How much progress has there been in the second-line treatment of multiple sclerosis: A 2017 update

NEUROL-1911; No. of Pages 12 revue neurologique xxx (2018) xxx–xxx

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Multiple Sclerosis on behalf SFSEP

How much progress has there been in the secondline treatment of multiple sclerosis: A 2017 update A. Maarouf a,b,c,*, C. Boutie`re c, A. Rico c, B. Audoin a,c, J. Pelletier a,c a

CRMBM UMR 7339 CNRS, Aix Marseille Universite´, 13005 Marseille, France AP–HM, Hoˆpital de la Timone, Poˆle d’Imagerie Me´dicale, CEMEREM, 13005 Marseille, France c AP–HM, Hoˆpital de la Timone, Poˆle de Neurosciences Cliniques, Service de Neurologie, 13005 Marseille, France b

info article

abstract

Article history:

In 1993, the US Food and Drug Administration (FDA) approved the first drug specifically for

Received 26 December 2017

treating multiple sclerosis (MS). More than two decades later, a dozen such treatments are

Received in revised form

now available. Of these, four are considered second-line treatments for use in escalation

24 January 2018

strategies and two new drugs are currently undergoing accreditation procedures. Soon, they

Accepted 26 January 2018

will provide clinicians with a range of six effective disease-modifying treatments (DMTs) to

Available online xxx

thwart the inflammatory processes in MS patients with active disease. However, while such a large number of DMTs for MS can help to control early inflammation, any decisions to be

Keywords:

made by clinicians have also been made substantially more complex. This complexity is

Multiple sclerosis

increased by the lack of head-to-head studies comparing these second-line therapies and

Second-line therapy

the benefit–risk profiles for each of these drugs, which are likely to vary among patients.

Induction

Ultimately, good awareness of the benefits and, more important, the risks of each MS DMT is

Escalation

crucial for the effective management of inflammation in MS.

Early treatment

1.

Introduction

In 1993, the first drug specifically to treat multiple sclerosis (MS) was approved by the US Food and Drug Administration (FDA) and now, more than two decades later, a dozen or so disease-modifying treatments (DMTs) are available. Two strategies are used in MS treatment: escalation and induction [1]. The escalation strategy is by far the most commonly used,

# 2018 Elsevier Masson SAS. All rights reserved.

and consists of the initial introduction of a safe but less effective drug, and an upgrade only in cases of failure of that first-line drug. However, among the MS DMTs now available, four are considered second-line treatments in the context of escalation strategy and, in addition, two new drugs are currently undergoing European Union (EU) and FDA accreditation procedures. Soon, they will be providing clinicians with a range of six highly effective DMTs to thwart the inflammatory

* Corresponding author at: Hoˆpital de la Timone, Poˆle d’Imagerie Me´dicale, CEMEREM, 13005 Marseille, France. E-mail address: [email protected] (A. Maarouf). Abbreviations: ALZ, alemtuzumab; DMT, disease-modifying treatments; EDSS, Expanded Disability Status Scale; FTY, fingolimod; IFN, interferon; MTX, mitoxantrone; MS, multiple sclerosis; MSFC, Multiple Sclerosis Functional Composite; NTZ, natalizumab; PML, progressive multifocal leukoencephalopathy; RRMS, relapsing–remitting multiple sclerosis. https://doi.org/10.1016/j.neurol.2018.01.369 0035-3787/# 2018 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Maarouf A, et al. How much progress has there been in the second-line treatment of multiple sclerosis: A 2017 update. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.01.369

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process in MS patients with active disease. However, having such a number of MS DMTs to help control early inflammation has also made clinicians’ choices considerably more complex. This complexity is all the greater due to the lack of head-tohead studies comparing these second-line therapies and the benefit–risk profiles of each drug, which will vary from one patient to another. Yet, good awareness of the benefits and, more important, the risks of each MS DMT is crucial for the effective management of inflammation in MS. Thus, the present review describes the second-line DMTs that are already available (mitoxantrone, natalizumab, fingolimod, alemtuzumab, rituximab) or will soon be available (ocrelizumab, cladribine) by presenting the results of evaluation studies in the literature, their reported side-effects and the main indications for which each one is used. This is followed by a discussion of the indications for second-line therapy, the monitoring strategy, and the difference between induction and escalation strategies in MS patients’ care.

2.

Mitoxantrone (MTX)

The first available second-line therapy, MTX is a synthetic anthracenedione initially used in cancer because of its cytostatic effects. In 1997, two pivotal controlled studies were published: the first compared monthly administration of 20-mg MTX plus methylprednisolone with methylprednisolone alone for 6 months, and found a dramatic increase in patients with no new enhancing lesions (90% vs 31%, respectively; P < 0.001) and a reduced number of relapses (7 vs 31, respectively; P < 0.01) [2]; and the second study, comparing MTX with placebo for 2 years, similarly found a reduction in disease activity as well as a smaller proportion of patients with confirmed progression [1 point in the Expanded Disability Status Scale (EDSS) score] at 2 years in the MTX group [3]. In 2002, an MTX trial in patients with active progressive MS was conducted, and reported positive effects on relapse rates and disability changes over 2 years [4]. In parallel, MTX was also assessed as induction therapy in MS [5–7]. In this study, 109 patients presenting with highly active MS, defined as at least 2 relapses in the previous year and gadolinium-enhanced lesion(s) on magnetic resonance imaging (MRI), were randomized into two groups, one receiving MTX for 6 months followed by interferon (IFN), and the other receiving only IFN. The 3-year risk of worsening disability was reduced by 65% in the MTX vs IFN group. Patients of the MTX group also presented with lower relapse rates and less lesion activity on MRI at each time point [5]. While the anti-inflammatory effects of MTX are now well established, its use is associated with some possibly severe, dose-dependent, side-effects, including congestive heart failure (0.4% if treatment is discontinued when the left ventricular ejection fraction (LVEF) is <50%) [8,9], acute leukemia in 0.6–0.8% of cases [10,11] and persistent amenorrhea in 12% [11]. Moreover, previous exposure to MTX increases the risk of progressive multifocal encephalopathy (PML) in patients receiving natalizumab [12]. Thus, the cumulative lifetime dose of MTX is limited to 72 mg/m2, and patients are monitored through blood cell counts and heart

function before, during and at least 5 years after MTX discontinuation [European Medicines Agency (EMA) recommendation]. Effective contraception is also required during therapy and for at least 6 months afterwards, and ways to preserve fertility should be discussed with patients. In addition, administration of live attenuated vaccines should be avoided (EMA recommendation). Thus, MTX therapy is mainly used for patients with highly active MS who rapidly develop disability and present with at least 1 gadolinium-enhanced lesion.

3.

Natalizumab (NTZ)

NTZ is a humanized antibody that blocks the very late antigen (VLA)-4 adhesion molecules present on lymphocytes, preventing their binding to their endothelial receptor [vascular cell adhesion molecule (VCAM)-1] and inhibiting their passage across the blood–brain barrier (BBB). This was the very first monoclonal antibody approved for MS. On the basis of positive results in a phase-II study [13], a 2-year phase-III study (AFFIRM) comparing NTZ 300 mg every 4 weeks with a placebo was conducted [14]. Patients in the NTZ group showed a 68% decrease in relapse rate after 1 year (primary endpoint) and a 42% reduction in risk of sustained progression of disability over 2 years (primary endpoint). On MRI, a reduction of 83% in the number of new or enlargening hyperintense T2-weighted lesions detected over 2 years, and a 92% reduction in gadolinium-enhanced lesions after both 1 and 2 years of follow-up, were evidenced in patients in the NTZ group compared with the placebo group. These results were confirmed in a second phase-III study (SENTINEL), which evaluated NTZ as an add-on to IFN therapy. The combination therapy resulted in a 54% reduction in relapse rate, an 83% reduction in new or enlargening T2 lesions on MRI and a 24% reduction in disability progression over a 2-year period [15]. The most commonly reported side-effects in these pivotal studies were fatigue, allergic reactions and ear–nose–throat (ENT) congestion [14,15]. However, the main NTZ risk is progressive multifocal leukoencephalopathy (PML). As of September 2017, 749 cases of PML have been reported [16], making NTZ-related PML (NTZ–PML) the third cause of PML, after human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) infections and blood cancers [17]. PML is an opportunistic infectious disease caused by John Cunningham Virus (JCV; named after a patient with lymphoma in whom the virus was first identified in 1971) [18]. The infection is characterized by intense demyelination, bizarre astrocytes and enlarged oligodendroglial nuclei with inclusions. PML overall incidence in NTZ-treated patients after 24 months is 4.22/1000 (95% CI: 3.93–4.54) patients [16], which is increased in those previously receiving immunosuppressant treatment or with an anti-JCV antibody index 0.9, although what the index value would be in such previously treated patients is unclear [19]. In addition, a recently identified biomarker, L-selectin (or CD62L), is currently being assessed in the stratification of risk for NTZ–PML. This adhesion molecule is present on the surface of lymphocytes, and its reduction in serum is associated with a higher risk of NTZ–PML [20,21]. Added to

Please cite this article in press as: Maarouf A, et al. How much progress has there been in the second-line treatment of multiple sclerosis: A 2017 update. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.01.369

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the anti-JCV antibody index, this should better identify patients at high PML risk, which probably represents <2% of NTZ-treated patients, so as not to deprive the vast majority of patients of an effective MS DMT [20]. Nevertheless, despite its promise, contradictory results have suspended L-selectin use until further investigations are available [22]. NTZ–PML is fatal in a quarter of affected patients, and the factors for a poor prognosis are advanced age, higher EDSS scores, delayed diagnosis, a greater cerebrospinal fluid (CSF) JCV load at diagnosis and extension of PML lesions on MRI [23]. Yet, despite numerous trials, no treatment has proved efficacious in treating PML [24–28]. However, mirtazapine is a potential candidate due to the suspected role of serotonin receptors in JCV-infected cells [29]. In cases of NTZ–PML, the usual strategy is clearance of NTZ by therapeutic plasma exchange [30], although recent data have failed to demonstrate any beneficial effects with such a procedure [31]. In this context, the best ‘treatment’ for NTZ–PML is prevention, with very careful supervision of patients treated with NTZ. NTZ exerts disease control only as long as its use is maintained. On withdrawal, it may be followed by rapid and sometimes severe rebound of disease activity. The switchover period should be <3 months, based on the assessed switching from NTZ to fingolimod [32,33]. Pregnancy is officially not recommended with NTZ; a registry of data from 355 pregnancies has reported a major birth-defect rate of 5% with no specific pattern of malformation [34]. While maternal–fetal antibody transfer is known to be marginal during the first trimester of gestation, it increases during the following two trimesters [35]. Thus, continuation of NTZ during the third trimester will expose newborns to the risk of transient hematological abnormalities, such as anemia and thrombocytopenia [36]. In addition, NTZ is known to pass into breast milk [37,38].

4.

Fingolimod (FTY)

FTY is a sphingosine-1-phosphate analog that binds to receptors on the surface of lymphocytes, thereby inducing receptor degradation, which inhibits the egress of lymphocytes from lymphoid tissue. Two pivotal studies (FREEDOMS I and II) have demonstrated the efficacy of FTY in relapsing MS. Compared with placebo, FTY was associated with lowered relapse rates of 48% [39] and 54% [40] over 2 years, while time to disability progression was reduced by one-third in the FTYtreated group (in FREEDOMS I only) [40]. On MRI, FTY was associated with a 75% reduction of new or enlargened T2 lesions and less brain volume loss (in FREEDOMS II) [39]. A third pivotal study (TRANSFORMS) compared FTY with IFN for 12 months: relapse rate was 40–51% lower, and the number of gadolinium-enhanced lesions on MRI was 55–72% lower in those receiving FTY [41]. Based on these studies, the selected FTY dose is 0.5 mg. In addition, a recent study (PARADIGMS) was conducted in a pediatric population aged 10–17 years and compared FTY with IFN: FTY was associated with an 82% reduction in relapse rate vs IFN over a 2-year period as well as a significant reduction in the number of new MS lesions on MRI [42].

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The safety profile of FTY is mostly related to the distribution of sphingosine-1-phosphate receptors and the fact that all lymphocytes are not similarly trapped. As receptors are also present in the heart, retina, liver and lungs, patients taking the drug may be exposed to bradycardia and atrioventricular (AV) conduction block at the time of initiation, and also hypertension, macular edema and increased levels of alanine aminotransferase [39–41]. In addition, FTY contraindication in patients with cardiac disease was recently reinforced. Thus, FTY should not be prescribed to: patients with myocardial infarction, unstable angina, stroke, transient ischemic attacks, decompensated heart failure (requiring hospitalization) or New York Heart Association (NYHA) Class III/IV heart failure in the past 6 months; patients with severe cardiac arrhythmias requiring treatment with Class Ia and Class III antiarrhythmic drugs; patients with Mobitz II seconddegree or third-degree AV block, or sinus disease if no pacemaker is worn; and patients with an initial corrected QT interval 500 ms. Patients generally present with lymphopenia, which predominantly affects naı¨ve and central memory T cells [43], with an increased risk of infectious diseases such as herpes simplex encephalitis and disseminated varicella zoster virus (VZV) infection [39–41]. If the VZV antibody test is negative before starting treatment, then vaccination is mandatory [44]. Moreover, PML has been reported in 79 patients, including 22 cases attributable to FTY [45], although none of these patients presented with chronic lymphopenia. Cutaneous monitoring is of particular importance due to the risk of skin cancers such as melanoma, and basal and squamous cell carcinoma [46–50], and also the risk of fungal infections [51–54]. Thus, meticulous skin examination before starting FTY is crucial, with repeat examinations every 6–12 months. Pregnancy studies of FTY in animals and in clinical trials [55] have suggested a high risk of teratogenicity, thereby requiring contraception during FTY treatment and for at least 2 months after its discontinuation, and the avoidance of breastfeeding while taking the drug [56]. No head-to-head studies have compared FTY with NTZ. Nevertheless, real-life observational studies suggest slightly greater efficacy with NTZ in terms of relapses and MRI lesion activity. A retrospective study compared 57 patients receiving NTZ with 30 taking FTY: while those using NTZ initially had more active disease, their relapse risk was reduced compared with the FTY group [57]. Another study compared 69 patients receiving NTZ with 36 receiving FTY; the choice of drug was based solely on JCV serology status to avoid other confounding factors, such as patients’ disease activity levels and clinicians’ biases concerning the drug. The results included significant differences in time to relapse and in numbers of gadoliniumenhancing lesions favoring NTZ [58]. Two studies used propensity score analysis to compare the two DMTs. This statistical method compares the effects of medical procedures, including treatments, by considering the covariates that predict whether or not a given procedure or treatment is administered and limits biases due to confounding variables that invariably influence treatment choices and, as a consequence, influence the results obtained in a simple group comparison. In the first study, of the 792 patients

Please cite this article in press as: Maarouf A, et al. How much progress has there been in the second-line treatment of multiple sclerosis: A 2017 update. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.01.369

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included [59], 578 were matched and given either NTZ (n = 407) or FTY (n = 171). Over a 12-month period, the proportion of relapse-free patients was greater in those switching to NTZ than to FTY; the hazard ratio (HR) for relapses was lower in the NTZ group, and 20% of the NTZ group showed a reduction in disability. In the second study, data from 326 patients treated with NTZ and 303 with FTY were evaluated, and showed that the number of patients with at least 1 relapse within the first and second years of treatment was lower with NTZ. Similar results were observed for new MRI lesions at both 1 and 2 years post-treatment [60]. Nevertheless, even if these studies suggest greater NTZ efficacy in controlling MS activity, their results need to be balanced against the relative safety and good tolerability of FTY, although the risk of treatment withdrawal due to adverse events was comparable between FTY and placebo/IFN groups [61].

5.

Alemtuzumab (ALZ)

ALZ is a humanized monoclonal antibody that targets CD52 on lymphocytes and monocytes, and is mainly used to treat blood cancers. Given its mode of action, ALZ can be used as an induction DMT for MS. After ALZ infusion, B cells recovered within 6 months, whereas T cells recovered more slowly, approaching the lower limit of normal after 12 months [62]. In one phase-II study (CAMMS223), 223 patients assigned to receive annual cycles of ALZ were compared with 111 patients who received IFN [63]. All patients had disease durations of 3 years and EDSS scores 3. ALZ significantly reduced the rate of sustained accumulation of disability by 66% and relapse rate by 72% compared with IFN. The mean EDSS score improved by 0.39 points with ALZ and worsened by 0.38 points with IFN over a 3-year follow-up. On MRI, there was a T2-weighted reduction in lesion volume over a 3-year period in all studied groups, which was more marked with ALZ treatment. Finally, between months 12 and 36, brain volume increased in the ALZ group, but decreased in the IFN group. Efficacy of ALZ was further confirmed by two phase-III studies: CARE-MS I compared ALZ with IFN in patients naı¨ve to treatment; and CARE-MS II included patients who relapsed despite first-line treatment [62,64]. The relapse rate was reduced by 49–54% in the ALZ group vs IFN group whereas, in CARE-MS II, 20% of IFN patients vs 13% of ALZ patients showed sustained rates of accumulation of disability, corresponding to a 42% improvement with ALZ treatment. The posology of ALZ based on these three studies was 12 mg, repeated for 5 days in the first year and for 3 days in the second year, with possible repetitions over years 3–5. The main limitation of ALZ use is its safety profile, as half the users secondarily develop an autoimmune disorder over a median 7-year follow-up period [65]. In the CAMMS223 study, there were two deaths, both in the ALZ group, including one due to immune thrombocytopenic purpura leading to premature suspension of ALZ uptake. However, by far the most frequent autoimmune disorder involves the thyroid gland and affects 20–40% of patients, while thyroidrelated events were associated with thyroid autoantibodies in 96% of cases [63]. Other described autoimmune disorders

included Coombs-positive autoimmune hemolytic anemia, glomerulonephritis with hematuria, proteinuria, slightly elevated antiglomerular basement membrane antibody and autoimmune pancytopenia [62,64]. Other side-effects were infusion reactions, recurrent herpesvirus infections requiring acyclovir 200 mg twice daily or for 1 month, starting with each course of ALZ infusion. Pregnancy should be avoided for at least 4 months following ALZ infusion [65], and administration of live attenuated vaccines is not recommended during therapy.

6.

Ocrelizumab (OCZ) and rituximab (RIX)

Although MS is considered a classic T-cell disease, the efficacy of anti-CD20 monoclonal antibodies (RIX) in relapsing–remitting MS (RRMS) was first reported by two studies in 2008 [66,67]. Antigen CD20 is expressed on the surface of preB cells and mature and immature B cells, but not on early proB or plasma cells. Antibodies directed against CD20 act by inducing complement-dependent cytotoxicity (mainly with RIX) or antibody-dependent cell-mediated cytotoxicity (mainly with OCZ), leading to massive apoptosis of CD20+ B cells. An initial open-label study of 26 patients followed for 72 weeks reported a reduction in mean gadolinium-enhanced lesions from 1.31 at trial entry to 0 at week 72, with 80.8% of patients relapse-free at the end of the trial [66]. In a doubleblind phase-II study published at the same time, RIX was associated with a >90% reduction in gadolinium-enhanced lesions and 50% fewer relapses compared with placebo [67]. These two preliminary studies included patients with at least 1 relapse and 1 gadolinium-positive lesion within the preceding year. In 2010, Naismith et al. [68] reported on a phase-II study of the potential efficacy of RIX as an add-on therapy in patients with clinically and radiologically active RRMS despite injectable immunomodulatory treatments. This study found an 88% reduction of contrast-enhanced lesions and an improvement in Multiple Sclerosis Functional Composite (MSFC) score at week 52. In 2011, a phase-II study demonstrated the superiority of OCZ compared with IFN beta-1 on MRI lesion activity [69]. More recently, the efficacy of OCZ was reported in two phase-III controlled studies (OPERA I and II), which included a total of 1656 RRMS patients [70]. Compared with IFN beta-1a, patients in the OCZ arm had lower rates of relapse (46%), and less MRI lesion activity (94%) and disease progression (HR: 0.60, 95% CI: 0.43–0.84). Recently, a retrospective study compared 461 patients receiving RIX who were propensity-score-matched with 922 patients receiving IFN or glatiramer acetate, and found an 87% reduction in relapse rate and a mean EDSS score decrease of 0.15  0.58 points after 24 months of RIX treatment vs 0.02  0.49 points with IFN/ glatiramer acetate [71]. The most commonly reported side-effects were infusionrelated reactions, upper respiratory tract infections, headaches and urinary tract infections. Four cases of neoplasm were found in the OPERA studies with OCZ vs two such cases with IFN [70]. Other side-effects reported with anti-CD20 were cytomegalovirus (CMV) disease, Pneumocystis jiroveci infection [72], hepatitis B reactivation [73] and PML [74]. However, of the

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57 reported PML cases, 52 were patients with blood cancers [74], whereas no cases of PML were reported in a retrospective Swedish study that followed, for 500 days, 114 patients positive for JCV serology who had switched from NTZ to RIX [75]. Given the modes of action of OCZ and RIX, vaccination should be done before anti-CD20 initiation or just before a new infusion if this was not possible before initiation. Also, in the absence of any confirmed data, pregnancy is not recommended during these treatments. While no direct comparisons of these two drugs with FTY have been performed, in 2016, a retrospective study compared the efficacy of RIX and FTY in controlling disease activity in patients switching from NTZ in the context of positive JCV serology. In these cases, RIX appeared to be more effective than FTY, with only 1.8% of patients experiencing clinical relapses vs 17.6%, respectively [75]. In addition, contrastenhancing lesions were found in 1.4% of patients in the RIX group compared with 24.2% in the FTY group.

[77]. Treatment administration was initially daily for the first 4 or 5 days of a 28-day period, and was repeated only once during the following month. A year later, provided that the lymphocyte count was >800/mm3 and subsequent to new pretherapeutic assessment, the same cycle of 2-week treatment was repeated. No additional treatment was necessary in years 3 and 4. Vaccination should be performed 4–6 weeks before starting cladribine; if this is not possible, then attenuated live vaccines should not be given before complete normalization of blood cell counts. Also, chemical or mechanical contraception during, and for at least 6 months after, cladribine administration is recommended whatever the patient’s gender, given the confirmed teratogenicity demonstrated in animal studies with the 2 mg/kg dose and thought to be due to the action of the drug on DNA [81]. Thus, cladribine is an option for patients with highly active or aggressive MS, although it has the drawback of a long-term increased risk of cancer.

7.

8. Is early and active control of inflammation useful in MS?

Cladribine

This precursor of 2-chloro-20 -deoxyadenosine 50 -triphosphate (CdATP) is phosphorylated by deoxycytidine kinase in the intracellular space. CdATP is an analog of purine bases, which accumulates and is incorporated into cellular DNA, resulting in inhibition of DNA synthesis via inhibition of DNA polymerase alpha. CdATP accumulation is primarily observed in cells with high deoxycytidine kinase activity, such as lymphocytes and hematopoietic cells. Thus, cladribine acts as an antineoplastic agent with potent immunosuppressant effects. An early phase-III randomized trial (CLARITY) evaluated oral cladribine vs placebo in 1326 patients and found, after 96 weeks, reductions in relapse rate (57%), in 3-month sustained progression of disability (33%), in gadoliniumenhanced lesions (86%) and in active lesions on T2-weighted MRI (73%) [76]. The study tested two doses, but retained only the 3.5 mg/kg dose. Reported side-effects included lymphocytopenia (21.6% of patients in the 3.5-mg group, and 31.5% of patients in the 5.25-mg group) and herpes zoster infection (shingles), and 10 neoplasms in the cladribine group, including four carcinomas and one melanoma, while one patient died from metastatic pancreatic carcinoma [76]. No PML with cladribine was described in MS [77], although cases of PML were previously reported in hairy cell leukemia [78]. Thus, monitoring the risk of lymphocytopenia is mandatory, and administration of cladribine should be suspended in cases of significant lymphocytopenia. Interestingly, a subgroup analysis of patients with highly active MS, defined as 1 relapse and 1 gadolinium-enhanced lesion within the past year despite MS DMT, or 2 relapses within the past year, showed greater benefit with oral cladribine [79,80]. Indeed, relapse rate decreased by 66% and risk of disability progression decreased by 82% in these highly active MS patients treated with cladribine vs placebo. However, because of the possible severe side-effects, a 96-week extension of the CLARITY trial was also performed (CLARITY EXT): the results revealed no additional side-effects and, instead, reinforced at 4-year results of the original study

Natural history studies have shown that MS is a severe disease, with at least 70% of patients developing severe disability [82] at a mean age of 54 years (EDSS score: 6) [83]. In addition, MS is associated with a shorter life expectancy [84]. Even in cases of apparently ‘benign’ evolution, when such patients were followed, almost half of them were no longer benign with each passing decade [85]. Thus, assuming that MS is primarily an inflammatory disease and that neuroaxonal loss is mainly due to the initial inflammation, active and early control of inflammation might prevent patients from developing irreversible disability. One open-label safety study evaluating NTZ (STRATA) [86] followed, for 240 weeks, 1094 patients who had participated in a previous pivotal NTZ study (AFFIRM [14], SENTINEL [15], GLANCE [87] or STARS), all of whom received further NTZ as part of STRATA. Those initially randomized to placebo or IFN in their previous studies had higher EDSS scores than patients randomized to NTZ at STRATA baseline (3.13 vs 2.90, respectively). Yet, on their inclusion in those previous studies, these patients’ EDSS scores were similar (2.36 vs 2.38, respectively). This difference persisted over the entire 240 weeks of the study. In STRATA, EDSS scores were generally stable (original placebo group: 3.13 at baseline vs 3.15 at 240 weeks; original NTZ group: 2.90 at baseline vs 2.79 at 240 weeks). Despite limitations such as midterm follow-ups and patients lost to follow-up, this kind of study suggests that early control of inflammation in MS might prevent increases in EDSS scores in the medium and long term. Another argument for active and early control of inflammation is that axonal loss [88] and brain atrophy [89,90] present early in MS, and are at least partly related to inflammation. Furthermore, it is clear that early disease activity, such as the number of relapses in the first 2 years [82,91], time to reach an EDSS score of 3 [91], and increased T2 lesion loads in the first 5 years [92] or presence of >10 T2 lesions at baseline [93], can predict longterm disability.

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On the other hand, the introduction of DMT before a second relapse is beneficial [93]. Indeed, the link demonstrated in cohort studies between early inflammation and long-term disability is further evidence that limiting early inflammation may prevent long-term disability and preserve quality of life. Also, inflammation in MS evolves according to an asymmetrical bell-shaped curve, as it mainly presents during the years surrounding the first clinical event [94]. Moreover, as DMT can only impact early inflammatory processes in MS, this means the therapeutic window for anti-inflammatory DMT action begins from the time of disease onset, but swiftly decreases over time in parallel with disease activity in a given patient [94].

9. When should second-line therapy be introduced in MS? According to EU drug administration guidelines, second-line therapy applies to MS patients whose first-line therapy was unsuccessful or with highly active disease. However, the key issue is how to define ‘non-responders’ and, likewise, ‘highly active disease’. Those considered ‘non-responders’ by the EMA are ‘‘patients with highly active disease activity despite a full and adequate course of treatment with at least one disease-modifying therapy’’. This means that patients presenting with at least 1 relapse despite 1 year of treatment with another DMT are those usually considered for second-line treatment. However, several studies have shown that persistent disease activity during the first year of IFN therapy is highly predictive of a non-response to first-line DMTs, thereby allowing early identification of patients requiring second-line DMT. One study showed that if a patient subject to relapses develops at least 2 new MRI lesions between IFN initiation and follow-up MRI at 12 months, the risk of relapse during months 12–36 is increased by an odds ratio (OR) of 8.3 (CI: 2.9–28.9) to 9.8 (CI: 2.6–53.4) [95]. Another study by the same team proposed a response score that can be used in clinical practice called the ‘modified Rio score’ [96], based on two criteria: number of relapses; and MRI findings. The sum of these two criteria is the final score: 1 point is added if the patient presents with >4–5 new T2 lesions at the end of the first year of IFN treatment; and 1–2 points are added if the patient presents with 1 or 2 relapses, respectively, within the first year of IFN; the final score is between 0 and 3; for scores of 2 or 3, the risk of relapse and disability progression at 12–36 months is increased. Finally, a multicenter study involving 1890 patients showed that activity during the first year of IFN treatment is strongly related to non-response [97]. Thus, the appearance of at least 3 new lesions or 1 relapse moderately increases the risk of non-response, whereas 3 new lesions with 1 relapse strongly increases the risk of nonresponse and 2 relapses strongly increases such a risk. These studies all demonstrate that non-responders can be identified according to their early responses to first-line therapy, thereby allowing clinicians to identify early on the need to escalate to a more effective drug. In line with these results, a recent study found that, if EMA criteria as used as markers of IFN failure, their specificity is very high (90%), whereas their sensitivity is

very low (34%), leading to a substantial proportion of undertreated patients [98]. Based on the level of disease activity (1 relapse, or 1 enhanced lesion, or 2 new T2 lesions), specificity is only slightly decreased (80%), yet sensitivity is significantly increased (68%). In any case, though, why should non-responders be so vigilantly identified? When a cohort of patients initially included in a pivotal study (comparing IFN with placebo) was assessed after an average of 15 years [99], in the original IFN group, the persistence of gadolinium-enhanced lesions during the first 2 years of treatment predicted severe worsening of EDSS scores (4.5 points over 15 years). In contrast, in patients originally given placebo, early disease activity was not associated with long-term disability. These results suggest than persistent disease activity over the first years of treatment is deleterious, and inflammation must be actively controlled at this initial stage. Highly active disease is rather more difficult to define and, to date, there is no consensus on either its definition or treatment. As safe first-line treatments are suboptimal for these patients and because, after a certain level of disability (EDSS scores 3 or 4), the disease appears to evolve linearly and independently of relapses compared with the first few years of disease [82,83], early identification of patients with highly active MS is even more crucial. The EMA has proposed the immediate initiation of a second-line DMT, such as NTZ or FTY, in patients with ‘‘rapidly evolving severe relapsing– remitting multiple sclerosis defined by 2 or more disabling relapses in 1 year, and with 1 or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous recent MRI’’. Yet, this ‘‘significant increase in T2 lesion load’’ was not clearly defined. A recent study attempted to estimate the prevalence of very highly active MS patients. In a population of 5891 patients, the authors found that up to 14.8% of patients could be considered to have highly active MS [100]. Thus, patients were classified into three groups according to their evolution: (i) those reaching an EDSS score of 6 after 5 years of disease duration; (ii) those reaching an EDSS score of 6 at age 40 years; and (iii) patients developing a secondarily progressive course within 3 years of relapsing onset. Interestingly, most of these patients had RRMS (74.5%, 92.8% and 100% in the above groups, respectively), indicating that a clear majority of these patients were eligible for treatment. Unfortunately, except for male gender and greater age at disease onset, no likely prognostic factor was identified. These results are in line with a previous natural history wherein 25% of patients reached EDSS scores of 3 within a mean 1.26 years from disease onset [82]. These considerations led Rush et al. [101] to propose, in 2015, a definition of aggressive MS including one or more of the following factors: (i) EDSS score of 4 within 5 years of onset; (ii) 2 relapses with incomplete resolution within the past year; (iii) 2 MRI studies showing new or enlargening lesions despite treatment; and (iv) no response to therapy with one or more DMTs for up to 1 year. Thus, a patient may be considered to have aggressive MS according to these Rush et al. criteria without fulfilling the indications for second-line therapy as defined by the EMA [2 relapses with 2 new T2 lesions, or 2 or 3 MRI studies during the first year of treatment consistently showing new lesions

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(with T2 or gadolinium)]. To identify patients at higher risk of developing aggressive MS, these authors also proposed including factors associated with a poor prognosis as identified by natural history studies: male gender [82,83,102]; older age (> 40 years) at onset [82,103]; frequent relapses within the first 2 years [82,83,91,103]; short time interval between the first and second relapse [82]; multifocal relapses [104]; partial or incomplete recovery after the first relapse [82,104]; attacks affecting motor, cerebellar, sphincteric and/or cognitive function [104,105]; high T2 lesion burden at onset (>10 lesions) [93]; presence of T1 lesions (‘black holes’) [106]; early central atrophy [107]; and presence of infratentorial lesions [108]. While these factors cannot be used as such for individual predictions of risk, they may still be helpful for ‘prescreening’ patients at higher risk who need close clinical and MRI monitoring.

10. How should responses to second-line treatment be evaluated? As presented above, all second-line therapies do not have the same benefit–risk ratios. DMTs with more serious side-effects, such as MTX, ALZ and cladribine, are more likely to be used in cases of failure with safer second-line DMTs such as FTY and NTZ, or in cases using induction strategies due to aggressive disease. Nevertheless and even more than with first-line DMTs, there is still considerable controversy over how to define second-line treatment failure. The first step is to collect strong and objective arguments: characterization of MRI lesion activity when the DMT is effective is essential. To this end, baseline MRI should be performed after the onset of DMT activity. For FTY and NTZ, MRI after 6 months may be recommended whereas, for ALZ, this should be 12 months after the last infusion. However, for MTX and cladribine, it is more difficult to make any recommendations as their cumulative doses are rapidly reached. Thus, the reference MRI would be more useful for estimating the end of immunosuppressive effects rather than escalation to more effective treatment; once this ‘baseline’ MRI has been performed, it is then recommended to do at least one MRI every 12 months. Nevertheless, there is still no consensus over the definition of a suboptimal response for second-line DMT. Some authors propose ‘no evident disease activity’ to the extent it is possible to demonstrate [109]. Thus, it remains important to bear in mind the need to exclude any other causes of treatment failure, such as antibodies against the DMT (as with NTZ) [110] or a differential diagnosis (for example, PML), before considering the observed abnormalities as signs of a suboptimal response to the DMT.

11.

Induction or escalation?

Escalation is by far the most commonly used strategy in MS patients, and consists of the initial introduction of a safe but less effective drug, with an upgrade only in cases of failure of that first-line drug. In this strategy, safety is prioritized over efficacy, which seems appropriate for the majority of RRMS patients, particularly during the initial years of the disease.

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IFN, glatiramer acetate, teriflunomide, dimethyl fumarate and daclizumab are considered first-line therapies, while MTX, NTZ, FTY, ALZ and cladribine are second-line therapies. In addition, as mentioned above, the escalation strategy requires close monitoring to detect suboptimal responses and to inform the need to switch to a more effective drug. However, this strategy is time-consuming and, as a consequence, inadequate for patients with highly active or aggressive MS [1]. In such cases, the induction strategy, which consists of starting with a DMT that rapidly controls disease activity followed by a long-term maintenance treatment, appears to be more appropriate. In active-disease patients, randomized studies have demonstrated that this strategy is much more effective than the use of first-line DMTs to control early disease activity and prevent midterm disability [5,111]. MTX, ALZ and cladribine are good candidates for the induction strategy due to their modes of action, despite the risks of developing cardiac or hematological side-effects with MTX [112], severe systemic autoimmune disorders with ALZ [62,64] and neoplasms with cladribine [76]. Over the past 15 years, MTX has largely been used for induction therapy [5,111] and has provided relative control of disease activity over the 5 years following a 6-month course of treatment [6]. An extension study of cladribine showed that it maintained its anti-inflammatory effect for 4 years [77]. However, further research, including real-life studies, is still required to properly evaluate cladribine as a useful tool in induction strategy. NTZ and RIX are also very effective for controlling highly active or aggressive MS, but cannot be considered good inducers because of their propensity to cause rebound of activity after their withdrawal. Indeed, a post hoc analysis of the AFFIRM and SENTINEL trials identified a subgroup of patients presenting with highly active disease (at least 2 relapses in the year prior to study entry and at least 1 gadolinium-enhanced lesion at study entry) whereas, in treatment-naı¨ve patients, NTZ was associated with an 81% reduction of the 2-year cumulative probability of relapse and a 64% reduction of sustained disability progression [113]. As for RIX, three studies enrolled patients with at least 1 relapse and 1 gadolinium-enhanced lesion. RIX was associated with a mean 90% reduction in contrast-enhanced lesions and a 50% reduction in relapses [66–68]. In addition, a recent study assessing RIX as a rescue therapy in 50 patients who presented with disease activity despite second-line therapy (MTX, NTZ or FTY) [114] found that the introduction of RIX as second-line treatment was associated with a lower annual relapse rate (from 0.8 to 0.18) and a smaller percentage of patients presenting with gadolinium-enhanced lesions (from 72% to 8%). On the other hand, FTY is not to be considered for induction strategies due to the amount of time (several months) it takes to reach sufficient efficacy, its lesser immunosuppressive effects compared with the other DMTs reviewed here and the recurrence of disease activity after its withdrawal.

12.

Conclusion

At present, given the dozen or so immunosuppressant drugs for MS as well as the development of autologous

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hematopoietic stem-cell transplantation [115], effective control of the inflammatory process arising from the peripheral immune system is finally a realistic possibility. Indeed, it is all the more feasible as this immune activity can easily be monitored through clinical and MRI assessments. Nevertheless, having tools does not always come with knowing how to use them, and further steps are still necessary to achieve precision medicine for MS patients. To make this happen, there is a strong need to identify robust prognostic markers to support treatment adaptations in patients with more active disease. Until then, patients at risk of highly active disease should be identified according to their previous natural history, MRI studies, level of disability and early responses to the first introduced treatment before any decision is made as to whether a more effective drug is needed. DMTs should always be selected according to the patient’s individual risk profile, and the least active disease possible should be the objective of treatment. Unfortunately, thus far, there has been no way to determine with certainty if early control of disease activity can indeed protect patients against long-term disability, although several arguments suggest that early inflammation plays a major role in long-term disability, thereby offering a compelling opportunity to change the evolution and management of MS.

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Disclosure of interest The authors declare that they have no competing interest.

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Acknowledgment

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Dr Ben Ridley, Aix Marseille Universite´, for his advice and comments on the manuscript.

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