Multiple Sclerosis and Related Disorders (2014) 3, 553–554
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
EDITORIAL
Editors' welcome Multiple Sclerosis is a multifaceted disease with major disagreement about its pathogenesis. This prompted us to introduce in the current issue of MSARD, the first in our ‘Controversies’ series (see below), and in the same vein, refer our readers to a review on MS genetics by Sawcer and colleagues in the July edition of Lancet Neurology (Sawcer et al., 2014). Although no single gene mutation has been implicated in MS, the presence of now over 100 common MS variants (polymorphisms) is emphasized in support of a genetic contribution to MS. Most variants relate to the HLA and the immune system which is proposed as evidence supporting an immune-based disease. This conclusion does not exclude the possibility of an infectious etiology as both HLA and the immune system are intricately involved in our response to infectious agents. A novel concept is proposed – Insufficient Non-redundant Unnecessary Sufficient (INUS) which helps explain the plurality of causation when a mutation cannot be found. The authors admit that current variants account only for about 25% of heritability and propose a new concept, namely ‘phantom heritability’! The current issue of MSARD spans 5 important areas namely, experimental autoimmune encephalomyelitis (EAE), epidemiology, therapeutics, immunology and MS neuro-cardiology. EAE has been the archetypal model for MS, or at least for inducible CNS inflammation, that has formed the basis of many etiologic theories and indeed therapies. Despite this, an important minority believe it is a poor model that is long overdue replacement. Read the arguments for and against as set out by Baker and Amor vs. Behan and Chaudhuri and come to your own conclusion. On a less controversial footing we have 4 articles focused on epidemiology. Mario Veloso extracted clinical data from studies of the natural history of MS to create a web-based decision support program, now available online. It should allow clinicians to predict the likelihood of further relapses following clinically isolated syndrome (CIS), long-term prognosis of disability, secondary progressive MS (SPMS) conversion, and appraise the effects of treatment. Validation by extended follow-up of this interesting model will be essential. In similar vein, Skoog and colleagues devised a model to predict the likelihood of secondary progression in relapsing
http://dx.doi.org/10.1016/j.msard.2014.07.005 2211-0348/& 2014 Published by Elsevier B.V.
disease. This was based on a large untreated MS Danish incidence cohort with five decades of follow-up. A prediction score was created that depended on three factors: age, type and time after the previous relapse. An online version is also available. Ramachandran and colleagues complement these findings in their UK dataset of 500 MSers. They found significant worsening of future disability when age of onset was greater than 30–35 years. Prompted by the sharp increase in women with MS, Magyari et al. used their cohort of 1403 patients to examine the effect of occupation, physical, or social environment on the incidence of MS in women compared to men. It was found that agricultural and outdoor work accounted for some of the excess in women but not educational level, housing conditions in youth, or the presence of unrelated children in the household. Next, we have 3 studies that evaluate first-dose effects of fingolimod. In the EPOC open-label multicentre study from North America reported here by Fox and associates, there were 263 MSers who continued with injectable therapies compared with 790 who switched without washout from injectables to fingolimod and observed for 6 months. Patient- and physician-reported treatment satisfaction was high with only slight excess of headache or fatigue. In the same cohort, Bruce and colleagues report the cardiovascular effects of the initial fingolimod dose. A transient decrease in mean heart rate and blood pressure occurred within 6 h but in general, the early unwanted effects were mild and benign. Lastly, DiMarco and co-workers report the first-dose effects of fingolimod on cardiac parameters using pooled phase 3 data from the FREEDOMS, FREEDOMSII and TRANSFORMS studies, giving a total of 3635 individuals. Fingolimod initiation evoked transient slowing of atrioventricular conduction and heart rate, neither of which required intervention. It would be reasonable to conclude that fingolimod is safe in the short term. The last article in this series (Ontaneda et al.) reviews the pros and cons of selecting appropriate disease modifying treatment, based on seven currently available MS therapies. It is recommended that the physician should adopt an individualized treatment plan with full prior discussion of the risks and benefits.
554 Turning to immunology, a paper by Holley et al evaluated ScFvRit:sFasL, a rituximab-derived antibody fragment that targets CD20, a B-cell marker expressed on a subset of T cells. CD20 positive inflammatory T-cells were demonstrated in the blood and non-active brain lesions of MS patients and were eliminated by ScFvRit:sFasL without depletion of B cells. Clearly this opens the way for a novel form of targeted immunotherapy. Next, Mulero and coworkers report a patient who experienced a severe MS relapse after the 5th dose of natalizumab, secondary to neutralizing antibodies as there was no evidence of progressive multifocal leukoencephalopathy. The patient was switched to fingolimod and the disease stabilized for the 12 month follow-up period. It is proposed that natalizumab antibodies neutralized the impact of natalizumab, which resulted in reconstitution of lymphocyte migration into the central nervous system and a rebound phenomenon similar to IRIS (immune reconstitution inflammatory syndrome) after stopping natalizumab. Finally MS neuro-cardiology – an emerging sub-speciality! Razazian and associates report increased prevalence of
B. Banwell et al. P wave dispersion (i.e. broadening) in MS, a phenomenon that might relate to increased sympathetic activity. Although measurement of P wave dispersion is sometimes difficult, it is an important phenomenon, given the acknowledged risk of atrial fibrillation and the known cardiac sideeffects of newer forms of immunotherapy, such as fingolimod.
Reference Sawcer S, Franklin RJ, Ban M. Multiple sclerosis genetics. Lancet Neurol 2014;13:700–9.
Editors in Chief Brenda Banwell, Gavin Giovannoni, Chris Hawkes, Fred Lublin
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
EDITORIAL
Editors' welcome Multiple Sclerosis is a multifaceted disease with major disagreement about its pathogenesis. This prompted us to introduce in the current issue of MSARD, the first in our ‘Controversies’ series (see below), and in the same vein, refer our readers to a review on MS genetics by Sawcer and colleagues in the July edition of Lancet Neurology (Sawcer et al., 2014). Although no single gene mutation has been implicated in MS, the presence of now over 100 common MS variants (polymorphisms) is emphasized in support of a genetic contribution to MS. Most variants relate to the HLA and the immune system which is proposed as evidence supporting an immune-based disease. This conclusion does not exclude the possibility of an infectious etiology as both HLA and the immune system are intricately involved in our response to infectious agents. A novel concept is proposed – Insufficient Non-redundant Unnecessary Sufficient (INUS) which helps explain the plurality of causation when a mutation cannot be found. The authors admit that current variants account only for about 25% of heritability and propose a new concept, namely ‘phantom heritability’! The current issue of MSARD spans 5 important areas namely, experimental autoimmune encephalomyelitis (EAE), epidemiology, therapeutics, immunology and MS neuro-cardiology. EAE has been the archetypal model for MS, or at least for inducible CNS inflammation, that has formed the basis of many etiologic theories and indeed therapies. Despite this, an important minority believe it is a poor model that is long overdue replacement. Read the arguments for and against as set out by Baker and Amor vs. Behan and Chaudhuri and come to your own conclusion. On a less controversial footing we have 4 articles focused on epidemiology. Mario Veloso extracted clinical data from studies of the natural history of MS to create a web-based decision support program, now available online. It should allow clinicians to predict the likelihood of further relapses following clinically isolated syndrome (CIS), long-term prognosis of disability, secondary progressive MS (SPMS) conversion, and appraise the effects of treatment. Validation by extended follow-up of this interesting model will be essential. In similar vein, Skoog and colleagues devised a model to predict the likelihood of secondary progression in relapsing
http://dx.doi.org/10.1016/j.msard.2014.07.005 2211-0348/& 2014 Published by Elsevier B.V.
disease. This was based on a large untreated MS Danish incidence cohort with five decades of follow-up. A prediction score was created that depended on three factors: age, type and time after the previous relapse. An online version is also available. Ramachandran and colleagues complement these findings in their UK dataset of 500 MSers. They found significant worsening of future disability when age of onset was greater than 30–35 years. Prompted by the sharp increase in women with MS, Magyari et al. used their cohort of 1403 patients to examine the effect of occupation, physical, or social environment on the incidence of MS in women compared to men. It was found that agricultural and outdoor work accounted for some of the excess in women but not educational level, housing conditions in youth, or the presence of unrelated children in the household. Next, we have 3 studies that evaluate first-dose effects of fingolimod. In the EPOC open-label multicentre study from North America reported here by Fox and associates, there were 263 MSers who continued with injectable therapies compared with 790 who switched without washout from injectables to fingolimod and observed for 6 months. Patient- and physician-reported treatment satisfaction was high with only slight excess of headache or fatigue. In the same cohort, Bruce and colleagues report the cardiovascular effects of the initial fingolimod dose. A transient decrease in mean heart rate and blood pressure occurred within 6 h but in general, the early unwanted effects were mild and benign. Lastly, DiMarco and co-workers report the first-dose effects of fingolimod on cardiac parameters using pooled phase 3 data from the FREEDOMS, FREEDOMSII and TRANSFORMS studies, giving a total of 3635 individuals. Fingolimod initiation evoked transient slowing of atrioventricular conduction and heart rate, neither of which required intervention. It would be reasonable to conclude that fingolimod is safe in the short term. The last article in this series (Ontaneda et al.) reviews the pros and cons of selecting appropriate disease modifying treatment, based on seven currently available MS therapies. It is recommended that the physician should adopt an individualized treatment plan with full prior discussion of the risks and benefits.
554 Turning to immunology, a paper by Holley et al evaluated ScFvRit:sFasL, a rituximab-derived antibody fragment that targets CD20, a B-cell marker expressed on a subset of T cells. CD20 positive inflammatory T-cells were demonstrated in the blood and non-active brain lesions of MS patients and were eliminated by ScFvRit:sFasL without depletion of B cells. Clearly this opens the way for a novel form of targeted immunotherapy. Next, Mulero and coworkers report a patient who experienced a severe MS relapse after the 5th dose of natalizumab, secondary to neutralizing antibodies as there was no evidence of progressive multifocal leukoencephalopathy. The patient was switched to fingolimod and the disease stabilized for the 12 month follow-up period. It is proposed that natalizumab antibodies neutralized the impact of natalizumab, which resulted in reconstitution of lymphocyte migration into the central nervous system and a rebound phenomenon similar to IRIS (immune reconstitution inflammatory syndrome) after stopping natalizumab. Finally MS neuro-cardiology – an emerging sub-speciality! Razazian and associates report increased prevalence of
B. Banwell et al. P wave dispersion (i.e. broadening) in MS, a phenomenon that might relate to increased sympathetic activity. Although measurement of P wave dispersion is sometimes difficult, it is an important phenomenon, given the acknowledged risk of atrial fibrillation and the known cardiac sideeffects of newer forms of immunotherapy, such as fingolimod.
Reference Sawcer S, Franklin RJ, Ban M. Multiple sclerosis genetics. Lancet Neurol 2014;13:700–9.
Editors in Chief Brenda Banwell, Gavin Giovannoni, Chris Hawkes, Fred Lublin
