Abstract

Background and objectives: The role of B cells in the pathogenic events leading to relapsing multiple sclerosis (R-MS) has only been recently elucidated. A pivotal step in defining this role has been provided by therapeutic efficacy of anti-CD20 monoclonal antibodies. Indeed, treatment with anti-CD20 can also alter number and function of other immune cells not directly expressing CD20 on their cell surface, whose activities can contribute to unknown aspects influencing therapeutic efficacy. We examined the phenotype and function of cytotoxic lymphocytes and Epstein-Barr virus (EBV)-specific immune responses in people with R-MS before and after ocrelizumab treatment.

Methods: In this prospective study, we collected blood samples from people with R-MS (n = 41) before and 6 and 12 months after initiating ocrelizumab to assess the immune phenotype and the indirect impact on cytotoxic functions of CD8+ T and NK cells. In addition, we evaluated the specific anti-EBV proliferative responses of both CD8+ T and NK lymphocytes as surrogate markers of anti-EBV activity.

Results: We observed that while ocrelizumab depleted circulating B cells, it also reduced the expression of activation and migratory markers on both CD8+ T and NK cells as well as their in vitro cytotoxic activity. A comparable pattern in the modulation of immune molecules by ocrelizumab was observed in cytotoxic cells even when patients with R-MS were divided into groups based on their prior disease-modifying treatment. These effects were accompanied by a significant and selective reduction of CD8+ T-cell proliferation in response to EBV antigenic peptides.

Discussion: Taken together, our findings suggest that ocrelizumab-while depleting B cells-affects the cytotoxic function of CD8+ and NK cells, whose reduced cross-activity against myelin antigens might also contribute to its therapeutic efficacy during MS.

Abstract

Background and purpose: Cladribine tablets, a purine analogue antimetabolite, offer a unique treatment regimen, involving short courses at the start of the first and second year, with no further treatment needed in years 3 and 4. However, comprehensive evidence regarding patient outcomes beyond the initial 24 months of cladribine treatment is limited.

Methods: This retrospective, multicenter study enrolled 204 patients with multiple sclerosis who had completed the 2-year course of cladribine treatment. The primary outcomes were therapeutic choices and clinical disease activity assessed by annualized relapse rate after the 2-year treatment course.

Results: A total of 204 patients were enrolled; most patients (75.4%) did not initiate new treatments in the 12 months postcladribine. The study found a significant reduction in annualized relapse rate at the 12-month follow-up after cladribine completion compared to the year prior to starting therapy (0.07 ± 0.25 vs. 0.82 ± 0.80, p < 0.001). Furthermore, patients with relapses during cladribine treatment were more likely to start new therapies, whereas older patients were less likely. The safety profile of cladribine was favorable, with lymphopenia being the primary registered adverse event.

Conclusions: This study provides insights into therapeutic choices and disease activity following cladribine treatment. It highlights cladribine's effectiveness in reducing relapse rates and disability progression, reaffirming its favorable safety profile. Real-world data, aligned with previous reports, draw attention to ocrelizumab and natalizumab as common choices after cladribine. However, larger, prospective studies for validation and a more comprehensive understanding of cladribine's long-term impact are necessary.

Keywords: cladribine; efficacy; multiple sclerosis; real‐world data; safety; treatment response.

Abstract

Background: Characterizing Cladribine tablets prescription pattern in daily clinical practice is crucial for optimizing multiple sclerosis (MS) treatment.

Objectives: To describe efficacy, safety profile and new disease-modifying therapy (DMT) prescriptions following Cladribine treatment.

Design: Independent retrospective cohort study in patients followed at six Italian MS centres.

Methods: Patients diagnosed with relapsing MS (RMS) according to 2017 McDonald criteria, who initiated Cladribine between January 2019 and May 2023, were included. A generalized linear regression model was built for the outcome DMT after Cladribine course. Heatmaps were generated based on weighted pivot tables to visualize the proportion of patients requiring DMT post-Cladribine.

Results: A total cohort of 352 patients was enrolled, 134 naïve to any DMT, 218 switchers from other DMTs. The last DMT was an injectable first-line DMT for 48 (22%) patients, oral first-line DMT for 141 (64.7%) patients, SP1 inhibitor-Fingolimod for 23 (10.6%) patients, and Natalizumab for 6 (2.7%) patients. Overall, Cladribine was efficacious and well tolerated, 12% of patients required a new DMT prescription after a median time of 24 months. The regression model revealed that patients aged >40 years at Cladribine prescription had a 16% decrease in likelihood of receiving a new DMT. Heatmaps showed patients previously on Fingolimod had a lower rate (72.2%) of being free from therapy after Cladribine.

Conclusion: In our multicentric real-world Italian study, Cladribine therapy is generally effective during the investigated follow-up period. Understanding key characteristics of patients responding best to Cladribine can help tailor therapeutic strategies for optimal outcomes.

Keywords: cladribine; long-term management; multiple sclerosis; prescription pattern.

Abstract

Background: Patients with multiple sclerosis (pwMS) treated with anti-CD20 or fingolimod showed a reduced humoral response to SARS-CoV-2 vaccines.

Objective: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in pwMS on different disease-modifying therapies (DMTs).

Methods: Data on the number of vaccinated patients and the number of patients with a breakthrough infection were retrospectively collected in 27 Italian MS centers. We estimated the rate of breakthrough infections and of infection requiring hospitalization per DMT.

Results: 19,641 vaccinated pwMS were included in the database. After a median follow-up of 8 months, we observed 137 breakthrough infections. Compared with other DMTs, the rate of breakthrough infections was significantly higher on ocrelizumab (0.57% vs 2.00%, risk ratio (RR) = 3.55, 95% CI = 2.74-4.58, p < 0.001) and fingolimod (0.58% vs 1.62%, RR = 2.65, 95% CI = 1.75-4.00, p < 0.001), while there were no significant differences in any other DMT group. In the ocrelizumab group the hospitalization rate was 16.7% versus 19.4% in the pre-vaccination era (RR = 0.86, p = 0.74) and it was 3.9% in all the other DMT groups versus 11.9% in the pre-vaccination period (RR = 0.33, p = 0.02).

Conclusions: The risk of breakthrough SARS-CoV-2 infections is higher in patients treated with ocrelizumab and fingolimod, and the rate of severe infections was significantly reduced in all the DMTs excluding ocrelizumab.

Keywords: COVID-19 vaccination; Multiple sclerosis; breakthrough infections.

Abstract

Introduction: Sphingosine-1-phosphate (S1P) receptor modulators, regulating the S1P/S1PR pathway, lead to lymphocyte sequestration in lymphoid organs, which results in peripheral lymphopenia. This study evaluates the degree of lymphopenia induced by S1P modulators in people with Multiple Sclerosis (MS): Ozanimod, Siponimod, Ponesimod, and Fingolimod.

Methods: We conducted a retrospective multicenter study across thirteen MS centers in Italy, including 191 MS patients (mean age 46.4 years; 61.3% women). Of these, 28.8% received Siponimod, 26.2% Ozanimod, 24.1% Fingolimod, and 20.9% Ponesimod. Lymphocyte counts were measured at baseline (T0), one month (T1), three months (T3), and six months (T6) post-treatment. Lymphopenia grades range from 0 (≥ 1.0 × 10^9 cells/L) to 4 (< 0.2 × 10^9 cells/L), according to Common Terminology Criteria for Adverse Events.

Results: At T1, Ozanimod showed a significantly higher mean lymphocyte count than Siponimod and Fingolimod (p < 0.001), Ponesimod higher mean lymphocyte count than Siponimod (p = 0.006). The differences persisted between Ozanimod than Siponimod and Fingolimod at T3 (p = 0.01 and p = 0.04), and between Ponesimod and Siponimod at T6 (p = 0.03). Severe lymphopenia cases were significantly higher in Siponimod than in Ponesimod and Ozanimod, at T1 (p = 0.001 and p = 0.0001). The differences remained significant between Ozanimod and Siponimod, at T3 (p = 0.001), and between Ponesimod and Siponimod, Fingolimod and Ozanimod, at T6 (p = 0.001). Grade 4 lymphopenia was observed in Ozanimod and Siponimod at T3.

Conclusion: This is the first real-world, head-to-head observational study comparing lymphopenia among different S1P modulators. Our results might assist in therapy choice depending on patients baseline hematological characteristics.

Keywords: Lymphopenia; Multiple sclerosis; Sphingosine-1-phosphate receptor modulators.

Abstract

Background and objectives: It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19-related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population.

Methods: Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score > 3 or at least 1 comorbidity, lower risk: EDSS score ≤ 3 and no comorbidities) by the χ2 test, and the risk excess was quantified by risk ratios (RRs).

Results: The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization (p < 0.001), RR = 2.19 for ICU admission (p < 0.001), and RR = 2.43 for death (p < 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, p = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, p = 0.04).

Discussion: Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon.

Abstract

Background and purpose: Clinical outcomes of multiple sclerosis (MS) patients affected by coronavirus disease 2019 (COVID-19) have been thoroughly investigated, but a further analysis on main signs and symptoms and their risk factors still needs attention. The objective of this study was to group together and describe based on similarity the most common signs and symptoms of COVID-19 in MS patients and identify all factors associated with their manifestation.

Method: Logistic and linear regression models were run to recognize factors associated with each pooled group of symptoms and their total number.

Results: From March 2020 to November 2021, data were collected from 1354 MS patients with confirmed infection of COVID-19. Ageusia and anosmia was less frequent in older people (odds ratio [OR] 0.98; p = 0.005) and more in smoker patients (OR 1.39; p = 0.049). Smoke was also associated with an incremental number of symptoms (OR 1.24; p = 0.031), substance abuse (drugs or alcohol), conjunctivitis and rash (OR 5.20; p = 0.042) and the presence of at least one comorbidity with shortness of breath, tachycardia or chest pain (OR 1.24; p = 0.008). Some disease-modifying therapies were associated with greater frequencies of certain COVID-19 symptoms (association between anti-CD20 therapies and increment in the number of concomitant symptoms: OR 1.29; p = 0.05). Differences in frequencies between the three waves were found for flu-like symptoms (G1, p = 0.024), joint or muscle pain (G2, p = 0.013) and ageusia and anosmia (G5, p &lt; 0.001). All cases should be referred to variants up to Delta.

Conclusion: Several factors along with the choice of specific therapeutic approaches might have a different impact on the occurrence of some COVID-19 symptoms.

Keywords: COVID-19; demyelinating diseases; disease-modifying treatment; multiple sclerosis; neurological disorders.

Abstract

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.

Keywords: COVID-19; SARS-CoV-2 vaccine; anti-CD20; booster dose; fingolimod; multiple sclerosis.

Abstract

Background: The MuSC-19 project is an Italian cohort study open to international partners that collects data on multiple sclerosis (MS) patients with COVID-19. During the second wave of the pandemic, serological tests became routinely available.

Objective: To evaluate the seroprevalence of anti-SARS-CoV-2 antibodies according to the use of disease-modifying therapy (DMT) in a subset of patients included in the MuSC-19 data set who had undergone a serological test.

Methods: We evaluated the association between positive serological test results and time elapsed since infection onset, age, sex, Expanded Disability Status Scale score, comorbidities and DMT exposure using a multivariable logistic model.

Results: Data were collected from 423 patients (345 from Italy, 61 from Turkey and 17 from Brazil) with a serological test performed during follow-up. Overall, 325 out of 423 tested patients (76.8%) had a positive serological test. At multivariate analysis, therapy with anti-CD20 was significantly associated with a reduced probability of developing antibodies after COVID-19 (odds ratio (OR) = 0.20, p = 0.002).

Conclusion: Patients with MS maintain the capacity to develop humoral immune response against SARS-COV-2, although to a lesser extent when treated with anti-CD20 drugs. Overall, our results are reassuring with respect to the possibility to achieve sufficient immunization with vaccination.

Keywords: Multiple sclerosis; Sars-COV-2; coronavirus; immunomodulatory therapies; immunosuppressive therapies.

Abstract

Background: Rituximab, an anti-CD20 monoclonal antibody leading to B lymphocyte depletion, is increasingly used as an off-label treatment option for multiple sclerosis (MS).

Objective: To investigate the effectiveness and safety of rituximab in relapsing-remitting (RR) and progressive MS.

Methods: This is a multicenter, retrospective study on consecutive MS patients treated off-label with rituximab in 22 Italian and 1 Swiss MS centers. Relapse rate, time to first relapse, Expanded Disability Status Scale (EDSS) progression, incidence of adverse events, and radiological outcomes from 2009 to 2019 were analyzed.

Results: A total of 355/451 enrolled subjects had at least one follow-up visit and were included in the outcome analysis. Annualized relapse rate significantly decreases after rituximab initiation versus the pre-rituximab start year in RRMS (from 0.86 to 0.09, p < .0001) and in secondary-progressive (SP) MS (from 0.34 to 0.06, p < .0001) and had a slight decrease in primary-progressive (PP) MS patients (from 0.12 to 0.07, p = 0.45). After 3 years from rituximab start, the proportion of patients with a confirmed EDSS progression was 14.6% in the RRMS group, 24.7% in the SPMS group, and 41.5% in the PPMS group. No major safety concerns arose.

Conclusion: Consistently with other observational studies, our data show effectiveness of rituximab in reducing disease activity in patients with MS.

Keywords: Rituximab; multiple sclerosis; primary progressive; real life; relapsing–remitting; secondary progressive.