Drugs For Multiple Sclerosis Research Articles

The influence of the COVID-19 pandemic on the prescription of multiple sclerosis medication in Germany

BackgroundReal-word evidence from diverse data sources is increasingly important in terms of generating rapid insights to effectively manage patient populations, especially during major public health disruptions such as the ongoing COVID-19 pandemic. Patients with chronic and inflammatory diseases - such as multiple sclerosis (MS) - were reported to experience potentially negative effects due to the use of immunosuppressive drugs in combination with a COVID-19 infection. In this research, we explored the impact of the COVID-19 pandemic on medication use in patients with MS in Germany. MethodsPatient-level pharmacy dispensing data from the Permea platform - covering approximately 44% of all community pharmacy dispensing in Germany - were analysed from 2019 − 2021. Longitudinal use patterns of MS medication and antidepressants and patient demographics were assessed. Daily variation in MS medication use was specifically studied around the dates of the first and second lockdowns in Germany. ResultsWe included data from 539,400 prescriptions which included at least 1 MS drug. The medication data showed a stable level of monthly prescriptions for MS medication at 2.02 ± 0.03 prescriptions per pharmacy during the study period. Although there was a sharp increase in daily prescriptions before the first lockdown (from an average 660.08 ± 137.59 daily prescriptions in the observed period to a maximum dispensing number of 998 daily prescriptions), the overall number of prescriptions remained at pre-pandemic levels (603 ± 90.31 daily prescriptions in 2019). Similar trends were observed for monthly co-prescribed antidepressant use per pharmacy (0.10 ± 0.01 in 2019–0.11 ± 0.02 in 2020). ConclusionThroughout the COVID-19 pandemic, the use of MS medications and co-prescribed antidepressants was stable. These insights from real-world data demonstrate the value of evidence-based insights for managing patient care.

EE488 How Is Real-World Data Used in Health Technology Assessments to Inform Reimbursement Decisions for Multiple Sclerosis Drugs? A European Perspective

EE488 How Is Real-World Data Used in Health Technology Assessments to Inform Reimbursement Decisions for Multiple Sclerosis Drugs? A European Perspective

Endocannabinoid levels in peripheral blood mononuclear cells of multiple sclerosis patients treated with dimethyl fumarate

The endocannabinoid system (ECS), a signalling network with immunomodulatory properties, is a potential therapeutic target in multiple sclerosis (MS). Dimethyl fumarate (DMF) is an approved drug for MS whose mechanism of action has not been fully elucidated; the possibility exists that its therapeutic effects could imply the ECS. With the aim of studying if DMF can modulate the ECS, the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were determined by liquid chromatography-mass spectrometry in peripheral blood mononuclear cells from 21 healthy donors (HD) and 32 MS patients at baseline and after 12 and 24 months of DMF treatment. MS patients presented lower levels of 2-AG and PEA compared to HD. 2-AG increased at 24 months, reaching HD levels. AEA and PEA remained stable at 12 and 24 months. OEA increased at 12 months and returned to initial levels at 24 months. Patients who achieved no evidence of disease activity (NEDA3) presented the same modulation over time as EDA3 patients. PEA was modulated differentially between females and males. Our results show that the ECS is dysregulated in MS patients. The increase in 2-AG and OEA during DMF treatment suggests a possible role of DMF in ECS modulation.

Using an animal model to predict the effective human dose for oral multiple sclerosis drugs.

The objective of this study was to determine the potential usefulness of an animal model to predict the appropriate dose of newly developed drugs for treating relapsing remitting multiple sclerosis (RRMS). Conversion of the lowest effective dose (LEffD) for mice and rats in the experimental autoimmune encephalomyelitis (EAE) model was used to predict the human effective dose utilizing the body surface area correction factor found in the 2005 US Food and Drug Administration (FDA) Guidance for Industry in selecting safe starting doses for clinical trials. Predictions were also tested by comparison with doses estimated by scaling up the LEffD in the model by the human to animal clearance ratio. Although initial proof-of-concept studies of oral fingolimod tested the efficacy and safety of 1.25 and 5mg in treating RRMS, the EAE animal model predicted the approved dose of this drug, 0.5mg daily. This approach would have also provided useful predictions of the approved human oral doses for cladribine, dimethyl fumarate, ozanimod, ponesimod, siponimod, and teriflunomide, drugs developed with more than one supposed mechanism of action. The procedure was not useful for i.v. dosed drugs, including monoclonal antibodies. We maintain that drug development scientists should always examine a simple allometric method to predict the therapeutic effective dose in humans. Then, following clinical studies, we believe that the animal model might be expected to yield useful predictions of other drugs developed to treat the same condition. The methodology may not always be predictive, but the approach is so simple it should be investigated.

Diroximel Fumarate as a Novel Oral Immunomodulating Therapy for Relapsing Forms of Multiple Sclerosis: A Review on the Emerging Data.

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disorder of the central nervous system. Disease-modifying drugs (DMDs) and subsequent adherence are crucial for preventing reversible episodes of neurological dysfunction and delayed onset of progressive accumulation of irreversible deficits. Yet, side effects may limit their usage in clinical practice. Gastrointestinal (GI) side effects are a significant limitation of the use of dimethyl fumarate (DMF), the most frequently prescribed oral DMD in MS worldwide. Diroximel fumarate (DRF) is a second-generation oral fumaric acid ester (FAE) that was developed as a formulation with better GI tolerability. The improved tolerability is assumed to be related to a lower synthesis of gut-irritating methanol. Other explanations for DRF's lower extent of GI irritation include a more modest off-target activity due to its chemical structure. The superior GI tolerability of DRF compared to DMF could be proven in clinical trials and lead to approval of DRF for the treatment of relapsing forms of MS/relapsing-remitting MS (United States Food and Drug Administration and European Medicines Agency, respectively). Here, we summarize the mode of action of oral FAE and compare the chemical and physiological characteristics of DMF and DRF. Moreover, we discuss the adverse effects of FAE and introduce the emerging preclinical and trial data leading to the approval of DRF in MS. This article additionally reviews our current understanding of coronavirus disease 2019 (COVID-19) and the efficacy of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination in people treated with FAE.

Immune cells transcriptome-based drug repositioning for multiple sclerosis.

Finding target genes and target pathways of existing drugs for drug repositioning in multiple sclerosis (MS) based on transcriptomic changes in MS immune cells. Based on transcriptome data from Gene Expression Omnibus (GEO) database, differentially expressed genes (DEGs) in MS patients without treatment were identified by bioinformatics analysis according to the type of immune cells, as well as DEGs in MS patients before and after drug administration. Hub target genes of the drug for MS were analyzed by constructing the protein-protein interaction network, and candidate drugs targeting 2 or more hub target genes were obtained through the connectivity map (CMap) database and Drugbank database. Then, the enriched pathways of MS patients without treatment and the enriched pathways of MS patients before and after drug administration were intersected to obtain the target pathways of the drug for MS, and the candidate drugs targeting 2 or more target pathways were obtained through Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We obtained 50 hub target genes for CD4+ T cells in Fingolimod for MS, 15 hub target genes for Plasmacytoid dendritic cells (pDCs) and 7 hub target genes for Peripheral blood mononuclear cells (PBMC) in interferon-β (IFN-β) for MS. 6 candidate drugs targeting two or more hub targets (Fostamatinib, Copper, Artenimol, Phenethyl isothiocyanate, Aspirin and Zinc) were obtained. In addition, we obtained 4 target pathways for CD19+ B cells and 15 target pathways for CD4+ T cells in Fingolimod for MS, 7 target pathways for pDCs and 6 target pathways for PBMC in IFN-β for MS, most of which belong to the immune system and viral infectious disease pathways. We obtained 69 candidate drugs targeting two target pathways. We found that applying candidate drugs that target both the "PI3K-Akt signaling pathway" and "Chemokine signaling pathway" (e.g., Nemiralisib and Umbralisib) or applying tyrosine kinase inhibitors (e.g., Fostamatinib) may be potential therapies for the treatment of MS.

S3093 Monotherapy for Multiple Autoimmune Diseases: The Novel Use of Ofatumumab for Concurrent Multiple Sclerosis and Autoimmune Hepatitis

Introduction: Autoimmune hepatitis (AIH) is a rare acute or chronic inflammatory liver disease, that can be associated with a variety of extrahepatic disorders, such as multiple sclerosis (MS). AIH has been reported both during and after treatment with immunomodulatory drugs for MS, such as interferon-beta and steroids, with its incidence in MS being 10-fold higher than the general population. Typically, those patients are treated with steroids and azathioprine as the first line of treatment according to AIH guidelines. However, in comparison to newer disease-modifying therapies (DMTs) for MS, azathioprine is less effective and requires further study. Notably, several studies have suggested a role for B-cell-driven autoimmune liver injury in AIH, and there have been reports of refractory AIH being successfully treated with rituximab, an anti-CD20 monoclonal antibody. Based on these results and the well-known role of B-cells in the underlying pathophysiology of MS, we postulated that anti-CD20 therapy may be effective in treating patients with concurrent MS and AIH, thereby helping to limit steroid duration and avoid the use of azathioprine. Case Description/Methods: We report the case of a 49-year-old previously healthy female who presented with symptoms and magnetic resonance imaging (MRI) findings consistent with relapsing-remitting MS (RRMS). On routine labs at initial presentation, she was incidentally found to have ALT/AST in the 500's range. An extensive work-up was completed, including a liver biopsy that showed a centrilobular necroinflammatory injury pattern suggest of early AIH without cirrhosis. The patient was started on oral budesonide followed by ofatumumab, an anti-CD20 monoclonal antibody approved for treatment of RRMS, as steroids were weaned. The patient’s liver enzymes returned to normal ranges within 12 weeks and have remained so now for approximately 8 months. Additionally, she has had no new clinical or imaging findings suggestive of MS disease activity. We present this as the first-reported case of the use of an anti-CD20 monoclonal antibody to treat both MS and AIH concurrently. Discussion: This case furthers our understanding of AIH by suggesting that the pathophysiology contributing to AIH is predominately B-cell related as this patient’s AIH was successfully treated with ofatumumab and a short course of budesonide. It highlights a possible alternative treatment modality for AIH that avoids a prolonged course of steroids and/or azathioprine. More research is still needed however.

Induction and Diverse Assessment Indicators of Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) is a typical autoimmune disease of the central nervous system (CNS) characterized by inflammatory infiltration, demyelination, and axonal damage. Currently, there are no measures to cure MS completely, but multiple disease-modifying therapies (DMT) are available to control and mitigate disease progression. There are significant similarities between the CNS pathological features of experimental autoimmune encephalomyelitis (EAE) and MS patients. EAE has been widely used as a representative model to determine MS drugs' efficacy and explore the development of new therapies for MS disease. Active induction of EAE in mice has a stable and reproducible effect and is particularly suitable for studying the effects of drugs or genes on autoimmune neuroinflammation. The method of immunizing C57BL/6J mice with myelin oligodendrocyte glycoprotein (MOG35-55) and the daily assessment of disease symptoms using a clinical scoring system is mainly shared. Given the complex etiology of MS with diverse clinical manifestations, the existing clinical scoring system can't satisfy the assessment of disease treatment. To avoid the shortcomings of a single intervention, new indicators to assess EAE based on clinical manifestations of anxiety-like moods and osteoporosis in MS patients are created to provide a more comprehensive assessment of MS treatment.

Integration of genomic variants and bioinformatic-based approach to drive drug repurposing for multiple sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease in the central nervous system (CNS) marked by inflammation, demyelination, and axonal loss. Currently available MS medication is limited, thereby calling for a strategy to accelerate new drug discovery. One of the strategies to discover new drugs is to utilize old drugs for new indications, an approach known as drug repurposing. Herein, we first identified 421 MS-associated SNPs from the Genome-Wide Association Study (GWAS) catalog (p-value < 5 × 10−8), and a total of 427 risk genes associated with MS using HaploReg version 4.1 under the criterion r2 > 0.8. MS risk genes were then prioritized using bioinformatics analysis to identify biological MS risk genes. The prioritization was performed based on six defined categories of functional annotations, namely missense mutation, cis-expression quantitative trait locus (cis-eQTL), molecular pathway analysis, protein-protein interaction (PPI), genes overlap with knockout mouse phenotype, and primary immunodeficiency (PID). A total of 144 biological MS risk genes were found and mapped into 194 genes within an expanded PPI network. According to the DrugBank and the Therapeutic Target Database, 27 genes within the list targeted by 68 new candidate drugs were identified. Importantly, the power of our approach is confirmed with the identification of a known approved drug (dimethyl fumarate) for MS. Based on additional data from ClinicalTrials.gov, eight drugs targeting eight distinct genes are prioritized with clinical evidence for MS disease treatment. Notably, CD80 and CD86 pathways are promising targets for MS drug repurposing. Using in silico drug repurposing, we identified belatacept as a promising MS drug candidate. Overall, this study emphasized the integration of functional genomic variants and bioinformatic-based approach that reveal important biological insights for MS and drive drug repurposing efforts for the treatment of this devastating disease.

Is there a role for off‐label high‐efficacy disease‐modifying drugs in progressive multiple sclerosis? A network meta‐analysis

Ocrelizumab and siponimod are the two on-label drugs used for progressive forms of multiple sclerosis (PMS). However, many patients with PMS do not have access to these high-efficacy disease-modifying drugs (DMDs). Off-label prescription of other high-efficacy DMDs (fingolimod, rituximab and natalizumab) may be a strategy to improve access to immunotherapy for these patients. We aim to compare on-label and off-label high-efficacy drugs for their effect on disability progression in PMS. In December 2021, we searched MEDLINE (PubMed), Embase, Cochrane Central and Scopus databases for randomized clinical trials involving patients with PMS. High-efficacy drugs were considered as intervention and placebos as comparison. The outcome contemplated was risk of Expanded Disability Severity Scale (EDSS) progression at 2 years. A network meta-analysis was performed to compare the relative risk of EDSS progression at 2 years compared with placebo in on-label and off-label drugs. We included five studies with 4526 patients. The median EDSS progression at 2 years in patients that received any immunotherapy was 30%, compared with 35% in placebo groups. Overall, the risk of bias of individual studies was low. Network analysis revealed overlapping confidence intervals in off-label drugs (CI95% 0.51-2.16) versus ocrelizumab (reference) and off-label drugs (CI 95% 0.53-1.96) versus siponimod (reference), suggesting similar efficacy. The same result was found even after excluding studies with the risk of publication bias. Off-label high efficacy immunotherapy in PMS has biological plausibility and presented similar effectiveness to on-label DMDs in this network meta-analysis. The use of fingolimod, rituximab or natalizumab may be a strategy that reduces costs and improves access to immunotherapy for patients with PMS.

Interferon-β Decreases the Hypermetabolic State of Red Blood Cells from Patients with Multiple Sclerosis.

Multiple sclerosis (MS) is an inflammatory disease characterized by damage to the myelin sheath surrounding axons in the central nervous system. While the exact mechanism of this destruction is unknown, excess nitric oxide (NO) and adenosine triphosphate (ATP) have been measured in tissues and fluids obtained from people with MS. Here, incubation of interferon-beta (IFN-β), an MS drug with an unknown mechanism of action, with red blood cells (RBCs) obtained from people with MS provide evidence of a potential hypermetabolic state in the MS RBC that is decreased with IFN-β intervention. Specifically, binding of all three components of an albumin/C-peptide/Zn2+ complex to MS RBCs was significantly increased in comparison to control RBCs. For example, the binding of C-peptide to MS RBCs was significantly increased (3.4 ± 0.1 nM) compared to control RBCs (1.6 ± 0.2 nM). However, C-peptide binding to MS RBCs was reduced to a value (1.6 ± 0.3 nM) statistically equal to that of control RBCs in the presence of 2 nM IFN-β. Similar trends were measured for albumin and Zn2+ binding to RBCs when in the presence of IFN-β. RBC function was also affected by incubation of cells with IFN-β. Specifically, RBC-derived ATP and measurable membrane GLUT1 were both significantly decreased (56 and 24%, respectively) in the presence of IFN-β. Collectively, our results suggest that IFN-β inhibits albumin binding to the RBC, thereby reducing its ability to deliver ligands such as C-peptide and Zn2+ to the cell and normalizing the basal hypermetabolic state.

Dimethyl fumarate improves cognitive impairment by enhancing hippocampal brain-derived neurotrophic factor levels in hypothyroid rats

BackgroundDimethyl fumarate (DMF) is an effective drug for multiple sclerosis and can improve the cognitive dysfunction caused by streptozotocin, but the effect on cognitive dysfunction caused by hypothyroidism is unclear.MethodsAfter the hypothyroidism rat model induced by propylthiouracil, we gave rats 25 mg/kg DMF by gavage. The body weight during model building and administration was recorded. The levels of T4 and T3 in serum were detected by an automatic biochemical analyzer. Morris water maze test was used to detect the effect of DMF on cognitive learning ability. The effect of DMF on Nissl bodies in the brain tissue was evaluated by Nissl staining. The mRNA and protein levels of BDNF in brain tissue were detected by quantitative reverse transcription-polymerase chain reaction and Western blot. The degrees of p-AKT/AKT and p-CREB/CREB in brain tissue were detected by Western blot.ResultsAfter DMF treatment, the body weight of hypothyroid rats recovered, and the levels of T3 and T4 in the serum were ameliorated. DMF also reduced the escape latency and distance traveled, and increased the swim speed. The number of Nissl bodies and expression of BDNF, p-AKT/AKT, and p-CREB/CREB in the brain tissue were increased after DMF treatment.ConclusionDMF improved the cognitive dysfunction of hypothyroid rats by increasing the level of BDNF in the brain tissue of hypothyroid rats.

Efficacy and Safety of Multiple Sclerosis Drugs Approved Since 2018 and Future Developments.

Multiple sclerosis treatment made substantial headway during the last two decades with the implementation of therapeutics with new modes of action and routes of application. We are now in the situation that second-generation molecules, approved since 2018, are on the market, characterized by reduced side effects using a more tailored therapeutic approach. Diroximel fumarate is a second-generation fumarate with reduced gastrointestinal side effects. Moreover, several novel, selective, sphingosine-1-phosphate receptor modulators with reduced off-target effects have been developed; namely siponimod, ozanimod, and ponesimod; all oral formulations. B-cell-targeted therapies such as ocrelizumab, given intravenously, and since 2021 ofatumumab, applied subcutaneously, complement the spectrum of novel therapies. The glycoengineered antibody ublituximab is the next anti-CD20 therapy about to be approved. Within the next years, oral inhibitors of Bruton’s tyrosine kinase, currently under investigation in several phase III trials, may be licensed for multiple sclerosis. Those developments currently offer an individualized multiple sclerosis therapy, targeting patient needs with substantial effects on relapses, disability progression, and implications for daily life. In this up-to-date review, we provide a holistic overview about novel developments of the therapeutic landscape and upcoming approaches for multiple sclerosis treatment.

Vaccinations in patients with multiple sclerosis: a real-world, single-center experience

ABSTRACT Vaccines prevent infections in patients with multiple sclerosis (MS). Though recommendations regarding vaccinating patients with MS have been recently published, real-world data regarding vaccines’ planning in patients receiving disease-modifying drugs (DMDs) for MS are missing. Our aim was, therefore, to describe vaccination coverage rates, timing-proposal and safety in real-life vaccinating patients with MS undergoing DMDs before the start of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination campaign. Patients followed at our MS-center were referred to individualized immunization-programs customized to Italian recommendations, patients’ risks, immunity to exanthematic diseases, ongoing DMDs, or therapy-start urgency. Disease-activity stated the need for an essential immunization-cycle, whose core was composed by four vaccines: meningococcal-B, pneumococcal conjugated, Haemophilus influenzae B, and meningococcal-ACWY vaccines. Vaccines were administered prior to the planned DMD-start when possible, inactivated-vaccines >2 weeks and live-vaccines >4 weeks before treatment-start. Patients received a 6-months clinical-/radiological-follow-up after immunization. One-hundred and ninety-five patients were vaccinated between April 2017 and January 2021. 124/195 (63.6%) started a vaccination-program before therapy-start/-switch and 108/124 (87.1%) effectively completed immunization before new therapy-start without any delay. The time needed for immunization-conclusion reached a median of 27 (confidence interval 22) days in 2020. No increase in clinical-/radiological-activity 3-/6-months after immunization was noted. In conclusion, our study confirmed feasibility and safety of a vaccination-protocol in patients with MS whose duration resulted in a median of 27 days.

Establishment of a human induced pluripotent stem cell line (TAUi008-A) derived from a multiple sclerosis patient

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system where the main pathogenetic events include demyelination and axonal degeneration. Here, we generated a human induced pluripotent stem cell (hiPSC) line from peripheral blood mononuclear cells of an MS patient utilizing Sendai virus reprogramming. The produced hiPSC line expressed pluripotency markers, differentiated into three germ layers, showed a normal karyotype and was free of virus vectors, transgenes and mycoplasma. Established hiPSCs are a valuable source for studies of MS disease modeling and drug discovery.

P-684 The impact of oral sphingosine-1-phosphate analogue on ovarian aging in women with multiple sclerosis

Abstract Study question Is there a protective effect of oral sphingosine-1-phosphate analogue (S1P) on ovarian reserve? Summary answer The use of oral long acting S1P analogue may reduce spontaneous primordial follicle loss and preserve ovarian reserve in women of reproductive age. What is known already The number of primordial follicles decrease by apoptosis with advancing age in women. Seramid pathway is one of the apoptosis regulatory pathways in human ovaries. An increase in the balance between ceramide and S1P in S1P direction, known as cell membrane sphingomyelins, inhibits follicular apoptosis. Fingolimod (Novartis, Germany), a long-acting oral analogue of S1P, is a drug used in the treatment of multiple sclerosis (MS). We have previously found that use of fingolimod might reduce the spontaneous follicular apoptosis and increase the number of residual primordial follicles in a rat model. Study design, size, duration A prospective cohort study. Twenty-one consecutive women in reproductive age to whom fingolimod therapy were commenced for MS at Hacettepe University, Department of Neurology in between 2018 – 2021were included. Participants/materials, setting, methods Regularly menstruating women under &amp;lt;38 years old was included. Serum Anti-Mullerian Hormone (AMH) levels were measured at the beginning of Fingolimod, 6th and 12th months of the treatment. The decrease in serum AMH levels were calculated and compared with standard AMH decrease in healthy women. Main results and the role of chance The mean±standard deviation (SD) age of the 21 patients was 26.95±6.07. The mean±SD of AMH level at the beginning was 2,62±1,64 ng/ml. The respective figure for the 6th month and 12th month were 3,10±2,02 and 1,70±1,70 ng/ml. Overall, there was an increase of 0.6 ng/ml in mean AMH during this period. AMH level decreased in 2 patients, remained unchanged in 2 patients, and increased in 5 patients. Limitations, reasons for caution High (∼50%) loss to follow-up rate is a main limitation. Wider implications of the findings Oral long-acting MS drug fingolimod may have a protective effect on ovarian reserve in human by reducing spontaneous follicle loss rate, studies with larger sample size and longer follow-up period is warranted to demonstrate this effect. Trial registration number not applicable

Single-Nucleus RNA-seq of Normal-Appearing Brain Regions in Relapsing-Remitting vs. Secondary Progressive Multiple Sclerosis: Implications for the Efficacy of Fingolimod.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease that alters central nervous system (CNS) functions. Relapsing-remitting MS (RRMS) is the most common form, which can transform into secondary-progressive MS (SPMS) that is associated with progressive neurodegeneration. Single-nucleus RNA sequencing (snRNA-seq) of MS lesions identified disease-related transcriptomic alterations; however, their relationship to non-lesioned MS brain regions has not been reported and which could identify prodromal or other disease susceptibility signatures. Here, snRNA-seq was used to generate high-quality RRMS vs. SPMS datasets of 33,197 nuclei from 8 normal-appearing MS brains, which revealed divergent cell type-specific changes. Notably, SPMS brains downregulated astrocytic sphingosine kinases (SPHK1/2) – the enzymes required to phosphorylate and activate the MS drug, fingolimod. This reduction was modeled with astrocyte-specific Sphk1/2 null mice in which fingolimod lost activity, supporting functionality of observed transcriptomic changes. These data provide an initial resource for studies of single cells from non-lesioned RRMS and SPMS brains.

Disease-Modifying Drugs for Multiple Sclerosis and Association With Survival

Background and ObjectivesWe examined the association between the disease-modifying drugs (DMDs) for multiple sclerosis (MS) and survival in a multiregion population-based study.MethodsWe accessed multiple administrative health databases from 4 Canadian provinces. Persons with MS were identified and followed from the most recent of the first MS or demyelinating event or January 1, 1996 (index date), until death, emigration, or December 31, 2017. Association between the first-generation and second-generation DMDs and all-cause mortality was examined using stratified Cox proportional hazard models, reported as adjusted hazard ratios (aHRs). Timing of DMD initiation was explored, with findings reported at 2, 5, or 10 years postindex date, representing very early, early, or late initiation.ResultsWe identified 35,894 persons with MS; 72% were female. The mean age at index date was 44.5 years (SD = 13.6). The total person-years of follow-up while DMD-exposed was 89,180, and total person-years while unexposed was 342,217. Compared with no exposure, exposure to any DMD or to any first-generation DMD was associated with a 26% lower hazard of mortality (both aHRs 0.74; 95% CI 0.56–0.98), while any second-generation DMD exposure was associated with a 33% lower hazard (aHR 0.67; 95% CI 0.46–0.98). Earlier DMD initiation (beta-interferon or glatiramer acetate vs no exposure) was associated with a significant mortality effect (p < 0.05), while later initiation was not (95% CIs included 1). However, the survival advantage with earlier initiation diminished over time, no longer reaching statistical significance at 15 years postindex date.DiscussionOur study demonstrates an association between the DMDs for MS and improved survival in the real-world setting.

Repurposing Histaminergic Drugs in Multiple Sclerosis.

Multiple sclerosis is an autoimmune disease with a strong neuroinflammatory component that contributes to severe demyelination, neurodegeneration and lesions formation in white and grey matter of the spinal cord and brain. Increasing attention is being paid to the signaling of the biogenic amine histamine in the context of several pathological conditions. In multiple sclerosis, histamine regulates the differentiation of oligodendrocyte precursors, reduces demyelination, and improves the remyelination process. However, the concomitant activation of histamine H1–H4 receptors can sustain either damaging or favorable effects, depending on the specifically activated receptor subtype/s, the timing of receptor engagement, and the central versus peripheral target district. Conventional drug development has failed so far to identify curative drugs for multiple sclerosis, thus causing a severe delay in therapeutic options available to patients. In this perspective, drug repurposing offers an exciting and complementary alternative for rapidly approving some medicines already approved for other indications. In the present work, we have adopted a new network-medicine-based algorithm for drug repurposing called SAveRUNNER, for quantifying the interplay between multiple sclerosis-associated genes and drug targets in the human interactome. We have identified new histamine drug-disease associations and predicted off-label novel use of the histaminergic drugs amodiaquine, rupatadine, and diphenhydramine among others, for multiple sclerosis. Our work suggests that selected histamine-related molecules might get to the root causes of multiple sclerosis and emerge as new potential therapeutic strategies for the disease.

Cladribine Treatment for MS Preserves the Differentiative Capacity of Subsequently Generated Monocytes, Whereas Its Administration In Vitro Acutely Influences Monocyte Differentiation but Not Microglial Activation.

Cladribine (2-chlorodeoxyadenosine, 2CdA) is one of the most effective disease-modifying drugs for multiple sclerosis (MS). Cladribine is a synthetic purine nucleoside analog that induces cell death of lymphocytes and oral cladribine treatment leads to a long-lasting disease stabilization, potentially attributable to immune reconstitution. In addition to its effects on lymphocytes, cladribine has been shown to have immunomodulatory effects on innate immune cells, including dendritic cells and monocytes, which could also contribute to its therapeutic efficacy. However, whether cladribine can modulate human macrophage/microglial activation or monocyte differentiation is currently unknown. The aim of this study was to determine the immunomodulatory effects of cladribine upon monocytes, monocyte-derived macrophages (MDMs) and microglia. We analyzed the phenotype and differentiation of monocytes from MS patients receiving their first course of oral cladribine both before and three weeks after the start of treatment. Flow cytometric analysis of monocytes from MS patients undergoing cladribine treatment revealed that the number and composition of CD14/CD16 monocyte subsets remained unchanged after treatment. Furthermore, after differentiation with M-CSF, such MDMs from treated MS patients showed no difference in gene expression of the inflammatory markers compared to baseline. We further investigated the direct effects of cladribine in vitro using human adult primary MDMs and microglia. GM-CSF-derived MDMs were more sensitive to cell death than M-CSF-derived MDMs. In addition, MDMs treated with cladribine showed increased expression of costimulatory molecules CD80 and CD40, as well as expression of anti-inflammatory, pro-trophic genes IL10 and MERTK, depending on the differentiation condition. Cladribine treatment in vitro did not modulate the expression of activation markers in human microglia. Our study shows that cladribine treatment in vitro affects the differentiation of monocytes into macrophages by modulating the expression of activation markers, which might occur similarly in tissue after their infiltration in the CNS during MS.