Multiple sclerosis: long-term outcomes in ethnic minorities. Analysis of a UK population-based registry.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is most frequent in Caucasian populations. However, studies of MS in other ethnic groups may offer unique insights into genetic and environmental influences on the disease, and data on long-term outcomes in these patients is limited. In this work clinical features and time to disability milestones were investigated in ethnic minority (EM) patients with MS in a UK population and comparisons were made to a Caucasian cohort from the same region. METHODS: In all, 1949 MS patients (1866 Caucasian, 83 EM) were identified from a regional disease registry. Cox proportional hazards regression was used to analyse the time to Expanded Disability Status Scale (EDSS) 3.0, 4.0 and 6.0. RESULTS: Ethnic minority patients were younger at disease onset (28.6 years vs. 32.8 years, P = 0.001), and primary progressive MS was less common (EM 4.8%, Caucasian 11.6%, P = 0.03). After correction for clinical variables, ethnicity was associated with time to EDSS 3.0 [EM: hazard ratio (HR) 1.75, P < 0.0001] and 4.0 (HR 1.46, P = 0.03), but not 6.0 (HR 1.5, P = 0.05). CONCLUSIONS: Ethnic minority patients reach early levels of fixed disability more rapidly than Caucasian patients, but this effect diminishes at later stages of the disease. This has implications for clinical management of these patients.

Multiple sclerosis and COVID-19: Assessing risk perception, patient behaviors and access to disease-modifying therapies.

BACKGROUND: Following the outbreak of COVID-19, global healthcare systems have had to rapidly adapt. People with multiple sclerosis (pwMS) were required to make decisions about their individual risk and consequent work and social behaviors. This study aimed to evaluate risk perception and patterns of shielding behavior amongst pwMS at the onset of the COVID-19 pandemic and the subsequent impact on patients' employment and access to disease modifying therapies (DMTs). METHODS: Postal surveys were sent to 1690 people within a UK population-based MS cohort during the first wave of the COVID-19 pandemic. Patients were surveyed on: (i) perceived vulnerability to COVID-19; (ii) isolation behavior; (iii) interruption to DMT; (iv) employment status; (v) level of satisfaction with their current working arrangement. RESULTS: Responses were received from 1000 pwMS. Two thirds of patients reported isolating at home during the first wave of the pandemic. This behavior was associated with increased age (p<0.0001), higher disability (p<0.0001) and use of high-efficacy DMTs (p = 0.02). The majority of patients reported feeling vulnerable (82%) with perceived vulnerability associated with higher EDSS (p<0.0001) and receiving a high-efficacy DMT (p = 0.04). Clinician-defined risk was associated with shielding behavior, with those at high-risk more likely to self-isolate/shield (p<0.0001). Patients on high-efficacy DMTs were more likely to have an interruption to their treatment (50%) during the first wave of the pandemic. Most pwMS experienced a change to their working environment, and most were satisfied with the adjustments. CONCLUSION: This study highlights the risk perception, social behavioral practices and changes to treatment experienced by pwMS during the first wave of the COVID-19 pandemic in a large, well-described UK cohort. The results may help inform management of pwMS during future pandemic waves.

KIF5A and the contribution of susceptibility genotypes as a predictive biomarker for multiple sclerosis.

There is increasing interest in the development of multiple sclerosis (MS) biomarkers that reflect central nervous system tissue injury to determine prognosis. We aimed to assess the prognostic value of kinesin superfamily motor protein KIF5A in MS by measuring levels of KIF5A in cerebrospinal fluid (CSF) combined with analysis of single nucleotide polymorphisms (SNPs; rs12368653 and rs703842) located within a MS susceptibility gene locus at chromosome 12q13-14 region. Enzyme-linked immunosorbent assay was used to measure KIF5A in CSF obtained from two independent biobanks comprising non-inflammatory neurological disease controls (NINDC), clinically isolated syndrome (CIS) and MS cases. CSF KIF5A expression was significantly elevated in progressive MS cases compared with NINDCs, CIS and relapsing-remitting MS (RRMS). In addition, levels of KIF5A positively correlated with change in MS disease severity scores (EDSS, MSSS and ARMSSS), in RRMS patients who had documented disease progression at 2-year clinical follow-up. Copies of adenine risk alleles (AG/AA; rs12368653 and rs703842) corresponded with a higher proportion of individuals in relapse at the time of lumbar puncture (LP), higher use of disease-modifying therapies post LP and shorter MS duration. Our study suggests that CSF KIF5A has potential as a predictive biomarker in MS and further studies into the potential prognostic value of analysing MS susceptibility SNPs should be considered.

COVID-19 in Multiple Sclerosis: Clinically reported outcomes from the UK Multiple Sclerosis Register.

BACKGROUND: In March 2020, the United Kingdom Multiple Sclerosis Register (UKMSR) established an electronic case return form, designed collaboratively by MS neurologists, to record data about COVID-19 infections in people with MS (pwMS). OBJECTIVES: Examine how hospital admission and mortality are affected by disability, age and disease modifying treatments (DMTs) in people with Multiple Sclerosis with COVID-19. METHODS: Anonymised data were submitted by clinical teams. Regression models were tested for predictors of hospitalisation and mortality outcomes. Separate analyzes compared the first and second 'waves' of the pandemic. RESULTS: Univariable analysis found hospitalisation and mortality were associated with increasing age, male gender, comorbidities, severe disability, and progressive MS; severe disability showed the highest magnitude of association. Being on a DMT was associated with a small, lower risk. Multivariable analysis found only age and male gender were significant. Post hoc analysis demonstrated that factors were significant for hospitalisation but not mortality. In the second wave, hospitalisation and mortality were lower. Separate models of the first and second wave using age and gender found they had a more important role in the second wave. CONCLUSIONS: Features associated with poor outcome in COVID-19 are similar to other populations and being on a DMT was not found to be associated with adverse outcomes, consistent with smaller studies. Once in hospital, no factors were predictive of mortality. Reassuringly, mortality appears lower in the second wave.

Greater loss of axons in primary progressive multiple sclerosis plaques compared to secondary progressive disease.

The pathological substrate of progressive disability in multiple sclerosis is hypothesized to be axonal loss. Differences in the demographic, pathological and radiological features of patients with primary progressive compared with secondary progressive multiple sclerosis raise the question as to whether they actually represent separate clinical entities. So far, large pathological studies comparing axonal damage between primary progressive and secondary progressive multiple sclerosis have not been reported. In this clinico-pathological study we examined the cervical spinal cord in patients with primary and secondary progressive multiple sclerosis. Human cervical spinal cord was derived at autopsy from 54 patients (17 primary progressive, 30 secondary progressive and 7 controls). Tissue was stained immunohistochemically and examined to determine: (i) the number of surviving corticospinal tract axons; (ii) the extent of grey and white matter demyelination; (iii) the degree of inflammation inside and outside of lesions; and (iv) the relationship between demyelination and axonal loss. Associated clinical data was used to calculate expanded disability status scale for each patient preceding death. Motor disability in the primary progressive and secondary progressive groups was similar preceding death. Secondary progressive multiple sclerosis patients showed considerably more extensive demyelination of both the white and grey matter of the cervical spinal cord. The total number of corticospinal axons was equally low in primary progressive and secondary progressive multiple sclerosis groups versus controls. The reduction of axonal density in demyelinated regions compared to normal appearing white matter was significantly more extensive in primary progressive versus secondary progressive patients (33% reduction versus 16% reduction, P < 0.001). These findings suggest axonal loss is the pathological substrate of progressive disability in both primary progressive and secondary progressive multiple sclerosis with a common plaque-centred mechanism. More extensive axonal loss within areas of demyelination in primary progressive multiple sclerosis could explain high levels of axonal loss observed in these patients despite low levels of demyelination.

Secondary antibody deficiency: a complication of anti-CD20 therapy for neuroinflammation.

B-cell depleting anti-CD20 monoclonal antibody therapies are being increasingly used as long-term maintenance therapy for neuroinflammatory disease compared to many non-neurological diseases where they are used as remission-inducing agents. While hypogammaglobulinaemia is known to occur in over half of patients treated with medium to long-term B-cell-depleting therapy (in our cohort IgG 38, IgM 56 and IgA 18%), the risk of infections it poses seems to be under-recognised. Here, we report five cases of serious infections associated with hypogammaglobulinaemia occurring in patients receiving rituximab for neuromyelitis optica spectrum disorders. Sixty-four per cent of the whole cohort of patients studied had hypogammaglobulinemia. We discuss the implications of these cases to the wider use of anti-CD20 therapy in neuroinflammatory disease.

Correction to: Secondary antibody deficiency: a complication of anti-CD20 therapy for neuroinflammation.

In the original article, the co-author's family name has been published incorrectly. The correct family name should be Constantinescu.

Ultra-high-field imaging distinguishes MS lesions from asymptomatic white matter lesions.

OBJECTIVES: To investigate whether multiple sclerosis (MS) and non-MS white matter brain lesions can be distinguished by their appearance on 7 T T2*-weighted MRI. METHODS: This was an observational study of 28 patients with MS and 17 patients with cerebral white matter lesions who did not have MS. Subjects were imaged using 7 T T2*-weighted imaging. White matter lesions were identified and analyzed for volume, location, and perivenous appearance. RESULTS: Out of 901 lesions identified in patients with MS, 80% were perivenous. In comparison, 19% of 428 lesions identified in patients without MS had a perivenous appearance. Seven-Tesla T2*-weighted MRI reliably distinguished all patients with clinically definite MS (>40% lesions appeared perivenous) from those without clinical MS (<40% lesions appeared perivenous). Perivenous lesion appearance was more predictive of MS (odds ratio [OR] 14, p < 0.001) than subcortical or periventricular lesion location (OR 4.5, p < 0.001, and OR 2.4, p = 0.009). Perivenous lesion appearance was observed with a similar frequency in patients with clinically isolated syndrome of demyelination and in early (gadolinium-enhancing) MS lesions. CONCLUSION: Perivenous lesion location on 7 T T2*-weighted imaging is predictive of the presence of demyelination. Optimization of this imaging technique at lower magnetic resonance field strengths would offer benefit for the diagnosis of MS.

Spotlight on teriflunomide.

Currently, licensed disease-modifying agents for multiple sclerosis (MS) all share the need for parenteral administration. Oral therapies would carry the advantage of convenience and greater acceptability. Teriflunomide is one of several oral agents currently undergoing Phase III investigation. This article describes the mode of action of teriflunomide which largely depends on inhibition of pyrimidine synthesis. We review the evidence so far on the efficacy of teriflunomide in animal models and Phase II human studies. In view of teriflunomides favourable safety profile it appears to be a promising oral alternative to interferon beta and glatiramer acetate. The ongoing Phase III investigations of teriflunomide as mono- and combination therapy are discussed.