Histoplasmosis in a fingolimod-treated patient: case report and scoping review.

Fingolimod is a sphingosine-1-phosphate receptor modulator used to treat multiple sclerosis. While fingolimod has been associated with an increased risk of cryptococcal meningitis, its correlation with other deep mycoses remains unclear. In this study, we conducted a scoping review of fingolimod associated with histoplasmosis, based on a case report, a literature review, and data from the FDA Adverse Events Reporting System (FAERS) as of January 24th, 2023. A 30-year-old Brazilian woman diagnosed with relapsing-remitting multiple sclerosis, receiving a daily dose of 0.5 mg of fingolimod, presented with a two-month history of fever and unintended weight loss, accompanied by lymphadenopathy, splenomegaly, and lung involvement was investigated. Biopsy of a lung nodule revealed fungal structures suggestive of Histoplasma sp. Additionally, serological testing yielded positive for Histoplasma capsulatum. Disseminated histoplasmosis should be considered in the differential diagnosis of febrile syndromes in patients undergoing fingolimod therapy for multiple sclerosis, particularly in the Americas, where this mycosis is endemic. Treatment with itraconazole and modification of immunotherapy can achieve excellent clinical outcomes.

Real-World Effectiveness and Safety of Cladribine in Multiple Sclerosis: Longitudinal Data From the Nationwide Registry in Argentina.

OBJECTIVE: The aim was to evaluate patient profiles, effectiveness and safety of cladribine (CLAD) in patients with relapsing-remitting multiple sclerosis in Argentina. METHODS: This was a substudy included in RelevarEM (MS and neuromyelitis optica registry in Argentina, NCT03375177). Patients with MS who received CLAD tablets and were followed up for at least 24 months were included. Clinical evaluations every 3 months collect information about: a) clinical relapses; b) progression of physical disability, evaluated through Expanded Disability Status Scale, and c) new lesions found in the magnetic resonance imaging. Lymphopenia was evaluated during the follow-up and defined as grade 1: absolute lymphocyte count (ALC) 800-999/µL; grade 2: ALC 500-799/µL; grade 3: ALC 200-499/µL and grade 4: ALC <200/µL. RESULTS: A total of 240 patients were included from 19 centers from Argentina. The mean annualized relapse rate during the 12-month pre-CLAD initiation was 1.19 ± 0.56 versus 0.22 ± 0.18 at month 12 and 0.19 ± 0.15 at month 24 ( P < 0.001). A total of 142 (59.2%) fulfilled the criteria of disease activity during the 12 months before treatment initiation, whereas 27 (11.3%) fulfilled it at month 12 and 38 (15.8%) at month 24, P < 0.001. Regarding no evidence of disease activity (NEDA), 202 (84.2%) patients achieved NEDA status at month 12 and 185 (77%) at month 24. The most frequent incidence density of lymphopenia for course 2 observed was also for grade 1, 6.1 (95% confidence interval [CI] = 5.5-7.1). The overall incidence density of lymphopenia grade 4 was 0.1 (95% CI = 0.06-0.19). CONCLUSION: This information will help when choosing the best treatment option for Argentinean patients.

Treatment patterns and persistence on disease modifying therapies for multiple sclerosis and its associated factors.

BACKGROUND: Effective interventions for Multiple Sclerosis require timely treatment optimization which usually involves switching disease modifying therapies. The patterns of prescription and the reasons for changing treatment in people with MS, especially in low prevalence populations, are unknown. OBJECTIVES: To describe the persistence, reasons of DMT switches and prescription patterns in a cohort of Colombian people with MS. METHODS: We conducted a retrospective observational study including patients with confirmed MS with at least one visit at our centre. We estimated the overall incidence rate of medication changes and assessed the persistence on medication with Kaplan-Meier survival estimates for individual medications and according to efficacy and mode of administration. The factors associated with changing medications were assessed using adjusted Cox proportional-hazards models. The reasons for switching medication changes were described, and the prescription patterns were assessed using network analysis, with measures of centrality. RESULTS: Seven hundred one patients with MS were included. Mean age was 44.3 years, and 67.9% were female. Mean disease duration was 11.3 years and 84.5% had relapsing MS at onset, with median EDSS of 1.0. Treatment was started in 659 (94%) of the patients after a mean of 3 years after MS symptom onset. Among them, 39.5% maintained their initial DMT, 29.9% experienced a single DMT change, while 18.7% went through two, and 11.9% had three or more DMT changes until the final follow-up. The total number of treatment modifications reached 720, resulting in an incidence rate of 1.09 (95% confidence interval: 1.01-1.17) per patient per year The median time to change after the first DMT was 3.75 years, and was not different according to the mode of administration or efficacy classification. The main reasons for changing DMT were MS activity (relapses, 56.7%; MRI activity, 18.6%), followed by non-serious adverse events (15.3%) and disability (11.1%). Younger age at MS onset, care under our centre and insurer status were the main determinants of treatment change. Network analysis showed that interferons and fingolimod were the most influential DMTs. CONCLUSIONS: A majority of patients switch medications, mostly due to disease activity, and in association with age and insurer status.

Burden of treatment and quality of life in relapsing remitting multiple sclerosis patients under early high efficacy therapy in Argentina: Data from the Argentinean registry.

The objective of this study was to describe and compare the burden of treatment (BOT) and the quality of life (QoL) in early high efficacy therapy (HET) vs. escalation therapy in relapsing remitting multiple sclerosis (RRMS) patients included in RelevarEM, the Argentinean registry of MS (RelevarEM, NCT 03,375,177). METHODS: cross sectional study conducted between September and December 2022. Participating patients were adults, RRMS patients who initiated (during the last three years) their treatment with a HET (natalizumab, ocrelizumab, alemtuzumab, cladribine) or with escalation treatment (beta interferon, glatiramer acetate, teriflunomide, dimethyl fumarate or fingolimod). Clinical and demographic aspect were collected. QoL and BOT was measured with the validated to Spanish MusiQol and BOT questionnaire. Propensity score (PS)-based nearest-neighbor matching was applied to homogenize groups. Comparisons were be done using a linear regression analysis model stratified by matched pairs, with BOT and QoL assessments as main outcomes. RESULTS: 269 patients were included in the analysis, mean age 33.7 ± 5.7 years, 193 (71.7 %) were female. A total of 136 patients were on early HET while 133 were on escalation therapy. In the entire group the mean total BOT score (±SD) was 48.5 ± 15.3 while in the group of patients receiving early HET we observed that the mean BOT score (±SD) was 43.5 ± 12.2 vs. 54.3 ± 13.3 in escalation treatment (p < 0.0001). Regarding the score QoL (±SD), in the entire sample we observed a global score of 77.4 ± 11.2. When we stratified groups, in HET (±SD) it was 81.3 ± 14 vs. 74.1 ± 18.3 in escalation therapy (p = 0.0003). CONCLUSION: in this multicenter study that included 269 patients from Argentina we observed in early HET a significantly lower BOT and higher QoL than patients receiving escalation therapy.

Excess weight increases the risk of sarcopenia in patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune neurodegenerative disease. Nutritional status influences the course of the disease, however, its relationship with sarcopenia needs further investigation. The aim of the study was to identify patients with sarcopenia and assess its association with nutritional status and the clinical course of the disease. METHODS: The study assessed 110 patients submitted to evaluation of sociodemographic characteristics, level of physical activity, nutritional status, and presence of sarcopenia. The clinical course of the disease, age at onset, disease duration, disease-modifying therapy, and expanded scale of disability status (EDSS) were investigated. RESULTS: Mean age was 37.17 (SD = 10.60) years, disease duration was 6.29 years (SD = 4.65), with a predominance of female gender (80.90 %), relapsing-remitting clinical form (RRMS) (89.10 %) and mild level of disability (EDSS median = 1.92). The group had excess weight (53.6 %) according to body mass index (BMI) and abdominal fat accumulation measured by waist circumference (WC) (53.6 %). High percentage of fat mass ( % FM) was observed in 54.5 % and 38.2 % of the patients according to bioimpedance (BIA) and ultrasound (US), respectively. It was observed that 15.5 % were at risk for sarcopenia, which was associated with excess weight, and high % FM (p<0.05). CONCLUSION: These findings highlight the importance of including nutritional status indicators, and sarcopenia assessment in the care of patients with MS.

Evaluation of the use of high-efficacy treatments (HETs) in patients with relapsing-remitting multiple sclerosis in Argentina.

BACKGROUND: Disease-modifying therapies (DMTs) in multiple sclerosis (MS) can be classified according to the efficacy in which they prevent inflammatory activity. To date, there are limited data regarding the use of high-efficacy treatments (HETs) in Latin America (LATAM). We aimed to analyze the use of HETs in Argentina, focusing on the clinical and sociodemographic characteristics of the patients who use these treatments and the changes in the trend of use over the years. METHODS: A retrospective cohort study was done using the Argentina MS patient registry, RelevarEM. Patients diagnosed with relapsing-remitting MS (RRMS) according to validated diagnostic criteria and under treatment with natalizumab, alemtuzumab, cladribine, rituximab or ocrelizumab were included. RESULTS: Out of 2450 RRMS patients under a DMT, 462 (19%) were on HETs. One third of those patients (35%) received HETs as the first treatment. The most frequent reason for switching to HETs was treatment failure to previous DMT (77%). The time from MS diagnosis to the first HET in treatment-naive patients was less than one year (IQR: 0-1 year) and in treatment-experienced patients it was 5 years (IQR: 3-9 years). Between 2015 and 2017 (P1), 729 patients included in RelevarEM started a new treatment, of which 85 (11.65%) were HETs. Between 2018 and 2020 (P2), 961 patients included in RelevarEM started a new treatment, of which 284 (29.55%) were HETs. When comparing P2 with P1, a significant increase in the use of HETs was observed (p < 0.01). The most frequently used HETs were alemtuzumab (50.59%) in P1, and cladribine (45.20%) in P2. CONCLUSION: The demographic and clinical characteristics of patients under HET in Argentina were identified. Based on a real-world setting, we found a significant trend towards and a rapid increase in the use of HETs in clinical practice in patients with RRMS.

Rituximab in the treatment of multiple sclerosis. Experience of a tertiary care hospital in Mexico.

BACKGROUND: Multiple sclerosis is a chronic, autoimmune, degenerative disease. Therapies targeting B-cells have been shown to be effective in its treatment; however, there are few studies evaluating their efficacy in the Mexican population. OBJECTIVE: To evaluate the clinical impact of rituximab in patients with newly-diagnosed relapsing-remitting multiple sclerosis (RRMS). MATERIAL AND METHODS: Real life, descriptive study, in which rituximab was evaluated as treatment for RRMS over a 24-month period. Pre- and post-treatment clinical variables were analyzed; a comparison was made between treatment-naïve and non-treatment-naïve patients. RESULTS: Twenty-eight patients with RRMS were included. Mean age at diagnosis was 30.7 years, and 22 patients were treatment-naïve (78.5 %). After 24 months, there was a mean reduction of 1.8 points in the EDSS scale and a decrease in the number of active lesions on magnetic resonance imaging; a significant difference in both variables could be established (p < 0.05). However, the logistic regression model did not show a relationship between the variables for achieving NEDA-3 criteria. No serious adverse events were observed. CONCLUSIONS: Treatment with rituximab resulted in significant clinical and radiological improvement in treatment-naïve and non-treatment-naïve Mexican patients with RRMS.

ANTECEDENTES: La esclerosis múltiple es una enfermedad crónica, autoinmune y degenerativa. Las terapias blanco contra los linfocitos B han probado ser efectivas en su tratamiento; sin embargo, existen pocos estudios que evalúen su eficacia en población mexicana. OBJETIVO: Evaluar el impacto clínico del rituximab en pacientes con esclerosis múltiple remitente recurrente (EMRR) de reciente diagnóstico. MATERIAL Y MÉTODOS: Estudio de vida real, descriptivo, en el que se evalúa rituximab como tratamiento de EMRR durante un periodo de 24 meses. Se analizaron variables clínicas pre y postratamiento; se realizó la comparación entre pacientes naïve y no naïve. RESULTADOS: Se incluyeron 28 pacientes con EMRR. La edad media al diagnóstico fue de 30.7 años y 22 pacientes fueron naïve (78.5 %). Después de 24 meses, se observó una reducción media de 1.8 puntos en EDSS y en el número de lesiones activas por resonancia magnética. Aunque se logró establecer una diferencia significativa en ambas variables con p < 0.05, el modelo de regresión logística no mostró una relación entre las variables para alcanzar un NEDA-3. No se observaron eventos adversos graves. CONCLUSIONES: El tratamiento con rituximab resultó en mejoría significativa clínica y radiológica en pacientes mexicanos con EMRR naïve y no-naïve.

Alemtuzumab for multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune, T-cell-dependent, inflammatory, demyelinating disease of the central nervous system, with an unpredictable course. Current MS therapies focus on treating and preventing exacerbations, and avoiding the progression of disability. At present, there is no treatment that is capable of safely and effectively reaching these objectives. Clinical trials suggest that alemtuzumab, a humanized monoclonal antibody, could be a promising option for MS. OBJECTIVES: To evaluate the benefits and harms of alemtuzumab alone or associated with other treatments in people with any form of MS. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 21 June 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in adults with any subtype of MS comparing alemtuzumab alone or associated with other medications versus placebo; another active drug; or alemtuzumab in another dose, regimen, or duration. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our co-primary outcomes were 1. relapse-free survival, 2. sustained disease progression, and 3. number of participants experiencing at least one adverse event. Our secondary outcomes were 4. participants free of clinical disability, 5. quality of life, 6. change in disability, 7. fatigue, 8. new or enlarging lesions on resonance imaging, and 9. dropouts. We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We included three RCTs (1713 participants) comparing intravenous alemtuzumab versus subcutaneous interferon beta-1a for relapsing-remitting MS. Participants were treatment-naive (two studies) or had experienced at least one relapse after interferon or glatiramer (one study). Alemtuzumab was given at doses of 12 mg/day or 24 mg/day for five days at months 0 and 12, or 24 mg/day for three days at months 12 and 24. Participants in the interferon beta-1a group received 44 µg three times weekly. Alemtuzumab 12 mg: 1. may improve relapse-free survival at 36 months (hazard ratio [HR] 0.31, 95% confidence interval [CI] 0.18 to 0.53; 1 study, 221 participants; low-certainty evidence); 2. may improve sustained disease progression-free survival at 36 months (HR 0.25, 95% CI 0.11 to 0.56; 1 study, 223 participants; low-certainty evidence); 3. may make little to no difference on the proportion of participants with at least one adverse event at 36 months (risk ratio [RR] 1.00, 95% CI 0.98 to 1.02; 1 study, 224 participants; low-certainty evidence), although the proportion of participants with at least one adverse event was high with both drugs; 4. may slightly reduce disability at 36 months (mean difference [MD] -0.70, 95% CI -1.04 to -0.36; 1 study, 223 participants; low-certainty evidence). The evidence is very uncertain regarding the risk of dropouts at 36 months (RR 0.81, 95% CI 0.57 to 1.14; 1 study, 224 participants; very low-certainty evidence). Alemtuzumab 24 mg: 1. may improve relapse-free survival at 36 months (HR 0.21, 95% CI 0.11 to 0.40; 1 study, 221 participants; low-certainty evidence); 2. may improve sustained disease progression-free survival at 36 months (HR 0.33, 95% CI 0.16 to 0.69; 1 study, 221 participants; low-certainty evidence); 3. may make little to no difference on the proportion of participants with at least one adverse event at 36 months (RR 0.99, 95% CI 0.97 to 1.02; 1 study, 215 participants; low-certainty evidence), although the proportion of participants with at least one adverse event was high with both drugs; 4. may slightly reduce disability at 36 months (MD -0.83, 95% CI -1.16 to -0.50; 1 study, 221 participants; low-certainty evidence); 5. may reduce the risk of dropouts at 36 months (RR 0.08, 95% CI 0.01 to 0.57; 1 study, 215 participants; low-certainty evidence). For quality of life, fatigue, and participants free of clinical disease activity, the studies either did not consider these outcomes or they used different measuring tools to those planned in this review. AUTHORS' CONCLUSIONS: Compared with interferon beta-1a, alemtuzumab may improve relapse-free survival and sustained disease progression-free survival, and make little to no difference on the proportion of participants with at least one adverse event for people with relapsing-remitting MS at 36 months. The certainty of the evidence for these results was very low to low.

Global DNA Methylation and Hydroxymethylation Levels in PBMCs Are Altered in RRMS Patients Treated with IFN-ß and GA-A Preliminary Study.

Multiple sclerosis (MS) is a chronic disease affecting the central nervous system (CNS) due to an autoimmune attack on axonal myelin sheaths. Epigenetics is an open research topic on MS, which has been investigated in search of biomarkers and treatment targets for this heterogeneous disease. In this study, we quantified global levels of epigenetic marks using an ELISA-like approach in Peripheral Blood Mononuclear Cells (PBMCs) from 52 patients with MS, treated with Interferon beta (IFN-ß) and Glatiramer Acetate (GA) or untreated, and 30 healthy controls. We performed media comparisons and correlation analyses of these epigenetic markers with clinical variables in subgroups of patients and controls. We observed that DNA methylation (5-mC) decreased in treated patients compared with untreated and healthy controls. Moreover, 5-mC and hydroxymethylation (5-hmC) correlated with clinical variables. In contrast, histone H3 and H4 acetylation did not correlate with the disease variables considered. Globally quantified epigenetic DNA marks 5-mC and 5-hmC correlate with disease and were altered with treatment. However, to date, no biomarker has been identified that can predict the potential response to therapy before treatment initiation.

Cost-Utility Analysis Comparing Ocrelizumab Versus Rituximab in the Treatment of Relapsing-Remitting Multiple Sclerosis: The Colombian Perspective.

OBJECTIVES: This study aimed to determine the cost-utility of ocrelizumab versus rituximab in patients with RRMS, from the perspective of the Colombian healthcare system. METHODOLOGY: Cost-utility study based on a Markov model, with a 50-year horizon and payer perspective. The currency was the US dollar for the year 2019, with a cost-effectiveness threshold of $5180 defined for Colombian health system. The model used annual cycles according to the health status determined by the disability scale. Direct costs were considered, and the incremental cost-effectiveness ratio per 1 quality-adjusted life-year (QALY) gained was used as the outcome measure. A discount rate of 5% was applied to costs and outcomes. Multiple one-way deterministic sensitivity analyses and 10 000 Monte Carlo simulation were conducted. RESULTS: For the treatment of patients with RRMS, ocrelizumab versus rituximab had an incremental cost-effectiveness ratio of $73 652 for each QALY gained. After 50 years, 1 subject treated with ocrelizumab earns 4.8 QALYs >1 subject treated with rituximab, but at a higher cost of $521 759 versus $168 752, respectively. Ocrelizumab becomes a cost-effective therapy if its price is discounted > 86% or if there is a high willingness to pay. CONCLUSIONS: Ocrelizumab was not a cost-effective drug as compared with rituximab in treating patients with RRMS in Colombia.

Disease activity after discontinuation of disease-modifying therapies in patients with multiple sclerosis in Argentina: data from the nationwide registry RelevarEM.

INTRODUCTION: The discontinuation of disease-modifying therapies (DMTs) in multiple sclerosis (MS) is commonly seen in real-world settings due to several factors. AREA COVER: The aim of this study is to describe the frequency of disease activity after discontinuation of DMTs in MS patients included in the Argentinean MS and NMOSD registry. DISCUSION: Patients with relapsing remitting MS (RRMS) and active secondary progressive MS (SPMS) were included based on the following criteria: they discontinued treatment for more than 6 months, they had been treated with a DMT for ≥2 years, and they had at least 6 months of follow-up in the registry after discontinuation. Demographic and clinical data were collected. Disease activity during follow-up was defined as the presence of a clinical relapse or a new magnetic resonance (MRI) lesion (either new lesions on T2-weighted sequence and/or contrast enhancement). Bivariate analysis was applied to identify clinical and demographic factors related to disease activity. CONCLUSION: We included 377 patients (75.5% RRMS, 22.5% SPMS) who had discontinued DMTs. The mean (SD) follow-up after discontinuation was 15.7 (7.9) months. After discontinuation, the presence of relapse was detected in 18.8% and 3.5% in RRMS and SPMS, respectively; and new MRI activity in 22% and 3.5%, respectively. We found that higher risk of relapse and MRI activity was associated with younger age (p < 0.001), shorter disease duration (p < 0.001), and RRMS phenotype (p = 0.006). Males showed higher MRI activity (p 0.011). This study provides real-world data that can guide physicians when considering discontinuation of DMTs.

Cladribina oral para tratamento de pacientes com esclerose múltipla remitente-recorrente altamente ativa, conforme protocolo do Ministério da Saúde / Oral cladribine for the treatment of patients with highly active relapsing-remitting multiple sclerosis, according to the Ministry of Health protocol

CONTEXTO: A esclerose múltipla é uma doença inflamatória crônica, que afeta o SNC, com quadro clínico incapacitante, como fadiga intensa, fraqueza muscular, alteração do equilíbrio da coordenação motora, disfunção intestinal e da bexiga, e que tem como consequência uma queda na qualidade de vida dos pacientes. Dentre as formas dessa doença há a esclerose múltipla remitente recorrente altamente ativa (EMRRaa). No Sistema Único de Saúde (SUS), os pacientes com EMRRaa possuem como 1ª linha de tratamento, o natalizumabe, que tem contraindicações para alguns pacientes. Assim, cladribina oral, apresenta-se como uma alternativa terapêutica para os pacientes com EMRRaa, com uma posologia facilitada na perspectiva do paciente e do sistema de saúde, uma vez que é um medicamento de administração oral com até 20 dias de tratamento nos dois primeiros anos, e com a menor carga de monitoramento durante o tratamento. PERGUNTA: Cladribina oral é eficaz, seguro e custo-efetivo para o tratamento de pacientes com esclerose múltipla remitente-recorrente altamente ativa quando comparado ao natalizumabe? EVIDÊNCIAS CIENTÍFICAS: As evidências clínicas da comparação entre a cladribina versus o natalizumabe foram apresentadas através de uma revisão sistemática com metanálise de comparação indireta, que utilizou o ensaio clínico pivot

High persistence and low adverse events burden in cladribine treated MS patients from Argentina.

BACKGROUND: Early initiation with high efficacy therapies seems to be better than an escalation approach in terms of disability prevention in patients with relapsing-remitting MS (RRMS). Although efficacy and safety of cladribine tablets have been shown in clinical trials, real-world evidence (RWE) studies from Latin America are scarce. OBJECTIVE: To describe the baseline characteristics of patients enrolled in the Argentina Patient Support Program (PSP) for cladribine tablets (Adveva®), with at least 1 treatment course, evaluate treatment persistence, adverse event reports from PSP patients and reported relapses characterization. METHODS: Anonymized data routinely collected by Adveva® team of patients that received the first dose of cladribine from April 16th 2018 to March 31st 2021 were analyzed. Treatment persistence was defined as the percentage of patients that initiated year 2 (Y2) from the population of patients with elapsed time since year 1 (Y1) cladribine tablet initiation of at least 18 months. In addition, using the pharmacovigilance data, reported adverse events and the time elapsed from treatment initiation to relapse were analyzed. RESULTS: The present analysis included 269 patients (mean age: 41.7 ± 16 years) that had initiated Y1 of cladribine tablets treatment between April 16th 2018 and March 31st 2021. Although only 29.4% (79/269) of our population was treatment naïve, the ratio of naïve/switch patients that initiated cladribine tablets increased from April 2018-March 2019 to April 2020-March 2021. From the 110 patients with elapsed time since treatment initiation ≥18 months, 101 patients initiated Y2 indicating a persistence level of 91.8%. During follow-up, 425 adverse events were reported, mainly MS relapse (8.9%, 38/425), fatigue (3.8%, 16/425) and headache (3.5%, 15/425). Lymphopenia and infections were rarely reported by RRMS patients treated with cladribine tablets. MS relapse was more frequently reported in patients switching from a previous treatment (87.5%, 27/32) than in the naïve cohort (12.5%, 5/32). CONCLUSIONS: The first real life experience in RRMS patients from Latin America demonstrated that the Adveva® enrolled support program patients have a high persistence level to oral treatment with cladribine tablets. Our results also confirmed the known safety profile of cladribine tablets, with a low incidence of lymphopenia and infections.

Brain volume loss and physical and cognitive impairment in naive multiple sclerosis patients treated with fingolimod: prospective cohort study in Buenos Aires, Argentina.

BACKGROUND: The percentage of brain volume loss (PBVL) has been classically considered as a biomarker in multiple sclerosis (MS). OBJECTIVE: The objective of the present study was to analyze if the PBVL during the 1st year after the onset of the disease predicts physical and cognitive impairment (CI). METHODS: Prospective study that included naïve patients without cognitive impairment who initiated MS treatment with fingolimod. Patients were followed for 3 years and relapses, expanded disability status scale (EDSS) progression (defined as worsening of 1 point on the EDSS), the annual PBVL (evaluated by structural image evaluation using normalization of atrophy [SIENA]), and the presence of CI were evaluated. Cognitive impairment was defined in patients who scored at least 2 standard deviations (SDs) below controls on at least 2 domains. The PBVL after 1 year of treatment with fingolimod was used as an independent variable, while CI and EDSS progression at the 3rd year of follow-up as dependent variables. RESULTS: A total of 71 patients were included, with a mean age of 35.4 ± 3 years old. At the 3rd year, 14% of the patients were classified as CI and 6.2% had EDSS progression. In the CI group, the PBVL during the 1st year was - 0.52 (±0.07) versus -0.42 (±0.04) in the no CI group (p < 0.01; odds ratio [OR] = 2.24; 95% confidence interval [CI]: 1.72-2.44). In the group that showed EDSS progression, the PBVL during the 1st year was - 0.59 (±0.05) versus - 0.42 (±0.03) (p < 0.01; OR = 2.33; 95%CI: 1.60-2.55). CONCLUSIONS: A higher PBVL during the 1st year in naïve MS patients was independently associated with a significant risk of CI and EDSS progression.

ANTECEDENTES: A porcentagem de perda de volume cerebral (PPVC) é um biomarcador na esclerose múltipla (EM). OBJETIVO: Analisar se a PPVC durante o 1° ano após o início da doença prediz deterioração física (DF) e cognitiva (DC) em pacientes com EM. MéTODOS: Estudo de coorte prospectivo que incluiu pacientes recém-diagnosticados sem comprometimento cognitivo que iniciaram tratamento com fingolimode. Os pacientes foram acompanhados por 3 anos, sendo avaliados a presença de recidivas, progressão da Escala Expandida do Estado de Incapacidade (EDSS, na sigla em inglês) (definida como agravamento de 1 ponto na EDSS), o PPVC anual (avaliado pela avaliação de imagem estrutural de atrofia normalizada [SIENA, na sigla em inglês) e a presença de DC (avaliada no início do estudo e nos 2° e 3° anos). O PPVC no 1° ano de tratamento com fingolimode foi utilizado como variável independente. RESULTADOS: foram incluídos 71 pacientes com idade média de 35,4 ± 3 anos. No 3° ano, 14% dos pacientes tiveram DC e 6,2% tiveram progressão de EDSS. No grupo DC, o PPVC durante o 1o ano foi - 0,52 (±0,07) versus - 0,42 (±0,04) no grupo sem DC (p < 0,01; razão de probabilidades [OR, na sigla em inglês] = 2,24; intervalo de confiança [IC] de 95%: 1,72­2,44). No grupo que apresentou progressão da EDSS, o PPVC durante o 1° ano foi de - 0,59 (±0,05) versus - 0,42 (±0,03) (p < 0,01; OR = 2,33; IC95%: 1,60­2,55). CONCLUSõES: Um maior PPVC durante o 1° ano foi associado a um risco significativo de progressão de DC e EDSS durante o seguimento.

Effects of pulsed electromagnetic field therapy on fatigue, walking performance, depression, and quality of life in adults with multiple sclerosis: a randomized placebo-controlled trial.

BACKGROUND: Multiple sclerosis has a great disability burden. Management of the disease is complex, and patients often seek new conservative approaches. OBJECTIVE: To investigate the effect of low-frequency pulsed electromagnetic field (PEMF) therapy, compared to placebo, on the level of fatigue, walking performance, symptoms of depression, and quality of life (QOL) in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Forty-four adults with RRMS and minimal to significant disability were randomly assigned to a 4-week protocol using a PEMF or a placebo whole-body mat. The PEMF group were initially treated with 15Hz frequency, gradually increased to 30Hz (intensity between 25-35µT). The primary outcome was fatigue, assessed with the Fatigue Severity Scale (FSS) and the Modified Fatigue Impact Scale (MFIS). Secondary measures included walking function (GAITRite system and Timed 25-Foot Walk test), the Beck Depression Inventory-II, and the Multiple Sclerosis International Quality of Life Questionnaire. Data were collected at baseline, after intervention, and at 3-months post-intervention (follow-up). RESULTS: There were no differences between groups for changes in fatigue symptoms from baseline to end of intervention (mean and 95% confidence interval FSS: -0.6, 95%CI: -1.3, 0.1; MFIS: -5.4, 95% CI: -15.1, 4.4) or at follow-up (FSS: -0.6, 95% CI: -1.4, 0.2; MFIS: -2.1, 95% CI: -10.9, 6.8). Similarly, both groups did not differ for any of the secondary outcomes at post-intervention or follow-up. CONCLUSIONS: Low-frequency PEMF therapy is no more effective than placebo to produce changes in fatigue, gait performance, severity of depression, and QOL in people with RRMS and minimal to significant disability.

Is there a role for off-label high-efficacy disease-modifying drugs in progressive multiple sclerosis? A network meta-analysis.

Ocrelizumab and siponimod are the two on-label drugs used for progressive forms of multiple sclerosis (PMS). However, many patients with PMS do not have access to these high-efficacy disease-modifying drugs (DMDs). Off-label prescription of other high-efficacy DMDs (fingolimod, rituximab and natalizumab) may be a strategy to improve access to immunotherapy for these patients. We aim to compare on-label and off-label high-efficacy drugs for their effect on disability progression in PMS. In December 2021, we searched MEDLINE (PubMed), Embase, Cochrane Central and Scopus databases for randomized clinical trials involving patients with PMS. High-efficacy drugs were considered as intervention and placebos as comparison. The outcome contemplated was risk of Expanded Disability Severity Scale (EDSS) progression at 2 years. A network meta-analysis was performed to compare the relative risk of EDSS progression at 2 years compared with placebo in on-label and off-label drugs. We included five studies with 4526 patients. The median EDSS progression at 2 years in patients that received any immunotherapy was 30%, compared with 35% in placebo groups. Overall, the risk of bias of individual studies was low. Network analysis revealed overlapping confidence intervals in off-label drugs (CI95% 0.51-2.16) versus ocrelizumab (reference) and off-label drugs (CI 95% 0.53-1.96) versus siponimod (reference), suggesting similar efficacy. The same result was found even after excluding studies with the risk of publication bias. Off-label high efficacy immunotherapy in PMS has biological plausibility and presented similar effectiveness to on-label DMDs in this network meta-analysis. The use of fingolimod, rituximab or natalizumab may be a strategy that reduces costs and improves access to immunotherapy for patients with PMS.

How to choose initial treatment in multiple sclerosis patients: a case-based approach.

BACKGROUND: Immunotherapy dramatically changed the natural history of multiple sclerosis (MS), which was classically associated with severe disability. Treatment strategies advocate that early control of disease activity is crucial to avoid progressive disability, and the use of high efficacy drugs may be beneficial, but safety is a concern. Choosing the disease-modifying therapy is challenging in clinical practice and should be further discussed. OBJECTIVE: To discuss the state of art of selecting the initial therapy for relapsing MS patients. METHODS: We used a case-based approach followed by clinical discussion, exploring therapeutic options in different MS settings. RESULTS: We presented clinical cases profile compatible with the use of MS therapies, classified into moderate and high efficacy. In the moderate efficacy group, we discussed interferons, glatiramer acetate, teriflunomide and dimethyl fumarate, while in the high efficacy group we discussed fingolimod, cladribine, natalizumab, ocrelizumab, alemtuzumab and ofatumumab. CONCLUSION: Advances in MS treatment are remarkable. Strong evidence supports the use of early high efficacy therapy. However, biomarkers, clinical and radiologic prognostic factors, as well as patients' individual issues, should be valued and considered for a personalized treatment decision.

Cladribina en esclerosis múltiple remitente recidivante de alta actividad / Cladribine in remitting multiple sclerosis high activity relapsing

La esclerosis múltiple (EM) es una enfermedad inflamatoria inmunomediada, desmielinizante y neurodegenerativa del sistema nervioso central. Es una de las principales causas de discapacidad en los adultos jóvenes. La enfermedad generalmente se presenta alrededor de los 30 años y las tasas de prevalencia alcanzan su punto máximo alrededor de los 50 años. La etiología de la EM no se encuentra del todo establecida. Se identifican distintas formas clínicas de acuerdo al modo de presentación y curso de la enfermedad, siendo la más frecuente la denominada Esclerosis Múltiple Recurrente Recidivante (EMRR). El curso más frecuente de la EMRR se caracteriza por recaídas y remisiones de síntomas neurológicos asociados a áreas de inflamación del SNC con recuperación total o parcial entre los brotes y acumulación gradual de discapacidad. Al cabo de dos décadas, más de la mitad de los pacientes no tratados entran en una fase con empeoramiento sostenido de la discapacidad independientemente de las recaídas, conocido como EM secundaria progressiva. La enfermedad presenta gran variabilidad en cuanto a su evolución clínica, severidad de las recaídas, así como en la progresión y gravedad de la discapacidad. Esto genera un impacto negativo sobre la calidad de vida de los pacientes tanto por la enfermedad como por los efectos adversos y la carga de los tratamientos, así como sobre la capacidad laboral y la afección al entorno familiar. El diagnóstico se realiza mediante un conjunto de criterios clínicos y de imágenes (conocidos como criterios de Mc Donalds, última versión 2017). El nivel de discapacidad generalmente es valorado con un instrumento específico conocido como escala ampliada del estado de discapacidad (EDSS), que consiste en una escala ordinal que va de 0 (estado clínico normal) a 10 (muerte por EM) midiendo cambios mediante incrementos de 0,5 a 1 puntos, iniciando en 0.3 Dicha escala tiene en cuenta distintas esferas del examen neurológico (funciones motoras, sensoriales, cerebelosas, tronco encefálico, visuales, intestinales y de vejiga, piramidales y otras funciones). OBJETIVO: El objetivo del presente informe es evaluar la eficacia, seguridad, recomendaciones, políticas de cobertura y aspectos económicos del tratamiento con cladribina oral en pacientes con EMRR-AA. METODOLOGÍA: Se realizó la búsqueda de evidencia en los sitios públicos de Pubmed, LILACS, BRISA/REDETSA-, CRD (del inglés, Centre for Reviews and Dissemination- University of York), Cochrane; Epistemónikos, el registro Clinicaltrials.gov, GIN (Guidelines International Network) en "buscadores genéricos de internet", sociedades científicas, sitios web de distintos organismos gubernamentales responsables de definir cobertura de medicamentos. En lo que respecta a ETS, la búsqueda incluyó: la Base de datos internacional para las ETS de INHATA (su sigla del inglés, International Network of Agencies for Health Technology Assessment), EUneHTA (European Network for Health Technology Assessment) Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), y en agencias tales como NICE (del inglés, National Institute for Health and Clinical Excellence) del Reino Unido; PBAC (del inglés, The Pharmaceutical Benefits Advisory Committee) de Australia; CADTH (del inglés, Canadian Agency for Drugs and Technologies in Health) de Canadá y CONITEC (del portugués, Comissão Nacional de Incorporação de Tecnologías no SUS) de Brasil. Se utilizó en pubmed la siguiente estrategia: (cladribine [MeSH] OR cladribine[tiab] OR mavenclad[tiab] OR disease modifying[tiab]) AND ("Multiple Sclerosis, RelapsingRemitting"[Mesh] OR "Multiple Sclerosis"[Mesh] OR multiple sclerosis, relapsingremitting[tiab] OR remitting-relapsing multiple sclerosis[tiab] OR multiple sclerosis, acute relapsing[tiab] OR acute relapsing multiple sclerosis[tiab]). Utilizando filtros de diseños: ensayos clínicos, revisiones sistemáticas y metaanálisis y temporales (2010-2021). RESULTADOS: Se presentan los resultados globales de la búsqueda bibliográfica y el flujograma que muestra las distintas instancias de valoración de los artículos identificados, de acuerdo a los criterios de inclusión y exclusión definidos a través de los componentes de la pregunta PICO, concluyendo con el número de artículos seleccionados para el contenido del presente informe. CONCLUSIONES: La EMRR constituye una enfermedad neurológica con curso clínico y pronóstico muy variable; si bien hay acuerdo en la existencia de grupos que pueden considerarse como con Alta Actividad de la enfermedad, no hay consenso internacional sobre su definición concreta, lo que dificulta estimar tanto su frecuencia como comparar el impacto de los tratamientos sobre su evolución en los distintos estudios que valoran diferentes fármacos y estrategias terapéuticas. Existe evidencia directa que reporta beneficio de cladribina con respecto a placebo en cuanto a la reducción en la TRA (Alta certeza) y progresión de la discapacidad confirmada por 6 meses (Moderada certeza) en pacientes con EMRR. El impacto sobre la progresión de la discapacidad por 6 meses podría ser superior en la población de Alta Actividad (Baja certeza). Con respecto al impacto en la calidad de vida, el mismo es incierto, debido a que la información para su evaluación mediante la herramienta específica para la enfermedad fue escasa, con pequeño número de pacientes evaluados para este desenlace (Muy Baja certeza) aunque podría generar mejoría cuando se midió con escalas generales (Baja certeza). La evidencia sobre la eficacia y seguridad comparativas de cladribina con respecto a las otras DME utilizadas generalmente en el tratamiento de esta subpoblación (Alta Actividad) proviene de comparaciones indirectas dada la falta de estudios que evalúen distintas DME cabeza a cabeza. Los MAR incluidos en el presente informe no reportan diferencias significativas de cladribina con respecto a los comparadores. Es importante considerar que la evidencia es insuficiente, las estimaciones resultan imprecisas y la heterogeneidad en distintas características de las poblaciones incluidas en los estudios, particularmente para el subgrupo de Alta Actividad, dificultan la interpretación de los resultados. No fue posible realizar una valoración formal de la certeza de la evidencia indirecta (MAR) mediante la metodología GRADE por no contar con la información necesaria; sin embargo, los hallazgos reportados (falta de diferencias significativas) fueron consistentes entre las dos RS. Las guías de práctica clínica y recomendaciones internacionales en su mayoría sugieren el uso de cladribina en EMRR-AA ya sea como primera línea de tratamiento en pacientes con enfermedad severa progresiva, como en segunda línea en aquellos que no presentan respuesta adecuada al tratamiento con otras DME. Enfatizan la necesidad de la selección del fármaco de acuerdo a las características individuales de los pacientes (actividad y severidad de la enfermedad, comorbilidades, etc). Respecto a políticas de cobertura, la mayoría de los países de altos ingresos recomienda el uso de cladribina cuando existe inadecuada respuesta o intolerancia a otro tratamiento previo para EMRR, o enfermedad severa, rápidamente progresiva, en algunos casos requiriendo reducción de costos. En Latinoamérica, Chile recomienda su cobertura bajo condiciones específicas (fallo documentado del tratamiento con otras DME o intolerancia o efectos adversos graves con otros tratamientos). participación de mercado de alemtuzumab, ocrelizumab, natalizumab y fingolimod. Cuando se evalúa el impacto presupuestario utilizando los precios a los que ha comprado los fármacos una obra social provincial deja de ser costo ahorrativo sólo cuando se analiza el desplazamiento del 100% de fingolimod, pero se demuestra costo ahorrativo frente al resto de los comparadores.

Cladribina oral no tratamento de pacientes com esclerose múltipla remitente-recorrente altamente ativa / Oral cladribine in the treatment of patients with highly relapsing-remitting multiple sclerosis active

INTRODUÇÃO: A esclerose múltipla é uma doença inflamatória crônica, que afeta o SNC, com quadro clínico incapacitante, como fadiga intensa, fraqueza muscular, alteração do equilíbrio da coordenação motora, disfunção intestinal e da bexiga, e que tem como consequência uma queda na qualidade de vida dos pacientes. Dentre as formas dessa doença há a EMRR altamente ativa, que possui uma janela de tratamento entre o primeiro evento desmielinizante e a progressão. No Sistema Único de Saúde (SUS), os pacientes com EMRR altamente ativa possuem como opções terapêuticas o Natalizumabe, de administração intravenosa e, que gera dificuldade operacionais relacionados a infusão, maior necessidade de um monitoramento dos pacientes, e alguns efeitos adversos graves. Assim, cladribina oral, apresenta-se como uma alternativa terapêutica para os pacientes com EMRR altamente ativa no SUS, com uma posologia facilitada na perspectiva do paciente e do sistema de saúde, uma vez que é um medicamento de administração oral com até 20 dias de tratamento nos dois primeiros anos, e com a menor carga de monitoramento e de custo operacional entre os tratamentos. TECNOLOGIA: Cladribina oral (Mavenclad®). PERGUNTA: Cladribina oral é eficaz, seguro e custo-efetivo para o tratamento de pacientes com esclerose múltipla remitente-recorrente altamente ativa quando comparado ao natalizumabe? EVIDÊNCIAS CLÍNICAS: As evidências clínicas da comparação entre a cladribina versus o natalizumabe foi apresentada através de uma revisão sistamática com meta-análise em rede, que utilizou o ensaio clínico pivot de cada tecnologia para a metanálise em rede, e assim foi classificada como de baixa qualidade por ser uma comparação indireta realizada com população não específica deste dossiê. Apoiado nesta evidência foi assumido que as tecnologias são similares, pois não apresentaram diferença estatisticamente significante nos diversos desfechos analisados. AVALIAÇÃO ECONÔMICA: Uma análise de custo-minimização foi realizada comparando o custo do tratamento, composto do custo de aquisição da medicação + administração + monitoramento + manejo dos eventos adversos. No entanto, os dados apresentados não estão de acordo com a posologia apresentada e o valor proposto para incorporação. Apesar do custo incremental de R$ 13.788,24 por paciente, ele está claramente subestimado. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário utilizou metodologia recomendada pelas diretrizes do Ministério da Saúde, utilizando demanda aferida com pesquisa no DATASUS, além de alguns dados de projeção de números do próprio demandante de market-share, no entanto, foi realizado uma análise de sensibilidade. A inconsistência dos custos apresentadas na análise de custo-minimização enviesa toda análise de impacto orçamentária e deve ser revista pelo demandante. EXPERIÊNCIAS INTERNACIONAIS: O Reino Unido, a Austrália, o Canadá, a Escócia e a Irlanda incorporaram a cladribina para o tratamento da EMRR. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Não há tecnologias identificadas no horizonte temporal para EMRR altamente ativa. PERSPECTIVA DO PACIENTE: A chamada pública de número 51/2021 para participar da Perspectiva do Paciente sobre o tema foi aberta de 13/09/2021 a 27/09/2021 e quarenta e duas pessoas se inscreveram. A indicação dos representantes titular e suplente para fazer o relato da experiência foi feita a partir a partir de sorteio realizado em plataforma digital com transmissão em tempo real acessível a todos os inscritos. No relato, a participante descreveu como o uso do medicamento em avaliação teve bons resultados no seu caso, destacando a comodidade do uso e a ausência de efeitos adversos. CONSIDERAÇÕES FINAIS: As evidências ainda demonstram incerteza na similaridade da cladribina em relação ao natalizumabe, não há um escopo de evidências mais robusta, pois não há estudos de comparação direta, e que envolva a população alvo específica. Desta forma, coloca a análise de custo-minimização em uma posição de risco em assumir a não diferença entre as tecnologias analisadas. Além disso, a análise de custo-minimização apresentada contém inconsistência, com possível valores subestimados, e deve ser revista para que os valores projetados fiquem o mais próximo dos dados de vida real. Desta forma, a cladribina, se mostra uma tecnologia dominada pelo natalizumabe, com a ressalva de sua administração via oral que traz comodidade ao portador de EMRR altamente ativa e o impedimento do uso nos casos de risco no desenvolvimento de LEMP. RECOMENDAÇÃO PRELIMINAR: o Plenário da Conitec, em sua 106ª Reunião Ordinária, no dia 09 de março de 2022, deliberou que a matéria fosse disponibilizada em Consulta Pública com recomendação preliminar desfavorável à incorporação, da cladribina oral para o tratamento de primeira linha da esclerose múltipla remitente-recorrente de pacientes com alta atividade da doença com opção de tratamento de natalizumabe no SUS. Os membros da Conitec consideraram que a evidência científica ainda é inconsistente, que há problemas na análise econômica e que mesmo subestimada é uma tecnologia dominada, dada a opção de uso do natalizumabe. CONSULTA PÚBLICA: Houve 1008 opiniões sobre a recomendação preliminar da Conitec, sendo 347 pelo formulário para contribuições técnico-científicas e 661 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Sendo que 1 concordou e 1007 discordaram. As 1007 contribuições foram avaliadas por descreverem os motivos de sua opinião em relação à recomendação inicial da Conitec. Os assuntos abordados pelos participantes foram: carga da doença da esclerose múltipla, preço do medicamento, acesso à saúde pelo SUS, pouco efeito colateral, facilidade na posologia e planejamento familiar. RECOMENDAÇÃO FINAL: o Plenário da Conitec, em sua 109ª Reunião Ordinária, no dia 09 de junho de 2022, deliberou por maioria simples, recomendar a não incorporação da cladribina oral para o tratamento de pacientes com esclerose múltipla remitente recorrente altamente ativa no SUS. Os membros da Conitec consideraram que não há evidência suficiente de que a cladribina oral seja similar ao natalizumabe e após discussão das contribuições públicas e nova proposta econômica do demandante, e a incerteza poderia ter impacto orçamenteario incerto no SUS. Por fim, foi assinado o Registro de Deliberação nº 745/2022. DECISÃO: Não incorporar a cladribina oral para o tratamento de primeira linha de pacientes com esclerose múltipla remitenterecorrente altamente ativa, no âmbito do Sistema Único de Saúde - SUS conforme a Portaria nº 66, publicada no Diário Oficial da União nº 129, seção 1, página 77, em 11 de julho de 2022.