MENACTRIMS Guidelines

MENA Committee for Research and Treatment in Multiple Sclerosis

Consensus Recommendations for the Diagnosis and Treatment of Multiple Sclerosis The Middle East North Africa Committee for Treatment and Research in Multiple Sclerosis (MENACTRIMS)

INTRODUCTION:

Multiple Sclerosis (MS) is a chronic demyelinating disorder of the central nervous system (CNS) that affects predominately patients aged 20-40 years. The epidemiology of MS is changing worldwide, as is the understanding of its immunopathogenesis and natural history with new evidence pointing towards a multifactorial etiology involving both environmental and genetic factors [1, 2]. The prevalence and incidence rates of MS have been steadily increasing worldwide over the last few decades including the Middle East [3-8]. The field of MS therapeutics is evolving rapidly as several novel treatments have been added to our armamentarium in the last decade. There is a clear need to unify and update the diagnostic and therapeutic paradigms across the Middle East as most countries in the region are in the process of establishing specialized MS centers. On the other hand, some diagnostic mimickers of MS, such as neurobrucellosis, neuro-Behçet, Toxocara canis myelitis [9], HTLV1infection, and others might be unique or much more common in the Middle East compared to Europe or North America, which necessitates a slightly different diagnostic approach. Neurologists from different countries in the Middle East with experience in the management of MS, met at a workshop to update previously published consensus guidelines for the diagnosis and treatment of MS [10].


DIAGNOSIS OF MULTIPLE SCLEROSIS:

The diagnosis of MS remains clinical despite recent advances in diagnostics including availability of several radiological and immunological surrogate markers. The diagnosis relies on incorporating clinical/paraclinical findings to prove dissemination in space and time, and exclude any alternative diseases that can explain the clinical findings at hand.

Historically, the diagnosis was based solely on clinical evidence of dissemination in time and space as proposed by Schumacher et al. in 1965 [11]. With the advent of MRI scans, immunological markers, and neurophysiologic techniques, Poser et al. incorporated certain paraclinical tests such as evoked potentials (EPs) and cerebrospinal fluid (CSF) oligoclonal bands (OCB) into the diagnostic criteria in 1983 [12]. With the development of effective disease modifying therapies (DMTs), it became primordial to identify patients with CIS (clinically isolated syndrome) at high risk of developing MS. The diagnostic criteria proposed by McDonald in 2001, and revised twice in 2005 and 2010, expanded the role of MRI in proving dissemination in space and time, and allowed for earlier diagnosis of MS [13, 14]. It is recommended to use the 2010 revised McDonald criteria for the diagnosis of relapsing and progressive forms of MS. However, in patients presenting with CIS suggestive of MS, clinical and paraclinical red flags should be sought, and alternative diagnoses excluded through a thorough history/physical examination, and extensive diagnostic work-up.

A list of the most common red flags is outlined in Table 1. Although CSF analysis is not required to establish the diagnosis of MS, it is recommended to obtain CSF in atypical presentations in order to exclude other diseases, especially in pediatric patients. The potential list of MS mimickers is exhaustive (Table 2), with a variety of available testing to exclude such possibilities. Considering such diagnostic alternatives randomly has a very low yield and leads to unnecessary workup. The differential and subsequent workup should be guided by ‘atypical’ clinical/paraclinical findings or red flags, which are specific to each case.

With respect to MRI protocol, it is recommended to adopt the 2009 revised guidelines of the Consortium of MS Centers MRI Protocol for the Diagnosis and Follow-up of MS [15]. In CIS patients, a repeat brain and cervical spine MRI with gadolinium is recommended at 3-6 months intervals, in order to demonstrate dissemination in time and space. Additional MRI sections through the thoracic cord may be performed if indicated by the clinical presentation.

In patients fulfilling the Okuda criteria for radiologically isolated syndrome (RIS), clinical and radiological (Brain and spine MRI) follow-up is appropriate [16]. Current evidence does not support initiation of disease modifying therapy before the development of a clinical event [17].


TREATMENT OF MULTIPLE SCLEROSIS

Acute Relapse (Attack):

Historically, ACTH (Adrenocorticotrophic Hormone) was widely used to treat acute relapses after FDA approval based on the study by Rose et al. [18]. Subsequently, several publications demonstrated the efficacy of Intravenous methylprednisolone (IV-MP) [19-21]. A Cochrane meta-analysis of ACTH and corticosteroids for acute MS exacerbations showed that both reduced disease progression within the first five weeks of treatment. There was a trend for better efficacy with methylprednisolone and IV treatment (class I evidence), but no significant difference between short (5 days) and extended (15 days) steroid treatment. Upper gastrointestinal and psychiatric side effects were more common in the oral high dose methylprednisolone group [22]. A more recent Cochrane meta-analysis of oral versus intravenous steroids for treatment of MS relapses showed no significant difference in efficacy between the two routes of administration. There was however a trend for higher incidence of adverse events in the oral group [23]. It is generally accepted that oral prednisone taper should be used only in selected patients considered to be at an increased risk of rebound within the following 2 weeks. A second course of high dose IV-MP has been recommended by certain consensus guidelines in patients failing to improve on the initial course, but no clinical evidence is available to support such approach [24]. A recent retrospective trial evaluated the efficacy of intramuscular (IM) or subcutaneous (SC) ACTH gel in 18 patients with acute relapses failing to improve on high dose MP. Most patients had clinical improvement with none of the adverse events reported with MP. Further studies are needed before firm recommendations can be made regarding the role of ACTH gel in acute MS relapses [25]. Nevertheless, it is important to recognize that the best route of administration of corticosteroids, the optimal dose and duration of treatment, and the preferred agent have yet to be firmly established.

In patients with severe deficits that fail to respond to IV-MP, plasmapheresis may be considered based on clinical evidence (Class II) from two randomized controlled trials (RCT) [26, 27]. Several case series demonstrated functional neurological improvement following plasmapheresis in patients who failed to improve on IV-MP or those with severe acute exacerbations [28-31]. The American Academy of Neurology guideline recommends considering plasmapheresis in patients with severe relapses that fail to respond to high dose steroids [32].

Intravenous Immunoglobulin (IVIG) is not recommended for routine use in the treatment of MS relapses given the insufficient evidence. However, in patients who have contra-indications to IV-MP and plasmapheresis, IVIG (2g/kg over 3-5 days) may be used based on the available supportive data [33, 34]

Recommendations:
It is recommended to treat acute MS relapses with a 3-5 day course of IV Methylprednisolone (IV-MP). It is appropriate to consider plasmapheresis in the treatment of patients with severe disability who fail to respond to IV-MP.


Clinically Isolated Syndrome (CIS):

Definition
CIS is defined as a single episode of neurological symptoms suggestive of MS, typically involving the optic nerve, brainstem/ cerebellum, spinal cord or cerebral hemisphere. Other possible explanations need to be ruled out by a comprehensive work-up.

Risks:
In the longest prospectively followed cohort of CIS patients, conversion rate to clinically definite MS (CDMS) was 43% at 5 years, 59% at 10 years, and 63% at 20 years [35]. More than a third of the patients that developed CDMS followed a benign course with no or minimal disability after a mean disease duration of 20 years. Most patients who are going to convert to CDMS do so within the first 5 years [36]. MRI remains the best predictor of conversion to CDMS. Studies have shown that the long-term risk of developing MS is 60-80% in CIS patients with demyelinating lesions on brain MRI, as compared to 20% in patients with a normal baseline MRI [37, 38]. The presence of a spinal cord lesion is associated with a higher risk of conversion to CDMS, especially in patients with non-spinal CIS [39, 40]. Oligoclonal bands in the CSF, multifocal presentation, the presence of ≥9 T2 lesions and possibly non-enhancing black holes on MRI, increase the risk of conversion to CDMS [37, 41-44]. Severe relapses with motor and cerebellar deficits, incomplete recovery, and multiple system involvement predict a more aggressive disease [45].

Treatment:
Four DMT, Interferon (IFN)-beta 1a SC, Interferon-beta 1a IM, Interferon-beta 1b SC, and Glatiramer Acetate (GA) SC, are currently approved for the treatment of CIS () based on several randomized clinical trials (Class I evidence). It is of note that the mean number of T2 lesions in patients recruited for those trials was significantly higher than in the natural history cohort patients [46]. The relative and absolute risk reductions for conversion to CDMS over 2 years in the various RCTS were 50% and 15-20% respectively [47-51]. Patients with more than 9 T2 and/or gadolinium-enhancing (Gad+) lesions had the greatest benefit [52]. More recent data suggests that the presence of more than 3 T2 lesions on baseline MRI predicts higher conversion rate to CDMS and risk of future disability [53, 54].
In a recent Phase III trial in CIS patients, teriflunomide, a novel oral DMT, reduced the relative risk of conversion to CDMS by 42.6% [55]. There were no serious adverse effects. Teriflunomide is currently under review by regulatory authorities for approval as treatment in patients with CIS.

Recommendations:
CIS patients should be offered any of the approved DMTs based on the available evidence showing efficacy in reducing the risk of conversion to definite MS. High risk patients with high MRI lesion load (> 9 T2 lesions), and/or severe relapses with incomplete recovery, are advised to start DMT early. It is appropriate to monitor low risk patients (those with normal baseline MRI) clinically and radiologically and offer treatment if they show signs of new demyelinating disease activity. In patients who fall in between the two risk groups, factors such as CSF oligoclonal bands, spinal lesions, relapse severity, extent of recovery, multifocal onset, and patient preference can influence the clinical decision. In that case, a brief watchful phase with a follow up brain/cervical spine MRI at 6 months or early DMD initiation are both appropriate.


Relapsing Remitting Multiple Sclerosis (RRMS):

Seven DMTs are currently approved as first-line therapy in RRMS without any restrictions: IFN-beta 1a IM, IFN-beta 1a SC, IFN-beta 1b SC, Peginterferon-beta 1a, GA, teriflunomide, and dimethyl fumarate (DMF), Three other DMTs are approved as first line therapy but with certain restrictions. Fingolimod is approved for initial treatment of RRMS in the USA, but can only be used in Europe for patients failing first line therapies or those with aggressive disease from onset. Alemtuzumab is approved in Europe as first line therapy for patients with active disease as defined by clinical and imaging features, but is still under review by the FDA. Natalizumab is approved as second line therapy or in patients with aggressive disease from onset.

Interferons & Glatiramer Acetate:
The use of IFN-beta and GA in RRMS is supported by class I evidence derived from several multicenter RCTs [56]. They show moderate efficacy in reducing relapse rate and risk of disability progression by approximately 30% [57-60]. Furthermore, early treatment with IFN-beta 1b SC was associated with 47% reduction in the hazard ratio for all-cause mortality over 21 years as compared with initial placebo treatment [61]. The major advantage of IFN-beta and GA is their long-term safety data accumulated over more than 2 decades. Their main drawback relates to their route of administration and acute side effects such as injection site reactions and flu-like symptoms, which have led to poor therapy adherence [62]. Peginterferon-beta-1a is a newly approved subcutaneous interferon. Its prolonged half-life through a process called pegylation allows for a single dosing every 2 weeks. In the ADVANCE trial, peginterferon-beta-1a reduced annualized relapse rate (ARR) by 36% and risk of disability progression by 38% with an adverse event profile similar to the rest of the Interferons [63].

Fingolimod:
Fingolimod is a sphingosine1-phosphate receptor modulator, which inhibits lymphocyte egress from lymph nodes resulting in reduced infiltration of potentially auto-aggressive lymphocytes into the CNS [64, 65]. Fingolimod was the first oral DMT approved for RRMS based on two phase III clinical trials [66, 67]. It reduced the ARR by 55% and 52% compared to placebo and IFN-beta 1a IM respectively, and the risk of disability progression by 30% compared to placebo only [66, 67]. In a subgroup analysis of patients with highly active disease despite IFN treatment in the year preceding enrollment, fingolimod reduced ARR by 61% relative to IFN-beta 1a IM along with reduction in lesion counts and brain volume loss [68]. In a real-world study using propensity-matched data from MSBase, patients switching to fingolimod due to breakthrough disease on first line DMTs had a 45% reduction in time to first relapse when compared to patients switching to other first line therapies such as IFN or GA [69]. In another real-world study using propensity-matched data from a US claims database, patients switching from IFN to fingolimod had a 62% reduction in ARR compared to those shifting to GA [70]. However, careful monitoring is needed due to several safety issues including bradycardia, macular edema and infections. Recent data from the international fingolimod pregnancy registry revealed a significant incidence of major congenital malformations in female patients exposed to the drug during the first trimester. Accordingly it is advisable for women with MS to discontinue fingolimod 2-3 months before attempting to get pregnant [71].

Teriflunomide:
Teriflunomide is a reversible inhibitor of the mitochondrial enzyme dihydro-orotate dehydrogenase (DHODH), which mediates de novo synthesis of pyrimidine in rapidly proliferating immune cells [72, 73]. Teriflunomide was the second oral DMT to receive FDA approval based on two phase III clinical trials in patients with RRMS. In the TOWER and TEMSO trials, teriflunomide at a dose of 14mg daily, reduced ARR by 36.3% and 31%, and the risk of disability progression by 31.5% and 30% respectively when compared to placebo [74, 75]. The lower dose (7mg) failed to show significant effect on disability measures. Teriflunomide is the only approved oral medication to have shown statistically significant effect on disability progression in both phase III trials. When compared to IFN-beta 1a SC in a randomized rater-blinded study, teriflunomide 14 mg daily did not show any difference in time to failure (defined as first occurrence of confirmed relapse or permanent treatment discontinuation for any cause)[76]. Overall, Teriflunomide is well tolerated and safe with rare and mild adverse events including hair thinning, elevation of serum liver enzymes and mild leucopenia. In addition, patients receiving teriflunomide are advised to use adequate methods of contraception since it is labeled as pregnancy category X based on animal studies. However, human pregnancy registries of teriflunomide and its precursor leflunomide did not show any increase in risk of congenital malformations as compared to the general population [77]. Teriflunomide can be quickly cleared from the body within 11 days using oral cholestyramine or charcoal.

Dimethyl Fumarate (DMF):
DMF is another oral medication that has recently been approved for the treatment of RRMS. It is a modified fumaric acid ester which promotes anti-inflammatory and cytoprotective activities that are mediated, at least in part, by the (Nrf2) antioxidant response pathway [78]. The drug was approved based on two phase III trials [79, 80]. In the DEFINE study, both doses of DMF (240 mg twice or three times per day) showed a significant reduction in ARR (53% and 48%), and disability progression (38% and 34%) as compared to placebo [79]. The results were replicated in the CONFIRM study in that both doses of DMF were associated with significant reduction in ARR (44% &, 51%) compared with placebo, but there was no significant effect on disability progression [80]. Although the study had an active comparator (GA), no significant differences in ARR or risk of disability progression were observed between DMF and GA. It should be noted however that the study was not powered to evaluate head-to-head treatment superiority [80]. In a recent subgroup analysis of the DEFINE and COFIRM trials, patients not responding to INF-beta in the year preceding randomization were looked at. DMF was generally safe and well tolerated; the most common AEs included flushing and gastrointestinal AEs (eg, diarrhea, nausea, vomiting). Two cases of progressive multifocal leukoencephalopathy (PML) were however reported with the use of fumarates in psoriasis, both in association with prolonged and significant lymphopenia [81].

Natalizumab:
Natalizumab was the first approved monoclonal antibody for RRMS [82]. It is a selective adhesion molecule inhibitor, that interferes with the influx of inflammatory cells into the brain by binding to the α4 subunit of the α4β1 integrin expressed on the surface of immune cells, preventing its interaction with the vascular cell adhesion molecule (VCAM1) on the endothelial cells [83]. In the phase III AFFIRM trial, natalizumab reduced the rate of clinical relapse by 68% and the risk of sustained disability progression by 42% compared to placebo [84]. This was supported by extensive post marketing data, reporting improved efficacy in patients switched from first line therapies due to suboptimal response [85-88]. A large Spanish observational study evaluated 825 patients who were treated with natalizumab for at least 1 year, of whom 93% had received prior immunotherapies. The percentage of patients with at least one relapse decreased from 89% in the year prior to treatment to 20% in the year after starting treatment, and 24% of patients showed improvement in their EDSS (p < 0.0001) [86]. However, due to the risk of (PML, estimated at around 3.45 per 1000 (95% CI 3.1- 3.79), its use was restricted to patients failing first line therapy or those with aggressive disease [89]. Infection with the JC virus (JCV) is a prerequisite for developing PML as all cases with prior testing were seropositive for JCV antibodies. Prior use of immunosuppressant and duration of natalizumab for more than 2 years increase the risk of PML[90]. A two-step enzyme-linked immunosorbent assay (ELISA) has been developed to detect JCV antibodies in serum [91]. The prevalence of JCV antibodies in MS patients is approximately 50– 60% with a 2– 3% rate of seroconversion annually [90, 92]. The risk of PML remains significantly low in seronegative patients (0.1/1000) or in seropositive patients with less than 2 years treatment and no prior use of immunosuppressants (0.7/1000). The risk however increases significantly reaching 11.2/1000 in seropositive patients treated with natalizumab for more than 2 years and with prior exposure to immunosuppressants [89]. It appears that JCV antibody titers above 1.5 are associated with increased risk while titers below 0.9 indicate a much lower risk of developing PML in patients without prior immunosuppressants use. On the other hand, natalizumab remains one of the well-tolerated DMTs with one of the highest efficacies in highly active RRMS patients [93]. Recent data showed a good safety profile in women exposed to natalizumab during their first trimester of pregnancy [94].

Alemtuzumab
Alemtuzumab is a humanized monoclonal antibody that has been approved in the European Union and other countries, and is currently under regulatory review in the United States for the treatment of active RRMS. Alemtuzumab targets the CD52 surface protein, which is present at high levels on T and B lymphocytes and to a lesser extent on other immune cells [95]. In a 2-year phase III RCT in 581 treatment-naïve early RRMS patients, alemtuzumab was associated with a significant 54.9% reduction in the risk of relapse at 2 years as compared to IFN beta- 1a SC (p < 0.0001). However, there was no significant difference in sustained accumulation of disability (8% Vs. 11%; p = 0•22) [96]. In a separate, 2-year phase III RCT, alemtuzumab was compared with IFN-beta 1a SC in 840 RRMS patients who had at least one relapse on IFN beta or GA. The relapse rate and risk of sustained accumulation of disability were reduced by 49.4% and 42% respectively compared to IFN beta-1a over 2 years [97]. Alemtuzumab was associated with frequent mild to moderate infusion reactions (managed with premedication) and increased rate of infections (predominately cutaneous herpes). Prophylactic acyclovir following alemtuzumab infusion reduced significantly the risk of herpes infection and is currently part of the treatment protocol. The major drawback however was related to delayed secondary autoimmune events with a peak incidence in the third year of therapy. Autoimmune thyroiditis was reported in almost 30% of patients, followed by immune thrombocytopenia in less than 1%, and rare cases of anti-glomerular basement membrane disease.


Treatment Algorithm For RRMS patients:

Given the increasing number of available DMTs , different treatment strategies have been proposed for initiation and escalation of therapy in patients with RRMS due to lack of class 1 evidence comparative data between the newer agents. Com¬paring across trials with different designs and baseline charac¬teristics is associated with inherent limitations. On the other hand, given the difference in mode of action of the new agents and the absence of such comparative data, lateral switching may be an acceptable option in patients with poor response to any of the DMTs. With the lack of class I evidence to support every therapeutic decision in MS, evidence-based medicine derived from clinical studies must be supplemented by real world evidence and expert opinion in order to decide on the best therapeutic option available for an individual patient. Ideally, in a not so far future, MS therapy will be tailored to individual patient needs based on different biological and radiological biomarkers. Taking all the of the above into consideration, we developed an algorithm for the treatment of MS based on the available scientific evidence, approved FDA and EMA indication labels, and expert opinion.

Treatment naïve-patients:
It is imperative to start DMTs early once the diagnosis of RRMS is established in order to reduce inflammation and secondary axonal loss in the CNS. Multiple studies have shown that early treatment might decrease the long-term accumulation of disability in patients with MS [98, 99].

Recommendations:
The following DMTs can be initiated in treatment naïve patients based on class1 evidence: IFN-beta, GA, Teriflunomide, and DMF. In patients with needle phobia, or contraindications/ adverse events related to the above DMTs, fingolimod is an acceptable alternative.
In patients with highly active disease, as defined by 2 disabling relapses in one year and the presence of Gd-enhancing lesions and /or high lesion load on baseline MRI, fingolimod, natalizumab, or alemtuzumab may be initiated following careful risk stratification (Serum JCV antibody, prior immunosuppressant use, cardiac disease, diabetes, retinal disorders, previous autoimmune diseases, and thyroid disorders).
If natalizumab is initiated in patients who are seronegative for JCV, it is recommended to test for the antibody every 6months. In patients who are seropositive for JCV or those who seroconvert during therapy, it is recommended to reassess benefit/risk ratio after 2 years of treatment. In patients with prior immunosuppressant use and on natalizumab therapy for more than 2 years, a shift to either alemtuzumab or fingolimod should be considered based on risk stratification


Suboptimal responders with breakthrough disease:
This term has been interchangeably used with treatment failure, or treatment non-responders. We prefer to avoid both terms as they imply that the specific DMT being used has failed, while a certain degree of disease activity is expected with most currently available MS therapies [100]. Certain confounding factors need to be considered before labeling a patient as suboptimal responder, including poor adherence to therapy, and an adequate DMT trial for at least 6-12 months. The advent of more potent therapies has made the “No Evidence of Disease Activity’ endpoint, as defined by absence of relapses, new MRI lesions, and disability progression, more attainable, and raised our level of concern to ongoing clinical or radiological disease activity in patients on DMTs. Although we still lack a clear definition of breakthrough disease, most current criteria are based on clinical relapses, MRI activity, and accumulation of disability. The 2 major efforts in providing evidence-based criteria for breakthrough disease came from Rio and his group [101, 102] and the Canadian Multiple Sclerosis Group (CMSWG) [103, 104]. The CMSWG based their criteria on different levels of concern, reflecting increasing clinical and radiological disease activity. Low, medium, and high levels of concern were defined for clinical relapses, MRI activity, and disability progression. Suboptimal response requiring a change in therapy was defined as the presence of one high, two medium, or three low levels of concern after one year of treatment. Applying the original CMSWG criteria to the PRISMS trial data, 89% of patients labeled as suboptimal responders at the end of the first year of therapy went on to develop significant breakthrough disease in the ensuing 3 years [103]. It is of note that the high level of concern for MRI activity requiring therapy change was defined as ≥ 3 active lesions (enhancing and/or new T2W lesions) [104]. In a recent systematic review of all studies assessing predictors of poor response to IFN-Beta therapy, patients with ≥ 2 new T2 or ≥ 1 gadolinium-enhancing lesions had significantly increased risk of both future relapses and progression [105].

The modified Rio score was based on statistical modeling using the PRISMS trial data. It was derived from the addition of 2 scores reflecting number of relapses (no relapse=0, 1 relapse=1, ≥ 2 relapses=2) and new T2W lesions (≤ 4 lesions=0, > 4 lesions=1) during the first year of therapy [102]. Progressive disability was not used in the final score as MRI lesions and relapses mediated the full effect on the final outcome. Disability progression in the subsequent 3 years occurred in 65% of patients with a modified Rio score of 2-3, and 24% of patients with a score of 0 at the end of the first year of treatment. Patients with an intermediate score of 1 were further stratified by a follow-up MRI at 18 months. The presence of ≥ 2 new T2W lesions on MRI or ≥ 1 relapse shifted them into the high-risk group [102].

In conclusion, the combined use of clinical and radiological criteria during the first year of therapy is best at identifying non-responders early in the disease course. We recommend that breakthrough disease should be considered in patients with clinically active disease (≥ 1 relapse and/or disability progression) and ≥ 2 active MRI lesions (Gd+ and/or new T2W), or in patients with severe relapses (defined as high concern by the CMSWG) or ≥3 active lesions.

Recommendations:
In patients with suboptimal response to first-line therapies as defined above, treatment escalation should be considered. Although no class I evidence supports therapy escalation to any of the currently available DMTs, fingolimod, natalizumab, and alemtuzumab, are all adequate choices based on currently available studies, and post-marketing experience. The choice among them should be based on risk stratification (Serum JCV antibody, prior immunosuppressant use, cardiac disease, diabetes, retinal disorders, previous autoimmune diseases, and thyroid disorders). If natalizumab is initiated in patients who are seronegative for JCV, it is recommended to test for the antibody every 6-months. In patients who are seropositive for JCV or those who seroconvert during therapy, it is recommended to reassess benefit/risk ratio after 2 years of treatment. In patients with prior immunosuppressant use and on natalizumab therapy for more than 2 years, a shift to either alemtuzumab or fingolimod should be considered based on risk stratification. In patients with evidence of clinical and/or radiological disease activity not fulfilling criteria for breakthrough disease, especially those with minor relapses, minimal disability, and full recovery (defined as low concern clinical activity by the CMSWG), lateral switch to another first line DMT with a different mechanism of action may be considered. On the other hand, a watchful period for 6 months with reassessment of risk at 18 months is also acceptable: in patients with ≥ 1 relapse or ≥2 new T2W on MRI, therapy escalation should be considered. In patients with evidence of breakthrough disease on any of the second line medications, a lateral switch should be considered based on the risk stratification strategy mentioned above before resorting to third line medications that are either used off-label such as rituximab or cyclophosphamide, or have a poor safety profile such as mitoxantrone.


Secondary Progressive Multiple Sclerosis (SPMS):

Secondary progressive MS is a challenging entity in terms of therapeutics as most clinical trials have failed to show significant efficacy in halting disease progression. For treatment purposes two subtypes of SPMS should be differentiated: SPMS with or without evidence of active inflammation, as defined by presence of superimposed relapses A European randomized trial comparing IFN Beta 1b SC to placebo showed a significant reduction in disability progression[106]. However, patients with superimposed relapses were included which could have affected the primary end point [106]. A similar trial conducted in the US failed to reproduce this result despite reduction in relapse rate and MRI activity [107]. Similar results were obtained when IFN Beta 1a SC was investigated [108]. Both drugs are currently approved in Europe for use in SPMS with relapses. Another trial with high dose IFN Beta 1a IM (60 mcg once weekly) failed to show any benefit on disability progression despite 44.4% reduction in the MSFC (MS Functional Composite) score [109]. A Cochrane review evaluating 5 RCTS of IFN Beta in 3122 patients with SPMS concluded that IFN Beta does not prevent the development of permanent physical disability in SPMS despite reduction in the risk of relapse and short term relapse-related disability, which could be related to the anti-inflammatory effects of IFNs [110].

Mitoxantrone (MX) is a cytotoxic agent, which acts by intercalating with DNA and inhibiting the topoisomerase II enzyme activity for DNA repair. [111] It was approved by the FDA for treatment of progressive MS based on a small phase III trial including 194 patients, considered to represent at best class II/III evidence due to inadequate blinding and small numbers[112]. A Cochrane review evaluating 3 trials, with 221 patients, showed that MX reduced disability progression and relapse rate in the short term (two years). Its use in clinical practice however, has decreased significantly in recent years due to a high rate of serious adverse events including cardiotoxicity (12%) and leukemia (0.8%) [113].

Other immunosuppressants such as cyclophosphamide, methotrexate and mycophenolate were evaluated in either single arm or small open-label unblinded trials, with suggested effects on short term disability progression. Such results however were not confirmed by large-scale randomized placebo-controlled trials [114-116].

Recommendations:
In SPMS patients with evidence of superimposed relapses, IFN beta 1b SC or IFN beta 1a SC (high dose) is recommended (Class I evidence). There is insufficient evidence to recommend continuation of IFN beta in SPMS patients who show disease progression. In SPMS patients without relapses, mitoxantrone may be offered after comprehensive discussion with the patient regarding its serious adverse event profile (Class II/III evidence). Short term 6 months trials with cyclophosphamide, methotrexate, or mycophenolate may be considered based on rate of disability progression, presence of enhancing lesions on MRI, and patient’s choice. Escalation therapy may be considered in SPMS with relapses and evidence of suboptimal response on IFN beta.


Primary Progressive Multiple Sclerosis (PPMS)

Several drugs have been evaluated for the treatment of PPMS in the last two decades but none of them showed any significant benefit in halting disease progression.[117-120].

Recommendations:
No treatment can be currently recommended for patients with PPMS.


CONCLUSION:

With evolving diagnostic criteria and the advent of new oral and parenteral therapies for MS, most current diagnostic and treatment algorithms need reevaluation and updating. Diagnostic and therapeutic decisions need to be made based on currently available scientific data as well as personal experience. The aim of this review is to provide recommendations and general guidelines for the diagnosis and treatment of MS based on scientific evidence and expert opinion.


TREATMENT ALGORITHM


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