Remote assessment of the impact of lockdown measures on mental health in multiple sclerosis patients

Background: Post-traumatic stress disorder (PTSD) has been reported in up to 15% ofgeneral population during and after the first wave of the COVID-19 pandemic. The pandemic has acted as a catalyst for the application of telemedicine in neurology. Objective(s): to evaluate the presence of PTSD symptoms as effect of the lockdown measures in people with MS (PwMS) using an e-health application specifically built for remote management of PwMS, SMcare2.0 application. Method(s): Between March 4, 2020 and July 5, 2020 (T0) PwMS who were using (n=290) the app were asked to fill in the Impact of Event Scale - Revised (IES-R) questionnaire to evaluate the presence of PTSD symptoms. The IES-R has 3 subscales: intrusion, hyperarousal, avoidance. The total IES-R score ranges from 0 to 88. A cut-off value of 33 of the total score was used to define the presence of PTSD symptoms (PTSD+). Only those PwMS who filled-in the questionnaire the first time were asked to answer again it when the lockdown measures were abolished (T1). Clinical and demographic data were extracted from the Italian MS register application and linked to the IES-R results. Baseline clinical characteristics of PwMS (classified on the basis of IES-R score) and the proportion of PTSD+, the subscales and the total score at T0 and T1 were compared. Result(s): During the lockdown 90 PwMS (31% response rate) completed the IES-R (62 F;mean (SD) age 40.1(1.0) years;median (IQR) EDSS score 2.3 (1-8);mean disease duration (SD) 10.7 (0.7)). Mean (SD) baseline subscales values were: intrusion 15.9 (7.1), hyperarousal 10.7 (5.0), avoidance 15.4 (6.7). Mean (SD) total IES-R score was 42.0 (17.0), 63 (70%) patients scored above 33 and were identified as having recently developed PTSD symptoms. No significant difference were found between PTSD+ and PTSD- patients in terms of age, EDSS and disease duration. At T1, when the lockdown measures were removed, the IES-R scores were significantly reduced in comparison to T0 scores (intrusion 8.6 (8.9), hyperarousal 6.0 (5.8), avoidance 8.4 (8.5), total score 4.8 (1.9), p<0.0001). The number of patients classified as PTSD+ was significantly reduced in comparison to T0 (16 (17.8%), p<0.0001). Conclusion(s): Our study demonstrated that PwMS during and after lockdown manifested post-traumatic stress symptoms. Furthermore, our results show how e-data collected can be useful in remotely monitoring patients and can be easily linked to clinical data collected by disease registries.

SARS-CoV-2 vaccination and COVID-19 infections in people with multiple sclerosis treated with ocrelizumab in the prospective, multicenter, noninterventional MuSicalE and CONFIDENCE studies

Background: Understanding outcomes of Coronavirus Disease 2019 (COVID-19) and the impact of COVID-19 vaccination deserve significant consideration for people with multiple sclerosis (MS) treated with ocrelizumab (OCR). Aim(s): To report the number, characteristics and outcomes of COVID-19 cases in all OCR-treated patients and in those with COVID-19 vaccination (i.e. breakthrough cases) in two realworld cohort studies. Method(s): We analysed data from OCR-treated patients enrolled in ongoing, prospective, noninterventional studies conducted in Germany (CONFIDENCE, EUPAS22951) and in 25 other countries (MuSicalE, NCT03593590). COVID-19 seriousness was assessed per ICH guidelines. Outcomes were captured as recovered, recovered with sequelae, recovering, not recovered or fatal. Vaccine breakthroughs were cases with COVID-19 onset >=14 days after completion of the primary immunisation schedule recommended for each COVID-19 vaccine platform. 'Unvaccinated' included patients without COVID-19 vaccination recorded (including the prevaccination era) or with incomplete immunisation scheme. Result(s): Analyses included 1,702 OCR-treated patients from MuSicalE (73.1% relapsing-remitting MS, 21.2% primary progressive MS [PPMS], 5.6% relapsing secondary progressive MS) and 2,784 from CONFIDENCE (81.7% relapsing MS, 18.3% PPMS). As of March 2022 (preliminary data), completion of primary immunisation schedule was recorded for 542 (31.8%) and 710 (25.5%) patients in each study, mainly with mRNA vaccines (72.3% and 93.8%). COVID-19 infection was reported in 189 and 122 patients in MuSicalE and CONFIDENCE (11.1% and 4.4% among all patients), mostly reported as nonserious (85.2% and 83.6%), including 71 and 31 vaccine breakthroughs (13.1% and 4.4% among fully vaccinated patients). The following rates were reported in vaccinated and unvaccinated patients in MuSicalE and CONFIDENCE, respectively: (a) hospitalisations, 8.5% (6/71) vs 16.0% (19/118) and 9.7% (3/31) vs 14.3% (13/91);(b) serious cases, 8.5% (6/71) vs 17.8% (21/118) and 9.7% (3/31) vs 18.7% (17/91);(c) fatalities, 1.4% (1/71) vs 2.5% (3/118) and 0 deaths vs 2.2% (2/91). In both studies, the majority of patients had fully recovered (79.9% and 74.6%) or were recovering (11.1% and 7.4%) at last follow-up. Updated vaccination rates will be presented. Conclusion(s): Most COVID-19 cases were nonserious in these OCR-treated patient cohorts. Initial data suggest more favourable clinical outcomes associated with COVID-19 vaccination.

Management of ocrelizumab in MS patients during the COVID-19 pandemic: an observational registry-based study

Introduction: Concerns have emerged during Covid-19 pandemic about management of Disease Modifying Therapies (DMTs) in patients with Multiple Sclerosis (pwMS). In particular, Ocrelizumab (OCR)-treated pwMS faced possible delays of scheduled infusions due to disruption of MS Centers activities as well as safety worries during lockdown periods. Objective(s): To assess changes of OCR infusion schedule in Italian pwMS during the first wave of COVID-19 pandemic (observation period: February-June 2020) and to investigate predictive factors determining delaying of OCR infusions. Material(s) and Method(s): Data were extracted from the Italian MS Register database. pwMS with an OCR infusion scheduled during the observation period and at least two previous OCR infusions were selected. Demographics (age, gender), disease characteristics (MS phenotype, disease duration, Expanded Disability Status Scale score, number of previous OCR infusions) and location of MS Centers among three Italian macro-regions (North, Center, South) were tested as potential predictors for treatment delay using univariable and multivariable linear model analyses. Result(s): Five-hundred ninety-nine pwMS (343 F/256 M;411 Relapsing MS/188 Progressive MS) from 65 MS centers were included in the analysis. Mean interval between two OCR infusions was 28.1 weeks (SD 2.72) before the observation period compared to 30.8 weeks (SD 5.45) during the observation period, with a mean delay of 2.7 weeks (p <0.001). No clinico-demographic factors emerged as predictors of infusion postponement, except for location of MS centers in the North of Italy (4.7 weeks vs 1.5 in the Center and 1.6 in the South). Such a difference was confirmed in multivariate analysis (p < 0.001) adjusting for prelockdown mean OCR infusion schedule. Conclusion(s): This large registry-based study shows that OCR infusions were significantly delayed during the first wave of COVID-19 pandemic in Italy. The location of the MS Centers in Northern Italy was the only predictor of OCR infusion postponement. This geographical area corresponds to the region in Italy that was hit first and more strongly by Covid-19 pandemic. The observed delay in OCR infusions disruptions of MS centers activities due to a drastic reduction of healthcare workers availability (because of infection/quarantine and/or reallocation in Covid Units) and concerns about using an immunosuppressive DMT like OCR during a new virus pandemic with many uncertainties.

Exploring the reasons behind Ocrelizumab infusions delay during the first wave of COVID-19 pandemic in Italy: results of a survey among MS centers

Introduction: MS centers (MSc) activities related to OCR management were strongly and diffusely hit during the first wave of COVID-19 pandemic. Concerns were mainly related to its immunosuppressive effects and the need for in-hospital administration. Objective(s): To investigate changes in OCR schedule among Italian MS centers participating to the Italian MS Register during the first wave of COVID-19 pandemic and to identify factors determining such changes. Material(s) and Method(s): A quick online survey was sent to 65 Italian MSc in order to collect from them the following data: macro-region (North, Center, South) location, number of OCRtreated patients, modifications of OCR schedule and a list of factors potentially influencing the postponement of OCR infusions (i.e. age, co-morbidity, MS phenotype, number of previous OCR cycles, disease severity/activity, CD-20 lymphocytes count, distance to MS center, fear of infection, inclusion in a research trial, infections trend, shortage of medical/paramedical staff for reallocation/ infection). Result(s): Among 55 MSc who answered the survey, 50 (91%) declared to have suspended or extended OCR interval dosing for at least one patient. The MSc that didn't modify OCR schedule were all from the South of Italy (33% of all South MSc). Main factors influencing OCR schedule delay were advanced age/comorbidity (70%) and pandemic trend in the area (72%), while recent MS-disease activity hindered OCR schedule modifications (65%). Conclusion(s): This study shows that most Italian MSc decided either to delay or suspend OCR treatment during the first wave of COVID-19 pandemic. Advanced age and co-morbidity and no evidence of recent MS-disease activity were the most relevant patient-dependent predictors of OCR postponement. Among patient-independent factors the most relevant factor was the local trend of infections. Contrary to what expected, the shortage of medical and/or paramedical staff in MSc did not come out as relevant. The disruption of OCR schedule during the first COVID-19 pandemic wave in Italy mostly reflected the geographical distribution and the impact on the National Health System of COVID- 19 pandemic.

An analysis of main symptoms of COVID-19 in MS patients and related risk factors

Introduction: MS patients affected by SARS-CoV-2 disease may present with a wide pattern of symptoms, not always suggestive of the severity of infection. A recent study has shown that main symptoms of Covid-19 can be grouped in seven different clusters. Risk and protective factors for their occurrence in MS patients has never been investigated. Objectives: To identify the most common symptoms of Covid-19 that are part of specific clusters in MS patients and evaluate all factors associated with their manifestation. Methods: As part of the MuSC-19 Italian project, all data were extracted from a dedicated web-based platform that allows researchers to evaluate the impact of Covid-19 on people affected by MS. After having tested the degree of agreement between different types of symptoms (Cohen's k), univariate and multivariate logistic regression models were applied to identify predicting factors for each group. Results: 1554 MS patients with confirmed Covid-19 and presenting at least one symptom referred to a specific cluster were analyzed. Patients presented nearly three groups of symptoms (mean: 2.8). The most common include fever/chills/rigor/fatigue/ cough (87%), followed by ageusia/anosmia (46%). Smoking habit was the most confirmed risk factor for developing a wide range of symptoms: common cold-like symptoms (OR:1.6, 95%CI:1.3- 2.1;p<0.001), joint and muscle pain (OR:1.3, 95%CI:1.1-1.7;p=0.037), gastrointestinal problems (OR:1.3, 95%CI: 1.1-1.7;p = 0.029), and loss of smell/taste (OR:1.4, 95%CI: 1.07-1.72;p=0.013). Smoking was confirmed also as risk factor for increasing the number of symptoms (OR:1.5, 95%CI:1.2-1.8;p<0.001), together with alcohol use (OR:1.25, 95%CI:1.1-1.5;p=0.021) and with assumption of anti-CD20 therapies (OR:1.7, 95%CI:1.2-2.5;p=0.004). Males have a lower risk for developing a major number of symptoms (OR:0.8, 95%CI:0.6 - 0.9;p=0.006). Finally, a lower EDSS was associated to a slight increment of symptoms, probably due to an already underlying presence of some common symptoms in most critical MS patients, which consequently were not reported (OR:0.9, 95%CI:0.8-0.9;p=0.005). Conclusions: Knowing possible risk factors and modifying some lifestyle behaviors might minimize the occurrence of Covid-19 symptoms. Anyway, further studies are needed for confirming these findings, and an additional follow up study on the presence of persistent symptoms after apparent Covid-19 resolution may help to better understand all possible risk factors.

The impact of PM2.5 on COVID-19 severity among Italian MS patients

Introduction: Studies have pointed out that air pollution longterm exposure may play a role in the severity and prognosis of SARS-CoV-2 infections. Additionally, air pollution has been associated to MS prevalence and course. However, the role of air pollution in COVID-19 severity has never been explored specifically among MS patients. Aims: To explore the association between air pollution assessed by PM2.5 levels and COVID-19 severity among MS patients. Methods: Demographic and clinical characteristics as well as data about Covid-19 severity were extracted from an Italian webbased platform (Musc-19 project) containing clinician-reported data from 118 Italian MS centers. PM2.5 ground-level concentrations were derived from air quality model results, as provided by the 'Copernicus Atmospheric Monitoring Service' (CAMS). Ordered logistic regression models were used to assess the association between PM2.5 (continuous and in tertiles) and Covid-19 prognosis (defined on three levels as mild course, hospitalization, and intensive care unit (ICU) admission or death) while controlling for possible confounders. Results: PM2.5 concentrations were available for 1517 MS patients, of whom 1321(87%) were classified as mild Covid-19 cases, 172(11%) were hospitalized and 24(2%) were admitted to ICU or died. Higher concentrations of PM2.5 were associated with increased odds of developing a worst Covid-19 prognosis (10-unit increase in PM2.5: OR(95% CI)=1.76(1.16-2.67) p-value=0.008;3rd vs 1st tertile: OR(95% CI)=1.74(1.17-2.59) p-value=0.006). Results remained consistent when we included only the Covid-19 cases confirmed by a nasopharyngeal swab (N=1087). Conclusions: Higher concentrations of PM2.5 are associated with Covid-19 severity among MS patients. Further studies are needed to evaluate the impact of other air pollutants, but urgent measures to reduce air pollution must be surely adopted.

The risk of COVID-19 in people with multiple sclerosis: A case-control study from the Italian MS Register

Background: Data collected from several international platforms provided important information about risk factors, including treatment exposure, impacting COVID-19 severity in people with multiple sclerosis (PwMS). However, up to now, factors increasing the risk of getting SARS-CoV2 infection in PwMS are not known. MS registers represent a suitable tool to provide denominators for risks assessment. Objectives: To assess risk factors for SARS-CoV2 infection in PwMS by using data collected in the Italian MS Register (IMSR). Methods: A case-control (1-2) study was set-up. PwMS with (cases) and without (controls) COVID-19 were identified within the IMRS and propensity-score matched by the date of COVID-19 diagnosis (cases) and the date of last visit (controls) and for the region of residence. COVID-19 risk was estimated by multivariable logistic regression models including demographic and clinical covariates. The role of DMTs exposure was assessed in 3 different models including: last recorded DMT or DMT sequences (induction strategy/escalation strategy/only first line DMT exposure/ never treated) or last DMTs grouped according to the place of administration (at hospital or self-administered at home). A minimal treatment exposure for each DMT was defined on the basis of the recognized minimal time required to be potentially effective. Results: A total of 779 [median (IQR) age: 42.40 years (33.00- 50.80);30.17% male] confirmed COVID-19 cases were matched to 1558 controls [46.90 years (37.50-55.70);35.82% male]. In all models, comorbidities, female sex and age were significantly associated (p<0.02) to a higher risk of getting COVID-19. Patients receiving Natalizumab as last DMT (OR (95% CI): 2.38(1.66-3.42), p<0.0001) and those who underwent an escalation treatment strategy (1.57 (1.16-2.13), p=0.003) were at significant higher COVID-19 risk. Moreover, the group of PwMS receiving last DMTs requiring hospital access (1.65(1.34-2.04), p<0.0001) showed a significant higher risk than those taking selfadministered DMTs at home. Conclusions: This case-control study embedded in the IMSR showed that PwMS at higher COVID-19 risk are younger, more frequently female and with comorbidities. Long-lasting escalation approach and last therapies that expose patients to the hospital environment seem to increase significantly the risk SARS-CoV2 infection in PwMS.

Different disease modifying therapies can increase or decrease Covid-19 severity in Multiple Sclerosis

Objective: To describe the effect of disease modifying therapies (DMT) on Covid-19 severity in a large cohort of Italian patients with Covid-19 and multiple sclerosis (MS). Background: We previously presented data from a nationwide study of persons with MS with suspected or confirmed Covid-19, collected from March 2020. In June we started collecting also asymptomatic patients, when serological tests started to be routinely done. Design/Methods: This was a retrospective multi-center observational study. We defined Covid-19 severity as a 4-level variable: Level 1=asymptomatic, level 2=symptomatic without signs of pneumonia, level 3=radiologically defined pneumonia or hospitalization, level 4=intensive care unit (ICU) or death. We analysed the impact of baseline variables on this outcome by a multivariable ordinal logistic model quantifying the association by Odds Ratio (OR). Results: On October 12, we enrolled 902 MS patients, 298 (33%) with confirmed and 604 (67%) with suspected Covid-19;37 (4%) were asymptomatic. The number of ICU/deaths were 8/95 (8%) among those treated with anti-CD20 therapies (mean age=41 years), 0/84 (0%) among those treated with Interferon (mean age=47 years) and 37/723 (5%) among those treated with other drugs (mean age=43 years). Among the 37 asymptomatic patients, 7/84 (8.3%) were in Interferon, 1/95 (1.1%) was on anti-CD20 and 29/723 (4%) were on other drugs. At multivariable analysis, independent risk factors for a severe Covid-19 were age (OR=1.05, p<0.001), EDSS(OR=1.13, p=0.02), Male sex(OR=1.44, p=0.057) and DMT used: Treatment with anti-CD20 (Ocrelizumab or Rituximab) increased the risk (OR=1.99, p=0.035) and treatment with Interferon reduced the risk (OR=0.48, p=0.05) of severe Covid-19 as compared to treatment with DMF, used as the reference DMT. Conclusions: This analysis confirms on a larger population the increase of risk of severe Covid-19 of anti-CD20 therapies and highlights the protective role of Interferon. Data on asymptomatic patients are rapidly accumulating and will provide useful information about this.

Migraine during COVID-19: Data from Second Wave Pandemic in an Italian Cohort

OBJECTIVES: The study aims to assess the impact of the second COVID-19 pandemic wave on migraine characteristics. METHODS: This is an observational cross-sectional study conducted on migraine patients previously interviewed during the first Italian pandemic outbreak. A second structured telephone interview was conducted between 20 November 2020 and 18 January 2021. We compared migraine characteristics among T0 (before pandemic), T1 (during the first pandemic phase), and T2 (during the second pandemic phase). RESULTS: Among the 433 patients interviewed during the first pandemic phase, 304 cases were finally considered. One hundred forty-eight patients had a control visit between March 2020 and December 2020, 120 had an in-person visit, 14 by phone, the remainder used telemedicine software provided by the hospital. Frequency of headache, number of symptomatic drugs and headache intensity worsened during T2, compared to T0 and T1, especially in episodic migraine. Headache intensity increased relating to the negative emotional impact of the pandemic. Migraine management during the pandemic did not influence the clinical outcome. CONCLUSION: The prolongation of the pandemic seems to have a negative impact on migraine evolution. The arousal and negative psychological behavior toward the COVID-19 outbreak seem to worsen migraine.