Risk of Multiple Sclerosis in People Living with HIV: An International Cohort Study.

OBJECTIVE: There has been interest in a possible negative association between HIV and multiple sclerosis (MS). We aimed to compare the risk of MS in a cohort of individuals living with HIV to that in the general population. METHODS: Population-based health data were accessed for 2 cohorts of HIV-positive persons from Sweden and British Columbia, Canada. Incident MS was identified using MS registries or a validated algorithm applied to administrative data. Individuals with HIV were followed from 1 year after the first clinical evidence of HIV or the first date of complete administrative health data (Canada = April 1, 1992 and Sweden = January 1, 2001) until the earliest of incident MS, emigration, death, or study end (Canada = March 31, 2020 and Sweden = December 31, 2018). The observed MS incidence rate in the HIV-positive cohort was compared to the expected age-, sex-, calendar year-, income-specific, and region of birth-specific rates in a randomly selected sample of >20% of each general population. The standardized incidence ratio (SIR) for MS following the first antiretroviral therapy exposure ("ART-exposed") was also calculated. RESULTS: The combined Sweden-Canada cohort included 29,163 (75% men) HIV-positive persons. During 242,248 person-years of follow-up, 14 incident MS cases were observed in the HIV-positive cohort, whereas 26.19 cases were expected. The SIR for MS in the HIV-positive population was 0.53 (95% confidence interval [CI] = 0.32-0.90). The SIR for MS following the first ART exposure was 0.55 (95% CI = 0.31-0.96). INTERPRETATION: This international population-based study demonstrated a lower risk of MS among HIV-positive individuals, and HIV-positive ART-exposed individuals. These findings provide support for further exploration into the relationship among HIV, ART, and MS. ANN NEUROL 2024;95:487-494.

Incidence and prevalence of paediatric-onset multiple sclerosis in two Canadian provinces: a population-based study representing over half of Canada's population.

BACKGROUND: Population-based studies estimating the epidemiology of paediatric-onset multiple sclerosis (PoMS) are scarce. METHODS: We accessed population-based health administrative data from two provinces in Canada, Ontario and British Columbia (BC). Individuals with PoMS were identified via a validated case definition. The index date ('MS onset') was the first demyelinating or MS specific claim recorded ≤18 years of age. We estimated the age-standardised annual incidence and prevalence of PoMS, and 95% CIs between 2003 and 2019. We used negative binomial regression models to assess the temporal changes in the annual crude incidence and prevalence of PoMS, and the ratios comparing sex groups. RESULTS: From 2003 to 2019, a total of 148 incident PoMS cases were identified in BC, and 672 in Ontario. The age-standardised annual incidence of PoMS was stable in both provinces, averaging 0.95 (95% CI 0.79 to 1.13) in BC and 0.98 (95%CI 0.84 to 1.12) in Ontario per 100 000 person-years. The incidence ratio by sex (female vs male) was also stable over the study period, averaging 1.5:1 (95% CI 1.06 to 2.08, BC) and 2.0:1 (95% CI 1.61 to 2.59, Ontario). The age-standardised prevalence per 100 000 people rose from 4.75 (2003) to 5.52 (2019) in BC and from 2.93 (2003) to 4.07 (2019) in Ontario, and the increase was statistically significant in Ontario (p=0.002). There were more female prevalent PoMS cases than males in both provinces. CONCLUSIONS: Canada has one of the highest rates of PoMS globally, and the prevalence, but not incidence, has increased over time. Allocation of resources to support the growing youth population with MS should be a priority.

Investigation of health care use and a possible prodrome before the first attack in NMOSD and MOGAD.

BACKGROUND: Prodromal phases are well recognized in many inflammatory and neurodegenerative diseases, including multiple sclerosis. We evaluated the possibility of a prodrome in aquaporin-4 antibody positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) using health administrative data. METHODS: We investigated individuals with AQP4 + NMOSD and MOGAD, confirmed by medical chart review, in Ontario, Canada. Each NMOSD and MOGAD participant was matched 1:5 to general population controls by sex, birth year, immigrant status, and region. Total outpatient visits and hospitalizations were compared in the 5 years preceding the incident attack in multivariable negative binomial models. RESULTS: We identified 96 people with AQP4 + NMOSD, matched to 479 controls, and 61 people with MOGAD, matched to 303 controls. In the 5 years preceding the incident attack, health care use was elevated for outpatient visits and hospitalizations for the NMOSD cohort (adjusted rate ratio (aRR): 1.47; 95% confidence interval (CI): 1.25-1.73; aRR: 1.67; 95% CI: 1.19-2.36, respectively) but not for MOGAD. Rate ratios steadily increased in NMOSD for outpatient visits in the 2 years preceding the incident attack. CONCLUSION: Our findings support a prodromal phase preceding clinical onset of AQP4 + NMOSD. Earlier recognition and management of NMOSD patients may be possible.

Incidence rate and prevalence of pediatric-onset multiple sclerosis in Sweden: A population-based register study.

BACKGROUND AND PURPOSE: Pediatric-onset multiple sclerosis (PoMS) is associated with high health care use. To plan resource allocation for this patient group, knowledge of the incidence rate and prevalence is important. However, such studies are scarce, few are population-based, and the methodology varies widely. We aimed to address this knowledge gap by performing a nationwide study of the incidence rate and prevalence of PoMS in Sweden, an area of high multiple sclerosis (MS) incidence and prevalence. METHODS: MS cases were identified by linking two nationwide registers, the National Patient Register and the Swedish MS Registry. MS cases having their first central nervous system demyelinating event or MS clinical onset before age 18 years were classified as pediatric onset. Incidence rate and prevalence were estimated annually over the study period (2006-2016) for the total population and stratified by sex and age group (<12, 12-15, and 16-17 years). Temporal trends and ratios between sexes and age groups were estimated. RESULTS: We identified 238 incident cases from 2006 to 2016, corresponding to an overall crude incidence rate of 1.12 per 100,000 person-years and an overall crude prevalence of 2.82 per 100,000 population. There was a higher incidence rate among females and the highest age category. The overall incidence rate and prevalence estimates remained stable during the study period. CONCLUSIONS: Sweden exhibits a consistently high incidence rate and prevalence of PoMS that has remained stable over time. This knowledge serves as a tool to aid in planning resource allocation and health services for this patient population.

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.

Low socioeconomic status was associated with a higher mortality risk in multiple sclerosis.

BACKGROUND: The relationship between socioeconomic status (SES) and mortality among persons with multiple sclerosis (PwMS) is poorly understood. OBJECTIVE: To investigate the association between SES and mortality risk in PwMS. METHODS: From health-administrative data, we identified 12,126 incident MS cases with a first demyelinating event (MS 'onset') occurring between 1994 and 2017. Cox proportional hazard model assessed the association between socioeconomic status quintiles (SES-Qs) at MS onset and all-cause mortality. RESULTS: Lower SES-Qs were associated with higher mortality risk; adjusted hazard ratios: SES-Q1 (most deprived) =1.61 (95% confidence interval (CI) = 1.36-1.91); SES-Q2 = 1.26 (95% CI = 1.05-1.50); SES-Q3 = 1.22 (95% CI = 1.02-1.46); SES-Q4 = 1.13 (95% CI = 0.94-1.35) versus SES-Q5 (least deprived). CONCLUSION: A lower SES was associated with higher mortality risk in PwMS.

Care consumption of people with multiple sclerosis: A multichannel sequence analysis in a population-based setting in British Columbia, Canada.

BACKGROUND: Persons with multiple sclerosis (PwMS) typically require complex multidisciplinary care, which is rarely formally assessed. OBJECTIVES: We applied multichannel sequence analysis (MCSA) to identify care consumption patterns by PwMS in British Columbia, Canada. METHODS: We created two cohorts, comprising incident and prevalent MS cases, using linked clinical and administrative data. We applied MCSA to quantify and compare the care pathways of PwMS, based on all-cause hospitalizations and physician visits (divided into five specialities). Care consumption clusters were characterized using demographic and clinical features. RESULTS: From 1048 incident and 3180 prevalent PwMS, the MCSA identified 12 and 6 distinct care consumption clusters over a median follow-up of 9.6 and 13.0 years, respectively. Large disparities between clusters were observed; the median number of annual consultations ranged from 5.6 to 21.3 for general practitioners, 1.2 to 4.6 for neurologists and 0 to 5.3 for psychiatrists in the incident cohort. Characteristics at MS symptom onset associated with the highest care consumption included high comorbidity burden and older age. There were similar disparities and associations for prevalent PwMS. CONCLUSION: The distinct patterns of care consumption, which were reminiscent of the heterogeneity of MS itself, may facilitate health service planning and evaluation, and provide a novel outcome measure in health research.

Emergency department use by persons with MS: A population-based descriptive study with a focus on infection-related visits.

We described emergency department (ED) visits (all visits and infection-related) by persons with multiple sclerosis (MS) in British Columbia, Canada (1 April 2012 to 31 December 2017). We identified 15,350 MS cases using health administrative data; 73.4% were women, averaging 51.4 years at study entry. Over 4.9 years of follow-up (mean), 56.0% of MS cases visited an ED (mean = 0.6 visits/person/year; total = 37,072 visits). A diagnosis was documented for 25,698 (69.3%) ED visits, and 18.4% (4725/25,698) were infection-related. Inpatient admissions were reported for 20.4% (5238/25,698) of all and 29.2% (1380/4725) of infection-related ED visits. Findings suggest that the ED plays a substantial role in MS healthcare and infection management.

Disease-modifying drugs for multiple sclerosis and subsequent health service use.

OBJECTIVE: We assessed the relationship between the multiple sclerosis (MS) disease-modifying drugs (DMDs) and healthcare use. METHODS: Persons with MS (aged ⩾18 years) were identified using linked population-based health administrative data in four Canadian provinces and were followed from the most recent of their first MS/demyelinating event or 1 January 1996 until the earliest of death, emigration, or study end (31 December 2017 or 31 March 2018). Prescription records captured DMD exposure, examined as any DMD, then by generation (first-generation (the injectables) or second-generation (orals/infusions)) and individual DMD. The associations with subsequent all-cause hospitalizations and physician visits were examined using proportional means model and negative binomial regression. RESULTS: Of 35,894 MS cases (72% female), mean follow-up was 12.0 years, with person-years of DMD exposure for any, or any first- or second-generation DMD being 63,290, 54,605 and 8685, respectively. Any DMD or any first-generation DMD exposure (versus non-exposure) was associated with a 24% lower hazard of hospitalization (adjusted hazard ratio, aHR: 0.76; 95% confidence intervals (CIs): 0.71-0.82), rising to 29% for the second-generation DMDs (aHR: 0.71; 95% CI: 0.58-0.88). This ranged from 18% for teriflunomide (aHR: 0.82; 95% CI: 0.67-1.00) to 44% for fingolimod (aHR: 0.56; 95% CI: 0.36-0.87). In contrast, DMD exposure was generally not associated with substantial differences in physician visits. CONCLUSION: Findings provide real-world evidence of a beneficial relationship between DMD exposure and hospitalizations.

Stability of the gut microbiota in persons with paediatric-onset multiple sclerosis and related demyelinating diseases.

OBJECTIVE: Examine if the gut microbiota composition changes across repeated samples in paediatric-onset multiple sclerosis (MS) or monophasic-acquired demyelinating syndromes (monoADS). METHODS: A total of 36 individuals (18 MS/18 monoADS) with ⩾2 stool samples were included. Stool sample-derived DNA was sequenced. Alpha/beta diversities and genus-level taxa were analysed. RESULTS: Mean ages at first sample procurement (MS/monoADS) = 18.0/13.8 years. Median time (months) between first/second samples = 11.2 and second/third = 10.3. Alpha/beta diversities did not differ between stool samples (p > 0.09), while one genus - Solobacterium did (p = 0.001). CONCLUSIONS: The gut microbiota composition in paediatric-onset MS and monoADS exhibited stability, suggesting that single stool sample procurement is a reasonable first approach.

Dealing With Treatment-Confounder Feedback and Sparse Follow-up in Longitudinal Studies: Application of a Marginal Structural Model in a Multiple Sclerosis Cohort.

The beta-interferons are widely prescribed platform therapies for patients with multiple sclerosis (MS). We accessed a cohort of patients with relapsing-onset MS from British Columbia, Canada (1995-2013), to examine the potential survival advantage associated with beta-interferon exposure using a marginal structural model. Accounting for potential treatment-confounder feedback between comorbidity, MS disease progression, and beta-interferon exposure, we found an association between beta-interferon exposure of at least 6 contiguous months and improved survival (hazard ratio (HR) = 0.63, 95% confidence interval 0.47, 0.86). We also assessed potential effect modifications by sex, baseline age, or baseline disease duration, and found these factors to be important effect modifiers. Sparse follow-up due to variability in patient contact with the health system is one of the biggest challenges in longitudinal analyses. We considered several single-level and multilevel multiple imputation approaches to deal with sparse follow-up and disease progression information; both types of approach produced similar estimates. Compared to ad hoc imputation approaches, such as linear interpolation (HR = 0.63), and last observation carried forward (HR = 0.65), all multiple imputation approaches produced a smaller hazard ratio (HR = 0.53), although the direction of effect and conclusions drawn concerning the survival advantage remained the same.

The multiple sclerosis prodrome: Emerging evidence, challenges, and opportunities.

A prodrome is considered an early set of signs or symptoms indicating the onset of a disease or illness. In multiple sclerosis (MS), the prodromal period is the months or years before our current, classic understanding of "MS symptom onset." Prodromal periods are well recognized in other neurodegenerative conditions and more recently have been shown in MS. In this Viewpoint, we reflect on the emerging evidence surrounding the MS prodrome, including features that may be common across chronic inflammatory and neurodegenerative diseases. Finally, we discuss the implications for future disease prevention in MS.

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.

Adherence to laboratory monitoring among people taking oral drugs for multiple sclerosis: A Canadian population-based study.

OBJECTIVE: To examine laboratory testing adherence by persons initiating an oral disease-modifying therapy (DMT) for multiple sclerosis (MS). METHODS: Population-based health administrative and laboratory data were accessed in British Columbia, Canada, to identify everyone filling their first prescription for dimethyl fumarate (DMF), fingolimod or teriflunomide (2011-2015). The proportion of people adherent to each drug monograph's recommended laboratory monitoring schedule, pre- and on-DMT, was estimated. The association between patient characteristics and adherence was examined using multivariable logistic regression. RESULTS: A total of 1016 people were included (DMF 567, fingolimod 253 and teriflunomide 196). The proportions of people adherent to pre-DMT liver and lymphocyte tests ranged from 88% to 91% and 91% to 94%, respectively, while 77% adhered to pre-DMF urinalysis. Adherence to the first on-DMT liver test was 89% for DMF (within 6 months), 61% for fingolimod (within 3 months) and 40% for teriflunomide (within 1 month). Men were less likely than women to have pre-DMF urinalysis (adjusted odds ratio (aOR); 95% confidence interval (CI): 0.40-0.95) or on-DMF liver (aOR: 0.46; 95% CI: 0.23-0.95) or lymphocyte (aOR: 0.47; 95% CI: 0.22-0.98) tests. CONCLUSIONS: Adherence to recommended laboratory testing was high (>77%) before oral DMT initiation, but lower once on drug. There is a need to understand the long-term consequences of suboptimal laboratory monitoring and sex differences in the DMT-treated MS population.

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.

Fatigue, sleep disorders, anaemia and pain in the multiple sclerosis prodrome.

BACKGROUND: There is increasing evidence of prodromal multiple sclerosis (MS). OBJECTIVE: The aim of this study was to determine whether fatigue, sleep disorders, anaemia or pain form part of the MS prodrome. METHODS: This population-based matched cohort study used linked administrative and clinical databases in British Columbia, Canada. The odds of fatigue, sleep disorders, anaemia and pain in the 5 years preceding the MS cases' first demyelinating claim or MS symptom onset were compared with general population controls. The frequencies of physician visits for these conditions were also compared. Modifying effects of age and sex were evaluated. RESULTS: MS cases/controls were assessed before the first demyelinating event (6863/31,865) or MS symptom onset (966/4534). Fatigue (adj.OR: 3.37; 95% CI: 2.76-4.10), sleep disorders (adj.OR: 2.61; 95% CI: 2.34-2.91), anaemia (adj.OR: 1.53; 95% CI: 1.32-1.78) and pain (adj.OR: 2.15; 95% CI: 2.03-2.27) during the 5 years preceding the first demyelinating event were more frequent among cases, and physician visits increased for cases relative to controls. The association between MS and anaemia was greater for men; that between MS and pain increased with age. Pre-MS symptom onset, sleep disorders (adj.OR: 1.72; 95% CI: 1.12-2.56) and pain (adj.OR: 1.53; 95% CI: 1.32-1.76) were more prevalent among cases. CONCLUSION: Fatigue, sleep disorders, anaemia and pain were elevated before the recognition of MS. The relative anaemia burden was higher in men and pain more evident among older adults.

Disparities in management and outcomes of myocardial infarction in multiple sclerosis: A matched cohort study.

BACKGROUND: Although multiple sclerosis (MS) confers an elevated risk of acute myocardial infarction (AMI), little is known about how it influences management of AMI. METHODS: Using population-based administrative (health) data from two Canadian provinces, we conducted a retrospective matched cohort study. We identified people with MS who had an incident AMI, and up to five AMI controls without MS matched on age, sex, and region. We compared the likelihood of undergoing cardiac catheterization within 30 days of AMI, time to revascularization, use of recommended pharmacotherapy post-AMI, and mortality at 30 and 365 days post-AMI using multivariable regression models adjusting for potential confounders. We pooled findings across provinces using meta-analysis. RESULTS: We identified 559 MS cases and 2523 matched controls. In the matched cohort, the MS cohort was less likely to undergo cardiac catheterization within 30 days of admission (odds ratio (OR) = 0.61; 95% confidence interval (CI) = 0.49-0.77), revascularization (hazard ratio (HR) = 0.78; 95% CI = 0.69-0.88), or to fill a prescription for recommended therapy. Mortality risk was higher in the MS cohort than in the matched cohort at 30 and 365 days post-AMI. CONCLUSION: Rates of diagnostic and therapeutic care, and survival after AMI were lower in the MS population than in a matched population.

Age-related decreases in relapses among adults with relapsing-onset multiple sclerosis.

BACKGROUND: Relapsing-onset multiple sclerosis (MS) typically starts in early- to mid-adulthood, yet the trajectory of disease activity over the subsequent lifetime remains poorly defined. Previous studies have not quantified the age-specific portion of decreases in annualized relapse rates (ARR). OBJECTIVE: The aim of this article is to determine, under a range of disease-related assumptions, the age-specific component of decreases in ARR over time among adults with relapsing-onset MS. METHODS: We used a simulation modeling approach to examine a range of assumptions about changes in ARR due to age versus disability status. Scenarios included variations in initial ARR and rate of worsening on the Expanded Disability Status Scale. Model parameters were developed through analysis of MS patients in British Columbia, Canada, and literature review. RESULTS: We found a substantial age-specific decrease in ARR in all simulated scenarios, independent of disability worsening. Under a range of clinically plausible assumptions, 88%-97% of the decrease was attributed to age and 3%-13% to disability. The age-specific decrease ranged from 22% to 37% per 5 years for a wide range of initial ARR (0.33-1.0). CONCLUSION: Decreases in ARR were due mostly to age rather than disability status. To facilitate informed decision making in MS, it is important to quantify the dynamic relationship between relapses and age.

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.

Interrogation of the Multiple Sclerosis Prodrome Using High-Dimensional Health Data.

BACKGROUND: There is growing evidence of a prodromal period in multiple sclerosis (MS). A better understanding of the prodrome may facilitate prompt recognition and treatment of MS as well as narrowing of the etiologically relevant -period when searching for MS risk factors. OBJECTIVES: To explore and further delineate the MS prodrome, we used statistical learning techniques to examine associations of physician-generated diagnostic codes and prescription medication classes in the 5 years before the first demyelinating-related claim for MS cases and matched population controls. METHODS: In this matched cohort study, we accessed data from linked health administrative hospital, physician, and prescription databases from British Columbia, Canada, between 1996 and 2013. We focused on 7 medication classes previously identified as associated with the MS prodrome: urinary anti-spasmodics, glucocorticoids, muscle relaxants, anti-epileptics, dopa-derivatives, benzodiazepine, and antivertigo preparations. Diagnostic codes associated with the use of each medication class were first identified using LASSO logistic regression analyses in two-thirds of the cohort and then validated using multivariate logistic regressions in the remaining cohort. RESULTS: Our analyses included 4,862 MS cases and 22,649 controls. Although the identified diagnostic codes showed fair to good predictive performance in 6 medication classes (C-index = 0.712-0.858), these codes failed to fully explain the higher usage of these medications by the MS cases. Compared to controls of the same age, sex, and diagnostic codes, MS cases had higher odds of filling a prescription for antivertigo preparations (adjusted OR [aOR] 2.48; 95% CI 1.92-3.19), anti-epileptics (aOR 2.34; 1.90-2.90), glucocorticoids (aOR 1.76; 1.52-2.03), urinary anti-spasmodics (aOR 1.72; 1.20-2.46), and muscle relaxants (aOR 1.33; 1.13-1.56). CONCLUSIONS: We observed markedly higher use of specific medications in MS cases in the 5 years before the first demyelinating claim. The overrepresentation of specific medications in MS cases, which was not fully explained by the physician diagnoses, may represent a signature of the MS prodrome.