Disease modifying therapies for relapsing multiple sclerosis
BMJ 2016; 354 doi: https://doi.org/10.1136/bmj.i3518 (Published 22 August 2016) Cite this as: BMJ 2016;354:i3518
- 1Department of Neurology, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ, 85259, USA
- 2Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA
- Correspondence to: D Wingerchuk wingerchuk.dean{at}mayo.edu
Abstract
Multiple sclerosis (MS) is a common, disabling, putatively autoimmune neurological disease with worldwide distribution. It typically begins as a relapsing disorder that later evolves to a secondary progressive phase. Inflammatory and neurodegenerative mechanisms seem to operate in both phases, but their relative contributions and interactions are incompletely understood. Disease modifying therapies (DMTs) approved for relapsing multiple sclerosis interfere with a variety of immunological mechanisms to reduce rates of relapse, accumulation of disease burden measured by magnetic resonance imaging (MRI), and decline in neurological function over the two to three year duration of typical randomized controlled trials. Benefits of longer duration of therapy on disability are less clear, as data beyond three years are largely limited to observational studies. However, current DMTs do not slow accrual of disability once progressive multiple sclerosis is established. This review summarizes the evidence about the use of approved DMTs and examines how to individualize treatment despite the absence of validated biomarkers to guide drug selection. Methods such as stratifying patients on the basis of estimated risk for future disability, weighing patient specific factors and preferences, and using objective outcomes to adjudicate treatment success are discussed. Emerging drug therapies and strategies are also reviewed.
Introduction
Multiple sclerosis is a chronic disease of the central nervous system with inflammatory and neurodegenerative immunopathological characteristics; interactions of genetic and environmental factors seem to be causative.1 2 It is the most common non-traumatic disabling neurological disease of young adults in developed nations. Multiple sclerosis is one of the costliest chronic diseases,3 and it reduces life expectancy by a median of seven years.4
Currently available disease modifying therapies (DMTs), all of which have immunomodulatory or immunosuppressive properties, improve the course of relapsing multiple sclerosis, the most common disease phenotype.5 However, current DMTs fail to benefit the later secondary progressive phase (secondary progressive multiple sclerosis—SPMS), in which neurodegenerative mechanisms assume overriding clinical importance.6 Early DMT treatment to control clinical and subclinical inflammatory disease activity has been recommended,7 but new risks associated with treatment have also emerged, including progressive multifocal leukoencephalopathy (PML—infection of the central nervous system with the John Cunningham virus (JCV))8 and secondary autoimmunity.9
The diverse efficacy and safety profiles of DMTs have resulted in greater emphasis on “personalized” approaches that tailor decisions about treatment to a patient’s disease characteristics and preferences.10 However, lack of prognostic and therapeutic biomarkers continues to hinder development of biologically based strategies.11 12 This review assesses the short term and long term efficacy and risks of available DMTs, as well as practical approaches to their use and monitoring. Emerging drugs that have the potential to further reshape the therapeutic landscape are also discussed.
Incidence and prevalence
Multiple sclerosis affects an estimated 2.5 million people worldwide, with considerable intraregional variability.13 The overall incidence rate is 3.6 (95% confidence interval 3.0 to 4.2) cases per 105 person years in women and 2.0 (1.5 to 2.4) in men.14 Estimates of prevalence range from about 2 per 105 population in sub-Saharan Africa and East Asia to 108-140 per 105 population in North America and Europe.13 Approximately 126 000 people in the United Kingdom (203.4 per 105 population) and more than 400 000 in the United States have multiple sclerosis.15 16
Sources and selection criteria
We searched Medline, Embase, and the Cochrane Database of Systematic Reviews (1992-April 2016) by using the following terms: “multiple sclerosis”, “relapsing”, “clinically isolated syndrome”, “radiologically isolated syndrome”, “interferon-beta”, “glatiramer acetate”, “natalizumab”, ”mitoxantrone”, ”fingolimod”, ”teriflunomide”, ”dimethyl fumarate”, ”alemtuzumab”, ”daclizumab”, ”ocrelizumab”, ”laquinimod”, ”stem cell transplantation”, and ”comorbidity”. We searched Medline, the National Guideline Clearinghouse (www.guideline.gov), and organizational websites for guidelines. We searched abstract listings from the 2015 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) conference and the 2016 American Academy of Neurology (AAN) conference. We prioritized selection of systematic reviews and large randomized controlled trials (RCTs) and used observational studies when RCTs were not available. Our data synthesis and recommendations were developed using available evidence and our clinical experience.
Background and rationale for disease modifying therapies
Relapsing multiple sclerosis is signaled by the occurrence of a clinical event of central nervous system dysfunction consistent with demyelination and evidence of dissemination in time based on magnetic resonance imaging (MRI) findings or a subsequent clinical attack.17 Updated definitions of clinical phenotypes (fig 1⇓) allow for the modifiers “active” or “inactive” based on detection of clinical relapses or MRI activity (for example, new or enlarging T2 weighted lesions or new gadolinium enhancing lesions).18 The clinically isolated syndrome (CIS) is an early multiple sclerosis phenotype (fig 2⇓) denoted by a first ever clinical attack and MRI findings suggestive of multiple sclerosis but without dissemination in time.18 19 Although it is not recognized as a distinct phenotype, incidental discovery of asymptomatic MRI lesions with location and morphology suggestive of multiple sclerosis, known as “radiologically isolated syndrome” (RIS), may represent preclinical multiple sclerosis in some patients (fig 2⇓).20 21
Fig 1 Multiple sclerosis clinical phenotypes and modifiers—2013 revisions. “Active” and “progression” statuses are determined at least annually. “Active” status is achieved if clinical relapses and/or magnetic resonance imaging activity (contrast enhancing lesions; new or unequivocally enlarging T2 weighted lesions) have occurred since previous assessment. “Progression” is determined by clinical evaluation of whether neurological disability has increased. If assessments are not available, activity and progression are considered “indeterminate.” Note that “active” CIS qualifies as RRMS if current multiple sclerosis diagnostic criteria are fulfilled. Adapted from Lublin et al18
Fig 2 Ideal timing of multiple sclerosis (MS) therapy and relation to disease course. Inflammatory (clinical relapses; magnetic resonance imaging (MRI) activity) and neurodegenerative (brain volume loss; progressive disability) aspects pertinent to relapsing MS are shown in this schematic. Brain volume decline begins even before clinical expression of disease and accumulation of most of inflammatory lesion burden. Disability can accrue in stepwise manner after relapses but steadily worsens as secondary progressive multiple sclerosis (SPMS) is established; by this point, available therapies are ineffective. Gradient of shaded “window for ideal treatment” segment represents diminishing opportunity to establish effective therapy with increasing time from onset of clinically isolated syndrome (CIS) through relapsing-remitting phase. “Potential treatment window” represents preclinical treatment, a goal for future research initiatives. EDSS=Expanded Disability Status Scale; RIS=radiologically isolated syndrome; RRMS=relapsing-remitting multiple sclerosis
Despite their varied immunological mechanisms,22 DMTs all improve the course of relapsing multiple sclerosis for the two to three year duration of controlled trials as assessed by reductions in annualized relapse rate (ARR) and MRI outcomes of disease burden such as lesion number and volume.23 24 25 26 27 28 29 Some DMTs reduce accrual of disability as measured by the Expanded Disability Status Scale (EDSS),30 which primarily reflects ambulatory status, and associated MRI measures including brain atrophy.31 Several DMTs are also approved for CIS because they delay evidence of dissemination in time. Biomarkers are not yet available to accurately establish diagnosis of preclinical multiple sclerosis; clinical and MRI surveillance, rather than drug therapy, is recommended for RIS.21
About 60-75% of untreated patients with relapsing multiple sclerosis experience two distinct but overlapping clinical phases: relapsing and secondary progressive.18 32 Progressive disease is manifest by continuous neurological deterioration believed to reflect neurodegeneration that likely begins at or near the onset of multiple sclerosis (fig 2⇑).22 Although relapses contribute to disability,33 34 conversion to SPMS, the latency of which is highly variable but usually about two decades, best predicts development of further irreversible neurological impairment such as ambulatory or cognitive dysfunction.35
The mechanisms responsible for conversion to SPMS are not well understood but are strongly associated with age and partially dissociated from occurrence and behavior of the preceding relapsing course.36 37 38 Importantly, current DMTs have shown no benefit for established SPMS or primary progressive multiple sclerosis (PPMS), although ocrelizumab is an exception.39 Collectively, these findings have led to the still controversial hypothesis that a “window of opportunity” exists during CIS or early multiple sclerosis during which therapies that eliminate signs of inflammatory disease activity could favorably influence risk or latency of SPMS.40 41 42
Preclinical multiple sclerosis that is diagnosed with the aid of biomarkers (in the setting of RIS) might further extend the window (fig 2⇑).43 44 45 Although compelling, this hypothesis remains largely unexamined because high quality RCTs are brief compared with the decades long evolution of multiple sclerosis, and biomarkers that predict a relapsing disease course, treatment response, and development of SPMS are lacking. Moreover, earlier diagnosis relies increasingly on interpretation of MRI, which heightens the risk of misdiagnosis and inappropriate DMT treatment.46
Summary of approved disease modifying therapies
The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have approved 14 DMTs for relapsing multiple sclerosis (table 1⇓). Treatment associated relative reductions in ARR and the risk or proportion of patients with disability progression (typically confirmed with two examinations 12 weeks apart, unless otherwise specified) are summarized below. Where possible, we report numbers needed to treat (NNT) for ARR and disability outcomes.5 47 Treatment related benefits on secondary brain MRI outcomes in RCTs include reductions in new gadolinium enhancing lesions, new or enlarging lesions on T2 weighted sequences, or both.
Approved disease modifying therapies for relapsing multiple sclerosis
Self injectable therapies
Interferon beta
Interferon beta preparations are first line therapies that promote redirection from pro-inflammatory Th1 to anti-inflammatory Th2 immune responses, alter related cytokines, and may increase regulatory T cells. Several interferon beta formulations are approved for CIS and delay clinical and/or MRI conversion to multiple sclerosis.48 49 50 51 In relapsing multiple sclerosis, pivotal placebo controlled RCTs showed relative reductions in two year ARR and risk of progression for weekly intramuscular interferon beta-1a (18% and 37% (NNT=9 for progression), respectively),52 alternate day subcutaneous interferon beta-1b (34% and 29%; NNT=6 for progression),53 54 and three times weekly subcutaneous interferon beta-1a (32% and 30%; NNT=6 for progression),55 as well as significant MRI effects.
The dose and frequency of interferon affect relapse and MRI outcomes. A systematic review of head to head RCTs concluded that high dose interferon beta formulations are superior for relapse control and MRI effects but not for disability outcomes.56 Neutralizing antibodies against interferon beta abrogate treatment benefits.57 58 Greater injection frequency contributes to non-adherence.59 Compared with placebo, subcutaneous pegylated interferon beta-1a injected every two weeks reduced ARR to a similar degree to other interferon betas (rate ratio 0.64, 95% confidence interval 0.50 to 0.83) and may reduce this problem.60
Glatiramer acetate
Glatiramer acetate consists of a mixture of polypeptides derived from four amino acids that may induce a Th1-Th2 shift and increase regulatory T cells. A pivotal placebo controlled RCT showed that subcutaneous daily glatiramer acetate 20 mg reduced ARR by 29% but did not affect disability progression; a separate RCT showed benefit on MRI outcomes.61 62 Glatiramer acetate reduced the rate of conversion from CIS to multiple sclerosis by 45%.63 Glatiramer acetate 40 mg three times weekly reduced ARR by 34% at one year compared with placebo, a similar result to the pivotal studies of 20 mg daily.64 In 2015 the FDA approved the first generic DMT, a substitutable form of the 20 mg glatiramer acetate preparation. An RCT showed that the primary outcome (MRI), safety, and tolerability of the generic and brand forms were equivalent.65
Daclizumab
Daclizumab, approved in 2016, is a humanized non-depleting monoclonal antibody directed against CD25, the high affinity α-subunit of the interleukin-2 receptor expressed on activated T cells. Daclizumab reduces activated T cell expansion and increases regulatory CD56+ (bright) natural killer cells, a possible therapeutic biomarker.66 The 52 week placebo controlled SELECT trial showed that subcutaneous daclizumab 150 mg every four weeks reduced the ARR by 54% and the risk of 24 week confirmed progression by 20% (NNT=6).67 The 96 week DECIDE RCT showed that daclizumab was superior to intramuscular interferon beta-1a in reducing ARR (45%) and improving MRI outcomes but not risk of progression.68 Adverse events that were more common in the daclizumab group than in the interferon beta-1a group included infections (65% v 57%; serious infection in 4% v 2%), cutaneous reactions (37% v 19%; serious events in 2% v <1%), and elevations in liver transaminase concentrations that were more than five times the upper limit of the normal range (6% v 3%).68 The FDA indicated that daclizumab should generally be used only in patients with an inadequate response to two or more multiple sclerosis drugs, but the EMA did not.69 70
Oral therapies
Fingolimod
Fingolimod received FDA approval as a first line treatment and EMA approval as a second line treatment. It down-regulates four sphingosine-1-phosphate receptor subtypes expressed on lymphocytes and other cell types, preventing egress of lymphocytes from lymphatic tissues and thereby reducing blood-brain barrier transmigration.71 72 In animal models, fingolimod has neuroprotective effects in the central nervous system.73
In the 24 month placebo controlled FREEDOMS RCT, fingolimod (0.5 mg/day) reduced ARR (54%), risk of disability progression (30%; NNT=16), and MRI outcomes.74 The 24 month FREEDOMS II trial found a 48% reduction in ARR compared with placebo (rate ratio 0.52, 95% confidence interval 0.40 to 0.66) and benefits on MRI outcomes but detected no effect on disability.75 The 12 month, double blind, double dummy TRANSFORMS trial showed that fingolimod reduced ARR by 50% compared with intramuscular interferon beta-1a and was superior on MRI measures, but progression rates were similar.76
Fingolimod increased the risk of varicella zoster virus infection compared with placebo (11 v 6 cases per 1000 patient years) in clinical trials, though not in extension studies, so patients must have documented varicella zoster virus immunity or pre-treatment immunization.76 77 Fatal disseminated varicella zoster virus and herpes simplex virus-1 infections occurred once each in the TRANSFORMS trial.76 Cryptococcal central nervous system and skin infections have also been reported.78 79 80 Three cases of PML associated with fingolimod monotherapy have been confirmed81; routine assessment of JCV antibody status and maintenance of vigilance for PML symptoms or MRI changes is reasonable.
Fingolimod has other organ specific side effects because of widespread sphingosine-1-phosphate receptor expression. First dose bradycardia, almost universal but rarely symptomatic, requires monitoring of vital signs for six hours after the first dose; extended cardiac telemetry monitoring is needed if excessive bradycardia is persistent or symptomatic. Contraindications include cardiac disorders (ischemia, conduction block syndromes, prolonged QTc interval), certain antiarrhythmics, and symptomatic cerebrovascular disease. Ophthalmological baseline and monitoring examinations are needed to detect macular edema (incidence ~0.5%; higher in patients with diabetes mellitus or previous uveitis).82 The EMA recommends dermatological assessment, especially for basal cell carcinoma.83 Selective sphingosine-1-phosphate modulators in development may eliminate some of the organ specific adverse effects.84
Teriflunomide
Teriflunomide is a once daily first line oral dihydroorotate dehydrogenase inhibitor that reduces synthesis of pyrimidine by proliferating immune cells.85 TEMSO was a 24 month placebo controlled RCT in which both approved doses (7 mg and 14 mg) reduced ARR by 31%, whereas only the 14 mg dose reduced disability progression (30%; NNT=14) and it had greater MRI benefits.86 The TOWER RCT treated patients for at least 48 weeks (and up to two years) and found 22.3% (7 mg) and 36.3% (14 mg) reductions in ARR relative to placebo. Only the 14 mg dose reduced risk of progression (hazard ratio 0.68, 95% confidence interval 0.47 to 1.00; NNT=5, based on proportion progression-free at 108 weeks).87 Teriflunomide also showed benefit for treatment of CIS; compared with placebo, it reduced the risk of multiple sclerosis defining relapse with both 14 mg (hazard ratio 0.574, 0.379 to 0.869) and 7 mg (0.628, 0.416 to 0.949) doses. It also reduced the risk of either relapse or new MRI lesions at the 14 mg dose (hazard ratio 0.651, 0.515 to 0.822) and at the 7 mg dose (0.686, 0.540 to 0.871).88
Adverse effects of teriflunomide include diarrhea (11-18%), alopecia (10-13%), elevated transaminases (8% occurrence of level more than three times the upper limit of normal; an FDA “black box” warns of potential serious hepatotoxicity), hypertension (5%), peripheral neuropathy (2%), and serious infection (2-3%).86 87 It has a prolonged half life owing to enterohepatic recirculation and may take many months to be eliminated after discontinuation unless accelerated to 11 days by administration of cholestyramine or activated charcoal. Reproductive counseling is necessary for women and men because teriflunomide is teratogenic and excreted in breast milk and semen.
Dimethyl fumarate
Dimethyl fumarate is a twice daily oral therapy for relapsing multiple sclerosis. It resembles a drug for psoriasis that contains fumaric acid esters (Fumaderm) but is an enteric coated tablet designed to improve gastrointestinal tolerability. Dimethyl fumarate is metabolized to monomethyl fumarate, which is eliminated by respiration with minimal hepatic or renal excretion. Dimethyl fumarate has immunomodulatory properties and may reduce oxidative stress leading to neuroprotection.89
The FDA and EMA approved dimethyl fumarate as first line therapy in 2013. Two 24 month RCTs, DEFINE and CONFIRM, showed that the approved 240 mg twice daily dose was superior to placebo, reducing ARR by 53% (NNT=9 for proportion relapse-free) for DEFINE and 44% (NNT=5) for CONFIRM.90 91 The risk of disability was significantly reduced only in DEFINE (38%; NNT=9).91 CONFIRM included a glatiramer acetate reference arm; a post hoc analysis showed no difference in clinical outcomes for twice daily dimethyl fumarate versus glatiramer acetate.90
Dimethyl fumarate is associated with self limited gastrointestinal upset and flushing, each occurring in about 30% of patients. Lymphocytes typically decline by 20-30% and should be monitored. A retrospective study showed a 17% incidence of persistent grade 2-3 lymphopenia; risk factors included age over 50 years, lower baseline lymphocyte count, and previous natalizumab treatment.92 PML has been reported with prolonged lymphopenia during use of compounded fumaric acid products or Fumaderm for psoriasis, with or without concomitant immunosuppressive drugs.93 94 Three cases of PML have been reported in multiple sclerosis patients taking dimethyl fumarate without previous natalizumab exposure; each had lymphopenia of below 0.5×109/L.95 Similar to a report of fatal PML in a psoriasis patient without severe lymphopenia,96 PML was recently reported in a dimethyl fumarate treated multiple sclerosis patient with lymphocyte levels not lower than 0.6×109/L and previous natalizumab use. The EMA recommends obtaining a complete blood count with differential every three months; both the EMA and FDA recommend considering discontinuation of dimethyl fumarate if the lymphocyte count is below 0.5×109/L for more than six months.97 98 Lymphopenic patients continuing dimethyl fumarate should be under PML surveillance, and JCV serological testing is reasonable.
Intravenous therapies
Natalizumab
The humanized monoclonal antibody natalizumab targets very late antigen-4, a ligand expressed on the surface of lymphocytes and monocytes. Natalizumab prevents the interaction between very late antigen-4 and its ligand, vascular cell adhesion molecule-1, blocking transmigration of activated lymphocytes between endothelial cells into the central nervous system.99
In a large 24 month placebo controlled RCT (AFFIRM) that enrolled mostly DMT-naive patients, natalizumab reduced the ARR by 68% (NNT=2 for proportion relapse-free) and the risk of disability progression by 42% (NNT=8).100 A second 24 month, placebo controlled RCT (SENTINEL) of patients with relapsing multiple sclerosis who had breakthrough attacks despite intramuscular interferon beta-1a treatment showed benefits of natalizumab on clinical outcomes (reductions of 55% for ARR and 24% for progression; rate ratio 0.76, 95% confidence interval 0.61 to 0.96; NNT=4).101 Both SENTINEL and AFFIRM showed significant benefits on several MRI outcomes.
Natalizumab is associated with risk of PML.102 103 As of May 2016, the global incidence of PML during natalizumab treatment was 4.22 (95% confidence interval 3.91 to 4.55) per 1000 patients.104 Three factors stratify risk: detection of serum JCV antibodies (indicating previous systemic JCV infection), previous use of immunosuppressive drugs, and use of natalizumab exceeding 24 months.8 105 The presence of all three factors is associated with risk of about 1.3%, whereas the estimated risk with none present is 0.01% (table 2⇓). Rare cases of PML have occurred in patients seronegative for JCV antibody, indicating a false negative test or very recent seroconversion.
Stratified estimates of risk of progressive PML associated with natalizumab therapy in patients seropositive for JCV antibody
Natalizumab is usually a later line therapy. It is generally avoided in patients seropositive for JCV but could be considered for 12-24 months in those not previously exposed to immunosuppressants. Because PML is disabling and not specifically treatable, monitoring of natalizumab treated patients, aided by a mandatory risk evaluation and mitigation strategy, should include regular clinical assessment, brain MRI (which may detect pre-symptomatic cases),106 107 and scheduled JCV serology retesting (for example, every three to six months). Use of serum and cerebrospinal fluid JCV antibody indices, measurement of L-selectin expressing CD4 T cells, and other methods may further refine risk stratification.108 109 110 111 A JCV antibody index below 0.9 is associated with lower risk for PML and an index above 1.5 is associated with higher risk,109 but observational studies found that natalizumab treatment was associated with increasing indices over time (0.091 units/year, or 13%) and high annual seroconversion rates (8.5-10.3%).112 113 Alternative treatments should be considered for patients who seroconvert. A recent patient with PML tested JCV seronegative two weeks before presentation, so vigilance is needed in all cases.114 Risk persists after discontinuation of natalizumab, and ongoing surveillance is recommended, especially for patients who transition to drugs associated with PML such as fingolimod or dimethyl fumarate.115 116 Suspicion of PML should prompt immediate withdrawal of natalizumab.
Alemtuzumab
Alemtuzumab is a humanized monoclonal antibody directed against CD52, a cell surface marker present on monocytes and lymphocytes. The standard treatment protocol calls for five intravenous infusions over one week, which results in profound depletion of T cells, especially CD4+ and natural killer cells, for more than a year, but B cells are repleted within five to six months. A second course of three infusions is repeated at one year; subsequent courses may be given but have not been studied in controlled trials.117 118
Three RCTs, including two phase III trials, evaluated alemtuzumab against three times weekly subcutaneous interferon beta-1a in patients with early relapsing multiple sclerosis.24 CARE-MS I evaluated the effect of 12 mg of alemtuzumab in treatment-naive patients.117 CARE-MS II studied both 12 mg and 24 mg doses in patients who had breakthrough disease activity while using interferon beta or glatiramer acetate.118 Both protocols were single blind (masked examiner only). CARE-MS I results showed that treatment with 12 mg alemtuzumab reduced ARR by 55% (NNT=5) but not EDSS progression, possibly owing to low progression rates in both study arms (11% for placebo, 8% for alemtuzumab). Alemtuzumab also prevailed on several secondary MRI endpoints and the proportion of patients who were “disease activity free” on both clinical and MRI measures. In CARE-MS II, 12 mg alemtuzumab reduced ARR by 49% (NNT=4) and sustained disability progression by 42% (NNT=12) and showed benefit on virtually all MRI variables compared with interferon beta-1a.118 The 24 mg dose was not superior to 12 mg but caused more adverse events. Extension studies suggest that many patients remain relapse-free for up to five years after starting the two course alemtuzumab protocol, but in one study about a third of patients underwent retreatment because of new relapses or MRI changes.119 120
Alemtuzumab is associated with significant risks, especially systemic autoimmunity manifest as thyroid disease (30% incidence at five years, including Graves’ disease), idiopathic thrombocytopenic purpura (2-3%), and Goodpasture’s syndrome (rare).118 119 Herpesvirus reactivation has been observed,121 and oral aciclovir treatment is recommended during and for 28 days after alemtuzumab infusions.
Patients should have demonstrable immunity to varicella zoster virus before treatment or receive vaccination; live virus vaccines should not be administered after treatment. Listeria meningitis and cryptosporidial infections have been reported121 122 123; however, to date, PML has not been described in association with alemtuzumab used for multiple sclerosis. Thyroid papillary carcinoma has been reported,117 monitoring for melanoma is recommended, and other malignancies remain a potential risk. A risk evaluation and mitigation strategy program requires complete blood count, serum creatinine, thyroid function test, and urine analysis before treatment and monthly (every three months for thyroid function) during treatment and for four years after the final dose. Alemtuzumab is typically used as a second or later line agent for breakthrough relapsing disease but may also be considered as an initial agent for highly active treatment-naive multiple sclerosis.117
Mitoxantrone
Mitoxantrone is an anthracenedione chemotherapeutic agent approved for worsening relapsing multiple sclerosis or SPMS. It showed benefit on a multidomain primary outcome measure that included relapse and disability variables.124 Mitoxantrone is rarely used owing to risks of acute leukemia, cardiotoxicity, and possibly colon cancer.125 126
Comparisons of DMTs’ efficacy
Few active comparator RCTs have been conducted in relapsing multiple sclerosis. Pivotal RCTs that used an available comparator instead of placebo (for example, alemtuzumab RCTs) and trials comparing interferon beta formulations were described in the previous section. A systematic review of five head to head RCTs found that interferon beta and glatiramer acetate had similar safety and efficacy outcomes at 24 months, although interferon beta had a greater effect on MRI outcomes.127 The CombiRX study is a three year, double blind, three arm (intramuscular interferon beta-1a, glatiramer acetate, combination interferon beta-1a plus glatiramer acetate) RCT included in the review. It showed that glatiramer acetate further reduced ARR by 31% compared with interferon beta, but no differences were seen between the three arms on disability measures and no clinical advantage of combination therapy.128 The single blind TENERE trial, which was not included in the review, compared teriflunomide with subcutaneous interferon beta-1a (44 μg three times weekly). It showed no differences in time to failure (relapse or treatment discontinuation) or in ARR between teriflunomide 14 mg and interferon beta-1a, but ARR was significantly higher with teriflunomide 7 mg.129
Between trial comparisons are challenging for many reasons, including trial design and differences between participants, revisions in the definition of multiple sclerosis, and lower ARR in the placebo arm over time.130 131 A network meta-analysis in 2016 showed that alemtuzumab, natalizumab, and fingolimod each outperformed all other DMTs for prevention of relapse measured at two years of treatment, with quality of evidence rated moderate or better.23 132 Only natalizumab had similar quality evidence supporting its superiority for reducing two year disability progression rates. Figure 3⇓ shows the outcomes of relapse and disability combined with treatment discontinuation rates to estimate overall benefits. These data support the conclusions of the Association of British Neurologists’ guidelines that alemtuzumab, natalizumab, and fingolimod represent the current highest efficacy tier of DMTs for relapsing multiple sclerosis.47
Fig 3 Summary of associations of disease modifying therapies for relapsing multiple sclerosis with benefit. This figure summarizes benefit (patients without new clinical relapses or disability worsening) and acceptability (patients who did not withdraw from treatment owing to adverse events) in network meta-analysis of more than 25 000 participants from placebo controlled and active comparator randomized controlled trials. GRADE=Grading of Recommendations Assessment, Development and Evaluation. *Interpretative example: for outcome of relapses over 24 months, probabilities (surface under cumulative ranking curve) for alemtuzumab was 97%, which implies that it is highly likely to be associated with best outcome of treatments assessed. By contrast, intramuscular interferon beta-1a had probability of 22% for relapses over 24 months, which was lowest value obtained for all assessed therapies. Adapted from Tramacere et al,132 with permission
Long term effects of disease modifying therapies
A variety of approaches, including extension studies, follow-up of original RCT participants, and retrospective and prospective cohort studies, have been used to judge the influence of DMTs on the long term course of multiple sclerosis. Many post-RCT open label extension studies exist but are most useful for assessing safety.133 134 135
A series of observational cohort studies suggested that DMTs could delay SPMS.136 137 138 In a retrospective study of original participants in the pivotal RCT of interferon beta-1b, those randomized to receive interferon beta-1b had roughly twice the duration of exposure over 21 years and 46.8% lower mortality than those randomized to placebo.139 A similar retrospective study showed that initial assignment to interferon beta-1b reduced disability assessed 16 years later.140 A large retrospective population based cohort study showed no benefit on progression of disability; it lacked initial randomization, however, and biases may have contributed to lack of evidence of benefit (for example, exclusion of patients with perceived “benign” disease),141 although other studies that adjusted for risk of disability to achieve more uniform cohorts report benefit.136 137 A large scale, six year prospective cohort study in the United Kingdom showed benefits of DMT use (interferon beta or glatiramer acetate) on effectiveness (disability progression) and cost effectiveness outcomes compared against a natural history cohort.142 Collectively, these studies are inconclusive but suggest that long term benefits may exist. However, they illustrate the challenges inherent in establishing meaningful therapeutic benefits in relatively unpredictable, multiphasic, chronic diseases for which patients are free to start, switch, and stop treatments.
Overview of disease modifying therapeutic strategies
Over the past decade, the prevailing practice can be described as an “escalation” approach in which treatment begins with a “platform” DMT such as interferon beta or glatiramer acetate. If this is deemed ineffective or intolerable, another platform drug or a higher efficacy therapy such as natalizumab is substituted.45 The rationale is that risk should be minimized and that surveillance for disease activity allows escalation of therapy in those patients who need it. Whether specific drug sequences influence outcomes with this paradigm is unknown.
A contrasting approach is “induction” therapy, in which a highly effective drug is used for a defined time period (usually one to two years) and followed by either observation or a lower risk maintenance treatment.143 Examples include induction with mitoxantrone followed by either glatiramer acetate or interferon beta,144 145 or, more recently, alemtuzumab followed by either observation or a platform therapy if necessary.117 This approach has been widely used for rheumatologic diseases and cancer, but its benefits have not been established for multiple sclerosis. Proponents point to the aforementioned early “window of opportunity” during which immunological therapies can be expected to maximally influence disease course.40
Combination therapy strategies have the potential incremental value of using two or more concomitant therapies with distinct individual mechanisms. Few RCTs have assessed combinations of two available DMTs by using a clinical primary endpoint. The largest RCT, the CombiRx study, showed no advantage of an interferon beta-1a/glatiramer acetate combination over monotherapy.128 Corticosteroids and general immunosuppressants have been tested in combination with an approved DMT, but insufficient evidence exists to support use of combinations of DMTs, and barriers include potential for additive toxicity and cost.
A practical and personalized approach to initial treatment of relapsing multiple sclerosis
Although drug mechanisms can occasionally be personalized for cancer on the basis of genomic or tissue specific DNA mutation detection and pathobiology, this approach is not feasible for multiple sclerosis. Nevertheless, optimization of treatment for relapsing multiple sclerosis remains a highly individualized process. We advocate an intermediate approach between the escalation and induction strategies, in which risk for future disability, comorbidities, personal preferences, and risk mitigation strategies are considered to select a therapy that provides the best compromise between efficacy and potential risk (fig 4⇓).
Fig 4 General approaches to selection of multiple sclerosis (MS) disease modifying therapies (DMTs). These algorithms are general approaches to facilitate selection of initial and subsequent relapsing DMTs for patients with mildly to moderately active MS (top panel) and highly aggressive MS (bottom panel). Highly effective therapies should be considered for patients with aggressive MS after stratification by John Cunningham virus (JCV) antibody status. First line therapies are used in an escalation strategy for patients with mild to moderate recent disease activity. Disease monitoring with integration of clinical and magnetic resonance imaging (MRI) data to adjudicate adherence to treatment, tolerability/adverse effects, and treatment failure then leads to decisions on continuation of current DMT, switching to another agent, or escalating to highly effective drug. AE=adverse event; other/RCT=consider other treatment options (such as autologous stem cell transplantation) or enrollment into a randomized controlled trial or other experimental study
Individual disability risk stratification
Despite the difficulties inherent in predicting an individual patient’s outcome, identification of clinical and MRI characteristics predictive of poorer outcome or meeting of criteria for “highly active” disease may justify more aggressive DMT selections at or soon after diagnosis (fig 4⇑). At presentation of CIS, factors such as greater number of T2 weighted brain MRI lesions (for example, more than 10 lesions), greater initial lesion volume, and early change in volume predict long term disability in cohorts followed from seven to 20 years.146 147 In relapsing multiple sclerosis, early attack rate is associated with long term outcomes.38 140 Several definitions of “highly active” or “aggressive” disease have been proposed for clinical use,143 148 149 or to facilitate subgroup analyses of RCT data,150 151 152 typically using a combination of two or more clinical relapses together with one or more of relapse severity, presence of multiple gadolinium enhancing MRI lesions, significant T2 lesion burden, or increase in EDSS score within the preceding year.
Detection of T1 black holes or cerebral atrophy suggests irreversible axonal injury and is associated with future disability. Evaluation of these factors together with other clinical and MRI variables (fig 5⇓) and demographic considerations, such as African-American race,153 may lead one to conclude that a highly effective therapy is indicated. Post hoc analyses of RCT data have been used to support the efficacy of natalizumab, alemtuzumab, and fingolimod for highly active disease.151 154
Fig 5 Considerations for selection of disease modifying therapy for relapsing multiple sclerosis (MS)
JCV serological status
Evaluation of JCV antibody status is an important step in selecting from high efficacy therapies because of the strong association of PML with natalizumab. Pre-treatment risk assessment can be carried out as outlined above; patients seropositive for JCV are generally not treated with natalizumab or are switched to another drug.
Patient specific factors
Many patient specific factors influence the timing and choice of DMT (fig 5⇑). Many patients are women of childbearing potential, and conception planning is recommended. No DMT has been established to be safe in pregnancy, but recent data show that fetal exposure to glatiramer acetate and interferon beta (first trimester) may not be harmful.155 156 If a woman’s clinical course has been favorable and she wishes to conceive in the near future, treatment may be deferred or withdrawn until pregnancy and breast feeding, which are associated with less multiple sclerosis activity, are complete.157 158
Adjudicating treatment success
Regular monitoring of compliance, tolerability, safety, and potential benefit of DMTs is necessary. In the absence of biomarkers, judgments about treatment efficacy depend on determining whether the disease is “active” or “progressive”18 (fig 1⇑) and comparing on-therapy and pre-therapy disease courses.
DMT failure can be straightforward if multiple or severe breakthrough attacks or obvious neurological worsening occurs. However, in practice, the threshold for this declaration is often less clear (for example, one mild relapse with good recovery or asymptomatic MRI lesion accrual). Investigators have attempted to find predictors of sustained treatment response and to implement the process of adjudicating treatment failure. A 15 year observational study of participants in an RCT of interferon beta-1a showed that occurrence of two or more gadolinium enhancing MRI lesions during the first two years of interferon beta-1a treatment was associated with EDSS progression; however, this relation was not observed in the placebo arm.159
Most formal approaches to assessing treatment failure use varying definitions of a “relapse/disability/MRI” paradigm.160 The Rio scoring system, also derived from relapsing multiple sclerosis patients treated with interferon beta-1a, consists of occurrence of relapses, disability progression (increase of 1 EDSS point confirmed at six months), and active MRI lesions (at least two new T2 or gadolinium enhancing lesions).161 Patients meeting at least two of these criteria were more likely to experience progressive disability or relapses during the following two years than were those who did not. A modified version of the Rio score based on relapses and focal MRI activity showed similar results.162
These findings emphasize the importance of early disease activity in predicting subsequent course, although the cohorts contributing to these data were not randomized or blinded to treatment allocation, and long term follow-up for major changes in disability was unavailable. Treatment decisions must be individualized; when only modest asymptomatic MRI changes occur, continued surveillance on current therapy may be appropriate.
Recently, the concept of aiming for “no evidence of disease activity” (NEDA) has gained attention. NEDA was originally defined as absence of clinical relapses, disability progression (EDSS), and new or enlarging T2 or gadolinium enhancing MRI lesions.163 The most recent proposal, NEDA-4, eliminates gadolinium enhancing lesions because they strongly correlate with relapses and adds absence of annual brain volume loss greater than 0.4%, a correlate of disability progression.164 NEDA status is binary, can be evaluated for any on-treatment time segment, and is difficult to maintain. In one observational study, 46% of patients achieved NEDA at one year but only 7.6% at seven years.165 Whether NEDA has predictive validity for long term disability outcomes is unclear. It includes variables with different but interrelated pathological implications (for example, relapses and MRI lesions as measures of inflammatory disease and brain volume loss potentially reflecting combined post-inflammatory effects and axonal loss). Furthermore, NEDA is a binary outcome that gives equal weight to change in any of its individual variables, but they may not have similar implications for future outcomes. Finally, automated brain atrophy measures and systematic serial MRI assessments with sequence and slice matching may not be routinely available in practice.166 167
Switching disease modifying therapies
Treatment failure or other factors may necessitate changes in treatment. Switching between first line agents with different mechanisms of action (for example, glatiramer acetate to interferon beta or vice versa) is reasonable, especially if adverse effects or compliance are specific to the initial agent (fig 4⇑, top). However, switching to attain better efficacy after treatment failure is problematic given the meager number of active comparison trials. Reassessment of whether a patient meets criteria for aggressive disease and evaluating JCV status for risk of PML is recommended when considering the next treatment choice. Escalation from a first line therapy to a second line drug usually reduces relapse rate on the basis of observational studies reporting outcomes at about one year post-switch.168 169 Recent observational studies compared switching to either fingolimod or natalizumab for patients with active disease despite first line therapy. A prospective international registry cohort reporting outcomes after a mean of one year showed that natalizumab was superior for relapse prevention and short term disability,169 and data from a two year French multicenter study favored natalizumab for relapse prevention and MRI outcomes.170 Thus, switching to natalizumab in JCV antibody seronegative patients is recommended over fingolimod. Similar comparative studies involving alemtuzumab are not yet available.
Washout periods (defined intervals between discontinuation of one therapy and starting of another) are often considered to avoid additive drug toxicity and immunosuppression. Occurrence of PML in patients taking oral DMTs and previously treated with natalizumab heightens concern about immunological carryover effects lasting several months. Disadvantages of washout periods include that they have not been shown to reduce PML risk and that patients are at risk for rebound multiple sclerosis activity, ranging from asymptomatic MRI lesions to severe relapses, after withdrawal of natalizumab or fingolimod.171 172
In patients stopping natalizumab, switching to fingolimod was superior to switching to a first line injectable drug for relapse prevention regardless of washout duration, on the basis of data from a prospective multicenter cohort study.173 A placebo controlled RCT showed that transition from natalizumab to fingolimod at eight or 12 weeks was associated with development of fewer MRI lesions than transition at 16 weeks.174 An observational study showed that the strongest predictor of disease activity after withdrawal of natalizumab was history of relapse within the previous six months.175
No approach including pulse corticosteroids seems to be effective in reducing rebound. For these reasons, transition periods of less than a month have been increasingly used, while maintaining PML surveillance during and after the transition period. A recent observational study showed that after stopping natalizumab in stable patients, switching to rituximab was associated with a lower relapse risk (1.8%) than switching to fingolimod (17.6%) 1.5 years later (hazard ratio 0.10, 0.02 to 0.43).176
Stopping therapy
Several medical and personal considerations may lead to drug discontinuation.177 In some instances, drug treatment is stopped altogether because of either advanced age or disability from SPMS, although pre-progression and post-progression relapses contributed to disability in a retrospective cohort study, leading to the recommendation to continue DMT for five years after onset of SPMS or to age 55.178
Conversely, a minority of patients with mild disease (some perhaps meeting some definitions of the controversial term “benign MS”)179 180 experience many years of clinical and MRI inactivity and wish to stop therapy. We advise establishing why a patient wishes to stop therapy, inquiring about tolerability and adherence, and reappraising the on-treatment clinical course, because disease activity often returns after stopping first line therapies.181 182 Should treatment be stopped, clinical and MRI reassessment six months later is advised.
Emerging disease modifying therapies
Ocrelizumab is a humanized anti-CD20 monoclonal antibody that depletes most B cell subsets. Two phase III RCTs in patients with relapsing MS showed clinical and MRI benefits.183 Ocrelizumab was recently reported to slow disability progression in PPMS,184 marking the first time a DMT for multiple sclerosis has shown benefit on both relapsing and primary progressive subtypes. Ofatumumab, a fully human subcutaneous anti-CD20 monoclonal antibody, showed favorable MRI outcomes, and a phase III trial is planned.185
Laquinimod is an oral immunomodulator that acts via the quinolone-3-carboxamide pathway and may have neuroprotective effects. In two phase III RCTs in patients with relapsing multiple sclerosis, laquinimod 0.6 mg/day showed greater effect on EDSS and brain atrophy than on relapses and gadolinium enhancing MRI lesions.186 An ongoing trial is also evaluating a higher dose of laquinimod (1.2 mg/day) with a primary outcome of time to confirmed disease progression.187
Protocols for myeloablative and non-myeloablative autologous stem cell transplantation have been developed with the goal of cure through immunological “rebooting” and elimination of putative autoreactive cells. Several studies have shown significant benefits on relapses and MRI activity in highly active relapsing disease but no benefit for established progressive multiple sclerosis.188 189 A randomized phase II study of intense immunosuppression followed by autologous stem cell transplantation found that it lowered MRI lesion accrual and relapse rate, but not disability, at four years compared with mitoxantrone.189 However, most data are from non-randomized, open label observational studies of relatively brief duration (most outcomes reported to two to three years) with high attrition rates.190 Moreover, effects of the transplanted stem cells are not distinguishable from effects of the conditioning regimen. Recurrence of inflammatory disease activity after three years occurs in some patients, showing that even aggressive immunosuppression is not curative for many.190 An uncontrolled study published in 2016 reported greater effects of an immunoablative approach for early aggressive multiple sclerosis with median follow-up of 6.7 years (and up to 13 years).191 None of the participants had a clinical relapse or new or enhancing MRI lesions, brain atrophy slowed, and 35% had sustained improvement in disability. However, one death occurred from hepatic necrosis and Klebsiella sepsis, and serious adverse events included febrile neutropenia (all participants), viral infections, and secondary autoimmunity. Autologous stem cell transplantation induction will need to prove superior to high efficacy DMTs to justify its morbidity and mortality risks, especially for patients not refractory to other approved treatments.
Disease modifying therapies, lifestyle modification, and comorbidities
Modification of risk factors for multiple sclerosis activity could enhance the benefits of DMTs. Although more data are needed, some RCTs or observational studies suggest that vitamin D3 supplementation, cessation of tobacco smoking, and modifying dietary salt are some potential opportunities.192 193 194 195 196 Furthermore, certain cardiovascular (ischemic heart disease, congestive heart failure), oncologic (meningiomas, urinary tract cancers), autoimmune (thyroid disease, inflammatory bowel disease, uveitis), and musculoskeletal (arthritis, fibromyalgia) disorders are more common than expected in multiple sclerosis cohorts.197 These comorbidities reduce quality of life and life expectancy, influence DMT selection, and increase disability.198 More research is needed to establish the benefits of management of comorbidities and potential interactions of these strategies with benefits of DMTs and on overall health.
Conclusions
The trend towards earlier treatment and the availability of powerful new therapies may prove beneficial for the long term health of patients, but more convincing data are needed. The hypothetical “window of treatment opportunity” could plausibly be extended to include preclinical RIS with the advent of valid diagnostic biomarkers. Similarly, biomarkers predictive of clinical outcomes (SPMS, disease severity) and therapeutic response could guide the personalized decision making process we outline and justify selection of highly efficacious but riskier DMTs early in the disease for selected patients. Prevention and cure remain elusive, but outcomes for people living with relapsing MS will likely be further improved by a combination of earlier diagnosis and implementation of DMTs, lifestyle modification, and management of comorbidities.
Guidelines
AAN guidelines on mitoxantrone and interferon beta neutralizing antibodies are based on high quality methods, but other AAN guidelines are outdated. Recent consensus papers from the Association of British Neurologists and the Multiple Sclerosis Coalition (eight US multiple sclerosis related organizations) do not report methods but contain key recommendations that are supported by high quality evidence. The UK National Institute for Health and Care Excellence (NICE) completed six technology appraisal guidelines of DMTs but no therapeutic guidelines
Glossary of abbreviations
AAN American Academy of Neurology
ARR annualized relapse rate
CIS clinically isolated syndrome
DMT disease modifying therapy
ECTRIMS European Committee for Treatment and Research in MS
EDSS Expanded Disability Status Scale
EMA European Medicines Agency
FDA US Food and Drug Administration
JCV John Cunningham virus
MRI magnetic resonance imaging
NEDA no evidence of disease activity
NNT number needed to treat
PML progressive multifocal leukoencephalopathy
PPMS primary progressive multiple sclerosis
RCT randomized controlled trials
RIS radiologically isolated syndrome
SPMS secondary progressive multiple sclerosis
Research questions
Can risk stratification profiles and/or biomarkers reliably predict long term disability for patients at the time of clinical presentation? Or pre-clinically?
Does early treatment of relapsing multiple sclerosis with highly effective DMTs reduce the risk of future progressive multiple sclerosis and long term disability? What is the magnitude of that effect?
Is achievement of NEDA predictive of less long term disability, and is integrating it into clinical practice feasible?
What are the key interactions between modifiable multiple sclerosis risk factors, comorbidities, and DMTs that optimize health outcomes for relapsing multiple sclerosis?
Patient involvement
We consulted a patient with relapsing multiple sclerosis who has used several therapies over nearly 20 years. She emphasized the importance of thorough and balanced discussions of the risks and benefits of disease modifying therapy, including communication of the limitations of knowledge gained from randomized controlled trials related to long term benefits on disability outcomes and progressive multiple sclerosis. We used this information to expand the discussion of the goals of disease modifying therapy and the section on personalized treatment selection strategies. She reviewed the final version of the manuscript
Footnotes
Contributors: DMW and BGW both designed, acquired data for, and drafted and revised the manuscript. Both authors approve of the final version to be published and agree to be accountable for all aspects of the work.
Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following interests: DMW receives research support from Alexion and TerumoBCT and personal compensation for consulting services provided to MedImmune for a neuromyelitis optica clinical trial adjudication panel; he has received personal compensation for consulting services from Chugai; BGW receives personal compensation for consulting services provided to MedImmune for a neuromyelitis optica clinical trial adjudication panel and for MS clinical trial DSMB membership from Novartis and Mitsubishi; he receives royalties from RSR Ltd and Oxford University for a patent on NMO-IgG as a diagnostic test for neuromyelitis optica and related disorders and has received personal compensation for consulting services from Elan, Chord Pharmaceuticals, GSK Pharmaceuticals, Ono Pharmaceuticals, and Chugai and MS clinical trial DSMB membership from Biogen.
Provenance and peer review: Commissioned; externally peer reviewed.