The risk of secondary progressive multiple sclerosis is geographically determined but modifiable.

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk.

Clinical validation of a multi-protein, serum-based assay for disease activity assessments in multiple sclerosis.

An 18-protein multiple sclerosis (MS) disease activity (DA) test was validated based on associations between algorithm scores and clinical/radiographic assessments (N = 614 serum samples; Train [n = 426; algorithm development] and Test [n = 188; evaluation] subsets). The multi-protein model was trained based on presence/absence of gadolinium-positive (Gd+) lesions and was also strongly associated with new/enlarging T2 lesions, and active versus stable disease (composite of radiographic and clinical evidence of DA) with improved performance (p < 0.05) compared to the neurofilament light single protein model. The odds of having ≥1 Gd+ lesions with a moderate/high DA score were 4.49 times that of a low DA score, and the odds of having ≥2 Gd+ lesions with a high DA score were 20.99 times that of a low/moderate DA score. The MSDA Test was clinically validated with improved performance compared to the top-performing single-protein model and can serve as a quantitative tool to enhance the care of MS patients.

External validation of a clinical prediction model in multiple sclerosis.

BACKGROUND: Timely initiation of disease modifying therapy is crucial for managing multiple sclerosis (MS). OBJECTIVE: We aimed to validate a previously published predictive model of individual treatment response using a non-overlapping cohort from the Middle East. METHODS: We interrogated the MSBase registry for patients who were not included in the initial model development. These patients had relapsing MS or clinically isolated syndrome, a recorded date of disease onset, disability and dates of disease modifying therapy, with sufficient follow-up pre- and post-baseline. Baseline was the visit at which a new disease modifying therapy was initiated, and which served as the start of the predicted period. The original models were used to translate clinical information into three principal components and to predict probability of relapses, disability worsening or improvement, conversion to secondary progressive MS and treatment discontinuation as well as changes in the area under disability-time curve (ΔAUC). Prediction accuracy was assessed using the criteria published previously. RESULTS: The models performed well for predicting the risk of disability worsening and improvement (accuracy: 81%-96%) and performed moderately well for predicting the risk of relapses (accuracy: 73%-91%). The predictions for ΔAUC and risk of treatment discontinuation were suboptimal (accuracy < 44%). Accuracy for predicting the risk of conversion to secondary progressive MS ranged from 50% to 98%. CONCLUSION: The previously published models are generalisable to patients with a broad range of baseline characteristics in different geographic regions.

Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis.

BACKGROUND: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. OBJECTIVE: To determine whether early non-disabling relapses predict disability accumulation in RRMS. METHODS: We redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. RESULTS: People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated (n = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs (n = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs (n = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. CONCLUSION: This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.

Central vein sign and paramagnetic rim sign: From radiologically isolated syndrome to multiple sclerosis.

The widespread use of magnetic resonance imaging (MRI) has led to an increase in incidental findings in the central nervous system. Radiologically isolated syndrome (RIS) is a condition where imaging reveals lesions suggestive of demyelinating disease without any clinical episodes consistent with multiple sclerosis (MS). The prognosis for RIS patients is uncertain, with some remaining asymptomatic while others progress to MS. Several risk factors for disease progression have been identified, including male sex, younger age at diagnosis, and spinal cord lesions. This article reviews two promising biomarkers, the central vein sign (CVS) and the paramagnetic rim sign (PRS), and their potential role in the diagnosis and prognosis of MS and RIS. Both CVS and PRS have been shown to be accurate diagnostic markers in MS, with high sensitivity and specificity, and have been useful in distinguishing MS from other disorders. Further research is needed to validate these findings and determine the clinical utility of these biomarkers in routine practice.

Early predictors of disability in paediatric multiple sclerosis: evidence from a multi-national registry.

BACKGROUND: Early recognition of markers of faster disability worsening in paediatric-onset multiple sclerosis (MS) is a key requisite of personalised therapy for children with MS at the earliest possible time. OBJECTIVE: To identify early predictors of rapid disability accrual in patients with paediatric-onset MS. METHODS: Using the global MSBase registry, we identified patients who were <18 years old at the onset of MS symptoms. The clinico-demographic characteristics examined as predictors of future MS Severity Score (MSSS) included sex, age at symptom onset, absence of disability at the initial assessment, maximum Expanded Disability Status Scale (EDSS) score, relapse frequency and presence of brainstem, pyramidal, visual or cerebellar symptoms in the first year. A Bayesian log-normal generalised linear mixed model adjusted for cumulative proportion of time on higher-efficacy disease-modifying therapies (DMTs) was used to analyse the data. RESULTS: 672 patients (70% female) contributing 9357 visits were included. The median age at symptom onset was 16 (quartiles 15-17) years. Older age at symptom onset (exp(ß)=1.10 (95% CI 1.04 to 1.17)), higher EDSS score (1.22 (1.12 to 1.34)) and pyramidal (1.31 (1.11 to 1.55)), visual (1.25 (1.10 to 1.44)) or cerebellar (1.18 (1.01 to 1.38)) symptoms in the first year were associated with higher MSSS. MSSS was reduced by 4% for every 24% increase in the proportion of time on higher-efficacy DMTs (0.96 (0.93 to 0.99)). CONCLUSIONS: A relatively later onset of MS in childhood, higher disability and pyramidal, visual or cerebellar symptoms during the first year predicted significant worsening in disability in patients with paediatric-onset MS. Persistent treatment with higher-efficacy DMTs was associated with a reduced rate of disability worsening.

The Brief International Cognitive Assessment in Multiple Sclerosis (BICAMS): Validation in Arabic and Lebanese Normative Values.

OBJECTIVE: Multiple sclerosis (MS) is often associated with cognitive deficits. Accurate evaluation of the MS patients' cognitive performance is essential for diagnosis and treatment recommendation. The Brief International Cognitive Assessment in Multiple Sclerosis (BICAMS), widely used cognitive testing battery, examines processing speed, verbal and visuospatial learning, and memory. Our study aims to examine the psychometric properties of an Arabic version of the BICAMS and to provide normative values in a Lebanese sample. METHOD: The BICAMS, comprised of the Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT-R), and a newly developed verbal learning/memory test, the Verbal Memory Arabic Test (VMAT), were administered on healthy subjects and MS patients. The sample consisted of 180 healthy individuals, of whom 63 were retested after 2-3 weeks. Forty-three MS patients matched with 43 healthy subjects based on age, sex, and years of education were assessed. A sample of 10 MS patients was also examined on two occasions. Test-retest reliability and criterion-related validity were examined, and regression-based norms were derived. RESULTS: The test-retest correlations showed good evidence of reliability with coefficients ranging between 0.64 and 0.73 in the healthy sample, and between 0.43 and 0.92 in the MS sample. The BICAMS was able to discriminate between MS patients and matched healthy participants on the SDMT and BVMT-R. Normative data were comparable to other studies. CONCLUSIONS: This new Arabic version of the BICAMS shows initial good psychometric properties. While good evidence of VMAT's reliability was shown in the healthy participants, less test-retest reliability in this tool was seen in the MS group, and partial criterion-related validity was evident. This renders further examination of the VMAT. We provide regression-based norms for a Lebanese sample and encourage the use of this battery in both research and clinical settings.

Central vein sign: A putative diagnostic marker for multiple sclerosis.

The presence of a "central vein sign" (CVS) has been introduced as a biomarker for the diagnosis of multiple sclerosis (MS) and shown to have the ability to accurately differentiate MS from other white matter diseases (MS mimics). Following the development of susceptibility-based magnetic resonance venography that allowed the in vivo detection of CVS, a standard CVS definition was established by introducing the "40% rule" that assesses the number of MS lesions with CVS as a fraction of the total number of lesions to differentiate MS lesions from other types of lesions. The "50% rule," the "three-lesion criteria," and the "six-lesion criteria" were later introduced and defined. Each of these rules had high levels of sensitivity, specificity, and accuracy in differentiating MS from other diseases, which has been recognized by the Magnetic Resonance Imaging in MS (MAGNIMS) group and the Consortium of MS Centers task force. The North American Imaging in Multiple Sclerosis Cooperative even provided statements and recommendations aiming to refine, standardize and evaluate the CVS in MS. Herein, we review the existing literature on CVS and evaluate its added value in the diagnosis of MS and usefulness in differentiating it from other vasculopathies. We also review the histopathology of CVS and identify available automated CVS assessment methods as well as define the role of vascular comorbidities in the diagnosis of MS.

Long-term cognitive deficits after traumatic brain injury associated with microglia activation.

Traumatic Brain Injury (TBI) is the most prevalent of all head injuries. Microglia play an essential role in homeostasis and diseases of the central nervous system. We hypothesize that microglia may play a beneficial or detrimental role in TBI depending on their state of activation and duration. In this study, we evaluated whether TBI results in a spatiotemporal change in microglia phenotype and whether it affects sensory-motor or learning and memory functions in male C57BL/6 mice. We used a panel of neurological and behavioral tests and a multi-color flow cytometry-based data analysis followed by unsupervised clustering to evaluate isolated microglia from injured brain tissue. We characterized several microglial phenotypes and their association with cognitive deficits. TBI results in a spatiotemporal increase in activated microglia that correlated negatively with spatial learning and memory at 35 days post-injury. These observations could define therapeutic windows and accelerate translational research to improve patient outcomes.

Notch receptors and Smad3 signaling cooperate in the induction of interleukin-9-producing T cells.

Interleukin 9 (IL-9) is a pleiotropic cytokine that can regulate autoimmune responses by enhancing regulatory CD4(+)FoxP3(+) T regulatory (Treg) cell survival and T helper 17 (Th17) cell proliferation. Here, we analyzed the costimulatory requirements for the induction of Th9 cells, and demonstrated that Notch pathway cooperated with TGF-ß signaling to induce IL-9. Conditional ablation of Notch1 and Notch2 receptors inhibited the development of Th9 cells. Notch1 intracellular domain (NICD1) recruited Smad3, downstream of TGF-ß cytokine signaling, and together with recombining binding protein (RBP)-Jκ bound the Il9 promoter and induced its transactivation. In experimental autoimmune encephalomyelitis (EAE), Jagged2 ligation regulated clinical disease in an IL-9-dependent fashion. Signaling through Jagged2 expanded Treg cells and suppressed EAE when administered before antigen immunization, but worsened EAE when administered concurrently with immunization by favoring Th17 cell expansion. We propose that Notch and Smad3 cooperate to induce IL-9 and participate in regulating the immune response.

Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration.

Inflammation-mediated neurodegeneration occurs in the acute and the chronic phases of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Classically activated (M1) microglia are key players mediating this process. Here, we identified Galectin-1 (Gal1), an endogenous glycan-binding protein, as a pivotal regulator of M1 microglial activation that targets the activation of p38MAPK-, CREB-, and NF-κB-dependent signaling pathways and hierarchically suppresses downstream proinflammatory mediators, such as iNOS, TNF, and CCL2. Gal1 bound to core 2 O-glycans on CD45, favoring retention of this glycoprotein on the microglial cell surface and augmenting its phosphatase activity and inhibitory function. Gal1 was highly expressed in the acute phase of EAE, and its targeted deletion resulted in pronounced inflammation-induced neurodegeneration. Adoptive transfer of Gal1-secreting astrocytes or administration of recombinant Gal1 suppressed EAE through mechanisms involving microglial deactivation. Thus, Gal1-glycan interactions are essential in tempering microglial activation, brain inflammation, and neurodegeneration, with critical therapeutic implications for MS.

Abatacept Targets T Follicular Helper and Regulatory T Cells, Disrupting Molecular Pathways That Regulate Their Proliferation and Maintenance.

Abatacept is a CTLA-4-Ig fusion protein that binds to the costimulatory ligands CD80 and CD86 and blocks their interaction with the CD28 and CTLA-4 receptors expressed by T cells, therefore inhibiting T cell activation and function. Abatacept has shown clinical efficacy in treating some autoimmune diseases but has failed to show clinical benefit in other autoimmune conditions. The reasons for these disparate results are not clear and warrant further investigation of abatacept's mode of action. Longitudinal specimens from the Immune Tolerance Network's A Cooperative Clinical Study of Abatacept in Multiple Sclerosis trial were used to examine the effects of abatacept treatment on the frequency and transcriptional profile of specific T cell populations in peripheral blood. We found that the relative abundance of CD4+ T follicular helper (Tfh) cells and regulatory T cells was selectively decreased in participants following abatacept treatment. Within both cell types, abatacept reduced the proportion of activated cells expressing CD38 and ICOS and was associated with decreased expression of genes that regulate cell-cycle and chromatin dynamics during cell proliferation, thereby linking changes in costimulatory signaling to impaired activation, proliferation, and decreased abundance. All cellular and molecular changes were reversed following termination of abatacept treatment. These data expand upon the mechanism of action of abatacept reported in other autoimmune diseases and identify new transcriptional targets of CD28-mediated costimulatory signaling in human regulatory T and Tfh cells, further informing on its potential use in diseases associated with dysregulated Tfh activity.

Cumulative administrations of gadolinium-based contrast agents: risks of accumulation and toxicity of linear vs macrocyclic agents.

Ever since gadolinium was found to deposit in the brain of patients with normal kidney function by Kanda et al. in 2014, several studies have been conducted to evaluate its effect on the patients' health. However, conflicting results were obtained regarding imaging in gadolinium retention. These finding were attributed to the chelating structure of the administered gadolinium-based contrast agent (GBCA): linear agents were found to accumulate in the dentate nucleus (DN) and the globus pallidus (GP) of subjects even after one dose. There are some contradictory results when assessing macrocyclic agents. In the following article, we review the basis of GBCAs characteristics and their side effects, as well as, the MRI studies that assessed the accumulation of gadolinium in the brain. Based on the results of several studies, in 2017, the European Medicine Agency requested the suspension of the marketing authorizations for three linear GBCAs: gadodiamide (Omniscan®), gadoversetamide (Optimark®) and gadopentate dimeglimine (Magnevist®) and limited the use of gadoxetate disodium (Primovist/Eovist®) and gadobenate dimeglumine (MultiHance®) to hepatic uptake for imaging poorly vascularized hepatic lesions. Accordingly, the FDA did not restrict GBCA use, but will continue to study their safety and urged clinicians to use these agents sparingly. All macrocyclic GBCAs continued however to be used as no available valid evidence linked them to brain gadolinium retention. Regardless of possible accumulation in the brain, there is no evidence to-date that gadolinium retention leads to any disease or disorders in subjects with normal renal function. Further investigations with long-term follow-up are needed.

Co-signaling Molecules in Neurological Diseases.

Inflammation plays an important role in the onset and progression of many neurological diseases. As the central nervous system (CNS) constitutes a highly specialized environment where immune activation can be detrimental, it is crucial to understand mechanisms by which the immune system is regulated during neurological diseases. The system of co-signaling pathways provides the immune system with the means to fine-tune immune responses by turning on and off immune cell activation. Studies of co-signaling molecules in neurological diseases and their animal models have highlighted the complexities of immune regulation within the CNS and the intricacies of the interplay between the different cells of the immune system and how they interact with the resident cells of the CNS. This complexity poses challenges when targeting co-signaling pathway to treat neurological diseases and may explain why no drugs targeting these pathways have been successfully developed this far. Here, we will review the current literature on some important co-signaling pathways in multiple sclerosis (MS), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, and ischemic stroke to understand these pathways in mediating and controlling neuroinflammation.

Rheumatoid arthritis-associated RBPJ polymorphism alters memory CD4+ T cells.

Notch signaling has recently emerged as an important regulator of immune responses in autoimmune diseases. The recombination signal-binding protein for immunoglobulin kappa J region (RBPJ) is a transcriptional repressor, but converts into a transcriptional activator upon activation of the canonical Notch pathway. Genome-wide association studies of rheumatoid arthritis (RA) identified a susceptibility locus, rs874040(CC), which implicated the RBPJ gene. Here, chromatin state mapping generated using the chromHMM algorithm reveals strong enhancer regions containing DNase I hypersensitive sites overlapping the rs874040 linkage disequilibrium block in human memory, but not in naïve CD4(+) T cells. The rs874040 overlapping this chromatin state was associated with increased RBPJ expression in stimulated memory CD4(+) T cells from healthy subjects homozygous for the risk allele (CC) compared with memory CD4(+) T cells bearing the protective allele (GG). Transcriptomic analysis of rs874040(CC) memory T cells showed a repression of canonical Notch target genes IL (interleukin)-9, IL-17 and interferon (IFN)γ in the basal state. Interestingly, activation of the Notch pathway using soluble Notch ligand, Jagged2-Fc, induced IL-9 and IL-17A while delta-like 4Fc, another Notch ligand, induced higher IFNγ expression in the rs874040(CC) memory CD4(+) T cells compared with their rs874040(GG) counterparts. In RA, RBPJ expression is elevated in memory T cells from RA patients compared with control subjects, and this was associated with induced inflammatory cytokines IL-9, IL-17A and IFNγ in response to Notch ligation in vitro. These findings demonstrate that the rs874040(CC) allele skews memory T cells toward a pro-inflammatory phenotype involving Notch signaling, thus increasing the susceptibility to develop RA.

SUMMIT (Serially Unified Multicenter Multiple Sclerosis Investigation): creating a repository of deeply phenotyped contemporary multiple sclerosis cohorts.

BACKGROUND: There is a pressing need for robust longitudinal cohort studies in the modern treatment era of multiple sclerosis. OBJECTIVE: Build a multiple sclerosis (MS) cohort repository to capture the variability of disability accumulation, as well as provide the depth of characterization (clinical, radiologic, genetic, biospecimens) required to adequately model and ultimately predict a patient's course. METHODS: Serially Unified Multicenter Multiple Sclerosis Investigation (SUMMIT) is an international multi-center, prospectively enrolled cohort with over a decade of comprehensive follow-up on more than 1000 patients from two large North American academic MS Centers (Brigham and Women's Hospital (Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB; BWH)) and University of California, San Francisco (Expression/genomics, Proteomics, Imaging, and Clinical (EPIC))). It is bringing online more than 2500 patients from additional international MS Centers (Basel (Universitätsspital Basel (UHB)), VU University Medical Center MS Center Amsterdam (MSCA), Multiple Sclerosis Center of Catalonia-Vall d'Hebron Hospital (Barcelona clinically isolated syndrome (CIS) cohort), and American University of Beirut Medical Center (AUBMC-Multiple Sclerosis Interdisciplinary Research (AMIR)). RESULTS AND CONCLUSION: We provide evidence for harmonization of two of the initial cohorts in terms of the characterization of demographics, disease, and treatment-related variables; demonstrate several proof-of-principle analyses examining genetic and radiologic predictors of disease progression; and discuss the steps involved in expanding SUMMIT into a repository accessible to the broader scientific community.

Gadolinium effect on thalamus and whole brain tissue segmentation.

PURPOSE: Gadolinium-based contrast agent (GBCA) effect on automated segmentation algorithms of subcortical gray matter (GM) is not fully known. The aim of this study is to determine gadolinium effect on the segmentation of the thalamus and whole brain tissue using different automated segmentation techniques. METHODS: Eighty-four multiple sclerosis (MS) patients underwent an MRI acquisition of two 3DT1-weighted sequences with and without gadolinium injection among which 10 were excluded after image quality check. Manual thalamic segmentation considered as gold standard was performed on unenhanced T1 images. volBrain and FSL-Anat were used to automatically segment the thalamus on both enhanced and unenhanced T1 and the degree of similitude (DICE) values were compared between manual and automatic segmentations. Whole brain tissue segmentation (GM, white matter (WM), and lateral ventricles (LV)) was also performed using SIENAX. A paired samples t test was applied to test the significance of DICE value differences between the thalamic manual and automatic segmentations of both enhanced and unenhanced T1 images. RESULTS: Significant differences (FSL-Anat 1.474% p < 0.001 and volBrain 1.990% p < 0.001) in DICE between thalamic manual and automatic segmentations on both enhanced and unenhanced images were observed. Automatic tissue segmentation showed a mean DICE of 81.5%, with LV having the lowest DICE value (74.2%). When compared to tissue segmentations, automatic thalamic segmentations by FSL-Anat or volBrain demonstrated a higher degree of similitude (FSL-Anat = 91.7% and volBrain = 90.7%). CONCLUSION: Gadolinium has a significant effect on subcortical GM segmentation. Although significant, the observed subtle changes could be considered acceptable when used for region-based analysis in perfusion or diffusion imaging.

Effect of vitamin D replacement on immunological biomarkers in patients with multiple sclerosis.

We aimed to investigate the immunologic effects of vitamin D replacement in RRMS patients. In a controlled single center study, patients deficient in 25-hydroxyvitamin D (serum level<25ng/ml) received 10,000IU/week cholecalciferol for 3months. Sufficient vitamin D patients (serum level>35ng/ml) were followed for the same period. Assessments were performed at baseline and at 3months. 25-hydroxyvitamin D levels increased significantly from baseline to month-3 in the deficient group after treatment and remained stable in the sufficient group. We observed a decreased interferon-γ (IFNγ) secretion by CD4+ T cells in vitamin D deficient group but not in the sufficient group, and a negative correlation between baseline serum vitamin D and IFNγ production. There was no change in the frequency of T helper or regulatory T cell subsets in either group. Increasing serum levels of 25-hydroxyvitamin D are associated with decreased production of IFNγ by CD4+ T cells.

ACCLAIM: A randomized trial of abatacept (CTLA4-Ig) for relapsing-remitting multiple sclerosis.

BACKGROUND: Costimulatory blockade of T lymphocytes with the CTLA4-Ig fusion protein abatacept could be an effective treatment for the immune-mediated neuroinflammatory disease relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: To evaluate efficacy and safety of abatacept in RRMS. METHODS: ACCLAIM (A Cooperative Clinical Study of Abatacept in Multiple Sclerosis) was a Phase II, randomized, double-blind, placebo-controlled, multi-center trial. In all, 65 of 123 planned participants with RRMS were randomized to monthly intravenous infusions of abatacept or placebo for 24 weeks in a 2:1 ratio, switched to the opposite treatment at 28 weeks, and received their final dose of study medication at 52 weeks. Enrollment was closed early due to slow accrual. The primary endpoint was the mean number of new gadolinium-enhancing (Gd+) lesions obtained on magnetic resonance imaging (MRI) scans performed every 4 weeks. RESULTS: No statistically significant differences were observed in mean number of new Gd+ MRI lesions between the abatacept and placebo groups. No statistically significant differences were observed in other MRI and clinical parameters of RRMS disease activity. Abatacept was well tolerated. CONCLUSION: The ACCLAIM study did not demonstrate efficacy of abatacept in reducing the number of new Gd+ MRI lesions, or clinical measures of disease activity in RRMS.

Comparative effect of 25(OH)D3 and 1,25(OH)2D3 on Th17 cell differentiation.

Vitamin D is a secosteroid hormone that plays an important regulatory role in calcium homeostasis and bone metabolism. Immune cells can both produce and respond to 1,25(OH)2D3. CD4+ T cells from vitamin D receptor (VDR) KO mice produce higher levels of IFN-γ and IL-17 than their wild type counterparts, and play a crucial role in the pathogenesis of autoimmune diseases (AID). We are particularly interested in studying the effect of vitamin D on pathogenic Th17 cells in humans. We investigated the in vitro effect of 1,25(OH)2D3 and 25(OH)D3 on the differentiation and cytokine production of primary CD4+ T cells from normal donors, and cultured in Th17 polarizing conditions. Both forms of vitamin D reduced the expression of pathogenic Th17 markers and their secretion of pro-inflammatory cytokines (IL-17A, IFN-γ). Furthermore, both vitamin D forms induced an expansion of CD25hi cells and upregulated their expression of CTLA-4 and Foxp3 regulatory markers.