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Introduction Disruption to clinical services, triggered by the COVID-19 pandemic, led to extended intervals between ocrelizumab treatments for some patients. Objectives To assess the rates of developing low immunoglobulin levels and timing of CD19+ B-cell count repopulation in a real-world clinical population. To assess for evidence of clinical or radiological MS disease activity with extended interval dosing of ocrelizumab. Methods We audited 712 patients given ocrelizumab by our seven clinical services. All monitoring of immunoglobulin levels and CD19+ cell counts were recorded. Disease activity was defined as on treatment clinical relapse, radiological activity, and EDSS progression. Results Low immunoglobulin levels developed in 102 patients, the odds ratio for developing hypogam- maglobulinaemia comparing extended to standard interval dosing was 0.42 (CI 0.22-0.81). Disease activity included 20 participants with clinical relapses and 72 with new MRI lesions. There was no evidence of excess clinical or radiological disease activity on switching to extended interval dosing. 38 had EDSS progression, giving an odds ratio comparing extended to standard interval dosing of 0.77 (CI 0.38-1.56). Conclusions This real-world data of extended interval dosing of ocrelizumab indicates lower rates of hypogammaglobulinaemia and no detrimental effect on short-term treatment efficacy.
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Background: Multiple sclerosis (MS) patients have been considered a higher-risk population for COVID-19 due to the high prevalence of disability and disease-modifying therapy use;however, there is little data in our Middle East and North Africa region (MENA) identifying clinical characteristics of MS associated with worse COVID-19 outcomes. Material(s) and Method(s): This a nationwide, multicenter, retrospective cohort study conducted between March 2020 and February 2021 and included MS patients with a suspected or confirmed COVID-19. Using data collected from the MENACTRIMS registry and local COVID-19 registries, the association of patient demographics, MS disease characteristics, and use of disease-modifying therapies with outcomes and severity of COVID-19 illness were evaluated by multivariate logistic models. Result(s): A total of 600 MS patients with suspected (n=58) or confirmed (n=542) COVID-19 (mean age: 36.4 +/- 10.16 years;414 (69%) females;mean disease duration: 8.3+/- 6.6 years) were analyzed. Seventy-three patients (12.2%) had a COVID-19 severity score of 3 or more, and 15 patients (2.5%) died of COVID-19. The median EDSS was 2.0 (range, 0-9.5), and 559 patients (93.2%) were receiving disease-modifying therapy (DMT). There was a higher proportion of patients with a COVID-19 severity score of 3 or more among patients treated with DMTs relative to untreated patients (82.9% vs 17.1%;P < .001), from whom the majority (n=117;19.7%) were maintained on anti-CD20 therapies such as ocrelizumab and rituximab. Comorbidities mainly hypertension and cardiovascular diseases, progressive MS, disease duration, and EDSS were associated with severe or worse COVID-19 disease outcome. Multivariate logistic regression analysis showed that older age (odds ratio per 10 years, 1.5 [95%CI, 1.1-2.0]), male gender (OR, 2.1 [95%CI. 1.2-3.8]), obesity (OR, 2.8 [95%CI, 1.3-5.8]), and treatment ocrelizumab/rituximab (OR for ocrelizumab, 4.6 [95%CI. 1.2-17.7], OR for rituximab, 14.1 [95%CI, 4.8-41.3]) or off-label immunosuppressive medications such as azathioprine or mycophenolate mofetil (OR, 8.8 [95%CI. 1.7-44.0]) were risk factors for moderate to severe COVID-19 requiring hospitalization. Surprisingly, smoking and diabetes were not identified as risk factors for severe COVID-19 disease in our cohort. Conclusion(s): In this registry-based cohort study of patients with MS, age, sex, EDSS, obesity, progressive MS were independent risk factors for severe COVID-19. Moreover, there was an association found between exposure to anti-CD20 DMTs and COVID-19 severity. Knowledge of these risk factors may help improve the clinical management of MS patients with COVID-19 infection.Copyright © 2022
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Objective(s): Type 1 Interferons (IFNs) modulate the antiviral immune response and have been used for the treatment of coronaviruses. This study aimed to determine any possible effects and safety concerns of the two most promising exogenously administrable interferons (IFNbeta1a and IFNbeta1b) on the severity outcomes of COVID-19 in multiple sclerosis (MS) patients hospitalized with COVID-19. Material(s) and Method(s): Using the electronic health records systems;this is a cross-sectional study of two years of hospital admissions in terms of COVID-19 in Iran from March 2019 to August 2021. The severities of COVID-19 outcomes were admitted to ICU, hospitalization days, and in-hospital mortality. MS patients with positive results from PCR were included. The data included demographic information, admission, and discharge dates, initial and final diagnoses, hospital inpatient services, including all drugs, admitted wards, procedures, and hospital mortality. A questionnaire was filled out with information on their MS diagnosis, MS medications at the time of COVID-19 admission, history of other chronic illnesses, history of smoking, height and weight, co-morbidity, and MS course (MS type, EDSS, MS duration) and disease-modifying therapies (DMT) at the time of COVID-19 admission (Rituximab, Fingolimod, IFNs, Glatiramer acetate, Dimethyl fumarate, Teriflunomide, Tysabri, and Azathioprine). Result(s): A total of 993 hospitalized MS patients were included in the study. IFNs were used in 28.8% of patients for the treatment of SARS-CoV-2 infection;26% IFNbeta1a and 3.5% IFNbeta1b. Among studied patients, 5.6% did not receive any DMT before their hospital admission. Almost half of the patients were under Rituximab(50.3%). The data were classified based on consuming DMTs. Except for patients who received Rituximab;there was not any significant association between taking IFNs and reducing the severity of COVID-19 outcomes in each DMT sub-group. In patients who were under Rituximab;taking IFNbeta1a for COVID-19 treatment had a significant association with longer hospitalization than patients not receiving it (median (IQR);8(7) vs. 6(4) days, respectively, p=0.000). In the logistic regression model, after adjusting confounding factors, there was a constant association between receiving IFNbeta1a and the risk of longer hospitalization (adjusted OR=2.46 95%CI: 1.46, 4.13). Conclusion(s): The current data suggest that MS healthcare providers should consider specific risks of exogenously IFNbeta1a for the treatment of COVID-19 based on MS medication therapies.Copyright © 2022
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Background: Disease-modifying drugs (DMDs) are an inseparable part of multiple sclerosis (MS) management, which have dramatically changed the prognosis and course of the disease. A change during DMD therapy, which includes switching or stopping (temporary or permanent) medication, can manipulate the goals and has various causes such as side effects, ineffectiveness of treatment, patient's preference, presence of concurrent diseases and pregnancy. Therefore, we aimed to investigate the patterns and causes of DMD change in patients with MS (PwMS) in Tehran, Iran. The understanding will help us identify opportunities to improve adherence and ultimately patient outcomes and health system efficiency through effective education, and recognition of more tolerable or simpler regimens. The aim of this study is to identify rate and pattern of DMDs among PwMS in Tehran. Material(s) and Method(s): The study population of this cross-sectional was all PwMS in Tehran province who had changed their DMD for any reason in the last 5 years until June 2, 2022. The basic information was extracted through nationwide MS registry of Iran (NMSRI), Tehran, where all MS data including diagnosis had been confirmed by trained neurologists based on the 2017 revisions of the McDonald criteria. Moreover, supplementary unregistered data were gathered through telephone follow-ups carried out by 6 trained physicians with precise quality checks. The questionnaires covered 5 aspects of MS including demographics, disease history, diagnosis, progress and treatment. DMDs were classified into 10 general classes. All participants were asked to attribute the change to distinct categories following a written pre-existing consent. IBM SPSS (version 23) was used for statistical analysis. All the steps taken were in complete adherence with the tenets of the declaration of Helsinki. Result(s): Among 1999 enrolled patients with a mean age of 36.9+/-9.4 and total disease duration of 7.06+/-5.8 years, 1315 experienced change (Group 1) during study period, while 684 did not (Group 2). There was no difference in terms of demographic characteristics between the two groups. On the other hand, Group 1 had longer disease durations and more comorbidities (P <0.001). Getting infected with COVID-19 more than 4 times was observed to be significantly higher in Group 1 (P =0.032). Unlike Patients with PPMS and RRMS, SPMS patients showed higher EDSS scores when experiencing no DMD change. The most widely used DMDs were interferons, while ocrelizumab was the least used drug. Corona virus had the most effect on the change of ocrelizumab. Conclusion(s): DMD change generally occurs independent of socioeconomic level. Since most of the patients (65.8%) experienced DMD change, which serves as the biggest cost component in PwMS, the economic aspects of MS management in this field should be considered in the future.Copyright © 2022
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Background: The national multiple sclerosis (MS) registry is aimed at monitoring and improving quality of care and providing feedback to improve health outcomes by systematic recording of data. In 2018, the nationwide MS registry of Iran (NMSRI) was initiated for collecting epidemiological data and information on health care provision for patients with MS. The aim of the current study was to introduce the role of implementing coronavirus disease 2019 (COVID-19) scale-up registry protocol in NMSRI and arrange the national MS generality with information obtained during the COVID-19 pandemic. Method(s): The NMSRI group set up a program with crucial elements to collect the data of patients with MS who developed COVID-19. All MS cases with confirmed diagnosis of COVID-19 were enrolled in this study. New elements were considered to be added into the dataset, including demographic characteristics, definite diagnosis of COVID-19 and its symptoms, history of comorbidities, history of medications and hospitalization, changes in magnetic resonance imaging (MRI), and infection outcomes. Result(s): The COVID-19 data collection program was designed in NMSRI to collect data of MS cases with COVID-19 infection. The data collection protocol was explained to neurologists through an online training workshop. To the date of the study, 21 centers from 17 provinces of Iran were involved in the COVID-19 databases promoting NMSRI and 612 participants were registered successfully. Conclusion(s): We extended an agreement on data collection and developed it in NMSRI with various contributors to discover a critical need for COVID-19 awareness and monitor clinical training in MS.Copyright © 2021 Iranian Neurological Association, and Tehran University of Medical Sciences Published by Tehran University of Medical Sciences.
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Introduction: COVID-19 pandemic has affected human communities around the world, and there is fear that people with chronic diseases such as Multiple sclerosis(MS) are more vulnerable to negative psychological effects. Objective(s): The aim of the present study was to assess the quality of sleep in patients with (MS) in comparison with healthy controls(HCs), during the COVID-19 pandemic and to identify its associated factors. Method(s): This was a cross-sectional survey study conducted with patients followed at the neurology department of Hbib bourguiba university hospital in sfax(Tunisia), during the month of november2020. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index(PSQI). The PSQI is a questionnaire assessing participants' sleep quality, sleep duration, and sleep disturbances and their severity during the past month.Participants with a PSQI <=5 are classified as 'good sleepers'. Result(s): Fifty two patients were included in the study. The mean age was 33.69 years(SD=9.21 years)and the sex ratio(F/H)was 4.77. Overall, our patients had higher scores of(PSQI)compared to HC and these differences were statistically significant(p < 0.05). The mean score of(PSQI)was 11.04(SD=3.003)and 11.53%were classified as 'good sleepers'. Unemployment was related to a poor sleep quality(p=0.0001). Patients with high EDSS(r=0.7;p=0.0001), high number of relapses(r=0.58 ;p=0.0001)were more likely to have sleep disturbance. There was a positive correlation between a poor sleep quality and the duration of disease(r=0.38;p=0.005). Conclusion(s): We identified that during the COVID-19pandemic patients with(MS)had a worse sleep quality. The COVID- 19pandemic poses a challenge to psychological resilience. More studies are warranted to better understand the long-term consequences of the pandemic on mental health of vulnerable people.
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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.
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Introduction: Balance impairments are common in multiple sclerosis (MS). Pilates is a popular alternative method for balance performance maintenance and improvement that may reduce the rapid symptoms worsening frequently associated with physical inactivity. An Italian network of fifteen experts in MS rehabilitation developed through a User-Centered Design approach the MS-FIT exergame, a Kinect-based tool, to autonomously train balance through Pilates exercises. The MS-FIT user executes the exercises shown by a teacher's avatar and improves the performances through the feedbacks on the execution correctness. Aim(s): This study (Clinical.Trials.gov, NCT04011579) aims at evaluating the feasibility of an at-home intervention with MS-FIT. Method(s): Feasibility was investigated in terms of adherence (sessions number), usability (usability items of Tele-healthcare Satisfaction Questionnaire, u-TSQ, satisfaction (Client Satisfaction Questionnaire, CSQ-8), safety (adverse events), and physical effectiveness (Timed UP-&-GO, TUG;Timed 25-Foot Walk, T25FW;2-Minutes Walking Test, 2MWT). Result(s): Forty-five people with MS (PwMS) were enrolled and randomized into the experimental (EXP, n=23) and control (CTRL, n=22) groups. During the 6 weeks of the study, only the usual physical activities were admitted (rehabilitation excluded) and, in addition, EXP had to practice MS-FIT at least three times a week. Due to organizational consequences of COVID pandemic, 8 subjects dropped-out (EXP, n=17;CTRL, n=20). The sample analysed showed the following characteristics: gender (EXP: 6M;CTRL: 7M), age (EXP: 41.9+/-9.6y;CTRL: 43.3+/-10.5y), course (EXP: 94.4% and CTRL: 95.0% relapsing-remitting), disease duration (EXP: 9.9+/-7.2y;CTRL: 12.5+/-9.8y) and EDSS (EXP: 2.6+/-0.8;CTRL: 2.6+/-0.8). EXP highly adhered to the MS-FIT training (23.6+/-6.1 sessions);the tool was usable (u-TSQ: 3.01/4);satisfaction was medium-tohigh (CSQ-8: 25.1/32);the training with MS-FIT was safe (no adverse events). The groups did not differ in TUG, T25FW and 2MWT. An analysis separate for each group showed a significant improvement only in EXP (TUG: pre 7.5+/-1.2s, post 7.0+/-1.2s, p<0.05;T25FW: pre 6.1+/-1.5s, post 5.0+/-1.2s, p<0.01;2MWT: pre 175.4+/-51.0m, post 194.1+/-56.9m, p<0.01). Conclusion(s): MS-FIT is well-accepted and effective and could be a complement of traditional MS interventions. Based on the results and participants' feedbacks MS-FIT has been refined and is used in an ongoing randomized controlled trial.
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Introduction: The Providence Ocrelizumab (OCR) Registry (POR) was established to monitor long-term treatment and safety outcomes after the approval of OCR in the US in 2017. Objective(s): To evaluate OCR treatment outcomes using real-world data from a community-based MS population. Method(s): Adult MS patients who have been prescribed and received at least one dose of OCR were eligible. Chart reviews were done at OCR start date and every 6 months by a trained RN. Expanded Disability Status Scale (EDSS) scores were determined by the treating provider on the OCR start date and yearly, thereafter. Result(s): Of the 509 patients enrolled from March 2017 to April 2022, 74.2% were female;mean (SD) age was 52.1 (12.6) years;82.7% had RMS, 11.0% had SPMS, and 6.7% had PPMS. Median time on OCR was 34.3 [17.2, 49.6] months. The RMS cohort had an annualized relapse rate (ARR) of 0.32 prior to starting OCR. Among all patients who had > 1 dose of OCR (n=449), ARR was 0.05 (SD 0.23) with 5 patients having 2 or more relapses. Median EDSS scores at 12 months were 3.0 [2.0, 4.5] (n=205) for RMS patients, 6.5 [6.5, 7.5] (n=33) for SPMS, and 6.5 [6.5, 7.5] (n=19) for PPMS. Infusion reactions occurred in 33% of patients during dose 1, becoming less frequent with subsequent doses. Respiratory infections have occurred in 37.5% of patients followed by urinary tract infections (UTI) (36.7%). 10% of patients have developed documented COVID-19. Of the 70 patients hospitalized, 27 patients had multiple hospitalizations. Over half of the hospitalizations were due to infections. 66% of these patients were 55 years or older. One hundred and twenty-nine (25.3%) patients have stopped OCR with a median time to discontinuation [IQR] of 20.5 [11.2,34.7] months;63 patients stopped due to side effects with recurrent infections being the main reason for stopping followed by fatigue/malaise. There have been 12 deaths, including 2 from COVID-19. There were no significant changes in Beck Depression Inventory (BDI). Modified Fatigue Inventory (MFIS), had significant improvement at 12 months (mean difference -3.6 (+/-14.2), (p=0.01). No change in the MFIS of the 17 patients switching from natalizumab. Conclusion(s): Our study showed that OCR was effective in controlling relapse and disability worsening and reported similar rates of infusion reactions compared to earlier phase III clinical trials. However, a quarter of our patients have stopped OCR, the majority stopping due to recurrent infections.
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Introduction: Studies have found associations between air pollution and pneumonia and air pollution is an established risk factors for common COVID-19 complications including pneumonia. Additionally, air pollutants have been identified as possible risk factors for MS onset and relapses. To our knowledge, only one study explored the impact of air pollution on Covid-19 severity specifically among MS patients but has only focused on PM2.5 exposures. Aim(s): We aim to evaluate the association between long-term exposure to air pollution and COVID-19 severity, described as developing pneumonia in a population of COVID-19-positive MS patients. Method(s): Data on COVID-19 infection among MS patients were extracted from an Italian web-based platform (Musc-19). A casecontrol study was designed including patients with and without pneumonia at a case-control ratio of 1:2 and 615 patients were included. The included patients were asked to provide information on the geographical area where they had spent most time in the previous 5 years. When this information was missing, the address of the MS center was used as a proxy and evaluated in sensitivity analysis. Air quality was assessed as annual average particulate matter (PM2.5 and PM10) and Nitrogen Dioxide (NO2) ground-level concentrations derived from air quality model results as provided by the 'Copernicus Atmospheric Monitoring Service', and evaluated as categorical exposures (terciles). The association between pollutants and COVID-19 pneumonia was studied using logistic regression models, also adjusting for confounders (age, sex, BMI, comorbidities, EDSS, MS type, duration and treatments). Result(s): Detailed exposure was obtained for 491 patients, of whom 34% had pneumonia. Higher concentrations of air pollutants were associated with increased odds of developing COVID-19 pneumonia in both unadjusted and adjusted models (Adjusted models estimates: PM2.5: 2nd vs 1st tercile OR(95% CI)=2.09 (1.20;3.65), 3rd vs 1st tercile OR(95% CI)=2.26(1.29;3.96);PM10: 2nd vs 1st tercile OR(95% CI)=1.83(1.05;3.20), 3rd vs 1st tercile OR(95% CI)=2.12(1.22;3.68);NO2: 3rd vs 1st tercile OR(95% CI)=2.12(1.21;3.69)). Results remained consistent in the sensitivity analysis. Conclusion(s): Higher long-term concentrations of PM2.5, PM10 and NO2 were associated with COVID-19 pneumonia among MS patients. Urgent measures to reduce air pollution should be adopted especially to protect the most vulnerable population.
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Neuromyelitis optica spectrum disorders (NMOSD) is an immunemediated inflammatory disorder of the central nervous system. SARS-CoV-2 infections not only affect the lungs but generally all organs including the central nervous system. The underlying pathophysiology for SARS-CoV-2 associated CNS disease is suspected to be immunogenic. Therefore, the question is whether COVID-19 can trigger relapses in NMOSD patients. On the other hand, there have been reports that COVID-19 vaccination may trigger a relapse. The aim of our study was to assess the risk of NMOSD relpase after SARS-CoV-2 infection or after vaccination. Department of Neurology Medical University of Warsaw is a reference center for treatment of NMOSD patients in Poland. Nowadays we are taking care on seventy-five patients meeting NMOSD diagnostic criteria. As of March 31, 2022, we registered 47 SARS-CoV-2 infections. Twenty-two SARS-CoV-2 infections were reported in patients prior to COVID-19 vaccination (19 females, 3 males). Mean age of patients was 49+/-10 years, mean EDSS 4.5+/-1.5. Twenty (90.9%) patients were on immunosuppressive therapy (rituximab -11, steroids-4, inebilizumab -2, azathioprine -1, satralizumab -1, mycophenolate mofetil -1). Twenty-five SARS-CoV-2 infections occurred after the full course of vaccination (23 females, 2 males). Mean age of patients was 50+/-12 years, mean EDSS 3.6+/-1.7. Twenty-three (92%) patients were on immunosuppressive therapy (rituximab - 12, inebilizumab - 1, azathioprine - 3, satralizumab - 3, mycophenolate mofetil - 4). Three patients had a relapse after COVID-19 (within three months). Two of these people were still unvaccinated at the time. These patients were not receiving full immunosuppressive treatment at the time (one patient developed COVID-19 right after the first dose of rituximab, the other patient received the last dose of rituximab 18 months earlier). The third patient was treated with rituximab and was fully vaccinated. NMOSD relapse occurred in 6% of patients confirmed with COVID-19. Thee risk of relapse was even lower (2%) among patients properly treated with immunosuppressants. Of our seventy-five patients, only two were not vaccinated against SARS-CoV-2. All patients receivedmRNA SARS-CoV-2 vaccines. No vaccine-related NMOSD attack has been reported. Conclusion(s): Patients with NMOSD treated with immunosuppressants have a low risk of a relapse due to COVID-19 infection. In our study mRNA COVID-19 vaccines do not increase the risk of a relapse.
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Introduction: The 'coronavirus disease of 2019' (COVID-19) is an acute infection caused by the novel 'severe acute respiratory syndrome coronavirus-2' which has evolved into an ongoing pandemic with more than six million case fatalities to date. Evidence from large-scale observational studies has consistently shown that simply having MS does not make affected subjects more susceptible to contract COVID-19 nor to become severely ill from the infection, as compared to the general population. Risk factors are similar in both settings and include older age, male gender, cardiovascular comorbidities, African- American ethnicity, progressive disease and B-cell depleting agents. However, the reverse relationship - i.e., the impact of COVID-19 on clinical disability related to MS - remains less well described. Objective(s): To explore whether COVID-19 is associated with accelerated disability worsening in patients with MS. Method(s): Since March 2020, demographics and COVID-19 severity (categorized as ambulatory, hospitalized, death) of patients with MS have been collected at the Belgian National MS Center in Melsbroek in case of COVID-19 diagnosis (i.e., positive polymerase chain reaction test). On February 28, 2022, this database was locked and consisted of 234 unique cases. Clinical disability measures - including Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk Test, 9-Hole Peg Test and Symbol Digit Modalities Test scores - were available from a larger local database, obtained during routine medical follow-up. For each of these parameters, the first two assessments before COVID-19 diagnosis (labelled T0 and T1, respectively;T1 is the closest to COVID-19 diagnosis), and the first thereafter (labelled T2), were retrieved for every COVID-19 case. Result(s): Mortality and hospitalisation rate in this cohort was 5/234 (2.1%) and 37/234 (15.8%), respectively. Among the survivors with complete EDSS data (N = 139), mean annualized EDSS score changes between T1 and T2 (i.e., including the COVID-19 infection) were significantly increased, as compared with the respective changes between T0 and T1 (i.e., not including the COVID-19 infection) (0.09 versus 0.36, p = 0.008). Similar effects were not found for the other clinical outcome measures. Conclusion(s): COVID-19 infection is associated with global disability worsening in patients with MS. Our findings highlight the importance of preventive measures against COVID-19 spreading within this population.
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Introduction: The role of ongoing disease-modifying therapy (DMT) in coronavirus disease 2019 (Covid-19) morbidity and mortality in people with multiple sclerosis (MS, pwMS) is uncertain. The MS International Federation recommends that pwMS continue their medication. Objective(s): To investigate the relationship between DMT used in MS patients and the risk of Covid-19 infection. Aim(s): The MS cohort of 3402 people followed for Covid-19 infection was included in this longitudinal cohort study. The whole MS cohort was interviewed at least once for information about Covid- 19, by text message, or by phone, during which 487 pwMS were determined with Covid-19 infection. A semi-structured interview, which included questions related to COVID-19 symptoms, recovery status, and duration of symptoms, was developed and performed by a team consisting medical doctor, nurse, and physiotherapist. Clinical information was obtained from the patient's medical records. Result(s): Of the 487 pwMS infected with Covid-19, 35 reported reinfections. The clinical and demographic profiles of participants were following: the mean age was 40.3+/-11.4, the mean disease duration was 10.7+/-8.2, the mean EDSS score was 1.7+/-2, 342 (70.2%) were female, 425 (87.3%) had relapsing-remitting MS, and 324 (6.5%) were working. The major differences regarding DMT between pwMS with and without Covid-19 infection were observed for fingolimod, ocrelizumab, and azathioprine. Fortythree (8.9%) people experienced the Covid-19 infection severely or critically;of those, 15 (34.9%) had MS treatment with ocrelizumab. Thirty-two (6.6%) patients reported that they were hospitalized;12 (37.5%) of these had been treated for MS with ocrelizumab. Fifty percent of pwMS who were treated in intensive care (7/14 patients) and died (3/6 patients) were being treated with ocrelizumab. As a result of the regression analysis, any additional risk factor on Covid-19 related to MS treatments was not detected, while working/being active in social life has a risk factor on the Covid-19 infection and it is course. Conclusion(s): The current data show that pwMS using ocrelizumab have a more severe course of Covid-19 infection than those using other DMTs. These data will guide the treatment of pwMS in cases of new Covid-19 variants or similar pandemic situations that may develop in the future.
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Introduction: Phase 2b trial (NCT03889639) findings in patients with relapsing multiple sclerosis showed central nervous systempenetrant Bruton's tyrosine kinase inhibitor tolebrutinib was well tolerated over 12 weeks and elicited dose-dependent reductions in new gadolinium-enhancing T1 and new/enlarging T2 lesions. Objective/Aim: To characterise tolebrutinib's safety and efficacy at Week 96 (2 years) in the phase 2b trial's long-term safety (LTS) extension (NCT03996291). Method(s): In LTS extension Part A, patients continued their core study tolebrutinib dose (5, 15, 30, or 60 mg/day) double-blind until the phase 3 study dose selection (60 mg/day). In Part B, patients received open-label tolebrutinib 60 mg/day. Safety was assessed via adverse event (AE) reporting. Efficacy outcomes included annualised relapse rate (ARR) and change from baseline Expanded Disability Status Scale (EDSS) score. Result(s): 124 of 125 patients completed Part A and transitioned to Part B;114 (90.5%) remained on study as of 7 March 2022. One patient receiving tolebrutinib 5 mg/day discontinued Part A because of progressive disease and 10 discontinued Part B because of AEs (n=3), perceived lack of efficacy (n=4), emigration (n=2), and patient decision (n=1). At Week 96, no new safety signals have been observed. The most common treatment-emergent AEs (TEAEs) were COVID-19 (20.8% [26/125]), headache (13.6% [17/125]), nasopharyngitis and upper respiratory tract infection (both 11.2% [14/125]), bacterial cystitis (7.2% [9/125]), and pharyngitis and arthralgia (both 5.6% [7/125]). No tolebrutinib dose effects for TEAEs or serious AEs were observed in Part A and no safety signals emerged for patients switching to tolebrutinib 60 mg/day in Part B. Of those who received tolebrutinib 60 mg/day for a minimum of 8 weeks, ARR was 0.17 (95% CI: 0.12, 0.25) and 80.6% remained relapse-free. Mean EDSS remained stable to Week 96. Conclusion(s): Through LTS Week 96, tolebrutinib 60 mg/day continues to show favourable safety, and is associated with a low ARR and stable disability status.
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Introduction: Many patients treated with Natalizumab experience end of dose interval (EDI) symptoms towards the end of the administration cycle. Objectives and aims: During the pandemic, to minimize patients accesses to the hospital and reduce exposure to Sars-CoV-2, we advised and asked patients undergoing treatment with Natalizumab if they wanted to be shifted from a Standard Interval Dosing (SID of 4 weeks) to and Extended Interval Dosing (EID of 5-6 weeks), regardless of their JCV index. Our main objective was to study prevalence and incidence of End of Dosing Interval (EDI) symptoms when Extended Interval Dosing (EID) was adopted, considering the variable prevalence of the wearing off effect. Method(s): We enrolled 87 patients, from May 2020 to January 2021, evaluated at baseline and during a 6 months follow-up with a survey focused on End of Dosing Interval Symptoms(EDIs), Fatigue Severity Scale (FSS), Expanded Disability Status Scale (EDSS) and Magnetic Resonance Imaging. Result(s): Among the 87 patients, 32(36.8%) reported End of Dose Interval (EDI) symptoms. Most common EDI symptom was fatigue (93.7%). Of note, among the patients with an EID (71), 16.9% patients reported a new onset of fatigue, where none was present before adopting the EID. Mean EDSS was higher in the group reporting EDI symptoms (3.6 EDI vs 2.2 non-EDI, p<0.05).Sphincterial functions were the ones that differed the most between the EDIsymptoms group and the non-EDI-symptoms group (1.4 EDIs vs 0.62 non-EDIs, p<0.05), among EDSS different components. Conclusion(s): The present study confirms that fatigue is the most common Natalizumab wearing-off symptom and 16.9% of patients develop a new onset of fatigue adopting an EID. Interestingly, there is a strong correlation between higher EDSS and fatigue in an EID setting. An increase of people suffering from fatigue is to be expected after adopting an EID, especially in the people with a higher EDSS and impairment of sphincterial functions. EID in our study does not compromise safety and efficacy of Natalizumab.
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Background: Whether vaccines play a role triggering or reactivating inflammation in Multiple Sclerosis (MS) has been long debated. There are few reports suggesting that Sars-Cov2 vaccines, as well as COVID-19 infection, may exacerbate relapses in MS. Studies on large cohorts are needed to establish the safety of Sars-Cov2 vaccines in the MS population. Aim(s): To assess the risk of clinical and radiological reactivation following Sars-Cov2 vaccines in patients with MS. Method(s): Patients with MS with known date of SarsCov2 vaccination were identified among those followed up at the Multiple Sclerosis Center of the Tor Vergata University Hospital. Data on clinical relapses and radiological activity (Gadolinium enhancing and new T2 lesions) in the 12 months before and after vaccination were extracted from clinical charts. Result(s): We enrolled 751 patients (64,7% female, mean age 45.9 +/- 11.63 years, 89.9% relapsing-remitting, 5.5% secondary progressive and 4.7% primary progressive, disease duration 11.2 +/- 8.11 years, median EDSS 2.0 [1.0 - 4.0], 12.1% untreated, 41.1% treated with first line immunomodulators and 46.7% with second line high efficacy treatments). Among them, 96.7% received mRNABNT162b2 (Pfizer), 2% mRNA-1273 (Moderna) and 1.3% other COVID-19 vaccines. In the whole cohort we did not find a significant increase of the rate of patients with relapse in the 12 months after vaccines (2.3%) compared to the 12 months before (2,9%, McNemar test, p=0.5), as well as of the rate of patients with radiological activity (both 11.5%, McNemar test, p=0.13). Similar findings were obtained separately analysing untreated patients, patients treated with first line and treated with second line drugs at the time of vaccination. Conclusion(s): Our preliminary results in a large monocentric cohort of MS patients suggest that vaccination with Sars-Cov2 vaccines does not induce disease reactivation. Further analyses are needed to confirm these findings.
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Background: Early high-efficacy treatment of multiple sclerosis (MS) may provide long-term clinical benefits, improving disease outcomes and patient quality of life. ENSEMBLE is a multicentre, open-label, single-arm Phase IIIb study, evaluating the effectiveness and safety of ocrelizumab (OCR) in patients with early-stage relapsing-remitting MS (RRMS). Aim(s): To report 2-year interim efficacy and safety data of the full cohort of patients with early-stage RRMS from the ENSEMBLE trial (NCT03085810), using no evidence of disease activity (NEDA)-3 as the primary endpoint. Method(s): Treatment-naive patients with early-stage RRMS (age 18-55 years;disease duration <=3 years;Expanded Disability Status Scale [EDSS] <=3.5;with one or more clinically reported relapse(s) or one or more signs of MRI activity in the prior 12 months) received OCR 600 mg every 24 weeks for 192 weeks (planned study duration). Key endpoints were NEDA-3 (defined as no relapses, 24-week [W] confirmed disability progression [CDP] and MRI activity [T1-weighted contract enhanced images or new/enlarging T2-weighted lesions, with MRI measurements rebaselined at W8]), annualised relapse rate (ARR), mean change in EDSS score from baseline (BL) and a safety overview. Result(s): BL demographics and disease characteristics of the ENSEMBLE population (N=1,225) were consistent with earlystage RRMS disease (patients <=40 years, 78.9%;female, 64.0%;median: Age, 32.0 years;duration since MS symptom onset, 0.74 years;duration since RRMS diagnosis, 0.22 years;BL EDSS score, 1.75;mean BL EDSS score [SD], 1.80 [0.93]). At W96, the majority of patients (n=857, 77.3%) had NEDA, 88.9% had no MRI activity, 93.4% had no relapses and 90.7% had no 24W-CDP. The adjusted ARR at W96 was low, 0.033 (95% CI, 0.026-0.042), and the mean (SD) EDSS score showed a statistically significant improvement between BL and W96, decreasing by 0.13 (0.89;p<0.0001), from 1.80 (0.93) to 1.67 (1.12). Safety results were consistent with prior OCR studies. Infections were reported by 760 (62.0%) patients;rates of serious infections were low (n=33 [2.7%] patients);32 (2.6%) of patients contracted a COVID-19 infection. Conclusion(s): In the ENSEMBLE study of treatment-naive patients with early-stage RRMS, disease activity based on clinical and MRI measures was minimal in most patients treated with ocrelizumab over 2 years;safety was consistent with prior ocrelizumab experience, with no new safety signals.
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Background: High-efficacy (HE) disease-modifying therapies (DMTs) for Multiple Sclerosis (MS), such as anti-CD20 monoclonal antibodies - i.e., Ocrelizumab (OCR) and Rituximab - may worsen COVID-19 course. Preliminary data suggest that two doses of mRNA COVID-19 vaccine (RNA-Vax) reduce the risk of breakthrough/severe COVID-19 in patients with MS (pwMS) under treatment with HE-DMTs. Little is known about the protective effect of a third booster dose of RNA-Vax in pwMS treated with most commonly used HE-DMTs, such as Natalizumab (NTZ), Fingolimod (FNG), and OCR. Aim(s): To compare COVID-19 course and outcomes in pwMS on NTZ, FNG, and OCR after receiving the third dose of RNA-Vax. Method(s): Inclusion criteria were: >18 years old, being treated with NTZ/OCR/FNG since the first vaccine dose, diagnosis of COVID-19 after a third booster dose of RNA-Vax, not being treated with steroids within the month prior to any vaccine dose or COVID-19. Result(s): 232 pwMS (63 NTZ, 106 OCR, 63 FNG) from 17 Italian MS centers were included in the analysis. pwMS on NTZ (37+/-9) were younger than those on OCR (42+/-10, p=0.026) and FNG (43+/-11, p=0.006);EDSS was higher in pwMS on OCR (3.0, IQR=1.5-5.5) than those on FNG (2.0, IQR=1.0-3.0, p=0.017). COVID-19 was diagnosed 65+/-41 days after receiving the third booster dose. PwMS on OCR compared with those on NTZ showed more frequently (p<0.02-0.001): fever >38degreeC (53.8% vs 20.6%), cough (67% vs 36.5%), dyspnea (18.9% vs 3.2%), longer symptoms duration (9.5+/-8.7 vs 6+/-4.6 days), use of NSAIDs (74.5% vs 52.4%), oxygen (7.5% vs 0%), antibiotics (45.3% vs 14.3%). PwMS on OCR compared with those on FNG needed more frequently the use of oxygen (7.5% vs 1.6%, p=0.002). PwMS on FNG compared with those on NTZ showed more frequently (p<0.03-0.002): fever >38degreeC (39.7% vs 20.6%), cough (65.1% vs 36.5%), dyspnea (15.9% vs 3.2%). There were no differences between the 3 groups of pwMS regarding: COVID-19 treatment with steroids or monoclonal antibodies, hospitalization, and full recovery or death (0%). Discussion and Conclusion(s): Breakthrough COVID-19 after a third booster dose of RNA-Vax was more symptomatic in pwMS on OCR and FNG than those on NTZ. Nevertheless, no deaths were reported and the Covid-19 course in terms of full recovery and hospitalization rates was not different across different HE-DMTs. These results support the efficacy of a third booster dose of RNA-Vax in preventing severe COVID-19 (with hospitalization/ death) in pwMS treated with most common HE-DMTs.
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Intoduction: In the phase 2b trial (NCT03889639), brain-penetrant Bruton's tyrosine kinase inhibitor tolebrutinib was well tolerated with dose-dependent reductions in new/enlarging MRI lesions. Objective/Aim: Report MRI, efficacy, and safety outcomes at Week (W)96 (2 years) of the phase 2b trial long-term safety (LTS) extension (NCT03996291) in relapsing MS patients with highly active disease (HAD). Method(s): In the double-blind portion of LTS (Part A), patients continued their core study tolebrutinib dose (5, 15, 30, or 60 mg/day). In the open-label Part B, all participants received 60 mg/day. HAD was defined as one relapse in the year prior to screening and one of the following: >1 gadolinium (Gd)- enhancing lesion within the prior 6 months, or >=9 T2 lesions at baseline (BL) or >=2 relapses in the prior year. Outcomes included Gd-enhancing and new/enlarging T2 lesions, annualized relapse rate (ARR), and Expanded Disability Status Scale (EDSS) score. Result(s): 61 patients met the HAD criteria at BL;60 continued in LTS Part A and 59 transitioned to Part B. As of 7 March 2022, 55 (92%) patients remained on study. New Gd-enhancing lesion counts remained low in the 60/60-mg arm through W96 and were reduced in other arms by W48 through W96, except for 5/60 at W96 (mean+/-SD at W96: 2.00+/-3.83, 0.56+/-1.04, 0.47+/-1.13, 0.23+/-0.44 in 5/60-, 15/60-, 30/60-, 60/60-mg arms, respectively). New/enlarging T2 lesion counts remained low for 15/60, 30/60, and 60/60 mg. T2 lesion volume remained unchanged for 60/60 mg. The most common treatment-emergent adverse events (TEAE) were COVID-19 (20%), nasopharyngitis (16.7%), headache (13.3%), and upper respiratory tract infection (8.3%). There was no dose-relationship for TEAE/serious AE in Part A and no new safety findings for patients switching to 60 mg in Part B. Of the patients who received tolebrutinib 60 mg/day for a minimum of 8 weeks, ARR was 0.10 (95% CI: 0.02, 0.66) and 92.9% remained relapse-free at W96. Mean EDSS scores were stable through W96. Conclusion(s): Through LTS Week 96, in the HAD cohort, tolebrutinib 60 mg demonstrated favourable safety (similar to the overall population), tolerability, and low ARR. New Gd-enhancing lesion counts remained low for the 60/60-mg arm.
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Background: An earlier follow-up study from the CogEx rehabilitation trial showed little change in symptoms of depression, anxiety and psychological distress during the first COVID-19 lockdown compared to pre-pandemic measurements. Objective(s): Here we provide a second follow-up set of behavioral data on the CogEx sample. Method(s): Data were obtained from the CogEx study, a randomized controlled trial of exercise and cognitive rehabilitation in people with progressive MS involving 11 centres in North America and Europe. Participants completed the same COVID Impact Survey and self-report measures of depression, anxiety and MS symptoms that had been obtained during the first pandemic lockdown period. Result(s): The average time between measurements was 11.4 (SD=5.56) months. Sample size declined from 131 to 72 largely because pandemic restrictions prevented data collection from sites in Denmark and England. There were no significant differences in age, sex, EDSS, disease course and duration between those who participated in the current follow-up study (n=74) and the group that could not (n=57). One participant caught Covid in the time between assessments. Participants now took a more negative view of their mental/psychological wellbeing (p=.0001), physical wellbeing (p=.0009) and disease course (p=.005) compared to their last assessment. Depression scores increased on the HADS-depression scale (p = .01) and now exceeded the clinically significant threshold of >= 8.0 for the first time. Anxiety scores on the HADS remained unchanged. Poorer mental wellbeing was predicted by HADS depression scores (p=.012) and a secondary-progressive disease course (p=.0004). Conclusions and Relevance: A longer follow-up period revealed the later onset of clinically significant depressive symptoms on the HADS and a decline in self-perceptions of mental and physical wellbeing associated with the COVID-19 pandemic.