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Monoclonal Antibodies in the Treatment of Relapsing Multiple Sclerosis: an Overview with Emphasis on Pregnancy, Vaccination, and Risk Management.

ABSTRACT: Monoclonal antibodies have become a mainstay in the treatment of patients with relapsing multiple sclerosis (RMS) and provide some benefit to patients with primary progressive MS. They are highly precise by specifically targeting molecules displayed on cells involved in distinct immune mechanisms of MS pathophysiology. They not only differ in the target antigen they recognize but also by the mode of action that generates their therapeutic effect. Natalizumab, an [Formula: see text]4[Formula: see text]1 integrin antagonist, works via binding to cell surface receptors, blocking the interaction with their ligands and, in that way, preventing the migration of leukocytes across the blood-brain barrier. On the other hand, the anti-CD52 monoclonal antibody alemtuzumab and the anti-CD20 monoclonal antibodies rituximab, ocrelizumab, ofatumumab, and ublituximab work via eliminating selected pathogenic cell populations. However, potential adverse effects may be serious and can necessitate treatment discontinuation. Most importantly, those are the risk for (opportunistic) infections, but also secondary autoimmune diseases or malignancies. Monoclonal antibodies also carry the risk of infusion/injection-related reactions, primarily in early phases of treatment. By careful patient selection and monitoring during therapy, the occurrence of these potentially serious adverse effects can be minimized. Monoclonal antibodies are characterized by a relatively long pharmacologic half-life and pharmacodynamic effects, which provides advantages such as permitting infrequent dosing, but also creates disadvantages regarding vaccination and family planning. This review presents an overview of currently available monoclonal antibodies for the treatment of RMS, including their mechanism of action, efficacy and safety profile. Furthermore, we provide practical recommendations for risk management, vaccination, and family planning.

SUBMITTER: Krajnc N

PROVIDER: S-EPMC8978776 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Multiple sclerosis (MS) shares an immune-mediated origin with psoriasis. Long-term safety and efficacy data generated in Europe from usage of fumaric acid formulations in the latter disease constituted grounds to investigate their effects in MS patients. Dimethyl fumarate (DMF) was found to be the active principle in those formulations and in vitro studies have demonstrated that DMF has immune-modulatory properties exerted through abilities to divert cytokine production toward a Th2 profile, both on lymphocytes and microglial cells. More importantly, DMF was discovered to impact the anti-oxidative stress cell machinery promoting the transcription of genes downstream to the activation of the nuclear factor (erythroid derived 2)-like2 (NRF2). DMF exposure increases the cytosol concentrations of NRF2, which besides immune regulatory effects, has the potential for cytoprotection on glial cells, oligodendrocytes and neurons. Extensive and rigorous clinical trials have assessed the efficacy and safety of DMF at the dose of 240 mg twice and three times a day in relapsing-remitting MS patients during one phase IIb and two phase III trials. Robust, positive results were obtained across a number of clinical and paraclinical parameters. In one study (DEFINE), the relative reductions of the adjusted annualized relapse rate of the low and high dose regimens in comparison with placebo were 53% and 48%, respectively (p?<?0.001 for both comparisons). In the other trial (CONFIRM), DMF decreased the annualized relapse rate in comparison with placebo by 44% in the lower and by 51% in higher dosage group (also p < 0.001). The number and size of lesions as detected by magnetic resonance imaging were also significantly decreased in comparison with the patients receiving DMF at every dosage. Multiple post hoc and subgroup analyses corroborated the clinical data, rendering DMF an appealing medication whose potential for impacting the degenerative aspects of MS remains to be explored.

Project description:IntroductionThe SARS-CoV-2 pandemic necessitated better understanding of the impact of disease-modifying therapies on COVID-19 outcomes and vaccination. We report characteristics of COVID-19 cases and vaccination status in ofatumumab-treated relapsing multiple sclerosis (RMS) patients.MethodsCOVID-19 data analyzed were from the ongoing, open-label, long-term extension phase 3b ALITHIOS study from December 2019 (pandemic start) and post-marketing cases from August 2020 (ofatumumab first approval) up to 25 September 2021. COVID-19 cases, severity, seriousness, outcomes, vaccination status, and breakthrough infection were evaluated.ResultsAs of 25 September 2021, 245 of 1703 patients (14.4%) enrolled in ALITHIOS receiving ofatumumab (median exposure: 2.45 years) reported COVID-19 (confirmed: 210; suspected: 35). Most COVID-19 was of mild (44.1%) or moderate (46.5%) severity, but 9% had severe/life-threatening COVID-19. There were 24 serious cases (9.8%) with 23 patients hospitalized; 22 recovered and 2 died. At study cut-off, 241 patients (98.4%) had recovered or were recovering or had recovered with sequelae and 2 (0.8%) had not recovered. Ofatumumab was temporarily interrupted in 39 (15.9%) patients. Before COVID-19 onset, IgG levels were within the normal range in all COVID-19-affected patients, while IgM was < 0.4 g/l in 23 (9.4%) patients. No patient had a reinfection. Overall, 559 patients were vaccinated (full, 476; partial, 74; unspecified, 9). Breakthrough infection was reported in 1.5% (7/476) patients, and 11 reported COVID-19 after partial vaccination. As of 25 September 2021, the Novartis Safety Database (~ 4713 patient-treatment years) recorded 90 confirmed COVID-19 cases receiving ofatumumab. Most cases were non-serious (n = 80), and ten were serious (1 medically significant, 9 hospitalized, 0 deaths). Among 36 of 90 cases with outcomes reported, 30 recovered and 6 did not recover.ConclusionCOVID-19 in RMS patients on ofatumumab was primarily of mild/moderate severity and non-serious in these observational data. Most recovered from COVID-19 without treatment interruption. Two people died with COVID-19. Breakthrough COVID-19 despite being fully/partially vaccinated was uncommon.

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Monoclonal Antibodies in the Treatment of Relapsing Multiple Sclerosis: an Overview with Emphasis on Pregnancy, Vaccination, and Risk Management.

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