outpatient setting 120,121 .

Management of relapses
Patients who fail to respond (or have contraindications) to corticosteroids may be eligible for therapeutic plasma exchange (five to seven sessions scheduled every other day) or intravenous human immunoglobulin G (usually 1 g/kg/ day for two days, or 0.4 g/kg/day for five days) 119 . It is noted that plasma exchange is likely more effective than intravenous immunoglobulin; however, it is not easily available in most centers in Brazil.

Symptomatic treatment and rehabilitation
Although a comprehensive review of symptomatic treatment and rehabilitation is beyond the scope of this guideline, the panel acknowledges the paramount importance of such aspects in the treatment of MS and highlights the need to proactively consider these resources and offer them to patients in need, whenever possible. We recommend accessing the Brazilian Academy of Neurology recommendations to review these treatments.
Symptoms and disability in the context of MS, such as neurogenic bladder and bowel dysfunction, neuropsychological conditions, sleep disorders, neuropathic pain and spasticity, are usually managed similarly as in the context of other neurological conditions. Nonetheless, it is worth bearing in mind that some MS-specific symptomatic drugs are available, namely tetrahydrocannabinol + cannabidiol for refractory spasticity and fampridine for gait dysfunction 122 .

Vitamin D3 supplementation
Vitamin D3 (cholecalciferol) is a fat-soluble hormone with numerous physiologic responses, including immune regulation 123 . Preliminary studies of vitamin D3 as an add-on therapy in MS have shown promising results, but none have yet provided significant evidence of a clinically meaningful effect on disease activity. Until the results of ongoing larger randomized controlled trials help elucidate the role of vitamin D supplementation in MS, the panel recommends to check the serum level of 25-OH-vitamin D3 in all patients with MS, and to consider supplementation on a case-by-case basis, in physiologic doses, i.e., sufficient to achieve serum levels between 40 and 100 ng/mL (100-150 nmol/L) 124 . After starting supplementation, serum levels should be re-checked after three months, to further tailor the dose, as MS patients may have a less robust response to supplementation compared to those without comorbidities 123 . The panel herein emphasizes that supraphysiological doses of vitamin D3, i.e., those leading to a serum level higher than 100 ng/mL, are not indicated, neither as an add-on nor as monotherapy in MS, due to potential systemic toxicity 124 .

FINAL REMARKS
This guideline provides an overview of the principles and general directions that should guide therapeutic decisions in MS. Overall, we highlight the need to start DMTs early in the course of MS, always conforming properly to the clinical phenotype, and changing them promptly in the case of treatment failure to prevent further relapses and accumulation of disability. We advocate for flexibility in the management of DMTs, so it can be tailored to individual circumstances (especially disease activity), rather than adhering to a rigid sequence of treatment lines.
We acknowledge that these recommendations are unable to cover all the situations that neurologists may face in the management of MS. Furthermore, the need for periodic revisions is anticipated, as further understanding of the disease and new medications become more rapidly available. Therefore, we encourage treating physicians to always review additional information (especially from each drug' s label), and to examine all the relevant factors on a case-by-case basis.