SARS-CoV-2 infection increases long-term multiple sclerosis disease activity and all-cause mortality in an underserved inner-city population.

BACKGROUND: Although certain subsets patients with multiple sclerosis (MS), an immune-mediated disorder, are at higher risk of worse acute COVID-19 outcomes compared to the general population, it is not clear whether SARS-CoV-2 infection impacts long-term outcomes compared with MS patients without COVID-19 infection. OBJECTIVES: This study investigated MS disease activity and mortality 3.5 years post SARS-CoV-2 infection and compared with MS patients without COVID-19. METHODS: This retrospective study evaluated 1,633 patients with MS in the Montefiore Health System in the Bronx from January 2016 to July 2023. This health system serves a large minority population and was an epicenter for the early pandemic and subsequent surges of infection. Positive SARS-CoV-2 infection was determined by a positive polymerase-chain-reaction test. Primary outcomes were all-cause mortality, and optic neuritis post SARS-CoV-2 infection. Secondary outcomes included change in disease-modifying therapy (DMT), treatment with high-dose methylprednisolone, cerebellar deficits, relapse, and all-cause hospitalization post-infection. RESULTS: MS patients with COVID-19 had similar demographics but higher prevalence of pre-existing major comorbidities (hypertension, type-2 diabetes, chronic obstructive pulmonary disease, congestive heart failure, chronic kidney disease, and coronary artery disease), optic neuritis, and history of high dose steroid treatment for relapses compared to MS patients without COVID-19. MS patients with COVID-19 had greater risk of mortality (adjusted HR=4.34[1.67, 11.30], p < 0.005), greater risk of post infection optic neuritis (adjusted HR=2.97[1.58, 5.58], p < 0.005), higher incidence of methylprednisolone treatment for post infection acute relapse (12.65% vs. 2.54 %, p < 0.001), and more hospitalization (78.92% vs. 66.81 %, p < 0.01), compared to MS patients without COVID-19. CONCLUSIONS: MS patients who survived COVID-19 infection experienced worse long-term outcomes, as measured by treatment for relapse, hospitalization and mortality. Identifying risk factors for worse long-term outcomes may draw clinical attention to the need for careful follow-up of at-risk individuals post-SARS-CoV-2 infection.

Autoimmunity Increases Susceptibility to and Mortality from Sepsis.

We recently demonstrated how sepsis influences the subsequent development of experimental autoimmune encephalomyelitis (EAE) presented a conceptual advance in understanding the postsepsis chronic immunoparalysis state. However, the reverse scenario (autoimmunity prior to sepsis) defines a high-risk patient population whose susceptibility to sepsis remains poorly defined. In this study, we present a retrospective analysis of University of Iowa Hospital and Clinics patients demonstrating increased sepsis prevalence among multiple sclerosis (MS), relative to non-MS, patients. To interrogate how autoimmune disease influences host susceptibility to sepsis, well-established murine models of MS and sepsis and EAE and cecal ligation and puncture, respectively, were used. EAE, relative to non-EAE, mice were highly susceptible to sepsis-induced mortality with elevated cytokine storms. These results were further recapitulated in LPS and Streptococcus pneumoniae sepsis models. This work highlights both the relevance of identifying highly susceptible patient populations and expands the growing body of literature that host immune status at the time of septic insult is a potent mortality determinant.

Breast Cancer Survival in Multiple Sclerosis: A Matched Cohort Study.

OBJECTIVE: To test the hypotheses that overall survival and cancer-specific survival after breast cancer diagnosis would be lower in persons with multiple sclerosis (MS) as compared to persons without MS using a retrospective matched cohort design. METHODS: We applied a validated case definition to population-based administrative data in Manitoba and Ontario, Canada, to identify women with MS. We linked the MS cohorts to cancer registries to identify women with breast cancer. Then we selected 4 breast cancer controls without MS matched on birth year, cancer diagnosis year, and region. We compared all-cause survival between cohorts using Cox proportional hazards regression adjusting for age at cancer diagnosis, cancer diagnosis period, income quintile, region, and Elixhauser comorbidity score. We compared cancer-specific survival between cohorts using a multivariable cause-specific hazards model. We pooled findings between provinces using meta-analysis. RESULTS: We included 779 patients with MS and 3,116 controls with breast cancer. Most patients with stage data (1,976/2,822 [70.0%]) were diagnosed with stage I or II breast cancer and the mean (SD) age at diagnosis was 57.8 (10.7) years. After adjustment for covariates, MS was associated with a 28% increased hazard for all-cause mortality (hazard ratio [HR] 1.28; 95% confidence interval [CI] 1.08-1.53), but was not associated with altered cancer-specific survival (HR 0.98; 95% CI 0.65-1.46). CONCLUSION: Women with MS have lower all-cause survival after breast cancer diagnosis than women without MS. Future studies should confirm these findings in other populations and identify MS-specific factors associated with worse prognosis.

Effects of Age and Disease Duration on Excess Mortality in Patients With Multiple Sclerosis From a French Nationwide Cohort.

OBJECTIVE: To determine the effects of current age and disease duration on excess mortality in multiple sclerosis (MS), we describe the dynamics of excess death rates over these 2 time scales and study the effect of age at MS clinical onset on these dynamics, separately in each initial phenotype. METHODS: We used data from 18 French MS expert centers participating in the Observatoire Français de la Sclérose en Plaques. Patients with MS living in metropolitan France and having a clinical onset between 1960 and 2014 were included. Vital status was updated on January 1, 2016. For each MS phenotype separately (relapsing onset [RMS] or primary progressive [PPMS]), we used an innovative statistical method to model the logarithm of excess death rates by a multidimensional penalized spline of age and disease duration. RESULTS: Among 37,524 patients (71% women, mean age at MS onset ± SD 33.0 ± 10.6 years), 2,883 (7.7%) deaths were observed and 7.8% of patients were lost to follow-up. For patients with RMS, there was no excess mortality during the first 10 years after disease onset; afterwards, whatever the age at onset, excess death rates increased with current age. From current age 70, the excess death rate values converged and became identical whatever the age at disease onset, which means that disease duration had no more effect. Excess death rates were higher in men, with an excess hazard ratio of 1.46 (95% confidence interval 1.25-1.70). In contrast, in patients with PPMS, excess death rates rapidly increased from disease onset, and were associated with age at onset, but not with sex. CONCLUSIONS: In RMS, current age has a stronger effect on MS mortality than disease duration, while their respective effects are not clear in PPMS.

A short-term exercise program in patients with multiple sclerosis: is body mass index important?

Obesity is a health problem that can exacerbate the symptoms of multiple sclerosis (MS). In the current study, we aimed to investigate the effectiveness of a short-term exercise program on fatigue, depression, anxiety, and walking performance in normal-weight and overweight patients with MS (PwMS). Sixty-two PwMS were divided into groups according to their BMI (BMI normal/BMI high). Also, they were all included in the exercise program. The participants took a moderate-intensity walking program 5 days a week for 4 weeks, including 30 min between 5 min of warm-up and 5 min of cooling periods. Also, patients underwent breathing, posture, flexibility, and stretching exercises for 4 weeks. Fatigue, depression, anxiety, 6-minute walking test (6MWT), and BMI were measured before and after the 4 weeks. After the exercise program, there were statistically significant improvements in fatigue, depression, anxiety, and the 6MWT. However, no relation could be detected between the examined variables and BMI. All patients participated effectively in the exercise program, regardless of BMI. The results obtained from this study support that a short-term exercise program is an effective therapeutic intervention, unrelated to BMI, in improving fatigue, depression, anxiety, and walking performance in PwMS.

Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis.

Importance: Emergence of SARS-CoV-2 causing COVID-19 prompted the need to gather information on clinical outcomes and risk factors associated with morbidity and mortality in patients with multiple sclerosis (MS) and concomitant SARS-CoV-2 infections. Objective: To examine outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with MS. Design, Setting, and Participants: This analysis used deidentified, cross-sectional data on patients with MS and SARS-CoV-2 infection reported by health care professionals in North American academic and community practices between April 1, 2020, and December 12, 2020, in the COVID-19 Infections in MS Registry. Health care professionals were asked to report patients after a minimum of 7 days from initial symptom onset and after sufficient time had passed to observe the COVID-19 disease course through resolution of acute illness or death. Data collection began April 1, 2020, and is ongoing. Exposures: Laboratory-positive SARS-CoV-2 infection or highly suspected COVID-19. Main Outcomes and Measures: Clinical outcome with 4 levels of increasing severity: not hospitalized, hospitalization only, admission to the intensive care unit and/or required ventilator support, and death. Results: Of 1626 patients, most had laboratory-positive SARS-CoV-2 infection (1345 [82.7%]), were female (1202 [74.0%]), and had relapsing-remitting MS (1255 [80.4%]). A total of 996 patients (61.5%) were non-Hispanic White, 337 (20.8%) were Black, and 190 (11.7%) were Hispanic/Latinx. The mean (SD) age was 47.7 (13.2) years, and 797 (49.5%) had 1 or more comorbidity. The overall mortality rate was 3.3% (95% CI, 2.5%-4.3%). Ambulatory disability and older age were each independently associated with increased odds of all clinical severity levels compared with those not hospitalized after adjusting for other risk factors (nonambulatory: hospitalization only, odds ratio [OR], 2.8 [95% CI, 1.6-4.8]; intensive care unit/required ventilator support, OR, 3.5 [95% CI, 1.6-7.8]; death, OR, 25.4 [95% CI, 9.3-69.1]; age [every 10 years]: hospitalization only, OR, 1.3 [95% CI, 1.1-1.6]; intensive care unit/required ventilator support, OR, 1.3 [95% CI, 0.99-1.7]; death, OR, 1.8 [95% CI, 1.2-2.6]). Conclusions and Relevance: In this registry-based cross-sectional study, increased disability was independently associated with worse clinical severity including death from COVID-19. Other risk factors for worse outcomes included older age, Black race, cardiovascular comorbidities, and recent treatment with corticosteroids. Knowledge of these risk factors may improve the treatment of patients with MS and COVID-19 by helping clinicians identify patients requiring more intense monitoring or COVID-19 treatment.

Cancer Incidence and Mortality Rates in Multiple Sclerosis: A Matched Cohort Study.

OBJECTIVE: To determine whether cancer risk differs in people with and without multiple sclerosis (MS), we compared incidence rates and cancer-specific mortality rates in MS and matched cohorts using population-based data sources. METHODS: We conducted a retrospective matched cohort study using population-based administrative data from Manitoba and Ontario, Canada. We applied a validated case definition to identify MS cases, then selected 5 controls without MS matched on birth year, sex, and region. We linked these cohorts to cancer registries, and estimated incidence of breast, colorectal, and 13 other cancers. For breast and colorectal cancers, we constructed Cox models adjusting for age at the index date, area-level socioeconomic status, region, birth cohort year, and comorbidity. We pooled findings across provinces using meta-analysis. RESULTS: We included 53,983 MS cases and 269,915 controls. Multivariable analyses showed no difference in breast cancer risk (pooled hazard ratio [HR] 0.92 [95% confidence interval (CI) 0.78-1.09]) or colorectal cancer risk (pooled HR 0.83 [95% CI 0.64-1.07]) between the cohorts. Mortality rates for breast and colorectal did not differ between cohorts. Bladder cancer incidence and mortality rates were higher among the MS cohort. Although the incidence of prostate, uterine, and CNS cancers differed between the MS and matched cohorts, mortality rates did not. CONCLUSION: The incidence of breast and colorectal cancers does not differ between persons with and without MS; however, the incidence of bladder cancer is increased. Reported differences in the incidence of some cancers in the MS population may reflect ascertainment differences rather than true differences.

Prevalencia e impacto de las comorbilidades en pacientes con esclerosis múltiple / Prevalence and impact of comorbidities in patients with multiple sclerosis

INTRODUCCIÓN: La esclerosis múltiple es una enfermedad crónica, de origen inflamatorio y degenerativo, del sistema nervioso central. Se caracteriza en la mayoría de los casos por la aparición de manera recurrente de brotes de déficit neurológico focal, que con el tiempo puede tornarse progresivo. Dado el carácter crónico de la enfermedad, los pacientes pueden presentar enfermedades adicionales (comorbilidades), que impactan de diferentes maneras en la historia natural de la enfermedad y en su tratamiento. OBJETIVO: Resumir la evidencia disponible respecto a la influencia de las comorbilidades en la historia natural de la esclerosis múltiple. DESARROLLO: Los pacientes con esclerosis múltiple tienen un riesgo mayor que la población general de desarrollar comorbilidades tanto agudas como crónicas. Se ha demostrado que las comorbilidades pueden retrasar el diagnóstico de esclerosis múltiple después del inicio clínico, incrementar la tasa de brotes y aumentar la tasa de acumulación de la discapacidad. Las comorbilidades también influyen en aspectos relacionados con la elección del tratamiento y la adhesión terapéutica. Finalmente, las comorbilidades también aumentan la tasa de mortalidad y la calidad de vida de los pacientes con esclerosis múltiple. CONCLUSIONES: El cribado, el diagnóstico y el tratamiento de las comorbilidades son un aspecto clave del cuidado de los pacientes con esclerosis múltiple para mejorar su pronóstico a largo plazo en cuanto a discapacidad, calidad de vida y mortalidad

INTRODUCTION: Multiple sclerosis is a chronic, inflammatory and degenerative disease of the central nervous system. In most cases it is characterised by the recurring focal neurological deficit, which may become progressive over time. Given the chronic nature of the disease, patients may present with additional diseases (comorbidities), which affect the natural history of the disease and its treatment in different ways. AIM: To summarise the available evidence regarding the influence of comorbidities on the natural history of multiple sclerosis. DEVELOPMENT: Patients with multiple sclerosis are at greater risk than the general population of developing both acute and chronic comorbidities. It has been shown that comorbidities can delay the diagnosis of multiple sclerosis after clinical onset, increase the rates of relapses and of accumulation of disability. Comorbidities also influence aspects of the choice of treatment and therapy adherence. Finally, comorbidities also increase the mortality rate and reduce the quality of life of patients with multiple sclerosis. CONCLUSIONS: Screening, diagnosis and treatment of comorbidities are a key aspect of caring for patients with multiple sclerosis to improve their long-term prognosis in terms of disability, quality of life and mortality

MSCOVID19: Using social media to achieve rapid dissemination of health information.

BACKGROUND AND OBJECTIVE: The global COVID-19 pandemic creates an obvious acute health care resourcing and response problem. The different timing of pandemic peak in geographically distinct locations creates a short window of response opportunity. Rapid dissemination of medical information from early affected areas to later ones is therefore crucial to optimise planning. Formulating the best system response for at-risk patient populations is especially complex. People with multiple sclerosis (pwMS) are exposed to long-term immunosuppressive disease modifying treatments (DMTs) and, in theory, could be at increased risk of contracting the virus and developing complications. Social media, such as Twitter, can provide a global platform to rapidly share information and individual experiences. METHODS AND RESULTS: This report summarizes the case experience of pwMS with COVID-19 infection in the first month of the pandemic as reported on Twitter using the #MSCOVID19 hashtag. 26 individual cases of COVID-19 in pwMS were reported from Europe and the United States of America. The cases involved a combination of relapsing and progressive MS phenotypes treated with a range of DMT (5 anti CD20 therapy, 4 cladribine, 4 fingolimod, 4 injectables, 3 alemtuzumab, 2 dimethyl fumarate, 2 untreated, 1 teriflunomide, 1 natalizumab). The cases shared present the earliest reported data on outcomes of COVID-19 infection in pwMS. Whilst limited, the cautiously reassuring nature of these early cases assisted in clinical management by allowing neurologists to continuously reassess their approach to DMT management.

Serum neurofilament light chain predicts long term clinical outcomes in multiple sclerosis.

Serum neurofilament light chain (NfL) is emerging as an important biomarker in multiple sclerosis (MS). Our objective was to evaluate the prognostic value of serum NfL levels obtained close to the time of MS onset with long-term clinical outcomes. In this prospective cohort study, we identified patients with serum collected within 5 years of first MS symptom onset (baseline) with more than 15 years of routine clinical follow-up. Levels of serum NfL were quantified in patients and matched controls using digital immunoassay (SiMoA HD-1 Analyzer, Quanterix). Sixty-seven patients had a median follow-up of 18.9 years (range 15.0-27.0). The median serum NfL level in patient baseline samples was 10.1 pg/mL, 38.5% higher than median levels in 37 controls (7.26 pg/mL, p = 0.004). Baseline NfL level was most helpful as a sensitive predictive marker to rule out progression; patients with levels less 7.62 pg/mL were 4.3 times less likely to develop an EDSS score of ≥ 4 (p = 0.001) and 7.1 times less likely to develop progressive MS (p = 0.054). Patients with the highest NfL levels (3rd-tertile, > 13.2 pg/mL) progressed most rapidly with an EDSS annual rate of 0.16 (p = 0.004), remaining significant after adjustment for sex, age, and disease-modifying treatment (p = 0.022). This study demonstrates that baseline sNfL is associated with long term clinical disease progression. sNfL may be a sensitive marker of subsequent poor clinical outcomes.

Epidemiology of multiple sclerosis in Santiago de Compostela (Spain).

OBJECTIVES: To analyze the frequency and demographic characteristics of multiple sclerosis (MS) in the Council of Santiago de Compostela (SPAIN). MATERIAL AND METHODS: The patients diagnosed with MS according to the McDonald 2010 diagnostic criteria were identified within the population of the District of Santiago de Compostela. Several sources were used (records and databases from Hospital, General Practitioners, Private Clinics, and the MS Patients Association). Demographic and clinical data were obtained from the electronic files. RESULTS: The incidence of MS between 2010 and 2015 was 8/100 000/year (95% CI: 6-10), and the prevalence on December 31, 2015, was 152/100 000 (95% CI: 127-176). The age-standardized prevalence (using the European Standard Population 2013) was 137 (95% CI: 114-159) and the incidence of 7 (95% CI: 2-12). The female:male ratio was 1.84, the mean age at the first symptom was 32.23 years, the diagnosis was delayed 3.12 years, and the mean EDSS was 2.82. 71.17% had relapsing-remitting MS, 16.55% secondary progressive MS, 7.59% primary progressive MS, and 0.69% progressive relapsing MS. A disease-modifying treatment was established in 62.76% of patients in a mean of 1.96 years after the diagnosis. CONCLUSIONS: The northwest of Spain is a high-risk area for MS, with frequencies similar to other Atlantic regions and higher than the rest of the country.

Risk Factors for Suicide in a National Sample of Veterans With Multiple Sclerosis.

OBJECTIVES: To examine risk factors in the year before suicide in a national sample of United States veterans with multiple sclerosis (MS), as well as means of suicide and receipt of mental health services prior to death. DESIGN: Case control study. Individuals in the Veterans Affairs MS National Data Repository were linked to the National Death Index Plus to obtain death records, including specific causes of death. Participants were veterans with MS who died by suicide and randomly selected nonsuicide MS controls (5 per participant) who were alive at the time of the index suicide. Mental health disorders and medical comorbidities were identified in the year before death for suicides and during the identical time period for controls. SETTING: Veterans Health Administration. PARTICIPANTS: Veterans (N=426) who received treatment for MS in the United States Veterans Health Administration between 1999 and 2011. There were 71 deaths by suicide and 355 randomly selected controls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Suicide. RESULTS: Results from the adjusted multivariable model suggest that the following factors were associated with an increased risk for suicide: male sex (odds ratio [OR], 3.60; 95% confidence interval [CI], 1.35-9.42), depression (OR, 1.82; 95% CI, 1.03-3.23), and alcohol use disorder (OR, 3.10; 95% CI, 1.38-6.96). Half (50.7%) had a mental health appointment in the year before suicide. The primary means of suicide was by firearm (62.0%). CONCLUSIONS: Routine assessment of suicide risk in individuals with MS is warranted, particularly for those with recent history of depression or alcohol use disorder.

Risk of Mortality in Immigrants with Multiple Sclerosis in Ontario, Canada.

INTRODUCTION: Little is known about how mortality in multiple sclerosis (MS) may differ based on sociodemographic factors, such as immigrant status. We compared mortality in immigrants versus long-term residents with MS in Ontario, Canada. METHODS: In this retrospective cohort study, we applied a validated algorithm to linked, population-based immigration and health administrative data to identify incident MS cases in Ontario between 1994 and 2014. We identified date of death, if it occurred. We used a Cox model adjusting for age, sex, income, and comorbidity, to compare survival in immigrants versus long-term residents. RESULTS: There were 23,603 incident MS cases of whom 1,410 (6.0%) were immigrants. After adjusting for covariates, risk of death was higher in immigrants in the first year after diagnosis (hazard ratio [HR] 1.66; 95% CI 1.05-2.63, p = 0.031). However, in years 1-5 (HR 0.63; 95% CI 0.40-0.98, p = 0.041) and 5-10 (HR 0.42; 95% CI 0.24-0.75, p = 0.003) after diagnosis, risk of death was lower in immigrants. Older age at onset and comorbidity were associated with higher mortality; female sex and higher socioeconomic status were associated with lower mortality. CONCLUSIONS: In this large population with universal access to health care, immigrants with MS had higher mortality compared to long-term residents in the first year after onset and lower mortality thereafter. Lower mortality in immigrants to Canada is well described and thought to be due to the healthy immigrant effect. Higher mortality in the first year after MS onset warrants further investigation as some early deaths may be preventable.

Population size estimation with interval censored counts and external information: Prevalence of multiple sclerosis in Rome.

We discuss Bayesian log-linear models for incomplete contingency tables with both missing and interval censored cells, with the aim of obtaining reliable population size estimates. We also discuss use of external information on the censoring probability, which may substantially reduce uncertainty. We show in simulation that information on lower bounds and external information can each improve the mean squared error of population size estimates, even when the external information is not completely accurate. We conclude with an original example on estimation of prevalence of multiple sclerosis in the metropolitan area of Rome, where five out of six lists have interval censored counts. External information comes from mortality rates of multiple sclerosis patients.

Multiple cause of death analysis in multiple sclerosis: A population-based study.

OBJECTIVE: To gain a better understanding of the complex patterns of causes that contribute to death due to multiple sclerosis (MS) by assessing the relationship between MS and other causes of death listed on death certificates. METHODS: Multiple cause of death data for all adult deaths (aged ≥18 years) in British Columbia, Canada, between 1986 and 2013 were accessed. All causes, as listed on the death certificate, whether underlying or contributing, were considered "any mention" causes. The associations between mention of MS on the death certificate and mention of other causes of death were examined by logistic regression, adjusted for age, sex, and calendar year (Bonferroni-corrected α level = 0.002). Findings were also sex-stratified. RESULTS: Among 771,288 deaths, MS was mentioned on 2,153 certificates. If MS was mentioned (versus not mentioned), there was a greater chance that specific conditions contributed to the death: respiratory infection (adjusted odds ratio [aOR], 3.03 [95% confidence interval (CI), 2.73-3.36]), aspiration pneumonia (aOR, 7.15 [95% CI, 6.23-8.22]), urinary tract infection (UTI) (aOR, 10.2 [95% CI, 8.7-12.0]), other infection including sepsis (aOR, 1.34 [95% CI, 1.15-1.56]), and skin disease (aOR, 5.06 [95% CI, 3.96-6.46]). Sex differences existed for urinary tract infection (men: aOR, 14.9 [95% CI, 11.5-19.3]; women: aOR, 8.00 [95% CI, 6.53-9.81]) and chronic respiratory disease (men = aOR, 1.36 [95% CI, 1.14-1.63]; women = aOR, 0.97 [95% CI, 0.84-1.13]). CONCLUSIONS: Deaths attributed to MS were commonly caused by infection (especially respiratory and urinary tract-related); conditions associated with advanced disability and immobility, such as aspiration pneumonia; and chronic respiratory disease in men. All are potentially modifiable; interventions that reduce the frequency or severity of these complications could improve survival in MS.

Comorbidity in multiple sclerosis: its temporal relationships with disease onset and dose effect on mortality.

BACKGROUND AND PURPOSE: We aimed to determine the burden of comorbidities at the time of diagnosis of multiple sclerosis (MS), the risk of developing new comorbidities after diagnosis and the effect of comorbidities on mortality in patients with MS. METHODS: This study used data from 2526 patients with incident MS and 9980 age-, sex- and physician-matched controls without MS identified from the UK Clinical Practice Research Datalink. RESULTS: Before the MS diagnosis, the adjusted odds ratio for the association between MS and a Charlson comorbidity index score of 1-2, 3-4 or ≥5 was 131 [95% confidence interval (CI), 1.17-1.47], 1.65 (95% CI, 1.20-2.26) or 3.26 (95% CI, 1.58-6.70), respectively. MS was associated with increased risks of cardiovascular and neurological/mental diseases. After diagnosis, the adjusted hazard ratio for the association between MS and an increased risk of developing comorbidities was 1.13 (95% CI, 1.00-1.29). The risk of developing any comorbidity in terms of neoplasms, musculoskeletal/connective tissue diseases or neurological/mental diseases was higher in MS. Patients with MS had a higher mortality risk compared with controls, with a hazard ratio of 2.29 (95% CI, 1.81-2.73) after adjusting for comorbidities. There was a dose effect of pre-existing comorbidities on mortality. CONCLUSIONS: Patients with MS have an increased risk of developing multiple comorbidities both before and after diagnosis and pre-existing comorbidities have an impact on survival.

Causes that Contribute to the Excess Mortality Risk in Multiple Sclerosis: A Population-Based Study.

BACKGROUND: Lifespan is 6-10 years shorter in multiple sclerosis (MS), but the reasons remain unclear. Using linked clinical- and population-based administrative health databases, we compared cause-specific mortality in an MS cohort to the general population. METHODS: MS patients in British Columbia (BC), Canada, were followed from the later of first MS clinic visit or January 1, 1986, to the earlier of death, emigration, or December 31, 2013. Comprehensive mortality information was obtained by linkage to BC's multiple-cause-of-death mortality data. Causes were grouped using International Classification of Disease codes. Standardized mortality ratios (SMRs) were calculated for underlying cause, and relative mortality ratios (RMRs) for any mention cause, by comparison to mortality rates in the age-, sex-, and calendar year-matched general population. Cause-specific relative mortality was explored by sex and disease course (relapsing onset and primary progressive). RESULTS: Among 6,629 MS patients with 104,236 patient-years of follow-up, 1,416 died. The all-cause mortality risk was increased relative to the general population (SMR 2.71; 95% CI 2.55-2.87). MS was the underlying cause in 50.4%, and a mentioned cause in 77.9%, of deaths. Mortality by underlying cause was higher than expected for genitourinary disorders/infections (SMR 3.55; 95% CI 2.25-5.32), respiratory diseases/infections (SMR 2.69; 95% CI 2.17-3.28), suicide (SMR 2.40; 95% CI 1.61-3.45), cardiovascular disease (SMR 1.57; 95% CI 1.36-1.81), and other infections/septicemia (SMR 1.83; 95% CI 1.15-2.78). Risks of death due to overall cancer, accidents, digestive system disorders, and endocrine/nutritional diseases as underlying causes were similar to the general population. However, mortality with any mention of accidents (RMR 2.71; 95% CI 2.22-3.29) or endocrine/nutritional diseases (RMR 1.75; 95% CI 1.46-2.09) was greater. Bladder cancer mortality was increased in women (SMR 3.87; 95% CI 1.42-8.42) but not men. No notable differences were observed by disease course. CONCLUSIONS: MS itself was the most frequent underlying cause of death. Infections (genitourinary, respiratory, and septicemia), suicides, cardiovascular disease, and accidents contributed significantly to the increased risk of death. Some findings differed by sex, but not disease course. Multiple-cause death data offer advantages over "traditional" use of underlying cause only.

Distribución geográfica de la mortalidad por esclerosis múltiple en adultos Colombia (2010-2015) / Geographic distribution of mortality due to multiple sclerosis in Colombia, 2010-2015

RESUMEN Objetivo Caracterizar la distribución geográfica de la mortalidad por esclerosis múltiple en Colombia entre 2010 y 2015. Métodos Estudio descriptivo. Análisis de la mortalidad a partir de certificados de defunción entre 2010 y 2015. Cálculo de tasas de mortalidad departamentales y municipales ajustadas por sexo y edad. Resultados El 56,8% de las defunciones ocurrieron en mujeres y 28,7% en personas de 50 a 59 años. En 2010 la tasa de mortalidad nacional fue de 0,28 por cada 100 000 personas, y Casanare registró la más alta (0,59 por cada 100 000 personas). En 2011, la tasa fue de 0,24, y Buenaventura registró la más alta (0,51). En 2012, la tasa fue de 0,27, y Guajira registró la más alta (0,34). En 2013, la tasa fue de 0,27, y la más alta se presentó en Arauca (0,83). En 2014, la tasa fue de 0,32, y la más alta ocurrió en Putumayo (1,14). En 2015 la tasa fue de 0,23 y Santa Marta registró la más alta (0,58). Por municipios, Sativanorte, Arcabuco (Boyacá), San Miguel, la Paz (Santander) y la Merced (Caldas) registraron las mayores tasas. Conclusiones El comportamiento de la mortalidad por esclerosis múltiple es similar en el periodo de estudio. La mayor carga de mortalidad se registró en mujeres y en los municipios de Santander y Boyacá.(AU)

ABSTRACT Objective To characterize the geographical distribution of extended mortality due to multiple sclerosis in Colombia between 2010 and 2015. Materials and Methods Descriptive study to analyze the geographical distribution of mortality rates from the death certificates between 2010 and 2015. State and municipal mortality rates were calculated and adjusted by age and sex. Results 56.8% of deaths occurred in women and 28.7% in people aged 50 to 59 years. In 2010, the national mortality rate was 0.28 per 100,000 people, and the highest was recorded in Casanare (0.59 per 100,000). In 2011, the rate was 0.24, and Buenaventura recorded the highest (0.51). In 2012, the rate was 0.27, and la Guajira recorded the highest (0.34). In 2013, the rate was 0.27, and the highest was in Arauca (0.83). In 2014, the rate was 0.32, and the highest was occurred in Putumayo (1.14). In 2015 the rate was 0.23 and Santa Marta recorded the highest (0.58). By municipalities, Sativanorte, Arcabuco (Boyacá), San Miguel, la Paz (Santander) and la Merced (Caldas) recorded the highest rates. Conclusion The pattern of mortality due to multiple sclerosis is similar in the study period. The highest burden of mortality was recorded in women and in municipalities of Santander and Boyacá.(AU)

Polymorphisms in the CIITA -168A/G (rs3087456) and CIITA +1614G/C (rs4774) may influence severity in multiple sclerosis patients.

It is currently unknown how genetic factors may influence the clinical course of multiple sclerosis (MS). OBJECTIVE: We examined the impact of CIITA polymorphisms -168A/G (rs3087456) and +1614G/C (rs4774) on the risk of disability progression, severity and on responses to first-line immunomodulator treatments. METHODS: Genomic DNA was extracted from blood samples. We used ABI3730xl and GeneMapper v.4.0 software to identify genotype variations. All patients were followed up and clinically reassessed at three-month intervals. Disability progression was measured by the Expanded Disability Status Scale and disease severity by the Multiple Sclerosis Spasticity Scale (MSSS). RESULTS: We included 37 men and 80 women. We found no evidence regarding the influence of the single nucleotide polymorphisms studied in the Expanded Disability Status Scale or therapeutic response of the evaluated drugs. We performed a logistic regression analysis with the MSSS and found that a less severe MS course was associated with wild type CIITA -168AA and CIITA +1614GG, as the chance of the patient progressing to MSSS2 and MSSS3 decreased in 61% and 75% with CIITA -168AA and 66% and 75% with CIITA +1614GG, respectively (p < 0.0001). Although less significant, the CIITA +1614 GC also pointed to a less severe MS course and the chance of the patient progressing to MSSS3 decreased 79% (p = 0.015). We also observed that the CIITA -168GG genotype was more frequent in MSSS2 and MSSS3 and had 40% lower odds ratio to becoming more severe MS. CONCLUSION: These data suggest that CIITA -168AA, CIITA +1614GG and CIITA +1614 GC polymorphisms may be associated with a better MS clinical course. This knowledge may be useful for a better understanding of MS and its therapeutic management.

Polymorphisms in the CIITA -168A/G (rs3087456) and CIITA +1614G/C (rs4774) may influence severity in multiple sclerosis patients / Os polimorfismos no gene CIITA - 168A/G (rs3087456) e CIITA +1614G/C (rs4774) podem influenciar a gravidade em pacientes com esclerose múltipla

ABSTRACT It is currently unknown how genetic factors may influence the clinical course of multiple sclerosis (MS). Objective: We examined the impact of CIITA polymorphisms −168A/G (rs3087456) and +1614G/C (rs4774) on the risk of disability progression, severity and on responses to first-line immunomodulator treatments. Methods: Genomic DNA was extracted from blood samples. We used ABI3730xl and GeneMapper v.4.0 software to identify genotype variations. All patients were followed up and clinically reassessed at three-month intervals. Disability progression was measured by the Expanded Disability Status Scale and disease severity by the Multiple Sclerosis Spasticity Scale (MSSS). Results: We included 37 men and 80 women. We found no evidence regarding the influence of the single nucleotide polymorphisms studied in the Expanded Disability Status Scale or therapeutic response of the evaluated drugs. We performed a logistic regression analysis with the MSSS and found that a less severe MS course was associated with wild type CIITA −168AA and CIITA +1614GG, as the chance of the patient progressing to MSSS2 and MSSS3 decreased in 61% and 75% with CIITA −168AA and 66% and 75% with CIITA +1614GG, respectively (p < 0.0001). Although less significant, the CIITA +1614 GC also pointed to a less severe MS course and the chance of the patient progressing to MSSS3 decreased 79% (p = 0.015). We also observed that the CIITA −168GG genotype was more frequent in MSSS2 and MSSS3 and had 40% lower odds ratio to becoming more severe MS. Conclusion: These data suggest that CIITA −168AA, CIITA +1614GG and CIITA +1614 GC polymorphisms may be associated with a better MS clinical course. This knowledge may be useful for a better understanding of MS and its therapeutic management.

RESUMO Atualmente não se sabe como os fatores genéticos podem influenciar o curso clínico da esclerose múltipla (EM). Objetivo: Examinamos o impacto dos polimorfismos CIITA −168A/G (rs3087456) e CIITA +1614G/C (rs4774) no risco de progressão da incapacidade, gravidade e resposta aos tratamentos imunomoduladores de primeira linha. Métodos: O DNA genômico foi extraído de amostras de sangue. Utilizamos o software ABI3730xl e GeneMapper v.4.0 (Applied Biosystems) para identificar variações genotípicas. Todos os pacientes foram acompanhados e reavaliados clinicamente em intervalos de três meses. A progressão da incapacidade foi medida pela EDSS e a gravidade da doença pelo MSSS. Resultados: Incluímos 37 homens e 80 mulheres. Não encontramos evidências sobre a influência dos SNPs estudados no EDSS e na resposta terapêutica aos fármacos avaliados. Realizamos uma análise de regressão logística com o MSSS e observamos uma evolução menos grave da EM associada aos tipos selvagens CIITA −168AA e CIITA +1614GG, pois a chance do paciente atingir MSSS2 e MSSS3 diminuiu em 61%/75%, e 66/75% respectivamente (p < 0,0001). Embora menos significativo, o CIITA +1614GC também foi relacionado com evolução menos grave da EM e a chance do paciente atingir o MSSS3 diminuiu 79% (p = 0,015). Nós também observamos que o genótipo CIITA −168GG foi mais frequente no MSSS2 e MSSS3 e teve uma razão de chance 40% menor para atingir forma mais grave da EM. Conclusão: Estes dados sugerem que os polimorfismos CIITA −168AA, CIITA +1614GG e CIITA +1614GC podem estar associados a um melhor curso clínico da EM. Este conhecimento pode ser útil para uma melhor compreensão da EM e o seu manejo terapêutico.