Tobacco smoking and multiple sclerosis: effects on occurrence, progression and mortality

Multiple Sclerosis is an immune mediated disease of the central nervous system associated with a wide range of mainly irreversible psychological and physical disabilities in young adults. Despite the invaluable knowledge gained from the research into the disease, its aetiology and mechanism of progression are poorly understood. The natural history of multiple sclerosis is complex and there are still many unanswered questions in respect to the risk factors associated with its development and the way that the disease evolves with age. Over the years numerous theories about the disease aetiology have been postulated, but the one that best describe the disease, on the basis of our current understanding, both in terms of susceptibility and progression is the gene-environment hypothesis. According to this hypothesis, multiple sclerosis occurs as the result of an exposure(s) to some unknown environmental factor(s) in genetically susceptible individuals. In multiple sclerosis, it has been hypothesised that tobacco smoking is associated with an increased risk of the disease occurrence and adverse effects on the progression of disabilities. Despite the relatively large amount of data on the adverse effect of smoking on multiple sclerosis risk and clinical course, data from a large population based cohort was lacking. The aim of the current work was to investigate the influence of tobacco smoking on the natural history of the disease from the risk of occurrence to mortality. In the first part of the investigation, our age- and sex-matched case-control study showed that tobacco smoking is associated with higher risk of disease occurrence. However, we did not observe any association between parental smoking during patients’ childhood and the risk of multiple sclerosis. When investigating the impact of tobacco smoking on the clinical course and prognosis of the disease, our cohort study failed to show any evidence of the influence of tobacco smoking on the risk of progressive onset multiple sclerosis. However, tobacco smoking was associated with more severe disease and significantly higher levels of psychological and physical disability in current smokers. Moreover, tobacco smoking in current smokers was associated with faster disability progression and shorter time to the progressive stage of the disease in patients with relapse onset multiple sclerosis. A significant impact of tobacco smoking on the risk of premature death and patients’ life expectancy was also evident in our data where tobacco smoking in our cohort was associated with more than 2.5-fold increase in the risk of premature death and almost 10 years reduction in the patients’ life expectancy. Our data also showed that tobacco smoking can account for some of the excess mortality seen in multiple sclerosis patients. A novel finding of our research was that smoking cessation significantly reduced patients’ risk of disease progression and premature death. Although the benefits of smoking cessation were greater for patients who stopped at earlier ages, cessation was found to be beneficial at all ages. To our knowledge, this is the first study that showed smoking cessation could potentially be beneficial in reducing the risk of disability progression and premature mortality in patients with multiple sclerosis. Overall, our findings point toward adverse health impact of tobacco smoking on the clinical course of multiple sclerosis from the occurrence to mortality

Tobacco smoking and multiple sclerosis: effects on occurrence, progression and mortality

Multiple Sclerosis is an immune mediated disease of the central nervous system associated with a wide range of mainly irreversible psychological and physical disabilities in young adults. Despite the invaluable knowledge gained from the research into the disease, its aetiology and mechanism of progression are poorly understood. The natural history of multiple sclerosis is complex and there are still many unanswered questions in respect to the risk factors associated with its development and the way that the disease evolves with age. Over the years numerous theories about the disease aetiology have been postulated, but the one that best describe the disease, on the basis of our current understanding, both in terms of susceptibility and progression is the gene-environment hypothesis. According to this hypothesis, multiple sclerosis occurs as the result of an exposure(s) to some unknown environmental factor(s) in genetically susceptible individuals. In multiple sclerosis, it has been hypothesised that tobacco smoking is associated with an increased risk of the disease occurrence and adverse effects on the progression of disabilities. Despite the relatively large amount of data on the adverse effect of smoking on multiple sclerosis risk and clinical course, data from a large population based cohort was lacking. The aim of the current work was to investigate the influence of tobacco smoking on the natural history of the disease from the risk of occurrence to mortality. In the first part of the investigation, our age- and sex-matched case-control study showed that tobacco smoking is associated with higher risk of disease occurrence. However, we did not observe any association between parental smoking during patients’ childhood and the risk of multiple sclerosis. When investigating the impact of tobacco smoking on the clinical course and prognosis of the disease, our cohort study failed to show any evidence of the influence of tobacco smoking on the risk of progressive onset multiple sclerosis. However, tobacco smoking was associated with more severe disease and significantly higher levels of psychological and physical disability in current smokers. Moreover, tobacco smoking in current smokers was associated with faster disability progression and shorter time to the progressive stage of the disease in patients with relapse onset multiple sclerosis. A significant impact of tobacco smoking on the risk of premature death and patients’ life expectancy was also evident in our data where tobacco smoking in our cohort was associated with more than 2.5-fold increase in the risk of premature death and almost 10 years reduction in the patients’ life expectancy. Our data also showed that tobacco smoking can account for some of the excess mortality seen in multiple sclerosis patients. A novel finding of our research was that smoking cessation significantly reduced patients’ risk of disease progression and premature death. Although the benefits of smoking cessation were greater for patients who stopped at earlier ages, cessation was found to be beneficial at all ages. To our knowledge, this is the first study that showed smoking cessation could potentially be beneficial in reducing the risk of disability progression and premature mortality in patients with multiple sclerosis. Overall, our findings point toward adverse health impact of tobacco smoking on the clinical course of multiple sclerosis from the occurrence to mortality

Smoking cessation and the reduction of disability progression in Multiple Sclerosis: a cohort study

Background: Smoking is associated with a more severe disease course in people with multiple sclerosis (MS). The magnitude of effect of smoking cessation on MS progression is unknown. The aim of this study was to quantify the impact of smoking cessation on reaching MS disability milestones. Methods: This is a cross-sectional study with retrospective reports. A comprehensive smoking questionnaire was sent to 1270 patients with MS registered between 1994 and 2013 in the Nottingham University Hospital MS Clinics database. Demographic and clinical data were extracted from the clinical database. Cox proportional hazard regression was used to estimate effects of smoke-free years on the time to Expanded Disability Status Scale (EDSS) scores 4.0 and 6.0. MS Impact Scale 29 (MSIS-29) and Patient Determined Disease Steps (PDDS) were used to assess the physical and psychological impact of smoking. Results: Each ‘smoke-free year’ was associated with 0.96 (95% CI: 0.95 to 0.97) times decreased risk of reaching EDSS 4.0 and 0.97 (95%CI: 0.95 to 0.98) times decreased risk of reaching EDSS 6.0. Non-smokers showed a significantly lower level of disability in all the self-reported outcomes compared with current smokers. Conclusion: The reduction in the risk of disability progression after smoking cessation is significant and time-dependent. The earlier the patients quit, the stronger the reduction in the risk of reaching disability milestones. The quantitative estimates of the impact of smoking cessation on reaching disability milestones in MS can be used in interventional trials

Association between early treatment of multiple sclerosis and patient-reported outcomes: a nationwide observational cohort study

Background Timing of disease-modifying therapy affects clinical disability in multiple sclerosis, but it is not known whether patient reported outcomes are also affected. This study investigates the relationship between treatment timing and patient-reported symptoms and health-related quality of life. Methods This was a nationwide observational cohort study of adults with relapsing multiple sclerosis, with disease onset between 2001 and 2016, and commenced on disease-modifying treatment within 4 years from disease onset. Patients commencing treatment within 0–2 years were compared with patients commencing treatment at 2–4 years. Indication bias was mitigated by propensity matching. Outcomes were patient-reported symptoms and health-related quality of life as measured by the Multiple Sclerosis Impact Scale (MSIS-29) and EuroQol-5 Dimensions-3 Level (EQ-5D). The follow-up period was 4–10 years from disease onset. Results There were 2648 patients (69% female, median age 32.8) eligible for matching. Mean follow-up time was 3.7 years. Based on 780 matched patients, each year of treatment delay was associated with a worse MSIS physical score by 2.75 points (95% CI 1.29 to 4.20), and worse MSIS psychological score by 2.02 points (95% CI 0.03 to 3.78), in the adjusted models. Among 690 matched patients, earlier treatment start was not associated with EQ-5D score during the follow-up. Conclusions Earlier commencement of disease-modifying treatment was associated with better patient-reported physical symptoms when measured using a disease-specific metric; however, general quality of life was not affected. This indicates that other factors may inform patients’ overall quality of life

A multiple sclerosis disease progression measure based on cumulative disability

BACKGROUND: Existing severity measurements in multiple sclerosis (MS) are often cross-sectional, making longitudinal comparisons of disease course between individuals difficult. OBJECTIVE: The objective of this study is to create a severity metric that can reliably summarize a patient's disease course. METHODS: We developed the nARMSS - normalized ARMSS (age-related MS severity score) over follow-up, using the deviation of individual ARMSS scores from the expected value and integrated over the corresponding time period. The nARMSS scales from -5 to +5; a positive value indicates a more severe disease course for a patient when compared to other patients with similar disease timings. RESULTS: Using Swedish MS registry data, the nARMSS was tested using data at 2 and 4 years of follow-up to predict the most severe quartile during the subsequent period up to 10 years total follow-up. The metric used was area under the curve of the receiver operating characteristic (AUC-ROC). This resulted in measurements of 0.929 and 0.941. In an external Canadian validation cohort, the equivalent AUC-ROCs were 0.901 and 0.908. CONCLUSION: The nARMSS provides a reliable, generalizable and easily measurable metric which makes longitudinal comparison of disease course between individuals feasible

Association between clinic-level quality of care and patient-level outcomes in multiple sclerosis

Background: Multiple sclerosis (MS) quality of care guidelines are consensus-based. The effectiveness of the recommendations is unknown.// Objective: To determine whether clinic-level quality of care affects clinical and patient-reported outcomes.// Methods: This nationwide observational cohort study included patients with adult-onset MS in the Swedish MS registry with disease onset 2005–2015. Clinic-level quality of care was measured by four indicators: visit density, magnetic resonance imaging (MRI) density, mean time to commencement of disease-modifying therapy, and data completeness. Outcomes were Expanded Disability Status Scale (EDSS) and patient-reported symptoms measured by the Multiple Sclerosis Impact Scale (MSIS-29). Analyses were adjusted for individual patient characteristics and disease-modifying therapy exposure.// Results: In relapsing MS, all quality indicators benefitted EDSS and physical symptoms. Faster treatment, frequent visits, and higher data completeness benefitted psychological symptoms. After controlling for all indicators and individual treatment exposures, faster treatment remained independently associated with lower EDSS (−0.06, 95% confidence interval (CI): −0.01, −0.10) and more frequent visits were associated with milder physical symptoms (MSIS-29 physical score: −16.2%, 95% CI: −1.8%, −29.5%). Clinic-level quality of care did not affect any outcomes in progressive-onset disease.// Conclusion: Certain quality of care indicators correlated to disability and patient-reported outcomes in relapse-onset but not progressive-onset disease. Future guidelines should consider recommendations specific to disease course..

Multiple sclerosis course and clinical outcomes in patients with comorbid asthma: a survey study

Objective: To determine if comorbid asthma is associated with accumulation of multiple sclerosis (MS)-related impairment and disability.Method: We sent a comprehensive questionnaire to a cohort of patients with MS and examined the association between comorbid asthma and reaching Expanded Disability Status Scale (EDSS) scores 4.0 and 6.0. Multiple Sclerosis Impact Scale (MSIS-29) scores were compared between patients with MS with and without comorbid asthma.Results: 680 patients participated in our study of whom 88 (12.9%) had comorbid asthma. There was no difference in the prevalence of asthma between our MS cohort and the England general population (OR: 0.89, 95% CI 0.68 to 1.17). We did not observe a significant association between having asthma and the risk of reaching EDSS scores 4.0 and 6.0 (HR: 1.29, 95% CI 0.93 to 1.77, and HR: 1.33, 95% CI 0.93 to 1.89, respectively) after controlling for confounders. Patients with MS with asthma reported higher level of psychological impairments (coefficient: 2.29, 95% CI 0.1 to 4.49).Conclusions: Asthma is a prevalent condition among patients with MS and it may contribute to the psychological impairment in MS. Although we did not observe significant association between comorbid asthma and physical disability in MS, it seems that the two conditions influence one another

Accurate classification of secondary progression in multiple sclerosis using a decision tree

BACKGROUND: The absence of reliable imaging or biological markers of phenotype transition in multiple sclerosis (MS) makes assignment of current phenotype status difficult. OBJECTIVE: The authors sought to determine whether clinical information can be used to accurately assign current disease phenotypes. METHODS: Data from the clinical visits of 14,387 MS patients in Sweden were collected. Classifying algorithms based on several demographic and clinical factors were examined. Results obtained from the best classifier when predicting neurologist recorded disease classification were replicated in an independent cohort from British Columbia and were compared to a previously published algorithm and clinical judgment of three neurologists. RESULTS: A decision tree (the classifier) containing only most recently available expanded disability scale status score and age obtained 89.3% (95% confidence intervals (CIs): 88.8-89.8) classification accuracy, defined as concordance with the latest reported status. Validation in the independent cohort resulted in 82.0% (95% CI: 81.0-83.1) accuracy. A previously published classification algorithm with slight modifications achieved 77.8% (95% CI: 77.1-78.4) accuracy. With complete patient history of 100 patients, three neurologists obtained 84.3% accuracy compared with 85% for the classifier using the same data. CONCLUSION: The classifier can be used to standardize definitions of disease phenotype across different cohorts. Clinically, this model could assist neurologists by providing additional information

Alcohol Consumption and Risk of Common Autoimmune Inflammatory Diseases—Evidence From a Large-Scale Genetic Analysis Totaling 1 Million Individuals

Purpose: Observational studies have suggested a protective effect of alcohol intake with autoimmune disorders, which was not supported by Mendelian randomization (MR) analyses that used only a few (<20) instrumental variables.Methods: We systemically interrogated a putative causal relationship between alcohol consumption and four common autoimmune disorders, using summary-level data from the largest genome-wide association study (GWAS) conducted on inflammatory bowel disease (IBD), rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE). We quantified the genetic correlation to examine a shared genetic similarity. We constructed a strong instrument using 99 genetic variants associated with drinks per week and applied several two-sample MR methods. We additionally incorporated excessive drinking as reflected by alcohol use disorder identification test score.Results: We observed a negatively shared genetic basis between alcohol intake and autoimmune disorders, although none was significant (rg = −0.07 to −0.02). For most disorders, genetically predicted alcohol consumption was associated with a slightly (10–25%) decreased risk of onset, yet these associations were not significant. Meta-analyzing across RA, MS, and IBD, the three Th1-related disorders yielded to a marginally significantly reduced effect [OR = 0.70 (0.51–0.95), P = 0.02]. Excessive drinking did not appear to reduce the risk of autoimmune disorders.Conclusions: With its greatly augmented sample size and substantially improved statistical power, our MR study does not convincingly support a beneficial role of alcohol consumption in each individual autoimmune disorder. Future studies may be designed to replicate our findings and to understand a causal effect on disease prognosis

Tobacco smoking and excess mortality in multiple sclerosis: a cohort study

OBJECTIVE: As patients with multiple sclerosis (MS) have more than 2.5-fold increased mortality risk, we sought to investigate the impact of tobacco smoking on the risk of premature death and its contribution to the excess mortality in MS patients. METHODS: We studied 1032 patients during the period 1994–2013 in a UK-based register. Cox regression model was used to investigate the impact of smoking on the risk of premature death, controlling for confounders. Smoking-specific mortality rates were compared with the UK general population. RESULTS: Of 923 patients with clinically definite MS, 80 (46 males and 34 females) had died by December 2012. HRs for death in current smokers and ex-smokers relative to never smokers were 2.70 (95% CI 1.59 to 4.58, p<0.001) and 1.30 (95% CI 0.72 to 2.32; p = 0.37). The standardised mortality ratio, compared with the UK general population, when stratified by smoking status was 3.83 (95% CI 2.71 to 5.42) in current smokers, 1.96 (95% CI 1.27 to 3.0) in ex-smokers and 1.27 (95% CI 0.87 to 1.86) in non-smokers. Never smokers and ex-smokers with MS had similar mortality rates compared with never smokers and ex-smokers without MS in the male British doctors cohort (1.12 (95% CI 0.63 to 1.97) and 0.54 (95% CI 0.26 to 1.14), respectively), while current smokers with MS had 84% higher rate of death compared with current smokers without MS (95% CI 1.24 to 2.72). CONCLUSIONS: Tobacco smoking can account for some of the excess mortality associated with MS and is a risk determinant for all-cause and MS-related death