BACKGROUND: Ocrelizumab is a monoclonal anti-CD20 antibody recently approved for adult patients with Relapsing Multiple Sclerosis (RMS). In addition, having shown neuroprotective effects, ocrelizumab is the first drug ever approved for early treatment of Progressive MS (PMS). Ocrelizumab mostly acts via the rapid depletion of the B cells expressing CD20. This depletion turns in a long-lasting change in B cells profile characterized by a reduction of its pro-inflammatory phenotype. Ocrelizumab also seems to display a neuroprotective effect, whose mechanisms of action have still to be elucidated. It has been demonstrated that anti-CD20 antibodies induce changes at the intracellular level, for instance by increasing levels of proteins such as serine/threonine and tyrosine kinases, as well as c-myc. These molecules, involved in cell signaling and proliferation, are strictly controlled by regulators, among which the most important is HuR, an ubiquitous RNA-binding protein whose expression is mediated by the above proteins and vice versa. HuR modulates gene expression by promoting or inhibiting translation in B lymphocytes; it has been found to play a key role in metabolic regulation after B cell activation, likely by virtue of its antioxidant effects, as well as induction of a proper humoral response. Finally, Retinal Nerve Fiber Layer (RNFL) thinning has been increasingly studied as a potential marker for neurodegeneration. This can be assessed via Optical Coherence Tomography (OCT). Thus, it can be hypothesized that ocrelizumab therapy provides additional protective effects by promoting qualitative changes in the immune response of PBMCs via HuR. AIM: aims of this pilot study in a cohort of RMS patients were: i) to describe the early effectiveness and safety of ocrelizumab; ii) to investigate HuR changes before and after the treatment with ocrelizumab; iii) to investigate the Retinal Nerve Fiber Layer thinning (RNFL) before and after the treatment with ocrelizumab. We also aimed at assessing the relationship between HuR expression, RNFL thinning and ocrelizumab. METHODS: we enrolled RMS adult patients followed at IRCCS Mondino Foundation of Pavia and open label treated with ocrelizumab. Demographical and clinical data were prospectively registered at baseline (T0), 6 weeks after baseline (T1) and 14 weeks after baseline (T2). HuR expression was investigated at T0, T1 and T2. Additionally, RNFL was investigated via Optical Coherence Tomography (OCT), performed at T0 and T2. PRELIMINARY RESULTS: in the present study, we included six adults RMS patients (2F and 4M). At ocrelizumab start mean age, disease duration and disability measured with EDSS were 37.8 (SD: 11.95) years; 7.69 (SD: 6.96) years; median 1.75, range 1, respectively. All patients completed the follow up, and during these observations no adverse events (AE) or serious AE (SAE) were reported. The majority of the patients reported no infusion related reactions. On treatment, one patient reported one clinical relapse. HuR expression and RNFL analysis are still ongoing. CONCLUSIONS: despite the short observational period, these preliminary results confirmed the good profile of ocrelizumab in real world setting. Additionally, the preliminary results of the effect of ocrelizumab on ELAV expression and RNFL will improve the knowledge of the neuroprotective mechanisms mediated by ocrelizumab in MS patients and will pave the path for further knowledge in neuroprotective field.
Terapia della sclerosi multipla con ocrelizumab: risultati preliminari in una coorte di pazienti con sclerosi multipla recidivante
Ocrelizumab therapy in multiple sclerosis: preliminary results in a cohort of relapsing multiple sclerosis patients
FURIA, ALESSANDRO
2018/2019
Abstract
BACKGROUND: Ocrelizumab is a monoclonal anti-CD20 antibody recently approved for adult patients with Relapsing Multiple Sclerosis (RMS). In addition, having shown neuroprotective effects, ocrelizumab is the first drug ever approved for early treatment of Progressive MS (PMS). Ocrelizumab mostly acts via the rapid depletion of the B cells expressing CD20. This depletion turns in a long-lasting change in B cells profile characterized by a reduction of its pro-inflammatory phenotype. Ocrelizumab also seems to display a neuroprotective effect, whose mechanisms of action have still to be elucidated. It has been demonstrated that anti-CD20 antibodies induce changes at the intracellular level, for instance by increasing levels of proteins such as serine/threonine and tyrosine kinases, as well as c-myc. These molecules, involved in cell signaling and proliferation, are strictly controlled by regulators, among which the most important is HuR, an ubiquitous RNA-binding protein whose expression is mediated by the above proteins and vice versa. HuR modulates gene expression by promoting or inhibiting translation in B lymphocytes; it has been found to play a key role in metabolic regulation after B cell activation, likely by virtue of its antioxidant effects, as well as induction of a proper humoral response. Finally, Retinal Nerve Fiber Layer (RNFL) thinning has been increasingly studied as a potential marker for neurodegeneration. This can be assessed via Optical Coherence Tomography (OCT). Thus, it can be hypothesized that ocrelizumab therapy provides additional protective effects by promoting qualitative changes in the immune response of PBMCs via HuR. AIM: aims of this pilot study in a cohort of RMS patients were: i) to describe the early effectiveness and safety of ocrelizumab; ii) to investigate HuR changes before and after the treatment with ocrelizumab; iii) to investigate the Retinal Nerve Fiber Layer thinning (RNFL) before and after the treatment with ocrelizumab. We also aimed at assessing the relationship between HuR expression, RNFL thinning and ocrelizumab. METHODS: we enrolled RMS adult patients followed at IRCCS Mondino Foundation of Pavia and open label treated with ocrelizumab. Demographical and clinical data were prospectively registered at baseline (T0), 6 weeks after baseline (T1) and 14 weeks after baseline (T2). HuR expression was investigated at T0, T1 and T2. Additionally, RNFL was investigated via Optical Coherence Tomography (OCT), performed at T0 and T2. PRELIMINARY RESULTS: in the present study, we included six adults RMS patients (2F and 4M). At ocrelizumab start mean age, disease duration and disability measured with EDSS were 37.8 (SD: 11.95) years; 7.69 (SD: 6.96) years; median 1.75, range 1, respectively. All patients completed the follow up, and during these observations no adverse events (AE) or serious AE (SAE) were reported. The majority of the patients reported no infusion related reactions. On treatment, one patient reported one clinical relapse. HuR expression and RNFL analysis are still ongoing. CONCLUSIONS: despite the short observational period, these preliminary results confirmed the good profile of ocrelizumab in real world setting. Additionally, the preliminary results of the effect of ocrelizumab on ELAV expression and RNFL will improve the knowledge of the neuroprotective mechanisms mediated by ocrelizumab in MS patients and will pave the path for further knowledge in neuroprotective field.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/22667