Neuromyelitis optica (NMO) is an autoimmune disease of the central nervous system in which aberrant antibody responses to the astrocytic water channel aquaporin 4 have been described. Experimental ...evidence is emerging that NMO is partly driven by the proinflammatory cytokine interleukin 6 (IL-6), which propagates the survival of disease-specific B cell subclasses, and deviates CD4+ T helper cell differentiation toward IL-17-producing T helper 17 cells. Tocilizumab is a recombinant humanized monoclonal antibody against the IL-6 receptor approved for treatment of rheumatoid arthritis.
To study clinical and paraclinical effects of tocilizumab in a patient with NMO.
Case report.
Academic neurology department.
A patient with highly active aquaporin 4–seropositive NMO who failed numerous immunosuppressive interventions, including high-dose corticosteroids, mitoxantrone, plasma exchange (PE), rituximab (anti-CD20), and alemtuzumab (anti-CD52), before receiving tocilizumab.
Clinical disability, magnetic resonance imaging, cytokines and transcription factors levels in the cerebrospinal fluid, and peripheral blood mononuclear cells.
A patient who continued to accumulate neurological disability and magnetic resonance imaging activity while receiving numerous immunoactive therapies stabilized, and eventually improved clinically and on magnetic resonance metrics after treatment initiation with tocilizumab. Treatment and clinical response correlated with a significant reduction of IL-6 levels in the CSF as well as a diminished expression of signal transducer and activator of transcription 3.
Tocilizumab might be effective in NMO, here in a patient not responding to leukocyte depletion. Our findings further support data that implicate IL-6 as a critical molecule in the immunopathogenesis of NMO, and a critical role for T cells in the pathogenesis of this disorder.
Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various ...disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, and Switzerland).
OBJECTIVE:To assess whether pretreatment-lymphocyte counts, treatment before fingolimod, age, sex, or body mass index (BMI) affects the risk of fingolimod-induced lymphopenia in patients with ...relapsing-remitting multiple sclerosis (RRMS).
METHODS:Data were obtained from a German multicenter, single-arm, open-label study of patients with RRMS treated with fingolimod, and findings were validated in an independent Swedish national pharmacovigilance study.
RESULTS:Four hundred eighteen patients with RRMS from Germany and 438 patients from Sweden were included. A nadir ≤0.2 × 10 lymphocytes/L was reached in 15% (95% confidence interval CI 12%–17%) of all 856 patients. Patients with lower starting lymphocyte counts (below 1.6 × 10/L) and patients with BMI lower than 18.5 kg/m (women only) were at higher risk of developing lymphopenia with values ≤0.2 × 10/L in the combined analysis, increasing the risk in these subgroups to 26% (95% CI 20%–31%) or 46% (95% CI 23%–71%), respectively. In the German cohort, infection rates were similar in patients who developed severe lymphopenia and those who did not.
CONCLUSIONS:Our findings suggest that patients with low baseline lymphocyte counts and underweight women in which fingolimod treatment will be initiated should possibly be monitored more closely.
Intravenous immunoglobulins represent an established therapy for the treatment of chronic immune-mediated neuropathies, specifically chronic inflammatory demyelinating polyradiculoneuropathies ...(CIDPs) as well as multifocal motor neuropathies (MMNs). For the treatment of antibody deficiency syndromes, subcutaneous immunoglobulins (SCIgs) have represented a mainstay for decades. An emerging body of evidence suggests that SCIg might also exhibit clinical efficacy in CIDP and MMN. This article reviews the current evidence for clinical effectiveness, as well as safety of SCIg for the treatment of immune-mediated neuropathies, and addresses remaining open questions in this context.
We conclude that despite the need for controlled long-term studies to demonstrate long-term efficacy of SCIg in immune-mediated neuropathies, SCIg may already represent a potential therapeutic alternative for selected patients.
The NOD mouse strain spontaneously develops autoimmune diabetes. A deficiency in costimulatory molecules, such as B7-2, on the NOD genetic background prevents diabetes but instead triggers an ...inflammatory peripheral neuropathy. This constitutes a shift in the target of autoimmunity, but the underlying mechanism remains unknown. In this study, we demonstrate that NOD mice deficient for isoforms of ICAM-1, which comediate costimulatory functions, spontaneously develop a chronic autoimmune peripheral neuritis instead of diabetes. The disease is transferred by CD4(+) T cells, which infiltrate peripheral nerves together with macrophages and B cells and are autoreactive against peripheral myelin protein zero. These Icam1(tm1Jcgr)NOD mice exhibit unaltered numbers of regulatory T cells, but increased IL-17-producing T cells, which determine the severity, but not the target specificity, of autoimmunity. Ab-mediated ICAM-1 blockade triggers neuritis only in young NOD mice. Thymic epithelium from Icam1(tm1Jcgr)NOD mice features an altered expression of costimulatory molecules and induces neuritis and myelin autoreactivity after transplantation into nude mice in vivo. Icam1(tm1Jcgr)NOD mice exhibit a specifically altered TCR repertoire. Our findings introduce a novel animal model of chronic inflammatory neuropathies and indicate that altered expression of ICAM-1 on thymic epithelium shifts autoimmunity specifically toward peripheral nerves. This improves our understanding of autoimmunity in the peripheral nervous system with potential relevance for human diseases.
Abstract
The objective of this study was to investigate confirmed progression independent of relapse activity in relapsing-remitting multiple sclerosis patients under long-term natalizumab treatment. ...We performed a retrospective, cross-sectional study of clinical data captured between 1994 and 2019 at two German multiple sclerosis tertiary referral centres. Data files of all relapsing-remitting multiple sclerosis patients treated with natalizumab for ≥24 months were analysed. Confirmed progression independent of relapse activity was defined as ≥12 week confirmed disability progression on a roving Expanded Disability Status Scale reference score by 1 point in patients with an Expanded Disability Status Scale score ≤3 or 0.5 in patients with an Expanded Disability Status Scale score ≥3.5 in the absence of a relapse. Cox proportional hazard models were used to analyse the probability of developing confirmed progression independent of relapse activity depending on both disease and natalizumab treatment duration. Among the 184 patients identified, 44 (24%) developed confirmed progression independent of relapse activity under natalizumab irrespective of the Expanded Disability Status Scale score at natalizumab onset. Time to confirmed progression independent of relapse activity was not affected by Expanded Disability Status Scale at natalizumab onset (categorized by Expanded Disability Status Scale score ≤3.5 versus >3.5) nor by duration of disease nor by duration of therapy. Confirmed progression independent of relapse activity occurred earlier in the disease course in patients with an earlier natalizumab therapy onset with regard to disease duration. A stepwise forward regression analysis revealed disease duration as the main factor for confirmed progression independent of relapse activity development (P = 0.005). Taken together, confirmed progression independent of relapse activity occurs in a substantial proportion of patients on long-term natalizumab treatment and independent of Expanded Disability Status Scale score at natalizumab onset. Our findings suggest that patients who are initiated on natalizumab early during disease course, usually in order to treat an aggressive clinical phenotype, have a higher risk of early confirmed progression independent of relapse activity.
Graf et al. aimed to assess the relevance of relapse-independent disease progression in relapsing remitting multiple sclerosis patients under long-term natalizumab treatment. In this study, more than 20% of multiple sclerosis patients developed relapse-independent disease progression, mostly linked to a more active disease course prior to natalizumab onset.
Graphical Abstract
Graphical Abstract
Multiple sclerosis (MS) represents the prototypic inflammatory autoimmune disorder of the central nervous system and the most common cause of neurological disability in young adults. The mainstays in ...the immunomodulatory therapy of MS are currently interferon beta and glatiramer acetate, both of which have proven to be clinically and paraclinically effective. Current clinical evidence indicates that treatment should be initiated as early as possible. In this review we summarize available data from clinical studies on clinical efficacy of immunomodulatory drugs for treating patients with multiple sclerosis.
Abstract There is an unmet need for more potent and convenient drugs in the treatment of patients diagnosed with multiple sclerosis (MS). Among five currently investigated oral drugs with an ongoing ...or completed phase III program, promising efficacy data for oral cladribine have recently been published. However, benefits need to be weighed against potential risks to define the role of this compound within current treatment regimens. Here we review present data on efficacy of oral cladribine and discuss known and anticipated risks of this drug.
The NOD mouse strain spontaneously develops autoimmune diabetes. A deficiency in costimulatory molecules, such as B7-2, on the NOD genetic background prevents diabetes but instead triggers an ...inflammatory peripheral neuropathy. This constitutes a shift in the target of autoimmunity, but the underlying mechanism remains unknown. In this study, we demonstrate that NOD mice deficient for isoforms of ICAM-1, which comediate costimulatory functions, spontaneously develop a chronic autoimmune peripheral neuritis instead of diabetes. The disease is transferred by CD4+ T cells, which infiltrate peripheral nerves together with macrophages and B cells and are autoreactive against peripheral myelin protein zero. These Icam1tm1JcgrNOD mice exhibit unaltered numbers of regulatory T cells, but increased IL-17-producing T cells, which determine the severity, but not the target specificity, of autoimmunity. Ab-mediated ICAM-1 blockade triggers neuritis only in young NOD mice. Thymic epithelium from Icam1tm1JcgrNOD mice features an altered expression of costimulatory molecules and induces neuritis and myelin autoreactivity after transplantation into nude mice in vivo. Icam1tm1JcgrNOD mice exhibit a specifically altered TCR repertoire. Our findings introduce a novel animal model of chronic inflammatory neuropathies and indicate that altered expression of ICAM-1 on thymic epithelium shifts autoimmunity specifically toward peripheral nerves. This improves our understanding of autoimmunity in the peripheral nervous system with potential relevance for human diseases.
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