Neurology® Clinical Practice
Multiple sclerosis
Podcast
Five new things Jacqueline A. Nicholas, MD, MPH Aaron L. Boster, MD Michael K. Racke, MD
Summary Preliminary studies have suggested that a high salt diet may play a role in the development of autoimmune disease and possibly multiple sclerosis (MS). Promising clinical trial results for 2 new therapies for MS have been reported. Dimethyl fumarate, also known by its investigational name BG-12, became the third oral disease-modifying therapy for MS to be Food and Drug Administration (FDA)–approved in March 2013. Interestingly, dimethyl fumarate served as the active compound used for the treatment of psoriasis for decades. Alemtuzumab remains under investigation and is not currently FDA-approved for treatment of MS. Other drugs currently approved for alternative indications are being investigated for use in MS. Additionally, an investigation of alternative dosing strategies for glatiramer acetate suggests that patients may benefit from a higher dose formulation and less frequent medication administration. Advances in basic science research have identified another potential autoantigenic target in MS, KIR4.1, which may provide further insight into MS pathophysiology.
M
ultiple sclerosis (MS) is an autoimmune, demyelinating disease of the CNS that can lead to neurologic disability. Well-known environmental risk factors for MS include smoking, low vitamin D, and Epstein-Barr virus infection. The search for additional environmental risk factors continues and a high salt diet has recently been implicated.1,2 Goals of diseasemodifying therapies (DMTs) are to reduce the risk of relapse, reduce the development of new MRI lesions, and slow disease progression. Here, we discuss new therapies (one Food and Drug Administration [FDA]–approved and others under continued investigation) along with The Ohio State University Department of Neurology, Columbus. Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp. Correspondence to: [email protected] 404
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Even though a direct link between salt and MS has not been demonstrated, a high salt diet may be the reason for the increased incidence of MS in recent decades. an alternate dosing study of a new formulation of glatiramer acetate (GA) for the management of relapsing-remitting MS (RRMS). We revisit lessons learned from recycling old drugs and reformulating such drugs for potential use in MS. Finally, KIR4.1 is a newly discovered potential autoantigenic target in MS.
Is a high salt diet a risk factor for multiple sclerosis? Recent studies have suggested that increased salt intake may be involved in provoking onset of autoimmune disease.1,2 Even though a direct link between salt and MS has not been demonstrated, a high salt diet may be the reason for the increased incidence of MS in recent decades. Kleinewietfeld et al.2 demonstrated that elevated sodium chloride concentrations in vivo increase T helper 17 (Th17) cells in human and mouse models. Their study also showed that highly pathogenic Th17 cells were produced under these conditions. Finally, mice fed a diet high in salt developed a more severe form of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Th17 cells are proinflammatory and a shift toward this response has been implicated in many autoimmune diseases including MS. Interleukin-23 (IL-23) enhances the Th17 response by signaling through the IL-23 receptor (IL-23R). Wu and colleges1 studied serum glucocorticoid kinase 1 (SGK1) and identified it as playing a key role following IL-23 signaling. This study demonstrated both in vitro and in vivo that SGK1 expression is induced by increased salt concentration resulting in enhanced IL-23R expression, thus promoting Th17 cell differentiation.1 Conversely, loss of SGK1 demonstrated that salt had no effect on Th17 differentiation via IL-23. This suggests a possible mechanism by which salt may potentiate autoimmunity. Further studies are needed to determine if high salt diet is involved in worsening of MS, but if proven, clinicians may begin to counsel patients on the importance of a low salt diet for reasons other than cardiovascular disease.
Alemtuzumab Alemtuzumab is a humanized anti-CD52 monoclonal antibody that rapidly depletes monocytes and B and T cells via antibody-dependent cellular toxicity (figure 1).3 The effects of treatment on the immune system are prolonged. Immune cell reconstitution with return to levels at the lower limit of normal range for monocytes and B cells occurs at 3 months, CD81 T cells around 30 months, and CD41 T cells at approximately 61 months.4 Interestingly, many patients’ lymphocyte counts do not repopulate to previous baseline total lymphocyte counts. In one study, only 39% of patients recovered to baseline total lymphocyte counts, with a median recovery time of 12.6 months.4 Alemtuzumab is FDA-approved for the treatment of leukemia, but has been used off-label in aggressive forms of MS. In MS clinical trials, alemtuzumab has been administered IV for 5 days followed by annual infusions for 3 days (optimal dose under investigation). Pivotal trials The initial phase III trial, CARE-MS I, was a 2-year randomized, rater-blinded, doubledummy active-comparator trial studying the efficacy and safety of annual alemtuzumab (12 mg IV administered daily for 5 days during the first year and for 3 days in year 2) vs subcutaneous interferon (IFN)-b-1a 44 mcg 3 times weekly in treatment-naive patients with
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Figure 1
Proposed mechanisms of action of highlighted multiple sclerosis therapies
(A) Alemtuzumab is a humanized anti-CD52 monoclonal antibody that rapidly depletes B and T cells via antibody dependent cellular toxicity. (B) Rituximab, ocrelizumab, and ofatumumab are all monoclonal antibodies that target CD20 on B cells leading to B-cell depletion. Rituximab is chimeric, while ocrelizumab and ofatumumab are humanized. (C) Dimethyl fumarate (DMF) acts through the Nrf-2 pathway resulting in cytoprotection, decreased oxidative stress, and reduced neuroinflammation through promotion of Th2 pathways. DMF inhibits dendritic cell maturation by decreasing interleukin (IL)-12 and IL-6. This results in decreased cytokine production of IL-17 and interferon (IFN)-g leading to a decreased Th1 and Th17 differentiation. (D) Glatiramer acetate (GA) is a polymer of glutamic acid, lysine, alanine, and tyrosine that may modify antigen-presenting cells to promote anti-inflammatory T-cell pathways with generation of CD41 T-regulatory cells, suppressor T-cell generation, and induction of immune tolerance.
active RRMS. There was a 55% reduction in absolute risk reduction (ARR), the study’s primary outcome, in the alemtuzumab arm as compared to IFN-b-1a (p , 0.0001).5 The trial failed to meet the second coprimary endpoint of time to 6-month sustained accumulation of disability (SAD). A total of 11% (n 5 20) of patients in the IFN-b-1a arm vs 8% (n 5 30) in the alemtuzumab arm experienced SAD (p 5 0.22). There was a reduction in the percent of patients with new or enlarging T2 lesions, gadolinium-enhancing lesions, and a 40% reduction in brain volume loss on MRI (p , 0.0001) as compared to IFN-b-1a. CARE-MS II, the second phase III trial, utilized the same design as CARE-MS I except enrolled patients had to have failed a prior MS DMT, defined as at least one relapse on therapy. This trial met both of its primary coendpoints with a 49% relapse rate reduction compared to IFN-b-1a–treated patients (p , 0.0001) and a 42% reduction in 6-month SAD favoring the alemtuzumab arm (p 5 0.0084).6 There was a reduction in the number of patients with new or enlarging T2 lesions (46% alemtuzumab vs 68% IFN; p , 0.0001), gadolinium-enhancing lesions (9% alemtuzumab vs 23% IFN; p , 0.0001), and brain volume loss (20.615% alemtuzumab vs 20.810% IFN; p 5 0.01) in the alemtuzumab arm as compared to IFN-b-1a.
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Safety Common alemtuzumab side effects include infusion reactions (headache, rash, and fever), mild to moderate infections (upper respiratory, urinary tract, and herpetic), and autoimmune thyroid disease (16%–18%). Infusion reactions declined with the second treatment course and were largely controlled by pretreatment with corticosteroids. The risk of herpetic infections was reduced in the clinical trials with acyclovir prophylaxis.5 Other autoimmune diseases associated with alemtuzumab use include a few cases of Goodpasture disease and idiopathic thrombocytopenic purpura (ITP).3 ITP is the most serious autoimmune disease associated with alemtuzumab and the index patient died from ITP in the early phase II trial CAMMS223 when early warning signs went unreported.3 A risk management program is now in place to monitor patients on alemtuzumab for early signs of ITP. Acquired autoimmunity from alemtuzumab can develop up to 5 years after treatment and therefore, continued clinical vigilance is required.3 Recycling available drugs for the treatment of MS Dimethyl fumarate (DMF), investigational name BG-12, is the most recent oral drug to be FDA-approved for relapsing forms of MS (figure 1). It serves as a prime example of a reformulated drug used for decades in the treatment of another autoimmune disease, psoriasis, which has demonstrated efficacy in MS. DEFINE, a phase III, 2-year, randomized, double-blind, placebo-controlled trial studying the efficacy and safety of oral BG-12 240 mg twice or thrice daily as compared to placebo in RRMS, demonstrated an approximate 50% risk reduction for an MS relapse in both treatment arms (ARR: 0.19 TID, 0.17 BID, 0.36 placebo; p , 0.001 for both comparisons), sustained 3-month progression of disability was reduced by 34%–38% for both treatment arms as compared to placebo (hazard ratio [HR] 0.62, p 5 0.005 twice daily, HR 0.66, p 5 0.01 thrice daily), and the number of new or enlarging T2 lesions on brain MRI at 2 years was reduced by 85% for twice daily BG-12 and 74% for thrice daily BG-12.7 CONFIRM, a phase III, 2-year, randomized, double-blind, placebocontrolled trial studying the efficacy and safety of oral BG-12 240 mg twice or thrice daily as compared to placebo that included an open-label reference arm with GA, demonstrated a significant reduction in ARR as compared to placebo (44% [ARR 5 0.22] twice daily, 51% [ARR 5 0.20] thrice daily, ARR 5 0.40 placebo; p , 0.001 for both comparisons; 29% [ARR 5 0.29] GA vs placebo [p 5 0.01]).8 Common adverse events associated with BG-12 include gastrointestinal events (nausea, diarrhea, bloating) in 10%–15%, flushing (erythema, pruritus, rash) in 31%–38%, most frequently during the first month on treatment, and 10%–30% drop in lymphocyte counts. No malignancies or opportunistic infections have been reported with BG-12.7,8 Since 1959, fumaric acid esters (FAEs) have been used for the treatment of psoriasis.9 In 1994, Fumaderm, a combination of DMF and monomethyl fumarate, was approved in Germany for the treatment of moderate to severe psoriasis.9 FAEs shift the proinflammatory Th1 cellular response to a less inflammatory Th2 response.10 The exact mechanism of DMF in vivo in MS has not been fully elucidated, but several in vitro studies have suggested the following mechanisms. Treatment with DMF results in a reduction in CD41 T cells, which produce IFN-g in patients with MS.11 Dimethyl fumarate is believed to exert its effects through the nuclear factor (erythroid derived 2)–like 2 transcriptional pathway (Nrf2), resulting in cytoprotection, decreased oxidative stress, and reduced neuro-inflammation (figure 1).12 Additionally, DMF inhibits dendritic cell maturation by decreasing production of IL-12 and IL-6, leading to reduced Th1 and Th17 cell differentiation.11,13 In dendritic cell and T cell coculture, DMF causes decreased production of IFN-g and IL-17, resulting in decreased Th1 and Th17 cell differentiation.11 Furthermore, suppression of extracellular signal-related kinase 1 and 2 (ERK1/2) by DMF results in reduced nuclear factor-ΚB signaling.11 Lessons learned Dimethyl fumarate was not the first drug used for an alternate indication that was later proven beneficial for the treatment of MS. Rituximab, a chimeric monoclonal antibody that targets
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Not every recycled drug shown to be efficacious in one autoimmune disease can be translated for use in another, even when common immunologic mechanisms are shared. CD20, predominantly on B cells, causes B-cell depletion. It is approved for use in non-Hodgkin lymphoma, rheumatoid arthritis refractory to tumor necrosis factor antagonists, and CD201 chronic lymphocytic leukemia (CLL). HERMES, a phase II, double-blind, 48-week trial comparing rituximab 1,000 mg IV on days 1 and 15 compared to placebo in patients with RRMS, demonstrated a reduction in new and total gadolinium-enhancing lesions (p . 0.001) and reduction in relapses at weeks 24 (p 5 0.02) and 48 (p 5 0.04) in favor of rituximab.14 The US patent for rituximab expires in 2016 and currently, phase III trials are not planned. This drug is unlikely to obtain approval for use in MS, although it is used off-label for this purpose. Analogues of rituximab, ocrelizumab, and ofatumumab are currently being studied for use in MS (figure 1). Like rituximab, ocrelizumab targets CD20 on B cells, but in contrast, it is a recombinant, humanized IgG1 monoclonal antibody expected to cause less infusion reactions as its humanized form may be less immunogenic. The phase II study of ocrelizumab in RRMS at high and low dose as compared to placebo and IFN-b-1a IM once weekly demonstrated 89%–95% relative risk reductions in total gadolinium-enhancing lesions on MRI at weeks 12 and 24.15 The phase II trial success led to phase III clinical trials currently under way to study the use of ocrelizumab for the treatment of RRMS and PPMS. Ofatumumab is a fully human recombinant anti-CD-20 monoclonal antibody that has been FDA-approved since 2009 for fludarabine- and alemtuzumabresistant CLL.16 A phase II study in RRMS did not raise safety concerns and demonstrated beneficial effects on MRI outcomes including reductions in new or enlarging T2 lesions, new gadolinium-enhancing, and total gadolinium-enhancing lesions.16 Clinicians and scientists who treat and study autoimmune diseases are frequently reminded of the complexity of autoimmune pathophysiology. Not every recycled drug shown to be efficacious in one autoimmune disease can be translated for use in another, even when common immunologic mechanisms are shared. A key example, ustekinumab, an anti IL-12/23p40 antibody used for treatment of psoriasis, did not work out as well for the treatment of MS as in the DMF story. Use of this antibody decreased EAE in rodents and primates, but failed to show a benefit vs placebo in a phase II clinical trial in RRMS.17 The success of DMF in MS provides hope that other available drugs used to combat autoimmunity may have potential in the treatment of MS.
Alternate dosing strategies for GA DMT GA acts through several proposed immunologic mechanisms to alter the disease course in MS (figure 1). GA is a random polymer of glutamic acid, lysine, alanine, and tyrosine that may modify antigen-presenting cells to promote anti-inflammatory T-cell pathways with generation of CD41 T-regulatory cells, suppressor T-cell generation, and induction of tolerance.18 At the ECTRIMS 2012 and American Academy of Neurology 2013 conferences, the results of the GALA study, a 1-year, phase III, randomized, double-blind, placebo-controlled trial examining the efficacy, safety, and tolerability of an investigational formulation of GA 40 mg/ 1 mL subcutaneous 3 times weekly compared to placebo in patients with RRMS was presented.19 GA 40 mg sq TIW significantly reduced the ARR, the primary endpoint, by 34.4% (p , 0.0001) as compared to placebo. Compared to placebo, the GA arm demonstrated a 34.4% reduction in cumulative number of new or enlarging T2 lesions (p , 0.0001) and a 44.8% decrease in the cumulative number of gadolinium-enhancing lesions
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Figure 2
KIR4.1 and aquaporin-4 colocalization within astrocytic endfeet
Efflux of potassium and osmotic water occurs through KIR4.1 and aquaporin-4 channels located in the astrocytic endfeet on vascular endothelium of the blood–brain barrier and nodes of Ranvier within the CNS. Both channels are suspected antigenic targets in autoimmune demyelinating disease.
(p , 0.0001).19 There were no unexpected side effects with the investigational formulation of GA in regards to prior experience with FDA-approved GA. For clinicians, this suggests that alternate day dosing of GA at a double dose formulation is effective in reducing ARR and new T2 and gadolinium-enhancing lesions on MRI. Without a head-to-head clinical trial comparing GA 20 mg subcutaneous daily (FDA approved dose) to the investigational formulation of GA 40 mg subcutaneous TIW, it is difficult to interpret the significance of the GALA results. Patients and clinicians would benefit from such a comparison as less frequent administration may result in improved tolerability and quality of life for patients with MS.
KIR4.1, a potential autoantigen in MS pathogenesis KIR4.1 may represent a novel antigenic target for a subgroup of patients with MS. Srivastava et al.20 identified serum IgG in a subgroup of patients with MS (n 5 186/397) that could bind to glial cells. This IgG antibody was specific for KIR4.1, a potassium channel located on astrocytic endfeet. It was present in 47% of patients with MS in the study, but in only ,1% of patients with other neurologic disorders (n 5 329). There were no patients with neuromyelitis optica (NMO) included in this study. NMO is an antibody-mediated disease with attacks primarily directed against aquaporin 4 (AQP4), a channel also located on astrocytes. Since KIR4.1 localizes with AQP4 on astrocytes, the question of whether KIR4.1 may also serve as a target in patients who are NMO IgG seronegative has been raised (figure 2).21 Of further interest, the subgroup of patients with MS with antibodies to
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• • • • •
Multiple sclerosis: Five new things High salt diet may be a risk factor for MS. Alemtuzumab is FDA-approved for the treatment of leukemia, but has been used off-label in aggressive forms of MS. Not every recycled drug shown to be efficacious in one autoimmune disease can be translated for use in MS, even when common immunologic mechanisms are shared. There are alternate dosing strategies for glatiramer acetate disease-modifying therapy. KIR4.1 is a potential autoantigen in MS pathogenesis.
KIR4.1 and in patients with NMO seropositive for NMO IgG the pathologic antibody is rarely detected within CSF, but highly prevalent within the serum. Eventually at some point in the course of the disease, 95% of patients with MS have detectable oligoclonal bands in the CSF. This indicates that the target of these clonally expanded antibodies in MS remains unknown.21 As more potential biomarkers are discovered, it will be possible for more directed DMTs to be developed and for useful diagnostic biomarkers to exist for the treating neurologist. MS remains the leading cause of nontraumatic disability in young adults. Advances in understanding the pathophysiology of MS will aid in the development of more targeted therapies, possible new applications of therapies for use in MS, and the discovery of new biomarkers. Early diagnosis and application of DMTs may change the natural history of the disease. Recently, several new therapies and promising biomarkers have emerged. The discovery of additional environmental risk factors for MS may aid in prevention of the disease. It is critical to the ongoing management of patients with MS to remain up to date and ready to integrate these new tools into clinical practice.
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Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 2011;378:1779–1787. Sorensen PS, Drulovic J, Hardova E, et al. Magnetic resonance imaging (MRI) efficacy of ofatumumab in relapsing-remitting multiple sclerosis: results of a phase II study. In: 63rd Annual Meeting of the American Academy of Neurology. Honolulu: American Academy of Neurology; 2011. Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol 2008;7:796–804. Racke MK, Lovett-Racke AE, Karandikar NJ. The mechanism of action of glatiramer acetate treatment in multiple sclerosis. Neurology 2010;74(suppl 1):S25–S30. Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadinov R, GALA Study Group. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol 2013;73:705–713. Srivastava R, Aslam M, Kalluri SR, et al. Potassium channel KIR4.1 as an immune target in multiple sclerosis. N Engl J Med 2012;367:115–123. Racke MK. Multiple sclerosis: the potassium channel KIR4.1-a potential autoantigen in MS. Nat Rev Neurol Epub 2012 Sep 18.
ACKNOWLEDGMENT The authors thank Christine Gillespie for the artistic illustration of the figures.
STUDY FUNDING No targeted funding reported.
DISCLOSURES J.A. Nicholas is supported by a Sylvia Lawry Fellowship grant from the National Multiple Sclerosis Society. A.L. Boster serves on Scientific Advisory Boards for Teva Neuroscience, Biogen Idec, Questcor, Novartis, and Medtronic; serves as a consultant for Novartis, Medtronic, Genzyme, and Questcor; and receives research support from Serono, Novartis, Biogen Idec, Jazz, Actellion, Roche, CNS Therapeutics, Teva Neuroscience, and Accorda. M.K. Racke serves on Scientific Advisory Boards for Accelerated Cure Project, Diogenix, Inc., Revalesio, Inc., and Novartis; serves as Editor-in-Chief of the Journal of Neuroimmunology and on the editorial boards of The Neurologist, Archives of Neurology, and Therapeutic Advances for Neurologic Disorders; serves as a consultant for Biogen Idec, Novartis, Relavesio, Inc., and Mylan; and receives research support from the NIH and the National Multiple Sclerosis Society. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.
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Multiple sclerosis: Five new things Jacqueline A. Nicholas, Aaron L. Boster and Michael K. Racke Neurol Clin Pract 2013;3;404-412 DOI 10.1212/CPJ.0b013e3182a78f94 This information is current as of October 14, 2013 Updated Information & Services
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References
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The Nerve! Readers Speak
this has remained unchanged from the days of James Parkinson. Why, then, in some countries is a patient more likely to get one of these radiologic tests and in another not? Is it just because the test is available that I am more likely to order it in a patient with atypical PD if I am practicing in the United States vs, say, India? Do neurologists in the United States practice better neurology than neurologists in India when it comes to PD? Is the care of a patient with PD better in France than, say, Brazil? I found myself asking all these questions and agree with Dr. Barbano that only large-scale high-quality standardized outcome data from different countries can help answer these questions. New York–Presbyterian Hospital. Disclosures: N. Sethi serves as Associate Editor for The Eastern Journal of Medicine.
Author Responds: Richard L. Barbano, MD, PhD, FAAN: As Dr. Sethi points out, the
use of ancillary testing in the diagnosis of PD, and the treatment of PD, varies from country to country. The availability of particular tests and medications almost certainly plays a role in this variability. Much progress has been made and despite the variability of choices, many treatments are helpful. One of the challenges facing neurologists today, however, is not just finding which approaches work, but which work best; which approaches not just improve symptoms, but which improve outcomes as measured in quality of life for the longest duration. The technology to analyze such data already exists. The challenge will be to organize a global effort to collect it. Department of Neurology, University of Rochester, and Department of Neurology, Rochester General Hospital, Rochester, NY Disclosures: R. Barbano serves on a Scientific Advisory Board for Allergan; serves as an Associate Editor for Neurology®: Clinical Practice; has served as an expert witness in legal proceedings including malpractice, but not involving commercial entities; and has received research support from Allergan and NIH, National Institute of Neurological Disorders and Stroke, ORDR: Dystonia Coalition Projects, Site PI.
1. Barbano RL. Standard strategies for diagnosis and treatment of patients with newly diagnosed Parkinson disease. Neurol Clin Pract 2013;3:475–476.
ERRATA Generic substitution of antiepileptic drugs: What’s a clinician to do? In the article “Generic substitution of antiepileptic drugs: What’s a clinician to do?” by Khichar Shubhakaran and Rekha Jakhar Khichar (Neurol Clin Pract 2013;3:457), there is an error in the second author’s name, which should read “Rekha Jakhar Khichar.” The editorial staff regrets the error.
Multiple sclerosis: Five new things In the article “Multiple sclerosis: Five new things” by JA Nicholas et al. (Neurol Clin Pract 2013;3:404– 412), there is an error on page 406. The first full sentence should read “There was a 55% reduction in annualized relapse rate (ARR), the study’s primary outcome.” The publisher regrets the error.
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Podcast
Five new things Jacqueline A. Nicholas, MD, MPH Aaron L. Boster, MD Michael K. Racke, MD
Summary Preliminary studies have suggested that a high salt diet may play a role in the development of autoimmune disease and possibly multiple sclerosis (MS). Promising clinical trial results for 2 new therapies for MS have been reported. Dimethyl fumarate, also known by its investigational name BG-12, became the third oral disease-modifying therapy for MS to be Food and Drug Administration (FDA)–approved in March 2013. Interestingly, dimethyl fumarate served as the active compound used for the treatment of psoriasis for decades. Alemtuzumab remains under investigation and is not currently FDA-approved for treatment of MS. Other drugs currently approved for alternative indications are being investigated for use in MS. Additionally, an investigation of alternative dosing strategies for glatiramer acetate suggests that patients may benefit from a higher dose formulation and less frequent medication administration. Advances in basic science research have identified another potential autoantigenic target in MS, KIR4.1, which may provide further insight into MS pathophysiology.
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ultiple sclerosis (MS) is an autoimmune, demyelinating disease of the CNS that can lead to neurologic disability. Well-known environmental risk factors for MS include smoking, low vitamin D, and Epstein-Barr virus infection. The search for additional environmental risk factors continues and a high salt diet has recently been implicated.1,2 Goals of diseasemodifying therapies (DMTs) are to reduce the risk of relapse, reduce the development of new MRI lesions, and slow disease progression. Here, we discuss new therapies (one Food and Drug Administration [FDA]–approved and others under continued investigation) along with The Ohio State University Department of Neurology, Columbus. Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp. Correspondence to: [email protected] 404
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Even though a direct link between salt and MS has not been demonstrated, a high salt diet may be the reason for the increased incidence of MS in recent decades. an alternate dosing study of a new formulation of glatiramer acetate (GA) for the management of relapsing-remitting MS (RRMS). We revisit lessons learned from recycling old drugs and reformulating such drugs for potential use in MS. Finally, KIR4.1 is a newly discovered potential autoantigenic target in MS.
Is a high salt diet a risk factor for multiple sclerosis? Recent studies have suggested that increased salt intake may be involved in provoking onset of autoimmune disease.1,2 Even though a direct link between salt and MS has not been demonstrated, a high salt diet may be the reason for the increased incidence of MS in recent decades. Kleinewietfeld et al.2 demonstrated that elevated sodium chloride concentrations in vivo increase T helper 17 (Th17) cells in human and mouse models. Their study also showed that highly pathogenic Th17 cells were produced under these conditions. Finally, mice fed a diet high in salt developed a more severe form of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Th17 cells are proinflammatory and a shift toward this response has been implicated in many autoimmune diseases including MS. Interleukin-23 (IL-23) enhances the Th17 response by signaling through the IL-23 receptor (IL-23R). Wu and colleges1 studied serum glucocorticoid kinase 1 (SGK1) and identified it as playing a key role following IL-23 signaling. This study demonstrated both in vitro and in vivo that SGK1 expression is induced by increased salt concentration resulting in enhanced IL-23R expression, thus promoting Th17 cell differentiation.1 Conversely, loss of SGK1 demonstrated that salt had no effect on Th17 differentiation via IL-23. This suggests a possible mechanism by which salt may potentiate autoimmunity. Further studies are needed to determine if high salt diet is involved in worsening of MS, but if proven, clinicians may begin to counsel patients on the importance of a low salt diet for reasons other than cardiovascular disease.
Alemtuzumab Alemtuzumab is a humanized anti-CD52 monoclonal antibody that rapidly depletes monocytes and B and T cells via antibody-dependent cellular toxicity (figure 1).3 The effects of treatment on the immune system are prolonged. Immune cell reconstitution with return to levels at the lower limit of normal range for monocytes and B cells occurs at 3 months, CD81 T cells around 30 months, and CD41 T cells at approximately 61 months.4 Interestingly, many patients’ lymphocyte counts do not repopulate to previous baseline total lymphocyte counts. In one study, only 39% of patients recovered to baseline total lymphocyte counts, with a median recovery time of 12.6 months.4 Alemtuzumab is FDA-approved for the treatment of leukemia, but has been used off-label in aggressive forms of MS. In MS clinical trials, alemtuzumab has been administered IV for 5 days followed by annual infusions for 3 days (optimal dose under investigation). Pivotal trials The initial phase III trial, CARE-MS I, was a 2-year randomized, rater-blinded, doubledummy active-comparator trial studying the efficacy and safety of annual alemtuzumab (12 mg IV administered daily for 5 days during the first year and for 3 days in year 2) vs subcutaneous interferon (IFN)-b-1a 44 mcg 3 times weekly in treatment-naive patients with
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Figure 1
Proposed mechanisms of action of highlighted multiple sclerosis therapies
(A) Alemtuzumab is a humanized anti-CD52 monoclonal antibody that rapidly depletes B and T cells via antibody dependent cellular toxicity. (B) Rituximab, ocrelizumab, and ofatumumab are all monoclonal antibodies that target CD20 on B cells leading to B-cell depletion. Rituximab is chimeric, while ocrelizumab and ofatumumab are humanized. (C) Dimethyl fumarate (DMF) acts through the Nrf-2 pathway resulting in cytoprotection, decreased oxidative stress, and reduced neuroinflammation through promotion of Th2 pathways. DMF inhibits dendritic cell maturation by decreasing interleukin (IL)-12 and IL-6. This results in decreased cytokine production of IL-17 and interferon (IFN)-g leading to a decreased Th1 and Th17 differentiation. (D) Glatiramer acetate (GA) is a polymer of glutamic acid, lysine, alanine, and tyrosine that may modify antigen-presenting cells to promote anti-inflammatory T-cell pathways with generation of CD41 T-regulatory cells, suppressor T-cell generation, and induction of immune tolerance.
active RRMS. There was a 55% reduction in absolute risk reduction (ARR), the study’s primary outcome, in the alemtuzumab arm as compared to IFN-b-1a (p , 0.0001).5 The trial failed to meet the second coprimary endpoint of time to 6-month sustained accumulation of disability (SAD). A total of 11% (n 5 20) of patients in the IFN-b-1a arm vs 8% (n 5 30) in the alemtuzumab arm experienced SAD (p 5 0.22). There was a reduction in the percent of patients with new or enlarging T2 lesions, gadolinium-enhancing lesions, and a 40% reduction in brain volume loss on MRI (p , 0.0001) as compared to IFN-b-1a. CARE-MS II, the second phase III trial, utilized the same design as CARE-MS I except enrolled patients had to have failed a prior MS DMT, defined as at least one relapse on therapy. This trial met both of its primary coendpoints with a 49% relapse rate reduction compared to IFN-b-1a–treated patients (p , 0.0001) and a 42% reduction in 6-month SAD favoring the alemtuzumab arm (p 5 0.0084).6 There was a reduction in the number of patients with new or enlarging T2 lesions (46% alemtuzumab vs 68% IFN; p , 0.0001), gadolinium-enhancing lesions (9% alemtuzumab vs 23% IFN; p , 0.0001), and brain volume loss (20.615% alemtuzumab vs 20.810% IFN; p 5 0.01) in the alemtuzumab arm as compared to IFN-b-1a.
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Safety Common alemtuzumab side effects include infusion reactions (headache, rash, and fever), mild to moderate infections (upper respiratory, urinary tract, and herpetic), and autoimmune thyroid disease (16%–18%). Infusion reactions declined with the second treatment course and were largely controlled by pretreatment with corticosteroids. The risk of herpetic infections was reduced in the clinical trials with acyclovir prophylaxis.5 Other autoimmune diseases associated with alemtuzumab use include a few cases of Goodpasture disease and idiopathic thrombocytopenic purpura (ITP).3 ITP is the most serious autoimmune disease associated with alemtuzumab and the index patient died from ITP in the early phase II trial CAMMS223 when early warning signs went unreported.3 A risk management program is now in place to monitor patients on alemtuzumab for early signs of ITP. Acquired autoimmunity from alemtuzumab can develop up to 5 years after treatment and therefore, continued clinical vigilance is required.3 Recycling available drugs for the treatment of MS Dimethyl fumarate (DMF), investigational name BG-12, is the most recent oral drug to be FDA-approved for relapsing forms of MS (figure 1). It serves as a prime example of a reformulated drug used for decades in the treatment of another autoimmune disease, psoriasis, which has demonstrated efficacy in MS. DEFINE, a phase III, 2-year, randomized, double-blind, placebo-controlled trial studying the efficacy and safety of oral BG-12 240 mg twice or thrice daily as compared to placebo in RRMS, demonstrated an approximate 50% risk reduction for an MS relapse in both treatment arms (ARR: 0.19 TID, 0.17 BID, 0.36 placebo; p , 0.001 for both comparisons), sustained 3-month progression of disability was reduced by 34%–38% for both treatment arms as compared to placebo (hazard ratio [HR] 0.62, p 5 0.005 twice daily, HR 0.66, p 5 0.01 thrice daily), and the number of new or enlarging T2 lesions on brain MRI at 2 years was reduced by 85% for twice daily BG-12 and 74% for thrice daily BG-12.7 CONFIRM, a phase III, 2-year, randomized, double-blind, placebocontrolled trial studying the efficacy and safety of oral BG-12 240 mg twice or thrice daily as compared to placebo that included an open-label reference arm with GA, demonstrated a significant reduction in ARR as compared to placebo (44% [ARR 5 0.22] twice daily, 51% [ARR 5 0.20] thrice daily, ARR 5 0.40 placebo; p , 0.001 for both comparisons; 29% [ARR 5 0.29] GA vs placebo [p 5 0.01]).8 Common adverse events associated with BG-12 include gastrointestinal events (nausea, diarrhea, bloating) in 10%–15%, flushing (erythema, pruritus, rash) in 31%–38%, most frequently during the first month on treatment, and 10%–30% drop in lymphocyte counts. No malignancies or opportunistic infections have been reported with BG-12.7,8 Since 1959, fumaric acid esters (FAEs) have been used for the treatment of psoriasis.9 In 1994, Fumaderm, a combination of DMF and monomethyl fumarate, was approved in Germany for the treatment of moderate to severe psoriasis.9 FAEs shift the proinflammatory Th1 cellular response to a less inflammatory Th2 response.10 The exact mechanism of DMF in vivo in MS has not been fully elucidated, but several in vitro studies have suggested the following mechanisms. Treatment with DMF results in a reduction in CD41 T cells, which produce IFN-g in patients with MS.11 Dimethyl fumarate is believed to exert its effects through the nuclear factor (erythroid derived 2)–like 2 transcriptional pathway (Nrf2), resulting in cytoprotection, decreased oxidative stress, and reduced neuro-inflammation (figure 1).12 Additionally, DMF inhibits dendritic cell maturation by decreasing production of IL-12 and IL-6, leading to reduced Th1 and Th17 cell differentiation.11,13 In dendritic cell and T cell coculture, DMF causes decreased production of IFN-g and IL-17, resulting in decreased Th1 and Th17 cell differentiation.11 Furthermore, suppression of extracellular signal-related kinase 1 and 2 (ERK1/2) by DMF results in reduced nuclear factor-ΚB signaling.11 Lessons learned Dimethyl fumarate was not the first drug used for an alternate indication that was later proven beneficial for the treatment of MS. Rituximab, a chimeric monoclonal antibody that targets
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Not every recycled drug shown to be efficacious in one autoimmune disease can be translated for use in another, even when common immunologic mechanisms are shared. CD20, predominantly on B cells, causes B-cell depletion. It is approved for use in non-Hodgkin lymphoma, rheumatoid arthritis refractory to tumor necrosis factor antagonists, and CD201 chronic lymphocytic leukemia (CLL). HERMES, a phase II, double-blind, 48-week trial comparing rituximab 1,000 mg IV on days 1 and 15 compared to placebo in patients with RRMS, demonstrated a reduction in new and total gadolinium-enhancing lesions (p . 0.001) and reduction in relapses at weeks 24 (p 5 0.02) and 48 (p 5 0.04) in favor of rituximab.14 The US patent for rituximab expires in 2016 and currently, phase III trials are not planned. This drug is unlikely to obtain approval for use in MS, although it is used off-label for this purpose. Analogues of rituximab, ocrelizumab, and ofatumumab are currently being studied for use in MS (figure 1). Like rituximab, ocrelizumab targets CD20 on B cells, but in contrast, it is a recombinant, humanized IgG1 monoclonal antibody expected to cause less infusion reactions as its humanized form may be less immunogenic. The phase II study of ocrelizumab in RRMS at high and low dose as compared to placebo and IFN-b-1a IM once weekly demonstrated 89%–95% relative risk reductions in total gadolinium-enhancing lesions on MRI at weeks 12 and 24.15 The phase II trial success led to phase III clinical trials currently under way to study the use of ocrelizumab for the treatment of RRMS and PPMS. Ofatumumab is a fully human recombinant anti-CD-20 monoclonal antibody that has been FDA-approved since 2009 for fludarabine- and alemtuzumabresistant CLL.16 A phase II study in RRMS did not raise safety concerns and demonstrated beneficial effects on MRI outcomes including reductions in new or enlarging T2 lesions, new gadolinium-enhancing, and total gadolinium-enhancing lesions.16 Clinicians and scientists who treat and study autoimmune diseases are frequently reminded of the complexity of autoimmune pathophysiology. Not every recycled drug shown to be efficacious in one autoimmune disease can be translated for use in another, even when common immunologic mechanisms are shared. A key example, ustekinumab, an anti IL-12/23p40 antibody used for treatment of psoriasis, did not work out as well for the treatment of MS as in the DMF story. Use of this antibody decreased EAE in rodents and primates, but failed to show a benefit vs placebo in a phase II clinical trial in RRMS.17 The success of DMF in MS provides hope that other available drugs used to combat autoimmunity may have potential in the treatment of MS.
Alternate dosing strategies for GA DMT GA acts through several proposed immunologic mechanisms to alter the disease course in MS (figure 1). GA is a random polymer of glutamic acid, lysine, alanine, and tyrosine that may modify antigen-presenting cells to promote anti-inflammatory T-cell pathways with generation of CD41 T-regulatory cells, suppressor T-cell generation, and induction of tolerance.18 At the ECTRIMS 2012 and American Academy of Neurology 2013 conferences, the results of the GALA study, a 1-year, phase III, randomized, double-blind, placebo-controlled trial examining the efficacy, safety, and tolerability of an investigational formulation of GA 40 mg/ 1 mL subcutaneous 3 times weekly compared to placebo in patients with RRMS was presented.19 GA 40 mg sq TIW significantly reduced the ARR, the primary endpoint, by 34.4% (p , 0.0001) as compared to placebo. Compared to placebo, the GA arm demonstrated a 34.4% reduction in cumulative number of new or enlarging T2 lesions (p , 0.0001) and a 44.8% decrease in the cumulative number of gadolinium-enhancing lesions
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Figure 2
KIR4.1 and aquaporin-4 colocalization within astrocytic endfeet
Efflux of potassium and osmotic water occurs through KIR4.1 and aquaporin-4 channels located in the astrocytic endfeet on vascular endothelium of the blood–brain barrier and nodes of Ranvier within the CNS. Both channels are suspected antigenic targets in autoimmune demyelinating disease.
(p , 0.0001).19 There were no unexpected side effects with the investigational formulation of GA in regards to prior experience with FDA-approved GA. For clinicians, this suggests that alternate day dosing of GA at a double dose formulation is effective in reducing ARR and new T2 and gadolinium-enhancing lesions on MRI. Without a head-to-head clinical trial comparing GA 20 mg subcutaneous daily (FDA approved dose) to the investigational formulation of GA 40 mg subcutaneous TIW, it is difficult to interpret the significance of the GALA results. Patients and clinicians would benefit from such a comparison as less frequent administration may result in improved tolerability and quality of life for patients with MS.
KIR4.1, a potential autoantigen in MS pathogenesis KIR4.1 may represent a novel antigenic target for a subgroup of patients with MS. Srivastava et al.20 identified serum IgG in a subgroup of patients with MS (n 5 186/397) that could bind to glial cells. This IgG antibody was specific for KIR4.1, a potassium channel located on astrocytic endfeet. It was present in 47% of patients with MS in the study, but in only ,1% of patients with other neurologic disorders (n 5 329). There were no patients with neuromyelitis optica (NMO) included in this study. NMO is an antibody-mediated disease with attacks primarily directed against aquaporin 4 (AQP4), a channel also located on astrocytes. Since KIR4.1 localizes with AQP4 on astrocytes, the question of whether KIR4.1 may also serve as a target in patients who are NMO IgG seronegative has been raised (figure 2).21 Of further interest, the subgroup of patients with MS with antibodies to
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• • • • •
Multiple sclerosis: Five new things High salt diet may be a risk factor for MS. Alemtuzumab is FDA-approved for the treatment of leukemia, but has been used off-label in aggressive forms of MS. Not every recycled drug shown to be efficacious in one autoimmune disease can be translated for use in MS, even when common immunologic mechanisms are shared. There are alternate dosing strategies for glatiramer acetate disease-modifying therapy. KIR4.1 is a potential autoantigen in MS pathogenesis.
KIR4.1 and in patients with NMO seropositive for NMO IgG the pathologic antibody is rarely detected within CSF, but highly prevalent within the serum. Eventually at some point in the course of the disease, 95% of patients with MS have detectable oligoclonal bands in the CSF. This indicates that the target of these clonally expanded antibodies in MS remains unknown.21 As more potential biomarkers are discovered, it will be possible for more directed DMTs to be developed and for useful diagnostic biomarkers to exist for the treating neurologist. MS remains the leading cause of nontraumatic disability in young adults. Advances in understanding the pathophysiology of MS will aid in the development of more targeted therapies, possible new applications of therapies for use in MS, and the discovery of new biomarkers. Early diagnosis and application of DMTs may change the natural history of the disease. Recently, several new therapies and promising biomarkers have emerged. The discovery of additional environmental risk factors for MS may aid in prevention of the disease. It is critical to the ongoing management of patients with MS to remain up to date and ready to integrate these new tools into clinical practice.
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Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 2011;378:1779–1787. Sorensen PS, Drulovic J, Hardova E, et al. Magnetic resonance imaging (MRI) efficacy of ofatumumab in relapsing-remitting multiple sclerosis: results of a phase II study. In: 63rd Annual Meeting of the American Academy of Neurology. Honolulu: American Academy of Neurology; 2011. Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol 2008;7:796–804. Racke MK, Lovett-Racke AE, Karandikar NJ. The mechanism of action of glatiramer acetate treatment in multiple sclerosis. Neurology 2010;74(suppl 1):S25–S30. Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadinov R, GALA Study Group. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol 2013;73:705–713. Srivastava R, Aslam M, Kalluri SR, et al. Potassium channel KIR4.1 as an immune target in multiple sclerosis. N Engl J Med 2012;367:115–123. Racke MK. Multiple sclerosis: the potassium channel KIR4.1-a potential autoantigen in MS. Nat Rev Neurol Epub 2012 Sep 18.
ACKNOWLEDGMENT The authors thank Christine Gillespie for the artistic illustration of the figures.
STUDY FUNDING No targeted funding reported.
DISCLOSURES J.A. Nicholas is supported by a Sylvia Lawry Fellowship grant from the National Multiple Sclerosis Society. A.L. Boster serves on Scientific Advisory Boards for Teva Neuroscience, Biogen Idec, Questcor, Novartis, and Medtronic; serves as a consultant for Novartis, Medtronic, Genzyme, and Questcor; and receives research support from Serono, Novartis, Biogen Idec, Jazz, Actellion, Roche, CNS Therapeutics, Teva Neuroscience, and Accorda. M.K. Racke serves on Scientific Advisory Boards for Accelerated Cure Project, Diogenix, Inc., Revalesio, Inc., and Novartis; serves as Editor-in-Chief of the Journal of Neuroimmunology and on the editorial boards of The Neurologist, Archives of Neurology, and Therapeutic Advances for Neurologic Disorders; serves as a consultant for Biogen Idec, Novartis, Relavesio, Inc., and Mylan; and receives research support from the NIH and the National Multiple Sclerosis Society. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.
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References
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this has remained unchanged from the days of James Parkinson. Why, then, in some countries is a patient more likely to get one of these radiologic tests and in another not? Is it just because the test is available that I am more likely to order it in a patient with atypical PD if I am practicing in the United States vs, say, India? Do neurologists in the United States practice better neurology than neurologists in India when it comes to PD? Is the care of a patient with PD better in France than, say, Brazil? I found myself asking all these questions and agree with Dr. Barbano that only large-scale high-quality standardized outcome data from different countries can help answer these questions. New York–Presbyterian Hospital. Disclosures: N. Sethi serves as Associate Editor for The Eastern Journal of Medicine.
Author Responds: Richard L. Barbano, MD, PhD, FAAN: As Dr. Sethi points out, the
use of ancillary testing in the diagnosis of PD, and the treatment of PD, varies from country to country. The availability of particular tests and medications almost certainly plays a role in this variability. Much progress has been made and despite the variability of choices, many treatments are helpful. One of the challenges facing neurologists today, however, is not just finding which approaches work, but which work best; which approaches not just improve symptoms, but which improve outcomes as measured in quality of life for the longest duration. The technology to analyze such data already exists. The challenge will be to organize a global effort to collect it. Department of Neurology, University of Rochester, and Department of Neurology, Rochester General Hospital, Rochester, NY Disclosures: R. Barbano serves on a Scientific Advisory Board for Allergan; serves as an Associate Editor for Neurology®: Clinical Practice; has served as an expert witness in legal proceedings including malpractice, but not involving commercial entities; and has received research support from Allergan and NIH, National Institute of Neurological Disorders and Stroke, ORDR: Dystonia Coalition Projects, Site PI.
1. Barbano RL. Standard strategies for diagnosis and treatment of patients with newly diagnosed Parkinson disease. Neurol Clin Pract 2013;3:475–476.
ERRATA Generic substitution of antiepileptic drugs: What’s a clinician to do? In the article “Generic substitution of antiepileptic drugs: What’s a clinician to do?” by Khichar Shubhakaran and Rekha Jakhar Khichar (Neurol Clin Pract 2013;3:457), there is an error in the second author’s name, which should read “Rekha Jakhar Khichar.” The editorial staff regrets the error.
Multiple sclerosis: Five new things In the article “Multiple sclerosis: Five new things” by JA Nicholas et al. (Neurol Clin Pract 2013;3:404– 412), there is an error on page 406. The first full sentence should read “There was a 55% reduction in annualized relapse rate (ARR), the study’s primary outcome.” The publisher regrets the error.
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