Search

Background: Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic infection caused by John Cunningham virus (JCV) reactivation, potentially associated with natalizumab (NTZ) treatment for Multiple Sclerosis (MS). The anti-JCV antibodies titre (JCV index) increases during NTZ treatment; however, the effects of other disease-modifying therapies (DMTs) on the JCV index have not been fully explored. Objective: The aim of the study was to evaluate changes in the JCV index during treatment with several DMTs. Methods: This longitudinal study evaluated the JCV index before starting DMT (T0) and during treatment with DMT (T1). Results: A total of 260 participants (65.4 % females, mean age 43 ± 11.3 ) were enrolled: 68 (26.2 %) treated with fingolimod (FTY), 65 (25 %) rituximab or ocrelizumab (RTX/OCR), 37 (14.2 %) dimethyl-fumarate (DMF), 29 (11.2 %) cladribine (CLD), 23 (8.8 %) teriflunomide (TFM), 20 (7.7 %) interferon or glatiramer acetate (IFN/GA), and 18 (6.9 %) alemtuzumab (ALM). At T1, the percentage of patients with JCV index 1.51 was found to be significantly reduced in the RTX/OCR group (51.6 % versus 37.5 %, p = 0.04). In the FTY group, a significant reduction in the percentage of patients with JCV index Conclusion: DMTs with a T and/or B depleting mechanism of action induced a significant reduction in the JCV index. These results may suggest new possible sequencing strategies potentially maximizing disease control while reducing the PML risk.

With the recent successful targeting of B lymphocytes in patients with multiple sclerosis (MS), treatment with anti-CD20 monoclonal antibodies (mAbs) may represent a promising managemental approach, particularly for those with relapsing/remitting MS (RRMS). A network meta-analysis was conducted based on a comprehensive search in Embase, PubMed, and the Cochrane Library to assess the comparative efficacy and safety of currently available anti-CD20 monoclonal antibodies (mAbs), including rituximab, ocrelizumab, and ofatumumab, versus a common comparator (interferon beta-1a [INFβ-1a]) in RRMS patients recruited in randomized clinical trials (RCTs). In a frequentist network meta-analytical model, annualized relapse rates (ARRs) and safety outcomes were expressed as risk ratios (RRs), whereas relapse-free events were expressed as odds ratios (ORs). Treatment ranking was performed using P-scores. The certainty of evidence was appraised using the GRADE approach. Five publications reported the outcomes of seven RCTs (3938 patients, 67.09% females). Compared to INFβ-1a, ocrelizumab reduced the risk of ARR (RR = 0.56, 95% CI, 0.50–0.64), serious adverse events (RR = 0.17, 95% CI, 0.09–0.30), and treatment discontinuation due to adverse events (SAEs, RR = 0.60, 95% CI, 0.39–0.93), and it was associated with higher odds of no relapses (OR = 2.47, 95% CI, 2.00–3.05). Ocrelizumab ranked best among all other treatments in terms of reducing ARR and SAEs. The quality of evidence was low for ocrelizumab, low to moderate for rituximab, and high for ofatumumab. Further large-sized, well-designed RCTs are needed to corroborate the efficacy and safety of ocrelizumab and other anti-CD20 mAbs in RRMS., Highlights • B cell depletion via the anti-CD20 therapy is promising in relapsing-remitting MS. • Data is currently available for ocrelizumab, rituximab, and ofatumumab. • Ocrelizumab was the most efficacious biological agent in reducing relapse. • Ocrelizumab reduced also the risk of treatment discontinuation due to adverse events.

Background and ObjectivesTo evaluate the immune-specific response after full severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination of patients with multiple sclerosis (MS) treated with different disease-modifying drugs by the detection of both serologic and T-cell responses.MethodsHealthcare workers (HCWs) and patients with MS, having completed the 2-dose schedule of an mRNA-based vaccine against SARS-CoV-2 in the past 2–4 weeks, were enrolled from 2 parallel prospective studies conducted in Rome, Italy, at the National Institute for Infectious diseases Spallanzani–IRCSS and San Camillo Forlanini Hospital. Serologic response was evaluated by quantifying the region-binding domain (RBD) and neutralizing antibodies. Cell-mediated response was analyzed by a whole-blood test quantifying interferon (IFN)–γ response to spike peptides. Cells responding to spike stimulation were identified by fluorescence-activated cell sorting analysis.ResultsWe prospectively enrolled 186 vaccinated individuals: 78 HCWs and 108 patients with MS. Twenty-eight patients with MS were treated with IFN-β, 35 with fingolimod, 20 with cladribine, and 25 with ocrelizumab. A lower anti-RBD antibody response rate was found in patients treated with ocrelizumab (40%, p < 0.0001) and fingolimod (85.7%, p = 0.0023) compared to HCWs and patients treated with cladribine or IFN-β. Anti-RBD antibody median titer was lower in patients treated with ocrelizumab (p < 0.0001), fingolimod (p < 0.0001), and cladribine (p = 0.010) compared to HCWs and IFN-β–treated patients. Serum neutralizing activity was present in all the HCWs tested and in only a minority of the fingolimod-treated patients (16.6%). T-cell–specific response was detected in the majority of patients with MS (62%), albeit with significantly lower IFN-γ levels compared to HCWs. The lowest frequency of T-cell response was found in fingolimod-treated patients (14.3%). T-cell–specific response correlated with lymphocyte count and anti-RBD antibody titer (ρ = 0.554, p < 0.0001 and ρ = 0.255, p = 0.0078 respectively). IFN-γ T-cell response was mediated by both CD4+ and CD8+ T cells.DiscussionmRNA vaccines induce both humoral and cell-mediated specific immune responses against spike peptides in all HCWs and in the majority of patients with MS. These results carry relevant implications for managing vaccinations, suggesting promoting vaccination in all treated patients with MS.Classification of EvidenceThis study provides Class III data that SARS-CoV-2 mRNA vaccination induces both humoral and cell-mediated specific immune responses against viral spike proteins in a majority of patients with MS.

Background Coronavirus disease of the 2019 pandemic caused much fear among people with chronic diseases and those on immunosuppressant treatment because of spreading knowledge that the infection has a fatal course in these populations. People with Multiple Sclerosis on ocrelizumab treatment share this fear too. We aimed to investigate treatment and lifestyle changes of people with multiple sclerosis on ocrelizumab treatment during the lockdown. Methods We surveyed 199 of our registered multiple sclerosis patients on ocrelizumab treatment by phone. Results In this survey, delays in treating 22 (11%) patients were not caused by fear of immunosuppressive drug use but rather by the general fear of contracting a fatal disease, which is the case during traveling and hospital visits. There was a positive correlation between living alone and treatment delay (P = .029), emphasizing the role of family support or just the presence of another person during the pandemic. Conclusion Vaccines might soon solve the pandemic's issue, which is not the case with multiple sclerosis progression, so we should think twice before discontinuing the treatment.

Traditionally, the management of active relapsing remitting MS was based on the, so-called, maintenance therapy, which is characterized by continuous treatment with particular disease modifying therapy (DMT), and a return of disease activity when the drug is discontinued. Another approach is characterized by a short treatment course of a DMT, which is hypothesized to act as an immune reconstitution therapy (IRT), with the potential to protect against relapses for years after a short course of treatment. Introduction of monoclonal antibodies in the treatment of MS has revolutionized MS treatment in the last decade. However, given the increasingly complex landscape of DMTs approved for MS, people with MS and neurologists are constantly faced with the question which DMT is the most appropriate for the given patient, a question we still do not have an answer to. In this product review, we will discuss the first DMT that acts as IRT, an anti-CD52 monoclonal antibody alemtuzumab and an anti CD20 monoclonal antibody, ocrelizumab that has the potential to act as an IRT, but is administered continuously. Special emphasis will be given on safety in the context of COVID-19 pandemics and vaccination strategies.

ObjectiveRandomised trials of type I anti-CD20 antibodies rituximab and ocrelizumab failed to show benefit in proliferative lupus nephritis (LN). We compared obinutuzumab, a humanised type II anti-CD20 monoclonal antibody that induces potent B-cell depletion, with placebo for the treatment of LN in combination with standard therapies.MethodsPatients with LN receiving mycophenolate and corticosteroids were randomised to obinutuzumab 1000 mg or placebo on day 1 and weeks 2, 24 and 26, and followed through week 104. The primary endpoint was complete renal response (CRR) at week 52. Exploratory analyses through week 104 were conducted. The prespecified alpha level was 0.2.ResultsA total of 125 patients were randomised and received blinded infusions. Achievement of CRR was greater with obinutuzumab at week 52 (primary endpoint, 22 (35%) vs 14 (23%) with placebo; percentage difference, 12% (95% CI −3.4% to 28%), p=0.115) and at week 104 (26 (41%) vs 14 (23%); percentage difference, 19% (95% CI 2.7% to 35%), p=0.026). Improvements in other renal response measures, serologies, estimated glomerular filtration rate and proteinuria were greater with obinutuzumab. Obinutuzumab was not associated with increases in serious adverse events, serious infections or deaths. Non-serious infusion-related reactions occurred more frequently with obinutuzumab.ConclusionsImproved renal responses through week 104 were observed in patients with LN who received obinutuzumab plus standard therapies compared with standard therapies alone. Obinutuzumab was well tolerated and no new safety signals were identified.Trial registration numberNCT02550652.

Made available in DSpace on 2022-04-28T19:46:29Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-11-09 Background and ObjectivesPeople with multiple sclerosis MS are a vulnerable group for severe coronavirus disease 2019 COVID-19, particularly those taking immunosuppressive disease-modifying therapies DMTs. We examined the characteristics of COVID-19 severity in an international sample of people with MS.MethodsData from 12 data sources in 28 countries were aggregated sources could include patients from 1-12 countries. Demographic age, sex, clinical MS phenotype, disability, and DMT untreated, alemtuzumab, cladribine, dimethyl fumarate, glatiramer acetate, interferon, natalizumab, ocrelizumab, rituximab, siponimod, other DMTs covariates were queried, along with COVID-19 severity outcomes, hospitalization, intensive care unit ICU admission, need for artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression adjusted for age, sex, MS phenotype, and Expanded Disability Status Scale EDSS score.ResultsSix hundred fifty-seven 28.1% with suspected and 1,683 61.9% with confirmed COVID-19 were analyzed. Among suspected plus confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalized, 5.4% and 7.2% were admitted to ICU, 4.1% and 5.4% required artificial ventilation, and 3.2% and 3.9% died. Older age, progressive MS phenotype, and higher disability were associated with worse COVID-19 outcomes. Compared to dimethyl fumarate, ocrelizumab and rituximab were associated with hospitalization adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.01-2.41; aOR 2.43, 95% CI 1.48-4.02 and ICU admission aOR 2.30, 95% CI 0.98-5.39; aOR 3.93, 95% CI 1.56-9.89, although only rituximab was associated with higher risk of artificial ventilation aOR 4.00, 95% CI 1.54-10.39. Compared to pooled other DMTs, ocrelizumab and rituximab were associated with hospitalization aOR 1.75, 95% CI 1.29-2.38; aOR 2.76, 95% CI 1.87-4.07 and ICU admission aOR 2.55, 95% CI 1.49-4.36; aOR 4.32, 95% CI 2.27-8.23, but only rituximab was associated with artificial ventilation aOR 6.15, 95% CI 3.09-12.27. Compared to natalizumab, ocrelizumab and rituximab were associated with hospitalization aOR 1.86, 95% CI 1.13-3.07; aOR 2.88, 95% CI 1.68-4.92 and ICU admission aOR 2.13, 95% CI 0.85-5.35; aOR 3.23, 95% CI 1.17-8.91, but only rituximab was associated with ventilation aOR 5.52, 95% CI 1.71-17.84. Associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Stratification by age, MS phenotype, and EDSS score found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity.DiscussionUsing the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalization, ICU admission, and need for artificial ventilation and of ocrelizumab with hospitalization and ICU admission. Despite the cross-sectional design of the study, the internal and external consistency of these results with prior studies suggests that rituximab/ocrelizumab use may be a risk factor for more severe COVID-19. CORe Department of Medicine and Neuroepidemiology Unit Melbourne School of Population and Global Health Menzies Institute for Medical Research University of Tasmania ESAT-STADIUS KU Leuven Department of Neurology Melbourne MS Centre Royal Melbourne Hospital MS International Federation Department of Clinical Neuroscience Swedish MS Registry Department of Neurology CHU Pontchaillou Karolinska Institutet Biomedical Research Institute-Data Science Institute Hasselt University Department of Medical Informatics University Medical Center Department of Computer Science and AI KU Leuven QMENTA Medpace Reference Laboratories Molecular Unit IConquerMS People-Powered Research Network Accelerated Cure Project for MS NeuroTransData Study Group NeuroTransData German MS-Register by the National MS Society MS Forschungs- und Projektentwicklungs-gGmbH MS Register Swansea University COViMS Division of Biostatistics Washington University in St. Louis Mellen Center for Multiple Sclerosis Cleveland Clinic Department of Neuroscience Central Clinical School Monash University Al-Amiri Hospital Kuwait City Dokuz Eylul University Neurology Department Hospital Universitario de CEMIC RELACOEM Australian MS Longitudinal Study Menzies Institute for Medical Research University of Tasmania Bulgarian SmartMS COVID-19 Dataset ABEM-Brazilian MS Patients Association Danish Multiple Sclerosis Registry Department of Neurology University Hospital Rigshospitalet Universidade Estadual Paulista Unesp Faculdade de Medicina REDONE.br-Brazilian Registry of Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders Irmandade da Santa Casa de Misericórdia de São Paulo Multiple Sclerosis University Center Ramos Mejia Hospital-EMA Imperial College Swansea University Mental Health Area MS and Demyelinating Diseases Hospital Británico de Buenos Aires EMA Servei de Neurologia-Neuroimmunologia Centre d'Esclerosi Múltiple de Catalunya Cemcat Vall d'Hebron Institut de Recerca Vall d'Hebron Hospital Universitari Universitat Autònoma de Barcelona Institute of Experimental Neurology Ospedale San Raffaele Universidade Estadual Paulista Unesp Faculdade de Medicina

The COVID-19 pandemic was announced in 2020, and many professional medical societies had to review their algorithms for the management of high-risk patients. In addition to risk factors such as overweight, age over 65 years, cardiovascular disease, diabetes mellitus, and bronchial asthma, other chronic diseases should also be emphasized, taking into account possible immunosuppressive therapy. This publication presents two clinical cases of COVID-19 infection in patients with multiple sclerosis treated with ocrelizumab. During the course of the disease, both patients developed a cytokine storm and were treated with IL-6 blockers. Both cases ended with recovery and a subsequent return to anti-B-cell therapy. Given the mechanism of action of ocrelizumab, there are higher risks of infectious complications, including with COVID-19, but mortality is not higher than the population average. The information published to date may serve as a reason to consider the use of extended dosing intervals to minimize the possible risks of COVID-19 infection, which are probably highest in the first months after infusion.

The risk of cancer associated with persons with multiple sclerosis (pwMS) prescribed with disease modifying therapies (DMTs) is not well established. This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database: VigiBase®. All consecutive reports of DMTs prescribed to pwMS (alemtuzumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon-β, natalizumab, ocrelizumab, and teriflunomide), and their serious adverse event cases were eligible, excluding those reporting immunosuppressant DMTs used as anticancer therapies. The primary outcome was the multivariate odds ratio of cancer reporting (r-OR) for DMTs prescribed to pwMS after imputation of missing data. There were 5966 cancer cases from 240,993 reports of DMTs prescribed to pwMS. After adjustments on age, sex, and geographical region, natalizumab (r-OR 1.74, 95% CI 1.63–1.87), interferon-β (r-OR 1.39, 95% CI 1.30–1.49), dimethyl fumarate (r-OR 1.35, 95% CI 1.25–1.46), and fingolimod (r-OR 1.15, 95% CI 1.06–1.24) were significantly associated with a greater cancer reporting, whereas alemtuzumab, glatiramer acetate, ocrelizumab, and teriflunomide were not, in the disproportionality analysis. As exploratory analyses, upper aerodigestive tract, breast, urinary including the male genitourinary tract, and nervous system cancers were associated with natalizumab, interferon-β, and dimethyl fumarate. Fingolimod was only associated with skin cancer types. Cancer cases reporting these four DMTs prescribed to pwMS were younger in age than for non-pwMS drugs in the VigiBase® (p

Purpose The aim of this study was to evaluate the cost effectiveness of cladribine compared with alemtuzumab, natalizumab, and ocrelizumab for the treatment of highly active multiple sclerosis (HAD-MS) from the perspective of the Chilean health care public sector. Materials and Methods A Markov model was used to compare costs and quality-adjusted life-years (QALYs) over a 45-year time horizon using a 3% discount rate for costs and outcomes. Natural history of the disease was modeled in terms of progression of disability according to the Expanded Disability Status Scale (EDSS). A network meta-analysis was used as a source of comparative effectiveness for disability progression and annual relapse rates. Differences in costs and outcomes were modeled for only 10 years due to high temporal uncertainty. Ocrelizumab was assumed to have the same efficacy as cladribine due to lack of data. Direct costs were taken from national tariffs and expressed in 2019 US dollars. Utilities for EDSS health states were obtained from the literature. Second-order uncertainty was characterized through deterministic and probabilistic sensitivity analysis. Findings Compared with natalizumab (the current strategy covered in Chile), cladribine is associated with incremental costs and QALYs of US$70,989 and 1.875, respectively (incremental cost-effectiveness ratio [ICER] $37,861). Ocrelizumab was extendedly dominated by cladribine and natalizumab, and alemtuzumab was dominated by cladribine. A scenario analysis of a 10% discount did not modify the results substantially, but showed a decrease in the ICER of cladribine versus natalizumab (ICER $29,833/QALY). Implications Cladribine is a new oral alternative to treat patients with HAD-MS that is expected to produce higher QALYs than all evaluated alternatives. In the context of a conservative analysis, cladribine cannot be considered cost effective for the Chilean health care public sector using a 1 GDP per capita threshold. However, under reasonable discount scenarios, cladribine becomes an attractive alternative for the health system.

PURPOSE OF THE REVIEW: To provide the latest evidence and treatment advances of multiple sclerosis in women of childbearing age prior to conception, during pregnancy and postpartum. RECENT FINDINGS: Recent changes permitting interferon beta (IFN-β) use in pregnancy and breastfeeding has broadened the choices of disease modifying treatments (DMTs) for patients with high relapse rates. Natalizumab may also be continued until 34 weeks of pregnancy for patients requiring persisting treatment. Drugs with a known potential of teratogenicity such as fingolimod or teriflunomide should be avoided and recommended wash-out times for medications such as cladribine, alemtuzumab or ocrelizumab should be considered. Teriflunomide and fingolimod are not recommended during breastfeeding, however, glatiramer acetate and IFN-β are considered to be safe. SUMMARY: The evidence of potential fetotoxicities and adverse pregnancy outcomes associated with DMTs is increasing, although more research is needed to evaluate the safety of drugs and to track long-term health outcomes for the mother and the child.

The success of selective B-cells depleting therapies, as the anti-CD20 antibodies, in patients with multiple sclerosis (MS) has confirmed that B-cells are critical in the immune pathogenesis of the disease. Ocrelizumab, a humanized monoclonal antibody that selectively targets CD20+ B-cells, profoundly suppresses acute inflammatory disease activity, representing a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS). It is also the first proven therapy able to slow disability progression in primary progressive multiple sclerosis (PPMS), particularly in patients with signs of acute radiological activity before being enrolled. Effectiveness has widely been demonstrated in randomized clinical trials (RCTs), and recently confirmed in open-label extension trials. Here, we review the role of B-cells in MS, the mechanism of action of ocrelizumab, its pharmacokinetics and pharmacodynamics, and the clinical data supporting its use, as well as safety data. We focus on issues related to the maintenance of immunocompetence, essential to ensure an immune response to either a primary infection or a vaccination. Lastly, we discuss about the possible role of ocrelizumab as an exit strategy from natalizumab-treated patients at risk of developing multifocal progressive leukoencephalopathy. In view of using ocrelizumab chronically, collecting long-term safety data and finding strategies to minimize adverse events will be extremely relevant.

Objectives. Immune reconstitution therapies (IRT), which include antibody-based cell-depleting therapies targeting CD52+ (alemtuzumab) or CD20+ (rituximab, ocrelizumab) leukocytes, are approved for the treatment of multiple sclerosis. Thyroid autoimmunity is a common adverse effect of alemtuzumab treatment, Graves’ disease (GD) being the most prevalent manifestation. To date, thyroid autoimmunity events have not been reported with CD20-targeting monoclonal antibodies. Case Report. A 59-year-old woman with primary progressive multiple sclerosis with no prior personal history of thyroid disease or autoimmunity, was diagnosed with GD 6 months following the first ocrelizumab infusion. She was asymptomatic and had no signs of ophthalmopathy. Due to the temporal association of GD diagnosis with ocrelizumab infusion, absence of symptoms and our experience with alemtuzumab-induced GD, we decided for an active surveillance strategy and antithyroid drugs were not started. She underwent spontaneous resolution of hyperthyroidism with thyroid-stimulating hormone (TSH) receptor antibodies (TRAb) negativity and a mild and transitory period of subclinical hypothyroidism, while she continued the biannually ocrelizumab administration schedule. To present date, she has maintained close clinical and biochemical surveillance with normal TSH, free thyroxine (fT4) and free triiodothyronine (fT3) levels and undetectable TRAb. Conclusions. This is the first case of GD reported after ocrelizumab administration. The timing, onset and course of this case is similar to alemtuzumab-induced GD, usually interpreted as an “immune reconstitution syndrome”; however, ocrelizumab cell count depletion is inferior in severity, cell population affected and duration of depletion. This case highlights the importance of pre-screening and follow-up with thyroid function tests in patients treated with ocrelizumab. As a novel therapeutic antibody, further investigation is required to unravel the causes of thyroid autoimmunity.

Background Recent observations suggest a lack of humoral response after SARS-CoV-2 vaccination in multiple sclerosis (MS) patients treated with fingolimod or ocrelizumab Objectives To assess serological response to SARS-CoV-2 vaccination in MS patients receiving these disease-modifying treatments (DMTs) in a real-life setting. Methods Retrospective clinical data collection from MS patients followed at San Raffaele Hospital MS Centre (Milan, Italy). All patients treated with fingolimod or ocrelizumab who had received a complete anti-COVID-19 vaccination course, with no clinical history suggestive of previous SARS-CoV-2 infection and with an available post-vaccination serological assay obtained at least 14 days after vaccination completion were considered for the study. Results We collected data from 32 MS patients, 16 treated with fingolimod and 16 receiving ocrelizumab. Among the fingolimod group 10 patients (62.5%) had a positive serological response after vaccination and among ocrelizumab-treated patients a positive serological test was found in six cases (37.5%). No relation between serological response and clinical features (i.e., treatment duration, time between vaccination and last treatment dose, and white blood cells count) was identified. Conclusions Our initial real-life experience suggests a variable antibody production in MS patients receiving these DMTs. At present, there are no sufficient data to do not recommend anti-SARS-CoV-2 vaccine in these patients.

ZaniukMarcin, Kozłowska Marta, Gorecka Adrianna, Zawiślak Magdalena,Zimnicki Patryk. Ocrelizumab as a breakthrogh in multiple sclerosis treatment.Journal of Education, Health and Sport. 2021;11(5):50-56. eISSN 2391-8306. DOI http://dx.doi.org/10.12775/JEHS.2021.11.05.005 https://apcz.umk.pl/czasopisma/index.php/JEHS/article/view/JEHS.2021.11.05.005 https://zenodo.org/record/4764315 The journal has had 5 points in Ministry of Science and Higher Education parametric evaluation. § 8. 2) and § 12. 1. 2) 22.02.2019. © The Authors 2021; This article is published with open access at Licensee Open Journal Systems of Nicolaus Copernicus University in Torun, Poland Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author (s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial license Share alike. (http://creativecommons.org/licenses/by-nc-sa/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. The authors declare that there is no conflict of interests regarding the publication of this paper. Received: 21.04.2021. Revised: 26.04.2021. Accepted: 15.05.2021. Ocrelizumab as a breakthrogh in multiple sclerosis treatment Marcin Zaniuk1, Marta Kozłowska1, Adrianna Gorecka1, Magdalena Zawiślak1, PatrykZimnicki1 1Uniwersytet Medyczny w Lublinie Abstract Multiple sclerosis is the most commonly occurring inflammatory disease of the nervous system. It is estimated that over 2 million people suffer from this disease. Currently SM is untreatable, one can only try to stop the progression of the disease or reduce severity of the symptoms. There have been numerous studies on the effectiveness of other monoclonal antibodies in the treatment of multiple sclerosis. A drug that offers a chance for a breakthrough in the treatment of multiple sclerosis is ocrelizumab. It is a monoclonal antibody directed against B lymphocytes expressing the CD20 antigen. Results of the studie confirm the efficacy of ocrelizumab in inhibiting ongoing nerve fiber degeneration and reducing the inflammation associated with it, as well as the near complete depletion of CD20+ B lymphocytes and partial depletion of CD20+ T lymphocytes. They also suggest that ocrelizumab is a safe and effective treatment for multiple sclerosis. Studies conducted on the therapeutic efficacy of ocrelizumab show that its effect on disease progression is superior compared to some current drugs. Ocrelizumab also has a similar safety profile to the currently used interferon β-1a. An important feature of ocrelizumab is its efficacy in the treatment of the primary progressive form of MS, where significant therapeutic efficacy with other drugs has not been seen to date. Keywords: ocrelizumab; multiple sclerosis; ppms; rrms; monoclonal antibody

Introduction. The aim of this study was to report the course and outcome of SARS-CoV-2 infection in multiple sclerosis (MS) patients treated with disease-modifying therapies (DMTs) in Poland. A major concern for neurologists worldwide is the course and outcome of SARS-CoV-2 infection in patients with MS treated with different DMTs. Although initial studies do not suggest an unfavourable course of infection in this group of patients, the data is limited. Materials and methods. This study included 396 MS patients treated with DMTs and confirmed SARS-CoV-2 infection from 28 Polish MS centres. Information concerning patient demographics, comorbidities, clinical course of MS, current DMT use, as well as symptoms of SARS-CoV-2 infection, need for pharmacotherapy, oxygen therapy, and/or hospitalisation, and short-term outcomes was collected up to 30 January 2021. Additional data about COVID-19 cases in the general population in Poland was obtained from official reports of the Polish Ministry of Health. Results. There were 114 males (28.8%) and 282 females (71.2%). The median age was 39 years (IQR 13). The great majority of patients with MS exhibited relapsing-remitting course (372 patients; 93.9%). The median EDSS was 2 (SD 1.38), and the mean disease duration was 8.95 (IQR 8) years. Most of the MS patients were treated with dimethyl fumarate (164; 41.41%). Other DMTs were less frequently used: interferon beta (82; 20.70%), glatiramer acetate (42; 10.60%), natalizumab (35;8.84%), teriflunomide (25; 6.31%), ocrelizumab (20; 5.05%), fingolimod (16; 4.04), cladribine (5; 1.26%), mitoxantrone (3; 0.76%), ozanimod (3; 0.76%), and alemtuzumab (1; 0.25%). The overall hospitalisation rate due to COVID-19 in the cohort was 6.81% (27 patients). Only one patient (0.3%) died due to SARS-CoV-2 infection, and three (0.76%) patients were treated with mechanical ventilation; 106 (26.8%) patients had at least one comorbid condition. There were no significant differences in the severity of SARS-CoV-2 infection regarding patient age, duration of the disease, degree of disability (EDSS), lymphocyte count, or type of DMT used. Conclusions and clinical implications. Most MS patients included in this study had a favourable course of SARS-CoV-2 infection. The hospitalisation rate and the mortality rate were not higher in the MS cohort compared to the general Polish population. Continued multicentre data collection is needed to increase the understanding of SARS-CoV-2 infection impact on the course of MS in patients treated with DMTs.

Scarce data are available about the impact of natalizumab (NTZ) and ocrelizumab (OCR) on male fertility in relapsing-remitting multiple sclerosis (RRMS). In this case–control prospective study, the gonadal steroids and the sperm parameters have been analysed at the time of the RRMS diagnosis and after 12 months from the beginning of the investigated therapies. Sixteen men with RRMS and sixteen matched healthy controls were included. At enrolment and after 12 months on therapy, the gonadal steroids and the sperm parameters of men with RRMS did not differ from the healthy controls. In conclusion, therapy with NTZ and OCR had no impact on fertility status in our cohort of men with RRMS. Further randomized and prospective studies are needed.

Background: The Association of British Neurologists (ABN) 2015 guidelines suggested classifying multiple sclerosis therapies according to their average relapse reduction. We sought to classify newer therapies (cladribine, ocrelizumab, ofatumumab, ozanimod) based on these guidelines. Materials & methods: Therapies were classified by using direct comparative trial results as per ABN guidelines and generating classification probabilities for each therapy based on comparisons versus placebo in a network meta-analysis for annualized relapse rate. Results: For both approaches, cladribine and ofatumumab were classified as high efficacy. Ocrelizumab and ozanimod (1.0 mg) were classified as moderate or high efficacy depending on the approach used. Conclusion: Cladribine and ofatumumab have an efficacy comparable with therapies classified in the ABN guidelines as high efficacy.

Multiple sclerosis (MS), which is a chronic inflammatory disease of the central nervous system, still represents one of the most common causes of persisting disability with an early disease onset. Growing evidence suggests B cells to play a crucial role in its pathogenesis and progression. Over the last decades, monoclonal antibodies (mabs) against the surface protein CD20 have been intensively studied as a B cell targeting therapy in relapsing MS (RMS) as well as primary progressive MS (PPMS). Pivotal studies on anti-CD20 therapy in RMS showed remarkable clinical and radiological effects, especially on acute inflammation and relapse biology. These results paved the way for further research on the implication of B cells in the pathogenesis of MS. Besides controlling relapse development in RMS, ocrelizumab (OCR) also showed clinical benefits in patients with PPMS and became the first approved drug for this disease course. In this review, we provide an overview of the current anti-CD20 mabs used or tested for the treatment of MS—namely rituximab (RTX), OCR, ofatumumab (OFA), and ublituximab (UB). Besides their effectiveness, we also discuss possible limitations and safety concerns especially in regard to long-term treatment, both for this class of drugs overall as well as for each anti-CD20 mab individually. Additionally, we elucidate to what extent anti-CD20 therapy may alter the function of other immune cells, both directly or indirectly. Finally, we cover the current knowledge on repopulation of CD20+ cells after cessation of anti-CD20 treatment and discuss future aspirations towards alternative, further developed B cell silencing therapies. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01048-z.

PURPOSE OF REVIEW: This review focuses on new evidence supporting the global immunization strategy for multiple sclerosis (MS) patients receiving disease-modifying drugs (DMDs), including the recently available vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. RECENT FINDINGS: New data strengthen the evidence against a causal link between MS and vaccination. Recent consensus statements agree on the need to start vaccination early. Timings for vaccine administration should be adjusted to ensure safety and optimize vaccine responses, given the potential interference of DMDs. Patients treated with Ocrelizumab (and potentially other B-cell depleting therapies) are at risk of diminished immunogenicity to vaccines. This has relevant implications for the upcoming vaccination against SARS-CoV-2. SUMMARY: An early assessment and immunization of MS patients allows optimizing vaccine responses and avoiding potential interference with treatment plans. Vaccinations are safe and effective but some specific considerations should be followed when vaccinating before, during, and after receiving immunotherapy. A time-window for vaccination taking into account the kinetics of B cell repopulation could potentially improve vaccine responses. Further understanding of SARS-CoV-2 vaccine response dynamics in MS patients under specific therapies will be key for defining the best vaccination strategy.

The CHORDS trial evaluated ocrelizumab (OCR) in patients with relapsing‐remitting multiple sclerosis who had a suboptimal response to previous disease‐modifying treatment. The objective of the present study was to assess the safety of shorter OCR infusions in a substudy of CHORDS. After completing four doses of OCR per initial US prescribing recommendations in the main study, participants in the substudy (N = 129) received a fifth dose over a 2‐h duration (vs. 3.5 h). Infusion‐related reactions occurred in 12.4% of patients. None were severe, life‐threatening or led to treatment discontinuation. Shorter infusion time did not change the safety profile of OCR. Clinicaltrials.gov (NCT0237856).

Objectives This study aims to evaluate the effects of ocrelizumab (OCZ) on familial Mediterranean fever (FMF) attacks in multiple sclerosis (MS) patients with FMF (MS+FMF patients). Patients and methods This retrospective observational study included 11 patients (2 males, 9 females; mean age 46.6±9.2; range, 22 to 55 years) with MS+FMF hospitalized between January 2016 and July 2019. Demographic, clinical, and laboratory parameters and patient reported outcomes were analyzed in patients treated with OCZ for 18 months. Results Combining OCZ with colchicine in MS+FMF patients significantly reduced the frequency of FMF attacks (p=0.003) and the frequency of joint attacks (p=0.002). Consistent with the clinical improvement, the maximum serum C-reactive protein levels were significantly decreased after combination therapy compared to before combination therapy (p=0.003). MS+FMF patients reported that FMF disease activity improved after OCZ therapy (Visual Analog Scale [VAS] 74±9.6 vs. VAS 46.5±8.1 mm, p=0.003). Conclusion Ocrelizumab therapy led to a prominent decrease in the frequency of FMF attacks, alleviated functional impairment, and improved quality of life in MS+FMF patients.

In the last decades, evidence suggesting the direct or indirect involvement of B cells on multiple sclerosis (MS) pathogenesis has accumulated. The increased amount of data on the efficacy and safety of B-cell-depleting therapies from several studies has suggested the addition of these drugs as treatment options to the current armamentarium of disease modifying therapies (DMTs) for MS. Particularly, rituximab (RTX), a chimeric monoclonal antibody directed at CD20 positive B lymphocytes resulting in cell-mediated apoptosis, has been demonstrated to reduce inflammatory activity, incidence of relapses and new brain lesions on magnetic resonance imaging (MRI) in patients with relapsing–remitting MS (RRMS). Additional evidence also demonstrated that patients with progressive MS (PMS) may benefit from RTX, which also showed to be well tolerated, with acceptable safety risks and favorable cost-effectiveness profile. Despite these encouraging results, RTX is currently approved for non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, several forms of vasculitis and rheumatoid arthritis, while it can only be administered off-label for MS treatment. Between Northern European countries exist different rules for using not licensed drug for treating MS. The Sweden MS register reports a high rate (53.5%) of off-label RTX prescriptions in relation to other annually started DMTs to treat MS patients, while Danish and Norwegian neurologists have to use other anti-CD20 drugs, as ocrelizumab, in most of the cases. In this paper, we review the pharmacokinetics, pharmacodynamics, clinical efficacy, safety profile and cost effectiveness aspects of RTX for the treatment of MS. Particularly, with the approval of new anti-CD20 DMTs, the recent worldwide COVID-19 emergency and the possible increased risk of infection with this class of drugs, this review sheds light on the use of RTX as an alternative treatment option for MS management, while commenting the gaps of knowledge regarding this drug.

Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune disease of unknown etiology, whose hallmark is the production of autoantibodies. B cells are promising targets for novel SLE therapies. In 2011, belimumab (Benlysta®), a fully humanized monoclonal antibody inhibiting B-cell activation and proliferation, was the first medication in 50 years to be approved by the US Food and Drug Administration to treat adult SLE. This review discusses the current experience with B-cell-targeted therapies, including those targeting B-cell-surface antigens (rituximab, ocrelizumab, ofatumumab, obinutuzumab, obexelimab, epratuzumab, daratumumab), B-cell survival factors (belimumab, tabalumab, atacicept, blisibimod), or B-cell intracellular functions (ibrutinib, fenebrutinib, proteasome inhibitors), for the management of SLE. It focuses on ongoing clinical trials and real-world post-marketing use, where available, including their safety profiles, and concludes with our recommendations for B-cell-centric approaches to the management of SLE.

AimsOcrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells and is indicated for treatment of patients with relapsing forms of multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The pharmacokinetics and pharmacodynamics of ocrelizumab in patients with RMS or PPMS were assessed.MethodsA population pharmacokinetic model was developed based on data from the Phase II study and the Phase III studies OPERA I and OPERA II in patients with RMS. Data from the ORATORIO Phase III study in patients with PPMS became available after model finalization and was used for external model evaluation.ResultsThe ocrelizumab serum concentration vs time course was accurately described by a 2-compartment model with time-dependent clearance. Body weight was found to be the main covariate. The area under the concentration-time curve over the dosing interval was estimated to be 26% higher for patients with RMS weighing 90kg when compared with the 60-90kg group. The terminal half-life of ocrelizumab was estimated as 26days. The extent of B-cell depletion in blood, as the pharmacodynamic marker, was greater with increasing ocrelizumab exposure.ConclusionThe pharmacokinetics of ocrelizumab was described with pharmacokinetic parameters typical for an immunoglobulin G1 monoclonal antibody, with body weight as the main covariate. The pharmacokinetics and B-cell depletion in blood were comparable across the RMS and PPMS trials, and the extent of blood B-cell depletion was greater with higher exposure.

Objective Pivotal trial have shown that patients with multiple sclerosis (MS) receiving ocrelizumab had better outcomes. However, data on ocrelizumab in clinical practice are limited. The aim of this study was to evaluate the preliminary safety profile and effectiveness of ocrelizumab treatment for multiple sclerosis (MS) in a real‐world clinical setting. Methods We conducted a retrospective study including consecutive patients from nine public hospitals in south‐eastern Spain who received ocrelizumab after it was approved. Results A total of 228 MS patients were included (144 with relapsing–remitting MS [RRMS], 25 secondary progressive MS [SPMS], and 59 primary progressive MS [PPMS]). Median follow‐up period was 12 months (range, 1‐32). No evidence of disease activity (NEDA) status at year 1 was achieved in 91.2% of the relapsing MS (RMS) population, while disability progression was detected in 37.5% of the PPMS patients (median follow‐up period, 19 months). The most common adverse events reported were infusion‐related reactions and infections, with the most common infections being urinary tract infections followed by upper respiratory infections and COVID‐19. Interpretation The preliminary results in our real‐world setting show that ocrelizumab presented excellent results in suppressing disease activity with a favorable and consistent safety profile.

Aim: To compare the efficacy of ofatumumab to other disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS). Materials & methods: A network meta-analysis was conducted to determine the relative effect of ofatumumab on annualized relapse rate and confirmed disability progression at 3 months and 6 months. Results: For each outcome, ofatumumab was as effective as other highly efficacious monoclonal antibody DMTs (i.e., alemtuzumab, natalizumab and ocrelizumab). Conclusion: Ofatumumab offers beneficial outcomes for RMS by reducing relapse and disability progression risk.

Objective This study evaluated work and activity impairment in patients with multiple sclerosis (MS) treated with ocrelizumab (OCR) versus other disease-modifying therapies (DMTs). Methods Data were obtained from the Adelphi Real World Disease Specific Programme for Multiple Sclerosis. Patients with relapsing–remitting or secondary progressive MS who completed surveys in 2018 and 2019 and received ≥ 6 months of an eligible therapy, including OCR, injectable therapy, and oral therapy, were included. Outcomes were assessed using the patient-reported Work Productivity and Activity Impairment questionnaire. Doubly robust estimation, which combined propensity score weighting and regression modeling, was used to compare treatments, controlling for baseline clinical and demographic characteristics. Results This study included 630 patients (OCR, n = 90; injectable DMT, n = 224; oral DMT, n = 316) with a mean (standard deviation) age of 42 (11) years. A greater proportion of OCR-treated patients had an Expanded Disability Status Scale score of ≥ 3 at treatment initiation compared with those receiving oral and injectable DMTs (51 vs. 15% and 15%, respectively), and a smaller proportion of OCR-treated patients received treatment for ≥ 1 year (43 vs. 90% and 92%, respectively). OCR-treated patients had higher odds of employment [odds ratio (95% confidence interval) 3.4 (1.5–7.7) vs. oral DMT, 5.6 (2.6–12.0) vs. injectable DMT], lower overall work productivity loss [difference (95% confidence interval) − 10.0% (− 6.1 to − 15.0%) vs. oral DMT, − 13.0% (− 8.5 to − 17.0%) vs. injectable DMT] and lower activity impairment [difference (95% confidence interval) − 11% (− 7.1 to − 16.0%) vs. oral DMT, − 9.7% (− 5.0 to − 14.0%) vs. injectable DMT]. Conclusion This real-world evidence suggests that patients with MS treated with OCR experience lower work and activity impairment than patients treated with other DMTs. Electronic supplementary material The online version of this article (10.1007/s40120-020-00224-1) contains supplementary material, which is available to authorized users., Plain Language Summary Multiple sclerosis (MS) is the most common progressive neurological disease in young adults. It typically starts between the ages of 20 and 40 years—arguably some of the most productive years of an individual’s life—and it has a large impact on many aspects of everyday life for the rest of a person’s life. The reduction in the ability to do routine activities, including working, results in a large economic burden. Disease-modifying treatments (DMTs) available for MS, particularly high-efficacy DMTs, have been shown to improve work productivity. This study looked at work and activity impairment using the Work Productivity and Activity Impairment Questionnaire in patients with MS who were treated with ocrelizumab (OCR) or other DMTs for ≥ 6 months. A total of 630 patients with relapsing–remitting MS (RRMS) or secondary progressive MS (SPMS) from the Adelphi Real World Disease Specific Programme for Multiple Sclerosis were included in the study, including 90, 316 and 224 patients who completed ≥ 6 months of treatment with OCR, oral or injectable therapy. Compared with patients receiving oral or injectable DMTs, those receiving OCR had higher odds of employment [odds ratio (OR) vs. oral DMT 3.4; OR vs. injectable DMT 5.6], lower overall work productivity impairment (difference vs. oral DMT − 10%; difference vs. injectable DMT − 13%) and lower activity impairment (difference vs. oral DMT − 11%; difference vs. injectable DMT − 9.7%). These findings in patients with RRMS or SPMS being treated in the real world suggest that OCR may reduce the impact of MS disease on work productivity more than other DMTs. Electronic supplementary material The online version of this article (10.1007/s40120-020-00224-1) contains supplementary material, which is available to authorized users.

There are a broad range of disease-modifying therapies (DMTs) available in relapsing-remitting multiple sclerosis (RRMS), but limited biomarkers exist to personalise DMT choice. All DMTs, including monoclonal antibodies such as rituximab and ocrelizumab, are effective in preventing relapses and preserving neurological function in MS. However, each agent harbours its own risk of therapeutic failure or adverse events. Pharmacogenetics, the study of the effects of genetic variation on therapeutic response or adverse events, could improve the precision of DMT selection. Pharmacogenetic studies of rituximab in MS patients are lacking, but pharmacogenetic markers in other rituximab-treated autoimmune conditions have been identified. This review will outline the wider implications of pharmacogenetics and the mechanisms of anti-CD20 agents in MS. We explore the non-MS rituximab literature to characterise pharmacogenetic variants that could be of prognostic relevance in those receiving rituximab, ocrelizumab or other monoclonal antibodies for MS. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-020-00950-2) contains supplementary material, which is available to authorized users.

Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. The disease is induced by antibodies, which are directed against the podocyte protein phospholipase A2 receptor 1 (PLA2R1-ab) in 80% of cases. B cell depleting treatments, most notably rituximab, a chimeric CD20-antibody, are often effective for treatment of MN. However, in 35–40% of patients rituximab fails to induce remission of disease and relapses after rituximab-induced remission are frequent. Therefore, alternative treatment options are necessary. Over the past years optimized antibodies targeting CD20 were designed to overcome side effects or sensitization to the murine fractions of rituximab and potentially improve B cell depletion. Ocrelizumab is a humanized B cell depleting antibody, approved for treatment of multiple sclerosis (MS). Here, we report the case of a patient who was diagnosed with MS and, 8 years later, developed PLA2R1-associated MN. Treatment for MS was switched to the CD20-antibody ocrelizumab, which was expected to deplete B cells and potentially induce remission of MN. After treatment with ocrelizumab PLA2R1-ab disappeared from the circulation and the patient developed remission of proteinuria. Ocrelizumab might be an efficacious treatment alternative for patients with MN who fail to achieve remission or are immunologically sensitized to rituximab. Electronic supplementary material The online version of this article (10.1007/s40620-020-00874-2) contains supplementary material, which is available to authorized users.

Primary progressive multiple sclerosis (PPMS) is an infrequent clinical form of multiple sclerosis (MS). Scarce information is available about PPMS in Latin America. The aim of this work is to describe the clinical and demographic characteristics of PPMS patients in Argentina. RelevarEM is a longitudinal, strictly observational registry in Argentina. Clinical and epidemiological data from PPMS patients were described. There were 144 cases of PPMS. They represented 7% of MS patients. The mean age was 44.1 years. The female:male ratio was 1.08. The mean Expanded Disability Status Scale (EDSS) score was 5.5 and the mean disease evolution time was 10.6 years. Oligoclonal bands were found in 72.9%. At the time of diagnosis, magnetic resonance imaging showed spinal cord lesions in 82.6% and contrast-enhancing brain lesions in 18.1% of patients. Almost one third of patients were treated with a disease-modifying drug, and ocrelizumab was the most frequently used (55.8%). PPMS is an infrequent subtype of MS and its recognition is of the highest importance as it has its own evolution, treatment, and prognosis. The importance of our research resides in providing local data and contributing to a better understanding of PPMS and its treatment in Latin America.

Introduction Studies investigating rates and risk factors for serious safety events (SSEs) during rituximab treatment of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and related disorders are limited. Methods Rituximab‐treated patients with MS, NMOSD, or related disorders at the Rocky Mountain and New York University MS Care Centers were included. The follow‐up period was defined as the time from the initial dose of rituximab up to 12 months of last dose of rituximab or ocrelizumab (in patients who switched). Clinician‐reported and laboratory data were retrospectively collected from electronic medical records. Results One‐thousand patients were included comprising 907 MS, 77 NMOSD, and 16 related disorders. Patients had a mean follow‐up of 31.1 months and a mean cumulative rituximab dose of 4012 mg. Of the 169 patients who switched to ocrelizumab, the mean ocrelizumab dose was 1141 mg. Crude incidence rate per 1000 person‐years (PY) for lymphopenia was 19.2, neutropenia 5.6, and hypogammaglobulinemia 17.8. Infections resulting in either hospitalization, IV antibiotics, or using antibiotics ≥14 days occurred at a rate of 38.6/1000 PY. Risk factors for infection were duration of therapy, male gender, increased disability, prior exposure to immunosuppression/chemotherapy, lymphopenia, and hypogammaglobulinemia. Particularly, wheelchair‐bound patients had 8.56‐fold increased odds of infections. Crude incidence rates of malignant cancer were 3.5, new autoimmune disease 2.3, thromboembolic event 3.1, and mortality of 5.4 per 1000 PY. Interpretation Rates of SSEs in patients with MS, NMOSD, and related disorders were low. Through properly assessing risk:benefit of B‐cell depleting therapy in neuroinflammatory disorders and continual monitoring, clinicians may decrease the risk of serious infections.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating and neurodegenerative disease with a multifactorial etiology of development. MS in most cases has a wave-like course (periods of exacerbations and remissions), over time, the disease becomes progressive, which worsens the quality of life of patients. The drugs disease-modifying therapies (DMT) has been actively used in clinical practice for more than 30 years to prevent exacerbations and progression of MS. In patients with MS, in which the disease occurs with frequent exacerbations and signs of radiological activity of the demyelinating process, according to magnetic resonance imaging (MRI) of the brain and spinal cord, it is recommended to use monoclonal antibody preparations. The only drug registered for the treatment of primary progressive MS is ocrelizumab. In addition, ocrelizumab is indicated for patients with remitting and secondary progressive MS. Ocrelizumab is a humanized monoclonal antibody that selectively depletes a population of CD20+ B cells. The article presents data from clinical studies of OPERA I and OPERA II and describes a clinical case from the practice of a neurologist. Depletion of the B cell population is achieved by several mechanisms, including antibody-dependent cell-mediated phagocytosis, antibody-dependent T cell-mediated cytotoxicity, complement-dependent cytotoxicity, and apoptosis induction. The issues of efficacy and safety of ocrelizumab therapy in patients with MS are considered.

ZusammenfassungOcrelizumab ist ein monoklonaler Antikörper, der sich gegen das Differenzierungsantigen CD20 richtet und zu einer effektiven längerfristigen Depletion von Lymphozyten, insbesondere von B‑Zellen, führt. Unlängst publizierte Phase-3-Studien belegen, dass Ocrelizumab sowohl bei der Behandlung der schubförmigen als auch der primär progressiven Multiplen Sklerose (MS) wirksam ist. Darauf basierend wurde Ocrelizumab als erstes Medikament zur Behandlung der primär chronisch-progredienten MS zugelassen. Um diesen Durchbruch besser in den Kontext des heutigen MS-Therapiekanons einordnen zu können, lohnt sowohl ein Blick zurück auf die Entwicklung der antikörpervermittelten CD20-Depletion als auch auf die der Zulassung zugrunde liegenden Studien sowie deren Extensionsphasen. Diese Übersichtsarbeit diskutiert die verfügbaren Daten zur Wirksamkeit und Sicherheit der langfristigen B‑Zell-Depletion bei MS-Patienten und erörtert den aktuellen Kenntnisstand zur Rolle von B‑Lymphozyten in der Immunpathogenese der MS.

A 41-year-old female diagnosed with multiple sclerosis began ocrelizumab treatment. She received her first treatment course without significant complication. After receiving the first maintenance dose 6 months later, she developed weakness, myalgias, gastrointestinal symptoms, headache, and intermittent fever persisting for 4 weeks. A working diagnosis of serum sickness was determined after excluding other probable entities. She received 3 days of 1 g methylprednisolone intravenously and five plasma exchanges, experiencing gradual improvement. Serum sickness has occurred with monoclonal antibodies including rituximab. This case of possible ocrelizumab-associated serum sickness suggests that clinicians should remain vigilant about this possibility with this medication.

Increased inflammation in the cerebral meninges is associated with extensive subpial cortical grey matter pathology in the forebrain and a more severe disease course in a substantial proportion of secondary progressive multiple sclerosis (SPMS) cases. It is not known whether this relationship extends to spinal cord pathology. We assessed the contribution of meningeal and parenchymal immune infiltrates to spinal cord pathology in SPMS cases characterized in the presence (F+) or absence (F−) of lymphoid‐like structures in the forebrain meninges. Transverse cryosections of cervical, thoracic and lumbar cord of 22 SPMS and five control cases were analyzed for CD20+ B cells, CD4+ and CD8+ T cells, microglia/macrophages (IBA‐1+), demyelination (myelin oligodendrocyte glycoprotein+) and axon density (neurofilament‐H+). Lymphoid‐like structures containing follicular dendritic cell networks and dividing B cells were seen in the spinal meninges of 3 out of 11 F+ SPMS cases. CD4+ and CD20+ cell counts were increased in F+ SPMS compared to F− SPMS and controls, whilst axon loss was greatest in motor and sensory tracts of the F+ SPMS cases (P

The majority of disease-modifying drugs (DMDs) available for the management of active relapsing–remitting multiple sclerosis (RMS) depend on continuous drug intake for maintained efficacy, with escalation to a more active drug when an unacceptable level of disease activity returns. Among continuously applied regimens, interferons and glatiramer acetate act as immunomodulators, while dimethyl fumarate, fingolimod, ocrelizumab, natalizumab and teriflunomide are associated with continuous immunosuppression. By contrast, immune reconstitution therapy (IRT) provides efficacy that outlasts a short course of treatment. Autologous hemopoietic stem cell transplantation is perhaps the classic example of IRT, but this invasive and intensive therapy has challenging side-effects. A short treatment course of a pharmacologic agent hypothesized to act as an IRT, such as Cladribine Tablets 3.5 mg/kg or alemtuzumab, can provide long-term suppression of MS disease activity, without need for continuous treatment (the anti-CD20 mechanism of ocrelizumab has the potential to act as an IRT, but is administered continuously, at 6-monthly intervals). Cladribine Tablets 3.5 mg/kg shows some selectivity in targeting adaptive immunity with a lesser effect on innate immunity. The introduction of IRT-like disease-modifying drugs (DMDs) challenges the traditional maintenance/escalation mode of treatment and raises new questions about how disease activity is measured. In this review, we consider a modern classification of DMDs for MS and its implications for the care of patients in the IRT era.

Introduction. The routine use of highly effective drugs that alter the course of multiple sclerosis requires careful patient selection in order to minimize the risks of possible adverse events. At present, drugs modifying the course of multiple sclerosis have been registered with different mechanisms of action. This makes it possible to implement individual selection of therapy taking into account the multifaceted pathogenesis of the disease. However, the presence of a burdened somatic anamnesis in the patient may significantly limit the choice of drugs by the attending physician. Aim: to gain experience in using ocrelizumab to treat patients with multiple sclerosis. Materials and methods. From 2018 ocrelizumab therapy was started in 52 MS patients: 32 patients with recurrent multiple sclerosis (MS) (23 with remitting multiple sclerosis (RMS) and 9 with secondary progressive MS with exacerbations) and 20 patients with primary progressive multiple sclerosis (PPMS). The drug was administered intravenously in drops with infusion in a dose of 600 mg every 6 months in a daytime regimen with an approved protocol of premedication and symptomatic therapy to prevent possible risks of adverse events. The initial dose was divided into 2 infusions of 300 mg at intervals of 2 weeks [5]. Before each infusion, detailed clinical blood analysis, biochemical blood tests, serological tests (HIV, hepatitis B and C, syphilis), and screening for tuberculosis (once a year) were necessarily repeated.The results. The achieved results clearly demonstrate high efficacy of ocrelizumab in the form of reduction of exacerbations frequency, disease activity according to MRI data and slower progression, which is compared with the data from previous OPERA I, OPERA II and ORATORIO clinical trials. After analysis of the data of dynamics of disability index according to EDSS scale there was observed stabilization in PPMS patients and a slight decrease in RMS patients. No exacerbations were registered in patients with RMS during the period of treatment, as well as no objective data on progression in patients with PPMS were noted.There is also good tolerance of therapy. However, the question remains as to how long the therapy should take into account the safety spectrum.

Background Multiple sclerosis (MS) is a chronic disease that requires lifelong treatment. A highly effective drug not only for relapsing but also for progressive forms of MS with a favorable safety profile is needed to further improve overall patient outcomes. Ocrelizumab, a recombinant humanized monoclonal antibody that selectively targets CD20-expressing B-cells, is the first drug indicated for the treatment of adult patients with relapsing forms of MS (RMS) and primary progressive MS (PPMS). Its safety and effectiveness profile has yet to be studied in a large, real-world setting. CONFIDENCE aims to further characterize the safety profile of ocrelizumab in routine clinical practice. In addition, real-world effectiveness data will be collected to complement the efficacy data documented in the pivotal clinical trials. Methods CONFIDENCE is a non-interventional, prospective, multicenter, long-term study collecting primary data from 3000 RMS and PPMS patients newly treated with ocrelizumab and 1500 patients newly treated with other selected MS disease-modifying therapies (DMTs). Treatment must be in accordance with the local label and follow routine practice. Data will be collected at approximately 250 neurological centers and practices across Germany. The recruitment period of 30 months started in April 2018. The observation period per patient is planned 7.5 to 10 years, depending on the date of inclusion, regardless of whether patients discontinue treatment. Visits follow routine practice and will be documented approximately every 6 months. The primary endpoint is the incidence and type of uncommon adverse events and death. Statistical analyses will be mainly descriptive and exploratory. Discussion CONFIDENCE is a large, non-interventional, post-authorization safety study that assesses long-term safety and effectiveness of ocrelizumab and other DMTs in a real-world setting. Data collected in CONFIDENCE will also be integrated into studies that have been developed to fulfil international regulatory requirements.

Dengue fever (DF) is an endemic infectious disease in tropical and subtropical regions. Ocrelizumab is a humanized monoclonal antibody that targets the CD20 antigen on B cells, which is approved for the treatment of both relapsing-remitting multiple sclerosis (RRMS) and primary-progressive multiple sclerosis (PPMS). We describe the favorable clinical outcome of DF in an RRMS patient treated with Ocrelizumab, who neither presented hemorrhagic or systemic shock symptoms nor reported neurological worsening.

DEAR SIRS, Whereas, B-cell depletion has proven very efcient at controlling disease activity in several auto-immune diseases, including MS, long-term or rare side efects of the treatment remain unknown. Adverse events related to B-cell depletion are notably an increase in the risk of shingles, herpesvirus infection or hypogammaglobulinemia […]

Fil: Marrodan, Mariano. Fleni. Departamento de Neurologia. Servicio de Neuroinmunologia y Enfermedades Desmielinizantes; Argentina.

Background and purpose: Real-world evidence regarding the effectiveness and safety of ocrelizumab for the treatment of multiple sclerosis (MS) is limited. The aim was to evaluate the effectiveness and safety of ocrelizumab treatment for MS in a real-world setting. Methods: A nationwide population-based cohort study was conducted where clinical and magnetic resonance imaging data of MS patients enrolled prospectively in the Danish Multiple Sclerosis Registry who initiated ocrelizumab treatment between January 2018 and November 2020 were analyzed. Results: A total of 1104 patients (85.7% relapsing–remitting MS [RRMS], 8.8% secondary progressive MS [SPMS], 5.5% primary progressive MS [PPMS]) were included, with a median follow-up period of 1.3 years. At baseline, the mean age was 41.4 years in the RRMS group, 44.5 years in the PPMS group and 50.3 years in the SPMS group. Median Expanded Disability Status Scale score was 2.5, 3.5 and 5.5, respectively. Most RRMS and SPMS patients had received previous disease-modifying therapies (87.5% and 91.8%, respectively), whereas PPMS patients were mostly treatment naïve (78.7%). After ocrelizumab initiation, 9.3% of the patients experienced a relapse and 8.7% a 24 weeks confirmed disability worsening. Conversely, 16.7% showed a 24 weeks confirmed disability improvement. After ~1 year of treatment, most patients (94.5%) were free of magnetic resonance imaging activity. Ocrelizumab was generally well tolerated, as side effects were only reported for 10% of patients, mostly consisting of infusion-related reactions and infections. Conclusions: It is shown that most MS patients treated with ocrelizumab are clinically stabilized and with an adverse event profile consistent with the experience from the pivotal clinical trials.

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease affecting the central nervous system (CNS), often characterized by the accumulation of irreversible clinical disability over time. During last years, there has been a dramatic evolution in several key concepts of immune pathophysiology of MS and in the treatment of this disease. The demonstration of the strong efficacy and good safety profile of selective B-cell-depleting therapies (such as anti-CD20 monoclonal antibodies) has significantly expanded the therapeutic scenario for both relapsing and progressive MS patients with the identification of a new therapeutic target. The key role of B cells in triggering MS disease has been also pointed out, determining a shift from the traditional view of MS activity as largely being ‘T-cell mediated’ to the notion that MS-related pathological processes involve bi-directional interactions between several immune cell types, including Bcells, both in the periphery and in the CNS. This review provides an updated overview of the involvement of Bcells in the immune pathophysiology and pathology of MS. We summarize the rationale regarding the use of anti-CD20 therapies and the results of the main randomized controlled trials and observational studies investigating the efficacy and safety profile of rituximab, ocrelizumab, ofatumumab and ublituximab. Suggestions regarding vaccinations and management of MS patients during COVID-19 pandemic with anti-CD20 therapies are also discussed. Finally, therapies under investigation and future perspectives of anti-CD20 therapies are taken into consideration.

OBJECTIVE: The objective of this study was to measure humoral responses after SARS-CoV-2 vaccination in MS patients treated with ocrelizumab (OCR) compared to MS patients without disease modifying therapies (DMTs) in relation to timing of vaccination and B-cell count.METHODS: OCR treated patients were divided into an early and a late group (cut-off time 12 weeks between infusion and first vaccination). Patients were vaccinated with mRNA-1273 (Moderna). B-cells were measured at baseline (time of first vaccination) and SARS-CoV-2 antibodies were measured at baseline, day 28, 42, 52 and 70.RESULTS: 87 patients were included (62 OCR patients, 29 patients without DMTs). At day 70, seroconversion occurred in 39.3% of OCR patients compared to 100% of MS patients without DMTs. In OCR patients, seroconversion varied between 26% (early group) to 50% (late group) and between 27% (low B-cells) to 56% (at least 1 detectable B-cell/µL).CONCLUSIONS: Low B-cell counts prior to vaccination and shorter time between OCR infusion and vaccination may negatively influence humoral response but does not preclude seroconversion. We advise OCR treated patients to get their first vaccination as soon as possible. In case of an additional booster vaccination, timing of vaccination based on B-cell count and time after last infusion may be considered.

Background: Patients with multiple sclerosis (MS) who are treated with monoclonal antibodies frequently report an increase of MS-related symptoms prior to the next dose known as the wearing-off phenomenon. The objective of this study was to assess the prevalence and predicting factors of the wearing-off phenomenon in patients with MS using ocrelizumab. Methods: This was a prospective cohort study in patients with MS receiving ocrelizumab ≥1 year. Most participants received B-cell guided personalized extended interval dosing to limit ocrelizumab exposure and hospital visits during the COVID-19 pandemic (cut-off ≥ 10 cells/µL). Participants completed questionnaires during ocrelizumab infusion and 2 weeks thereafter. Demographics, clinical and radiological characteristics, CD19 B-cell counts, and serum neurofilament light (sNfL) levels were collected. Data were analyzed using logistic regression analyses. Results: Seventy-one (61%) out of 117 participants reported the wearing-off phenomenon during ocrelizumab treatment. The most frequently reported symptoms were fatigue, cognitive disability and sensory symptoms. Wearing-off symptoms started < 1 week (11%), 1–4 weeks (49%) or more than 4 weeks (37%) before ocrelizumab infusion. Fifty participants (43%) reported a current wearing-off phenomenon at the first questionnaire. Higher body mass index (threshold BMI ≥ 25) increased the odds of reporting a current wearing-off phenomenon (OR 2.70, 95% CI 1.26 to 5.80, p = .011). Infusion interval, EDSS score, MRI disease activity, clinical relapses, CD19 B-cell counts, and sNfL levels were no predictors. Disappearance of the wearing-off phenomenon occurred in the first week after ocrelizumab infusion in most participants. Participants with a current wearing-off phenomenon significantly improved in self-reported physical and psychological functioning after ocrelizumab infusion. Reporting the wearing-off phenomenon did not influence treatment satisfaction. Forty of 109 participants (37%) reported post-infusion symptoms, such as fatigue, flu-like symptoms or walking difficulties. These post-infusion symptoms started directly or in the first week after ocrelizumab infusion and disappeared within 2 weeks. Conclusions: The wearing-off phenomenon is reported by more than half of patients with MS using ocrelizumab. Only BMI was identified as a predicting factor. The wearing-off phenomenon was not elicited by extending infusion intervals or higher B-cell counts. The wearing-off phenomenon of ocrelizumab therefore does not seem to reflect suboptimal control of MS disease activity.

European journal of neurology 29(3), 790-801 (2022). doi:10.1111/ene.15171, Published by Wiley-Blackwell, Oxford [u.a.]