Based on the known and emerging biology of autoimmune diseases and COVID‐19, it was hypothesised that whilst B‐cell depletion should not necessarily expose people to severe SARS‐CoV‐2‐related issues, ...it may inhibit or blunt the protective immunity following infection and vaccination. This is supported clinically, as the majority of SARS‐CoV‐2 infected, CD20‐depleted people with autoimmunity, have recovered. However, in CD‐20 treated people until naïve B‐cells repopulate, based on B‐cell repopulation‐kinetics and vaccination responses, from published rituximab, and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data shown here suggests that it may be possible to undertake dose‐interruption to maintain inflammatory disease control, whilst allowing effective vaccination against SARS‐CoV‐29, if and when an effective vaccine is available.
Summary
Although most autoimmune diseases are considered to be CD4 T cell‐ or antibody‐mediated, many respond to CD20‐depleting antibodies that have limited influence on CD4 and plasma cells. This includes rituximab, oblinutuzumab and ofatumumab that are used in cancer, rheumatoid arthritis and off‐label in a large number of other autoimmunities and ocrelizumab in multiple sclerosis. Recently, the COVID‐19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments. However, based on the known and emerging biology of autoimmunity and COVID‐19, it was hypothesised that while B cell depletion should not necessarily expose people to severe SARS‐CoV‐2‐related issues, it may inhibit protective immunity following infection and vaccination. As such, drug‐induced B cell subset inhibition, that controls at least some autoimmunities, would not influence innate and CD8 T cell responses, which are central to SARS‐CoV‐2 elimination, nor the hypercoagulation and innate inflammation causing severe morbidity. This is supported clinically, as the majority of SARS‐CoV‐2‐infected, CD20‐depleted people with autoimmunity have recovered. However, protective neutralizing antibody and vaccination responses are predicted to be blunted until naive B cells repopulate, based on B cell repopulation kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here. This suggests that it may be possible to undertake dose interruption to maintain inflammatory disease control, while allowing effective vaccination against SARS‐CoV‐29, if and when an effective vaccine is available.
Aims
Indices of brain volume grey matter, white matter (WM), lesions are being used as outcomes in clinical trials of patients with multiple sclerosis (MS). We investigated the relationship between ...cortical volume, the number of neocortical neurons estimated using stereology and demyelination.
Methods
Nine MS and seven control hemispheres were dissected into coronal slices. On sections stained for Giemsa, the cortex was outlined and optical disectors applied using systematic uniform random sampling. Neurons were counted using an oil immersion objective (× 60) following stereological principles. Grey and WM demyelination was outlined on myelin basic protein immunostained sections, and expressed as percentages of cortex and WM respectively.
Results
In MS, the mean number of neurons was 14.9 ± 1.9 billion vs. 24.4 ± 2.4 billion in controls (P < 0.011), a 39% difference. The density of neurons was smaller by 28% (P < 0.001) and cortical volume by 26% (P = 0.1). Strong association was detected between number of neurons and cortical volume (P < 0.0001). Demyelination affected 40 ± 13% of the MS neocortex and 9 ± 12% of the WM, however, neither correlated with neuronal loss. Only weak association was detected between number of neurons and WM volume.
Conclusion
Neocortical neuronal loss in MS is massive and strongly predicted by cortical volume. Cortical volume decline detected in vivo may be similarly indicative of neuronal loss. Lack of association between neuronal density and demyelination suggests these features are partially independent, at least in chronic MS.
Clinical trials are probably the most informative experiments to help an understanding of multiple sclerosis (MS) biology. Recent successes with CD20‐depleting antibodies have focused attention ...towards B cell subsets as important mediators in MS. The trial of tabalumab (NTC00882999), which inhibits B cell activation factor (BAFF), is reported and reviewed and this trial is contrasted with the trial on the inhibition of a proliferation‐inducing ligand (APRIL) and BAFF using atacicept (NCT00642902). Both tabalumab and atacicept induce depletion of mature B cells and inhibit antibody formation, but they fail to deplete memory B cells and do not inhibit relapsing MS. Atacicept is reported to augment memory B cell responses and may precipitate relapse, suggesting the importance of APRIL. However, BAFF inhibition can enhance peripheral blood memory B cell responses, which was not associated with augmented relapse. Although other interpretations are possible, these data further support the hypothesis that memory B cells may be of central importance in relapsing MS, as they are the major CD20+ B cell subset expressing APRIL receptors. They also suggest that quantitative and/or qualitative differences in B cell responses or other factors, such as an immune‐regulatory effect associated with APRIL, may be important in determining whether MS reactivates following neutralization of peripheral B cell maturation and survival factors.
Multiple sclerosis (MS) is a common inflammatory, demyelinating and degenerative disease of the central nervous system. The majority of people with MS present with symptoms due to spinal cord damage, ...and in more advanced MS a clinical syndrome resembling that of progressive myelopathy is not uncommon. Significant efforts have been undertaken to predict MS-related disability based on short-term observations, for example, the spinal cord cross-sectional area measured using MRI. The histo-pathological correlates of spinal cord MRI changes in MS are incompletely understood, however a surge of interest in tissue microstructure has recently led to new approaches to improve the precision with which MRI indices relate to underlying tissue features, such as myelin content, neurite density and orientation, among others. Quantitative MRI techniques including T1 and T2, magnetisation transfer (MT) and a number of diffusion-derived indices have all been successfully applied to post mortem MS spinal cord. Combining advanced quantification of histological features with quantitative - particularly diffusion-based - MRI techniques provide a new platform for high-quality MR/pathology data generation. To more accurately quantify grey matter pathology in the MS spinal cord, a key driver of physical disability in advanced MS, remains an important challenge of microstructural imaging.
Objective
To explore the potential of a post-processing technique combining FLAIR and T
2
* (FLAIR*) to distinguish between lesions caused by multiple sclerosis (MS) from cerebral small vessel ...disease (SVD) in a clinical setting.
Methods
FLAIR and T
2
* head datasets acquired at 3T of 25 people with relapsing MS (pwRMS) and ten with pwSVD were used. After post-processing, FLAIR* maps were used to determine the proportion of white matter lesions (WML) showing the ‘vein in lesion’ sign (VIL), a characteristic histopathological feature of MS plaques. Sensitivity and specificity of MS diagnosis were examined on the basis of >45% VIL
+
and >60% VIL
+
WML, and compared with current dissemination in space (DIS) MRI criteria.
Results
All pwRMS had >45% VIL
+
WML (range 58–100%) whilst in pwSVD the proportion of VIL
+
WML was significantly lower (0–64%; mean 32±20%). Sensitivity based on >45% VIL
+
was 100% and specificity 80% whilst with >60% VIL
+
as the criterion, sensitivity was 96% and specificity 90%. DIS criteria had 96% sensitivity and 40% specificity.
Conclusion
FLAIR* enables VIL
+
WML detection in a clinical setting, facilitating differentiation of MS from SVD based on brain MRI.
Key points
• FLAIR* in a clinical setting allows visualization of veins in white matter lesions.
• Significant proportions of MS lesions demonstrate a vein in lesion on MRI.
• Microangiopathic lesions demonstrate a lower proportion of intralesional veins than MS lesions.
• Intralesional vein-based criteria may complement current MRI criteria for MS diagnosis.
Abstract
Background
Compensation for industrial disease in the UK may be obtained in two ways. A State scheme includes a list of accepted associations between occupations and diseases with evidence ...of a causative association. Epidemiological evidence of a doubled risk in the occupation concerned is usually required. This takes no account of variation of exposures within occupations, excluding many occupations where risk is less than doubled. In such cases, compensation for a perceived industrial illness may be obtained in Civil Courts, where excessive exposures can be considered.
Aims
To show that in the Civil Courts evidence of excessive exposure may lead to compensation for diseases which are not yet compensable as Industrial Injuries in the UK and to draw attention to the association of multiple sclerosis (MS) with solvent exposure.
Methods
We report the case of an industrial spray painter, who claimed his MS had been caused by high-level exposure to organic solvents, and our examination of the epidemiological evidence submitted.
Results
The painter received compensation by an out-of-court settlement, despite the overall epidemiological risk in relation to solvent exposure having been shown to be less than doubled. The evidence hinged on individual risk in relation to high exposure, genetic susceptibility and demonstration of a plausible mechanism.
Conclusions
High organic solvent exposure may lead to the development of MS. Those giving evidence in Court need to be able to discuss the epidemiological and toxicological issues in relation to exposure in the individual case.
We report the case of a man who successfully obtained out-of-court compensation from his employer for multiple sclerosis following excessive exposure to organic solvents at work. We discuss the epidemiological evidence that led to this settlement and its relevance to industrial disease compensation in cases when the overall risk of the disease is less than doubled, a criterion that is required in UK no-fault awards under Industrial Injuries regulation.
Evidence suggests that Epstein-Barr virus (EBV) plays a role in triggering or perpetuating disease activity in multiple sclerosis (MS).
We investigated 100 subjects (50 clinically isolated syndrome ...CIS, 25 relapsing-remitting RR MS, 25 primary progressive PP MS) for 1) evidence of EBV reactivation and 2) disease activity as indicated by serial gadolinium (Gd)-enhanced MRIs over a 5-year period. EBV DNA in blood was quantified by real-time quantitative PCR and EBV serology for anti-Epstein-Barr virus nuclear antigen 1 (EBNA-1) immunoglobulin G (IgG), anti-viral capsid antigen (VCA) IgG, and anti-EBV IgM. Data were analyzed using repeated measures analysis, analysis of variance, and logistic regression analysis.
All subjects had serologic evidence of previous EBV infection, but no lytic reactivation was detected. Significant differences in EBNA-1 IgG titers were found between subgroups, highest in the RRMS cohort compared with PPMS (p < 0.001) and CIS (p < 0.001). Gd-enhancing lesions on MRI correlated with EBNA-1 IgG (r = 0.33, p < 0.001) and EBNA-1:VCA IgG ratio (r = 0.36, p < 0.001). EBNA-1 IgG also correlated with change in T2 lesion volume (r = 0.27, p = 0.044) and Expanded Disability Status Scale score (r = 0.3, p = 0.035).
The correlation between elevated Epstein-Barr virus nuclear antigen 1 (EBNA-1) immunoglobulin G (IgG) and gadolinium-enhancing lesions suggests an association between Epstein-Barr virus (EBV) infection and multiple sclerosis (MS) disease activity. The heightened immune response to EBV in MS is specifically related to EBNA-1 IgG, a marker of the latent phase of the virus. The lack of association between acute viral reactivation in the peripheral blood and Gd(+) lesions suggests a limited role of the former in driving disease activity.
Background and purpose
Lumbar puncture (LP) is a key diagnostic procedure in medicine. Post lumbar puncture headache (PLPHA) is a well recognized complication of LP. Evidence suggests that using ...atraumatic needles for diagnostic LP (ATNLP) reduces risk of PLPHA. However, clinicians in Europe and the USA routinely use traumatic needles for diagnostic LP (TNLP). The occurrence of PLPHA following ATNLP and TNLP was compared in a clinical setting. Further, a survey was performed exploring use of ATNLP amongst UK neurologists.
Methods
Service development study. Patients were followed up 2 and 7 days after LP using blinded telephone assessment. A questionnaire was developed to assess use of ATNLP amongst UK neurologists. Frequency, onset, duration and severity of PLPHA were recorded as were use of analgesia, general practitioner consultations, hospital readmissions, days off work due to PLPHA and cost. Neurologists were asked about their familiarity with, and use of, ATNLP.
Results
One hundred and nine participants attending the Royal London Hospital were included, and 74 attendees of the Association of British Neurologists 2012 conference completed an on‐site questionnaire. ATNLP reduced the rate of PLPHA (27.1% vs. 60.4%; P < 0.01). In those participants who developed PLPHA symptoms were short lived (mean 50 h vs. 94 h, P = 0.02) and less severe after ATNLP. Use of ATNLP led to significant cost savings. Only one in five UK neurologists regularly use ATNLP stating lack of training and availability of atraumatic needles as main reasons.
Conclusions
ATNLP significantly reduces the risk of PLPHA. Training is required 3 to facilitate a change from TNLP to ATNLP amongst clinicians.
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