Multiple Sclerosis and Related Disorders (]]]]) ], ]]]–]]]
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
EDITORIAL
Editors' welcome In this issue: “Clinical, therapeutic and cognitive outcome insights into MS” The present issue of MSARD contains a wide array of topics from clinical metrics of fatigue to biochemical alterations in lipid biogenesis. In an interesting evaluation of web-behavior, coined “infoepidemiology” reveals that the majority of online searches relating to MS center around celebrities who publically acknowledge their disease. Searches are also now more specific and relate to MS therapy or symptoms, as opposed to the broader search term “multiple sclerosis” – perhaps reflecting increasing sophistication of the internet audience (Brigo et al.). While the article did not delve into the content of web information, future studies exploring the influence of web-derived information, particularly information relating to celebrity views or treatment of celebrities, on patient behavior would be of interest. A detailed review of JC virus and progressive multifocal leukoencephalopathy (PML) is also provided – a timely and comprehensive overview that should be read by all clinicians prescribing the increasingly potent therapies for MS. In a second review article, the role of deep brain stimulation (DBS) for MS symptoms is provided. DBS has been shown to reduce pain particularly facial pain, tremor, and potentially for bladder dysfunction (detrusor overactivity). Reduction in tremor and a reduced likelihood of tremor over time is reported in patients receiving natalizumab (Rinker et al.) – raising the possibility that certain MS-related chronic symptoms may be reduced by more potent immunotherapies in MS. Several articles focus on clinical aspects of the disease. Roohani et al. challenge current perception that late-onset MS (first symptom after age 50 years) is a progressive disease from onset by showing that of 44% of 124 lateonset MS patients (identified from 3700 MS patients cared for in four MS centers in the USA) experienced relapsingremitting MS, 28% were diagnosed with SPMS, and only 20% were classified as primary progressive MS. The importance of relapses in MS is presented through questionnaire data from 103 MS patients treated with first line therapies in the United Kingdom (Duddy et al.). Relapses led to work absenteeism in 67% of patients, approximately 40% of whom had to then reduce work hours at least temporarily, and 60%
http://dx.doi.org/10.1016/j.msard.2014.05.004 2211-0348/& 2014 Published by Elsevier B.V.
of whom reported that they required additional support in the home during the relapse. The emotional burden of relapse-related limitation in function emerged as a major area of focus. While there may exist a reporting bias in the sample collected, the results nonetheless emphasize the impact of relapses on patient quality of life – an important consideration for therapies that reduce relapse rate. The impact of MS on clinical function was examined by Barr et al., who demonstrate that slowing of reaction time follows a 6 min walk test in individuals with MS-related motor impairment. These findings provide a reproducible measure for exercise-induced motor fatigue that may more relevantly reflect the day to day experience of individuals living with MS. The use of a fatigue-inducing activity prior to measures of reaction time, such as the 6 min walk, may serve as a valuable means to evaluate the impact of therapies on fatigue and motor performance. Cognitive performance, known to be impaired in 40–60% of MS patients at some point in their disease, was evaluated in two manuscripts in the present issue. Rosti-Otajarvi et al. evaluate cognitive performance as a correlate of disease phenotype and disease severity (as measured by quality of life indices or indices of mood). As expected, physical disability scores were higher in patients with progressive MS, but the authors did not find a strong relationship between disease phenotype and cognitive performance, quality of life indices or mood. An exception applied to relapsing-remitting patients who performed better on the symbol digit modality test than did the SPMS or PPMS patients. These findings support the more global impact of MS on cognition that appears relatively independent of physical disability and suggests that the clinical expression of MS in terms of relapses is not directly related to cognitive impairment. The long-term trajectory of cognitive performance of 22 patients evaluated for up to 18 years and treated as part of an interferon-beta1a study is reported by Strober et al. The proportion of patients impaired increased over time, as did the extent of impairment, best assessed by the symbol digit modality test. Of note, the physical disability (as measured by the EDSS) did not differ at follow-up testing in those patients with cognitive impairment vs. those who
2 had remained cognitively intact, supporting the observations of Rosti-Otajarvi et al. that cognitive impairment is not closely aligned with other metrics of clinical disease severity. The emergence of oral therapies for MS has been heralded by patients as a major advance in the tolerability of treatments for relapsing-remitting disease. Kappos et al. provide safety data for fingolimod (0.5 mg daily dosing) exposure in 3500 patients, derived from the pivotal Phase III trial (FREEDOMS), from two further trials, and from postmarketing reporting. As anticipated, patients receiving fingolimod were more likely than those on placebo to experience symptomatic bradycardia (0.5%), macular edema (0.4%), and elevation in liver transaminases (9%). Perhaps surprisingly, no increase in serious infections was noted, although death from disseminated herpetic infection has occurred in two patients and culture-negative fungal infection in one other. Of a total 31 deaths reported in patients receiving fingolimod, 10 were unexplained, and post-marketing label changes specifically indicate that fingolimod should be avoided in patients with pre-existing cardiovascular disease or in patients concurrently receiving medications that alter cardiac status (such as beta-blockers). Phillips et al. discuss tolerability of a second oral therapy namely delayed release dimethyl fumarate (DMF), and suggest how to manage the common gastrointestinal side effects. Thirty MS experts completed a questionnaire regarding their patients experience with DMF. General suggestions were included about education of patients concerning the risk of flushing, administration of DMF with food, and the occasional need for anti-emetics or antidiarrheal therapies are presented. In addition to oral therapies, MS patients may now be prescribed intravenous therapies, notably natalizumab. In the present issue, Sangalli et al. describe the post-natalizumab clinical course of patients who discontinued therapy after 12 months of natalizumab exposure. There is a “high risk” window between months 2 and 10 after the last injection
B. Banwell et al. when most patients experience re-emergence of clinical MS disease activity. Administration of interferon-beta, glatiramer acetate, or fingolimod in the first year post natalizumab increased the likelihood of remaining “disease-activity free” to 30% as compared to patients not receiving therapy. Those who returned to natalizimab therapy regained disease control, in comparison to patients receiving other therapies, although the study is not designed to evaluate treatment efficacy comprehensively. In addition to clinically-focused manuscripts, biochemical analyses of CSF are presented. The lipid composition of the brain is altered in MS as described by Vuletic et al. who compared CSF levels of apoE, phospholipid transfer protein (PLTP), cholesterol and 25-hydrocholesterol between patients with MS and inflammatory and non-inflammatory controls. They then evaluate the relationship between CSF values and MRI metrics of brain volume in the MS group. Overall, MS patients have reduced apoE and PLTP compared to non-inflammatory controls but similar concentrations to that found in the CSF of patients with other inflammatory brain disorders. As such, CSF analysis of apoE and PLTP is unlikely to serve as an MS-specific biomarker panel, but may function as a correlate of disease severity given that the combination of apoE and PLTP concentrations contributed to the variance in brain volume within the MS group. In summary, the present issue of MSARD provides up-todate and clinically relevant new information about MS disease cognitive impact, and describes potential avenues for symptom management. The safety of emerging new therapies is a major theme of the present issue – clearly topical and relevant to clinicians and patients.
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 In this issue: “Clinical, therapeutic and cognitive outcome insights into MS” The present issue of MSARD contains a wide array of topics from clinical metrics of fatigue to biochemical alterations in lipid biogenesis. In an interesting evaluation of web-behavior, coined “infoepidemiology” reveals that the majority of online searches relating to MS center around celebrities who publically acknowledge their disease. Searches are also now more specific and relate to MS therapy or symptoms, as opposed to the broader search term “multiple sclerosis” – perhaps reflecting increasing sophistication of the internet audience (Brigo et al.). While the article did not delve into the content of web information, future studies exploring the influence of web-derived information, particularly information relating to celebrity views or treatment of celebrities, on patient behavior would be of interest. A detailed review of JC virus and progressive multifocal leukoencephalopathy (PML) is also provided – a timely and comprehensive overview that should be read by all clinicians prescribing the increasingly potent therapies for MS. In a second review article, the role of deep brain stimulation (DBS) for MS symptoms is provided. DBS has been shown to reduce pain particularly facial pain, tremor, and potentially for bladder dysfunction (detrusor overactivity). Reduction in tremor and a reduced likelihood of tremor over time is reported in patients receiving natalizumab (Rinker et al.) – raising the possibility that certain MS-related chronic symptoms may be reduced by more potent immunotherapies in MS. Several articles focus on clinical aspects of the disease. Roohani et al. challenge current perception that late-onset MS (first symptom after age 50 years) is a progressive disease from onset by showing that of 44% of 124 lateonset MS patients (identified from 3700 MS patients cared for in four MS centers in the USA) experienced relapsingremitting MS, 28% were diagnosed with SPMS, and only 20% were classified as primary progressive MS. The importance of relapses in MS is presented through questionnaire data from 103 MS patients treated with first line therapies in the United Kingdom (Duddy et al.). Relapses led to work absenteeism in 67% of patients, approximately 40% of whom had to then reduce work hours at least temporarily, and 60%
http://dx.doi.org/10.1016/j.msard.2014.05.004 2211-0348/& 2014 Published by Elsevier B.V.
of whom reported that they required additional support in the home during the relapse. The emotional burden of relapse-related limitation in function emerged as a major area of focus. While there may exist a reporting bias in the sample collected, the results nonetheless emphasize the impact of relapses on patient quality of life – an important consideration for therapies that reduce relapse rate. The impact of MS on clinical function was examined by Barr et al., who demonstrate that slowing of reaction time follows a 6 min walk test in individuals with MS-related motor impairment. These findings provide a reproducible measure for exercise-induced motor fatigue that may more relevantly reflect the day to day experience of individuals living with MS. The use of a fatigue-inducing activity prior to measures of reaction time, such as the 6 min walk, may serve as a valuable means to evaluate the impact of therapies on fatigue and motor performance. Cognitive performance, known to be impaired in 40–60% of MS patients at some point in their disease, was evaluated in two manuscripts in the present issue. Rosti-Otajarvi et al. evaluate cognitive performance as a correlate of disease phenotype and disease severity (as measured by quality of life indices or indices of mood). As expected, physical disability scores were higher in patients with progressive MS, but the authors did not find a strong relationship between disease phenotype and cognitive performance, quality of life indices or mood. An exception applied to relapsing-remitting patients who performed better on the symbol digit modality test than did the SPMS or PPMS patients. These findings support the more global impact of MS on cognition that appears relatively independent of physical disability and suggests that the clinical expression of MS in terms of relapses is not directly related to cognitive impairment. The long-term trajectory of cognitive performance of 22 patients evaluated for up to 18 years and treated as part of an interferon-beta1a study is reported by Strober et al. The proportion of patients impaired increased over time, as did the extent of impairment, best assessed by the symbol digit modality test. Of note, the physical disability (as measured by the EDSS) did not differ at follow-up testing in those patients with cognitive impairment vs. those who
2 had remained cognitively intact, supporting the observations of Rosti-Otajarvi et al. that cognitive impairment is not closely aligned with other metrics of clinical disease severity. The emergence of oral therapies for MS has been heralded by patients as a major advance in the tolerability of treatments for relapsing-remitting disease. Kappos et al. provide safety data for fingolimod (0.5 mg daily dosing) exposure in 3500 patients, derived from the pivotal Phase III trial (FREEDOMS), from two further trials, and from postmarketing reporting. As anticipated, patients receiving fingolimod were more likely than those on placebo to experience symptomatic bradycardia (0.5%), macular edema (0.4%), and elevation in liver transaminases (9%). Perhaps surprisingly, no increase in serious infections was noted, although death from disseminated herpetic infection has occurred in two patients and culture-negative fungal infection in one other. Of a total 31 deaths reported in patients receiving fingolimod, 10 were unexplained, and post-marketing label changes specifically indicate that fingolimod should be avoided in patients with pre-existing cardiovascular disease or in patients concurrently receiving medications that alter cardiac status (such as beta-blockers). Phillips et al. discuss tolerability of a second oral therapy namely delayed release dimethyl fumarate (DMF), and suggest how to manage the common gastrointestinal side effects. Thirty MS experts completed a questionnaire regarding their patients experience with DMF. General suggestions were included about education of patients concerning the risk of flushing, administration of DMF with food, and the occasional need for anti-emetics or antidiarrheal therapies are presented. In addition to oral therapies, MS patients may now be prescribed intravenous therapies, notably natalizumab. In the present issue, Sangalli et al. describe the post-natalizumab clinical course of patients who discontinued therapy after 12 months of natalizumab exposure. There is a “high risk” window between months 2 and 10 after the last injection
B. Banwell et al. when most patients experience re-emergence of clinical MS disease activity. Administration of interferon-beta, glatiramer acetate, or fingolimod in the first year post natalizumab increased the likelihood of remaining “disease-activity free” to 30% as compared to patients not receiving therapy. Those who returned to natalizimab therapy regained disease control, in comparison to patients receiving other therapies, although the study is not designed to evaluate treatment efficacy comprehensively. In addition to clinically-focused manuscripts, biochemical analyses of CSF are presented. The lipid composition of the brain is altered in MS as described by Vuletic et al. who compared CSF levels of apoE, phospholipid transfer protein (PLTP), cholesterol and 25-hydrocholesterol between patients with MS and inflammatory and non-inflammatory controls. They then evaluate the relationship between CSF values and MRI metrics of brain volume in the MS group. Overall, MS patients have reduced apoE and PLTP compared to non-inflammatory controls but similar concentrations to that found in the CSF of patients with other inflammatory brain disorders. As such, CSF analysis of apoE and PLTP is unlikely to serve as an MS-specific biomarker panel, but may function as a correlate of disease severity given that the combination of apoE and PLTP concentrations contributed to the variance in brain volume within the MS group. In summary, the present issue of MSARD provides up-todate and clinically relevant new information about MS disease cognitive impact, and describes potential avenues for symptom management. The safety of emerging new therapies is a major theme of the present issue – clearly topical and relevant to clinicians and patients.
Editors-in-Chief Brenda Banwell, Gavin Giovannoni, Chris Hawkes, Fred Lublin
