Publications by authors named "A Rubstein"

7 Publications

Acting centrally or peripherally: A renewed interest in the central nervous system penetration of disease-modifying drugs in multiple sclerosis.

Mult Scler Relat Disord 2021 Sep 14;56:103264. Epub 2021 Sep 14.

Hospital Ramos Mejía, Universidad de Buenos Aires, Argentina.

With the recent approval of cladribine tablets, siponimod and ozanimod, there has been a renewed interest into the extent to which these current generation disease-modifying therapies (DMTs) are able to cross into the central nervous system (CNS), and how this penetration of the blood-brain barrier (BBB) may influence their ability to treat multiple sclerosis (MS). The integrity of the CNS is maintained by the BBB, blood-cerebrospinal fluid barrier, and the arachnoid barrier, which all play an important role in preserving the immunological environment and homeostasis within the CNS. The integrity of the BBB decreases during the course of MS, with a putative temporal relationship to disease worsening. Furthermore, it is currently considered that progression of the disease is mediated mainly by resident cells of the CNS. The existing literature provides evidence to show that some of the current generation DMTs for MS are able to penetrate the CNS and potentially exert direct effects on CNS-resident cells, in particular the CNS-penetrating prodrugs cladribine and fingolimod, and other sphingosine-1 phosphate receptor modulators; siponimod and ozanimod. Other current generation DMTs appear to be restricted to the periphery due to their high molecular weight or physicochemical properties. As more effective brain penetrant therapies are developed for the treatment of MS, there is a need to understand whether the potential for direct effects within the CNS are of significance, and whether this brings additional benefits over and above treatment effects mediated in the periphery. In turn, this will require an improved understanding of the structure and function of the BBB, the role it plays in MS and subsequent treatments. This narrative review summarizes the data supporting the biological plausibility of a potential benefit from therapeutic molecules entering the CNS, and discusses the potential significance in the current and future treatment of MS.
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September 2021

Therapeutic plasma exchange in MS refractory relapses: Long-term outcome.

Mult Scler Relat Disord 2021 Jul 25;55:103168. Epub 2021 Jul 25.

Department of Neurology. Fleni. Buenos Aires, Argentina. Electronic address:

Introduction: Therapeutic plasma exchange (TPE) is considered a treatment option for steroid-refractory multiple sclerosis (MS) relapses. Our objective was to assess long-term clinical response to TPE in MS steroid-refractory exacerbations.

Methods: Retrospective study of relapsing remitting MS (RRMS) patients presenting intravenous methylprednisolone (IVMPS)-refractory relapses, who underwent TPE. Response to TPE was assessed at 1, 3, 6, 12 and 24-months post-treatment, and compared to a second group of RRMS patients with similar demographic and clinical characteristics presenting, IVMPS-refractory relapses but not treated with TPE. Multivariate regression analysis was used to assess potential predictors of significant clinical response.

Results: Between 2011 to 2020, a total of 23 RRMS patients were treated with TPE. Twenty-one patients not receiving the treatment served as controls. No differences in demographic or clinical characteristics, or predictors of clinical improvement after TPE were detected between groups. Seventy-eight percent of patients treated with TPE presented clinical improvement at 24 months. TPE-treated patients presented lower EDSS scores at 6 and at 24 months. Younger age, presence of gadolinium-enhancing lesions and TPE treatment were associated with better clinical outcomes. No life-threatening side effects were reported.

Conclusions: TPE is a safe and well tolerated procedure that decreases long-term disability in RRMS patients with IVMPS-refractory relapses.
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July 2021

Prognostic indicators of improvement with therapeutic plasma exchange in pediatric demyelination.

Neurology 2019 11 23;93(22):e2065-e2073. Epub 2019 Oct 23.

From the Department of Neurology (A.S., M.H.R., S.L.V., M.C.V., S.P.S., S.T.) and Transfusion Medicine (G.M., R.A., A.M.P.), National Pediatric Hospital Dr. J.P. Garrahan; and Private Institute of Statistics (A.R.), Buenos Aires, Argentina.

Objectives: To determine the safety and clinical benefit of therapeutic plasma exchange (TPE) as rescue therapy in children with acute inflammatory demyelinating CNS syndromes and to identify baseline prognostic indicators of treatment improvement.

Methods: This single-center retrospective pediatric cohort included all consecutive patients admitted to our hospital over the period from 2003 to 2017 because of a steroid-refractory acute CNS event presumed to be inflammatory who required TPE. Functional status assessment to identify improvement included the following performance category scales: visual outcome, bladder control, gait, and Expanded Disability Status Scale (EDSS). These assessments were performed before and after TPE in every patient.

Results: Sixty-five children requiring TPE to treat 78 CNS attacks were included for analysis. Median age at TPE was 10.5 years (1.9-18 years); 45% were girls. Seropositivity (aquaporin-4 water channel-immunoglobulin G [IgG] or myelin oligodendrocyte glycoprotein-IgG) was found in 20 of 42 (48%) patients. Attack phenotypes leading to TPE were optic neuritis (ON) in 42%, longitudinally extensive transverse myelitis (LETM) in 31%, ON + LETM in 15%, and other combined syndromes in 11%. Overall, moderate to marked neurologic improvement was observed in 72% of children at the end of TPE and in 88.5% at 6 months of follow-up. Lower baseline scores on the EDSS, visual outcome, and gait scales were found to be independent prognostic indicators of treatment benefit. Sex, age at onset and at TPE, attack phenotype, disease duration, and time from attack onset to TPE initiation were not significantly associated with treatment outcome. Adverse events were observed in 31 of 524 (5.9%) procedures, being severe in 4.

Conclusions: TPE was an effective rescue therapy associated with functional improvement. No therapeutic window for TPE initiation was identified in this pediatric cohort. Overall frequency of adverse events was low; however, serious events should be anticipated and avoided.

Classification Of Evidence: This study provides Class IV evidence that for children with acute inflammatory demyelinating CNS syndromes, TPE leads to functional improvement.
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November 2019

Barriers against a successful MS treatment: The importance of effectiveness beyond efficacy.

Mult Scler Relat Disord 2019 May 7;30:129-135. Epub 2019 Feb 7.

Neurology Department, Hospital Italiano y Español de La Plata, La Plata, Argentina.

Current multiple sclerosis (MS) therapeutic options have significantly increased treatment algorithm complexity. This urges physicians to take into account multiple factors in the decision-making process and make an even more thorough analysis of the risk-benefit balance. We carried out a descriptive review aiming to assess some factors that endanger the proper MS treatment fulfillment, focusing mainly on Latin American countries. Firstly, it is paramount to warrant the correct, fair and timely treatment access. We found that disease modifying drugs (DMDs) access is highly variable among different countries and even different regions within a country. In this sense less than 35% of MS patients in Latin American have access to treatment. Secondly, adherence depends on some characteristics such as the way of administration, treatment length and side effects, among others. Finally, chronic immune suppression has become a common consequence of most DMDs. Hence, the different mechanisms of action and their safety profile should be taken carefully into consideration when choosing a specific drug. These three areas of interest related to a single medication, adherence, access to it and mechanism of action, are of utmost importance when trying to achieve effectiveness instead of just efficacy.
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May 2019

Increased High Molecular Weight FGF2 in Endocrine-Resistant Breast Cancer.

Horm Cancer 2018 10 28;9(5):338-348. Epub 2018 Jun 28.

Instituto de Biología y Medicina Experimental (IBYME), CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina.

Endocrine resistance may develop as a consequence of enhanced growth factor signaling. Fibroblast growth factor 2 (FGF2) consists of a low and several high molecular weight forms (HMW-FGF2). We previously demonstrated that antiprogestin-resistant mammary carcinomas display lower levels of progesterone receptor A isoforms (PRA) than B isoforms (PRB). Our aim was to evaluate the role of FGF2 isoforms in breast cancer progression. We evaluated FGF2 expression, cell proliferation, and pathway activation in models with different PRA/PRB ratios. We performed lentiviral infections of different FGF2 isoforms using the human hormone-responsive T47D-YA cells, engineered to only express PRA, and evaluated tumor growth, metastatic dissemination, and endocrine responsiveness. We assessed FGF2 expression and localization in 81 human breast cancer samples. Antiprogestin-resistant experimental mammary carcinomas with low PRA/PRB ratios and T47D-YB cells, which only express PRB, displayed higher levels of HMW-FGF2 than responsive variants. HMW-FGF2 overexpression in T47D-YA cells induced increased tumor growth, lung metastasis, and antiprogestin resistance compared to control tumors. In human breast carcinomas categorized by their PRA/PRB ratio, we found nuclear FGF2 expression in 55.6% of tumor cells. No differences were found between nuclear FGF2 expression and Ki67 proliferation index, tumor stage, or tumor grade. In low-grade tumor samples, moderate to high nuclear FGF2 levels were associated to carcinomas with low PRA/PRB ratio. In conclusion, we show that HMW-FGF2 isoforms are PRB targets which confer endocrine resistance and are localized in the nuclei of breast cancer samples. Hence, targeting intracellular FGF2 may contribute to overcome tumor progression.
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October 2018