COVID-19 vaccine hesitancy among Italian people with multiple sclerosis.

INTRODUCTION: Vaccine hesitancy promotes the spread of infectious diseases including COVID-19 virus, limiting the herd immunity. Complications caused by COVID-19 in people with multiple sclerosis forced governments to ensure them prior access to vaccinations. Their propensity to be vaccinated needs to be assessed to promote adhesion to vaccination programs. The aim of this study was to explore the COVID-19 vaccine hesitancy rate in pwMS. METHODS: We conducted an observational study recruiting patients affected by multiple sclerosis followed at MS Clinical and Research Unit of Tor Vergata University, Rome. We invited them to fill in an online survey about their intent to get COVID-19 vaccination. Fisher's exact test and Kruskal-Wallis test were performed to explore differences in sociodemographic, clinical, and emotional variables relative to the opinions about vaccinations. An exploratory factor analysis (EFA) was performed to assess the factorial structure of the questionnaire; Pearson's correlations between the factors and Big Five personality dimensions were also calculated. RESULTS: Of 276 respondents, 90% was willing to get vaccinated, while only 1.4% was sure to refuse the vaccination. Education level, opinions on safety and efficacy of vaccines, and emotional status were found to be associated to the propensity of getting the COVID-19 vaccination (respectively: p = 0.012, p < 0.001, and p = 0.0001). Moreover, general opinions on healthcare system were related to the intention to get vaccinated. CONCLUSION: Our results reinforce the importance of a good relationship between doctor and patient and the need to adapt doctors' communication strategy to patients' personalities and beliefs.

Exposure to natalizumab throughout pregnancy: effectiveness and safety in an Italian cohort of women with multiple sclerosis.

OBJECTIVE: Assessing the risk of clinical and radiological reactivation during pregnancy and post partum in women with multiple sclerosis (MS) treated with natalizumab (NTZ) throughout pregnancy (LONG_EXP) compared with women interrupting treatment before (NO_EXP) and within >-30 days and ≤90 days from conception (SHORT_EXP), and describing newborns' outcomes. METHODS: Maternal clinical and radiological outcomes and obstetric and fetal outcomes were retrospectively collected and compared among groups (NO_EXP, SHORT_EXP, LONG_EXP). Predictors of clinical and radiological reactivation were investigated through univariable and multivariable analysis. RESULTS: 170 eligible pregnancies from 163 women referring to 29 Italian MS centres were included. Annualised relapse rate (ARR) was significantly lower in LONG_EXP (n=66, 0.02 (0.001-0.09)) compared with NO_EXP (n=31, 0.43 (0.21-0.75), p=0.002) and SHORT_EXP (n=73, 0.46 (0.30-0.66), p=0.0004) during pregnancy, and in LONG_EXP (0.12 (0.05-0.24)) compared with SHORT_EXP (0.30 (0.17-0.50), p=0.008) during post partum. Gadolinium-enhancing (Gd+) lesions were less frequent in LONG_EXP (n=6/50, 2.00%) compared with NO_EXP (n=9/21, 42.86%) and SHORT_EXP after delivery (n=17/49, 34.69%, p=0.010).Delaying NTZ resumption after delivery significantly increased the risk of relapses (OR=1.29 (95% CI 1.07 to 1.57), p=0.009) and Gd+ lesions (OR=1.49 (95% CI 1.17 to 1.89, p=0.001). Newborns' weight, length, head circumference and gestational age did not differ among groups after adjusting for confounders. Anaemia was tracked in 4/69 LONG_EXP newborns. Congenital anomaly rate was within the expected range for the untreated MS population. CONCLUSIONS: Our findings indicate that in women with MS treated with NTZ before conception, continuation of NTZ throughout pregnancy and its early resumption after delivery mitigate the risk of clinical and radiological reactivation. This approach has no major impact on newborns' outcomes.

Breakthrough SARS-CoV-2 infections in MS patients on disease-modifying therapies.

BACKGROUND: Patients with multiple sclerosis (pwMS) treated with anti-CD20 or fingolimod showed a reduced humoral response to SARS-CoV-2 vaccines. OBJECTIVE: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in pwMS on different disease-modifying therapies (DMTs). METHODS: Data on the number of vaccinated patients and the number of patients with a breakthrough infection were retrospectively collected in 27 Italian MS centers. We estimated the rate of breakthrough infections and of infection requiring hospitalization per DMT. RESULTS: 19,641 vaccinated pwMS were included in the database. After a median follow-up of 8 months, we observed 137 breakthrough infections. Compared with other DMTs, the rate of breakthrough infections was significantly higher on ocrelizumab (0.57% vs 2.00%, risk ratio (RR) = 3.55, 95% CI = 2.74-4.58, p < 0.001) and fingolimod (0.58% vs 1.62%, RR = 2.65, 95% CI = 1.75-4.00, p < 0.001), while there were no significant differences in any other DMT group. In the ocrelizumab group the hospitalization rate was 16.7% versus 19.4% in the pre-vaccination era (RR = 0.86, p = 0.74) and it was 3.9% in all the other DMT groups versus 11.9% in the pre-vaccination period (RR = 0.33, p = 0.02). CONCLUSIONS: The risk of breakthrough SARS-CoV-2 infections is higher in patients treated with ocrelizumab and fingolimod, and the rate of severe infections was significantly reduced in all the DMTs excluding ocrelizumab.

Patient's point of view on the use of telemedicine in multiple sclerosis: a web-based survey.

Restrictions in the access to healthcare facilities during COVID-19 pandemic have raised the need for remote monitoring of chronic medical conditions, including multiple sclerosis (MS). In order to enable the continuity of care in these circumstances, many telemedicine applications are currently tested. While physicians' preferences are commonly investigated, data regarding the patients' point of view are still lacking. We built a 37 items web-based survey exploring patients' propensity, awareness, and opinions on telemedicine with the aim to evaluate the sustainability of this approach in MS. Analysing 613 questionnaires out of 1093 that were sent to persons with MS followed at the Multiple Sclerosis Center of Tor Vergata University, Rome, we found that more than half of respondents (54%) were open to having a televisit. Propensity toward telemedicine significantly depended on having a higher income (p = 0.037), living farther from the center (p = 0.038), using computer and tablet (p = 0.010) and using the Internet for other remote activities (p < 0.001), conversely it was not influenced by any specific disease characteristics (i.e. degree of disability). The main advantages and disadvantages of televisit reported by participants were respectively saving time (70%) and impossibility to measure physical parameters (71%). Although the majority of respondents are in favour of televisit, so far this approach is restricted to those displaying better socioeconomic conditions and higher familiarity with technology. Implications of the study are that telemedicine platforms should be better tailored to patients' demands in order to spread the use of telemedicine, to enhance usability and to increase patients' adherence.

Operationalization of a frailty index in patients with multiple sclerosis: A cross-sectional investigation.

BACKGROUND: Frailty is an age-related status of increased vulnerability to stressors caused by the accumulation of multiple health deficits. This construct may allow to capture the clinical complexity of patients with multiple sclerosis (MS). OBJECTIVE: To investigate the relationship between frailty and the clinical manifestations of MS. METHODS: Patients with MS were consecutively enrolled at five tertiary dedicated services. Disability and fatigue were assessed. The phenotypes of MS were also identified. Frailty was measured using a frailty index (FI), computed by cumulatively considering 42 age-related multidimensional health deficits. RESULTS: Overall, 745 MS patients (mean age = 48.2 years, standard deviation = 11.7 years; women 68%) were considered. The median FI value was 0.12 (interquartile range = 0.05-0.19) and the 99th percentile was 0.40. FI scores were associated with MS disease duration, disability, fatigue, as well as with the number of previous disease-modifying treatments and current symptomatic therapies. A logistic regression analysis model showed that FI score was independently associated with the secondary progressive phenotype. CONCLUSION: Frailty is significantly associated with major characteristics of MS. The findings of the present cross-sectional investigation should be explored in future longitudinal studies.

Skin Thickening of the Scalp and High Signal Intensity of Dentate Nucleus in Multiple Sclerosis: Association With Linear Versus Macrocyclic Gadolinium-Based Contrast Agents Administration.

OBJECTIVE: The aim of this study was to assess the presence of detectable changes of skin thickness on clinical brain magnetic resonance imaging (MRI) scans in patients with MS, history of multiple gadolinium-based contrast agents (GBCAs) administrations, and evidence of gadolinium deposition in the brain. MATERIALS AND METHODS: In this observational cross-sectional study, 71 patients with MS who underwent conventional brain MRI with an imaging protocol including enhanced 3D volumetric interpolated breath-hold examination (VIBE) T1-weighted with fat saturation were assessed. Patients with bilateral isointense dentate nucleus on unenhanced T1-weighted images were assigned to group A (controls without MRI evidence of gadolinium deposition), and patients with visually hyperintense dentate nuclei were assigned to group B. Qualitative and quantitative assessment of the skin thickness were performed. RESULTS: Group A included 27 patients (median age, 33 years [IQR, 27-46]; 20 women), and group B included 44 patients (median age, 42 years [IQR, 35-53]; 29 women). Qualitative and quantitative assessment of the skin revealed significant differences between group A and group B. The average skin-to-scalp thickness ratios was significantly higher in group B than in group A (mean ± standard deviation = 0.52 ± 0.02 in group B vs 0.41 ± 0.02 in group A, P < 0.0001) and showed a positive correlation with the total number of enhanced MRI scans ( r = 0.39; 95% confidence interval, 0.17-0.57, P < 0.01). CONCLUSIONS: Brain MRI detects increased skin thickness of the scalp in patients with MS and dentate nucleus high signal intensity on unenhanced T1-weighted images and shows positive association with previous exposures to linear GBCAs rather than macrocyclic GBCAs.

A specific anti-COVID-19 BNT162b2 vaccine-induced early innate immune signature positively correlates with the humoral protective response in healthy and multiple sclerosis vaccine recipients.

Objectives: The very rapidly approved mRNA-based vaccines against SARS-CoV-2 spike glycoprotein, including Pfizer-BioNTech BNT162b2, are effective in protecting from severe coronavirus disease 2019 (COVID-19) in immunocompetent population. However, establishing the duration and identifying correlates of vaccine-induced protection will be crucial to optimise future immunisation strategies. Here, we studied in healthy vaccine recipients and people with multiple sclerosis (pwMS), undergoing different therapies, the regulation of innate immune response by mRNA vaccination in order to correlate it with the magnitude of vaccine-induced protective humoral responses. Methods: Healthy subjects (n = 20) and matched pwMS (n = 22) were longitudinally sampled before and after mRNA vaccination. Peripheral blood mononuclear cell (PBMC)-associated type I and II interferon (IFN)-inducible gene expression, serum innate cytokine/chemokine profile as well as binding and neutralising anti-SARS-COV-2 antibodies (Abs) were measured. Results: We identified an early immune module composed of the IFN-inducible genes Mx1, OAS1 and IRF1, the serum cytokines IL-15, IL-6, TNF-α and IFN-γ and the chemokines IP-10, MCP-1 and MIG, induced 1 day post second and third BNT162b2 vaccine doses, strongly correlating with magnitude of humoral response to vaccination in healthy and MS vaccinees. Moreover, induction of the early immune module was dramatically affected in pwMS treated with fingolimod and ocrelizumab, both groups unable to induce a protective humoral response to COVID-19 vaccine. Conclusion: Overall, this study suggests that the vaccine-induced early regulation of innate immunity is mediated by IFN signalling, impacts on the magnitude of adaptive responses and it might be indicative of vaccine-induced humoral protection.

Anti-HBs titers are not decreased after treatment with oral Cladribine in patients with Multiple Sclerosis vaccinated against Hepatitis B virus.

BACKGROUND: Oral cladribine is a novel treatment for Multiple Sclerosis (MS). It is a purine nucleoside antimetabolite analogue that is incorporated into the DNA, resulting in single-strand breaks in DNA and apoptosis of replicating lymphocytes. Specifically, Cladribine induces limited depletion of CD4 and CD8 T cell subsets and more marked depletion of memory B cell subsets. Therefore, natural and acquired humoral responses against pathogens may be potentially reduced. The aim of this study was to assess longitudinal variation of antiHBs titers in patients with MS treated with Cladribine. METHODS: Patients with MS treated with 1 cycle of Cladribine (3,5 mg/kg) and previously vaccinated against Hepatitis B virus (HBV) were enrolled. Anti-HBs titers were compared before and after 12 months from Cladribine treatment. Total lymphocyte count was also analysed. RESULTS: Among the 13 RMS patients (10 F, 3 M, mean age 33,8, SD 5,9) enrolled, all had anti-HBs titers >10 mg/dl at baseline. Anti-HBs titer dropped below the reference value at 12 months after Cladribine only in 1 case. Pre-post Cladribine mean anti-HBs values were not significantly different considering the whole cohort (Wilcoxon-Mann-Whitney Test p = 0,762). Four patients had grade 1 and 1 patient grade 2 lymphocytopenia at 12 months. CONCLUSIONS: Cladribine does not seem to reduce humoral immune responses in subjects previously vaccinated against HBV, even in case of lymphocytopenia. These results, if confirmed in larger populations, appear reassuring also for other vaccinations (i.e. COVID19). The low impact of Cladribine on plasma cells may explain such findings.

Safety of Natalizumab infusion in multiple sclerosis patients during active SARS-CoV-2 infection.

COVID-19 pandemic represented a challenge in the management of treatments for Multiple Sclerosis (MS), such as Natalizumab (NTZ). NTZ interferes with the homing of lymphocytes into the central nervous system, reducing immune surveillance against opportunistic infection. Although NTZ efficacy starts to decline 8 weeks after the last infusion, increasing the risk of disease reactivation, evidence is lacking on the safety of reinfusion during active SARS-CoV-2 infection. We report clinical outcomes of 18 pwMS receiving NTZ retreatment during confirmed SARS-CoV-2 infection. No worsening of infection or recovery delay was observed. Our data supports the safety of NTZ redosing in these circumstances.

Influence of Previous Disease-Modifying Drug Exposure on T-Lymphocyte Dynamic in Patients With Multiple Sclerosis Treated With Ocrelizumab.

BACKGROUND AND OBJECTIVES: To investigate the longitudinal dynamic of lymphocyte subsets during treatment with ocrelizumab (OCR) in patients with multiple sclerosis (PwMS). METHODS: A multicenter retrospective study was conducted in 161 PwMS starting treatment with OCR grouped in naive (naive, n = 40), switching from fingolimod (FTY, n = 52), and switching from other immunomodulating drugs (other, n = 69). Mean lymphocyte subset (total, CD3+, CD4+, CD8+, CD20+, and natural killer) counts were analyzed at baseline, 6 months, and 12 months. Rate of lymphocytopenia for each subset was calculated at all time points in all groups. RESULTS: Mean total, CD3+, and CD4+ counts were significantly different among groups (p < 0.001) at all time points, whereas CD8+ and CD20+ counts only at baseline (p = 0.0157; p < 0.001), consistently lower in FTY. After adjustment for baseline values, interaction time*group was not statistically significant (p > 0.05 for each subset). The odds of lymphopenia were significantly higher among FTY patients compared with naive for total, CD3+, CD4+, and CD20+ cells at baseline, for total and CD4+ cells at the sixth month, and for total cells at the 12th month. DISCUSSION: OCR per se exerts a modest depleting effect on T cells that seems rather due to a carryover phenomenon of previous therapies, particularly FTY. These data may help in the overall evaluation of the risk/benefit profile of treatment sequencing.

T-cell responses to SARS-CoV-2 in multiple sclerosis patients treated with ocrelizumab healed from COVID-19 with absent or low anti-spike antibody titers.

BACKGROUND: Disease modifying therapies for multiple sclerosis (MS) can impair the specific immune response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Specifically, it is recognized that ocrelizumab reduces or abrogates anti-SARS-CoV-2 antibody production after natural infection or vaccination, while very little is known about T-cell responses. METHODS: We developed an interferon (IFN)-γ release assay (IGRA) to detect T-cell responses specific to SARS-CoV-2 after overnight stimulation of whole blood with peptide libraries covering the immunodominant sequence domains of the Spike glycoprotein (S) and the Nucleocapsid phosphoprotein (N). RESULTS: Five patients with MS receiving ocrelizumab treatment for at least 1 year and recovered from SARS-CoV-2 infection were enrolled in the study. Despite the absence or the very low concentration of anti-S antibodies, a T-cell response was detectable in all the five MS patients. These results are in accordance with the marked reduction of peripheral B-lymphocyte absolute counts induced by ocrelizumab, that, conversely, did not affect peripheral blood T-lymphocyte subset absolute and relative counts and CD4/CD8 ratio. CONCLUSIONS: The detection of specific T-cell responses to SARS-CoV-2 in patients receiving B-cell depleting therapies represents a useful tool to improve the diagnostic approach in SARS-CoV-2 infection and to accurately assess the immunological response after natural infection or vaccination.

B- and T-Cell Responses After SARS-CoV-2 Vaccination in Patients With Multiple Sclerosis Receiving Disease Modifying Therapies: Immunological Patterns and Clinical Implications.

Background: Vaccination campaign to contrast the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has raised the issue of vaccine immunogenicity in special populations such as people with multiple sclerosis (PwMS) on highly effective disease modifying treatments (DMTs). While humoral responses to SARS-CoV-2 mRNA vaccines have been well characterized in the general population and in PwMS, very little is known about cell-mediated responses in conferring protection from SARS-CoV-2 infection and severe coronavirus disease-2019 (COVID-19). Methods: PwMS on ocrelizumab, fingolimod or natalizumab, vaccinated with two doses of mRNABNT162b2 (Comirnaty®) vaccine were enrolled. Anti-Spike (S) and anti-Nucleoprotein (N) antibody titers, IFN-gamma production upon S and N peptide libraries stimulation, peripheral blood lymphocyte absolute counts were assessed after at least 1 month and within 4 months from vaccine second dose administration. A group of age and sex matched healthy donors (HD) were included as reference group. Statistical analysis was performed using GraphPad Prism 8.2.1. Results: Thirty PwMS and 9 HDs were enrolled. All the patients were negative for anti-N antibody detection, nor reported previous symptoms of COVID-19. Peripheral blood lymphocyte counts were assessed in PwMS showing: (i) reduction of circulating B-lymphocytes in PwMS on ocrelizumab; (ii) reduction of peripheral blood B- and T-lymphocyte absolute counts in PwMS on fingolimod and (iii) normal B- and T-lymphocyte absolute counts with an increase in circulating CD16+CD56+ NK-cells in PwMS on natalizumab. Three patterns of immunological responses were identified in PwMS. In patients on ocrelizumab, anti-S antibody were lacking or reduced, while T-cell responses were normal. In patients on fingolimod both anti-S titers and T-cell mediated responses were impaired. In patients on natalizumab both anti-S titers and T-cell responses were present and comparable to those observed in HD. Conclusions: The evaluation of T-cell responses, anti-S titers and peripheral blood lymphocyte absolute count in PwMS on DMTs can help to better characterize the immunological response after SARS-CoV-2 vaccination. The evaluation of T-cell responses in longitudinal cohorts of PwMS will help to clarify their protective role in preventing SARS-CoV-2 infection and severe COVID-19. The correlation between DMT treatment and immunological responses to SARS-CoV-2 vaccines could help to better evaluate vaccination strategies in PwMS.

Adherence to social distancing and use of personal protective equipment and the risk of SARS-CoV-2 infection in a cohort of patients with multiple sclerosis.

Background Aiming to safeguard its population from COVID19 infection, Italian government provided specific advices, especially to fragile individuals such those affected by Multiple Sclerosis (MS), to respect social distancing, to arrange remote work and to use personal protective equipment (PPE). The aim of this study is to investigate real adherence to these measures among MS patients and to evaluate its impact on exposure to infection. Methods MS patients followed at the MS center of Tor Vergata University hospital, Rome, Italy were asked to complete an anonymous 35-items web-survey exploring demographics, residency, employment, social distancing habits, use of PPE, MS features and COVID19 infection data, including self-reported information about contacts with SARS-CoV-2 positive/presumed positive persons. In order to estimate adherence to social distancing and use of PPE, an overall 'Lockdown Score' (LS) on 0-10 scale was created analyzing four main domains (Working (0 - 4), Social distancing and PPE use (0 - 4), Assistance for shopping needs (0 - 2), Residency (-2 - 0)). Mean scores for several pre-defined subgroups of patients were compared using both univariable and multivariable analyses. Accuracy of the score in discriminating subjects at higher risk of coming in contact with SARS-CoV-2 positive/presumed positive individuals was calculated as the area under the receiver-operator characteristic curve (AUC). The optimal cut-off was identified and used to dichotomize LS (high/ low). Logistic regression model was applied to estimate individuals' characteristics associated with high/low LS and odds ratio of coming in contact with SARS-CoV-2 positive/presumed positive persons based on continous and dichotomised LS. Results Respondents (N = 551) had a mean(±SD) overall LS of 6.52±2.11 (Working 3.16±1.19, Social distancing and PPE use 2.69±1.33, Assistance 0.66± 0.62, Residency penalty applied in 4 cases). Female, disabled and unemployed individuals had significantly higher mean LS (p<0.05). The AUC of the LS was 0.68 (95% CI, 0.59-0.77) and the optimal LS cut-off for discrimination was 6.0. Consistently, female, disabled and unemployed individuals had higher odd of getting a high LS (≥ 6) compared to male, independent and employed (p<0.05). Odd of coming in contact with SARS-CoV-2 positive/presumed positive individuals was significantly reduced for one-unit increase in LS (0.74 (95% CI: 0.64-0.85)) and among individuals with high LS (0.37 (95% CI: 0.19-0.72)). Only one subject among respondents declared to have been diagnosed with COVID19. Conclusions MS patients, especially those with social unfavorable conditions, demonstrated good adherence to social distancing and use of protection equipment. Implementing domains, such as social assistance, may improve protection from infection. LS score is potentially able to identify subjects with behaviors at greater risk of infection, although it needs to be validated against MS population living in higher incidence areas.