Summary In the past 20 years the treatment scenario of multiple sclerosis has radically changed. The increasing availability of effective disease-modifying therapies has shifted the aim of ...therapeutic interventions from a reduction in relapses and disability accrual, to the absence of any sign of clinical or MRI activity. The choice for therapy is increasingly complex and should be driven by an appropriate knowledge of the mechanisms of action of the different drugs and of their risk-benefit profile. Because the relapsing phase of the disease is characterised by inflammation, treatment should be started as early as possible and aim to re-establish the normal complex interactions in the immune system. Before starting a treatment, neurologists should carefully consider the state of the disease, its prognostic factors and comorbidities, the patient's response to previous treatments, and whether the patient is likely to accept treatment-related risks in order to maximise benefits and minimise risks. Early detection of suboptimum responders, thanks to accurate clinical monitoring, will allow clinicians to redesign treatment strategies where necessary.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Summary The uneven distribution of multiple sclerosis (MS) across populations can be attributed to differences in genes and the environment and their interaction. Prevalence and incidence surveys ...could be affected by inaccuracy of diagnosis and ascertainment, and prevalence also depends on survival. These sources of error might play a part in the geographical and temporal variations. Our literature search and meta-regression analyses indicated an almost universal increase in prevalence and incidence of MS over time; they challenge the well accepted theory of a latitudinal gradient of incidence of MS in Europe and North America, while this gradient is still apparent for Australia and New Zealand; and suggest a general, although not ubiquitous, increase in incidence of MS in females. The latter observation should prompt epidemiological studies to focus on changes in lifestyle in females. New insights into gene–environment and gene–gene interactions complicate interpretations of demographic epidemiology and have made obsolete the idea of simple causative associations between genes or the environment and MS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background:
Comorbidity is an area of increasing interest in multiple sclerosis (MS).
Objective:
The objective of this review is to estimate the incidence and prevalence of comorbidity in people with ...MS and assess the quality of included studies.
Methods:
We searched the PubMed, SCOPUS, EMBASE and Web of Knowledge databases, conference proceedings, and reference lists of retrieved articles. Two reviewers independently screened abstracts. One reviewer abstracted data using a standardized form and the abstraction was verified by a second reviewer. We assessed study quality using a standardized approach. We quantitatively assessed population-based studies using the I2 statistic, and conducted random-effects meta-analyses.
Results:
We included 249 articles. Study designs were variable with respect to source populations, case definitions, methods of ascertainment and approaches to reporting findings. Prevalence was reported more frequently than incidence; estimates for prevalence and incidence varied substantially for all conditions. Heterogeneity was high.
Conclusion:
This review highlights substantial gaps in the epidemiological knowledge of comorbidity in MS worldwide. Little is known about comorbidity in Central or South America, Asia or Africa. Findings in North America and Europe are inconsistent. Future studies should report age-, sex- and ethnicity-specific estimates of incidence and prevalence, and standardize findings to a common population.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Comorbidity in Multiple Sclerosis Magyari, Melinda; Sorensen, Per Soelberg
Frontiers in neurology,
08/2020, Volume:
11
Journal Article
Peer reviewed
Open access
Comorbidities in patients with multiple sclerosis (MS) has become an area of increasing interest in the recent years. A comorbidity is defined as any additional disease that coexists in an individual ...with a given index disease and that is not an obvious complication of the index disease. The aim of this review is to describe the current evidence regarding the range of comorbidities in the population with MS reported in different countries and the current knowledge about the influence of comorbidities on the clinical features and therapeutic challenges in MS. Certain comorbidities are more prevalent in people with MS such as depression, anxiety, cerebro- and cardiovascular diseases, and certain autoimmune disorders such as diabetes, thyroid disease, and inflammatory bowel disease. A previous perception of a trend toward a lower overall risk of cancer in patients with MS appears to be challenged, but there is no evidence on any higher occurrence of malignancies in the population with MS. Comorbidities may modify the clinical presentation of MS, and have implications for treatment choice, adherence, and outcome. Several comorbid conditions are associated with increased disability progression, including diabetes, hypertension, and chronic obstructive pulmonary disease. Comorbidities are common in MS from the time of diagnosis and may account for some of the heterogeneity observed in MS, including diagnostic delay, clinical presentation, degree of disability progression, rate of health care utilization, working ability, employment status, and quality of life. Coexisting diseases and polypharmacy increase the complexity of patient management and poses major challenges, particularly with the increasing number of immunosuppressive disease-modifying therapies.
In this 96-week, placebo-controlled trial, oral cladribine reduced relapse rates and lowered the risk of sustained disability in patients with relapsing–remitting multiple sclerosis. Patients who ...were treated with cladribine had large reductions in lymphocyte counts and more infections, including herpes zoster and one death from reactivation of tuberculosis.
Oral cladribine reduced relapse rates and lowered the risk of sustained disability in patients with relapsing–remitting multiple sclerosis. Patients had large reductions in lymphocyte counts and more infections, including herpes zoster and one death from reactivation of tuberculosis.
Multiple sclerosis is a chronic and debilitating autoimmune disorder of the central nervous system, in which T and B cells are believed to play a major pathophysiological role.
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Treatment benefits and disease modification can be obtained with the currently approved parenteral immunomodulatory and immunosuppressant therapies: interferon beta, glatiramer acetate, mitoxantrone, and natalizumab. However, treatment responses are often less than complete, and concern regarding safety and side-effect profiles may limit the general use of these drugs. The need for parenteral administration may present relative or absolute barriers to access, limiting treatment adherence and long-term outcomes.
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Intracellular accumulation of the active . . .
Background:
In the 2-year CLARITY study, cladribine tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing–remitting multiple ...sclerosis (MS).
Objective:
To assess the safety and efficacy of cladribine treatment in a 2-year Extension study.
Methods:
In this 2-year Extension study, placebo recipients from CLARITY received cladribine 3.5 mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5 mg/kg or placebo, with blind maintained.
Results:
A total of 806 patients were assigned to treatment. Adverse event rates were generally similar between groups, but lymphopenia Grade ⩾ 3 rates were higher with cladribine than placebo (Grade 4 lymphopenia occurred infrequently). In patients receiving cladribine 3.5 mg/kg in CLARITY and experiencing lymphopenia Grade ⩾ 3 in the Extension, >90% of those treated with cladribine 3.5 mg/kg and all treated with placebo in the Extension, recovered to Grade 0–1 by study end. Cladribine treatment in CLARITY produced efficacy improvements that were maintained in patients treated with placebo in the Extension; in patients treated with cladribine 3.5 mg/kg in CLARITY, approximately 75% remained relapse-free when given placebo during the Extension.
Conclusion:
Cladribine tablets treatment for 2 years followed by 2 years’ placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. No clinical improvement in efficacy was apparent following further treatment with cladribine tablets after the initial 2-year treatment period in this trial setting.
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Summary Background On the basis of various clinical and MRI measurements, the phase 3 Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study in patients with relapsing–remitting ...multiple sclerosis (RRMS) showed that short-course oral treatment with cladribine at cumulative doses of 3·5 and 5·25 mg/kg over 96 weeks was more effective than placebo. Achieving sustained freedom from disease activity is becoming a viable treatment goal in RRMS; we therefore aimed to assess the effects of cladribine on this composite outcome measure by doing a post-hoc analysis of data from the CLARITY study. Methods Freedom from disease activity is composed of three components that are commonly used individually as endpoints in clinical trials; it is defined as the patient having no relapse, no 3-month sustained change in expanded disability status scale (EDSS) score, and no new MRI lesions (no T1 gadolinium-enhancing or active T2 lesions) over a specified period. We assessed the effect of two doses of cladribine tablets versus placebo on the proportion of patients who were free from disease activity based on the individual components, all pair-wise combinations, and the composite of the three components (freedom from disease activity). Freedom from disease activity was analysed at 24, 48, and 96 weeks, and in subgroups of patients stratified according to baseline demographic and disease characteristics (age, disease duration, previous treatment with disease-modifying therapy, T1 gadolinium-enhancing lesion number, T2 lesion volume, EDSS score, number of previous relapses, and highly active disease). Findings Of the 1326 patients randomly assigned to treatment in the CLARITY study, 1192 were assessable for freedom from disease activity at 96 weeks. Over 24 weeks, 266 (67%) of 395 patients in the cladribine 3·5 mg/kg group and 283 (70%) of 406 in the cladribine 5·25 mg/kg group were free from disease activity, versus 145 (39%) of 373 in the placebo group (odds ratio OR 3·31, 95% CI 2·46–4·46 for the 3·5 mg/kg group; and 3·68, 2·73–4·97 for the 5·25 mg/kg group; both p<0·0001). Over 48 weeks, 208 (54%) of 384 patients in the cladribine 3·5 mg/kg group and 222 (56%) of 396 patients in the cladribine 5·25 mg/kg group were free from disease activity, versus 86 (24%) of 360 patients in the placebo group (OR 3·80, 2·77–5·22 for the 3·5 mg/kg group; 4·13, 3·02–5·66 for the 5·25 mg/kg group; both p<0·0001). Over 96 weeks, 178 (44%) of 402 patients in the cladribine 3·5 mg/kg group and 189 (46%) of 411 patients in the cladribine 5·25 mg/kg group were free from disease activity, versus 60 (16%) of 379 patients in the placebo group (OR 4·28, 3·05–6·02 for the 3·5 mg/kg group; 4·62, 3·29–6·48 for the 5·25 mg/kg group; both p<0·0001). The effects of cladribine tablets on freedom from disease activity were significant across all patient subgroups. Interpretation Treatment with cladribine tablets significantly increased the proportion of patients with sustained freedom from disease activity over 96 weeks compared with placebo. Sustained freedom from disease activity could become an important measure of therapeutic response in RRMS. Funding Merck Serono SA–Geneva, Switzerland; an affiliate of Merck, Darmstadt, Germany.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Multiple sclerosis (MS) is an inflammatory and neurodegenerative demyelinating disease of the central nervous system (CNS), most likely autoimmune in origin, usually beginning in early adulthood. The ...aetiology of the disease is not well understood; it is viewed currently as a multifactorial disease which results from complex interactions between genetic predisposition and environmental factors, of which a few are potentially modifiable. Improving our understanding of these factors can lead to new and more effective approaches to patient counselling and, possibly, prevention and management of the disease. The 2016 focused workshop of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) addressed the topic of environmental, modifiable risk factors for MS, gathering experts from around the world, to collate experimental and clinical research into environmental factors that have been associated with the disease onset and, in a few cases, disease activity and progression. A number of factors, including infections, vitamin D deficiency, diet and lifestyle factors, stress and comorbidities, were discussed. The meeting provided a forum to analyse available evidence, to identify inconsistencies and gaps in current knowledge and to suggest avenues for future research.
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In the absence of a vaccine or effective treatment for COVID-19, countries have adopted nonpharmaceutical interventions (NPIs) such as social distancing and full lockdown. An objective and ...quantitative means of passively monitoring the impact and response of these interventions at a local level is needed.
We aim to explore the utility of the recently developed open-source mobile health platform Remote Assessment of Disease and Relapse (RADAR)-base as a toolbox to rapidly test the effect and response to NPIs intended to limit the spread of COVID-19.
We analyzed data extracted from smartphone and wearable devices, and managed by the RADAR-base from 1062 participants recruited in Italy, Spain, Denmark, the United Kingdom, and the Netherlands. We derived nine features on a daily basis including time spent at home, maximum distance travelled from home, the maximum number of Bluetooth-enabled nearby devices (as a proxy for physical distancing), step count, average heart rate, sleep duration, bedtime, phone unlock duration, and social app use duration. We performed Kruskal-Wallis tests followed by post hoc Dunn tests to assess differences in these features among baseline, prelockdown, and during lockdown periods. We also studied behavioral differences by age, gender, BMI, and educational background.
We were able to quantify expected changes in time spent at home, distance travelled, and the number of nearby Bluetooth-enabled devices between prelockdown and during lockdown periods (P<.001 for all five countries). We saw reduced sociality as measured through mobility features and increased virtual sociality through phone use. People were more active on their phones (P<.001 for Italy, Spain, and the United Kingdom), spending more time using social media apps (P<.001 for Italy, Spain, the United Kingdom, and the Netherlands), particularly around major news events. Furthermore, participants had a lower heart rate (P<.001 for Italy and Spain; P=.02 for Denmark), went to bed later (P<.001 for Italy, Spain, the United Kingdom, and the Netherlands), and slept more (P<.001 for Italy, Spain, and the United Kingdom). We also found that young people had longer homestay than older people during the lockdown and fewer daily steps. Although there was no significant difference between the high and low BMI groups in time spent at home, the low BMI group walked more.
RADAR-base, a freely deployable data collection platform leveraging data from wearables and mobile technologies, can be used to rapidly quantify and provide a holistic view of behavioral changes in response to public health interventions as a result of infectious outbreaks such as COVID-19. RADAR-base may be a viable approach to implementing an early warning system for passively assessing the local compliance to interventions in epidemics and pandemics, and could help countries ease out of lockdown.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE:To investigate the effect of chronic comorbidity on the time of diagnosis of multiple sclerosis (MS) and on mortality in MS.
METHODS:We conducted a population-based, nationwide cohort study ...including all incident MS cases in Denmark with first MS symptom between 1980 and 2005. To investigate the time of diagnosis, we compared individuals with and without chronic comorbidity using multinomial logistic regression. To investigate mortality, we used Cox regression with time-dependent covariates, following study participants from clinical MS onset until endpoint (death) or to the end of the study, censuring at emigration.
RESULTS:We identified 8,947 individuals with clinical onset of MS between 1980 and 2005. In the study of time of diagnosis, we found statistically significant odds ratios for longer diagnostic delays with cerebrovascular comorbidity (2.01 1.44–2.80; <0.0005), cardiovascular comorbidity (4.04 2.78–5.87; <0.0005), lung comorbidity (1.93 1.42–2.62; <0.0005), diabetes comorbidity (1.78 1.04–3.06; 0.035), and cancer comorbidity (2.10 1.20–3.67; 0.009). In the mortality study, we found higher hazard ratios with psychiatric comorbidity (2.42 1.67–3.01; <0.0005), cerebrovascular comorbidity (2.47 2.05–2.79; <0.0005), cardiovascular comorbidity (1.68 1.39–2.03; <0.0005), lung comorbidity (1.23 1.01–1.50; 0.036), diabetes comorbidity (1.39 1.05–1.85; 0.021), cancer comorbidity (3.51 2.94–4.19; <0.0005), and Parkinson disease comorbidity (2.85 1.34–6.06; 0.007).
CONCLUSIONS:An increased awareness of both the necessity of neurologic evaluation of new neurologic symptoms in persons with preexisting chronic disease and of optimum treatment of comorbidity in MS is critical.
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