Localized Colitis Associated With Cholecystectomy in Multiple Sclerosis Patient Treated With Ocrelizumab.

Our understanding of multiple sclerosis (MS) has led to the development of new therapeutic strategies, including ocrelizumab, a third-generation humanized anti-CD20 antibody. Ocrelizumab is largely well tolerated with favorable effectiveness, however, it has been associated with reports of colitis presenting weeks to months following infusion. We present a case of severe localized colitis in the setting of recent surgery and chronic ocrelizumab use. High-dose IV hydrocortisone was initiated, and the patient showed gradual improvement. Repeat imaging after discharge showed near-complete resolution of the patient's condition. This case aims to increase awareness of possible postoperative severe localized colitis in MS patients on Ocrevus.

Comparison of injective related reactions following ofatumumab and ocrelizumab in patients with multiple sclerosis: data from the European spontaneous reporting system.

Introduction: In 2021 ofatumumab, a recombinant human anti-CD20 monoclonal antibody (mAb) already authorized for the treatment of chronic lymphocytic leukemia, received the marketing approval for the treatment of relapsing forms of multiple sclerosis (MS). Differently from ocrelizumab, that is administered intravenously, ofatumumab if the first anti-CD20 mAb to be administered subcutaneously without a premedication. Methods and objectives: In this study we aimed to describe and compare the main characteristics of Individual Case Safety Reports (ICSRs) describing the occurrence of Injective Related Reactions (IRRs) following the treatment with ocrelizumab and ofatumumab reported in the Eudravigilance (EV) database during years 2021-2023. Results: A total of 860 ICSRs with either ofatumumab and ocrelizumab as suspected drug were retrieved from Eudravigilance, of which 51% associated with ofatumumab and 49% with ocrelizumab. The majority of patients who experienced IRRs following ocrelizumab belonged to the age group of 18-64 years (73%), while the age-group was mostly not specified (55%) in ICSRs reporting ofatumumab as suspected. The distribution of gender was almost similar in the two groups, with the majority of ICSRs related to female patients. "Pyrexia" was the Preferred Term (PT) most reported for ofatumumab, while "Infusion related reaction" were more frequently reported with ocrelizumab. Premedication drugs were reported in 148 ICSRs. Out of 89 ICSRs for which the Time to Event (TTE) was calculated, 74 reported IRRs that occurred the same day of the drug administration. Discussion: Based on the results of this study, although a risk of ofatumumab-induced IRRs cannot be excluded, it should be considered as manageable considering that the drug seems to be mostly associated with the occurrence of fever. Thus, it is important to continue to closely monitor the use of these in clinical practice to improve the knowledge on their long-term safety.

Ocrelizumab-induced organizing pneumonia in multiple sclerosis: case report and literature review.

Patients with relapsing-remitting multiple sclerosis should be offered disease-modifying therapies as part of their management. Recommended options include integrin antagonist therapy including natalizumab as well as anti-CD20 monoclonal antibodies like, ocrelizumab, rituximab, ofatumumab, and ublituximab. These therapies reduce relapse rates and slow brain lesion accumulation. Disease-modifying therapies selection may depend on patient preferences, potential fetal harm, and specific drug risks, requiring continuous monitoring via tracking clinical relapses and new MRI brain lesions. Natalizumab carries a risk of progressive multifocal leukoencephalopathy, particularly in anti-JCV antibody-positive patients, necessitating regular monitoring. Ocrelizumab, rituximab, and ublituximab are associated with an increased risk of infections (especially respiratory and skin infections), infusion reactions, and hypogammaglobulinemia. Ocrelizumab additionally poses a heightened risk of immune-mediated colitis and breast cancer, and it is contraindicated for patients with active hepatitis B due to the risk of viral reactivation. Ublituximab has been noted to be linked to potential fetal harm. We report the case of a 42-year-old male with relapsing-remitting multiple sclerosis on ocrelizumab who developed persistent fever and shortness of breath, two weeks after his last ocrelizumab dose. Despite antibiotic treatment for suspected pneumonia, his symptoms persisted. A chest CT scan revealed multifocal ground-glass opacities suggestive of organizing pneumonia, likely secondary to ocrelizumab. The patient's condition improved with high-dose corticosteroids, underscoring the importance of vigilance for extremely rare ocrelizumab-associated pulmonary side effects and the need for prompt, appropriate intervention.

SARS-CoV-2-Specific Immune Cytokine Profiles to mRNA, Viral Vector and Protein-Based Vaccines in Patients with Multiple Sclerosis: Beyond Interferon Gamma.

Disease-modifying therapies (DMTs) impact the cellular immune response to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccines in patients with multiple sclerosis (pwMS). In this study, we aim to elucidate the characteristics of the involved antigen-specific T cells via the measurement of broad cytokine profiles in pwMS on various DMTs. We examined SARS-CoV-2-specific T cell responses in whole blood cultures characterized by the release of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-13, IL-17A, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α), as well as antibodies (AB) targeting the SARS-CoV-2 spike protein in pwMS following either two or three doses of mRNA or viral vector vaccines (VVV). For mRNA vaccination non-responders, the NVX-CoV2373 protein-based vaccine was administered, and immune responses were evaluated. Our findings indicate that immune responses to SARS-CoV-2 vaccines in pwMS are skewed towards a Th1 phenotype, characterized by IL-2 and IFN-γ. Additionally, a Th2 response characterized by IL-5, and to a lesser extent IL-4, IL-10, and IL-13, is observed. Therefore, the measurement of IL-2 and IL-5 levels could complement traditional IFN-γ assays to more comprehensively characterize the cellular responses to SARS-CoV-2 vaccines. Our results provide a comprehensive cytokine profile for pwMS receiving different DMTs and offer valuable insights for designing vaccination strategies in this patient population.

De-escalation of Disease-Modifying Therapy for People with Multiple Sclerosis Due to Safety Considerations: Characterizing 1-Year Outcomes in 25 People Who Switched from Ocrelizumab to Diroximel Fumarate.

INTRODUCTION: Switching disease-modifying therapy (DMT) may be considered for relapsing-remitting multiple sclerosis (RRMS) if a patient's current therapy is no longer optimal. This was particularly important during the recent COVID-19 pandemic because of considerations around immune deficiency and impaired vaccine response associated with B cell-depleting DMTs. This real-world, single-center study aimed to evaluate change or decline in functional ability and overall disease stability in people with RRMS who were switched from B cell-depleting ocrelizumab (OCRE) to diroximel fumarate (DRF) because of safety concern related to the COVID-19 pandemic. METHODS: Adults with RRMS were included if they had been clinically stable for ≥ 1 year on OCRE. Data collected at baseline and 1 year post switch included relapse rate, magnetic resonance imaging (MRI), blood work for assessment of peripheral immune parameters, the Cognitive Assessment Battery (CAB), optical coherence tomography (OCT), and patient-reported outcomes (PROs). RESULTS: Participants (N = 25) had a mean (SD) age of 52 (9) years, and a mean (SD) duration of 26 (8) months' treatment with OCRE before the switch to DRF. Median washout duration since the last OCRE infusion was 7 months (range 4-18 months). No participants relapsed on DRF during follow-up, and all remained persistent on DRF after 1 year. There were no significant changes in peripheral immune parameters, other than an increase in the percentage of CD19+ cells 1 year after switching (p < 0.05). Similarly, there were no significant changes in CAB, OCT, and PROs. CONCLUSION: These preliminary findings suggest that transition to DRF from OCRE may be an effective treatment option for people with RRMS who are clinically stable but may need to switch for reasons unrelated to effectiveness. Longer follow-up times on larger samples are needed to confirm these observations.

Clinical and magnetic resonance imaging outcomes in pediatric-onset MS patients on fingolimod and ocrelizumab.

BACKGROUND: Observational studies looking at clinical a++nd MRI outcomes of treatments in pediatric MS, could assess current treatment algorithms, and provide insights for designing future clinical trials. OBJECTIVE: To describe baseline characteristics and clinical and MRI outcomes in MS patients initiating ocrelizumab and fingolimod under 18 years of age. METHODS: MS patients seen at 12 centers of US Network of Pediatric MS were included in this study if they had clinical and MRI follow-up and started treatment with either ocrelizumab or fingolimod prior to the age of 18. RESULTS: Eighty-seven patients initiating fingolimod and 52 initiating ocrelizumab met the inclusion criteria. Before starting fingolimod, mean annualized relapse rate was 0.43 (95 % CI: 0.29 - 0.65) and 78 % developed new T2 lesions while during treatment it was 0.12 (95 % CI: 0.08 - 1.9) and 47 % developed new T2 lesions. In the ocrelizumab group, the mean annualized relapse rate prior to initiation of treatment was 0.64 (95 % CI: 0.38-1.09) and a total of 83 % of patients developed new T2 lesions while during treatment it was 0.09 (95 % CI: 0.04-0.21) and none developed new T2 lesions. CONCLUSION: This study highlights the importance of evaluating current treatment methods and provides insights about the agents in the ongoing phase III trial comparing fingolimod and ocrelizumab.

Old and New Strategies in the Treatment of Pediatric Multiple Sclerosis: A Personal View for a New Treatment Approach.

Up to 10 years ago the most common approach to the treatment of pediatric MS (ped-MS) was to start with IFNB or GA (so-called first-line therapies or moderate-efficacy disease-modifying therapies [ME-DMTs]) and to switch to more aggressive treatments (or high-efficacy disease-modifying therapies [HE-DMTs]) in non-responder patients. The use of HE-DMTs as first choice was recommended in selected cases with an active, aggressive form of MS. Indications for the treatment of ped-MS were essentially derived from data of observational studies. Recently, results of three randomized clinical trials have been published as well as data from many observational studies evaluating the effect of new and more active DMTs, with clear evidence that HE-DMTs are more effective than ME-DMTs. Therefore, the paradigm of treatment for patients with MS onset before 18 years of age should be changed, offering treatment with HE-DMTs as first option, because of their superior effectiveness to prevent relapses and disease progression. HE-DMTs present an overall reassuring safety profile and obtain better adherence to treatment.

Analysis of Evusheld safety and efficacy in multiple sclerosis patients.

BACKGROUND: In December 2021, the U.S. Food and Drug Administration issued emergency use authorization for the combination monoclonal antibodies tixagevimab and cilgavimab (Evusheld - AstraZeneca) for COVID-19 pre-exposure prophylaxis. While COVID-19 vaccination is recommended for multiple sclerosis (MS) patients, there is concern for insufficient antibody response in patients receiving B-cell depleting therapies. The literature is sparse regarding the safety and efficacy of Evusheld use in MS patients. OBJECTIVE: We sought to investigate the administration, safety, and efficacy of Evusheld in MS patients. METHODS: Participants were consecutively recruited from the UCSD MS Center from July 2022 to October 2022. We conducted both a review of medical records and a prospective cohort study. Inclusion criteria included prior diagnosis of MS and eligibility for Evusheld injection due to use of B-cell depleting disease modifying therapy (DMT). All eligible patients were evaluated to determine uptake of Evusheld use. Participant surveys were distributed to Evusheld recipients that evaluated for potential Evusheld side effects and COVID-19 vaccination and infection history. The proportion of COVID-19 infections among participants with or without Evusheld use were compared using Fisher's exact test, and a negative binomial regression analysis was used to evaluate risk for COVID-19 infection after Evusheld administration. RESULTS: A review of medical records showed that 79 MS patients were offered Evusheld by their clinicians during the recruitment period; 48 patients ultimately received the injection. Forty-two participants consented to the prospective cross-sectional study (mean age 46.4 years, 71.8 % female), of which 33 individuals received Evusheld. All participants received at least one COVID-19 vaccination dose, with 92.3 % receiving the initial series and at least one booster dose. One-third (30.8 %) of participants had a previous COVID-19 infection. DMTs included ocrelizumab, rituximab, and ofatumumab. Of the 33 participants who received Evusheld, 10 (30.3 %) reported experiencing at least one side effect. Injection site reactions included pain (most common), itchiness, and redness. General side effects included fatigue (most common), headache, muscle pain, and weakness. Of the 33 participants who received Evusheld, seven participants (21.2 %) tested positive for COVID-19 within 6 months of Evusheld injection. In an unadjusted binomial regression analysis, Evusheld administration was associated with a reduction in COVID-19 infection risk (OR 0.22, 95 % CI 0.05 - 1.02, p = 0.05). After adjusting for age and sex, Evusheld administration was still associated with a lower COVID-19 infection risk though it did not achieve nominal significance (OR 0.21, 95 % CI 0.04 - 1.09, p = 0.06). Of the 9 participants who were offered but did not receive Evusheld, five (55.6 %) tested positive for COVID-19 (p = 0.04 with Pearson's chi square test and p = 0.09 on Fisher's exact test). CONCLUSIONS: Our medical records data demonstrated that only 61 % of MS patients offered Evusheld received the injection. Evusheld seems to be largely well-tolerated. No serious adverse effects were reported. The use of Evusheld was associated with fewer COVID-19 infections, but this did not reach nominal statistical significance in the modest sample size. The lessons learned from the initial Evusheld experience may be applied to future interventions directed at infection prevention in MS patients on immunomodulatory therapies.

Memory B cell-guided extended interval dosing of ocrelizumab in multiple sclerosis.

BACKGROUND: Ocrelizumab (OCR) is an anti-CD20 monoclonal antibody approved for the treatment of relapsing-remitting and primary-progressive multiple sclerosis (MS). We aimed to evaluate the effectiveness of an individualized OCR extended interval dosing (EID), after switching from standard interval dosing (SID). METHODS: This was a retrospective, observational, single-centre study including MS patients regularly followed at the Neurocenter of Southern Switzerland. After a cumulative OCR dose ⩾1200 mg, stable patients were switched to EID (OCR infusions following CD19+ 27+ memory B cell repopulation). RESULTS: A total of 128 patients were included in the study, and 113 (88.3%) were switched to EID with a median interval of 9.9 (8.8-11.8) months between infusions. No clinical relapses occurred; 2 (1.8%) patients experienced disability worsening. Three (2.7%) and 2 (1.8%) patients experienced new T2 brain and spinal lesions, respectively. There was a mild decrease in IgG and IgM concentrations during both SID and EID OCR regimens (ß = -0.23, p = 0.001 and ß = -0.07, p < 0.001, respectively). CONCLUSION: Switch to personalized dosing of OCR based on CD19+ 27+ memory B cell repopulation led to a great extension of the interval between infusions, with maintained clinical and radiological efficacy. Given the potential advantages in terms of safety and health costs, EID OCR regimens should be further investigated.

The ocrelizumab wearing-off phenomenon is associated with reduced immunomodulatory response and increased neuroaxonal damage in multiple sclerosis.

OBJECTIVE: The wearing-off phenomenon is common in people with multiple sclerosis (MS) treated with ocrelizumab. We aim to evaluate the presence and severity of wearing-off to ocrelizumab in relation to demographic and MS clinical variables, immune profiling, and a marker of neuroaxonal damage (plasma neurofilament light chain (pNfl)). METHODS: This cross-sectional study included MS patients treated with ocrelizumab from at least 1 year. Wearing-off questionnaire and blood samples were collected between 21 and 23 weeks after the previous ocrelizumab infusion. Lymphocyte subpopulations were evaluated on peripheral blood using flow cytometry. PNfl was evaluated using fully automated chemiluminescent enzyme immunoassay. RESULTS: We included 106 people with MS (age 49.5 ± 11.6 years; females 42.3%; wearing-off 57.6%). On regression models, wearing-off was associated with higher pNfl, CD8, CD3, and CD3CD27 lymphocytes. Most frequent wearing-off symptoms were cognitive, sensory, and balance problems; wearing-off started < 1 week (9.4%), 1-4 weeks (10.7%) or > 4 weeks (10.7%) before infusion; 44.8% of the complaints were moderate to severe. Severity of wearing-off was associated with higher pNfl and CD8 lymphocytes. CONCLUSIONS: Wearing-off is common in people with MS treated with ocrelizumab, and is associated with reduced immunomodulation (higher T lymphocytes) and increased neuroaxonal damage, suggesting reduced treatment response.

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

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

Real-world effectiveness, safety and immunogenicity of ocrelizumab in turkish multiple sclerosis patients: a single-center experience for 4-year follow-up.

OBJECTIVE: The aim of this study was to evaluate postmarketing ocrelizumab safety and effectiveness in a real-world population with multiple sclerosis (MS) and matching these parameters among MS disease types. METHODS: This was a retrospective, single-center study with MS patients treated with ocrelizumab. Demographic, clinical characteristics and immunological data were analyzed, including annualized relapse rate (ARR), relapse-free rate, Expanded Disability Status Scale (EDSS), complete blood count parameters, immunoglobulin (Ig) levels, liver function tests (LFT), hepatitis markers and adverse events in the 4-year follow-up. A total of 96 patients, 22 with relapsing-remitting MS (RRMS), 54 with secondary progressive MS (SPMS), and 20 with primary progressive MS (PPMS) who were treated with at least two doses of ocrelizumab between January 2018 and September 2023 were included in the study. RESULTS: Sixty-five (68%) were women and 31 (32%) were men. The mean age was 48.4 ± 11.1 years (20-70 years). Ninety-three patients were evaluated in the first year, 65 in the second year, 39 in the third year and 24 in the fourth year of treatment. 96% of patients were relapse-free rate in the first year, 91% in the second year, 85% in the third year and 75% in the fourth year. Eighty-six percent of patients were progression free in the 1st year of treatment, 71% in the 2nd year, in 64% in the 3rd year, and in 62% in the 4th year. During the follow-up of the cases, EDSS remained stable in 77% of RRMS patients, improved in 14%, and worsened in 9%; while EDSS remained stable in 65% of SPMS patients with attacks, it improved in 9% and worsened in 26%; while EDSS remained stable in 60% of PPMS patients, worsening was observed in 40%. There is a significant decrease in IgM and IgG values during the follow-up of ocrelizumab therapy (p < 0.001, p = 0.014). There is no significant difference in IgA, lymphocyte and neutrophil values (p = 0.713, p = 0.086, p = 0.999). No significant relationship was found between low serum IgM levels and the risk of developing infection (p > 0.05). Liver function tests was found to be within normal limits in 94% of the patients over a 4-year period. No hepatitis B, C or A infection, hepatitis B reactivation, tuberculosis, HIV infection, malignancy or drug related death occurred during 4-years follow-up. The most common side effect during ocrelizumab treatment is urinary tract infection (29%); others were upper respiratory tract infections (13%), numbness/tingling of the face, trunk, or extremities (8%), insomnia (6%), headache (5%), and soft tissue infections (cellulitis and dental abscess, 2%). CONCLUSIONS: Our results show that ocrelizumab reduces the frequency of attacks and prevent the disease progression in RRMS patients, and reducing the disease progression by primarily stabilizing EDSS scores in SPMS with attacks and PPMS. It is thought that the relatively high rates of urinary tract infection detected in this study may be related with advanced stage of the disease. The absence of hepatitis B reactivation, chronic infection or malignancy in the 4-year follow-up of our cases supports the long-term safety of ocrelizumab treatment. Ocrelizumab may be preferred as an effective and reliable treatment of different types of MS due to non-serious side effects.

Altered Cerebrospinal Fluid Neurofilament Light Chain but Not Neurogranin Levels Are Associated with Response to Ocrelizumab Treatment in Relapsing-Remitting Multiple Sclerosis: A Preliminary Study.

INTRODUCTION: Ocrelizumab is a CD20-targeting monoclonal antibody used for treatment of multiple sclerosis (MS). Serum and cerebrospinal fluid (CSF) neurofilament light (NFL) chain levels are reduced in MS patients under ocrelizumab treatment indicating a preventive action against neuro-axonal degeneration. Our aim, in this preliminary study, was to explore the impact of ocrelizumab treatment on synaptic integrity through assessment of neurogranin levels. METHODS: Thirteen relapsing-remitting multiple sclerosis (RRMS) patients resistant to first-line immunomodulating agents were enrolled and followed up for 24 months under ocrelizumab treatment. Disease activity was monitored by periodic EDSS, MSSS, and cranial-spinal MRI assessments. No evidence of disease activity (NEDA)-3 was determined, and CSF levels of NFL (marker of neuro-axonal integrity) and neurogranin (marker of synaptic integrity) were measured by ELISA at baseline and 12-month ocrelizumab treatment. RESULTS: Seven RRMS patients, who preserved NEDA-3 status during 24-month follow-up, showed ≥30% NFL level decrease, whereas 6 patients with stable/increased NFL levels displayed relapse, MRI lesion, or disability progression. Although most RRMS patients exhibited increased CSF levels of neurogranin under ocrelizumab treatment, patients with and without neurogranin level increase did not differ in terms of clinical features and NEDA-3 status. Baseline neurogranin levels negatively correlated with baseline EDSS scores. CONCLUSION: Our results confirm that NFL effectively monitors treatment response of RRMS patients under ocrelizumab treatment. Neurogranin does not appear to exhibit a similar benefit in screening of RRMS disease activity. Nevertheless, lower neurogranin levels are associated with increased disability in RRMS indicating a potential disease activity biomarker function.

NEDA-3 achievement in early highly active relapsing remitting multiple sclerosis patients treated with Ocrelizumab or Natalizumab.

BACKGROUND: in the early stages of Multiple Sclerosis (MS), initiating high-efficacy disease-modifying therapy (HE DMTs) may represent an optimal strategy for delaying neurological damage and long-term disease progression, especially in highly active MS patients (HAMS). Natalizumab (NAT) and Ocrelizumab (OCR) are recognized as HE DMTs with significant anti-inflammatory effects. This study investigates NEDA-3 achievement in treatment-naïve HAMS patients receiving NAT or OCR over three years. METHODS: we retrospectively enrolled treatment-naïve HAMS patients undergoing NAT or OCR, collecting demographic, clinical, and instrumental data before and after treatment initiation to compare with propensity score analysis disease activity, time to disability worsening, and NEDA-3 achievement. RESULTS: we recruited 281 HAMS patients with a mean age of 32.7 years (SD 10.33), treated with NAT (157) or OCR (124). After three years, the Kaplan-Meier probability of achieving NEDA-3 was 66.0 % (95 % CI: 57.3 % - 76.0 %) with OCR and 68.2 % (95 % CI: 59.9 % - 77.7 %) with NAT without significant differences between the two groups (p = 0.27) DISCUSSION AND CONCLUSION: starting HE DMT with monoclonal antibodies for HAMS could achieve NEDA-3 in a high percentage of patients without differences between NAT or OCR.

Effects of anti-CD20 therapy on circulating and intrathecal follicular helper T cell subsets in multiple sclerosis.

Follicular helper T (Tfh) cells and their interplay with B cells likely contribute to the pathogenesis of relapsing-remitting multiple sclerosis (RRMS). Tfh cells are enriched in cerebrospinal fluid (CSF) in RRMS, but effects of anti-CD20 therapy are unknown. We investigated Tfh cells in controls, untreated and anti-CD20-treated patients with RRMS using flow cytometry. CSF Tfh cells were increased in untreated patients. Compared to paired blood samples, CD25- Tfh cells were enriched in CSF in RRMS, but not in controls. Contrast-enhancing brain MRI lesions and IgG index correlated with CSF CD25- Tfh cell frequency in untreated patients with RRMS. Anti-CD20 therapy reduced the numbers of circulating PD1+ Tfh cells and CD25- Tfh cells, and the frequency of CSF CD25- Tfh cells. The study suggests that CD25- Tfh cells are recruited to the CSF in RRMS, associated with focal inflammation, and are reduced by anti-CD20 therapy.

Ocrelizumab and ofatumumab comparison: an Italian real-world propensity score matched study.

BACKGROUND: The management of Multiple Sclerosis (MS) has undergone transformative evolution with the introduction of high-efficacy disease-modifying therapies (DMTs), specifically anti-CD20 monoclonal antibodies, such as ocrelizumab (OCR) and ofatumumab (OFA). MATERIALS AND METHODS: This is an independent retrospective cohort study in Relapsing MS (RMS) patients followed at eight Italian MS centers who initiated treatment with OCR or OFA in the participating centers and with at least 12 months on therapy. A generalized linear regression model inverse probability of treatment weight (IPTW) PS-adjusted was performed to evaluate the relationship between annualized relapse rate (ARR) and treatment groups. No evidence of disease activity-NEDA-3 at 12-month score was also collected. Safety profile of the investigated DMTs was recorded. RESULTS: A total cohort of 396 RMS patients fulfilled the required criteria and were enrolled in the study. Out of them, 216 had a prescription of OCR and 180 of OFA. The mean follow-up was 13.2 ± 1.9 months. The estimated means for ARR did not show differences between the two groups, 0.059 for patients on OCR and 0.038 for patients on OFA (p = 0.185). The generalized regression model IPTW PS-adjusted did not reveal differences between patients on OCR and OFA (ExpBOFA 0.974, 95%CI 934-1.015, p = 0.207). NEDA-3 at 12 months was experienced by 199(92.1%) patients on OCR and 170(94.4%) patients on OFA (p = 0.368). Generally, both therapies exhibit good tolerability. CONCLUSIONS: The treatment with OCR and OFA resulted in comparable control of disease activity with good safety profile. Our results need further validation in larger multicentre studies with long-term follow-up.

Anti-CD20 monoclonal antibodies in multiple sclerosis: Rethinking the current treatment strategy.

Anti-CD20 monoclonal antibodies are highly-effective B-cell-depleting therapies in multiple sclerosis (MS). These treatments have expanded the arsenal of highly effective disease-modifying therapies, and have changed the landscape in understanding the pathophysiology of MS and the natural course of the disease. Nevertheless, these treatments come at the cost of immunosuppression and risk of serious infections, diminished vaccination response and treatment-related secondary hypogammaglobulinemia. However, the COVID pandemic has given way to a possibility of readapting these therapies, with most notably extended dosing intervals. While these new strategies show efficacy in maintaining inflammatory MS disease control, and although it is tempting to speculate that tailoring CD20 therapies will reduce the negative outcomes of long-term immunosuppression, it is unknown whether they provide meaningful benefit in reducing the risk of treatment-related secondary hypogammaglobulinemia and serious infections. This review highlights the available anti-CD20 therapies that are available for treating MS patients, and sheds light on encouraging data, which propose that tailoring anti-CD20 monoclonal antibodies is the next step in rethinking the current treatment strategy.

Rehabilitation Outcomes in Multiple Sclerosis Patients on Ocrelizumab Diagnosed With West Nile Virus Encephalitis.

Multiple sclerosis (MS) has a global prevalence exceeding two million people and is a leading cause of non-traumatic physical disability. MS can be treated with ocrelizumab, an anti-CD20 monoclonal antibody. West Nile virus (WNV) is the most common cause of mosquito-borne viral encephalitis in North America. It can lead to neuroinvasive WNV disease (WNND) affecting the brain and peripheral nervous system, especially in immunocompromised patients, such as those being treated with ocrelizumab for MS. WNND is exceedingly rare and reported in less than 1% of cases of WNV. It has been established that inpatient rehabilitation improves functional outcomes in patients with MS and those with WNND. However, the inpatient rehabilitation outcomes in patients diagnosed with both WNND and MS have not been reported. In this study, we aimed to examine the rehabilitation outcomes of MS patients on ocrelizumab diagnosed with WNND. We performed a retrospective chart review of patients with MS treated with ocrelizumab, who were diagnosed with WNND and admitted to a single facility. Rehabilitation outcomes were assessed using functional independence measure (FIM) scores on admission and discharge. Three patients met the inclusion criteria; two in acute rehab, and one in the long-term acute care hospital (LTACH). Both patients admitted to acute inpatient rehabilitation showed an improvement in FIM scores from admission to discharge, one patient from 9 to 16 and the other from 14 to 54. However, the patient admitted to the LTACH had no improvement in FIM score from admission to discharge. Patients admitted to acute rehab were ultimately discharged home, while the patient admitted to the LTACH required discharge to a subacute rehabilitation facility. Based on our findings, intense and prolonged comprehensive inpatient rehabilitation is associated with improved functional outcomes and increased likelihood of discharge to home in this population suffering from both central and peripheral nervous system involvement due to MS and WNND.

Extended interval dosing with ocrelizumab in multiple sclerosis.

BACKGROUND: This study investigates clinical and biomarker differences between standard interval dosing (SID) and extended interval dosing (EID) of ocrelizumab therapy in multiple sclerosis (MS). METHODS: This is a prospective, double-arm, open-label, multi-center study in Denmark. Participants diagnosed with MS on ocrelizumab therapy >12 months were included (n = 184). Clinical, radiological, and blood-based biomarker outcomes were evaluated. MRI disease activity, relapses, worsening of neurostatus, and No Evidence of Disease Activity-3 (NEDA-3) were used as a combined endpoint. RESULTS: Out of 184 participants, 107 participants received EID (58.2%), whereas 77 participants received SID (41.8%). The average extension was 9 weeks with a maximum of 78 weeks. When comparing EID to SID, we found higher levels of B-cells, lower serum concentrations of ocrelizumab, and similar levels of age-adjusted NFL and GFAP in the two groups. No difference in NEDA-3 between EID and SID was demonstrated (hazard ratio: 1.174, p = 0.69). Higher levels of NFL were identified in participants with disease activity. Body mass index correlated with levels of ocrelizumab and B-cells. CONCLUSION: Extending one treatment interval of ocrelizumab on average 9 weeks and up to 78 weeks did not result in clinical, radiological, or biomarker evidence of worsening compared with SID.

Comparing the Risk of Infusion-Related Reactions and Tolerability in Patients Given Cetirizine or Diphenhydramine Prior to Ocrelizumab Infusion (PRECEPT).

Background: Ocrelizumab is an effective medication for multiple sclerosis. However, infusion-related reactions (IRRs) are a concern for patients and may lead to discontinuation of ocrelizumab. To minimize IRRs, pre-medications are administered. However, from our experience, these medications, especially diphenhydramine, can cause marked drowsiness. The primary objective of this study was to evaluate whether cetirizine is non-inferior to diphenhydramine in limiting the proportion and severity of reactions from ocrelizumab infusions. Methods: Twenty participants were serially randomized in a 1:1 ratio to receive 10 mg of cetirizine or 25 mg of diphenhydramine orally prior to their first three ocrelizumab infusions. Results: The rate of IRRs in this study was similar across both treatment groups with no increase in the risk of severity, and no grade 3 IRRs. Further, patients receiving cetirizine experienced a reduction in fatigue. While there was not a significant difference in global satisfaction, this score increased over time in the cetirizine arm while it remained unchanged in the diphenhydramine arm. Conclusions: Overall, our results suggest that cetirizine does not increase the risk of infusion-related reactions compared to diphenhydramine.