B. Hemmer

Class II HLA interactions modulate genetic risk for multiple sclerosis.

Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01–HLA-DRB1*15:01 and HLA-DQB1*03:01–HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.

Population structure and HLA DRB1*1501 in the response of subjects with multiple sclerosis to first-line treatments

Using retrospectively collected outcome data for treatment naïve subjects treated with either glatiramer acetate (GA) (n=332) or interferon beta (IFN β) (n=424), we replicated the lack of a significant difference in efficacy between these treatments. Further, for both treatments, we observed a decline in the hazard of a relapse over time, which may suggest the existence of subsets of subjects with differential responses to each treatment. The HLA DRB1 1501 allele explained some of this variation in event-free survival while on GA, and we found suggestive evidence that an IRF8 polymorphism influences event-free survival in IFN β treated subjects.

Environmental modifiable risk factors for multiple sclerosis: Report from the 2016 ECTRIMS focused workshop:

Multiple sclerosis (MS) is an inflammatory and neurodegenerative demyelinating disease of the central nervous system (CNS), most likely autoimmune in origin, usually beginning in early adulthood. The aetiology of the disease is not well understood; it is viewed currently as a multifactorial disease which results from complex interactions between genetic predisposition and environmental factors, of which a few are potentially modifiable. Improving our understanding of these factors can lead to new and more effective approaches to patient counselling and, possibly, prevention and management of the disease. The 2016 focused workshop of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) addressed the topic of environmental, modifiable risk factors for MS, gathering experts from around the world, to collate experimental and clinical research into environmental factors that have been associated with the disease onset and, in a few cases, disease activity and progression. A number of factors, including infections, vitamin D deficiency, diet and lifestyle factors, stress and comorbidities, were discussed. The meeting provided a forum to analyse available evidence, to identify inconsistencies and gaps in current knowledge and to suggest avenues for future research.

Patent foramen ovale is not associated with an increased risk of stroke recurrence.

Background and Purpose:u2002 Despite numerous studies suggesting a relationship between paradoxical embolism from a patent foramen ovale (PFO) and stroke, the role of PFO as a risk factor for cerebral ischaemia remains controversial. We therefore sought to determine the association between a RLS detected by contrast‐enhanced transcranial Doppler ultrasonography (c‐TCD) and recurrent stroke in an unselected population sample.

Lesion patterns in patients with cryptogenic stroke with and without right-to-left-shunt.

Background and purpose:u2002 Despite numerous studies, the role of patent foramen ovale (PFO) as a risk factor for stroke due to paradoxical embolism is still controversial. On the assumption that specific lesion patterns, in particular multiple acute ischaemic lesions on diffusion‐weighted magnetic resonance imaging, indicate a cardioembolic origin, we compared the MRI findings in stroke patients with right‐to‐left shunt (RLS) and those without.

[Acute disseminated encephalomyelitis. Pathogenesis, diagnosis, treatment, and prognosis].

ZusammenfassungDie akute disseminierte Enzephalomyelitis (ADEM) ist typischerweise eine monophasische demyelinisierende Erkrankung des zentralen Nervensystems (ZNS), von der am häufigsten Kinder betroffen sind. Das klinische Bild dieser Erkrankung manifestiert sich meist in Folge einer Infektion oder Impfung. Diesbezüglich sind zahlreiche virale und bakterielle Krankheitserreger sowie Impfstoffe mit der ADEM assoziiert worden. Untersuchungen in Tiermodellen haben zudem gezeigt, dass vermutlich sowohl primäre als auch sekundäre Immunantworten an der Entstehung dieser entzündlichen demyelinisierenden ZNS-Erkrankung beteiligt sind. Die Diagnose einer ADEM ist wahrscheinlich, wenn ein zeitlicher Zusammenhang zwischen einer infektiösen Erkrankung bzw. Impfung sowie dem Auftreten subakuter, im ZNS lokalisierter Komplikationen determiniert werden kann. In der Bildgebung des Gehirns mittels Magnetresonanztomographie (MRT) finden sich in der Regel ausgedehnte, multifokale Marklagerveränderungen. Während im Liquor meist eine Pleozytose und Proteinerhöhung nachweisbar sind, sind oligoklonale Banden nicht immer vorhanden. Die Behandlung der ADEM erfolgt in der Regel mit antiinflammatorischen und immunsuppressiven Medikamenten, und die Prognose ist im Allgemeinen gut.SummaryAcute disseminated encephalomyelitis (ADEM) is typically a monophasic, demyelinating disease of the CNS that predominantly affects children. Typically, its clinical symptoms follow an infection or vaccination. In this regard, numerous viral and bacterial pathogens as well as several vaccinations have been associated with ADEM. Studies from animal models suggest that primary and secondary autoimmune responses may contribute to CNS inflammation and demyelination in ADEM. The diagnosis of ADEM is strongly suggested by a close temporal relationship between a viral infection or immunization and the onset of neurologic symptoms, and it is supported by extensive, multifocal, subcortical white-matter disease on brain magnetic resonance imaging. While mild lymphocytic pleocytosis and elevated proteins are detectable in the CSF in ADEM, oligoclonal bands are not always present. Treatment of this disorder consists of anti-inflammatory and immunosuppressive therapies, and the prognosis is generally considered favorable.

ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis

Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years. There is therefore a need for a reference tool compiling current data to aid professionals in treatment decisions. The objective was to develop an evidence‐based clinical practice guideline for the pharmacological treatment of people with MS.

Serum antibodies to conformational and linear epitopes of myelin oligodendrocyte glycoprotein are not elevated in the preclinical phase of multiple sclerosis

Background: The proposed predictive value of serum anti-myelin antibodies for the development of multiple sclerosis after a first clinically isolated syndrome was recently challenged. Objective: To investigate myelin autoantibodies before first disease manifestation using different detection methods. Methods: Patients with multiple sclerosis who had donated blood at a time prior to development of clinically isolated syndrome were identified via the German National Multiple Sclerosis Society. Control sera were obtained from age- and gender-matched blood donors. IgG-/IgM-antibodies against the extracellular part of native, cell surface-expressed myelin oligodendrocyte glycoprotein were detected by flow cytometry. Antibodies against linear epitopes were identified by immunoblot using recombinant myelin oligodendrocyte glycoprotein (aa1-125) and human myelin basic protein preparations. Results: Fifty eight serum samples from 25 patients covering an interval of 7.3 years—2 months prior to disease onset were available. Longitudinal investigations were performed in 19 patients (2—14 samples per patient, 7 years—2 months prior to disease onset). No significant differences in the prevalence or titres of anti-myelin antibodies were detected between sera of preclinical individuals and healthy donors by either flow cytometry or immunoblot. There was no correlation between interval before clinically isolated syndrome and autoantibody status. Occurrence of antibodies was not associated with symptomatology/severity of clinically isolated syndrome. Conclusion: Neither anti-myelin autoantibodies against cell surface-expressed native myelin oligodendrocyte glycoprotein nor against linear epitopes have a predictive or discriminative role during the preclinical disease phase for developing clinically isolated syndrome or multiple sclerosis later in life.

[Risk stratification of progressive multifocal leukoencephalopathy under natalizumab: recommendations for JC virus serology].

ZusammenfassungDie JC-Virus (JCV)-assoziierte progressive multifokale Leukenzephalopathie (PML) ist eine schwerwiegende unerwünschte Arzneimittelwirkung, die unter der Behandlung einer Multiplen Sklerose (MS) mit Natalizumab (Tysabri®) in seltenen Fällen auftreten kann. Neben den bekannten Risikofaktoren – Behandlungsdauer über 24xa0Monate hinaus sowie eine vorangegangene immunsuppressive Therapie – wurde nun auch eine serologische Untersuchung zum Nachweis sog. Anti-JCV-Antikörper zur Risikostratifizierung in den Zulassungstext der Substanz mit aufgenommen. Unzweifelhaft stellt die JCV-Serologie ein Werkzeug zur PML-Risiko-Stratifzierung von MS-Patienten unter Natalizumab-Therapie dar. Die bisherige Datenlage und die wissenschaftlichen Entwicklungen zur Validität des Assays wurden bisher aber nicht unabhängig bestätigt.Der vorliegende Artikel erläutert daher Möglichkeiten und Grenzen einer solchen Untersuchung und gibt auf der Basis des zur Verfügung stehenden Wissens konkrete Empfehlungen für die klinische Anwendung dieser neuen Untersuchung.SummaryJC virus (JCV)-associated progressive multifocal leukoencephalopathy (PML) represents a rare but serious side effect of natalizumab (Tysabri®) in the treatment of patients with relapsing forms of multiple sclerosis (MS). Two factors that may increase the risk of PML have been identified: treatment duration beyond 24xa0months and prior immunosuppressive therapy. Recently determination of anti-JCV antibodies mirroring JCV infection has allowed a third factor to be added to this list, and a positive serological test has been included as a risk factor on the label of natalizumab. Clearly, JCV serology represents a tool for PML risk stratification in MS patients treated with natalizumab. However, current data as well as the experimental development of the underlying assay have not been validated by an independent laboratory.The present article discusses possibilities and challenges of this assay and, based on our present knowledge, provides recommendations for the clinical implementation in daily practice.

Risikostratifizierung einer progressiven multifokalen Leukenzephalopathie unter Natalizumab

ZusammenfassungDie JC-Virus (JCV)-assoziierte progressive multifokale Leukenzephalopathie (PML) ist eine schwerwiegende unerwünschte Arzneimittelwirkung, die unter der Behandlung einer Multiplen Sklerose (MS) mit Natalizumab (Tysabri®) in seltenen Fällen auftreten kann. Neben den bekannten Risikofaktoren – Behandlungsdauer über 24xa0Monate hinaus sowie eine vorangegangene immunsuppressive Therapie – wurde nun auch eine serologische Untersuchung zum Nachweis sog. Anti-JCV-Antikörper zur Risikostratifizierung in den Zulassungstext der Substanz mit aufgenommen. Unzweifelhaft stellt die JCV-Serologie ein Werkzeug zur PML-Risiko-Stratifzierung von MS-Patienten unter Natalizumab-Therapie dar. Die bisherige Datenlage und die wissenschaftlichen Entwicklungen zur Validität des Assays wurden bisher aber nicht unabhängig bestätigt.Der vorliegende Artikel erläutert daher Möglichkeiten und Grenzen einer solchen Untersuchung und gibt auf der Basis des zur Verfügung stehenden Wissens konkrete Empfehlungen für die klinische Anwendung dieser neuen Untersuchung.SummaryJC virus (JCV)-associated progressive multifocal leukoencephalopathy (PML) represents a rare but serious side effect of natalizumab (Tysabri®) in the treatment of patients with relapsing forms of multiple sclerosis (MS). Two factors that may increase the risk of PML have been identified: treatment duration beyond 24xa0months and prior immunosuppressive therapy. Recently determination of anti-JCV antibodies mirroring JCV infection has allowed a third factor to be added to this list, and a positive serological test has been included as a risk factor on the label of natalizumab. Clearly, JCV serology represents a tool for PML risk stratification in MS patients treated with natalizumab. However, current data as well as the experimental development of the underlying assay have not been validated by an independent laboratory.The present article discusses possibilities and challenges of this assay and, based on our present knowledge, provides recommendations for the clinical implementation in daily practice.