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Autoimmune diseases are an important field for the development of bone marrow transplantation, or hematopoietic stem cell transplantation. In Europe alone, almost 3000 procedures have been registered so far. The Brazilian Society for Bone Marrow Transplantation (Sociedade Brasileira de Transplantes de Medula Óssea) organized consensus meetings for the Autoimmune Diseases Group, to review the available literature on hematopoietic stem cell transplantation for autoimmune diseases, aiming to gather data that support the procedure for these patients. Three autoimmune diseases for which there are evidence-based indications for hematopoietic stem cell transplantation are multiple sclerosis, systemic sclerosis and Crohn's disease. The professional stem cell transplant societies in America, Europe and Brazil (Sociedade Brasileira de Transplantes de Medula Óssea) currently consider hematopoietic stem cell transplantation as a therapeutic modality for these three autoimmune diseases. This article reviews the evidence available.

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). in press, CA extern

In clinical practice, the diagnosis of secondary progressive multiple sclerosis (SPMS) is often delayed, retrospective and non-reproducible, as there are no consensus criteria that define the advent of SPMS. Early identification of SPMS is essential to improve patient care.Eight regional board meetings in France involving 56 multiple sclerosis (MS) experts (neurologists) were convened to discuss diagnostic criteria for SPMS. Subsequently, a national board meeting of 13 neurologists (with an expert representing each geographical region) was held to review points of convergence or divergence between regions and to develop a national consensus document.Based on the discussions from the regional boards, the MS experts at the national board retained the worsening of the EDSS score, with compatible clinical features, as the only consensus criterion for the diagnosis of SPMS in clinical practice. The patient should have experienced during at least the previous 6 months and in the absence of any relapse, a worsening in the EDSS score of +1.0 point (if the previous EDSS was≤5.0) or of +0.5 point (if the previous EDSS was≥5.5), with a pyramidal or cerebellar functional system score≥2 and without setting a minimum EDSS score; or, in case of a stable EDSS score≥4.0, a worsening of a functional score. This worsening should be confirmed within 3 to 6 months. According to the MS experts, the patient's age, duration of illness and a minimal threshold EDSS score are only risk factors for transition to SPMS. Patient reports during consultation and cognitive impairment are important warning signs, which should trigger an objective assessment with specific tests or closer monitoring. Clinical relapse and/or MRI activities are non-discriminatory for making the diagnosis of SPMS.The experts defined precise diagnostic criteria adapted to clinical practice for earlier identification of SPMS, paving the way for better management of this stage of the disease.

During the past decades autoimmune diseases have been usually treated with immunosuppressive drugs mostly active on T-Cell mediated responses. Only in recent years, with our extended knowledge of the pathogenic mechanisms of autoreactive disorders and the tremendous development of new therapeutic monoclonal antibodies, anti-B-Cell therapies have emerged as a new option for treating autoimmune diseases. The rationale for this changeover from T-Cell to B-Cell targeted therapies resides in the recently accumulated evidence of the role of B-Cells in the pathogenesis of autoimmune diseases and in the generation of tissue damage. Targeting memory and effector BCells may then disrupt the production of pathogenic antibodies, counteract the role of B-Cells in sustaining antigen presentation to T-Cells and block the synthesis of B-Cell activation cytokines. The anti-CD20 monoclonal antibody Rituximab was first introduced more than 20 years ago for the treatment of CD20+ chronic B-lymphoproliferative disorders, and was then successfully experimented in the treatment of an ever-increasing spectrum of autoimmune diseases. Newer anti-CD20 monoclonal antibodies have been introduced more recently, which vary in their biological effects. The need for laboratory indicators that may help the rational usage and follow-up of anti-CD20 treatments has now emerged, due to the high variability of individual response, to the markedly different outcomes in the various diseases and to the controversial role of pathogenic autoantibodies as indicators of disease activity. Flow cytometric (FCM) analyses to identify and enumerate the B-cell functional subsets in the peripheral blood have been developed in recent years. They can be used to assess the degree and the persistence of memory B-Cell depletion, the quality and the timing of B-Cell reconstitution, along with the highly sensitive FCM counting technique needed for the detection of extremely low cell levels. The long-term aim of this innovative approach is to provide clinicians with a tool for a safer and more rational usage of anti-CD20 agents.

Background and objectives: Treatment of spasticity poses a major challenge given the complex clinical presentation and variable efficacy and safety profiles of available drugs. We present a systematic review of the pharmacological treatment of spasticity in multiple sclerosis (MS) patients. Methods: Controlled trials and observational studies were identified. Scientific evidence was evaluated according to pre-specified levels of certainty. Results: The evidence supports the use of baclofen, tizanidine and gabapentin as first-line options. Diazepam or dantrolene could be considered if no clinical improvement is seen with the previous drugs. Nabiximols has a positive effect when used as add-on therapy in patients with poor response and/or tolerance to first-line oral treatments. Despite limited evidence, intrathecal baclofen and intrathecal phenol show a positive effect in severe spasticity and suboptimal response to oral drugs. Conclusion: The available studies on spasticity treatment offer some insight to guide clinical practice but are of variable methodological quality. Large, well-designed trials are needed to confirm the effectiveness of antispasticity agents and to produce evidence-based treatment algorithms.

Multiple sclerosis (MS) lesions are characterized by inflammatory demyelination and reactive gliosis, and although remyelination occurs in some lesions it is limited and incomplete. Leukemia inhibitory factor (LIF) is an important cytokine that stimulates oligodendrocyte proliferation and survival in vitro. Opalin is a unique molecular marker for mature oligodendrocytes. The aim of this study was to demonstrate the role of LIF on Opalin and myelin oligodendrocyte glycoprotein (MOG) expression in the cerebral cortex of cuprizone-induced MS mice. The mice were treated with cuprizone for five weeks in order to induce MS. The mice were then divided into 3 groups. The first group was injected intraperitoneally (IP) with LIF for six weeks in the amount of 30 µg/kg bw per day. The second group (SHAM) was injected IP with normal saline and the third group was left without injection as a control. After six weeks the mice were killed, the cerebral cortex was harvested, and the expression of MOG and Opalin was studied. Using western blotting we found that LIF increases Opalin and MOG expression in the cerebral cortex extracts as compared to SHAM and control groups. However, no significant difference in the Opalin and MOG expression was seen between SHAM and control groups. It is concluded that LIF may have an important role in the process of remyelination by increasing Opalin expression and MOG expression.

OBJECTIVE: To evaluate the effect of the Assistive Device Selection, Training and Education Program (ADSTEP) on falls and walking and sitting activity in people with multiple sclerosis (PwMS). DESIGN: Randomized controlled trial. SETTING: Veterans affairs medical center. PARTICIPANTS: PwMS (N=40) using a walking aid at baseline who had fallen in the previous year. INTERVENTIONS: Participants were randomly assigned to ADSTEP or control. ADSTEP had 6 weekly, 40-minute, 1-on-1 sessions with a physical therapist, starting with walking aid selection and fitting, followed by task-oriented progressive gait training. Control was usual medical care with the option of ADSTEP after the study. MAIN OUTCOME MEASURES: The following were assessed at baseline, intervention completion, and 3 months later: falls, timed Up and Go, timed 25-foot walk, 2-minute walk, Four Square Step Test, International Physical Activity Questionnaire, Quebec User Evaluation of Satisfaction with Assistive Technologies, Multiple Sclerosis Walking Scale-12, Activities-Specific Balance Confidence Scale, and Multiple Sclerosis Impact Scale-29. Effect on these outcomes was estimated by a 2-by-2 repeated measures general linear model. RESULTS: Fewer ADSTEP than control participants fell (χ(2)=3.96, P.05. ADSTEP 117.53±148.40min/d; control 46.43 ±58.55min/d; d=0.63). CONCLUSIONS: ADSTEP prevents falls, reduces sitting, and may increase walking in PwMS.

This paper explores the nature of the nursing contribution to chronic disease management (CDM) and identifies a number of key nursing activities within CDM both at the individual patient and care system levels. The activities were identified following a detailed review of the literature (160 reports and studies of nursing practice) relating to three tracer disorders: diabetes, chronic obstructive pulmonary disease and multiple sclerosis. The paper examines these activities collectively to generate models expressing some of the core functions of nursing within CDM. The paper illustrates some of the changing characteristics of nursing roles within CDM. More fundamentally, the paper questions the position of nursing in relation to the technologies that define CDM systems and proposes four levels of contribution: the nurse as technology; the nurse as technologist; the nurse as system engineer; and the nurse as architect. These different levels reflect distinctions in the nature of the nursing gaze and power relations within the health care workforce. The paper also highlights how nurses are failing to develop the evidence for their practice in CDM. The paper concludes that there is a need for some clear principles to guide clinical practice and encourage innovation in CDM. It is argued that the principles should not be rule-bound but define a distinctive nursing gaze that will position the nursing profession within the health care system and in relation to other professions. The gaze should incorporate the needs of the individual patient and the care system that they inhabit.

Cognitive impairment in multiple sclerosis (MS) is common, debilitating and burdensome. Key evidence from trials was reviewed to enable recommendations to be made to guide clinical practice and research. Behavioural and pharmacological interventions on cognition reported in published studies were reviewed. Most studies evaluating behavioural treatment for impairment in learning and memory, deficits of attention and executive function have demonstrated some improvement. Controlled studies in relapsing remitting MS indicate interferon (IFN) β-1b and IFN β-1a were associated with modest cognitive improvement. The effects of symptomatic therapies such as modafinil and donepezil are inconsistent. Most studies yielding positive findings have significant methodological difficulties limiting the confidence in making any broad treatment recommendations. There are no published reports of glatiramer acetate, natalizumab and fingolimod being effective in improving cognition in controlled trials. The effects of disease modifying therapies in other forms of MS and clinically isolated syndrome have not yielded positive results. Data linking behavioural therapy, symptomatic treatment or disease modifying treatment, to either reducing cognitive decline or improving impaired cognition are limited and inconsistent. The treatment and prevention of cognitive impairment needs to remain a key research focus, identifying new interventions and improving clinical trial methodology.

The site is strewn with the bones of men from both sides who fell in the battle, with those of the Persians quite distinct from those of the Egyptians, just as they were when the fighting originally began; and so brittle are the skulls of the Persians that, should you wish to make a hole in one, you would have only to tap it with a single pebble, whereas those of the Egyptians are so tough that it would be a challenge to smash them through, even if you pounded at them with a rock. Why should this be so? The locals gave a reason which seems to me eminently plausible: namely, that Egyptians are in the habit of shaving their heads from the very earliest days of their childhood, so that the bone ends up thickened by exposure to the sun. This explanation of the toughness of Egyptian skulls also serves to suggest why Persian skulls should be so brittle: the Persians keep their heads out of the sun from birth by wearing conical felt caps, or tiaras.

The unique clinical characteristics of primary progressive multiple sclerosis (PPMS) pose particular diagnostic difficulties, both in excluding other causes of progressive syndromes and in confirming the diagnosis of MS, which is not adequately addressed by current diagnostic criteria. This article presents new diagnostic criteria developed by a group of investigators on the basis of a review of their considerable experience with PPMS. (We conclude that at least 1 year of clinical progression must be documented before a diagnosis of PPMS is made.) Three levels of diagnostic certainty have been defined-definite, probable, and possible--based on clinical findings, abnormal cerebrospinal fluid, abnormalities on magnetic resonance imaging (MRI) of the brain and spinal cord, and evoked potentials. In definite PPMS, evidence of intrathecal synthesis of immunoglobulin G together with one of the following three MRI criteria is required: (1) nine brain lesions, (2) two spinal cord lesions, or (3) four to eight brain lesions and one spinal cord lesion. Preliminary testing of these criteria was carried out on a cohort of 156 patients participating in a European natural history study of PPMS: 64% fulfilled the criteria for definite PPMS, 35% for probable PPMS, and only 1% for possible PPMS. These criteria now require prospective validation in a cohort of newly diagnosed patients and by postmortem examination.

The January 2011 Special Issue of IEEE Transactions on Information Technology in Biomedicine includes selected papers from Information Technology in Biomedicine (ITAB 2009), held in the month of October in Cyprus. The overall objective of ITAB 2009 was to cover the state of the art in Information Technology Applications in Biomedicine, under the theme 'Citizen centered e-health systems in a global healthcare environment'. The Issue contains paper by Karagiannis and colleagues that investigates the performance of empirical mode decomposition (EMD) on ECGs. The paper by Stylianides introduces a novel, open source middleware framework for communication with medical devices and an application using the middleware named intensive care window (ICW). Cunningham and colleagues propose a home-based tool designed to monitor and assess peripheral motor symptoms. Loizou and colleagues introduce the use of multiscale AM FM texture analysis of multiple sclerosis (MS) using MR images from the brain. 15 1 3 10 Cited By :1

Background: Haematopoietic stem cell transplantation (HSCT) has been tried in the last 15 years as a therapeutic option in patients with poor-prognosis autoimmune disease who do not respond to conventional treatments. Worldwide, more than 600 patients with multiple sclerosis (MS) have been treated with HSCT, most of them having been recruited in small, single-centre, phase 1–2 uncontrolled trials. Clinical and magnetic resonance imaging outcomes from case series reports or Registry-based analyses suggest that a major response is achieved in most patients; quality and duration of response are better in patients transplanted during the relapsing–remitting phase than in those in the secondary progressive stage. Objectives: An interdisciplinary group of neurologists and haematologists has been formed, following two international meetings supported by the European and American Blood and Marrow Transplantation Societies, for the purpose of discussing a controlled clinical trial, to be designed within the new scenarios of evolving MS treatments. Conclusions: Objectives of the trial, patient selection, transplant technology and outcome assessment were extensively discussed. The outcome of this process is summarized in the present paper, with the goal of establishing the background and advancing the development of a prospective, randomized, controlled multicentre trial to assess the clinical efficacy of HSCT for the treatment of highly active MS.

To determine the impact of multiple sclerosis (MS) on patient attendance at dental practices and maintenance of oral health.A cross-sectional postal questionnaire-based study.Leicestershire, United Kingdom.People with MS in Leicestershire identified from local health authority records (n = 476).Number registered at dental practice, frequency of attendance, issues and perspectives relating to attendance and maintenance of oral health.A response rate of 61% (n = 289) was obtained. When compared to the general population, a higher number of people with MS were registered with a dentist (49%:88%) and displayed more frequent practice attendance (71%:81%) in the past year. People with MS reported difficulties in attending a dentist and maintaining oral health, which were exacerbated by deterioration in general health. Problems relating to reduced personal mobility had the greatest impact on attendance.MS has a negative impact on perceived patient attendance and maintenance of oral health. Patients with a progressive disability could benefit greatly from the provision of preventive oral health care. The importance of seeking care earlier rather than later needs to be emphasised to both professionals and patients alike. Further efforts are required to increase awareness of the importance of oral health to the quality of life of people with MS and ensure that individuals with physical disabilities receive the same access to dental services as the able-bodied.

SummaryUsing the paper chromatographic technic significant changes in the protein patterns have been demonstrated in patients with multiple sclerosis. We are unable to state at present the relationship of these changes to the activity of the disease, but our evidence would seem to indicate that they may occur concomitantly with, or immediately following the onset of exacerbation. Furthermore the changes in protein patterns revert to normal during remissions.

Three methods for evaluation of serum lipoprotein abnormalities were compared: paper electrophoresis using buffer containing albumin, ultracentrifugation at d 1.21, and thin-layer starch-gel electrophoresis. Analyses by paper electrophoresis and by ultracentrifugation of 109 sera of patients with cholesterol levels between 78 and 1150 mg/100 ml showed that the electrophoretic procedure while not quantitative was an effective procedure for detecting and helping in classification of the type of serum lipoprotein abnormality. Paper electrophoresis is a valuable procedure in screening for lipoprotein abnormalities and can be used as a guide for additional studies. Thin-layer starchgel electrophoresis did not always give results comparable to those of the other two procedures. In study of certain sera (for example, in pigeon serum and some myeloma sera) lipoprotein subfractions were more clearly resolved by starch-gel electrophoresis than by paper electrophoresis or ultracentrifugation. Ultracentrifugal and starch-gel electrophoretic techniques can be used effectively when more complete information is needed or when unusual materials are being studied.

Dr Wekerle began by highlighting the problems associated with the investigation of patients with multiple sclerosis. Whilst he thought it very likely that the disease was an autoimmune one, he reminded the audience that we still do not know what the target autoantigen is, have almost no access to the target tissue and, are as yet, unable to transfer the disease with human material. He suggested therefore that most of our knowledge on multiple sclerosis, to date, had to rely on animal models of the disease. He went on to highlight the two animal models that he had worked with; the first is the EAE Lewis rat in which the disease is inducible with myelin or myelin basic protein (MBP) in complete Freund’s adjuvant. He pointed out that the T cells and the pathogenesis of this disease were CD4+ T cells which were specific for MBP. In the mouse models that he has worked with, he reported that differences in haplotypes in mice lead to differences in the epitopes of the MBP autoantigen that they recognize so that, for example, the PL/J mice see the 1–11 amino acid sequence of the autoantigen, whereas the SJL/J mice see the 90–101 amino acid sequence. In contrast, the Lewis rat encephalytogenic T cell clones seemed to be seeing the amino acid sequence 68–88 of MBP. Using these T cell clones it was possible to show that they transferred disease.

Despite great progress in the diagnosis and therapy of multiple sclerosis (MS) some problems remain unsolved. For example, should immunologically negative cases also be classified as multiple sclerosis? In addition, we are still waiting for medication which will have a definite impact on the natural course of the disease.

Foamy macrophages containing abundant intracellular myelin remnants are an important pathological hallmark of multiple sclerosis. Reducing the intracellular lipid burden in foamy macrophages is considered a promising therapeutic strategy to induce a phagocyte phenotype that promotes central nervous system repair. Recent research from our group showed that sustained intracellular accumulation of myelin-derived lipids skews these phagocytes toward a disease-promoting and more inflammatory phenotype. Our data now demonstrate that disturbed lipophagy, a selective form of autophagy that helps with the degradation of lipid droplets, contributes to the induction of this phenotype. Stimulating autophagy using the natural disaccharide trehalose reduced the lipid load and inflammatory phenotype of myelin-laden macrophages. Importantly, trehalose was able to boost remyelination in the ex vivo brain slice model and the in vivo cuprizone-induced demyelination model. In summary, our results provide a molecular rationale for impaired metabolism of myelin-derived lipids in macrophages, and identify lipophagy induction as a promising treatment strategy to promote remyelination. Abbreviations: Baf: bafilomycin a1; BMDM: bone marrow-derived macrophage; CD68: CD68 antigen; CNS: central nervous system; LD: lipid droplet; LIPE/HSL: lipase, hormone sensitive; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MBP: myelin basic protein; MGLL: monoglyceride lipase; MS: multiple sclerosis; NO: nitric oxide; NOS2/iNOS: nitric oxide synthase 2, inducible; ORO: oil red o; PNPLA2: patatin-like phospholipase domain containing 2; PLIN2: perilipin 2; TEM: transmission electron microscopy; TFEB: transcription factor EB; TOH: trehalose.

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.

Cognitive impairment is a common aspect of multiple sclerosis (MS) for which there are no treatments. Reduced brain N-acetylaspartylglutamate (NAAG) levels are linked to impaired cognition in various neurological diseases, including MS. NAAG levels are regulated by glutamate carboxypeptidase II (GCPII), which hydrolyzes the neuropeptide to N-acetyl-aspartate and glutamate. GCPII activity is upregulated multifold in microglia following neuroinflammation. Although several GCPII inhibitors, such as 2-PMPA, elevate brain NAAG levels and restore cognitive function in preclinical studies when given at high systemic doses or via direct brain injection, none are clinically available due to poor bioavailability and limited brain penetration. Hydroxyl-dendrimers have been successfully used to selectively deliver drugs to activated glia. Methods: We attached 2-PMPA to hydroxyl polyamidoamine (PAMAM) dendrimers (D-2PMPA) using a click chemistry approach. Cy5-labelled-D-2PMPA was used to visualize selective glial uptake in vitro and in vivo. D-2PMPA was evaluated for anti-inflammatory effects in LPS-treated glial cultures. In experimental autoimmune encephalomyelitis (EAE)-immunized mice, D-2PMPA was dosed biweekly starting at disease onset and cognition was assessed using the Barnes maze, and GCPII activity was measured in CD11b+ hippocampal cells. Results: D-2PMPA showed preferential uptake into microglia and robust anti-inflammatory activity, including elevations in NAAG, TGFβ, and mGluR3 in glial cultures. D-2PMPA significantly improved cognition in EAE mice, even though physical severity was unaffected. GCPII activity increased >20-fold in CD11b+ cells from EAE mice, which was significantly mitigated by D-2PMPA treatment. Conclusions: Hydroxyl dendrimers facilitate targeted drug delivery to activated microglia. These data support further development of D-2PMPA to attenuate elevated microglial GCPII activity and treat cognitive impairment in MS.

The protein myelin oligodendrocyte glycoprotein (MOG) is a key component of myelin and an autoantigen in the disease multiple sclerosis (MS). Post‐translational N‐glycosylation of Asn31 of MOG seems to play a key role in modulating the immune response towards myelin. This is mediated by the interaction of Lewis‐type glycan structures in the N‐glycan of MOG with the DC‐SIGN receptor on dendritic cells (DCs). Here, we report the synthesis of an unnatural Lewis X (LeX)‐containing Fmoc‐SPPS‐compatible asparagine building block (SPPS=solid‐phase peptide synthesis), as well as asparagine building blocks containing two LeX‐derived oligosaccharides: LacNAc and Fucα1‐3GlcNAc. These building blocks were used for the glycosylation of the immunodominant portion of MOG (MOG31‐55) and analyzed with respect to their ability to bind to DC‐SIGN in different biological setups, as well as their ability to inhibit the citrullination‐induced aggregation of MOG31‐55. Finally, a cytokine secretion assay was carried out on human monocyte‐derived DCs, which showed the ability of the neoglycopeptide decorated with a single LeX to alter the balance of pro‐ and anti‐inflammatory cytokines, inducing a tolerogenic response., Immunomodulation. A novel asparagine solid‐phase peptide synthesis building block harboring a Lewis X type DC‐SIGN ligand has been synthesized (see scheme) and incorporated into the immunodominant portion of myelin oligodendrocyte glycoprotein (MOG31‐55). This glycopeptide was evaluated for its ability to inhibit citrullination‐induced aggregation of MOG35‐55, to bind to DC‐SIGN in vitro and for its immunomodulatory effects on human dendritic cells, with the Lewis X yielding a tolerogenic response.

Introduction Recent studies of lipids in multiple sclerosis derive from at least two lines of thought, which may perhaps eventually converge. One is the theory that a fault in lipid metabolism may be involved. Swank * is one of the proponents of this argument, and he has extended his theory into practice by advocating a low-fat diet. Other investigations on the serum lipids in multiple sclerosis, however, have agreed in finding little evidence for a quantitative abnormality in the cholesterol, phospholipids, or lipoproteins.† The second approach is based on the search for breakdown products of myelin in the spinal fluid. Myelin is a lipoprotein complex whose exact chemical analysis has not yet been accomplished. One possible way to find out how the myelin is destroyed would be to identify its breakdown products. This, then, would offer some indication as to location or type of bond which had been disrupted. The present