Background:
Rituximab, an anti-CD20 monoclonal antibody leading to B lymphocyte depletion, is increasingly used as an off-label treatment option for multiple sclerosis (MS).
Objective:
To investigate ...the effectiveness and safety of rituximab in relapsing–remitting (RR) and progressive MS.
Methods:
This is a multicenter, retrospective study on consecutive MS patients treated off-label with rituximab in 22 Italian and 1 Swiss MS centers. Relapse rate, time to first relapse, Expanded Disability Status Scale (EDSS) progression, incidence of adverse events, and radiological outcomes from 2009 to 2019 were analyzed.
Results:
A total of 355/451 enrolled subjects had at least one follow-up visit and were included in the outcome analysis. Annualized relapse rate significantly decreases after rituximab initiation versus the pre-rituximab start year in RRMS (from 0.86 to 0.09, p < .0001) and in secondary-progressive (SP) MS (from 0.34 to 0.06, p < .0001) and had a slight decrease in primary-progressive (PP) MS patients (from 0.12 to 0.07, p = 0.45). After 3 years from rituximab start, the proportion of patients with a confirmed EDSS progression was 14.6% in the RRMS group, 24.7% in the SPMS group, and 41.5% in the PPMS group. No major safety concerns arose.
Conclusion:
Consistently with other observational studies, our data show effectiveness of rituximab in reducing disease activity in patients with MS.
In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) affects immune response to antigens. Therefore, post-vaccination serological assessments are needed to evaluate the ...effect of the vaccine on SARS-CoV-2 antibody response.
We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech,Inc or mRNA-1273, Moderna Tx,Inc). A blood collection before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche-Diagnostics). The log-transform of the antibody levels was analyzed by multivariable linear regression.
780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariable analysis, the antibody levels of patients on ocrelizumab (201-fold decrease (95%CI=128–317), p < 0·001), fingolimod (26-fold decrease (95%CI=16–42), p < 0·001) and rituximab (20-fold decrease (95%CI=10–43), p < 0·001) were significantly reduced as compared to untreated patients. Vaccination with mRNA-1273 resulted in a systematically 3·25-fold higher antibody level (95%CI=2·46–4·27) than with the BNT162b2 vaccine (p < 0·001). The antibody levels on anti-CD20 therapies correlated to the time since last infusion, and rituximab had longer intervals (mean=386 days) than ocrelizumab patients (mean=129 days).
In pwMS, anti-CD20 treatment and fingolimod led to a reduced humoral response to mRNA-based SARS-CoV-2 vaccines. As mRNA-1273 elicits 3·25-higher antibody levels than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 treatment or fingolimod. Combining our data with those on the cellular immune response to vaccines, and including clinical follow-up, will contribute to better define the most appropriate SARS-CoV-2 vaccine strategies in the context of DMTs and MS.
FISM2021/Special-Multi/001; Italian Ministry of Health‘Progetto Z844A 5 × 1000′.
Using placebo data from 3 randomized multiple sclerosis (MS) trials with uniform inclusion criteria, we investigated heterogeneity of Expanded Disability Status Scale (EDSS) progression by ...geographical areas. Our analysis revealed a significantly lower EDSS progression in Eastern European countries (10.8%) compared with Western Europe (13.1%) or the USA/Canada (21.4%, p < 0.001); EDSS improvement behaved the same way. This heterogeneity is not explained by differences of baseline variables. No differences were detected on more easily quantifiable measures, the Timed 25‐Foot Walk or the Multiple Sclerosis Functional Composite. At a time when disease progression represents the target for future interventions in MS, establishment of more quantitative and objective outcomes remains a key priority of MS research. Ann Neurol 2018;84:621–625
In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in patients with MS (pwMS) under different DMTs and to identify correlates of reduced protection.
This is a prospective ...Italian multicenter cohort study, long-term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis) study. 1855 pwMS scheduled for SARS-CoV-2 mRNA vaccination were enrolled and followed up to a mean time of 10 months. The cumulative incidence of breakthrough Covid-19 cases in pwMS was calculated before and after December 2021, to separate the Delta from the Omicron waves and to account for the advent of the third vaccine dose.
1705 pwMS received 2 m-RNA vaccine doses, 21/28 days apart. Of them, 1508 (88.5%) had blood assessment 4 weeks after the second vaccine dose and 1154/1266 (92%) received the third dose after a mean interval of 210 days (range 90-342 days) after the second dose. During follow-up, 131 breakthrough Covid-19 infections (33 during the Delta and 98 during the Omicron wave) were observed. The probability to be infected during the Delta wave was associated with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.57, p < 0.001); the protective role of antibodies was preserved over the whole follow up (HR=0.57, 95%CI=0.43-0.75, p < 0.001), with a significant reduction (HR=1.40, 95%CI=1.01-1.94, p=0.04) for the Omicron cases. The third dose significantly reduced the risk of infection (HR=0.44, 95%CI=0.21-0.90,p=0.025) during the Omicron wave.
The risk of breakthrough SARS-CoV-2 infections is mainly associated with reduced levels of the virus-specific humoral immune response.
Supported by FISM - Fondazione Italiana Sclerosi Multipla – cod. 2021/Special-Multi/001 and financed or co-financed with the ‘5 per mille’ public funding
•RTX is effective in preventing attacks in patients with NMOSD.•No concerning safety issues occurred in our real-life cohort.•Use of specific induction and maintenance regimen might boost RTX ...efficacy.•RTX could be less effective in MOG-ab positive patients.
To evaluate disease activity according to rituximab (RTX) induction and maintenance regimens in a multicenter real-life dataset of NMOSD patients.
This is an observational-retrospective multicentre study including patients with NMOSD treated with RTX in 21 Italian and 1 Swiss centers. Demographics, relapse rate and adverse events over the follow-up were summarized taking into account induction strategy (two-1 g infusions at a 15-day interval (IND-A) vs. 375 mg/m2/week infusions for one month (IND-B)) and maintenance therapy (regimen A (M-A) with fixed time-points infusions vs. regimen B (M-B) based on cytofluorimetric driven reinfusion regimens, the least further subdivided according to CD19+ B cells (M-B1) or CD27+ memory B cells (M-B2) monitoring).
131 subjects were enrolled, 127 patients completed the induction regimen and 119 patients had at least one follow-up visit and were included in the outcome analysis. Median follow-up was 1.7 years (range 0.1–11.6). Annualized relapse rate (ARR) was 1.7 in the year before RTX start and decreased to 0.19 during the follow-up. Both ARR and Time to first relapse (TTFR) analysis showed a trend toward an increased disease activity for IND-B and M-A. No patients with MT-B2 experienced relapses during the follow-up. Number of relapses in the year before RTX initiation and having received a previous treatment were significantly associated with higher ARR and reduced TTFR in the multivariate analysis.
We confirm RTX efficacy in NMOSD patients. Use of specific induction and maintenance protocols is warranted in order to foster RTX efficacy and to reduce costs and side effects.
Abstract Background In recent years the impact of disease-modifying drugs on long-term progression in multiple sclerosis (MS) was assessed both in observational studies and in extension of randomized ...controlled trial (RCT). Aim of this work was to quantitatively summarize by a meta-analysis the long-term impact of immunomodulatory drugs (Interferon-Beta (IFN-β) or Glatiramer Acetate (GA)) in relapsing-remitting (RR) MS patients. Methods We collected all published observational studies reporting the long-term efficacy of IFN-β or GA in RRMS patients. The primary outcome was the treatment effect on progression to a sustained EDSS score of 6 or to the Secondary Progressive (SP) phase. A non-parametric approach was adopted to test the overall treatment effect significance, while a random effect model was used to obtain a pooled quantitative estimate of the treatment benefit, in terms of hazard-ratios (HR) or Relative Risks, with their 95% confidence interval (CI). Results Fourteen studies, on a total of 13,238 RRMS patients, were included in the meta-analysis. All studies but two reported a consistent effect of immunomodulatory treatment on long-term disease progression; the pooled effect on progression to EDSS 6 or SP was significant ( p <0.01) when tested by the non-parametric test. The quantitative estimate of the treatment effect in reducing progression to EDSS 6 in the subset of studies reporting this outcome was HRpooled =0.49 (95% CI: 0.34–0.69), p <0.001. Conclusions Treatment with immunomodulators seems to reduce long-term probability of disability progression. Additional well-designed observational studies could help to confirm these findings.
OBJECTIVEWe wanted to evaluate efficacy on inflammatory parameters of rituximab (RTX)-personalized reinfusion scheme using a memory B cell–based treatment regimen.
METHODSThis is a prospective, ...uncontrolled, open-label study including patients with MS treated with RTX in 2 Italian MS units. All patients were treated with RTX induction, followed by maintenance infusion at the dosage of 375 mg/m, according to memory B cell repopulation (0.05% of peripheral-blood mononuclear cells PBMCs for the first 2 years, 0.1% of PBMC for the third year). MS activity was assessed as clinical or MRI activity.
RESULTSOne hundred two patients were included in the analysis. Mean follow-up was 2.40 years (range 0.57–7.15 years). The annualized relapse rate (ARR) was 0.67 in the year before RTX start and decreased to 0.01 in the 3 years after RTX initiation (global ARR). The proportion of patient with MS activity (i.e., relapse or MRI activity) was 63.16% in the year before RTX start and decreased to 8.7% (0–6 months), 1.3% (6–12 months), 0% (12–24 months), and 0% (24–36 months). Annualized RTX infusion rates were 1.67 (95% confidence interval CI1.43–1.94), 0.76 (95% CI0.58–0.98), and 0.78 (95% CI0.52–1.12) for the first 3 years after RTX initiation, respectively. Patients were reinfused with a mean infusion interval of 367 days (range 181–839 days).
CONCLUSIONThe results of this study show that the memory B cell–based RTX reinfusion protocol is able to reduce the mean number of RTX reinfusions with persistent reduction of disease activity.
CLASSIFICATION OF EVIDENCEThis study provides Class IV evidence that for patients with MS, a memory B cell–based RTX reinfusion protocol can reduce the mean number of RTX reinfusions with persistent reduction of disease activity.
Prion diseases are neurodegenerative conditions characterized by the conformational conversion of the cellular prion protein (PrPC), an endogenous membrane glycoprotein of uncertain function, into ...PrPSc, a pathological isoform that replicates by imposing its abnormal folding onto PrPC molecules. A great deal of evidence supports the notion that PrPC plays at least two roles in prion diseases, by acting as a substrate for PrPSc replication, and as a mediator of its toxicity. This conclusion was recently supported by data suggesting that PrPC may transduce neurotoxic signals elicited by other disease-associated protein aggregates. Thus, PrPC may represent a convenient pharmacological target for prion diseases, and possibly other neurodegenerative conditions. Here, we sought to characterize the activity of chlorpromazine (CPZ), an antipsychotic previously shown to inhibit prion replication by directly binding to PrPC. By employing biochemical and biophysical techniques, we provide direct experimental evidence indicating that CPZ does not bind PrPC at biologically relevant concentrations. Instead, the compound exerts anti-prion effects by inducing the relocalization of PrPC from the plasma membrane. Consistent with these findings, CPZ also inhibits the cytotoxic effects delivered by a PrP mutant. Interestingly, we found that the different pharmacological effects of CPZ could be mimicked by two inhibitors of the GTPase activity of dynamins, a class of proteins involved in the scission of newly formed membrane vesicles, and recently reported as potential pharmacological targets of CPZ. Collectively, our results redefine the mechanism by which CPZ exerts anti-prion effects, and support a primary role for dynamins in the membrane recycling of PrPC, as well as in the propagation of infectious prions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Neuronal ceroid lipofuscinoses (CNL) are lysosomal storage diseases that represent the most common cause of dementia in children. To date, 13 autosomal recessive (AR) and 1 autosomal dominant (AD) ...gene have been characterized. Biallelic variants in
cause CLN7 type, with nearly 50 pathogenic variants, mainly truncating and missense, reported so far. Splice site variants require functional validation. We detected a novel homozygous non-canonical splice-site variant in
in a 5-year-old girl who presented with progressive neurocognitive impairment and microcephaly. The diagnostic procedure was elicited by clinical genetics first, and then confirmed by cDNA sequencing and brain imaging. Inferred by the common geographic origin of the parents, an autosomal recessive inheritance was hypothesized, and SNP-array was performed as the first-line genetic test. Only three AR genes lying within the observed 24 Mb regions of homozygosity were consistent with the clinical phenotype, including
,
and
. The cerebral and cerebellar atrophy detected in the meantime by MRI, along with the suspicion of accumulation of ceroid lipopigment in neurons, prompted us to perform targeted
sequencing. Following the detection of a splice site variant of uncertain significance, skipping of exon 8 was demonstrated by cDNA sequencing, and the variant was redefined as pathogenic.
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