Accepted Manuscript Title: Consensus Recommendations for the Diagnosis and Treatment of Multiple Sclerosis in Kuwait Author: R. Alroughani A. Ashkanani J. Al-Hashel R. Khan A. Thussu K.J. Alexander P. Vembu K. Sharfuddin S. Lamdhade J.K. John S. Alkhashan M. Abualmelh S. Al-Shammri PII: DOI: Reference:
S0303-8467(16)30041-5 http://dx.doi.org/doi:10.1016/j.clineuro.2016.02.001 CLINEU 4304
To appear in:
Clinical Neurology and Neurosurgery
Received date: Revised date: Accepted date:
27-8-2014 17-11-2015 2-2-2016
Please cite this article as: Alroughani R, Ashkanani A, Al-Hashel J, Khan R, Thussu A, Alexander KJ, Vembu P, Sharfuddin K, Lamdhade S, John JK, Alkhashan S, Abualmelh M, Al-Shammri S.Consensus Recommendations for the Diagnosis and Treatment of Multiple Sclerosis in Kuwait.Clinical Neurology and Neurosurgery http://dx.doi.org/10.1016/j.clineuro.2016.02.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Consensus Recommendations for the Diagnosis and Treatment of Multiple Sclerosis in Kuwait R. Alroughani1,2*, A. Ashkanani1, J. Al-Hashel3,4, R. Khan3, A. Thussu1,2, KJ Alexander3, P. Vembu3, K. Sharfuddin3, S. Lamdhade1, JK. John3, S. Alkhashan5, M. Abualmelh6, S. AlShammri3,7 1
Division of Neurology, department of Medicine, Amiri hospital, Kuwait
2
Neurology Clinic, Dasman Diabetes Institute, Kuwait
3
Department of Neurology, Ibn Sina Hospital, Kuwait
4
Department of Medicine, Kuwait University, Kuwait
5
Division of Neurology, department of medicine, Farwaniya Hospital, Kuwait
6
Division of Neurology, department of medicine, Al-Adan Hospital, Kuwait
7
Division of Neurology, department of medicine, Mubarak Al-Kabeer Hospital, Kuwait
Corresponding Author: Raed. A. Alroughani, MD, FRCPC Department of Medicine, Division of Neurology, Amiri Hospital Arabian Gulf Street, Sharq, 13041, Kuwait. Tel: +965 2245005 Ext 4444 Fax: +965 22467499 Email: [email protected]
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Highlights:
Multiple Sclerosis remains a clinical diagnosis supported by McDonald diagnostic criteria. Ruling out mimickers of multiple sclerosis is important to reach the diagnosis with high accuracy. A personalized treatment approach based on risk versus benefit analysis is recommended. A multi-disciplinary team approach has been increasingly utilized in management of MS patients.
Abstract. Objectives: We aim to develop consensus recommendations to guide neurologists in the community for the diagnosis and treatment of MS. Methods: After reviewing the available literature, a group of neurologists with expertise in MS met to discuss the evidence and develop consensus recommendations for the diagnosis and treatment of MS. Results: The revised 2010 McDonald criteria is the established diagnostic criteria for MS and has wide international acceptance among international MS experts. Several red flags in the history and examination, along with certain laboratory tests were pointed out to exclude MS mimickers in the diagnostic phase. The available approved disease modifying therapies (DMTs) were listed in an algorithmic fashion based on initial assessment of disease severity and disease breakthrough while on DMTs. Risk stratification based on the benefit versus risk ratio was used to help choosing the appropriate therapy to MS patients using an “individualized therapy” approach. The requirements for initiation and monitoring of treated MS patients were highlighted with emphasis on early identification of disease breakthrough, adverse events, and safety concerns. The role of multi-disciplinary MS clinics was discussed and a guide for referral to specialized MS clinics was developed. Conclusions: Consensus recommendations have been developed to guide local neurologists on the diagnosis and treatment of patients with MS. Implementation of the revised 2010 McDonald diagnostic criteria was advised while a personalized treatment approach was recommended using a treatment algorithm based on risk stratification and patient-centered outcomes. Keywords: Multiple sclerosis, Diagnosis, Treatment, Recommendations, Risk stratification
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INTRODUCTION: Multiple Sclerosis (MS) is a chronic demyelinating disorder of the central nervous system (CNS) which predominately affects patients aged 20-40 years. The epidemiology of MS is changing worldwide as the understanding of the natural history continues to show new trends in clinical consequences of disease activity and disability progression with a moving target of several pathological mechanisms involving environmental and genetic factors [1, 2]. The prevalence and incidence rates are increasing in Kuwait and in the neighboring gulf countries in the last 2 decades [3, 4]. The field of demyelinating disease is evolving as new diagnostic criteria have been established and novel treatments have been added to the armamentarium. There is a need to unify the approach to MS diagnosis and treatment among neurologists in the community in order to optimize the care of MS patients based on up-to-date evidence-based medicine and wellestablished practice guidelines. The goal of this document is to present a logical stepwise evidence-based approach to the diagnosis and management of MS patients..
METHODS: A group of neurologists involved in the care of MS patients. The panel consisted of academic, hospital-based and community general neurologists with expertise in MS, along with specialized MS neurologists in order to ensure a wide diversity of opinions. A search of the literature was performed and the panel met to discuss the updated evidence in order to develop local consensus and practice recommendations for the diagnosis and treatment of Multiple Sclerosis with special emphasis on the practice in Kuwait.
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RESULTS & DISCUSSION: Diagnosis of Multiple Sclerosis: The diagnosis of MS remains clinical despite the recent advances in diagnostics and the availability several radiological and neuro-immunological surrogate markers. The diagnosis relies on comprehensive history taking and neurological examination to determine the dissemination in time and space of certain clinical symptoms/signs while incorporating paraclinical tests to exclude mimickers. In 1983, Poser et al. incorporated certain paraclinical tests such as MRI, evoked potentials (EPs) and CSF oligoclonal bands (OCB) into the diagnostic criteria [5]. As the understanding of the natural history of the disease improved through assessments of long-term registries, it was important to identify cohorts who were destined to develop MS after presenting with their first clinical event. Hence, the term clinically isolated syndrome (CIS) was introduced in the diagnostic criteria proposed by McDonald et al. in 2001 [6] which was revised in 2010 emphasizing the notion of dissemination in time and space in the diagnosis of MS using MRI techniques which remains the best surrogate marker to date [7].
The panel agreed on the application of the 2010 revised McDonald criteria as a first line of diagnosis work-up. However, they stressed on the fact that clinical and paraclinical red flags should be sought and excluded before applying the diagnostic criteria. A detailed approach to identification of red flags is outlined in table 1. The panel pointed out the regional characteristics of clinical presentations and disease progression, which differ from cohorts studied in the western countries where the criteria were developed. Furthermore, the panel encouraged continued clinical and laboratory monitoring of patients with atypical presentations who might
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be labeled as CIS. The panel recommended obtaining CSF in patients with atypical presentations and patients under 18 years of age.
The panel suggested a unified approach when explaining the CIS terminology to the patients. They encouraged the use of the term CIS suggestive of MS (CISSMS) in patients who did not fulfill the dissemination in time and space criteria but had typical clinical and MRI characteristics [8, 9]. This would lessen the diagnostic confusion among patients who are not usually aware of the differences between MS and CIS. By using the term CISSMS, physicians would be able to discuss the future risk of the development of the second clinical attack and be aware of the need of clinical and radiological monitoring in the first 5 years. The “wait and see” approach and the statement of “no better explanation” were highlighted with emphasis on careful history taking / neurological examination and proper timing in conducting additional or followup investigations [10].
In the last two decades, Neuromyelitis optica (NMO), which, is an uncommon inflammatory demyelinating CNS disorder that is distinct from MS, appeared to evolve in the differential diagnosis of MS [11]. Autoantibodies that target aquaporin-4 (AQP4-IgG) are highly specific for NMO and have helped define a spectrum of disease beyond the classic definition. A revised diagnostic criteria improved the yield of identifying NMO patients by instituting major criteria (evidence of acute optic neuritis and transverse myelitis) and minor criteria (at least two out of three of the following: MRI brain non-diagnostic for MS, MRI spinal cord lesion extending over three or more vertebral segments or NMO-IgG seropositivity) [12]. However, some NMO patients might not exhibit AQP4-IgG and additional clinical and radiological features such as
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involvement of area posterma, brainstem, and diencephalon could be seen in a spectrum of NMO patients. Hence, a new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG) has been suggested. The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of seronegative NMOSD [13].
Given the wide use of MRI in the diagnostic process of several neurological conditions other than MS (e.g. headaches), patients diagnosed with Radiologically Isolated Syndrome (RIS) have been increasingly identified. RIS was first introduced in 2009 [14] to define a relevant cohort of individuals routinely encountered in clinical practice who are at risk for future demyelinating events. A recent retrospective multi-center study assessed the 5-year risk of the first clinical demyelinating event in 451 RIS patients with a mean follow-up time of 4.4 years. A meaningful number (34%) of RIS subjects developed their first demyelinating events (i.e. CIS) within a 5year period from the initial MRI brain study. An age < 37 years, male sex, and spinal cord involvement appear to be the most important independent predictors of symptom onset [15].
The panel recommended minimal routine laboratory screening consisted of CBC, LFT/RFT, ANA / pANCA, cANCA, CRP/ESR, ENA, RF, Serum ACE level, TSH, Vitamin B12 level, and Anti-cardiolipin antibodies. Additional specific investigations may be necessary when suspecting certain MS mimickers as outlined in table 2.
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With respect to the routine use of MRI in clinical practice, MS protocols based on the proposed 2009 revised guidelines of the Consortium of MS Centers MRI Protocol for the Diagnosis and Follow-up of MS was recommended [16]. The panel recommended performing Brain and cervical spine with gadolinium at baseline and at 3-6 months intervals, in order to detect dissemination in time and space in CIS patients. Additional MRI sections of the thoracic cord may be performed when indicated. Spinal STIR sequence is to be incorporated in the MRI protocol to improve sensitivity of detecting spinal lesions and to better assess the accumulation of spinal lesions with time in order to avoid misdiagnosis with NMO. The panel agreed on the following diagnostic approaches regarding specific situations:
CSF analysis is recommended in CIS patients not satisfying the revised 2010 McDonalds criteria, patients with atypical presentations, pediatric cohorts, and in certain patients with suspected other demyelinating disorders such as acute disseminated encephalomyelitis “ADEM” or NMO.
RIS patients should be evaluated in the MS clinic or by experienced neurologists prior to the initiation of extensive diagnostic investigations. Neurologists should take into consideration patients` preferences, as few patients may not want to start a diagnosis nor further work up. Once the RIS diagnosis is discussed, the panel recommends clinical and radiological follow up at 6-12 months intervals, and to withhold CSF testing at the initial stage. If the follow up MRI study shows dissemination in time and space, the diagnostic process for a possible demyelination disorder should be initiated.
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AQP4-IgG testing is recommended in patients who are suspected to have NMO based on clinical or radiological features. It may be performed in a centralized laboratory preferably equipped with cell-based techniques for better sensitivity.
Treatment of Multiple Sclerosis Acute Relapse (Attack): Relapses may present early throughout the course in patients with relapsing remitting MS or may be superimposed in patients with progressive relapsing MS. Relapses are closely related to disease progression in the first five years especially in patients accumulating residual disabilities [17, 18]. A relapse is defined as new or recurrent neurologic symptoms not associated with fever or infection that lasted for at least 24 hours and was accompanied by new neurologic signs confirmed by the examining neurologist. Systemic corticosteroids are the mainstay treatment for acute relapses. Several publications showed the efficacy of Intravenous Methyl Prednisolone (IV-MP) in the treatment of acute relapses when compared to placebo, ACTH and dexamethasone in late 1980s [19-21]. A Cochrane meta-analysis showed a trend for better efficacy of IV-MP but there was no significant difference between its use for a short (5 days) and extended period (15 days). The adverse effects of IV use were comparable to oral prednisone, which were mainly gastrointestinal and psychiatric manifestations [22]. The use of oral prednisone taper following IV-MP was used in many centers following the results of Optic Neuritis Treatment Trial (ONTT) which concluded that the IV-MP followed by oral prednisone speeds the recovery of visual loss [23]. Although not all optic neuritis patients were diagnosed with MS, the results had a bearing impact on the treatment of acute MS relapses. In patients who did not respond to IV-MP, plasmapheresis was the only second line option supported by clinical evidence based on two small RCT (level II evidence) [24, 25]. Several case 8 | P a g e
reports revealed functional neurological improvement after plasmapheresis in patients who were unresponsive to IV-MP or with severe acute exacerbations [26-29]. Early initiation of plasmapheresis, male gender and preserved reflexes were predictors of favourable response.[30] A retrospective study evaluating 41 patients, showed that time from symptom onset to plasmapheresis was significantly shorter in patients who improved compared with those who did not respond. A response might be seen even at 60 days after the relapse onset but with a decreasing response rate [26]. The American Academy of Neurology guidelines recommend using plasma exchange for severe relapses in remitting-relapsing MS unresponsive to corticosteroids [31]. The panel further discussed several issues in the treatment of MS relapses, which were summarized below:
Pseudo-relapses should be differentiated from true relapses by taking the appropriate history of preceding infections and performing the necessary work up such as chest X-ray and urinalysis.
Patients with suspected relapses should be evaluated urgently in the outpatient clinics within 1 week. The response to corticosteroid treatment should be evaluated within 2 week after the institution of initial IV-MP course. 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 [32].
In patients with psychiatric manifestations (e.g. psychosis), the benefit of IV-MP should be weighted against the risk. A short course (3-day) of IV-MP is preferred and caution with oral prednisone taper should be exercised.
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Any relapse that poses a functional impairment such as pyramidal and cerebellar symptoms/ signs should be treated while the benefits versus the risks of corticosteroids should be considered for sensory relapses.
It was generally accepted that oral prednisone taper should be only used in selected patients where the risk of rebound relapse is high in the subsequent 2 weeks.
Plasmapheresis might be offered to patients who fail to show any functional recovery or still have significant functional impairment by 2-6 weeks following the administration of the last IV-MP course. Since it may quite invasive, the benefits and the risks of plasmapheresis should be discussed with the patients especially in patients who have unfavourable prognostic indicators.
Routine use of Intravenous Immunoglobulin (IVIG) is not recommended for the treatment of MS relapses given the insufficient evidence. However, in patients who have contraindications to IV-MP and plasmapheresis, IVIG (2g/kg over 3-5 days) may be used based on the available supportive data [33, 34].
Recommendations: IV Methylprednisolone (IV-MP) one gram daily for 3-5 days +/- tapering oral steroids for 1-2 weeks is recommended for the treatment of acute relapses. It is appropriate to consider plasmapheresis (5-7 sessions over 2 weeks) in the treatment of patients with severe disability who fail to respond to IV-MP.
Clinically Isolated Syndrome (CIS): Definition CIS is defined as the first episode (monophasic) with either monofocal or multifocal neurological
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symptoms/signs suggestive of MS typically involving the optic nerve, brainstem/ cerebellum, spinal cord or cerebral hemisphere. The panel stressed that the symptoms and signs should be typical of CNS inflammation and there are no better explanations after excluding mimickers by comprehensive work-up when indicated. Risks: CIS conversion to MS has been studied extensively in the last decade. 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]. 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 ≥ 9 T2 lesions at the baseline brain MRI increases the risk of conversion in the first 5 years [9, 39]. Spinal cord lesions and positive oligoclonal bands in CSF are associated with increased risk of conversion to CDMS [40, 41]. Treatment: The decision to treat CIS patients with DMTs is challenging. The decision depends on several key factors, which include clinical (recovery or residual disability following the first attack) and radiological (number and location of MRI lesions) characteristics, the presence of oligoclonal bands, and patients` perception and understanding of the future risk of developing definitive MS. It is imperative that a comprehensive discussion of early institution of DMTs is initiated with patients who are at high risk of conversion. There are four approved DMTs (Interferon beta 1a SC, Interferon beta 1a IM, Interferon beta 1b SC, and Glatiramer Acetate SC) based on class I evidence supported by randomized clinical
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trials (RCTs). The relative and absolute risk reductions for conversion to CDMS over 2 years in the various RCTS were 50% and 15-20% respectively [42-46]. Patients with more than 9 T2 and/or gadolinium-enhancing (Gad+) lesions had the greatest benefit [47]. The panel discussed the recent update on TOPIC, a phase III study assessing teriflunomide, a novel oral, DMTs in 618 CIS patients [48]. Teriflunomide 14mg reduced the risk of conversion to CDMS by 42.6% (p=0.0087). Teriflunomide is currently under review by regulatory authorities for approval as treatment in patients with CIS. Recommendations: CIS patients may 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 severe relapses/ residual disabilities and/or high MRI lesion load (> 9 T2 or Gad-enhancing lesions) are advised to start DMTs early. It is appropriate to monitor low risk patients (those with normal baseline MRI) clinically and radiologically and to 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 DMT initiation is appropriate.
Relapsing Remitting Multiple Sclerosis (RRMS): Seven DMTs have been approved by the FDA to be used in RRMS as a first-line therapy: IFNbeta 1a IM, IFN-beta 1a SC, IFN-beta 1b SC, GA, teriflunomide, fingolimod, and dimethyl fumarate (DMF). However, fingolimod was approved as a second line therapy in Europe except in cases of aggressive disease, which will be discussed later. Recently, alemtuzumab was
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approved in Europe, Canada and Australia as a treatment for active MS while it was restricted in the USA for the use in patients who showed inadequate response to two or more DMTs. Here, we review the efficacy and safety of the approved DMTs. A treatment algorithm and recommendation of initiation, escalation and monitoring of RRMS on different DMTs follow this. Interferon & Glatiramer Acetate: The use of IFN-Beta and GA in RRMS is supported by class I evidence given results shown by several multi-center RCTs [49]. They offer a modest efficacy in reducing the annualized relapse rate (ARR) and disease progression assessed by EDSS score by approximately 30% [50-53]. Furthermore, early treatment with IFN-beta -1b SC was associated with a 47% reduction in the hazard ratio for all-cause mortality over 21 years compared with initial placebo treatment [54]. IFN-beta and GA accumulated long-term safety data over the last 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 [55].
Fingolimod: Fingolimod is a sphingosine1-phosphate receptor (S1P) modulator, which inhibits lymphocyte egress from lymph nodes resulting in a reduced infiltration of potentially auto-aggressive lymphocytes into the CNS [56, 57]. Fingolimod was the first oral DMT approved for RRMS based on two phase III clinical trials [58, 59]. 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 [58, 59]. A 24-month extension study showed persistent effects of fingolimod and similar efficacy against IFN beta 1a IM [60]. A subgroup analysis of highly
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disease-active patients despite IFNβ treatment in the preceding year, showed that fingolimod reduced ARR by 61% relative to IFNβ-1a along with reductions in lesion counts and brain volume loss [61]. Fingolimod has been shown to improve the quality of life, which may lead to better long-term adherence to therapy [62]. However, careful monitoring upon initiation and follow-up should be exercised due to several safety issues including cardiac conduction abnormalities, 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 [63].
Teriflunomide: Teriflunomide is a reversible inhibitor of the mitochondrial enzyme dihydro-orotate dehydrogenase (DHODH), which is relevant for the de novo synthesis of pyrimidine in proliferating immune cells [64]. Teriflunomide was the second oral DMT to receive regulatory approval based on three phase III clinical trials in patients with RRMS [65-67]. In the TOWER trial, teriflunomide showed 36.3% and 31.5% reduction in ARR and 12-week sustained disability progression when compared to placebo [65]. Similar findings were seen in the TEMSO trial where ARR and the risk of sustained disability progression were reduced by 31% and 30% respectively [66]. 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 phase 3, rater-blinded study, teriflunomide did not show any difference in time to failure (defined as first occurrence of confirmed relapse or permanent treatment discontinuation for any cause) [67].
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Overall, Teriflunomide is well tolerated and safe with rare and mild adverse events including hair thinning, elevation of serum liver enzymes and mild leucopenia. 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 [68]. Teriflunomide can be quickly cleared from the body within 11 days using oral cholestyramine or charcoal. Dimethyl Fumarate (DMF): DMF is the third oral medication that has been recently 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 nuclear factor (erythroid-derived 2)-like 2, also known as (Nrf2) antioxidant response pathway [69]. The regulatory approval was granted based on the results of two 2-year phase III RCTs [70, 71]. In the DEFINE study which included 1234 RRMS patients, both doses of DMF (240 mg twice or three times per day) showed significant reduction in the ARR (53% and 48%), and the risk of disability progression (38% and 34%) as compared to placebo [70]. 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. However, there was no significant benefit in preventing sustained disability progression with either dose when compared to placebo at 2 years [71]. Although the study had an active comparator (GA), no significant differences in clinical and MRI outcomes were observed between DMF and GA. It should be noted that the study was not powered to evaluate head-tohead treatment superiority [71]. There were improvements in patient-reported outcome measures of physical and mental functions, quality of life, and general well being in the DEFINE study
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[72] . DMF was generally safe and well tolerated; adverse events included flushing, gastrointestinal AEs (e.g., diarrhea, nausea, vomiting), lymphopenia and elevated liver enzymes. In October 2014, a fatal case of progressive multifocal leukoencephalopathy (PML) was reported after exposure to DMF for 4.5 years in a naïve MS patient in the setting of prolonged (over 3.5 years), severe grade 3 lymphopenia (lymphocyte count fluctuated between 200-580 cell/µL) [73]. This was the first case of PML associated with DMF. In the past, other cases of PML have been reported with the use of fumaric acid esters in lymphopenic patients with psoriasis, although in the majority of these cases, the causal relationship could not be clarified (e.g. other risks for PML were present) [74]. Consequently, it is advised to monitor patients receiving DMF who experience lymphopenia regularly and at close intervals as clinically indicated.
Natalizumab: Natalizumab 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 [75]. Natalizumab was the first approved monoclonal antibody for RRMS. The 2-year phase III placebo-controlled RCT investigated natalizumab in 942 RRMS naïve-patients. It reduced the rate of clinical relapse by 68% and the risk of sustained disability progression by 42% compared to placebo [76]. A second phase III trial evaluated 1171 MS patients who had at least one relapse during the 12 months prior to recruitment while on IFN beta 1a IM where patients were randomly assigned to receive continued IFN beta 1a IM in combination with natalizumab or placebo for up to 2 years [77]. Combination therapy showed significant ARR reduction (0.34 vs. 0.75; P < 0.001) and 24% reduction in the risk of sustained
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disability progression over 2 years. However, two cases of PML were diagnosed in the combination arm [77]. Due to the risk of PML which was 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 [78]. 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[79]. A two-step enzyme-linked immunosorbant assay (ELISA) has been developed to detect the presence of JCV antibodies in serum [80]. The prevalence of JCV antibodies in MS patients is approximately 50– 60% with a 2– 3% rate of seroconversion annually [79, 81]. The risk of PML remains significantly low in seronegative patients (0.1/1000) or in seropositive patients with less than 2 years of treatment and no prior use of immunosuppressants (0.7/1000). The risk, however, of PML increases significantly reaching 11.2/1000 in seropositive patients who were exposed to prior immunosuppressants and received natalizumab for more than 2 years [78]. 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 [82]. Anti JCV antibody testing is still an unproven concept when used in assessing the risk stratification since the test was not validated in a prospective large cohort of MS patients exposed to various DMTs. Therefore, the duration of natalizumab exposure and prior use of immunosuppressants remain the most useful parameters in the risk stratification. On the other hand, natalizumab remains one of the well-tolerated DMTs with low incidence of hypersensitivity reactions [76]. Natalizumab has been shown to improve fatigue, cognition, depression, and walking speed [83]. Recent data showed a good safety profile in women exposed to natalizumab during their first trimester of pregnancy [84].
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Alemtuzumab Alemtuzumab is a humanized monoclonal antibody that has been recently approved for active relapsing MS (EMA label) or patients who showed inadequate response to two or more indicated DMTs (FDA label). 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 [85]. In a 2-year phase III RCT which included 581 treatment-naïve early RRMS patients, alemtuzumab was associated with a significant 54.9% reduction in the risk of relapse at 2 years compared with IFN beta- 1a SC. However, there was no significant difference in the sustained accumulation of disability (8% Vs. 11%; p = 0·22) [86]. In a separate, 2-year phase III RCT (CARE-MS II), 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 the risk of sustained accumulation of disability were reduced by 49.4% and 42% respectively compared to IFN beta-1a over 2 years [87]. Alemtuzumab treatment has been commonly associated with mild to moderate infusion reactions 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 was related to the occurrence of potential delayed secondary autoimmune adverse 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 [86, 87].
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Treatment Algorithm for RRMS patients: Given the increasing number of the available DMTs, different treatment strategies have been implicated in both initiation and escalation approaches in patients with RRMS. The panel has adopted a personalized treatment approach based on the benefit/risk ratio, tolerability and convenience. The panel used the available scientific evidence and the approved indication labels given by the regulatory authorities in US and Europe while developing the treatment algorithm. One reason is the lack of level 1 evidence comparative data between the newer agents. Second, the panel felt that labeling a certain drug as a first line may preclude its use as a second line and vice versa. It should be noted that the use of the term “second-line therapy” by the regulatory bodies was based on safety concerns raised during their clinical trials or post-marketing occurrence of serious adverse events rather than scientific evidence. Third, 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. Therefore, 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. 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. Two algorithms (figures 1 & 2) were suggested based on disease characteristics (non-aggressive versus aggressive). Aggressive RRMS patients were defined as patients with rapidly evolving severe relapsing remitting course presented with 2 or more disabling relapses in the previous year and at least one gadolinium-enhancing lesion on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.
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Patients who do not fulfill the above definition are considered non-aggressive in the treatment algorithm. 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 [54, 88]. Recommendations: The following DMTs (IFN Beta, GA, teriflunomide, DMF) can be initiated in treatment-naïve patients based on level 1 evidence. 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).
Suboptimal responders: This term has been interchangeably used with other terms such as treatment failure or treatment non-response. 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 [89].The threshold of treatment failure is inherently subjective and may be defined 20 | P a g e
differently by the treating neurologists. Several factors have to be considered before labeling the patient as a suboptimal responder, which include the duration of treatment exposure (preferably at least 6-12 months) adherence to DMTs, and the presence of specific antibodies (e.g. neutralizing antibodies for IFN beta, and anti-natalizumab antibody). In the real clinical setting, isolated radiological activities and infrequent mild relapses with complete recovery might not be worrisome, and escalation based on these two indications may exhaust the treatment options within a short period [89]. On the other hand, the available measures of disease severity, such as EDSS or MSFC may not be good tools to estimate treatment response in clinical practice [90, 91]. The panel adopted the notion of “level of concern” in the decision-making process of lateral switching or escalation therapy as suggested by the Canadian MS working group [92]. The levels of concerns were divided into 3 categories (low, medium and high) depending on relapses, disease progression and MRI activity. Low level of concerns can be documented by one of the following: one relapse with prompt recovery, not necessitating corticosteroids OR ≤1 point increase in EDSS (in patients with EDSS ≤3.5), < 1 point increase in the EDSS (in patients with EDSS 4-5.0), clinically documented progression (in patients with EDSS ≥5.5) OR 1 Gadenhancing/ new T2 lesion. Medium level of concern consists of one of the following: a relapse with moderate affection of the daily activities, moderate motor/cerebellar presentation and incomplete recovery at 3 months OR two-point increase in EDSS at 6 months (in patients with EDSS ≤3.5), 1 point increase in the EDSS at 6 months (in patients with EDSS 4-5.0), 0.5 point increase in the EDSS (in patients with EDSS ≥5) OR 2 Gad-enhancing/ new T2 lesion. High level of concern can be achieved by more than one relapse in the first year of treatment requiring hospitalization, severe motor/ cerebellar involvement resulting in severe functional impairment with incomplete recovery at 6 months OR >2 points increase in the EDSS at 6 months (in
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patients with EDSS ≤3.5), >1 point increase in the EDSS increase at 6 months (in patients with EDSS 4-5.0), > 0.5 point increase in the EDSS (in patients with EDSS ≥ 5.5) OR ≥ 3 Gadenhancing/ new T2 lesions. Escalation therapy should be considered if three “low”, two “medium”, or one “high” level(s) of concerns were observed when assessing suboptimal response [92]. Alemtuzumab has class I evidence in this category of patients based on the results of CARE-MS II study [87], while the effectiveness of natalizumab and fingolimod is being derived mainly by subgroup analysis of their pivotal RCTs, and post-marketing studies [93-97]. Using propensitymatched 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 [93]. 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) [96]. Recommendation: In patients with suboptimal response to first-line therapies as defined above, treatment escalation to fingolimod, natalizumab, or alemtuzumab should be considered. 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).
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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 suboptimal response on any of the second line medications, a lateral switch should be considered based on the risk stratification strategy mentioned above before resorting to off-label therapies such as rituximab, or cyclophosphamide. Lateral switching between IFN beta/GA/teriflunomide/DMF, may be considered in suboptimal responders who have low level of concern or when the patient opted not to escalate given the associated future risks.
The panel highlighted general principles in the algorithm:
Natalizumab may be switched in seropositive patients to fingolimod or alemtuzumab after 2 years of exposure to natalizumab or when the anti-JCV antibody index level is rising on subsequent testing to levels above 1.5.
In pediatric patients (aged 16 years of old and younger), IFN/GA are recommended for treatment naïve MS patients. Natalizumab may be used in aggressive disease in treatment of naïve patients or those who failed IFN/GA, since the newly approved agents (DMF, teriflunomide, fingolimod, alemtuzumab) are not recommended for this age group.
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Secondary Progressive Multiple Sclerosis (SPMS): Secondary progressive MS is a challenging entity in terms of therapeutics as most clinical trials failed to show significant but rather a relatively modest efficacy in halting disease progression. The European multicenter on IFN beta-1b in SPMS (EUSPMS), a randomized trial comparing IFN Beta -1b SC to placebo showed delayed time to confirmed progression as compared to placebo [98]. However, a subgroup analysis suggested that the patients who had superimposed relapses and active MRI lesions might benefit from treatment [98]. The North American Study of IFN beta-1b (NASPMS) was stopped early as it failed to show statistically significant difference in the primary endpoint between the placebo and the IFN Beta 1b groups despite the improvement in the relapse rate and MRI activity [99]. The Secondary Progressive Efficacy Trial of Rebif (IFN Beta- 1a SC) in MS (SPECTRIMS) showed that the treatment was not associated with significant benefit when compared to placebo [100]. Furthermore, a high dose IFN Beta 1a IM (60 mcg once weekly) failed to show treatment benefit on the time to EDSS worsening in the MSFC (MS Functional Composite) [101]. A Cochrane review evaluated 5 RCTs including 3122 patients concluded that IFN beta does not prevent the development of permanent physical disability (the risk of progression sustained at 6 months after 3 years of treatment) in SPMS despite the reduction in the risk of relapses and short term relapse-related disability which could be related to the anti-inflammatory effects of IFNs [102].
Mitoxantrone (MTX) is a cytotoxic agent, which acts by intercalating with DNA and inhibiting the topoisomerase II enzyme activity for DNA repair resulting in reducing the number of B cells, inhibiting T helper cell function, and augmenting T cell suppressor activity [103]. It was approved by the FDA for the treatment of progressive MS given its evidence in reducing
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neurological disability and/or the frequency of clinical relapses in patients with secondary progressive, progressive relapsing or worsening relapsing-remitting multiple sclerosis. The positive data came from the 2-year MIMS trials, which enrolled 194 patients. The mitoxantrone arm experienced significant benefits in the primary endpoint, which was a composite of five measures (change in expanded disability status scale, change in ambulation index, adjusted total number of treated relapses, time to first treated relapse and change in standardized neurological status) when compared to the placebo arm [104]. A Cochrane review evaluated 3 trials, which included 221 patients in the analysis, showed that MTX reduced the progression of disability and frequency of relapses in the short term (two years). However, the authors recommended its use in patients with worsening RRMS and SPMS with evidence of persistent inflammatory activity given the concerns of cardiotoxicity (12%) and leukaemias (0.8%), which have been increasingly reported [105]. Other immunosuppressants such as cyclophosphamide, methotrexate and mycophenolate have been assessed in either single arm or small open-label unblinded trials. There were positive effects on disease progression in the short term but the results were not replicated by large-scale randomized placebo-controlled trials [106-108]. Recommendations: In SPMS patients with evidence of relapses, IFN beta 1b SC or IFN beta 1a SC (high dose) is recommended (Level 1 evidence). There is insufficient evidence to recommend continuation of IFN beta in SPMS patients who showed disease progression. In SPMS patients who had breakthrough disease despite IFN beta treatment, mitoxantrone may be offered as a second line therapy after comprehensive discussion with the patient on the associated risk of cardiotoxicity, leukemia and infections (class II/III evidence).
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Primary Progressive Multiple Sclerosis (PPMS) Several DMTs were evaluated for the treatment of PPMS in the last two decades but none had shown significant benefit in halting disease progression [109-112]. There was a glimmer of hope in achieving an effective treatment using Rituximab, a monoclonal antibody targeting CD20 antigen, in a large phase II/III RCT involving 439 PPMS patients over a period of 96 weeks [109]. Despite the significant reduction in MRI activity by 32%, Rituximab failed to meet the primary endpoint, which was the time to confirmed progression (30.2% vs. 8.5%; p =0.14). A subgroup analyses suggest beneficial effects in younger patients, particularly those with inflammatory lesions. Several factors could have attributed to the lack of efficacy including patients` selection (older male with less active disease), duration (short duration to assess improvement in disease progression) and methodology of assessment (EDSS may not the best parameter to capture slow progression) [113, 114]. Recommendations: There are no available approved DMTs for PPMS. A therapeutic trial with Rituximab for 1 year may be considered in patients who had gad-enhancing lesions (level U evidence).
Monitoring Patients While On Disease Modifying Therapies Patients who were started on DMTs should be monitored regularly for suboptimal response/ disease progression or adverse events. It is recommended to evaluate patients clinically every 3 months where certain assessments are performed. A history of a suspected relapse, ongoing symptoms (e.g. cognitive, neurogenic bladder, fatigue) and any adverse events should be documented. A general neurological examination and EDSS assessments should be performed.
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Where possible, the panel recommends performing 25-feet walk and SDMT. Given the increasing use of Optical Coherence Tomography (OCT), it is recommended to use OCT as adjunctive tool to longitudinally evaluate the macular volume and retinal nerve layer fiber over time [115, 116]. A radiological follow-up with gadolinium-enhanced MRI brain/ C-Spine (using STIR techniques) is recommended at 6 months after the initiation of DMTs and annually while on the same DMTs. If a relapse or disease progression is suspected, a follow-up MRI may be considered when it is going to affect the clinical decision of future management (e.g. escalation).
Anti-JC virus antibody testing should be performed periodically (every 6 months) in patients receiving natalizumab. Seronegative patients may sero-convert over time and the risk stratification should be re-addressed. Seropositive patients should not be precluded from receiving natalizumab if clinically indicated; however, they need to be monitored closely and risk-benefit assessment should be addressed periodically especially when the antibody index is > 1.5 and had been on natalizumab for more than 2 years. It should be noted that anti JCV antibody testing is still an unproven concept when used in assessing the risk stratification since the test was not validated in a prospective large cohort of MS patients exposed to various DMTs. Therefore, the duration of natalizumab exposure and prior use of immunosuppressants remain the most useful parameters in the risk stratification. In JCV seropositive patients who had been on natalizumab for > 2 years. frequent (3-4 months) MRI scanning using T2-FLAIR and diffusion-weighted sequences in combination with conventional T2-weighted images is recommended for screening patients at high risk of developing PML [117]. In patients with MRI lesions suggestive of PML, the MRI protocol should be extended to include contrast-enhanced T1-weighted imaging to detect inflammatory features and the possible coincidence of PML and
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PML-immune reconstitution inflammatory syndrome (IRIS), particularly during follow-up [118]. When PML is suspected, natalizumab-should be suspended. An urgent MRI brain with gadolinium and CSF JCV DNA should be performed urgently to exclude PML before resuming natalizumab..
Safety monitoring for specific DMTs (as per the FDA recommendations): IFN Beta/ GA: o CBC/LFT every 6 months Teriflunomide:
Before starting treatment, patients must be fully counseled on the potential for serious risk to the fetus and it advised that they use reliable methods of contraception. If pregnancy does occur during treatment, the drug should be immediately discontinued and an accelerated elimination procedure should be initiated.
Obtain transaminase and bilirubin levels within 6 months before initiation of therapy. Monitor ALT levels at least monthly for six months after starting teriflunomide.
Obtain CBC within 6 months before the initiation of treatment. Further monitoring should be based on signs and symptoms of infection
Check blood pressure before the initiation of teriflunomide.
Fingolimod:
Prior to initiation: o Obtain cardiac history (recent myocardial infarction, bradyarrhythmias, type II/III cardiac failure) and history of the use of Class Ia or Class III anti-arrhythmic drugs. o Obtain history of prior infection with chicken pox or herpes zoster. If unknown,
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consider varicella IgG testing. Vaccinate patients who have never been vaccinated and give a booster 1 month later which should occur at least 1 month prior to initiation of the first dose of fingolimod o Perform an examination of the fundus including the macula before treatment initiation. Patients with diabetes mellitus or a history of uveitis are at increased risk. o Women of childbearing potential should use effective contraception to avoid pregnancy during and for 2 months after stopping treatment. o Drug-interactions: QT prolonging drugs (e.g beta blockers, calcium channel blockers), and Ketoconazole. o Obtain baseline CBC/ LFT
First Dose Monitoring: o Observe all patients for bradycardia for at least 6 hours after first dose with hourly pulse and blood pressure measurement. Obtain electrocardiogram (ECG) prior to dosing and at end of observation period. o Patients who develop heart rate
S0303-8467(16)30041-5 http://dx.doi.org/doi:10.1016/j.clineuro.2016.02.001 CLINEU 4304
To appear in:
Clinical Neurology and Neurosurgery
Received date: Revised date: Accepted date:
27-8-2014 17-11-2015 2-2-2016
Please cite this article as: Alroughani R, Ashkanani A, Al-Hashel J, Khan R, Thussu A, Alexander KJ, Vembu P, Sharfuddin K, Lamdhade S, John JK, Alkhashan S, Abualmelh M, Al-Shammri S.Consensus Recommendations for the Diagnosis and Treatment of Multiple Sclerosis in Kuwait.Clinical Neurology and Neurosurgery http://dx.doi.org/10.1016/j.clineuro.2016.02.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Consensus Recommendations for the Diagnosis and Treatment of Multiple Sclerosis in Kuwait R. Alroughani1,2*, A. Ashkanani1, J. Al-Hashel3,4, R. Khan3, A. Thussu1,2, KJ Alexander3, P. Vembu3, K. Sharfuddin3, S. Lamdhade1, JK. John3, S. Alkhashan5, M. Abualmelh6, S. AlShammri3,7 1
Division of Neurology, department of Medicine, Amiri hospital, Kuwait
2
Neurology Clinic, Dasman Diabetes Institute, Kuwait
3
Department of Neurology, Ibn Sina Hospital, Kuwait
4
Department of Medicine, Kuwait University, Kuwait
5
Division of Neurology, department of medicine, Farwaniya Hospital, Kuwait
6
Division of Neurology, department of medicine, Al-Adan Hospital, Kuwait
7
Division of Neurology, department of medicine, Mubarak Al-Kabeer Hospital, Kuwait
Corresponding Author: Raed. A. Alroughani, MD, FRCPC Department of Medicine, Division of Neurology, Amiri Hospital Arabian Gulf Street, Sharq, 13041, Kuwait. Tel: +965 2245005 Ext 4444 Fax: +965 22467499 Email: [email protected]
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Highlights:
Multiple Sclerosis remains a clinical diagnosis supported by McDonald diagnostic criteria. Ruling out mimickers of multiple sclerosis is important to reach the diagnosis with high accuracy. A personalized treatment approach based on risk versus benefit analysis is recommended. A multi-disciplinary team approach has been increasingly utilized in management of MS patients.
Abstract. Objectives: We aim to develop consensus recommendations to guide neurologists in the community for the diagnosis and treatment of MS. Methods: After reviewing the available literature, a group of neurologists with expertise in MS met to discuss the evidence and develop consensus recommendations for the diagnosis and treatment of MS. Results: The revised 2010 McDonald criteria is the established diagnostic criteria for MS and has wide international acceptance among international MS experts. Several red flags in the history and examination, along with certain laboratory tests were pointed out to exclude MS mimickers in the diagnostic phase. The available approved disease modifying therapies (DMTs) were listed in an algorithmic fashion based on initial assessment of disease severity and disease breakthrough while on DMTs. Risk stratification based on the benefit versus risk ratio was used to help choosing the appropriate therapy to MS patients using an “individualized therapy” approach. The requirements for initiation and monitoring of treated MS patients were highlighted with emphasis on early identification of disease breakthrough, adverse events, and safety concerns. The role of multi-disciplinary MS clinics was discussed and a guide for referral to specialized MS clinics was developed. Conclusions: Consensus recommendations have been developed to guide local neurologists on the diagnosis and treatment of patients with MS. Implementation of the revised 2010 McDonald diagnostic criteria was advised while a personalized treatment approach was recommended using a treatment algorithm based on risk stratification and patient-centered outcomes. Keywords: Multiple sclerosis, Diagnosis, Treatment, Recommendations, Risk stratification
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INTRODUCTION: Multiple Sclerosis (MS) is a chronic demyelinating disorder of the central nervous system (CNS) which predominately affects patients aged 20-40 years. The epidemiology of MS is changing worldwide as the understanding of the natural history continues to show new trends in clinical consequences of disease activity and disability progression with a moving target of several pathological mechanisms involving environmental and genetic factors [1, 2]. The prevalence and incidence rates are increasing in Kuwait and in the neighboring gulf countries in the last 2 decades [3, 4]. The field of demyelinating disease is evolving as new diagnostic criteria have been established and novel treatments have been added to the armamentarium. There is a need to unify the approach to MS diagnosis and treatment among neurologists in the community in order to optimize the care of MS patients based on up-to-date evidence-based medicine and wellestablished practice guidelines. The goal of this document is to present a logical stepwise evidence-based approach to the diagnosis and management of MS patients..
METHODS: A group of neurologists involved in the care of MS patients. The panel consisted of academic, hospital-based and community general neurologists with expertise in MS, along with specialized MS neurologists in order to ensure a wide diversity of opinions. A search of the literature was performed and the panel met to discuss the updated evidence in order to develop local consensus and practice recommendations for the diagnosis and treatment of Multiple Sclerosis with special emphasis on the practice in Kuwait.
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RESULTS & DISCUSSION: Diagnosis of Multiple Sclerosis: The diagnosis of MS remains clinical despite the recent advances in diagnostics and the availability several radiological and neuro-immunological surrogate markers. The diagnosis relies on comprehensive history taking and neurological examination to determine the dissemination in time and space of certain clinical symptoms/signs while incorporating paraclinical tests to exclude mimickers. In 1983, Poser et al. incorporated certain paraclinical tests such as MRI, evoked potentials (EPs) and CSF oligoclonal bands (OCB) into the diagnostic criteria [5]. As the understanding of the natural history of the disease improved through assessments of long-term registries, it was important to identify cohorts who were destined to develop MS after presenting with their first clinical event. Hence, the term clinically isolated syndrome (CIS) was introduced in the diagnostic criteria proposed by McDonald et al. in 2001 [6] which was revised in 2010 emphasizing the notion of dissemination in time and space in the diagnosis of MS using MRI techniques which remains the best surrogate marker to date [7].
The panel agreed on the application of the 2010 revised McDonald criteria as a first line of diagnosis work-up. However, they stressed on the fact that clinical and paraclinical red flags should be sought and excluded before applying the diagnostic criteria. A detailed approach to identification of red flags is outlined in table 1. The panel pointed out the regional characteristics of clinical presentations and disease progression, which differ from cohorts studied in the western countries where the criteria were developed. Furthermore, the panel encouraged continued clinical and laboratory monitoring of patients with atypical presentations who might
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be labeled as CIS. The panel recommended obtaining CSF in patients with atypical presentations and patients under 18 years of age.
The panel suggested a unified approach when explaining the CIS terminology to the patients. They encouraged the use of the term CIS suggestive of MS (CISSMS) in patients who did not fulfill the dissemination in time and space criteria but had typical clinical and MRI characteristics [8, 9]. This would lessen the diagnostic confusion among patients who are not usually aware of the differences between MS and CIS. By using the term CISSMS, physicians would be able to discuss the future risk of the development of the second clinical attack and be aware of the need of clinical and radiological monitoring in the first 5 years. The “wait and see” approach and the statement of “no better explanation” were highlighted with emphasis on careful history taking / neurological examination and proper timing in conducting additional or followup investigations [10].
In the last two decades, Neuromyelitis optica (NMO), which, is an uncommon inflammatory demyelinating CNS disorder that is distinct from MS, appeared to evolve in the differential diagnosis of MS [11]. Autoantibodies that target aquaporin-4 (AQP4-IgG) are highly specific for NMO and have helped define a spectrum of disease beyond the classic definition. A revised diagnostic criteria improved the yield of identifying NMO patients by instituting major criteria (evidence of acute optic neuritis and transverse myelitis) and minor criteria (at least two out of three of the following: MRI brain non-diagnostic for MS, MRI spinal cord lesion extending over three or more vertebral segments or NMO-IgG seropositivity) [12]. However, some NMO patients might not exhibit AQP4-IgG and additional clinical and radiological features such as
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involvement of area posterma, brainstem, and diencephalon could be seen in a spectrum of NMO patients. Hence, a new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG) has been suggested. The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of seronegative NMOSD [13].
Given the wide use of MRI in the diagnostic process of several neurological conditions other than MS (e.g. headaches), patients diagnosed with Radiologically Isolated Syndrome (RIS) have been increasingly identified. RIS was first introduced in 2009 [14] to define a relevant cohort of individuals routinely encountered in clinical practice who are at risk for future demyelinating events. A recent retrospective multi-center study assessed the 5-year risk of the first clinical demyelinating event in 451 RIS patients with a mean follow-up time of 4.4 years. A meaningful number (34%) of RIS subjects developed their first demyelinating events (i.e. CIS) within a 5year period from the initial MRI brain study. An age < 37 years, male sex, and spinal cord involvement appear to be the most important independent predictors of symptom onset [15].
The panel recommended minimal routine laboratory screening consisted of CBC, LFT/RFT, ANA / pANCA, cANCA, CRP/ESR, ENA, RF, Serum ACE level, TSH, Vitamin B12 level, and Anti-cardiolipin antibodies. Additional specific investigations may be necessary when suspecting certain MS mimickers as outlined in table 2.
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With respect to the routine use of MRI in clinical practice, MS protocols based on the proposed 2009 revised guidelines of the Consortium of MS Centers MRI Protocol for the Diagnosis and Follow-up of MS was recommended [16]. The panel recommended performing Brain and cervical spine with gadolinium at baseline and at 3-6 months intervals, in order to detect dissemination in time and space in CIS patients. Additional MRI sections of the thoracic cord may be performed when indicated. Spinal STIR sequence is to be incorporated in the MRI protocol to improve sensitivity of detecting spinal lesions and to better assess the accumulation of spinal lesions with time in order to avoid misdiagnosis with NMO. The panel agreed on the following diagnostic approaches regarding specific situations:
CSF analysis is recommended in CIS patients not satisfying the revised 2010 McDonalds criteria, patients with atypical presentations, pediatric cohorts, and in certain patients with suspected other demyelinating disorders such as acute disseminated encephalomyelitis “ADEM” or NMO.
RIS patients should be evaluated in the MS clinic or by experienced neurologists prior to the initiation of extensive diagnostic investigations. Neurologists should take into consideration patients` preferences, as few patients may not want to start a diagnosis nor further work up. Once the RIS diagnosis is discussed, the panel recommends clinical and radiological follow up at 6-12 months intervals, and to withhold CSF testing at the initial stage. If the follow up MRI study shows dissemination in time and space, the diagnostic process for a possible demyelination disorder should be initiated.
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AQP4-IgG testing is recommended in patients who are suspected to have NMO based on clinical or radiological features. It may be performed in a centralized laboratory preferably equipped with cell-based techniques for better sensitivity.
Treatment of Multiple Sclerosis Acute Relapse (Attack): Relapses may present early throughout the course in patients with relapsing remitting MS or may be superimposed in patients with progressive relapsing MS. Relapses are closely related to disease progression in the first five years especially in patients accumulating residual disabilities [17, 18]. A relapse is defined as new or recurrent neurologic symptoms not associated with fever or infection that lasted for at least 24 hours and was accompanied by new neurologic signs confirmed by the examining neurologist. Systemic corticosteroids are the mainstay treatment for acute relapses. Several publications showed the efficacy of Intravenous Methyl Prednisolone (IV-MP) in the treatment of acute relapses when compared to placebo, ACTH and dexamethasone in late 1980s [19-21]. A Cochrane meta-analysis showed a trend for better efficacy of IV-MP but there was no significant difference between its use for a short (5 days) and extended period (15 days). The adverse effects of IV use were comparable to oral prednisone, which were mainly gastrointestinal and psychiatric manifestations [22]. The use of oral prednisone taper following IV-MP was used in many centers following the results of Optic Neuritis Treatment Trial (ONTT) which concluded that the IV-MP followed by oral prednisone speeds the recovery of visual loss [23]. Although not all optic neuritis patients were diagnosed with MS, the results had a bearing impact on the treatment of acute MS relapses. In patients who did not respond to IV-MP, plasmapheresis was the only second line option supported by clinical evidence based on two small RCT (level II evidence) [24, 25]. Several case 8 | P a g e
reports revealed functional neurological improvement after plasmapheresis in patients who were unresponsive to IV-MP or with severe acute exacerbations [26-29]. Early initiation of plasmapheresis, male gender and preserved reflexes were predictors of favourable response.[30] A retrospective study evaluating 41 patients, showed that time from symptom onset to plasmapheresis was significantly shorter in patients who improved compared with those who did not respond. A response might be seen even at 60 days after the relapse onset but with a decreasing response rate [26]. The American Academy of Neurology guidelines recommend using plasma exchange for severe relapses in remitting-relapsing MS unresponsive to corticosteroids [31]. The panel further discussed several issues in the treatment of MS relapses, which were summarized below:
Pseudo-relapses should be differentiated from true relapses by taking the appropriate history of preceding infections and performing the necessary work up such as chest X-ray and urinalysis.
Patients with suspected relapses should be evaluated urgently in the outpatient clinics within 1 week. The response to corticosteroid treatment should be evaluated within 2 week after the institution of initial IV-MP course. 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 [32].
In patients with psychiatric manifestations (e.g. psychosis), the benefit of IV-MP should be weighted against the risk. A short course (3-day) of IV-MP is preferred and caution with oral prednisone taper should be exercised.
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Any relapse that poses a functional impairment such as pyramidal and cerebellar symptoms/ signs should be treated while the benefits versus the risks of corticosteroids should be considered for sensory relapses.
It was generally accepted that oral prednisone taper should be only used in selected patients where the risk of rebound relapse is high in the subsequent 2 weeks.
Plasmapheresis might be offered to patients who fail to show any functional recovery or still have significant functional impairment by 2-6 weeks following the administration of the last IV-MP course. Since it may quite invasive, the benefits and the risks of plasmapheresis should be discussed with the patients especially in patients who have unfavourable prognostic indicators.
Routine use of Intravenous Immunoglobulin (IVIG) is not recommended for the treatment of MS relapses given the insufficient evidence. However, in patients who have contraindications to IV-MP and plasmapheresis, IVIG (2g/kg over 3-5 days) may be used based on the available supportive data [33, 34].
Recommendations: IV Methylprednisolone (IV-MP) one gram daily for 3-5 days +/- tapering oral steroids for 1-2 weeks is recommended for the treatment of acute relapses. It is appropriate to consider plasmapheresis (5-7 sessions over 2 weeks) in the treatment of patients with severe disability who fail to respond to IV-MP.
Clinically Isolated Syndrome (CIS): Definition CIS is defined as the first episode (monophasic) with either monofocal or multifocal neurological
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symptoms/signs suggestive of MS typically involving the optic nerve, brainstem/ cerebellum, spinal cord or cerebral hemisphere. The panel stressed that the symptoms and signs should be typical of CNS inflammation and there are no better explanations after excluding mimickers by comprehensive work-up when indicated. Risks: CIS conversion to MS has been studied extensively in the last decade. 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]. 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 ≥ 9 T2 lesions at the baseline brain MRI increases the risk of conversion in the first 5 years [9, 39]. Spinal cord lesions and positive oligoclonal bands in CSF are associated with increased risk of conversion to CDMS [40, 41]. Treatment: The decision to treat CIS patients with DMTs is challenging. The decision depends on several key factors, which include clinical (recovery or residual disability following the first attack) and radiological (number and location of MRI lesions) characteristics, the presence of oligoclonal bands, and patients` perception and understanding of the future risk of developing definitive MS. It is imperative that a comprehensive discussion of early institution of DMTs is initiated with patients who are at high risk of conversion. There are four approved DMTs (Interferon beta 1a SC, Interferon beta 1a IM, Interferon beta 1b SC, and Glatiramer Acetate SC) based on class I evidence supported by randomized clinical
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trials (RCTs). The relative and absolute risk reductions for conversion to CDMS over 2 years in the various RCTS were 50% and 15-20% respectively [42-46]. Patients with more than 9 T2 and/or gadolinium-enhancing (Gad+) lesions had the greatest benefit [47]. The panel discussed the recent update on TOPIC, a phase III study assessing teriflunomide, a novel oral, DMTs in 618 CIS patients [48]. Teriflunomide 14mg reduced the risk of conversion to CDMS by 42.6% (p=0.0087). Teriflunomide is currently under review by regulatory authorities for approval as treatment in patients with CIS. Recommendations: CIS patients may 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 severe relapses/ residual disabilities and/or high MRI lesion load (> 9 T2 or Gad-enhancing lesions) are advised to start DMTs early. It is appropriate to monitor low risk patients (those with normal baseline MRI) clinically and radiologically and to 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 DMT initiation is appropriate.
Relapsing Remitting Multiple Sclerosis (RRMS): Seven DMTs have been approved by the FDA to be used in RRMS as a first-line therapy: IFNbeta 1a IM, IFN-beta 1a SC, IFN-beta 1b SC, GA, teriflunomide, fingolimod, and dimethyl fumarate (DMF). However, fingolimod was approved as a second line therapy in Europe except in cases of aggressive disease, which will be discussed later. Recently, alemtuzumab was
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approved in Europe, Canada and Australia as a treatment for active MS while it was restricted in the USA for the use in patients who showed inadequate response to two or more DMTs. Here, we review the efficacy and safety of the approved DMTs. A treatment algorithm and recommendation of initiation, escalation and monitoring of RRMS on different DMTs follow this. Interferon & Glatiramer Acetate: The use of IFN-Beta and GA in RRMS is supported by class I evidence given results shown by several multi-center RCTs [49]. They offer a modest efficacy in reducing the annualized relapse rate (ARR) and disease progression assessed by EDSS score by approximately 30% [50-53]. Furthermore, early treatment with IFN-beta -1b SC was associated with a 47% reduction in the hazard ratio for all-cause mortality over 21 years compared with initial placebo treatment [54]. IFN-beta and GA accumulated long-term safety data over the last 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 [55].
Fingolimod: Fingolimod is a sphingosine1-phosphate receptor (S1P) modulator, which inhibits lymphocyte egress from lymph nodes resulting in a reduced infiltration of potentially auto-aggressive lymphocytes into the CNS [56, 57]. Fingolimod was the first oral DMT approved for RRMS based on two phase III clinical trials [58, 59]. 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 [58, 59]. A 24-month extension study showed persistent effects of fingolimod and similar efficacy against IFN beta 1a IM [60]. A subgroup analysis of highly
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disease-active patients despite IFNβ treatment in the preceding year, showed that fingolimod reduced ARR by 61% relative to IFNβ-1a along with reductions in lesion counts and brain volume loss [61]. Fingolimod has been shown to improve the quality of life, which may lead to better long-term adherence to therapy [62]. However, careful monitoring upon initiation and follow-up should be exercised due to several safety issues including cardiac conduction abnormalities, 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 [63].
Teriflunomide: Teriflunomide is a reversible inhibitor of the mitochondrial enzyme dihydro-orotate dehydrogenase (DHODH), which is relevant for the de novo synthesis of pyrimidine in proliferating immune cells [64]. Teriflunomide was the second oral DMT to receive regulatory approval based on three phase III clinical trials in patients with RRMS [65-67]. In the TOWER trial, teriflunomide showed 36.3% and 31.5% reduction in ARR and 12-week sustained disability progression when compared to placebo [65]. Similar findings were seen in the TEMSO trial where ARR and the risk of sustained disability progression were reduced by 31% and 30% respectively [66]. 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 phase 3, rater-blinded study, teriflunomide did not show any difference in time to failure (defined as first occurrence of confirmed relapse or permanent treatment discontinuation for any cause) [67].
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Overall, Teriflunomide is well tolerated and safe with rare and mild adverse events including hair thinning, elevation of serum liver enzymes and mild leucopenia. 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 [68]. Teriflunomide can be quickly cleared from the body within 11 days using oral cholestyramine or charcoal. Dimethyl Fumarate (DMF): DMF is the third oral medication that has been recently 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 nuclear factor (erythroid-derived 2)-like 2, also known as (Nrf2) antioxidant response pathway [69]. The regulatory approval was granted based on the results of two 2-year phase III RCTs [70, 71]. In the DEFINE study which included 1234 RRMS patients, both doses of DMF (240 mg twice or three times per day) showed significant reduction in the ARR (53% and 48%), and the risk of disability progression (38% and 34%) as compared to placebo [70]. 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. However, there was no significant benefit in preventing sustained disability progression with either dose when compared to placebo at 2 years [71]. Although the study had an active comparator (GA), no significant differences in clinical and MRI outcomes were observed between DMF and GA. It should be noted that the study was not powered to evaluate head-tohead treatment superiority [71]. There were improvements in patient-reported outcome measures of physical and mental functions, quality of life, and general well being in the DEFINE study
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[72] . DMF was generally safe and well tolerated; adverse events included flushing, gastrointestinal AEs (e.g., diarrhea, nausea, vomiting), lymphopenia and elevated liver enzymes. In October 2014, a fatal case of progressive multifocal leukoencephalopathy (PML) was reported after exposure to DMF for 4.5 years in a naïve MS patient in the setting of prolonged (over 3.5 years), severe grade 3 lymphopenia (lymphocyte count fluctuated between 200-580 cell/µL) [73]. This was the first case of PML associated with DMF. In the past, other cases of PML have been reported with the use of fumaric acid esters in lymphopenic patients with psoriasis, although in the majority of these cases, the causal relationship could not be clarified (e.g. other risks for PML were present) [74]. Consequently, it is advised to monitor patients receiving DMF who experience lymphopenia regularly and at close intervals as clinically indicated.
Natalizumab: Natalizumab 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 [75]. Natalizumab was the first approved monoclonal antibody for RRMS. The 2-year phase III placebo-controlled RCT investigated natalizumab in 942 RRMS naïve-patients. It reduced the rate of clinical relapse by 68% and the risk of sustained disability progression by 42% compared to placebo [76]. A second phase III trial evaluated 1171 MS patients who had at least one relapse during the 12 months prior to recruitment while on IFN beta 1a IM where patients were randomly assigned to receive continued IFN beta 1a IM in combination with natalizumab or placebo for up to 2 years [77]. Combination therapy showed significant ARR reduction (0.34 vs. 0.75; P < 0.001) and 24% reduction in the risk of sustained
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disability progression over 2 years. However, two cases of PML were diagnosed in the combination arm [77]. Due to the risk of PML which was 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 [78]. 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[79]. A two-step enzyme-linked immunosorbant assay (ELISA) has been developed to detect the presence of JCV antibodies in serum [80]. The prevalence of JCV antibodies in MS patients is approximately 50– 60% with a 2– 3% rate of seroconversion annually [79, 81]. The risk of PML remains significantly low in seronegative patients (0.1/1000) or in seropositive patients with less than 2 years of treatment and no prior use of immunosuppressants (0.7/1000). The risk, however, of PML increases significantly reaching 11.2/1000 in seropositive patients who were exposed to prior immunosuppressants and received natalizumab for more than 2 years [78]. 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 [82]. Anti JCV antibody testing is still an unproven concept when used in assessing the risk stratification since the test was not validated in a prospective large cohort of MS patients exposed to various DMTs. Therefore, the duration of natalizumab exposure and prior use of immunosuppressants remain the most useful parameters in the risk stratification. On the other hand, natalizumab remains one of the well-tolerated DMTs with low incidence of hypersensitivity reactions [76]. Natalizumab has been shown to improve fatigue, cognition, depression, and walking speed [83]. Recent data showed a good safety profile in women exposed to natalizumab during their first trimester of pregnancy [84].
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Alemtuzumab Alemtuzumab is a humanized monoclonal antibody that has been recently approved for active relapsing MS (EMA label) or patients who showed inadequate response to two or more indicated DMTs (FDA label). 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 [85]. In a 2-year phase III RCT which included 581 treatment-naïve early RRMS patients, alemtuzumab was associated with a significant 54.9% reduction in the risk of relapse at 2 years compared with IFN beta- 1a SC. However, there was no significant difference in the sustained accumulation of disability (8% Vs. 11%; p = 0·22) [86]. In a separate, 2-year phase III RCT (CARE-MS II), 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 the risk of sustained accumulation of disability were reduced by 49.4% and 42% respectively compared to IFN beta-1a over 2 years [87]. Alemtuzumab treatment has been commonly associated with mild to moderate infusion reactions 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 was related to the occurrence of potential delayed secondary autoimmune adverse 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 [86, 87].
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Treatment Algorithm for RRMS patients: Given the increasing number of the available DMTs, different treatment strategies have been implicated in both initiation and escalation approaches in patients with RRMS. The panel has adopted a personalized treatment approach based on the benefit/risk ratio, tolerability and convenience. The panel used the available scientific evidence and the approved indication labels given by the regulatory authorities in US and Europe while developing the treatment algorithm. One reason is the lack of level 1 evidence comparative data between the newer agents. Second, the panel felt that labeling a certain drug as a first line may preclude its use as a second line and vice versa. It should be noted that the use of the term “second-line therapy” by the regulatory bodies was based on safety concerns raised during their clinical trials or post-marketing occurrence of serious adverse events rather than scientific evidence. Third, 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. Therefore, 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. 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. Two algorithms (figures 1 & 2) were suggested based on disease characteristics (non-aggressive versus aggressive). Aggressive RRMS patients were defined as patients with rapidly evolving severe relapsing remitting course presented with 2 or more disabling relapses in the previous year and at least one gadolinium-enhancing lesion on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.
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Patients who do not fulfill the above definition are considered non-aggressive in the treatment algorithm. 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 [54, 88]. Recommendations: The following DMTs (IFN Beta, GA, teriflunomide, DMF) can be initiated in treatment-naïve patients based on level 1 evidence. 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).
Suboptimal responders: This term has been interchangeably used with other terms such as treatment failure or treatment non-response. 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 [89].The threshold of treatment failure is inherently subjective and may be defined 20 | P a g e
differently by the treating neurologists. Several factors have to be considered before labeling the patient as a suboptimal responder, which include the duration of treatment exposure (preferably at least 6-12 months) adherence to DMTs, and the presence of specific antibodies (e.g. neutralizing antibodies for IFN beta, and anti-natalizumab antibody). In the real clinical setting, isolated radiological activities and infrequent mild relapses with complete recovery might not be worrisome, and escalation based on these two indications may exhaust the treatment options within a short period [89]. On the other hand, the available measures of disease severity, such as EDSS or MSFC may not be good tools to estimate treatment response in clinical practice [90, 91]. The panel adopted the notion of “level of concern” in the decision-making process of lateral switching or escalation therapy as suggested by the Canadian MS working group [92]. The levels of concerns were divided into 3 categories (low, medium and high) depending on relapses, disease progression and MRI activity. Low level of concerns can be documented by one of the following: one relapse with prompt recovery, not necessitating corticosteroids OR ≤1 point increase in EDSS (in patients with EDSS ≤3.5), < 1 point increase in the EDSS (in patients with EDSS 4-5.0), clinically documented progression (in patients with EDSS ≥5.5) OR 1 Gadenhancing/ new T2 lesion. Medium level of concern consists of one of the following: a relapse with moderate affection of the daily activities, moderate motor/cerebellar presentation and incomplete recovery at 3 months OR two-point increase in EDSS at 6 months (in patients with EDSS ≤3.5), 1 point increase in the EDSS at 6 months (in patients with EDSS 4-5.0), 0.5 point increase in the EDSS (in patients with EDSS ≥5) OR 2 Gad-enhancing/ new T2 lesion. High level of concern can be achieved by more than one relapse in the first year of treatment requiring hospitalization, severe motor/ cerebellar involvement resulting in severe functional impairment with incomplete recovery at 6 months OR >2 points increase in the EDSS at 6 months (in
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patients with EDSS ≤3.5), >1 point increase in the EDSS increase at 6 months (in patients with EDSS 4-5.0), > 0.5 point increase in the EDSS (in patients with EDSS ≥ 5.5) OR ≥ 3 Gadenhancing/ new T2 lesions. Escalation therapy should be considered if three “low”, two “medium”, or one “high” level(s) of concerns were observed when assessing suboptimal response [92]. Alemtuzumab has class I evidence in this category of patients based on the results of CARE-MS II study [87], while the effectiveness of natalizumab and fingolimod is being derived mainly by subgroup analysis of their pivotal RCTs, and post-marketing studies [93-97]. Using propensitymatched 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 [93]. 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) [96]. Recommendation: In patients with suboptimal response to first-line therapies as defined above, treatment escalation to fingolimod, natalizumab, or alemtuzumab should be considered. 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).
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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 suboptimal response on any of the second line medications, a lateral switch should be considered based on the risk stratification strategy mentioned above before resorting to off-label therapies such as rituximab, or cyclophosphamide. Lateral switching between IFN beta/GA/teriflunomide/DMF, may be considered in suboptimal responders who have low level of concern or when the patient opted not to escalate given the associated future risks.
The panel highlighted general principles in the algorithm:
Natalizumab may be switched in seropositive patients to fingolimod or alemtuzumab after 2 years of exposure to natalizumab or when the anti-JCV antibody index level is rising on subsequent testing to levels above 1.5.
In pediatric patients (aged 16 years of old and younger), IFN/GA are recommended for treatment naïve MS patients. Natalizumab may be used in aggressive disease in treatment of naïve patients or those who failed IFN/GA, since the newly approved agents (DMF, teriflunomide, fingolimod, alemtuzumab) are not recommended for this age group.
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Secondary Progressive Multiple Sclerosis (SPMS): Secondary progressive MS is a challenging entity in terms of therapeutics as most clinical trials failed to show significant but rather a relatively modest efficacy in halting disease progression. The European multicenter on IFN beta-1b in SPMS (EUSPMS), a randomized trial comparing IFN Beta -1b SC to placebo showed delayed time to confirmed progression as compared to placebo [98]. However, a subgroup analysis suggested that the patients who had superimposed relapses and active MRI lesions might benefit from treatment [98]. The North American Study of IFN beta-1b (NASPMS) was stopped early as it failed to show statistically significant difference in the primary endpoint between the placebo and the IFN Beta 1b groups despite the improvement in the relapse rate and MRI activity [99]. The Secondary Progressive Efficacy Trial of Rebif (IFN Beta- 1a SC) in MS (SPECTRIMS) showed that the treatment was not associated with significant benefit when compared to placebo [100]. Furthermore, a high dose IFN Beta 1a IM (60 mcg once weekly) failed to show treatment benefit on the time to EDSS worsening in the MSFC (MS Functional Composite) [101]. A Cochrane review evaluated 5 RCTs including 3122 patients concluded that IFN beta does not prevent the development of permanent physical disability (the risk of progression sustained at 6 months after 3 years of treatment) in SPMS despite the reduction in the risk of relapses and short term relapse-related disability which could be related to the anti-inflammatory effects of IFNs [102].
Mitoxantrone (MTX) is a cytotoxic agent, which acts by intercalating with DNA and inhibiting the topoisomerase II enzyme activity for DNA repair resulting in reducing the number of B cells, inhibiting T helper cell function, and augmenting T cell suppressor activity [103]. It was approved by the FDA for the treatment of progressive MS given its evidence in reducing
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neurological disability and/or the frequency of clinical relapses in patients with secondary progressive, progressive relapsing or worsening relapsing-remitting multiple sclerosis. The positive data came from the 2-year MIMS trials, which enrolled 194 patients. The mitoxantrone arm experienced significant benefits in the primary endpoint, which was a composite of five measures (change in expanded disability status scale, change in ambulation index, adjusted total number of treated relapses, time to first treated relapse and change in standardized neurological status) when compared to the placebo arm [104]. A Cochrane review evaluated 3 trials, which included 221 patients in the analysis, showed that MTX reduced the progression of disability and frequency of relapses in the short term (two years). However, the authors recommended its use in patients with worsening RRMS and SPMS with evidence of persistent inflammatory activity given the concerns of cardiotoxicity (12%) and leukaemias (0.8%), which have been increasingly reported [105]. Other immunosuppressants such as cyclophosphamide, methotrexate and mycophenolate have been assessed in either single arm or small open-label unblinded trials. There were positive effects on disease progression in the short term but the results were not replicated by large-scale randomized placebo-controlled trials [106-108]. Recommendations: In SPMS patients with evidence of relapses, IFN beta 1b SC or IFN beta 1a SC (high dose) is recommended (Level 1 evidence). There is insufficient evidence to recommend continuation of IFN beta in SPMS patients who showed disease progression. In SPMS patients who had breakthrough disease despite IFN beta treatment, mitoxantrone may be offered as a second line therapy after comprehensive discussion with the patient on the associated risk of cardiotoxicity, leukemia and infections (class II/III evidence).
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Primary Progressive Multiple Sclerosis (PPMS) Several DMTs were evaluated for the treatment of PPMS in the last two decades but none had shown significant benefit in halting disease progression [109-112]. There was a glimmer of hope in achieving an effective treatment using Rituximab, a monoclonal antibody targeting CD20 antigen, in a large phase II/III RCT involving 439 PPMS patients over a period of 96 weeks [109]. Despite the significant reduction in MRI activity by 32%, Rituximab failed to meet the primary endpoint, which was the time to confirmed progression (30.2% vs. 8.5%; p =0.14). A subgroup analyses suggest beneficial effects in younger patients, particularly those with inflammatory lesions. Several factors could have attributed to the lack of efficacy including patients` selection (older male with less active disease), duration (short duration to assess improvement in disease progression) and methodology of assessment (EDSS may not the best parameter to capture slow progression) [113, 114]. Recommendations: There are no available approved DMTs for PPMS. A therapeutic trial with Rituximab for 1 year may be considered in patients who had gad-enhancing lesions (level U evidence).
Monitoring Patients While On Disease Modifying Therapies Patients who were started on DMTs should be monitored regularly for suboptimal response/ disease progression or adverse events. It is recommended to evaluate patients clinically every 3 months where certain assessments are performed. A history of a suspected relapse, ongoing symptoms (e.g. cognitive, neurogenic bladder, fatigue) and any adverse events should be documented. A general neurological examination and EDSS assessments should be performed.
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Where possible, the panel recommends performing 25-feet walk and SDMT. Given the increasing use of Optical Coherence Tomography (OCT), it is recommended to use OCT as adjunctive tool to longitudinally evaluate the macular volume and retinal nerve layer fiber over time [115, 116]. A radiological follow-up with gadolinium-enhanced MRI brain/ C-Spine (using STIR techniques) is recommended at 6 months after the initiation of DMTs and annually while on the same DMTs. If a relapse or disease progression is suspected, a follow-up MRI may be considered when it is going to affect the clinical decision of future management (e.g. escalation).
Anti-JC virus antibody testing should be performed periodically (every 6 months) in patients receiving natalizumab. Seronegative patients may sero-convert over time and the risk stratification should be re-addressed. Seropositive patients should not be precluded from receiving natalizumab if clinically indicated; however, they need to be monitored closely and risk-benefit assessment should be addressed periodically especially when the antibody index is > 1.5 and had been on natalizumab for more than 2 years. It should be noted that anti JCV antibody testing is still an unproven concept when used in assessing the risk stratification since the test was not validated in a prospective large cohort of MS patients exposed to various DMTs. Therefore, the duration of natalizumab exposure and prior use of immunosuppressants remain the most useful parameters in the risk stratification. In JCV seropositive patients who had been on natalizumab for > 2 years. frequent (3-4 months) MRI scanning using T2-FLAIR and diffusion-weighted sequences in combination with conventional T2-weighted images is recommended for screening patients at high risk of developing PML [117]. In patients with MRI lesions suggestive of PML, the MRI protocol should be extended to include contrast-enhanced T1-weighted imaging to detect inflammatory features and the possible coincidence of PML and
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PML-immune reconstitution inflammatory syndrome (IRIS), particularly during follow-up [118]. When PML is suspected, natalizumab-should be suspended. An urgent MRI brain with gadolinium and CSF JCV DNA should be performed urgently to exclude PML before resuming natalizumab..
Safety monitoring for specific DMTs (as per the FDA recommendations): IFN Beta/ GA: o CBC/LFT every 6 months Teriflunomide:
Before starting treatment, patients must be fully counseled on the potential for serious risk to the fetus and it advised that they use reliable methods of contraception. If pregnancy does occur during treatment, the drug should be immediately discontinued and an accelerated elimination procedure should be initiated.
Obtain transaminase and bilirubin levels within 6 months before initiation of therapy. Monitor ALT levels at least monthly for six months after starting teriflunomide.
Obtain CBC within 6 months before the initiation of treatment. Further monitoring should be based on signs and symptoms of infection
Check blood pressure before the initiation of teriflunomide.
Fingolimod:
Prior to initiation: o Obtain cardiac history (recent myocardial infarction, bradyarrhythmias, type II/III cardiac failure) and history of the use of Class Ia or Class III anti-arrhythmic drugs. o Obtain history of prior infection with chicken pox or herpes zoster. If unknown,
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consider varicella IgG testing. Vaccinate patients who have never been vaccinated and give a booster 1 month later which should occur at least 1 month prior to initiation of the first dose of fingolimod o Perform an examination of the fundus including the macula before treatment initiation. Patients with diabetes mellitus or a history of uveitis are at increased risk. o Women of childbearing potential should use effective contraception to avoid pregnancy during and for 2 months after stopping treatment. o Drug-interactions: QT prolonging drugs (e.g beta blockers, calcium channel blockers), and Ketoconazole. o Obtain baseline CBC/ LFT
First Dose Monitoring: o Observe all patients for bradycardia for at least 6 hours after first dose with hourly pulse and blood pressure measurement. Obtain electrocardiogram (ECG) prior to dosing and at end of observation period. o Patients who develop heart rate
