Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region. Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.

IMPORTANCE Uncertainty remains about how aggressively to treat early multiple sclerosis. High-efficacy disease-modifying therapies (DMTs) are often reserved for individuals expressing poor prognostic features at baseline. OBJECTIVE To analyze long-term outcomes in a population-based cohort according to initial treatment strategy. DESIGN, SETTING AND PARTICIPANTS In this cohort study, data were derived from January 1998 to December 2016, and analysis was performed in January 2017. From a total of 720 patients prescribed a DMT, 592 (82%) were included in analysis. Reasons for exclusion were first treated elsewhere or privately (n = 39), clinical trial participant (n = 25), and insufficient clinical data (n = 45). EXPOSURES Patients were classified according to first-line treatment strategy: high-efficacy (early intensive treatment [EIT]) or moderate-efficacy DMT (escalation [ESC]). MAIN OUTCOMES AND MEASURES Primary outcome was 5-year change in Expanded Disability Status Scale score. Secondary outcome was time to sustained accumulation of disability (SAD). Models were adjusted for sex, age at treatment, year of starting DMT, and escalation to high-efficacy treatment in the ESC group. RESULTS Mean (SD) age of 592 patients at symptom onset was 27.0 (9.4) years. Mean (SD) 5-year change in Expanded Disability Status Scale score was lower in the EIT group than the ESC group (0.3 [1.5] vs 1.2 [1.5]); this remained significant after adjustment for relevant covariates (β = −0.85; 95% CI, −1.38 to −0.32; P = .002). Median (95% CI) time to SAD was 6.0 (3.17-9.16) years for EIT and 3.14 (2.77-4.00) years for ESC (P = .05). For those within the ESC group who escalated to high-efficacy DMT as second-line treatment, median (95% CI) time to SAD was 3.3 years (1.8-5.6; compared with EIT group log-rank test P = .08). After adjustment for relevant covariates, there was no difference in hazard of SAD between the groups. However, 60% of those who escalated to high-efficacy DMTs were observed to develop SAD while still receiving initial moderate-efficacy treatment before escalation. CONCLUSIONS AND RELEVANCE In a real-life setting, long-term outcomes were more favorable following early intensive therapy vs first-line moderate-efficacy DMT. Contemporary surveillance strategies and escalation protocols may be insufficiently responsive. This finding is particularly relevant as patients in real-world practice are typically selected for an EIT approach to therapy on the basis of clinical and radiological features predictive of a poor outcome. These data support the need for a prospective randomized clinical trial.

This study provides Class IV evidence that the risk of AID after alemtuzumab treatment for MS is time-limited and modified by external factors.

The impact of relapses on long-term disability in multiple sclerosis remains unclear; however some evidence suggests that relapses play an important role in determining subsequent prognosis. We report on outcome, prognostic factors for recovery and the contribution of relapses to the accumulation of fixed disability in a large series of patients with documented relapses. Two hundred and seventy-nine relapses in 182 patients were assessed before, during and after relapse by expanded disability status scale and data analysed to assess degree of recovery. Factors affecting outcome were considered including sex, age and site of relapse. Mean EDSS prior to relapse was 3.73, during relapse 5.18 and post relapse 4.23. Mean interval to post relapse assessment was 127 days post relapse. Mean residual change in EDSS score (pre to post relapse) was 0.50 points. Overall 49.4 % of patients had a residual increase in disability post relapse of at least 0.5 EDSS points and 32.7 % had an increase of at least 1 point. No significant difference was observed in mean residual EDSS for sex, site of relapse or age at relapse or in the proportion of patients with a residual increase in disability of > or = 1 EDSS point post relapse. 14.4 % of patients had no increase in EDSS score during relapse compared to pre relapse. These results suggest that acute relapses are commonly associated with an objective worsening of disability in the majority of patients with MS and that recovery is incomplete in approximately half and not influenced by gender, age or site of lesion. Therapies which reduce relapse frequency and/or severity might therefore be expected to slow or prevent worsening of disability if initiated prior to the onset of more permanent damage.

Recent change in disease incidence and prevalence in this population is likely to be the result of environmental factors that have been operative in the past few decades in women alone and infers avoidable risk factors. Modelling of current overall incidence suggests a further increase in prevalence to 260 per 100 000 population within the next 20-40 years. Further studies are needed in order to identify recent changes in sex specific environment and lifestyle that confer susceptibility.