Dynamic Evolution of Humoral and T-Cell Specific Immune Response to COVID-19 mRNA Vaccine in Patients with Multiple Sclerosis Followed until the Booster Dose.

This study characterizes antibody and T-cell immune responses over time until the booster dose of COronaVIrus Disease 2019 (COVID-19) vaccines in patients with multiple sclerosis (PwMS) undergoing different disease-modifying treatments (DMTs). We prospectively enrolled 134 PwMS and 99 health care workers (HCWs) having completed the two-dose schedule of a COVID-19 mRNA vaccine within the last 2-4 weeks (T0) and followed them 24 weeks after the first dose (T1) and 4-6 weeks after the booster (T2). PwMS presented a significant reduction in the seroconversion rate and anti-receptor-binding domain (RBD)-Immunoglobulin (IgG) titers from T0 to T1 (p < 0.0001) and a significant increase from T1 to T2 (p < 0.0001). The booster dose in PwMS showed a good improvement in the serologic response, even greater than HCWs, as it promoted a significant five-fold increase of anti-RBD-IgG titers compared with T0 (p < 0.0001). Similarly, the T-cell response showed a significant 1.5- and 3.8-fold increase in PwMS at T2 compared with T0 (p = 0.013) and T1 (p < 0.0001), respectively, without significant modulation in the number of responders. Regardless of the time elapsed since vaccination, most ocrelizumab- (77.3%) and fingolimod-treated patients (93.3%) showed only a T-cell-specific or humoral-specific response, respectively. The booster dose reinforces humoral- and cell-mediated-specific immune responses and highlights specific DMT-induced immune frailties, suggesting the need for specifically tailored strategies for immune-compromised patients to provide primary prophylaxis, early SARS-CoV-2 detection and the timely management of COVID-19 antiviral treatments.

Natalizumab extended-interval dosing in a real-life setting.

BACKGROUND: Natalizumab is a high-efficacy therapy for recurrent multiple sclerosis (RMS) with a four-week administration interval. Controlled trials have shown that extending this interval to six weeks led to better safety without increasing the risk of relapse. We aimed to analyze the safety of extending the natalizumab interdose interval from 4 to 6 weeks in a real-life setting. METHODS: This monocentric retrospective self-controlled study included adult patients with RMS treated with natalizumab with a four-week interval between infusions for a minimum of six months, before switching to a six-week interval. The main outcomes were the incidence of MS relapse, new MRI lesions, and MRI activity signs during the two periods, with patients being their own controls. RESULTS: Fifty-seven patients were included in the analysis. The mean (95%CI) annualized relapse rate (AAR) before natalizumab introduction was 1.03 (0.52; 1.55). During the four-week interval dosing period, no patient presented with an MS relapse, and seven (13.5%) patients had new MRI lesions. During the six-week interval dosing period, no relapse was observed and two (3.6%) patients had new MRI lesions. CONCLUSION: We did not observe more relapses or signs of MRI activity when extending the interval between natalizumab infusions from four to six weeks.

The Impact of SARS-CoV-2 Infection in Unvaccinated Multiple Sclerosis Patients on Disease-Modifying Therapies.

OBJECTIVE: Disease-modifying therapies (DMTs) in multiple sclerosis (MS) may affect the course and outcome of COVID-19, but withholding them could permit disease activity. This study aimed to understand the course of COVID-19 in unvaccinated patients with MS on disease-modifying therapies. SUBJECTS AND METHODS: This descriptive study examined the course of COVID-19 among infected patients with MS followed up at a large tertiary center in Kuwait between March 1, 2020, and March 1, 2021. All subjects were outpatients at the time of data collection. RESULTS: We studied 51 patients with MS confirmed to be infected with SARS-CoV-2 using real-time polymerase chain reaction. Of these patients, 33/51 were female, median age was 35 years (IQR 27-39 years), median Expanded Disability Status Scale score was 1.5 (IQR zero-3), and 47/51 had RRMS. B-cell-depleting agents (ocrelizumab and rituximab) were given to 19 patients, another 19 were on immune cell traffickers (fingolimod and natalizumab), and 13 were on other DMT treatments (alemtuzumab, cladribine, interferon-beta, dimethyl fumarate, and teriflunomide). 43/51 of these patients experienced mild COVID-19, not requiring hospitalization. None of the subjects experienced MS relapses during infection. Two patients on rituximab had a moderate course of the illness, which required hospitalization for oxygen support, but did not need mechanical ventilation; the rest of the subjects remained asymptomatic. CONCLUSIONS: These findings suggest that DMT may not adversely affect the course of COVID-19 in MS patients; however, patients on B-cell-depleting agents trended toward a worse outcome.

T cell responses to SARS-CoV-2 vaccination differ by disease-modifying therapy for multiple sclerosis.

Immune responses in people with multiple sclerosis (pwMS) receiving disease-modifying therapies (DMTs) have been of significant interest throughout the COVID-19 pandemic. Lymphocyte-targeting immunotherapies, including anti-CD20 treatments and sphingosine-1-phosphate receptor (S1PR) modulators, attenuate Ab responses after vaccination. Evaluation of cellular responses after vaccination, therefore, is of particular importance in these populations. In this study, we used flow cytometry to analyze CD4 and CD8 T cell functional responses to SARS-CoV-2 spike peptides in healthy control study participants and pwMS receiving 5 different DMTs. Although pwMS receiving rituximab and fingolimod therapies had low Ab responses after both 2 and 3 vaccine doses, T cell responses in pwMS taking rituximab were preserved after a third vaccination, even when an additional dose of rituximab was administered between vaccine doses 2 and 3. PwMS taking fingolimod had low detectable T cell responses in peripheral blood. CD4 and CD8 T cell responses to SARS-CoV-2 variants of concern Delta and Omicron were lower than to the ancestral Wuhan-Hu-1 variant. Our results indicate the importance of assessing both cellular and humoral responses after vaccination and suggest that, even in the absence of robust Ab responses, vaccination can generate immune responses in pwMS.

mRNA versus inactivated virus COVID-19 vaccines in multiple sclerosis: Humoral responses and protectivity-Does it matter?

BACKGROUND: COVID-19 vaccines are recommended for people with multiple sclerosis (pwMS). Adequate humoral responses are obtained in pwMS receiving disease-modifying therapies (DMTs) after vaccination, with the exception of those receiving B-cell-depleting therapies and non-selective S1P modulators. However, most of the reported studies on the immunity of COVID-19 vaccinations have included mRNA vaccines, and information on inactivated virus vaccine responses, long-term protectivity, and comparative studies with mRNA vaccines are very limited. Here, we aimed to investigate the association between humoral vaccine responses and COVID-19 infection outcomes following mRNA and inactivated virus vaccines in a large national cohort of pwMS receiving DMTs. METHODS: This is a cross-sectional and prospective multicenter study on COVID-19-vaccinated pwMS. Blood samples of pwMS with or without DMTs and healthy controls were collected after two doses of inactivated virus (Sinovac) or mRNA (Pfizer-BioNTech) vaccines. PwMS were sub-grouped according to the mode of action of the DMTs that they were receiving. SARS-CoV-2 IgG titers were evaluated by chemiluminescent microparticle immunoassay. A representative sample of this study cohort was followed up for a year. COVID-19 infection status and clinical outcomes were compared between the mRNA and inactivated virus groups as well as among pwMS subgroups. RESULTS: A total of 1484 pwMS (1387 treated, 97 untreated) and 185 healthy controls were included in the analyses (male/female: 544/1125). Of those, 852 (51.05%) received BioNTech, and 817 (48.95%) received Sinovac. mRNA and inactivated virus vaccines result in similar seropositivity; however, the BioNTech vaccination group had significantly higher antibody titers (7.175±10.074) compared with the Sinovac vaccination group (823±1.774) (p<0.001). PwMS under ocrelizumab, fingolimod, and cladribine treatments had lower humoral responses compared with the healthy controls in both vaccine types. After a mean of 327±16 days, 246/704 (34.9%) of pwMS who were contacted had COVID-19 infection, among whom 83% had asymptomatic or mild disease. There was no significant difference in infection rates of COVID-19 between participants vaccinated with BioNTech or Sinovac vaccines. Furthermore, regression analyses show that no association was found regarding age, sex, Expanded Disability Status Scale score (EDSS), the number of vaccination, DMT type, or humoral antibody responses with COVID-19 infection rate and disease severity, except BMI Body mass index (BMI). CONCLUSION: mRNA and inactivated virus vaccines had similar seropositivity; however, mRNA vaccines appeared to be more effective in producing SARS-CoV-2 IgG antibodies. B-cell-depleting therapies fingolimod and cladribine were associated with attenuated antibody titer. mRNA and inactive virus vaccines had equal long-term protectivity against COVID-19 infection regardless of the antibody status.

Antibody response elicited by the SARS-CoV-2 vaccine booster in patients with multiple sclerosis: Who gains from it?

BACKGROUND AND PURPOSE: Although two doses of COVID-19 vaccine elicited a protective humoral response in most persons with multiple sclerosis (pwMS), a significant group of them treated with immunosuppressive disease-modifying therapies (DMTs) showed less efficient responses. METHODS: This prospective multicenter observational study evaluates differences in immune response after a third vaccine dose in pwMS. RESULTS: Four hundred seventy-three pwMS were analyzed. Compared to untreated patients, there was a 50-fold decrease (95% confidence interval [CI] = 14.3-100.0, p < 0.001) in serum SARS-CoV-2 antibody levels in those on rituximab, a 20-fold decrease (95% CI = 8.3-50.0, p < 0.001) in those on ocrelizumab, and a 2.3-fold decrease (95% CI = 1.2-4.6, p = 0.015) in those on fingolimod. As compared to the antibody levels after the second vaccine dose, patients on the anti-CD20 drugs rituximab and ocrelizumab showed a 2.3-fold lower gain (95% CI = 1.4-3.8, p = 0.001), whereas those on fingolimod showed a 1.7-fold higher gain (95% CI = 1.1-2.7, p = 0.012), compared to patients treated with other DMTs. CONCLUSIONS: All pwMS increased their serum SARS-CoV-2 antibody levels after the third vaccine dose. The mean antibody values of patients treated with ocrelizumab/rituximab remained well below the empirical "protective threshold" for risk of infection identified in the CovaXiMS study (>659 binding antibody units/mL), whereas for patients treated with fingolimod this value was significantly closer to the cutoff.

Immune Response to Seasonal Influenza Vaccination in Multiple Sclerosis Patients Receiving Cladribine.

Cladribine has been approved for the treatment of multiple sclerosis (MS) and its administration results in a long-lasting depletion of lymphocytes. As lymphopenia is known to hamper immune responses to vaccination, we evaluated the immunogenicity of the influenza vaccine in patients undergoing cladribine treatment at different stages vs. controls. The antibody response in 90 cladribine-treated MS patients was prospectively compared with 10 control subjects receiving platform immunotherapy (NCT05019248). Serum samples were collected before and six months after vaccination. Response to vaccination was determined by the hemagglutination-inhibition test. Postvaccination seroprotection rates against influenza A were comparable in cladribine-treated patients and controls (H1N1: 94.4% vs. 100%; H3N2: 92.2% vs. 90.0%). Influenza B response was lower in the cladribine cohort (61.1% vs. 80%). The increase in geometric mean titers was lower in the cladribine group vs. controls (H1N1: +98.5 vs. +188.1; H3N2: +225.3 vs. +300.0; influenza B: +40.0 vs. +78.4); however, titers increased in both groups for all strains. Seroprotection was achieved irrespective of vaccination timing and lymphocyte subset counts at the time of vaccination in the cladribine cohort. To conclude, cladribine-treated MS patients can mount an adequate immune response to influenza independently of treatment duration and time interval to the last cladribine administration.

Symptomatic COVID-19 course and outcomes after three mRNA vaccine doses in multiple sclerosis patients treated with high-efficacy DMTs.

BACKGROUND: Little is known about COVID-19 course and outcomes after a third booster dose of mRNA vaccine against SARS-CoV-2 (mRNA-Vax) in patients with multiple sclerosis (pwMS) treated with ocrelizumab (OCR) and fingolimod (FNG), which showed a weakened immune response to mRNA-vax. OBJECTIVES: The aim of this study was to evaluate COVID-19 course and outcomes in pwMS on OCR and FNG after receiving the third dose of mRNA-Vax and to compare it with pwMS on natalizumab (NTZ). METHODS: Inclusion criteria: >18 years of age, being treated with OCR/FNG/NTZ since the first mRNA-Vax dose; COVID-19 after a third booster dose of mRNA-Vax; no steroids use. RESULTS: Overall, 290 pwMS (79 NTZ, 126 OCR, and 85 FNG) from 17 Italian MS centers were included. Age, Expanded Disability Status Scale (EDSS) score, MS phenotype, disease, and treatment duration were significantly different across groups. PwMS who had COVID-19 on OCR and FNG compared with those on NTZ were slightly more symptomatic with higher hospitalization rates (11.1% vs 7.1% vs 1.3%, respectively). Regression models showed that the majority of the differences observed were not related to the disease-modifying treatments (DMTs) used. No fatal cases were observed. CONCLUSION: Our results support the effectiveness of the third booster dose of mRNA-Vax against severe forms of COVID-19 in pwMS treated with OCR and FNG.

SARS-CoV-2 pandemic as a model to assess the relationship between intercurrent viral infections and disease activity in Multiple Sclerosis: A propensity score matched case-control study.

INTRODUCTION: An association between intercurrent viral respiratory infections and exacerbations of Multiple Sclerosis (MS) disease activity has been proposed by several studies. Considering the rapid spread of SARS-CoV2 worldwide and the systematic effort to immediately detect all incident cases with specific diagnostic tests, the pandemic can represent an interesting experimental model to assess the relationship between viral respiratory infections and MS disease activity. AIMS AND METHODS: In this study, we have performed a propensity score matched case-control study with a prospective clinical/MRI follow-up, on a cohort of relapsing-remitting MS (RRMS) patients who tested positive for SARS-CoV2 in the period 2020-2022, with the aim to evaluate if the SARS-CoV2 infection influences the short-term risk of disease activity. Controls (RRMS patients not exposed to SARS-CoV-2, using 2019 as the reference period) were matched 1:1 with cases for age, EDSS, sex and disease-modifying treatment (DMT) (moderate efficacy vs high efficacy). Differences in relapses, MRI disease activity and confirmed disabilty worsening (CDW) between cases in the 6 months following the SARS-CoV-2 infection, and controls in a similar 6 months reference period in 2019 were compared. RESULTS: We identified 150 cases of SARS-CoV2 infection in the period March 2020 - March 2022, out of a total population of approximately 1500 MS patients, matched with 150 MS patients not exposed to SARS-CoV2 (controls). Mean age was 40.9 ± 12.0 years in cases and 42.0 ± 10.9 years in controls, mean EDSS was 2.54±1.36 in cases and 2.60±1.32 in controls. All patients were treated with a DMT, and a considerable proportion with a high efficacy DMT (65.3% in cases and 66% in controls), reflecting a typical real world RRMS population. 52.8% of patients in this cohort had been vaccinated with a mRNA Covid-19 vaccine. We did not observe a significant difference in relapses (4.0% cases, 5.3% controls; p = 0.774), MRI disease activity (9.3% cases, 8.0% controls; p = 0.838), CDW (5.3% cases, 6.7% controls; p = 0.782) in the 6 months after SARS-CoV-2 infection between cases and controls. CONCLUSION: Using a propensity score matching design and including both clinical and MRI data, this study does not suggest an increased risk of MS disease activity following SARS-CoV-2 infection. All MS patients in this cohort were treated with a DMT, and a considerable number with a high efficacy DMT. These results therefore may not be applicable to untreated patients, for which the risk of increased MS disease activity after SARS-CoV-2 infection may not be excluded. A possible hypothesis explaining these results could be that SARS-CoV2 is less prone, compared to other viruses, to induce exacerbations of MS disease activity; another possible interpretation of these data might be that DMT is able to effectively suppress the increase of disease activity triggered by SARS-CoV2 infection.

Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic.

The immune system plays a significant role in multiple sclerosis. While MS was historically thought to be T cell-mediated, multiple pieces of evidence now support the view that B cells are essential players in multiple sclerosis pathogenic processes. High-efficacy disease-modifying therapies that target the immune system have emerged over the past two decades. Anti-CD20 monoclonal antibodies selectively deplete CD20+ B and CD20+ T cells and efficiently suppress inflammatory disease activity. These monotherapies prevent relapses, reduce new or active magnetic resonance imaging brain lesions, and lessen disability progression in patients with relapsing multiple sclerosis. Rituximab, ocrelizumab, and ofatumumab are currently used in clinical practice, while phase III clinical trials for ublituximab have been recently completed. In this review, we compare the four anti-CD20 antibodies in terms of their mechanisms of action, routes of administration, immunological targets, and pharmacokinetic properties. A deeper understanding of the individual properties of these molecules in relation to their efficacy and safety profiles is critical for their use in clinical practice.

Seroconversion following COVID-19 vaccination: can we optimize protective response in CD20-treated individuals?

Although there is an ever-increasing number of disease-modifying treatments for relapsing multiple sclerosis (MS), few appear to influence coronavirus disease 2019 (COVID-19) severity. There is concern about the use of anti-CD20-depleting monoclonal antibodies, due to the apparent increased risk of severe disease following severe acute respiratory syndrome corona virus two (SARS-CoV-2) infection and inhibition of protective anti-COVID-19 vaccine responses. These antibodies are given as maintenance infusions/injections and cause persistent depletion of CD20+ B cells, notably memory B-cell populations that may be instrumental in the control of relapsing MS. However, they also continuously deplete immature and mature/naïve B cells that form the precursors for infection-protective antibody responses, thus blunting vaccine responses. Seroconversion and maintained SARS-CoV-2 neutralizing antibody levels provide protection from COVID-19. However, it is evident that poor seroconversion occurs in the majority of individuals following initial and booster COVID-19 vaccinations, based on standard 6 monthly dosing intervals. Seroconversion may be optimized in the anti-CD20-treated population by vaccinating prior to treatment onset or using extended/delayed interval dosing (3-6 month extension to dosing interval) in those established on therapy, with B-cell monitoring until (1-3%) B-cell repopulation occurs prior to vaccination. Some people will take more than a year to replete and therefore protection may depend on either the vaccine-induced T-cell responses that typically occur or may require prophylactic, or rapid post-infection therapeutic, antibody or small-molecule antiviral treatment to optimize protection against COVID-19. Further studies are warranted to demonstrate the safety and efficacy of such approaches and whether or not immunity wanes prematurely as has been observed in the other populations.

Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis.

OBJECTIVE: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). METHODS: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. RESULTS: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. INTERPRETATION: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists. ANN NEUROL 2021;89:780-789.

Third COVID-19 vaccine dose for people with multiple sclerosis who did not seroconvert following two doses of BBIBP-CorV (Sinopharm) inactivated vaccine: A pilot study on safety and immunogenicity.

Background: People with multiple sclerosis (pwMS) on anti-CD20 therapies (aCD20) and fingolimod have shown inadequate humoral responses to COVID-19 vaccines. Objective: The objective of the study was to pilot larger studies by demonstrating the safety and comparing the immunogenicity of different types of third doses in seronegative pwMS after two doses of BBIBP-CorV inactivated vaccine. Methods: In December 2021, subject to receiving their third dose, being COVID-19-naiive, and receiving no corticosteroid within two months, we measured the level of anti-SARS-CoV-2-Spike IgG in pwMS seronegative after two shots of BBIBP-CorV inactivated vaccine. Results: We included 20/29 pwMS who received adenoviral vector (AV), 7/29 who received inactivated, and 2/29 who received conjugated third doses. No serious adverse events were reported two weeks post-third dose. The pwMS receiving AV third doses showed significantly increased IgG concentrations, while only the ones not on aCD20 and fingolimod responded to inactivated third doses. An ordinal logistic multivariable generalized linear model indicated that age (per year ß: -0.10, P = 0.04), type of disease-modifying therapy (aCD20 ß: -8.36, P <0.01; fingolimod ß: -8.63, P = 0.01; others: reference), and type of third dose (AV or conjugated ß: 2.36, P = 0.02; inactivated: reference) are predictive of third dose immunogenicity among pwMS who remain seronegative after two shots of BBIBP-CorV vaccine. Statistical significance was not achieved for variables sex, MS duration, EDSS, duration of DMT, duration of third dose to IgG test, and duration from last aCD20 infusion to third dose. Conclusion: This preliminary pilot study highlights the need for further research to determine the optimal COVID-19 third dose vaccination strategy for pwMS living in areas where BBIBP-CorV vaccine has been used.

JCV seroconversion rate during the SARS COVID-19 pandemic.

The transmission route of the John Cunningham virus (JCV) is not clearly understood. The high prevalence of JCV in urine and sewage and the stability of the viral particles observed suggest that contaminated water, food, and fomites could be the vehicles of JCV transmission through the oral route. Multiple Sclerosis (MS) patients treated with Natalizumab are at risk of developing progressive multifocal leukoencephalopathy (PML), and hence, JCV serology is monitored for risk stratification. Social restrictions introduced in 2020 which intended to limit the transmission of SARS-CoV-2 are associated with decreased rates of other communicable diseases, as has been shown in recent observational studies. We evaluated the prevalence of seroconversion prior to and during the coronavirus disease (COVID -19) pandemic based on clinical records of JCV serology status in a single-center cohort of Natalizumab-treated Multiple Sclerosis patients. We hypothesized that seroconversion rates would decrease due to behavioral changes. However, seroconversion rates were stable during the COVID-19 pandemic compared to the pre-pandemic. These findings support the notion that JCV is transmitted via the GI tract rather than the respiratory system.

A prospective study of cellular immune response to booster COVID-19 vaccination in multiple sclerosis patients treated with a broad spectrum of disease-modifying therapies.

BACKGROUND: Most people with Multiple Sclerosis (pwMS) are subjected to immunomodulatory disease-modifying treatments (DMTs). As a result, immune responses to COVID-19 vaccinations could be compromised. There are few data on cellular immune responses to the use of COVID-19 vaccine boosters in pwMS under a broad spectrum of DMTs. METHODS: In this prospective study, we analysed cellular immune responses to SARS-CoV-2 mRNA booster vaccinations in 159 pwMS with DMT, including: ocrelizumab, rituximab, fingolimod, alemtuzumab, dimethyl fumarate, glatiramer acetate, teriflunomide, natalizumab and cladribine. RESULTS: DMTs, and particularly fingolimod, interact with cellular responses to COVID-19 vaccination. One booster dose does not increase cellular immunity any more than two doses, except in the cases of natalizumab and cladribine. SARS-CoV-2 infection combined with two doses of vaccine resulted in a greater cellular immune response, but this was not observed after supplementary booster jabs. Ocrelizumab-treated pwMS who had previously received fingolimod did not develop cellular immunity, even after receiving a booster. The time after MS diagnosis and disability status negatively correlated with cellular immunity in ocrelizumab-treated pwMS in a booster dose cohort. CONCLUSIONS: After two doses of SARS-CoV-2 vaccination, a high response yield was achieved, except in patients who had received fingolimod. The effects of fingolimod on cellular immunity persisted for more than 2 years after a change to ocrelizumab (which, in contrast, conserved cellular immunity). Our results confirmed the need to find alternative protective measures for fingolimod-treated people and to consider the possible failure to provide protection against SARS-CoV-2 when switching from fingolimod to ocrelizumab.

High persistence and low adverse events burden in cladribine treated MS patients from Argentina.

BACKGROUND: Early initiation with high efficacy therapies seems to be better than an escalation approach in terms of disability prevention in patients with relapsing-remitting MS (RRMS). Although efficacy and safety of cladribine tablets have been shown in clinical trials, real-world evidence (RWE) studies from Latin America are scarce. OBJECTIVE: To describe the baseline characteristics of patients enrolled in the Argentina Patient Support Program (PSP) for cladribine tablets (Adveva®), with at least 1 treatment course, evaluate treatment persistence, adverse event reports from PSP patients and reported relapses characterization. METHODS: Anonymized data routinely collected by Adveva® team of patients that received the first dose of cladribine from April 16th 2018 to March 31st 2021 were analyzed. Treatment persistence was defined as the percentage of patients that initiated year 2 (Y2) from the population of patients with elapsed time since year 1 (Y1) cladribine tablet initiation of at least 18 months. In addition, using the pharmacovigilance data, reported adverse events and the time elapsed from treatment initiation to relapse were analyzed. RESULTS: The present analysis included 269 patients (mean age: 41.7 ± 16 years) that had initiated Y1 of cladribine tablets treatment between April 16th 2018 and March 31st 2021. Although only 29.4% (79/269) of our population was treatment naïve, the ratio of naïve/switch patients that initiated cladribine tablets increased from April 2018-March 2019 to April 2020-March 2021. From the 110 patients with elapsed time since treatment initiation ≥18 months, 101 patients initiated Y2 indicating a persistence level of 91.8%. During follow-up, 425 adverse events were reported, mainly MS relapse (8.9%, 38/425), fatigue (3.8%, 16/425) and headache (3.5%, 15/425). Lymphopenia and infections were rarely reported by RRMS patients treated with cladribine tablets. MS relapse was more frequently reported in patients switching from a previous treatment (87.5%, 27/32) than in the naïve cohort (12.5%, 5/32). CONCLUSIONS: The first real life experience in RRMS patients from Latin America demonstrated that the Adveva® enrolled support program patients have a high persistence level to oral treatment with cladribine tablets. Our results also confirmed the known safety profile of cladribine tablets, with a low incidence of lymphopenia and infections.

Modifiable risk factors of COVID-19 in patients with multiple sclerosis: a single-centre case-control study.

BACKGROUND: Disease and treatment-associated immune system abnormalities may confer higher risk of Coronavirus disease 2019 (COVID-19) to people with multiple sclerosis (PwMS). We assessed modifiable risk factors associated with COVID-19 in PwMS. METHODS: Among patients referring to our MS Center, we retrospectively collected epidemiological, clinical and laboratory data of PwMS with confirmed COVID-19 between March 2020 and March 2021 (MS-COVID, n = 149). We pursued a 1:2 matching of a control group by collecting data of PwMS without history of previous COVID-19 (MS-NCOVID, n = 292). MS-COVID and MS-NCOVID were matched for age, expanded disability status scale (EDSS) and line of treatment. We compared neurological examination, premorbid vitamin D levels, anthropometric variables, life-style habits, working activity, and living environment between the two groups. Logistic regression and Bayesian network analyses were used to evaluate the association with COVID-19. RESULTS: MS-COVID and MS-NCOVID were similar in terms of age, sex, disease duration, EDSS, clinical phenotype and treatment. At multiple logistic regression, higher levels of vitamin D (OR 0.93, p < 0.0001) and active smoking status (OR 0.27, p < 0.0001) emerged as protective factors against COVID-19. In contrast, higher number of cohabitants (OR 1.26, p = 0.02) and works requiring direct external contact (OR 2.61, p = 0.0002) or in the healthcare sector (OR 3.73, p = 0.0019) resulted risk factors for COVID-19. Bayesian network analysis showed that patients working in the healthcare sector, and therefore exposed to increased risk of COVID-19, were usually non-smokers, possibly explaining the protective association between active smoking and COVID-19. CONCLUSIONS: Higher Vitamin D levels and teleworking may prevent unnecessary risk of infection in PwMS.

Switching from natalizumab administration at the day hospital to administration at home. A 1 year prospective study of patient experience and quality of life in 30 consecutive patients with multiple sclerosis (TYSAD-35).

BACKGROUND: In the context of the COVID-19 pandemic, French health authorities allowed the home administration of natalizumab by a healthcare-at-home service. We evaluated the patients' perception of care quality following the transition from day-hospital to home natalizumab administration. METHODS: Thirty relapsing-remitting multiple sclerosis (MS) patients treated with natalizumab were prospectively evaluated for one year after changing onto a home treatment procedure, using MusiCare, the first MS-specific questionnaire to evaluate patient experience and MusiQol. A numerical rating scale score for satisfaction and a dedicated questionnaire concerning patient experience were completed after each infusion. The primary endpoint was the mean difference in MusiCare score between baseline and 12 months. RESULTS: From June 2020 to November 2021, 306 infusions were performed at home. Three patients withdrew from the study (one lost to follow-up and two preferred to return at the day hospital). No worsening of patient experience or quality of life was observed. The mean scores of the Musicare dimensions were higher at 12 months than at baseline, significantly for the "relationship with healthcare professionals" (p = 0.0203). The MusiQol global score remained stable but the coping and friendship dimensions were significantly better at M12 than at baseline (p = 0.0491 and p = 0.0478, respectively). The satisfaction questionnaire highlighted some pain during the infusions (21.8%) and contradictions between healthcare professionals (17.2%). The mean score for satisfaction with care was 9.1/10. No safety concerns were identified. CONCLUSION: The positive experience of patients with home natalizumab administration provides an important opportunity to improve the quality of patient care.

Humoral immune responses remain quantitatively impaired but improve qualitatively in anti-CD20-treated patients with multiple sclerosis after three or four COVID-19 vaccinations.

OBJECTIVE: To analyze anti-SARS-CoV-2-S1-IgG levels, avidity, Omicron BA.2 variant neutralizing capacity, and SARS-CoV-2-specific T cells in anti-CD20-treated patients with multiple sclerosis (aCD20pwMS) after two, three, or four COVID-19 vaccinations. RESULTS: Frequencies of aCD20pwMS with detectable SARS-CoV-2-S1-IgG increased moderately between two (31/61 (51%)), three (31/57 (54%)), and four (17/26 (65%)) vaccinations. However, among patients with detectable SARS-CoV-2-S1-IgG, frequencies of high avidity (6/31 (19%) vs 11/17 (65%)) and Omicron neutralizing antibodies (0/10 (0%) vs 6/10 (60%)) increased strongly between two and four vaccinations. SARS-CoV-2-specific T cells were detectable in >92% after two or more vaccinations. CONCLUSION: Additional vaccinations qualitatively improve SARS-CoV-2 antibody responses.