RRMS Patients Research Articles

Substantial and comparable suppression of disease activity following early initiation of cladribine tablets, ocrelizumab or alemtuzumab as first pharmacologic treatment for relapsing multiple sclerosis: A real world study

BackgroundWe describe the efficacy and safety of recent high efficacy disease DMTs in DMT-naive patients with highly active RMS. MethodsThis was a retrospective, cross sectional study from the Kuwait national MS registry. Patients with RMS who received alemtuzumab, cladribine tablets or ocrelizumab as their first DMT for RMS, with ≥2 year of follow up were included. The primary endpoint was the change in relapse rate from treatment initiation to 1 year; changes in disability (Expanded Disability Status Scale [EDSS]), radiologic activity, the proportion with no evidence of disease activity-3 (NEDA-3), and the frequency of adverse events were secondary endpoints. ResultsAmong 123 RRMS patients, 59 received ocrelizumab, 32 received cladribine tablets and 32 received alemtuzumab. About two-thirds (65%) were women. Substantial and similar (p>0.05) reductions occurred at the end of follow-up in annual relapse rate (by 93.2% for ocrelizumab, 87.5% for cladribine tablets, and 90.6% for alemtuzumab). The proportion with new T2 of gadolinium-enhancing MRI lesions across the three groups was reduced from 85–100% to 7–13%. Rates of confirmed disability progression were low (ocrelizumab 6.9%, cladribine tablets 3.1%, alemtuzumab 0%; p=0.280); disability was reduced in 15%, 22% and 38%, respectively. NEDA-3 was observed in 89.8%, 87.5%, and 84.4, respectively (p=0.784). No new or unexpected safety issues occurred. ConclusionOcrelizumab, cladribine tablets and alemtuzumab reduced relapse rates and MRI activity, and prevented disease progression, when are initiated early in DMT-naive RMS patients. These data support the early use of high-efficacy DMTs for people with highly active RMS.

Relapsing-remitting multiple sclerosis patients exhibit differential natural killer functional subpopulations.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) and has been known as T-cell mediated. However, the contribution of multiple cell types, notably natural killer (NK) cells, has also been reported. To quantify circulating total NK cells and its subpopulations, CD56 dim and bright, and to characterize the functional phenotype and IFN-γ and TNF-α production in relapsing-remitting patients treated with IFN-β and in apparently healthy controls. CD56bright NK cells were found to be the least represented subpopulation. In relapse patients, the frequencies of IFN-γ-producing NK cells and their subpopulations were significantly decreased. In remission patients, CD56dim NK cells expressed high levels of HLA-DR and CD54. These results suggest that remission RRMS patients, although in an inactive stage of MS, present circulating NK cells with an activation phenotype, supporting the idea that NK cells may be relevant mediators in the MS pathophysiology.

Plasma Lipidomic Profiling Using Mass Spectrometry for Multiple Sclerosis Diagnosis and Disease Activity Stratification (LipidMS).

This investigation explores the potential of plasma lipidomic signatures for aiding in the diagnosis of Multiple Sclerosis (MS) and evaluating the clinical course and disease activity of diseased patients. Plasma samples from 60 patients with MS (PwMS) were clinically stratified to either a relapsing-remitting (RRMS) or a chronic progressive MS course and 60 age-matched controls were analyzed using state-of-the-art direct infusion quantitative shotgun lipidomics. To account for potential confounders, data were filtered for age and BMI correlations. The statistical analysis employed supervised and unsupervised multivariate data analysis techniques, including a principal component analysis (PCA), a partial least squares discriminant analysis (oPLS-DA) and a random forest (RF). To determine whether the significant absolute differences in the lipid subspecies have a relevant effect on the overall composition of the respective lipid classes, we introduce a class composition visualization (CCV). We identified 670 lipids across 16 classes. PwMS showed a significant increase in diacylglycerols (DAG), with DAG 16:0;0_18:1;0 being proven to be the lipid with the highest predictive ability for MS as determined by RF. The alterations in the phosphatidylethanolamines (PE) were mainly linked to RRMS while the alterations in the ether-bound PEs (PE O-) were found in chronic progressive MS. The amount of CE species was reduced in the CPMS cohort whereas TAG species were reduced in the RRMS patients, both lipid classes being relevant in lipid storage. Combining the above mentioned data analyses, distinct lipidomic signatures were isolated and shown to be correlated with clinical phenotypes. Our study suggests that specific plasma lipid profiles are not merely associated with the diagnosis of MS but instead point toward distinct clinical features in the individual patient paving the way for personalized therapy and an enhanced understanding of MS pathology.

Quantiferon Monitor Testing Sheds Light on Immune System Disparities between Multiple Sclerosis Patients and Healthy Individuals.

The aim of this study was to conduct QuantiFERON Monitor (QFM) testing in patients with multiple sclerosis (MS), which is used to monitor the state of the immune system through the non-specific stimulation of leukocytes followed by determining the level of interferon-gamma (IFN-γ) released from activated cells. Additionally, we tested the level of selected cytokines (IFN-α, IFN-γ, IL-1α, IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-6, IL-7, IL-10, IL-15, IL-33, VEGF) from stimulated blood samples to further understand the immune response. This study builds upon a previously published study, utilizing activated serum samples that were initially used for IFN-γ determination. However, our current focus shifts from IFN-γ to exploring other cytokines that could provide further insights into the immune response. A screening was conducted using Luminex technology, which yielded promising results. These results were then further elaborated upon using ELISA to provide a more detailed understanding of the cytokine profiles involved. This study, conducted from August 2019 to June 2023, included 280 participants: 98 RRMS patients treated with fingolimod (fMS), 96 untreated patients with progressive MS (pMS), and 86 healthy controls (HC). Our results include Violin plots showing elevated IL-1α in pMS and fMS. Statistical analysis indicated significant differences in the interleukin levels between groups, with IL-1ra and age as key predictors in differentiating HC from pMS and IL-1ra, IL-1α, age, and EDSS in distinguishing pMS from fMS. These findings suggest cytokines' potential as biomarkers in MS progression and treatment response.

High temperature requirement A1 and macrophage migration inhibitory factor in the cerebrospinal fluid; a potential marker of conversion from relapsing-remitting to secondary progressive multiple sclerosis

BackgroundPredictive and prognostic biomarkers for multiple sclerosis (MS) remain a significant gap in MS diagnosis and treatment monitoring. Currently, there are no timely markers to diagnose the transition to secondary progressive MS (SPMS). ObjectiveThis study aims to evaluate the discriminatory potential of the High temperature requirement serine protease (HTRA1)/Macrophage migration inhibitory factor (MIF) cerebrospinal fluid (CSF) ratio in distinguishing relapsing-remitting (RRMS) patients from SPMS patients. MethodsThe MIF and HTRA1 CSF levels were determined using ELISA in healthy controls (n = 23), RRMS patients before (n = 22) and after 1 year of dimethyl fumarate treatment (n = 11), as well as in SPMS patients before (n = 11) and after 2 years of mitoxantrone treatment (n = 7). The ability of the HTRA1/MIF ratio to discriminate the different groups was determined using receiver operating curve (ROC) analyses. ResultsThe ratio was significantly increased in treatment naïve RRMS patients while decreased again in SPMS patients at baseline. Systemic administrated disease modifying treatment (DMT) only significantly affected the ratio in RRMS patients. ROC analysis demonstrated that the ratio could discriminate treatment naïve RRMS patients from SPMS patients with 91% sensitivity and 100% specificity. ConclusionThe HTRA1/MIF ratio is a strong candidate as a MS biomarker for SPMS conversion.

The Use of Nitrosative Stress Molecules as Potential Diagnostic Biomarkers in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) of still unclear etiology. In recent years, the search for biomarkers facilitating its diagnosis, prognosis, therapy response, and other parameters has gained increasing attention. In this regard, in a previous meta-analysis comprising 22 studies, we found that MS is associated with higher nitrite/nitrate (NOx) levels in the cerebrospinal fluid (CSF) compared to patients with non-inflammatory other neurological diseases (NIOND). However, many of the included studies did not distinguish between the different clinical subtypes of MS, included pre-treated patients, and inclusion criteria varied. As a follow-up to our meta-analysis, we therefore aimed to analyze the serum and CSF NOx levels in clinically well-defined cohorts of treatment-naïve MS patients compared to patients with somatic symptom disorder. To this end, we analyzed the serum and CSF levels of NOx in 117 patients (71 relapsing-remitting (RR) MS, 16 primary progressive (PP) MS, and 30 somatic symptom disorder). We found that RRMS and PPMS patients had higher serum NOx levels compared to somatic symptom disorder patients. This difference remained significant in the subgroup of MRZ-negative RRMS patients. In conclusion, the measurement of NOx in the serum might indeed be a valuable tool in supporting MS diagnosis.

Differentiating multiple sclerosis from cerebral small vessel disease using diffusion tensor imaging and magnetic resonance spectroscopy on normally appearing thalami

BackgroundDiffusion tensor imaging (DTI) and magnetic resonance spectroscopy (1H-MRS) can detect the microstructural changes in normal-appearing conventional MRI. So, they may differentiate between multiple sclerosis (MS) cases and cerebral small vessel disease (CSVD). This work aimed to investigate if MRS and DTI are helpful in differentiating between MS and CSVD cases. MethodsThe study was conducted on 90 subjects divided into three groups: 30 relapsing–remitting MS patients, 30 patients with MRI showing CSVD, and 30 healthy controls. Diffusion tensor imaging measuring thalamic FA, ADC values, and 1H-MRS were conducted on patients and controls. ResultsThalamic FA values were significantly higher in the RRMS group than in the control and CSVD groups (P < 0.001, for each) but significantly lower in the CSVD group than the control group (P < 0.001). Moreover, thalamic ADC values were significantly higher in the CSVD group than in the control and MS groups (P < 0.001, for each). Also, thalamic NAA values were significantly lower in RRMS and CSVD groups than in controls (P < 0.001 for each). Still, they were significantly lower in the RRMS group than the CSVD group only on the left side (P = 0.004). The thalamic NAA/Cr values were significantly lower in RRMS (P < 0.001 for both sides) and CVSD than in controls (P = 0.044 and 0.036, for RT and LT sides, respectively). ConclusionsThalamic DTI and 1H-MRS can help detect the microstructural changes in normal-appearing thalami in RRMS and CSVD patients. Moreover, they can help differentiate MS from CSVD patients.

Alterations in the innate and adaptive immune system in a real-world cohort of multiple sclerosis patients treated with ocrelizumab

B cell depletion by the anti-CD20 antibody ocrelizumab is effective in relapsing-remitting (RR) and primary progressive (PP) multiple sclerosis (MS). We investigated immunological changes in peripheral blood of a real-world MS cohort after 6 and 12 months of ocrelizumab.All RRMS and most PPMS patients (15/20) showed treatment response. Ocrelizumab not only reduced CD20+ B cells, but also numbers of CD20+ T cells. Absolute numbers of monocytes, dendritic cells and CD8+ T cells were increased, while CD56hi natural killer cells were reduced after ocrelizumab. The residual B cell population shifted towards transitional and activated, IgA+ switched memory B cells, double negative B cells, and antibody-secreting cells. Delaying the treatment interval by 2–3 months increased mean B cell frequencies and enhanced naive B cell repopulation. Ocrelizumab reduced plasma levels of interleukin(IL)-12p70 and interferon(IFN)-α2.These findings will contribute to understanding ineffective treatment responses, dealing with life-threatening infections and further unravelling MS pathogenesis.

Serum NOXs and Iron Metabolism Biomarkers in RRMS Patients

Serum NOXs and Iron Metabolism Biomarkers in RRMS Patients

Late-onset multiple sclerosis: disability trajectories in relapsing-remitting patients of the Italian MS Registry.

Generally infrequent, multiple sclerosis (MS) with late onset (LOMS) is characterized by an onset over the age of 50 and a mainly progressive course, while relapsing-remitting (RR) forms are less frequently observed and explored. This study aimed to characterize a large cohort of MS patients with RRMS at onset to assess the baseline factors related to the worst disability trajectories and explore the role of LOMS. The data were extracted from the Italian MS Register (IMSR). Disability trajectories, defined using at least two and up to twenty expanded disability status scale (EDSS) assessments annually performed, were implemented using group-based trajectory models (GBTMs) to identify different groups with the same trajectories over time. MS profiles were explored using multinomial logistic regression. A total of 16,159 RR patients [1012 (6.26%) presented with LOMS] were analyzed. The GBTM identified four disability trajectories. The group with the most severe EDSS trend included 12.3% of the patients with a mean EDSS score > 4, which increased over time and exceeded 6 score. The group with medium severity EDSS trend comprised 21.9% of the patients and showed a change in EDSS > 3 scores over time. The largest group with 50.8% of patients reported a constant EDSS of 2 score. Finally, the benign group comprised 14.9% of the patients with a low and constant EDSS of 1 score over time. The probability of being in the worst groups increased if the patient was male; had LOMS or experienced brainstem, spinal, or supratentorial symptoms. Four MS severity profiles among RRMS patients in the IMSR have been reported, with LOMS being associated with a rapid worsening of EDSS scores. These findings have important implications for recognizing and managing how older age, aging, and age-related factors interact with MS and its evolution.

Comparative Assessment of Simoa and Lumipulse for Measuring Serum Neurofilament Light Chain in Multiple Sclerosis Patients

Background: The assessment of serum neurofilament light chain (sNfL) is increasingly significant in the field of neurology. In multiple sclerosis (MS), it proves valuable as a marker for monitoring disease activity and treatment response.Objective: To compare the Simoa and Lumipulse platforms for measuring sNfL and to establish age‐specific reference ranges within a substantial cohort of individuals diagnosed with MS.Methods: Two hundred sixty‐one sNfL measurements from a cohort of 229 MS patients were analyzed with Simoa and Lumipulse. Reference ranges for sNfL were established for three age groups (18–39 years, 40–59 years, and &gt; 60 years) selecting data from 166 patients with stable relapsing–remitting MS.Results: While sNfL levels correlated between assays, Lumipulse exhibited values higher than Simoa. Passing–Bablok’s analysis confirmed linearity between the two datasets, and the Bland–Altman comparison further supported the agreement between the methods. Analyzing reference ranges for sNfL across three age groups in stable RRMS patients revealed significant differences between the groups on each of the platforms. Although the values followed the same trend, each technology utilized distinct reference ranges.Conclusion: Simoa and Lumipulse platforms proved equally effective in monitoring patients with MS. The enhanced accessibility of the Lumipulse platform facilitates the expansion of research on sNfL as a biomarker for monitoring MS, thus offering promising opportunities for broader accessibility and advancement in this field.

Evaluation of drivers of treatment switch in relapsing multiple sclerosis: a study from the Italian MS Registry.

Active relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) are currently defined as "relapsing MS" (RMS). The aim of this cross-sectional study was to assess drivers of treatment switches due to clinical relapses in a population of RMS patients collected in the Italian MS and Related Disorders Register (I-MS&RD). RRMS and SPMS patients with at least one relapse in a time window of 2years before of data extraction were defined as RMS. Factors associated with disease-modifying therapy (DMT) switching due to clinical activity were assessed through multivariable logistic regression models in which treatment exposure was included as the last recorded DMT and the last DMT's class [moderate-efficacy (ME), high-efficacy (HE) DMTs and anti-CD20 drugs]. A cohort of 4739 RMS patients (4161 RRMS, 578 SPMS) was extracted from the I-MS&RD. A total of 2694 patients switching DMTs due to relapses were identified. Switchers were significantly (p < 0.0001) younger, less disabled, more frequently affected by an RR disease course in comparison to non-switcher patients. The multivariable logistic regression models showed that Alemtuzumab (OR 0.08, 95% CI 0.02-0.37), Natalizumab (0.48, 0.30-0.76), Ocrelizumab (0.1, 0.02-0.45) and Rituximab (0.23, 0.06-0.82) exposure was a protective factor against treatment switch due to relapses. Moreover, the use of HE DMTs (0.43, 0.31-0.59), especially anti-CD20 drugs (0.14, 0.05-0.37), resulted to be a protective factor against treatment switch due to relapses in comparison with ME DMTs. More than 50% of RMS switched therapy due to disease activity. HE DMTs, especially anti-CD20 drugs, significantly reduce the risk of treatment switch.

Impulsivity and attention deficit-hyperactivity symptoms among patients with relapsing-remitting multiple sclerosis: a case-control study

ABSTRACT Background and objectives Multiple sclerosis(MS) is a progressive, autoimmune, neurodegenerative disease.Studies have suggested that autoimmune diseases play a role in the pathogenesis of Attention deficit and hyperactivity disorder(ADHD).We aim to evaluate ADHD symptoms among patients with RRMS(pwRRMS). Methods The study included 48 RRMS patients and 54 healthy controls. ADHD symptoms were assessed by self-report questionnaires and performance tests.Beck Depression Inventory (BDI), Turgay’s Turkish version of Adult-ADD/ADHD (A-ADHD), Barratt Impulsivity Scale (BIS-11), and World Health Organization Quality of Life-Short Form (WHOQoL-Bref) were completed by the participants.Stroop Colour and Word Interference Test – TBAG Form (SCWT); was used for assessing cognitive function by a trained psychiatrist. Fatigue Severity Scale (FSS) and Expanded Disability Status Scale (EDSS) were used to evaluate by pwRRMS. Results PwRRMS had significantly higher attention-deficit scores and poor performance in all SCWT subtests.All SCWT scores were positively correlated with MS duration.A-ADHD-Total scores were negatively correlated with the age of MS diagnosis.A moderate positive correlation was found between falls and A-ADHD-total scores, and psychomotor speed.A moderate negative correlation was found between WHOQoL-Bref scores and BID, FSS, ADHD-Attention Deficit, SCWT-3, SCWT-5, and SCWT-interference.In multivariate linear regression analyzes, attention-deficit predicted EDSS positively, while depressive symptoms, attention-deficit, and psychomotor speed time were negative predictors of physical health quality. Conclusions In pwRRMS, cognitive dysfunctions such as response inhibition and intervention control, which are symptoms of attention deficit and impulsivity, have been shown to reduce the overall QoL. Among the strategies to reduce the impact of RRMS disease on patients’ lives, it is essential to implement programs to prevent depression and increase cognitive reserve.

B-cell activating factor gene variants in multiple sclerosis: Possible associations with disease susceptibility among females

Although B cells and B cell activating factor (BAFF) have been previously implicated in MS pathogenesis, data regarding the genetic influence of BAFF polymorphisms on MS susceptibility are limited. Here we aim to explore whether BAFF polymorphisms could contribute to MS susceptibility.156 RRMS patients fulfilling the revised McDonald criteria for MS diagnosis and 220 HCs were enrolled. Clinical, laboratory, and imaging characteristics were recorded. BAFF rs9514827, rs1041569, and rs9514828 polymorphisms were assessed by RFLP-PCR in DNA samples extracted from whole peripheral blood.The BAFF rs1041569 TT genotype along with the CTT and TTC haplotypes were associated with significantly increased risk for MS development in female MS patients compared to healthy female counterparts. These findings were not confirmed in males. The rs1041569 BAFF variant together with the CTT and TTC BAFF haplotypes derived from the BAFF rs9514827, rs1041569, and rs9514828 polymorphisms may represent novel genetic contributors to the development of MS in females.

Serum Reactive Antibodies against the N-Methyl-D-Aspartate Receptor NR2 Subunit-Could They Act as Potential Biomarkers?

Synaptic dysfunction and disrupted communication between neuronal and glial cells play an essential role in the underlying mechanisms of multiple sclerosis (MS). Earlier studies have revealed the importance of glutamate receptors, particularly the N-methyl-D-aspartate (NMDA) receptor, in excitotoxicity, leading to abnormal synaptic transmission and damage of neurons. Our study aimed to determine whether antibodies to the NR2 subunit of NMDAR are detected in MS patients and evaluate the correlation between antibody presence and clinical outcome. Furthermore, our focus extended to examine a possible link between NR2 reactivity and anti-coagulant antibody levels as pro-inflammatory molecules associated with MS. A cross-sectional study was carried out, including 95 patients with MS and 61 age- and gender-matched healthy controls (HCs). The enzyme-linked immunosorbent assay was used to detect anti-NR2 antibodies in serum samples of participants along with IgG antibodies against factor (F)VIIa, thrombin, prothrombin, FXa, and plasmin. According to our results, significantly elevated levels of anti-NR2 antibodies were detected in MS patients compared to HCs (p < 0.05), and this holds true when we compared the Relapsing-Remitting MS course with HCs (p < 0.05). A monotonically increasing correlation was found between NR2 seropositivity and advanced disability (rs = 0.30; p < 0.01), anti-NR2 antibodies and disease worsening (rs = 0.24; p < 0.05), as well as between antibody activity against NR2 and thrombin (rs = 0.33; p < 0.01). The presence of anti-NR2 antibodies in MS patients was less associated with anti-plasmin IgG antibodies [OR:0.96 (95%CI: 0.92-0.99); p < 0.05]; however, such an association was not demonstrated when analyzing only RRMS patients. In view of our findings, NR2-reactive antibodies may play, paving the way for further research into their potential as biomarkers and therapeutic targets in MS.

Can neurofilament lightchain as endpoint in Phase 2 derisk clinical disability worsening in Phase 3 in multiple sclerosis?

BackgroundNeurofilament lightchain has been proposed as a Phase 2 endpoint in clinical trials for multiple sclerosis. We evaluated via simulations the extent to which a positive Phase 2 trial would derisk a Phase 3 trial where the primary endpoint is time to confirmed clinical disability worsening. MethodsUsing a prior distribution of the treatment effect on neurofilament lightchain and a model linking it with clinical disability worsening constructed using the FREEDOMS trial in RRMS patients, the probability of success of two randomized controlled Phase 2 and Phase 3 trials were computed for different scenarios. ResultsThe strength of the correlation between both treatment effects and the success criteria of the Phase 2 trial impact the ability of the Phase 2 to derisk Phase 3. Being more stringent with the success criteria in Phase 2 can increase the Phase 3 PoS by more than 20% after a positive Phase 2 study. Increasing the sample size of the Phase 2 has no substantial impact on the derisking. ConclusionUnder some assumptions a positive Phase 2 trial with neurofilament lightchain as primary endpoint can to a certain extent derisk a Phase 3 trial with clinical disability worsening as primary endpoint.

Effectiveness and Safety of Teriflunomide in Relapsing-Remitting Multiple Sclerosis and Improvements in Quality of Life: Results from the Real-World TERICARE Study.

Teriflunomide is a once-daily oral immunomodulator approved for relapsing forms of multiple sclerosis (MS) or relapsing-remitting multiple sclerosis (RRMS; depending on the local label), based on extensive evidence from clinical trials and a real-world setting on efficacy, tolerability and patient-reported benefits. The TERICARE study assessed the impact of teriflunomide treatment over 2years on health-related quality of life (HRQoL) and some of the most common and disabling symptoms of MS, such as fatigue and depression. This prospective observational study in Spain included RRMS patients treated with teriflunomide for ≤ 4weeks. The following patient-reported outcomes (PROs) were collected at baseline and every 6months for 2years: the 29-item Multiple Sclerosis Impact Scale version 2 (MSIS-29), the 21-item Modified Fatigue Impact Scale (MFIS-21), the Beck Depression Inventory (BDI-II), the Short Form (SF)-Qualiveen and theTreatment Satisfaction Questionnaire for Medication v1.4 (TSQM). Annualised relapse rate (ARR), disability progression according to the Expanded Disability Status Scale (EDSS), and no evidence of disease activity (NEDA-3) were also assessed. A total of 325 patients were analysed. Patients had a mean (SD) age of 43.2years (10.4), a mean baseline EDSS score of 1.75 (1.5), a mean number of relapses in the past 2years of 1.5 (0.7), and 64% had received prior disease-modifying therapy (DMT). Patients showed significant improvements in the psychological domain of MSIS-29 from 35.9 (26.6) at baseline to 29.4 (25.5) at 18months (p = 0.004) and 29.0 (24.6) at 24months (p = 0.002). Levels of fatigue and depression were also reduced. After 2years of treatment with teriflunomide, ARR was reduced to 0.17 (95% CI 0.14-0.21) from the baseline of 0.42 (95% CI 0.38-0.48), representing a 60.1% reduction. Mean EDSS scores remained stable during the study, and 79.9% of patients showed no disability progression. 54.7% of patients achieved NEDA-3 in the first 12months, which increased to 61.4% during months 12-24. Patients reported increased satisfaction with treatment over the course of the study, regardless of whether they were DMT naive or not. Teriflunomide improves psychological aspects of HRQoL and maintains low levels of fatigue and depression. Treatment with teriflunomide over 2years is effective in reducing ARR and disability progression.

Effect of rs1058240 polymorphism in 3′-UTR of GATA3 gene on potential binding of miRNAs and its association with RRMS risk: bioinformatics analysis and case-control study

Aim Multiple sclerosis is believed to be an autoimmune disease that is influenced by T helper (Th) cell differentiation. GATA3 plays an important role in reducing the development and severity of MS by shifting the differentiation of Th cells to Th2 and regulatory T cells while inhibiting the differentiation of Th1 and Th17 cells. Considering the functional role of rs1058240 SNP in the 3’-UTR of GATA3 mRNA, the association of target SNP with the risk of RRMS was examined. Methods Genomic DNA was extracted from whole blood samples of 200 RRMS patients and 226 healthy individuals as a control group. Different genotypes of rs1058240 SNP were determined using the RFLP-PCR technique. Statistical analysis was performed using SPSS software and χ2 and logistic regression tests. The stability of GATA3 mRNA secondary structures and the binding patterns of GATA3-miRNAs with different alleles were evaluated using RNAfold and RNAhybrid programs, respectively. Results The results indicated that the GATA3 rs1058240 G allele (p value = 0.010, OR = 1.45, CI = 1.09-1.93) and GG genotype (adjusted p value = 0.017, OR = 2.27, 95%CI = 1.16-4.44) increased the risk of RRMS, particularly in women (adjusted p value = 0.006, OR = 2.99, 95%CI = 1.37-6.52). Bioinformatics analysis revealed that although the allelic variation of this polymorphism had only a slight effect on mRNA stability (-177 to −177.20), the G allele significantly increased miRNA binding strength and miRNA-mRNA thermodynamic stability for hsa-miR-337-5p, hsa-miR-4445-3p, hsa-miR-4485-3p, hsa-miR-95-3p (ΔMFE > 0) compared to the A allele. Conclusion The G allele and GG genotype of rs1058240 in GATA3 mRNA 3’-UTR were found to be risk factors for increasing the susceptibility to RRMS.

Retinal clues for selective neuronal loss in multiple sclerosis.

The relationship between the cell body layer and the dendritic network layer of the retina and cognitive performance (CP) in MS patients has not been examined separately. The objective of this study is to predict cognitive impairment (CI) in RRMS patients and to examine the relationship between CP and ganglion cell layer (GCL), inner plexiform layer (IPL), and GCL divided by IPL (GCL/IPL). Ophthalmological evaluation, retinal segmentation, and Symbol Digit Modalities Test (SDMT) were performed on 102 RRMS patients and 54 healthy subjects. The relationships of GCL, IPL, and GCL/IPL with CP in eyes without a history of optic neuritis were investigated using Spearman's correlation. Models were created by accepting 1 standard deviation less of the SDMT mean of the control group as the limit for CI. The cutoff value of the GCL/IPL variable that could predict CI was calculated by ROC analysis, and the ability to accurately predict CI was tested with binary logistic regression. No correlation was found between OCT parameters and CP in healthy subjects. Correlation was found between GCL thickness and GCL/IPL variable and CP in RRMS patients (r=0.235, r=0.667 respectively). A GCL/IPL value of 1.255 was able to identify CI with 81.8% sensitivity and 75.9% specificity (AUC=0.844, LR=3.38) and predicted CI with 74.5% accuracy (Nagelkerke R2=0.439). In RRMS patients, the IPL thickness is unrelated to CP. Therewithal, the GCL/IPL-CP relationship is stronger than the GCL-CP relationship and GCL/IPL can predict CI.

The fluctuations of expression profiles of critical genes in the miRNA maturation process and pro-and anti-inflammatory cytokines in the pathogenesis and progression of multiple sclerosis.

Multiple sclerosis (MS) is a central nervous system disease known for immune-mediated demyelination, inflammatory, and neurodegeneration symptoms. Discovering molecular biomarkers to classify RRMS and SPMS patients, monitor the disease activity, and response to particular treatments is one area that has received notable attraction. MicroRNA (miRNA), a single-stranded non-coding RNA molecule, is a significant regulator of gene expression recruited in pathogenic mechanisms in diverse diseases, especially cancer and MS. Also, the relapsing-remitting features of MS exhibit that both inflammatory and anti-inflammatory cytokines are effective in the progression of the disease over time. It was assessed the expression patterns of the genes (Drosha, Pasha(DGCR8), and Dicer) encoding the critical enzymes in the processing steps of miRNA maturation and major pro-inflammatory and anti-inflammatory cytokines (IFN-α, IFN-β, and IL-6) in blood cells of 40 MS patients (two groups of 10 men and women in both clinical courses of RR and SPMS patients) in comparison with 20 healthy control group (10 males and 10 females). The highest transcription activity of Drosha was observed for RRMS patients (4.2 and 3.6-fold, respectively), and the expression ratio was down regulated in male and female patients with SPMS (3.9- and 3.1-fold, respectively). Considering the studied cytokines, the increase in expression ratio of IL-6 in SPMS patients and the decrease in transcript abundance of INF-α, and INF-β cytokines are consistent with the progression of the disease. Our findings showed that the high and low transcriptional levels of the considered genes seem to be effective in the pathogenesis and progression of MS.