Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants.

Human regulatory T cells (T(reg) cells) that develop from conventional T cells (T(conv) cells) following suboptimal stimulation via the T cell antigen receptor (TCR) (induced T(reg) cells (iT(reg) cells)) express the transcription factor Foxp3, are suppressive, and display an active proliferative and metabolic state. Here we found that the induction and suppressive function of iT(reg) cells tightly depended on glycolysis, which controlled Foxp3 splicing variants containing exon 2 (Foxp3-E2) through the glycolytic enzyme enolase-1. The Foxp3-E2-related suppressive activity of iT(reg) cells was altered in human autoimmune diseases, including multiple sclerosis and type 1 diabetes, and was associated with impaired glycolysis and signaling via interleukin 2. This link between glycolysis and Foxp3-E2 variants via enolase-1 shows a previously unknown mechanism for controlling the induction and function of T(reg) cells in health and in autoimmunity.

Disentangling multiple sclerosis phenotypes through Mendelian disorders: A network approach.

BACKGROUND: The increasing knowledge about multiple sclerosis (MS) pathophysiology has reinforced the need for an improved description of disease phenotypes, connected to disease biology. Growing evidence indicates that complex diseases constitute phenotypical and genetic continuums with "simple," monogenic disorders, suggesting shared pathomechanisms. OBJECTIVES: The objective of this study was to depict a novel MS phenotypical framework leveraging shared physiopathology with Mendelian diseases and to identify phenotype-specific candidate drugs. METHODS: We performed an enrichment testing of MS-associated variants with Mendelian disorders genes. We defined a "MS-Mendelian network," further analyzed to define enriched phenotypic subnetworks and biological processes. Finally, a network-based drug screening was implemented. RESULTS: Starting from 617 MS-associated loci, we showed a significant enrichment of monogenic diseases (p < 0.001). We defined an MS-Mendelian molecular network based on 331 genes and 486 related disorders, enriched in four phenotypic classes: neurologic, immunologic, metabolic, and visual. We prioritized a total of 503 drugs, of which 27 molecules active in 3/4 phenotypical subnetworks and 140 in subnetwork pairs. CONCLUSION: The genetic architecture of MS contains the seeds of pathobiological multiplicities shared with immune, neurologic, metabolic and visual monogenic disorders. This result may inform future classifications of MS endophenotypes and support the development of new therapies in both MS and rare diseases.

Clinical and Immunological Impact of Ocrelizumab Extended Interval Dosing in Multiple Sclerosis: A Single-Center, Real-World Experience.

Ocrelizumab (OCR), an anti-CD20 monoclonal antibody, is approved for treating relapsing remitting (RR) and primary progressive (PP) multiple sclerosis (MS). The standard interval dosing (SID) regimen requires intravenous infusions every six months. Experience of extended dosing due to COVID-19 pandemic-related issues suggests that this strategy may provide comparable efficacy while reducing treatment burden and healthcare costs. This study aimed to evaluate clinical effectiveness, changes in B- and T-cell count, and immunoglobulin dynamics associated with extended interval dosing (EID) of ocrelizumab in a real-world setting. We retrospectively included RRMS or PPMS patients treated with OCR that had already received two OCR cycles and with at least 6 months of follow up after the last infusion. EID was defined as a ≥4 weeks delay compared to SID. Clinical outcomes were occurrence of relapses, MRI activity, 6-months confirmed disability progression (CDP) and their combination (No Evidence of Disease Activity, NEDA-3). We also evaluated changes in CD19+ B cell count, CD4+ and CD8+ T cell count, immunoglobulin titers, and occurrence of hypogammaglobulinemia (hypo-Ig). Frequency tests, multivariate regression models, and survival analysis were applied as appropriate. We analyzed data on 93 subjects (75.3% RRMS) for a total of 389 infusions (272 SID, 117 EID). Clinical and MRI activity, CDP, and NEDA 3 did not significantly differ between EID and SID. EID was associated with lower rates of B-cell depletion. T-cell dynamics and incidence of hypo-Ig were comparable following EID and SID. Hypo-IgG at index infusion was associated with further occurrence of hypo-IgG; male sex and hypo-IgM at index infusion were independently associated with hypo-IgM. In conclusion, OCR EID does not impact MS clinical and radiological outcomes, although it interferes with B-cell dynamics. These findings provide support for a tailored schedule of OCR in MS.

Peripheral Biomarkers in Manifest and Premanifest Huntington's Disease.

Huntington's disease (HD) is characterized by clinical motor impairment (e.g., involuntary movements, poor coordination, parkinsonism), cognitive deficits, and psychiatric symptoms. An inhered expansion of the CAG triplet in the huntingtin gene causing a pathogenic gain-of-function of the mutant huntingtin (mHTT) protein has been identified. In this review, we focus on known biomarkers (e.g., mHTT, neurofilament light chains) and on new biofluid biomarkers that can be quantified in plasma or peripheral blood mononuclear cells from mHTT carriers. Circulating biomarkers may fill current unmet needs in HD management: better stratification of patients amenable to etiologic treatment; the initiation of preventive treatment in premanifest HD; and the identification of peripheral pathogenic central nervous system cascades.

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.

Anti-SARS-CoV-2 T-stem cell memory persists in ocrelizumab-treated MS patients.

BACKGROUND: Development of long-lasting anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) T-cell responses in persons with multiple sclerosis (pwMS) treated with ocrelizumab is questioned. OBJECTIVE: Investigate antiviral T-cell responses after infection with SARS-CoV-2 in ocrelizumab-treated pwMS. Control groups included ocrelizumab-treated pwMS without SARS-CoV-2 infection, and non-MS individuals with and without SARS-CoV-2 infection. METHODS: Peripheral blood mononuclear cells were stimulated with SARS-CoV-2 peptide pools and T-cell reactivity was assessed by ELISPOT for interferon (IFN)-γ detection, and by multiparametric fluorescence-activated cell sorting (FACS) analyses for assessment and characterization of T-cell activation. RESULTS: ELISPOT assay against the spike and the N protein of SARS-CoV-2 displayed specific T-cell reactivity in 28/29 (96%) pwMS treated with ocrelizumab and infected by SARS-CoV-2, similar to infected persons without MS. This reactivity was present 1 year after infection and independent from the time of ocrelizumab infusion. FACS analysis following stimulation with SARS-CoV-2 peptide pools showed the presence of activation-induced markers (AIMs) in both CD4+ and CD8+ T-cell subsets in 96% and 92% of these individuals, respectively. Within naïve AIM+ CD4+ and CD8+ T-cells, we detected T memory stem cells, suggesting the acquisition of long-term memory. CONCLUSIONS: B-cell depletion using ocrelizumab does not impair the development of long-lasting anti-SARS-CoV-2 T-cell responses.

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.

Defining the course of tumefactive multiple sclerosis: A large retrospective multicentre study.

BACKGROUND AND PURPOSE: Tumefactive multiple sclerosis (TuMS) (i.e., MS onset presenting with tumefactive demyelinating lesions [TDLs]) is a diagnostic and therapeutic challenge. We performed a multicentre retrospective study to describe the clinical characteristics and the prognostic factors of TuMS. METHODS: One hundred two TuMS patients were included in this retrospective study. Demographic, clinical, magnetic resonance imaging (MRI), laboratory data and treatment choices were collected. RESULTS: TuMS was found to affect women more than men (female:male: 2.4), with a young adulthood onset (median age: 29.5 years, range: 11-68 years, interquartile range [IQR]: 38 years). At onset, 52% of TuMS patients presented with the involvement of more than one functional system and 24.5% of them with multiple TDLs. TDLs most frequently presented with an infiltrative MRI pattern (38.7%). Cerebrospinal fluid immunoglobulin G oligoclonal bands were often demonstrated (76.6%). In 25.3% of the cases, more than one acute-phase treatment was administered, and almost one-half of the patients (46.6%) were treated with high-efficacy treatments. After a median follow-up of 2.3 years (range: 0.1-10.7 years, IQR: 3.4 years), the median Expanded Disability Status Scale (EDSS) score was 1.5 (range: 0-7, IQR: 2). Independent risk factors for reaching an EDSS score ≥3 were a higher age at onset (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.03-1.14, p < 0.01), a higher number of TDLs (OR: 1.67, 95% CI: 1.02-2.74, p < 0.05) and the presence of infiltrative TDLs (OR: 3.34, 95% CI: 1.18-9.5, p < 0.001) at baseline. CONCLUSIONS: The management of TuMS might be challenging because of its peculiar characteristics. Large prospective studies could help to define the clinical characteristics and the best treatment algorithms for people with TuMS.

A Case of Double Standard: Sex Differences in Multiple Sclerosis Risk Factors.

Multiple sclerosis is a complex, multifactorial, dysimmune disease prevalent in women. Its etiopathogenesis is extremely intricate, since each risk factor behaves as a variable that is interconnected with others. In order to understand these interactions, sex must be considered as a determining element, either in a protective or pathological sense, and not as one of many variables. In particular, sex seems to highly influence immune response at chromosomal, epigenetic, and hormonal levels. Environmental and genetic risk factors cannot be considered without sex, since sex-based immunological differences deeply affect disease onset, course, and prognosis. Understanding the mechanisms underlying sex-based differences is necessary in order to develop a more effective and personalized therapeutic approach.

A cell type-specific transcriptomic approach to map B cell and monocyte type I interferon-linked pathogenic signatures in Multiple Sclerosis.

Alteration in endogenous Interferon (IFN) system may profoundly impact immune cell function in autoimmune diseases. Here, we provide evidence that dysregulation in IFN-regulated genes and pathways are involved in B cell- and monocyte-driven pathogenic contribution to Multiple Sclerosis (MS) development and maintenance. In particular, by using an Interferome-based cell type-specific approach, we characterized an increased susceptibility to an IFN-linked caspase-3 dependent apoptotic cell death in both B cells and monocytes of MS patients that may arise from their chronic activation and persistent stimulation by activated T cells. Ongoing caspase-3 activation functionally impacts on MS monocyte properties influencing the STAT-3/IL-16 axis, thus, driving increased expression and massive release of the bio-active IL-16 triggering and perpetuating CD4+ T cell migration. Importantly, our analysis also identified a previously unknown multi-component defect in type I IFN-mediated signaling and response to virus pathways specific of MS B cells, impacting on induction of anti-viral responses and Epstein-barr virus infection control in patients. Taking advantage of cell type-specific transcriptomics and in-depth functional validation, this study revealed pathogenic contribution of endogenous IFN signaling and IFN-regulated cell processes to MS pathogenesis with implications on fate and functions of B cells and monocytes that may hold therapeutic potential.

Abortion induces reactivation of inflammation in relapsing-remitting multiple sclerosis.

OBJECTIVE: To investigate clinical and radiological outcomes of women with relapsing-remitting multiple sclerosis (RRMS) undergoing abortion. METHODS: An independent, multicentre retrospective study was conducted collecting data from eight Italian MS centres. We compared the preconception and postabortion annualised relapse rate (ARR) and number of Gadolinium enhancing (Gd+) lesions, by analyses of covariance. Variables associated with postabortion clinical and MRI activity were investigated using Poisson regression models; each abortion was considered as a statistical unit. RESULTS: From 1995 to 2017, we observed 188 abortions (17 elective) in 153 women with RRMS. Abortions occurred after a mean time of 9.5 (4.4) weeks from estimated conception date. In 86 events out of 188, conception happened during treatment with disease modifying drugs. The mean postabortion ARR (0.63±0.74) was significantly increased (p=0.037) compared with the preconception year (0.50±0.71) as well as the postabortion mean number of new Gd+ lesions (0.77±1.40 vs 0.39±1.04; p=0.004). Higher likelihood of relapses was predicted by higher preconception ARR, discontinuation of preconception treatment and elective abortion; the occurrence of new Gd+ lesions was associated with higher preconception number of active lesions, discontinuation of preconception treatment, shorter length of pregnancy maintenance and elective abortion. CONCLUSIONS: Abortion was associated with clinical and radiological inflammatory rebound remarkably in the first 12 months postevent. Deregulated proinflammatory processes arising at the early stages of pregnancy might play a role both in MS reactivation and abortion. Women with MS should be counselled about these risks of abortion and followed up accordingly.

Thymosin-α1 expands deficient IL-10-producing regulatory B cell subsets in relapsing-remitting multiple sclerosis patients.

BACKGROUND: B cells are key pathogenic effectors in multiple sclerosis (MS) and several therapies have been designed to restrain B cell abnormalities by directly targeting this lymphocyte population. OBJECTIVES: Moving from our data showing a Toll-like receptor (TLR)7-driven dysregulation of B cell response in relapsing-remitting multiple sclerosis (RRMS) and having found a low serum level of Thymosin-α1 (Tα1) in patients, we investigated whether the addition of this molecule to peripheral blood mononuclear cells (PBMCs) would influence the expansion of regulatory B cell subsets, known to dampen autoimmune inflammation. METHODS: Serum Tα1 level was measured by enzyme immunoassay. Cytokine expression was evaluated by Cytometric Bead Array (CBA), enzyme-linked immunosorbent assay (ELISA), and real-time reverse transcription polymerase chain reaction (RT-PCR). B cell subsets were analyzed by flow cytometry. RESULTS: Tα1 pre-treatment induces an anti-inflammatory status in TLR7-stimulated RRMS PBMC cultures, reducing the secretion of pro-inflammatory interleukin (IL)-6, IL-8, and IL-1ß while significantly increasing the regulatory IL-10 and IL-35. Indeed, Tα1 treatment enhanced expansion of CD19+CD24+CD38hi transitional-immature and CD24low/negCD38hi plasmablast-like regulatory B cell subsets, which likely inhibit both interferon (IFN)-γ and IL-17 production. CONCLUSION: Our study reveals a deficient ability of B cells from MS patients to differentiate into regulatory subsets and unveils a novel anti-inflammatory and repurposing potential for Tα1 in MS targeting B cell response.

Altered intestinal permeability in patients with relapsing-remitting multiple sclerosis: A pilot study.

BACKGROUND: Alterations of intestinal permeability (IP) may contribute to the pathophysiology of immune-mediated diseases. OBJECTIVE: We investigated the possible association between IP changes and multiple sclerosis (MS). METHODS: We studied 22 patients with relapsing-remitting multiple sclerosis (RRMS) and 18 age- and sex-matched healthy donors (HDs), including five twin pairs (one concordant, and four discordant for disease). Measurement of lactulose (L) and mannitol (M; two non-metabolized sugars) levels in urine samples, after an oral load, allowed to quantify gut dysfunction. RESULTS: The proportion of participants with increased IP was significantly higher in patients than in HDs (16/22 (73%) versus 5/18 (28%); p = 0.001). Accordingly, the L/M urinary ratio showed significantly higher values in patients than in controls ( p = 0.0284). Urinary mannitol concentration was significantly lower in patients than in controls ( p = 0.022), suggesting a deficit of absorption from intestinal lumen. Such changes did not appear related to patients' clinical-radiological features. CONCLUSION: The relatively high proportion of IP changes in RR-MS patients seems to confirm our work hypothesis and warrants more work to confirm the result on a larger sample, and to understand the implications for related immunological disturbances and intestinal microbiota alterations. Our finding may also have relevance for oral treatments, recently introduced in clinical practice.

Interferon-ß therapy specifically reduces pathogenic memory B cells in multiple sclerosis patients by inducing a FAS-mediated apoptosis.

Growing evidences put B lymphocytes on a central stage in multiple sclerosis (MS) immunopathology. While investigating the effects of interferon-ß (IFN-ß) therapy, one of the most used first-line disease-modifying drugs for the treatment of relapsing-remitting MS, in circulating B-cell sub-populations, we found a specific and marked decrease of CD27+ memory B cells. Interestingly, memory B cells are considered a population with a great disease-driving relevance in MS and resulted to be also target of B-cell depleting therapies. In addition, Epstein-Barr virus (EBV), associated with MS etiopathogenesis, harbors in this cell type and an IFN-ß-induced reduction of the memory B-cell compartment, in turn, resulted in a decreased expression of the EBV gene latent membrane protein 2A in treated patients. We found that in vivo IFN-ß therapy specifically and highly induced apoptosis in memory B cells, in accordance with a strong increase of the apoptotic markers Annexin-V and active caspase-3, via a mechanism requiring the FAS-receptor/TACI (transmembrane activator and CAML interactor) signaling. Thus, efficacy of IFN-ß therapy in MS may rely not only on its recognized anti-inflammatory activities but also on the specific depletion of memory B cells, considered to be a pathogenic cell subset, reducing their inflammatory impact in target organs.

Treatment modifiers across different regimens of natalizumab treatment in MS: An Italian real-world experience.

Despite its widespread use in clinical practice, the effectiveness of natalizumab extended interval dosing (EID) adopted from treatment start across different treatment intervals and individual modifiers (body mass index - BMI) is still under-investigated. Here, seven-hundred and forty-five multiple sclerosis (MS) patients, exposed to natalizumab for 3.30 â€‹± â€‹1.34 years, were retrospectively enrolled in an observational multicenter study. After stratifying patients in EID or standard interval dosing (SID), we assessed differences in time to relapse, MRI activity and Expanded Disability Status Scale (EDSS) progression. The primary analysis was conducted on patients exposed to EID interval from 5 weeks and 1 day to 7 weeks, while a secondary analysis included also EID periods up to 8 weeks. An additional analysis explored the impact of BMI. No differences in time to first relapse, time to radiological activity, time to EDSS progression or time to EDA (evidence of disease activity) were detected between SID and EID group (EID interval from 5 weeks to 1 day to 7 weeks). When including EID periods from 7 weeks and 1 day to 8 weeks, the EID group showed a trend towards higher risk of experience clinical relapses than the SID group. A higher EDA risk was also identified in EID patients with BMI above median. In conclusion, a higher risk of relapses seems to occur for EID above 7 weeks. Independently from the EID scheme adopted, higher BMI increases the risk of EDA in these patients.

Frailty and relapse activity in multiple sclerosis: A longitudinal observation.

Recent cross-sectional investigations suggest a relationship between frailty, as measured by Frailty Index (FI), and multiple sclerosis (MS). However, if and how frailty is associated with relapse activity in MS is still unknown. To explore this issue, a one-year follow-up study involving 471 patients was conducted. A univariate regression model showed an inverse association between baseline FI score and the presence of relapse, which was also confirmed in the multivariate model. These results suggest that frailty may reflect pathophysiological mechanisms involved in MS disease activity and that the FI may be used as an enrichment criterion in clinical trials.

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.

Quality of care provided by Multiple Sclerosis Centers during Covid-19 pandemic: Results of an Italian multicenter patient-centered survey.

BACKGROUND: Covid-19 pandemic impacted on management of people with Multiple Sclerosis (pwMS). Level of satisfaction of pwMS regarding the care received by the staff of Multiple Sclerosis Centers (MSCs) during the pandemic was not fully investigated. In a large patient-centered multicenter study, the therapeutic adherence and quality of care of MSCs was assessed. METHODS: In April-May 2021, an online survey was widespread by 16 Italian MSCs. Frequencies, percentages and/or means and standard deviations were calculated to describe the sample. ANOVAs were performed to evaluate the effect of sociodemographic and clinical variables on overall pwMS' rating of MSC assistance. RESULTS: 1670 pwMS completed the survey (67.3% women). During the pandemic, 88% did not change their disease modifying therapy schedule, and 89.1% reached their MSCs with no or little difficulties. Even if only 1.3% of participants underwent a tele-health follow-up visit with their MSC staff, the 80.1% believed that tele-health services should be improved regardless of pandemic. 92% of participants were satisfied of how their MSC took charge of their needs; ANOVAs revealed an effect of disease duration on pwMS' level of satisfaction on MSCs management during the pandemic. CONCLUSIONS: The results revealed an efficient MSCs response to Covid-19 pandemic and provided the basis for the implementing of tele-health services that would further improve the taking charge of patients, particularly those with longer disease, higher disability, and/or living far from their MSC.

The impact of COVID-19 on people with multiple sclerosis: A comparison of Italian and United States cohorts.

BACKGROUND/OBJECTIVES: The present cross-national study addressed the relationship among three pandemic-related variables and multiple sclerosis (MS) disability outcomes among people with MS in Italy and the United States (US). METHODS: This cross-sectional web-based study was administered to 708 patients with MS from the US and Italy in late Spring through mid-Summer of 2020. Pandemic-related variables assessed worry, self-protection, and post-traumatic growth. The Performance Scales© assessed MS disability. Multivariate multiple regression models addressed, separately by country, the relationship among worry, protection, and post-traumatic growth with MS disability, after covariate adjustment. RESULTS: The Italian sample (n = 292) was younger and less disabled than the US group (n = 416). After covariate adjustment, all three pandemic-related variables were associated with MS disability outcomes in the US sample, but only worry and post-traumatic growth were associated in the Italian sample. Worse cognitive and depression symptoms were associated with worry, and lesser mobility disability was associated with endorsed growth in both countries. More disability variables were associated with worry and growth in the Italian sample. CONCLUSIONS: The pandemic's negative aspects were associated with worse disability in both countries, and reported post-traumatic growth was associated with lesser disability. These findings may suggest directions for clinical intervention.