Response to interferon-beta treatment in multiple sclerosis patients: A genome-wide association study

Up to 50% of multiple sclerosis (MS) patients do not respond to interferon-beta (IFN-β) treatment and determination of response requires lengthy clinical follow-up of up to 2 years. Response predictive genetic markers would significantly improve disease management. We aimed to identify IFN-β treatment response genetic marker(s) by performing a two-stage genome-wide association study (GWAS). The GWAS was carried out using data from 151 Australian MS patients from the ANZgene/WTCCC2 MS susceptibility GWAS (responder (R)=51, intermediate responders=24 and non-responders (NR)=76). Of the single-nucleotide polymorphisms (SNP) that were validated in an independent group of 479 IFN-β-treated MS patients from Australia, Spain and Italy (R=273 and NR=206), eight showed evidence of association with treatment response. Among the replicated associations, the strongest was observed for FHIT (Fragile Histidine Triad; combined P-value 6.74 × 10−6) and followed by variants in GAPVD1 (GTPase activating protein and VPS9 domains 1; combined P-value 5.83 × 10−5) and near ZNF697 (combined P-value 8.15 × 10−5)

Prediction of multiple sclerosis outcomes when switching to ocrelizumab

Background: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab. Objective: To determine predictors of relapse and disability progression when switching from another DMT to ocrelizumab. Methods: Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT; interferon-β/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab) and washout duration (<1 month, 1–2 months or 2–6 months). Survival analyses including multivariable Cox proportional hazard regression models were used to identify predictors of on-ocrelizumab relapse within 1 year, and 6-month confirmed disability progression (CDP). Results: After adjustment, relapse hazard when switching from fingolimod was greater than other pDMTs, but only in the first 3 months of ocrelizumab therapy (hazard ratio (HR) = 3.98, 95% confidence interval (CI) = 1.57–11.11, p = 0.004). The adjusted hazard for CDP was significantly higher with longer washout (2–6 m compared to <1 m: HR = 9.57, 95% CI = 1.92–47.64, p = 0.006). Conclusion: The risk of disability worsening during switch to ocrelizumab is reduced by short treatment gaps. Patients who cease fingolimod are at heightened relapse risk in the first 3 months on ocrelizumab. Prospective evaluation of strategies such as washout reduction may help optimise this switch

Symptomatology of multiple sclerosis relapses varies in relation to demographic and clinical factors

Introduction: Our knowledge of incidence and outcomes of MS relapses with specific symptomatology is limited. For example, optic neuritis is more common in early MS and the ability to recover deteriorates with longer disease duration. However, a comprehensive evaluation of multiple sclerosis relapse phenotypes, comprising clinical presentations, severity, impact and recovery, and capturing full spectrum of MS courses, duration and patient demography, has not yet been done. Aim: To identify patterns of clinical MS relapses, their impact on specific neuroanatomical locations and their associations with demographic and clinical parameters. Methods: Information about relapse symptomatology was collected prospectively in 17,555 eligible patients and 104,333 patient-years recorded in MSBase, an international observational MS registry. In a proportion of the relapses, information about relapse severity, impact on activities of daily living and recovery was available. Associations between relapse phenotype and patient characteristics were tested with a series of multivariable logistic regression models. Principal component analysis was conducted to assess the tendency of the specific relapse locations to be involved sequentially in individual patients. Results: Of 63,343 relapses, the majority affected pyramidal and sensory functions. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were recorded mostly in earlier disease and less commonly in relapsing-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women more commonly presented with sensory or visual symptoms, while men were more prone to pyramidal, brainstem and cerebellar relapses. Relapses were likely to recur within the previously affected locations (odd ratios 1.8 – 5, p = 10^-13), with pyramidal, sphincter and sensory relapses often converging within the same individuals (eigenvalue = 2.1, loadings 0.59-0.68). Sensory relapses had a lower impact on daily activities and together with visual and brainstem relapses showed better recovery than the other relapse presentations. Finally, relapse severity increased and the ability to recover decreased with age or more advanced disease. Conclusions: Patterns of clinical relapse symptomatology vary with respect to demographic and clinical factors, including age, sex, MS duration, course and stage

Relapse incidence in women and men throughout the course of multiple sclerosis: An MSBase cohort study

Introduction: Only one large retrospective cohort study and several smaller analyses examined predictors of relapse incidence in MS. Sex, age and MS duration were suggested as determinants of relapse activity. While in relapsing-remitting MS women are overrepresented in the ratio of 3:1 to men, in primary progressive disease both sexes are represented equally. A lower probability of relapse in men could be the reason for this change, with primary progressive (PP) MS representing the “extreme” of low relapse activity. Aims: To evaluate effect of sex on the incidence of MS relapses. To assess the hypothesis that the female-to-male ratio increases gradually with relapse activity and that PPMS represents a non-relapsing extreme along this continuum. To directly compare effects of age and MS duration on relapse incidence. Methods: Annualised relapse rates were calculated using the MSBase registry. Patients with incomplete data or less than one year of follow-up were excluded. Patients with PPMS were only included in the sex ratio analysis. Relapse incidences over 40 years of MS duration or up to 70 years of age were compared between females and males using Andersen-Gill and Poisson models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and PPMS. All models were adjusted for therapy and pregnancy. Results: Among 11,570 eligible patients with relapse-onset MS (82,552 patient-years), 48,362 relapses were recorded. Relapse frequency was 17.7% higher in females compared to males. Within the initial five years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 to >=4 relapses per year, respectively. The magnitude of this sex effect increased at longer MS duration and older age. However, the female-to-male ratio in patients with relapse-onset MS and zero relapses in any given year was double that of the patients with PPMS. Patient age was a more important determinant of decline in relapse incidence than disease duration. Conclusions: Females are predisposed to higher relapse activity than males. However, this sex-related effect does not explain the markedly lower female-to-male ratio in PPMS. Decline in relapse activity over time is more closely related to patient age than MS duration. This information helps us better understand the effects of sex and time on relapse incidence and define PPMS as an entity distinct from the relapse-onset MS