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Novel Immunomodulatory Approaches for the Management of Multiple Sclerosis OH Kantarci1, I Pirko1 and M Rodriguez2 We provide a focused review of novel immunomodulatory approaches for the treatment of multiple sclerosis, the most common acquired inflammatory demyelinating disease of humans. The requirement for such a review was stimulated by the emerging application of novel oral medications and the need for the practicing physician to place these within the treatment paradigm. We provide a conceptual diagram of our current view of the pathogenesis of demyelination and remyelination in this disorder. In addition, we include a working template on how to use a tier 1 and tier 2 approach to medications as the disease worsens in the individual. We emphasize the approach of treatment based on “individualized medicine,” tailored to the specific needs of each patient. In the future, we envision new drugs to enhance remyelination and protect neurons and axons from death in order to promote central nervous system regeneration and repair. Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, commonly affecting young people in their most productive years. It is the second leading cause of disability after trauma among young adults.1 MS is a heterogeneous disease from the standpoint of clinical symptoms, response to treatment, and radiological features, and even from the standpoint of neuropathology. Neuropathologically different phases of MS are characterized by interplay between different levels of inflammation–demyelination, remyelination, and axonal loss (Figure 1). Initially, a T-cell–mediated autoimmunity with the classic paradigm of a shift toward TH1/17 (“bad for MS”) vs. Th2 (“good for MS”) may be the inducing event. However, this early paradigm mainly derives from animals used in MS drug development and is unlikely to be universally applicable to MS. Pathology studies have suggested that MS is a heterogeneous disease, with four patterns of new lesion development, which is heterogeneous among individuals but homogeneous within any given individual and persists over time. The four patterns include T-cell–mediated mechanisms, antibody- and complement-mediated demyelination, distal oligodendrogliopathy and apoptosis, and primary oligodendrocyte degeneration.2 The clinical spectrum of MS likely reflects this pathological heterogeneity, in addition to other factors (such as lesion location and genetic predisposition to more vs. less efficient repair) leading to heterogeneous outcomes. MS typically extends from an asymptomatic phase, starting at an unknown age with an unknown duration, to clinically symptomatic phases (Figure 2). These phases
are known as radiologically isolated syndrome, clinically isolated syndrome (CIS), single-attack MS (SAMS), relapsing–remitting MS (RRMS), single-attack progressive MS (SAPMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS). Currently, no clinical trials have attempted to prevent the onset of symptomatic MS in otherwise asymptomatic individuals. Specifically, there is no evidence to suggest that treating patients with radiologically isolated syndrome prevents or delays progression to a symptomatic phase. However, we can presume that future trials in this area would be designed similarly to trials designed for the first clinical attack of MS-CIS. The only difference would be the outcome, that is, prevention or delay of the first clinical attack of MS rather than the second clinical event, as was the case in CIS trials. This review will focus on available and upcoming treatment modalities for three clinical phenomena of MS: relapses, pseudorelapses, and progressive disease course. Over the past few decades, a number of treatment modalities targeting several biological pathways presumably involved in MS have become available for preventing relapses or shortening a relapse course (Figure 1). Several of these presumed pathways are based on animal models of demyelination rather than actual proof of efficacy in MS. Some of the immunomodulatory–immunosuppressive treatment modalities in MS are also carryovers from other autoimmune disorders on the assumption that the majority of MS pathology is mediated via similar autoimmune mechanisms. Although the latter assumption is debatable, and the treatment modalities do not primarily target
1Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA. 2Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA. Correspondence: M Rodriguez ([email protected])
Received 9 August 2013; accepted 13 September 2013; advance online publication 20 November 2013. doi:10.1038/clpt.2013.196 Clinical pharmacology & Therapeutics
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Illustrated by Zina Deretsky, Dr. Katarci, Dr. Pirko, and Dr. Rodriguez
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Figure 1 Model of the immunopathogenesis of MS (it is not possible to show the time axis or provide definite proof for the time sequence of events in this paradigm). We show the interaction between the cellular and the humoral immune system components, the neurons, astrocytes, myelin, and medications. Blue arrows indicate a favorable immune effect. Red arrows indicate a detrimental immune effect. Green arrows leading from medications indicate a stimulatory effect by the medication. A truncated green line leading from the medication indicates an inhibitory effect. A black line indicates migration of a cell. The effector line dashed with a “?” indicates an unclear or unproven but intriguing action. The balance between inflammation demyelination, axonal injury, and remyelination is emphasized. This model utilizes knowledge gained through studies of the natural history of MS, animal and toxic models of MS, pathological samples obtained at various stages of disease progression, proposed mechanisms of action of current and upcoming disease-modifying medications, known failure of these medications in preventing or slowing down the purely progressive phase of MS, and, last, the vast genetic epidemiology studies indicating multiple pathways in MS. The mechanisms illustrated represent a combination of all major pathways involved in MS pathogenesis. Based on the known interindividual heterogeneity of MS, specific mechanisms predominate in an immunopattern-specific manner during new lesion formation. In addition, some mechanisms are tied to stages of MS (e.g., induction of MS, maintenance of MS, provocation of relapses, induction of progressive phase, and maintenance of progressive phase). A clear understanding of the phases of MS, as illustrated in Figure 2, will aid in choosing the best medications for different phases of MS. The text discusses effects of medications. Although many other effects are possible, the most likely ones are illustrated. Most of the medication effects occur outside the central nervous system, but some actions may affect the central nervous system. The neuroprotective effects suggested for some medications (BG12 and glatiramer acetate) are not proven. However, this area may yield future success in helping MS patients. B, B cells; CD4, CD4+ T cells; CD8, CD8+ T cells; Mo, macrophage; MS, multiple sclerosis; NK, natural killer cells; NO, nitric oxide; OG, oligodendrocytes; ROS, reactive oxygen species. All cytokines are labeled by their common immune nomenclature.
the neurodegenerative, progressive component of MS, these treatments have nevertheless proven successful in decreasing inflammation and preventing relapses. Selecting disease-modifying agents (DMAs) from the currently available array requires a tiered approach. To illustrate how 2
to incorporate developments of the past 20 years into clinical care, we present one possible approach, certainly not the only approach, to MS management. We would like to emphasize that flexibility and openness to change will alleviate patient and physician frustration as new options become available for MS www.nature.com/cpt
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Phases of multiple sclerosis - defined as of 2013 Dissemination in space† of lesions in MRI
Incidentally discovered white matter changes in an MRI suggestive of demyelinating disease*
Dissemination in time† of lesions in MRI OR positive CSF‡ No proven prophylactic treatment
RIS CIS
Clinical attack suggestive of inflammatorydemyelination**
SAMS
Previous RIS
Dissemination in space† of lesions by MRI, clinical examination or evoked potentials Dissemination in time† of lesions by MRI 2nd attack (propective or objective historical)
Insidious onset progressive neurological dysfunction of ≥1 year***
Acute treatment of relapses & Treatment for prevention of relapses (refer to following figures)
Previous RRMS
SPMS
Previous SAMS
SAPMS
Previous RIS
PPMS
RRMS Ongoing clinical relapses OR Evidence of new lesions typical of MS in follow-up MRIs
2 of 3 of the following: ≥1 T2 lesions in ≥1 of 3 brain areas (periventricular, juxtacortical, infratentorial) OR ≥2 T2 lesions in the spinal cord OR positive CSF‡
Figure 2 Different phases of MS ranging from asymptomatic to progressive disease. We utilize these diagnostic criteria, which we modified from the 2010 McDonald criteria for diagnosis of each phase of MS. *Incidental white matter changes in an MRI suggest demyelinating disease while presenting symptoms do not follow an appropriate time course of onset, stabilization, and recovery suggestive of demyelination. Symptoms may be subjective or explained by alternative diagnoses. **Clinical attack suggests inflammatory demyelination (appropriate time course of onset, stabilization, and recovery) in the absence of other explanation and objective lesion on examination, MRI, or visual evoked potential. ***Insidious onset progressive neurological dysfunction of ≥1 year (prospective or retrospective) suggests demyelination in the absence of other explanation, and objective lesion appears on examination, MRI, or evoked potentials in the area of the CNS indicated by symptoms. †For practical purposes, dissemination in space in MRI is defined as having: ≥1 T2 lesions in ≥2 of 4 areas in the CNS (periventricular, juxtacortical, infratentorial, and spinal cord); dissemination in time in MRI is defined as simultaneous presence of asymptomatic Gd+ and Gd– lesions or a new T2 lesion on follow-up. ‡Positive CSF is defined as isoelectric-focusing evidence of oligoclonal bands and/or elevated IgG index. CSF, cerebrospinal fluid; CIS, clinically isolated syndrome; CNS, central nervous system; IgG, immunoglobulin G; MRI, magnetic resonance imaging; MS, multiple sclerosis; PPMS, primary progressive MS; RIS, radiologically isolated syndrome; RRMS, relapsing-remitting MS; SAMS, single-attack MS; SAPMS, single-attack progressive MS; SPMS, secondary progressive MS.
treatment. There are many variations in MS practice that may not fit the presented model, and such an algorithmic approach should always be treated as a general guideline. Even in our own practice, we may deviate from the proposed “standardized” approach, as we believe that a fully individualized, patient-centered approach is the best in the management of chronic diseases such as MS. DEFINITION OF PHASES OF MS AS RELATED TO TREATMENT DECISIONS
A diagnosis of MS requires the dissemination in time and space of independent inflammatory-demyelinating attacks (asymptomatic or symptomatic). Asymptomatic attacks are diagnosed during clinical or paraclinical examinations by radiological examinations. In 2010, the McDonald criteria3 were revised to account for subclinical magnetic resonance imaging (MRI) activity, in addition to clinical activity, at the initial presentation.4 We have adapted and modified these criteria in our clinical practice (Figure 2). This is not an exact replica of the criteria, which were originally developed to guide uniformity in clinical trials, but rather an adaptation appropriate to our clinical practice. The contemporary diagnosis of MS has evolved significantly with multiple modifications to diagnostic criteria since 2005.4,5 The pre-2005 diagnostic criteria were based solely on Clinical pharmacology & Therapeutics
disseminated clinical relapses. The current diagnostic criteria include subclinical disease activity. Although most patients experience symptomatic disease at one point, some remain asymptomatic and are discovered to have MS during autopsy.6,7 When patients are discovered in an asymptomatic or preclinical phase of MS with lesion formation and without symptoms observed on MRI obtained for other reasons (e.g., migraines), this is known as radiologically isolated syndrome.8–10 Once the first symptom of MS appears, this clinical scenario is known as CIS. CIS evolves in an age-dependent fashion to either multiple symptomatic attacks, known as RRMS, or further new asymptomatic MRI activity, known as SAMS. We have introduced a new diagnostic category to separate the patients previously categorized as CIS but who, as defined by the most recent MS criteria,4 fulfill the radiological criteria for the diagnosis of MS. We call this group the SAMS group, as opposed to the RRMS group, per the criteria. The separation of SAMS from CIS and RRMS is significant from a treatment-application perspective. The primary outcome measure in earlier clinical trials in CIS was the development of a second clinical event or clinically definite MS by the Poser criteria.11,12 Of the patients enrolled in one of these studies, 72% fulfilled the radiological criteria for MS during enrollment, and 30% had enhancing lesions.13 Therefore, approximately one-third of these patients 3
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qualify as SAMS, whereas the others qualify as CIS.4 Given the high correlation between the effect size and higher lesion loads from the original CIS trials as discussed in detail further in this review, it is logical to suggest that the responders to diseasemodifying treatments in these trials had SAMS. It is unknown whether CIS, as defined by current MS criteria,4 would actually respond positively to MS drugs within the previous trial design paradigms. For most patients, a progressive disease course is characterized by an insidiously worsening neurological dysfunction (as opposed to discrete clinical attacks). When a progressive course follows RRMS, it is labeled as SPMS. If progression starts after a SAMS-type presentation, we label that as SAPMS.14 Some patients (~25%) will develop only one or a relatively few symptomatic attacks and not experience progression.14 Approximately 10% of patients will reach the typical age of progression without symptomatic attacks but then start to have symptomatic MS with progressive disease course at initiation, which is known as PPMS. Attacks can also continue during any of the progressive disease phases (PPMS, SAPMS, and SPMS) of MS.14 We discuss clinical definitions further in specific sections referring to treatment approaches to individual phases of MS. ACUTE TREATMENT OF RELAPSES IN MS
From a management perspective, we need to give top priority to treatment of relapses in MS (Figure 3). True symptomatic relapses (attacks, exacerbations) should be differentiated from pseudorelapses (pseudoattacks, pseudoexacerbations). Pseudorelapses are generally recurrences of existing symptoms, usually in the setting of infections or other causes of increased body temperature, fatigue, and stress unaccompanied by objective lesion development or new neurological examination findings. They typically last 3 relapses within 6 months, limited recovery, and multiple enhancing lesions (especially with early evolution into chronic T1 black holes). A wider definition of severe MS (i.e., fewer relapses) may be justified in the future if risk stratification in tier 2 medications can be done more precisely. MRI, magnetic resonance imaging; MS, multiple sclerosis.
Disability Status Scale scores upon entry may achieve better response.69 This is expected because the RRR will be easier to detect in these groups. Side effects of all interferon-β compounds are injectionsite reactions, flu-like symptoms (low-grade fever, myalgias, and headache; these lessen in frequency after a few months of treatment), mild liver-enzyme elevation, and lymphopenia. Depression and attempted suicide were more common among the treated patients. In our experience and per the previous studies, once-a-week i.m. interferon-β administrations tend to produce fewer side effects, but these tend to be more prolonged, particularly in the case of the flu-like side effects, than other interferon-β administrations. The patient’s lifestyle plays a significant role in the choice of individual interferon-β compounds. Glatiramer acetate
GA is a synthetic mixture of polypeptides produced by the random combinations of the four most common amino acids in myelin basic protein. Daily s.c. injection of GA leads to an RRR of 10%, an ARR of 7%, and an NNT of 14 over 2 years to Clinical pharmacology & Therapeutics
increase the relapse-free number by 1.70 Based on these numbers, GA is less efficacious than all interferon-β preparations. It is slower acting (≥6 months of use). However, it has several advantages.64,71,72 GA does not cause flu-like side effects. There is no need of blood monitoring, and it does not lead to the neutralizing antibodies that can plague interferon-β use (discussed later). Therefore, GA has found its place in the tier 1 medications (Figure 4). Natalizumab
Natalizumab is a humanized α-4 integrin antibody that inhibits the migration of all leukocytes (except for neutrophils) to target organs.73 A phase II study established that a 300 mg monthly dose of natalizumab reduced the number of gadolinium-enhancing lesions by 90% and the clinical relapse rate by over 50% as compared with placebo (RRR of 50%, ARR of 19%, and an NNT of 5 over 6 months to increase the proportion of relapse-free patients by 1).74 Subsequently, two phase III studies revealed very consistent results: AFFIRM (RRR of 49%, ARR of 23%, and an NNT of 4 over 1 year to increase the relapse-free proportion by 1) and 7
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Baseline JCV PCR (−)
Baseline JCV PCR (+) but no previous chronic immunosuppressants
Natalizumab
Baseline JCV PCR (+) AND previous chronic immunosuppressants Fingolimod as below
Fingolimod alone as below OR Natalizumab × 1 year (monitor brain MRI every 3 months) followed by Fingolimod as below
Monitor brain MRI & JCV PCR every 6 months
Mitoxantrone full dose within 2 years
Previously tolerated Tier 1 medication
Continued MS activity***
High cardiac risk patient at start
MRI follow-up† JCV PCR (+)
Fingolimod Natalizumab 3 relapses within 6 months, limited recovery, and multiple enhancing lesions (especially with early evolution into chronic T1 black holes). A wider definition of severe MS (i.e., fewer relapses) may be justified in the future if risk stratification in tier 2 medications can be done more precisely. ***We define continued MS activity practically as a relapse and ≥2 new MS-related lesion formations in the MRI within the last follow-up period or a patient with ≥3 new lesion formations per year, especially with gadolinium enhancement, even in the absence of any new relapse. We see this as a reason to change management strategy. †MRI (brain and cervical spinal cord) follow-up at 6 months, 12 months, 36 months, 60 months, and as needed thereafter (e.g., after management changes). MRI, magnetic resonance imaging; MS, multiple sclerosis.
SENTINEL (RRR of 31%, ARR of 17%, and an NNT of 6 over 1 year to increase the relapse-free proportion by 1). The proportion of patients without clinical and MRI activity was 46% in the natalizumab group and 14% in the placebo group. Based on these studies, natalizumab is clearly more effective than all the previously discussed tier 1 medications. However, due to the unfortunate incidence of PML among patients taking natalizumab, this very effective treatment has been relegated to second-line treatment as discussed later.75,76 The frequency of PML occurrence with natalizumab use is ~1 out of 1,000 in the early studies. Newer observations suggest that the risk is specific to patients with anti-JC virus (JCV) antibodies and a history of immunosuppressant use (e.g., azathioprine, methotrexate, mitoxantrone, and cyclophosphamide). With both of these factors present, the risk of PML may be as high as 11 out of 1,000, and the number is updated multiple times a year on the company site (http://www.tysabri.com/safetywith-tysabri.xml). The Stratify JCV Antibody test is available free 8
of charge to health-care providers, and we recommend testing for this antibody before treatment initiation. Patients with negative test results should be rechecked periodically (i.e., every 6–12 months) due to the estimated false-negative rate of 3% along with true conversion from seronegative to seropositive state. Symptoms of PML may be difficult to distinguish from MS symptoms solely on the basis of clinical evidence. Therefore, continued MRI monitoring (every 6 months) is also necessary. It is unclear at this time, however, if MRI monitoring for PML will still be necessary for patients who remain JCV antibody negative (Figure 5). Fingolimod
Fingolimod inhibits lymphocyte egress from secondary lymphoid tissues and the thymus by acting on the S1P1 receptor and is the first approved oral medication for RRMS. Fingolimod leads to an RRR of 50%, an ARR of 22%, and NNT of 4 over 2 years to increase the relapse-free proportion of by 1.77 These www.nature.com/cpt
state numbers suggest an efficacy closer to natalizumab and stronger than interferon-β compounds.78 Unfortunately, the side effects of fingolimod are substantial and include fatal infections (primary Varicella zoster and Herpes simplex encephalitis), bradycardia and atrioventricular block, hypertension, macular edema, skin cancer, and elevated liver-enzyme levels. Fingolimod is now contraindicated (the Food and Drug Administration advises against its use) in the following situations: (i) patients who experienced myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization or class III/IV heart failure in the previous 6 months; (ii) history or presence of Mobitz type II second-degree or thirddegree atrioventricular block or sick sinus syndrome, unless patient has a functioning pacemaker; (iii) baseline QTc interval ≥500 ms; and (iv) treatment with class Ia or class III antiarrhythmic drugs. In addition, we recommend an eye examination prior to treatment, along with assessment of varicella zoster virus serum status and vaccination to seronegative patients. Liverfunction test results should also be reviewed prior to treatment. Due to the significant side effects and lack of long-term safety data (as compared with established tier 1 medications), we offer fingolimod currently as a tier 2 medication choice (Figure 5). Mitoxantrone
Mitoxantrone is an anthracenedione chemotherapeutic agent mainly used in transforming MS phenotypes (relapsing MS to progressive MS), in which increased relapse activity is leading to stepwise irreversible disability in a short period of time.79 Administration of i.v. mitoxantrone every 3 months stabilizes or improves several clinical and functional outcome measures. The greatest concern regarding this medication is its dose-dependent cardiac toxicity, which leads to fatal congestive heart failure and limits the cumulative lifetime maximum dose to 140 mg/m2. We generally avoid exceeding a total lifetime dose of 96 mg/m2 (8 doses of 12 mg/m2). Patients receiving mitoxantrone should also be monitored every 3 months with echocardiograms or multigated acquisition (MUGA) scans to determine the ejection fraction. Reduction in the ejection fraction should prompt discontinuation of this therapy. Besides the cardiac side effects, mitoxantrone may cause menstrual irregularities or overall ablation of the menstrual cycle, which may be permanent. The incidence of mitoxantrone therapy–related acute leukemia in MS patients is ~0.05–0.1%.80 Although initially studied in SPMS, the benefit for patients with relapse-independent progression is uncertain. One would need to treat 11 patients with SPMS for 2 years to prevent 1 person from worsening by 1.0 Expanded Disability Status Scale point, a rather modest benefit for significant toxicity.79 We utilize mitoxantrone currently as an alternative to failed tier 2 medication in highly active individuals (Figure 5). Cyclophosphamide is applied in a way very similar to that for mitoxantrone as a tier 2 medication in our practice. AN EXAMPLE PROTOCOL FOR PREVENTION OF RELAPSES IN MS
We follow patients deemed likely to remain relapse free on the basis of the “benign” characteristics discussed earlier Clinical pharmacology & Therapeutics
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(Figures 4–5). In our practice, these patients generally fall into one of two categories: (i) patients with SAMS (per our definition) barely fulfilling 2010 McDonald Radiological Criteria for dissemination in time and space for MS and almost complete (≥85% by examination or history) recovery from the current inflammatory–demyelinating attack and (ii) RRMS patients not on any prophylactic treatment for MS, with significant intervals (≥5 years) between relapses, almost complete (≥85% by examination or history) recovery from individual relapses, and no significant interval subclinical (MRI) lesion accumulation. In select patients with severe-disease onset, we skip tier 1 medications and initiate induction treatment with one of the tier 2 medications (Figure 5). The definition of severe MS at onset is largely a judgment call by the treating MS specialist. We define severe-disease onset conservatively: >3 relapses within 6 months, limited recovery, and multiple enhancing lesions (especially with evolution into chronic T1 black holes early on). On the basis of our own practice, we would regard this definition as a guideline. A less conservative definition that requires fewer relapses to define severe MS may be justified in the future if risk stratification in tier 2 medications can be done more precisely. For all other patients, unless the patient requests otherwise, we initiate treatment with a tier 1 medication (Figure 4). Depending on side effects and utilizing risk-stratification strategies from existing evidence, we have generated an algorithm used in follow-up. However, this approach should be modified by the needs of individual patients, availability of medications, and future advances in pharmacotherapy for MS. The appearance of neutralizing autoantibodies (NAbs) in ~40% of patients after 3 years of interferon-β 1b treatment leads to failure of continued interferon-β treatment. NAbs can also cross-react with natural interferon-β to interfere with its function, and switching preparations does not change the pattern of antibody response.68 Although the long-term effects of NAbs are unknown, rushing to treatment with interferon-β in otherwise stable individuals may potentially impair the natural interferon response. This is a hypothetical consideration for delaying the initiation of any DMA or trying GA in patients with limited, nondisabling, early-disease activity (Figure 4). Also, NAbs occur only half as often with interferon-β 1a as with interferon-β 1b (~20% vs. 40%), which is another reason to prefer interferon-β 1a. In our practice, we test NAbs in patients with severe recurrences or unexpected increases in MRI activity in the setting of previous stability on interferons. If NAbs are positive, we consider switching to GA or stronger tier 2 medications in severe cases. If there are no NAbs (true failure of interferon-β), then we add monthly corticosteroids for a brief period and/or switch to tier 2 medications (Figure 5). The initiation of tier 2 medications (Figure 5) is guided by several principles: (i) natalizumab is a very effective and convenient (once monthly infusion) clinical and subclinical relapse- prevention strategy but is associated with PML risk; (ii) the risk of PML can be stratified by the presence of JCV antibody in serum testing, both at the beginning and throughout the course of treatment; (iii) chemotherapy use ahead of natalizumab increases the 9
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risk of PML; (iv) fingolimod carries the risk of significant cardiac and visual toxicity; and (v) mitoxantrone has significant cardiac and bone marrow toxicity with limited lifetime dose. In practice, we recommend natalizumab with active monitoring through the TOUCH program in the United States for patients who fail tier 1 medications, test negative for JCV, and have no history of chemotherapy exposure. If JCV tests subsequently turn positive, we offer to discontinue the medication but inform patients that the first 2 years of natalizumab treatment are relatively safe. At the 2-year time point, due to increased risk, we again offer patients the option to discontinue the medication. If patients remain negative for JCV, we recommend continuing medication. The current data indicate that
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Novel Immunomodulatory Approaches for the Management of Multiple Sclerosis OH Kantarci1, I Pirko1 and M Rodriguez2 We provide a focused review of novel immunomodulatory approaches for the treatment of multiple sclerosis, the most common acquired inflammatory demyelinating disease of humans. The requirement for such a review was stimulated by the emerging application of novel oral medications and the need for the practicing physician to place these within the treatment paradigm. We provide a conceptual diagram of our current view of the pathogenesis of demyelination and remyelination in this disorder. In addition, we include a working template on how to use a tier 1 and tier 2 approach to medications as the disease worsens in the individual. We emphasize the approach of treatment based on “individualized medicine,” tailored to the specific needs of each patient. In the future, we envision new drugs to enhance remyelination and protect neurons and axons from death in order to promote central nervous system regeneration and repair. Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, commonly affecting young people in their most productive years. It is the second leading cause of disability after trauma among young adults.1 MS is a heterogeneous disease from the standpoint of clinical symptoms, response to treatment, and radiological features, and even from the standpoint of neuropathology. Neuropathologically different phases of MS are characterized by interplay between different levels of inflammation–demyelination, remyelination, and axonal loss (Figure 1). Initially, a T-cell–mediated autoimmunity with the classic paradigm of a shift toward TH1/17 (“bad for MS”) vs. Th2 (“good for MS”) may be the inducing event. However, this early paradigm mainly derives from animals used in MS drug development and is unlikely to be universally applicable to MS. Pathology studies have suggested that MS is a heterogeneous disease, with four patterns of new lesion development, which is heterogeneous among individuals but homogeneous within any given individual and persists over time. The four patterns include T-cell–mediated mechanisms, antibody- and complement-mediated demyelination, distal oligodendrogliopathy and apoptosis, and primary oligodendrocyte degeneration.2 The clinical spectrum of MS likely reflects this pathological heterogeneity, in addition to other factors (such as lesion location and genetic predisposition to more vs. less efficient repair) leading to heterogeneous outcomes. MS typically extends from an asymptomatic phase, starting at an unknown age with an unknown duration, to clinically symptomatic phases (Figure 2). These phases
are known as radiologically isolated syndrome, clinically isolated syndrome (CIS), single-attack MS (SAMS), relapsing–remitting MS (RRMS), single-attack progressive MS (SAPMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS). Currently, no clinical trials have attempted to prevent the onset of symptomatic MS in otherwise asymptomatic individuals. Specifically, there is no evidence to suggest that treating patients with radiologically isolated syndrome prevents or delays progression to a symptomatic phase. However, we can presume that future trials in this area would be designed similarly to trials designed for the first clinical attack of MS-CIS. The only difference would be the outcome, that is, prevention or delay of the first clinical attack of MS rather than the second clinical event, as was the case in CIS trials. This review will focus on available and upcoming treatment modalities for three clinical phenomena of MS: relapses, pseudorelapses, and progressive disease course. Over the past few decades, a number of treatment modalities targeting several biological pathways presumably involved in MS have become available for preventing relapses or shortening a relapse course (Figure 1). Several of these presumed pathways are based on animal models of demyelination rather than actual proof of efficacy in MS. Some of the immunomodulatory–immunosuppressive treatment modalities in MS are also carryovers from other autoimmune disorders on the assumption that the majority of MS pathology is mediated via similar autoimmune mechanisms. Although the latter assumption is debatable, and the treatment modalities do not primarily target
1Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA. 2Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA. Correspondence: M Rodriguez ([email protected])
Received 9 August 2013; accepted 13 September 2013; advance online publication 20 November 2013. doi:10.1038/clpt.2013.196 Clinical pharmacology & Therapeutics
1
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Illustrated by Zina Deretsky, Dr. Katarci, Dr. Pirko, and Dr. Rodriguez
state
Figure 1 Model of the immunopathogenesis of MS (it is not possible to show the time axis or provide definite proof for the time sequence of events in this paradigm). We show the interaction between the cellular and the humoral immune system components, the neurons, astrocytes, myelin, and medications. Blue arrows indicate a favorable immune effect. Red arrows indicate a detrimental immune effect. Green arrows leading from medications indicate a stimulatory effect by the medication. A truncated green line leading from the medication indicates an inhibitory effect. A black line indicates migration of a cell. The effector line dashed with a “?” indicates an unclear or unproven but intriguing action. The balance between inflammation demyelination, axonal injury, and remyelination is emphasized. This model utilizes knowledge gained through studies of the natural history of MS, animal and toxic models of MS, pathological samples obtained at various stages of disease progression, proposed mechanisms of action of current and upcoming disease-modifying medications, known failure of these medications in preventing or slowing down the purely progressive phase of MS, and, last, the vast genetic epidemiology studies indicating multiple pathways in MS. The mechanisms illustrated represent a combination of all major pathways involved in MS pathogenesis. Based on the known interindividual heterogeneity of MS, specific mechanisms predominate in an immunopattern-specific manner during new lesion formation. In addition, some mechanisms are tied to stages of MS (e.g., induction of MS, maintenance of MS, provocation of relapses, induction of progressive phase, and maintenance of progressive phase). A clear understanding of the phases of MS, as illustrated in Figure 2, will aid in choosing the best medications for different phases of MS. The text discusses effects of medications. Although many other effects are possible, the most likely ones are illustrated. Most of the medication effects occur outside the central nervous system, but some actions may affect the central nervous system. The neuroprotective effects suggested for some medications (BG12 and glatiramer acetate) are not proven. However, this area may yield future success in helping MS patients. B, B cells; CD4, CD4+ T cells; CD8, CD8+ T cells; Mo, macrophage; MS, multiple sclerosis; NK, natural killer cells; NO, nitric oxide; OG, oligodendrocytes; ROS, reactive oxygen species. All cytokines are labeled by their common immune nomenclature.
the neurodegenerative, progressive component of MS, these treatments have nevertheless proven successful in decreasing inflammation and preventing relapses. Selecting disease-modifying agents (DMAs) from the currently available array requires a tiered approach. To illustrate how 2
to incorporate developments of the past 20 years into clinical care, we present one possible approach, certainly not the only approach, to MS management. We would like to emphasize that flexibility and openness to change will alleviate patient and physician frustration as new options become available for MS www.nature.com/cpt
state
art
Phases of multiple sclerosis - defined as of 2013 Dissemination in space† of lesions in MRI
Incidentally discovered white matter changes in an MRI suggestive of demyelinating disease*
Dissemination in time† of lesions in MRI OR positive CSF‡ No proven prophylactic treatment
RIS CIS
Clinical attack suggestive of inflammatorydemyelination**
SAMS
Previous RIS
Dissemination in space† of lesions by MRI, clinical examination or evoked potentials Dissemination in time† of lesions by MRI 2nd attack (propective or objective historical)
Insidious onset progressive neurological dysfunction of ≥1 year***
Acute treatment of relapses & Treatment for prevention of relapses (refer to following figures)
Previous RRMS
SPMS
Previous SAMS
SAPMS
Previous RIS
PPMS
RRMS Ongoing clinical relapses OR Evidence of new lesions typical of MS in follow-up MRIs
2 of 3 of the following: ≥1 T2 lesions in ≥1 of 3 brain areas (periventricular, juxtacortical, infratentorial) OR ≥2 T2 lesions in the spinal cord OR positive CSF‡
Figure 2 Different phases of MS ranging from asymptomatic to progressive disease. We utilize these diagnostic criteria, which we modified from the 2010 McDonald criteria for diagnosis of each phase of MS. *Incidental white matter changes in an MRI suggest demyelinating disease while presenting symptoms do not follow an appropriate time course of onset, stabilization, and recovery suggestive of demyelination. Symptoms may be subjective or explained by alternative diagnoses. **Clinical attack suggests inflammatory demyelination (appropriate time course of onset, stabilization, and recovery) in the absence of other explanation and objective lesion on examination, MRI, or visual evoked potential. ***Insidious onset progressive neurological dysfunction of ≥1 year (prospective or retrospective) suggests demyelination in the absence of other explanation, and objective lesion appears on examination, MRI, or evoked potentials in the area of the CNS indicated by symptoms. †For practical purposes, dissemination in space in MRI is defined as having: ≥1 T2 lesions in ≥2 of 4 areas in the CNS (periventricular, juxtacortical, infratentorial, and spinal cord); dissemination in time in MRI is defined as simultaneous presence of asymptomatic Gd+ and Gd– lesions or a new T2 lesion on follow-up. ‡Positive CSF is defined as isoelectric-focusing evidence of oligoclonal bands and/or elevated IgG index. CSF, cerebrospinal fluid; CIS, clinically isolated syndrome; CNS, central nervous system; IgG, immunoglobulin G; MRI, magnetic resonance imaging; MS, multiple sclerosis; PPMS, primary progressive MS; RIS, radiologically isolated syndrome; RRMS, relapsing-remitting MS; SAMS, single-attack MS; SAPMS, single-attack progressive MS; SPMS, secondary progressive MS.
treatment. There are many variations in MS practice that may not fit the presented model, and such an algorithmic approach should always be treated as a general guideline. Even in our own practice, we may deviate from the proposed “standardized” approach, as we believe that a fully individualized, patient-centered approach is the best in the management of chronic diseases such as MS. DEFINITION OF PHASES OF MS AS RELATED TO TREATMENT DECISIONS
A diagnosis of MS requires the dissemination in time and space of independent inflammatory-demyelinating attacks (asymptomatic or symptomatic). Asymptomatic attacks are diagnosed during clinical or paraclinical examinations by radiological examinations. In 2010, the McDonald criteria3 were revised to account for subclinical magnetic resonance imaging (MRI) activity, in addition to clinical activity, at the initial presentation.4 We have adapted and modified these criteria in our clinical practice (Figure 2). This is not an exact replica of the criteria, which were originally developed to guide uniformity in clinical trials, but rather an adaptation appropriate to our clinical practice. The contemporary diagnosis of MS has evolved significantly with multiple modifications to diagnostic criteria since 2005.4,5 The pre-2005 diagnostic criteria were based solely on Clinical pharmacology & Therapeutics
disseminated clinical relapses. The current diagnostic criteria include subclinical disease activity. Although most patients experience symptomatic disease at one point, some remain asymptomatic and are discovered to have MS during autopsy.6,7 When patients are discovered in an asymptomatic or preclinical phase of MS with lesion formation and without symptoms observed on MRI obtained for other reasons (e.g., migraines), this is known as radiologically isolated syndrome.8–10 Once the first symptom of MS appears, this clinical scenario is known as CIS. CIS evolves in an age-dependent fashion to either multiple symptomatic attacks, known as RRMS, or further new asymptomatic MRI activity, known as SAMS. We have introduced a new diagnostic category to separate the patients previously categorized as CIS but who, as defined by the most recent MS criteria,4 fulfill the radiological criteria for the diagnosis of MS. We call this group the SAMS group, as opposed to the RRMS group, per the criteria. The separation of SAMS from CIS and RRMS is significant from a treatment-application perspective. The primary outcome measure in earlier clinical trials in CIS was the development of a second clinical event or clinically definite MS by the Poser criteria.11,12 Of the patients enrolled in one of these studies, 72% fulfilled the radiological criteria for MS during enrollment, and 30% had enhancing lesions.13 Therefore, approximately one-third of these patients 3
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qualify as SAMS, whereas the others qualify as CIS.4 Given the high correlation between the effect size and higher lesion loads from the original CIS trials as discussed in detail further in this review, it is logical to suggest that the responders to diseasemodifying treatments in these trials had SAMS. It is unknown whether CIS, as defined by current MS criteria,4 would actually respond positively to MS drugs within the previous trial design paradigms. For most patients, a progressive disease course is characterized by an insidiously worsening neurological dysfunction (as opposed to discrete clinical attacks). When a progressive course follows RRMS, it is labeled as SPMS. If progression starts after a SAMS-type presentation, we label that as SAPMS.14 Some patients (~25%) will develop only one or a relatively few symptomatic attacks and not experience progression.14 Approximately 10% of patients will reach the typical age of progression without symptomatic attacks but then start to have symptomatic MS with progressive disease course at initiation, which is known as PPMS. Attacks can also continue during any of the progressive disease phases (PPMS, SAPMS, and SPMS) of MS.14 We discuss clinical definitions further in specific sections referring to treatment approaches to individual phases of MS. ACUTE TREATMENT OF RELAPSES IN MS
From a management perspective, we need to give top priority to treatment of relapses in MS (Figure 3). True symptomatic relapses (attacks, exacerbations) should be differentiated from pseudorelapses (pseudoattacks, pseudoexacerbations). Pseudorelapses are generally recurrences of existing symptoms, usually in the setting of infections or other causes of increased body temperature, fatigue, and stress unaccompanied by objective lesion development or new neurological examination findings. They typically last 3 relapses within 6 months, limited recovery, and multiple enhancing lesions (especially with early evolution into chronic T1 black holes). A wider definition of severe MS (i.e., fewer relapses) may be justified in the future if risk stratification in tier 2 medications can be done more precisely. MRI, magnetic resonance imaging; MS, multiple sclerosis.
Disability Status Scale scores upon entry may achieve better response.69 This is expected because the RRR will be easier to detect in these groups. Side effects of all interferon-β compounds are injectionsite reactions, flu-like symptoms (low-grade fever, myalgias, and headache; these lessen in frequency after a few months of treatment), mild liver-enzyme elevation, and lymphopenia. Depression and attempted suicide were more common among the treated patients. In our experience and per the previous studies, once-a-week i.m. interferon-β administrations tend to produce fewer side effects, but these tend to be more prolonged, particularly in the case of the flu-like side effects, than other interferon-β administrations. The patient’s lifestyle plays a significant role in the choice of individual interferon-β compounds. Glatiramer acetate
GA is a synthetic mixture of polypeptides produced by the random combinations of the four most common amino acids in myelin basic protein. Daily s.c. injection of GA leads to an RRR of 10%, an ARR of 7%, and an NNT of 14 over 2 years to Clinical pharmacology & Therapeutics
increase the relapse-free number by 1.70 Based on these numbers, GA is less efficacious than all interferon-β preparations. It is slower acting (≥6 months of use). However, it has several advantages.64,71,72 GA does not cause flu-like side effects. There is no need of blood monitoring, and it does not lead to the neutralizing antibodies that can plague interferon-β use (discussed later). Therefore, GA has found its place in the tier 1 medications (Figure 4). Natalizumab
Natalizumab is a humanized α-4 integrin antibody that inhibits the migration of all leukocytes (except for neutrophils) to target organs.73 A phase II study established that a 300 mg monthly dose of natalizumab reduced the number of gadolinium-enhancing lesions by 90% and the clinical relapse rate by over 50% as compared with placebo (RRR of 50%, ARR of 19%, and an NNT of 5 over 6 months to increase the proportion of relapse-free patients by 1).74 Subsequently, two phase III studies revealed very consistent results: AFFIRM (RRR of 49%, ARR of 23%, and an NNT of 4 over 1 year to increase the relapse-free proportion by 1) and 7
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Baseline JCV PCR (−)
Baseline JCV PCR (+) but no previous chronic immunosuppressants
Natalizumab
Baseline JCV PCR (+) AND previous chronic immunosuppressants Fingolimod as below
Fingolimod alone as below OR Natalizumab × 1 year (monitor brain MRI every 3 months) followed by Fingolimod as below
Monitor brain MRI & JCV PCR every 6 months
Mitoxantrone full dose within 2 years
Previously tolerated Tier 1 medication
Continued MS activity***
High cardiac risk patient at start
MRI follow-up† JCV PCR (+)
Fingolimod Natalizumab 3 relapses within 6 months, limited recovery, and multiple enhancing lesions (especially with early evolution into chronic T1 black holes). A wider definition of severe MS (i.e., fewer relapses) may be justified in the future if risk stratification in tier 2 medications can be done more precisely. ***We define continued MS activity practically as a relapse and ≥2 new MS-related lesion formations in the MRI within the last follow-up period or a patient with ≥3 new lesion formations per year, especially with gadolinium enhancement, even in the absence of any new relapse. We see this as a reason to change management strategy. †MRI (brain and cervical spinal cord) follow-up at 6 months, 12 months, 36 months, 60 months, and as needed thereafter (e.g., after management changes). MRI, magnetic resonance imaging; MS, multiple sclerosis.
SENTINEL (RRR of 31%, ARR of 17%, and an NNT of 6 over 1 year to increase the relapse-free proportion by 1). The proportion of patients without clinical and MRI activity was 46% in the natalizumab group and 14% in the placebo group. Based on these studies, natalizumab is clearly more effective than all the previously discussed tier 1 medications. However, due to the unfortunate incidence of PML among patients taking natalizumab, this very effective treatment has been relegated to second-line treatment as discussed later.75,76 The frequency of PML occurrence with natalizumab use is ~1 out of 1,000 in the early studies. Newer observations suggest that the risk is specific to patients with anti-JC virus (JCV) antibodies and a history of immunosuppressant use (e.g., azathioprine, methotrexate, mitoxantrone, and cyclophosphamide). With both of these factors present, the risk of PML may be as high as 11 out of 1,000, and the number is updated multiple times a year on the company site (http://www.tysabri.com/safetywith-tysabri.xml). The Stratify JCV Antibody test is available free 8
of charge to health-care providers, and we recommend testing for this antibody before treatment initiation. Patients with negative test results should be rechecked periodically (i.e., every 6–12 months) due to the estimated false-negative rate of 3% along with true conversion from seronegative to seropositive state. Symptoms of PML may be difficult to distinguish from MS symptoms solely on the basis of clinical evidence. Therefore, continued MRI monitoring (every 6 months) is also necessary. It is unclear at this time, however, if MRI monitoring for PML will still be necessary for patients who remain JCV antibody negative (Figure 5). Fingolimod
Fingolimod inhibits lymphocyte egress from secondary lymphoid tissues and the thymus by acting on the S1P1 receptor and is the first approved oral medication for RRMS. Fingolimod leads to an RRR of 50%, an ARR of 22%, and NNT of 4 over 2 years to increase the relapse-free proportion of by 1.77 These www.nature.com/cpt
state numbers suggest an efficacy closer to natalizumab and stronger than interferon-β compounds.78 Unfortunately, the side effects of fingolimod are substantial and include fatal infections (primary Varicella zoster and Herpes simplex encephalitis), bradycardia and atrioventricular block, hypertension, macular edema, skin cancer, and elevated liver-enzyme levels. Fingolimod is now contraindicated (the Food and Drug Administration advises against its use) in the following situations: (i) patients who experienced myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization or class III/IV heart failure in the previous 6 months; (ii) history or presence of Mobitz type II second-degree or thirddegree atrioventricular block or sick sinus syndrome, unless patient has a functioning pacemaker; (iii) baseline QTc interval ≥500 ms; and (iv) treatment with class Ia or class III antiarrhythmic drugs. In addition, we recommend an eye examination prior to treatment, along with assessment of varicella zoster virus serum status and vaccination to seronegative patients. Liverfunction test results should also be reviewed prior to treatment. Due to the significant side effects and lack of long-term safety data (as compared with established tier 1 medications), we offer fingolimod currently as a tier 2 medication choice (Figure 5). Mitoxantrone
Mitoxantrone is an anthracenedione chemotherapeutic agent mainly used in transforming MS phenotypes (relapsing MS to progressive MS), in which increased relapse activity is leading to stepwise irreversible disability in a short period of time.79 Administration of i.v. mitoxantrone every 3 months stabilizes or improves several clinical and functional outcome measures. The greatest concern regarding this medication is its dose-dependent cardiac toxicity, which leads to fatal congestive heart failure and limits the cumulative lifetime maximum dose to 140 mg/m2. We generally avoid exceeding a total lifetime dose of 96 mg/m2 (8 doses of 12 mg/m2). Patients receiving mitoxantrone should also be monitored every 3 months with echocardiograms or multigated acquisition (MUGA) scans to determine the ejection fraction. Reduction in the ejection fraction should prompt discontinuation of this therapy. Besides the cardiac side effects, mitoxantrone may cause menstrual irregularities or overall ablation of the menstrual cycle, which may be permanent. The incidence of mitoxantrone therapy–related acute leukemia in MS patients is ~0.05–0.1%.80 Although initially studied in SPMS, the benefit for patients with relapse-independent progression is uncertain. One would need to treat 11 patients with SPMS for 2 years to prevent 1 person from worsening by 1.0 Expanded Disability Status Scale point, a rather modest benefit for significant toxicity.79 We utilize mitoxantrone currently as an alternative to failed tier 2 medication in highly active individuals (Figure 5). Cyclophosphamide is applied in a way very similar to that for mitoxantrone as a tier 2 medication in our practice. AN EXAMPLE PROTOCOL FOR PREVENTION OF RELAPSES IN MS
We follow patients deemed likely to remain relapse free on the basis of the “benign” characteristics discussed earlier Clinical pharmacology & Therapeutics
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(Figures 4–5). In our practice, these patients generally fall into one of two categories: (i) patients with SAMS (per our definition) barely fulfilling 2010 McDonald Radiological Criteria for dissemination in time and space for MS and almost complete (≥85% by examination or history) recovery from the current inflammatory–demyelinating attack and (ii) RRMS patients not on any prophylactic treatment for MS, with significant intervals (≥5 years) between relapses, almost complete (≥85% by examination or history) recovery from individual relapses, and no significant interval subclinical (MRI) lesion accumulation. In select patients with severe-disease onset, we skip tier 1 medications and initiate induction treatment with one of the tier 2 medications (Figure 5). The definition of severe MS at onset is largely a judgment call by the treating MS specialist. We define severe-disease onset conservatively: >3 relapses within 6 months, limited recovery, and multiple enhancing lesions (especially with evolution into chronic T1 black holes early on). On the basis of our own practice, we would regard this definition as a guideline. A less conservative definition that requires fewer relapses to define severe MS may be justified in the future if risk stratification in tier 2 medications can be done more precisely. For all other patients, unless the patient requests otherwise, we initiate treatment with a tier 1 medication (Figure 4). Depending on side effects and utilizing risk-stratification strategies from existing evidence, we have generated an algorithm used in follow-up. However, this approach should be modified by the needs of individual patients, availability of medications, and future advances in pharmacotherapy for MS. The appearance of neutralizing autoantibodies (NAbs) in ~40% of patients after 3 years of interferon-β 1b treatment leads to failure of continued interferon-β treatment. NAbs can also cross-react with natural interferon-β to interfere with its function, and switching preparations does not change the pattern of antibody response.68 Although the long-term effects of NAbs are unknown, rushing to treatment with interferon-β in otherwise stable individuals may potentially impair the natural interferon response. This is a hypothetical consideration for delaying the initiation of any DMA or trying GA in patients with limited, nondisabling, early-disease activity (Figure 4). Also, NAbs occur only half as often with interferon-β 1a as with interferon-β 1b (~20% vs. 40%), which is another reason to prefer interferon-β 1a. In our practice, we test NAbs in patients with severe recurrences or unexpected increases in MRI activity in the setting of previous stability on interferons. If NAbs are positive, we consider switching to GA or stronger tier 2 medications in severe cases. If there are no NAbs (true failure of interferon-β), then we add monthly corticosteroids for a brief period and/or switch to tier 2 medications (Figure 5). The initiation of tier 2 medications (Figure 5) is guided by several principles: (i) natalizumab is a very effective and convenient (once monthly infusion) clinical and subclinical relapse- prevention strategy but is associated with PML risk; (ii) the risk of PML can be stratified by the presence of JCV antibody in serum testing, both at the beginning and throughout the course of treatment; (iii) chemotherapy use ahead of natalizumab increases the 9
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risk of PML; (iv) fingolimod carries the risk of significant cardiac and visual toxicity; and (v) mitoxantrone has significant cardiac and bone marrow toxicity with limited lifetime dose. In practice, we recommend natalizumab with active monitoring through the TOUCH program in the United States for patients who fail tier 1 medications, test negative for JCV, and have no history of chemotherapy exposure. If JCV tests subsequently turn positive, we offer to discontinue the medication but inform patients that the first 2 years of natalizumab treatment are relatively safe. At the 2-year time point, due to increased risk, we again offer patients the option to discontinue the medication. If patients remain negative for JCV, we recommend continuing medication. The current data indicate that
