The effect of national disease-modifying therapy subsidy policy on long-term disability outcomes in people with multiple sclerosis.

BACKGROUND: Disease-modifying therapies (DMTs) are used to treat people with relapsing-onset multiple sclerosis (ROMS), but our knowledge is largely limited to their short-term effects. OBJECTIVE: To determine (1) the impact of national-level DMT subsidy policy on DMT use and health outcomes in people with MS (PwMS) and (2) the long-term effects of DMT on disability and quality of life (QoL; 5-level EQ-5D version (EQ-5D-5L) utility value). METHODS: This observational cohort study compared Australian and New Zealand populations with different levels of DMT availability 10-20 years post-ROMS diagnosis. Between-country differences were assessed using standardised differences. Associations were assessed with multivariable linear regression models. RESULTS: We recruited 328 Australians and 256 New Zealanders. The Australian cohort had longer DMT treatment duration, greater proportion of disease course treated and shorter duration between diagnosis and starting DMT. The Australian cohort had lower median Expanded Disability Status Scale (EDSS) (3.5 vs 4.0) and Multiple Sclerosis Severity Score (MSSS) (3.05 vs 3.71) and higher QoL (0.71 vs 0.65). In multivariable models, between-country differences in disability and QoL were largely attributed to differential use of DMT. CONCLUSIONS: This study provides evidence for the impact of national-level DMT policy on disability outcomes in PwMS. Where DMTs are more accessible, PwMS experienced less disability progression and improved QoL 10-20 years post-diagnosis.

Incidence and prevalence of NMOSD in Australia and New Zealand.

OBJECTIVES: We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry. BACKGROUND: NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established. METHODS: Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases. RESULTS: NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD. CONCLUSIONS: NMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry.

Evolving Identification of Blood Cells Associated with Clinically Isolated Syndrome: Importance of Time since Clinical Presentation and Diagnostic MRI.

It is not clear how the profile of immune cells in peripheral blood differs between patients with clinically isolated syndrome (CIS) and healthy controls (HC). This study aimed to identify a CIS peripheral blood signature that may provide clues for potential immunomodulatory approaches early in disease. Peripheral blood mononuclear cells (PBMCs) were collected from 18 people with CIS, 19 HC and 13 individuals with other demyelinating conditions (ODC) including multiple sclerosis (MS). Individuals with CIS separated into two groups, namely those with early (≤14 days post-diagnostic magnetic resonance imaging (MRI); n = 6) and late (≥27 days; n = 12) blood sampling. Transitional B cells were increased in the blood of CIS patients independently of when blood was taken. However, there were two time-dependent effects found in the late CIS group relative to HC, including decreased CD56bright NK cells, which correlated significantly with time since MRI, and increased CD141+ myeloid dendritic cell (mDC2) frequencies. Higher CD1c+ B cells and lower non-classical monocyte frequencies were characteristic of more recent demyelinating disease activity (ODC and early CIS). Analysing cell populations by time since symptoms (subjective) and diagnostic MRI (objective) may contribute to understanding CIS.

Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females.

BACKGROUND: In recent years, a relationship between Helicobacter pylori and many disease conditions has been reported, however, studies in its relationship with multiple sclerosis (MS) have had contradictory results. OBJECTIVE: To determine the association between the H. pylori infection and MS. METHODS: 550 patients with MS were included in the study and were matched by gender and year of birth to 299 controls. Patients were assessed for clinical and demographic parameters. An enzyme immunoassay was used to detect the presence of specific IgG antibodies against H. pylori in the serum sample of both groups. RESULTS: H. pylori seropositivity was found to be lower in the patients with MS than in controls (16% vs 21%) with the decrease pertaining to females (14% vs 22%, p=0.027) but not males (19% vs 20%, p=1.0). When adjusted for age at onset, year of birth and disease duration, H. pylori seropositive females presented with a lower disability score than seronegative females (p=0.049), while among males the reverse was true (p=0.025). There was no significant association between H. pylori seropositivity and relapse rate. CONCLUSIONS: Our results could reflect a protective role of H. pylori in the disease development. However, it may be that H. pylori infection is a surrogate marker for the 'hygiene hypothesis', a theory which postulates that early life infections are essential to prime the immune system and thus prevent allergic and autoimmune conditions later in life. The fact that the association between H. pylori seropositivity and MS risk was seen almost exclusively in females requires further investigation.

A new era in the treatment of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system with a multifactorial aetiology and highly variable natural history. A growing understanding of the immunopathogenesis of the condition has led to an expanding array of therapies for this previously untreatable disease. While a cure for MS remains elusive, the potential to reduce inflammatory disease activity by preventing relapses and minimising disease progression is achievable. The importance of early treatment in minimising long-term disability is increasingly recognised. Most of the newer, more effective therapies are associated with risks and practical problems that necessitate an active management strategy and continuous vigilance. While the initiation of these therapies is likely to remain the responsibility of neurologists, other specialist physicians and general practitioners will be involved in the identification and management of adverse effects.

ENSEMBLE PLUS: final results of shorter ocrelizumab infusion from a randomized controlled trial.

INTRODUCTION: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study. METHODS: ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing-remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs. RESULTS: At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [- 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion. CONCLUSION: ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions. CLINICAL TRIALS REGISTRATION: Substudy of ENSEMBLE (NCT03085810). REGISTRATION: March 21, 2017.

Using the EQ-5D-5L to investigate quality-of-life impacts of disease-modifying therapy policies for people with multiple sclerosis (MS) in New Zealand.

BACKGROUND: Health state utilities (HSU) are a health-related quality-of-life (HRQoL) input for cost-utility analyses used for resource allocation decisions, including medication reimbursement. New Zealand (NZ) guidelines recommend the EQ-5D instruments; however, the EQ-5D-5L may not sufficiently capture psychosocial health. We evaluated HRQoL among people with multiple sclerosis (MS) in NZ using the EQ-5D-5L and assessed the instrument's discriminatory sensitivity for a NZ MS cohort. METHODS: Participants were recruited from the NZ MS Prevalence Study. Participants self-completed a 45-min online survey that included the EQ-5D-5L/EQ-VAS. Disability severity was classified using the Expanded Disability Status Scale (EDSS) to categorise participant disability as mild (EDSS: 0-3.5), moderate (EDSS: 4.0-6.0) and severe (EDSS: 6.5-9.5). Anxiety/depression were also measured using the Hospital Anxiety and Depression Score (HADS). In the absence of an EQ-5D-5L NZ tariff, HSUs were derived using an Australian tariff. We evaluated associations between HSUs and participant characteristics with linear regression models. RESULTS: 254 participants entered the study. Mean age was 55.2 years, 79.5% were female. Mean (SD) EQ-5D-5L HSU was 0.58 (0.33). Mean (SD) HSUs for disability categories were: mild 0.80 ± 0.17, moderate 0.57 ± 0.21 and severe 0.14 ± 0.32. Twelve percent reported HSU = 1.0 (i.e., no problems in any domain). Participants who had never used a disease-modifying therapy reported a lower mean HSU. Multivariable modelling found that the HADS anxiety score was not associated with EQ-5D-5L. CONCLUSIONS: HRQoL for people with MS in NZ was lower than comparable countries, including Australia. We suggest a comparison with other generic tools that may have improved sensitivity to mental health.

Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.

OBJECTIVE: To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci. METHODS: We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease. RESULTS: We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934(T) at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10(-8)) near EOMES, rs2150702(G) in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10(-8)), and rs6718520(A) in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10(-8)). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10(-6) , some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1). INTERPRETATION: We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS.

Changes in serum neurofilament light chain levels following narrowband ultraviolet B phototherapy in clinically isolated syndrome.

OBJECTIVE: To determine whether serum neurofilament light chain (sNfL) levels are suppressed in patients with the clinically isolated syndrome (CIS) following narrowband ultraviolet B phototherapy (UVB-PT). METHODS: sNfL levels were measured using a sensitive single-molecule array assay at baseline and up to 12 months in 17 patients with CIS, 10 of whom received UVB-PT, and were compared with healthy control (HC) and early relapsing remitting multiple sclerosis (RRMS) group. sNfL levels were correlated with magnetic resonance imaging total lesion volume (LV) determined using icobrain version 4.4.1 and with clinical outcomes. RESULTS: Baseline median sNfL levels were significantly higher in the CIS (20.6 pg/mL, interquartile range [IQR] 13.7-161.4) and RRMS groups (36.6 pg/ml [IQR] 16.2-212.2) than in HC (10.7 pg/ml [IQR] 4.9-21.5) (p = .012 and p = .0002, respectively), and were strongly correlated with T2 and T1 LV at 12 months (r = .800; p = .014 and r = .833; p = .008, respectively) in the CIS group. Analysis of changes in sNfL levels over time in the CIS group showed a significant cumulative suppressive effect of UVB-PT in the first 3 months (UVB-PT -10.6% vs non-UVB-PT +58.3%; p = .04) following which the levels in the two groups converged and continued to fall. CONCLUSIONS: Our findings provide the basis for further studies to determine the utility of sNfL levels as a marker of neuro-axonal damage in CIS and early MS and for assessing the efficacy of new therapeutic interventions such as UVB-PT.

Response to treatment in NMOSD: the Australasian experience.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is associated with significant morbidity and mortality. Several therapies have been recommended for NMOSD and more recently clinical trials have demonstrated efficacy for three monoclonal antibody therapies. We present a retrospective observational study of treatment response in NMOSD. METHODS: This was a retrospective, unblinded, observational study of treatment efficacy for rituximab and traditional immunosuppressive therapy in patients with AQP4 antibody positive NMOSD. Treatment efficacy was assessed using annualised relapse rates (ARR), time to first relapse and expanded disability status scale (EDSS) scores. RESULTS: Complete relapse and treatment data were available for 43/68 (63%) of AQP4 antibody positive NMOSD cases covering 74 episodes of treatment. In a time to first relapse analysis rituximab showed a risk ratio of 0.23 (95% CI 0.08 - 0.65) when compared with no treatment and there was a non-significant reduction in ARR of 35% compared to pre-treatment. ß-interferon (p = 0.0002) and cyclophosphamide (p = 0.0034) were associated with an increased ARR compared to pre-treatment. Rituximab (median 4.0 [range 0.0 - 7.0]; p = 0.042) and traditional immunosuppressive therapy (median 4.0 [range 0.0 - 8.0]; p = 0.016) were associated with a lower final EDSS compared to ß-interferon (median 6.0 [range 4.0 - 7.5]). CONCLUSIONS: These data provide additional support for the use of rituximab in preference to traditional immunosuppressive agents and MS disease modifying therapies as first line treatment of NMOSD.

Hypothalamic lesions in multiple sclerosis.

OBJECTIVES: To determine the frequency of hypothalamic lesions in patients with multiple sclerosis (MS) using conventional MRI (cMRI) protocols. METHODS: Brain cMRI (1.5 Tesla) scans of 105 Caucasian patients with classical MS (50 with stable and 55 with more active disease) and 12 patients with longitudinal extensive myelopathy (LEM) were reviewed retrospectively. NMO-IgG antibody was assayed in patients with hypothalamic lesions. RESULTS: Hypothalamic lesions were found in 13.3% of MS patients and in none of the LEM patients. A higher frequency of hypothalamic lesions was found in patients with active MS (18.2%) than in the stable group (8.0%), but this did not reach statistical significance (p=0.13). Patients with hypothalamic lesions also had more lesions in other cerebral structures. None of the LEM patients had hypothalamic lesions. No patients with hypothalamic lesions were positive for NMO-IgG. CONCLUSIONS: Hypothalamic lesions in MS are more frequent than previously reported and are not associated with NMO-IgG antibody.

HLA-DR allele polymorphism and multiple sclerosis in Chinese populations: a meta-analysis.

BACKGROUND: The association of human leukocyte antigen (HLA) genes and multiple sclerosis (MS) has been extensively investigated in Caucasians, but less so in Oriental races such as Chinese. OBJECTIVES: To review studies on association of HLA class II alleles with MS in the Chinese population. METHODS: An extensive search for published studies up to June 2010 was performed in the electronic databases. The meta-analysis facilities in the NCSS statistical package were utilized to analyze the findings in these studies. The odds ratios (ORs) of HLA-DR allele distributions in MS were analyzed against controls. RESULTS: Eleven case-control studies were identified: nine genotyping and two serotyping studies. Six genotyping studies were suitable for HLA-DRB1 allele meta-analysis, which showed that HLA-DRB1*15 was associated with risk of MS in the combined group (308 cases and 407 controls; OR 1.39) while the HLA-DRB1*09 and HLA-DRB1*0901 alleles were protective. When the equivalent serotypes in these six studies were combined with the results from the two serotyping studies (431 cases and 652 controls) for a meta-analysis of HLA-DR serotypes, HLA-DR2 was a risk factor (OR 1.63) and HLA-DR9 was strongly protective in the combined group (OR 0.64). CONCLUSIONS: Although limited data are available, our meta-analysis suggests that HLA-DR2/DRB1*15 are also associated with risk of MS in the Chinese population but less strongly so than in Western MS populations, whereas HLA-DR9 alleles appear to confer resistance in this population.

MRI Patterns Distinguish AQP4 Antibody Positive Neuromyelitis Optica Spectrum Disorder From Multiple Sclerosis.

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), "bright spotty" (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS.

Influence of HLA-DRB1 allele heterogeneity on disease risk and clinical course in a West Australian MS cohort: a high-resolution genotyping study.

BACKGROUND: Previous studies on the influence of HLA-DRB1 alleles on multiple sclerosis (MS) susceptibility and clinical course have mostly employed the 2-point genotyping method. OBJECTIVE: To assess the influence of HLA-DRB1 alleles and allele interactions on disease risk and clinical course in a large West Australian MS patient cohort using high-resolution genotyping. METHODS: Four digit HLA-DRB1 genotyping was performed on a group of 466 clinically definite or probable MS patients from the Perth Demyelinating Diseases Database and 189 healthy Caucasian controls from the Busselton Community Health Study. RESULTS: In addition to the known risk allele HLA-DRB1*1501, evidence of increased susceptibility to MS was found for three additional alleles, DRB1*0405, DRB1*1104 and DRB1*1303, though the power was insufficient to sustain significance for these when crudely Bonferroni corrected over all alleles considered. DRB1*0701 was found to be protective even after correction for multiple comparisons. In addition we found evidence that the DRB1*04 sub-allele HLA-DRB1*0407 and HLA-DRB1*0901 may be protective. Among the diplotypes, the highest estimated risk was in HLA-DRB1*1501/*0801 heterozygotes and DRB1*1501 homozygotes and the lowest in HLA-DRB1*0701/*0101 heterozygotes. There was no significant gender association with HLA-DRB1*1501 overall, but the HLA-DRB1*1501/*1104 risk genotype was significantly associated with female gender. HLA-DRB1*1501 was the strongest risk allele in both primary progressive MS and relapsing-remitting MS. CONCLUSION: Our results demonstrate the advantages of high-resolution HLA genotyping in recognizing risk-modifying alleles and allele combinations in this patient cohort and in recognizing the differential effects of HLA-DRB1*04 and DRB1*11 sub-alleles.

Modifying effects of HLA-DRB1 allele interactions on age at onset of multiple sclerosis in Western Australia.

The contribution of genetic factors to the age at onset in multiple sclerosis is poorly understood. Our objective was to investigate the disease modifying effects of HLA-DRB1 alleles and allele interactions on age at onset of multiple sclerosis. High-resolution four-digit HLA-DRB1 genotyping was performed in a cohort of 461 multiple sclerosis patients from the Perth Demyelinating Diseases Database. Carriage of the HLA-DRB1*1501 risk allele was not significantly associated with age at onset but HLA-DRB1*0801 was associated with a later onset of the disease. The HLA-DRB1*0401 allele was associated with a reduced age at onset when combined with DRB1*1501 but may delay age at onset when combined with DRB1*0801. These findings indicate that epistatic interactions at the HLA-DRB1 locus have significant modifying effects on age at onset of multiple sclerosis and demonstrate the value of high-resolution genotyping in detecting such associations.

Low level of systemic autoimmunity in Western Australian multiple sclerosis patients.

Previous autoantibody (AAb) studies in multiple sclerosis MS have produced conflicting results. The objective of this study was to determine AAb frequency and association with the HLA-DRB1 genotype. Antinuclear antibody, antithyroid peroxidase and anti-aquaporin-4 assays and HLA-DRB1 genotyping were performed in 198 MS patients and 188 controls. There were no significant differences in AAb frequency or titres between MS and control subjects. AQP4-IgG was not found in any MS patients. There was no correlation between AAbs and HLA-DRB1 alleles. In conclusion, this study failed to confirm previous reports of increased AAbs in MS or to show an association between HLA-DRB1 genotype and the presence of AAbs.