924595 research-article20202020 MSJ0010.1177/1352458520924595Multiple Sclerosis JournalG Arrambide, E Iacobaeus MULTIPLE SCLEROSIS MSJ JOURNAL Meeting Review Aggressive multiple sclerosis (2): Treatment Multiple Sclerosis Journal 2020, Vol. 26(9) 1045­–1063 DOI: 10.1177/ https://doi.org/10.1177/1352458520924595 1352458520924595 https://doi.org/10.1177/1352458520924595 Georgina Arrambide , Ellen Iacobaeus, Maria Pia Amato, Tobias Derfuss , © The Author(s), 2020. Sandra Vukusic , Bernhard Hemmer , Lou Brundin and Mar Tintore for the 2018 ECTRIMS Focused Workshop Group* Article reuse guidelines: sagepub.com/journals- permissions Abstract: The natural history of multiple sclerosis (MS) is highly heterogeneous. A subgroup of patients Correspondence to: M Tintore has what might be termed aggressive MS. These patients may have frequent, severe relapses with incom- Servei de Neurologia- Neuroimmunologia, Centre plete recovery and are at risk of developing greater and permanent disability at the earlier stages of the d’Esclerosi Múltiple de disease. Their therapeutic window of opportunity may be narrow, and while it is generally considered that Catalunya (Cemcat), Vall d’Hebron Institut de Recerca, they will benefit from starting early with a highly efficacious treatment, a unified definition of aggressive Hospital Universitari Vall d’Hebron, Universitat MS does not exist and data on its treatment are largely lacking. Based on discussions at an international Autònoma de Barcelona, focused workshop sponsored by the European Committee for Treatment and Research in Multiple Scle- Edifici Cemcat, Pg. Vall d’Hebron 119-129, 08035 rosis (ECTRIMS), we review our current knowledge about treatment of individuals with aggressive MS. Barcelona, Spain. We analyse the available evidence, identify gaps in knowledge and suggest future research needed to mtintore@cem-cat.org Georgina Arrambide fill those gaps. A companion paper details the difficulties in developing a consensus about what defines Mar Tintore aggressive MS. Servei de Neurologia- Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Vall Keywords: Aggressive, highly active, multiple sclerosis, disability, relapsing–remitting, treatment d’Hebron Institut de Recerca, Hospital Universitari Vall response d’Hebron, Universitat Autònoma de Barcelona, Date received: 13 November 2019; revised: 18 March 2020; accepted: 16 April 2020. Barcelona, Spain Ellen Iacobaeus Lou Brundin Division of Neurology, Introduction we considered radiological, clinical and biological Department of Clinical Over the past 25 years, more than a dozen therapies features that might be used to obtain such a consen- Neuroscience, Karolinska Institute, Stockholm, Sweden have been approved by regulators for use in MS.1 sus. Two recent papers proposed reaching an Maria Pia Amato Safety and efficacy have been demonstrated through Expanded Disability Status Scale (EDSS) ⩾ 6.0 Department NEUROFARBA, prospective randomized controlled clinical trials, within 10 years of disease onset as aggressive MS University of Florence, Florence, Italy/IRCCS most often including subjects with relapsing forms of (please refer to the companion paper7 for a more Fondazione Don Carlo the disease, relatively early in the disease process, and detailed discussion).8,9 These and several other defini- Gnocchi, Florence, Italy Tobias Derfuss with demonstrated inflammatory underlying disease tions are based on relapse frequency or severity, lack Departments of Neurology biology.2,3 Historically, such patients have been of recovery, disability accrual or magnetic resonance and Biomedicine, University Hospital Basel, University of deemed to be a subgroup that most likely benefits imaging (MRI) lesions. Basel, Basel, Switzerland from treatment, and thus trial populations have been Sandra Vukusic enriched to focus on these individuals. Only recently While it is tempting to extrapolate results from past Service de neurologie, sclérose en plaques, have clinical trials been successful in subjects with successful clinical trials to all patients with MS when pathologies de la myéline progressive forms of MS (pMS).4,5 considering treatment options, data are not necessar- et neuro-inflammation, and Centre de Référence des ily applicable to individuals with a more aggressive Maladies Inflammatoires A long-recognized subgroup of patients has what disease because of differences in underlying disease Rares du Cerveau et de la Moelle, Hôpital might be termed aggressive MS. An aggressive dis- processes,10 demographic considerations that may Neurologique Pierre ease course may manifest from onset or develop dur- have an impact on treatment outcomes,6 differences in Wertheimer, Hospices Civils de Lyon, Lyon, France/ ing the disease course. These patients may have comorbidities11 and other factors compared with the Centre des Neurosciences de frequent, severe relapses with incomplete recovery general relapsing MS trial population. Lyon, Observatoire Français de la Sclérose en Plaques, and are at risk of developing greater and permanent INSERM 1028 et CNRS disability within a short time frame.6,7 Although it was While prospective randomized clinical trial data on UMR5292, Lyon, France/ Faculté de médecine Lyon not possible to come to consensus about a definition treatment of enriched populations of aggressive MS of aggressive MS at the end of the workshop, are largely lacking, suggestive evidence is available journals.sagepub.com/home/msj 1045 Multiple Sclerosis Journal 26(9) Est, Université Claude Table 1. Treatment of severe relapse: types of patients included and definitions of relapse severity. Bernard Lyon 1, Lyon, France Author Treatment Type of inflammatory demyelinating Definition of severe relapse Bernhard Hemmer Department of Neurology, diseases studied Klinikum rechts der Isar, School of Medicine, Weinshenker et al.15 PLEX CDMS, acute transverse myelitis, One or more of the following: coma, Technical University of acute disseminated encephalomyelitis, aphasia, acute severe cognitive Munich, Munich, Germany/ Munich Cluster for Systems Marburg variant of MS, NMO, dysfunction, hemiplegia, paraplegia Neurology (SyNergy), recurrent myelitis and focal cerebral or quadriplegia Munich, Germany demyelination *Participants of the Keegan et al.16 PLEX MS, NMO, Marburg variant of MS Severe attack not defined: ECTRIMS Focused Workshop on Aggressive MS and ADEM retrospective analysis of patients are listed in Supplemental receiving PLEX for CNS Table 1. demyelinating diseases between 1984 and 2000a Schilling et al.17 PLEX CIS, RRMS and NMO Corticosteroid-refractory relapses Magana et al.18 PLEX Probable or definite MS (RR, SP, PP), Corticosteroid-refractory CNS IDD NMOSD (NMO, LETM, recurrent ON), monophasic ON, ADEM, short TM and CIS Llufriu et al.19 PLEX MS, CIS, Marburg disease, ADEM, Non-responders to corticosteroid NMO, idiopathic ON and idiopathic treatment (at least one course of TM IV methylprednisolone 1 g/day for 3–5 days) Meca-Lallana et al.22 PLEX RRMS, CIS, recurrent myelitis, TM, Corticosteroid-refractory CNS IDD LETM, ADEM, Baló’s concentric sclerosis and NMO Mauch et al.23 IA RRMS, SPMS and NMO Corticosteroid-unresponsive relapses Schimrigk et al.24 IA RRMS and pMS with relapses Corticosteroid-refractory MS relapse Visser et al.25 IVIg CDMS A relapse with ⩾ 1-point increase in the EDSS PLEX: plasma exchange; CDMS: clinically definite multiple sclerosis; MS: multiple sclerosis; NMO: neuromyelitis optica; ADEM: acute disseminated encephalomyelitis; CNS: central nervous system; CIS: clinically isolated syndrome; RRMS: relapsing–remitting multiple sclerosis; RR: relapsing–remitting; SP: secondary progressive; PP: primary progressive; NMOSD: neuromyelitis optica spectrum disorders; LETM: longitudinally extensive transverse myelitis; ON: optic neuritis; TM: transverse myelitis; IDD: inflammatory demyelinating diseases; IA: immunoadsorption; SPMS: secondary progressive multiple sclerosis; pMS: progressive MS; IVIg: intravenous immunoglobulin; EDSS: Expanded Disability Status Scale. aOf the 59 patients, 25 were included in the 1999 PLEX clinical trial.13 from other types of studies, including data from and clinical characteristics, and prognosis of aggres- other relapsing inflammatory demyelinating dis- sive MS, as well as the methods used to try to reach a eases (Table 1) and data from subgroups of patients consensus definition are presented in a companion in MS clinical trials using a variety of descriptions article.7 Prior to the workshop, specific treatments or of what is considered aggressive disease (Tables 2– groups of treatments were assigned to different partici- 4). Here, we present what is known about treatment pating MS specialists who conducted a relevant litera- of more aggressive forms of MS and provide sug- ture search on PubMed including but not limited to the gestions for future research to fill gaps in knowl- terms: ‘treatment x’ AND ‘multiple sclerosis’ OR edge about the best therapeutic management of ‘MS’ AND ‘aggressive’ OR ‘highly active’. The search these patients. was performed up to March 2018 with no limits on language. At the workshop, attendees (Supplemental Table 1) presented and discussed available evidence Materials and methods that could inform treatment options for their assigned Aggressive MS, its definition and management were subgroup of patients based on data derived from post discussed at the 1–2 March 2018 Focused Workshop hoc analyses, subgroup analyses, meta-analyses, reg- on Aggressive Multiple Sclerosis held in Brussels, istries, cohorts and the scarce treatment trials designed Belgium, supported by the European Committee for especially for aggressive MS. Subsequent to the work- Treatment and Research in Multiple Sclerosis shop, the discussions were summarized and the refer- (ECTRIMS). A review of the pathology, demographic ences were updated using a similar literature search 1046 journals.sagepub.com/home/msj Table 2. Studies investigating the use of oral DMTs for the treatment of aggressive MS.a. Author Study and DMT Definition(s) of aggressive MS Disease activity outcomes Disability outcomes NEDA as outcome journals.sagepub.com/home/msj Bar-Or J DEFINE a. ⩾ 2 relapses in the 12 months prior to study entry ARR at 2 years compared to CDP at 2 years, HR NA et al.26 subgroup b. T2 lesion volume ⩾ median of the study placebo, RR (95% CI) (95% CI)c: analysis, DMFb population a. 0.446 (0.296–0.673) a. 0.67 (0.38–1.20) c. Gd+ lesions at baseline b. 0.374 (0.226–0.619) b. 0.58 (0.30–1.12) c. 0.321 (0.175–0.589) c. 0.56 (0.25–1.26) Hutchinson CONFIRM a. ⩾ 2 relapses in the 12 months prior to study entry ARR at 2 years compared to Not analysed (non- NA et al.27 subgroup b. T2 lesion volume ⩾ median of the study placebo, RR (95% CI) significant results in the analysis, DMFb population a. 0.664 (0.422–1.043) ITT population of the c. Gd+ lesions at baseline b. 0.497 (0.302–0.819) CONFIRM trial) c. 0.490 (0.276–0.871) Devonshire FREEDOMS Group E: treatment-naïve patients with rapidly ARR at 2 years compared to CDP at 2 years, HR NA et al.28 subgroup evolving severe RRMS (⩾ 2 relapses within the placebo, RR (95% CI): (95% CI)e: analysis, year prior to study inclusion and ⩾ 1 Gd+ lesions at 0.33 (0.18–0.62), p = 0.0006 0.73 (0.25–2.07), fingolimodd baseline) p = 0.55 Derfuss FREEDOMS and Disease activity despite previous DMTs: ARR at 2 years compared to CDP at 6 months, HR NA et al.29 FREEDOMS II ⩾ 1 relapse in the previous year and either ⩾ 1 Gd+ placebo, RR (95% CI): (95% CI): post hoc analysis, lesion or ⩾ 9 T2 lesions at baseline, and/or as many 0.52 (0.40–0.69), p < 0.001 0.5 (0.34–.90), fingolimod or more relapses in the year before baseline as in the p = 0.016 previous year Derfuss FREEDOMS, a. ⩾ 3 relapses in the 2 years prior to study inclusion ARR at 2 years compared to NA NA et al.30 FREEDOMS b. ⩾ 1 Gd+ lesions at baseline placebo: relative reduction II and c. Baseline EDSS ⩾ 3.0 of 46%–59% across the three TRANSFORMS subgroups (p < 0.001 for all pooled data, comparisons) fingolimodd ARR at 1 year compared to IM IFN-β1a: relative reduction of 39%–51% (p < 0.001 for b. and p < 0.01 for a. and c.) Prosperini Propensity score- a. Non-responders to first-line DMTs: either ⩾ 2 NA NA NEDA-3f at 2 years: et al.36 matched cohort relapses or 1 relapse associated with a residual EDSS a. Natalizumab 67% study comparing score ⩾ 2.0 in the previous year while on DMTs versus fingolimod natalizumab, b. HA, treatment-naïve patients: ⩾ 2 relapses in the 42%, p = 0.034 fingolimod and previous year and ⩾ 1 Gd+ lesion on brain or spinal b. Natalizumab 75% self-injectables cord MRI versus fingolimod 67%, p > 0.2 (Continued) 1047 G Arrambide, E Iacobaeus et al. 1048 Table 2. (Continued) Author Study and DMT Definition(s) of aggressive MS Disease activity outcomes Disability outcomes NEDA as outcome Huisman Systematic a. HA RRMS: unchanged or increased relapse rate or ARR at 2 years, HR (CrIs)g,h: 3-month CDP at -- et al.37 review and meta- ongoing severe relapses compared with the previous a. Fingolimod versus DMF: 0.91 2 years, HR (CrIs)i: analysis, efficacy year despite treatment with ⩾ 1 DMT (0.57–1.47); SUCRA 82.0% a. Fingolimod versus of fingolimod b. RES MS: ⩾ 2 disabling relapses in the past year, versus 67.9% DMF: 0.55 (0.27–1.12); relative to and ⩾ 1 Gd+ lesions on MRI or increase in the T2 b. Fingolimod versus SUCRA 96.7% for DMF in a. and lesion load compared with a previous MRI natalizumab: 1.72 (0.84–3.53); fingolimod; DMF not natalizumab in b. SUCRA 53.4% versus 96.5% available Multiple Sclerosis Journal 26(9) b. Fingolimod versus natalizumab: 1.62 (0.51–5.13); SUCRA 46.1% versus 89.0% Giovannoni CLARITY post ⩾ 2 relapses in the previous year and either ⩾ 1 T1 NA NA NEDAj at 96 weeks, et al.31 hoc and subgroup Gd+ lesions or ⩾ 9 T2 lesions on baseline MRI cladribine (3.5 mg/ analysis, kg) compared to cladribine placebo, OR (95% CI)k: 4.28 (3.05–6.02), p < 0.0001 Giovannoni CLARITY post Two overlapping, categorical subgroups: ARR at 2 years compared to 6-month CDP, HR Proportion of et al.32 hoc and subgroup a. HRA: ⩾ 2 relapses during the year prior to study placebo, RR (95% CI): (95% CI): patients achieving analysis, entry, whether on DMT or not a. 0.32 (0.22–047) a. 0.18 (0.08–0.44) NEDAj, OR (95% cladribine 3.5 mg/ b. HRA + DAT: ⩾ 2 relapses during the year prior b. 0.33 (0.23–0.48) b. 0.18 (0.07–0.43) CI): kg to study entry, whether on DMT or not, and patients Cumulative new Gd+ lesions, a. 8.02 (3.93–16.35) with ⩾ 1 relapse during the year prior to study entry RR (95% CI): b. 7.82 (4.03–15.19) while on therapy with other DMTs and ⩾ 1 Gd+ 0.087 (0.052–0.144) lesions or ⩾ 9 lesions 0.077 (0.046–0.128) DMT: disease-modifying treatment; MS: multiple sclerosis; NEDA: no evidence of disease activity; DMF: dimethyl fumarate; Gd+: gadolinium-enhancing; ARR: annualized relapse rate; RR: risk ratios; 95% CI: 95% confidence intervals; CDP: confirmed disability progression; HR: hazard ratios; NA: not assessed; ITT: intention-to-treat analysis; RRMS: relapsing–remitting multiple sclerosis; EDSS: Expanded Disability Status Scale; IFN: interferon; IM: intramuscular; HA: highly active; MRI: magnetic resonance imaging; RES: rapidly evolving severe; SUCRA: surface under the cumulative ranking curve; OR: odds ratio; HRA: high relapse activity; DAT: disease activity on treatment. ap-values shown when available. bResults for DMF BID. Results for DMF TID were similar (data not shown). c ⩾ 1.0-point increase in the EDSS in patients with a baseline score ⩾ 1.0, or a ⩾ 1.5-point increase in patients with a baseline score of 0, sustained for 12 weeks. dResults for fingolimod 0.5 mg. Results for fingolimod 1.25 mg were similar (data not shown). eTime to disability progression confirmed after 3 months: increase in 1-point on the EDSS from baseline, or 0.5 points if the EDSS score was ⩾ 5.5. fAbsence of clinical relapses, disability worsening and radiological activity. gCredible intervals (CrIs) used instead of CIs. CrIs assume the true value of the point estimate is within 95% of the range, whereas CIs assume that, if the analysis was replicated 100 times, 95% of the CIs would include the true value of the parameter. hHRs < 1 favour fingolimod and > 1 favour the comparator. i6-month confirmed disability progression also available for subgroup b. comparison, with similar results to 3-month CDP. jNo relapses, no 3-month sustained change in EDSS and no T1 Gd+ or active T2 lesions. Time to NEDA not specified. kSimilar results at 24 and 48 weeks and with cladribine 5.25 mg/kg. journals.sagepub.com/home/msj Table 3. Studies investigating the use of monoclonal antibodies for the treatment of aggressive MS. Author Study and DMT Definition(s) of aggressive MS Disease activity outcomes Disability outcomes NEDA as outcome journals.sagepub.com/home/msj Kappos AFFIRM post hoc ⩾ 2 relapses in the year before ARR at 3 months, compared to NA NA et al.33 analysis, natalizumab study entry and ⩾ 1 Gd+ placebo, RR (95% CI): lesion at study entry 0.32 (0.15–0.69), p < 0.01 Havrdova AFFIRM post hoc ⩾ 2 relapses in the year before NA NA Absence of disease activitya et al.34 analysis, natalizumab study entry and ⩾ 1 Gd+ over 2 years compared lesion at study entry to placebo, % absolute difference (95% CI) a. Clinical: 48.5 (36.0–61.0), p < 0.0001 b. Radiological: 34.7 (25.4–44.0), p < 0.0001 c. Clinical and radiological: 25.7 (17.7–33.7), p < 0.0001 Hutchinson AFFIRM and 1. ⩾ 3 relapses in the year prior ARR at 2 years, RR (95% CI): 12-week CDP at 2 years, HR NA et al.35 SENTINEL post hoc to screening a. 0.20 (0.10–0.42), p < 0.001 (95% CI): analysis, natalizumab 2. ⩾ 9 lesions at baseline b. 0.41 (0.25–0.68), p < 0.001 a. 0.29 (0.11–0.77), p = 0.012 3. ⩾ 1 Gd+ lesions at baseline a. 0.33 (0.26–0.42), p < 0.001 b. 0.55 (0.23–1.29), p = 0.168 a. Natalizumab versus placebo b. 0.41 (0.35–0.49), p < 0.001 a. 0.56 (0.42–0.75), p < 0.001 b. Natalizumab plus IFN-β1a a. 0.28 (0.21–0.39), p < 0.001 b. 0.72 (0.56–0.92), p = 0.008 versus IFN-β1a alone b. 0.30 (0.23–0.40), p < 0.001 a. 0.48 (0.31–0.75), p = 0.001 b. 0.59 (0.40–0.87), p = 0.007 Hutchinson AFFIRM subanalysis, ⩾ 2 relapses in the year prior ARR over 2 years, % reduction 12-week CDP at 2 yearsb, NA et al.35 natalizumab to study entry and ⩾ 1 Gd+ compared to placebo, RR (95% compared to placebo, HR lesion at study entry CI): (95% CI): 81% (0.28 vs 1.46), p < 0.001 0.47 (0.24–0.93), p = 0.029 Hutchinson SENTINEL ⩾ 2 relapses in the year prior ARR over 2 years, % reduction 12-week CDP at 2 yearsb, NA et al.35 subanalysis, to study entry and ⩾ 1 Gd+ natalizumab + IFN-β1a versus natalizumab + IFN-β1a versus natalizumab lesion at study entry IFN-β1a alone: IFN-β1a alone, HR (95% CI): 76% (0.28 vs 1.16), p < 0.001 0.39 (0.21–0.74), p = 0.004 Lorscheider Registry of the ⩾ 1 relapse in the year Natalizumab compared to Compared to fingolimod, HR NA et al.38 Swiss Federation before switching from IFN- fingolimod over a 2-year period, (95% CI):d for Common β or glatiramer acetate to HR (95% CI) for a. and RR (95% 12-month CDP: 0.9 (0.5–1.5), Tasks of Health natalizumab or fingolimodc CI) for b.:d p = 0.62e Insurances, patients Relapse-free patients: 12-month disability on natalizumab and 0.5 (0.4–0.8), p < 0.001 improvement: 1.8 (1.1–2.7), fingolimod ARR: 0.5 (0.3–0.8), p = 0.001 p = 0.01f (Continued) 1049 G Arrambide, E Iacobaeus et al. 1050 Table 3. (Continued) Author Study and DMT Definition(s) of aggressive MS Disease activity outcomes Disability outcomes NEDA as outcome Curti Hospital-based a. Unchanged or increased Natalizumab compared to Compared to fingolimod over Compared to fingolimod, et al.39 multi-centric study relapse rate or ongoing severe fingolimod over a 2-year period: a 2-year period, (%) for CDP, NEDA after 2 years of with prospectively relapses compared with the ARR, multivariate OR (95% CI): OR (95% CI) for CDR: treatment, (%): Multiple Sclerosis Journal 26(9) collected data, previous year despite treatment 0.52 (0.26–1.04), p = 0.06 CDPg: 39.0% versus 22.0%, p = 0.04 natalizumab and with ⩾ 1 DMT, or b. Patients New/enlarging T2 lesions, mean 9.0% versus 6.7%, p = 0.62 fingolimod with a rapidly evolving severe (SD): CDRh: course: ⩾ 2 disabling relapses 0.17 (0.62) versus 0.63 (1.46), 3.76 (1.07–13.22), p = 0.03 in the past year and ⩾ 1 Gd+ p = 0.003 lesions on MRI or significant Gd+ lesions, mean (SD): increase in T2 lesion load 0.02 (0.13) versus 0.00 (0.00), NA compared with a previous MRI Cobo-Calvo Hospital-based study ⩾ 2 relapses and disability Freedom from clinical activityi, n Freedom from radiological Freedom of disease activityk, et al.40 with prospectively progression ⩾ 1 point during (%): activityj, n (%): n (%): collected data, the year before natalizumab a. 49/70 (70.0%) a. 59/70 (84.3%) a. 43/70 (61.4%) natalizumab initiation sustained for at least b. 42/56 (75.0%) b. 50/52 (96.2%) b. 38/52 (73.1%) 6 months c. 31/56 (55.4%) c. 44/52 (84.6%) c. 25/52 (48.1%) a. After 1 year of treatment b. During the second year c. After 2 years of treatment Coles CAMMS223 post hoc > 2 relapses in the year prior ARR, at 36 months, compared to 6-month CDPl, m,n, at Clinical disease activity et al.41 and subset analysis, to inclusion SC IFN-β1aj,k, RR (95% CI): 36 months, alemtuzumab (relapses and CDP) at alemtuzumab 0.203 (0.098–0.420), p < 0.0001 compared to SC IFN-β1a, HR 36 months, compared to SC (95% CI): IFN-β1a, HR (95% CI): 0.340 (0.128–0.905), p = 0.031 0.240 (0.127–0.454), SRD (HR): 5.906 p < 0.0001 Le Page Study (type) n = 8 RRMS before treatment: mean Disease activity: EDSS improvement after first Disease-free at last follow-up et al.42 RRMS, n = 8 SPMS, (range) ARR of 2.9 (1–5), and One switched to glatiramer acetate alemtuzumab cycle: after one cycle: 4 alemtuzumab, either EDSS worsened by 2.2 (0–5) after a mild relapse and one active 1.9 (0–4.0) points Two remained disease-free during mitoxantrone points, and a mean number of lesion at 18 months follow-up One patient had a sustained for 25 and 33 months but treatment Gd+ lesions > 15 (2 to > 20) improvement for 2 years but required a second cycle of or ⩾ 12 months then worsened progressively alemtuzumab, after which after mitoxantrone without any MRI activity they remained disease-free at withdrawal last follow-up (Continued) journals.sagepub.com/home/msj Table 3. (Continued) Author Study and DMT Definition(s) of aggressive MS Disease activity outcomes Disability outcomes NEDA as outcome Turner OPERA I and OPERA ⩾ 1 relapse in the year prior ARR over 2 years, % reduction 12-week CDP at 2 years, % NA journals.sagepub.com/home/msj et al.43 II subgroup analysis, to randomization and ⩾ 9 T2 compared to SC IFN-β1a: reduction compared to SC ocrelizumab lesions or ⩾ 1 T1 Gd+ lesion 68% (p < 0.001) IFN-β1a: at baseline Gd-enhancing lesions over 2 years, 53% (p = 0.035)p reduction compared to IFN β1a sc: 98% (p < 0.001) New or enlarging T2 lesions over 2 years, reduction compared to SC IFN-β1a: 80% (p < 0.001) Durozard French retrospective Refractory RRMS: ⩾ 1 ARR, rituximab compared to EDSS, rituximab compared to NEDA at the last clinical et al.44 multicentre study, off- T1 Gd + lesion and/or previous immunosuppressive previous immunosuppressive evaluation while on label rituximab new T2 lesions despite treatment, median (range): treatment, median (range): rituximab, n (%): treatment with fingolimod, 0 (0–1.87) versus 0.6 (0–3.8), 4.0 (0–7.5) versus 4.5 (0–7.0), 35/50 (approximately 70%) natalizumab, mitoxantrone, p < 0.0001 p < 0.0001 cyclophosphamide or Gd+ lesions before versus after alemtuzumabq switching to rituximab, %:r 72% versus 8%, p < 0.0001 MS: multiple sclerosis; DMT: disease-modifying treatment; NEDA: no evidence of disease activity; Gd+: gadolinium-enhancing; ARR: annualized relapse rate; RR: rate ratio; 95% CI: 95% confidence interval; IFN: interferon; CDP: confirmed disability progression; HR: hazard ratio; MRI: magnetic resonance imaging; OR: odds ratio; SD: standard deviation; CDR: confirmed disability regression; SRD: sustained reduction in disability; RRMS: relapsing–remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis; EDSS: Expanded Disability Status Scale. aNo relapses, no progression of disability (sustained for 12 weeks), no Gd+ lesions and no new or enlarging T2-hyperintense lesions. bSimilar results for 24-week CDP at 2 years. cMean (SD) number of relapses in the year prior to inclusion after matching: 2.8 (2.0) for natalizumab and 2.7 (3.1) for fingolimod. dAfter propensity score matching. eIncrease in ⩾ 1.5 points from an EDSS score of 0, ⩾ 1.0 point from an EDSS score of 1.0–5.5, or ⩾ 0.5 point from an EDSS score of ⩾ 6.0. fDecrease in ⩾ 1 EDSS step or 0.5 steps if baseline EDSS ⩾ 6.0. gIncrease in ⩾ 1.0 points if baseline EDSS score < 5.5 or ⩾ 0.5 point if baseline EDSS ⩾ 5.5, confirmed at 6 months. hDecrease in ⩾ 1 point if baseline EDSS < 5.5 or ⩾ 0.5 points if baseline EDSS ⩾ 5.5, confirmed at 6 months. iNo relapses or increase in disability. jAbsence of both new lesions and Gd+ lesions. kNo relapses, no increase in disability and absence of both new lesions and Gd+ lesions. lResults at 24 months were similar. mPooled 12 and 24 mg analysis. n ⩾ 1.0-point increase in EDSS score if the baseline EDSS score was > 0, or a ⩾ 1.5 increase if the baseline EDSS score was 0, sustained for a 6-month period. Results for CDP sustained for 3 months were similar. oDecrease in EDSS score by ⩾ 1 point, sustained for a consecutive 6-month period, for patients with a baseline EDSS score ⩾ 2.0; given patients with a baseline EDSS score of 0 are not accessible for SRD; in accordance to a previous study,86 only patients with an EDSS score ⩾ 2.0 at baseline were included in the analysis. p24-week CDP: 50% (p = 0.082). qOf fingolimod, natalizumab, mitoxantrone, cyclophosphamide or alemtuzumab as treatments prior to rituximab, only the first three DMTs were included in the analysis after patient selection. rGd+ lesions on first MRI after rituximab initiation. 1051 G Arrambide, E Iacobaeus et al. 1052 Table 4. Studies investigating the use of aHSCT in the treatment of aggressive MS. Author Study Definition(s) of aggressive MS Disease activity outcomes Disability outcomes NEDA as outcome Fagius Case series Early, malignant MS: Relapses in patient-months: Median (range) EDSS NA et al.45 Mobilization: CP (2 g/m2) and frequent (⩾ 4/year) and severe Before aHSCT: 61 relapses Before aHSCT: 7.0 (3.5–8.0) G-CSF (5 μg/kg). (EDSS ⩾ 6.0) relapses, disease in 82 patient-months Improvement after aHSCT: 3.5 Conditioning: BEAMa for all duration or duration of aggressive After aHSCT: one relapse (1.0–7.0) except a boy who received CP disease ⩽ 1.5 years, and clearly in 289 patient-months 50 mg/kg daily for 4 days documented recent improvement periods indicative of non- irreversible damage of the CNS Multiple Sclerosis Journal 26(9) Atkins Multi-centric, single-group Multiple early relapses, early With up to 13 years of With up to 13 years of follow- Primary outcome: et al.46 Phase 2 trial development of sustained follow-up after aHSCT: up after aHSCT: activity-free Mobilization: CP (4.5 g/m2) disability measured by EDSS No relapses occurred 70% of patients had no survival at 3 yearsc, and filgrastim (10 μg/kg/day for affecting motor control with No Gd+ or new T2 lesions disability accrual incidence with 10 days) cerebellar or pyramidal functional were seen on 314 MRIs 35% had a sustained person-time in Conditioning: busulfan system scores ⩾ 3.0 within 5 years improvement of their EDSS years (95% CI): every 6 hours for 16 doses, of disease onset, evidence of score 69.6 (46.6–84.2) CP (50 mg/kg/day for ongoing clinical disease activity 4 days), and rabbit ATG despite ⩾ 1 year of DMT or (1.25 mg/kg/day for 4 days). immunosuppressive treatmentb, and EDSS of 3.0–6.0 with a cerebellar or pyramidal functional system score ⩾ 3.0 Nash Phase 2, multicentre high- EDSS 3.0–5.5 at baseline and Relapse-free survival: 86.9 Progression-free survival: 91.3 Primary endpoint: et al.47 dose immunosuppression and disease duration < 15 years, with (69.5–94.7)% (74.7–97.2)% event-free survivalf autologous transplantation for failure of DMTd MRI activity-free survival: Disability improvement, evaluated through MS (HALT-MS) clinical trial 86.3 (68.1–94.5)% median (IQR) EDSS change: 5 years after Mobilization: filgrastim (16 µg/ −0.5 (−1.5 to 0, p = 0.001) in aHSCT, Kaplan– kg/day for 4 days) patients who completed the Meier (95% CI) Conditioning: BEAM, rabbit ATG study 69.2 (50.2–82.1)% (2.5 mg/kg/day for 2 days) and No treatment-related mortalitye filgrastim (5 µg/kg/day for 14 days and tapering over 2 weeks) Mancardi ASTIMS, multicentre, SPMS or RRMS that accumulates Primary endpoint: Disability accrual at NA et al.48 randomized, Phase 2 study to disability between relapses, cumulative number of new 4 years: aHSCT 57% versus assess the effect of aHSCT with a documented worsening T2 lesions in the 4 years mitoxantrone 48%, p = 0.50 versus mitoxantrone on disease during the last yearg, in spite after randomization, activity in MS of conventional therapyh and compared to mitoxantrone Mobilization: CP (4 g/m2 in presence of ⩾ Gd+ lesions on (n = 17), RR (95% CI): 1 day) and filgrastim (5 mg/kg MRI, and EDSS score between 0.21 (0.10–0.48), p = 0.00016 until completion of the stem cell 3.5 and 6.5 Zero Gd+ lesions at 4 years: harvest aHSCT 100% versus Conditioning: BEAM and rabbit mitoxantrone 56%, p = 0.029 ATG (3.75 mg/kg/day for 2 days) ARR (RR, 95% CI): 0.36 (0.15–0.88), p = 0.026 (Continued) journals.sagepub.com/home/msj Table 4. (Continued) Author Study Definition(s) of aggressive MS Disease activity outcomes Disability outcomes NEDA as outcome journals.sagepub.com/home/msj Muraro Long-term, multicentre, At the time of aHSCT, 171 of 281 NA Progression-free survivali at NA et al.49 observational, retrospective patients (60.9%) had 5 years, n = 231, Kaplan–Meier cohort study of patients who received ⩾ 2 DMTs. The most (95% CI) received aHSCT between represented subtype was SPMS All: 46 (42–54)% January 1995 and December (186 of 281 patients, 66.2%), and RRMS: 73 (57–88)% 2006 the median EDSS score was 6.5 SPMS: 33 (24–42)% (range, 1.5–9.0) Sormani Meta-analysis of 15 studies Median (range) follow-up time of ARR (11 of 15 studies), Rate of disease progression, NEDA (5 of 15 et al.50 including 764 patients from 41.7 (24–80.4) months. Baseline pooled estimate rate post- pooled estimate rate (95% CI) studies), proportion 1995 to 2016 EDSS (p < 0.001), disease transplant (95% CI) 17.1 (9.7–24.5)% at 2 years (range) duration (p = 0.08) and the 0.037 (0.028–0.047) 23.3 (16.3–31.8)% at 5 years 83 (70–92)% at proportion of patients At 2 years in studies with less 2 years with pMS (p < 0.001) were lower RRMS, 24.8 (16.7–32.9)% 67 (59–70)% at in versus 7.8 (1.3–14.2)% in 5 years reports > 2005. studies with more RRMS In total, 14 out of 15 studies were TRM, pooled estimate rate open-label uncontrolled studies, (95% CI): 1 study was the experimental arm By year of transplant: 0.3 of a randomized study; 5 studies (0–2.0)% > 2005 versus 3.6 were retrospective and 10 were (2.2–6.0)% ⩽ 2005, p = 0.014 assessed prospectively By phenotype: 1.0 (0.4–2.6)% if higher proportion of RRMS versus 3.4 (1.9–6.0)% if lower proportion of RRMS aHSCT: autologous haematopoietic stem cell transplantation; MS; multiple sclerosis; NEDA: no evidence of disease activity; CP: cyclophosphamide; G-CSF: granulocyte colony stimulating factor; BEAM: carmustine (BCNU), etoposide, cytosine-arabinoside, melphalan; EDSS: Expanded Disability Status Scale; CNS: central nervous system; NA: not assessed; DMT: disease-modifying treatment; ATG: anti-thymocyte globulin:d+:: gadolinium-enhancing; MRI: magnetic resonance imaging; IQR95% CI: 95% confidence interval; : interquartile range; SPMS: secondary progressive multiple sclerosis; RRMS: relapsing–remitting multiple sclerosis; IFN: interferon; RR: rate ratio; vs: versus; TRM: transplant-related mortality; ARR: annualized relapse rate. aBEAM dose not specified. bEither ⩾ 2 disabling relapses in the year before enrolment, 3 disabling relapses in the 2 years before enrolment or deterioration of the EDSS in the 18 months before enrolment (1.0 point if EDSS ⩽ 5.0 or 0.5 points if EDSS > 5.5). cNo relapses, new or Gd+ lesions and sustained progression of EDSS. d ⩾ 2 relapses over 18 months while on DMT and associated with a ⩾ 4-week sustained EDSS increase (1.0 for EDSS 3.0–3.5 or 0.5 for EDSS 4.0–5.5). eThree deaths occurred during follow-up at 2.5, 3.5 (MS-related) and 4.5 years (cardiorespiratory arrest). fSurvival without death or disease activity (disability progression, relapse or new lesions on MRI). gOne step of EDSS or 0.5 when EDSS is between 5.5 and 6.5. hIFN β or glatiramer acetate or immunosuppressive therapy. iProgression: increase in 1 point in the EDSS score confirmed at 12 months (0.5 points if the baseline EDSS score was ⩾ 5.5) compared with the pre-treatment baseline, which was defined as the last assessment before mobilization of peripheral blood stem cells (for peripherally mobilized autologous grafts) or before immunosuppressive conditioning (for bone marrow autologous grafts). 1053 G Arrambide, E Iacobaeus et al. Multiple Sclerosis Journal 26(9) strategy. Gaps in knowledge were identified, and strat- corticosteroid-refractory superimposed relapses in egies for future research to better understand treatment secondary progressive MS (SPMS).20,21 of aggressive MS were discussed. MRI predictors of response to PLEX include the pres- ence of gadolinium-enhancing (Gd+) lesions and Results lesions with mass effect, according to results from an exploratory analysis of 153 patients with central nerv- Acute treatment ous system inflammatory demyelinating diseases.18 Relapses, including frequency, duration and severity, Conversely, a smaller observational, pilot study, are clinical indicators of MS disease activity. While including 15 patients with different demyelinating usually self-limiting, some relapses can be disabling diseases, showed no significant association between and recovery can be incomplete, resulting in long-term the degree of resolution of the radiological activity accumulating disability.12 Clinical trials of agents for and the clinical response to PLEX.22 treating relapsing forms of MS (rMS) have examined the impact of treatment on relapse rate, but few have In contrast to PLEX, immunoadsorption (IA) removes examined the impact on shortening the duration or antibodies and immune complexes while avoiding reducing the severity of a relapse. Trials assessing plasma product substitution.23,24 Similarly to PLEX, relapse treatments often have heterogeneous inclusion results from retrospective studies suggest that IA criteria, including patients with differing MS pheno- might be most effective after three such procedures in types and sometimes different demyelinating diseases MS patients with corticosteroid-refractory relapses.23 (Table 1). Moderate to marked improvement from attack-related disability as measured by the EDSS can be observed High-dose corticosteroids. High-dose intravenous in approximately 70% of cases, including a subset of (IV) or oral corticosteroids are the first-line treatment patients with pMS and relapses.24 However, its wide- for relapses in MS.13,14 Corticosteroids are believed to spread use is limited and this procedure is not have an impact on MS relapses by exerting a rapid approved in some countries.23 immunosuppressant effect.11 Data indicate that IV or oral corticosteroids decrease the severity of relapses Intravenous immunoglobulin. Evidence of the effect as measured by the EDSS or the Kurtzke Functional of intravenous immunoglobulin (IVIg) on relapses in System Scale and speed patient recovery in rMS,12–14 aggressive MS is very limited. A small, randomized, but evidence of its effect on relapses in pMS is very double-blind, placebo-controlled pilot study in 19 MS limited.13 patients compared the efficacy of IVIg given with IV corticosteroids to IV corticosteroids alone to promote Plasmapheresis and immunoadsorption. Plasma recovery from moderate to severe relapses. The pri- exchange (PLEX) has been used for patients with mary outcome was the EDSS level at 4 weeks. No sta- persistently severe neurological deficits, although tistically significant differences were found in the definitions of severity vary among studies.12 Evi- median change in EDSS (p = 0.81). Furthermore, the dence of usefulness of PLEX in MS arises largely median time to improvement of at least one point on from a randomized, sham-controlled, double-masked the EDSS was 14 days in both groups (p = 0.95).25 trial in patients with severe attacks of inflammatory demyelinating diseases (not all with MS) who failed Based on these published results, limited evidence to recover after IV high-dose methylprednisolone appears to support the use of PLEX and IA for corti- treatment.15 Moderate or greater improvement costeroid-refractory MS relapses. However, IVIg occurred in 42.1% of courses of active treatment appears to have no effect in severe relapses (Table 1). with PLEX compared to 5.9% of courses of sham treatment (p = 0.011). Initiation of treatment within the first 20 days of an attack was one of the factors Disease-modifying treatments associated with moderate or marked improvement, Tables 2–4 summarize the different studies assessing and a beneficial effect was also observed with treat- treatment in patients with aggressive MS. Definitions ment within the first 20–60 days in some cases.16 In used in the cited studies for aggressive rMS vary from general, clinical improvement was seen after three exclusively clinical or radiological to combinations of PLEX treatments,17,18 and continuing improvement both. Many of these studies compare disease-modify- was observed as late as 6 months after the comple- ing treatments (DMTs) to placebo or to first-line treat- tion of PLEX in treatment responders.15,16,18,19 Only ments.26–35 In the following text, we focus on studies anecdotal evidence exists for a role of PLEX in with drug–drug comparisons; studies assessing naïve 1054 journals.sagepub.com/home/msj G Arrambide, E Iacobaeus et al. patients who started a high-efficacy DMT and studies Conversely, a study based on a national registry assessing patients who switched from first-line to using propensity score matching in patients switch- high-efficacy DMT or from one high-efficacy DMT ing to second-line DMTs after breakthrough disease to another. Of note, there are no specific studies on while on IFN-β or glatiramer acetate did demon- treatment for aggressive pMS. strate natalizumab was more effective than fingoli- mod in reducing the number of relapses and Importantly, although not available at the time of the improving disability.38 Although the selection crite- workshop, data since have shown a superiority of mon- ria for this study did not restrict patient selection to oclonal antibodies (Mabs) over oral DMTs. Most of cases with highly active disease, the mean (SD) said studies were not included in this review because: number of relapses in the year prior to inclusion was (1) they do not assess patients with aggressive MS, (2) 2.8 (2.0) for patients switching to natalizumab and it is impossible to determine if the included subjects 2.7 (3.1) for patients switching to fingolimod, which have aggressive MS according to the baseline charac- might be considered a relatively high relapse rate for teristics or (3) they do include a subgroup with aggres- included subjects. Another hospital-based study also sive MS but it is not evaluated individually. demonstrated natalizumab was superior to fingoli- mod in inducing regression of disability and NEDA Oral and intravenous DMTs. Dimethyl fumarate at 2 years.39 There were, however, no significant dif- (DMF) was assessed in a subgroup analysis of patients ferences between medications when comparing the with high clinical or radiological activity in the clinical components of NEDA individually. These DEFINE and CONFIRM trials.26,27 However, results results could be due to the small sample size after were not compared to other DMTs in this analysis. propensity score matching and dropouts in the fin- golimod group due to breakthrough disease. Fingolimod has been compared to other DMTs and showed a greater effect on the annualized relapse rate Post hoc subgroup analyses of the CLARITY clinical (ARR) compared with interferon (IFN)-β1a in trial in patients with high disease activity compared patients with high clinical or radiological activity.30 cladribine to placebo.31,32 A recent analysis suggested However, fingolimod might not be as effective as that patients with highly active MS have a better Mabs and its superiority over DMF is not clear. A pro- response to cladribine than those with a milder dis- pensity score-matching analysis assessed no evidence ease course. This analysis classified patients into two of disease activity (NEDA-3) at 2 years in two patient overlapping, categorical subgroups: the high relapse datasets after starting natalizumab, fingolimod or activity (HRA) and the HRA plus disease activity on self-injectables: one study included patients with high treatment (HRA + DAT) subgroups.32 During clad- clinical activity despite first-line DMTs and one ribine treatment, the ARR was lower in HRA versus included highly active, treatment-naïve patients.36 non-HRA patients and in HRA + DAT versus non- When comparing natalizumab and fingolimod, the HRA + DAT patients, although without reaching sta- proportion of patients with NEDA-3 was greater for tistical significance. Similarly, the risk of new Gd+ natalizumab than fingolimod in the first dataset, lesions decreased slightly in patients with a more whereas in the second, the difference did not reach active disease.32 statistical significance, probably due in part to the smaller size of that cohort.36 A prospective hospital-based study assessed 70 patients with highly active MS treated with natali- A systematic review and meta-analysis of highly zumab, of whom 97.1% had received a previous active rMS and rapidly evolving severe MS explored DMT. The proportion of patients free of clinical and the efficacy of fingolimod relative to DMF and natali- overall disease activity was 60.0%–70.0% at 1 year zumab.37 In the highly active relapsing–remitting but decreased to approximately 50.0% after 2 years. multiple sclerosis (RRMS) population, a trend Conversely, freedom from radiological activity was favoured fingolimod over DMF in reducing the ARR consistently high throughout the study period.40 and confirmed disability progression. In the rapidly evolving severe MS population, patients on fingoli- Alemtuzumab has been compared to IFN-β1a in a mod had a non-statistically significant increase in the post hoc and subset analysis of the CAMMS223 trial. ARR and in confirmed disability progression com- Results favoured alemtuzumab in patients with fre- pared to patients on natalizumab.37 This meta-analysis quent relapses.41 In a single small study of alemtu- has limitations due to its retrospective assessment and zumab as rescue therapy after mitoxantrone in patients was not powered to indicate differences only in sub- with rMS and SPMS, some subjects showed EDSS jects with a highly active or severe disease. improvement and NEDA.42 journals.sagepub.com/home/msj 1055 Multiple Sclerosis Journal 26(9) Finally, ocrelizumab has shown increased treatment with caution due to the absence of direct compari- benefits relative to IFN-β1a by reducing disease sons.51 aHSCT is still considered experimental in MS, activity and disability progression in a subgroup of with a need to demonstrate a sound risk/benefit pro- rMS patients with highly active disease.43 Similarly, file in a well-defined target population (Table 4). rituximab has proven effective in patients with rMS with persistent disease activity despite treatment with Mitoxantrone. The efficacy of mitoxantrone has other high-efficacy DMTs, such as fingolimod, natali- been assessed against methylprednisolone or pla- zumab or mitoxantrone44 (Tables 2 and 3). cebo in studies, including both RRMS and SPMS.52,53 One of the rare trials including a well- Autologous haematopoietic stem cell transplanta- defined highly active population studied the effect tion. Autologous haematopoietic stem cell transplan- of short-term immunosuppression with mitoxan- tation (aHSCT) is used to induce long-term trone in patients with aggressive RRMS, defined immunosuppression and immune reconstitution in as ⩾ 2 relapses or an EDSS increase ⩾ 2 points in aggressive forms of MS. To date in MS, it has been the 12 preceding months, ⩾ 1 Gd-enhancing lesion mostly used as an escalation therapy approach when and baseline EDSS between 2.5 and 5.0. The time to more than one first- or second-line DMTs has failed. worsen by ⩾ 1 point in EDSS at 3 months was delayed in patients who received mitoxantrone plus Early evidence on the efficacy of aHSCT came as methylprednisolone for 6 months before switching small case series showing a significant improvement to IFN-β, compared to patients receiving IFN-β plus in EDSS and reduction in number of relapses.45 methylprednisolone for 6 months who then contin- Results from two Phase 2 clinical trials (one includ- ued treatment with IFN-β alone.54 Nevertheless, use ing both rMS and pMS patients and one with rMS of mitoxantrone has declined due to serious adverse patients only) support the efficacy of aHSCT in events and it should be considered only in individ- patients with high clinical activity. In these studies, ual cases. two-thirds of subjects were free of disease activity at 3 and 5 years and no treatment-related mortality was reported in one of the trials.46,47 Another Phase 2 trial Special situations and populations compared aHSCT and mitoxantrone in rMS and pMS Pregnancy. Pregnancy risks should be discussed with patients with high clinical and radiological activity, patients and spouses before starting any DMT.55 using cumulative number of new T2 lesions after Information on treatment of patients with highly 4 years as primary endpoint.48 Compared to mitox- active MS during pregnancy is limited. Most data antrone, aHSCT reduced the number of new T2 come from studies and observations on individuals lesions by 79.0% and also had an effect on Gd+ with a broad spectrum of MS phenotypes and severi- lesions and ARR, but no difference was found in dis- ties. Therapies which can be administered throughout ability progression.48 A long-term, multicentre, pregnancy or those which are stopped at conception observational, retrospective cohort of rMS and pMS but have lasting effects throughout pregnancy should patients who received aHSCT showed that the over- be considered. all 5-year probability of progression-free survival was 46.0%, and the size effect was greater in RRMS Immune reconstitution treatments administered in than in SPMS patients. Importantly, factors increas- short courses, such as alemtuzumab, cladribine and ing the risk of overall worse survival after aHSCT are probably rituximab, offer a window of opportunity in older age, pMS, more than two previous DMTs and a patients with aggressive MS planning a pregnancy high EDSS.49 (typically 4–6 months after the last dose, with some authors suggesting 1 month in the case of rituxi- These findings are supported by a meta-analysis eval- mab).56–59 To minimize the risk of recurrent disease uating the rate of disease progression and NEDA after activity in patients stable while using natalizumab, aHSCT. At 5 years, the pooled rate of progression was continuing treatment until the beginning of the third 23.3% and NEDA was observed in 67.0% of patients. trimester or throughout pregnancy should be consid- In general, progression-free survival in patients has ered, as the haematological changes reported in increased in studies post-2005, in younger patients exposed newborns are temporary and not clinically with EDSS ⩽ 5.5 and in rMS.50 Finally, when aHSCT relevant.55,60 In the rare occurrence of aggressive MS is compared to first- and second-line DMTs tested in developing in a pregnant woman, natalizumab or anti- Phase 3 trials, NEDA at 2 years was greater in patients CD20 therapies might be considered, but evidence of undergoing aHSCT than in those receiving placebo or their safety and efficacy in such a situation is scant. DMTs. However, these results should be interpreted This is an area for future research. Fingolimod is 1056 journals.sagepub.com/home/msj G Arrambide, E Iacobaeus et al. contraindicated not only due to the risk of recurrent In summary, children with aggressive MS could ben- disease activity after stopping treatment, but mainly efit from initiating a more efficacious DMT from the due to the increased risk of major birth defects in start.69,74 Such a strategy takes the generally higher exposed infants.61 disease activity in this population into account, but it will have to be prospectively studied. The long-term After delivery, early reintroduction of DMTs is advis- impact of such therapies in children, including clini- able if prior therapies do not have long-lasting thera- cal and immunological developmental milestones, peutic effects.62,63 In case of relapses, PLEX has been remains unknown. used successfully during pregnancy,64 but caution should be used since it can aggravate IRIS-like phe- Senior patients. There are no data regarding DMT in nomena following natalizumab discontinuation.65,66 senior patients (> 65 years of age at time of treatment) There is no specific evidence supporting the use of IA with aggressive MS. In this age group, the safety and or IVIg as alternatives to PLEX in pregnant women tolerability of highly effective DMTs in very active with highly active MS. cases may be affected by MS- and age-related comor- bidities.10,75–77 Given that senior patients are usually Children. Severe relapses in children with MS have excluded from clinical trials, encouraging their repre- been treated with repeated corticosteroid boluses, sentation in prospective trials would increase the PLEX, IVIg, rituximab and cyclophosphamide with available evidence but, to date, real-world data (regis- varying degrees of benefit.67–69 However, inclusion tries, observational cohorts) may be the best source of of patients with demyelinating diseases other than information for this patient group. MS cannot be ruled out in some of these studies, so their relevance to a paediatric MS population may be limited. How to manage and prevent complications of high-efficacy treatments A retrospective single-centre study identified paediat- Risk-minimizing strategies before, during and after ric patients with highly active disease according to the treatment with high-efficacy DMTs are reviewed in definition in German guidelines70 (⩾ 1 attack within detail elsewhere.78 It is important to note that the the previous year and ⩾ 9 T2 lesions or ⩾ 1 Gd+ time frame to implement such strategies is likely lesion while under first-line DMT. At diagnosis, ⩾ 2 narrower in patients with aggressive MS. In addi- attacks and EDSS worsening within the last 12 months tion, the occurrence and management of adverse and ⩾ 1 Gd+ lesion or a significant increase in T2 events may be different for aggressive and non- lesions within the last 6–12 months). The 12-month aggressive MS depending on the comorbidities that period before and after treatment initiation with natal- may be associated with more severe MS and the izumab or fingolimod was studied. After 1 year of adverse event profile of individual treatments. A list treatment, relapse rate was reduced by 95.2% in natal- of some adverse events related to the immunosup- izumab-treated patients and 75.0% in fingolimod- pressive effects of these DMTs is shown in treated patients. Significant reductions were also Supplemental Table 2. observed in MRI parameters of disease activity. When compared to a historical cohort of patients with mild- Beyond treatment-related AEs, all patients should to-moderate disease activity treated with first-line receive vaccinations as indicated in their respective therapies, patients on natalizumab or fingolimod had regions, with special considerations depending on the a 44.0% reduction in mean EDSS.71 type of vaccination and the MS treatment plan. A 4 to 6-week interval is typically recommended between Other than these, there are no treatment studies spe- administration of live-attenuated vaccines and initia- cifically addressing highly active disease in chil- tion of high-efficacy treatments.79,80 Until new data dren. Nevertheless, most children present with a emerge supporting the safety of live-attenuated vac- higher disease activity than adults and can be con- cines in patients treated with immunosuppressive sidered as having aggressive MS simply by their therapies, such vaccines are contraindicated during natural history. In the PARADIGMS clinical trial72 therapy and for a variable period after treatment ter- in paediatric MS, fingolimod was associated with a mination, usually ranging from 2 to 6 months.81 Data lower ARR (relative difference of 82.0%) and with support the effectiveness of vaccinations (sometimes less accumulation of MRI-detected brain lesions reduced compared to placebo) during treatment with than IM IFN-β1a. Evidence relating to the use of natalizumab, fingolimod or DMF, indicating that rituximab in children is minimal and not focused in inactivated, subunit and toxoid vaccines can be highly active MS.73 administered in such cases.81 journals.sagepub.com/home/msj 1057 Multiple Sclerosis Journal 26(9) Achievements, gaps in knowledge and future studies show that highly active patients with rMS are perspectives good candidates for this treatment, but such studies Considering available evidence to date regarding lack active comparators. treatment in patients with aggressive MS, direct data are limited. The PLEX randomized, sham-controlled Consequently, more rigorous prospective studies are trial for severe attacks15 and the mitoxantrone and needed to confirm which treatments are the best methylprednisolone randomized multicentre study in option for patients with aggressive MS. Examples rMS54 were the only trials we identified that included include the ongoing trials comparing aHSCT to high- patients with an aggressive disease. However, the for- efficacy treatments in patients with breakthrough dis- mer was not limited to patients with MS and the latter ease despite first- or second-line DMTs.83 When included patients with different MS phenotypes. considering a trial design for aggressive MS, a first step would be to consider the features that best define Therefore, many open issues remain. An important this phenotype early in the disease course to inform limitation to address the questions on treatment is the the inclusion criteria. A second step would consist in lack of a unified definition of aggressive MS. Before identifying a medium-term (2–3 years) endpoint any consensus on treatment of aggressive MS can be related to, for example, EDSS 6.0 at 10 years, sensi- obtained, it will be particularly important to develop a tive enough to occur frequently in the control group. unified definition of aggressive disease. To the extent The next steps would be selecting the active compara- possible, paraclinical and clinical biomarkers may aid tor the control group will receive and hypothesizing stratify the more severe cases of both relapsing and the expected reduction in outcome events with the pMS phenotypes. As mentioned before, two studies more efficacious DMT. It is then that the sample size have recently proposed EDSS ⩾ 6.0 at 10 years as a can be calculated. Finally, a decision on performing a definition of aggressive MS,8,9 but this proposal needs conventional clinical trial or a pragmatic trial can be to be validated in other cohorts or registries. In addi- made according to the sample size. tion, it is important to assess whether other biomarkers of aggressive disease (i.e. potentially neurofilament It is important to consider that head-to-head com- light chain levels, atrophy measures) may have an parative studies require very large sample sizes to added value to NEDA-3 and other scores of break- demonstrate the differential efficacy and safety through disease. using the current outcome measures. Conducting pragmatic trials is a different approach that evaluates Open issues also remain regarding treatment of severe the effectiveness of an intervention in the real-world attacks: does oral methylprednisolone act as quickly setting.84 These trials are designed to test interven- and effectively as the IV form when an equivalent tions in the full spectrum of everyday clinical set- dose is used? Is 1 g/day the best dose in these cases? tings to maximize applicability and generalizability. When should treatment be escalated to PLEX? Can Pragmatic trials measure mostly patient-centred out- natalizumab or anti-CD20 Mabs be used as treatments comes, whereas conventional trials focus on measur- of severe attacks? able symptoms or biomarkers.85 Examples of such trials are TREAT-MS and DELIVER-MS, which Concerning the use of DMTs, an escalation paradigm compare two treatment paradigms: early highly does not appear to be a good option in patients with effective therapy versus escalation of therapy.86 aggressive MS. Based on current data, their window However, these two trials are not designed specifi- of therapeutic opportunity is narrow, as response to cally for aggressive MS. DMTs is better early in the disease course and in younger patients with minimal disability.6,82 Rather In addition, evidence from long-term follow-up of than escalating, starting a high-efficacy treatment in patients included in clinical trials and large, real- these instances would likely be a better option to limit world cohorts assessing different subgroups of the possibilities of breakthrough disease. Nevertheless, patients with MS, including pMS and special popula- the evidence for conducting such approach is limited tions with aggressive MS, may provide useful data because pivotal trials were not focused in patients when controlled trials are not feasible. with aggressive MS. As for the post hoc analyses from the DMTs pivotal clinical trials, they are limited Finally, we are aware that limitations on treatment to comparisons with placebo or self-injectables, short access to highly efficacious DMTs vary widely from term and underpowered to demonstrate any signifi- country to country, mostly due to financial restric- cant differences among DMTs in the more aggressive tions. We hope papers such as this one may help MS subpopulations. In the case of aHSCT, the most recent specialists provide information about the usefulness 1058 journals.sagepub.com/home/msj G Arrambide, E Iacobaeus et al. of starting a highly efficacious DMT in patients with Funding aggressive MS to their local regulatory agencies. The author(s) disclosed receipt of the following finan- cial support for the research, authorship, and/or publi- Acknowledgements cation of this article: The workshop on which the The authors thank ECTRIMS for financial and admin- manuscript is based was supported in its entirety by istrative support of the focused workshop that served the European Committee on Treatment and Research as the basis for this paper and all workshop attendees in Multiple Sclerosis (ECTRIMS). (Supplemental Table 2) for their participation. All attendees had the opportunity to review and comment ORCID iDs upon an advanced draft of the manuscript prior to sub- Georgina Arrambide https://orcid.org/0000-0002 mission. They also thank Dr Stephen C. Reingold for -2657-5510 assistance with manuscript writing and editing, sup- Tobias Derfuss https://orcid.org/0000-0001-8431 ported by ECTRIMS. -8769 Sandra Vukusic https://orcid.org/0000-0001-7337 Declaration of Conflicting Interests -7122 The author(s) declared the following potential con- Bernhard Hemmer https://orcid.org/0000-0001 flicts of interest with respect to the research, author- -5985-6784 ship, and/or publication of this article: G.A. has Mar Tintore https://orcid.org/0000-0001-9999-5359 received compensation for consulting services or par- ticipation in advisory boards from Sanofi, Merck and Supplemental material Roche; research support from Novartis; travel Supplemental material for this article is available expenses for scientific meetings from Novartis, Roche online. and Stendhal; and speaking honoraria from Sanofi and Merck. E.I. has honoraria for advisory boards or lec- turing for Sanofi Genzyme and Merck outside the sub- mitted work. 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