Humoral Response to SARS-COV-2 Vaccination in Patients with Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder: A Real-World Study.

INTRODUCTION: The risk of SARS-CoV-2 infection or severe coronavirus disease 2019 (COVID-19) has been shown to increase in patients with multiple sclerosis (MS). Vaccination is recommended in this patient population, and the effect of disease-modifying treatments (DMTs) on response to vaccination should be considered. METHODS: This prospective, observational, cross-sectional study investigated humoral response after COVID-19 vaccination as well as possible predictors for response in patients with MS and other neuroinflammatory diseases who received DMTs in routine clinical practice in Spain. Responses were compared versus those seen in healthy controls. RESULTS: After vaccination against COVID-19, most patients with MS developed an immune response comparable to that of healthy individuals. However, approximately half of patients receiving a sphingosine-1-phosphate modulator (SP1-M, fingolimod or siponimod) or a B-cell-depleting agent (aCD20, ocrelizumab or rituximab) did not develop protective antibodies, although patients receiving other DMTs had humoral immune responses comparable to healthy controls. Lymphocyte count was not associated with reduced humoral response in patients receiving an SP1-M or aCD20, whereas, in patients receiving an aCD20 or SP1-M, older age was associated with lower anti-SARS-CoV-2 spike protein immunoglobulin G antibody levels. CONCLUSIONS: Treatment with aCD20 or SP1-M therapies appears to be associated with a lower humoral response to vaccines against SARS-CoV-2. Vaccination prior to initiation of these DMTs should be recommended whenever possible.

Treatment with natalizumab during pregnancy in multiple sclerosis: The experience of implementing a clinical practice protocol (NAP-30).

BACKGROUND: Pregnancy planning in women with highly active multiple sclerosis (HAMS) who need a high-efficacy disease-modifying therapy (heDMT) currently requires a careful risk-benefit evaluation. This includes minimizing fetal drug toxicity and preventing MS reactivation. We describe our experience with natalizumab in women with HAMS and unplanned pregnancy by implementing a clinical practice protocol (NAP-30) designed to maintain the effectiveness of natalizumab during pregnancy, reduce fetal exposure and prevent complications. METHODS: This was an observational retrospective study including women with HAMS on active treatment with natalizumab who became unexpectedly pregnant in the period 2018-2021 and continued this treatment during pregnancy according to the NAP-30 protocol. MS clinical and radiological variables were analyzed before and during pregnancy and in the postpartum period, along with maternal and fetal toxicity during pregnancy and safety findings in newborns. We also describe the NAP-30 protocol, which includes the use of a bridging dose to adjust and maintain natalizumab infusions every 6 weeks during pregnancy up to week 30 and scheduled delivery at week 40. RESULTS: Six women (one in her first gestation) with a median age of 31.5 years at the onset of pregnancy (min-max: 24-37 years) were included. All were negative for anti-John Cunningham virus (JCV) antibodies and were on treatment with intravenous natalizumab 300 mg every 4 weeks. At the time of conception, three patients had received 12, 17 and 53 infusions of natalizumab, respectively, while for the remaining three patients natalizumab was their first DMT (two patients had received 6 infusions and one patient had received 3 infusions of natalizumab). All six patients received 6 doses of natalizumab during pregnancy according to the NAP-30 protocol. After delivery, all six patients restarted natalizumab every 4 weeks (median: 3 days; range: 2-4 days). No patients had relapses during pregnancy or at 6 months postpartum, nor did they develop any general health or laboratory abnormalities. The MRI scan performed at 4-6 months postpartum showed no new T2 lesions or gadolinium-enhancing lesions. No miscarriages or threatened miscarriages were reported. One of the patients underwent elective preterm delivery at week 35 after mild-to-moderate anemia was detected by fetal Doppler scan. The newborn had low birth weight (2080 g) and mild anemia, which resolved within two months with oral iron supplementation. The other infants were born with normal birth weight and showed no blood count abnormalities. After a median follow-up of 10 months, all six babies showed normal development with no complications detected. CONCLUSIONS: Based on our experience, the implementation of the NAP-30 protocol in women with HAMS and unplanned pregnancy undergoing treatment with natalizumab allows the continuation of natalizumab during pregnancy, with a very favorable clinical and radiological effectiveness and maternal-fetal safety profile during pregnancy and postpartum. Both in pregnancy with HAMS and in general, and particularly for successful implementation of the NAP-30 protocol, obstetric support and monitoring is essential for adequate pregnancy management.

Generation of RRMS and PPMS specific iPSCs as a platform for modeling Multiple Sclerosis.

The advent of cellular reprogramming technology converting somatic cells into induced pluripotent stem cells (iPSCs) has revolutionized our understandings of neurodegenerative diseases that are otherwise hard to access and model. Multiple Sclerosis (MS) is a chronic demyelinating, inflammatory disease of central nervous system eventually causing neuronal death and accompanied disabilities. Here, we report the generation of several relapsing-remitting MS (RRMS) and primary progressive MS (PPMS) iPSC lines from MS patients along with their age matched healthy controls from peripheral blood mononuclear cells (PBMC). These patient specific iPSC lines displayed characteristic embryonic stem cell (ESC) morphology and exhibited pluripotency marker expression. Moreover, these MS iPSC lines were successfully differentiated into neural progenitor cells (NPC) after subjecting to neural induction. Furthermore, we identified the elevated expression of cellular senescence hallmarks in RRMS and PPMS neural progenitors unveiling a novel drug target avenue of MS pathophysiology. Thus, our study altogether offers both RRMS and PPMS iPSC cellular models as a good tool for better understanding of MS pathologies and drug testing.

Prevention of rebound effect after natalizumab withdrawal in multiple sclerosis. Study of two high-dose methylprednisolone schedules.

BACKGROUND: Natalizumab (NTZ) is a disease-modifying treatment (DMT) in multiple sclerosis (MS) whose discontinuation can produce a "rebound effect", consisting of severe clinical deterioration and/or evidence of disease reactivation on magnetic resonance imaging (MRI). OBJECTIVE: To analyze the efficacy of two treatment schedules with intravenous methylprednisolone (IVMP) administered during the washout period of natalizumab (i.e., before starting another DMT) in preventing the rebound phenomenon. METHODS: Five-year retrospective study of NTZ withdrawals after at least 24 uninterrupted doses. Two IVMP schedules were tested. In schedule 1 (3-month washout), 1, 2, and 3 g of IVMP were administered on the first, second, and third month respectively. In schedule 2 (2-month washout), 1 and 2 g of IVMP were administered on the first and second month respectively. A new DMT was started 10 days after the end of each schedule. Rebound was defined as at least one clinical relapse plus rebound activity on MRI (>5 gadolinium-enhanced lesions and a number of new/T2-enhanced and/or gadolinium-enhanced lesions greater than before initiation of NTZ) during washout or at 6 months after new DMT initiation (6M-DMT). Clinical and MRI evaluations were performed at 3, 6, 12, and 24 months after initiation of the new DMT. RESULTS: Fifty patients (68% women) were included, with a mean (SD) age of 37.76 (10.88) years and pre-NTZ annualized relapse rate (ARR) of 1.78 (1.04). During NTZ therapy, mean Expanded Disability Status Scale (EDSS) score was 3.7 (1.73) and ARR was 0.23 (0.39). The ARR (mean of both schedules) was 0.1 (0.71) during washout and 0.32 (0.84) at 6M-DMT. Rebound was observed in 10% of cases (n = 5), with no significant clinical or radiological differences (p>0.05) between the two IVMP schedules. Rebound was observed in younger patients and was associated with new MRI lesions and higher ARR at 3M-DMT and 6M-DMT respectively, with no difference in EDSS after 2 years of follow-up. Neither the ARR before NTZ initiation nor the choice of new DMT after NTZ discontinuation was associated with development of rebound effect. CONCLUSIONS: Both IVMP schedules were well tolerated during NTZ washout and rebound was observed in only 10% of cases. In our experience, administration of IVMP during NTZ washout could reduce the possibility of a rebound effect.

Possible Influence of the Route of Treatment Administration on Treatment Adherence in Patients With Multiple Sclerosis.

PURPOSE: Multiple sclerosis is a chronic, demyelinating, and degenerative disease of the central nervous system with an immune-based pathologic origin. The present pilot study aimed to assess whether the change in the route of treatment administration is associated with a variation in adherence and whether there is a change in quality of life, treatment satisfaction, and fatigue. METHODS: Patients with relapsing-remitting multiple sclerosis who were >18 years of age and who used to receive immunomodulatory parenteral treatment and were ready to change administration route were eligible for the study. Data were collected at baseline and 3 months later. Adherence, quality of life, treatment satisfaction, and fatigue were measured via the following questionnaires: Morisky-Green questionnaire on patient-reported medication adherence, Multiple Sclerosis Quality of Life Instrument, Treatment Satisfaction Questionnaire for Medication, and Modified Fatigue Impact Scale. FINDINGS: The study sample included 30 patients (mean age, 43.2 years; age range, 24-71 years; 60% female and 40% male). There was a significant improvement in adherence (p = 0.048). Mean (SD) physical and mental health quality-of-life summary scores varied from 52.50 (24.15) and 54.13 (21.24) to 67.55 (20.92) and 62.30 (21.75) (p < 0.001 and p = 0.001, d = -0.426 and d = -0.643, respectively). In the Treatment Satisfaction Questionnaire for Medication, an improvement of the score was observed in effectiveness of the medication (p = 0.0041, d = -0.563), adverse effects of the medication (p < 0.001, d = -0.976), convenience of the medication (p < 0.001, d = -1.235), and global satisfaction (p = 0.006, d = -0.725). Patients had a higher mean (SD) score (45.13 [26.7]) on the Modified Fatigue Impact Scale while receiving injectable treatment compared with that obtained with oral treatment (34.86 [23.16]; p = 0.009, d = 0.41). IMPLICATIONS: When the route of administration changed from injectable to oral, there was an increase in adherence, quality of life, and degree of patient satisfaction with their treatment and a decrease in the degree of fatigue.

NIK controls classical and alternative NF-κB activation and is necessary for the survival of human T-cell lymphoma cells.

PURPOSE: Peripheral T-cell lymphomas (PTCL) are a heterogeneous entity of neoplasms with poor prognosis, a lack of effective therapies, and a largely unknown molecular pathology. Deregulated NF-κB activity has been associated with several lymphoproliferative diseases, but its importance in T-cell lymphomagenesis is poorly understood. We investigated the function of the NF-κB-inducing kinase (NIK), in this pathway and its role as a potential molecular target in T-cell lymphomas. EXPERIMENTAL DESIGN: We used immunohistochemistry to analyze the expression of different NF-κB members in primary human PTCL samples and to study its clinical impact. With the aim of inhibiting the pathway, we used genetic silencing of NIK in several T-cell lymphoma cell lines and observed its effect on downstream targets and cell viability. RESULTS: We showed that the NF-κB pathway was activated in a subset of PTCLs associated with poor overall survival. NIK was overexpressed in a number of PTCL cell lines and primary samples, and a pivotal role for NIK in the survival of these tumor cells was unveiled. NIK depletion led to a dramatic induction of apoptosis in NIK-overexpressing cell lines and also showed a more pronounced effect on cell survival than inhibitor of kappa B kinase (IKK) knockdown. NIK silencing induced a blockage of both classical and alternative NF-κB activation and reduced expression of several prosurvival and antiapoptotic factors. CONCLUSIONS: The results of the present study indicate that NIK could be a promising therapeutic target in these aggressive malignancies.