Ofatumumab – A Potential Subcutaneous B-cell Therapy for Relapsing Multiple Sclerosis

Background: Off-label use of intravenous immunoglobulin has been reported for the treatment of recurrent spontaneous pregnancy loss and selected cases of multiple sclerosis. However, the use of subcutaneous immunoglobulin has not been reported in these settings. Methods and results: We report on tolerability and clinical efficacy of subcutaneous immunoglobulin therapy in a woman with the unusual association of IgG4 subclass deficiency, C4 hypocomplementemia, localized scleroderma, unexplained spontaneous pregnancy loss and multiple sclerosis. Weekly infusions of subcutaneous immunoglobulin were self-administered at home (6 grams/week, Hizentra®) during the next pregnancy after abortion. Interferon beta-1a for the treatment of relapsing-remitting multiple sclerosis was stopped before pregnancy. During pregnancy only subcutaneous immunoglobulin was administered. The patient was found to have 4% of CD3+CD16/CD56+ (Natural Killer (NK) /T cells). The patient delivered a healthy baby (Apgar score 9 at 5 minutes) at 37 weeks gestation. During pregnancy and 3 months follow-up after delivery no multiple sclerosis flare-ups were observed. NK-T cell percentages remained stable. Conclusions: Our observation indicates that subcutaneous immunoglobulin therapy was well tolerated and efficacious in a selected case of unexplained abortion and multiple sclerosis.

Alpha-lipoic acid and frataxin: A new indication for an old antioxidant?

To conduct systematic long-term follow-up (LTFU) of patients in the Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) study to provide up to 8 years of safety, clinical and MRI outcomes on subcutaneous (s.c.) interferon (IFN) beta-1a in relapsing-remitting multiple sclerosis (RRMS). The original cohort of 560 patients was randomized to IFNbeta-1a, 44 or 22 microg three times weekly (TIW) or to placebo; after 2 years, patients on placebo were rerandomized to active treatment and the blinded study continued for a further 4 years. The LTFU visit was scheduled 7 to 8 years after baseline. LTFU was attended by 68.2% of the original PRISMS study cohort (382/560 patients). 72.0% (275/382) were still receiving IFNbeta-1a s.c. TIW. Patients originally randomized to IFNbeta-1a 44 microg s.c. TIW showed lower Expanded Disability Status Scale progression, relapse rate and T2 burden of disease up to 8 years compared with those in the late treatment group. Brain parenchymal volume did not show differences by treatment group. Overall, 19.7% of patients progressed to secondary progressive MS between baseline and LTFU (75/381). No new safety concerns were identified and treatment was generally well tolerated. Despite the limitations inherent in any long-term study (for example, potential differences between returning and nonreturning patients), these results indicate that patients with relapsing-remitting multiple sclerosis can experience sustained benefit over many years from early interferon beta-1a subcutaneous therapy three times weekly compared with patients whose treatment is delayed. This effect was more apparent in the patients receiving the higher dose.

MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans

Detection of Atypical Femur Fractures

Several groups have recently described the endothelial cells (EC) as an important target of pathological mediators in multiple sclerosis (MS). Despite the recognition of the EC as a significant target in MS and a possible beneficiary of Beta-interferon therapy, the structural changes which occur in the cerebrovascular endothelium and the effects of interferon-â1b on these changes have not been closely evaluated. Disruption or dysregulation of the blood brain barrier (BBB) in MS represents a loss of endothelial integrity, which may facilitate the transendothelial migration of activated leukocytes responsible for the development of demyelinating lesions of MS. We used proteomics (2-dimensional gel electrophoresis and MALDI-MS) to characterize the effects of serum from MS patients with active disease (with and without interferon-â1b therapy) on human cerebral endothelial cells. The results of this study revealed the up- and down-regulation of expression of several proteins related to vascular development, cell structure, and cell cycle control. Using this approach we identified 14-3-3 ε, metavinculin, myosin-9, plasminogen, reticulocalbin-2 and-3, ribonuclease/ angiogenin inhibitor 1, annexin A1, tropomyosin and Ras-related protein Rap-1A as potential new markers of active MS disease. A better understanding of the alterations within the cerebrovascular endothelium in MS pathogenesis of MS may lead to development of more potent therapies in MS. β

Mild COVID-19 infection in a patient with multiple sclerosis and severe depletion of T-lymphocyte subsets due to alemtuzumab

This article discusses acute exacerbations (relapses) of multiple sclerosis (MS). Relapses are a hallmark of MS and are often associated with significant functional impairment and decreased quality of life. This review discusses the proposed pathophysiology of MS relapses, triggering factors, associated markers, variants of clinical presentation, and diagnostic recommendations. Most MS exacerbations are followed by a period of repair leading to clinical remission; however, residual deficits may persist after MS relapse and contribute to the stepwise progression of disability. Treatment of MS relapses is important as it helps to shorten the duration of disability associated with their course. Successful treatment of relapse helps patients with MS obtain a vital sense of being able to gain control over the disease. Patients with relapsing MS who receive treatment report better outcomes than those who are simply observed. This article discusses treatment options for MS relapse, including systemic corticosteroids, adrenocorticotropic hormone, and plasma exchange. Recent findings related to the mechanisms of action of steroids and adrenocorticotropic hormone are also reviewed, and other potential therapies are assessed. A proposed algorithm for MS relapse management is presented, including strategies for steroid-resistant MS exacerbations. MS relapses need to be recognized in a timely manner and treated using recommended therapeutic methods.

EP 35. Deep brain stimulation for multiple sclerosis related tremor: Clinical reports

Purpose of ReviewCOVID-19 has posed a continuously evolving challenge for providers caring for patients with multiple sclerosis (MS). While guidelines from national and international organizations came quickly, these have required constant reassessment and modification as the pandemic has progressed. This review aims to assess the first 2 years of literature on COVID-19 relevant to the clinical management of patients with MS. In particular, we will review how MS impacts the risk of COVID-19 infection, how disease-modifying therapies may alter this risk, and explore considerations regarding disease-modifying therapy (DMT) and vaccination for COVID-19. We will also explore potential ways in which a COVID-19 infection may impact multiple sclerosis. Our goal is to provide an overarching review of the major findings at this stage of the pandemic relevant to those that care for patients with MS.Recent FindingsOver the course of the COVID-19 pandemic, providers have had to re-evaluate the priorities in the management of MS. A growing number of studies have evaluated the relevant risk factors and considerations regarding MS and particular disease-modifying therapies.SummaryThe long-term impacts of the pandemic on the health of those with MS will continue to be revealed. In general, most patients with MS do not need major revisions to their treatment plan due to COVID-19 risk. However, individuals who are older, more disabled, and on more potent therapies may need to consider strategies for decreasing their overall risk. Regardless, continued improvement in our understanding of interactions between infections, disease-modifying therapy, and MS are paramount to optimizing the care of those with MS going forward.

BackgroundNeuromyelitis optica (NMO) is a severely disabling inflammatory disorder of the central nervous system and is often misdiagnosed as multiple sclerosis (MS). There is increasing evidence that treatment options shown to be beneficial in MS, including interferon-β (IFN-β), are detrimental in NMO.Case presentationWe here report the first Caucasian patient with aquaporin 4 (AQP4) antibody (NMO-IgG)-seropositive NMO presenting with a tumefactive brain lesion on treatment with IFN-β. Disease started with relapsing optic neuritis and an episode of longitudinally extensive transverse myelitis (LETM) in the absence of any brain MRI lesions or cerebrospinal fluid-restricted oligoclonal bands. After initial misdiagnosis of multiple sclerosis (MS) the patient received subcutaneous IFN-β1b and, subsequently, subcutaneous IFN-β1a therapy for several years. Under this treatment, the patient showed persisting relapse activity and finally presented with a severe episode of subacute aphasia and right-sided hemiparesis due to a large T2 hyperintensive tumefactive lesion of the left brain hemisphere and a smaller T2 lesion on the right side. Despite rituximab therapy two further LETM episodes occurred, resulting in severe neurological deficits. Therapeutic blockade of the interleukin (IL)-6 signalling pathway by tocilizumab was initiated, followed by clinical and radiological stabilization.ConclusionOur case (i) illustrates the relevance of correctly distinguishing NMO and MS since these disorders differ markedly in their responsiveness to immunomodulatory and -suppressive therapies; (ii) confirms and extends a previous report describing the development of tumefactive brain lesions under IFN-β therapy in two Asian NMO patients; and (iii) suggests tocilizumab as a promising therapeutic alternative in highly active NMO disease courses.

Susceptibility to experimental autoimmune encephalomyelitis is associated with altered B-cell subsets distribution and decreased serum BAFF levels

Persistent neuroinflammation is now recognized as a chief pathological component of practically all neurodegenerative diseases. Neuroinflammation in the central nervous system (CNS), is accompanied with immune responses of glial cells. Glial cells respond to pathological stimuli through antigen presentation, and cytokine and chemokine signaling. Therefore, limiting CNS inflammation represents prospective therapeutic approach in diseases like Alzheimer's, amyotrophic lateral sclerosis, Parkinson's, ischemia, various psychiatric disorders and Multiple sclerosis (MS). As a complex disease, MS is characterized by neuroinflamation, demyelination and sequential axonal loss. Due to unknown etiology and the heterogeneous presentation of the disease, MS is hard to treat and the search for potential therapeutics is wide and meticulous. However, finding a proper antineuroinflammatory drug may bring an advance in selecting novel treatment regimens of ample of neurodegenerative diseases and neurological disorders. The present review gives the overview of the existing and potential therapies in MS, aimed to modulate neuroinflammation and ensure neuroprotection.

Medical cannabis use in Canadians with multiple sclerosis

Ageing and multiple sclerosis