Soluble Receptor Isoform of IFN-Beta (sIFNAR2) in Multiple Sclerosis Patients and Their Association With the Clinical Response to IFN-Beta Treatment

Alternative splicing; Soluble receptors; IFNAR; Interferon beta; Multiple sclerosisEmpalmament alternatiu; Receptors solubles; IFNAR; Interferó beta; Esclerosi múltipleSplicing alternativo; Receptores solubles; IFNAR; Interferón beta; Esclerosis múltiplePurpose: Interferon beta receptor 2 subunit (IFNAR2) can be produced as a transmembrane protein, but also as a soluble form (sIFNAR2) generated by alternative splicing or proteolytic cleavage, which has both agonist and antagonist activities for IFN-β. However, its role regarding the clinical response to IFN-β for relapsing-remitting multiple sclerosis (RRMS) is unknown. We aim to evaluate the in vitro short-term effects and after 6 and 12 months of IFN-β therapy on sIFNAR2 production and their association with the clinical response in MS patients. Methods: Ninety-four RRMS patients were included and evaluated at baseline, 6 and 12 months from treatment onset. A subset of 41 patients were classified as responders and non-responders to IFN-β therapy. sIFNAR2 serum levels were measured by ELISA. mRNA expression for IFNAR1, IFNAR2 splice variants, MxA and proteases were assessed by RT-PCR. The short-term effect was evaluated in PBMC from RRMS patients after IFN-β stimulation in vitro. Results: Protein and mRNA levels of sIFNAR2 increased after IFN-β treatment. According to the clinical response, only non-responders increased sIFNAR2 significantly at both protein and mRNA levels. sIFNAR2 gene expression correlated with the transmembrane isoform expression and was 2.3-fold higher. While MxA gene expression increased significantly after treatment, IFNAR1 and IFNAR2 only slightly increased. After short-term IFN-β in vitro induction of PBMC, 6/7 patients increased the sIFNAR2 expression. Conclusions: IFN-β administration induces the production of sIFNAR2 in RRMS and higher levels might be associated to the reduction of therapeutic response. Thus, levels of sIFNAR2 could be monitored to optimize an effective response to IFN-β therapy.This research was funded by grants from the Instituto de Salud Carlos III and co-funded by European Regional Development Fund (ERDF), Technological Development Project in health DTS/1800045 to BO-M. BO-M holds a contract from Red Andaluza de Investigacion Clínica y Traslacional en Neurología (Neuro-reca) (RIC-0111-2019). PA-G is supported by Promoción de Empleo Joven e Implantación de la Garantía Juvenil 2018 (PEJ2018-002719-A). JR-B is supported by grants from Red Temática de Investigación Cooperativa, Red Española de Esclerosis Multiple REEM (RD16/0015/0010). LL holds a Nicolás Monardes research contract (RC-002-2019) from the Andalusian Ministry of Health and Family. IB-M holds a pFIS contract (FI19/00139) from the Spanish Science and Innovation Ministry

Natalizumab-immunogenicity evaluation in patients with infusion related events or disease exacerbations

IntroductionNatalizumab is a biologic drug for relapsing-remitting multiple sclerosis that may induce the generation of anti-drug antibodies in some patients. Anti-natalizumab antibodies (ANA) increase the risk of adverse events and reduce efficacy, being useful biomarkers for monitoring treatment response.MethodsRetrospective observational study including MS patients treated with natalizumab that experienced infusion-related events (IRE) or disease exacerbations (DE). ANA were tested by Elisa including a screening and a confirmation assay. Patients were further classified as transient (one positive result) or persistent (two or more positive results) ANA.ResultsA total of 1251 MS patients were included and 153 (12.3%) had ANA with at least one single point determination, which were more frequent among patients with IRE compared to those with DE (21,6% vs.10.8%) during the first six infusions. Two or more determinations ANA were performed in 184 patients, being 31.5% permanently positive and 7.1% transiently positive. Interestingly, 26.1% of patients that experienced DE had persistent ANA, while 2.6% were transient. In contrast, 43% of patients with IRE had persistent ANA, and 9.3% had transient antibodies. Patients with persistent antibodies had more frequently high levels at the first sampling compared to patients with transient ANA.ConclusionReal-world evidence shows that the presence of ANA is behind an important percentage of patients treated with natalizumab that experience IRE, as well as DE but in a lower degree. These findings support the need to systematically evaluate ANA towards a personalized management of these patients to avoid undesired complications

Case Report: Autoimmune Psychosis in Chromosome 22q11.2 Deletion Syndrome

Chromosome 22q11.2 deletion syndrome (22q11DS) is characterized by congenital cardiac abnormalities, hypoplastic thymus, palatal abnormalities, and hypocalcemia, although other clinical features are frequent such as autoimmune and psychiatric disorders. One-third of the patients have psychotic disorders, frequently followed by developmental regression and long-term cognitive disturbances. Despite humoral and cellular immunodeficiency are common in 22q11DS, it is associated with an increased prevalence of autoimmune disorders such as idiopathic thrombocytopenic purpura and juvenile idiopathic arthritis, likely due to immune dysregulations associated with thymic abnormalities, which plays a major role in self-tolerance. We report an unique case of a 14-year-old girl with 22q11DS that presented with subacute psychotic symptoms, intolerance to antipsychotics, CSF pleocytosis, and EEG abnormalities, that was successfully treated with empiric immunotherapy after fulfilling criteria for probable seronegative autoimmune encephalitis and probable autoimmune psychosis. The autoimmune etiology of these clinical features of 22q11DS has never been postulated despite the predisposition of this syndrome to present autoimmune disorders. We suggest the systematic evaluation with serum and CSF neuronal antibodies, MRI, and EEG of patients with 22q11DS that develop subacute psychotic symptoms or rapidly progressive cognitive decline. Early immunomodulatory therapies should be carefully considered if criteria of probable autoimmune psychosis or possible autoimmune encephalitis are fulfilled, as it may prevent long-term disabilities. Further studies are required to assess the autoimmune origin of psychosis and cognitive impairment associated with 22q11DS.Ye

Current Status of Biomarkers in Anti-N-Methyl-D-Aspartate Receptor Encephalitis

The discovery of biomarkers in rare diseases is of paramount importance to allow a better diagnosis, improve predictions of outcomes, and prompt the development of new treatments. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare autoimmune disorder associated with the presence of antibodies targeting the GluN1 subunit of the NMDAR. Since it was discovered in 2007, large efforts have been made towards the identification of clinical, paraclinical, and molecular biomarkers to better understand the immune mechanisms that govern the course of the disease as well as to define predictors of treatment response and long-term outcomes. However, most of these biomarkers are still in an exploratory phase, with only a few candidates reaching the final phases of the always-complex process of biomarker development, mainly due to the low incidence of the disease and its recent description. Clinical and paraclinical markers are probably the most widely explored in anti-NMDAR encephalitis, five of them combined in a clinical score to predict 1 year outcome. On the contrary, soluble molecules, such as persistent antibody positivity, antibody titers, cytokines, and other inflammatory mediators, have been proposed as biomarkers of clinical activity, inflammation, prognosis, and treatment response, but further studies are required for their clinical validation including larger and more homogenous cohorts of patients. Similarly, genetic susceptibility biomarkers are still in the exploratory phase and, therefore, weak conclusions can for now only be achieved. Thus, further studies are warranted to define biomarkers and unravel the underlying mechanisms driving rare diseases such as anti-NMDAR encephalitis. Future international collaborative studies with prospective designs that enable the enrollment of large cohorts will allow for the identification and validation of novel biomarkers for clinical decision-making.This work was developed within the BETPSY project, which was supported by a public grant overseen by the Agence Nationale de la Recherche (ANR), as part of the second Investissements d’Avenir program (ANR-18-RHUS-0012), and was performed within the framework of the LABEX CORTEX (ANR-11-LABX-0042) of the Université de Lyon operated by the ANR. N.L.C.P. received a grant from the Biomedical Research Institute of Málaga (IBIMA).Ye

Incidence and case fatality rate of COVID-19 in patients with active epilepsy.

This article estimates the incidence and fatality of coronavirus disease 2019 (COVID-19) and identifies potential risk factors for fatality in patients with active epilepsy. This is a cross-sectional observational study of patients with active epilepsy and COVID-19. A control group was used to compare the cumulative incidence and case-fatality rate (CFR). The main outcomes of the study were cumulative incidence, defined as number of patients with active epilepsy and COVID-19 admitted to an emergency department divided by the total number of patients with epilepsy at risk, and CFR based on the number of deaths during the enrollment period. Multiple logistic regression analysis was performed to investigate risk factors for fatality in patients with active epilepsy. Of the 1,537 patients who fulfilled the inclusion criteria, 21 (1.3%) had active epilepsy. The cumulative incidence (95% confidence interval [CI]) of COVID-19 in patients with epilepsy was higher (1.2% [0.6-2.4]) compared to the population without epilepsy (0.5% [0.5-0.5]). In reverse transcription PCR-positive patients, there were no significant differences in CFR in patients with active epilepsy compared to patients without epilepsy (33.3% vs 8.3%; p = 0.266). Of the 21 patients with active epilepsy, 5 (23%) died. In multivariate analysis, the factor associated with fatality in patients with active epilepsy was hypertension (odds ratio [OR] 2.8 [95% CI 1.3-21.6]). In another model, age (OR 1.0 [95% CI 1.0-1.1]) and epilepsy (OR 5.1 [95% CI 1.3-24.0]) were associated with fatality during hospitalization. COVID-19 cumulative incidence was higher in patients with active epilepsy. Epilepsy was associated with fatality during hospitalization. Hypertension was associated with fatality in patients with epilepsy

Cytokine dynamics and targeted immunotherapies in autoimmune encephalitis.

Autoimmune encephalitides constitute a diverse group of immune-mediated central nervous system disorders mainly characterized by the presence of antibodies targeting neuronal or glial antigens. Despite the notable contribution of antibody discovery to the understanding of their physiopathology, the specific immune cells and inflammatory mediators involved in autoimmune encephalitis are still poorly defined. However, cytokines have recently emerged as crucial signalling molecules in the pathogenesis of autoimmune encephalitis. Cytokines are biologically active, soluble, low-molecular-weight proteins or glycoproteins involved in a wide variety of physiological functions, including central nervous system development and homeostasis, immune surveillance, as well as proliferation and maturation of immune cells. Since unbalanced cytokine expression is considered a hallmark of many autoimmune central nervous system disorders, their identification and quantification has become an essential element in personalized medicine applied to the field of neuroimmunology. Several studies have explored the cytokine profile of autoimmune encephalitis, but their interpretation and comparison is challenging due to their small sample sizes and extremely high heterogeneity, especially regarding the cytokines analysed, type of sample used, and associated neural antibody. Only the cytokine profile of anti-N-methyl-D-aspartate receptor encephalitis has extensively been investigated, with findings suggesting that, although humoral immunity is the main effector, T cells may also be relevant for the development of this disorder. A better understanding of cytokine dynamics governing neuroinflammation might offer the opportunity of developing new therapeutic strategies against specific immune cells, cytokines, antibodies, or intracellular signalling cascades, therefore leading to better outcomes and preventing undesired side effects of the presently used strategies. In this review, we first summarize the current knowledge about the role of cytokines in the pathogenesis of autoimmune encephalitis, combining theoretical analysis with experimental validations, to assess their suitability as clinical biomarkers. Second, we discuss the potential applicability of the novel targeted immunotherapies in autoimmune encephalitis depending on the immunobiology of the associated antibody, their limitations, as well as the main limitations that should be addressed in future studies

Prognostic Value of Persistent CSF Antibodies at 12 Months in Anti-NMDAR Encephalitis

International audienceBackground and Objectives Anti-NMDA receptor (NMDAR) encephalitis is defined by the presence of antibodies (Abs) targeting the NMDAR in the CSF. This study aimed to determine the prognostic value of persistent CSF NMDAR-Abs during follow-up. Methods This retrospective observational study included patients diagnosed with anti-NMDAR encephalitis in the French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis and for whom CSF samples were obtained at diagnosis and >4 months of follow-up to evaluate CSF NMDAR-Ab persistence. Because patients were tested for CSF NMDAR-Abs at different time points, samples were stratified into different periods of follow-up (i.e., 12 months was considered for the 9- to 16-month follow-up period). Results Among the 501 patients diagnosed with anti-NMDAR encephalitis between January 2007 and June 2020, 89 (17%) were tested between 4 and 120 months for CSF NMDAR-Abs after clinical improvement and included in the study (75/89 women, 84%; median age 20 years, interquartile range [IQR] 16–26). During follow-up, 21 of 89 (23%) patients had a relapse after a median time of 29 months (IQR 18–47), and 20 of 89 (22%) had a poor outcome (mRS ≥3) after a median last follow-up of 36 months (IQR 19–64). Most patients (69/89, 77%) were tested at the 12-month follow-up period, and 42 of 69 (60%) of them had persistent CSF NMDAR-Abs. When comparing patients with persistent or absent CSF NMDAR-Abs at 12 months, poor outcome at the last follow-up was more frequent in the former (38% vs 8%, p = 0.01), who had relapses more often (23% vs 7%), which also appeared earlier in the course of the disease (90% during the following 4 years of follow-up vs 20%), although no significant difference was observed at long-term follow-up ( p = 0.15). In addition, patients with persistent CSF NMDAR-Abs at 12 months had higher titers of CSF NMDAR-Abs at diagnosis. Discussion In this study, patients with persistent CSF NMDAR-Abs at 12 months were more likely to have subsequent relapses and a poor long-term outcome. However, these findings should be interpreted with caution because of the variability in the time of sampling of this study. Future prospective studies are required to validate these results in larger cohorts

Neurological outcomes in immune checkpoint inhibitor-related neurotoxicity

International audienceAbstract While the spectrum of neurological immune checkpoint inhibitor-related adverse events is expanding, patients’ outcomes are not well documented. This study aimed to assess outcomes of neurological immune-related adverse events and to identify prognostic factors. All patients experiencing grade ≥2 neurological immune-related adverse events identified at two clinical networks (French Reference Center for Paraneoplastic Neurological Syndromes, Lyon; and OncoNeuroTox, Paris) over five years were included. Modified Rankin scores were assessed at onset, 6, 12, 18 months, and last visit. A multi-state Markov model was used to estimate the transition rates between minor disability (mRS <3), severe disability (mRS 3-5), and death (mRS 6), over the study period. The state-to-state transition rates were estimated using maximum likelihood and variables were introduced into the different transitions to study their effects. A total of 147 patients were included out of 205 patients with a suspicion of neurological immune-related adverse events. The median age was 65 years (range 20–87) and 87/147 patients (59.2%) were male. Neurological immune-related adverse events involved the peripheral nervous system in 87/147 patients (59.2%), the central nervous system in 51/147 (34.7%), and both systems in 9/147 (6.1%). Paraneoplastic-like syndromes were observed in 30/147 patients (20.4%). Cancers included lung cancers (36.1%), melanoma (30.6%), urological cancers (15.6%), and others (17.8%). Patients were treated with programmed cell death protein (ligan) 1 (PD(L)1) inhibitors (70.1%), CTLA4 inhibitors (3.4%) or both (25.9%). Severe disability was reported in 108/144 patients (75.0%) at onset and in 33/146 patients (22.6%) at last visit (median follow-up duration: 12 months, range 0.5–50); 48/147 (32.7%) patients died, from cancer progression (17/48, 35.4%), neurological toxicity (15/48, 31.2%), other causes (10/48, 20.8%) or unknown causes (6/48, 12.5%). The rate of transition from severe to minor disability independently increased with melanoma [compared to lung cancer, hazard ratio = 3.26, 95%CI (1.27; 8.41)] and myositis/neuromuscular junction disorders [hazard ratio = 8.26, 95%CI (2.90; 23.58)], and decreased with older age [hazard ratio = 0.68, 95%CI (0.47; 0.99)] and paraneoplastic-like syndromes [hazard ratio = 0.29, 95%CI (0.09; 0.98)]. In patients with neurological immune-related adverse events, myositis/neuromuscular junction disorders and melanoma increase the transition rate from severe to minor disability, while older age and paraneoplastic-like syndromes result in poorer neurological outcomes; future studies are needed to optimize the management of such patients