Spasticity treatment patterns among people with multiple sclerosis: a Swedish cohort study.

BACKGROUND: Spasticity is common among people with multiple sclerosis (MS), but there are few studies of spasticity treatment patterns. We aim to describe associations with spasticity treatment measured primarily by oral baclofen use. METHODS: This cohort study using Swedish registers included 1826 and 3519 people with incident and prevalent MS (pwIMS, pwPMS) respectively, followed from 2005 to 2014. Cox regression assessed factors associated with new baclofen prescriptions and its discontinuation. RESULTS: A total of 10% of pwIMS and 19% of pwPMS received baclofen, a drug prescribed specifically for spasticity in Sweden, of which many patients had relapsing-remitting course. Prescriptions occurred soon after MS diagnosis: pwIMS received baclofen typically within 6 months of diagnosis, and pwPMS within 3 years. Younger patients compared with older patients were three times more likely to receive baclofen with similar disability level measured using Expanded Disability Severity Scores (EDSS). Patients aged 18-44 years with EDSS 3.0-5.0 have an HR for baclofen use of 5.62 (95% CI 2.91 to 10.85) and EDSS 6+ have an HR of 15.41 (95% CI 7.07 to 33.58) compared with individuals with EDSS 0-2.5. In comparison, patients aged 45+ years with EDSS 3.0-5.0 have an HR of 2.05 (95% CI 1.10 to 3.82) and EDSS 6+ an HR of 4.26 (95% CI 1.96 to 9.17). Baclofen discontinuation was high: 49% (95% CI 0.42 to 0.57) of pwIMS discontinued within 150 days of dispensation, 90% discontinued within 2 years including patients with progressive course or higher EDSS. Associations among pwPMS and sensitivity analyses including additional treatments were similar. CONCLUSIONS: Younger patients with MS are more likely to receive baclofen compared with older patients with MS. High rates of baclofen discontinuation highlight the need for more tolerable and efficacious spasticity treatments and monitoring of spasticity among people with MS.

Risk of serious infections in multiple sclerosis patients by disease course and disability status: Results from a Swedish register-based study.

Background and objectives: Serious infections are an emerging concern with increasing use of potent immunomodulation in multiple sclerosis (MS), but the extent to which MS disease features influence infectious susceptibility is poorly characterized. The objective of this study was to assess the associations of MS disease course and disability status with risk of serious infections. Methods: A cohort of 8660 MS patients was individually matched on age, sex and region of residence with 86,600 people without MS from the general population using national registers in Sweden. The study period was from 1996 to 2012, with follow-up until December 31, 2014. The main outcomes were infection as the underlying or contributory cause of death or infection-related hospital admission identified in the Cause of Death and Patient registers. MS disease course (relapsing-remitting or progressive disease) and Expanded Disability Status Scale (EDSS) score (six and over or below six) were extracted from the MS Register Hazard ratios (HRs) for any serious infection were estimated using flexible parametric models. Results: During a median follow-up of 9.6 years (interquartile range = 5.5-13.5 years), 1337 MS patients experienced a serious infection. Compared with individually matched people without MS, risk of serious infection was greater for progressive disease (HR = 3.80; 95% CI 3.52: 4.09) than relapsing-remitting disease (HR = 1.77; 95% CI: 1.62:1.93). A similar pattern of risk was seen for dichotomised EDSS score (HR = 4.26; 95% CI 3.87: 4.70 for EDSS 6.0-9.5 and HR = 1.30; 95% CI 1.1853: 1.43 for EDSS 0.0-5.5). Overall, associations with greater disability did not notably differ by immunomodulatory therapy use, but associations with lower disability were more pronounced in patients receiving these therapies. Conclusions: Disease course or EDSS score (which may be more readily available than MS course in some patients) should be considered in individual management and monitoring of MS patients, including assessing benefit-risk of therapies that influence general immune function.

Association of Infectious Mononucleosis in Childhood and Adolescence With Risk for a Subsequent Multiple Sclerosis Diagnosis Among Siblings.

Importance: Epstein-Barr virus and its acute manifestation, infectious mononucleosis (IM), are associated with an increased risk of multiple sclerosis (MS). Whether this association is confounded by susceptibility to infection is still debated. Objective: To assess whether hospital-diagnosed IM during childhood, adolescence, or young adulthood is associated with subsequent MS diagnosis independent of shared familial factors. Design, Setting, and Participants: This population-based cohort study used the Swedish Total Population Register to identify individuals born in Sweden from January 1, 1958, to December 31, 1994. Participants aged 20 years were followed up from January 1, 1978, to December 31, 2018, with a median follow-up of 15.38 (IQR, 8.68-23.55; range, 0.01-40.96) years. Data were analyzed from October 2020 to July 2021. Exposure: Hospital-diagnosed IM before 25 years of age. Main Outcomes and Measures: Diagnoses of MS from 20 years of age were identified. Risk of an MS diagnosis associated with IM in childhood (birth to 10 years of age), adolescence (11-19 years of age), and early adulthood (20-24 years of age [time-dependent variable]) were estimated using conventional and stratified (to address familial environmental or genetic confounding) Cox proportional hazards regression. Results: Of the 2 492 980 individuals (1 312 119 men [52.63%] and 1 180 861 women [47.37%]) included, 5867 (0.24%) had an MS diagnosis from 20 years of age (median age, 31.50 [IQR, 26.78-37.54] years). Infectious mononucleosis in childhood (hazard ratio [HR], 1.98; 95% CI, 1.21-3.23) and adolescence (HR, 3.00; 95% CI, 2.48-3.63) was associated with an increased risk of an MS diagnosis that remained significant after controlling for shared familial factors in stratified Cox proportional hazards regression (HRs, 2.87 [95% CI, 1.44-5.74] and 3.19 [95% CI, 2.29-4.46], respectively). Infectious mononucleosis in early adulthood was also associated with risk of a subsequent MS diagnosis (HR, 1.89; 95% CI, 1.18-3.05), but this risk was attenuated and was not significant after controlling for shared familial factors (HR, 1.51; 95% CI, 0.82-2.76). Conclusions and Relevance: These findings suggest that IM in childhood and particularly adolescence is a risk factor associated with a diagnosis of MS, independent of shared familial factors.

Hospital-diagnosed infections before age 20 and risk of a subsequent multiple sclerosis diagnosis.

The involvement of specific viral and bacterial infections as risk factors for multiple sclerosis has been studied extensively. However, whether this extends to infections in a broader sense is less clear and little is known about whether risk of a multiple sclerosis diagnosis is associated with other types and sites of infections such as the CNS. This study aims to assess if hospital-diagnosed infections by type and site before age 20 years are associated with risk of a subsequent multiple sclerosis diagnosis and whether this association is explained entirely by infectious mononucleosis, pneumonia, and CNS infections. Individuals born in Sweden between 1970 and 1994 were identified using the Swedish Total Population Register (n = 2 422 969). Multiple sclerosis diagnoses from age 20 years and hospital-diagnosed infections before age 20 years were identified using the Swedish National Patient Register. Risk of a multiple sclerosis diagnosis associated with various infections in adolescence (11-19 years) and earlier childhood (birth-10 years) was estimated using Cox regression, with adjustment for sex, parental socio-economic position, and infection type. None of the infections by age 10 years were associated with risk of a multiple sclerosis diagnosis. Any infection in adolescence increased the risk of a multiple sclerosis diagnosis (hazard ratio 1.33, 95% confidence interval 1.21-1.46) and remained statistically significant after exclusion of infectious mononucleosis, pneumonia, and CNS infection (hazard ratio 1.17, 95% confidence interval 1.06-1.30). CNS infection in adolescence (excluding encephalomyelitis to avoid including acute disseminated encephalitis) increased the risk of a multiple sclerosis diagnosis (hazard ratio 1.85, 95% confidence interval 1.11-3.07). The increased risk of a multiple sclerosis diagnosis associated with viral infection in adolescence was largely explained by infectious mononucleosis. Bacterial infections in adolescence increased risk of a multiple sclerosis diagnosis, but the magnitude of risk reduced after excluding infectious mononucleosis, pneumonia and CNS infection (hazard ratio 1.31, 95% confidence interval 1.13-1.51). Respiratory infection in adolescence also increased risk of a multiple sclerosis diagnosis (hazard ratio 1.51, 95% confidence interval 1.30-1.75), but was not statistically significant after excluding infectious mononucleosis and pneumonia. These findings suggest that a variety of serious infections in adolescence, including novel evidence for CNS infections, are risk factors for a subsequent multiple sclerosis diagnosis, further demonstrating adolescence is a critical period of susceptibility to environmental exposures that raise the risk of a multiple sclerosis diagnosis. Importantly, this increased risk cannot be entirely explained by infectious mononucleosis, pneumonia, or CNS infections.

Higher body mass index at ages 16 to 20 years is associated with increased risk of a multiple sclerosis diagnosis in subsequent adulthood among men.

BACKGROUND: Evidence for the association between body mass index (BMI) and multiple sclerosis (MS) among men remains mixed. OBJECTIVE AND METHODS: Swedish military conscription and other registers identified MS after age of 20 years and BMI at ages 16-20 years (N = 744,548). RESULTS: Each unit (kg/m2) BMI increase was associated with greater MS risk (hazard ratio and 95% confidence interval = 1.034, 1.016-1.053), independent of physical fitness (1.021, 1.001-1.042). Categorised, overweight and obesity were associated with statistically significant raised MS risk compared to normal weight, but not after adjustment for physical fitness. CONCLUSION: MS risk rises with increasing BMI, across the entire BMI range.

Military service and related risk factors for amyotrophic lateral sclerosis.

BACKGROUND: The cause of amyotrophic lateral sclerosis (ALS) is unknown, but occupations have been explored as a potential proxy measure of risk. There is a substantial body of literature connecting military service to ALS. We aimed to summarize and assess the quality of this evidence. METHODS: Systematic review of the literature, including observational studies which explored one of the following exposures: general military service (army, air force, marines, or navy); or specific exposures associated with military service measured among military personnel. The outcome of interest was ALS incidence, which could include onset, diagnosis, or death from ALS. RESULTS: A total of 2642 articles were screened. Following exclusion, 19 articles remained for inclusion in the systematic review, including 1 meta-analysis and 18 original observational studies. Most studies were of moderate quality. In general, the relationship between military service was suggestive of an increased risk, particularly among Gulf War and WWII veterans. Exposure to pesticides (including Agent Orange) certain chemicals (exhaust, burning agents), heavy metals, and head trauma appeared to increase the risk of ALS among military personnel. CONCLUSIONS: There is a possible association between military service and the subsequent development of ALS; however, the evidence was limited. Studies were generally hindered by small sample sizes and inadequate follow-up time. Future studies should endeavor to objectively measure specific exposures, or combinations thereof, associated with military service, as this will be of vital importance in implementing preventative strategies into military organizations.

Comorbid disease burden among MS patients 1968-2012: A Swedish register-based cohort study.

BACKGROUND: People with multiple sclerosis (pwMS) have increased comorbid disease (CMD) risk. Most previous studies have not considered overall CMD burden. OBJECTIVE: To describe lifetime CMD burden among pwMS. METHODS: PwMS identified using Swedish registers between 1968 and 2012 (n = 25,476) were matched by sex, age, and county of residence with general-population comparators (n = 251,170). Prevalence, prevalence ratios (PRs), survival functions, and hazard ratios by MS status, age, and time period compared seven CMD: autoimmune, cardiovascular, depression, diabetes, respiratory, renal, and seizures. RESULTS: The magnitude of the PRs for each CMD and age group decreased across time, with higher PRs in earlier time periods. Before 1990, younger age groups had higher PRs, and after 1990, older age groups had higher PRs. Male pwMS had higher burden compared with females. Overall, renal, respiratory, and seizures had the highest PRs. Before 2001, 50% of pwMS received a first/additional CMD diagnosis 20 years prior to people without MS, which reduced to 4 years after 2001. PwMS had four times higher rates of first/additional diagnoses in earlier time periods, which reduced to less than two times higher in recent time periods compared to people without MS. CONCLUSION: Swedish pwMS have increased CMD burden compared with the general population, but this has reduced over time.

The DQB1*03:02 Genotype and Treatment for Pain in People With and Without Multiple Sclerosis.

Murine models have demonstrated that the major histocompatibility complex (MHC) is associated with pain-like behavior in peripheral nerve injury, however, the same association has not been shown when considering injury to the central nervous system (CNS), which more closely mimics the damage to the CNS experienced by MS patients. Previous research has indicated the DQB1*03:02 allele of the class II HLA genes as being associated with development of neuropathic pain in persons undergoing inguinal hernia surgery or with lumbar spinal disk herniation. Whether this HLA allele plays a part in susceptibility to pain, has not, as far as we are aware, been previously investigated. This study utilizes information on DQB1*03:02 alleles as part of the EIMS, GEMS, and IMSE studies in Sweden. It also uses register data for 3,877 MS patients, and 4,548 matched comparators without MS, to assess whether the DQB1*03:02 allele is associated with prescribed pain medication use, and whether associations with this genotype differ depending on MS status. Our results showed no association between the DQB1*03:02 genotype and pain medication in MS patients, with an adjusted odds ratio (OR) of 1.02 (95% CI 0.85-1.24). In contrast, there was a statistically significant association of low magnitude in individuals without MS [adjusted OR 1.18 (95% CI 1.03-1.35)], which provides support for HLA influence on susceptibility to pain in the general population. Additionally, the effect of zygosity was evident for the non-MS cohort, but not among MS patients, suggesting the DQB1*03:02 allele effect is modified by the presence of MS.

Hospital diagnosed pneumonia before age 20 years and multiple sclerosis risk.

INTRODUCTION: Respiratory inflammation has been proposed as a risk factor for MS. This study aims to determine if hospital-diagnosed pneumonia in adolescence (before age 20 years) is associated with subsequent multiple sclerosis (MS). METHODS: This case-control study included incident MS cases after age 20 years identified using the Swedish national registers. Cases were matched with 10 general population controls by age, sex and region. Pneumonia diagnoses were identified between 0-5, 6-10, 11-15 and 16-20 years of age. Conditional logistic regression models adjusted for infectious mononucleosis (IM) and education calculated ORs with 95% CIs. Urinary tract infections (UTIs), a common complication of MS, before age 20 years were included as a control diagnosis for reverse causation. RESULTS: There were 6109 cases and 49 479 controls included. Pneumonia diagnosed between age 11-15 years was associated with subsequent MS (adj OR 2.00, 95% CI 1.22 to 3.27). Although not statistically significant, sensitivity analyses showed similar magnitude associations of pneumonia between age 11-15 years and MS. No statistically significant associations with MS for pneumonia at other age groups were observed. Adjustment for IM had no notable effect on associations, but was statistically significantly associated with MS. UTIs were not associated with MS. CONCLUSION: Pneumonia at 11-15 years of age was associated with MS, suggesting a possible role for inflammation of the respiratory system in the aetiology of MS during a period of susceptibility in adolescence. Further research on respiratory infections prior to MS onset should be conducted to replicate this finding and determine explanatory causal mechanisms.