Feelings of depression, pain and walking difficulties have the largest impact on the quality of life of people with multiple sclerosis, irrespective of clinical phenotype.

BACKGROUND: The symptoms that have the largest impact on health-related quality of life (HRQoL) in people with multiple sclerosis (MS) may vary by MS phenotype (relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS)). Knowing these symptoms assists in symptom management. OBJECTIVE: To examine the associations between 13 common MS symptoms and HRQoL in the total sample and stratified by MS phenotype. METHOD: The study included 1985 participants. HRQoL was measured with two multi-attribute utility instruments: assessment of quality of life with eight dimensions (AQoL-8D) and European quality of life with five dimensions and five levels for each dimension (EQ-5D-5L). Multivariable linear regression was used to identify the symptoms that had the largest impact on the HRQoLs. RESULTS: Feelings of depression, pain, fatigue, and feelings of anxiety were most strongly associated with AQoL-8D and EQ-5D-5L. Walking difficulties additionally contributed to reduced EQ-5D-5L. The strongest single predictors in the multivariable analyses were feelings of depression or pain for AQoL-8D and walking difficulties for EQ-5D-5L, irrespective of MS phenotype. CONCLUSION: The strongest single predictors for the AQoL-8D and EQ-5D-5L were feelings of depression, pain and walking difficulties, irrespective of MS phenotype. Reducing these symptoms may have the largest impact on improving HRQoL in all MS phenotypes of people with MS.

Change in multiple sclerosis prevalence over time in Australia 2010-2017 utilising disease-modifying therapy prescription data.

OBJECTIVE: Determine the prevalence of multiple sclerosis (MS) in Australia in 2017 using MS-specific disease-modifying therapy (DMT) prescription data and estimate the change in prevalence from 2010. METHODS: DMT prescriptions were extracted from Australia's Pharmaceutical Benefits Scheme (PBS) data for January-December 2017. Percentages of people with MS using DMTs (DMT penetrance) were calculated using data from the Australian MS Longitudinal Study. Prevalence was estimated by dividing the total number of monthly prescriptions by 12 (except alemtuzumab), adjusted for DMT penetrance and Australian population estimates. Prevalences in Australian states/territories were age-standardised to the Australian population. Comparisons with 2010 prevalence data were performed using Poisson regression. RESULTS: Overall DMT penetrance was 64%, and the number of people with MS in Australia in 2017 was 25,607 (95% confidence interval (CI): 24,874-26,478), a significant increase of 4324 people since 2010 (p < 0.001). The prevalence increased significantly from 95.6/100,000 (2010) to 103.7/100,000 (2017), with estimates highest in Tasmania in 2017 (138.7/100,000; 95% CI: 137.2-140.1) and lowest in Queensland (74.6/100,000; 95% CI: 73.5-75.6). From 2010 to 2017 using the median latitudes for each state/territory, the overall latitudinal variation in MS prevalence was an increase of 3.0% per degree-latitude. CONCLUSION: Consistent with global trends, Australia's MS prevalence has increased; this probably reflecting decreased mortality, increased longevity and increased incidence.

Modelling the impact of multiple sclerosis on life expectancy, quality-adjusted life years and total lifetime costs: Evidence from Australia.

OBJECTIVES: To quantify life expectancy (LE), quality-adjusted life years (QALYs) and total lifetime societal costs for a hypothetical cohort of Australians with multiple sclerosis (MS). METHODS: A 4-state Markov model simulated progression from no/mild to moderate and severe disability and death for a cohort of 35-year-old women over a lifetime horizon. Death risks were calculated from Australian life tables, adjusted by disability severity. State-dependent relapse probabilities and associated disutilities were considered. Probabilities of MS progression and relapse were estimated from AusLong and TasMSL MS epidemiological databases. Annual societal (direct and indirect) costs (2017 Australian dollars) and health-state utilities for each state were derived from the Australian MS Longitudinal Study. Costs were discounted at 5% annually. RESULTS: Mean (95% confidence interval (CI)) LE from age 35 years was 42.7 (41.6-43.8) years. This was 7.5 years less than the general Australian population. Undiscounted QALYs were 28.2 (26.3-30.0), a loss of 13.1 QALYs versus the Australian population. Discounted lifetime costs were $942,754 ($347,856-$2,820,219). CONCLUSION: We have developed a health economics model of the progression of MS, calculating the impact of MS on LE, QALYs and lifetime costs in Australia. It will form the basis for future cost-effectiveness analyses of interventions for MS.

Comorbidities are prevalent and detrimental for employment outcomes in people of working age with multiple sclerosis.

BACKGROUND: More work is needed to understand the burden of comorbidities in people with multiple sclerosis (MS). OBJECTIVE: To assess prevalence of 30 comorbidities and impacts of comorbidities on employment outcomes in a working-aged MS cohort. METHODS: Participants were from the Australian MS Longitudinal Study (n = 929). Information on specific comorbidity was obtained (whether or not each was present, doctor-diagnosed, limited their activities and being treated). RESULTS: Comorbidities most frequently reported to limit activities were osteoarthritis (51%), migraines (40%), anxiety (33%), depression (29%) and allergies (18%). Mean MS-related work productivity loss in past 4 weeks was 1.3 days for those without comorbidities and 2.5 days for those with any comorbidity. The annual population costs of work productivity loss were highest for people with depression, allergies, anxiety, migraines and osteoarthritis. Higher number of comorbidities was associated with more work productivity loss and a higher likelihood of not working. These associations were substantially reduced after adjustment for MS symptom severity. CONCLUSIONS: Comorbidities substantially impact employment outcomes and these effects were mainly mediated through MS symptom severity. This suggests that optimal and simultaneous management of comorbidities may be a viable strategy to reduce MS symptom severity, which in turn could improve employment outcomes.

Redefining the Multiple Sclerosis Severity Score (MSSS): The effect of sex and onset phenotype.

BACKGROUND: The Multiple Sclerosis Severity Score (MSSS) is a widely used measure of the disability progression rate. However, the global MSSS may not be the best basis for comparison between all patient groups. OBJECTIVE: We evaluated sex-specific and onset phenotype-specific MSSS matrices to determine if they were more effective than the global MSSS as a basis for comparison within these subsets. METHODS: Using a large international dataset of multiple sclerosis (MS) patient records and the original MSSS algorithm, we constructed global, sex-specific and onset phenotype-specific MSSS matrices. We compared matrices using permutation analysis. RESULTS: Our final dataset included 30,203 MS cases, with 28.9% males and 6.5% progressive-onset cases. Our global MSSS matrix did not differ from previously published data (p > 0.05). The progressive-onset-specific matrix differed significantly from the relapsing-onset-specific matrix (p < 0.001), with lower MSSS attributed to cases with the same Expanded Disability Status Score (EDSS) and disease duration. When evaluated with a simulation, using an onset-specific MSSS improved statistical power in mixed cohorts. There were no significant differences by sex. CONCLUSION: The differences in the disability accrual rate between progressive- and relapsing-onset MS have a significant effect on MSSS. An onset-specific MSSS should be used when comparing the rate of disability progression among progressive-onset cases and for mixed cohorts.

Increasing prevalence of primary biliary cholangitis in Victoria, Australia.

BACKGROUND AND AIM: The prevalence of primary biliary cholangitis (PBC) reported in different countries varies significantly and in some parts of the world appears to be increasing. The aim of this study was to determine the 2013 prevalence of PBC in Victoria, Australia, and to determine the time trend by comparing it with previous studies undertaken in 1991 and 2002. METHODS: Four case-finding methods were used to identify cases of PBC in Victoria: (1) physicians' survey; (2) tertiary hospital search; (3) liver transplant database search; and (4) private pathology antimitochondrial antibody search. RESULTS: The prevalence of PBC in Victoria, Australia, is 189.0 per million using all four methods. The average annual increase in prevalence from 1991 to 2013 was 7.7 per million per year. Using the same case-finding methods as the 1991 Victorian prevalence study (methods 1 and 2), the prevalence of PBC increased from 19.1 per million in 1991 to 49.4 per million in 2002 (P < 0.001) and to 80.7 per million in 2013 (P < 0.001). CONCLUSIONS: The current prevalence of PBC in Victoria is significantly higher than previously reported. The use of private pathology-based case-finding methods is important in identifying the maximum number of PBC cases.

Predictors of Change in Employment Status and Associations with Quality of Life: A Prospective International Study of People with Multiple Sclerosis.

Purpose This prospective international study aimed to assess the changes in employment, and predictors thereof, and associated change in mental health quality of life in people with multiple sclerosis (MS). Methods People with MS were recruited online through social media, forums and newsletters to complete an online English-language survey in 2012 and again in 2015, to assess changes in employment and clinical characteristics. Results 1276 people with MS of working age were included of whom 35.9% were employed full time, 25.6% part-time, 3.1% were unemployed and seeking employment, 19.7% were retired due to disability and 15.7% were not in the labour force. Part/full time employment decreased from 61.4 to 57.1% of the sample 2.5 years later, and 25.5% experienced some change in employment status. Lower level of education and higher level of disability at baseline predicted loss of employment at follow-up. 62.0% of the sample indicated that MS impacted on employment over their lifetime, associated with a lower level of education and progressive MS at time of diagnosis. Retiring due to disability was predictive of a decreased mental health related QOL score. Conclusion Employment status was negatively impacted by MS for most participants. We showed for the first time that employment loss was prospectively associated with poorer mental health related quality of life. Employment support including vocational services, reasonable flexibility in the workplace, and legal protection against discrimination should be widely available to assist people with MS, especially for those with progressive onset MS, higher disability and lower levels of education who are at higher risk of employment loss.

Latitude continues to be significantly associated with the prevalence of multiple sclerosis: an updated meta-analysis.

OBJECTIVES: Previous studies have demonstrated a strong latitudinal gradient in multiple sclerosis (MS) prevalence. Herein, we present a meta-analysis of the latitudinal gradient of MS prevalence including studies published since our 2011 review, seeking to assess the latitudinal gradient and whether it has changed since our previous analysis. METHODS: Studies published up to December 2018 were located via Embase, Web of Knowledge and PubMed, using standardised search terms; data were extracted from peer-reviewed studies and these studies added to those from our previous analysis. Where age-specific data were available, prevalence estimates were age-/sex-standardised to the 2009 European population. Prevalence estimates were adjusted for study prevalence year and ascertainment methods. The latitudinal association with MS prevalence was assessed by meta-regression. RESULTS: A total of 94 studies met inclusion criteria, yielding 230 new prevalence points and 880 altogether with those from the prior study. There was a significant positive gradient in time-corrected MS prevalence with increasing latitude (5.27/100 000 per degree latitude), attenuating slightly to 4.34/100 000 on age-standardisation, these associations persisting on adjustment for ascertainment method. Of note, the age-standardised gradient was consistently significantly enhanced from our previous study, regardless of whether it was as-measured, time-corrected or adjusted for ascertainment methods. Certain areas, such as the Scandinavian and Atlantic Coast/Central Europe regions, showed changes in MS prevalence gradient over time, but other regional gradients were similar. CONCLUSIONS: This new meta-analysis confirms that MS prevalence is still strongly positively associated with increasing latitude and that the gradient is increasing, suggesting that potentially modifiable environmental factors, such as sun exposure, are still strongly associated with MS risk.

Lipid-related genetic polymorphisms significantly modulate the association between lipids and disability progression in multiple sclerosis.

OBJECTIVE: To investigate whether lipid-related or body mass index (BMI)-related common genetic polymorphisms modulate the associations between serum lipid levels, BMI and disability progression in multiple sclerosis (MS). METHODS: The association between disability progression (annualised Expanded Disability Status Scale (EDSS) change over 5 years, ΔEDSS) and lipid-related or BMI-related genetic polymorphisms was evaluated in a longitudinal cohort (n=184), diagnosed with MS. We constructed a cumulative genetic risk score (CGRS) of associated polymorphisms (p<0.05) and examined the interactions between the CGRS and lipid levels (measured at baseline) in predicting ΔEDSS. All analyses were conducted using linear regression. RESULTS: Five lipid polymorphisms (rs2013208, rs9488822, rs17173637, rs10401969 and rs2277862) and one BMI polymorphism (rs2033529) were nominally associated with ΔEDSS. The constructed lipid CGRS showed a significant, dose-dependent association with ΔEDSS (ptrend=1.4×10-6), such that participants having ≥6 risk alleles progressed 0.38 EDSS points per year faster compared with those having ≤3. This CGRS model explained 16% of the variance in ΔEDSS. We also found significant interactions between the CGRS and lipid levels in modulating ΔEDSS, including high-density lipoprotein (HDL; pinteraction=0.005) and total cholesterol:high-density lipoprotein ratio (TC:HDL; pinteraction=0.030). The combined model (combination of CGRS and the lipid parameter) explained 26% of the disability variance for HDL and 27% for TC:HDL. INTERPRETATION: In this prospective cohort study, both lipid levels and lipid-related polymorphisms individually and jointly were associated with significantly increased disability progression in MS. These results indicate that these polymorphisms and tagged genes might be potential points of intervention to moderate disability progression.

Estimating MS-related work productivity loss and factors associated with work productivity loss in a representative Australian sample of people with multiple sclerosis.

BACKGROUND: Little is known about the work productivity loss in multiple sclerosis (MS). OBJECTIVES: To quantify the MS-related work productivity loss and to compare factors associated with labour force participation and work productivity loss. METHODS: Participants were from the Australian MS Longitudinal Study. MS-related work productivity loss included absenteeism (time missed from work) and presenteeism (reduced productivity while working). Data were analysed using log-binomial and Cragg hurdle regression. RESULTS: Among 740 MS employees, 56% experienced any work productivity loss due to MS in the past 4 weeks. The mean total work productivity loss was 2.5 days (14.2% lost productive time), absenteeism 0.6 days (3.4%) and presenteeism 1.9 days (10.8%)), leading to AU$6767 (US$4985, EURO€4578) loss per person annually. Multivariable analyses showed that work productivity was determined most strongly by symptoms, particularly 'fatigue and cognitive symptoms' and 'pain and sensory symptoms', while older age, and lower education level were also predictive of not being in the labour force. CONCLUSION: MS-related presenteeism was three times higher than absenteeism, highlighting the importance of presenteeism being included in employment outcomes. The dominance of symptom severity as predictors of both work participation and productivity loss emphasises the need for improved management of symptoms.

Polymorphism in the serotonin transporter gene polymorphisms ( 5-HTTLPR) modifies the association between significant life events and depression in people with multiple sclerosis.

BACKGROUND: In the general population, variation in the serotonin-transporter-linked polymorphic region ( 5-HTTLPR) has been shown to modify the association between stressful events and depression/anxiety. This has not been examined in people with multiple sclerosis (MS). OBJECTIVE: We examined the interaction between significant life events (SLE), 5-HTTLPR and depression/anxiety. METHODS: A population-based longitudinal cohort of 198 people with MS was followed biannually for 2.5 years. Depression and anxiety symptoms were measured at each review using the Hospital Anxiety and Depression Scale (HADS). SLEs were assessed using a questionnaire based on the Social Readjustment Rating Scale. RESULTS: We found an interaction between SLE load in the previous 12 months and functional variation in the 5-HTTLPR allele type in predicting depression, with the association between SLE load and depression being stronger for those with S/S allele type (ß = 0.21 (95% confidence interval (CI): 0.09-0.33) per 10-unit increase) and S/L (ß = 0.14 (95% CI: 0.05-0.24)) compared to L/L allele type (ß = 0.04 (95% CI: -0.05 to 0.24); pinteraction < 0.001). No convincing evidence of an interaction was found with anxiety. CONCLUSION: We found that the association between SLE load and MS depression severity was stronger among those with one or two copies of the short allele of the 5-HTTLPR. The identification of a gene-environment interaction between SLEs and depression in a population where depression is partly disease-driven is novel.

Estimation of annual probabilities of changing disability levels in Australians with relapsing-remitting multiple sclerosis.

BACKGROUND: Transition probabilities are the engine within many health economics decision models. However, the probabilities of progression of disability due to multiple sclerosis (MS) have not previously been estimated in Australia. OBJECTIVES: To estimate annual probabilities of changing disability levels in Australians with relapsing-remitting MS (RRMS). METHODS: Combining data from Ausimmune/Ausimmune Longitudinal (2003-2011) and Tasmanian MS Longitudinal (2002-2005) studies (n = 330), annual transition probabilities were obtained between no/mild (Expanded Disability Status Scale (EDSS) levels 0-3.5), moderate (EDSS 4-6.0) and severe (EDSS 6.5-9.5) disability. RESULTS: From no/mild disability, 6.4% (95% confidence interval (CI): 4.7-8.4) and 0.1% (0.0-0.2) progressed to moderate and severe disability annually, respectively. From moderate disability, 6.9% (1.0-11.4) improved (to no/mild state) and 2.6% (1.1-4.5) worsened. From severe disability, 0.0% improved to moderate and no/mild disability. Male sex, age at onset, longer disease duration, not using immunotherapies greater than 3 months and a history of relapse were related to higher probabilities of worsening. CONCLUSION: We have estimated probabilities of changing disability levels in Australians with RRMS. Probabilities differed between various subgroups, but due to small sample sizes, results should be interpreted with caution. Our findings will be helpful in predicting long-term disease outcomes and in health economic evaluations of MS.

Modifiable factors associated with depression and anxiety in multiple sclerosis.

OBJECTIVES: Modifiable lifestyle factors are implicated in multiple sclerosis (MS) symptoms but their role in mood is unclear. This study aimed to investigate associations between lifestyle and depression and anxiety in Australian participants with MS. MATERIALS AND METHODS: Self-reported data from the Australian Multiple Sclerosis Longitudinal Study included the Hospital Anxiety and Depression Scale (HADS) and lifestyle measurements from 1500 participants. SNAP score (range 0-5) was the sum of non-smoking, sufficient fruit/vegetable intake, non-hazardous alcohol consumption, sufficient physical activity and healthy BMI. Analyses by log-binomial and linear regression were adjusted for confounding. RESULTS: Symptoms of depression and anxiety were prevalent in 27% and 40%, respectively; 20% had both. Mean SNAP score was 2.7/5; only 3% met all healthy lifestyle recommendations. Only 10% reported adequate fruit/vegetable intake, and 22% reported a combination of unhealthy BMI, inadequate physical activity and inadequate nutrition. A healthier SNAP score was associated with lower depression prevalence (adjusted prevalence ratio 0.83 [95% CI 0.75, 0.92] per unit increase) and depression severity (adjusted ß-0.44 [95% CI -0.64, -0.24]), but not with anxiety. CONCLUSIONS: Modifiable lifestyle factors are associated with lower frequency and severity of depression, but not anxiety, in Australian people with multiple sclerosis. The associations between a healthier SNAP score and lower depression are likely bi-directional. SNAP risk factor prevalence and co-occurrence, especially inadequate nutrition and low physical activity, were high among Australians with MS.

Effects of multiple sclerosis disease-modifying therapies on employment measures using patient-reported data.

BACKGROUND: The direct comparative evidence on treatment effects of available multiple sclerosis (MS) disease-modifying therapies (DMTs) is limited, and few studies have examined the benefits of DMTs on employment outcomes. We compared the effects of DMTs used in the previous 5 years on improving the work attendance, amount of work and work productivity of people with MS. METHODS: The Australian MS Longitudinal Study collected data from participants on DMTs usage from 2010 to 2015 and whether DMTs contributed to changes in employment outcomes. We classified 11 DMTs into three categories based on their clinical efficacy (ß-interferons and glatiramer acetate as category 1; teriflunomide and dimethyl fumarate as category 2; fingolimod, natalizumab, alemtuzumab and mitoxantrone as category 3). Each DMT used by a participant was treated as one observation and analysed by log-multinomial regression. RESULTS: Of the 874 participants included, 1384 observations were generated. Those who used category 3 (higher efficacy) DMTs were 2-3 times more likely to report improvements in amount of work, work attendance and work productivity compared with those who used category 1 (classical injectable) DMTs. Natalizumab was associated with superior beneficial effects on patient-reported employment outcomes than fingolimod (RR=1.76, 95% CI 1.02 to 3.03 for increased work attendance and RR=1.46, 95% CI 1.02 to 2.10 for increased work productivity). CONCLUSIONS: Those using the higher efficacy (category 3) DMTs, particularly fingolimod and natalizumab, reported significant increases in amount of work, work attendance and work productivity, suggesting they have important beneficial effects on work life in people with MS.

Common genetic variation within miR-146a predicts disease onset and relapse in multiple sclerosis.

Despite extensive studies focusing on the changes in expression of microRNAs (miRNAs) in multiple sclerosis (MS) compared to healthy controls, few studies have evaluated the association of genetic variants of miRNAs with MS clinical course. We investigated whether a functional polymorphism in the MS associated miR-146a gene predicted clinical course (hazard of conversion to MS and of relapse, and annualized change in disability), using a longitudinal cohort study of persons with a first demyelinating event followed up to their 5-year review. We found the genotype (GC+CC) of rs2910164 predicted relapse compared with the GG genotype (HR=2.09 (95% CI 1.42, 3.06), p=0.0001), as well as a near-significant (p=0.07) association with MS conversion risk. Moreover, we found a significant additive interaction between rs2910164 and baseline anti-EBNA-1 IgG titers predicting risk of conversion to MS (relative excess risk due to interaction [RERI] 2.39, p=0.00002) and of relapse (RERI 1.20, p=0.006). Supporting these results, similar results were seen for the other EBV-correlated variables: anti-EBNA-2 IgG titers and past history of infectious mononucleosis. There was no association of rs2910164 genotype for disability progression. Our findings provide evidence for miR-146a and EBV infection in modulating MS clinical course.

An adverse lipid profile and increased levels of adiposity significantly predict clinical course after a first demyelinating event.

OBJECTIVE: To investigate the prospective associations between adiposity and lipid-related variables and conversion to multiple sclerosis (MS), time to subsequent relapse and progression in disability. METHODS: A cohort of 279 participants with a first clinical diagnosis of central nervous system demyelination was prospectively followed to 5-year review. Height, weight, waist and hip circumference were measured, and serum samples taken for measurement of lipids and apolipoproteins. Survival analysis was used for conversion to MS and time to relapse, and linear regression for annualised change in disability (Expanded Disability Status Scale). RESULTS: Higher body mass index (BMI; adjusted HR (aHR): 1.22 (1.04 to 1.44) per 5 kg/m2 increase), hip circumference (aHR: 1.32 (1.12 to 1.56) per 10 cm increase) and triglyceride levels (aHR: 1.20 (1.03 to 1.40) per unit increase) were associated with increased risk of subsequent relapse, while adiposity and lipid-related measures were not associated with conversion to MS. In addition, higher BMI (ß: 0.04 (0.01 to 0.07) per 5 kg/m2 increase), hip circumference (ß: 0.04 (0.02 to 0.08) per 10 cm increase), waist circumference (ß: 0.04 (0.02 to 0.07) per 10 cm increase), total cholesterol to high-density lipoprotein ratio (TC/HDL ratio; ß: 0.05 (0.001 to 0.10) and non-HDL; ß: 0.04 (0.001 to 0.08) at study entry) were associated with a higher subsequent annual change in disability. CONCLUSIONS: Higher levels of adiposity, non-HDL and TC/HDL ratio were prospectively associated with a higher rate of disability progression, and higher adiposity and triglycerides were associated with relapse but not with conversion to MS. Improving the lipid profile and losing weight into the healthy range could reduce the accumulation of disability.

Genetic variation in the gene LRP2 increases relapse risk in multiple sclerosis.

BACKGROUND: Due to the lack of prospective studies with longitudinal data on relapse, past genetic studies have not attempted to identify genetic factors that predict relapse risk (the primary endpoint of many pivotal clinical trials testing the efficacy of multiple sclerosis (MS) disease-modifying drugs) at a genome-wide scale. METHODS: We conducted a genome-wide association analysis (GWAS) to identify genetic variants that predict MS relapse risk, using a three-stage approach. First, GWAS was conducted using the southern Tasmania MS Longitudinal Study with 141 cases followed prospectively for a mean of 2.3 years. Second, GWAS was conducted using the Ausimmune Longitudinal Study with 127 cases having a classic first demyelinating event followed for 5 years from onset. Third, the top hits with p<5.0×10-6 from the first two stages were combined with a longitudinal US paediatric MS cohort with 181 cases followed for 5 years after onset. Predictors of time to relapse were evaluated by a mixed effects Cox model. An inverse variance fixed effects model was then used to undertake a meta-analysis. RESULTS: In the pooled results, using these three unique longitudinal MS cohorts, we discovered one novel locus (LRP2; most significant single nucleotide polymorphism rs12988804) that reached genome-wide significance in predicting relapse risk (HR=2.18, p=3.30×10-8). LRP2 is expressed on the surface of many central nervous system cells including neurons and oligodendrocytes and is a critical receptor in axonal guidance. CONCLUSIONS: The finding of a genetic locus that has extensive effects on neuronal development and repair is of interest as a potential modulator of MS disease course.

Stressful life events and the risk of initial central nervous system demyelination.

BACKGROUND: There is substantial evidence that stress increases multiple sclerosis disease activity, but limited evidence on its association with the onset of multiple sclerosis. OBJECTIVE: To examine the association between stressful life events and risk of first demyelinating event (FDE). METHODS: This was a multicentre incident case-control study. Cases ( n = 282 with first diagnosis of central nervous system (CNS) demyelination, including n = 216 with 'classic FDE') were aged 18-59 years. Controls without CNS demyelination ( n = 558) were matched to cases on age, sex and study region. Stressful life events were assessed using a questionnaire based on the Social Readjustment Rating Scale. RESULTS: Those who suffered from a serious illness in the previous 12 months were more likely to have an FDE (odds ratio (OR) = 2.35 (1.36, 4.06), p = 0.002), and when we limited our reference group to those who had no stressful life events, the magnitude of effect became stronger (OR = 5.41 (1.80, 16.28)). The total stress number and stress load were not convincingly associated with the risk of an FDE. CONCLUSION: Cases were more likely to report a serious illness in the previous 12 months, which could suggest that a non-specific illness provides an additional strain to an already predisposed immune system.

Role of genetic susceptibility variants in predicting clinical course in multiple sclerosis: a cohort study.

BACKGROUND: The genetic drivers of multiple sclerosis (MS) clinical course are essentially unknown with limited data arising from severity and clinical phenotype analyses in genome-wide association studies. METHODS: Prospective cohort study of 127 first demyelinating events with genotype data, where 116 MS risk-associated single nucleotide polymorphisms (SNPs) were assessed as predictors of conversion to MS, relapse and annualised disability progression (Expanded Disability Status Scale, EDSS) up to 5-year review (ΔEDSS). Survival analysis was used to test for predictors of MS and relapse, and linear regression for disability progression. The top 7 SNPs predicting MS/relapse and disability progression were evaluated as a cumulative genetic risk score (CGRS). RESULTS: We identified 2 non-human leucocyte antigen (HLA; rs12599600 and rs1021156) and 1 HLA (rs9266773) SNP predicting both MS and relapse risk. Additionally, 3 non-HLA SNPs predicted only conversion to MS; 1 HLA and 2 non-HLA SNPs predicted only relapse; and 7 non-HLA SNPs predicted ΔEDSS. The CGRS significantly predicted MS and relapse in a significant, dose-dependent manner: those having ≥5 risk genotypes had a 6-fold greater risk of converting to MS and relapse compared with those with ≤2. The CGRS for ΔEDSS was also significant: those carrying ≥6 risk genotypes progressed at 0.48 EDSS points per year faster compared with those with ≤2, and the CGRS model explained 32% of the variance in disability in this study cohort. CONCLUSIONS: These data strongly suggest that MS genetic risk variants significantly influence MS clinical course and that this effect is polygenic.

Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis.

BACKGROUND: Age at onset (AAO) in multiple sclerosis (MS) is an important marker of disease severity and may have prognostic significance. Understanding what factors can influence AAO may shed light on the aetiology of this complex disease, and have applications in the diagnostic process. METHODS: The study cohort of 22 162 eligible patients from 21 countries was extracted from the MSBase registry. Only patients with MS aged ≥16 years were included. To reduce heterogeneity, only centres of largely European descent were included for analysis. AAO was defined as the year of the first symptom suggestive of inflammatory central nervous system demyelination. Predictors of AAO were evaluated by linear regression. RESULTS: Compared with those living in lower latitudes (19.0-39.9°), onset of symptoms was 1.9 years earlier for those at higher latitudes (50.0-56.0°) (p=3.83×10-23). A reciprocal relationship was seen for ambient ultraviolet radiation (UVR), with a significantly increasing AAO for patients with MS per each quartile increment of ambient UVR (p=1.56×10-17). We found that the AAO of female patients was ∼5 months earlier than male patients (p=0.002). AAO of progressive-onset patients with MS were ∼9 years later than relapsing-onset patients (p=1.40×10-265). CONCLUSIONS: An earlier AAO in higher latitude regions was found in this worldwide European-descent cohort and correlated inversely with variation in latitudinal UVR. These results suggest that environmental factors which act at the population level may significantly influence disease severity characteristics in genetically susceptible populations.