Multiple Sclerosis Risk Among Anti-tumor Necrosis Factor Alpha Users: A Methodological Review of Observational Studies Based on Real-world Data.

Epidemiologic studies on the risk of multiple sclerosis (MS) or demyelinating events associated with anti-tumor necrosis factor alpha (TNFα) use among patients with rheumatic diseases or inflammatory bowel diseases have shown conflicting results. Causal directed acyclic graphs (cDAGs) are useful tools for understanding the differing results and identifying the structure of potential contributing biases. Most of the available literature on cDAGs uses language that might be unfamiliar to clinicians. This article demonstrates how cDAGs can be used to determine whether there is a confounder, a mediator or collider-stratification bias and when to adjust for them appropriately. We also use a case study to show how to control for potential biases by drawing a cDAG depicting anti-TNFα use and its potential to contribute to MS onset. Finally, we describe potential biases that might have led to contradictory results in previous studies that examined the effect of anti-TNFα and MS, including confounding, confounding by contraindication, and bias due to measurement error. Clinicians and researchers should be cognizant of confounding, confounding by contraindication, and bias due to measurement error when reviewing future studies on the risk of MS or demyelinating events associated with anti-TNFα use. cDAGs are a useful tool for selecting variables and identifying the structure of different biases that can affect the validity of observational studies.

Risk of Multiple Sclerosis Among Users of Antitumor Necrosis Factor α in 4 Canadian Provinces: A Population-Based Study.

BACKGROUND AND OBJECTIVES: Antitumor necrosis factor α (TNFα) agents are a class of biologic drugs used for the treatment of several immune-mediated conditions. An increased risk of multiple sclerosis (MS) with their use has been suggested, but studies have been limited. Relevant population-based epidemiologic data linking anti-TNFα to MS are scarce. The objective was to compare the risk of MS in anti-TNFα users with nonusers among patients with rheumatic disease (RD) or inflammatory bowel disease (IBD). METHODS: A nested case-control study was conducted. Population-based health care-linked databases from 4 Canadian provinces were used. All patients with RD or IBD residing within a participating province between January 2000 and March 2018 were identified by validated case definitions. Any anti-TNFα dispensation in the 2 years before the index date (MS onset) was identified. Incident onset MS cases were ascertained using a validated algorithm. Up to 5 controls were matched to each MS case based on birth year ±3 years, disease duration, and health authority (based on region of residence). Conditional logistic regressions were used to calculate the incidence rate ratio (IRR) after adjusting for potential confounders. A meta-analysis was conducted to provide pooled estimates across provinces using random-effects models. RESULTS: Among 296,918 patients with RD patients, 462 MS cases (80.1% female, mean [SD] age, 47.4 [14.6] years) were matched with 2,296 controls (59.5% female, mean [SD] age, 47.4 [14.5] years). Exposure to anti-TNFα occurred in 18 MS cases and 42 controls. After adjusting for matching variables, sex, and the Charlson Comorbidity Index, the pooled IRR was 2.05 (95% CI, 1.13-3.72). Among 84,458 patients with IBD, 190 MS cases (69.5% female, mean [SD] age, 44.3 [12.3] years) were matched with 943 controls (54.1% female, mean [SD] age, 44.2 [12.2] years). Exposure to anti-TNFα occurred in 23 MS cases and 98 controls. The pooled adjusted IRR was 1.35 (95% CI, 0.70-2.59). DISCUSSION: The use of anti-TNFα was associated with an increased risk of MS compared with nonusers, especially among patients with RD. These findings could help clinicians and patients with RD to make more informed treatment decisions. Further studies are needed to validate these results for patients with IBD.

Polypharmacy and multiple sclerosis: A population-based study.

BACKGROUND: Little is known about polypharmacy and multiple sclerosis (MS). OBJECTIVES: To estimate polypharmacy prevalence in a population-based MS cohort and compare persons with/without polypharmacy. METHODS: Using administrative and pharmacy data from Canada, we estimated polypharmacy prevalence (⩾5 concurrent medications for >30 consecutive days) in MS individuals in 2017. We compared the characteristics of persons with/without polypharmacy and described the number of polypharmacy days, the most common medication classes contributing to polypharmacy and hyper-polypharmacy prevalence (⩾10 medications). RESULTS: Of 14,227 included individuals (75% women), mean age = 55.4 (standard deviation (SD): 13.2) years; 28% (n = 3995) met criteria for polypharmacy (median polypharmacy days = 273 (interquartile range (IQR): 120-345)). Odds of polypharmacy were higher for women (adjusted odds ratio (aOR) = 1.14; 95% confidence intervals (CI):1.04-1.25), older individuals (aORs 50-64 years = 2.04; 95% CI:1.84-2.26; ⩾65 years = 3.26; 95% CI: 2.92-3.63 vs. <50 years), those with more comorbidities (e.g. ⩾3 vs. none, aOR = 6.03; 95% CI: 5.05-7.22) and lower socioeconomic status (SES) (e.g. most (SES-Q1) vs. least deprived (SES-Q5) aOR = 1.64; 95% CI: 1.44-1.86). Medication classes most commonly contributing to polypharmacy were as follows: antidepressants (66% of polypharmacy days), antiepileptics (47%), and peptic ulcer drugs (41%). Antidepressants were most frequently co-prescribed with antiepileptics (34% of polypharmacy days) and peptic ulcer drugs (27%). Five percent of persons (716/14,227) experienced hyper-polypharmacy. CONCLUSION: More than one in four MS persons met criteria for polypharmacy. The odds of polypharmacy were higher for women, older persons, and those with more comorbidities, but lower SES.

Safety profile of ocrelizumab for the treatment of multiple sclerosis: a systematic review.

INTRODUCTION: We systematically reviewed adverse events (AEs) for ocrelizumab for multiple sclerosis (MS). AREAS COVERED: We searched Medline, Embase, Web of Science, and Toxicology Data Network-TOXLINE (inception to 8-July-2020), clinical trial registries, and product monographs for any clinical trials, observational studies or case reports examining AEs to ocrelizumab. Studies with/without a comparator drug or placebo were eligible. EXPERT OPINION: Seventy-eight records were included (4 randomized controlled trials (RCTs), 4 open-label trials, 29 observational studies, and 27 case reports). AEs affected 2756/4498 (61.3%) of ocrelizumab-exposed patients. The most common AEs were infections (n=1342, 39.2% of ocrelizumab-exposed patients) and infusion-related reactions (n=1391, 26.2%). Compared to beta-interferon, infections were more likely in ocrelizumab-exposed patients (Risk Ratio (RR)=1.10; 95% confidence interval (CI):1.01-1.19), including: herpes-related (RR=1.75; 95%CI:1.11-2.76), respiratory tract-related (RR=1.42; 95%CI:1.10-1.84 and RR=1.61; 95%CI:1.10-2.35), nasopharyngitis (RR=1.47; 95%CI:1.13-1.90), and rhinitis (RR=4.00; 95%CI:1.13-14.14). Infusion-related reactions (RR range: 1.57-4.42) were more common for ocrelizumab versus placebo or beta-interferon. From pooled analyses (three RCTs), the risk of 'any' serious AE did not differ significantly between the ocrelizumab and comparator groups. However, insufficient data were available to assess longer-term AEs, e.g., malignancy.

Phenome-wide examination of comorbidity burden and multiple sclerosis disease severity.

OBJECTIVE: We assessed the comorbidity burden associated with multiple sclerosis (MS) severity by performing a phenome-wide association study (PheWAS). METHODS: We conducted a PheWAS in 2 independent cohorts: a discovery (Boston, United States; 1993-2014) and extension cohort (British Columbia, Canada; 1991-2008). We included adults with MS, ≥1 Expanded Disability Status Scale (EDSS) score, and ≥1 International Classification of Diseases (ICD) code other than MS. We calculated the Multiple Sclerosis Severity Score (MSSS) using the EDSS. We mapped ICD codes into PheCodes (phenotypes), using a published system with each PheCode representing a unique medical condition. Association between the MSSS and the presence of each condition was assessed using logistic regression adjusted for covariates. RESULTS: The discovery and extension cohorts included 3,439 and 4,876 participants, respectively. After Bonferroni correction and covariate adjustments, a higher MSSS was associated with 37 coexisting conditions in the discovery cohort. Subsequently, 16 conditions, including genitourinary, infectious, metabolic, epilepsy, and movement disorders, met the reporting criteria, reaching the Bonferroni threshold of significance with the same direction of effect in the discovery and extension cohort. Notably, benign neoplasm of the skin was inversely associated with the MSSS. CONCLUSION: The phenome-wide approach enabled a systematic interrogation of the comorbidity burden and highlighted clinically relevant medical conditions associated with MS severity (beyond MS-specific consequences) and defines a roadmap for comprehensive investigation of comorbidities in chronic neurologic diseases. Further prospective investigation of the bidirectional relationship between disability and comorbidities could inform the individualized patient management.

Alemtuzumab and prescription medication use in the MS population.

Medications are indicated to minimize adverse reactions with alemtuzumab treatment for multiple sclerosis, but polypharmacy can be problematic. We characterized prescriptions filled by 160 individuals before, during and after first infusion of alemtuzumab (Dec/2013-Jun/2017). Ninety-five percent of individuals filled ≥1 prescription(s) before alemtuzumab across 87 unique drug classes, averaging 5.3 prescriptions/person over 47 weeks. During the infusion period, 90% filled ≥1 prescription(s) for 40 new drug classes, averaging 2.2 prescriptions/person over 5 weeks. Twenty-four percent refilled ≥1 of these prescription(s) after alemtuzumab across 17 drug classes, averaging 0.3 refills/person over 24 weeks. There was substantial medication burden throughout the study.

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.

Higher health care use before a clinically isolated syndrome with or without subsequent MS.

BACKGROUND: To establish whether a unique multiple sclerosis (MS) prodrome exists by comparing health care utilization in the five-year period before initial presentation with optic neuritis (ON) or transverse myelitis (TM) among those who were and were not subsequently diagnosed with MS. METHODS: Using population-based administrative health data we conducted a retrospective cohort study in three Canadian provinces. We identified individuals with a clinically isolated syndrome (ON or TM), who were eventually diagnosed with MS (CIS-MS) or not (CIS-non MS), and a control cohort matched on age, sex and region without a CIS. We compared rates of hospitalization, physician services use and prescription drug use in the five years before the first ON or TM claim (labeled years -1,-2,-3,-4,-5) using negative binomial regression models adjusted for age, sex, socioeconomic status and index year. RESULTS: We identified 1,155 CIS-MS cases, 20,638 CIS-non MS cases, and 108,726 matched controls. Compared to matched controls, the CIS-MS cohort had a higher hospitalization rate (years -5 and -1), physician visits (all years) and prescription drug use (years -4 and -1). Compared to matched controls, the CIS-non MS cohort had a higher rate of hospitalizations (all years), physician visits (all years) and prescription drug use (all years). CONCLUSION: Health care use was higher in individuals with a CIS than without a CIS in the five years before an incident demyelinating event, regardless of whether they were subsequently diagnosed with MS. This suggests that there is a prodromal period before CIS which is not unique to MS.

Identifying optic neuritis and transverse myelitis using administrative data.

OBJECTIVE: We aimed to validate administrative case definitions to identify individuals with optic neuritis (ON) or transverse myelitis (TM), and to distinguish which of these individuals had a monophasic presentation versus multiple sclerosis (MS). METHODS: Using population-based administrative (health claims) data from Manitoba, Canada, we developed case definitions for ON and TM, and distinguished individuals who had monophasic presentations (ON-nonMS, TM-nonMS) versus those later diagnosed with MS (ON-MS, TM-MS). We compared performance of these case definitions to diagnoses based on medical records review in a reference cohort (n = 1251) using sensitivity, specificity, positive predictive value and negative predictive value. We estimated the annual incidence of these conditions for a three-year period (2011-2013). RESULTS: When compared to medical records, using ≥1 physician visit, the case definition for ON had good sensitivity (88.5%), and specificity (82.7%) whereas the case definition for TM had low sensitivity (25.9%) and higher specificity (89.0%). Findings for the other case definitions tested were: ON-MS (sensitivity: 84.1%, specificity: 83.9%), ON-nonMS (sensitivity: 66.7%, specificity 98.5%), TM-MS (sensitivity: 22.2%, specificity: 90.4%), and TM-nonMS (sensitivity: 3.7%, specificity: 99.7%). After applying the ON and TM case definitions to administrative data, the average annual incidence of ON over the period 2011-2013 was 75.9 per 100,000 person-years (95%CI: 72.8, 79.1) and of TM was 18.3 per 100,000 person-years (95%CI: 16.8, 19.8). CONCLUSION: Administrative data can be used to identify individuals with incident ON and TM, and to distinguish those with monophasic syndromes from those with an incident presentation of MS.

Sun exposure over the life course and associations with multiple sclerosis.

OBJECTIVE: To examine sun exposure and multiple sclerosis (MS) over the life course (ages 5-15 and 16-20 years, every 10 years thereafter). METHODS: Cases with MS (n = 151) and age-matched controls (n = 235) from the Nurses' Health Study cohorts completed summer, winter, and lifetime sun exposure history questionnaires. Cumulative ambient ultraviolet (UV)-B (based on latitude, altitude, cloud cover) exposure before MS onset was expressed as tertiles. Seasonal sun exposure was defined as low vs high hours per week (summer [≤9 vs >10 h/wk]; winter [≤3 vs >4 h/wk]). Relative risks (RRs) and 95% confidence intervals (CIs) were estimated via conditional logistic regression with adjustment for body mass index, ancestry, smoking, and vitamin D supplementation. RESULTS: Most participants were white (98%); the mean age at MS onset was 39.5 years. Living in high (vs low) UV-B areas before MS onset was associated with a 45% lower MS risk (adjusted RR 0.55, 95% CI 0.42-0.73). Similar reduced risks (51%-52%) for medium or high exposure were observed at ages 5 to 15 years and at 5 to 15 years before MS onset (adjusted p < 0.05). At age 5 to 15 years, living in a high (vs low) UV-B area and having high (vs low) summer sun exposure were associated with a lower MS risk (RR 0.45, 95% CI 0.21-0.96). CONCLUSION: Living in high ambient UV-B areas during childhood and the years leading up to MS onset was associated with a lower MS risk. High summer sun exposure in high ambient UV-B areas was also associated with a reduced risk.

Drug exposure and the risk of multiple sclerosis: A systematic review.

BACKGROUND: Several environmental and lifestyle factors have been associated with multiple sclerosis (MS) risk, including some pharmacological treatments. We systematically reviewed the literature on prescription drug exposure and MS risk. METHODS: Six databases were searched for original observational studies reporting drug exposure and MS risk published before 2017. RESULTS: Thirteen articles fulfilled inclusion criteria. Exposure to neither amiloride nor valproic acid was associated with MS (adjusted hazard ratio (adj.HR = 1.34;95% CI:0.81-2.20; adj.HR = 1.30;95%CI:0.44-3.80, respectively). Four studies explored oral contraceptive exposure and reported no association with MS; while a single study found an increased risk (odds ratio [adj.OR] = 1.52;95%CI:1.21-1.91). While penicillin exposure was associated with reduced risk of developing MS (adj.OR = 0.5;95%CI:0.3-0.9), a later study observed an elevated risk for penicillin (adj.OR = 1.21;95%CI:1.10-1.27) and all antibiotics (adj.OR = 1.41;95%CI:1.29-1.53), which was potentially attributed to underlying infection. Anti-tumor necrosis factor-alpha (TNFα) was not associated with MS risk in persons with inflammatory bowel disease (standard morbidity ratio = 4.2;95%CI:0.1-23.0) and arthritis (standardized incidence ratio = 1.38;95%CI:0.69-2.77); however, men exposed to anti-TNFα who also had arthritis and individuals with ankylosing spondylitis were at an increased risk (standardized incidence ratios = 3.91;95%CI:1.47-10.42 and 3.48;95%CI:1.45-8.37, respectively). A reduced risk of MS was observed with exposure to the beta2-adrenergic agonist fenoterol (adj.OR = 0.58;95%CI:0.45-0.76), and the sedating histamine 1-receptor antagonists (adj.OR = 0.2;95%CI:0.1-0.8), but not the non-sedating equivalent (adj.OR = 0.8;95%CI:0.4-1.6). CONCLUSIONS: The suggestion that some drugs may prevent MS is intriguing and warrants further study. In addition, further pharmacovigilance is needed to assess the safety of anti-TNFα drugs in specific populations in the context of MS risk.

Application of pharmacogenomics to investigate adverse drug reactions to the disease-modifying treatments for multiple sclerosis: a case-control study protocol for dimethyl fumarate-induced lymphopenia.

INTRODUCTION: Adverse drug reactions (ADRs) are a global public health issue. The potential for pharmacogenomic biomarkers has been demonstrated in several therapeutical areas, including HIV infection and oncology. Dimethyl fumarate (DMF) is a licensed disease-modifying therapy for the treatment of multiple sclerosis (MS). The use of DMF in MS has been associated with a severe reduction in lymphocyte counts and reports of progressive multifocal leukoencephalopathy. Here, we outline the protocol for a case-control study designed to discover genomic variants associated with DMF-induced lymphopenia. The ultimate goal is to replicate these findings and create an efficient and adaptable approach towards the identification of genomic markers that could assist in mitigating adverse drug reactions in MS. METHODS AND ANALYSIS: The population sample will comprise DMF-exposed patients with MS, with cases representing those who developed lymphopenia and controls who did not. DNA genotyping will take place using a high-throughput genome-wide array. Fine mapping and imputation will be performed to focus in on the potentially causal variants associated with lymphopenia. Multivariable logistic regression will be used to compare genotype and allele frequencies between the cases and the controls, with consideration of potential confounders. The association threshold will be set at p<1.0×10-5 for the discovery of genomic association analyses to select variants for replication. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the respective research ethics board, which includes written informed consent. Findings will be disseminated widely, including at scientific conferences, via podcasts (targeted at both healthcare professionals as well as patients and the wider community), through patient engagement and other outreach community events, written lay summaries for all participants and formal publication in peer-reviewed scientific journals.

Adherence to disease-modifying therapies for multiple sclerosis and subsequent hospitalizations.

PURPOSE: The aim of this study was to examine the association between optimal adherence to first-line disease-modifying therapies (DMT) for multiple sclerosis (MS) and hospitalizations. METHODS: We used population-based administrative data from three Canadian provinces. All individuals receiving DMT (interferon-B-1b, interferon-B-1a, or glatiramer acetate) between January 1, 1996, and December 31, 2011 (British Columbia); March 31, 2012 (Manitoba); or March 31, 2014, (Saskatchewan) were included. Adherence was estimated for the first year of DMT (year 0), using the medication possession ratio (MPR). The association between optimal adherence (MPR ≥ 80%) and all-cause and MS-specific hospitalizations in the subsequent 1, 2, and 5 years was assessed using Hurdle Poisson and logistic regression. Rate and odds ratios were adjusted (aRR and aOR) for sociodemographic factors and prior health-care utilization. RESULTS: Overall, 4746 subjects were followed for a mean 7.8 (SD 4.0) years; 3598 (76%) were women. Optimal DMT adherence was achieved in 3564/4746 (75.1%) subjects. Subsequent all-cause and MS-specific hospitalizations were lower for subjects with optimal versus suboptimal adherence, but none reached statistical significance (1-year period, aRR = 0.77, 95%CI: 0.47-1.26; aOR = 0.80, 95%CI: 0.52-1.25). Similar findings were observed in the 2-year and 5-year periods. Prior health-care utilization (hospitalizations and medications) was associated with future hospitalizations; for every additional medication class, the 5-year all-cause hospitalization rate and likelihood of an MS-specific hospitalization increased by 5% and 11%, respectively (aRR = 1.05, 95%CI: 1.02-1.07; and aOR = 1.11, 95%CI: 1.07-1.14). CONCLUSIONS: Hospitalization rates were lower in subjects with optimal DMT adherence, but findings were not statistically significant. Prior hospitalization and polypharmacy were associated with increased risk for future hospitalizations in MS. Copyright © 2017 John Wiley & Sons, Ltd.

Determinants of neurological disease: Synthesis of systematic reviews.

Systematic reviews were conducted to identify risk factors associated with the onset and progression of 14 neurological conditions, prioritized as a component of the National Population Health Study of Neurological Conditions. These systematic reviews provided a basis for evaluating the weight of evidence of evidence for risk factors for the onset and progression of the 14 individual neurological conditions considered. A number of risk factors associated with an increased risk of onset for more than one condition, including exposure to pesticides (associated with an increased risk of AD, amyotrophic lateral sclerosis, brain tumours, and PD; smoking (AD, MS); and infection (MS, Tourette syndrome). Coffee and tea intake was associated with a decreased risk of onset of both dystonia and PD. Further understanding of the etiology of priority neurological conditions will be helpful in focusing future research initiatives and in the development of interventions to reduce the burden associated with neurological conditions in Canada and internationally.

Factors associated with onset, relapses or progression in multiple sclerosis: A systematic review.

Multiple sclerosis (MS) is a chronic disease of the central nervous system with an unidentified etiology. We systematically reviewed the literature on the possible risk factors associated with MS disease onset, relapses and progression from 1960 to 2012 by accessing six databases and including relevant systematic reviews, meta-analyses, case-control or cohort studies. The focus was on identifying modifiable risk factors. Fifteen systematic reviews and 169 original articles were quality assessed and integrated into a descriptive review. Best evidence, which included one or more prospective studies, suggested that lower exposure to sunlight and/or lower serum vitamin D levels were associated with an increased risk of developing MS onset and subsequent relapses, but a similar quality of evidence was lacking for disease progression. Prospective studies indicated that cigarette smoking may increase the risk of MS as well as accelerate disease progression, but whether smoking altered the risk of a relapse was largely unknown. Infections were implicated in both risk of developing MS and relapses, but data for progression were lacking. Specifically, exposure to the Epstein-Barr virus, particularly if this manifested as infectious mononucleosis during adolescence, was associated with increased MS risk. Upper respiratory tract infections were most commonly associated with an increase in relapses. Relapse rates typically dropped during pregnancy, but there was no strong evidence to suggest that pregnancy itself altered the risk of MS or affected long-term progression. Emerging research with the greatest potential to impact public health was the suggestion that obesity during adolescence may increase the risk of MS; if confirmed, this would be of major significance.

Disability progression in aggressive multiple sclerosis.

OBJECTIVE: To examine disease progression in 'aggressive' multiple sclerosis (MS), British Columbia, Canada (1980-2009). METHODS: Aggressive (or 'malignant') MS was defined as Expanded Disability Status Scale (EDSS) ⩾6 within 5 years from onset. The first EDSS ⩾6 was termed 'baseline'. Within 2, 3 and 5 years post-baseline, patients were categorized as follows: 'worsened' or 'improved', relative to baseline EDSS (the remainder exhibited no change or had no new scores). The associations between patient characteristics (sex, relapsing onset/primary progressive, onset age, onset symptoms, disease duration, cumulative prior relapses and baseline EDSS) and worsening in disability were examined longitudinally using logistic regression. RESULTS: Of the 225/4341 (5.2%) aggressive/malignant MS patients, 134 (59.6%) were female, 167 (74.2%) were relapsing onset, 94 (41.8%) had received disease-modifying drugs at some point and the mean follow-up was 8.7 years. The proportion of patients who 'worsened' increased from 40.4% to 57.8%, while those who 'improved' varied little (range, 8.9%-10.2%). The odds of worsening increased with disease duration (adjusted odds ratio (AOR) = 1.36; 95% confidence interval (CI) = 1.22-1.52) and the presence of primary progressive (vs relapsing-onset) MS (AOR = 1.85; 95% CI = 1.01-3.38). CONCLUSION: Apart from disease duration and a primary progressive course, no clinically useful associations of subsequent disease worsening in patients with aggressive/malignant MS were identified.

Sex differences in comorbidity at diagnosis of multiple sclerosis: A population-based study.

OBJECTIVE: To determine the prevalence of comorbidity in the multiple sclerosis (MS) population at the time of MS diagnosis. We also compared the prevalence of comorbidity in the MS population to that in a matched cohort from the general population. METHODS: Using population-based administrative health data from 4 Canadian provinces, we identified 23,382 incident MS cases and 116,638 age-, sex-, and geographically matched controls. We estimated the prevalence of hypertension, diabetes, hyperlipidemia, heart disease, chronic lung disease, epilepsy, fibromyalgia, inflammatory bowel disease, depression, anxiety, bipolar disorder, and schizophrenia at MS diagnosis using validated case definitions. We compared the populations using rate ratios. RESULTS: Of the MS cases, 16,803 (71.9%) were female. The most prevalent comorbidity was depression (19.1%). Compared to the matched population, all comorbidities except hyperlipidemia were more common in the MS population. Relative to the matched populations, the prevalence of hypertension was 16% higher for women with MS and 48% higher for men with MS, thus there was a disproportionately higher prevalence of hypertension in men with MS than women. Men with MS also had a disproportionately higher prevalence than women with MS for diabetes, epilepsy, depression, and anxiety. CONCLUSIONS: Comorbidity is more common than expected in MS, even around the time of diagnosis. The prevalence of psychiatric comorbidity is particularly high and highlights the need for clinical attention to this issue. The observed sex-specific differences in the burden of comorbidity in MS, which differ from those in the matched population, warrant further investigation.

Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: A prospective multisite study.

BACKGROUND: Depression and anxiety are common among people with multiple sclerosis (MS), as are adverse health behaviours, but the associations between these factors are unclear. OBJECTIVE: To evaluate the associations between cigarette smoking, alcohol use, and depression and anxiety in MS in a cross-Canada prospective study. METHODS: From July 2010 to March 2011 we recruited consecutive MS patients from four MS clinics. At three visits over two years, clinical and demographic information was collected, and participants completed questionnaires regarding health behaviours and mental health. RESULTS: Of 949 participants, 75.2% were women, with a mean age of 48.6 years; most had a relapsing-remitting course (72.4%). Alcohol dependence was associated with increased odds of anxiety (OR: 1.84; 95% CI: 1.32-2.58) and depression (OR: 1.53; 95% CI: 1.05-2.23) adjusting for age, sex, Expanded Disability Status Scale (EDSS), and smoking status. Smoking was associated with increased odds of anxiety (OR: 1.29; 95% CI: 1.02-1.63) and depression (OR: 1.37; 95% CI: 1.04-1.78) adjusting for age, sex, EDSS, and alcohol dependence. Alcohol dependence was associated with an increased incidence of depression but not anxiety. Depression was associated with an increased incidence of alcohol dependence. CONCLUSION: Alcohol dependence and smoking were associated with anxiety and depression. Awareness of the effects of adverse health behaviours on mental health in MS might help target counselling and support for those 'at risk'.

Effectiveness and cost-effectiveness of interferon beta and glatiramer acetate in the UK Multiple Sclerosis Risk Sharing Scheme at 6 years: a clinical cohort study with natural history comparator.

BACKGROUND: In 2002, the UK's National Institute for Clinical Excellence (NICE) concluded that interferon beta and glatiramer acetate would be cost effective as disease-modifying therapies (DMTs) for multiple sclerosis only if the short-term disability benefits reported in clinical trials were maintained. The UK Multiple Sclerosis Risk Sharing Scheme (RSS) was established to assess whether disability progression was consistent with a cost-effectiveness target of £36 000 per quality-adjusted life-year projected over 20 years. We aimed to evaluate the long-term effectiveness and cost-effectiveness of these DMTs by comparing a cohort of patients with relapsing-remitting multiple sclerosis enrolled in the UK RSS with a natural history cohort from British Columbia, Canada. METHODS: In our clinical cohort we included patients starting a DMT who were enrolled in the UK RSS who had relapsing multiple sclerosis at baseline and had at least one further clinical assessment. In our control cohort we included patients in the British Columbia multiple sclerosis database (BCMS; data collection 1980-96) who met the same eligibility criteria as for the RSS cohort. We compared disability progression at 6 years for RSS patients with untreated progression modelled from BCMS patients using continuous Markov and multilevel models. The primary outcomes were the progression ratio (treated vs untreated) measured both in Expanded Disability Status Scale (EDSS) score and utility. A ratio of less than 100% for EDSS implied slower than expected progression on treatment compared with off treatment; a utility ratio of 62% or less implied that the DMTs were cost effective. FINDINGS: 5610 patients starting a DMT were enrolled in the UK RSS between Jan 14, 2002, and July 13, 2005 (72 sites), of whom 4137 were included in our clinical cohort. We included 898 BCMS patients in the control cohort who met the RSS inclusion criteria and had at least one EDSS score after baseline. RSS patients had a mean follow-up of 5·1 years (SD 1·4). Both models showed slower EDSS progression than predicted for untreated controls (Markov model, 75·8% [95% CI 71·4-80·2]; multilevel model, 60·0% [56·6-63·4]). Utility ratios were consistent with cost-effectiveness (Markov model, 58·5% [95% CI 54·2-62·8]; multilevel model, 57·1% [53·0-61·2]). INTERPRETATION: Findings from this large observational study of treatment with interferon beta or glatiramer acetate provide evidence that their effects on disability in patients with relapsing-remitting multiple sclerosis are maintained and cost effective over 6 years. Similar modelling approaches could be applied to other chronic diseases for which long-term controlled trials are not feasible. FUNDING: Health Departments of England, Wales, Scotland, and Northern Ireland, Biogen Idec, Merck Serono, Bayer Schering Pharmaceuticals, Teva Pharmaceuticals Industries, UK National Institute of Health Research's Health Technology Assessment Programme.

Risk factors associated with the onset of relapsing-remitting and primary progressive multiple sclerosis: a systematic review.

Multiple sclerosis (MS) is a chronic central nervous system disease with a highly heterogeneous course. The aetiology of MS is not well understood but is likely a combination of both genetic and environmental factors. Approximately 85% of patients present with relapsing-remitting MS (RRMS), while 10-15% present with primary progressive MS (PPMS). PPMS is associated with an older onset age, a different sex ratio, and a considerably more rapid disease progression relative to RRMS. We systematically reviewed the literature to identify modifiable risk factors that may be associated with these different clinical courses. We performed a search of six databases and integrated twenty observational studies into a descriptive review. Exposure to Epstein-Barr virus (EBV) appeared to increase the risk of RRMS, but its association with PPMS was less clear. Other infections, such as human herpesvirus-6 and chlamydia pneumoniae, were not consistently associated with a specific disease course nor was cigarette smoking. Despite the vast literature examining risk factors for the development of MS, relatively few studies reported findings by disease course. This review exposes a gap in our understanding of the risk factors associated with the onset of PPMS, our current knowledge being predominated by relapsing-onset MS.