REVIEWS Aggressive multiple sclerosis: proposed definition and treatment algorithm Carolina A. Rush, Heather J. MacLean and Mark S. Freedman Abstract | Multiple sclerosis (MS) is a CNS disorder characterized by inflammation, demyelination and neurodegeneration, and is the most common cause of acquired nontraumatic neurological disability in young adults. The course of the disease varies between individuals: some patients accumulate minimal disability over their lives, whereas others experience a rapidly disabling disease course. This latter subset of patients, whose MS is marked by the rampant progression of disability over a short time period, is often referred to as having ‘aggressive’ MS. Treatment of patients with aggressive MS is challenging, and optimal strategies have yet to be defined. It is important to identify patients who are at risk of aggressive MS as early as possible and implement an effective treatment strategy. Early intervention might protect patients from irreversible damage and disability, and prevent the development of a secondary progressive course, which thus far lacks effective therapy. Rush, C. A. et al. Nat. Rev. Neurol. advance online publication 2 June 2015; doi:10.1038/nrneurol.2015.85

Introduction

Division of Neurology, Ottawa Hospital Multiple Sclerosis Research Unit, University of Ottawa, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada (C.A.R., H.J.M., M.S.F.). Correspondence to: C.A.R. [email protected]

Multiple sclerosis (MS) is a chronic autoimmune dis­ order, marked in its early stages by inflammatory demyelin­ation of the CNS. Early damage is mediated by an immune attack that is probably orchestrated by autoreactive T and B cells, as well as macrophages, that infiltrate the CNS. This attack ultimately leads to demyelin­ation and early axonal transection.1 Later in the course of the disease, the pathology evolves into more-diffuse, indolent inflammation with progressive neurodegeneration.2 The transition between the early and later phases of disease is clinically unclear, and the inflammatory and neurodegenerative processes prob­ ably occur in parallel. Current therapies seem to address only the early damage. Disease-modifying treatments (DMTs) developed specifically for patients with MS have been used for the past two and a half decades. Prior to the develop­ ment of DMTs, therapy addressing the disease course was confined to immunosuppressive agents—such as cyclophosphamide—­t hat were limited by their inherent toxicities, allowing only short-term use or maximum lifetime dosages. At best, these early thera­ pies were shown to suppress disease for a few years. Additionally, because of their toxicity, immunosuppres­ sive treatments tended to be reserved for patients with Competing interests C.A.R. has acted as a consultant or advisor for Biogen, EMD Serono, Genzyme and Teva. H.J.M. has acted as a consultant or advisor for Biogen and Novartis. M.S.F. has acted as a consultant, advisor or steering-committee member for Actelion, Bayer Healthcare, Biogen, EMD Serono, Genzyme, Novartis, Opexa, Sanofi and Teva. He is a member of Genzyme’s speakers’ bureau, and has served on a study adjudication committee for Chugai.

more-advanced disease. We have subsequently learned that the early disease activity drives long-term disabil­ ity;3,4 therefore, it is extremely important that uncon­ trolled, potentially harmful disease is identified quickly and treated effectively. For patients with typical forms of relapsing MS, several treatment algorithms have been proposed. Often, these algorithms start with modestly effective but relatively safe first-line treatments, and then either switch laterally to an alternative first-line agent or move to second-line or even third-line agents if patients’ responses to therapy are judged to be suboptimal. A subgroup of patients with relapsing MS follow a more aggressive disease course marked by a precipitous accumulation of physical and cognitive deficits, often despite treatment with one or more DMTs. Many neurologists refer to these patients as having ‘aggressive’ MS, and the general consensus is that the severe nature of this disease requires treatment decisions to be made with urgency. Unfortunately, there is no consistency in either the definition of this type of MS or the treatment algorithm for these patients. In this Review, we will define aggressive MS, and survey the currently available treatment modalities and their efficacy in this patient population. We then propose a standard treatment algorithm for patients with a­ ggressive MS.

What is aggressive MS?

Definitions of aggressive MS have been vague or ambig­ uous, owing to use of different parameters and disabil­ ity assessment criteria. Common to all definitions is the early, unexpected acquisition of disability followed by frequent relapses (often with incomplete resolution) and highly active disease seen on MRI. Pragmatically, aggressive MS has been defined as any type of MS that

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REVIEWS Key points ■■ Patients with aggressive multiple sclerosis (MS) are at increased risk of rapid accrual of disability and disease progression, so early detection is critical ■■ The window of opportunity for treating patients with aggressive MS is narrow, thus, conventional treatment paradigms need to be reconsidered ■■ Aggressive disease warrants aggressive treatment ■■ Therapeutic agents vary extensively throughout the world in terms of their availability, licensing, usage experience and logistics of implementation ■■ Diligent monitoring is crucial for the timely discovery of suboptimal response to therapy

is associated with repeated severe attacks and acceler­ ated accrual of disability—put more simply, ‘rapidly ­progressive’ MS.

Variable terminology Occasionally, the term ‘malignant’ MS has been used to describe aggressive phenotypes of MS, but this is another ambiguous term that—despite wide usage—means dif­ ferent things to different people. Moreover, ‘malignant’ can imply disease activity that is unstoppable, whereas we believe that ‘aggressive’ emphasizes that this form of MS is still treatable. Many authors reserve the term malignant for fulminant forms of MS that deteriorate so rapidly from the outset as to be almost monophasic, and result in death within months to a few years. One such example is the Marburg variant of MS, which is classi­ cally characterized by extensive necrotic and/or tumefac­ tive lesions with mass effect. Indeed, the Marburg variant is perhaps the most extreme disease on the aggressive MS spectrum. Other groups have used the terms malignant and aggressive interchangeably. In 1996, the US National MS Society (NMSS) Advisory Committee on Clinical Trials in Multiple Sclerosis defined the clinical subtypes of MS as relapsing–remitting, primary progressive, secondary progressive and progressive relapsing.5 A definition of malignant MS was also included, namely, “disease with a rapid progressive course, leading to significant disability in multiple neurologic systems or death in a relatively short time after disease onset.”5 Interestingly, despite recent (and increasing) emphasis on early detection of patients with aggressive MS, the original definition of malignant MS was not modified by the NMSS Advisory Committee in its latest publication in 2013.6 One group of authors described malignant MS as accrual of an Expanded Disability Status Scale (EDSS) score of 6 points within 5 years of disease onset.7 These authors also differentiated subtypes of malignant MS. In 487 patients, only 12% had malignant MS, and these patients could be further divided into transient malig­ nant or sustained malignant on the basis of whether relapses or sustained progression represented the main contribution to disability status. Older, male patients and smokers were more likely to attain sustained malig­ nant status; conversely, younger patients with brainstem relapses were more likely to be considered to have tran­ siently malignant MS. This study, therefore, identified specific clinical features of patients in whom opportune intervention might make a difference.

A more recent study expanded on the definition of aggressive MS to include three subgroups based on EDSS score and the time to develop secondary progressive MS (SPMS).8 Patients with so-called AMS1 reached 6 points on the EDSS within 5 years of MS onset, patients with AMS2 reached 6 points by age 40 years, and patients with AMS3 developed SPMS within 3 years of a relapsingonset disease course. Out of a database of 5,891 patients, 5.5% fulfilled the criteria for AMS1, 14% for AMS2 and 4% for AMS3. Surprisingly, and very importantly with respect to treatment considerations, of the first two definitions (which could include primary progressive MS [PPMS]), 74.5% of patients with AMS1 and 92.8% of patients with AMS2 had relapsing-onset disease. The authors concluded that aggressive MS could be identified in 4–14% of patients, depending on the definition used, and that the majority of these patients had relapsing-­ onset MS and were, therefore, still amenable to treat­ ment using immunomodulatory, i­ mmunosuppressive or ­immunoablative therapies. Another definition of aggressive MS has been used to identify eligible candidates for immunoablative therapy followed by autologous haematopoietic stem cell trans­ plantation (aHSCT). Referred to as having ‘highly active’ MS, these patients are at increased risk of poor prognosis. This definition encompasses the failure of conventional treatment to control disease, frequent, severe (disabling) relapses, and MRI activity (new T2 or gadoliniumenhancing lesions).9 Patients considered for this type of treatment are often also restricted by age, disability level (that is, EDSS score), and the time since initiation of their first treatment.

Working definition We believe that many of the previous definitions are overly restrictive and lack sensitivity. Too often, these criteria fail to identify at-risk patients who should be offered potentially helpful, yet aggressive, treatment before substantial permanent disability is incurred. No consensus exists on the speed of progression or degree of disability sufficient for aggressive MS, but we can assume that reaching an EDSS score of 6 points probably repre­ sents an upper limit beyond which the risk–benefit ratio for an aggressive treatment is unfavourable. Most of these patients would be well into the secondary progressive phase of their illness. Some have argued that an EDSS score of 4 points in patients with relapsing–remitting MS (RRMS) is already a strong indicator of advancing disease, and that further relapses, even if prevented, are unlikely to change the course of progression.10 We suggest that aggressive MS can be defined as RRMS with one or more of the following features: ■■ EDSS score of 4 within 5 years of onset ■■ Multiple (two or more) relapses with incomplete reso­ lution in the past year ■■ More than two MRI studies showing new or enlarging T2 lesions or gadolinium-enhancing lesions despite treatment ■■ No response to therapy with one or more DMTs for up to 1 year

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REVIEWS Identifying aggressive MS Data from natural history studies provide invaluable information about poor prognostic factors—present at disease onset or during follow-up—that might help identify patients at risk of aggressive MS (Box 1). These factors include male sex, disease onset at an older age than average, cognitive impairment, and multifocal attacks involving motor, cerebellar and/or sphincter systems. Attack characteristics may provide additional prognostic information when severity and degree of recovery are evaluated. MRI metrics also provide important markers for prog­ nosis both at onset and follow-up of disease activity. Though useful, current MRI measures have not yet been shown to distinguish an aggressive pattern of disease in the absence of concurrent clinical information, either at disease onset or early in the course of disease.

The need for early disease control

Population studies have indicated that relapses occuring in the first 2 years of MS drive early disease progression, with diminishing contribution from later relapses (after year 3). The time to accumulate 3 points on the EDSS is a strong, independent determinant of the time to reach 6, 8 and 10 points, and early relapse rates and short inter­ attack intervals are also predictors of rapid conversion to SPMS.11 Long-term follow-up studies suggest that late outcomes can be predicted on the basis of factors present early in the disease. In patients presenting with optic neuritis, high MRI lesion load correlated with dis­ ability 20 years later, and in patients who ultimately con­ verted from RRMS to SPMS, the rate of lesion volume change was three times higher than in those who did not convert.12 Evidence over the past decade points to a window of opportunity for effective treatment in patients with MS, which covers the period of peak CNS inflammation.13 This window opens following a clear first demyelinating attack, and probably closes early after the development of SPMS. Detecting where in the window a particu­ lar patient lies can be quite challenging, especially in patients with aggressive MS where the window is narrow and liable to close quickly. Current DMTs target the early type of CNS inflam­ mation that is believed to substantially contribute to demyelin­ation and axonal damage. Therefore, these thera­pies are more effective when the inflammatory process is prevalent, as in the early stages of disease. Early disability progression seems to be driven by inflam­ mation, but later progression is associated with an illdefined chronic neurodegenerative process, which is mostly unamenable to treatment with currently available therapies. The goal of treatment is to minimize the accu­ mulation of irreversible disability and, ultimately, to slow or stop disease progression, thus minimizing long-term disability and preserving a good quality of life. Therefore, conventional treatment paradigms need to be reconsid­ ered in patients with aggressive MS, so as to avoid late identification and subsequent treatment with aggressive treatments that offer too little too late.

Box 1 | Factors that might suggest aggressive MS Clinical features Demographics ■■ Male sex74,75 ■■ Older age (>40 years) at onset76,77 ■■ African American78,79 ■■ African–Latin American80 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 Type of attack ■■ Multifocal81–84 ■■ Partial or incomplete recovery85,86 ■■ Attack affects motor,3,73,80 cerebellar,81,87,88 sphincteric81,89–91 or cognitive functions92 Relapse frequency ■■ Frequent relapses in the first 2–5 years3,4,10 ■■ Short interattack interval86,93 Disease course ■■ Rapid accrual of disability, e.g. EDSS score of 3.0 within 5 years, with superimposed relapses3 MRI features At onset ■■ High T2 lesion burden94–97 ■■ More than two gadolinium-enhancing lesions94,98 ■■ Presence of T1 lesions (‘black holes’)99 ■■ Early discernable atrophy100,101 ■■ Infratentorial lesions102 At follow-up ■■ Presence of new T2 lesions103,104 ■■ One or more new gadolinium-enhancing lesions103,104 Abbreviations: EDSS, Expanded Disability Status Scale; MS, multiple sclerosis.

Standard treatments in aggressive MS

The treatment of patients with MS has become very chal­ lenging, given the extensive selection of therapies and new agents with more-complex mechanisms of action, and greater risks and adverse effects. Here, we will discuss agents that we believe are suitable for treating aggressive MS. Part of our proposed definition for aggressive MS requires a failure to control the disease early on with conventional first-line or even second-line therapies. We believe that many of these early treatments fall short in patients with aggressive MS by failing to effec­ tively diminish the disease-causing inflammatory cells. Indeed, many patients with aggressive MS have shown resistance to DMTs that either hamper the ability of these disease-causing cells to gain access to the CNS (for example, natalizumab), or that sequester disease-causing cells in lymph nodes (for example, fingolimod). Though not required for our definition, most patients with aggressive MS will probably have tried one or both of these types of treatments. We believe that treatment of aggressive MS requires agents capable of eliminating disease-causing cells, such as alemtuzumab, cladribine, cyclophosphamide, mitoxantrone, rituximab, and even immuno­ablation followed by aHSCT. The availabil­ ity, licensing, clinical experience and implementation

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REVIEWS Table 1 | Treatments for aggressive multiple sclerosis Drug

Protocol

Adverse effects*

Monitoring

Alemtuzumab

12 mg infusion daily for 5 days, followed by a second course of 12 mg daily for 3 days at month 12 from first course26,105,106

Infusion-related reactions (93%): mild to moderate (>90%), serious reactions (3%)

No specific recommendation

Infections (71%): serious infections (2.7%), nasopharyngitis, upper airway tract infections, urinary tract infections

No specific recommendation

Thyroid disorders (36%): hyperthyroidism, hypothroidism, Graves disease, thyroid ophthalmopathy

Thyroid-stimulating hormone every 3 months, monthly symptom-monitoring survey‡

Superficial fungal infections (12%): oral candidiasis, vaginal candidiasis

No specific recommendation

Herpesvirus infections (3%): cervical human papilloma virus infection (2%), oral herpes simplex, varicella zoster infections (0.3%)

Annual screening for human papilloma virus‡

Haematological disorders (1%): immune thrombocytopenic purpura, other cytopenias (neutropenia, haemolytic anaemia, pancytopenia)

Monthly cell count with differential, and symptom monitoring survey‡

Nephropathies (0.3%): anti-glomerularmembrane, membranous glomerulonephritis

Monthly serum creatinine and urinalysis with microscopy‡

Cladribine

Scripps protocol (0.875 mg/kg daily for 4 days every 6 months)106

Possible long-term risk of malignancy

Cancer screening

Mitoxantrone

MIMS protocol (12 mg /m2 every 3 months for 24 months),51 French British Study protocol (12–20 mg monthly plus 1 g methylprednisolone monthly for 6 months)52

Permanent amenorrhoea (22–26%)108,109

No specific recommendation

Cardiotoxicity (10%),110 systolic dysfunction (12%), heart failure (0.4%)

Echocardiogram or multigated acquisition scan annually for 5 years post-treatment

Leukaemia (1%)110

Cell counts every 6 months for 10 years

Haemorrhagic cystitis (7–15%)111,112

Urinalysis and cytology every 6 months; if cytology is abnormal, perform cytoscopy annually

Bladder cancer (5.7%),113 infertilty (33.0–44.7%)114,115

No specific recommendation

Brain atrophy116,117

No specific recommendation

Lifetime maximum: 140 mg/m2

Cyclophosphomide

Induction protocol (600 mg/m2 daily for 5 days plus methylprednisolone and bimonthly boosters),36 pulse protocol (800–1,000 mg/m2 monthly for 12–24 months; with or without methylprednisolone),39 high-dose protocol (120–200 mg/kg daily for 5 days) Lifetime maximum: 80–100 g

46

*Besides those directly related to immunosuppression. ‡After alemtuzumab, monitoring should be continued for 48 months following the last treatment course.

logistics of these therapies vary extensively throughout the world. Patients that meet our criteria for aggressive MS are at high risk of imminent disease progression, and their window of therapeutic opportunity is closing rapidly. These patients, therefore, warrant a definitive treatment rather than a temporary fix. First-line agents will have failed, and current second-line agents—such as fin­ golimod or natalizumab—exert disease control only as long as their use is maintained: stoppage of these drugs is associated with a return of disease activity. A more gradual return of disease activity is seen with fingoli­ mod,14,15 but cessation of natalizumab is associated with a rapid, sometimes severe, and even lethal rebound of activity in patients with aggressive MS.16,17 The likelihood of successfully treating aggressive MS with fingolimod is low given the partial benefit observed for patients with ‘highly active’ RRMS in clinical trials.18 Similarly, although natalizumab treatment has been reported

anecdotally in some patients with aggressive MS,19 its role is limited by factors including the propensity to develop progressive multifocal leukoencephalopathy after extended use, along with the risk of severe rebound should the drug be stopped suddenly.

Specific treatments for aggressive MS

The available agents for aggressive MS (Table 1) share the ability to substantially deplete disease-causing auto­ immune cells. In many cases, not all of these cells are eliminated, and the different drugs are distinguished by the length of time required before the cells come back and disease activity returns. In some cases, retreatment with another course of therapy may be possible, but in other cases compounded treatments might lead to new toxicity. Given the risk of rebound MS activity, it might be appropriate to employ a first-line DMT following the treatment course, so as to extend the benefit obtained with the aggressive treatment.

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REVIEWS Alemtuzumab Alemtuzumab is a humanized monoclonal antibody directed against CD52, a surface antigen present at high levels on T and B lymphocytes. Alemtuzumab rapidly and selectively depletes lymphocytes systemically, pro­ ducing a sustained depletion for up to 1 year, followed by lymphocyte repopulation and homeostatic resetting of the immune system. This drug also has a role in regu­ latory T-cell activation and promotes lymphocyte apop­ tosis.20,21 It is approved mainly for patients with RRMS who experience breakthrough disease, and has proven ineffective for SPMS.22 Alemtuzumab is probably the most useful current therapy to employ as an induction agent for treat­ ing aggressive MS, and its use is particularly common in Europe.23–25 It was first used in open-label trials of patients with MS as early as 1991, and demonstrated significant reductions in MRI measures of disease activ­ ity and in relapse rate. Subsequent large phase III trials attested to its benefit in both treatment-naive patients with MS and those with breakthrough disease: the drug slowed disease progression and improved EDSS scores in patients with breakthrough MS, compared with first-line high-dose interferon treatment.26 The biggest concern with alemtuzumab is the emergence of autoimmune disorders, which occurs in approximately one-third of patients, and can be quite remote (up to 4 years) from the last dose.27 A course of treatment with alemtuzumab entails five con­secutive days of treatment in the first year and three con­secutive days in the second year. Unlike other agents with maximal lifetime exposure limits, alemtu­ zumab can apparently be used beyond 2 years, as a 3-day annual treatment, should the disease return. Data from extensions of the two phase III trials showed that more than 80% of patients did not require retreatment during the third year.28,29 Cladribine Cladribine is a synthetic purine nucleoside and anti­ metabolite that acts as antineoplastic agent with immuno­suppressive effects. It somewhat selectively reduces lymphocyte subpopulations, especially CD4+ and CD8+ cells owing to their lack of alternative degrading enzymes. Animal data suggest that the drug is capable of crossing the blood–brain barrier.30 Parenteral cladribine was found to be beneficial for patients with RRMS in early phase II studies, 31 but was shown to be of no benefit for SPMS.32 Oral clad­ ribine has been studied in a large phase III study of patients with RRMS (n >1,000).33 After 96 weeks, both trialled doses produced significant reductions in clini­ cal relapses and MRI-visible disease activity, and also slowed disease progression, particularly in a subgroup of patients with ‘highly active’ MS. Oral cladribine was subsequently studied in patients with breakthrough disease in a phase II study.34 Patients treated with both IFN‑β and cladribine had fewer relapses and gadolinium-­ enhancing lesions compared with the patients taking only IFN‑β. Similarly, cladribine was shown to delay

conversion to clinically definite MS in patients with a first d ­ emyelinating event.35 Clinical development of oral cladribine has ceased, but parenteral infusions can still be used. Typically, cladribine is given as an induction therapy over four consecutive days repeated every 6 months for a 2-year treatment course, which is similar to the oral regimens in the phase II and phase III studies. Where available—and where haematological expertise is adequate—­cladribine remains an option for patients with aggressive MS, although it purportedly has the drawback of a long-term increase in the risk of cancer.

Cyclophosphamide Cyclophosphamide is a wide-spectrum alkylating com­ pound used in patients with cancer or autoimmune diseases. It is a nonspecific cell-cycle cytotoxic agent that exerts its effects on B and T cells, suppressing both humoral and cell-mediated immunity,36 and has been used in the treatment of MS for the past 40 years. Initial case reports and series, followed by open-label trials, suggested that cyclophosphamide was a promis­ ing treatment for MS. In the 1980s, the lack of any MS DMTs led to an explosion of interest in this drug. Several randomized controlled trials were conducted in patients with progressive MS, but yielded conflicting results. The Northeast Cooperative MS Treatment Group con­ ducted a 2-year randomized trial in 256 patients with RRMS, testing different regimens of cyclophosphamide induction, followed in some cases by monthly infusions. Treatment with monthly cyclophosphamide boosters was associated with better disease stabilization compared with induction alone. Patients with good responses tended to be young, with recent conversion to the progressive phase, and had SPMS rather than PPMS.37 However, the Canadian Cooperative Study showed no benefit of cyclo­ phosphamide treatment in patients with SPMS.38 These results are likely to be related to the different cyclophos­ phamide regimens, and to the inclusion of more patients with progressive MS in the Canadian study. Over the years, many small, often single-centre, studies have demonstrated a potential benefit of cyclophospha­ mide in patients with refractory, fulminant or rapidly progressive MS. This drug was shown to at least tem­ porarily slow down disease progression or limit further disabling attacks for 12 or 24 months, depending on the study.39–42 High (immunoablative) cyclophosphamide doses were first used in 2006, and proved to be safe and effective,43,44 with clinical and radiological stability reportedly lasting over 3 years.45 MRI studies have also supported the use of cyclo­ phosphamide as rescue treatment. Monthly infusion of ­cyclophosphamide in five patients with aggressive MS— who were refractory to several previous therapies—led to a dramatic reduction in gadolinium-enhancing lesions and even in T2 lesion load.46 A subsequent study showed an 81% decrease in gadolinium-enhancing lesions during the 2 years after cyclophosphamide treatment.47 Several combination studies (of IFN‑β and cyclophosphamide) have also shown noteworthy effects on MRI activity.48,49

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REVIEWS Cyclophosphamide has a highly unfavourable toxi­ city profile, with limitations on lifetime cumulative dose around 80–100 g. Increased risk of malignancy, haemor­ rhagic cystitis, and gonadotoxicity are the most feared adverse effects. The risk of bladder cancer was thought to be particularly high after cyclophosphamide treat­ ment; however, a recent study found the rate to be similar between patients treated with this drug and the general population.50 This point of contrast with older studies is perhaps due to the use of parenteral cyclophosphamide instead of the oral formulation used previously. Several cyclophosphamide regimens are in regular use, but there is no evidence that any one is superior. High, immunoablative cyclophosphamide doses are currently used as stand-alone treatment or as a bridge for aHSCT. Despite the known downside of cyclophosphamide, its efficacy, low cost, extensive availability and long clinical experience put it on the list of potentially useful agents for treating aggressive MS.

Mitoxantrone Mitoxantrone is an anthracenedione similar to doxo­ rubicin. It inhibits proliferation of B cells and T cells, and suppresses cytokines secreted by type 1 T-helper cells (such as TNF and IL‑12).51 Mitoxantrone was approved for the treatment of MS in 2000, and is recommended for patients who are refractory to first-line DMTs. In the pivotal clinical trials, most patients who benefited from mitoxantrone were young, had frequent relapses and low EDSS scores, and had early SPMS or RRMS, and/or aggressive MS.52,53 A Cochrane review in 2013 concluded that mitox­ antrone had moderate effects on disability progression and relapses in patients with persistent inflammatory activity, but the article recommended alternative agents with a more favourable risk–benefit ratio.54 The most commonly used mitoxantrone regimen is the induction protocol, which minimizes cumulative dose, adverse effects and long-term toxicity (including cardiotoxicity and leukaemia). Lifetime cumulative doses should not exceed 140 mg/m2. A full course of mitox­ antrone treatment can stabilize patients with aggressive MS for 5 years or more.55 If maximal lifetime doses are used, patients might need maintenance therapy with a ­first-line agent, such as IFN‑β56 or glatiramer acetate.57,58 Rituximab Rituximab is a partially humanized monoclonal antibody that targets the CD20 antigen on B cells, leading to deple­ tion of circulating B cells.59 Though only tested in shortterm studies of patients with MS (longer studies used the similar agent ocrelizumab60), rituximab has frequently been used in patients with refractory disease, but with limited success. While rituximab has been extremely powerful at controlling MRI activity,61,62 its success at long-term control of relapses is unknown. Other open questions include whether the treatment regimen needs to be sustained, whether intermittent treatment follow­ ing a course of 1‑2 years is necessary, whether the drug can be followed safely with other DMTs, and whether

the treatment has long-term safety issues. In other con­ ditions such as rheumatoid arthritis, periodic use of rituximab can control disease with or without the use of concurrent agents. In many parts of the world, rituximab is still very expensive and, therefore, is not a readily available option. We present this agent not to endorse its use, but to acknowledge that some have used it instead of the other drugs listed above to treat aggressive MS. There are too many unknowns about the application of rituximab to aggressive MS, which can only be addressed by evidence from properly conducted trials.

Haematopoietic stem cell transplantation Immunoablative therapy followed by rescue with aHSCT has been used for the past two decades to manage severe and treatment-refractory autoimmune diseases, includ­ ing MS. The premise of aHSCT is that it produces an ‘immune reset’, whereby the aberrantly overactive immune system is eliminated by intense immuno­ suppression, and a more tolerant immunity arises, devoid of autoreactive cells.63 More than 800 patients with MS around the world have been treated with aHSCT during this 20-year period. Early studies selected moreseverely disabled patients to establish the safety of the pro­cedure, but demonstrated little in the way of efficacy, and treatment-­related mortality was as high as 5%. More recently, trials have focused on patients with highly active disease that is refractory to treatment with conventional DMTs. These studies have yielded more-­encouraging results with better safety data: treatment-related mor­ tality is now around 1%, 64 perhaps owing to factors including the selection of patients who were not severely disabled and who had less-advanced disease, as well as to general improvements in p ­ ost-transplant care. Several transplant conditioning regimens are currently in use by different groups, but no evidence exists for one protocol being superior. Also, whether the intensity of the conditioning protocol influences the outcome is uncer­ tain. Nonmyeloablative regimens used in the past have traded reduced toxicity for reduced efficacy in terms of halting MRI activity and/or relapses.65 In one study, 80% of patients exhibited relapse-free survival over 4 years, and significant improvements in EDSS performance were seen in the majority of patients.66 However, 20% of these patients relapsed within 4 years of the aHSCT procedure, raising questions over the utility of such a treatment regimen relative to others that produce longer-lasting remissions. In the HALT MS trial, which used a mediumintensity conditioning protocol, 86.6% of patients were relapse-free at the time of the 3‑year interim report, and progression-free survival was 90.9% over the 3 years.67 In our own experience, after a much higher-intensity myelo­ ablative conditioning regimen and a CD34+-selected graft, patients followed for a median of 6.7 years from transplant were free of relapses or new MRI activity but, nevertheless, around 30% showed disease progression (H. L. Atkins, personal communication). The ASTIMS trial showed that aHSCT was superior to mitoxantrone in reducing MRI activity and annualized

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REVIEWS relapse rates in patients with aggressive MS. In the aHSCT group, no gadolinium-enhancing lesions were seen in any of the patients at the end of the 4 year followup, demonstrating the potent and durable effect of this aHSCT protocol on inflammatory activity.68 These promising results, and increasing clinical exper­ tise, have kindled multinational efforts to further investi­ gate the role of aHSCT in the treatment of aggressive MS, and to assess long-term efficacy and safety. However, this type of treatment should be restricted to centres with transplant haematology expertise.

Induction versus escalation

The classic paradigm of escalation and maintenance therapy—which prioritizes safety over efficacy—is appro­ priate for most patients with RRMS, provided that they are closely monitored to detect suboptimal response. This approach, where individuals start with first-line agents and are switched to second-line or even third-line agents if they exhibit breakthrough disease, is inadequate for patients with aggressive MS, who have a narrow treat­ ment window and might lose the opportunity to control their disease. In this context, it is important to tailor initial therapies to maximize efficacy, trading off the higher risk. An induction approach has been considered and used for many years in patients deemed to have aggressive forms of MS. The problem with this ‘hit hard and early’ approach has been trying to single out patients who really warrant such aggressive treatment involving highly potent agents early in the disease course, with the potential for serious and possibly irreversible toxicity. Induction pro­ tocols could be used in a limited fashion—such as a few doses of mitoxantrone, cladribine or cyclophosphamide—­ and over a limited period of time, followed by a main­ tenance agent that is not associated with progressive multifocal leukoencephalopathy, such as a first-line DMT. Alternatively, one could move immediately to a more definitive therapy such as alemtuzumab, and maintain control with repeated treatments as necessary. Finally, the induction approach could lead to early instigation of aHSCT, which could be viewed as a definitive treat­ ment, presumably with no need for further main­tenance therapy. The duration of the induction treatment is often limited by specific toxicities, cumulative doses and the selection of an ‘exit strategy’. The therapeutic response must be monitored closely in both induction and escala­ tion treatment paradigms, to identify partial responders and non-responders in a timely fashion.

Treatment algorithm

No treatment algorithms for patients with aggressive MS currently exist, and none of the major DMT trials focused on patients who meet our definition of aggres­ sive MS. We propose a potential model specifically ­tailored to this type of patient (Figure 1); however, there is no optimal strategy for the sequencing of these thera­ pies. Moreover, the availability of the various therapies will vary between centres, depending on familiarity, ­experience and haematological support.

The key goal in the treatment of aggressive MS is to induce and maintain rapid remission. ‘NEDA’ (no evi­ dence of disease activity) is a new concept of disease control, and should be the ultimate goal of all DMTs, although one caveat concerning this concept should be noted.69 In the early stages of RRMS, many patients achieve NEDA even without treatment (that is, in the placebo group of trials); however, this scenario is unlikely in patients with aggressive MS, who almost invariably demonstrate damaging disease activity in the absence of definitive treatment. Therefore, ‘as close as possible to NEDA’ would be a more relevant treatment goal in patients with aggressive MS.

Selection of suitable patients Patient characteristics worthy of consideration include desire for pregnancy, comorbidities, previous use of immunosuppressants, JC virus seropositivity, geographi­ cal parameters, health insurance coverage, and personal preferences (of the patient and the treating neurologist). These factors all directly determine the treatment selec­ tion, and might also inform the sequencing of therapies, although much is unknown about the effects of moving between DMTs and potentially immunosuppressive therapies. The order in which treatments are used might predispose patients to increased long-term toxicity. The treatment strategies employed in patients with aggressive MS must be monitored to accumulate more safety data. Frequently, risk tolerance differs substantially between patients and their neurologists. Some studies have shown that patients with MS are willing to take more risks than are their treating neurologists, possibly owing to patients’ poor perceptions of their own disease.70–72 Risk-averse patients are probably more likely to choose less-effective drugs with better safety and/or adverse effects profiles, whereas risk-tolerant patients might accept higher uncertainty if greater efficacy is possible. This risk– benefit gap needs to be discussed and negotiated on an individual basis. Selection of treatments aHSCT has been used as a treatment for aggressive MS, but its availability varies around the world. It should only be considered in centres with the haematological and neurological expertise to treat patients with aggres­ sive MS, in view of the specific issues that these patients encounter after aHSCT. The complex nature of aHSCT is beyond the scope of this Review, and we refer inter­ ested readers to another recent review.73 For some young patients, or individuals who are otherwise deemed to be within the therapeutic window of opportunity, aHSCT may be appropriate after other treatments have failed. Additionally, in certain cases, treatment-naive patients who experience a particularly aggressive disease course could be good candidates for aHSCT, provided that they have undergone a rigorous selection process. If aHSCT is not an option, alemtuzumab would be a proven first choice in patients who continue to exhibit disease activity after up to a year of failed treatment with one or more agents. Alemtuzumab has proven

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REVIEWS Failure of 1st/2nd-line treatment

Alemtuzumab

Immunosuppression

Cyclophosphamide

Mitoxantrone

Cladribine Maintenance therapy IFN-β or glatiramer acetate (or teriflunomide?)

Monitor closely every 3 months Consider re-treatment and escalation in case of breakthrough disease

Re-treatment regimen

Re-treatment regimen

Ongoing disease activity

Immunoablation and aHSCT

Figure 1 | Proposed treatment algorithm for aggressive MS. To meet our definition of aggressive MS,Nature patients will not| have Reviews Neurology responded to one or more therapies for up to 1 year. Some of these patients might warrant induction therapy with aHSCT, whereas others are better suited to escalation via alemtuzumab and/or immunosuppressive agents (cyclophosphamide, mitoxantrone or cladribine). If disease activity returns after a period of success with alemtuzumab or the immunosuppressants, these agents can be used again, assuming that lifetime cumulative toxicity limits have not been reached (Table 1). Maintenance therapy with first-line agents (such as IFN-β) might also be beneficial. If MS remains refractory, we recommend moving quickly to aHSCT where possible. Patients should be assessed clinically every 3 months and radiologically every 6 months, and only minimal evidence of continued disease activity should be necessary before further treatment escalation. Abbreviations: aHSCT, autologous haematopoietic stem cell therapy; MS, multiple sclerosis.

efficacy and manageable adverse effects in patients with aggressive MS. However, in the CARE-MS II trial, the annual­ized relapse rate after alemtuzumab treatment was still 0.26, and 13% of patients continued to progress. Although this treatment was significantly better than the comparator, high-dose IFN‑β, this level of effectiveness might not be acceptable in certain cases of aggressive MS. In our algorithm (Figure 1), if alemtuzumab maintains good disease control over the first 2 years of the treat­ ment course, we would recommend using it intermit­ tently thereafter. However, if the drug fails to control aggressive disease within the first year, we would suggest moving quickly to aHSCT. If aHSCT is not an avail­able option, we recommend moving to another form of potent immunosuppression—­such as cyclophosphamide, mitoxantrone or even cladribine—to induce remission. Whether the use of these immunosuppressants after alemtuzumab failure would provide additional benefit remains uncertain, however. In theory, they could be options as a last resort. Cyclophosphamide and mitox­ antrone have limited utility owing to their cumulative toxicity, but if disease activity can be controlled, the benefit might ­subsequently be maintained with a safe first-line agent. In regions where neither aHSCT nor alemtuzumab is available, the immunosuppressive agents cladribine, cyclophosphamide and mitoxantrone would be the first logical consideration in the therapeutic algorithm, always bearing in mind the risk–benefit equation, and assessing

toxicity and cumulative doses. Patients can either stabi­ lize or continue to exhibit a suboptimal response. If refractory disease is evident, a second course of immuno­ suppression could be attempted. However, the safety of immunosuppressants following many of the current DMTs, especially agents such as natalizumab, has not been established. If, after a period of clinical stability following alem­ tuzumab or cladribine treatment, patients experience a resurgence of disease activity, either of these agents could be used again (a 3-day course of alemtuzumab, or two 6‑monthly treatments with cladribine) to induce remission. Patients with breakthrough disease follow­ ing cyclophosphamide or mitoxantrone therapy can be retreated with either of these agents, assuming that life­ time cumulative toxicity limits have not been reached. If cyclophosphamide or mitoxantrone are not options due to cumulative dose restrictions, alemtuzumab, cladribine or escalation to aHSCT should be considered. Severe disease—that is, repeated relapses, new MRI activity and/or unrelenting disability progression—may be unstoppable in certain patients, who fail to respond to increasingly potent agents over the years. For individuals beyond the window of opportunity, who have accrued substantial disability and treatment-related toxicity, the journey would, unfortunately, end here. To assess the response to treatment in patients with aggressive MS, we recommend low thresholds of accept­ able disease activity. Diligent monitoring is critical

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REVIEWS to capture suboptimal response in a timely fashion. However, there is no consensus regarding how often these patients should be monitored. We suggest clinical assessment of patients every 3 months and radiologi­ cal assessment every 6 months. We need to accept only minimal evidence of continued disease activity (such as relapses, MRI activity or EDSS progression) as a reason to further escalate t­ reatment: in other words, we must strive to achieve NEDA.

Conclusions

Early detection of aggressive MS is critical, because these patients are at much higher risk of early progression than are other patients with MS. Furthermore, aggressive MS tends to be refractory to conventional DMTs. Opportune and tailored implementation of treatment strategies spe­ cific to this set of patients may have a positive impact 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

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on disease severity and neurological disability. No consensus on how to treat aggressive MS has yet been reached, but we propose an approach that might assist in the identification and management of this particularly challenging condition. The use of more-aggressive treatment agents will require ongoing safety surveillance. Organizing clinical trials for patients with aggressive MS is another chal­ lenge, as it would be unethical to offer either a placebo or a DMT that is unlikely to have benefit, and studies would require multiple centres given the infrequency of this patient group (around 10% of all cases of MS). Perhaps with a more uniform definition of aggressive MS, data can begin to be compiled from small single-centre studies. This analysis could help to determine what treat­ ment regimen might offer superior benefit and safety to patients in urgent need of effective disease control.

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