Relapsing-remitting Form Of Multiple Sclerosis Research Articles

Treatment of Multiple Sclerosis with Cladribine Tablets: Literature Review and the Guidance of the Lithuanian Association of Neurologists

Cladribine is a disease-modifying drug used for the treatment of the highly active relapsing-remitting form of multiple sclerosis. Cladribine is a purine nucleoside analogue which selectively targets lymphocyte subpopulations involved in the pathogenesis of multiple sclerosis, and therefore it is classified as an immune reconstitution therapy drug. Two short courses of cladribine tablets given over two years significantly reduce the multiple sclerosis relapse rate and disability progression. For most patients, the effect persists in the third and the fourth year. This makes cladribine convenient for patients with multiple comorbidities, difficulties in adhering to their prescribed treatment regimen, those planning a pregnancy, or those for whom long-term immunosuppression is undesirable. Cladribine tablets are denoted by good safety characteristics, with the most prominent adverse effect being lymphopenia, which does not lead to an increased risk of infections other than Herpes zoster.However, in clinical practice, there are a number of issues related both to the initial administration of cladribine tablets and the strategy of treatment in different clinical situations during the first-to-fourth years of treatment, and particularly after the fourth year. Although there are no contraindications for additional courses of cladribine tablets, the product information does not provide detailed guidance on their continued use. During more than five years after the approval of the medicinal product, the new clinical trial data and the Real-World Evidence (RWE) on the efficacy and safety of cladribine tablets have become available, based on which, several national and international expert panels, as well as the Lithuanian Association of Neurologists, have issued guidance on the use of cladribine tablets reviewed in this article. Upon reactivation of the disease, additional courses of cladribine tablets or other disease-modifying therapies may be prescribed, depending on various factors related to the severity of the relapse, patient characteristics, and previously used medications. If the patient’s condition remains stable after the fourth year, extension of the treatment-free period with the structured monitoring approach could be appropriate.

Explicit and implicit abilities in humor processing in patients with relapsing-remitting multiple sclerosis

ABSTRACT Sociocognitive impairment is well known in the relapsing-remitting form of multiple sclerosis (RR-MS). The purpose of the present study was to assess explicit and implicit humor abilities in this population. Based on clinical observation and contrary to the current cognitive model, we hypothesized that implicit performances (happy facial expressions) would be better than explicit ones (humor judgment assessed by explicit humor comprehension, subjective feeling of amusement as a conscious appreciation of funniness, and verbal justifications of funniness). Twenty-five RR-MS patients and twenty-five healthy participants completed the tasks. Their face was filmed during humor ratings. Patients’ results suggest that 32% of them showed an impairment in explicit humor comprehension, with normal facial expressions. Both groups found great difficulty in justifying the cause of their amusement. All these results may suggest the existence of a supplementary implicit pathway in humor processing. The preservation of this implicit pathway may be advantageous for future remediation. Contrary to the current model, we found that the subjective feeling of amusement was preserved when comprehension was impaired. Further studies will be needed to clarify this component, and adjust the theoretical modeling.

HUMORAL IMMUNITY IN PATIENTS WITH MULTIPLE SCLEROSIS

Introduction. More than 1 million people in the world suffer from multiple sclerosis (MS). The etiology of MS remains not fully understood. The main role in the pathogenesis of MS belongs to the combination of chronic inflammation and neurodegenerative processes, in the genesis of which autoimmune processes play a significant role. Progress in studying the mechanisms of the pathological process of demyelinating diseases has been achieved mainly thanks to immunological research. One of the manifestations of activation of humoral immunity in MS is increased synthesis of immunoglobulins in brain tissue and cerebrospinal fluid
 The aim of the study. To study the state of humoral immunity in multiple sclerosis patients with different types of disease course
 Research methods. 68 patients with a verified diagnosis of multiple sclerosis (MS) based on the MacDonald et al criteria aged 19 to 65 years (37 women, 29 men) were examined. The primary progressive type of the course was established in 19 patients, the secondary-progressive - in 3, the remitting-relapsing type of the course - in 26 patients. The control group consisted of 80 practically healthy male volunteers aged 25-45 years.
 The concentration of immunoglobulins A, G, M in blood serum was determined by the Mancini method (1965). The content of circulating immune complexes (CIC) in blood serum was determined by the method of precipitation in polyethylene glycol.
 Results and discussion. The highest content of Ig A was observed in the group of patients with primary progressive form of MS, which was 3.7 times higher than normal values and 1.2 times higher than in the general group of MS patients. In the group of patients with the secondary progressive form of MS, the content of Ig A was 3.1 times higher than in the control group and 1.2 times lower than in the group with the primary progressive form. In the group of patients with relapsing-remitting form of MS, there was an increase in the level of Ig A three times relative to the normal indicator, and a decrease (by 1.2 times) relative to the level in the group with a primary progressive form of MS.
 The content of Ig M in the blood serum of patients with MS exceeded the norm by 5 times. In the group with the primary progressive form of MS, the level of Ig M was 3.5 times higher than the level in the control group and 1.5 times lower than the level in the group of patients with MS. In patients with secondary progressive form of MS, the content of Ig M was 2.6 times higher than the norm, but 1.3 times lower than the level in the group with primary progressive form of MS and 1.9 times lower than in the group of patients with MS. In patients with the relapsing-remitting form of MS, the level of Ig M was: 4.6 times higher than the level in the control group and 1.7 times higher than the content in patients with the secondary-progressive form of MS, and also 1.3 times higher, than in the group with the primary progressive form.
 In all groups of patients with MS with different types of the course of the disease, the most pronounced increase in the level of Ig G was noted.
 The highest level of CIC was recorded in the general group of patients with MS and in the group with secondary progressive form of MS.
 Conclusions. An imbalance of the humoral link of immunity was observed in patients with multiple sclerosis. A probable increase in the concentration of Ig A in the blood serum of patients with multiple sclerosis indicates the presence of infection of the mucous membranes, which is especially pronounced in patients with the primary progressive form of multiple sclerosis. A significant increase in the content of Ig G in the blood serum of patients with multiple sclerosis indicates a chronic course of the process, which is especially evident in the relapsing-relapsing form of multiple sclerosis. An increased concentration of IgM in the blood serum of patients with multiple sclerosis may indicate an exacerbation of the course of chronic inflammation, especially in the case of relapsing-remitting multiple sclerosis. The detected fluctuations of the average content of CIC in the blood serum of patients with multiple sclerosis did not go beyond the physiological norm.

Why do we so rarely recognise and treat the primary progressive form of multiple sclerosis?

The primary progressive form of multiple sclerosis is characterised by a systematic increase in disability from the onset of the disease, usually without overlapping relapses. It is estimated that it accounts for 10–15% of all cases of multiple sclerosis, occurs with similar frequency in both sexes, and its symptoms appear at an older age, usually after 40. The initial manifestation usually consists of pyramidal symptoms and myelopathy. The most typical symptoms include progressive gait and sphincter function impairment. Symptoms of cerebellar syndrome, truncal syndromes, as well as visual and cognitive disturbances are less common. The clinical course with characteristic symptomatology resulting from the location of the changes primarily in the spinal cord, followed by the occurrence of initial symptoms, means that this form of multiple sclerosis requires careful differential diagnosis. It should be differentiated primarily from diseases causing lower limb paresis (myelopathy associated with vitamin B12 deficiency, amyotrophic lateral sclerosis, spinal cerebellar ataxia, neuromyelitis optica spectrum disorder, Wernicke’s encephalopathy, Lyme disease, and spinal cord tumours). The diagnosis of primary progressive multiple sclerosis should be guided by the current 2017 McDonald diagnostic criteria. Understanding these criteria and being aware of the differences from the most common relapsing-remitting form of multiple sclerosis can be helpful in speeding up the diagnosis and implementing effective treatment. Even though new treatment options have emerged in recent years, primary progressive multiple sclerosis is still little known and too rarely recognised.

Early use of high efficacy therapies in pediatric forms of relapsing-remitting multiple sclerosis: A real-life observational study.

Pediatric forms of multiple sclerosis are more active than those in adults. Yet, the effectiveness of different therapeutic approaches is not well studied in this population. Our objective was to compare the effectiveness of the early use of high efficacy therapies (HETs) with the effectiveness of moderate efficacy therapies (METs) in children with MS. This observational study included patients diagnosed with pediatric MS, at 4 hospital centers in France, during a 10-year period. METs included: interferon β-1a, glatiramer acetate, dimethyl fumarate, teriflunomide; HETs included: fingolimod, natalizumab, ocrelizumab, alemtuzumab. The primary endpoint was the occurrence of a new relapse, the secondary endpoint was EDSS worsening. Sixty-four patients were included in the analysis (80% women; mean age 15.5 years, 81% treated with MET) with a median follow-up of 22.5 months. At baseline, 52 patients were on MET (interferon β-1a, glatiramer acetate, dimethyl fumarate, teriflunomide) and 12 patients were on HET (natalizumab, ocrelizumab). The cumulative probability of being relapse-free at 6.5 years was 23.3% on MET, vs 90.9% on HET (p=0.013). The cumulative probability of no EDSS worsening did not differ between the 2 groups. Patients starting with METs had much higher clinical disease activity than those starting early with HETs. Rapid initiation of more aggressive treatment may allow better disease control; however, the data on EDSS worsening are not conclusive.

Cognitive impairment in multiple sclerosis: when to think about it?

Cognitive disorders are present in 30 to 45% of relapsing-remitting forms of multiple sclerosis and in up to 50-75% of progressive forms. They bear a negative impact on the quality of life and predict an unfavorable disease progression. According to guidelines, screening based on objective measurement such as the Single Digit Modality Test (SDMT) should be performed at the time of diagnosis and then on an annual basis. Confirmation of diagnosis and management are performed in collaboration with neuropsychologists. Increased awareness from patients and healthcare professionals is important to ensure earlier management and prevent negative consequences on the patients professional and family life.

Effectiveness of Anti-Cluster of Differentiation 20 as a Disease-Modifying Therapy in Multiple Sclerosis Across Its Different Phenotypes at the University Hospital of Caen.

BackgroundMultiple sclerosis is a chronic, demyelinating disorder occurring primarily as two main forms of relapsing-remitting multiple sclerosis (RRMS) found predominantly in women, and primary progressive multiple sclerosis (PPMS) occurring predominantly in men. In this retrospective single-center study, we aimed to explore the effects of anti-cluster of differentiation (CD)20 treatment for both relapsing-remitting and primary progressive forms of multiple sclerosis (MS) in a population-based cohort treated at the university hospital. MethodologyThe diagnostic factors being assessed were forms of multiple sclerosis (MS), age at first relapse, whereas therapeutic factors were age at first disease-modifying therapy (DMT), age at starting anti-CD20, reason to switch to anti-CD20 and the duration of anti-CD20 treatment. Primary outcomes measured were number of relapses and progression in disability as measured by the Expanded Disability Status Scale, while secondary outcomes measures being assessed number of cerebral lesions on MRI and level of IgG at the beginning and end of the 12-month treatment.ResultsTreatment with anti-CD20 demonstrated a reduction in number of relapses 12 months after treatment, no change in the progression of disability in RRMS type, but an increase in PPMS type. No change was observed in cerebral MRI lesions at the end of treatment after 12 months. A statistically significant reduction in serum IgG value was observed after 12 months from the start of treatment, where only one out of 26 (3.8%) patients developed hypogammaglobulinemia with IgG less than 6 g/L but none developed hypogammaglobulinemia of less than 5 g/L.ConclusionAnti-CD20 antibodies as disease-modifying therapy can profoundly impact the course and progression of MS in both its forms if utilized at an earlier stage in patients and therefore greatly improve the quality of life in patients living with multiple sclerosis.

Preclinical model of multiple sclerosis: Focal, chemical or viral demyelination.

Multiple Sclerosis (MS) is characterized by the presence of demyelinating lesions in the Central Nervous System (CNS). The demyelination is accompanied by axonal degeneration and the activation of cells of the innate and adaptive immune systems that accumulate around the demyelinated plaques. Oligodendrocyte cell dysfunction and death are also evident. In the relapsing-remitting form of MS, this dysfunction is followed by periods of recovery, and newly mature oligodendrocytes have the ability to remyelinate the pathological axons. To specifically study the localized demyelination/remyelination processes, animal models involving specific demyelinating toxins or viruses have been generated. Through these models the pathological effects on oligodendrocytes can be analyzed, and pharmacological treatments that can restore oligodendrocyte myelination capabilities can be assessed. Here we describe the most commonly used models of toxic or viral demyelination, and provide protocols to induce and analyze them.

The Effects of PDE Inhibitors on Multiple Sclerosis: a Review of in vitro and in vivo Models.

Multiple sclerosis (MS) is a chronic inflammatory and immune-mediated disease, whose current therapeutic means are mostly effective in the relapsing-remitting form of MS, where inflammation is still prominent, but fall short of preventing long term impairment. However, apart from inflammationmediated demyelination, autoimmune mechanisms play a major role in MS pathophysiology, constituting a promising pharmacological target. Phosphodiesterase (PDE) inhibitors have been approved for clinical use in psoriasis and have undergone trials suggesting their neuroprotective effects, rendering them eligible as an option for accessory MS therapy. In this review, we discuss the potential role of PDE inhibitors as a complementary MS therapy. We conducted a literature search through which we screened and comparatively assessed papers on the effects of PDE inhibitor use, both in vitro and in animal models of MS, taking into account a number of inclusion and exclusion criteria. In vitro studies indicated that PDE inhibitors promote remyelination and axonal sustenance, while curbing inflammatory cell infiltration, hindering oligodendrocyte and neuronal loss and suppressing cytokine production. In vivo studies underlined that these agents alleviate symptoms and reduce disease scores in MS animal models. PDE inhibitors proved to be effective in addressing various aspects of MS pathogenesis both in vitro and in vivo models. Given the latest clinical trials proving that the PDE4 inhibitor Ibudilast exerts neuroprotective effects in patients with progressive MS, research on this field should be intensified and selective PDE4 inhibitors with enhanced safety features should be seriously considered as prospective complementary MS therapy.

Extracellular Vesicles as Pro- and Anti-inflammatory Mediators, Biomarkers and Potential Therapeutic Agents in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease of the central nervous system (CNS) characterized by multiple demyelinating lesions in the spinal cord and brain. Neuronal disruption caused by myelin loss or demyelination, which may accompany axonal changes, leads to multiple neurological symptoms. They may transiently appear for weeks during periods of disease worsening (relapse) in relapsing-remitting form of MS (RRMS). Although a number of genetic, metabolic and environmental factors influencing the development of MS have been identified, the precise mechanisms involved in the CNS tissue damage in MS are still poorly understood. Recent studies have revealed a significant role of circulating extracellular vesicles (EVs) in many diseases. EVs are known to serve as a cellular communication tool between two cell types either in close proximity or in different parts of the body. During the recent development in understanding of the pathogenesis of MS, studies have revealed the possible role of EVs in MS. Furthermore, circulating EVs can be used as a biomarker for monitoring disease progression and activity of MS, and they can also be therapeutic reagents or targets of therapy. In this review we overview and discuss in detail about generation of EVs and their diversified roles in MS.

Assessment of fatigue, cognition and depression in correlation with the applied immunomodulating treatment based on the Lodz registry of patients with multiple sclerosis

Introduction: Multiple sclerosis is the most common chronic inflammatory demyelinating disease of the central nervous system, mainly affecting young people. A breakthrough in the treatment of multiple sclerosis was the introduction of immunomodulating drugs that affect the natural course of the disease as well as improve the quality of life of patients. Aim of the study: To establish a possible association between the level of cognitive disorders, fatigue, depression and the used immunomodulating treatment (disease-modifying treatment) in patients with the relapsing-remitting form of multiple sclerosis. Materials and methods: The research material consisted of 169 patients with multiple sclerosis (diagnosed according to the 2010 McDonald criteria) with the relapsing-remitting form of multiple sclerosis. The subjects were divided into two groups: the test group – receiving disease-modifying treatment (n = 132), undergoing immunomodulatory therapy, and the control group – untreated multiple sclerosis (n = 37), patients who did not receive immunomodulating therapy. Methods: multiple sclerosis patient registry – RejSM questionnaire; Beck Depression Inventory II (BD-II); postural function assessment – MMSE (Mini-Mental State Examination); FACIT quality of life (Functional Assessment of Chronic Illness Therapy – Fatigue; FACIT Fatigue Scale, FFS). Patients from both groups underwent tests (BD-II, MMSE, FFS) at two time points: at baseline (I) and after 12 months of immunomodulating treatment (II). Results: The post-hoc test (Tukey’s) showed a decrease in Beck Depression Inventory and FACIT-F scores which was statistically significant only in the disease-modifying treatment group. The results indicate that the use of interferon beta causes a significant reduction in depression (p < 0.0001) and fatigue (p < 0.0001) between the measured time points. The FACIT scores were significantly different between the time points for those treated with glatiramer acetate (p < 0.0001). In the case of MMSE evaluation, the patients receiving disease-modifying treatment did not differ significantly between the beginning and end of the study (p = 0.1210). Conclusions: The results of our research indicate that disease-modifying treatment used in patients with the relapsing-remitting form of multiple sclerosis has a beneficial effect in terms of improving their quality of life and reducing the symptoms of depression.

Homonymous visual field defects in patients with multiple sclerosis: results of computerised perimetry and optical coherence tomography.

Visual dysfunction is frequent in multiple sclerosis, usually resulting from retrobulbar optic neuritis or papillitis. Less frequently, demyelinating lesions can affect the retrochiasmal pathways. There are few reports of homonymous visual field defects (HVFD) in multiple sclerosis and little is known about their evolution. The purpose of this study was to better define both the clinical profile and the evolution of HVFD in patients with multiple sclerosis. We performed a retrospective study of all multiple sclerosis patients who presented HVFD and were examined by automated static perimetry. A subset of patients benefited from macular assessment with optical coherence tomography (OCT). We also reviewed the worldwide literature on the subject. Twenty patients were retrieved from the neuro-ophthalmology database of the Hôpital Ophtalmique Jules-Gonin. There were 11 women and 9 men, and their average age was 35 ± 11 years. The relapsing-remitting form of multiple sclerosis was most common (18/20; 90%), the primary progressive form (1/20; 5%) and the secondary progressive form (1/20; 5%) were rare. HVFD were the presenting symptom of multiple sclerosis in seven patients (35%). The recovery was complete in 12/20 patients (60%), and the median time to recovery was 10 weeks (2-13 weeks). An incomplete recovery was found in 5/20 subjects (25%) and no recovery occurred in 3/20 subjects (15%). Magnetic resonance imaging disclosed a definite lesion explaining the HVFD in 7/11 patients: five within the optic radiations (71.4%), one within the optic tract (14.3%) and one within the lateral geniculate nucleus (14.3%). Our results were comparable to those compiled from our literature search (29 publications, totalling 70 cases). A recurrent episode of HVFD occurred in three patients (15%). OCT was performed in 10/20 patients. Retinal ganglion cell layer thickness was assessed and revealed a homonymous thinning in three patients, diffuse unilateral or bilateral thinning (resulting from previous episodes of optic neuritis) in six patients, and normal retinal ganglion cell layer thickness in one patient. HVFD in multiple sclerosis are found mostly in young patients with relapsing-remitting multiple sclerosis, which is consistent with the epidemiology of multiple sclerosis. HVFD can be the first manifestation of multiple sclerosis and have a relatively good prognosis. Like optic neuritis, HVFD can recur. The incidence of HVFD in multiple sclerosis is unknown, as it is probably underdiagnosed. Systematic automated static perimetry and OCT could help to determine the true incidence of HVFD in multiple sclerosis. &nbsp.

Attitudes of patients with relapsing-remitting form of multiple sclerosis using disease-modifying drugs in Montenegro regarding COVID-19 pandemic

BackgroundIn the days of the reorganization of healthcare systems due to SARS-Cov2 pandemic, patients suffering from chronic diseases are being often neglected. The aim of our study was to examine the attitudes and behaviors of patient suffering from relapsing-remitting form of multiple sclerosis using disease-modifying drugs in Montenegro in relation to the current pandemic. MethodsThe research was conducted through an online-generated questionnaire during the peak of the pandemic. ResultsThere is a high level of concern about COVID-19 (3.22±1.23), especially about safety behavior intensification (3.80±1.29). Possibility of relapse during pandemic was considered as moderate (2.06±1.42), but relapse symptoms would be reported by the majority of subjects (1.55±1.23). Our unemployed patients statistically more often reported that they had more frequent mood changes, but also that they felt more energy loss. Surprisingly, there was no difference among the subjects according to smoking status. According therapy groups there was significant difference between the groups regarding some variables: patients using ocrelizumab are most concerned about COVID-19; patients using interferon beta 1a i.m. statistically more often have frequent changes in their mood, memory problems, poor appetite, feeling of nausea or upset stomach and patients on fingolimod have bigger afraid of coming to regular visits. ConclusionOur patients showed concern about their disease future status in the current epidemic era, but also showed a high degree of trust in physicians and the overall health system.

Monomethyl fumarate has better gastrointestinal tolerability profile compared with dimethyl fumarate

BackgroundMonomethyl fumarate (MMF) is the pharmacologically active metabolite of dimethyl fumarate (DMF). MMF formulated as Bafiertam™ 190 mg and DMF formulated as Tecfidera 240 mg deliver bioequivalent exposure of MMF and therefore possess the same efficacy/safety profiles. DMF is a widely used oral treatment for relapsing-remitting forms of multiple sclerosis (RRMS) but is limited in some patients, primarily female, by issues with gastrointestinal (GI) tolerability. MethodsThis was a randomized, double-blind, head-to-head, 5-week study evaluating the GI tolerability of MMF 190 mg vs DMF 240 mg, administered twice daily in healthy subjects, using a derivative of the self-administered Modified Overall Gastrointestinal Symptom Scale (MOGISS). Subjects were stratified (3:1, female:male) and randomized (1:1) to the treatments. The primary endpoint was the Area Under the Curve (AUC) in each of the individual symptoms in the MOGISS over the 5-week treatment period. Other endpoints included the AUC over the 5-week treatment period in the MOGISS composite and total scores; duration and severity of GI events; Number and percentage of subjects reporting GI events during the overall treatment period, and assessment of safety/tolerability. ResultsInferential analysis of the hierarchical testing of overall treatment differences in each MOGISS symptom AUC occurred in a predefined sequence starting with Abdominal Pain. For each symptom, LSMean AUC values were lower for MMF than DMF, however, the first primary endpoint, Abdominal Pain, was not statistically different between treatments; thus, all subsequent statistical analyses were considered exploratory. The side effects and safety profiles observed were consistent with the known profiles of DMF, with no new or unique safety concerns noted. ConclusionsBafiertam showed an improved gastrointestinal tolerability profile compared with Tecfidera, with less severe GI events and fewer days of self-assessed GI symptoms, fewer GI adverse events, and lower discontinuation rates because of GI adverse events.

Why patients with multiple sclerosis perceive improvement of gait during treatment with natalizumab?

Gait impairment is one of the common manifestations of multiple sclerosis (MS) and contributes to a loss of quality of life. Natalizumab, an anti-α4 integrin monoclonal antibody, has been shown to have an effect in treatment of MS, reducing relapses and inflammatory lesions. Aim of our study was to assess how patients perceive gait impairment over the first year of treatment with natalizumab and what is the objective correlate of this change. This is an open-label prospective observational study. Subjective gait evaluation was measured by Multiple Sclerosis Walking Scale-12 (MSWS-12). Objective gait assessment included Timed 25-Foot Walk Test (T25FW) and spatiotemporal parameters of gait measured by a GAITRite instrument during a self-selected speed of walking (normal walk) and a fast speed of walking (fast walk). We analysed data of 50 patients with a relapsing-remitting form of MS, median EDSS 3.5 (range 1.5-5). MSWS-12 score significantly decreased between the baseline and month 12 of treatment (p < 0.001). Walking velocity and step length were significantly improved in Normal walk tests (p < 0.001). During the Fast walk tests, a step length and a double support time of the gait cycle were significantly improved (p = 0.001). Change in MSWS-12 score confirmed the clinically significant improvement of gait in patients with MS treated with natalizumab for 1 year. The analysis of spatiotemporal gait parameters has shown a significant improvement in self-selected gait velocity and step length.

Multiplexed Gene Expression as a Characterization of Bioactivity for Interferon Beta (IFN-β) Biosimilar Candidates: Impact of Innate Immune Response Modulating Impurities (IIRMIs).

Recombinant human interferon-β (rhIFN-β) therapy is the first-line treatment in relapsing-remitting forms of multiple sclerosis (MS). The mechanism of action underlying its therapeutic activity is only partially understood as IFN-βs induce the expression of over 1000 genes modifying multiple immune pathways. Currently, assessment of potency for IFN-β products is based on their antiviral effect, which is not linked to its therapeutic effect. Here, we explore the use of a multiplexed gene expression system to more broadly characterize IFN-β bioactivity. We find that MM6 cells stimulated with US-licensed rhIFN-βs induce a dose-dependent and reproducible pattern of gene expression. This pattern of gene expression was used to compare the bioactivity profile of biosimilar candidates with the corresponding US-licensed rhIFN-β products, Rebif and Betaseron. While the biosimilar candidate for Rebif matched the pattern of gene expression, there were differences in the expression of a subset of interferon-inducible genes including CXCL-10, CXCL-11, and GBP1 induced by the biosimilar candidate for Betaseron. Assessment of product impurities in both products suggested that the difference was rooted in the presence of innate immune response modulating impurities (IIRMIs) in the licensed product. These studies indicate that determining the expression levels for an array of reporter genes that monitor different pathways can be informative as part of the demonstration of biosimilarity or comparability for complex immunomodulatory products such as IFN-β, but the sensitivity of each gene to potential impurities in the product should be examined to fully understand the results.

Differentiation of Cognitive Deficit Profiles in Multiple Sclerosis Patients: Latent Profile Analysis

Objective: The purpose of this study was to ascertain whether the application of the Audio Recorded Cognitive Screen (ARCS) in cognitive functioning screening of persons with multiple sclerosis (MS) differentiates profiles of existing cognitive deficits (CDs) and whether this instrument can discriminate accurately between subjects who are cognitively intact (CI) and those with a cognitive disorder. Subjects and Methods: The research was conducted on a sample of 359 subjects, with two subsets of participants: 108 persons with a relapsing-remitting form of MS and 251 persons from the general population. Results: We labeled the three profiles obtained by applying the ARCS questionnaire: the CI profile, the profile of CI with visuospatial difficulties, and the profile of persons with CD. Conclusion: ARCS has the ability to differentiate persons with a CD from those without, both in a sample of persons suffering from MS and in a sample of persons from the general population. This finding indicates that this instrument is well suited for profiling the cognitive status into specific categories, which puts it among the instruments with a wide range of implementation.

Variants of Mitochondrial Genome and Risk of Multiple Sclerosis Development in Russians

For the first time in the history of ethnic Russians, an association analysis the development of multiple sclerosis (MS) was performed for the mitochondrial haplogroups H, J, K, and U, as well as for the individual mitochondrial DNA (mtDNA) polymorphisms discriminating these haplogroups (m.1719G > A, m. 7028C > T, m.9055G > A, m.10398A > G, m.12308A > G). A total of 283 unrelated patients with the relapsing-remitting form of MS and 290 healthy controls were enrolled in the study. Association of haplogroup J with MS was observed (P = 0.0055, OR = 2.00 [95% CI 1.21-3.41]). After gender stratification, the association remained significant in women (P = 0.0083, OR = 2.20 [95% CI 1.19-4.03]). A multilocus analysis of the association between combinations of mtDNA haplogroups with variants of 38 nuclear immune-related genes and MS risk was carried out. MS-associated biallelic combinations of haplogroup J with the alleles CCL5 rs2107538*A, PVT1 rs2114358*G, TNFSF14 rs1077667*C, and IL4 rs2243250*C, which were not associated with MS individually, were identified. For the combination of haplogroup J and the CCL5*A allele (P = 0.00043, OR = 5.47 [95% CI 1.85-16.15]), a epistatic (synergistic) interaction between the components was established using two statistical criteria: the PFLINT value in the Fisher-like interaction numeric test and the synergy factor, SF (PFLINT = 0.025, SF = 4.32 [95% CI 1.20-15.60]). The combination of haplogroup J and the PVT1*G allele is characterized by PFLINT = 0.084; SF = 3.05 [95% CI 1.00-9.31] and can also be epistatic. Thus, interaction between nuclear and mitochondrial genome components in the risk of developing MS was demonstrated for the first time.

Cholesterol level correlate with disability score in patients with relapsing-remitting form of multiple sclerosis

BackgroundMultiple sclerosis (MS) is an autoimmune disease characterised by demyelination. There are many environmental factors that can affect the progression of this disease. It is necessary to better understand the impact of these factors in MS pathogenesis and progression. ObjectivePresent study investigates the relationship of total cholesterol serum levels and other parameters contributing to cardiovascular risk - homocysteine and serum lipid parameters (triglycerides, HDL, LDL) - with the progression of MS (EDSS score). MethodsThe study involved 169 patients diagnosed with MS. Total homocysteine levels were measured by high-performance liquid chromatography. Serum lipid parameters were measured with enzymatic kits. ResultsThere was no difference observed between homocysteine levels in MS patients and controls. Dyslipidaemia seems to be associated with MS progression, particularly in women with relapsing-remitting form of MS. ConclusionPositive correlation of total and LDL cholesterol with disability score in patients with relapsing-remitting form of MS suggests that lipid parameters could have a negative effect on the disease progression.

Glatiramer Acetate Enhances Myeloid-Derived Suppressor Cell Function via Recognition of Paired Ig-like Receptor B.

Glatiramer acetate (GA; Copaxone) is a copolymer therapeutic that is approved by the Food and Drug Administration for the relapsing-remitting form of multiple sclerosis. Despite an unclear mechanism of action, studies have shown that GA promotes protective Th2 immunity and stimulates release of cytokines that suppress autoimmunity. In this study, we demonstrate that GA interacts with murine paired Ig-like receptor B (PIR-B) on myeloid-derived suppressor cells and suppresses the STAT1/NF-κB pathways while promoting IL-10/TGF-β cytokine release. In inflammatory bowel disease models, GA enhanced myeloid-derived suppressor cell-dependent CD4+ regulatory T cell generation while reducing proinflammatory cytokine secretion. Human monocyte-derived macrophages responded to GA by reducing TNF-α production and promoting CD163 expression typical of alternative maturation despite the presence of GM-CSF. Furthermore, GA competitively interacts with leukocyte Ig-like receptors B (LILRBs), the human orthologs of PIR-B. Because GA limited proinflammatory activation of myeloid cells, therapeutics that target LILRBs represent novel treatment modalities for autoimmune indications.