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The scenario of multiple sclerosis (MS) treatment has changed profoundly in recent decades. In this setting, one of two strategies is usually used: escalation or induction. The first involves a pyramid of possible treatments of increasing efficacy (but also increasing safety risks) that are introduced progressively as needed. The induction strategy, on the other hand, immediately pursues higher efficacy, since drugs with a higher risk profile are used from the outset. Understanding which of these treatment strategies is themoresuitablefor agiven patientisthe firststepin the therapeutic decision-making process. Prognostic factors evaluated on the basis of the clinical presentation and any disease activity on magnetic resonance imaging (MRI) should guide and help clinicians in making their choices. Even though the pathogenesis of MS is not yet completely understood, specific pathological changes are known to occur in the adaptive and innate immune system over the course of the disease. To date, treatment has been based mainly on two drugs, mitoxantrone and cyclophosphamide, autologous haematopoietic stem cell therapy (within clinical trial setting), but new compounds are now emerging. Among the new treatments, alemtuzumab and cladribine appear to be valid candidates as induction drugs. In this review we provide an overview of induction strategies based on literature evidence and our own past experiences, providing descriptions of clinical cases. We also outline the future perspectives in this field. Keywords: Induction strategy, Highly active multiple sclerosis, Immunosuppression Background he/she can self-treat or instead needs therapy to be Multiple sclerosis (MS) is a progressive and highly delivered by a healthcare professional. debilitating disease that places a high burden both on Accordingly, in neurological clinical practice, as in individual patients and on society. Current disease-modify- other medical fields, efforts are being made to develop ing therapies (DMTs) for MS are effective for decreasing re- an “individualized treatment” approach. The challenge lapses and slowing progression, but they fail to adequately faced by specialists in the field of MS, in particular, is to address a series of needs in terms of treatment, disability identify the most effective drug and strategy for each in- avoidance and the importance of considering patients’ dividual patient at each phase of the disease, that is to own priorities in order to improve their lives. Goal choose a therapeutic approach which has necessary effi- assessment and individualization of therapy should cacy to treat the actual disease. In recent decades, two thus take into account current disease activity and strategies for managing MS therapies have been recog- disability, the patient’s lifestyle and preferred treat- nized: escalation (Fig. 1a), where treatment starts with ment administration route, as well as whether or not lower-risk, lower-efficacy DMTs and only moves on to more aggressive treatments if the ongoing approach fails; and induction (Fig. 1b), which can be defined as treat- ment based on the use of high-efficacy DMTs with a * Correspondence: firstname.lastname@example.org sustained, long-term biological effect in treatment-naïve Department of Neurosciences, S Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87, 00152 Rome, Italy patients. Induction therapy is based on the early use of Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ruggieri et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:5 Page 2 of 12 had functional and radiological benefits over the first 7 years of disease history and can even include drug ta- pering and (partial, temporary or permanent) discon- tinuation . The span of available treatment that can be used as induction therapy is somewhat narrow compared to current DMTs. In the last decade’s mitoxantrone (MTX), cyclophosphamides (Cys) and autologous haematopoi- etic stem cell therapy (within clinical trial setting) have been used with this aim. New and recently approved treatment whose mechanism of actions let to define them as possibly induction therapy may include alemtu- zumab (AZB) and cladribine. According to their label, even fingolimod and natalizumab, can be employed as treatment options in naïve patients if the disease course is considered particularly aggressive. Despite the high ef- fectiveness of both treatment they should not be chosen as induction therapies because their quickly reversible mechanisms of action predispose patients to a return of disease activity following treatment discontinuation (Fig. 2). Although the definition of induction or escalation Fig. 1 Iconographic representation of Escalation and Induction Strategies. strategy neatly define a practical approach, our choice of a ESCALATION: Escalation therapy consists of early start of first-line DMDs. treatment, regardless of the strategy chosen, should If first line DMDs are ineffective or partially effective, on-going therapy is nevertheless be based on three simple questions: Why? switched to second-line drugs. b INDUCTION: Induction therapy supports the early use of immunosuppressive drugs followed by long-term When? How? . maintenance treatment, generally with the use of immunomodulatory agents In this review we focus on induction strategy, looking at the latest literature evidences and trying to answer to immunosuppressive drugs followed by long-term main- the above questions in the light of our own clinical tenance treatment, generally with immunomodulatory experiences. agents. The concept of induction strategy takes his first steps Rationale and pathological background in oncology and rheumatology practice where, one drug The induction strategy concept in MS is based on know- followed by long-term maintenance treatment with a dif- ledge of the interplay between two main aspects of the ferent drug, has proved its utility on long term outcomes disease, in short, on knowledge of the immunological . Accordingly to different oncology expertise this mechanisms underlying MS pathology and the way in scheme has been used from head and neck tumors, to which, at different levels, these influence the phenotyp- lung cancer and leaukemias. For istance an optimal use ical expression of the disease. of the same antileukemic agents (developed from the 1950s through the 1980s), along with a rigorous applica- tion of prognostic factors for risk-directed therapy in clinical trials, resulted in a continuos improvement in treatment outcome. The goal of remission-induction therapy was to eradicate more than 99% of the initial load of leukemia cells and to reconstitute normal hematopoiesis and a normal performance status. When normal hematopoiesis is restored, patients in remission become candidates for intensification (consolidation) therapy . During the BeSt study, a multicentre randomized sin- gle blind trial that integrated targeted treatment and tight control with a comparison of 4 treatment strategies in recent onset rheumatoid arthritis (RA), authors Fig. 2 Potential inductive effect of DMDs in Multiple Sclerosis showed that early and maintained targeted treatment Ruggieri et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:5 Page 3 of 12 MS is a complex disease in whose development gen- i.e. one that has the capacity to bring about near to total etic factors, immunological components and environ- immune suppression followed by gradual restoration of mental influences all play a role. MS pathological the immune cell population through a modified path- changes occur in the adaptive and innate immune sys- way. Since in our treatment landscape we still do not tem over the course of the disease. Although the disease have drugs able to modify the neurodegenerative com- trigger is still unknown, it has been established that ponent of disease, one would want to time treatment to T-cells attack myelin components, including myelin coincide with the presence of ongoing inflammation. basic protein, myelin oligodendrocyte glycoprotein and This concept has been defined has “treatment window” proteolipid protein. But the pathological mechanisms  in which we can detect the early opportunity to influ- consist of more than just an autoimmune attack against ence the accumulation of irreversible long-term damage, a single target. In MS, T-cells react to an initial myelin choosing high-efficacy therapy that targets both focal epitope displayed by an antigen-presenting cell (such as and diffuse pathology thus having a favorable impact on a dendritic cell) that is linked to a particular major histo- long-term outcomes . However induction strategy, compatibility complex protein. After symptoms decline, and particularly those drugs that are considered to be persistent inflammation may induce a new wave of as good candidate to fall in this category, cannot be used in yet unactivated T-cells to enter the central nervous sys- every patients due to safety concerns that are often asso- tem (CNS), where, in the presence of a co-stimulatory ciated with their use. The high efficacy of these treat- signal, they become primed to new epitopes — a ments needs to be weighed individually by their phenomenon named “epitope spreading” . Immune relatively higher risk profile. infiltration from the periphery constitutes a prominent feature of early-stage MS and T-cells (CD 4+, CD8+, Selection of patients natural killer) can enter the CNS through different sites Given the relatively greater risks inherent in the use of (meningeal blood vessels, subarachnoid space, choroid high-efficacy DMTs, patients who may potentially bene- plexus). These cells, in the presence of an activated fit from early use of these treatments must be selected CNS-resident immune system, promote demyelination with great care. Indeed, in view of evidence that through direct cell contact-dependent mechanisms and high-efficacy therapies carry greater safety risks, the in- through the action of soluble inflammatory and neuro- duction strategy has generally been reserved for patients toxic factors. Later on in the disease course immune cell whose disease is very active and aggressive in terms of infiltration decreases, perhaps due to exhaustion of clinical relapses or disease activity on magnetic reson- adaptive immune cells as a result of chronic antigen ex- ance imaging (MRI). Patients falling into this category posure. Thus, chronic CNS inflammation may help to are defined “highly active”, a label that not only indicates sustain the neurodegenerative process through the ac- the presence of very active and aggressive disease at the tion of cells that have entered or are already resident time of observation, but may also indicate the presence within the CNS, along with oxidative stress responses, of concomitant negative prognostic factors. energy deficiencies, ionic imbalances and the failure of The main problem in pursuing an induction strategy is neuroprotective and regenerative mechanisms . that, by definition, it is more effective in the early stage This immunological cascade, here extremely simpli- of disease, but giving the chronic and long lasting nature fied, may be seen as a two-stage process that can explain of MS, understand and label the disease at its onset is the phenotypic expression of the disease. This consists particularly challenging. For this reason a great effort of an initial phase in which relapses represent the main has been put to define those clinical and paraclinical aspects of the illness and patients show a mild level of characteristics that allow us to define a patient as highly disability, and a second phase in which clinicians usually active or not. observe a slow but irreversible progression of the dis- Longterm natural history studies  provide precious ability, which gradually becomes more severe . On the information about negative prognostic factor presenting basis of this evidence, the rationale behind induction early at onset or during follow-up and infer that late dis- strategy is thus to influence the initial inflammatory ability can be predicted on the basis these factor, though phases, so as to avoid the subsequent chronic phase that helping in identify patients at risk of a more aggressive helps to maintain the neurodegenerative process and disease course  (Table 1). An epidemiological study leads to irreversible disability. The advantage of induc- assessed on a database of 5891 patients with MS, the tion therapy can be seen as a “resetting” of the immuno- proportion of patients that could be defined as affected logical system to prevent the phenomenon of epitope by “aggressive MS” according to an Expanded Disability spreading which can result in better control of disease Status Scale (EDSS) of 6 (reached in 5 years or before activity. In order to obtain this effect it is fundamental the age of 40) or development of secondary progressive to choose a drug with a specific mechanism of action, MS (SPMS). Interestingly out of a percentage of 4–14% Ruggieri et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:5 Page 4 of 12 Table 1 Negative Prognostic factors in naïve MS patients  Clinical Feature Demographics � Male sex � Older age (> 40 years) at onset Relapse severity � ≥1-point change on EDSS, ≥2-point change on any individual functional system, or ≥ 1-point change on any two functional systems � Steroid requirement � Hospitalization Relapse frequency � Frequent relapses in the first 2 years � Short time interval between relapses Disease Course � Rapid increase of disability (e.g EDSS score ≥ 4) in 12 months MRI charatersitics � High T2 lesion load � More than two gadolinium-enhancing lesions � Presence of T1 lesions (‘black holes’) � Infratentorial lesions of patients falling into the pervious definition, the major- the latter has been used only off-label or in clinical trials, ity of these patients had relapsingonset MS and were, for due to the lack of adequate phase III studies, it has not this reason, possibly candidate to disease modifying been formally approved for treatment of MS. treatment . Usually patients with frequent relapses at MTX is an anti-neoplastic anthracenedione derivative the time of diagnosis and those who accumulate a large that is related to the class of anthracyclines. It is usually number of focal lesions detected on T2-weighted MRI administered intravenously at a dose of 12 mg/m every sequences or gadolinium (Gd)-enhancing lesions within three months until a maximum total cumulative dose of the first five years become disabled more quickly than 140 mg/m has been reached, but this therapeutic regi- patients who do not . men may vary. In recent years, use of MTX has de- Taking into account the heterogeneous pathological creased due to the risk of severe adverse events . processes underlying MS and the complexity of the dis- Following a pivotal trial  and an observational ease, a composite evaluation that considers several mea- study  in highly active relapsing-remitting MS sures might be able to furnish a more comprehensive (RRMS) and SPMS patients, MTX was tested in a estimation of disease activity. Despite the evident diffi- three-year clinical and MRI study in aggressive MS pa- culties in selecting univocally patients with precise char- tients defined as those who had experienced two or acteristics and negative prognostic factors at beginning more relapses in the previous 12 months and shown one of the disease, the following main criteria for identifying or more Gd-enhancing MRI lesion . One hundred potential good candidate for induction treatment have and nine patients were randomized into two groups: 54 been recognized among others: a younger age (ideally patients received MTX monthly (12 mg/m ; maximum under 40 years old), a pure relapsing-remitting (RR) 20 mg) combined with 1 g of MP for six months form of MS, at least two relapses within the previous followed by interferon (IFN) for the last 27 months; the 12 months, a severe relapse resulting in an EDSS score ≥ other 55 patients received IFN-beta-1b (250 mg subcuta- 4ora scoreincreaseof two or more points within neously every other day) for three years combined with the previous 12 months, and the presence of two or 1 g of MP monthly for the first six months. The primary more additional Gd-enhancing lesions on a recent endpoint was the time to worsen by at least one EDSS MRI scan . point, confirmed at three months. The two patient This can be emphasized with a slogan adopted from groups had comparable clinical and demographic fea- an awareness campaign used in ischemic stroke patho- tures at inclusion. The patients underwent a complete logical studies: “time is brain”. Thus we would affirm neurological examination every three months and that “timing” matters in MS and indicate that the opti- spin-echo MRI at inclusion and at months 9, 24 and 36. mal timing would be in the evidence of significant clin- The time to worsen by at least one EDSS point, con- ical and MRI inflammatory activity without acquired firmed at 3 months, was delayed by 18 months in the irreversible disability . MTX group compared with the IFN group (p < 0.012). The three-year risk of worsening disability was reduced Treatment choices: Past and present experiences by 65% in the MTX group relative to the IFN group Several clinical trials have investigated potential induc- (11.8% vs 33.6%). The proportion of patients who tion treatment drugs. In the first MS treatment era, remained relapse-free was increased in the MTX group MTX and Cys, two immunosuppressant drugs, were (p < 0.008). The MTX patients had a 61.7% reduced re- widely used. In this treatment approach, even though lapse rate, a reduced number of Gd-enhancing lesions at Ruggieri et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:5 Page 5 of 12 month 9, and a slower accumulation of new T2 lesions five days followed by maintenance therapy) in 17 pa- at each time point . tients with fulminant MS, defined as worsening of more Another controlled study , by a different research than one and a half points on the EDSS for more than group, enrolled 40 RRMS patients with 1–15 Gd-enhan- three months. In 24 months, 69% of patients were clinic- cing lesions on MRI and EDSS scores of 0–6.5. The pa- ally stable or improved . tients were randomized to receive either short-term In a two-year randomized trial, researchers compared induction therapy with MTX (three 12 mg/m infusions, the effect of 12 months of induction therapy with Cys one per month) followed by 12 months of daily glatira- followed by IFN-beta versus IFN-beta alone. The authors mer acetate (GA) therapy at 20 mg/day subcutaneously enrolled 20 active RRMS patients, defined as those who for a total of 15 months (n = 21), or GA at 20 mg/day had had at least one relapse and one Gd-enhancing le- for 15 months (n = 19). MRI scans were performed at sion detected on MRI during the previous year. Patients months 6, 9, 12 and 15. The MTX-GA induction treat- were randomized to receive Cys monthly (to induce a ment led to an 89% greater reduction [relative risk = leucopoenia below 1000× mm ) plus methylprednisolone 0.11, p = 0.0001] in the number of Gd-enhancing lesions (MP) 1 g for 12 months followed by IFN-beta for a further at months 6 and 9 compared to GA alone and a 70% 12 months (cy group) or IFN-beta alone for two years greater reduction (relative risk = 0.30, p = 0.0147) at (IFN-beta group). The authors observed a reduction in the months 12 and 15. Mean relapse rates were 0.16 and relapse rate and in the number of Gd-enhancing lesions at 0.32 in the MTX-GA and GA group respectively. During the end of follow-up (24 months). Relapse-free patients at the 15-month study, 81% of MTX-GA patients and 79% the end of the second year amounted to 80% in the Cys of GA patients remained relapse free . group versus 40% in the IFN-beta group . Due to increasing concerns regarding the safety profile A retrospective review of a closely followed population of MTX, in 2001 a French multicenter prospective study of 32 MS patients treated with high-dose Cys (200 mg/ of a large cohort of MS patients was set up. This study kg intravenous infusion over four days) followed by entailed annual updates for at least the first five years maintenance therapy with GA was performed in a US after initiation of MTX therapy. In total, 802 patients center with the aim of assessing the safety and efficacy were treated with a mean cumulative dose of 72 mg/m . of this treatment regimen. The annualized relapse rate They were then followed up through clinical, hematological (ARR) was reduced from 1.37 in the two years prior to and echocardiographic examinations for the five years treatment to 0.27 over a mean post-treatment follow-up following the start of the treatment. One of the 802 period of 14 months (range 0.5–33.8). The mean num- patients (0.1%) developed acute congestive heart fail- ber of Gd-enhanced lesions was reduced from 0.86 (± ure. Two cases of therapy-related leukemia (0.25%) 1.6) at baseline to 0 at 12 months and 0.08 (± 0.28) at were detected 20 months after starting MTX (one pa- 15–24 months. In total, 55% of patients had no evidence tient died while a remission of 8 years was reported of disease activity at follow-up. Infectious complications for the other). Of the 317 women treated before the occurred in 47% with no long-term morbidity and no age of 45, 17.3% developed persistent age-dependent deaths . amenorrhea (5.4% before 35 years of age, 30.7% after Long-term use of Cys is limited by its well-known 35 years of age) . The risk of acute leukemia has bladder toxicity, which is manifested as hemorrhagic also been estimated by other research groups, which cystitis and bladder cancer. This event may occur a few reported rates higher than  or similar to that years after cessation of the therapy. Hemorrhagic cystitis reported in the French cohort. can be seen in up to 4.5% of MS patients treated with Cys is an alkylating chemotherapeutic agent related to Cys . The risk of bladder cancer appears to increase nitrogen mustard that binds to DNA and interferes with as a function of the total dose. In a retrospective study mitosis and cell replication, and hence targets rapidly of 2351 patients with MS, two women and five men dividing cells . Treatment regimens vary: one con- (0.29%) had bladder cancer. In the 850 chronically cathe- sists of intermittent pulse therapy given monthly or bi- terized patients, the incidence was 0.7%. In the subgroup monthly over a one- to three-year period, administered of 70 patients previously treated with Cys, five chronic- intravenously at an adjusted dose to obtain a leucopoe- ally catheterized patients (5.7%) had bladder cancer. The nia target, or at a fixed dose ; with another, infusion mean time from the last dose of Cys until the diagnosis of 200 mg/kg of Cys over four days to induce profound of neoplasm was 5.8 years (range 3–10 years). No other leucopenia is followed by temporary use of filgastrim Cys-induced tumors emerged . (granulocyte-colony stimulating factor) to hasten en- Intense immunosuppression followed by autologous dogenous granulocyte recovery . hematopoietic stem cell transplantation (aHSCT) has One of the first trials using Cys in MS was an been an option during the last twenty years for those pa- open-label study with intravenous Cys (500 mg/m for tients that experience accumulated disability regardless Ruggieri et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:5 Page 6 of 12 of treatment or rapidly worsening or fulminant MS, with presentations to our every day clinical practice in the frequent relapses. The aim of aHSCT treatment is the present years and challenge ourselves on which com- total depletion of autoreactive cells, followed by the infu- pound we might chose giving the current enriched sion of autologous hematopoietic stem cells to reestab- treatment armamentarium. Indeed, both cases are lish and reset the aberrant hematolymphopoietic system characterized by a severe clinical onset and poor . Approximately 800 patients with MS have been prognostic factors at onset. In the first case a strong treated with aHSCT worldwide, always in clinical trial immunosuppression with MTX was started immedi- settings. ately after diagnosis of MS. In the second case - on Initial studies selected more-severely disabled patients the contrary - i.m. IFNbeta 1a was started and then to establish the safety of the procedure, but didn’t MTX was used as rescue therapy. achieve good results in terms of efficacy, and were characterize by an high mortality rate up to 5%. Lately, Case report 1 A 34-year-old right-handed woman was treatment-related mortality rates decreased from 7.3% admitted to hospital on the May 31st, 2006 with acute for the period 1995–2000 to 1.3% during the period onset of dizziness, visual impairment in her right eye and 2001–2007  . This might be seen as a consequence tingling in all four limbs. Her history included a recent of better selection of patients who were not inexorably episode (February 2006, three months earlier) of disabled and who had less-advanced disease, as well as non-painful visual field impairment in her right eye. She to general advances in post-transplant care . Differ- was diagnosed by an ophthalmologist with optic neuritis ent transplant procedures are currently in use, but given (ON) and treated with oral prednisolone, obtaining a lack of comparative studies no evidence exists for one complete regression of the symptoms. Her general exam- regimen being superior to another. The ASTIMS trial, a ination was otherwise normal. A cerebral CT scan multicenter, phase II, randomized trial including 21 pa- showed a hypodense white matter lesion in the left tem- tients with SP or RRMS, compared the impact of aHSCT poral lobe (maximum diameter: 1 mm) and one in the vs MTX on disease activity measured by MRI. aHSCT left frontal lobe (maximum diameter: 7 mm). On MRI reduced by 79% the number of new T2 lesions as com- multiple areas in the white matter (the periventricular pared to MTX (rate ratio 0.21, p = 0.00016) and Gd + le- area, corpus callosum, bilateral cerebellar peduncles, sions (rate ratio = 0.19, 95% CI 0.09–0.41, p < 0.0001) as centrum semiovale bilaterally) had an appearance con- well as the annualized relapse rate. No treatment group sistent with demyelination; most of these areas appeared difference was detected in the progression of disability. confluent. At least eight lesions showed contrast enhance- Early adverse events were considered as expected and ment after Gd injection. occurred at least in 80% of treated cases. SAE occurred The patient was admitted to the neurology ward where in the aHSCT arm only and resolved without sequelae a neurological examination revealed horizontal and ver- . Despite these encouraging results, and improve- tical diplopia, mild left lower motor neuron 7th cranial ment of clinical expertise, this type of treatment need to nerve palsy, pyramidal weakness of the left arm[(Medical be performed only in selected centers with known Research Council (MRC) scale scores of 4/5 proximally neurological and hematological expertise. Furthermore and 2/3 distally], dysmetria in the four limbs (left > whether the procedure is really effective in modifying right), and brisk reflexes with a left extensor plantar re- the progressive course of the disease, to assess long-term flex; sensation could not be evaluated. Gait was not eval- efficacy and safety deserves additional evalutation in uated because of recent stem cell transplantation for phase III trials. aseptic necrosis of femoral head (of uncertain etiology). Autoimmune blood screening was normal, as were sen- Clinical experience sory and motor evoked potentials, and thorax and abdo- Here we present two illustrative clinical cases that out- men CT scans. stand the concept of different outcomes accordingly to Oligoclonal bands were detected in the cerebrospinal different timing in choosing treatment. Of course the fluid (CSF), with fewer bands in the serum, consistent cases below refers to a past treatment era and probably with intrathecal synthesis of immunoglobulin. CSF ana- nowadays our approach would be diverse. However our lysis was negative for enterovirus, herpes simplex virus aim is to present a clinical scenario, despite of the drug types 1 and 2, varicella zoster virus and John Cunning- used, that can exemplify the concept of “window of op- ham (JC) virus on polymerase chain reaction. CSF bac- portunity”. Thus regardless of date and consequent terial and tuberculosis culture was negative. Serology treatment scheme applied, the clinical cases below repre- was negative for HIV, HTLV, Borrelia, syphilis and JC sent an opportunity to reflect on the consequence of a virus. The patient had normal full blood count values particular choice given a particular time during the and renal, liver and thyroid function values. Vitamin disease course. We can easily transfer these clinical B12 and folate levels were also normal. Antibody test Ruggieri et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:5 Page 7 of 12 results (aquaporin, anti-double stranded DNA, ENA and In July 2006 the patient experienced acute bladder re- anti-neutrophil cytoplasmic antibody) were normal. MRI tention and sensory impairment below spinal level T3. of the brain (with single-dose Gd) performed during He was administered IVMP 1 g per day for five days. hospitalization confirmed the presence, in the white mat- In December 2006 the patient presented a new medul- ter, of multiple areas consistent with demyelination; a lary syndrome. MRI showed a new T11-L1 spinal lesion brainstem and a cerebellar lesion each showed Gd en- with contrast enhancement. hancement. MRI of the cervical spine showed a demyelin- IFN was stopped and MTX, bimonthly, was started in ating lesion at C5-C6 level. The patient was diagnosed January 2007. After six infusions of MTX the cerebellar with MS and treated with intravenous methyl prednisol- syndrome improved dramatically, and this improvement one (IVMP), 1 g per day for five days, which produced a was maintained over time. MTX was administered for weak improvement of the symptoms. Intraorbital cortico- two years and stopped when the maximum dose allowed steroids were injected to reduce optic nerve inflamma- was reached. In March 2009 GA was prescribed as tion, with minimal results. maintenance therapy. After informed discussion with the patient and her In December 2010 a clinical relapse was reported, con- family about starting her on a DMT, an immunosuppres- sisting of an acute right pyramidal syndrome. This was sive drug was suggested. In July 2006 the patient started treated with corticosteroids. Over the following six receiving MTX 10 mg/m bimonthly. No side effects were months, the patient experienced two episodes of ON, reported. In September 2006 an MRI showed new T2 le- resulting in permanent reduction of visual acuity bilat- sions in the posterior left brainstem and in the parietal erally. On a brain MRI scan performed in June 2010, lobe, even though no new symptoms were reported; these supratentorial lesions were found to be increased. possibly dated back to the previous July, when MTX had Treatment with GA was stopped and the patient was just been started. Thereafter, complete clinical and radio- switched to fingolimod as a second-line therapy. Treat- logical stabilization was achieved. In September 2008 the ment with natalizumab was ruled out due to the patient became pregnant. Her pregnancy was unremark- patient’s positive JC virus antibody status. able and she gave birth to a healthy child. Over the subsequent years this patient has experienced In September 2009 patient started treatment with a slow clinical worsening characterized by gait and vis- high-dose IFN-beta-1a. She has had no further relapses; ual acuity impairment. to date, clinical and radiological follow-up continues to show complete stabilization of her condition. Treatment choices: Future perspectives The past 10 years have seen the introduction of several new compounds for treating MS, characterized by differ- Case report 2 A 23-year-old man was admitted to our ent mechanisms of action and different administration clinic in November 2004 due to subacute onset of dys- routes. Among these newly available or soon-to-be avail- arthria and cerebellar ataxia. A brain and spine MRI able treatments, we can identify two drugs that have was performed and showed multiple areas of high signal emerged as induction treatments, whose administration in the white matter, consistent with demyelination (the should be followed by the use of already established and periventricular area, corpus callosum, bilateral cerebellar less aggressive medications. peduncles, bilateral centrum semiovale, cerebellar hemi- AZB is a monoclonal antibody that recognizes the spheres, and spinal levels C2-C3 and C3-C4 and C5-C6). CD52 epitope located on the surface of mononuclear + + A brainstem lesion showed Gd enhancement. Neuro- cells; CD52 is primarily expressed on CD4 and CD8 T logical examination detected horizontal and vertical dip- lymphocytes, B-cells, and monocytes. Administered lopia, rotating and horizontal pendular nystagmus, alone (12 mg per day, intravenously, for five days, with a pyramidal weakness of the left arm (MRC scale score 4/ re-treatment at the same dose for three days one year 5), reduced sensitivity below T2 level, dysmetria (left > later), AZB has a profound and sustained effect on the right), hypotonia, brisk reflexes with bilateral extensor inflammatory process and can cause lasting global plantar response, ataxic gait of both cerebellar and sen- immunosuppression. sory origin, neurogenic bladder. Full autoimmune blood Upon binding to CD52, AZB rapidly and effectively screening was normal and the patient was diagnosed eliminates circulating CD52 cells via antibody and with MS and started on IFN-beta-1a intramuscularly. complement-mediated depletion. Soon after administra- Follow-up MRI in May 2005 showed new T2 lesions in tion of the compound, circulating lymphocytes are virtu- the frontal white matter, and a new T2 lesion located at ally undetectable in peripheral blood. Subsequently, the spinal level D3. In September 2005 the patient experi- adaptive immune system is reconstituted from precursor enced blurred vision and was treated with IVMP 1 g per cells or mature cells that have escaped depletion. The day for five days. dynamics of this repopulation differ according to cell Ruggieri et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:5 Page 8 of 12 lineages: monocytes and B-cells are the first to repopu- how AZB reduces relapse rates, disability worsening, and late in the peripheral blood, approximately 3–6 months the rate of brain volume loss over the long term. In a sig- after treatment. T-cells, particularly CD4 cells, reappear nificant proportion of patients, preexisting disability more slowly, with normal levels once again detectable remained stable or improved . Nonetheless the present after 2–3 years and pretreatment levels only after almost of safety issues such as infusion related reaction, develop- five years have elapsed . ment of autoimmunity caused by T-cell repopulation In a three-year phase II trial in early MS, annual AZB occuring through reconstitution of T-cells in the thymus infusion was compared with administration of an or proliferation of mature cells, infections have been con- IFN-beta-1a preparation . Patients enrolled in this firmed. While infusion-associated reactions observed are study had early, active MS, and were naïve to prior im- quite manageable by clinicians, increased risk of infections munotherapy for MS other than steroids. AZB treatment (e.g: Listeria monocytogenes, herpes virus, cytomegalo- reduced disability progression, improved disability scores, virus), and secondary autoimmunity (e.g: idiopathic and decreased relapse rate by 70% compared with thrombocytopenic purpura, Graves’s disease Goodpas- IFN-beta-1a, but this trial was interrupted early as three ture’s syndrome) associated with AZB required a strict patients developed idiopathic thrombocytopenia, and one and rigorous monitoring even long after last treatment of them died. Post hoc analyses showed that, at year 3, cycle . To do so a clinical surveillance program for 73% of the patients treated with AZB were free from AZB has been established; protocol-defined laboratory clinical disease activity, a state defined as absence of monitoring including differential blood count, serum cre- six-month sustained accumulation of disability and re- atinine, and urine analysis before administration and lapse, compared with 43% in the IFN-beta-1a group (HR, monthly thereafter as well physician and patient education 0.33; p < 0.0001) . have been recommended continuing for 4 years after the In a phase III trial, the superiority of AZB over last dose of AZB or longer if warranted . This implies IFN-beta on relapse rates was confirmed, but its effect a precise patient selection relying on individual diligence on disability was not replicated . Although the phase and extreme compliance to the monitoring program. II and phase III studies both enrolled patients with Taking into consideration that AZB leads to significant RRMS and active disease, they differed mainly in the long-lasting modification in the adaptive immunity cells treatment history of the target populations (naive versus and that no sufficient data on sequencing therapies after treatment failure). In a five-year follow-up of the phase AZB are available to date to guide the clinician’s choice, II extension, the risk of sustained accumulation of dis- some authors suggest treating with first line medication ability from baseline to year 5 was reduced by 69% (p = (interferon or GA) those patients with breakthrough dis- 0.0005) in the AZB 12 mg group compared to the ease . IFN-beta-1a group . Recent evidence has underlined Cladribine is an adenosine deaminase-resistant purine the long-term beneficial effects of using AZB, with a nucleoside analog that preferentially reduces lymphocyte very low proportion of AZB-treated patients from the subpopulations. Cladribine pro-drug enters cells via pur- CARE-MS studies being found to progress from RRMS ine nucleoside transporters and, once inside the cell, to SPMS (CARE-MS I, 1.1%; CARE-MS II, 3.7%) over undergoes initial phosphorylation by deoxycytidine kin- six years of follow-up in the absence of continuous treat- ase. Lymphocytes are particularly susceptible to this ef- ment. These results are, of course, based on defined cri- fect because of their high intracellular ratio of teria applied to the CARE-MS patient population, and deoxycytidine kinase to 5′-nucleotidase. The accumula- they therefore require further confirmation in real-world tion of cladribine nucleotides disrupts DNA synthesis cohorts . and repair processes and ultimately leads to a sustained The main safety issues with regard to the use of AZB reduction in lymphocytes. Cladribine is able to cross the concern the risk of developing of Graves disease and blood-brain barrier and is, therefore, likely to act on cells other adverse events that have been observed, such as in both the periphery and the CNS; it appears to have a Goodpasture syndrome, neoplasms and opportunistic greater effect on CD4+ T-cells than on the CD8+ T-cell infections. population . AZB has been approved in Europe and Canada for Building on the experience with parenteral cladribine, highly active RRMS; more recently it has received regu- a short-course of treatment with cladribine tablets was latory approval from the Food and Drug Administration investigated for RRMS in the phase III CLARITY study in the USA. . The dosing regimen consisted of four courses of Up to know, 13.000 MS patients have been treated treatment during the first 48 weeks (weeks 1, 5, 9 and with AZB around the world gathering information from 13), followed by two further courses (starting at weeks patients involved in aforementioned clinical trial extension 48 and 52). They received a cumulative dose of either and in real world clinical practice. These data confirmed 3.5 or 5.35 mg/kg over the 96-week study, respectively). Ruggieri et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:5 Page 9 of 12 Treatment with cladribine tablets, 3.5 or 5.25 mg/kg, End Date of the PREMIERE is established for November significantly reduced the ARR at 96 weeks (relative 2018. A first report of pooled safety data has been pre- reduction 57.6 and 54.5%, respectively, vs placebo, both sented during the last American Academy of Neurology p < 0.001) and resulted in significantly more relapse-free meeting held in Boston in April 2017. During a study patients at week 96 (79.7 and 78.9% vs 60.9%, respect- period of 194 weeks (mean), as expected Lymphopenia ively; odds ratios: 2.53 and 2.43, both p < 0.001) . was expected from cladribine tablets’ mode of action, lym- ORACLE (ORAlCLadribine in Early MS) was a phopenia was reported more frequenly in cladribine 96-week, randomized, double-blind, placebo-controlled, treated patients than in placebo group. Consequentely international trial involving more than 616 clinically iso- herpes zoster was reported more frequently in patients ex- lated syndrome patients. Cladribine, compared with pla- periencing Grade 3 or 4 lymphopenia; no clustering of cebo, significantly delayed the time to conversion to types of malignancy, and no malignancies commonly asso- clinically definite MS; the authors reported a 62% risk ciated with immunosuppression were observed during the reduction for 5.25 mg/kg dose (HR 0.38; 95% CI 0.25– follw-up period . 0.58; p < 0.0001), and a 67% risk reduction for 3.5 mg/kg In July 2016, the European Medicines Agency accepted dose (HR 0.33; 95% CI 0.21–0.51; p < 0.0001). The for review the marketing authorization application for high-dose cladribine treatment, versus placebo, resulted cladribine tablets as a treatment for RRMS and its posi- in a 91% risk reduction for new or persisting T1 tive decision was stated in august 2017. Gd-enhancing lesions, and a 73% risk reduction for new Since the compound has just been released on the or enlarging T2 lesions . During the open-label market and given the relatively small population of pa- phase of the ORACLE study, all the participants who tients in which cladribine has been used until now, more converted to definite MS were offered the possibility to data are certainly warranted and future real world stud- continue on a twice-weekly maintenance therapy with ies, along with clinician experience, will provide them IFN-beta-1a. The point estimate of the ARR in the accordingly. The results presented above, especially open-label period was lower in patients originally ran- those regarding safety issues, need to be interpreted with domized to cladribine tablets 3.5 mg/kg vs placebo in caution due to the relatively short follow-up period. the double-blind treatment period . In clinical trial Despite these limitations, data derived from clinical trial settings, cladribine has shown a good tolerability profile; on efficacy and safety as well the administration protocol despite the lymphopenia that has been observed in and route are encouraging. Anyway the usage of cladribine-treated patients, the overall incidence of in- IFN-beta-1a during the open label phase of ORACLE fections was similar across treatment groups. However, study has draft a possible treatment approach to be in the CLARITY study, herpes zoster infection was re- followed. ported in eight patients in the cladribine 3.5 mg/kg group and in 12 patients in the 5.25 mg/kg group, and Conclusions was inversely correlated with the lymphocyte counts The range of possible treatments for MS has undergone (p = 0.003) . Moreover the risk of cancer (0.34%) was a rapid expansion in recent years, and while this devel- significantly higher in the cladribine than in the placebo opment certainly represents an enormous resource, on groups . However a meta-analysis of phase III trials of the other hand it presents every MS specialist with licensed DMDs for RRMS patients and CLARITY study major challenges. aimed to compare the cancer risk associated with cladri- A considerable body of evidence supports the bene- bine, assesed that the rate of cancer was similar between fit of early treatment compared to delayed treatment; the phase III trial of cladribine and all other phase III trials indeed, disability has been shown to continue to ac- of DMDs in RRMS patiens. Moreover a significant differ- cumulate when therapies are started in the later dis- ence emerged when comparing the placebo groups of ease stages. CLARITY (no cancers) with the placebo arms of all other The two case reports presented herein are paradig- phase III trials included in this study . matic in this regard. In case report 1, the patient was To better define the long-term safety profile of this considered, from the first observation, to be at high risk drug, all patients previously enrolled in any clinical trial of disability progression, as she presented several nega- with cladribine are invited to join the PREMIERE (Pro- tive prognostic factors. The clinician decided to start spective Observational Long-term Safety Registry of with immunosuppression as an induction treatment Multiple Sclerosis Patients Who Have Participated in followed by a maintenance therapy with a first-line drug. Cladribine Clinical Studies) study. The follow-up will The patient has remained stable over a long period of consist of over 10,000 patient years of exposure, in total, time. with follow-up in some patients exceeding eight years at The patient described in case report 2 presented several completion (clinicatrial.gov: NCT01013350). The planned negative prognostic factors at disease onset, associated Ruggieri et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:5 Page 10 of 12 with a high risk of disease progression. In this case, programs and, especially, weigh up, on a patient-by-pati- first-line therapy was started despite several clinical and ent basis, the benefits versus the risk outcomes. In other MRI parameters have already demonstrated a high disease words, even though definite clinical or radiological surro- activity. Thus, the induction therapy was then suggested gate markers of disability prediction are not fully available with minimal advantages during the follow-up. So that a as yet, clinicians need to evaluate the risk of serious ad- second line therapy was needed. verse events in individual patients and identify those with In this context two critical points should be underlined: a high risk of developing disability. This task will become easier when longer-term safety data, able to help neurolo- 1. In highly active patients an induction treatment gists make more robust decisions, become available for should be started as soon as possible. these new compounds too. Unfortunately, since now we have few data about the The hypothesis that early treatment with high efficacy better treatment alternatives after induction strategy DMTs such as AZB or cladribine could result in better when long-lasting effect of “inductive agent” on the im- disease control and improved long term disease outcomes mune system will be added to the a further “immuno- compared to the later commencement of high-efficacy modulation”. A long term study has shown that a short DMTs is a crucial point to clarify in order to optimize the (6-months) course of MTX followed by maintenance management of MS patients. therapy with an immunomodulatory drug such as inter- In a recent systematic review the timing of high-efficay feron beta or GA, brings about a rapid reduction in dis- therapy in relapsing remitting multiple sclerosis has been ease activity and subsequent sustained disease control evaluated. The authors concluded that earlier treatment [19, 21, 46]. No data are available about long-term main- with high-efficacy, higher risk therapies for RR MS lead to tenance treatment if induction is achieved with AZB, a better control of relapse activity than their later initi- Cladribine or hematopoietic cell-stem transplantation ation. However they also underlined that the evidence re- and actual wider scenario of first line drugs needs to be garding the effect of the timing of high efficacy therapies considered. On the other hand, application of induction on disability outcomes is conflicting and randomized treatment paradigm in rheumatology has shown that, clinical trials (RCT) or quality observation studies are using modern synthetic disease modifying antirheumatic warranted to answer this question . drugs suppression of rheumatoid activity can be a realis- tic option, even after discontinuation of drugs . The 2. Early identification of non-responders is crucial in absence of RCT and substantial real life data on this order to allow the clinician to rapidly reach an optimal issue requires that clinician and patients need to share therapeutic decision with regard to the introduction of care decision matching the level of risk a patient is will- a more aggressive treatment. ing to accept and his prognostic factors. In any case the initial treatment choice and its timing Several papers proposed how to define and monitor is crucial as suggested by other discipline experience and response to MS treatments, and concluded that here is by the few data on MS, waiting for RCT or quality ob- still no shared consensus on definition of treatment re- servation studies needed to answer this question. sponse. One important weakness when evaluating tools Abbreviations for assessing treatment response is that the vast majority (aHSCT): Intense immunosuppression followed by autologous hematopoietic of studies are based upon patients on IFNB and GA stem cell transplantation; AZB: Alemtuzumab; CNS: Central nervous system; CSF: Cerebrospinal fluid; Cys: Cyclophosphamide; DMTs: Disease-modifying treatment, with limited data from cohorts of patients therapies; EDSS : Expanded Disability Status Scale; GA: Glatiramer acetate; treated more effective drugs, such as AZB or cladribine. Gd: Gadolinium; IFN: Interferon; IVMP: Intravenous methyl prednisolone; In our opinion, considering the lack of definition of JC: John Cunningham; MP: Methylprednisolone; MRC: Medical Research Council; MRI: Magnetic resonance imaging; MS: Multiple sclerosis; MTX: Mitoxantrone; treatment response for AZB and cladribine, the presence ON: Optic neuritis; RA: Rheumatoid arthritis; RCT: Randomized clinical of disease activity occurring after immune cell-depletive trial; RR: Relapsing-remitting; RRMS: Relapsing-remitting multiple sclerosis; agents, such as AZB or cladribine, can be contemplated SP: Secondary progressive; SPMS: Secondary progressive multiple sclerosis as an indication to retreat the patient. Availability of data and materials The decision to delay a more aggressive treatment is Data sharing not applicable to this article as no datasets were generated or often based on safety concerns perceived by the clin- analyzed during the current study. ician. Indeed, more aggressive treatments, as well as showing higher efficacy in controlling disease activity, Authors’ contributions SR, SP and CG wrote the manuscript. CG and CT revised the manuscript. are usually characterized by a higher risk profile because All authors read and approved the final manuscript. of their mechanisms of action. Nonetheless safety issues should not limit the use of these treatments; instead, Ethics approval and consent to participate clinicians need to strictly follow adequate monitoring Not applicable Ruggieri et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:5 Page 11 of 12 Consent for publication multiple sclerosis: a randomised multicentre study of active disease using Not applicable MRI and clinical criteria. J Neurol Neurosurg Psychiatry. 1997;62:112–8. 18. Le Page E, Leray E, Taurin G, Coustans M, Chaperon J, Edan G. Mitoxantrone as induction therapy in aggressive relapsing remitting multiple sclerosis: a Competing interests descriptive analysis of 100 consecutive patients. Rev Neurol. 2006;162:185–94. SR has received fees as invited speaker or travel expenses for attending 19. Edan G, Comi G, Le Page E, Leray E, Rocca MA, Filippi M. Mitoxantrone prior meeting from Biogen, Teva, Merk-Sereno. SP has received fees as invited to interferon beta-1b in aggressive relapsing multiple sclerosis: a 3-year speaker from Biogen, Teva, Sanofi, Novartis and Almirall. CT received honoraria randomised trial. J Neurol Neurosurg Psychiatry. 2011;82(12):1344–50. for speaking from Biogen, Sanofi-Aventis. Teva, Bayer-Schering and Novartis. 20. Vollmer T, Panitch H, Bar-Or A, Dunn J, Freedman M, Gazda S, et al. Glatiramer CG has received fees as invited speaker or travel expenses for attending acetate after induction therapy with mitoxantrone in relapsing multiple meeting from Biogen, Merck-Serono, Teva, Sanofi, Novartis, Genzyme. sclerosis. Mult Scler J. 2008;14:663–70. Authors have nothing to disclose related to this manuscript. 21. Le Page E, Leray E, Edan G, Grp FMS. Long-term safety profile of mitoxantrone in a French cohort of 802 multiple sclerosis patients: a 5-year prospective study. Mult Scler J. 2011;17:867–75. Publisher’sNote 22. Martinelli V, Cocco E, Capra R, Salemi G, Gallo P, Capobianco M, et al. Acute Springer Nature remains neutral with regard to jurisdictional claims in myeloid leukemia in Italian patients with multiple sclerosis treated with published maps and institutional affiliations. mitoxantrone. Neurology. 2011;77(21):1887–95. 23. Stroet A, Hemmelmann C, Starck M, Zettl U, Dörr J, Friedemann P, et al. 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