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Background: The modifiable risk factor exerting the most substantial influence on the development and disease course of multiple sclerosis (MS) is cigarette smoking. Furthermore, smoking is associated with a higher risk of suffering from one or more comorbidities and potentially contributes to polypharmacy. We aimed to use personality tests to explore health-promoting and harmful patient characteristics. Objective: To investigate two important factors influencing the course of MS – the degree of smoking dependence and the status of polypharmacy – in association with personality traits. Design: This is a bicentric, cross-sectional study. Methods: We collected sociodemographic, clinical and medical data from patients with MS ( n = 375) at two German neurological clinics. The participants were asked to complete the NEO Five-Factor Inventory (NEO-FFI) and the Temperament and Character Inventory-Revised (TCI-R). Relationships between variables were examined using correlation analyses, and differences between groups were examined using linear models. Current smokers with MS were also asked to complete the Fagerström questionnaire to categorize them into patients with mild, moderate and severe smoking dependence. Results: In our sample, 67.5% were women, and the mean age was 48.1 years. The patients had a median Expanded Disability Status Scale of 3.0 at a median disease duration of 10 years. Patients with MS with severe smoking dependence had on average a significantly higher neuroticism score in the NEO-FFI compared to those with mild or moderate smoking dependence. Patients with MS and polypharmacy had significantly higher neuroticism scores than those without. In the extraversion scale of the NEO-FFI, patients with MS and polypharmacy had significantly lower scores on average. Significant differences were also found when analysing the TCI-R in patients with MS and heavy smoking dependence, with higher scores for harm avoidance (HA) and lower scores for reward dependence, self-directedness (S-D) and cooperativeness (CO) in various subscales. Polypharmacy in patients with MS was associated with higher scores for HA and self-transcendence. Furthermore, patients with polypharmacy showed lower values than patients without polypharmacy in individual subscales of the dimensions of persistence, S-D and CO. Conclusion: Using the NEO-FFI, we were able to show that neuroticism is a detrimental trait and extraversion a protective trait in patients with MS in relation to nicotine dependence and polypharmacy. In addition, the evaluation of the TCI-R showed that high HA as well as low S-D and CO scores were more common in patients with MS and nicotine dependence or polypharmacy. With this knowledge, the risk of polypharmacy and smoking can be understood in the context of personality characteristics and targeted treatment and counselling can be provided.

Abstract The recent SARS-CoV-2 pandemic and the vaccination campaign posed a challenge to patients with autoimmune disease, such as multiple sclerosis (MS). We aimed for investigating whether psychological/sociodemographic/clinical characteristics of MS patients are associated with SARS-CoV-2 vaccination status and self-reported vaccination side effects (SEs). We have asked patients with MS about their willingness to receive recommended standard vaccinations pre-pandemically since June 2019. Between 10/2021 and 01/2022, we surveyed 193 of these MS patients about their current SARS-CoV-2 vaccination status, their perception of vaccination-related SEs, and reasons for and against SARS-CoV-2 vaccination. 75.6% of the patients declared their willingness to receive standard vaccinations before the pandemic. 84.5%, 78.2%, and 13.0% of the patients had received the first, second, and third SARS-CoV-2 vaccination, respectively, until the follow-up survey. The most common reason for not getting vaccinated against SARS-CoV-2 was concern about possible side effects (82.1%), followed by the belief that the vaccines had not been adequately tested (64.3%). Vaccination-related SEs were reported by 52.8% of the patients. Younger age, higher education, lower degree of disability, relapsing disease course, shorter disease duration, not receiving a disease-modifying therapy and higher anxiety and depression levels were associated with the occurrence of certain vaccination-related SEs. Concerns about novel vaccines are widespread among MS patients and necessitate targeted education of the patients, especially to those with more severe psychopathological symptoms (anxiety or depression) and those who are generally skeptical of vaccination.

Abstract Background Multiple sclerosis (MS) is a chronic, inflammatory and neurodegenerative disease that leads to irreversible damage to the brain and spinal cord. The goal of so-called "immune reconstitution therapies" (IRTs) is to achieve long-term disease remission by eliminating a pathogenic immune repertoire through intense short-term immune cell depletion. B cells are major targets for effective immunotherapy in MS. Objectives The aim of this study was to analyze the gene expression pattern of B cells before and during IRT (i.e., before B-cell depletion and after B-cell repopulation) to better understand the therapeutic effects and to identify biomarker candidates of the clinical response to therapy. Methods B cells were obtained from blood samples of patients with relapsing–remitting MS (n = 50), patients with primary progressive MS (n = 13) as well as healthy controls (n = 28). The patients with relapsing MS received either monthly infusions of natalizumab (n = 29) or a pulsed IRT with alemtuzumab (n = 15) or cladribine (n = 6). B-cell subpopulation frequencies were determined by flow cytometry, and transcriptome profiling was performed using Clariom D arrays. Differentially expressed genes (DEGs) between the patient groups and controls were examined with regard to their functions and interactions. We also tested for differences in gene expression between patients with and without relapse following alemtuzumab administration. Results Patients treated with alemtuzumab or cladribine showed on average a > 20% lower proportion of memory B cells as compared to before IRT. This was paralleled by profound transcriptome shifts, with > 6000 significant DEGs after adjustment for multiple comparisons. The top DEGs were found to regulate apoptosis, cell adhesion and RNA processing, and the most highly connected nodes in the network of encoded proteins were ESR2, PHB and RC3H1. Higher mRNA levels of BCL2, IL13RA1 and SLC38A11 were seen in patients with relapse despite IRT, though these differences did not pass the false discovery rate correction. Conclusions We show that B cells circulating in the blood of patients with MS undergoing IRT present a distinct gene expression signature, and we delineated the associated biological processes and gene interactions. Moreover, we identified genes whose expression may be an indicator of relapse risk, but further studies are needed to verify their potential value as biomarkers.

Abstract Vaccination is a key strategy for controlling the SARS-CoV-2 pandemic. Acceptance of SARS-CoV-2 vaccines by chronically ill patients, such as multiple sclerosis (MS) patients, plays an important role in prevention of complicated disease course. This longitudinal, prospective, multi-centre-study of German MS-patients aimed to detect socio-demographic, clinical, or psychological determinants of attitudes towards standard vaccines, SARS-CoV-2 vaccines, and governmental measures before/during the pandemic. Exactly 404 MS-patients were investigated by standardized questionnaires and structured interviews on socio-demographic, clinical-neurological, and psychological characteristics, vaccination status, and vaccination from June 2019. Data on SARS-CoV-2 vaccination willingness were collected in two follow-up assessments (1st: June to July 2020, before SARS-CoV-2 vaccine availability, N = 200; 2nd: March to May 2021, after SARS-CoV-2 vaccine availability, N = 157). Age, sex, MS course type, depression, and personality characteristics (Extraversion, Novelty seeking, Self-directedness, and Cooperativeness) were significantly associated with vaccination willingness. Although the majority of MS-patients showed SARS-CoV-2 vaccination willingness at both follow-ups (1st: 60%, 2nd: 61%), a substantial proportion had concerns and were undecided or opposed to vaccination. Socio-demographic variables like age and sex, psychopathological status, and various personality characteristics might influence vaccination willingness and should be considered when discussing with MS-patients about SARS-CoV-2 vaccination.

Patients with multiple sclerosis (MS) often take multiple drugs at the same time to modify the course of disease, alleviate neurological symptoms and manage co-existing conditions. A major consequence for a patient taking different medications is a higher risk of treatment failure and side effects. This is because a drug may alter the pharmacokinetic and/or pharmacodynamic properties of another drug, which is referred to as drug-drug interaction (DDI). We aimed to predict interactions of drugs that are used by patients with MS based on a deep neural network (DNN) using structural information as input. We further aimed to identify potential drug-food interactions (DFIs), which can affect drug efficacy and patient safety as well. We used DeepDDI, a multi-label classification model of specific DDI types, to predict changes in pharmacological effects and/or the risk of adverse drug events when two or more drugs are taken together. The original model with ~34 million trainable parameters was updated using >1 million DDIs recorded in the DrugBank database. Structure data of food components were obtained from the FooDB database. The medication plans of patients with MS (n = 627) were then searched for pairwise interactions between drug and food compounds. The updated DeepDDI model achieved accuracies of 92.2% and 92.1% on the validation and testing sets, respectively. The patients with MS used 312 different small molecule drugs as prescription or over-the-counter medications. In the medication plans, we identified 3748 DDIs in DrugBank and 13,365 DDIs using DeepDDI. At least one DDI was found for most patients (n = 509 or 81.2% based on the DNN model). The predictions revealed that many patients would be at increased risk of bleeding and bradycardic complications due to a potential DDI if they were to start a disease-modifying therapy with cladribine (n = 242 or 38.6%) and fingolimod (n = 279 or 44.5%), respectively. We also obtained numerous potential interactions for Bruton’s tyrosine kinase inhibitors that are in clinical development for MS, such as evobrutinib (n = 434 DDIs). Food sources most often related to DFIs were corn (n = 5456 DFIs) and cow’s milk (n = 4243 DFIs). We demonstrate that deep learning techniques can exploit chemical structure similarity to accurately predict DDIs and DFIs in patients with MS. Our study specifies drug pairs that potentially interact, suggests mechanisms causing adverse drug effects, informs about whether interacting drugs can be replaced with alternative drugs to avoid critical DDIs and provides dietary recommendations for MS patients who are taking certain drugs.

Background: Although effective contraception is strongly recommended during the therapy of women with multiple sclerosis (MS) with some immunomodulatory drugs, unplanned pregnancies still occur. Adequate medication management is essential to avoid foetal harm in the event of an unplanned pregnancy. Objective: The aim was to screen for medications used in women of childbearing age with MS that may pose a risk of side effects on foetal development. Methods: Sociodemographic, clinical and medication data were collected from 212 women with MS by structured interviews, clinical examinations and medical records. Using the databases from Embryotox, Reprotox, the Therapeutic Goods Administration and on the German summaries of product characteristics, we assessed whether the taken drugs were potentially harmful regarding the foetal development. Results: The majority of patients (93.4%) were taking one or more drugs for which a possible harmful effect on the foetus is indicated in at least one of the four databases used. This proportion was even higher in patients who used hormonal contraceptives (birth control pills or vaginal rings) (PwCo, n = 101), but it was also quite high in patients who did not use such contraceptives (Pw/oCo, n = 111) (98.0% and 89.2%, respectively). PwCo were significantly more likely to take five or more medications with potential foetal risk according to at least one database than Pw/oCo (31.7% versus 6.3%). PwCo were also more severely disabled (average Expanded Disability Status Scale score: 2.8 versus 2.3) and more frequently had comorbidities (68.3% versus 54.1%) than Pw/oCo. Conclusion: Data on the most commonly used drugs in MS therapy were gathered to study the risk of possible drug effects on foetal development in female MS patients of childbearing age. We found that the majority of drugs used by patients with MS are rated as having a potential risk of interfering with normal foetal development. More effective contraception and special pregnancy information programmes regarding the therapy management during pregnancy should be implemented to reduce potential risks to mother and child. Plain Language Summary Use of drugs not recommended during pregnancy by women with multiple sclerosis Introduction: Patients with multiple sclerosis (MS) often have to take different drugs simultaneously. During the therapy with some immunomodulatory drugs, effective contraception is strongly recommended. Nevertheless, unplanned pregnancies occur regularly in women with MS. Methods: Here, we investigated whether the 212 patients included in this study were taking drugs with known possibility of harm to the development of an unborn child. This was done using four different drug databases. Results: A subset of 111 patients was not taking hormonal contraceptives (birth control pills or vaginal rings). Of those, 99 patients were taking at least one drug that is not recommended during pregnancy according to at least one of the four databases. Most of the medications taken have the potential to affect normal foetal development. Conclusion: To ensure safe use of medications, the patients should be reminded of the importance of effective contraception.

BackgroundMultiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system to which a genetic predisposition contributes. Over 200 genetic regions have been associated with increased disease risk, but the disease-causing variants and their functional impact at the molecular level are mostly poorly defined. We hypothesized that single-nucleotide polymorphisms (SNPs) have an impact on pre-mRNA splicing in MS.MethodsOur study focused on 10 bioinformatically prioritized SNP–gene pairs, in which the SNP has a high potential to alter alternative splicing events (ASEs). We tested for differential gene expression and differential alternative splicing in B cells from MS patients and healthy controls. We further examined the impact of the SNP genotypes on ASEs and on splice isoform expression levels. Novel genotype-dependent effects on splicing were verified with splicing reporter minigene assays.ResultsWe were able to confirm previously described findings regarding the relation of MS-associated SNPs with the ASEs of the pre-mRNAs from GSDMB and SP140. We also observed an increased IL7R exon 6 skipping when comparing relapsing and progressive MS patients to healthy subjects. Moreover, we found evidence that the MS risk alleles of the SNPs rs3851808 (EFCAB13), rs1131123 (HLA-C), rs10783847 (TSFM), and rs2014886 (TSFM) may contribute to a differential splicing pattern. Of particular interest is the genotype-dependent exon skipping of TSFM due to the SNP rs2014886. The minor allele T creates a donor splice site, resulting in the expression of the exon 3 and 4 of a short TSFM transcript isoform, whereas in the presence of the MS risk allele C, this donor site is absent, and thus the short transcript isoform is not expressed.ConclusionIn summary, we found that genetic variants from MS risk loci affect pre-mRNA splicing. Our findings substantiate the role of ASEs with respect to the genetics of MS. Further studies on how disease-causing genetic variants may modify the interactions between splicing regulatory sequence elements and RNA-binding proteins can help to deepen our understanding of the genetic susceptibility to MS.

Background: Patients with multiple sclerosis (MS) often undergo complex treatment regimens, resulting in an increased risk of polypharmacy and potential drug-drug interactions (pDDIs). Drug interaction databases are useful for identifying pDDIs to support safer medication use.Objective: To compare three different screening tools regarding the detection and classification of pDDIs in a cohort of MS patients. Furthermore, we aimed at ascertaining sociodemographic and clinical factors that are associated with the occurrence of severe pDDIs.Methods: The databases Stockley’s, Drugs.com and MediQ were used to identify pDDIs by screening the medication schedules of 627 patients. We determined the overlap of the identified pDDIs and the level of agreement in pDDI severity ratings between the three databases. Logistic regression analyses were conducted to determine patient risk factors of having a severe pDDI.Results: The most different pDDIs were identified using MediQ (n = 1,161), followed by Drugs.com (n = 923) and Stockley’s (n = 706). The proportion of pDDIs classified as severe was much higher for Stockley’s (37.4%) than for Drugs.com (14.4%) and MediQ (0.9%). Overall, 1,684 different pDDIs were identified by at least one database, of which 318 pDDIs (18.9%) were detected with all three databases. Only 55 pDDIs (3.3%) have been reported with the same severity level across all databases. A total of 336 pDDIs were classified as severe (271 pDDIs by one database, 59 by two databases and 6 by three databases). Stockley’s and Drugs.com revealed 47 and 23 severe pDDIs, respectively, that were not included in the other databases. At least one severe pDDI was found for 35.2% of the patients. The most common severe pDDI was the combination of acetylsalicylic acid with enoxaparin, and citalopram was the drug most frequently involved in different severe pDDIs. The strongest predictors of having a severe pDDI were a greater number of drugs taken, an older age, living alone, a higher number of comorbidities and a lower educational level.Conclusions: The information on pDDIs are heterogeneous between the databases examined. More than one resource should be used in clinical practice to evaluate pDDIs. Regular medication reviews and exchange of information between treating physicians can help avoid severe pDDIs.

Background: Multiple sclerosis (MS) is the most common immune-mediated demyelinating disease in younger adults. Patients with MS (PwMS) are vulnerable to the presence of potential drug–drug interactions (pDDIs) and potential drug–food interactions (pDFIs) as they take numerous medications to treat MS, associated symptoms and comorbidities. Knowledge about pDDIs and pDFIs can increase treatment success and reduce side effects. Objective: We aimed at determining the frequency and severity of pDDIs and pDFIs in PwMS, with regard to polypharmacy. Methods: In the cross-sectional study, we analysed pDDIs and pDFIs of 627 PwMS aged ⩾18 years. Data collection was performed through patient record reviews, clinical examinations and structured patient interviews. pDDIs and pDFIs were identified using two DDI databases: Drugs.com Interactions Checker and Stockley’s Interactions Checker . Results: We identified 2587 pDDIs (counted with repetitions). Of 627 PwMS, 408 (65.1%) had ⩾ 1 pDDI. Polypharmacy (concomitant use of ⩾ 5 drugs) was found for 334 patients (53.3%). Patients with polypharmacy (Pw/P) were found to have a 15-fold higher likelihood of having ⩾ 1 severe pDDI compared with patients without polypharmacy (Pw/oP) (OR: 14.920, p

Summary: Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with a well-established genetic contribution to susceptibility. Over 200 genetic regions have been linked to the inherited risk of developing MS, but the disease-causing variants and their functional effects at the molecular level are still largely unresolved. We hypothesised that MS-associated single-nucleotide polymorphisms (SNPs) affect the recognition and enzymatic cleavage of primary microRNAs (pri-miRNAs). Methods: Our study focused on 11 pri-miRNAs (9 primate-specific) that are encoded in genetic risk loci for MS. The levels of mature miRNAs and potential isoforms (isomiRs) produced from those pri-miRNAs were measured in B cells obtained from the peripheral blood of 63 MS patients and 28 healthy controls. We tested for associations between SNP genotypes and miRNA expression in cis using quantitative trait locus (cis-miR-eQTL) analyses. Genetic effects on miRNA stem-loop processing efficiency were verified using luciferase reporter assays. Potential direct miRNA target genes were identified by transcriptome profiling and computational binding site assessment. Findings: Mature miRNAs and isomiRs from hsa-mir-26a-2, hsa-mir-199a-1, hsa-mir-4304, hsa-mir-4423, hsa-mir-4464 and hsa-mir-4492 could be detected in all B-cell samples. When MS patient subgroups were compared with healthy controls, a significant differential expression was observed for miRNAs from the 5’ and 3’ strands of hsa-mir-26a-2 and hsa-mir-199a-1. The cis-miR-eQTL analyses and reporter assays pointed to a slightly more efficient Drosha-mediated processing of hsa-mir-199a-1 when the MS risk allele T of SNP rs1005039 is present. On the other hand, the MS risk allele A of SNP rs817478, which substitutes the first C in a CNNC sequence motif, was found to cause a markedly lower efficiency in the processing of hsa-mir-4423. Overexpression of hsa-mir-199a-1 inhibited the expression of 60 protein-coding genes, including IRAK2, MIF, TNFRSF12A and TRAF1. The only target gene identified for hsa-mir-4423 was TMEM47. Interpretation: We found that MS-associated SNPs in sequence determinants of pri-miRNA processing can affect the expression of mature miRNAs. Our findings complement the existing literature on the dysregulation of miRNAs in MS. Further studies on the maturation and function of miRNAs in different cell types and tissues may help to gain a more detailed functional understanding of the genetic basis of MS. Funding: This study was funded by the Rostock University Medical Center (FORUN program, grant: 889002), Sanofi Genzyme (grant: GZ-2016-11560) and Merck Serono GmbH (Darmstadt, Germany, an affiliate of Merck KGaA, CrossRef Funder ID: 10.13039/100009945, grant: 4501860307). NB was supported by the Stiftung der Deutschen Wirtschaft (sdw) and the FAZIT foundation. EP was supported by the Landesgraduiertenförderung Mecklenburg-Vorpommern.

Abstract Background Multiple sclerosis (MS) affects about three times more women than men. Due to variable MS courses, multiple therapies are necessary in clinical practice. Objective We aimed at conducting sex-specific analyses of MS patients regarding polypharmacy (≥ 5 drugs) and at identifying differences in the medication spectrum. Methods Clinico-demographic data were gathered from 306 patients using clinical examinations, structured patient interviews, and patient records. Statistical data analyses were performed to evaluate whether the same or different factors are associated with polypharmacy in both genders. Results Women (N = 218) and men (N = 88) showed similar polypharmacy rates (56.0% vs. 58.0%; p = 0.799). For both genders, higher age, severe disability degrees, comorbidities, and inpatient treatment were significantly associated with a higher polypharmacy risk. Low educational levels were predictors of polypharmacy only in women. Fampridine (p

Background: Rituximab (RTX), a CD20 depleting agent, is a frequently used off-label treatment for multiple sclerosis (MS), while mitoxantrone (MTX) is approved, albeit rarely used for active relapsing MS (RMS). However, observational data comparing RTX and MTX effectiveness and safety are scarce. Objective: We aimed to compare effectiveness and safety of MTX and RTX in patients with active RMS. Methods: From combined retrospective clinical data of three MS centers, we selected patients who had received at least one infusion of RTX or MTX and had at least a 6-month clinical follow-up available. Treatment groups were compared by propensity score (PS)-adjusted regression and inverse PS-weighted generalized estimated equation models regarding disability progression, relapse activity, and adverse events (AEs). Results: We included 292 RMS patients (mean age 41.8 years, 71.6% female) who received RTX (119 patients, mean age 36.8 years, 74.8% female) or MTX (173 patients mean age 45.3 years, 69.4% female). Using both PS methods, we did not find a significant effect favoring RTX or MTX treatment regarding the probability of disability worsening or relapse occurrence. However, RTX treatment was associated with a significantly lower probability of severe AEs and AEs. Conclusions: RTX shows comparable effectiveness but a favorable safety profile compared with MTX in active RMS.

Multiple sclerosis (MS) is a chronic autoimmune disease of the brain and spinal cord causing a wide range of symptoms such as impaired walking capability, spasticity, fatigue, and pain. The insulin-like growth factor (IGF) system has regulatory functions for the induction of inflammatory pathways in experimental encephalomyelitis. We have therefore assessed expression and regulation of the IGF system on the level of IGFs and IGFBPs in serum and cerebrospinal fluid (CSF) in the course of four repeated triamcinolone acetonide (TCA) administrations in two female and four male MS patients. Sample series of 20 treatment cycles were analyzed. IGF-I and IGF-II were quantified by ELISAs, and IGFBPs were analyzed by quantitative Western ligand (qWLB) and Western immunoblotting (WIB) in order to differentiate intact and fragmented IGFBPs. The ratios of fragmented to intact IGFBP-2 and -3 were calculated in serum and CSF. Finally, the ratios of IGF-I and IGF-II to the total IGF-binding activity, quantified by qWLB, were determined as an indicator of IGF-related bioactivity. After the fourth TCA administration, the average level of IGF-I was increased in serum (p < 0.001). The increase of IGF-I concentrations in serum resulted in an increased ratio of IGF-I to IGFBPs in the circulation. By contrast in CSF, fragmentation of IGFBP-2 and IGFBP-3 and the ratio of IGF-II to intact IGFBPs were decreased at the fourth TCA administration (p < 0.01). Furthermore, reduced fragmentation of IGFBP-3 in CSF was accompanied by increased concentrations of intact IGFBP-3 (p < 0.001). We conclude that reduced fragmentation of IGFBPs and concomitant reduction of IGF-II to IGFBP ratios indicate regulation of bioactivity of IGF-II in CSF during repeated intrathecal TCA administration in MS patients.

Background: Therapeutic plasma exchange (TPE) is frequently used in glucocorticosteroid (GCS)-refractory multiple sclerosis (MS) relapses. Data regarding predictors of treatment response are scarce. The objective of this study was to analyze predictive factors for response to TPE in GCS-refractory MS patients. Methods: A total of 118 MS patients in two tertiary MS centers were analyzed. Primary outcome was TPE response defined as marked, mild, or no improvement. Secondary outcome was change in expanded disability status scale (ΔEDSS). ΔEDSS and relapse activity within 6 months after TPE were studied. Results: Marked or mild improvement was observed in 78.8% of patients. ΔEDSS correlated significantly inversely with time from relapse to start of TPE (τ = –0.239, p = 0.001), age (τ = 0.182, p = 0.009) and disease duration (τ = –0.167, p = 0.017). In multivariate analysis, TPE response was predicted by diagnosis of relapsing MS [odds ratio (OR): 3.1], gadolinum-enhancement on magnetic resonance imaging (OR 3.2), age (OR 0.5 per 5 years older) and time from relapse onset to TPE (OR 0.7 per 7 days longer). Conclusion: Patients with longer disease duration and higher EDSS pre and post-TPE were more likely to show further disability progression or relapses within 6 months after TPE. No sustained effects were observed during the follow-up period.

Background and Aims: Multiple sclerosis (MS) is the most common neuroimmunological disease of the central nervous system in young adults. Despite recommended contraception, unplanned pregnancies can occur in women of childbearing age with MS. MS- and comorbidities-related multimedication in these patients represents a potential risk. We aimed to raise awareness regarding the frequency of polypharmacy and drug–drug interactions (DDIs) in female MS patients of childbearing age. Methods: Sociodemographic, clinical and pharmaceutical data were collected through patient records, clinical investigations and structured patient interviews of 131 women with MS. The clinical decision support software MediQ was used to identify potential DDIs. A medication and DDI profile of the study population was created by statistical analysis of the recorded data. Results: Of the 131 female MS patients, 41.2% were affected by polypharmacy (concurrent use of ⩾5 drugs). Polypharmacy was associated with higher age, higher degree of disability, chronic progressive MS disease course and comorbidities. With an average intake of 4.2 drugs per patient, a total of 1033 potential DDIs were identified. Clinically relevant DDIs were significantly more frequent in patients with polypharmacy than in patients without polypharmacy (31.5% versus 5.2%; Fisher’s exact test: p

Background: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease whose aetiology is not fully understood. The female sex is clearly predominant, with a sex ratio between 2 and 3. In primary progressive MS the sex ratio almost balances out. Since the age at onset is higher for patients with progressive onset (POMS) than for relapsing onset (ROMS), it can be hypothesized that the age at onset is a decisive factor for the sex ratio. Methods: To address this aspect, we compare clinical and demographic data between females and males for the different disease courses within the population of the German MS Register by the German MS Society. Only patients with complete details in mandatory data items and a follow-up visit since 01. Jan 2018 were included. Results: A total of 18,728 patients were included in our analyses, revealing a female-to-male ratio of 2.6 (2.7 for patients with ROMS and 1.3 for POMS). The age at diagnosis is higher in patients with POMS (43.3 and 42.3 years for females and males versus 32.1 and 33.2 years, respectively). Females irrespective of disease course are statistically significantly more often affected by cognitive impairment (POMS: p = 0.013, ROMS: p = 0.001) and depression (POMS: p = 0.002, ROMS: 0.001) and suffer more often from pain (POMS and ROMS: p

In patients suffering from multiple sclerosis (MS), intrathecal injection of triamcinolone acetonide (TCA) has been shown to improve symptoms of spasticity. Although repeated intrathecal injection of TCA has been used in a number of studies in late-stage MS patients with spinal cord involvement, no clinical-chemical data are available on the distribution of TCA in cerebrospinal fluid (CSF) or serum. Moreover, the effects of intrathecal TCA administration on the concentrations of endogenous steroids remain poorly understood. Therefore, we have quantified TCA and selected endogenous steroids in CSF and serum of TCA-treated MS patients suffering from spasticity. Concentrations of steroids were quantified by LC-MS, ELISA, or ECLIA and compared with the blood-brain barrier status, diagnosed with the Reibergram. The concentration of TCA in CSF significantly increased during each treatment cycle up to >5 μg/ml both in male and female patients (p < 0.001). Repeated TCA administration also evoked serum concentrations of TCA up to >30 ng/ml (p < 0.001) and severely depressed serum levels of cortisol and corticosterone (p < 0.001). In addition, concentrations of circulating estrogen were significantly suppressed (p < 0.001). Due to the potent suppressive effects of TCA on steroid hormone concentrations both in the brain and in the periphery, we recommend careful surveillance of adrenal function following repeated intrathecal TCA injections in MS patients.

Polypharmacy (PP) is a common problem in modern medicine, especially known to affect patients with chronic diseases such as multiple sclerosis (MS). With an increasing number of drugs taken, the risk of potential drug–drug interactions (pDDIs) is rising. This study aims to assess the prevalence and clinical relevance of polypharmacy and pDDIs in patients with MS. Pharmacological data of 627 patients with MS were entered into two drug–drug-interaction databases to determine the number and severity of pDDIs for each patient. The patients were divided into those with and without PP (total PP and prescription medication PP (Rx PP)). Of the 627 patients included, 53.3% and 38.6% had total PP and Rx PP, respectively. On average, every patient took 5.3 drugs. Of all patients, 63.8% had at least one pDDI with a mean of 4.6 pDDIs per patient. Less than 4% of all pDDIs were moderately severe or severe. Medication schedules should be checked for inappropriate medication and for possible interacting drugs to prevent pDDIs. Physicians as well as pharmacists should be more sensitive towards the relevance of pDDIs and know how they can be detected and avoided.

Telomeres are protective structures at the ends of linear chromosomes. Shortened telomere lengths (TL) are an indicator of premature biological aging and have been associated with a wide spectrum of disorders, including multiple sclerosis (MS). MS is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system. The exact cause of MS is still unclear. Here, we provide an overview of genetic, environmental and lifestyle factors that have been described to influence TL and to contribute to susceptibility to MS and possibly disease severity. We show that several early-life factors are linked to both reduced TL and higher risk of MS, e.g., adolescent obesity, lack of physical activity, smoking and vitamin D deficiency. This suggests that the mechanisms underlying the disease are connected to cellular aging and senescence promoted by increased inflammation and oxidative stress. Additional prospective research is needed to clearly define the extent to which lifestyle changes can slow down disease progression and prevent accelerated telomere loss in individual patients. It is also important to further elucidate the interactions between shared determinants of TL and MS. In future, cell type-specific studies and advanced TL measurement methods could help to better understand how telomeres may be causally involved in disease processes and to uncover novel opportunities for improved biomarkers and therapeutic interventions in MS.

Genome-wide association studies have identified more than 200 genetic variants to be associated with an increased risk of developing multiple sclerosis (MS). Still, little is known about the causal molecular mechanisms that underlie the genetic contribution to disease susceptibility. In this study, we investigated the role of the single-nucleotide polymorphism (SNP) rs1414273, which is located within the microRNA-548ac stem-loop sequence in the first intron of the CD58 gene. We conducted an expression quantitative trait locus (eQTL) analysis based on public RNA-sequencing and microarray data of blood-derived cells of more than 1000 subjects. Additionally, CD58 transcripts and mature hsa-miR-548ac molecules were measured using real-time PCR in peripheral blood samples of 32 MS patients. Cell culture experiments were performed to evaluate the efficiency of Drosha-mediated stem-loop processing dependent on genotype and to determine the target genes of this underexplored microRNA. Across different global populations and data sets, carriers of the MS risk allele showed reduced CD58 mRNA levels but increased hsa-miR-548ac levels. We provide evidence that the SNP rs1414273 might alter Drosha cleavage activity, thereby provoking partial uncoupling of CD58 gene expression and microRNA-548ac production from the shared primary transcript in immune cells. Moreover, the microRNA was found to regulate genes, which participate in inflammatory processes and in controlling the balance of protein folding and degradation. We thus uncovered new regulatory implications of the MS-associated haplotype of the CD58 gene locus, and we remind that paradoxical findings can be encountered in the analysis of eQTLs upon data aggregation. Our study illustrates that a better understanding of RNA processing events might help to establish the functional nature of genetic variants, which predispose to inflammatory and neurological diseases.

BACKGROUND:Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system. Given the chronic and heterogenous nature of the disease, treatment with various therapies is a frequent scenario in clinical practice. In persons with chronic morbidity such as MS patients, polypharmacy can give rise to considerable health problems. OBJECTIVES:The aim of the present study was to examine the frequency of polypharmacy among relapsing-remitting (RR) MS patients as well as to analyse sociodemographic and clinical factors, which might be associated with polypharmacy (use of five or more medications). Differences in medication between MS patients with and without secondary illnesses (PwSI and Pw/oSI), between men and women and between patients with and without polypharmacy (PwP and Pw/oP) were examined. METHODS:For 145 RRMS outpatients, we prospectively collected data by means of anamnesis, patient records, clinical examination and a structured patient interview. This was followed by comparative analyses of various patient subgroups (PwP vs. Pw/oP, PwSI vs. Pw/oSI, men vs. women). RESULTS:The proportion of included MS patients with polypharmacy (use of ≥5 medications) was 30.3%. PwP were significantly older than Pw/oP (45.9 vs. 41.7 years), had a lower level of education and showed a significantly higher median EDSS score (3.0 vs. 2.0). Comorbidities (p

Long-term assessment of ambulatory behavior and joint motion are valuable tools for the evaluation of therapy effectiveness in patients with neuromuscular disorders and gait abnormalities. Even though there are several tools available to quantify ambulatory behavior in a home environment, reliable measurement of joint motion is still limited to laboratory tests. The aim of this study was to develop and evaluate a novel inertial sensor system for ambulatory behavior and joint motion measurement in the everyday environment. An algorithm for behavior classification, step detection, and knee angle calculation was developed. The validation protocol consisted of simulated daily activities in a laboratory environment. The tests were performed with ten healthy subjects and eleven patients with multiple sclerosis. Activity classification showed comparable performance to commercially available activPAL sensors. Step detection with our sensor system was more accurate. The calculated flexion-extension angle of the knee joint showed a root mean square error of less than 5° compared with results obtained using an electro-mechanical goniometer. This new system combines ambulatory behavior assessment and knee angle measurement for long-term measurement periods in a home environment. The wearable sensor system demonstrated high validity for behavior classification and knee joint angle measurement in a laboratory setting.

Despite considerable advances in the treatment of multiple sclerosis, current drugs are only partially effective. Most patients show reduced disease activity with therapy, but still experience relapses, increasing disability, and new brain lesions. Since there are no reliable clinical or biological markers of disease progression, long-term prognosis is difficult to predict for individual patients. We identified 18 studies that suggested genes expressed in blood as predictive biomarkers. We validated the prognostic value of those genes with three different microarray data sets comprising 148 patients in total. Using these data, we tested whether the genes were significantly differentially expressed between patients with good and poor courses of the disease. Poor progression was defined by relapses and/or increase of disability during a two-year follow-up, independent of the administered therapy. Of 110 genes that have been proposed as predictive biomarkers, most could not be confirmed in our analysis. However, the G protein-coupled membrane receptor GPR3 was expressed at significantly lower levels in patients with poor disease progression in all data sets. GPR3 has therefore a high potential to be a biomarker for predicting future disease activity. In addition, we examined the IL17 cytokines and receptors in more detail and propose IL17RC as a new, promising, transcript-based biomarker candidate. Further studies are needed to better understand the roles of these receptors in multiple sclerosis and its treatment and to clarify the utility of GPR3 and IL17RC expression levels in the blood as markers of long-term prognosis.