Differential gene expression in B cells and T helper cells following high-dose glucocorticoid therapy for multiple sclerosis relapse.

BACKGROUND: Despite remarkable advances in the therapy of multiple sclerosis (MS), patients with MS may still experience relapses. High-dose short-term methylprednisolone (MP) remains the standard treatment in the acute management of MS relapses due to its potent anti-inflammatory and immunosuppressive properties. However, there is a lack of studies on the cell type-specific transcriptome changes that are induced by this synthetic glucocorticoid (GC). Moreover, it is not well understood why some patients do not benefit adequately from MP therapy. METHODS: We collected peripheral blood from MS patients in relapse immediately before and after ∼3-5 days of therapy with MP at 4 study centers. CD19+ B cells and CD4+ T cells were then isolated for profiling the transcriptome with high-density arrays. The patients' improvement of neurological symptoms was evaluated after ∼2 weeks by the treating physicians. We finally analyzed the data to identify genes that were differentially expressed in response to the therapy and whose expression differed between clinical responders and non-responders. RESULTS: After MP treatment, a total of 33 genes in B cells and 55 genes in T helper cells were significantly up- or downregulated. The gene lists overlap in 10 genes and contain genes that have already been described as GC-responsive genes in the literature on other cell types and diseases. Their differential expression points to a rapid and coordinated modulation of multiple signaling pathways that influence transcription. Genes that were previously suggested as potential prognostic biomarkers of the clinical response to MP therapy could not be confirmed in our data. However, a greater increase in the expression of genes encoding proteins with antimicrobial activity was detected in CD4+ T cells from non-responders compared to responders. CONCLUSION: Our study delved into the cell type-specific effects of MP at the transcriptional level. The data suggest a therapy-induced ectopic expression of some genes (e.g., AZU1, ELANE and MPO), especially in non-responders. The biological consequences of this remain to be explored in greater depth. A better understanding of the molecular mechanisms underlying clinical recovery from relapses in patients with MS will help to optimize future treatment decisions.

Time to Disability Milestones and Annualized Relapse Rates in NMOSD and MOGAD.

OBJECTIVE: To investigate accumulation of disability in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) in a changing treatment landscape. We aimed to identify risk factors for the development of disability milestones in relation to disease duration, number of attacks, and age. METHODS: We analyzed data from individuals with NMOSD and MOGAD from the German Neuromyelitis Optica Study Group registry. Applying survival analyses, we estimated risk factors and computed time to disability milestones as defined by the Expanded Disability Status Score (EDSS). RESULTS: We included 483 patients: 298 AQP4-IgG+ NMOSD, 52 AQP4-IgG-/MOG-IgG- NMOSD patients, and 133 patients with MOGAD. Despite comparable annualized attack rates, disability milestones occurred earlier and after less attacks in NMOSD patients than MOGAD patients (median time to EDSS 3: AQP4-IgG+ NMOSD 7.7 (95% CI 6.6-9.6) years, AQP4-IgG-/MOG-IgG- NMOSD 8.7) years, MOGAD 14.1 (95% CI 10.4-27.6) years; EDSS 4: 11.9 (95% CI 9.7-14.7), 11.6 (95% lower CI 7.6) and 20.4 (95% lower CI 14.1) years; EDSS 6: 20.1 (95% CI 16.5-32.1), 20.7 (95% lower CI 11.6), and 37.3 (95% lower CI 29.4) years; and EDSS 7: 34.2 (95% lower CI 31.1) for AQP4-IgG+ NMOSD). Higher age at onset increased the risk for all disability milestones, while risk of disability decreased over time. INTERPRETATION: AQP4-IgG+ NMOSD, AQP4-IgG-/MOG-IgG- NMOSD, and MOGAD patients show distinctive relapse-associated disability progression, with MOGAD having a less severe disease course. Investigator-initiated research has led to increasing awareness and improved treatment strategies appearing to ameliorate disease outcomes for NMOSD and MOGAD. ANN NEUROL 2024;95:720-732.

Side effects following vaccination in multiple sclerosis: a prospective, multi-centre cohort study.

Vaccines play a crucial role in preventing infections in patients with multiple sclerosis (MS), although concerns have been raised about potential worsening of the underlying disease. To investigate this, we conducted a prospective, multicentre, non-randomized observational study assessing changes in disease activity, safety, and clinical tolerability of vaccination in 222 MS patients on disease-modifying drugs. The majority of patients were female (76.6%) and 89.6% had relapsing-remitting MS. The vaccines administered were primarily seasonal influenza (56.3%) or tetanus-based vaccines (33.8%). Disease activity, as measured by annualized relapse rate, decreased significantly from 0.64 the year prior to vaccination to 0.38 in the following year. Moreover, the extended disability status scale remained stable within six months after vaccination in comparison to pre-vaccination values. Side effects were reported in 19.2% of vaccinated subjects, most commonly local side effects (65.2%) or flu-like symptoms (34.8%). Our findings suggest that standard non-live vaccines are safe and well-tolerated in MS patients and do not negatively impact disease activity.

Transcriptome alterations in peripheral blood B cells of patients with multiple sclerosis receiving immune reconstitution therapy.

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.

Correlation of Nabiximols Dose to Steady-State Concentrations of Cannabinoids in Urine Samples from Patients with Multiple Sclerosis.

Therapeutic drug monitoring of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is based on a complex procedure and is therefore not possible in most laboratories, especially in emergency cases. This work addresses the question of whether therapeutic drug monitoring of nabiximols can be performed using an immunological urine-based test system for cannabinoid abuse. Seventeen patients with multiple sclerosis were included in this study. Administered doses of nabiximols were correlated with immunologically determined urine concentrations of cannabinoids using the DRITM Cannabinoid (THC) Assay. Significant correlations with the administered nabiximols doses were found for creatinine-normalized urine concentrations of cannabinoids without (r = 0.675; p = 0.0015) and after (r = 0.650; p = 0.0044) hydrolysis, as well as for gas-chromatography-coupled mass spectrometry (GC/MS)-measured concentrations of the THC metabolite 11-nor-9-carboxy-Δ9-THC (THC-COOH) in urine samples (r = 0.571; p = 0.0084) by Pearson's correlation. In addition, doses were significantly correlated with plasma THC-COOH concentrations (r = 0.667; p = 0.0017) measured by GC/MS. Simple immunological cannabinoid measurements in urine samples could provide an estimate of nabiximols dosage, although the correlations obtained here were weak because of the small number of patients observed. Longitudinal monitoring of individual patients is expected to exhibit good results of therapeutic drug monitoring of nabiximols.

Implication of genetic variants in primary microRNA processing sites in the risk of multiple sclerosis.

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.

Vaccination and immunotherapies in neuroimmunological diseases.

Neuroimmunological diseases and their treatment compromise the immune system, thereby increasing the risk of infections and serious illness. Consequently, vaccinations to protect against infections are an important part of the clinical management of these diseases. However, the wide variety of immunotherapies that are currently used to treat neuroimmunological disease - particularly multiple sclerosis and neuromyelitis optica spectrum disorders - can also impair immunological responses to vaccinations. In this Review, we discuss what is known about the effects of various immunotherapies on immunological responses to vaccines and what these effects mean for the safe and effective use of vaccines in patients with a neuroimmunological disease. The success of vaccination in patients receiving immunotherapy largely depends on the specific mode of action of the immunotherapy. To minimize the risk of infection when using immunotherapy, assessment of immune status and exclusion of underlying chronic infections before initiation of therapy are essential. Selection of the required vaccinations and leaving appropriate time intervals between vaccination and administration of immunotherapy can help to safeguard patients. We also discuss the rapidly evolving knowledge of how immunotherapies affect responses to SARS-CoV-2 vaccines and how these effects should influence the management of patients on these therapies during the COVID-19 pandemic.

The risk of infections for multiple sclerosis and neuromyelitis optica spectrum disorder disease-modifying treatments: Eighth European Committee for Treatment and Research in Multiple Sclerosis Focused Workshop Review. April 2021.

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.

Rituximab versus mitoxantrone: comparing effectiveness and safety in advanced relapsing multiple sclerosis.

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.

[The corona pandemic and multiple sclerosis: vaccinations and their implications for patients-Part 2: vaccine technologies]. / Die Corona-Pandemie und Multiple Sklerose: Impfungen und deren Implikationen für Patienten ­ Teil 2: Impfstofftechnologien.

Along with the challenges posed by the globally circulating COVID-19 pandemic, there have been some epochal advances in the field of vaccine technologies. In addition to the traditionally used dead, live and protein-based vaccines, vector-based and gene-based vaccines gained enormous attention in the course of this health crisis. The aim of this article is to provide an overview of multiple sclerosis (MS) and vaccination, recent advances in the SARS-CoV­2 vaccine landscape as well as a detailed discussion of the various vaccine technologies. Finally, clear recommendations in the context of disease-modifying treatment and vaccination in MS are highlighted.

[The corona pandemic and multiple sclerosis: vaccinations and their implications for patients-Part 1: recommendations]. / Die Corona-Pandemie und Multiple Sklerose: Impfungen und deren Implikationen für Patienten ­ Teil 1: Empfehlungen.

The ongoing COVID-19 pandemic is a global health crisis. New challenges are constantly emerging especially for the healthcare system, not least with the emergence of various viral mutations. Given the variety of immunomodulatory and immunosuppressive therapies for multiple sclerosis (MS) and the immense developments in vaccine production, there is a high need of information for people with MS. The aim of this article is therefore to provide an overview of MS and COVID-19 as well as to clarify the implications for patients with MS, especially regarding vaccination and to formulate appropriate recommendations.

Therapeutic plasma exchange in steroid-refractory multiple sclerosis relapses. A retrospective two-center study.

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.

Tick-borne encephalitis vaccination in multiple sclerosis: A prospective, multicenter study.

OBJECTIVE: To assess the changes in disease activity after tick-borne encephalitis (TBE) vaccination in patients with multiple sclerosis (MS) on a variety of disease-modifying drugs and to assess the immunogenicity, safety, and clinical tolerability of the vaccine in this patient group. METHODS: We conducted a prospective, multicenter, nonrandomized observational study. We enrolled 20 patients with MS receiving TBE vaccination who had been on disease-modifying treatment (DMT) for at least 6 months. Serum samples were obtained before and after 4 weeks of vaccination to determine the specific TBE antibody response. MS disease activity (Expanded Disability Status Scale and relapse rates) was evaluated for 1 year after immunization. Local and systemic adverse events were registered. RESULTS: In 20 subjects with TBE vaccination, the annualized relapse rate decreased from 0.65 in the year before vaccination to 0.21 in the following year. Expanded Disability Status Scale remained stable during the 2-year period before vaccination and 1 year after vaccination (range: 1.50-1.97). The geometric mean titer (GMT) increased from 169 Vienna units per milliliter (VIEU/mL) to 719 VIEU/mL 4 weeks after vaccination (p = 0.001), and 77.8% had protective antibody titers after vaccination. In 9 patients treated with beta interferons, GMT increased from 181 VIEU/mL to 690 VIEU/mL (p = 0.018). Three subjects treated with glatiramer acetate developed a 2- to 9.6-fold increase. Patients treated with fingolimod developed the lowest increase in antibody titer. CONCLUSION: TBE vaccination showed good tolerability and was safe in patients with MS. MS disease activity was not increased, and annualized relapse rates decreased after vaccination. Vaccine response differs according to the underlying DMT. TRIAL REGISTRATION: ClinicalTrials.gov, clinicaltrials.gov, Identifier: NCT02275741.

[Indications for varicella zoster and herpes zoster vaccination in multiple sclerosis: current situation]. / Varicella-zoster- und Herpes-zoster-Impfindikation bei Multipler Sklerose: aktuelle Situation.

In patients with multiple sclerosis (MS) primary varicella zoster virus (VZV) infections (chickenpox) or reactivation (shingles, herpes zoster) pose a particular challenge for neurologists and physicians in everyday clinical practice. On the one hand the various immunotherapeutic agents for treatment of MS have differently expressed risks for VZV-associated infections and on the other hand the currently available vaccination strategies (dead vs. live vaccines, single vs. combination vaccines) require an individualized approach. Moreover, in addition to the optimal timing of vaccination during the course of MS, the appropriate vaccine and, where indicated, the use of antiviral drugs should be determined.

Vaccination in Multiple Sclerosis: Friend or Foe?

Multiple sclerosis (MS) is a debilitating disease of the central nervous systems (CNS). Disease-modifying treatments (including immunosuppressive treatments) have shown positive effects on the disease course, but are associated with systemic consequences on the immune system and may increase the risk of infections and alter vaccine efficiency. Therefore, vaccination of MS patients is of major interest. Over the last years, vaccine hesitancy has steadily grown especially in Western countries, partly due to fear of sequelae arising from vaccination, especially neurological disorders. The interaction of vaccination and MS has been discussed for decades. In this review, we highlight the immunology of vaccination, provide a review of literature and discuss the clinical consideration of MS, vaccination and immunosuppression. In conclusion, there is consensus that MS cannot be caused by vaccines, neither by inactivated nor by live vaccines. However, particular attention should be paid to two aspects: First, in immunocompromised patients, live vaccines may lead to a stronger immune reaction with signs of the disease against which the patients have been vaccinated, albeit in weakened form. Second, protection provided by vaccination should be controlled in patients who have been vaccinated while receiving immunomodulatory or immunosuppressive treatment. In conclusion, there is evidence that systemic infections can worsen MS, thus vaccination will lower the risk of relapses by reducing the risk of infections. Therefore, vaccination should be in general recommended to MS patients.

A genetic variant associated with multiple sclerosis inversely affects the expression of CD58 and microRNA-548ac from the same gene.

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.

Immunogenicity and predictors of response to a single dose trivalent seasonal influenza vaccine in multiple sclerosis patients receiving disease-modifying therapies.

AIMS: To evaluate the immunogenicity and safety of a seasonal influenza vaccine in a cohort of multiple sclerosis (MS) patients receiving different immunomodulating/immunosuppressive therapies and assess predictors of immune response. METHODS: A prospective, multicenter, non-randomized observational study including 108 patients receiving a trivalent seasonal influenza vaccination was conducted. Influenza-specific antibody titers (H1N1, H3N2, and influenza B) were measured to evaluate rates of seroprotection and seroconversion/significant titer increase. Univariable and multivariable analyses were performed to identify prognostic factors of vaccination outcomes. RESULTS: Regarding the whole cohort, seroprotection rates >70% were achieved for each influenza strain. Interferon-treated patients reached high seroprotection rates (>84%). Good seroprotection rates were seen in patients treated with glatiramer acetate. In particular for H3N2, response rates were low in natalizumab-treated patients and in the small subgroup of fingolimod-treated patients. Patients with a previous disease-modifying therapy and a longer disease duration were less likely to respond sufficiently. No severe adverse events were reported. MS disease activity was not increased after a one-year follow-up period. CONCLUSION: Vaccination led to good immunogenicity, especially in MS patients treated with interferons and glatiramer acetate. At least for the H1N1 strain, rates of seroprotection and seroconversion/significant titer increase were high (>70% and >60%, respectively) for all therapeutic subgroups. Patients with a longer duration of the disease are exposed to an increased risk of insufficient immune response to vaccination.

Intravenous immunoglobulin treatment in multiple sclerosis: A prospective, rater-blinded analysis of relapse rates during pregnancy and the postnatal period.

BACKGROUND: Multiple sclerosis (MS) affects predominantly young women. Currently available disease-modifying drugs have neither been approved during pregnancy nor nursing. AIMS: Evaluating the effect of treatment with intravenous immunoglobulin (IVIg) in MS patients with desire to have a baby. METHODS: In all, 70 MS patients were either treated with IVIg before conception, during first trimester of pregnancy and 12 months postnatal (group I, n = 38) or started IVIg after delivery for 12 months (group II, n = 23) or were untreated (group III, n = 9). Relapse rates and disease progression were analyzed. RESULTS: Pre-gestational relapse rates differed between groups. Lowest relapse rates were observed during late pregnancy, followed by an elevated relapse rate after delivery compared to the pre-pregnancy year and the first trimester. Only in group I, the postnatal relapse rate did not exceed the relapse rate before conception. IVIg treatment did not influence disease progression after delivery. CONCLUSIONS: In MS patients, IVIg treatment during and/or after delivery is an option to reduce the incidence of relapses during pregnancy and the postnatal period. Surprisingly, untreated patients becoming pregnant showed an increase in the relapse rate in the first trimester compared with the pre-gestational period. How alterations of hormone status during pregnancy affect disease activity in MS has to be further investigated.

Transcriptome profiling of peripheral blood immune cell populations in multiple sclerosis patients before and during treatment with a sphingosine-1-phosphate receptor modulator.

AIMS: Fingolimod is a sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of the relapsing form of multiple sclerosis (MS). It prevents the egress of lymphocyte subpopulations from lymphoid tissues into the circulation. Here, we explored the broad effects of fingolimod on gene expression in different immune cell subsets. METHODS: Utilizing 150 high-resolution microarrays from Affymetrix, we obtained the transcriptome profiles of 5 cell populations, which were separated from the peripheral blood of MS patients prior to and following oral administration of fingolimod. RESULTS: After 3 months of treatment, significant transcriptome shifts were seen in CD4+ and CD8+ cells, which is mainly attributable to the selective homing of naive T cells and central memory T cells. Although the number of B cells was greatly reduced in the blood of fingolimod-treated MS patients, the analysis of differential expression in CD19+ cells identified only a small set of 42 genes, which indicated a slightly higher frequency of transitional B cells. The transcriptome signatures of CD14+ monocytes and CD56+ natural killer cells were not affected. CONCLUSION: Our study corroborates changes in the composition of circulating immune cells in response to fingolimod and delineates the respective implications at the RNA level. Our data may be valuable for comparing the effects of novel S1P receptor modulating agents, which may be a therapeutic option for patients with secondary progressive MS as well.

Fingolimod alters the transcriptome profile of circulating CD4+ cells in multiple sclerosis.

Multiple sclerosis is a demyelinating disease affecting the central nervous system. T cells are known to contribute to this immune-mediated condition. Fingolimod modulates sphingosine-1-phosphate receptors, thereby preventing the egress of lymphocytes, especially CCR7-expressing CD8+ and CD4+ T cells, from lymphoid tissues. Using Affymetrix Human Transcriptome Arrays (HTA 2.0), we performed a transcriptome profiling analysis of CD4+ cells obtained from the peripheral blood of patients with highly active relapsing-remitting multiple sclerosis. The samples were drawn before the first administration of fingolimod as well as 24 hours and 3 months after the start of therapy. Three months after treatment initiation, 890 genes were found to be differentially expressed with fold-change >2.0 and t-test p-value < 0.001, among them several microRNA precursors. A subset of 272 genes were expressed at lower levels, including CCR7 as expected, while 618 genes showed an increase in expression, e.g., CCR2, CX3CR1, CD39, CD58 as well as LYN, PAK1 and TLR2. To conclude, we studied the gene expression of CD4+ cells to evaluate the effects of fingolimod treatment, and we identified 890 genes to be altered in expression after continuous drug administration. T helper cells circulating in the blood during fingolimod therapy present a distinct gene expression signature.