Low vitamin D and/or sun exposure have been associated with increased risk of multiple sclerosis (MS) onset. However, comparatively, few studies have prospectively examined associations between these ...factors and clinical course.
To evaluate the association of sun exposure parameters and vitamin D levels with conversion to MS and relapse risk in a prospectively monitored cohort of 145 participants followed after a first demyelinating event up to 5-year review (AusLong Study).
Sun exposure prior to and after onset measured by annual questionnaire; ultraviolet radiation (UVR) "load" estimated by location of residence over the life course and ambient UVR levels. Serum 25-hydroxyvitamin D 25(OH)D concentrations measured at baseline, 2/3-year, and 5-year review. MS conversion and relapse assessed by neurologist assessment and medical record review.
Over two-thirds (69%) of those followed to 5-year review (100/145) converted to MS, with a total of 252 relapses. Higher pre-MS onset sun exposure was associated with reduced risk of MS conversion, with internal consistency between measures and dose-response relationships. Analogous associations were also seen with risk of relapse, albeit less strong. No consistent associations were observed between postonset sun exposure and clinical course, however. Notably, those who increased their sun exposure during follow-up had significantly reduced hazards of MS conversion and relapse. Serum 25(OH)D levels and vitamin D supplementation were not associated with conversion to MS or relapse hazard.
We found that preonset sun exposure was protective against subsequent conversion to MS and relapses. While consistent associations between postonset sun exposure or serum 25(OH)D level and clinical course were not evident, possibly masked by behavior change, those participants who markedly increased their sun exposure demonstrated a reduced MS conversion and relapse hazard, suggesting beneficial effects of sun exposure on clinical course.
Several lines of evidence suggest that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS) but complete mapping of the whole network has been elusive. One of the reasons ...is that there are several clinical subtypes of MS and transcription factors that may be involved in one subtype may not be in others. We investigate the possibility that this network could be mapped using microarray technologies and contemporary bioinformatics methods on a dataset derived from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS) and 45 age-matched healthy controls.
We have used two different analytical methodologies: a non-standard differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that are statistically overrepresented in genes that are either differentially expressed (or differentially co-expressed) in cases and controls (e.g., V$KROX_Q6, p-value <3.31E-6; V$CREBP1_Q2, p-value <9.93E-6, V$YY1_02, p-value <1.65E-5).
Our analysis uncovered a network of transcription factors that potentially dysregulate several genes in MS or one or more of its disease subtypes. The most significant transcription factor motifs were for the Early Growth Response EGR/KROX family, ATF2, YY1 (Yin and Yang 1), E2F-1/DP-1 and E2F-4/DP-2 heterodimers, SOX5, and CREB and ATF families. These transcription factors are involved in early T-lymphocyte specification and commitment as well as in oligodendrocyte dedifferentiation and development, both pathways that have significant biological plausibility in MS causation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A number of studies have been conducted with the onset of secondary progressive multiple sclerosis as an inclusion criterion or an outcome of interest. However, a standardized objective definition of ...secondary progressive multiple sclerosis has been lacking. The aim of this work was to evaluate the accuracy and feasibility of an objective definition for secondary progressive multiple sclerosis, to enable comparability of future research studies. Using MSBase, a large, prospectively acquired, global cohort study, we analysed the accuracy of 576 data-derived onset definitions for secondary progressive multiple sclerosis and first compared these to a consensus opinion of three neurologists. All definitions were then evaluated against 5-year disease outcomes post-assignment of secondary progressive multiple sclerosis: sustained disability, subsequent sustained progression, positive disability trajectory, and accumulation of severe disability. The five best performing definitions were further investigated for their timeliness and overall disability burden. A total of 17 356 patients were analysed. The best definition included a 3-strata progression magnitude in the absence of a relapse, confirmed after 3 months within the leading Functional System and required an Expanded Disability Status Scale step ≥4 and pyramidal score ≥2. It reached an accuracy of 87% compared to the consensus diagnosis. Seventy-eight per cent of the identified patients showed a positive disability trajectory and 70% reached significant disability after 5 years. The time until half of all patients were diagnosed was 32.6 years (95% confidence interval 32-33.6) after disease onset compared with the physicians' diagnosis at 36 (35-39) years. The identified patients experienced a greater disease burden median annualized area under the disability-time curve 4.7 (quartiles 3.6, 6.0) versus non-progressive patients 1.8 (1.2, 1.9). This objective definition of secondary progressive multiple sclerosis based on the Expanded Disability Status Scale and information about preceding relapses provides a tool for a reproducible, accurate and timely diagnosis that requires a very short confirmation period. If applied broadly, the definition has the potential to strengthen the design and improve comparability of clinical trials and observational studies in secondary progressive multiple sclerosis.
IntroductionOcrelizumab (OCR) is a humanised anti-CD20+ monoclonal antibody for the treatment of Multiple Sclerosis.ObjectivesIn Australian MSBase clinics, we describe baseline characteristics of ...relapsing-remitting MS (RRMS) patients treated with OCR, treatment pathways and early clinical outcomes.MethodsSecondary analysis using MSBase Registry data for RRMS patients with OCR initiation within 3 months of MSBase recorded visit. Descriptive statistics included demographics, disease course/duration, prior disease modifying therapies (DMT) and EDSS. Relapse data was described in patients with ≥6 months follow-up.ResultsAs of 4 June 2020, MSBase included 624 eligible Australian RRMS patients newly treated with OCR. Median age at OCR initiation was 42.5 years. OCR was first line therapy in 18.9% of patients. Most frequent DMT’s in the 12 months prior to OCR were natalizumab (32.1%) and fingolimod (24.8%). Of 434 RRMS patients with ≥6 months follow-up, 392 remained relapse free (90.3%; 95% CI 81.6, 99.7) over a mean OCR exposure of 1.35 years. In this group, the annualized relapse rate (ARR) was 0.10 (95% CI 0.08-0.13), compared to an ARR of 0.83 in the 24 months pre-OCR start. Treatment discontinuation was recorded for 20 of these 434 patients In the overall RRMS cohort, treatment persistence at 12 and 24 months was 94.3% (95%CI: 90.9%-96.1%%) and 88.7% (95%CI 77.2%-94.0%), respectively.ConclusionAlmost 20% of RRMS patients treated with OCR in Australian MSBase centres received OCR as a first line treatment. During OCR treatment, relapses and OCR discontinuations were rare.
Background
Anxiety and depression are common in multiple sclerosis (MS). We evaluated the prevalence and factors associated with anxiety, depression and fatigue at the 5‐year review of a longitudinal ...cohort study following a first clinical diagnosis of CNS demyelination (FCD).
Methods
Cases with a FCD were recruited soon after diagnosis and followed annually thereafter. A variety of environmental, behavioural and clinical covariates were measured at five‐year review. Anxiety and depression were measured using the Hospital Anxiety & Depression Scale (HADS), and fatigue by the Fatigue Severity Scale (FSS).
Results
Of the 236 cases, 40.2% had clinical anxiety (median HADS‐A: 6.0), 16.0% had clinical depression (median HADS‐D: 3.0), and 41.3% had clinical fatigue (median FSS: 4.56). The co‐occurrence of all three symptoms was 3.76 times greater than expectation. Younger age, higher disability, concussion or other disease diagnosis were independently associated with a higher anxiety score; male sex, higher disability, being unemployed, less physical activity, and antidepressant and/or anxiolytic‐sedative medication use were independently associated with a higher depression score. Higher disability, immunomodulatory medication use, other disease diagnosis and anxiolytic‐sedative medication use were independently associated with having fatigue, while female sex, higher BMI, having had a concussion, being unemployed and higher disability were associated with a higher fatigue score.
Conclusion
These results support previous findings of the commonality of anxiety, depression and fatigue in established MS and extend this to post‐FCD and early MS cases. The clustering of the three symptoms indicates that they may share common antecedents.
Age at symptom onset (ASO) is a prognostic factor that could affect the accrual of disability in multiple sclerosis (MS) patients. Some factors are known to influence the risk of multiple sclerosis ...(MS), but their influence on the ASO is less well-investigated.
Examine the associations between known or emerging MS risk factors and ASO.
This was a multicenter study, incident cases (
= 279) with first clinical diagnosis of demyelinating event aged 18-59 years recruited at four Australian centres (latitudes 27°-43°S), from 1 November 2003 to 31 December 2006. Environmental/behavioral variables and initial symptoms were recorded at baseline interview. Linear regression was used to assess the association between risk factors and ASO.
Five factors were significantly associated with ASO: a history of tobacco smoking was associated with 3.05-years later ASO (
= 0.002); a history of marijuana use was associated with 6.03-years earlier ASO (
< 0.001); progressive-onset cases had 5.61-years later ASO (
= 0.001); an initial presentation of bowel & bladder and cerebral dysfunctional were associated with 3.39 (
= 0.017) and 4.37-years (
= 0.006) later ASO, respectively. Other factors, including sex, offspring number, latitude of study site, history of infectious mononucleosis,
genotype, 25(OH)D levels, and ultraviolet radiation exposure were not associated with ASO. Including all five significant variables into one model explained 12% of the total variance in ASO.
We found a novel association between a history of tobacco smoking and later onset, whereas marijuana use was associated with earlier onset. Behavioral factors seem important drivers of MS onset timing although much of the variance remains unexplained.
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.
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).
Higher body mass index (BMI; adjusted HR (aHR): 1.22 (1.04 to 1.44) per 5 kg/m
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 (β: 0.04 (0.01 to 0.07) per 5 kg/m
increase), hip circumference (β: 0.04 (0.02 to 0.08) per 10 cm increase), waist circumference (β: 0.04 (0.02 to 0.07) per 10 cm increase), total cholesterol to high-density lipoprotein ratio (TC/HDL ratio; β: 0.05 (0.001 to 0.10) and non-HDL; β: 0.04 (0.001 to 0.08) at study entry) were associated with a higher subsequent annual change in disability.
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.
To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an ...independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 × 10−11; rs10876994, P = 2.7 × 10−10; rs12368653, P = 1.0 × 10−7) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 × 10−7; rs1569723, P = 2.9 × 10−7). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 × 10−184; CD58, P = 9.6 × 10−8; EVI5-RPL5, P = 2.5 × 10−6; IL2RA, P = 7.4 × 10−6; CLEC16A, P = 1.1 × 10−4; IL7R, P = 1.3 × 10−3; TYK2, P = 3.5 × 10−3) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Acute haemorrhagic leukoencephalitis (AHLE) is a rare and rapidly fatal disease of unknown aetiology. There is a paucity of literature on the presentation and management of this rare disease.
We ...report the case of a 33-year-old female presenting with headache and left-sided apraxia. Imaging revealed a right-sided white matter lesion with extensive cytotoxic oedema. Pathology was suggestive of AHLE. She underwent an open excisional biopsy and was treated with high-dose corticosteroids. Three months since symptom onset she remains clinically well with resolving apraxia and radiological appearance.
This case may represent a milder spectrum of AHLE, which responded favourably to corticosteroids.
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